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April 29, 2021
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https://www.sciencedaily.com/releases/2021/04/210429104936.htm
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Research advances emerging DNA sequencing technology
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Nanopore technology shows promise for making it possible to develop small, portable, inexpensive devices that can sequence DNA in real time. One of the challenges, however, has been to make the technology more accurate.
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Researchers at The University of Texas at Dallas have moved closer toward this goal by developing a nanopore sequencing platform that, for the first time, can detect the presence of nucleobases, the building blocks of DNA and RNA. The study was published online Feb. 11 and is featured on the back cover of the April print edition of the journal "By enabling us to detect the presence of nucleobases, our platform can help improve the sensitivity of nanopore sequencing," said Dr. Moon Kim, professor of materials science and engineering and the Louis Beecherl Jr. Distinguished Professor in the Erik Jonsson School of Engineering and Computer Science.Currently, most DNA sequencing is done through a process that involves preparing samples in the lab with fluorescent dye and using lasers to determine the sequence of the four nucleobases, the fundamental units of the genetic code: adenine (A), cytosine (C), guanine (G) and thymine (T). Each nucleobase emits a different wavelength when illuminated, allowing scientists to determine the sequence.In nanopore sequencing, a DNA sample is uncoiled, and the hairlike strand is fed through a tiny hole, or nanopore, typically in a fabricated membrane. As it moves through the nanopore, the DNA strand disturbs the electrical current flowing through the membrane. The current responds differently based on the characteristics of a DNA molecule, such as its size and shape."The electrical signal changes as the DNA moves through the nanopore," Kim said. "We can read the characteristics of the DNA by monitoring the signal."One of the challenges in advancing nanopore sequencing has been the difficulty of controlling the speed of the DNA strand as it moves through the nanopore. The UT Dallas team's research focused on addressing that by fabricating an atomically thin solid-state -- or nonbiological -- membrane coated with titanium dioxide, water and an ionic liquid to slow the speed of the molecules through the membrane. The water was added to the liquid solution to amplify the electrical signals, making them easier to read."By enabling us to detect the presence of nucleobases, our platform can help improve the sensitivity of nanopore sequencing."The next step for researchers will be to advance the platform to identity each nucleobase more quickly. Kim said the platform also opens possibilities for sequencing other biomolecules."The ultimate goal is to have a hand-held DNA sequencing device that is fast, accurate and can be used anywhere," Kim said. "This would reduce the cost of DNA sequencing and make it more accessible."
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Biology
| 2,021 |
April 29, 2021
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https://www.sciencedaily.com/releases/2021/04/210429104933.htm
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Avocado discovery may point to leukemia treatment
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A compound in avocados may ultimately offer a route to better leukemia treatment, says a new University of Guelph study.
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The compound targets an enzyme that scientists have identified for the first time as being critical to cancer cell growth, said Dr. Paul Spagnuolo, Department of Food Science.Published recently in the journal Leukemia cells have higher amounts of an enzyme called VLCAD involved in their metabolism, said Spagnuolo."The cell relies on that pathway to survive," he said, explaining that the compound is a likely candidate for drug therapy. "This is the first time VLCAD has been identified as a target in any cancer."His team screened nutraceutical compounds among numerous compounds, looking for any substance that might inhibit the enzyme. "Lo and behold, the best one was derived from avocado," said Spagnuolo.Earlier, his lab looked at avocatin B, a fat molecule found only in avocados, for potential use in preventing diabetes and managing obesity. Now he's eager to see it used in leukemia patients."VLCAD can be a good marker to identify patients suitable for this type of therapy. It can also be a marker to measure the activity of the drug," said Spagnuolo. "That sets the stage for eventual use of this molecule in human clinical trials."Currently, about half of patients over 65 diagnosed with AML enter palliative care. Others undergo chemotherapy, but drug treatments are toxic and can end up killing patients."There's been a drive to find less toxic drugs that can be used."Referring to earlier work using avocatin B for diabetes, Spagnuolo said, "We completed a human study with this as an oral supplement and have been able to show that appreciable amounts are fairly well tolerated."
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Biology
| 2,021 |
April 29, 2021
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https://www.sciencedaily.com/releases/2021/04/210429095159.htm
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A new strain of a well-known probiotic might offer help for infants' intestinal problems
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Lacticaseibacillus rhamnosus GG, or LGG, is the most studied probiotic bacterium in the world. However, its features are not perfect, as it is unable to utilise the milk carbohydrate lactose or break down the milk protein casein. This is why the bacterium grows poorly in milk and why it has to be separately added to probiotic dairy products.
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In fact, attempts have been made to make L. rhamnosus GG better adjust to milk through genetic engineering. However, strict restrictions have prevented the use of such modified bacteria in human food.Thanks to a recent breakthrough made at the University of Helsinki, Finland, with researchers from the National Institute for Biotechnology and Genetic Engineering, Pakistan, features have now been successfully added to the LGG probiotic without gene editing, making it thrive and grow in milk.The method used is known as conjugation, which is a technique utilised by certain bacterial groups to transfer their traits to other bacteria. In the process, a bacterium produces a copy of its plasmid, a ring-shaped piece of DNA in the bacterium. Next, the bacterium transfers the plasmid to an adjacent bacterium. The spread of plasmids, which carry traits useful for bacteria, can be rapid among bacterial communities.In the case of Lacticaseibacillus rhamnosus GG, the plasmid that provided the ability to make use of lactose and casein originated in a specific Lactococcus lactis bacterial strain grown in the same place."The new LGG strain is not genetically modified, which makes it possible to consume it and any products containing it without any permit procedures," says the project leader, Professor of Microbiology Per Saris from the Faculty of Agriculture and Forestry, University of Helsinki.The new strain can be used as a starting point in the development of new dairy products where the probiotic concentration increases already in the production stage. In other words, the probiotic need not be separately added to the final product.Furthermore, the new LGG strain can potentially be better equipped to grow, for example, in the infant gut where it would be able to utilise the lactose and casein found in breastmilk, producing more lactic acid than the original strain."Lactic acid lowers the pH of the surface of the intestine, reducing the viability of many gram-negative pathogenic bacteria, such as E. coli, Salmonella and Shigella, which threaten the health of infants. Moreover, in larger numbers the new LGG strain can potentially be more effective at protecting infants than the old strain. After all, LGG has previously been shown to alleviate infantile atopic dermatitis and boost the recovery of the gut microbiota after antibiotic therapies."The researchers are in negotiations on the further application of their discovery.
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Biology
| 2,021 |
April 28, 2021
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https://www.sciencedaily.com/releases/2021/04/210428162514.htm
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Structural changes in snap-frozen proteins
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Researchers at the University of Bonn and the research center caesar have succeeded in ultra-fast freezing proteins after a precisely defined period of time. They were able to follow structural changes on the microsecond time scale and with sub-nanometer precision. Owing to its high spatial and temporal resolution, the method allows tracking rapid structural changes in enzymes and nucleic acids. The results are published in the
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If you want to know what the spatial structure of a biomolecule looks like, you have a formidable arsenal of tools at your disposal. The most popular ones are electron microscopy and X-ray diffraction, which can reveal even the smallest details of a protein. However, a significant limitation of those methods is that they usually deliver static images, which are often insufficient to understand biomolecular processes in precise mechanistic terms. Therefore, a long-term goal of many research groups worldwide has been to track the movements within a macromolecule such as a protein over time while it carries out its work, just like in a movie. The research groups led by Prof. Dr. Olav Schiemann from the Institute of Physical and Theoretical Chemistry at the University of Bonn and Prof. Dr. Benjamin Kaupp from the research center caesar of the Max Planck Society have now come a step closer to achieving this goal.They chose an ion channel for their investigation. This is a protein that forms miniscule pores in the cell membrane that are permeable to charged particles called ions. "This channel is normally closed," Schiemann explains. "It only opens when a cellular messenger, called cAMP, binds to it. We wanted to know how exactly this process works."To do so, the researchers first mixed the channel protein and cAMP and then rapidly froze the solution. In the frozen state, the protein structure can now be analyzed. For their method to work, they had attached molecular electromagnets at two points in the channel. The distance between these magnets can be determined with a precision of a few Angstrom (ten billionths of a millimeter) using a sophisticated method called PELDOR, which works like a molecular ruler. In recent years, the method was significantly refined and improved in Schiemann's group."However, this only gives us a static image of cAMP binding to the ion channel," Schiemann says. "We therefore repeated the freezing process at different times after mixing the two molecules. This allowed reconstructing the movements in the protein after cAMP binding -- just like a movie, which is also made up of a sequence of images."At the center of this procedure is a sophisticated method that allows samples to be mixed and frozen very quickly at a precise point in time. The technique, called "microsecond freeze hyperquenching" (abbreviated MHQ), was originally developed at Delft University, but later fell into disuse. It was rediscovered and decisively refined by Kaupp's group."In the MHQ device, the cAMP molecule and the ion channel are mixed at ultrafast speed," Kaupp explains. "Then the mixture is shot as a hair-thin stream onto a very cold metal cylinder at -190 °C, which rotates 7,000 times per minute. It was particularly challenging to transfer the frozen samples for the PELDOR measurement from the metal plate into thin glass tubes, and to keep them frozen meanwhile. We had to design and build special tools for that."The entire mixing and freezing process takes only 82 microseconds (one microsecond equals a millionth of a second). "This allows us to visualize very rapid changes in the spatial structure of proteins," explains Tobias Hett, one of the two doctoral students who contributed significantly to the success. The advantage of the method is its combination of high spatial and temporal resolution. "This represents a major step forward in studying dynamic processes in biomolecules," Kaupp emphasizes.The researchers now plan to use their method to take a closer look at other biomolecules. They hope to gain new insights, for example into the functioning of enzymes and nucleic acids. The importance of such insights is best illustrated by the recent worldwide surge of structural research on the SARS coronavirus-2: The so-called spike protein of the virus also undergoes a structural change when human cells are infected. Clarifying this mechanism will provide valuable information how to target the infection mechanism with new drugs.The preparation of the samples, the experimental execution, and the analysis of the data is very complex. The results of the study therefore also reflect a successful scientific cooperation with researchers led by Prof. Dr. Helmut Grubmüller of the Max Planck Institute for Biophysical Chemistry in Göttingen and Prof. Dr. Heinz-Jürgen Steinhoff of the University of Osnabrück.
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Biology
| 2,021 |
April 28, 2021
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https://www.sciencedaily.com/releases/2021/04/210428133006.htm
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Using nanobodies to block a tick-borne bacterial infection
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Tiny molecules called nanobodies, which can be designed to mimic antibody structures and functions, may be the key to blocking a tick-borne bacterial infection that remains out of reach of almost all antibiotics, new research suggests.
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The infection is called human monocytic ehrlichiosis, and is one of the most prevalent and potentially life-threatening tick-borne diseases in the United States. The disease initially causes flu-like symptoms common to many illnesses, and in rare cases can be fatal if left untreated.Most antibiotics can't build up in high enough concentrations to kill the infection-causing bacteria, Ehrlichia chaffeensis, because the microbes live in and multiply inside human immune cells. Commonly known bacterial pathogens like Streptococcus and E. coli do their infectious damage outside of hosts' cells.Ohio State University researchers created nanobodies intended to target a protein that makes E. chaffeensis bacteria particularly infectious. A series of experiments in cell cultures and mice showed that one specific nanobody they created in the lab could inhibit infection by blocking three ways the protein enables the bacteria to hijack immune cells."If multiple mechanisms are blocked, that's better than just stopping one function, and it gives us more confidence that these nanobodies will really work," said study lead author Yasuko Rikihisa, professor of veterinary biosciences at Ohio State.The study provided support for the feasibility of nanobody-based ehrlichiosis treatment, but much more research is needed before a treatment would be available for humans. There is a certain urgency to coming up with an alternative to the antibiotic doxycycline, the only treatment available. The broad-spectrum antibiotic is unsafe for pregnant women and children, and it can cause severe side effects."With only a single antibiotic available as a treatment for this infection, if antibiotic resistance were to develop in these bacteria, there is no treatment left. It's very scary," Rikihisa said.The research is published this week in The bacteria that cause ehrlichiosis are part of a family called obligatory intracellular bacteria. E. chaffeensis not only requires internal access to a cell to live, but also blocks host cells' ability to program their own death with a function called apoptosis -- which would kill the bacteria."Infected cells normally would commit suicide by apoptosis to kill the bacteria inside. But these bacteria block apoptosis and keep the cell alive so they can multiply hundreds of times very rapidly and then kill the host cell," Rikihisa said.A longtime specialist in the Rickettsiales family of bacteria to which E. chaffeensis belongs, Rikihisa developed the precise culture conditions that enabled growing these bacteria in the lab in the 1980s, which led to her dozens of discoveries explaining how they work. Among those findings was identification of proteins that help E. chaffeensis block immune cells' programmed cell death.The researchers synthesized one of those proteins, called Etf-1, to make a vaccine-style agent that they used to immunize a llama with the help of Jeffrey Lakritz, professor of veterinary preventive medicine at Ohio State. Camels, llamas and alpacas are known to produce single-chain antibodies that include a large antigen binding site on the tip.The team snipped apart segments of that binding site to create a library of nanobodies with potential to function as antibodies that recognize and attach to the Etf-1 protein and stop E. chaffeensis infection."They function similarly to our own antibodies, but they're tiny, tiny nano-antibodies," Rikihisa said. "Because they are small, they get into nooks and crannies and recognize antigens much more effectively."Big antibodies cannot fit inside a cell. And we don't need to rely on nanobodies to block extracellular bacteria because they are outside and accessible to ordinary antibodies binding to them."After screening the candidates for their effectiveness, the researchers landed on a single nanobody that attached to Etf-1 in cell cultures and inhibited three of its functions. By making the nanobodies in the fluid inside E. coli cells, Rikihisa said her lab could produce them at an industrial scale if needed -- packing millions of them into a small drop.She collaborated with co-author Dehua Pei, professor of chemistry and biochemistry at Ohio State, to combine the tiny molecules with a cell-penetrating peptide that enabled the nanobodies to be safely delivered to mouse cells.Mice with compromised immune systems were inoculated with a highly virulent strain of E. chaffeensis and given intracellular nanobody treatments one and two days after infection. Compared to mice that received control treatments, mice that received the most effective nanobody showed significantly lower levels of bacteria two weeks after infection.With this study providing the proof of principle that nanobodies can inhibit E. chaffeensis infection by targeting a single protein, Rikihisa said there are multiple additional targets that could provide even more protection with nanobodies delivered alone or in combination. She also said the concept is broadly applicable to other intracellular diseases."Cancers and neurodegenerative diseases work in our cells, so if we want to block an abnormal process or abnormal molecule, this approach may work," she said.This study was supported by the National Institutes of Health.
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Biology
| 2,021 |
April 28, 2021
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https://www.sciencedaily.com/releases/2021/04/210428113807.htm
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Stress slows the immune response in sick mice
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The neurotransmitter noradrenaline, which plays a key role in the fight-or-flight stress response, impairs immune responses by inhibiting the movements of various white blood cells in different tissues, researchers report April 28th in the journal
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"We found that stress can cause immune cells to stop moving and prevents immune cells from protecting against disease," says senior study author University of Melbourne's Scott Mueller (@SMuellerLab) of the Peter Doherty Institute for Infection and Immunity (Doherty Institute). "This is novel because it was not known that stress signals can stop immune cells from moving about in the body and performing their job."One main function of the sympathetic nervous system (SNS) is to coordinate the fight-or-flight stress response -- a group of changes that prepare the body to fight or take flight in stressful or dangerous situations to protect itself from possible harm. Most tissues, including the lymph nodes and spleen, are innervated by SNS fibers. Stress-induced activation of the SNS can suppress immune responses, but the underlying mechanisms have been poorly characterized. "We hypothesized that SNS signals might modify the movement of T cells in tissues and lead to compromised immunity," Mueller says.White blood cells, also known as leukocytes, travel constantly throughout the body and are highly motile within tissues, where they locate and eradicate pathogens and tumors. Although the movement of leukocytes is critical for immunity, it has not been clear how these cells integrate various signals to navigate within tissues. "We also speculated that neurotransmitter signals might be a rapid way to modulate leukocyte behavior in tissues, in particular during acute stress that involves increased activation of the SNS," Mueller says.To test this idea, the researchers used advanced imaging to track the movements of T cells in mouse lymph nodes. Within minutes of being exposed to noradrenaline, T cells that had been rapidly moving stopped in their tracks and retracted their arm-like protrusions. This effect was transient, lasting between 45 and 60 minutes. Localized administration of noradrenaline in the lymph nodes of live mice also rapidly halted the cells. Similar effects were observed in mice that received noradrenaline infusions, which are used to treat patients with septic shock -- a life-threatening condition that occurs when infection leads to dangerously low blood pressure. This finding suggests that therapeutic treatment with noradrenaline might impair leukocyte functions."We were very surprised that stress signals had such a rapid and dramatic effect on how immune cells move," Mueller says. "Since movement is central to how immune cells can get to the right parts of the body and fight infections or tumors, this rapid movement off-switch was unexpected."Other experiments revealed that SNS signals inhibit the migration of distinct immune cells, including B cells and dendritic cells, exerting these effects in different tissues such as skin and liver. Additional results suggest that the effects of SNS activation on cell motility may be mediated by the constriction of blood vessels, reduced blood flow, and oxygen deprivation in tissues, resulting in an increase in calcium signaling in leukocytes."Our results reveal that an unanticipated consequence of modulation of blood flow in response to SNS activity is the rapid sensing of changes in oxygen by leukocytes and the inhibition of motility," Mueller says. "Such rapid paralysis of leukocyte behavior identifies a physiological consequence of SNS activity that explains, at least in part, the widely observed relationship between stress and impaired immunity."Moreover, SNS signals impaired protective immunity against pathogens and tumors in various mouse models, decreasing the proliferation and expansion of T cells in the lymph nodes and spleen. For example, treatment with SNS-stimulating molecules rapidly stopped the movements of T cells and dendritic cells in mice infected with herpes simplex virus 1 and reduced virus-specific T cell recruitment to the site of the skin infection. Similar effects were observed in mice with melanoma and in mice infected with a malarial parasite."Our data suggest that SNS activity in tissues could impact immune outcomes in diverse diseases," Mueller says. "Further insight into the impact of adrenergic receptor signals on cellular functions in tissues may inform the development of improved treatments for infections and cancer."The degree to which SNS activation affects leukocyte behavior or disease outcomes in humans remains to be determined. Notably, increased SNS activity is prominent in patients with obesity and heart failure, while psychological stress can cause blood vessel constriction in patients with heart disease. An unappreciated impact of increased SNS activity, particularly in individuals with underlying health conditions, might be impaired leukocyte behavior and functions. The findings may also have important health implications for patients who use SNS-activating drugs to treat diseases such as heart failure, sepsis, asthma, and allergic reactions.Moving forward, the researchers will further examine the mechanisms by which immune cells are affected by SNS stress signals and explore relevant strategies to boost anti-cancer responses in patients. "This knowledge will allow us to test the impact of drugs that block the sympathetic stress pathway, such as beta blockers, on the outcomes of vaccination and cancer treatments," Mueller says. "These types of drugs might be safe treatment options for patients where stress could contribute to poor immune function."
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Biology
| 2,021 |
April 28, 2021
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https://www.sciencedaily.com/releases/2021/04/210428113737.htm
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Major advance enables study of genetic mutations in any tissue
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For the first time, scientists are able to study changes in the DNA of any human tissue, following the resolution of long-standing technical challenges by scientists at the Wellcome Sanger Institute. The new method, called nanorate sequencing (NanoSeq), makes it possible to study how genetic changes occur in human tissues with unprecedented accuracy.
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The study, published today (28 April) in The tissues in our body are composed of dividing and non-dividing cells. Stem cells renew themselves throughout our lifetimes and are responsible for supplying non-dividing cells to keep the body running. The vast majority of cells in our bodies are non-dividing or divide only rarely. They include granulocytes in our blood, which are produced in the billions every day and live for a very short time, or neurons in our brain, which live for much longer.Genetic changes, known as somatic mutations, occur in our cells as we age. This is a natural process, with cells acquiring around 15-40 mutations per year. Most of these mutations will be harmless, but some of them can start a cell on the path to cancer.Since the advent of genome sequencing in the late twentieth century, cancer researchers have been able to better understand the formation of cancers and how to treat them by studying somatic mutations in tumour DNA. In recent years, new technologies have also enabled scientists to study mutations in stem cells taken from healthy tissue.But until now, genome sequencing has not been accurate enough to study new mutations in non-dividing cells, meaning that somatic mutation in the vast majority of our cells has been impossible to observe accurately.In this new study, researchers at the Wellcome Sanger Institute sought to refine an advanced sequencing method called duplex sequencing1. The team searched for errors in duplex sequence data and realised that they were concentrated at the ends of DNA fragments, and had other features suggesting flaws in the process used to prepare DNA for sequencing.They then implemented improvements to the DNA preparation process, such as using specific enzymes to cut DNA more cleanly, as well as improved bioinformatics methods. Over the course of four years, accuracy was improved until they achieved fewer than five errors per billion letters of DNA.Dr Robert Osborne, an alumnus of the Wellcome Sanger Institute who led the development of the method, said: "Detecting somatic mutations that are only present in one or a few cells is incredibly technically challenging. You have to find a single letter change among tens of millions of DNA letters and previous sequencing methods were simply not accurate enough. Because NanoSeq makes only a few errors per billion DNA letters, we are now able to accurately study somatic mutations in any tissue."The team took advantage of NanoSeq's improved sensitivity to compare the rates and patterns of mutation in both stem cells and non-dividing cells in several human tissue types.Surprisingly, analysis of blood cells found a similar number of mutations in slowly dividing stem cells and more rapidly dividing progenitor cells2. This suggested that cell division is not the dominant process causing mutations in blood cells. Analysis of non-dividing neurons and rarely dividing cells from muscle also revealed that mutations accumulate throughout life in cells without cell division, and at a similar pace to cells in the blood.Dr Federico Abascal, the first author of the paper from the Wellcome Sanger Institute, said: "It is often assumed that cell division is the main factor in the occurrence of somatic mutations, with a greater number of divisions creating a greater number of mutations. But our analysis found that blood cells that had divided many times more than others featured the same rates and patterns of mutation. This changes how we think about mutagenesis and suggests that other biological mechanisms besides cell division are key."The ability to observe mutation in all cells opens up new avenues of research into cancer and ageing, such as studying the effects of known carcinogens like tobacco or sun exposure, as well as discovering new carcinogens. Such research could greatly improve our understanding of how lifestyles choices and exposures to carcinogens can lead to cancer.A further benefit of the NanoSeq method is the relative ease with which samples can be collected. Rather than taking biopsies of tissue, cells can be collected non-invasively, such as by scraping the skin or swabbing the throat.Dr Inigo Martincorena, a senior author of the paper from the Wellcome Sanger Institute, said: "The application of NanoSeq on a small scale in this study has already led us to reconsider what we thought we knew about mutagenesis, which is exciting. NanoSeq will also make it easier, cheaper and less invasive to study somatic mutation on a much larger scale. Rather than analysing biopsies from small numbers of patients and only being able to look at stem cells or tumour tissue, now we can study samples from hundreds of patients and observe somatic mutations in any tissue."
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Biology
| 2,021 |
April 28, 2021
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https://www.sciencedaily.com/releases/2021/04/210428080939.htm
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Espresso, latte or decaf? Genetic code drives your desire for coffee
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Whether you hanker for a hard hit of caffeine or favour the frothiness of a milky cappuccino, your regular coffee order could be telling you more about your cardio health than you think.
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In a world first study of 390,435 people, University of South Australia researchers found causal genetic evidence that cardio health -- as reflected in blood pressure and heart rate -- influences coffee consumption.Conducted in partnership with the SAHMRI, the team found that people with high blood pressure, angina, and arrythmia were more likely to drink less coffee, decaffeinated coffee or avoid coffee altogether compared to those without such symptoms, and that this was based on genetics.Lead researcher and Director of UniSA's Australian Centre for Precision Health, Professor Elina Hyppönen says it's a positive finding that shows our genetics actively regulate the amount of coffee we drink and protect us from consuming too much."People drink coffee for all sorts of reasons -- as a pick me up when they're feeling tired, because it tastes good, or simply because it's part of their daily routine," Prof Hyppönen says."But what we don't recognise is that people subconsciously self-regulate safe levels of caffeine based on how high their blood pressure is, and this is likely a result of a protective genetic a mechanism."What this means is that someone who drinks a lot of coffee is likely more genetically tolerant of caffeine, as compared to someone who drinks very little."Conversely, a non-coffee drinker, or someone who drinks decaffeinated coffee, is more likely prone to the adverse effects of caffeine, and more susceptible to high blood pressure."In Australia, one in four men, and one in five women suffer from high blood pressure, with the condition being a risk factor for many chronic health conditions including stroke, heart failure and chronic kidney disease.Using data from the UK Biobank, researchers examined the habitual coffee consumption of 390,435 people, comparing this with baseline levels of systolic and diastolic blood pressure, and baseline heart rate. Causal relationships were determined via Mendelian randomization.Prof Hyppönen says how much coffee we drink is likely to be an indicator of our cardio health."Whether we drink a lot of coffee, a little, or avoid caffeine altogether, this study shows that genetics are guiding our decisions to protect our cardio health," Prof Hyppönen says."If your body is telling you not to drink that extra cup of coffee, there's likely a reason why. Listen to your body, it's more in tune with what your health than you may think."
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Biology
| 2,021 |
April 27, 2021
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https://www.sciencedaily.com/releases/2021/04/210427182212.htm
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RNA scientists identify many genes involved in neuron development
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Neurons result from a highly complex and unique series of cell divisions. For example, in fruit flies, the process starts with stem cells that divide into mother cells (progenitor cells), that then divide into precursor cells that eventually become neurons.
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A team of the University of Michigan (U-M), spearheaded by Nigel Michki, a graduate student, and Assistant Professor Dawen Cai in the departments of Biophysics (LS&A) and Cell and Developmental Biology at the Medical School, identified many genes that are important in fruit flies' neuron development, and that had never been described before in that context.Since many genes are conserved across species such as between fruit flies (Drosophila), mice, and humans, what is learnt in flies can also serve as a model to better understand other species, including humans. "Now that we know which genes are involved in this form of neurogenesis in flies, we can look for them in other species and test for them. We work on a multitude of organisms at U-M and we've the potential to interrogate across organisms," explains Michki. "In my opinion, the work we did is one of the many pieces that will inform other work that will inform disease," adds Michki. "This is why we do foundational research like this one."Flies are also commonly used in many different types of research that might benefit from having a more comprehensive list of the fly genes with their associated roles in neuron cell development.Neurons are made from stem cells that massively multiply before becoming neurons. In the human brain, the process is extremely complex, involving billions of cells. In the fly brain, the process is much simpler, with around 200 stem cells for the entire brain. The smaller scale allows for a fine analysis of the neuronal cell division process from start to finish.In flies, when the stem cell divides, it yields another stem cell and a progenitor cell. When this last one divides, it makes a so-called precursor cell that divides only once and gives rise to two neurons. Genes control this production process by telling the cells either to divide -- and which particular type of cell to produce -- or to stop dividing.To this day, only a few of the genes that control this neuron development process have been identified and in this publication in In particular, at the progenitors' stage, the scientists identified three genes that are important at this stage for defining what 'kind' of neuron each progenitor will make; these particular genes had never been described before in this context. They also validated previously known marker genes that are known to regulate the cell reproduction process.When they applied their analysis technique to the other phases of the neuron development process, they also recorded the expression of additional genes. However, it is still unknown why these genes go up in expression at different steps of the neuron development process and what role they actually play in these different steps. "Now that many candidate genes are identified, we are investigating the roles they play in the neuron maturation and fate determination process," says Cai. "We are also excited to explore other developmental timepoints to illustrate the dynamic changes of the molecular landscape in the fly brain.""This work provides rich information on how to program stem cell progeny into distinct neuron types as well as how to trans-differentiate non-neuronal cell types into neurons. These findings will have significant impact on the understanding of the normal brain development as well as on neuron regeneration medicine," adds Cheng-Yu Lee, a Professor from the U-M Life Sciences Institute who collaborated with the Cai Lab.This study is mostly based on high-throughput single-cell RNA-sequencing techniques. The scientists took single cells from fruit flies' brains and sequenced the RNA, generating hundreds of gigabytes of data in only one day. From the RNA sequences, they could determine the developmental stage of each neuron. "We now have a very good understanding of how this process goes at the RNA level," says Michki.The team also used traditional microscope observations to localize where these different RNAs are being expressed in the brain. "Combining in silico analysis and in situ exploration not only validates the quality of our sequencing results, but also restores the spatial and temporal relationship of the candidate genes, which is lost in the single cell dissociation process," says Cai.At the beginning of their study, the scientists analyzed the large data set with open-source software. Later, they developed a portal (MiCV) that eases the use of existing computer services and allows to test for repeatability. This portal can be utilized for cell and gene data analysis from a variety of organs and does not require computer programming experience. "Tools like MiCV can be very powerful for researchers who are doing this type of research for the first time and who want to quickly generate new hypotheses from their data," says Michki. "It saves a lot of time for data analysis, as well as expenses on consultant fees. The ultimate goal is to allow scientists to focus more on their research rather than on sometimes daunting data analysis tools." The MiCV tool is currently being commercialized.
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Biology
| 2,021 |
April 27, 2021
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https://www.sciencedaily.com/releases/2021/04/210427122422.htm
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New duckbilled dinosaur discovered in Japan
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An international team of paleontologists has identified a new genus and species of hadrosaur or duck-billed dinosaur, Yamatosaurus izanagii, on one of Japan's southern islands.
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The fossilized discovery yields new information about hadrosaur migration, suggesting that the herbivors migrated from Asia to North America instead of vice versa. The discovery also illustrates an evolutionary step as the giant creatures evolved from walking upright to walking on all fours. Most of all, the discovery provides new information and asks new questions about dinosaurs in Japan.The research, "A New Basal Hadrosaurid (Dinosauria: Ornithischia) From the latest Cretaceous Kita-ama Formation in Japan implies the origin of Hadrosaurids," was recently published in Hadrosaurs, known for their broad, flattened snouts, are the most commonly found of all dinosaurs. The plant-eating dinosaurs lived in the Late Cretaceous period more than 65 million years ago and their fossilized remains have been found in North America, Europe, Africa and Asia.Uniquely adapted to chewing, hadrosaurs had hundreds of closely spaced teeth in their cheeks. As their teeth wore down and fell out, new teeth in the dental battery, or rows of teeth below existing teeth, grew in as replacements. Hadrosaurs' efficient ability to chew vegetation is among the factors that led to its diversity, abundance and widespread population, researchers say.The Yamatosaurus' dental structure distinguishes it from known hadrosaurs, says Fiorillo, senior fellow at SMU's Institute for the Study of Earth and Man. Unlike other hadrosaurs, he explains, the new hadrosaur has just one functional tooth in several battery positions and no branched ridges on the chewing surfaces, suggesting that it evolved to devour different types of vegetation than other hadrosaurs.Yamatosaurus also is distinguished by the development of its shoulder and forelimbs, an evolutionary step in hadrosaurid's gait change from a bipedal to a quadrupedal dinosaur, he says."In the far north, where much of our work occurs, hadrosaurs are known as the caribou of the Cretaceous," says Fiorillo. They most likely used the Bering Land Bridge to cross from Asia to present-day Alaska and then spread across North America as far east as Appalachia, he says. When hadrosaurs roamed Japan, the island country was attached to the eastern coast of Asia. Tectonic activity separated the islands from the mainland about 15 million years ago, long after dinosaurs became extinct.The partial specimen of the Yamatosaurus was discovered in 2004 by an amateur fossil hunter in an approximately 71- to 72-million-year-old layer of sediment in a cement quarry on Japan's Awaji Island. The preserved lower jaw, teeth, neck vertebrae, shoulder bone and tail vertebra were found by Mr. Shingo Kishimoto and given to Japan's Museum of Nature and Human Activities in the Hyogo Prefecture, where they were stored until studied by the team."Japan is mostly covered with vegetation with few outcrops for fossil-hunting," says Yoshitsugu Kobayashi, professor at Hokkaido University Museum. "The help of amateur fossil-hunters has been very important."Kobayashi has worked with SMU paleontologist Tony Fiorillo since 1999 when he studied under Fiorillo as a Ph.D. student. They have collaborated to study hadrosaurs and other dinosaurs in Alaska, Mongolia and Japan. Together they created their latest discovery's name. Yamato is the ancient name for Japan and Izanagi is a god from Japanese mythology who created the Japanese islands, beginning with Awaji Island, where Yamatosaurus was found.Yamatosaurus is the second new species of hadrosaurid that Kobayashi and Fiorillo have identified in Japan. In 2019 they reported the discovery of the largest dinosaur skeleton found in Japan, another hadrosaurid, Kamuysaurus, discovered on the northern Japanese island of Hokkaido."These are the first dinosaurs discovered in Japan from the late Cretaceous period," Kobayashi says. "Until now, we had no idea what dinosaurs lived in Japan at the end of the dinosaur age," he says. "The discovery of these Japanese dinosaurs will help us to fill a piece of our bigger vision of how dinosaurs migrated between these two continents," Kobayashi says.
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Biology
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April 27, 2021
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https://www.sciencedaily.com/releases/2021/04/210427113813.htm
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Scientists reveal how brain cells in Alzheimer's go awry, lose their identity
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Despite the prevalence of Alzheimer's, there are still no treatments, in part because it has been challenging to study how the disease develops. Now, scientists at the Salk Institute have uncovered new insights into what goes awry during Alzheimer's by growing neurons that resemble -- more accurately than ever before -- brain cells in older patients. And like patients themselves, the afflicted neurons appear to lose their cellular identity.
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The findings, published April 27, 2021, in the journal "We know the risk of Alzheimer's increases exponentially with age, but due to an incomplete understanding of age-dependent pathogenesis, it's been difficult to develop effective treatments," says Professor and Salk President Rusty Gage, the paper's senior author. "Better models of the disease are vital for getting at the underlying drivers of this relationship."In an earlier study, the Gage lab had shown a new way that skin samples can be used to create brain cells. These induced neurons more accurately reflect the age of the person they came from (unlike neurons made from the more commonly used induced pluripotent stem cells). The new study builds on that finding and is the first to use skin cells from people with Alzheimer's to create induced neurons that have the characteristics of neurons found in patients' brains."The vast majority of Alzheimer's cases occur sporadically and have no known genetic cause," says Jerome Mertens, an assistant adjunct professor at Salk and first author of the paper, who was also involved in that earlier work. "Our goal here was to see if induced neurons that we generated from Alzheimer's patients could teach us anything new about the changes that take place in these cells when the disease develops."In the current research, the investigators collected skin cells from 13 patients with sporadic, age-related Alzheimer's. They also used cells from three people who have the more rare, inherited form of the disease. As a control, they collected skin cells from 19 people who were matched for age but did not have Alzheimer's. Using a specialized type of skin cells called fibroblasts, they generated induced neurons from each of the cell donors. They then compared the molecular differences in the cells among those who had Alzheimer's to the cells of those who didn't.The investigators found that the induced neurons made from the cells of people with Alzheimer's had distinct characteristics that were different from the healthy control subjects' cells. For one thing, the Alzheimer's cells had a lack of synaptic structures, which are important for sending signals to each other. They also had changes in their signaling pathways, which control cell function, indicating that the cells were stressed. Additionally, when the researchers analyzed the cells' transcriptomes -- a type of analysis that shows what proteins the cells are making -- they found the induced Alzheimer's neurons had very similar molecular signatures to immature nerve cells found in the developing brain.According to Mertens, who is also an assistant professor at the University of Innsbruck in Tyrol, Austria, the neurons seem to have lost their mature identity, and this de-differentiation, in which cells lose their specialized characteristics, has also been described in cancer cells. He suggests the finding opens up the door for new studies."While more research is needed, the changes associated with the transformation of these cells represent potential targets for therapeutics," Gage adds.
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Biology
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April 27, 2021
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https://www.sciencedaily.com/releases/2021/04/210427110654.htm
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New chemical tool that sheds light on how proteins recognize and interact with each other
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A research group led by Professor Xiang David LI from the Research Division for Chemistry and the Department of Chemistry, The University of Hong Kong, has developed a novel chemical tool for elucidating protein interaction networks in cells. This tool not only facilitates the identification of a protein's interacting partners in the complex cellular context, but also simultaneously allows the 'visualisation' of these protein-protein interactions. The findings were recently published in the scientific journal
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In the human body, proteins interact with each other to cooperatively regulate essentially every biological process ranging from gene expression and signal transduction, to immune response. As a result, dysregulated protein interactions often lead to human diseases, such as cancer and Alzheimer's disease. In modern biology, it is important to comprehensively understand protein interaction networks, which has implications in disease diagnosis and can facilitate the development of treatments.To dissect complex protein networks, two questions need to be answered: the 'who' and 'how' of protein binding. The 'who' refers to the identification of a protein's interacting partners, whereas the 'how' refers to the specific 'binding regions' that mediate these interactions. Answering these questions is challenging, as protein interactions are often too unstable and too transient to detect. To tackle this issue, Professor Li's group has previously developed a series of tools to 'trap' the protein-to-protein interactions with a chemical bond. This is possible because these tools are equipped with a special light-activated 'camera' -- diazirine group that capture every binding partner of a protein when exposed to UV light. The interactions can then be examined and interpreted. Unfortunately, the 'resolution' of this 'camera' was relatively low, meaning key information about how proteins interact with each other was lost. To this end, Professor Li's group has now devised a new tool (called ADdis-Cys) that has an upgraded 'camera' to improve the 'resolution'. An alkyne handle installed next to the diazirine makes it possible to 'zoom in' to clearly see the binding regions of the proteins. Coupled with state-of-the-art mass spectrometry , ADdis-Cys is the first tool that can simultaneously identify a protein's interacting partners and pinpoint their binding regions.In the published paper, Professor Li's lab was able to comprehensively identify many protein interactions -- some known and some newly discovered -- that are important for the regulation of essential cellular processes such as DNA replication, gene transcription and DNA damage repair. Most importantly, Professor Li's lab was able to use ADdis-Cys to reveal the binding regions mediating these protein interactions. This tool could lead to the development of chemical modulators that regulate protein interactions for treating human diseases. As a research tool, ADdis-Cys will find far-reaching applications in many areas of study, particularly in disease diagnosis and therapy.
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Biology
| 2,021 |
April 27, 2021
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https://www.sciencedaily.com/releases/2021/04/210427110642.htm
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Researchers show new holistic approach to genetics and plant breeding
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The research was conducted at the Department of Food Science at the University of Copenhagen (UCPH FOOD) with professor emeritus Lars Munck as coordinator and builds on earlier work since 1963 at Svaloef Plant Breeding Institute and the Carlsberg Laboratory.
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The research shows how, with the help of a fast, non-destructive and green analysis method, near-infrared spectroscopy (NIRS), we can obtain a global overview that mirrors how the entire chemical composition of nutrients in a barley grain is changed, for example, by a mutation in a single gene. This is in contrast to current conventional plant breeding, where you do not have an overview of all the changes that the barley grain undergoes when a single gene is modified.Lars Munck and his team have studied barley grains from different barley lines using near-infrared spectroscopy (NIRS). In a split second, this method can provide a "chemical fingerprint" (read more about Near-infrared spectroscopy below) of the barley grains, which describes the chemical-physical composition of the grains, including the nutrients. The researchers analysed the resulting intact spectra by comparing and calibrating them to barley lines of known composition using mathematics (chemometrics)."We were surprised by the precision that characterises the chemical fingerprints of the grains from the NIRS spectra. At the same time, it surprised us to find that we got the same classification result if we instead used the secondary nutrients/metabolites determined by a more complicated measurement method called gas chromatography mass spectrometry as the chemical fingerprint. Using two different types of analysis with completely different focuses, we arrived at the same classification result," explains Lars Munck and continues:"This is coherence in a nutshell -- all local fingerprints are part of the plant's self-organising network and affect the plant's overall global chemical-physical fingerprints."One of the barley lines examined was found to have a higher content of the essential amino acid lysine compared to a normal barley. The high content of lysine gives good growth in feeding studies with pigs, but the yield in the field was horrible and with a low starch content."By analysing the high-lysine barley lines that were crossed with high starch barley lines bringing high yield, we could use measurements of NIRS fingerprints to select lines with a high content of both lysine and starch, which thus gave higher yields. At the same time, global coherence also allowed us to gain knowledge about the optimal combination of genetic traits for a specific quality purpose," explains Lars Munck, who believes that this is a radical advancement compared to today's plant breeding that is focused on one gene-chemical trait combination at a time."With a more holistic approach, allowed by the NIRS method -- we can instead examine the chemical fingerprint totality of the different plant lines, and quickly obtain an overview of what material is available and thus target and select lines from the variable crossing pool that are high quality by calibrating to interesting marker lines" says Lars Munck.In the discipline of plant breeding, people speak of the genotype, which describes the plant's genetic material, and the phenotype, which describes the traits that can be observed directly or can be measured chemically and thus may be characterised using NIRS.The approach when using NIRS phenotyping is to change the order of the plant breeding procedure to start by screening the different barley lines for all of their chemical properties represented by fingerprints. This is done by calibrating to known barley lines that have one or more of the desired chemical properties (e.g., high starch content). Only at the end when you have selected the optimal barley line, you make an in-depth determination of the genes that are changed. When searching for an expression for the whole organism, using NIRS fingerprints provides a far more nuanced result, allowing you to examine the overall chemistry of an organism rather than examining each individual gene combination separately. Because coherence guarantees that all fingerprint aspects of an individual communicate you can manage the global composition from very different fingerprint positions."With the new method, we have closed the large knowledge gap that exists in the genetics between genotype and phenotype. Now molecular biology will finally have an outlet for its impressive library of primary gene functions, where the result of total contribution of changed genes to a functioning plant can be studied as a whole," says Lars Munck and continues:"Molecular biology has come up with crucial solutions for genetic diseases, resistance and vaccinations against diseases. But in this success story, we have forgotten that it is not the gene that is the biological unit, but that it is the self-organised individual that uses its inner "calculator" to organize the internal interaction coherence precisely and reproducibly," says Lars Munck.The researchers call this interaction, which is shown in barley grains using NIRS fingerprints and which they believe can be transferred to all living organisms, global coherence."When change occurs in a single or in several of the plant's genes or in the environment, the chemistry and the implicite morphology of the whole organism changes as the plant reorganises itself to obtain a new coherent balance point. This unifying force, coherence, was previously defined in the physics between light beams and atoms in non-living matter and we have now discovered coherence in biology as a macroscopic chemical fingerprint, that we call global coherence. It explains how living matter can replicate itself into recognizable individuals," explains Lars Munck.The importance of the introduction of macroscopic chemical fingerprint coherence in biology that coordinates physical morphological structures with chemical is a fundamental discovery and highly simplifying complement to molecular genetic indepth understand to gene expression.
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Biology
| 2,021 |
April 27, 2021
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https://www.sciencedaily.com/releases/2021/04/210427110620.htm
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Treating severe COVID-19 cases
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Scientific studies rarely focus on long non-coding RNA molecules (lncRNAs), even though they potentially regulate several diseases. The role of several lncRNAs in anti-viral inflammatory response regulation has recently been reported. Considering their significant regulatory function in immune response, researchers from the Azrieli Faculty of Medicine of Bar-Ilan University sought to identify lncRNAs co-expressed with human genes involved in immune-related processes during severe SARS-CoV-2 infection in the lungs.
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Recent studies demonstrated that patients afflicted with severe SARS-CoV-2 infections present increased levels of pro-inflammatory plasma cytokines, as opposed to milder cases, highlighting the release of inflammatory cytokines as being central to COVID-19 severity. However, the underlying molecular mechanisms responsible for dysfunctional immune responses during COVID-19 infection remain elusive.In a paper recently published in the journal The finding suggests that the aberrant expression of lncRNAs can be associated with cytokine storms and anti-viral responses during severe SARS-CoV-2 infection. Thus, the present study uncovers the potential associations of lncRNAs in cytokine and interferon signaling during the response to severe SARS-CoV-2 infection in the lungs. This could provide valuable insight into pro-inflammatory cytokine production and how to mitigate it. It could also potentially be utilized as a future drug target to combat the hyper-inflammation caused by SARS-CoV-2 infection."It is remarkable that a major part of the human genome is filled in by non-coding regulatory elements, formerly known as "junk DNA." Among these are the long non-coding RNAs (lncRNAs). These lncRNAs are receiving more and more recognition as the potential regulators of several diseases," says Dr. Milana Frenkel-Morgenstern, of Bar-Ilan University's Azrieli Faculty of Medicine, who led the study with Prof. David Karasik.This study sheds light on the mechanisms behind COVID-19 severity and dysfunctional immune responses. Understanding the molecular interactions behind the immune dysfunction during severe COVID-19 infection in the lungs should help inform the design and development of novel approaches for treating severe COVID-19 patients.The researchers plan to validate their findings on human samples in collaboration with several of Israel's health care centers. Further, they will aim to determine which drugs from their COVID-19 drug database may inhibit the cytokine storm generation in COVID-19, and will design experiments to test the efficacy of those drugs.This study was supported by a grant from the COVID-19 Data Science Institute (DSI) at Bar-Ilan University and a PBC fellowship for outstanding postdoctoral researchers from China and India (to Dr. Sumit Mukherjee, who participated in the research) from the Israel Council for Higher Education.
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Biology
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April 27, 2021
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https://www.sciencedaily.com/releases/2021/04/210427110617.htm
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Switching to light
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Much as yeast serves in bakeries as single-celled helper, the bacterium
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"We've called the new system BLADE -- blue light-inducible AraC dimers in Escherichia coli," explains Romano. Scientists control the expression of a desired gene in the bacterium Optogenetics uses proteins that respond to light to regulate cell functions. "BLADE is intended for use in synthetic biology, microbiology, and biotechnology. We show that our tool can be used in a targeted manner, that it is fast and reversible," comments Di Ventura. To demonstrate with what precision BLADE responds to light, Di Ventura and her team made bacteriographs: images created from bacterial cultures. BLADE consists of a light-sensitive protein and a transcription factor: a protein that binds a specific sequence of the DNA found in the so-called promoter region of a gene and controls whether the corresponding gene is read by the cell machinery. The researchers controlled with BLADE the expression of the gene coding for a fluorescent protein to create the bacteriographs.The Freiburg scientists illuminated the bacterial lawn through a photomask glued to the lid of petri dishes. The bacteria fluoresced at the point at which they were illuminated, because BLADE was activated: The images were created under a fluorescence microscope. In another experiment, the researchers used BLADE to regulate genes that made Di Ventura holds one of the core professorships at BIOSS -- Centre for Biological Signalling Studies and coordinates Research Area C: Re-building and Biotechnology. At the Cluster of Excellence CIBSS -- Centre for Integrative Biological Signalling Studies, Di Ventura is participating in the development of so-called control-of-function technologies, such as optogenetic tools.
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Biology
| 2,021 |
April 27, 2021
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https://www.sciencedaily.com/releases/2021/04/210427110605.htm
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New method preserves viable fruit fly embryos in liquid nitrogen
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Cryopreservation, or the long-term storage of biomaterials at ultralow temperatures, has been used across cell types and species. However, until now, the practical cryopreservation of the fruit fly (Drosophila melanogaster) -- which is crucial to genetics research and critical to scientific breakthroughs benefiting human health -- has not been available.
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"To keep alive the ever-increasing number of fruit flies with unique genotypes that aid in these breakthroughs, some 160,000 different flies, laboratories and stock centers engage in the costly and frequent transfer of adults to fresh food, risking contamination and genetic drift," said Li Zhan, a postdoctoral associate with the University of Minnesota College of Science and Engineering and the Center for Advanced Technologies for the Preservation of Biological Systems (ATP-Bio).In new research published in Nature Communications, a University of Minnesota team has developed a first-of-its-kind method that cryopreserves fruit fly embryos so they can be successfully recovered and developed into adult insects. This method optimizes embryo permeabilization and age, cryoprotectant agent composition, different phases of nitrogen (liquid vs. slush), and post-cryopreservation embryo culture methods.Researchers were able to:show that the method is broadly applicable and easily adopted by non-specialists, with it being successfully implemented in 25 distinct strains for fruit flies from different sources (e.g., laboratories);demonstrate that for most strains, more than 50% of embryos hatch and more than 25% of the resulting larvae develop into adults after cryopreservation; andshow that flies retain normal sex ratio, fertility and original mutation after successive crypropreservation through generations and long-time storage in liquid nitrogen."Our multi-disciplinary team is pleased to contribute an accessible protocol to cryopreserve numerous strains of Drosophila, an important biomedical model, while also hopefully informing other insect and related species embryo preservation," said study co-author John Bischof, director of the Institute for Engineering in Medicine and a professor in the College of Science and Engineering and Medical School.As humans share more than half of their genes with the fruit fly, Drosophila research and its implications for human health are significant."By studying mutants in the Drosophila model system, it can reveal how those genes function in human development and disease," said Tom Hays, head of the Department of Genetics, Cell Biology and Development in the Medical School and College of Biological Sciences. "Fly studies have provided crucial insights on human diseases from Alzheimer's to Zika and revealed genetic pathways and mechanisms underlying embryonic development, olfaction and innate immunity."Beyond training individuals in this method, the University of Minnesota team is looking to adapt it to other applications."It will be important to understand the genetics that influence cryopreservation in Drosophila and other insects," said study co-author Mingang Li, a research associate in the Department of Genetics, Cell Biology and Development. "This method could support research aimed at pest control for Drosophila suzukii, a fruit fly that infests ripening fruits and has become a pest in the Americas and Europe, as well as for malaria research in Anopheles mosquitoes."Funding for the research was provided by the U.S. National Institutes of Health, the National Science Foundation, ATP-Bio from the Institute for Engineering in Medicine, and the University's Doctoral Dissertation Fellowship.
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Biology
| 2,021 |
April 27, 2021
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https://www.sciencedaily.com/releases/2021/04/210427094749.htm
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New research on why mutations in a gene leads to mitochondrial disease
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Monash University researchers have uncovered for the first time the reason mutations in a particular gene lead to mitochondrial disease.
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The finding, published in Mitochondria are critical structures within living cells that play a central role in energy conversion and their job is to process oxygen and take in the sugars and proteins from the food we eat to produce the energy our bodies need to function properly. Mitochondria produce 90 per cent of the energy our body needs to function.Mitochondrial disease is an inherited, chronic illness that can present at birth or develop later in life and occurs when mitochondria fail to produce enough energy for the body to function properly. The cells of the optic nerve and the inner ear are particularly sensitive to mitochondrial defects due to the high energy requirements to transfer information to the brain, but Mitochondrial diseases can affect almost any part of the body.Using a combination of cutting-edge technologies, the study found that loss of TMEM126A results in an isolated complex I deficiency -- a common form of mitochondrial disease where a critical enzyme called complex I is reduced -- and that the TMEM126A protein binds to a number of complex I subunits and additional proteins that help build the enzyme, known as assembly factors."Now we know that TMEM126A is important in helping to build this protein needed to provide energy for the mitochondria organelles, we can look at future therapies that can perhaps bypass TMEM126A function and find other ways to help cells make energy," Professor Ryan said.First author Dr Luke Formosa adds: "Now that we know what TMEM126A does in mitochondria, we can start to investigate treatments that might work for individuals with mutations in this gene, which could lead to less severe loss of vision and hearing."
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Biology
| 2,021 |
April 27, 2021
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https://www.sciencedaily.com/releases/2021/04/210427094746.htm
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The bluest of blue: A new algae-based switch is lighting up biological research
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Several organisms possess "ion channels" (gateways that selectively allow charged particles called ions to enter the cells and are integral for cell function) called "channelrhodopsins," that can be switched on and off with the help of light. Different channelrhodopsins respond to different wavelengths in the light spectrum. These channels can be expressed in foreign organisms (animals even in human) by means of genetic engineering, which in turn finds applications in optogenetics, or the application of light to modulate cellular and gene functions. So far, the shortest wavelength that a channelrhodopsin responds to was blue.
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However, recently, a group of scientists from the Nagoya Institute of Technology, Japan, and Jawaharlal Nehru University, India, have identified a channelrhodopsin that responds to an even shorter indigo blue wavelength of light. In their study published in Nature's It is known that KnChR is made up of a seven-cell membrane spanning region, which forms the pore that allows the entry and exit of different ions. This region is followed by a protein moiety including a peptidoglycan binding domain. In order to investigate the properties of KnChR, the researchers performed extensive genetic and electrophysiological experiments.What was perhaps the most exciting result was that they could identify the role of the "cytoplasmic domain." All known channelrhodopsins have a large "cytoplasmic domain," or region that is located in the internal area of the cell. As Prof. Kandori explains, "All currently known channelrhodopsins comprise a large cytoplasmic domain, whose function is elusive. We found that the cytoplasmic domain of KnChR modulates the ion channel properties."Accordingly, the results of the experiments showed that changing the lengths of the cytoplasmic domain caused the changes in ion channel closure. Particularly, the shortening of the domain resulted in increased channel 'open time' by more than ten-fold. In addition, the researchers also identified two arginine amino acid residues, namely R287 and R291, in the same region, which played an important role in the properties of generated light currents. They found that KnChR exhibited maximal sensitivity at 430 nm and 460 nm, making it the 'bluest' channelrhodopsin.Overall, the researchers have faith in the KnChR being helpful in biological systems requiring specific excitation parameters. When asked about the implications of these findings, Prof. Tsunoda, who is the corresponding author of the study suggests, "KnChR would expand the optogenetics tool kit, especially for dual light applications when short-wavelength excitation is required." What this means is that the light-operated property of KnChR can be applied in targeted manipulation of an organism's biological functions, in a research setting. A few examples would include manipulation of neuronal and myocyte activities.
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Biology
| 2,021 |
April 27, 2021
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https://www.sciencedaily.com/releases/2021/04/210427085754.htm
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SARS-CoV-2 curtails immune response in the gut
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In an effort to determine the potential for COVID-19 to begin in a person's gut, and to better understand how human cells respond to SARS-CoV-2, the scientists used human intestinal cells to create organoids -- 3D tissue cultures derived from human cells, which mimic the tissue or organ from which the cells originate. Their conclusions, published in the journal
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"Previous research had shown that SARS-CoV-2 can infect the gut," says Theodore Alexandrov, who leads one of the two EMBL groups involved. "However, it remained unclear how intestinal cells mount their immune response to the infection."In fact, the researchers were able to determine the cell type most severely infected by the virus, how infected cells trigger an immune response, and -- most interestingly -- that SARS-CoV-2 silences the immune response in infected cells. These findings may shed light on the pathogenesis of SARS-CoV-2 infection in the gut, and indicate why the gut should be considered to fully understand how COVID-19 develops and spreads.According to Sergio Triana, lead author and a doctoral candidate in EMBL's Alexandrov team, the researchers observed how infected cells seem to start a cascade of events that produce a signalling molecule called interferon."Interestingly, although most cells in our mini guts had a strong immune response triggered by interferon, SARS-CoV-2-infected cells did not react in the same way and instead presented a strong pro-inflammatory response," Sergio says. "This suggests that SARS-CoV-2 interferes with the host signalling to disrupt an immune response at the cellular level."Coronaviruses, including SARS-CoV-2, cause infection by latching on to specific protein receptors found on the surface of certain cell types. Among these receptors is the protein ACE2. Interestingly, the researchers showed that the infection is not explained solely by the presence of ACE2 on the surface of the cells, highlighting our still limited knowledge about COVID-19, even after a year of tremendous research efforts worldwide.As the disease progressed in the organoids, the researchers used single-cell RNA sequencing, which involves several techniques to amplify and detect RNA. Among these single-cell technologies, Targeted Perturb-seq (TAP-seq) provided sensitive detection of SARS-CoV-2 in infected organoids. Lars Steinmetz's research group at EMBL recently developed TAP-seq, which the researchers combined with powerful computational tools, enabling them to detect, quantify, and compare expression of thousands of genes in single cells within the organoids."This finding could offer insights into how SARS-CoV-2 protects itself from the immune system and offer alternative ways to treat it," Lars says. "Further study can help us understand how the virus grows and the various ways it impacts the human immune system."
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Biology
| 2,021 |
April 27, 2021
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https://www.sciencedaily.com/releases/2021/04/210422102836.htm
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Fat-footed tyrannosaur parents could not keep up with their skinnier adolescent offspring
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New research by the University of New England's Palaeoscience Research Centre suggests juvenile tyrannosaurs were slenderer and relatively faster for their body size compared to their multi-tonne parents.
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The research, published in the UNE PhD student and study leader, Nathan Enriquez -- in international collaboration with the Philip J. Currie Dinosaur Museum, University of Alberta, Royal Ontario Museum, University of Bologna and the Grande Prairie Regional College -- believes the findings contribute a new line of evidence to previous findings based on bone anatomy and computer models of muscle masses."The results suggest that as some tyrannosaurs grew older and heavier, their feet also became comparably more bulky," Mr Enriquez said."Fully grown tyrannosaurs were believed to be more robust than younger individuals based on their relatively shorter hind limbs and more massive skulls, but nobody had explored this growth pattern using fossil footprints, which are unique in that they can provide a snapshot of the feet as they appeared in life, with outlines of the soft, fleshy parts of the foot that are rarely preserved as fossils.Footprints can be ambiguous and hard to interpret correctly -- the shape of a footprint may be influenced by the type of ground surface that is stepped on and the motions of the animal making the footprints. In addition, the exact identity of the animal may not always be clear. These challenges have previously limited the use of fossil footprints in understanding dinosaur growth.The answer lay in the Grande Prairie region of Northern Alberta, Canada, where the research team worked with well-preserved samples of footprints of different sizes that are suggested to belong to the same type of animal."We explored a remote dinosaur footprint site where we discovered a new set of large carnivorous dinosaur footprints within very similar rocks to those which have produced tyrannosaur tracks in the past," Mr Enriquez said."Based on the relatively close proximity between these discoveries and their nearly equivalent ages -- about 72.5 million years old -- we suggest they may indeed belong to the same species."We were also careful to assess the quality of preservation in each footprint, and only considered specimens which were likely to reflect the shape of the actual feet that produced them."Once the team had a suitable sample, they analysed the outlines of each specimen using a method called geometric morphometrics. This process removes the effect of overall size differences between each footprint and shows what the most important differences in track shape are."The greatest difference in shape was found to be the relative width and surface area of the heel impression, which significantly increased in size between smaller and larger footprints," Mr Enriquez said."The smaller tracks are comparably slender, while the biggest tyrannosaur tracks are relatively broader and had much larger heel areas. This makes sense for an animal that is becoming larger and needs to support its rapidly increasing body weight. It also suggests the relative speed of these animals decreased with age."Increasingly bulky feet in the adults aligns with previous suggestions that juvenile tyrannosaurs would have been faster and more agile for their body size in comparison to their parents, and means that we can add footprints as another line of evidence in the debate over tyrannosaur growth."Lastly, it demonstrates the usefulness of footprints for investigating a potentially wider range of ideas about the lives of extinct species than has been considered previously."
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Biology
| 2,021 |
April 27, 2021
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https://www.sciencedaily.com/releases/2021/04/210427085757.htm
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Skin and bones repaired by bioprinting during surgery
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Fixing traumatic injuries to the skin and bones of the face and skull is difficult because of the many layers of different types of tissues involved, but now, researchers have repaired such defects in a rat model using bioprinting during surgery, and their work may lead to faster and better methods of healing skin and bones.
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"This work is clinically significant," said Ibrahim T. Ozbolat, Hartz Family Career Development Associate Professor of Engineering Science and Mechanics, Biomedical Engineering and Neurosurgery, Penn State. "Dealing with composite defects, fixing hard and soft tissues at once, is difficult. And for the craniofacial area, the results have to be esthetically pleasing."Currently, fixing a hole in the skull involving both bone and soft tissue requires using bone from another part of the patient's body or a cadaver. The bone must be covered by soft tissue with blood flow, also harvested from somewhere else, or the bone will die. Then surgeons need to repair the soft tissue and skin.Ozbolat and his team used extrusion bioprinting and droplet bioprinting of mixtures of cells and carrier materials to print both bone and soft tissue. They report their results in "There is no surgical method for repairing soft and hard tissue at once," said Ozbolat. "This is why we aimed to demonstrate a technology where we can reconstruct the whole defect -- bone to epidermis -- at once."The researchers attacked the problem of bone replacement first, beginning in the laboratory and moving to an animal model. They needed something that was printable and nontoxic and could repair a 5-millimeter hole in the skull. The "hard tissue ink" consisted of collagen, chitosan, nano-hydroxyapatite and other compounds and mesenchymal stem cells -- multipotent cells found in bone marrow that create bone, cartilage and bone marrow fat.The hard tissue ink extrudes at room temperature but heats up to body temperature when applied. This creates physical cross-linkage of the collagen and other portions of the ink without any chemical changes or the necessity of a crosslinker additive.The researchers used droplet printing to create the soft tissue with thinner layers than the bone. They used collagen and fibrinogen in alternating layers with crosslinking and growth enhancing compounds. Each layer of skin including the epidermis and dermis differs, so the bioprinted soft tissue layers differed in composition.Experiments repairing 6 mm holes in full thickness skin proved successful. Once the team understood skin and bone separately, they moved on to repairing both during the same surgical procedure."This approach was an extremely challenging process and we actually spent a lot of time finding the right material for bone, skin and the right bioprinting techniques," said Ozbolat.After careful imaging to determine the geometry of the defect, the researchers laid down the bone layer. They then deposited a barrier layer mimicking the periosteum, a heavily vascularized tissue layer that surrounds the bone on the skull."We needed the barrier to ensure that cells from the skin layers didn't migrate into the bone area and begin to grow there," said Ozbolat.After laying down the barrier, the researchers printed the layers of dermis and then the epidermis."It took less than 5 minutes for the bioprinter to lay down the bone layer and soft tissue," said Ozbolat.The researchers performed more than 50 defect closures and achieved 100% closure of soft tissue in four weeks. The closure rate for bone was 80% in six weeks, but Ozbolat noted that even with harvested bone replacement, bone closure usually does not reach 100% in six weeks.According to Ozbolat, blood flow to the bone is especially important and inclusion of vascularizing compounds is a next step.The researchers also want to translate this research to human applications and are continuing to work with neurosurgeons, craniomaxillofacial surgeons and plastic surgeons at Penn State Hershey Medical Center. They operate a larger bioprinting device on larger animals.
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Biology
| 2,021 |
April 26, 2021
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https://www.sciencedaily.com/releases/2021/04/210426140912.htm
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Life science research result reporting set for boost under new system
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A new guideline for reporting research results has been developed to improve reproducibility, replication, and transparency in life sciences.
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The new Research Materials, Design, Analysis and Reporting (MDAR) Framework will harmonise the recording of outcomes across several major journals, its developers say.Existing guidelines address specific parts of biomedical research, such as ARRIVE -- which relates to animal research -- and CONSORT, associated with clinical trial reporting.The MDAR Framework -- developed by a team from the University of Edinburgh, the Centre for Open Science and six major journal publishers -- complements these by establishing basic minimum reporting requirements and best practice recommendations.The Framework is outlined in a new publication in the Experimentation with various guidelines has resulted in a fragmented landscape, which, even though it has improved reporting, has increased the burden on authors' and editors' time.According to the team, the flexibility of the Framework provides an opportunity for harmonization across journal publishing, making it easier for authors to know what is expected when submitting a manuscript and improve portability between journals.This flexibility will also make it simpler for publishers to adopt. They will be able to select sections of the Framework that are most appropriate to the scope of specific journals.The Framework includes an optional checklist for authors, editors or reviewers and explanatory documents to aid implementation.The checklist was piloted on 289 manuscripts submitted to 13 different journals. Feedback from authors, editors and external experts was then used to improve the Framework.The team hope that the Framework will also be helpful for other organizations, such as funders who can indicate reporting expectations to their grantees when studies are first designed.Professor Malcolm Macleod, Academic Lead for Research Improvement and Research Integrity, University of Edinburgh, said: "Improving research is challenging -- it requires ongoing effort, adapting to the changing demands and circumstances of the time. No single intervention will be sufficient, but we hope that the MDAR framework can contribute to the range of initiatives which support improvement."The six publishers that worked on the Framework include The full set of MDAR resources is available in a Collection on the Open Science Framework. It will be maintained and updated as a community resource.Veronique Kiermer, Chief Scientific Officer at Sowmya Swaminathan, Head of Editorial Policy and Research Integrity, Nature Portfolio, Springer Nature, said: "Through my work across multiple journals, I have learned that improving publication quality is a complex task, with each journal presenting its own set of challenges. The MDAR framework can be applied broadly and flexibly so that journals can choose a level of implementation appropriate to their needs. The MDAR framework can be applied broadly and flexibly so that journals can choose a level of implementation appropriate to their needs."David Mellor, Director of Policy from the Center for Open Science, said: "This framework will add clarity for researchers, readers, and journals in order to lower barriers to replicating empirical findings. We at COS are happy to steward MDAR so that it can remain a viable practice for the foreseeable future."
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Biology
| 2,021 |
April 26, 2021
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https://www.sciencedaily.com/releases/2021/04/210426100606.htm
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Nanobodies inhibit SARS-CoV-2 infection
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Australian researchers have identified neutralising nanobodies that block the SARS-CoV-2 virus from entering cells in preclinical models.
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The discovery paves the way for further investigations into nanobody-based treatments for COVID-19.Published in Antibodies are key infection-fighting proteins in our immune system. An important aspect of antibodies is that they bind tightly and specifically to another protein.Antibody-based therapies, or 'biologics', harness this property of antibodies, enabling them to bind to a protein involved in disease.Nanobodies are unique antibodies -- tiny immune proteins -- produced naturally by alpacas in response to infection.As part of the research, a group of alpacas in regional Victoria were immunised with a synthetic, non-infectious part of the SARS-CoV-2 'spike' protein to enable them to generate nanobodies against the SARS-CoV-2 virus.WEHI Associate Professor Wai-Hong Tham, who led the research, said the establishment of a nanobody platform at WEHI allowed an agile response for the development of antibody-based therapies against COVID-19."The synthetic spike protein is not infectious and does not cause the alpacas to develop disease -- but it allows the alpacas to develop nanobodies," she said."We can then extract the gene sequences encoding the nanobodies and use this to produce millions of types of nanobodies in the laboratory, and then select the ones that best bind to the spike protein."Associate Professor Tham said the leading nanobodies that block virus entry were then combined into a 'nanobody cocktail'."By combining the two leading nanobodies into this nanobody cocktail, we were able to test its effectiveness at blocking SARS-CoV-2 from entering cells and reducing viral loads in preclinical models," she said.ANSTO's Australian Synchrotron and the Monash Ramaciotti Centre for Cryo-Electron Microscopy were critical resources in the project, allowing the research team to map how the nanobodies bound to the spike protein and how this impacted the virus' ability to bind to its human receptor.Hariprasad Venugopal, Senior Microscopist from the Monash Ramaciotti Centre for Cryo-Electron Microscopy, said the study highlighted the importance of open-access to high-end Cryo-EM facilities."We were able to directly image and map the neutralising interaction of the nanobodies with the spike protein using Cryo-EM at near atomic resolution," Mr Venugopal said."Cryo-EM has been an important drug discovery tool in the global response to the COVID-19 pandemic."By mapping the nanobodies, the research team was able to identify a nanobody that recognised the SARS-CoV-2 virus, including emerging global variants of concern. The nanobody was also effective against the original SARS virus (SARS-CoV), indicating it may provide cross-protection against these two globally significant human coronaviruses."In the wake of COVID-19, there is a lot of discussion about pandemic preparedness. Nanobodies that are able to bind to other human beta-coronaviruses -- including SARS-CoV-2, SARS-CoV and MERS -- could prove effective against future coronaviruses as well," Associate Professor Tham said.This work was made possible with funding from the Medical Research Future Fund, the Hengyi Group and the Victorian Government.
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Biology
| 2,021 |
April 26, 2021
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https://www.sciencedaily.com/releases/2021/04/210426085903.htm
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Genome sequencing delivers hope and warning for the survival of the Sumatran rhinoceros
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A study led by researchers at the Centre for Palaeogenetics in Stockholm shows that the last remaining populations of the Sumatran rhinoceros display surprisingly low levels of inbreeding. The researchers sequenced the genomes from 21 modern and historical rhinoceros' specimens, which enabled them to investigate the genetic health in rhinos living today as well as a population that recently became extinct. These findings are published today in the journal
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With less than 100 individuals remaining, the Sumatran rhinoceros is one of the most endangered mammal species in the world. Recent reports of health issues and low fecundity have raised fears that the remaining populations are suffering from inbreeding problems. However, very little has been known about the genetic status of these enigmatic rhinos.To investigate whether the Sumatran rhinoceros is threatened by genetic factors, the researchers sequenced the genomes from 16 individuals representing the present-day populations on Borneo and Sumatra and the recently extinct population on the Malaysian Peninsula. This enabled them to estimate inbreeding levels, genetic variation, and the frequency of potentially harmful mutations in the populations. Moreover, by also sequencing the genomes from five historical samples, the researchers could investigate the genetic consequences of the severe population decline of the past 100 years."To our surprise, we found relatively low inbreeding levels and high genetic diversity in the present-day populations on Borneo and Sumatra," says Johanna von Seth, PhD student at the Centre for Palaeogenetics and co-lead author on the paper.The researchers think that the comparatively low inbreeding levels in the present-day rhinos is due to the decline in population size having happened very recently. This means that inbreeding hasn't yet caught up with the current small population size. This is good news for the conservation management of the remaining populations, since it implies that there is still time to preserve the species' genetic diversity. However, the researchers also found that there are many potentially harmful mutations hidden in the genomes of these individuals, which could spell bad news for the future."Unless the populations start increasing in size, there is a high risk that inbreeding levels will start rising, and consequently that genetic diseases will become more common," cautions Nicolas Dussex, postdoctoral researcher at the Centre for Palaeogenetics who also co-led the study.The research team's findings from the recently extinct population on the Malaysian Peninsula serve as a stark warning of what might soon happen to the remaining populations in Borneo and Sumatra. A comparison of historical and modern genomes showed that the Malaysian Peninsula population experienced a rapid increase in inbreeding levels before it went extinct. Moreover, the researchers observed changes in the frequency of potentially harmful mutations that are consistent with inbreeding depression, a phenomenon where closely related parents produce offspring that suffer from genetic disease. These results imply that the two remaining populations could suffer a similar fate if their inbreeding levels start to increase."The Sumatran rhino is by no means out of the woods. But at least our findings provide a path forward, where we might still be able to rescue a large part of the species' genetic diversity," says Love Dalén, professor of evolutionary genetics at the Centre for Palaeogenetics.In order to minimize the risk of extinction, the researchers say that it is imperative that the population size increases. They also suggest that actions can be taken to enable the exchange of genes between Borneo and Sumatra, for example by translocating individuals or using artificial insemination. A comparison of genomes from these two islands provided no evidence that such genetic exchange could lead to an introduction of genes that are less well adapted to the local environment. The researchers also point out that genome sequencing could be used as a tool to identify particular individuals with low amounts of potentially harmful mutations, and that such individuals would be especially well-suited for this type of genetic exchange.In a wider perspective, the study highlights the potential of modern-day genome sequencing technology in guiding conservation efforts for endangered species across the globe. The study was supported by the National Genomics Infrastructure at SciLifeLab in Sweden, and was a collaboration between researchers from several different countries that included geneticists as well as experts on conservation management and reproductive biology.The Centre for Palaeogenetics is a joint research centre funded by Stockholm University and the Swedish Museum of Natural History.
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Biology
| 2,021 |
April 26, 2021
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https://www.sciencedaily.com/releases/2021/04/210426085900.htm
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Discovery of an elusive cell type in fish sensory organs
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One of the evolutionary disadvantages for mammals, relative to other vertebrates like fish and chickens, is the inability to regenerate sensory hair cells. The inner hair cells in our ears are responsible for transforming sound vibrations and gravitational forces into electrical signals, which we need to detect sound and maintain balance and spatial orientation. Certain insults, such as exposure to noise, antibiotics, or age, cause inner ear hair cells to die off, which leads to hearing loss and vestibular defects, a condition reported by 15% of the US adult population. In addition, the ion composition of the fluid surrounding the hair cells needs to be tightly controlled, otherwise hair cell function is compromised as observed in Ménière's disease.
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While prosthetics like cochlear implants can restore some level of hearing, it may be possible to develop medical therapies to restore hearing through the regeneration of hair cells. Investigator Tatjana Piotrowski, PhD, at the Stowers Institute for Medical Research is part of the Hearing Restoration Project of the Hearing Health Foundation, which is a consortium of laboratories that do foundational and translational science using fish, chicken, mouse, and cell culture systems."To gain a detailed understanding of the molecular mechanisms and genes that enable fish to regenerate hair cells, we need to understand which cells give rise to regenerating hair cells and related to that question, how many cell types exist in the sensory organs," says Piotrowski.The Piotrowski Lab studies regeneration of sensory hair cells in the zebrafish lateral line. Located superficially on the fish's skin, these cells are easy to visualize and to access for experimentation. The sensory organs of the lateral line, known as neuromasts, contain support cells which can readily differentiate into new hair cells. Others had shown, using techniques to label cells of the same embryonic origin in a particular color, that cells within the neuromasts derive from ectodermal thickenings called placodes.It turns out that while most cells of the zebrafish neuromast do originate from placodes, this isn't true for all of them.In a paper published online April 19, 2021, in "I initially thought it was an artifact of the research method," says Julia Peloggia, a predoctoral researcher at The Graduate School of the Stowers Institute for Medical Research, co-first author of this work along with another predoctoral researcher, Daniela Münch. "Especially when we are looking just at the nuclei of cells, it's pretty common in transgenic animal lines that the labels don't mark all of the cells," adds Münch.Peloggia and Münch agreed that it was difficult to discern a pattern at first. "Although these cells have a stereotypical location in the neuromast, they're not always there. Some neuromasts have them, some don't, and that threw us off," says Peloggia.By applying an experimental method called single-cell RNA sequencing to cells isolated by fluorescence-activated cell sorting, the researchers identified these cells as ionocytes -- a specialized type of cell that can regulate the ionic composition of nearby fluid¬. Using lineage tracing, they determined that the ionocytes derived from skin cells surrounding the neuromast. They named these cells neuromast-associated ionocytes.Next, they sought to capture the phenomenon using time-lapse and high-resolution live imaging of young larvae."In the beginning, we didn't have a way to trigger invasion by these cells. We were imaging whenever the microscope was available, taking as many time-lapses as possible -- over days or weekends -- and hoping that we would see the cells invading the neuromasts just by chance," says Münch.Ultimately, the researchers observed that the ionocyte progenitor cells migrated into neuromasts as pairs of cells, rearranging between other support cells and hair cells while remaining associated as a pair. They found that this phenomenon occurred all throughout early larval, later larval, and well into the adult stages in zebrafish. The frequency of neuromast-associated ionocytes correlated with developmental stages, including transfers when larvae were moved from ion-rich embryo medium to ion-poor water.From each pair, they determined that only one cell was labeled by a Notch pathway reporter tagged with fluorescent red or green protein. To visualize the morphology of both cells, they used serial block face scanning electron microscopy to generate high-resolution three-dimensional images. They found that both cells had extensions reaching the apical or top surface of the neuromast, and both often contained thin projections. The Notch-negative cell displayed unique "toothbrush-like" microvilli projecting into the neuromast lumen or interior, reminiscent of that seen in gill and skin ionocytes."Once we were able to see the morphology of these cells -- how they were really protrusive and interacting with other cells -- we realized they might have a complex function in the neuromast," says Münch."Our studies are the first to show that ionocytes invade sensory organs even in adult animals and that they only do so in response to changes in the environment that the animal lives in," says Peloggia. "These cells therefore likely play an important role allowing the animal to adapt to changing environmental conditions."Ionocytes are known to exist in other organ systems. "The inner ear of mammals also contains cells that regulate the ion composition of the fluid that surrounds the hair cells, and dysregulation of this equilibrium leads to hearing and vestibular defects," says Piotrowski. While ionocyte-like cells exist in other systems, it's not known whether they exhibit such adaptive and invasive behavior."We don't know if ear ionocytes share the same transcriptome, or collection of gene messages, but they have similar morphology to an extent and may possibly have a similar function, so we think they might be analogous cells," says Münch. Our discovery of neuromast ionocytes will let us test this hypothesis, as well as test how ionocytes modulate hair cell function at the molecular level," says Peloggia.Next, the researchers will focus on two related questions -- what causes these ionocytes to migrate and invade the neuromast, and what is their specific function?"Even though we made this astounding observation that ionocytes are highly motile, we still don't know how the invasion is triggered," says Peloggia. "Identifying the signals that attract ionocytes and allow them to squeeze into the sensory organs might also teach us how cancer cells invade organs during disease." While Peloggia plans to investigate what triggers the cells to differentiate, migrate, and invade, Münch will focus on characterizing the function of the neuromast-associated ionocytes. "The adaptive part is really interesting," explains Münch. "That there is a process involving ionocytes extending into adult stages that could modulate and change the function of an organ -- that's exciting."Other coauthors of the study include Paloma Meneses-Giles, Andrés Romero-Carvajal, PhD, Mark E. Lush, PhD, and Melainia McClain from Stowers; Nathan D. Lawson from the University of Massachusetts Medical School; and Y. Albert Pan, PhD, from Virginia Tech Carilion.The work was funded by the Stowers Institute for Medical Research and the National Institute of Child Health and Human Development of the National Institutes of Health (award 1R01DC015488-01A1). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.Humans cannot regenerate inner ear hair cells, which are responsible for detecting sound, but non-mammalian vertebrates can readily regenerate sensory hair cells that are similar in function. During the quest to understand zebrafish hair cell regeneration, researchers from the lab of Investigator Tatjana Piotrowski, PhD, at the Stowers Institute for Medical Research discovered the existence of a cell type not previously described in the process.The research team found newly differentiated, migratory, and invasive ionocytes located in the sensory organs that house the cells giving rise to new hair cells in larval and adult fish. The researchers published their findings online April 19, 2021, in
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Biology
| 2,021 |
April 27, 2021
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https://www.sciencedaily.com/releases/2021/04/210427094814.htm
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How oxygen radicals protect against cancer
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Originally, oxygen radicals -- reactive oxygen species, or ROS for short -- were considered to be exclusively harmful in the body. They are produced, for example, by smoking or UV radiation. Because of their high reactivity, they can damage many important molecules in cells, including the hereditary molecule DNA. As a result, there is a risk of inflammatory reactions and the degeneration of affected cells into cancer cells.
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Because of their damaging effect, however, ROS are also deliberately produced by the body, for example by immune or lung epithelial cells, which destroy invading bacteria and viruses with ROS. This requires relatively high ROS concentrations. In low concentrations, on the other hand, ROS play an important role as signalling molecules. For these tasks, ROS are specifically produced by a whole group of enzymes. One representative of this group of enzymes is Nox4, which continuously produces small amounts of HResearchers at Goethe University Frankfurt, led by Professor Katrin Schröder, have now discovered that by producing HMolecular investigations showed that the HSevere DNA damage -- e.g. double strand breaks -- occurs somewhere in the body every day. Cells react very sensitively to such DNA damage, setting a whole repertoire of repair enzymes in motion. If this does not help, the cell activates its cell death programme -- a precautionary measure of the body against cancer. When such damage goes unrecognised, as occurs in the absence of Nox4, it spurs cancer formation.Prof. Katrin Schröder explains the research results: "If Nox4 is missing and there is therefore no H
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Biology
| 2,021 |
April 23, 2021
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https://www.sciencedaily.com/releases/2021/04/210423130228.htm
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Force transmission between cells orchestrates collective cellular motion
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How do the billions of cells communicate in order to perform tasks? The cells exert force on their environment through movement -- and in doing so, they communicate. They work as a group in order to infiltrate their environment, perform wound healing and the like. They sense the stiffness or softness of their surroundings and this helps them connect and organize their collective effort. But when the connection between cells is distrubeddisturbed, a situation just like when cancer is initiated, can appear.
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Assistant Professor Amin Doostmohammadi at the Niels Bohr Institute, University of Copenhagen has investigated the mechanics of cell movement and connection in an interdisciplinary project, collaborating with biophysicists in France, Australia, and Singapore, using both computer modelling and biological experiments. The result is now published in Amin Doostmohammadi explains: "We need to understand how cells translate this "knowledge from sensing" at the individual cell level and transform it into action on the collective level. This is still kind of a black box in biology -- how do cell talk to their neighbors and act as a collective?"Individual cells have a contractile mode of motion: they pull on the surface they are located on to move themselves forward. However, cells lining up cavities and surfaces in our body, like the tubes of blood vessels or the cells at the surface of organs, are able to generate extensile forces. They do the opposite, they stretch instead of contract -- and they form strong connections with their neighbors. Contractile cells are able to switch to becoming extensile cells, when coming into contact with their neighbors. If, for instance, when contractile cells sense a void or an empty space, like when a wound appears, they can loosen their cell -- cell connection, become more individual, and when healing the wound, they form strong connections with their neighbors again, becoming extensile, closing the gap, so to speak.The cells connect to their neighbors by adherens junctions. They connect their internal cytoskeleton to one another and become able to transmit forces through the strong contacts. "So we asked ourselves what would happen if we prohibited the cells from making this strong connection -- and it turned out that extensile, strongly connected cells turned into contractile cells with weaker connections. This is significant, because the loss of this contact is the hallmark of cancer initiation. The cells losing contact start behaving more as individuals and become able to infiltrate their surroundings. This process also happens when an embryo develops, but the key difference here is that when the healthy cells have achieved their goal, like forming an organ, they go back to their original form. Cancer cells do not. They are on a one way street," Amin Doostmohammadi says.How cells "decide" when to go from one form to another is a complicated mix of reacting to their environment, changes in the chemical composition of it, the mechanical stiffness or softness of the tissue -- and many proteins in the cells are involved in the process. The key finding of this study is that this reaction to surroundings is constantly shifting: There is a constant cross-talk between cell -- surroundings and cell -- cell, and this is what determines the actions and reactions of the cells."We must always be careful, when talking about a serious and very complex disease like cancer," Amin Doostmohammadi says. "But what we can say is that this study brings us one step closer to understanding the basic mechanics of cell behavior, when the cells go from the normal behavior to the aggressive, cancer type cell behavior. So, one of the big questions this study raises is if we might be able to target the mechanics of the cells by some form of therapy or treatment, instead of targeting the DNA or chemical composition of the cells themselves? Could we target the environment instead of the cells? This is basic research, connecting physics and biology, into the mechanics of cell behavior, based on their sensing and responding to the surroundings and coordinating their effort -- our improved understanding of this may well lead to new therapies, and there are trials going on at the moment at a preliminary stage."
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Biology
| 2,021 |
April 23, 2021
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https://www.sciencedaily.com/releases/2021/04/210423130117.htm
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Fight or flight response may hinge on protein in skeletal muscular system
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Researchers at the University of Cincinnati say a regulatory protein found in skeletal muscle fiber may play an important role in the body's fight or flight response when encountering stressful situations.
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The protein, fast skeletal myosin binding protein-C (fMyBP-C), plays a foundational role in the proper regulation of contractile structure and function in the body's fast twitch muscles -- these muscles produce sudden bursts of power to sprint into action, jump or lift heavy objects. Fast skeletal myosin binding protein-C modulates the speed and force of fast skeletal muscle contraction."This response is very critical for the higher animal and human survival. Just imagine, you are walking through a forest and suddenly you see a tiger in front of you," says Sakthivel Sadayappan, PhD, a professor in the UC Division of Cardiovascular Health and Disease. "You will immediately act, either to fight or run away from the animal. For that action, fast muscle is essential, and fast myosin binding protein-C is the key molecule to regulate the speed of action."Myosin-binding protein-C is a thick filament regulatory protein found in striated muscle in both the heart and skeletal system. The protein performs different functions in the two organs, regulating contractility in the heart and playing a role in the development of fast and slow muscle fibers in skeletal muscle tissue.Sadayappan along with researchers at UC College of Medicine, Florida State University, the University of Massachusetts Medical School and the Illinois Institute of Technology published research in the scholarly journal The study's lead author is Taejeong Song, PhD, a postdoctoral fellow in the Sadayappan Lab at the UC College of Medicine.Song says that research examined the role of the protein in fast-twitch muscles by generating a knockout mouse -- an animal in which researchers have either inactivated, replaced or disrupted the existing fast myosin binding protein-C gene to study its impact."We found that knockout mice demonstrated a reduced ability to exercise, showed less maximal muscle force and a diminished ability for muscle to recover from injury," explains Sadayappan. "Our study concludes that fast myosin binding protein-C is essential in regulating the force generation and speed of contraction of fast muscles."Song says advancing the knowledge of fast myosin binding protein-C may someday assist in addressing skeletal muscular disorders."Individuals lose their ability of muscle force generation for various reasons," says Song. "They may be extremely inactive or hospitalized for long periods of time. Aging may also be the cause for some. We also think if we can manipulate the workings of fast myosin binding protein-C in skeletal muscle that we can prevent or at least slow down the loss of muscle function in genetic muscle disease such as distal arthrogryposis. Our research is trying to figure out this problem in human health."
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Biology
| 2,021 |
April 23, 2021
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https://www.sciencedaily.com/releases/2021/04/210423095406.htm
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Bacteria and viruses infect our cells through sugars: Now researchers want to know how they do it
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Sugar is not just something we eat. On the contrary. Sugar is one of the most naturally occurring molecules, and all cells in the body are covered by a thick layer of sugar that protects the cells from bacteria and virus attacks. In fact, close to 80 per cent of all viruses and bacteria bind to the sugars on the outside of our cells.
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Sugar is such an important element that scientists refer to it as the third building block of life -- after DNA and protein. And last autumn, a group of researchers found that the spike protein in corona virus needs a particular sugar to bind to our cells efficiently.Now the same group of researchers have completed a new study that further digs into the cell receptors to which sugars and thus bacteria and virus bind.'We have established how the sugars bind to and activate the so-called Siglec receptors that regulate immunity. These receptors play a major role, as they tell the immune system to decrease or increase activities. This is an important mechanism in connection with autoimmune diseases', says the first author of the study, Postdoc Christian Büll from the Copenhagen Center for Glycomics (CCG) at the University of Copenhagen.When the immune system receives wrong signals, it can lead to autoimmune diseases, which is when the immune system attacks itself. The Siglec receptors receive signals via the sialic acid sugar, a carbohydrate that typically closes the sugar chains on the surface of our cells. When Siglec receptors meet the right sugar chains, the immune system is told to dampen or activate.'As part of the new study, we have created a cell library that can be used to study how various sugars bind to and interact with receptors. We have done this by creating tens of thousands of cells each containing a bit of the unique sugar language, which enables us to distinguish them from one another and to study their individual effect and process. This knowledge can help us develop better treatment options in the future', says Associate Professor Yoshiki Narimatsu from CCG, who also contributed to the study.'The surface of the cells in the library is the same as the one found on cells in their natural environment. This means that we can study the sugars in an environment with the natural occurrence of e.g. proteins and other sugars, and we can thus study the cells in the form in which virus and bacteria find them', Yoshiki Narimatsu explains.Working on the new study, the researchers identified the sugars that bind to the specific receptor that plays a main role in the development of Alzheimer's disease.'Our main finding concerns the Siglec-3 receptor. Mutations in the Siglec-3 receptor is already known to play a role in connection with Alzheimer's, but we did not know what the receptor specifically binds to. Our method has now identified a potential natural sugar that binds specifically to the Siglec-3 receptor. This knowledge represents an important step forwards in understanding the genetic defects that cause a person to develop the disease', says Christian Büll.The creation of the sugar libraries was funded by the Lundbeck Foundation and the Danish National Research Foundation.
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Biology
| 2,021 |
April 23, 2021
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https://www.sciencedaily.com/releases/2021/04/210423092636.htm
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Living cells: Individual receptors caught in the act of coupling
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A new imaging technique developed by scientists at Columbia University Vagelos College of Physicians and Surgeons and St. Jude Children's Research Hospital captures movies of receptors on the surface of living cells in unprecedented detail and could pave the way to a trove of new drugs.
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The researchers used the technique to zoom in on individual receptor proteins on the surface of living cells to determine if the receptors work solo or come together to work as pairs. This work appeared in the April issue of "If two different receptors come together to form a dimer with distinctive function and pharmacology, this might allow for a new generation of drugs with greater specificity and reduced side effects," says Jonathan Javitch, MD, PhD, the Lieber Professor of Experimental Therapeutics in Psychiatry at VP&S.G-protein coupled receptors (GPCRs) are some of medicine's most important molecules: About one-third of today's drugs work by targeting a GPCR. The possibility that GPCRs form heterodimers -- consisting of two different flavors of GPCR -- is an especially exciting prospect for the development of better drugs."The potential of GPCR heterodimers for improved pharmacotherapies, including for disorders such as schizophrenia and depression, is exciting and has drawn us to the field," Javitch says.But for decades, scientists have hotly debated whether most GPCRs form dimers or work alone. Much of this impasse stemmed from the relatively poor spatial resolution of current techniques. Different GPCRs in a cell have been captured near each other, but it was unclear if the receptors were working together."The controversy over receptor dimerization has only grown fiercer with conflicting data from different labs using different methods," Javitch says.Using a new, more powerful technique based on single-molecule fluorescence resonance energy transfer (smFRET), Javitch and Scott C. Blanchard from St. Jude Children's and Weill Cornell show that dimers can be tracked as they move on the cell surface and how long they last. This method takes advantage of a change in fluorescence that occurs when proteins, labeled with different fluorescent markers, are extremely close to each other. The resolution in this approach is more than 10 times greater than previous techniques.This new and exciting technique entails multiple innovations in dyes, labeling technology, protein engineering, imaging, and software that enabled tracking of individual and coupled receptors.Not only does this method detect GPCR dimers, it also allows, for the first time, a clear view of how receptors in a living cell change shape when activated. This will provide researchers a better understanding of how drugs can differentially impact the same receptors."With this method, we can now explore receptor interactions and activation mechanisms with unprecedented resolution, giving us an opportunity to investigate new therapeutic approaches," Javitch says.
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Biology
| 2,021 |
April 23, 2021
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https://www.sciencedaily.com/releases/2021/04/210423092633.htm
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Recreating the earliest stages of life
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In their effort to understand the very earliest stages of life and how they can go wrong, scientists are confronted with ethical issues surrounding the use of human embryos. The use of animal embryos is also subject to restrictions rooted in ethical considerations. To overcome these limitations, scientists have been trying to recreate early embryos using stem cells.
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One of the challenges in creating these so-called synthetic embryos is to generate all the cell types normally found in a young embryo before it implants into the wall of the uterus. Some of these cells eventually give rise to the placenta. Others become the amniotic sac in which the fetus grows. Both the placenta and the amniotic sac are crucial for the survival of the fetus, and defects in these embryo components are major causes of early pregnancy loss.A group of scientists from Gladstone Institutes, the Center for iPS Cell Research and Application (CiRA) from Kyoto University, and the RIKEN Center for Biosystems Dynamics Research in Kobe, Japan, has now demonstrated the presence of precursors of the placenta and the amniotic sac in synthetic embryos they created from mouse stem cells."Our findings provide strong evidence that our system is a good model for studying the early, pre-implantation stages of embryo development," says Kiichiro Tomoda, PhD, research investigator at the recently opened iPS Cell Research Center at Gladstone and first author of the study published in the journal Ultimately, this knowledge might help scientists develop strategies to decrease infertility due to early embryonic development gone awry.The new findings could also shed light on a defining property of the earliest embryo cells that has been difficult to capture in the lab: their ability to produce all the cell types found in the embryo and, ultimately, the whole body. Scientists refer to this property as "totipotency.""Totipotency is a very unique and short-lived property of early embryonic cells," says Cody Kime, PhD, an investigator at the RIKEN Center for Biosystems Dynamics Research and the study's senior author."It has been much harder to harness in the lab than pluripotency," he adds, referring to the ability of some cells to give rise to several -- but not all -- cell types. "A very exciting prospect of our work is the ability to understand how we can reprogram cells in the lab to achieve totipotency."To generate synthetic embryos, the scientists started from mouse pluripotent stem cells that normally give rise to the fetus only -- not the placenta or amniotic sac. They can grow these cells, called epiblast stem cells, and multiply them indefinitely in the lab.In previous work, the team had discovered a combination of nutrients and chemicals that could make epiblast stem cells assemble into small cell structures that closely resemble pre-implantation embryos. In fact, the structures could even reach the implantation stage when transferred into female mice, though they degenerated shortly thereafter."This meant that we might successfully reprogram the epiblast cells to revert to an earlier stage, when embryonic cells are totipotent, and provided a clue to how we might generate both the fetus and the tissues that support its implantation," explains Tomoda, who is also a program-specific research center associate professor at CiRA.To build on that work and better understand the reprogramming process, the scientists needed molecular resolution. In their new study, they turned to single-cell RNA sequencing, a technique that allows scientists to study individual cells based on the genes they turn on or off.After analyzing thousands of individual cells reprogrammed from epiblast stem cells, and sifting the data through computer-powered analyses, they confirmed that, after 5 days of reprogramming, some cells closely resembled all three precursors of the fetus, the placenta, and the amniotic sac.Moreover, as they were grown in the lab for a few more days, the three cell types displayed more distinct molecular profiles with striking similarity to real embryonic model cells. This is the same as would be expected during the growth of a normal embryo, when the three tissues acquire distinct physical properties and biological functions."Our single-cell RNA-sequencing analysis confirms the emergence in our synthetic embryo system of the cell types that lead to the three fundamental components of an early mammalian embryo," says Kime. "In addition, it unveils in amazing detail the genes and biological pathways involved in the development of these precursors and their maturation into specific tissues."This knowledge provides a comprehensive backdrop against which to understand the mechanisms of early embryo development and the possible causes of its failure.For now, the scientists plan to work on ways to increase the efficiency of their reprogramming process, so as to reliably produce large amounts of pre-implantation-like synthetic embryos for further studies. This would allow them to carry out experiments that were up to now unthinkable, such as large-scale screens for gene mutations that disrupt early embryos. And it may shed light on the causes of pregnancy loss due to early embryo failure.They also want to better understand the molecular steps involved in reprogramming. In particular, they plan to look earlier than 5 days into the reprogramming process, with the hope of pinpointing truly totipotent cells at the origin of their synthetic embryos."The discovery that we could reprogram cells to adopt earlier, more pluripotent states revolutionized developmental biology 15 years ago," says Tomoda, referring to the discovery of induced pluripotent stem cells by his and Kime's mentor, Nobel Laureate Shinya Yamanaka."In the last few years, the field of synthetic embryology utilizing stem cells has seen a true explosion," he says. "Our method of generating synthetic embryos is simpler than others, and quite efficient. We think it will be a great resource for many labs."
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Biology
| 2,021 |
April 22, 2021
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https://www.sciencedaily.com/releases/2021/04/210422181907.htm
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Lithium treats intellectual defects in mouse model of Bardet-Biedl Syndrome
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Mice with symptoms that mimic Bardet-Biedl Syndrome (BBS) have difficulty with learning and generating new neurons in the hippocampus. However, according to a new study by Thomas Pak, Calvin Carter, and Val Sheffield of the University of Iowa, published April 22nd in the journal
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BBS is a rare genetic disorder that causes intellectual disability, vision loss and obesity, and sometimes kidney problems and extra fingers and toes. It is one of several ciliopathies, which are diseases that stem from defective cilia -- tiny, finger-like projections on the surface of cells that play important roles in moving fluids, sensing the environment and signaling between cells. Pak, Carter, Sheffield and colleagues wanted to learn more about how ciliopathies cause intellectual disability, so they studied a type of mouse with the same symptoms as people with BBS.In the new study, the researchers showed that normal mice could quickly be trained to associate a specific environment to a fearful event, but the BBS mice had a harder time with fear memory. Further investigation showed that these learning problems come from an inability to make new neurons in the hippocampus. Treating the mice with lithium, however, increased cell production and improved their learning and memory.Intellectual disability is the most common type of neurodevelopmental disorder, but few drugs are available to treat it. The new study suggests that lithium may be an effective treatment for the learning and memory defects caused by BBS, and the researchers suggest that further studies should be performed to test the use of this FDA-approved drug. The new findings also demonstrate a novel role for cilia in learning and memory in the brain, potentially improving our understanding of the mechanisms that cause intellectual disability.Pak adds, "A mouse model of a cilia disease, Bardet-Biedl Syndrome, has impaired fear memory and hippocampal neurogenesis. In this mouse model, lithium treatment improves fear memory and hippocampal neurogenesis."
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Biology
| 2,021 |
April 22, 2021
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https://www.sciencedaily.com/releases/2021/04/210422150349.htm
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Anti-aging compound improves muscle glucose metabolism in people
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A natural compound previously demonstrated to counteract aspects of aging and improve metabolic health in mice has clinically relevant effects in people, according to new research at Washington University School of Medicine in St. Louis.
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A small clinical trial of postmenopausal women with prediabetes shows that the compound NMN (nicotinamide mononucleotide) improved the ability of insulin to increase glucose uptake in skeletal muscle, which often is abnormal in people with obesity, prediabetes or Type 2 diabetes. NMN also improved expression of genes that are involved in muscle structure and remodeling. However, the treatment did not lower blood glucose or blood pressure, improve blood lipid profile, increase insulin sensitivity in the liver, reduce fat in the liver or decrease circulating markers of inflammation as seen in mice.The study, published online April 22 in the journal Among the women in the study, 13 received 250 mg of NMN orally every day for 10 weeks, and 12 were given an inactive placebo every day over the same period."Although our study shows a beneficial effect of NMN in skeletal muscle, it is premature to make any clinical recommendations based on the results from our study," said senior investigator Samuel Klein, MD, the William H. Danforth Professor of Medicine and Nutritional Science and director of the Center for Human Nutrition. "Normally, when a treatment improves insulin sensitivity in skeletal muscle, as is observed with weight loss or some diabetes medications, there also are related improvements in other markers of metabolic health, which we did not detect in our study participants."The remarkable beneficial effects of NMN in rodents have led several companies in Japan, China and in the U.S. to market the compound as a dietary supplement or a neutraceutical. The U.S. Food and Drug Administration is not authorized to review dietary supplement products for safety and effectiveness before they are marketed, and many people in the U.S. and around the world now take NMN despite the lack of evidence to show clinical benefits in people.The researchers studied 25 postmenopausal women who had prediabetes, meaning they had higher than normal blood sugar levels, but the levels were not high enough to be diagnosed as having diabetes. Women were enrolled in this trial because mouse studies showed NMN had the greatest effects in female mice.NMN is involved in producing an important compound in all cells, called nicotinamide adenine dinucleotide (NAD). NAD plays a vital role in keeping animals healthy. Levels of NAD decline with age in a broad range of animals, including humans, and the compound has been shown to contribute to a variety of aging-associated problems, including insulin resistance in studies conducted in mice. Supplementing animals with NMN slows and ameliorates age-related decline in the function of many tissues in the body.Co-investigator Shin-ichiro Imai, MD, PhD, a professor of developmental biology and of medicine who has been studying NMN for almost two decades and first reported on its benefits in mice said, "This is one step toward the development of an anti-aging intervention, though more research is needed to fully understand the cellular mechanisms responsible for the effects observed in skeletal muscle in people."Insulin enhances glucose uptake and storage in muscle, so people who are resistant to insulin are at increased risk for developing Type 2 diabetes. But the researchers caution that more studies are needed to determine whether NMN has beneficial effects in the prevention or management of prediabetes or diabetes in people. Klein and Imai are continuing to evaluate NMN in another trial involving men as well as women.
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Biology
| 2,021 |
April 22, 2021
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https://www.sciencedaily.com/releases/2021/04/210422123643.htm
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Stress test finds cracks in the resistance of harmful hospital bugs
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Research has identified critical factors that enable dangerous bacteria to spread disease by surviving on surfaces in hospitals and kitchens.
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The study into the mechanisms which enable the opportunistic human pathogen To survive outside their host, pathogenic bacteria must withstand various environmental stresses. One mechanism is the sugar molecule, trehalose, which is associated with a range of external stresses, particularly osmotic shock -- sudden changes to the salt concentration surrounding cells.Researchers at the John Innes Centre analysed how trehalose is metabolised by Combining analytical biochemistry and reverse genetics -- using mutated bacteria lacking key functions -- they show that trehalose metabolism in Experiments showed that disruption of either trehalose or glycogen pathways significantly reduced the ability of The study found that while both trehalose and glycogen are important for stress tolerance in The findings raise the possibility of targeting the trehalose and glycogen pathways to limit pathogen survival on human-made surfaces."We have shown how a dangerous human pathogen An unexpected finding was how the bacteria operates different pathways for different stresses, said Dr Malone: "Conventional wisdom says that trehalose was responsible for both phenotypes, but we have shown that trehalose only protects against osmo-stress and glycogen is needed to protect against desiccation. We were also surprised to see such a marked drop in surface survival when we disrupted the pathways in the bugs."The next step for the research is to understand how trehalose and glycogen metabolic pathways are regulated in
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Biology
| 2,021 |
April 22, 2021
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https://www.sciencedaily.com/releases/2021/04/210422123616.htm
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Fighting harmful bacteria with nanoparticles
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In the arms race "humankind against bacteria," bacteria are currently ahead of us. Our former miracle weapons, antibiotics, are failing more and more frequently when germs use tricky maneuvers to protect themselves from the effects of these drugs. Some species even retreat into the inside of human cells, where they remain "invisible" to the immune system. These particularly dreaded pathogens include multi-resistant staphylococci (MRSA), which can cause life-threatening diseases such as sepsis or pneumonia.
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In order to track down the germs in their hidouts and eliminate them, a team of researchers from Empa and ETH Zurich is now developing nanoparticles that use a completely different mode of action from conventional antibiotics: While antibiotics have difficulty in penetrating human cells, these nanoparticles, due to their small size and structure, can penetrate the membrane of affected cells. Once there, they can fight the bacteria.The team of Inge Herrmann and Tino Matter has used cerium oxide, a material with antibacterial and anti-inflammatory properties in its nanoparticle form. The researchers combined the nanoparticles with a bioactive ceramic material known as bioglass. Bioglass is of interest in the medical field because it has versatile regenerative properties and is used, for example, for the reconstruction of bones and soft tissues.They then synthesized flame-made nanoparticle hybrids made of cerium oxide and bioglass. The particles have already been successfully used as wound adhesives, whereby several interesting properties can be utilized simultaneously: Thanks to the nanoparticles, bleeding can be stopped, inflammation can be dampened and wound healing can be accelerated. In addition, the novel particles show a significant effectiveness against bacteria, while the treatment is well tolerated by human cells.Recently, the new technology was successfully patented. The team has now published its results in the scientific journal The researchers were able to show the interactions between the hybrid nanoparticles, the human cells and the germs using electron microscopy, among other methods. If infected cells were treated with the nanoparticles, the bacteria inside the cells began to dissolve. However, if the researchers specifically blocked the uptake of the hybrid particles, the antibacterial effect was gone.The particles' exact mode of action is not yet fully understood. It has been shown that other metals also have antimicrobial effects. However, cerium is less toxic to human cells than, for instance, silver. Scientists currently assume that the nanoparticles affect the cell membrane of the bacteria, creating reactive oxygen species that lead to the destruction of the germs. Since the membrane of human cells is structurally different, our cells are not affected by this process.The researchers think that resistance is less likely to develop against a mechanism of this kind. "What's more, the cerium particles regenerate over time, so that the oxidative effect of the nano-particles on the bacteria can start all over again," says Empa researcher Tino Matter. In this way, the cerium particles could have a long-lasting effect.Next, the researchers want to analyze the interactions of the particles in the infection process in more detail in order to further optimize the structure and composition of the nanoparticles. The goal is to develop a simple, robust antibacterial agent that is effective inside infected cells.staphylococci. They can retreat into cells of the skin, connective tissue, bones and even the immune system. The mechanism of this persistence is not yet fully understood.Staphylococci are mostly harmless germs that can be found on the skin and mucous membranes. Under certain conditions, however, the bacteria flood the body and cause severe inflammation, or even lead to toxic shock and sepsis. This makes staphylococci the main cause of death from infections with only one single type of pathogen.The increasing number of staphylococcal infections that no longer respond to treatment with antibiotics is particularly precarious. MRSA, multi-resistant germs, are particularly feared in hospitals where, as nosocomial pathogens, they cause poorly treatable wound infections or colonize catheters and other medical equipment. In total, around 75,000 hospital infections occur in Switzerland every year, 12,000 of which are fatal.The chemical element cerium was unjustly named after the dwarf planet Ceres; the silvery metal is currently making a big splash. As cerium oxide, it is incorporated into car catalytic converters, and it is also used in the manufacture of products as diverse as self-cleaning ovens, windscreens and light-emitting diodes (LEDs). Its antimicrobial and anti-inflammatory properties also make it interesting for medical applications.
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Biology
| 2,021 |
April 22, 2021
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https://www.sciencedaily.com/releases/2021/04/210422102857.htm
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Scientists provide new insights into the citric acid cycle
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Researchers have new insights into the citric acid cycle: Certain bacteria can use this central metabolic pathway 'backwards', but to do so they must have very high concentrations of the enzyme citrate synthase and of carbon dioxide. This pathway may be a relic from the early development of life.
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The citric acid cycle is an important metabolic pathway that enables living organisms to generate energy by degrading organic compounds into carbon dioxide (CO₂). The first step in the cycle is usually performed by the enzyme citrate synthase, which builds citrate. But, in the absence of oxygen (under anaerobic conditions), some bacteria can perform the reverse cycle: They can build up biomass from CO₂. In this so-called reversed citric acid cycle, citrate synthase is replaced by ATP-citrate lyase, which consumes cells' universal energy carrier ATP (adenosine triphosphate) to cleave citrate instead of forming it. However, a few years ago, a research team led by Ivan Berg (University of Münster) and Wolfgang Eisenreich (Technical University of Munich) discovered that instead of requiring ATP-citrate lyase for the reversed cycle, some anaerobic bacteria can use citrate synthase itself to catalyze citrate cleavage without consuming ATP. Now, the same team found that bacteria using this metabolic pathway (the reversed citric acid cycle through citrate synthase), depend on very high concentrations of both the enzyme and carbon dioxide.As a comparison, the CO₂ concentration in air is around 0.04%, but bacteria using this pathway require at least 100 times more than that for their growth. The researchers assume that such CO₂ concentration-dependent pathways could have been widespread on the primordial earth, since the CO₂ concentration was high at the time. Therefore, this metabolic pathway may be a relic of early life. The results of the study have been published in the journal "Nature" (online in advance).The team studied the anaerobic bacteria These findings could also be of interest for biotechnology. With the knowledge that autotrophic organisms using this "backward cycle" depend on the CO₂ concentration, scientists can apply it to more efficiently convert substrates into value-added products.The scientists wanted to understand what factor determines whether the citric acid cycle runs "forwards" or "backwards" in the bacteria. Cultivating the bacteria under different conditions, they noticed that the growth of these organisms was highly dependent on the CO₂ concentration in the gas phase. In detail, the high CO₂ concentration was needed to allow the function of another important enzyme, pyruvate synthase. This enzyme is responsible for assembling acetyl coenzyme A (acetyl-CoA), the product of the "reversed cycle." The high CO₂ concentration drives the pyruvate synthase reaction in the direction of carboxylation and the entire cycle backwards, enabling CO₂ to be converted into biomass. The studied The "backward cycle" that uses citrate synthase for citrate cleavage cannot be bioinformatically predicted, as it does not have the key enzymes whose presence can be used as a marker for the functioning of the pathway. Therefore, as an identifying feature for bioinformatic analyzes, the scientists used the detected high levels of citrate synthase in these bacteria's protein cocktail. Using a special analysis tool, the researchers were able to predict the production levels of individual proteins. With this trick, it was possible to predict the functioning of the "backward cycle" for inorganic carbon fixation in many anaerobic bacteria.The scientists also showed that no gene regulation was necessary for switching from the oxidative ("forward") to the reductive ("reverse") direction. "This means that the cells can react very quickly on the availability of the carbon source in the environment" says Ivan Berg. "They use either the reductive direction to fix CO₂, if the concentration of CO₂ is high, or the oxidative direction, if another carbon source is available."The methods used in the study were mass spectrometry and 13C-isotope analyses, enzyme measurements, protein quantification as well as media and amino acid analyses using chromatographic and spectrometric methods (LC/MS or GC/MS). With bioinformatic methods, they examined the occurrence of certain nucleotide base combinations (codons) in order to make predictions about the production of individual proteins.
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Biology
| 2,021 |
April 22, 2021
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https://www.sciencedaily.com/releases/2021/04/210422102845.htm
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New therapy target for malignant melanomas in dogs
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Scientists have shown that the biological molecule PD-L1 is a potential target for the treatment of metastasized oral malignant melanoma in dogs.
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There are a number of cancers that affect dogs, but there are far fewer diagnosis and treatment options for these canine cancers. However, as dogs and humans are both mammals, it is likely that strategies and treatments for cancers in humans can be used for canine cancer, with minor modifications.A team of scientists, including Associate Professor Satoru Konnai from the Faculty of Veterinary Medicine at Hokkaido University, have demonstrated that an anti-cancer therapy that targets the cancer marker PD-L1 -- a target that has shown great promise for treating cancer in humans -- is effective for canine cancer as well. Their findings were published in the journal The proteins Programmed Cell Death 1 (PD-1) and its associated molecule, PD-ligand 1 (PD-L1) are involved in the immune response in humans. PD-L1 is overexpressed by many types of cancer in humans, enabling these cancers to suppress the immune response. Studies in mice models and in human cell lines have shown that PD-1 and PD-L1 have great promise in the treatment of cancer as blocking them strengthens the immune response to cancer.Malignant melanomas are a canine cancer that is both relatively common and fatal. In particular, oral malignant melanomas (OMMs) are highly invasive and metastatic; with treatment, the median survival time is less than two months. As new treatments are needed for this cancer, the scientists chose to explore the options available.The scientists first developed a novel anti-PD-L1 monoclonal antibody to detect PD-L1 in various canine cancers by immunohistochemical staining. Using this antibody, they demonstrated that malignant canine cancers expressed PD-L1; out of 20 samples for each cancer tested, nasal adenocarcinoma, transitional cell carcinoma, osteosarcoma and mammary adenocarcinoma had a 100% positive rate, while anal sac gland carcinoma and OMM had a 95% positive rate.A prior pilot study had shown that another canine chimeric anti-PD-L1 monoclonal antibody had anti-tumor effect against OMM, when tested on nine dogs. For the current study scientists selected 29 dogs with primary OMM and pulmonary metastasis, where the melanoma has spread to the lungs, and most of which had been subjected to at least one round of treatment. These dogs were treated with the chimeric antibody every two weeks, and other interventions to achieve local control of cancer were allowed.The survival time of dogs treated with the chimeric antibody was significantly longer, with a median survival time of 143 days, compared to 54 days for the control group, from historical data. Thirteen dogs had measurable cancer (i.e., at least one tumor >10 mm in diameter in CT scan), while 16 had non-measurable cancer (all tumors < 10 mm in diameter in CT scan). Five dogs showed tumor response, where the tumor reduced or disappeared due to the treatment. In one of these, all detectable tumors disappeared. In two other dogs, all detectable tumors disappeared, resulting in survival times longer than a year. In the last two dogs, all tumors in the lungs disappeared, but oral and lymph node tumors persisted. The increase in survival time correlated positively with radiation therapy that was simultaneous or began within eight weeks of treatment with the chimeric antibody."Our findings are limited by the small size of the historical control group," says Satoru Konnai. "Nevertheless, as there is no systemic therapy that prolongs the survival of dogs with pulmonary metastatic OMM, the increased survival time encourages the further development of anti-PD-L1 therapy in dogs."
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Biology
| 2,021 |
April 22, 2021
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https://www.sciencedaily.com/releases/2021/04/210422093912.htm
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Freeze! Executioner protein caught in the act
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A new molecular 'freeze frame' technique has allowed WEHI researchers to see key steps in how the protein MLKL kills cells.
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Small proteins called 'monobodies' were used to freeze MLKL at different stages as it moved from a dormant to an activated state, a key process that enables an inflammatory form of cell death called necroptosis. The team were able to map how the three-dimensional structure of MLKL changed, revealing potential target sites that might be targets for drugs -- a potential new approach to blocking necroptosis as a treatment for inflammatory diseases.The research, which was published in MLKL is a key protein in necroptosis, being the 'executioner' that kills cells by making irreparable holes in their exterior cell membrane. This allows the cell contents to leak out and triggers inflammation -- alerting nearby cells to a threat, such as an infection.Ms Garnish said MLKL was activated within a protein complex called a 'necrosome' which responded to external signals."While we know which proteins activate MLKL, and that this involves protein phosphorylation, nobody had been able to observe any detail about how this changes MLKL at the structural level. It happens so fast that it's essentially a 'molecular blur'," she said.A new technology -- monobodies -- developed by Professor Koide's team, was key to revealing how MLKL changed.Monobodies that specifically bound to different 'shapes' of MLKL were used to capture these within cells, Mr Meng said."These monobodies prevented MLKL from moving out of these shapes -- so we could freeze MLKL into its different shapes," he said."We then used structural biology to generate three-dimensional maps of these shapes which could be compared. This revealed that MLKL passed through distinct shape changes as it transitioned from being activated through to breaking the cell membrane."Associate Professor Murphy said the structures provided the first formal evidence for how MLKL changed its shape after it was activated."Until now, we've speculated that this happens, but it was only with monobodies that we could actually prove there are distinct steps in MLKL activation," he said."Necroptosis is an important contributor to inflammatory conditions such as inflammatory bowel disease. There is intense interest in MLKL as a key regulator of necroptosis -- and how it could be blocked by drugs as a potential new anti-inflammatory therapy."The research was supported by the Australian Government National Health and Medical Research Council and Department of Education, Skills and Employment, a Melbourne Research Scholarship, the Wendy Dowsett Scholarship, an Australian Institute of Nuclear Science and Engineering Postgraduate Research Award, the Australian Cancer Research Foundation, the US National Institutes of Health and the Victorian Government.The Australian Synchrotron's MX beamlines were critical infrastructure for the project.
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Biology
| 2,021 |
April 22, 2021
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https://www.sciencedaily.com/releases/2021/04/210422093832.htm
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Membranes unlock potential to vastly increase cell-free vaccine production
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By cracking open a cellular membrane, Northwestern University synthetic biologists have discovered a new way to increase production yields of protein-based vaccines by five-fold, significantly broadening access to potentially lifesaving medicines.
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In February, the researchers introduced a new biomanufacturing platform that can quickly make shelf-stable vaccines at the point of care, ensuring they will not go to waste due to errors in transportation or storage. In its new study, the team discovered that enriching cell-free extracts with cellular membranes -- the components needed to made conjugate vaccines -- vastly increased yields of its freeze-dried platform.The work sets the stage to rapidly make medicines that address rising antibiotic-resistant bacteria as well as new viruses at 40,000 doses per liter per day, costing about $1 per dose. At that rate, the team could use a 1,000-liter reactor (about the size of a large garden waste bag) to generate 40 million doses per day, reaching 1 billion doses in less than a month."Certainly, in the time of COVID-19, we have all realized how important it is to be able to make medicines when and where we need them," said Northwestern's Michael Jewett, who led the study. "This work will transform how vaccines are made, including for bio-readiness and pandemic response."The research will be published April 21 in the journal Jewett is a professor of chemical and biological engineering at Northwestern's McCormick School of Engineering and director of Northwestern's Center for Synthetic Biology. Jasmine Hershewe and Katherine Warfel, both graduate students in Jewett's laboratory, are co-first authors of the paper.The new manufacturing platform -- called in vitro conjugate vaccine expression (iVAX) -- is made possible by cell-free synthetic biology, a process in which researchers remove a cell's outer wall (or membrane) and repurpose its internal machinery. The researchers then put this repurposed machinery into a test tube and freeze-dry it. Adding water sets off a chemical reaction that activates the cell-free system, turning it into a catalyst for making usable medicine when and where it's needed. Remaining shelf-stable for six months or longer, the platform eliminates the need for complicated supply chains and extreme refrigeration, making it a powerful tool for remote or low-resource settings.In a previous study, Jewett's team used the iVAX platform to produce conjugate vaccines to protect against bacterial infections. At the time, they repurposed molecular machinery from Escherichia coli to make one dose of vaccine in an hour, costing about $5 per dose."It was still too expensive, and the yields were not high enough," Jewett said. "We set a goal to reach $1 per dose and reached that goal here. By increasing yields and lowering costs, we thought we might be able to facilitate greater access to lifesaving medicines."Jewett and his team discovered that the key to reaching that goal lay within the cell's membrane, which is typically discarded in cell-free synthetic biology. When broken apart, membranes naturally reassemble into vesicles, spherical structures that carry important molecular information. The researchers characterized these vesicles and found that increasing vesicle concentration could be useful in making components for protein therapeutics such as conjugate vaccines, which work by attaching a sugar unit -- that is unique to a pathogen -- to a carrier protein. By learning to recognize that protein as a foreign substance, the body knows how to mount an immune response to attack it when encountered again.Attaching this sugar to the carrier protein, however, is a difficult, complex process. The researchers found that the cell's membrane contained machinery that enabled the sugar to more easily attach to the proteins. By enriching vaccine extracts with this membrane-bound machinery, the researchers significantly increased yields of usable vaccine doses."For a variety of organisms, close to 30% of the genome is used to encode membrane proteins," said study co-author Neha Kamat, who is an assistant professor of biomedical engineering at McCormick and an expert on cell membranes. "Membrane proteins are a really important part of life. By learning how to use membrane proteins effectively, we can really advance cell-free systems."
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Biology
| 2,021 |
April 22, 2021
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https://www.sciencedaily.com/releases/2021/04/210414100128.htm
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Lab study solves textbook problem: How cells know their size
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Scientists have searched for years to understand how cells measure their size. Cell size is critical. It's what regulates cell division in a growing organism. When the microscopic structures double in size, they divide. One cell turns into two. Two cells turn into four. The process repeats until an organism has enough cells. And then it stops. Or at least it is supposed to.
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The complete chain of events that causes cell division to stop at the right time is what has confounded scientists. Beyond being a textbook problem, the question relates to serious medical challenges: Cells that stop dividing too soon can cause defects in growing organisms. Uncontrolled cell growth can lead to cancers or other disorders.A study from Dartmouth, published in "The early embryo is an ideal place to study cell size control," said Amanda Amodeo, an assistant professor of biology at Dartmouth and the lead researcher. "The cells we work with are eggs that are visible to the eye. They don't need to grow before dividing, so it allows us to look at connections that are obscured in adult cells."According to the study, a set amount of the protein histone H3 is loaded into an embryo before fertilization and is used up as the embryo divides into more cells. As histones are consumed to accommodate the growing number of nuclei, they release the enzyme Chk1 to bind with another protein, CDC25, to stop the multiplication of cells.The research is technical, but the mechanism is relatively straightforward: With histone H3 out of the way in a growing cell, the stop enzyme Chk1 finds and disables the protein that triggers cell cycle progression, CDC25."The key to our research result was coming up with the possibility that unusually large amounts of histone H3 may feed into the stop enzyme," said Yuki Shindo a postdoctoral research fellow at Dartmouth and first author of the paper. "Once we noticed that, we were able to test this idea in our living test tube, fruit fly eggs."The new research builds on earlier studies which found that a biological constant exists between the size of a genome and the size of a cell. Researchers knew that once a balance point was achieved, cells would stop duplicating, but didn't understand how cells could determine the ratio.To find the answer to the long-running question, the research team studied fruit fly eggs. Because of their large size compared to other cells, the team was able to get a different perspective on the cell cycle."We've had all of the pieces for years but couldn't quite get them to fit together," said Amodeo. "Once we recognized that H3 interacts directly with both DNA and Chk1, the work went very fast. Everything worked the first time, which is a good sign that the hypothesis is right."Since the same molecules that control cell division -- histone H3, CDC25 and Chk1 -- are all identified in cancer and other ailments, the finding can help researchers that are seeking answers to questions related to development and disease."We were originally curious about a basic biological question on how cells in a growing egg make a decision to stop at the correct timing," said Shindo. "We are now excited that our findings may also have an important implication for a broader context such as disease."Research conducted for this study was performed at and supported by the Lewis-Sigler Institute at Princeton University as well as by grants from the Japan Society for the Promotion of Science, the Uehara Memorial Foundation, and the Japanese Biochemical Society.
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Biology
| 2,021 |
April 21, 2021
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https://www.sciencedaily.com/releases/2021/04/210421124646.htm
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Mice master complex thinking with a remarkable capacity for abstraction
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Categorization is the brain's tool to organize nearly everything we encounter in our daily lives. Grouping information into categories simplifies our complex world and helps us to react quickly and effectively to new experiences. Scientists at the Max Planck Institute of Neurobiology have now shown that also mice categorize surprisingly well. The researchers identified neurons encoding learned categories and thereby demonstrated how abstract information is represented at the neuronal level.
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A toddler is looking at a new picture book. Suddenly it points to an illustration and shouts 'chair'. The kid made the right call, but that does not seem particularly noteworthy to us. We recognize all kinds of chairs as 'chair' without any difficulty. For a toddler, however, this is an enormous learning process. It must associate the chair pictured in the book with the chairs it already knows -- even though they may have different shapes or colors. How does the child do that?The answer is categorization, a fundamental element of our thinking. Sandra Reinert, first author of the study explains: "Every time a child encounters a chair, it stores the experience. Based on similarities between the chairs, the child's brain will abstract the properties and functions of chairs by forming the category 'chair'. This allows the child to later quickly link new chairs to the category and the knowledge it contains."Our brain categorizes continuously: not only chairs during childhood, but any information at any given age. What advantage does that give us? Pieter Goltstein, senior author of the study says: "Our brain is trying to find a way to simplify and organize our world. Without categorization, we would not be able to interact with our environment as efficiently as we do." In other words: We would have to learn for every new chair we encounter that we can sit on it. Categorizing sensory input is therefore essential for us, but the underlying processes in the brain are largely unknown.Sandra Reinert and Pieter Goltstein, together with Mark Hübener and Tobias Bonhoeffer, group leader and director at the Max Planck Institute of Neurobiology, studied how the brain stores abstract information like learned categories. Since this is difficult to investigate in humans, the scientists tested whether mice categorize in a way similar to us. To do so, they showed mice different pictures of stripe patterns and gave them a sorting rule. One animal group had to sort the pictures into two categories based on the thickness of the stripes, the other group based on their orientation. The mice were able to learn the respective rule and reliably sorted the patterns into the correct category. After this initial training phase, they even assigned patterns of stripes they had not seen before into the correct categories -- just like the child with the new book.And not only that: when the researchers switched the sorting rules, the mice ignored what they had learned before and re-sorted the pictures according to the new rule -- something we humans do all the time while learning new things. Therefore, the study demonstrates for the first time to what extent and with which precision mice categorize and thereby approach our capacity for abstraction.With this insight, the researchers were now able to investigate the basis of categorization in the mouse brain. They focused on the prefrontal cortex, a brain region which in humans is involved in complex thought processes. The investigations revealed that certain neurons in this area become active when the animals sort the striped patterns into categories. Interestingly, different groups of neurons reacted selectively to individual categories.Tobias Bonhoeffer explains: "The discovery of category-selective neurons in the mouse brain was a key point. It allowed us for the first time to observe the activity of such neurons from the beginning to the end of category learning. This showed that the neurons don't acquire their selectivity immediately, but only gradually develop it during the learning process."The scientists argue that the category-selective neurons in prefrontal cortex only play a role once the acquired knowledge has been shifted from short-term to long-term memory. There, the cells store the categories as part of semantic memory -- the collection of all factual knowledge. In this context, we should keep in mind that the categories we learn are the brain's way to make our world simpler. However, that also means that those categories are not necessarily 'right' or correctly reflect reality.By investigating category learning in the mouse, the study adds important details to the neuronal basis of abstract thinking and reminds us that complex thoughts are not only reserved for us humans.
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Biology
| 2,021 |
April 21, 2021
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https://www.sciencedaily.com/releases/2021/04/210421082852.htm
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Gaps in genetic knowledge affect kiwi conservation efforts
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Kiwi are iconic birds that have been severely impacted by deforestation and predation from invasive mammals since the arrival of humans in New Zealand. The remaining kiwi can be split into 14 clusters that are now treated as separate conservation management units. A review published in
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Although studies indicate that kiwi differ genetically between areas, there is little understanding of the extent of local adaptations and breeding changes on populations. The work highlights the need for a more detailed understanding of the genetics of different species for wildlife conservation."Using kiwi as an example, we hope to convey that results from any genetic studies cannot be easily translated into genetic management policy. On the contrary, studies using informative markers and strategic sample regimes are required if the goal is diverse and long-term successful populations," said lead author Malin Undin, PhD, of Massey University, in New Zealand.
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Biology
| 2,021 |
April 20, 2021
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https://www.sciencedaily.com/releases/2021/04/210420183149.htm
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Drug development platform could provide flexible, rapid and targeted antimicrobials
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When disease outbreaks happen, response time in developing and distributing treatments is crucial to saving lives. Unfortunately, developing custom drugs as countermeasures is often a slow and difficult process.
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But researchers at the University of Colorado Boulder have created a platform that can develop effective and highly specific peptide nucleic acid therapies for use against any bacteria within just one week. The work is detailed in Nature The Facile Accelerated Specific Therapeutic (FAST) platform was created by Associate Professor Anushree Chatterjee and her team within the Department of Chemical and Biological Engineering. It can quickly produce new antibiotics for any system or disease -- from highly adaptive microbial super bugs to radiation poisoning in astronauts -- that are specifically designed to selectively target just the bacteria of interest. The paper demonstrates significant growth inhibition and other positive responses in resistant bacteria such as E. coli, which are adapting to current treatments much faster than new drugs can hit the market.Traditional drug discovery methods usually take 10 or more years and are specific to one bug or another. That is because they are based on identifying molecules from one bacteria that can then be used against other bacteria to promote human health. Unfortunately, evolution over billions of years has resulted in bacteria strains today that are increasingly resistant to this kind of approach -- aided in part by recent over prescription of antibiotics by doctors. FAST, on the other hand, can be used for any bug and enables speedy identification and testing of molecules that target new mechanisms in pathogens -- getting ahead of that curve.Kristen Eller, a PhD candidate in the Chatterjee Group, is the first author on the new paper. She said the FAST system utilizes bacteria's genetic makeup to design specific and targeted antibiotics that stop their natural means of producing essential proteins, causing them to die. She added that the platform also provides a unique strategy to deliver these treatments to bacteria that are traditionally hard to target because they reside within our own host cells. To get around this, the platform essentially utilizes bacteria's natural ability to invade our own cells and manipulates it instead to be a carrier of the therapeutic."The applications for the real world are immense in that we have created a platform -- not just a single therapeutic," she said. "It is adaptive, dynamic and can be altered to target any bacterial species that is a threat while also being modulated to develop antivirals as needed."Recently, another paper published in PNAS showed the use of the FAST platform to create novel antibiotics against a clinical isolate of carbapenem-resistant E. coli that was found to be resistant to pretty much all antibiotics.Chatterjee said that last aspect is particularly important as particular strains evolve, change and become more resistant over time. The goal, she said, is to rapidly create tailored treatments specific to the region in question, the person seeking treatment or even the global health situation for example."The technology we use to treat these kinds of health issues has to be smart enough to keep up with evolving organisms and also quick enough to respond to real-time crisis," she said. "Within this platform there are multiple steps where you can design and create new drug targets, which is really key."Chatterjee said the platform could eventually be modified to develop antivirals for treatment of common colds, the flu and most pressingly, COVID-19. For now, her team is working on collecting more data to develop potential COVID-19 treatments and beginning to work towards clinical trials."We need to think out of the box when it comes to keeping up with pathogens because they are always advancing and changing," she said. "If we can establish these processes and techniques now, then we will be much better prepared next time there is a pandemic or outbreak."
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Biology
| 2,021 |
April 20, 2021
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https://www.sciencedaily.com/releases/2021/04/210420160909.htm
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'Undruggable' cancer protein becomes druggable, thanks to shrub
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A chemist from Purdue University has found a way to synthesize a compound to fight a previously "undruggable" cancer protein with benefits across a myriad of cancer types.
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Inspired by a rare compound found in a shrub native to North America, Mingji Dai, professor of chemistry and a scientist at the Purdue University Center for Cancer Research, studied the compound and discovered a cost-effective and efficient way to synthesize it in the lab. The compound -- curcusone D -- has the potential to help combat a protein found in many cancers, including some forms of breast, brain, colorectal, prostate, lung and liver cancers, among others. The protein, dubbed BRAT1, had previously been deemed "undruggable" for its chemical properties. In collaboration with Alexander Adibekian's group at the Scripps Research Institute, they linked curcusone D to BRAT1 and validated curcusone D as the first BRAT1 inhibitor.Curcusones are compounds that come from a shrub named Jatropha curcas, also called the purging nut. Native to the Americas, it has spread to other continents, including Africa and Asia. The plant has long been used for medicinal properties -- including the treatment of cancer -- as well as being a proposed inexpensive source of biodiesel.Dai was interested in this family of compounds -- curcusone A, B, C and D."We were very interested by these compounds' novel structure," Dai said. "We were intrigued by their biological function; they showed quite potent anti-cancer activity and may lead to new mechanisms to combat cancer."Researchers tested the compounds on breast cancer cells and found curcusone D to be extremely effective at shutting down cancer cells. The protein they were targeting, BRAT1, regulates DNA damage response and DNA repair in cancer cells. Cancer cells grow very fast and make a lot of DNA. If scientists can damage cancer cells' DNA and keep them from repairing it, they can stop cancer cells from growing."Our compound can not only kill these cancer cells, it can stop their migration," Dai said. "If we can keep the cancer from metastasizing, the patient can live longer."Stopping cancer from spreading throughout the body -- metastasizing -- is key to preserving a cancer patient's life. Once cancer starts to migrate from its original organ into different body systems, new symptoms start to develop, often threatening the patient's life."For killing cancer cells and stopping migration, there are other compounds that do that," Dai said. "But as far as inhibiting the BRAT1 protein, there are no other compounds that can do that."Dai and his team believe that as effective as curcusone D is by itself, it may be even more potent as part of a combination therapy. They tested it alongside a DNA damaging agent that has already been approved by the Food and Drug Administration and found that this combination therapy is much more effective.One difficulty in studying curcusones as potential cancer treatments is that, while the shrub they come from is common and inexpensive, it takes massive amounts of the shrub to yield even a small amount of the compounds. Even then, it is difficult to separate the compounds they were interested in from the rest of the chemicals in the shrub's roots."In nature, the plant doesn't produce a lot of this compound," Dai said. "You would need maybe as much as 100 pounds of the plant's dry roots to get just about a quarter teaspoon of the substance -- a 0.002% yield."That small yield is relevant for production, because if it is effective as a cancer treatment, pharmacists will need a lot more of it. Additionally, having an abundant supply of the compounds makes studying them easier, quicker and less expensive."That's why a new synthesis is so important," Dai said. "We can use the synthesis to produce more compounds in a purer form for biological study, allowing us to advance the field. From there, we can make analogs of the compound to improve its potency and decrease the potential for side effects."The next step will be to test the compound to ensure that it is not toxic to humans, something the researchers are optimistic about since the shrub it came from has been used as a traditional medicine in a number of cultures. Already, researchers from other entities have reached out to test the compound on the cancers they study, bringing hope for renewed therapeutics for treating the disease."Many of our most successful cancer drugs have come from nature," Dai said. "A lot of the low-hanging fruit, the compounds that are easy to isolate or synthesize, have already been screened and picked over. We are looking for things no one has thought about before. Once we have the chemistry, we can build the molecules we're interested in and study their biological function."This research was funded through grants from the National Institutes of Health and the National Science Foundation. Patent application U.S. 63/084,594 covers this finding.
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Biology
| 2,021 |
April 20, 2021
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https://www.sciencedaily.com/releases/2021/04/210420121526.htm
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Certain gut microbes make mosquitoes more prone to carry malaria parasite
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Dietary sugars and gut microbes play a key role in promoting malaria parasite infection in mosquitoes. Researchers in China have uncovered evidence that mosquitoes fed a sugar diet show an increased abundance of the bacterial species Asaia bogorensis, which enhances parasite infection by raising the gut pH level. The study appears April 20 in the journal
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"Our work opens a new path for investigations into the role of mosquito-microbiota metabolic interactions concerning their disease-transmitting potential," says co-senior study author Jingwen Wang of Fudan University in Shanghai, China. "The results may also provide useful insights for the development of preventive strategies for vector control."Mosquitoes rely on nectar-derived sugars, such as glucose, for energy, survival, and reproduction. Similarly, glucose is the primary energy source supporting the proliferation of Plasmodium -- malaria parasites that are transmitted to human hosts by female mosquitoes of the genus Anopheles. Some indirect evidence also suggests that carbohydrate metabolism influences the capability of mosquitoes to transmit malaria parasites. Although glucose metabolism is expected to play a role in regulating Plasmodium infection in mosquitoes, the underlying mechanisms have not been clear.To address this question, Wang teamed up with co-senior study author Huiru Tang of Fudan University. They found that feeding Anopheles stephensi mosquitoes a solution containing glucose for five days increased the number of Plasmodium berghei oocytes in the midgut after infection with the parasite. But mosquitoes treated with an antibiotic cocktail did not show this effect, pointing to a critical role for gut microbes in the sugar-induced enhancement of Plasmodium infection.The sugar diet specifically increased the abundance of A. bogorensis in the mosquito midgut. Infected mosquitoes that were fed glucose and colonized only with A. bogorensis showed an increased number of P. berghei oocytes. Taken together, the findings suggest that sugar intake promotes Plasmodium infection in mosquitoes by increasing the proliferation of A. bogorensis. Additional experiments provided evidence that this bacterial species mediates the sugar-induced enhancement of infection by raising the midgut pH level, which facilitates the sexual development of P. berghei."Our study provides crucial molecular insights into how the complex interplay between glucose metabolism of mosquitos and a component of their gut microbiota, A. bogorensis, influences malaria parasite infection," Tang says. "Targeting mosquito glucose metabolism might be a promising strategy to prevent malaria parasite transmission."The study also provides evidence that the specific sugar composition of plant saps might influence malaria transmission by affecting the proliferation of A. bogorensis. Specifically, Parthenium hysterophorus -- a plant species that mosquitoes feed on quite frequently -- did not promote A. bogorensis proliferation or P. berghei infection when compared with other mosquito-preferred plants. According to the authors, planting this species might reduce malaria transmission. But further studies are needed to investigate the influence of natural plant saps on the microbiota composition of field mosquitoes and to examine the influence of A. bogorensis from field mosquitoes on malaria parasite infection.The researchers will continue to investigate the metabolic interactions between mosquitos and their microbiota and the influence of these interactions on pathogen transmission. "Our goal is to find out the key metabolites or chemicals that could inhibit malaria parasite infection in mosquitoes," Wang says.
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Biology
| 2,021 |
April 20, 2021
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https://www.sciencedaily.com/releases/2021/04/210420121511.htm
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A gene finding links severe canine juvenile epilepsy to mitochondrial dysfunction
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In a study conducted at the University of Helsinki, researchers found a cause for severe epilepsy resulting in death in Parson Russell Terrier puppies at a few months of age. A change in the PITRM1 gene can lead to a dysfunction of mitochondria, the cellular energy pumps. Concurrently, amyloid-β accumulation and widespread neurodegeneration associated with Alzheimer's disease were identified in the puppies' brains. Changes to the PITRM1 gene in humans also cause a severe but slowly progressing brain disease.
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Some Parson Russell Terrier puppies were seen to suddenly develop epileptic seizures at 6 to 12 weeks of age. The disease progressed very rapidly, in a matter of hours in the worst cases, to a situation where the seizures were continuous and unresponsive to medication."All of the sick dogs either died spontaneously or had to be euthanised. On the tissue level, neuronal necroses, or dead neurons, were identified throughout the brains of the deceased dogs. In the neurons, we observed crowding of mitochondria, the cellular energy pumps, and accumulation of amyloid-β typical of Alzheimer's disease. Such an accumulation is expected to be found in old dogs only," says Docent Marjo Hytönen from the University of Helsinki and the Folkhälsan Research Center.With the help of several research groups at the University of Helsinki and international partners, samples were collected from around Europe, making it possible to pinpoint the gene defect underlying the disease to the PITRM1 gene. This gene encodes an enzyme that is important to mitochondrial function. Due to their responsibility for cellular energy metabolism, mitochondria are key to the functioning of cells."In the study, we determined the presence of the variant in nearly 30,000 dogs from 374 breeds, identifying the gene defect only in Parson Russell Terriers. Fortunately, the carrier frequency was low, only 5%. The findings will benefit dogs immediately, as a gene test made available based on the results helps identify carriers and avoid breeding them to produce sick puppies. We have already previously reported the gene test results for the roughly 700 dogs tested in the study," says Professor Hannes Lohi from the University of Helsinki.The disease associated with Parson Russell Terriers is a recessive trait, which means that, for the disease to develop, the defective gene must be copied from both parents to the offspring. The defect is found in this specific breed only."The PITRM1 protein serves as a kind of mitochondrial cleaner that breaks up unnecessary pieces of protein and also the harmful amyloid-β. The accumulation of these substances in mitochondria disturbs their function, while neurons in particular tolerate deficient cellular respiration poorly, which explains the early-onset neurodegeneration in dogs. The gene defect results in the disappearance of two amino acids in the PITRM1 enzyme and inhibits it from functioning normally," Hytönen says.In humans, changes in the same PITRM1 gene also cause neurodegeneration that results in cerebellar ataxia with psychiatric and cognitive abnormalities."The human disease progresses slower, but the clinical picture and mechanisms are similar. Our canine study confirms the significance of PITRM1 to mitochondrial and neuronal function, also strengthening the link between mitochondrial dysfunction and neurodegeneration. For now, there are few human patients diagnosed with this disease, which makes the canine model groundbreaking in terms of understanding it," says Professor Lohi.
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Biology
| 2,021 |
April 20, 2021
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https://www.sciencedaily.com/releases/2021/04/210420121457.htm
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Crucial action needed for coral reefs
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An international group of scientific experts co-directed by CNRS oceanographer Jean-Pierre Gattuso* has stated the requirements for coral reef survival in an article published in
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The team of scientists, which comprises members of the Pew Marine Fellows Programme and of the Ocean Solutions Initiative, modelled future reef changes for two COOf the 16 possible actions for limiting the decline of coral reefs presented in the scientific literature, a massive energy transition is the most effective and the only plausible one on the global scale. Actions that may be taken on regional and local levels -- e.g. designation of marine protected areas or selection of species best suited to new environmental conditions -- may increase the adaptation potential of corals.The group asserts that saving reefs accordingly requires international political support, comparable to that rallied for campaigns against certain diseases.*Research Professor at the Laboratoire d'Océanographie de Villefranche (CNRS / Sorbonne University) and Associate Scientist at IDDRI.
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Biology
| 2,021 |
April 20, 2021
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https://www.sciencedaily.com/releases/2021/04/210420121419.htm
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Fearsome tyrannosaurs were social animals, study shows
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The fearsome tyrannosaur dinosaurs that ruled the northern hemisphere during the Late Cretaceous period (66-100 million years ago) may not have been solitary predators as popularly envisioned, but social carnivores similar to wolves, according to a new study.
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The finding, based on research at a unique fossil bone site inside Utah's Grand Staircase-Escalante National Monument containing the remains of several dinosaurs of the same species, was made by a team of scientists including Celina Suarez, University of Arkansas associate professor of geosciences."This supports our hypothesis that these tyrannosaurs died in this site and were all fossilized together; they all died together, and this information is key to our interpretation that the animals were likely gregarious in their behavior," Suarez said.The research team also include scientists from the U.S. Bureau of Land Management, Denver Museum of Nature and Science, Colby College of Maine and James Cook University in Australia. The study examines a unique fossil bone site inside Grand Staircase-Escalante National Monument called the "Rainbows and Unicorns Quarry" that they say exceeded the expectations raised even from the site's lofty nickname."Localities [like Rainbows and Unicorns Quarry] that produce insights into the possible behavior of extinct animals are especially rare, and difficult to interpret," said tyrannosaur expert Philip Currie in a press release from the BLM. "Traditional excavation techniques, supplemented by the analysis of rare earth elements, stable isotopes and charcoal concentrations convincingly show a synchronous death event at the Rainbows site of four or five tyrannosaurids. Undoubtedly, this group died together, which adds to a growing body of evidence that tyrannosaurids were capable of interacting as gregarious packs."In 2014, BLM paleontologist Alan Titus discovered the Rainbows and Unicorns Quarry site in Grand Staircase-Escalante National Monument and led the subsequent research on the site, which is the first tyrannosaur mass death site found in the southern United States. Researchers ran a battery of tests and analyses on the vestiges of the original site, now preserved as small rock fragments and fossils in their final resting place, and sandbar deposits from the ancient river."We realized right away this site could potentially be used to test the social tyrannosaur idea. Unfortunately, the site's ancient history is complicated," Titus said. "With bones appearing to have been exhumed and reburied by the action of a river, the original context within which they lay has been destroyed. However, all has not been lost." As the details of the site's history emerged, the research team concluded that the tyrannosaurs died together during a seasonal flooding event that washed their carcasses into a lake, where they sat, largely undisturbed until the river later churned its way through the bone bed."We used a truly multidisciplinary approach (physical and chemical evidence) to piece the history of the site together, with the end-result being that the tyrannosaurs died together during a seasonal flooding event," said Suarez.Using analysis of stable carbon and oxygen isotopes and concentrations of rare earth elements within the bones and rock, Suarez and her then-doctoral student, Daigo Yamamura, were able to provide a chemical fingerprint of the site. Based on the geochemical work, they were able to conclusively determine that the remains from the site all fossilized in the same environment and were not the result of an attritional assemblage of fossils washed in from a variety of areas."None of the physical evidence conclusively suggested that these organisms came to be fossilized together, so we turned to geochemistry to see if that could help us. The similarity of rare earth element patterns is highly suggestive that these organisms died and were fossilized together," said Suarez.Excavation of the quarry site has been ongoing since its discovery in 2014 and due to the size of the site and volume of bones found there the excavation will probably continue into the foreseeable future. In addition to tyrannosaurs, the site has also yielded seven species of turtles, multiple fish and ray species, two other kinds of dinosaurs, and a nearly complete skeleton of a juvenile (12-foot-long) Deinosuchus alligator, although they do not appear to have all died together like the tyrannosaurs."The new Utah site adds to the growing body of evidence showing that tyrannosaurs were complex, large predators capable of social behaviors common in many of their living relatives, the birds," said project contributor, Joe Sertich, curator of dinosaurs at the Denver Museum of Nature & Science. "This discovery should be the tipping point for reconsidering how these top carnivores behaved and hunted across the northern hemisphere during the Cretaceous."Future research plans for the Rainbows and Unicorns Quarry fossils include additional trace element and isotopic analysis of the tyrannosaur bones, which paleontologists hope will determine with a greater degree of certainty the mystery of Teratophoneus' social behavior.In stark contrast to the social interaction between humans and among many species of animals, paleontologists have long debated whether tyrannosaurs lived and hunted alone or in groups.Based on findings at a site in Alberta, Canada, with over 12 individuals, the idea that tyrannosaurs were social with complex hunting strategies was first formulated by Philip Currie over 20 years ago. This idea has been widely debated, with many scientists doubting the giant killing machines had the brainpower to organize into anything more complex than what is observed in modern crocodiles. Because the Canadian site appeared to be an isolated case, skeptics claimed it represented unusual circumstances that did not reflect normal tyrannosaur behavior. Discovery of a second tyrannosaur mass death site in Montana again raised the possibility of social tyrannosaurs, but this site was still not widely accepted by the scientific community as evidence for social behavior. The researcher's findings at the Unicorns and Rainbows Quarry provides even more compelling evidence that tyrannosaurs may have habitually lived in groups.
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Biology
| 2,021 |
April 20, 2021
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https://www.sciencedaily.com/releases/2021/04/210420092921.htm
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Analysis of famous fossil helps unlock when humans and apes diverged
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A long-awaited, high-tech analysis of the upper body of famed fossil "Little Foot" opens a window to a pivotal period when human ancestors diverged from apes, new USC research shows.
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Little Foot's shoulder assembly proved key to interpreting an early branch of the human evolutionary tree. Scientists at the Keck School of Medicine of USC focused on its so-called pectoral girdle, which includes collarbones, shoulder blades and joints.Although other parts of Little Foot, especially its legs, show humanlike traits for upright walking, the shoulder components are clearly apelike, supporting arms surprisingly well suited for suspending from branches or shimmying up and down trees rather than throwing a projectile or dangling astride the torso like humans.The Little Foot fossil provides the best evidence yet of how human ancestors used their arms more than 3 million years ago, said Kristian J. Carlson, lead author of the study and associate professor of clinical integrative anatomical sciences at the Keck School of Medicine."Little Foot is the Rosetta stone for early human ancestors," he said. "When we compare the shoulder assembly with living humans and apes, it shows that Little Foot's shoulder was probably a good model of the shoulder of the common ancestor of humans and other African apes like chimpanzees and gorillas."The apelike characteristics will likely attract considerable intrigue as science teams around the world have been examining different parts of the skeleton to find clues to human origins. The USC-led study, which also involved researchers at the University of Wisconsin, the University of Liverpool and the University of the Witwatersrand in South Africa, among others, was published today in the The journal devoted a special issue to Little Foot analyses from a global research group, which looked at other parts of the creature's skeleton. The process is somewhat akin to the story of blind men and the elephant, each examining one part in coordination with others to explain the whole of something that's not fully understood.The Little Foot fossil is a rare specimen because it's a near-complete skeleton of an Australopithecus individual much older than most other human ancestors. The creature, probably an old female, stood about 4 feet tall with long legs suitable for bipedal motion when it lived some 3.67 million years ago. Called "Little Foot" because the first bones recovered consisted of a few small foot bones, the remains were discovered in a cave in South Africa in the 1990s. Researchers have spent years excavating it from its rock encasement and subjecting it to high-tech analysis.While not as widely known as the Lucy skeleton, another Australopithecus individual unearthed in East Africa in the 1970s, Carlson said Little Foot is older and more complete.The USC-led research team zeroed in on the shoulder assemblies because Little Foot provides the oldest and most intact example of this anatomy ever found. Those bones provide telltale clues of how an animal moves. In human evolution, he said, these parts had to change form before our ancestors could live life free of trees, walk the open savannah and use their arms for functions other than supporting the weight of the individual.The scientists compared the creature's shoulder parts to apes, hominins and humans. Little Foot was a creature adapted to living in trees because the pectoral girdle suggests a creature that climbed trees, hung below branches and used its hands overhead to support its weight.For example, the scapula, or shoulder blade, has a big, high ridge to attach heavy muscles similar to gorillas and chimpanzees. The shoulder joint, where the humerus connects, sits at an oblique angle, useful for stabilizing the body and lessening tensile loads on shoulder ligaments when an ape hangs beneath branches. The shoulder also has a sturdy, apelike reinforcing structure, the ventral bar. And the collarbone has a distinctive S-shaped curve commonly found in apes.Those conclusions mean that the structural similarities in the shoulder between humans and African apes are much more recent, and persisted much longer, than has been proposed, Carlson said."We see incontrovertible evidence in Little Foot that the arm of our ancestors at 3.67 million years ago was still being used to bear substantial weight during arboreal movements in trees for climbing or hanging beneath branches," he said. "In fact, based on comparisons with living humans and apes, we propose that the shoulder morphology and function of Little Foot is a good model for that of the common ancestor of humans and chimpanzees 7 million to 8 million years ago."The scientists were able to achieve remarkably clear images of the fossils. That's because the bones, painstakingly excavated for many years, are in good condition and uniquely complete. The scientists examined them using micro-CT scans, which can detect minute features on the surface of an object, peer deep inside a bone, measure the density of an object and generate a 3D model without harming the fossil.USC professors in collaboration with the Natural History Museum of Los Angeles County host a formidable array of paleontologists, augmented by anatomical specialists at the Keck School of Medicine. The museum was not part of this study.
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Biology
| 2,021 |
April 20, 2021
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https://www.sciencedaily.com/releases/2021/04/210419110136.htm
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Supplement treats schizophrenia in mice, restores healthy 'dance' and structure of neurons
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A simple dietary supplement reduces behavioral symptoms in mice with a genetic mutation that causes schizophrenia. After additional experiments, including visualizing the fluorescently stained dancing edge of immature brain cells, researchers concluded that the supplement likely protects proteins that build neurons' cellular skeletons.
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The supplement betaine was first isolated from sugar beets and is often associated with sweetness or umami flavor. Healthy levels of betaine come from both external food sources and internal synthesis in the body. Betaine supplements are already used clinically to treat the metabolic disease homocystinuria."I don't encourage anyone to take betaine for no reason, if a doctor has not recommended it. But, we know this drug is already used clinically, so repurposing it to treat schizophrenia should be safe," said Project Professor Nobutaka Hirokawa, M.D., Ph.D., from the University of Tokyo Graduate School of Medicine who led the recent research project. Hirokawa has been a member of the Japan Academy, a national honorary organization recognizing scientific achievement, since 2004 and received a Person of Cultural Merit award from the Japanese government in 2013.Schizophrenia is estimated to affect about 1 in 100 people globally and is one of the top 15 leading causes of disability worldwide."There are treatments for schizophrenia, but they have side effects and unfortunately there is still no effective drug for patients to take that we can explain biochemically why it works," explained Hirokawa.Genetic studies of people diagnosed with schizophrenia have found possible links between the disease and variations in the kinesin family 3b (kif3b) gene as well as another gene involved in the body's internal synthesis of betaine.Hirokawa and his lab members have categorized all 45 members of the kinesin superfamily of genes in mammals, most of which encode motor proteins that move materials throughout the cell. Normally, the KIF3B protein links together with another kinesin superfamily protein and transports cargo throughout a neuron by traveling up and down the cell's skeleton.Mice used in the recent research had only one functional copy of the kif3b gene and are often used as an animal model of schizophrenia. These mice avoid social interactions and show the same weak response as human patients with schizophrenia in a test called prepulse inhibition, which measures how startled they are by a sudden, loud sound preceded by a quieter sound.Kif3b mutant mice raised on a diet supplemented with three times the normal amount of betaine had normal behavior, indicating that betaine supplements could treat schizophrenia symptoms.To figure out why betaine had this effect on mice, researchers grew nerve cells with the kif3b mutation in the laboratory and added fluorescent labels so they could watch the cellular skeleton take shape.The shape of a healthy neuron is reminiscent of a tree: a cell body surrounded by branches, the dendrites, attached to a long trunk, the axon. Kif3b mutant neurons grown in the lab have an unusual, hyperbranched structure with too many dendrites. Similar hyperbranched neurons are also seen in brain samples donated by people with schizophrenia, regardless of what treatments or medications they took while they were alive.During healthy neuron development, the main body of the cell fills with a skeleton component called tubulin. Meanwhile, the front growth cone of the cell builds outwards in a spiky, erratic dance due to the movements of another skeleton component called filamentous actin. In kif3b mutants, this dancing movement, which experts refer to as lamellipodial dynamics, is noticeably reduced and the division between tubulin and actin is blurred.The actin in a neuron's cellular skeleton is assembled in part by another protein called CRMP2. Chemical analyses of the brains of kif3b mutant mice and human schizophrenia patients reveal significant chemical damage to CRMP2, which causes the proteins to clump together.Betaine is known to prevent the type of chemical damage, carbonyl stress, that causes this CRMP2 dysfunction."In postmortem brains of schizophrenia patients, CRMP2 is the protein in the brain with the most carbonyl stress. Betaine likely eliminates the carbonyl stress portion of the schizophrenia equation," said Hirokawa.By protecting CRMP2 from damage, betaine treatment allows kif3b mutant neurons to build proper structures. With a structurally sound skeleton to navigate, the remaining functional KIF3B protein can shuttle cargo around the cell. Other test tube experiments revealed that KIF3B and CRMP2 can bind together, but their exact relationship remains unclear."We know that the amount of betaine decreases in schizophrenia patients' brains, so this study strongly suggests betaine could be therapeutic for at least some kinds of schizophrenia," said Hirokawa.The UTokyo research team is planning future collaborations with pharmaceutical companies and clinical studies of betaine supplements as a treatment for schizophrenia.This research is a peer-reviewed experimental study in mice and human cells published in the journal
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Biology
| 2,021 |
April 19, 2021
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https://www.sciencedaily.com/releases/2021/04/210419182113.htm
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Tiny implantable tool for light-sheet imaging of brain activity
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Tools that allow neuroscientists to record and quantify functional activity within the living brain are in great demand. Traditionally, researchers have used techniques such as functional magnetic resonance imaging, but this method cannot record neural activity with high spatial resolution or in moving subjects. In recent years, a technology called optogenetics has shown considerable success in recording neural activity from animals in real time with single neuron resolution. Optogenetic tools use light to control neurons and record signals in tissues that are genetically modified to express light-sensitive and fluorescent proteins. However, existing technologies for imaging light signals from the brain have drawbacks in their size, imaging speed, or contrast that limit their applications in experimental neuroscience.
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A technology called light-sheet fluorescence imaging shows promise for imaging brain activity in 3D with high speed and contrast (overcoming multiple limitations of other imaging technologies). In this technique, a thin sheet of laser light (light-sheet) is directed through a brain tissue region of interest, and fluorescent activity reporters within the brain tissues respond by emitting fluorescence signals that microscopes can detect. Scanning a light sheet in the tissue enables high-speed, high-contrast, volumetric imaging of the brain activity.Currently, using light-sheet fluorescence brain imaging with nontransparent organisms (like a mouse) is difficult because of the size of the necessary apparatus. To make experiments with nontransparent animals and, in the future, freely moving animals feasible, researchers will first need to miniaturize many of the components.A key component for the miniaturization is the light-sheet generator itself, which needs to be inserted into the brain and thus must be as small as possible to avoid displacing too much brain tissue. In a new study reported in The researchers used nanophotonic technology to create ultrathin silicon-based photonic neural probes that emit multiple addressable thin sheets of light with thicknesses <16 micrometers over propagation distances of 300 micrometers in free space. When tested in brain tissues from mice that were genetically engineered to express fluorescent proteins in their brains, the probes permitted the researchers to image areas as large as 240 ?m × 490 ?m. Moreover, the level of image contrast was superior to that with an alternative imaging method called epifluorescence microscopy.Describing the significance of his team's work, the study's lead author, Wesley Sacher, says, "This new implantable photonic neural probe technology for generating light sheets within the brain circumvents many of the constraints that have limited the use of light-sheet fluorescence imaging in experimental neuroscience. We predict that this technology will lead to new variants of light-sheet microscopy for deep brain imaging and behavior experiments with freely moving animals."Such variants would be a boon to neuroscientists seeking to understand the workings of the brain.
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Biology
| 2,021 |
April 19, 2021
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https://www.sciencedaily.com/releases/2021/04/210419182050.htm
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New algorithm uses online learning for massive cell data sets
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The fact that the human body is made up of cells is a basic, well-understood concept. Yet amazingly, scientists are still trying to determine the various types of cells that make up our organs and contribute to our health.
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A relatively recent technique called single-cell sequencing is enabling researchers to recognize and categorize cell types by characteristics such as which genes they express. But this type of research generates enormous amounts of data, with datasets of hundreds of thousands to millions of cells.A new algorithm developed by Joshua Welch, Ph.D., of the Department of Computational Medicine and Bioinformatics, Ph.D. candidate Chao Gao and their team uses online learning, greatly speeding up this process and providing a way for researchers world-wide to analyze large data sets using the amount of memory found on a standard laptop computer. The findings are described in the journal "Our technique allows anyone with a computer to perform analyses at the scale of an entire organism," says Welch. "That's really what the field is moving towards."The team demonstrated their proof of principle using data sets from the National Institute of Health's Brain Initiative, a project aimed at understanding the human brain by mapping every cell, with investigative teams throughout the country, including Welch's lab.Typically, explains Welch, for projects like this one, each single-cell data set that is submitted must be re-analyzed with the previous data sets in the order they arrive. Their new approach allows new datasets to the be added to existing ones, without reprocessing the older datasets. It also enables researchers to break up datasets into so-called mini-batches to reduce the amount of memory needed to process them."This is crucial for the sets increasingly generated with millions of cells," Welch says. "This year, there have been five to six papers with two million cells or more and the amount of memory you need just to store the raw data is significantly more than anyone has on their computer."Welch likens the online technique to the continuous data processing done by social media platforms like Facebook and Twitter, which must process continuously-generated data from users and serve up relevant posts to people's feeds. "Here, instead of people writing tweets, we have labs around the world performing experiments and releasing their data."The finding has the potential to greatly improve efficiency for other ambitious projects like the Human Body Map and Human Cell Atlas. Says Welch, "Understanding the normal complement of cells in the body is the first step towards understanding how they go wrong in disease."
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Biology
| 2,021 |
April 19, 2021
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https://www.sciencedaily.com/releases/2021/04/210419135753.htm
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Unique mode of cell migration on soft 'viscoelastic' surfaces
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Inside your body, cell movement plays a crucial role in many significant biological processes, including wound healing, immune responses and the potential spread of cancer.
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"Most people don't die from having a primary tumor," said Kolade Adebowale, a graduate student in chemical engineering, and a member of the Chemical Biology Interface (CBI) graduate program in Chemistry, Engineering & Medicine for Human Health (ChEM-H) at Stanford University. "The problem is when cancer cells from the tumor acquire the ability to metastasize or move to different parts of the body."As an attempt to advance studies of cell migration, Adebowale and colleagues in the lab of Ovijit Chaudhuri, associate professor of mechanical engineering at Stanford, have worked to develop and test new types of material that closely imitate the real tissue that surrounds cells. New findings built on this work, published April 19 in "We found that it makes a big difference if the cancer cells are on a very rigid plastic or if they're on a soft and viscoelastic material, like a Jell-O," said Adebowale, who is lead author of the paper. "This adds to a lot of recent evidence that the behavior of cancer is not just about the cancer cells -- it is also about the environment that the cancer cells interact with."Cell migration is traditionally studied on a hard, transparent piece of polymer called "tissue culture plastic" or elastic hydrogels, like soft contact lenses. Based on these studies, the current belief is that cells cannot migrate on hydrogels that are too soft. However, the researchers aim to mimic the real-life biological tissues on which cells migrate -- which are soft and not purely elastic, like a rubber band, but viscoelastic."They are solid materials, but they also have viscous and liquid characteristics that allow them to flow over longer timescales," Adebowale said.Examples of viscoelastic materials like the ones created for the research include bread dough, mozzarella and silly putty, according to Chaudhuri. These materials initially resist deformation, like an elastic material, but viscously relax that resistance over time.When the researchers studied the movement of cancer cells on their more tissue-like substrate, the results contradicted existing expectations."We found that when the substrate is viscoelastic, the cells can migrate quite robustly, even though it is soft," said Chaudhuri, who is senior author of the paper.Not only did the study find that cells can migrate on soft, viscoelastic substrates, the researchers also discovered the migration movement is unique. On a stiff, 2D surface like tissue culture plastic, cells adhere to the surface and form a fan-like protrusion. This protrusion, called a lamellipodium, drives forward motion by extending the leading edge forward and pushing off the surface. On the viscoelastic materials the team created, the cells didn't spread out so extensively. Instead, they used thin, spike-like protrusions called filopodia to drive their movement. Further, their experiments showed the cells use what's called a "molecular clutch" to migrate on the substrates."Imagine you're moving on ice. If you don't have enough adhesion to the ice, and try to run, you're not going to go anywhere," said Chaudhuri. "You really need a strong grip to push off and move forward. That's what the molecular clutch does for cells."Robustly migrating cells on rigid tissue culture plastic form strong adhesions to the substrate. The authors observed that cells on soft, viscoelastic substrates are also able to migrate robustly but, importantly, these cells are able to do so with fewer, weak adhesions -- like the cells are moving on their tippy-toes, not their entire foot."I think what was most surprising was that the material property -- viscoelasticity -- can have such a dramatic impact on the ability of cells to migrate," said Adebowale.The fact that the mode of cell migration that the researchers observed is not seen on hard substrates or substrates that are only elastic shows how viscoelasticity is essential to the behavior of cells -- and therefore important to replicate in future studies."This challenges the textbook view of how we understand cell migration," said Chaudhuri. "Cells migrate differently on viscoelastic tissue than they do on glass, plastic petri dishes or elastic gels. So, if we want to study cell migration, we need to use viscoelastic substrates."While the study looked at single-cell migration, cancer cells migrate as a group in the body and various stages in development involve the collective movement of cells. Next, the researchers hope to answer the question of how viscoelasticity impacts collective cell migration.
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Biology
| 2,021 |
April 19, 2021
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https://www.sciencedaily.com/releases/2021/04/210419110138.htm
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Defects in a specific cell type may cause ulcerative colitis
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There are many variants of "goblet cells" in the intestines and they seem to have different functions, according to a new study from the University of Gothenburg. The study indicates that defects in goblet cells of a particular type may be a factor contributing to ulcerative colitis, an inflammatory bowel disease.
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The entire inside of our intestines is covered by a thin layer of mucus that protects the fragile mucous membrane (mucosa) from bacteria and other microorganisms. If the microorganisms repeatedly come into contact with the intestinal mucosa, inflammation and even cell changes may result. These increase the risk of intestinal cancer. In a healthy colon, the mucus layer is up to a millimeter thick. This layer, which undergoes complete renewal hourly, is formed from cells of a special type, known as goblet cells.In the present study, now published in the journal "We believe this is important knowledge that may enable us to influence the protective function of the gut in the future. The system that maintains the protective intestinal mucus layer seems to be able to change its functions, and we could utilize this capacity by reprogramming the layer with various signals, for example by using new drugs," says Malin Johansson, Associate Professor at Sahlgrenska Academy, University of Gothenburg, who led the research behind the present study.The most impermeable part of the mucus layer is formed by glands in the gut. In particular, the research team studied one of the specific types of goblet cells, found on the outermost surface of the mucosa. These goblet cells provide another type of mucus, which contributes to the protection of the gut but allows certain nutrients to pass through."If the function of these specific cells is impaired, we see that unprotected cell surfaces arise. These lead to inflammation, both in studies on mice and in samples from patients with ulcerative colitis," Johansson says.In the study, these specific goblet cells seemed to be repelled by the mucosa earlier than normal in patients with ulcerative colitis. Accordingly, the cells became fewer."To our surprise, we were able to observe this both in patients with active ulcerative colitis and in those who were temporarily asymptomatic. This indicates that premature rejection of the particular goblet cells we've been studying damages the mucus protection and that this is a contributing cause of inflammatory bowel disease. It could also be a partial explanation for these patients' elevated cancer risk," Johansson says.There are some 30,000 people in Sweden with ulcerative colitis, which is a chronic but intermittent inflammatory bowel disease.
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Biology
| 2,021 |
April 16, 2021
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https://www.sciencedaily.com/releases/2021/04/210416194925.htm
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Simulations reveal how dominant SARS-CoV-2 strain binds to host, succumbs to antibodies
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Large-scale supercomputer simulations at the atomic level show that the dominant G form variant of the COVID-19-causing virus is more infectious partly because of its greater ability to readily bind to its target host receptor in the body, compared to other variants. These research results from a Los Alamos National Laboratory-led team illuminate the mechanism of both infection by the G form and antibody resistance against it, which could help in future vaccine development.
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"We found that the interactions among the basic building blocks of the Spike protein become more symmetrical in the G form, and that gives it more opportunities to bind to the receptors in the host -- in us," said Gnana Gnanakaran, corresponding author of the paper published today in Researchers knew that the variant, also known as D614G, was more infectious and could be neutralized by antibodies, but they didn't know how. Simulating more than a million individual atoms and requiring about 24 million CPU hours of supercomputer time, the new work provides molecular-level detail about the behavior of this variant's Spike.Current vaccines for SARS-CoV-2, the virus that causes COVID-19, are based on the original D614 form of the virus. This new understanding of the G variant -- the most extensive supercomputer simulations of the G form at the atomic level -- could mean it offers a backbone for future vaccines.The team discovered the D614G variant in early 2020, as the COVID-19 pandemic caused by the SARS-CoV-2 virus was ramping up. These findings were published in Cell. Scientists had observed a mutation in the Spike protein. (In all variants, it is the Spike protein that gives the virus its characteristic corona.) This D614G mutation, named for the amino acid at position 614 on the SARS-CoV-2 genome that underwent a substitution from aspartic acid, prevailed globally within a matter of weeks.The Spike proteins bind to a specific receptor found in many of our cells through the Spike's receptor binding domain, ultimately leading to infection. That binding requires the receptor binding domain to transition structurally from a closed conformation, which cannot bind, to an open conformation, which can.The simulations in this new research demonstrate that interactions among the building blocks of the Spike are more symmetrical in the new G-form variant than those in the original D-form strain. That symmetry leads to more viral Spikes in the open conformation, so it can more readily infect a person.A team of postdoctoral fellows from Los Alamos -- Rachael A. Mansbach (now assistant professor of Physics at Concordia University), Srirupa Chakraborty, and Kien Nguyen -- led the study by running multiple microsecond-scale simulations of the two variants in both conformations of the receptor binding domain to illuminate how the Spike protein interacts with both the host receptor and with the neutralizing antibodies that can help protect the host from infection. The members of the research team also included Bette Korber of Los Alamos National Laboratory, and David C. Montefiori, of Duke Human Vaccine Institute.The team thanks Paul Weber, head of Institutional Computing at Los Alamos, for providing access to the supercomputers at the Laboratory for this research.The Paper: "The SARS-CoV-2 Spike variant D614G favors an open conformational state," The Funding: The project was supported by Los Alamos Laboratory Directed Research and Development project 20200706ER, Director's Postdoctoral fellowship, and the Center of Nonlinear Studies Postdoctoral Program at Los Alamos.
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Biology
| 2,021 |
April 16, 2021
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https://www.sciencedaily.com/releases/2021/04/210416131923.htm
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New CRISPR technology offers unrivaled control of epigenetic inheritance
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Scientists have figured out how to modify CRISPR's basic architecture to extend its reach beyond the genome and into what's known as the epigenome -- proteins and small molecules that latch onto DNA and control when and where genes are switched on or off.
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In a paper published April 9, 2021, in the journal Because the epigenome plays a central role in many diseases, from viral infection to cancer, CRISPRoff technology may one day lead to powerful epigenetic therapies. And since this approach doesn't involve any DNA edits, it's likely to be safer than conventional CRISPR therapeutics, which have been known to cause unwanted and potentially harmful changes to the genome."Though genetic and cellular therapies are the future of medicine, there are potential safety concerns around permanently changing the genome, which is why we're trying to come up with other ways to use CRISPR to treat disease," said Luke Gilbert, PhD, a professor at UCSF's Helen Diller Family Comprehensive Cancer Center and co-senior author of the new paper.Conventional CRISPR is equipped with two pieces of molecular hardware that make it an effective gene-editing tool. One component is a DNA-snipping enzyme, which gives CRISPR the ability to alter DNA sequences. The other is a homing device that can be programmed to zero in on any DNA sequence of interest, imparting precise control over where edits are made.To build CRISPRoff, the researchers dispensed with conventional CRISPR's DNA-snipping enzyme function while retaining the homing device, creating a stripped-down CRISPR capable of targeting any gene, but not editing it. Then they tethered an enzyme to this barebones CRISPR. But rather than splicing DNA, this enzyme acts on the epigenome.The new tool targets a particular epigenetic feature known as DNA methylation, which is one of many molecular parts of the epigenome. When DNA is methylated, a small chemical tag known as a methyl group is affixed to DNA, which silences nearby genes. Although DNA methylation occurs naturally in all mammalian cells, CRISPRoff offers scientists unprecedented control over this process. Another tool described in the paper, called CRISPRon, removes methylation marks deposited by CRISPRoff, making the process fully reversible."Now we have a simple tool that can silence the vast majority of genes," said Jonathan Weissman, PhD, Whitehead Institute member, co-senior author of the new paper and a former UCSF faculty member. "We can do this for multiple genes at the same time without any DNA damage, and in a way that can be reversed. It's a great tool for controlling gene expression."Based on previous work by a group in Italy, the researchers were confident that CRISPRoff would be able to silence specific genes, but they suspected that some 30 percent of human genes would be unresponsive to the new tool.DNA consists of four genetic letters -- A, C, G, T -- but, in general, only Cs next to Gs can be methylated. To complicate matters, scientists have long believed that methylation could only silence genes at sites in the genome where CG sequences are highly concentrated, regions known as "CpG islands."Since nearly a third of human genes lack CpG islands, the researchers assumed methylation wouldn't switch these genes off. But their CRISPRoff experiments upended this epigenetic dogma."What was thought before this work was that the 30 percent of genes that do not have CpG islands were not controlled by DNA methylation," said Gilbert. "But our work clearly shows that you don't require a CpG island to turn genes off by methylation. That, to me, was a major surprise."Easy-to-use epigenetic editors like CRISPRoff have tremendous therapeutic potential, in large part because, like the genome, the epigenome can be inherited.When CRISPRoff silences a gene, not only does the gene remain off in the treated cell, it also stays off in the descendants of the cell as it divides, for as many as 450 generations.To the researchers' surprise, this held true even in maturing stem cells. Though the transition from stem cell to differentiated adult cell involves a significant rewiring of the epigenome, the methylation marks deposited by CRISPRoff were faithfully inherited in a significant fraction of cells that made this transition.These findings suggest that CRISPRoff would only need to be administered once to have lasting therapeutic effects, making it a promising approach for treating rare genetic disorders -- including Marfan syndrome, which affects connective tissue, Job's syndrome, an immune system disorder, and certain forms of cancer -- that are caused by the activity of a single damaged copy of a gene.The researchers noted that although CRISPRoff is exceptionally promising, further work is needed to realize its full therapeutic potential. Time will tell if CRISPRoff and similar technologies are indeed "the future of medicine."
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Biology
| 2,021 |
April 16, 2021
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https://www.sciencedaily.com/releases/2021/04/210416115957.htm
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Virologists develop broadly protective coronavirus vaccines
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A candidate vaccine that could provide protection against the COVID-19 virus and other coronaviruses has shown promising results in early animal testing.
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The candidate coronavirus vaccines, created by Virginia Tech's University Distinguished Professor X.J. Meng and UVA Health's Professor Steven L. Zeichner, prevented pigs from being becoming ill with a pig coronavirus, porcine epidemic diarrhea virus (PEDV).The researchers have recently published their findings in the "The candidate vaccine was developed using an innovative vaccine platform targeting a highly conserved genomic region of coronaviruses," said Meng, a University Distinguished Professor in the Department of Biomedical Sciences and Pathobiology in the Virginia-Maryland College of Veterinary Medicine. "The new vaccine platform utilizes a genome-reduced bacteria to express the coronavirus vaccine antigen on its surface. Such a vaccine platform can be manufactured with low cost in existing facilities around the world, which could meet the pandemic demand."Their coronavirus vaccine offers several advantages that could overcome major obstacles to global vaccination efforts. It would be easy to store and transport, even in remote areas of the world, and could be produced in mass quantities using existing vaccine-manufacturing factories."Our new platform offers a new route to rapidly produce vaccines at very low cost that can be manufactured in existing facilities around the world, which should be particularly helpful for pandemic response," said Zeichner.The new vaccine-production platform involves synthesizing DNA that directs the production of a piece of the virus that can instruct the immune system how to mount a protective immune response against a virus.That DNA is inserted into another small circle of DNA called a plasmid that can reproduce within bacteria. The plasmid is then introduced into bacteria, instructing the bacteria to place pieces of proteins on their surfaces. The technique uses the common bacteria One major innovation is that the "Killed whole-cell vaccines are currently in widespread use to protect against deadly diseases like cholera and pertussis. Factories in many low-to-middle-income countries around the world are making hundreds of millions of doses of those vaccines per year now, for a $1 per dose or less," Zeichner said. "It may be possible to adapt those factories to make this new vaccine. Since the technology is very similar, the cost should be similar too."The entire process, from identifying a potential vaccine target to producing the gene-deleted bacteria that have the vaccine antigens on their surfaces, can take place very quickly, in only two to three weeks, making the platform ideal for responding to a pandemic.The team's candidate vaccines take an unusual approach in that it targets a part of the spike protein of the virus, the "viral fusion peptide," that is highly universal among coronaviruses. The fusion peptide has not been observed to differ at all in the many genetic sequences of SARS-CoV-2, the virus that causes COVID-19, that have been obtained from thousands of patients around the world during the course of the pandemic."With the emergence of various SARS-CoV-2 variants, a vaccine targeting a conserved region of all coronaviruses, such as the fusion peptide, may potentially lead to a broadly protective candidate vaccine. Such a vaccine, if successful, would be of significant value against variant virus strains," said Meng, who is also the founding director of the Center for Emerging, Zoonotic, and Arthropod-borne Pathogens in the Fralin Life Sciences Institute at Virginia Tech.To create their vaccine, the researchers used the new vaccine platform, synthesizing the DNA with the instructions to make the fusion peptide and engineered bacteria to place the proteins on the surface of the bacteria that had a large number of its genes removed, then grew and inactivated the bacteria to make the candidate coronavirus vaccine.Meng and Zeichner made two vaccines, one designed to protect against COVID-19, and another designed to protect against the pig coronavirus, PEDV. PEDV and SARS-CoV-2, the virus that causes COVID-19, are both coronaviruses, but they are distant relatives. PEDV and SARS-CoV-2, like all coronaviruses, share a number of core amino acids that constitute the fusion peptide. PEDV infects pigs, causing diarrhea, vomiting, and high fever and has been a large burden on pig farmers around the world. When PEDV first appeared in pig herds in the U.S. in 2013, it killed millions of pigs in the United States alone.One advantage of studying PEDV in pigs is the researchers could study the ability of the vaccines to offer protection against a coronavirus infection in its native host -- in this case, pigs. The other models that have been used to test COVID-19 vaccines study SARS-CoV-2 in nonnative hosts, such as monkeys or hamsters, or in mice that have been genetically engineered to enable them to be infected with SARS-CoV-2. Pigs are also very similar in physiology and immunology to people -- they may be the closest animal models to people other than primates.In some unexpected results, Meng and Zeichner observed that both the candidate vaccine against PEDV and the candidate vaccine against SARS-CoV-2 protected the pigs against illness caused by PEDV. The vaccines did not prevent infection, but they protected the pigs from developing severe symptoms, much like the observations made when primates were tested with candidate COVID-19 vaccines. The vaccines also primed the immune system of the pigs to mount a much more vigorous immune response to the infection. If both the PEDV and the COVID-19 vaccines protected the pigs against disease caused by PEDV and primed the immune system to fight the disease, it is reasonable to think that the COVID-19 vaccine would also protect people against severe COVID-19 disease.Additional testing -- including human trials -- would be required before the COVID-19 vaccine could be approved by the federal Food and Drug Administration or other regulatory agencies around the world for use in people, but the collaborators are pleased by the early successes of the vaccine-development platform."Although the initial results in the animal study are promising, more work is needed to refine both the vaccine platform using different genome-reduced bacterial strains and the fusion peptide vaccine target," said Meng. "It will also be important to test the fusion peptide vaccine in a monkey model against SARS-CoV-2 infection."Zeichner added that he was encouraged that a collaboration between UVA and Virginia Tech, schools with a well-known sports rivalry, has produced such promising results."If UVA and Virginia Tech scientists can work together to try to do something positive to address the pandemic, then maybe there is some hope for collaboration and cooperation in the country at large," said Zeichner.The research team consisted of Denicar Lina Nascimento Fabris Maeda, Hanna Yu, Nakul Dar, Vignesh Rajasekaran, Sarah Meng, and Steven L. Zeichner from UVA Health; and Debin Tian, Hassan Mahsoub, Harini Sooryanarain, Bo Wang, C. Lynn Heffron, Anna Hassebroek, Tanya LeRoith, and Xiang-Jin Meng from the Virginia-Maryland College of Veterinary Medicine at Virginia Tech.Zeichner is the McClemore Birdsong Professor in the departments of Pediatrics and Microbiology, Immunology, and Cancer Biology; the director of the Pendleton Pediatric Infectious Disease Laboratory; and part of UVA Children's Child Health Research Center. Meng is a University Distinguished Professor and director of the Virginia Tech Center for Emerging, Zoonotic, and Arthropod-borne Pathogens and a member of Virginia Tech's Department of Biomedical Sciences and Pathobiology.Their vaccine-development work was supported by the Pendleton Pediatric Infectious Disease Laboratory, the McClemore Birdsong endowed chair and by support from the University of Virginia Manning Fund for COVID-19 Research and from the Ivy Foundation. The work was also partially supported by the Virginia-Maryland College of Veterinary Medicine and Virginia Tech internal funds.
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Biology
| 2,021 |
April 16, 2021
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https://www.sciencedaily.com/releases/2021/04/210416120116.htm
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Study reveals how some antibodies can broadly neutralize ebolaviruses
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Some survivors of ebolavirus outbreaks make antibodies that can broadly neutralize these viruses -- and now, scientists at Scripps Research have illuminated how these antibodies can disable the viruses so effectively. The insights may be helpful for developing effective therapies.
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Ebolavirus is a family of often-deadly viruses that includes Ebola virus and many lesser-known viruses such as Bundibugyo virus, Sudan virus and Reston virus.Structural biologists at Scripps Research used electron microscopy techniques to visualize a set of antibodies that target a key site on these viruses called the "glycan cap." Their research showed that the antibodies work against ebolaviruses using the same three mechanisms to prevent the virus from infecting host cells.The research, published in "We now understand the molecular basis for these antibodies' abilities to neutralize ebolviruses with broad reactivity against different viral species," says the study's first author Daniel Murin, PhD, a staff scientist in the laboratory of Andrew Ward, PhD.Ward, a professor in the Department of Integrative Structural and Computational Biology at Scripps Research, says he hopes the work will contribute the development of a "cocktail" of therapeutic antibodies that can save lives by treating many forms of the Ebola virus."The goal is to provide doctors in Ebola-prone regions their best weapon yet against these deadly outbreaks," Ward says. "The insights we have gained through our structural studies of the virus show how this may be possible."The first known ebolavirus, now called Zaire ebolavirus or simply Ebola virus, was identified in 1976, named for the site of an outbreak that year near the Ebola river in what was then Zaire and is now the Democratic Republic of Congo.Other species have since been added to this family of viruses, including Sudan ebolavirus and Bundibugyo ebolavirus. Ebola viruses colonize African fruit bats, often cause disease in chimpanzees and other non-human primates, and trigger outbreaks in humans every few years, on average. Infected people develop a hemorrhagic syndrome that is fatal in roughly half of untreated cases.Vaccines against Ebola have been developed recently but have not yet been widely used. And although antibody-based treatments also have been developed, none has been shown effective against a broad range of ebolavirus species.Nevertheless, studies in recent years have shown that some survivors of Ebola infections carry antibodies that, in lab-dish tests, can neutralize multiple ebolavirus species. A surprisingly high proportion of these broadly neutralizing antibodies target the glycan cap, a sugar-slathered site on a stalk-like protein -- called the glycoprotein -- that enables Ebola viruses to enter host cells.In the new study, Murin and Ward, along with their colleagues in the James Crowe Lab at Vanderbilt University where the antibodies were isolated, used electron microscopy to analyze a set of glycan cap-targeting antibodies from survivors of various ebolaviruses. Their aim was to understand better how these antibodies target the virus so effectively.Their analysis suggested that the most broadly effective of these glycan cap-targeting antibodies hit the same vulnerable site on the glycan cap, allowing them to thwart viral infectivity in three ways.First, the antibody displaces a long viral structure near the glycan cap in a way that destabilizes the entire viral glycoprotein structure, sometimes causing it to fall apart.Second, the glycan cap antibody -- when it binds to its target site -- can block a key event in the infection process, in which an enzyme called a cathepsin cleaves off the glycan cap. Blocking this cleavage event blocks the glycoprotein's ability to enter host cells.Finally, the glycan cap antibody, by displacing the loose structure near the glycan cap, enables another type of neutralizing antibody to bind to a separate vulnerable site on the virus. Thus, a glycan cap antibody can "synergize" with another antibody to hit the virus significantly harder than either antibody does alone.The scientists also determined the key genetic elements that allow glycan-cap antibodies to thwart ebolaviruses in these three ways.Now that they have illuminated how these broadly neutralizing antibodies work, Ward, Murin and colleagues are testing them as parts of a next-generation antibody cocktail that they hope will be able to treat the Zaire, Sudan and Bundibugyo ebolaviruses.
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Biology
| 2,021 |
April 15, 2021
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https://www.sciencedaily.com/releases/2021/04/210415142904.htm
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Scientists generate human-monkey chimeric embryos
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Investigators in China and the United States have injected human stem cells into primate embryos and were able to grow chimeric embryos for a significant period of time -- up to 20 days. The research, despite its ethical concerns, has the potential to provide new insights into developmental biology and evolution. It also has implications for developing new models of human biology and disease. The work appears April 15 in the journal
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"As we are unable to conduct certain types of experiments in humans, it is essential that we have better models to more accurately study and understand human biology and disease," says senior author Juan Carlos Izpisua Belmonte, a professor in the Gene Expression Laboratory at the Salk Institute for Biological Sciences. "An important goal of experimental biology is the development of model systems that allow for the study of human diseases under in vivo conditions."Interspecies chimeras in mammals have been made since the 1970s, when they were generated in rodents and used to study early developmental processes. The advance that made the current study possible came last year when this study's collaborating team -- led by Weizhi Ji of Kunming University of Science and Technology in Yunnan, China -- generated technology that allowed monkey embryos to stay alive and grow outside the body for an extended period of time.In the current study, six days after the monkey embryos had been created, each one was injected with 25 human cells. The cells were from an induced pluripotent cell line known as extended pluripotent stem cells, which have the potential to contribute to both embryonic and extra-embryonic tissues. After one day, human cells were detected in 132 embryos. After 10 days, 103 of the chimeric embryos were still developing. Survival soon began declining, and by day 19, only three chimeras were still alive. Importantly, though, the percentage of human cells in the embryos remained high throughout the time they continued to grow."Historically, the generation of human-animal chimeras has suffered from low efficiency and integration of human cells into the host species," Izpisua Belmonte says. "Generation of a chimera between human and non-human primate, a species more closely related to humans along the evolutionary timeline than all previously used species, will allow us to gain better insight into whether there are evolutionarily imposed barriers to chimera generation and if there are any means by which we can overcome them."The investigators performed transcriptome analysis on both the human and monkey cells from the embryos. "From these analyses, several communication pathways that were either novel or strengthened in the chimeric cells were identified," Izpisua Belmonte explains. "Understanding which pathways are involved in chimeric cell communication will allow us to possibly enhance this communication and increase the efficiency of chimerism in a host species that's more evolutionarily distant to humans."An important next step for this research is to evaluate in more detail all the molecular pathways that are involved in this interspecies communication, with the immediate goal of finding which pathways are vital to the developmental process. Longer term, the researchers hope to use the chimeras not only to study early human development and to model disease, but to develop new approaches for drug screening, as well as potentially generating transplantable cells, tissues, or organs.An accompanying Preview in This work was supported by the National Key Research and Development Program, the National Natural Science Foundation of China, Major Basic Research Project of Science and Technology of Yunnan, Key Projects of Basic Research Program in Yunnan Province, High-level Talent Cultivation Support Plan of Yunnan Province and Yunnan Fundamental Research Projects, UCAM, and the Moxie Foundation.
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Biology
| 2,021 |
April 15, 2021
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https://www.sciencedaily.com/releases/2021/04/210415141855.htm
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Parasites and kelp forests
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Even the mention of parasites can be enough to make some people's skin crawl. But to recent UC Santa Barbara doctoral graduate Dana Morton these creepy critters occupy important ecological niches, fulfilling roles that, in her opinion, have too often been overlooked.
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That's why Morton has just released the most extensive ecological food web that includes parasites. Eight years in the making, the dataset includes over 21,000 interactions between 942 species, all thoroughly annotated. The detailed description, published in the journal Understanding who eats whom, or trophic interactions, in an ecosystem is prime information for biologists. These relationships alone can tell researchers a great deal about a system, its complexity and even its overall health. However, ecologists often overlook parasites when investigating these interactions, perhaps because parasitology only recently joined the sphere of ecology, emerging from the medical sciences."But you can't overlook parasite interactions once you know about them," said Morton. "If you're ignoring half of the interactions in the system, you don't really know what's going on in that system."Previous work led by her mentors, Armand Kuris and Kevin Lafferty in the Department of Ecology, Evolution, and Marine Biology, found that parasites were common in estuarine food webs. But Morton wanted to tackle a more diverse ecosystem. Given the body of research conducted on California's kelp forests, she thought it would be easy enough to simply add parasites and small, free-living invertebrates to an existing network. But she quickly realized that previous food webs compiled for the kelp forest were too coarse to build on. They focused on big fish eating little fish, but gave less attention to mammals, birds and invertebrates. She'd need to start from scratch.First Morton compiled a list of species that call the kelp forest home. She and her co-authors used basically every credible source they could find. They pored over literature reviews and got data from long-term research projects, like the Santa Barbara Coastal Long Term Ecological Research Program and the Channel Islands National Park Kelp Forest Monitoring program. She also sought out fellow divers, and when that wasn't enough, Morton and her team conducted their own field sampling.Morton especially acknowledged the help she received from undergraduate student volunteers and experts throughout the process, including Milton Love, Bob Miller, Christoph Pierre, Christian Orsini and Clint Nelson at UC Santa Barbara; Mark Carr at UC Santa Cruz; Ralph Appy at Cabrillo Marine Aquarium; and David Kushner at Channel Islands National Park.The authors' next task was discerning all the interactions, which fell primarily into three sorts: predator-prey, parasite-host and predator-parasite. Morton's general rule was that every animal had to eat something, and every node should have at least one connection.It soon became clear that adults and juveniles often have different roles in food webs, requiring more detail than other food webs usually contain. This also was an exhaustive task that required scouring academic literature and databases, conducting field observations and dissections and talking with expert researchers.By combining information on predator-prey and parasite-host relationships, Morton was able to infer some relationships based strictly on logical reasoning. For example, this helped to determine whether an ingested parasite was likely to die or infect the predator that ate its host.Each node on the food web -- corresponding to a particular species or life stage -- had a reference in its entry. In fact, Morton made sure that the entire web was replete with metadata. "We don't want food webs to be just these black boxes where you don't know how they were put together, so you don't know how to use them appropriately," she said.She was particularly attentive to uncertainty, and estimated her confidence for each of the tens of thousands of putative relationships. For instance, certain parasites may turn up in only one or two specimens simply because they are rare, rather than due to any specialization. Unobserved but real interactions between hosts and parasites create a false negative in the food web.Morton, therefore, estimated the probability of false-negative links for every potential host-parasite interaction. If an absent interaction had more than a 50% change of a false negative, then she assigned it as a link in the network. She also removed parasite species that were especially prone to false negatives, to reduce overall error.She also included an estimate of her confidence for each of the tens of thousands of putative relationships.A major challenge Morton faced was simply knowing when the project was done. There are few sharp divides in the ocean; ecosystems are incredibly interconnected, and many species that live in the kelp forest also inhabit other ecosystems in Southern California. This project could have crept its way to becoming an account of the entire eastern Pacific.To keep it from ballooning, Morton limited the study to the rocky reef in the depth range of giant kelp. She also made no attempt to include viruses and bacteria, nor did she specify the many phytoplankton species. Eventually the food web reached a point where additions did not change the overall structure of the network, indicating that the web was converging toward a complete account.Morton's years of work yielded a comprehensive food web comprising 492 free-living species and 450 parasites. Accounting for specific life stages brings the total nodes to 1,098, with 21,956 links between them."This is the first food web for a really structurally complex marine ecosystem, that's really dynamic and open," Morton said. She was amazed by the extent to which the network expanded after accounting for often overlooked groups of organisms. Including small, free-living invertebrates doubled the network size. Adding parasite interactions doubled it again.The results highlight something she suspected all along: "Whether or not you decide to build a food web (which I would not recommend)," she joked, "you could still think about the parasites that might be participating in the system. If you're missing half of the interactions you['re probably missing a huge part of the picture."Parasites were even more prevalent in the kelp forest food web than in the estuarine food webs that inspired her project. Although a parasite-filled food web might sound unhealthy, according to Morton, it is actually a good sign because parasites often need complex food chains to complete their lifecycles. "Finding a lot of parasites indicates that there are intact trophic structures and high species diversity," she said.The parasites are only present because the kelp forest provides so many opportunities for them. Kelp forests are well known biodiversity hotspots, particularly those in the Santa Barbara Channel, which lie at the confluence of the cold-water communities north of Point Conception and the warm-water communities of Southern and Baja California."This new look at kelp forest food webs puts fishes in the back seat," said co-author Kevin Lafferty, Morton's advisor at the Marine Science Institute. "Most of the action is with the invertebrates. And most of those invertebrates were parasites."Morton was surprised to find a large number of parasites that use birds and mammals as their final hosts. This suggests that birds and mammals have a larger presence in the kelp forest ecosystem than she expected.As for next steps, Morton has already set to work comparing her kelp forest food web to the few other intertidal and lake food webs in the literature that include parasites. She also plans to study how the kelp forest food web might change as the ocean warms. But the main point of publishing her data, she said, was to inform conservation efforts and resource management in kelp forest ecosystems.When studying ecosystems, there's often a big cloud of unknowns that lead to a lot of variability in the data. "My hope in doing this was to provide people with the resources to get a more mechanistic understanding of what they're seeing," Morton said, "because now they basically have a map of all the things that possibly could be happening in this ecosystem."
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Biology
| 2,021 |
April 15, 2021
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https://www.sciencedaily.com/releases/2021/04/210415141829.htm
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Bearded dragon embryos become females either through sex chromosomes or hot temperatures
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Bearded dragon embryos can use two different sets of genes to become a female lizard -- one activated by the sex chromosomes and the other activated by high temperatures during development. Sarah Whiteley and Arthur Georges of the University of Canberra report these new findings April 15th in the journal
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In many reptiles and fish, the sex of a developing embryo depends on the temperature of the surrounding environment. This phenomenon, called temperature-dependent sex determination, was discovered in the 1960s, but the molecular details of how it happens have eluded scientists despite half a century of intensive research. Researchers investigated the biochemical pathways required to make a female in the new study by studying this phenomenon in bearded dragons. Male bearded dragons have ZZ sex chromosomes, while females have ZW sex chromosomes. However, hot temperatures can override ZZ sex chromosomes, causing a male lizard to develop as a female.Whiteley and Georges compared which genes were turned on during development in bearded dragons with ZW chromosomes compared to ZZ animals exposed to high temperatures. They discovered that initially, different sets of developmental genes are active in the two types of females, but that ultimately the pathways converge to produce ovaries. The findings support recent research proposing that ancient signaling processes inside the cell help translate high temperatures into a sex reversal.The new study is the first to show that there are two ways to produce an ovary in the bearded dragon and bringing us closer to understanding how temperature determines sex. The study also identifies several candidate genes potentially involved in temperature-dependent sex determination. These findings lay the foundation for future experiments to tease out each gene's role in sensing temperature and directing sexual development.Whiteley adds, ""The most exciting component of this work is the discovery that the mechanism involves ubiquitous and highly conserved cellular processes, signaling pathways and epigenetic processes of chromatin modification. This new knowledge is bringing us closer to understanding how temperature determines sex, so it is a very exciting time to be in biology."
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Biology
| 2,021 |
April 15, 2021
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https://www.sciencedaily.com/releases/2021/04/210415114132.htm
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Study of marten genomes suggests coastal safe havens aided peopling of Americas
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How did the first humans migrate to populate North America? It's one of the great scientific puzzles of our day, especially because forbidding glaciers covered most of Canada, Alaska and Pacific Northwest during the Last Glacial Maximum (LGM). These glaciers limited human movements between northern ice-free areas, like the Beringia Land Bridge, and southern ice-free areas, like the continental United States.
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Now, research from the University of Kansas into the whole genomes of the American pine marten and Pacific pine marten -- weasel-like mammals that range today from Alaska to the American Southwest -- could shed light on how the first humans populated the Americas.The study used genomic sequence data to determine biogeographic, colonization and demographic histories of martens in North America, and it found that a coastal population of Pacific martens may have inhabited forested refuges along the ice-bound coastline of Alaska and Canada during the LGM. According to the research, published in the "The 'Coastal Refugium Hypothesis' is the idea that there were pockets of ice-free land along the coast of northwestern North America, and also communities of organisms that lived in these areas," said lead author Jocelyn Colella, assistant professor of ecology & evolutionary biology at KU and assistant curator of mammals with the KU Biodiversity Institute and Natural History Museum. "Carnivores, like martens, take a lot of resources to sustain. They need something to eat -- and martens in particular are considered 'forest-associated,' meaning they also need complex forests in order to complete their life cycles. Evidence of martens in this area suggests there may have also been forests, not just tundra and ice, which is different than what we previously thought."These forested pockets along the coastline where the coastal Pacific marten dwelled also could have served as sanctuaries for humans where they may have hunted, foraged and found access to shelter and supplies along their icy journey."Presumably, migrating humans along the coast would have been seafaring -- probably using some type of boat," Colella said. "But humans have to eat, too, and so the next question is, were we good enough fishermen to live solely off of the sea, or were there other resources? It looks like there may have been substantially more resources in these areas: plants, small mammals, maybe we even ate martens. Who knows?"Colella and her colleagues first sequenced the marten's whole genome and then performed analyses with powerful computers to determine when the different species diverged (or split off from a common ancestor and became distinct species) and infer the historical distributions of martens along the complex Northwestern Coast."You can compare genomes from different species to see how their evolutionary histories differ, and we do this a lot with phylogenies -- a phylogeny is kind of like a family tree, it shows the evolutionary relationships between different organisms," Colella said. "There appear to be two different lineages of Pacific marten -- one coastal lineage found on three islands along the North Pacific coast and then another continental lineage located in areas of the American Southwest, but also in the Pacific Northwest and California mountain ranges. We found a deep history for coastal Pacific martens along the North Pacific Coast -- our dates show about 100,000 years, which means they've been there since the Last Glacial Maximum when ice covered most of North America. At that time, these martens may have been isolated off the coast in ice-free areas -- or 'glacial refugia' -- available to terrestrial animals, meaning there was also terrestrial area available for humans migrating along the coast."While marten genomes show them inhabiting these coastal refuges during the LGM, so far the fossil record hasn't confirm this idea, according to Colella. However, the KU researcher believes some fossils may need to be reexamined."Scientists haven't found a lot of marten fossils from this time period along the coast," she said. "But, a lot of the fossils they have found are incomplete, sometimes just teeth, and it's hard to identify species by just their teeth. Interestingly, coastal Pacific martens are found only on islands where their semi-aquatic relative, mink, are not found -- it's possible that coastal Pacific martens have filled that niche instead. In fact, my previous work on marten morphology found that coastal martens are larger than martens on the mainland, so it's possible that some fossils may have been identified as mink but are actually be martens."Although the coastal Pacific marten isn't today classified as a distinct species, Colella believes the research indicates it should be."This is the first time we've detected the coastal Pacific marten, and it's really different from mainland Pacific marten," she said. "The problem is we don't yet have enough samples to say it's a distinct species. The next step is to compare the morphology of the two groups and increase our genetic sample sizes, so we can test the species status of the insular Pacific marten. Pacific martens have this really weird geographic range -- with the coastal group found on just a couple islands off the coast of Southeast Alaska and the mainland group found in Pacific Northwest and California forests, but also on mountaintops in New Mexico and Utah. Alaskan islands are very different from the Pacific Northwest, which is very different from the Southwest. Based on their distribution today, it seems that the Pacific martens were historically more widespread. It's kind of amazing, as we start to look at the genetics of some of these animals, just how little we know."
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Biology
| 2,021 |
April 15, 2021
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https://www.sciencedaily.com/releases/2021/04/210415114120.htm
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The architect of genome folding
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The DNA molecule is not naked in the nucleus. Instead, it is folded in a very organized way by the help of different proteins to establish a unique spatial organization of the genetic information. This 3D spatial genome organization is fundamental for the regulation of our genes and has to be established de novo by each individual during early embryogenesis. Researchers at the MPI of Immunobiology and Epigenetics in Freiburg in collaboration with colleagues from the Friedrich Mischer Institute in Basel now reveal a yet unknown and critical role of the protein HP1a in the 3D genome re-organization after fertilisation. The study published in the scientific journal
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The information of the human genome is encoded by approximately 3 billion DNA base pairs and packaged into 23 pairs of chromosomes. If all chromosomes could be disentangled and linearly aligned, they would be a thin thread of about 2 meters. The DNA molecule must be extensively packaged to fit inside the nucleus, the size of which is in the micrometer range. "The DNA thread is not simply stuffed into the cell nucleus. Instead, it is folded in a very organized way to ensure that different parts of the genome, sometimes several thousand base pairs away from each other, can intercommunicate for appropriate gene functions," says Nicola Iovino, group leader at the MPI of Immunobiology and Epigenetics in Freiburg.Part of this packaging are histone proteins acting as spools around which DNA is winded and thereby compacted. This complex of DNA and proteins is called chromatin. As such, chromatin is the fundament for further packaging of the genetic material into chromosomes whose structure is mostly known for its characteristic cross shape. The chromosomes themself occupy distinct positions within the nucleus, known as chromosome territories, that also enable efficient packaging and organization of the genome.The full machinery contributing to this 3D chromatin organization remains unexplored. Now the lab of Nicola Iovino at the MPI in Freiburg, in collaboration with Luca Giorgetti from the Friedrich Miescher Institute in Basel (Switzerland), was able to show the fundamental role of the heterochromatin protein 1a (HP1a) in the reorganization of the 3D chromatin structure after fertilization. By combining powerful Drosophila genetics with 3D genome modeling, they discovered that HP1a is required to establish a proper chromatin 3D structure at multiple hierarchical levels during early embryonic development.The degree of packaging as well as the corresponding gene activity is influenced by epigenetic modifications. These are small chemical groups that are installed on the histones. "Proteins that carry out these epigenetic modifications can be thought of as being either writers, erasers or reader of the given epigenetic modification. We discovered that the reader protein HP1a is required to establish chromatin structure during early embryonic development in Drosophila," says Fides Zenk, first-author of the study.Early embryonic development is a particularly interesting time window to study the processes governing the organization of chromatin. At fertilization, two highly specialized cells -- sperm and egg -- fuse. The resulting totipotent zygote will ultimately give rise to all the different cells of the body. Interestingly most of the epigenetic modifications that shape chromatin are erased and have to be established de novo. In Drosophila, the lab of Nicola Iovino had previously shown that after fertilization chromatin undergoes major restructuring events. Thus, it is the ideal model system to study the processes underlying the establishment of chromatin structure.When the genome of the zygote is activated for the first time after fertilization, it triggers global de novo 3D chromatin reorganization including a clustering of highly compacted regions around the centromere (pericentromeric), the folding of chromosome arms and the segregation of chromosomes into active and inactive compartments. "We identified HP1a as an important epigenetic regulator necessary to maintain individual chromosome integrity but also central for establishing the global structure of the genome in the early embryo," says Nicola Iovino.These findings and data collected in Drosophila embryos have then been used by collaborators from the Friedrich Miescher Institute (FMI) lead by Luca Giorgetti to build realistic three-dimensional models of chromosomes. This is possible because chromosomes inside the cell nucleus are polymers, very large molecules composed of chains of smaller components (monomers) -- in this case consecutive DNA base pairs and the DNA-binding proteins that together constitute the chromatin fiber. Like all other polymers, be it silk, polyethylene or polyester, chromatin obeys a general set of physical laws described by a branch of physics known as 'polymer physics'. These laws can be encoded into computer programs and used to simulate the three-dimensional shape of chromosomes in the nucleus."The advantage of this approach is that it allows simulating the effects of very large numbers of mutations. This enables researchers to explore scenarios that are beyond experimental reach, such as the simultaneous depletion of many different proteins that would require years of lab work. By comparing simulations with the outcome of experiments, this approach also allows to test alternative hypotheses concerning the mechanisms that lay at the basis of experimental observations," says Luca Giorgetti, group leader at the Friedrich Miescher Institute in Basel.In this case, FMI researchers used polymer models of the entire Drosophila genome to ask the question: based on the basic laws of polymer physics, is it possible that the depletion of a single protein -- HP1 -- leads to a massive change in the associations and shape of chromosomes in the nucleus? Or are additional mechanisms needed to explain the experimental observations? "We found that removal of the protein to its binding sites in the simulations accounted for the full set of experimental results, thus providing further confirmation that HP1 plays a key role in establishing the three-dimensional structure of the genome" says Yinxiu Zhan, co-first-author of the study.
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Biology
| 2,021 |
April 15, 2021
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https://www.sciencedaily.com/releases/2021/04/210415114112.htm
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New 'time machine' technique to measure cells
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Using a new single-cell technique, WEHI researchers have uncovered a way to understand the programming behind how stem cells make particular cell types.
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The research uncovered 30 new genes that program stem cells to make the dendritic cells that kick-start the immune response.By uncovering this process, the researchers hope they will be able to find new immunotherapy treatments for cancer, and plan to expand this technique in other areas such as discovering new drug targets in tumour initiation.Led by Dr Shalin Naik, Dr Luyi Tian, Ms Sara Tomei and Mr Jaring Schreuder and published in The research team developed a new technique to link the gene expression of a single cell with what cell types it made."We invented a technique called 'SIS-seq' in order to study 'sister' cells that descended in parallel from the 'mother' stem cell," Dr Naik said."As RNA sequencing destroys the single stem cell, you are only able to measure the genetic contents of the cell but lose the chance to know what it would have made. So, there is no way of then going back in time to find that out.""By letting a single stem cell divide only a few times, not all the way, we were able to test the sisters separately. Some were tested for what they made, and others were tested for their genetic contents.""In this way, we have been able to link the genes with the cell types that are made."Dr Naik said the findings would not have been possible without advances in technology that enabled the team to answer multiple questions simultaneously."Using a CRISPR screen, we tested 500 genes that predicted dendritic cell fate and discovered 30 new genes that actually program dendritic cells to be made," he said.Dr Naik said the breakthrough could pave the way for new drug targets to fight cancer and improve immunotherapy treatment."We've now got a list of genes to try and generate or boost human dendritic cells in a petri dish for immunotherapy," he said."And we are going to expand the use of this technology to find the genes that program the generation of each of the different human immune cell types."By examining cells at the single-cell level using this technique, researchers also intend to find the 'big bang' moment in cancer development in order to create new drug targets to fight cancer and improve immunotherapy."Using our time machine technique, we hope to be able to pinpoint which of the normal programs in tissue generation are hijacked by cancer causing genes in single cells and then use this information to find new targets for therapy," Dr Naik said.This work was made possible with funding from the National Health and Medical Research Council, the Australia Research Council, the Victorian Cancer Agency and the Victorian Government.
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Biology
| 2,021 |
April 15, 2021
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https://www.sciencedaily.com/releases/2021/04/210415090718.htm
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Study strengthens links between red meat and heart disease
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An observational study in nearly 20,000 individuals has found that greater intake of red and processed meat is associated with worse heart function. The research is presented at ESC Preventive Cardiology 2021, an online scientific congress of the European Society of Cardiology (ESC).
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"Previous studies have shown links between greater red meat consumption and increased risk of heart attacks or dying from heart disease," said study author Dr. Zahra Raisi-Estabragh of Queen Mary University of London, UK. "For the first time, we examined the relationships between meat consumption and imaging measures of heart health. This may help us to understand the mechanisms underlying the previously observed connections with cardiovascular disease."The study included 19,408 participants of the UK Biobank. The researchers examined associations of self-reported intake of red and processed meat with heart anatomy and function.Three types of heart measures were analysed. First, cardiovascular magnetic resonance (CMR) assessments of heart function used in clinical practice such as volume of the ventricles and measures of the pumping function of the ventricles. Second, novel CMR radiomics used in research to extract detailed information from heart images such as shape and texture (which indicates health of the heart muscle). Third, elasticity of the blood vessels (stretchy arteries are healthier).The analysis was adjusted for other factors that might influence the relationship including age, sex, deprivation, education, smoking, alcohol, exercise, high blood pressure, high cholesterol, diabetes, and body mass index (BMI) as a measure of obesity.The researchers found that greater intake of red and processed meat was associated with worse imaging measures of heart health, across all measures studied. Specifically, individuals with higher meat intake had smaller ventricles, poorer heart function, and stiffer arteries -- all markers of worse cardiovascular health.As a comparison, the researchers also tested the relationships between heart imaging measures and intake of oily fish, which has previously been linked with better heart health. They found that as the amount of oily fish consumption rose, heart function improved, and arteries were stretchier.Dr. Raisi-Estabragh said: "The findings support prior observations linking red and processed meat consumption with heart disease and provide unique insights into links with heart and vascular structure and function."The associations between imaging measures of heart health and meat intake were only partially explained by high blood pressure, high cholesterol, diabetes, and obesity."It has been suggested that these factors could be the reason for the observed relationship between meat and heart disease," said Dr. Raisi-Estabragh. "For example, it is possible that greater red meat intake leads to raised blood cholesterol and this in turn causes heart disease. Our study suggests that these four factors do play a role in the links between meat intake and heart health, but they are not the full story."She noted that the study did not look into alternative mechanisms. But she said: "There is some evidence that red meat alters the gut microbiome, leading to higher levels of certain metabolites in the blood, which have in turn been linked to greater risk of heart disease."Dr. Raisi-Estabragh said: "This was an observational study and causation cannot be assumed. But in general, it seems sensible to limit intake of red and processed meat for heart health reasons."
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Biology
| 2,021 |
April 14, 2021
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https://www.sciencedaily.com/releases/2021/04/210414202436.htm
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Lipid research may help solve COVID-19 vaccine challenges
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New research by University of Texas at Dallas scientists could help solve a major challenge in the deployment of certain COVID-19 vaccines worldwide -- the need for the vaccines to be kept at below-freezing temperatures during transport and storage.
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In a study published online April 13 in The Moderna and Pfizer/BioNTech COVID-19 vaccines use lipid nanoparticles -- basically spheres of fat molecules -- to protect and deliver the messenger RNA that generates a vaccine recipient's immune response to the SARS-CoV-2 virus."The expense of keeping these vaccines very cold from the time they're made to the time they're delivered is a challenge that needs to be addressed, especially because many countries don't have sufficient infrastructure to maintain this kind of cold chain," said Dr. Jeremiah Gassensmith, associate professor of chemistry and biochemistry and of bioengineering at UT Dallas and a corresponding author of the study. "Although we did not include in this work the specific lipid nanoparticles used in current COVID-19 vaccines, our findings are a step toward stabilizing a lipid nanoparticle in a way that's never been done before, so far as we know."The idea for the research project began during a coffee-break discussion between Gassensmith and Dr. Gabriele Meloni, a corresponding co-author of the study and assistant professor of chemistry and biochemistry in the School of Natural Sciences and Mathematics at UT Dallas.Gassensmith's area of expertise is biomaterials and metal-organic frameworks, while Meloni's research focus is transmembrane transporter proteins. These proteins reside within cell membranes and are crucial for moving a variety of small molecules, including ions and trace metals, in and out of cells for several purposes."Membrane proteins sit in a cell membrane, which is a lipid bilayer," Meloni said. "To study their structure and biophysical and biochemical properties, we must extract these proteins from the membrane using detergents and then reconstitute them back into an artificial membrane -- a proteoliposome -- that mimics the proteins' natural environment."Lipid nanoparticles and liposomes are similar in structure, and neither are thermodynamically stable at room temperature, Gassensmith said. The lipid structures can fuse or aggregate, exposing any embedded membrane proteins or cargo to degradation."One of the challenges in my field of research is that both membrane proteins and lipid bilayers are very delicate and intrinsically metastable, and we're trying to combine them in order to understand how these proteins function," Meloni said. "We have to handle them carefully and prepare them fresh each time. They cannot be stored for long periods and are not easily shipped to colleagues in other labs."The researchers joined forces to develop a methodology to stabilize this kind of lipid system and demonstrated their results using transmembrane proteins from Meloni's lab as a case study.They mixed liposomes -- some with embedded proteins, some without -- with a combination of two inexpensive chemicals, zinc acetate and methylimidazole, in a buffer solution. In about a minute, a crystal matrix began to form around individual liposomes."We think that the lipids interact with the zinc just strongly enough to form an initial zinc-methylimidazole structure that then grows around the lipid sphere and completely envelops it, like an exoskeleton," Gassensmith said. "It's analogous to biomineralization, which is how certain animals form shells. We sort of co-opted nature in creating this totally fake shell, where the biomacromolecules -- the lipids and proteins -- catalyze the growth of this exoskeleton."The ability of biomimetic shells to form around biological molecules is not new, Gassensmith said, but the process hasn't worked well with lipids or liposomes because the metal salts that comprise the shell material suck water out of the liposomes by osmosis and cause them to explode."One of the keys to this research was identifying the buffer solution in which everything resides," Gassensmith said.Three graduate students collaborated on the project to develop the unique buffer medium that allows the reaction to occur."The buffer medium maintains the ionic strength of the solution and keeps the pH stable so that when you add a huge amount of metal salts, it doesn't osmotically shock the system," said Fabián Castro BS'18, a chemistry doctoral student in Gassensmith's lab and a lead author of the study.Castro and co-lead authors Sameera Abeyrathna and Nisansala Abeyrathna, chemistry doctoral students (and siblings) in Meloni's lab, worked together to develop the buffer formulation.Once the biomolecules have grown a shell, they are locked in, and the lipids remain stable. While the exoskeleton is very stable, it has a fortuitous Achilles' heel."The shell will dissolve if it encounters something that is attracted to zinc," Gassensmith said. "So, to release and reconstitute the liposomes, we used a zinc chelating factor called EDTA (ethylenediaminetetraacetic acid), which is a common, inexpensive food additive and medicine used to treat lead poisoning."In addition to the laboratory experiments, in another proof-of concept exercise, Gassensmith mailed through the U.S. Postal Service a sample of the stabilized lipid particles to his mother in Rhode Island. She shipped them back to Texas, but because the COVID-19 pandemic forced the shutdown of most UT Dallas research labs in 2020, the samples sat untouched for about two months until the graduate students returned to campus to examine them. Although the informal experiment lasted much longer than the researchers had expected, the samples survived and functioned "just fine," Gassensmith said."This project required two different types of expertise -- my group's expertise in membrane transport proteins and Dr. Gassensmith's long track record working with metal-organic frameworks," Meloni said. "Our success clearly demonstrates how such collaborative research can bring about novel and useful results."Other UT Dallas authors of the study in the Department of Chemistry and Biochemistry include Dr. Ron Smaldone, associate professor; doctoral students Yalini Wijesundara, Olivia Brohlin, Alejandra Durand Silva and Shashini Diwakara; and Michael Luzuriaga PhD'20. Researchers from Graz University of Technology in Austria also contributed to the work.The research was funded in part by the National Science Foundation, National Institute of General Medical Sciences of the National Institutes of Health (R35GM128704), The Welch Foundation, the U.S. Army Combat Capabilities Development Command Army Research Laboratory, the UT Dallas Office of Research's Seed Program for Interdisciplinary Research, the Mexican National Council of Science and Technology, the European Union's Horizon 2020 Program, and the Central European Research Infrastructure Consortium.
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Biology
| 2,021 |
April 14, 2021
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https://www.sciencedaily.com/releases/2021/04/210414155018.htm
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RNA holds the reins in bacteria: Researchers observe RNA controlling protein synthesis
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To better understand how RNA in bacteria gives rise to protein -- and along the way, target these processes in the design of new antibiotics -- researchers are turning their attention to the unique way this process happens in bacteria.
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In eukaryotic cells, transcription (the process by which information in a DNA strand is copied into messenger RNA) and translation (the process by which a protein is synthesized by the ribosome from the mRNA) are two successive steps. In bacteria, they occur simultaneously: As the RNA is being synthesized by RNA polymerase, the ribosome comes in to make the proteins.This synchronicity allows for so-called "transcription-translation coupling," wherein the first ribosome can immediately follow and couple with the transcribing RNA polymerase. It is a new area of research that promises to bring insights into processes unique to bacteria that could be targeted with great specificity in the design of antibiotics.Now, University of Michigan researchers have directly observed previously hidden RNA regulatory mechanisms within such couplings. The results, spearheaded jointly by postdoctoral fellows Surajit Chatterjee and Adrien Chauvier of the U-M Department of Chemistry and the U-M Center for RNA Biomedicine, are published in the The new results promise to have important implications for the future design of antibiotics that could target the coupling mechanism instead of targeting the transcription or translation processes separately."With RNA emerging as a major factor in our daily lives -- note the SARS-CoV-2 viral genome and the mRNA vaccines to combat its replication -- we are at a crossroads where the interplay between RNAs and proteins in their ubiquitous complexes becomes an attractive prospective target for the medicines of the future, including to fight drug-resistant bacterial strains," said senior author Nils Walter, professor of chemistry.In particular, the researchers found that modulating the translation of a nascent mRNA affects the downstream synthesis of the mRNA itself. When translation is stopped or delayed, the transcription rate is slowed down to avoid overproduction of RNA that would only be degraded in the cell.To conveniently modulate translation efficiency, the researchers exploited the features of a structured RNA, called a translational riboswitch, embedded near the start of an mRNA of the anthrax bacterium Bacillus anthracis. This RNA changes structure when binding a specific small ligand to reduce translation in response to environmental cues.The current study shows that the riboswitch -- generally thought to only affect translation -- can in fact regulate both translation and transcription by exploiting their coupling. By using the riboswitch ligand to slow translation initiation, or inhibitors to delay or stop translation, the scientists observed effects also on the speed of RNA polymerase.The authors expanded a combination of single-molecule fluorescence microscopy techniques to monitor the dynamic interactions of the transcription and translation machineries during different stages of coupling. They also developed a unique strategy to directly watch transcription-translation coupling in real-time, detecting that the small riboswitch controls the much larger transcription and translation machineries. The work thus surpasses and brings to life previous structure-based studies that provided only snapshots of the already coupled machineries.The researchers say their results establish important foundations for future RNA research. They explain that the question of how other cellular factors contribute to establishing and maintaining transcription-translation coupling is still enigmatic, raising questions that remain to be investigated. This work could also bring insights into similar biological processes in other pathogenic organisms."It is fascinating to see how the huge transcription and translation machineries are held by a tiny mRNA for a controlled gene expression process in bacteria," said Chatterjee.Chatterjee and Chauvier are senior postdoctoral fellows in the Walter lab within the U-M Department of Chemistry. They are interested in translational and transcriptional riboswitches, respectively. In this study, they combined their knowledge and interest for each aspect of the coupling."To me, it's not so much about bacteria, but rather about the biological processes of translation and transcription," Chauvier said. "Genetic regulation is a timely coordinated process and synchronization is the key for the bacteria to adapt to external threats."Chatterjee, Chauvier and Walter were joined in the effort by graduate student Shiba Dandpat and collaborator Professor Irina Artsimovitch of Ohio State University.
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Biology
| 2,021 |
April 14, 2021
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https://www.sciencedaily.com/releases/2021/04/210414154933.htm
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Dietary cocoa improves health of obese mice; likely has implications for humans
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Supplementation of cocoa powder in the diet of high-fat-fed mice with liver disease markedly reduced the severity of their condition, according to a new study by Penn State researchers, who suggest the results have implications for people.
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Cocoa powder, a popular food ingredient most commonly used in the production of chocolate, is rich in fiber, iron and phytochemicals reported to have positive health benefits, including antioxidant polyphenols and methylxanthines, noted study leader Joshua Lambert, professor of food science in the College of Agricultural Sciences."While it is typically considered an indulgence food because of its high sugar and fat content, epidemiological and human-intervention studies have suggested that chocolate consumption is associated with reduced risk of cardio-metabolic diseases including stroke, coronary heart disease and Type 2 diabetes," Lambert said. "So, it made sense to investigate whether cocoa consumption had an effect on non-alcohol-related fatty liver disease, which is commonly associated with human obesity."This study has several strengths, Lambert explained. It used a commercially available cocoa product at a "physiologically achievable dose" -- meaning its equivalent could be duplicated by humans. "Doing the calculations, for people it works out to about 10 tablespoons of cocoa powder a day," he said. "Or, if you follow the directions on the Hershey's box of cocoa powder, that's about five cups of hot cocoa a day."The high-fat-fed mouse is a well-established, diet-induced model of obesity, Lambert added. By waiting until mice were already obese before beginning cocoa treatment, researchers were able to test the protective effects of cocoa in a model that better simulates the current public health situation related to non-alcohol-related fatty liver disease.That's important, Lambert pointed out, because a significant proportion of the world's population has preexisting obesity and non-alcohol-related fatty liver disease. "Given the high proportion of people in the United States and other parts of the world with obesity, there is a need to develop potentially effective dietary interventions rather than just preventive agents," he said.For this study, researchers examined changes in fatty liver disease, markers of oxidative stress, antioxidant response and cell damage in high-fat-fed obese mice treated with a diet supplemented with 80 mg cocoa powder per gram of food -- roughly a pinch per quarter teaspoon -- for eight weeks.In findings recently published in the The mechanisms by which cocoa imparts health benefits are not well understood, but previous studies in Lambert's lab showed that extracts from cocoa and some of the chemicals in cocoa powder can inhibit the enzymes that are responsible for digesting dietary fat and carbohydrate.The result, he proposes, is that when mice get cocoa as part of their diet, these compounds in the cocoa powder prevent the digestion of dietary fat. When it can't be absorbed, the fat passes through their digestive systems. A similar process may occur with cocoa in humans, he hypothesizes.In view of this new information about cocoa powder, Lambert is not recommending that obese people -- or anyone -- simply add five cups of hot cocoa to their daily routine and change nothing else in their diet. But he does advise, based on what he has learned in this study, to consider substituting cocoa for other foods, particularly high-calorie snack foods."This exchange is potentially beneficial, especially in combination with a healthy overall diet and increased physical activity," he said. "If you go to the gym and work out, and your reward is you go home and have a cup of cocoa, that may be something that helps get you off the couch and moving around."Also involved in the research were Mingyao Sun, Yeyi Gu and Shannon Glisan, former graduate students in the Department of Food Science.The research received technical support from the Penn State Genomics Core Facility and the Penn State Laboratory Animal Program. The National Institutes of Health, the U.S. Department of Agriculture and the Silvio and Edith Crespo Faculty Award partially funded this research. Blommer Chocolate Co., East Greenville, Pennsylvania, provided a gift of cocoa powder for the research.
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Biology
| 2,021 |
April 14, 2021
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https://www.sciencedaily.com/releases/2021/04/210414131959.htm
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Plasma device designed for consumers can quickly disinfect surfaces
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The COVID-19 pandemic has cast a harsh light on the urgent need for quick and easy techniques to sanitize and disinfect everyday high-touch objects such as doorknobs, pens, pencils, and personal protective gear worn to keep infections from spreading. Now scientists at the U.S. Department of Energy's (DOE) Princeton Plasma Physics Laboratory and the New Jersey Institute of Technology (NJIT) have demonstrated the first flexible, hand-held, device based on low-temperature plasma -- a gas that consists of atoms, molecules, and free-floating electrons and ions -- that consumers can quickly and easily use to disinfect surfaces without special training.
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Recent experiments show that the prototype, which operates at room temperature under normal atmospheric pressure, can eliminate 99.99 percent of the bacteria on surfaces, including textiles and metals in just 90 seconds. The device has shown a still-higher 99.9999 percent effectiveness when used with the antiseptic hydrogen peroxide. Scientists think it will be similarly effective against viruses. "We're testing it right now with human viruses," said PPPL physicist Sophia Gershman, first author of a paper in The positive results were welcome at PPPL, which is widening its fusion research and plasma science portfolios. "We are very excited to see plasmas used for a broader range of applications that could potentially improve human health," said Jon Menard, deputy director for research at PPPL.The flexible hand-held device, called a dielectric barrier discharge (DBD), is built like a sandwich, Gershman said. "It's a high-voltage slice of bread on cheese that is an insulator and a grounded piece of bread with holes in it," she said.The high-voltage slice of "bread" is an electrode made of copper tape. The other slice is a grounded electrode patterned with holes to let the plasma flow through. Between these slices lies the "cheese" of insulating tape. "Basically it's all flexible tape like Scotch tape or duct tape," Gershman said. "The ground electrode faces the users and makes the device safe to use."The room-temperature plasma interacts with air to produce what are called reactive oxygen and nitrogen species -- molecules and atoms of the two elements -- along with a mixture of electrons, currents, and electrical fields. The electrons and fields team up to enable the reactive species to penetrate and destroy bacteria cell walls and kill the cells.Room-temperature plasmas, which compare with the fusion plasmas PPPL studies that are many times hotter than the core of the sun, are produced by sending short pulses of high-speed electrons through gases like air, creating the plasma and leaving no time for it to heat up. Such plasmas are also far cooler than the thousand-degree plasmas that the laboratory studies to synthesize nanoparticles and conduct other research.A special feature of the device is its ability to improve the action of hydrogen peroxide, a common antiseptic cleanser. "We demonstrate faster disinfection than plasma or hydrogen peroxide alone in stable low power operation," the authors write. "Hence, plasma activation of a low concentration hydrogen peroxide solution, using a hand-held flexible DBD device results in a dramatic improvement in disinfection."Achieving these results was a novel collaboration that brought together the plasma physics expertise of PPPL and the biological know-how of a laboratory at NJIT. "While we usually are a neurobiology lab that studies locomotion, we were eager to collaborate with PPPL on a project related to COVID-19," said Gal Haspel, a professor of biological sciences at NJIT and a co-author of the paper.Performing the plasma disinfection tests was co-author Maria Benem Harreguy, a graduate student in biological sciences at NJIT, with assistance from Gershman. "She did all the experiments and without her we wouldn't have this study," Gershman said.The idea for this research began "as soon as we got into the COVID lockdown last March," said PPPL physicist and co-author Yevgeny Raitses, who directs the Princeton Collaborative Temperature Plasma Research Facility (PCRF) -- a joint venture of PPPL and Princeton University supported by the DOE Office of Science (FES) that provided resources for this work through a user project. "We at PCRF were thinking of how to help in fighting against COVID through our low-temperature plasma research, and it's been exciting for us to continue this collaboration," he said.Raitses guided the PPPL side of the project, which included setting up the DBD based on a printed surface design and characterizing the plasma discharge in this device, and oversaw the ongoing collaboration with NJIT. Going forward, he said, "we are working to get access to a facility in which we will be able to apply the DBD and other relevant devices against the SARS CoV-2 virus" that causes COVID-19. "Also under way is research with immunologists and virologists at Princeton University and Rutgers University to expand the applicability of developed plasma devices to a broader range of viruses."
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Biology
| 2,021 |
April 14, 2021
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https://www.sciencedaily.com/releases/2021/04/210414131945.htm
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Shape-shifting Ebola virus protein exploits human RNA to change shape
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The human genome contains the instructions to make tens of thousands of proteins. Each protein folds into a precise shape -- and biologists are taught that defined shape dictates the protein's destined function. Tens of thousands of singular shapes drive the tens of thousands of needed functions.
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In a new "We're all taught that proteins have 'a' structure," says study co-leader Erica Ollmann Saphire, Ph.D., professor at La Jolla Institute for Immunology (LJI) and member of the LJI Center for Infectious Disease and Vaccine Research. "Ebola virus's VP40 protein, however, changes itself into different structures at different times, depending on the function needed."VP40 is the protein that gives Ebola virus its distinctive string-like shape. Saphire's previous studies showed that VP40 can take on a two-molecule, butterfly-shaped "dimer" or an eight-molecule, wreath-like "octamer" form.There are dramatic rearrangements of the protein as it transforms from one to the other. The dimer is what physically constructs new viruses that emerge and release from infected cells. The octamer functions only inside the infected cell, in a controlling role, directing other steps of the viral life cycle.The new study shows exactly what triggers these structural changes. The researchers found that VP40 senses and relies on particular human mRNA to make the transformation from the dimer to octamer.Saphire worked with study co-corresponding author Scripps Research Professor Kristian Andersen, Ph.D. to deeply sequence RNAs captured and selected by VP40 inside cells. VP40 selected particular sequences, most often found in the untranslated tails of human mRNA.Saphire lab postdoctoral fellows Hal Wasserman Ph.D. and co-first author Sara Landeras Bueno, Ph.D. , worked with purified VP40 in test tubes to get a glimpse of the dimer-to-octamer transformation in action. The duo tested many combinations of RNA molecules to try to trigger the transformation and found that particular human mRNA sequences rich in bases guanine and adenine were ideal for driving the same conformational change in vitro that they saw in high-resolution structures of VP40."We were very excited and surprised to see that the RNA that triggers this change comes from the host cell and not the virus," says Landeras Bueno. "The virus is hijacking the host cell -- this is another example of a virus acting like a parasite."Saphire says the study sheds light on the fundamentals of how information is encoded in the genome. There's the genetic code, of course, but Ebola virus also controls how VP40 is deployed during different stages of its life cycle. "It has an additional layer of programming," Saphire says.The new study also offers further evidence that VP40 is a promising target for effective therapies. Because Ebola virus cannot spread without VP40, the virus is unlikely to acquire VP40 mutations that let it "escape" antibody therapies. This vulnerability has led the LJI team to think of VP40 as Ebola's Achilles' heel."VP40 fulfills an elaborate system of requirements for Ebola virus, so we don't expect it to change much," says Wasserman. "That means if we could attack VP40 specifically, the virus would be helpless."Wasserman says the octamer's regulatory function is still slightly mysterious. The octamer is known to be essential to the Ebola virus life cycle, but more work needs to be done to understand how this VP40 structure controls Ebola virus replication.Saphire is very interested in investigating whether other viruses -- or living organisms -- have proteins with the same "structural plasticity" as VP40. "I've always wanted to know if this kind of functionality is more common in biology than we think," she says.
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Biology
| 2,021 |
April 14, 2021
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https://www.sciencedaily.com/releases/2021/04/210414113547.htm
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Roadside invader: The higher the traffic, the easier the invasive common ragweed disperses
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Common ragweed is an annual plant native to parts of the United States and southern Canada. It's an invasive species that has spread to Europe. An important agricultural weed, this plant is particularly well-adapted to living at roadsides, and there are several theories why.
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Its rapid expansion in Europe can't be explained by its natural dispersal rate, which is limited to distances of around 1 meter. Rather, there are other factors in play, human-mediated, that support its invasion success -- along roads, for example, it spreads mainly thanks to agricultural machineries, soil movements, roadside maintenance and road traffic.Studying common ragweed's distribution patterns is important, because its allergenic pollen affects human health, mainly in southeast Central Europe, Italy and France. Finding out where it thrives, and why, can help with the management and control of its populations.This is why scientists Andreas Lemke, Sascha Buchholz, Ingo Kowarik and Moritz von der Lippe of the Technical University of Berlin and Uwe Starfinger of the Julius Kühn Institute set out to explore the drivers of roadside invasions by common ragweed. Mapping 300 km of roadsides in a known ragweed hotspot in Germany's state of Brandenburg, they recorded plant densities at roadsides along different types of road corridors and subject to different intensities of traffic over a period of five years. They then explored the effect of traffic density and habitat type, and their interactions, on the dynamics of these populations. Their research is published in the open-access, peer-reviewed journal Surprisingly, high-traffic road cells displayed a consistently high population growth rate even in shaded and less disturbed road sections -- meaning that shading alone would not be enough to control ragweed invasions in these sections. Population growth proceeded even on roadsides with less suitable habitat conditions -- but only along high-traffic roads, and declined with reduced traffic intensity. This indicates that seed dispersal by vehicles and by road maintenance can compensate, at least partly, for less favorable habitat conditions. Disturbed low-traffic road cells showed constantly high population growth, highlighting the importance of disturbance events in road corridors as a driver for common ragweed invasions.These findings have practical implications for habitat and population management of ragweed invasions along road networks. Reducing the established roadside populations and their seed bank in critical parts of the road network, introducing an adjusted mowing regime and establishing a dense vegetation layer can locally weaken, suppress or eradicate roadside ragweed populations.
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Biology
| 2,021 |
April 14, 2021
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https://www.sciencedaily.com/releases/2021/04/210414100136.htm
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Superbug killer: New nanotech destroys bacteria and fungal cells
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Researchers have developed a new superbug-destroying coating that could be used on wound dressings and implants to prevent and treat potentially deadly bacterial and fungal infections.
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The material is one of the thinnest antimicrobial coatings developed to date and is effective against a broad range of drug-resistant bacteria and fungal cells, while leaving human cells unharmed.Antibiotic resistance is a major global health threat, causing at least 700,000 deaths a year. Without the development of new antibacterial therapies, the death toll could rise to 10 million people a year by 2050, equating to $US100 trillion in health care costs.While the health burden of fungal infections is less recognised, globally they kill about 1.5 million people each year and the death toll is growing. An emerging threat to hospitalised COVID-19 patients for example is the common fungus, Aspergillus, which can cause deadly secondary infections.The new coating from a team led by RMIT University in Melbourne, Australia, is based on an ultra-thin 2D material that until now has mainly been of interest for next-generation electronics.Studies on black phosphorus (BP) have indicated it has some antibacterial and antifungal properties, but the material has never been methodically examined for potential clinical use.The new research, published in the American Chemical Society's journal Applied Materials & Interfaces, reveals that BP is effective at killing microbes when spread in nanothin layers on surfaces like titanium and cotton, used to make implants and wound dressings.Co-lead researcher Dr Aaron Elbourne said finding one material that could prevent both bacterial and fungal infections was a significant advance."These pathogens are responsible for massive health burdens and as drug-resistance continues to grow, our ability to treat these infections becomes increasingly difficult," Elbourne, a Postdoctoral Fellow in the School of Science at RMIT, said."We need smart new weapons for the war on superbugs, which don't contribute to the problem of antimicrobial resistance."Our nanothin coating is a dual bug killer that works by tearing bacteria and fungal cells apart, something microbes will struggle to adapt to. It would take millions of years to naturally evolve new defences to such a lethal physical attack."While we need further research to be able to apply this technology in clinical settings, it's an exciting new direction in the search for more effective ways to tackle this serious health challenge."Co-lead researcher Associate Professor Sumeet Walia, from RMIT's School of Engineering, has previously led groundbreaking studies using BP for artificial intelligence technology and brain-mimicking electronics."BP breaks down in the presence of oxygen, which is normally a huge problem for electronics and something we had to overcome with painstaking precision engineering to develop our technologies," Walia said."But it turns out materials that degrade easily with oxygen can be ideal for killing microbes -- it's exactly what the scientists working on antimicrobial technologies were looking for."So our problem was their solution."As BP breaks down, it oxidises the surface of bacteria and fungal cells. This process, known as cellular oxidisation, ultimately works to rip them apart.In the new study, first author and PhD researcher Zo Shaw tested the effectiveness of nanothin layers of BP against five common bacteria strains, including E. coli and drug-resistant MRSA, as well as five types of fungus, including Candida auris.In just two hours, up to 99% of bacterial and fungal cells were destroyed.Importantly, the BP also began to self-degrade in that time and was entirely disintegrated within 24 hours -- an important feature that shows the material would not accumulate in the body.The laboratory study identified the optimum levels of BP that have a deadly antimicrobial effect while leaving human cells healthy and whole.The researchers have now begun experimenting with different formulations to test the efficacy on a range of medically-relevant surfaces.The team is keen to collaborate with potential industry partners to further develop the technology, for which a provisional patent application has been filed.
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Biology
| 2,021 |
April 14, 2021
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https://www.sciencedaily.com/releases/2021/04/210413194027.htm
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Power of light and oxygen clears Alzheimer's disease protein in live mice
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A small, light-activated molecule recently tested in mice represents a new approach to eliminating clumps of amyloid protein found in the brains of Alzheimer's disease patients. If perfected in humans, the technique could be used as an alternative approach to immunotherapy and used to treat other diseases caused by similar amyloids.
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Researchers injected the molecule directly into the brains of live mice with Alzheimer's disease and then used a specialized probe to shine light into their brains for 30 minutes each day for one week. Chemical analysis of the mouse brain tissue showed that the treatment significantly reduced amyloid protein. Results from additional experiments using human brain samples donated by Alzheimer's disease patients supported the possibility of future use in humans."The importance of our study is developing this technique to target the amyloid protein to enhance clearance of it by the immune system," said Yukiko Hori, a lecturer at the University of Tokyo and co-first author of the research recently published in The small molecule that the research team developed is known as a photo-oxygenation catalyst. It appears to treat Alzheimer's disease via a two-step process.First, the catalyst destabilizes the amyloid plaques. Oxygenation, or adding oxygen atoms, can make a molecule unstable by changing the chemical bonds holding it together. Laundry detergents or other cleaners known as "oxygen bleach" use a similar chemical principle.The catalyst is designed to target the folded structure of amyloid and likely works by cross-linking specific portions called histidine residues. The catalyst is inert until it is activated with near-infrared light, so in the future, researchers imagine that the catalyst could be delivered throughout the body by injection into the bloodstream and targeted to specific areas using light.Second, the destabilized amyloid is then removed by microglia, immune cells of the brain that clear away damaged cells and debris outside healthy cells. Using mouse cells growing in a dish, researchers observed microglia engulfing oxygenated amyloid and then breaking it down in acidic compartments inside the cells."Our catalyst binds to the amyloid-specific structure, not to a unique genetic or amino acid sequence, so this same catalyst can be applied to other amyloid depositions," said Professor Taisuke Tomita, who led the project at the University of Tokyo.The American Society of Clinical Oncology estimates that each year in the U.S., 4,000 people are diagnosed with diseases caused by amyloid outside of the brain, collectively known as amyloidosis.The photo-oxygenation catalyst should be capable of removing amyloid protein, regardless of when or where it formed in the body. Although some existing Alzheimer's disease treatments can slow the formation of new amyloid plaques, eliminating existing plaques is especially important in Alzheimer's disease because amyloid begins aggregating years before symptoms appear.The research team is now working to modify the design of the catalyst so it can be activated by shining light through the skull.This research is a peer-reviewed experimental studying using mice and human tissue samples. Human temporal cortex brain samples used in this research came from the Alzheimer's Disease Core Center (ADCC) and the Center for Neurodegenerative Disease Research (CNDR) at the University of Pennsylvania in the U.S.
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Biology
| 2,021 |
April 14, 2021
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https://www.sciencedaily.com/releases/2021/04/210414132012.htm
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New method of artificially creating genetic switches for yeast
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A group of researchers from Kobe University and Chiba University has successfully developed a flexible and simple method of artificially producing genetic switches for yeast, a model eukaryotic organism. The group consisted of Researcher TOMINAGA Masahiro
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Genetic switches are gene regulatory networks that control gene expression. The researchers established a platform for creating genetic switches that could be applied to the development of sophisticated, artificially controlled yeast cells to produce large quantities of valuable compounds. These research results were published in *1 Technology Research Association of Highly Efficient Gene Design (TRAHED) researcher. *2 Ibid. Vice Director of the Kobe Center. *3 Ibid. Director of the Kobe Center.The number and type of genes that an organism possesses do not solely determine its life functions. The timing and quantity of proteins produced by a gene (i.e. gene expression) are other factors that are known to result in significant alterations. In the field of synthetic biology, recent advances have made it possible to generate many novel cell functions by artificially controlling the expression of certain genes. Genetic switches are necessary in order to control the rate and timing of gene expression. A genetic switch (Figure 1) is a regulatory system that turns the expression of a particular gene 'on' or 'off' in response to a stimulus (or inducer) from either inside or outside the cell (for example, the presence of a chemical substance). Consequently, genetic switches are an essential tool for synthetic biology, which aims to artificially design and construct cellular functions.Many genetic switches have been developed for simple, single cell organisms (prokaryotes) such as When constructing genetic switches, it is very difficult to predict where and how to alter the switches to enable gene expression to be controlled. Evolutionary molecular engineering is a useful method for determining this (Figure 2). The method involves creating a library of genetic switch variants by randomly inducing mutation (*2) in part of or the entire genetic switch, and then selecting the variants that show intended performance. Although it is easy to produce a large number of variants, the desired variants within this number must be quickly identified. An artificial process of elimination (selection) was carried out to select the cells that remained both when gene expression was 'off' and when gene expression was turned 'on' by a specific inducer. However, if the selection is too strong or too weak, it is not possible to single out the best variants. Although it is necessary to select functional genetic switch variants that are suitably robust in both 'on' and 'off' states, it is very difficult to predict how strong the selection should be beforehand.The team of researchers from Kobe University and Chiba University established a workflow system whereby they could generate selections of varying strengths in parallel by changing the type or concentration of the chemicals used for selection. After selecting a group of variants, the researchers exposed each one to an external stimulus (inducer) and analyzed the extent to which this turned gene expression on by observing the change in the level of light emitted from GFPs (green fluorescent proteins). This allowed them to determine the most appropriate selection, in other words to easily identify genetic switch variants that demonstrated a high level of performance. Using this method, the researchers successfully developed three new genetic switches that were as efficient as the best-performing switch developed for yeast up until now.By integrating these three genetic switches, the researchers produced yeast that could biosynthesize orange pigment (The selection method developed by this research group will expedite the development of a wide range of genetic switches for yeast, with various performance levels and characteristics. This will also lead to a rapid increase in the number of genes that can be controlled in parallel. Combining these new genetic switches will make it possible to artificially design cellular functions. For example, this could contribute towards the development of sophisticated, artificially regulated yeast cells for producing large quantities of useful organic compounds.
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Biology
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April 13, 2021
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https://www.sciencedaily.com/releases/2021/04/210413194030.htm
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Dueling evolutionary forces drive rapid evolution of salamander coloration
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Two opposing evolutionary forces explain the presence of the two different colors of spotted salamander egg masses at ponds in Pennsylvania, according to a new study led by a Penn State biologist. Understanding the processes that maintain biological diversity in wild populations is a central question in biology and may allow researchers to predict how species will respond to global change.
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Spotted salamanders (Ambystoma maculatum) are a widespread species that occur across the eastern United States and return to temporary ponds in the spring to reproduce. Female salamanders lay their eggs in clumps called egg masses, which are either opaque white or completely clear. Females lay the same color egg masses throughout their life, but it is unclear what causes the different coloration, or if either of these colors confers an advantage to the eggs -- for example if one color is less obvious to predators."We usually think of evolution operating over hundreds or thousands of years, but in reality, the evolutionary processes at play in a system can influence each generation of animals," said Sean Giery, Eberly Postdoctoral Research Fellow at Penn State and leader of the research team. "In this study, we resurveyed ponds that were originally studied in the early 1990s, which gave us a unique opportunity to explore the evolutionary processes that shape the frequencies of the two egg mass color types, or morphs, that we see today."Giery resurveyed a network of 31 ponds in central Pennsylvania, noting the color of salamander egg masses as well as environmental characteristics at each pond. The ponds were originally surveyed in 1990 and 1991 by then Penn State Professor of Biology Bill Dunson and his students. The new study appears April 14 in the journal The research team found that salamander population sizes and pond chemistry remained stable over the last three decades. When averaged across the region, the overall frequency of each egg color morph also remained the same -- about 70% white egg masses in both 1990 and 2020 -- but in many cases the frequency within individual ponds changed drastically."At the scale of individual ponds, it's an extremely dynamic system," said Giery. "They don't just reach one frequency and stay there. By focusing on individual ponds rather than just the region as a whole, we could tease apart what is driving these changes in population frequencies. In this case, we found two opposing evolutionary processes -- selection and drift."The researchers uncovered strong signatures of an evolutionary process called genetic drift, which can result in morph frequencies changing due to chance. In small populations, drift is more likely to have a major effect, for example with one of the morphs disappearing entirely. As expected due to drift, the researchers found that the frequencies of each morph changed more dramatically in ponds with fewer egg masses."However, none of the ponds completely shifted to one morph or the other, which suggests something else might also be going on," said Giery. "We found that ponds at the extremes in the 1990s -- with a high frequency of clear or a high frequency of white egg masses -- became less extreme, shifting toward the overall mean for the region. This supports the idea that 'balancing selection' is operating in this system."Balancing selection is a type of natural selection that can help preserve multiple traits or morphs in a population. According to Giery, one possible explanation for balancing selection in egg mass color is that the rare morph in a pond -- regardless of the actual color -- has an advantage, which would lead to the rare morph becoming more common. Another possibility is that the white morph has an advantage in some ponds while the clear morph has an advantage in others, and movement of salamanders between the ponds leads to the persistence of both morphs."Ultimately we found a tension between these two evolutionary processes, with genetic drift potentially leading to a reduction of diversity in this system, and balancing selection working to maintain it," said Giery.The researchers are currently surveying egg masses in ponds outside of Pennsylvania to explore if morph frequencies differ in other regions and whether these evolutionary processes operate in the same way over a larger scale."Although we did not see a relationship between egg mass color and environmental characteristics in this study, it's possible that environmental characteristics at a larger scale might drive an optimal frequency for each region," said Giery. "By looking at a much larger scale, we can get a better idea of whether there are regional optimums and how they are maintained. Understanding the processes that maintain biological diversity may ultimately help us predict how wild animals will adapt in our changing world."
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Biology
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April 13, 2021
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https://www.sciencedaily.com/releases/2021/04/210413170657.htm
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Unlocking richer intracellular recordings
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Behind every heartbeat and brain signal is a massive orchestra of electrical activity. While current electrophysiology observation techniques have been mostly limited to extracellular recordings, a forward-thinking group of researchers from Carnegie Mellon University and Istituto Italiano di Tecnologia has identified a flexible, low-cost, and biocompatible platform for enabling richer intracellular recordings.
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The group's unique "across the ocean" partnership started two years ago at the Bioelectronics Winter School (BioEl) with libations and a bar napkin sketch. It has evolved into research published today in A key leader in this work, Tzahi Cohen-Karni, associate professor of biomedical engineering and materials science and engineering, has studied the properties, effects, and potential applications of graphene throughout his entire career. Now, he is taking a collaborative step in a different direction, using a vertically-grown orientation of the extraordinary carbon-based material (3DFG) to access the intracellular compartment of the cell and record intracellular electrical activity.Due to its unique electrical properties, graphene stands out as a promising candidate for carbon-based biosensing devices. Recent studies have shown the successful deployment of graphene biosensors for monitoring the electrical activity of cardiomyocytes, or heart cells, outside of the cells, or in other words, extracellular recordings of action potentials. Intracellular recordings, on the other hand, have remained limited due to ineffective tools...until now."Our aim is to record the whole orchestra -- to see all the ionic currents that cross the cell membrane -- not just the subset of the orchestra shown by extracellular recordings," explains Cohen-Karni. "Adding the dynamic dimension of intracellular recordings is fundamentally important for drug screening and toxicity assay, but this is just one important aspect of our work.""The rest is the technology advancement," Cohen-Karni continues. "3DFG is cheap, flexible and an all-carbon platform; no metals involved. We can generate wafer-sized electrodes of this material to enable multi-site intracellular recordings in a matter of seconds, which is a significant enhancement from an existing tool, like a patch clamp, which requires hours of time and expertise."So, how does it work? Leveraging a technique developed by Michele Dipalo and Francesco De Angelis, researchers at Istituto Italiano di Tecnologia, an ultra-fast laser is used to access the cell membrane. By shining short pulses of laser onto the 3DFG electrode, an area of the cell membrane becomes porous in a way, allowing for electrical activity within the cell be recorded. Then, the cardiomyocytes are cultured to further investigate interactions between the cells.Interestingly, 3DFG is black and absorbs most of the light, resulting in unique optical properties. Combined with its foam-like structure and enormous exposed surface area, 3DFG has many desirable traits that are needed to make small biosensors."We have developed a smarter electrode; an electrode that allows us better access," emphasizes Cohen-Karni. "The biggest advantage from my end is that we can have access to this signal richness, to be able to look into processes of intracellular importance. Having a tool like this will revolutionize the way we can investigate effects of therapeutics on terminal organs, such as the heart."As this work moves forward, the team plans to apply its learnings in large-scale cell/tissue interfaces, to better understand tissue development and toxicity of chemical compounds (e.g. drug toxicity).
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Biology
| 2,021 |
April 13, 2021
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https://www.sciencedaily.com/releases/2021/04/210413124347.htm
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Inside the protein channel that keeps bacteria alive
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Almost all bacteria rely on the same emergency valves -- protein channels that pop open under pressure, releasing a deluge of cell contents. It is a last-ditch effort, a failsafe that prevents bacteria from exploding and dying when stretched to the limit. If we understood how those protein channels worked, antibiotic drugs could be designed to open them on demand, draining a bacterium of its nutrients by exploiting a floodgate common to many species.
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But these channels are tricky to operate in the lab. And how precisely they open and close, passing through a sub-conducting state and ending in a desensitized state under the influence of mechanical forces, remains poorly understood. Now, new research from the laboratory of Rockefeller's Thomas Walz introduces a novel method to activate and visualize these channels, making it possible to explain their function. The findings shed light on key membrane proteins in bacteria, and the same method can be used to improve our understanding of similar channels in humans."We were actually able to see the entire cycle of the protein channel passing through a series of functional stages," Walz says.Walz has long focused upon MscS, a protein embedded in bacterial membranes that opens in response to mechanical force. MscS proteins exist in a closed state while resting in a thick membrane. Scientists once suspected that, when fluid build-up causes the cell to swell and puts tension on the membrane, it stretches so thin that its proteins protrude. Thrust into an unfamiliar environment, the protein channels snap open, releasing the contents of the cell and relieving pressure until the membrane returns to its original thickness and its channels slam shut.But when Yixiao Zhang, a postdoctoral associate in the Walz group, tested this theory over five years ago, reconstituting MscS proteins into small custom-designed membrane patches, he discovered that it was impossible to prise the channel open by thinning membranes within the natural range. "We realized that membrane thinning is not how these channels open," Walz says.These custom patches, called nanodiscs, allow researchers to study proteins in an essentially native membrane environment and to visualize them with cryo-electron microscopy. Walz and Zhang resolved to push the limits of nanodisc technology, removing membrane lipids with ?-cyclodextrin, a chemical used to excise cholesterol from cell cultures. This induced tension in the membrane, and Walz and his team could observe with cryo-electron microscopy as the channel reacted accordingly -- eventually snapping closed for good, a phenomenon known as desensitization.What they observed matched computer simulations, and a new model for the function of MscS emerged. When fluid builds up inside the cell, they found, lipids are called in from all corners to help ease tension throughout the membrane. If the situation becomes dire, even lipids associated with the MscS channels flee. Without lipids keeping them closed, the channels have the legroom to pop open."We could see that, when you expose the membranes to ?-cyclodextrin, the channels open and then close again," Walz says.Walz and Zhang's new method of manipulating nanodiscs with ?-cyclodextrin will allow researchers studying dozens of similar mechanosensitive protein channels to, at long last, test their hypotheses in the lab. Many such proteins play key roles in humans, from hearing and sense of touch to the regulation of blood pressure. Of more immediate interest, however, is the prospect of exploiting protein channels that many different bacteria rely upon to survive. Novel drug targets are a particular necessity, given the rise of dangerous antibiotic resistant bacteria such as MRSA.MscS and the related bacterial protein channel MscL are "extremely interesting drug targets," Walz says. "Almost every bacterium has one of these proteins. Because these channels are so widely distributed, a drug that targets MscS or MscL could become a broad-spectrum antibiotic."
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Biology
| 2,021 |
April 13, 2021
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https://www.sciencedaily.com/releases/2021/04/210413124340.htm
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Aging signatures across diverse tissue cells in mice
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Researchers have identified molecular signatures of the aging process in mice, publishing their results today in the open-access
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Their analyses provide one of the most comprehensive characterisations of the molecular signatures of aging across diverse types of cells from different tissues in a mammal, and will aid future studies on aging and related topics.Aging leads to the decline of major organs and is the main risk factor for many diseases, including cancer, cardiovascular and neurodegenerative diseases. While previous studies have highlighted different hallmarks of the aging process, the underlying molecular and cellular mechanisms remain unclear.To gain a better understanding of these mechanisms, the Tabula Muris Consortium created the single-cell transcriptomic dataset, called Tabula Muris Senis (TMS). The TMS contains over 300,000 annotated cells from 23 tissues and organs of male and female mice. "These cells were collected from mice of diverse ages, making the data a tremendous opportunity to study the genetic basis of aging across different tissues and cell types," says first author Martin Jinye Zhang, Postdoctoral Researcher in the Department of Epidemiology, Harvard University, Boston, US.The original TMS study mainly explored the cell-centric effects of aging, aiming to characterise changes in the composition of cell types within different tissues. In the current gene-centric study, Zhang and colleagues focused on changes in gene expression that occur during the aging process across different cell types.Using the TMS data, they identified aging-dependent genes in 76 cell types from 23 tissues. They then characterised the aging behaviours of these genes that were both shared among all cell types ('globally') and specific to different tissue cells."We found that the cell-centric and gene-centric perspectives of the previous and current studies are complementary, as gene expression can change within the same cell type during aging, even if the composition of cells in the tissue does not vary over time," explains co-senior author Angela Oliveira Pisco, Associate Director of Bioinformatics at the Chan Zuckerberg Biohub, San Francisco, US. "The identification of many shared aging genes suggests that there is a coordinated global aging behaviour in mice."The team then used this coordinated activity to develop a single-cell aging score based on the global aging genes. This new high-resolution aging score revealed that different tissue-cell types in the same animal can have a different aging status, shedding light on the diverse aging process across different types of cells."Taken together, our results provide a characterisation of aging genes across a wide range of tissue-cell types in the mouse," concludes senior author James Zou, Assistant Professor of Biomedical Data Science at Stanford University, Stanford, US, and a Chan Zuckerberg Biohub Investigator. "In addition to providing new biological insights on the aging process, this work serves as a comprehensive reference for researchers working in related fields."
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Biology
| 2,021 |
April 13, 2021
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https://www.sciencedaily.com/releases/2021/04/210413114122.htm
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Molecular assembly line to design, test drug compounds streamlined
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Researchers from North Carolina State University have found a way to fine-tune the molecular assembly line that creates antibiotics via engineered biosynthesis. The work could allow scientists to improve existing antibiotics as well as design new drug candidates quickly and efficiently.
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Bacteria -- such as "We already use bacteria to make a number of drugs for us," says Edward Kalkreuter, former graduate student at NC State and lead author of a paper describing the research. "But we also want to make alterations to these compounds; for example, there's a lot of drug resistance to erythromycin. Being able to make molecules with similar activity but improved efficacy against resistance is the general goal."Picture an automobile assembly line: each stop along the line features a robot that chooses a particular piece of the car and adds it to the whole. Now substitute erythromycin for the car, and an acyltransferase (AT) -- an enzyme -- as the robot at the stations along the assembly line. Each AT "robot" will select a chemical block, or extender unit, to add to the molecule. At each station the AT robot has 430 amino acids, or residues, which help it select which extender unit to add."Different types of extender units impact the activity of the molecule," says Gavin Williams, professor of chemistry, LORD Corporation Distinguished Scholar at NC State and corresponding author of the research. "Identifying the residues that affect extender unit selection is one way to create molecules with the activity we want."The team used molecular dynamic simulations to examine AT residues and identified 10 residues that significantly affect extender unit selection. They then performed mass spectrometry and in vitro testing on AT enzymes that had these residues changed in order to confirm their activity had also changed. The results supported the computer simulation's predictions."These simulations predict what parts of the enzyme we can change by showing how the enzyme moves over time," says Kalkreuter. "Generally, people look at static, nonmoving structures of enzymes. That makes it hard to predict what they do, because enzymes aren't static in nature. Prior to this work, very few residues were thought or known to affect extender unit selection."Williams adds that manipulating residues allows for much greater precision in reprogramming the biosynthetic assembly line."Previously, researchers who wanted to change an antibiotic's structure would simply swap out the entire AT enzyme," Williams says. "That's the equivalent of removing an entire robot from the assembly line. By focusing on the residues, we're merely replacing the fingers on that arm -- like reprogramming a workstation rather than removing it. It allows for much greater precision."Using these computational simulations to figure out which residues to replace is another tool in the toolbox for researchers who use bacteria to biosynthesize drugs."
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Biology
| 2,021 |
April 13, 2021
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https://www.sciencedaily.com/releases/2021/04/210413114047.htm
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Genetic predisposition to schizophrenia may increase risk of psychosis from cannabis use
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It has been long been known that cannabis users develop psychosis more often than non-users, but what is still not fully clear is whether cannabis actually causes psychosis and, if so, who is most at risk. A new study published in
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"These results are significant because they're the first evidence we've seen that people genetically prone to psychosis might be disproportionately affected by cannabis," said lead author Dr. Michael Wainberg, Scientist the Krembil Centre for Neuroinformatics at CAMH. "And because genetic risk scoring is still in its early days, the true influence of genetics on the cannabis-psychosis relationship may be even greater than what we found here."Using data from the UK Biobank, a large-scale biomedical database containing participants' in-depth genetic and health information, the authors analyzed the relationship between genetics, cannabis use and psychotic experiences across more than 100,000 people. Each person reported their frequency of past cannabis use, and whether they had ever had various types of psychotic experiences, such as auditory or visual hallucinations. The researchers also scored each person's genetic risk for schizophrenia, by looking at which of their DNA mutations were more common among schizophrenia patients than among the general population.Overall, people who had used cannabis were 50 per cent more likely to report psychotic experiences than people who had not. However, this increase was not uniform across the study group: among the fifth of participants with the highest genetic risk scores for schizophrenia, it was 60 per cent, and among the fifth with the lowest scores, it was only 40 per cent. In other words, people genetically predisposed to schizophrenia were at disproportionately higher risk for psychotic experiences if they also had a history of cannabis use.Notably, because much less is known about the genetics of schizophrenia in non-white populations, the study's analysis was limited to self-reported white participants. "This study, while limited in scope, is an important step forward in understanding how cannabis use and genetics may interact to influence psychosis risk," added senior author Dr. Shreejoy Tripathy, Independent Scientist at the Krembil Centre for Neuroinformatics, who supervised the study. "The more we know about the connection between cannabis and psychosis, the more we can inform the public about the potential risks of using this substance. This research offers a window into a future where genetics can help empower individuals to make more informed decisions about drug use."
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Biology
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April 13, 2021
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https://www.sciencedaily.com/releases/2021/04/210413110620.htm
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Simple genetic modification aims to stop mosquitoes spreading malaria
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Altering a mosquito's gut genes to make them spread antimalarial genes to the next generation of their species shows promise as an approach to curb malaria, suggests a preliminary study published today in
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The study is the latest in a series of steps toward using CRISPR-Cas9 gene-editing technology to make changes in mosquito genes that could reduce their ability to spread malaria. If further studies support this approach, it could provide a new way to reduce illnesses and deaths caused by malaria.Growing mosquito resistance to pesticides, as well as malaria parasite resistance to antimalarial drugs, has created an urgent need for new ways to fight the disease. Gene drives are being tested as a new approach. They work by creating genetically modified mosquitoes that, when released into the environment, would spread genes that either reduce mosquito populations or make the insects less likely to spread the malaria parasite. But scientists must prove that this approach is safe and effective before releasing genetically modified mosquitoes into the wild."Gene drives are promising tools for malaria control," says first author Astrid Hoermann, Research Associate at Imperial College London, UK. "But we wanted a clear pathway for safely testing such tools in countries where the disease most commonly occurs."In the study, Hoermann and colleagues genetically modified the malaria-transmitting mosquito Anopheles gambiae. They used the CRISPR-Cas9 technology to insert a gene that encodes an antimalarial protein amidst genes that are turned on after the mosquito eats a blood meal. The team did this in a manner that allowed the whole section of DNA to also function as a gene drive that could be passed on to most of the mosquitoes' offspring. They initially inserted the gene along with a fluorescent marker to help them track it in three different spots in the DNA, and then later removed the marker, leaving only a minor genetic modification behind.Next, the team bred the mosquitoes to see if they were able to successfully reproduce and remain healthy. They also tested how well the malaria parasite developed in the mosquitoes' guts. Their experiments provide preliminary evidence that this approach to genetic modifications could create successful gene drives."These genetic modifications are passive, and could be tested in the field and undergo a stringent regulatory process to ensure they are safe and effective in blocking the parasite without raising concerns of accidental spread in the environment," explains senior author Nikolai Windbichler, Senior Lecturer at the Department of Life Sciences, Imperial College London. "However, once we combine them with other mosquitoes with an active gene drive, they turn into gene drives themselves without the need for any further changes. Our approach thus brings gene drives one step closer to being tested in the field as a malaria elimination strategy."
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Biology
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April 13, 2021
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https://www.sciencedaily.com/releases/2021/04/210413081415.htm
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Ancient ammonoids' shell designs may have aided buoyancy control
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Ammonoids, ancestors of today's octopus, squid and cuttlefish, bobbed and jetted their way through the oceans for around 340 million years beginning long before the age of the dinosaurs. If you look at the fossil shells of ammonoids over the course of that 340 million years, you'll notice something striking -- as time goes on, the wavy lines inside the shell become more and more complex, eventually becoming frilled almost like the edges of kale leaves.
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These wavy lines are called sutures, and they reflect the complexity of the edges of septa, or the walls that separated the chambers in the ammonoids' shells. Researchers previously focused on the roles of these complex structures in resisting pressure on the shell, but University of Utah researchers provide evidence for a different hypothesis. Complex sutures, they found, retained more liquid through surface tension, possibly helping the ammonoids fine-tune their buoyancy. Their results are published in Scientific Reports.Due to an unfortunate lack of living ammonoids, the researchers had to turn to another method to understand the function of shell structure: 3-D printed models."These hypotheses couldn't be tested without being able to create incredibly accurate models of these intricate features," says David Peterman, lead author of the study and a postdoctoral scholar in the Department of Geology and Geophysics. "The 3-D printed models allow the fabrication of incredibly intricate chamber walls that have details comparable to the living animals."Although ammonoids are long extinct, we can look at their distant living relative, the chambered nautilus, to understand how their shells work.If you look at a cross-section of a nautilus shell, you'll see that the shell is divided into chambers, each one separated by cup-shaped divider walls -- septa. The suture lines are the intersections of these septa with the internal shell wall. "The earliest sutures were essentially straight lines in ammonoid ancestors like the nautiloids," Peterman says. And just as the sutures became more intricate and complex over evolutionary time in ammonoids, the septa developed more complex and fractal-like edges. "Some species," he says, "had sutures so complex that there was hardly any free space where the septa meet the shell."If ammonoids developed the complex sutures and septa as a result of evolution, they must confer some survival advantage, right? Most research on ammonoids has focused on the hypothesis that the complex septa gave the shell strength. "Mechanical functional interpretations generally concern stress resistance," Peterman says, "with more complex divider walls acting as buttresses."But several studies, he says, have challenged that hypothesis. An alternative hypothesis is that the intricate surfaces of the septa could change their surface tension, allowing more water to stick and improving the refilling of the shell chambers with water. This matters because that's the mechanism the ammonoids likely used to control their buoyancy during growth, in response to weight changes, and perhaps for vertical movement.Peterman, assistant professor Kathleen Ritterbush and colleagues set out to test that hypothesis. But first they'd need some septa. The chambers of fossilized ammonoids are typically filled with lithified mud or minerals, Peterman says, necessitating another approach.Using virtual modelling, the researchers custom-designed example septal surfaces in various sizes and with varying levels of complexity. Virtual modeling, Peterman says, allowed for the fabrication of hypothetical surfaces as well. "For example," he says, "one of the most complex sutures out there, from the shell of The team added to the models a coating of micro-dispersed oxidized cellulose to help the water stick to the surface. Nautilus shells have a similar coating. "While nautilids are distant relatives of ammonoids, in some ways they serve as our best analogues for the function of ammonoid shells," Peterman says.The experimental process was relatively simple: weigh each model dry, dunk it in water, rotate it to drain the water held on by gravity, and then weigh it again to see how much water remained, held on by surface tension.But the results showed clearly that the more complex structures held more water. And the more complex folds were especially effective at holding water in larger models. The results suggest, Peterman says, that complex septal surfaces may have helped with more precise and active buoyancy control. Ritterbush adds that they may also have enabled better balance, bigger size and external shapes that favor speed.Ammonoids hit the peak of suture complexity just before their extinction, along with the dinosaurs, at the end of the Cretaceous. Only the simply-sutured nautilids survived, but there were likely other factors at play aside from suture complexity that enabled their survival.Their study lays the groundwork for this physiological function to be further explored, along with its relationship to ammonoid ecology. The development of advanced computing workflows and smart materials will eventually allow these enigmatic creatures to be "resurrected" with functioning models."While we won't be able to revive these animals like the dinosaurs in Jurassic Park," Peterman says, "computer simulations and experiments such as these are the closest we will get to bringing these ecologically significant cephalopods back to life."
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Biology
| 2,021 |
April 13, 2021
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https://www.sciencedaily.com/releases/2021/04/210413092509.htm
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A novel, quick, and easy system for genetic analysis of SARS-CoV-2
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SARS-CoV-2 is the virus responsible for the COVID-19 pandemic. We know that mutations in the genome of SARS-CoV-2 have occurred and spread, but what effect do those mutations have? Current methods for studying mutations in the SARS-CoV-2 genome are very complicated and time-consuming because coronaviruses have large genomes, but now a team from Osaka University and Hokkaido University have developed a quick, PCR-based reverse genetics system for analyzing SARS-CoV-2 mutations.
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This system uses the polymerase chain reaction (PCR) and a circular polymerase extension reaction (CPER) to reconstruct the full-length cDNA of viral genome. This process does not involve the use of bacteria, which can introduce further unwanted mutations, and takes only two weeks using simple steps to generate infectious virus particles. Previous methods took a couple of months and were very complicated procedures."This method allows us to quickly examine the biological features of mutations in the SARS-CoV-2," says lead author of the study Shiho Torii. "We can use the CPER technique to create recombinant viruses with each mutation and examine their biological features in comparison with the parental virus." The large circular genome of SARS-CoV-2 can be constructed from smaller DNA fragments that can then be made into a viable viral genome with CPER, and used to infect suitable host cells. A large amount of infectious virus particles can be recovered nine days later."We believe that our CPER method will contribute to the understanding of the mechanisms underlying propagation and pathogenesis of SARS-CoV-2, as well as help determine the biological significance of emerging mutations," explains corresponding author Yoshiharu Matsuura. "This could accelerate the development of novel therapeutics and preventative measures for COVID-19." The team also suggest that the use of the CPER method will allow researchers to insert "reporter genes" into the SARS-CoV-2 genome to "tag" genes or proteins of interest. This will enable a greater understanding of how SARS-CoV-2 infects cells and causes COVID-19, assisting with the development of therapies. The CPER method could even allow a recombinant virus that is unable to cause disease to be generated, which could be used as a safe and effective vaccine for SARS-CoV-2.Mutations are arising in the SARS-CoV-2 population all the time, as well as questions as to what those mutations do and whether they could affect the efficacy of vaccines. "Our simple and rapid method allows scientists around the globe to characterize the mutants, which is a vital step forward in our fight against the SARS-CoV-2," says Takasuke Fukuhara of the research group.
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Biology
| 2,021 |
April 12, 2021
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https://www.sciencedaily.com/releases/2021/04/210412161913.htm
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Gut epithelium muscles up against infection
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To maximise absorption of nutrients from the diet, the intestinal mucous membrane has a large surface area. However, this also makes it vulnerable to attack from aggressive gut microbes. A new study by Uppsala University researchers now shows that the surface layer of the mucosa, known as the epithelium, can rapidly contract when it recognises a bacterial attack. The results are published in the journal
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Every year, hundreds of millions of people worldwide suffer from bacterial gut infections of one kind or another, which are often hard to treat. Antibiotics can kill the normal flora of the intestine, and this environment offers many recesses where bacteria can lurk. The growing emergence of resistance, moreover, means that many types of antibiotic no longer have any effect on the bacteria.Mikael Sellin and his research group at the Science for Life Laboratory (SciLifeLab) and the Department of Medical Biochemistry and Microbiology, Uppsala University, have been studying the interplay between the intestinal mucosa and microorganisms. Their hope is that, by understanding how the mucosa distinguishes between friend and foe and modifies its behaviour accordingly, they can pave the way for better ways of treating aggressive bacterial disease in the future.Aggressive intestinal bacteria, such as Salmonella, have the ability to invade the mucosal epithelial cells and then spread further in the body. In the new study, the researchers found that a protein complex ("the inflammasome") located inside the epithelial cells recognises the invasion at once. The inflammasome sends alarm signals to other, surrounding epithelial cells, causing them to contract. This increases the packing of the epithelial cells locally in infected areas, which proved necessary to prevent the epithelium from tearing because of the damage later caused by the infection.The study was made feasible by new technology for growing intestinal tissue from both mice and humans, outside of the body. With advanced microscopy, the scientists could follow in real time how aggressive bacteria invade the intestinal mucosa, and how the mucosa responds to the attack.Besides the research group led by Mikael Sellin, several other researchers at Uppsala University, the University Hospital and international institutions contributed to the study.
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Biology
| 2,021 |
April 12, 2021
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https://www.sciencedaily.com/releases/2021/04/210412161853.htm
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Researchers engineer probiotic yeast to produce beta-carotene
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Researchers have genetically engineered a probiotic yeast to produce beta-carotene in the guts of laboratory mice. The advance demonstrates the utility of work the researchers have done to detail how a suite of genetic engineering tools can be used to modify the yeast.
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"There are clear advantages to being able to engineer probiotics so that they produce the desired molecules right where they are needed," says Nathan Crook, corresponding author of the study and an assistant professor of chemical and biomolecular engineering at North Carolina State University. "You're not just delivering drugs or nutrients; you are effectively manufacturing the drugs or nutrients on site."The study focused on a probiotic yeast called Saccharomyces boulardii. It is considered probiotic because it can survive and thrive in the gut, whereas most other yeast species either can't tolerate the heat or are broken down by stomach acid. It also can inhibit certain gut infections.Previous research had shown that it was possible to modify S. boulardii to produce a specific protein in the mouse gut. And there are many well-established tools for genetically engineering baker's yeast, S. cerevisiae -- which is used in a wide variety of biomanufacturing applications. Crook and his collaborators wanted to get a better understanding of which genetic engineering tools would work in S. boulardii.Specifically, the researchers looked at two tools that are widely used for gene editing with the CRISPR system and dozens of tools that were developed specifically for modifying S. cerevisiae."We were a little surprised to learn that most of the S. cerevisiae tools worked really well in S. boulardii," Crook says. "Honestly, we were relieved because, while they are genetically similar, the differences between the two species are what make S. boulardii so interesting, from a therapeutic perspective."Once they had established the viability of the toolkit, researchers chose to demonstrate its functionality modifying S. boulardii to produce beta-carotene. Their rationale was both prosaic and ambitious."On the one hand, beta-carotene is orange -- so we could tell how well we were doing just by looking at the colonies of yeast on a petri dish: they literally changed color," Crook says. "On a more ambitious level, we knew that beta-carotene is a major provitamin A carotenoid, which means that it can be converted into vitamin A by the body -- and we knew that vitamin A deficiency is a major public health problem in many parts of the world. So why not try to develop something that has the potential to be useful?"Researchers tested the modified S. boulardii in a mouse model and found that the yeast cells successfully created beta-carotene in the guts of mice."This is a proof of concept, so there are a lot of outstanding questions," Crook says. "How much of this beta-carotene is getting absorbed by the mice? Are these biologically relevant amounts of beta-carotene? Would it work in humans? All of those are questions we'll have to address in future work. But we're excited to see what happens. And we're excited that these tools are now publicly available for use by others in the research community."The work was done with support from the National Science Foundation, under grant CBET-1934284; and the Novo Nordisk Foundation, under grant NNF19SA0035474.
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Biology
| 2,021 |
April 12, 2021
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https://www.sciencedaily.com/releases/2021/04/210412142727.htm
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A multidimensional view of the coronavirus
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What exactly happens when the corona virus SARS-CoV-2 infects a cell? In an article published in
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When a virus enters a cell, viral and cellular protein molecules begin to interact. Both the replication of the virus and the reaction of the cells are the result of complex protein signaling cascades. A team led by Andreas Pichlmair, Professor of Immunopathology of Viral Infections at the Institute of Virology at TUM, and Matthias Mann, Head of the Department of Proteomics and Signal Transduction at the Max Planck Institute of Biochemistry, has systematically recorded how human lung cells react to individual proteins of the covid-19 pathogen SARS-CoV-2 and the SARS coronavirus, the latter of which has been known for some time.To this end, more than 1200 samples were analyzed using the state-of-the-art mass spectrometry techniques and advanced bioinformatic methods. The result is a freely accessible dataset that provides information on which cellular proteins the viral proteins bind to and the effects of these interactions on the cell. In total, 1484 interactions between viral proteins and human cellular proteins were discovered. "Had we only looked at proteins, however, we would have missed out on important information," says Andreas Pichlmair. "A database that only includes the proteome would be like a map containing just the place names but no roads or rivers. If you knew about the connections between the points on that map, you could gain much more useful information."According to Pichlmair, important counterparts to the network of traffic routes on a map are protein modifications called phosphorylation and ubiquitination. Both are processes in which other molecules are attached to proteins, thereby altering their functions. In a listing of proteins, these changes are not measured, so that there is no way of knowing whether proteins are active or inactive, for example. "Through our investigations, we systematically assign functions to the individual components of the pathogen, in addition to the cellular molecules that are switched off by the virus," explains Pichlmair. "There has been no comparable mapping for SARS-CoV-2 so far," adds Matthias Mann. "In a sense, we have taken a close look at five dimensions of the virus during an infection: its own active proteins and its effects on the host proteome, ubiquitinome, phosphoproteome and transcriptome."Among other things, the database can also serve as a tool to find new drugs. By analyzing protein interactions and modifications, vulnerability hotspots of SARS-CoV-2 can be identified. These proteins bind to particularly important partners in cells and could serve as potential starting points for therapies. For example, the scientists concluded that certain compounds would inhibit the growth of SARS-CoV-2. Among them were some whose antiviral function is known, but also some compounds which have not yet been studied for efficacy against SARS-CoV-2. Further studies are needed to determine whether they show efficacy in clinical use against Covid-19."Currently, we are working on new anti Covid-19 drug candidates, that we have been able to identify through our analyses," says Andreas Pichlmair. "We are also developing a scoring system for automated identification of hotspots. I am convinced that detailed data sets and advanced analysis methods will enable us to develop effective drugs in a more targeted manner in the future and limit side effects in advance."
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Biology
| 2,021 |
April 12, 2021
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https://www.sciencedaily.com/releases/2021/04/210412121214.htm
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How cells control the physical state of embryonic tissues
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In the earliest stage of life, animals undergo some of their most spectacular physical transformations. Once merely blobs of dividing cells, they begin to rearrange themselves into their more characteristic forms, be they fish, birds or humans. Understanding how cells act together to build tissues has been a fundamental problem in physics and biology.
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Now, UC Santa Barbara professor Otger Campàs, who also holds the Mellichamp Chair in Systems Biology and Bioengineering, and Sangwoo Kim, a postdoctoral fellow in professor Campàs lab, have approached this question, with surprising findings."When you have many cells physically interacting with each other, how does the system behave collectively? What is the physical state of the ensemble?" said Campàs.Indeed, he explained, embryonic cellular tissue is a "weird material," with each cell consuming chemical energy and using it to apply forces to its neighbors and coordinate their actions. In-vitro studies with cells in synthetic dishes provide only part of the picture, he added; by studying cells in their native environment, the living embryo, they could find out how cells control their collective state and the phase transitions that emerge from their symphony of pushes and pulls.In a paper published in "To fully understand the physical behavior of embryonic tissues, all key aspects of embryonic tissues at cellular scales should be taken into account in the model as emergent tissue properties derives from interactions at the cellular scale," said Kim, the lead author of the study. "There are numerous models to study embryonic tissues, but there is no general framework that includes those key features, hindering the holistic understanding of the physical behaviors of embryonic tissues."Embryonic tissue, according to the researchers, behaves physically somewhat like an aqueous foam, a system composed of individual pockets of air clumped together in a liquid. Think soap suds or beer froth."In the case of foam, its structure and dynamics are governed by surface tension," Kim said. Analogous forces are found where cells come into contact with each other in embryonic tissue, on both the inner faces of the cell membranes and between cells."Effective forces acting on cell-to-cell junctions are governed by cortical tension and cell-to-cell adhesion," Kim said, "so the net force at the cell-to-cell contacts can be modeled as an effective surface tension."However, unlike the more static forces between cells in typical foams, the forces between cells in embryonic tissue are dynamic."Cells in tissues do not generate static forces, but rather display dynamic pushing and pulling over time," Campàs explained. "And we find that it is actually these tension fluctuations that effectively 'melt' the tissue into a fluid state." It is this fluidity of the tissue that allows cells to reorganize and shape the tissues, he explained.The researchers put their model to the test by measuring how forces change over time in embryonic zebrafish, a popular model organism for those studying vertebrate development. Relying on a technique developed in the Campàs Lab using tiny magnetic droplets inserted between cells in embryonic zebrafish, they were able to confirm, by the way the droplet deformed, the dynamic forces behind the fluid state of the tissue.Their finding that tension fluctuations are responsible for the fluidity of tissue during development stands in contrast to the generally accepted notion that changes in adhesion between cells is the critical factor that controlled the fluidity of the tissue -- if the adhesion between cells reached a certain high threshold, the tissue would become fluid."But since cell forces and tensions fluctuate in embryos, it could be that these played an important role in tissue fluidization," Campàs said. "So when we ran the simulations and did the experiments, we realized that actually the jiggling was way more important for the fluidization than the adhesion." The fluid state of the tissue is the result of the dynamics of forces, rather than changes in static cell tension or adhesion.The findings of this study could have implications in the field of physics, particularly in the realm of active matter -- systems of many individual units that each consume energy and apply mechanical forces that collectively exhibit emergent collective behaviors. The study could also inform studies in biology, in investigations of how changes in individual cell parameters could control the global state of the tissue such as with embryonic development or with tumors.
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Biology
| 2,021 |
April 12, 2021
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https://www.sciencedaily.com/releases/2021/04/210412114853.htm
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Technique allows mapping of epigenetic information in single cells at scale
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Histones are tiny proteins that bind to DNA and hold information that can help turn on or off individual genes. Researchers at Karolinska Institutet have developed a technique that makes it possible to examine how different versions of histones bind to the genome in tens of thousands of individual cells at the same time. The technique was applied to the mouse brain and can be used to study epigenetics at a single-cell level in other complex tissues. The study is published in the journal
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"This technique will be an important tool for examining what makes cells different from each other at the epigenetic level," says Marek Bartosovic, post-doctoral fellow at the Department of Medical Biochemistry and Biophysics, Karolinska Institute. "We anticipate that it will be widely implemented by the broad biomedical community in a wide variety of research fields."Even though all cells in our bodies contain exactly the same genetic information written in DNA, they read and execute this information differently. For example, a neuron in the brain reads the DNA differently than a skin cell or a fat cell. Epigenetics play a crucial role in the interpretation of the genetic information and allows the cells to execute specialized functions.Modification of histones is one type of epigenetic information. Histones are attached to DNA like beads on a string and decorate it as "epigenetic stickers." These stickers label which genes should be turned on or off. All together this system coordinates to ensure that thousands of genes are switched on or off at the right place and time and in the right cell.To better understand how cells become different and specialized, it is important to know which parts of the DNA are marked by which histone "stickers" in each individual organ and in each individual cell within that organ. Until recently, it was not possible to look at histone modifications of an individual cell. To examine the histone modifications in one specific cell type, a very high number of cells and cumbersome methods of cell isolation would be required. The final epigenetic histone profile of one cell type would then be an averaged view of thousands of cells.In this study, the researchers describe a method that introduces a new way of looking at histone modifications in unprecedented detail in a single cell and at a large scale. By coupling and further optimizing other epigenomic techniques, the researchers were able to identify gene regulatory principles for brain cells in mice based on their histone profile."Our method -- single-cell CUT&Tag -- makes it possible to examine tens of thousands of single cells at the same time, giving an unbiased view of the epigenetic information in complex tissues with unparalleled resolution," Gonçalo Castelo-Branco, associate professor at the Department of Medical Biochemistry and Biophysics, Karolinska Institute, says. "Next, we would like to apply single-cell CUT&Tag in the human brain, both in development and in various diseases. For instance, we would like to investigate which epigenetic processes contribute to neurodegeneration during multiple sclerosis and whether we would be able to manipulate these processes in order to alleviate the disease."
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Biology
| 2,021 |
April 12, 2021
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https://www.sciencedaily.com/releases/2021/04/210412114837.htm
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Pain receptors linked to the generation of energy-burning brown fat cells
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A new source of energy expending brown fat cells has been uncovered by researchers at the Joslin Diabetes Center, which they say points towards potential new therapeutic options for obesity. According to the new report, published in
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Specifically, the authors point to smooth muscle cells expressing the Trpv1 receptor and identify them as a novel source of energy-burning brown fat cells (adipocytes). This should translate into increased overall energy expenditure -- and ultimately, researchers hope reduced weight.Brown fat or brown adipose tissue is a distinct type of fat that is activated in response to cold temperatures. Its primary role is to produce heat to help maintain body temperature and it achieves that by burning calories. This has raised the prospect that such calorie burning can be translated into weight loss, particularly in the context of obesity."The capacity of brown and beige fat cells to burn fuel and produce heat, especially upon exposure to cold temperatures, have long made them an attractive target for treating obesity and other metabolic disorders," said senior author Yu-Hua Tseng. "And yet, the precise origins of cold-induced brown adipocytes and mechanisms of action have remained a bit of a mystery."The source of these energy-burning fat cells was previously considered to be exclusively related to a population of cells that express the receptor Pdgfrα (platelet-derived growth factor receptor alpha). However, wider evidence suggests other sources may exist. Identifying these other sources would then open up potential new targets for therapy that would get around the somewhat uncomfortable use of cold temperatures to try to treat obesity.The team initially investigated the general cellular makeup of brown adipose tissue from mice housed at different temperatures and lengths of time. Notably, they employed modern single-cell RNA sequencing approaches to try to identify all types of cells present. This avoided issues of potential bias towards one particular cell type -- a weakness of previous studies, according to the authors."Single-cell sequencing coupled with advanced data analysis techniques has allowed us to make predictions in silico about the development of brown fat," said co-author Matthew D. Lynes. "By validating these predictions, we hope to open up new cellular targets for metabolic research."As well as identifying the previously known Pdgfrα-source of energy-burning brown fat cells, their analysis of the single-cell RNA sequencing data suggested another distinct population of cells doing the same job -- cells derived from smooth muscle expressing Trpv1*. The receptor has previously been identified in a range of cell types and is involved in pain and heat sensation.Further investigations with mouse models confirmed that the Trpv1-positive smooth muscle cells gave rise to the brown energy-burning version of fat cells especially when exposed to cold temperatures. Additional experiments also showed that the Trpv1-positive cells were a source for beige fat cells that appear in response to cold in white fat, further expanding the potential influence of Trpv1-expressing precursor cells."These findings show the plasticity of vascular smooth muscle lineage and expand the repertoire of cellular sources that can be targeted to enhance brown fat function and promote metabolic health," added the lead author.Brown adipose tissue is the major thermogenic organ in the body and increasing brown fat thermogenesis and general energy expenditure is seen as one potential approach to treating obesity, added Shamsi."The identification of Trpv1-expressing cells as a new source of cold-induced brown or beige adipocytes suggests it might be possible to refine the use of cold temperatures to treat obesity by developing drugs that recapitulate the effects of cold exposure at the cellular level," said Tseng.The authors note that Trpv1 has a role in detecting multiple noxious stimuli, including capsaicin (the pungent component in chili peppers) and that previous studies suggest administration in both humans and animals results in reduced food intake and increased energy expenditure.Tseng added: "Further studies are now planned to address the role of the Trpv1 channel and its ligands and whether it is possible to target these cells to increase numbers of thermogenic adipocytes as a therapeutic approach towards obesity."Other contributors to the research include Mary Piper (Harvard T.H. Chan School of Public Health, Boston, MA), Li-Lun Ho (Massachusetts Institute of Technology, Cambridge, MA), Tian Lian Huang (Joslin Diabetes Center), Anushka Gupta and Aaron Streets (University of California-Berkley, CA).Funding for the study was provided by US National Institutes of Health grants, the National Institute of Diabetes and Digestive and Kidney Diseases and the American Diabetes Association. Full details are available in the
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Biology
| 2,021 |
April 12, 2021
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https://www.sciencedaily.com/releases/2021/04/210412114812.htm
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Bigger brains gave squirrels the capacity to move up in the world
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Squirrels and other tree-dwelling rodents evolved to have bigger brains than their burrowing cousins, a study suggests.
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This greater brain power has given them key abilities needed to thrive in woodland habitats, including better vision and motor skills, and improved head and eye movements, researchers say.Scientists have shed light on how the brains of rodents -- a diverse group that accounts for more than 40 per cent of all mammals -- have changed since they evolved around 50 million years ago.Few studies looking into factors affecting brain size in mammals have taken account of extinct species. Previous research was also not able to reveal changes to the size of key parts of the brain.Researchers from the University of Edinburgh used CT scans of skulls from 38 living and extinct rodent species to examine how the animals' brains have changed over time. The data shows that rodents' body mass, lifestyle and evolutionary history have affected the overall size of their brains and specific regions within it.The relative brain size of tree squirrels has increased over time, driven largely by a sharp fall in their body mass, the team says.Two key regions of the brain -- including the neocortex, which is involved in vision and motor skills -- also became larger in species living in trees. The petrosal lobules -- which help with stabilising eye movements as the head rotates and tracks moving objects -- also increased in size. Enlargement of these regions has helped tree-dwelling rodents adapt to life in complex environments, the team says.By contrast, these parts of the brain are smaller in squirrels' closest living relatives -- mountain beavers, which live in burrows -- and some extinct rodent species that had a similar lifestyle. This is likely because burrowing rodents spend most of their time underground with little light, meaning good vision might be less crucial for them, than those in trees.The research, published in the journal Dr Ornella Bertrand, of the University of Edinburgh's School of GeoSciences, who led the study, said: "Squirrels' ancestors were at an important juncture 34 million years ago. They were smaller than their closest extinct relatives, and there were far fewer primates living in trees than today, which opened up a new niche for them. When trees became available to them, squirrels' ancestors seized the opportunity. This transition was a key evolutionary step for squirrels as it enabled them to acquire larger and more complex brains."
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Biology
| 2,021 |
April 12, 2021
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https://www.sciencedaily.com/releases/2021/04/210412114742.htm
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New Jurassic flying reptile reveals the oldest opposed thumb
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A new 160-million-year-old arboreal pterosaur species, dubbed 'Monkeydactyl', has the oldest true opposed thumb -- a novel structure previously not known in pterosaurs.
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An international team of researchers from China, Brazil, UK, Denmark and Japan have described a new Jurassic pterosaur Kunpengopterus antipollicatus, which was discovered in the Tiaojishan Formation of Liaoning, China.It is a small-bodied darwinopteran pterosaur, with an estimated wingspan of 85 cm. Most importantly, the specimen was preserved with an opposed pollex ("thumb") on both hands.The species name 'antipollicatus' means 'opposite thumbed' in ancient Greek, in light of the opposed thumb of the new species. This is the first discovery of a pterosaur with an opposed thumb. It also represents the earliest record of a true opposed thumb in Earth's history. The researchers published their discovery today in the journal A true opposed pollex is mostly present in mammals (e.g. primates) and some tree frogs, but extremely rare among extant reptiles except for chameleons. This discovery adds to the list that darwinopteran pterosaurs such as K. antipollicatus also evolved an opposed thumb.The research team scanned the fossil of K. antipollicatus using micro-computed tomography (micro-CT), a technique making use of X-ray to image an object. By studying its forelimb morphology and musculature, they suggest that K. antipollicatus could have used its hand for grasping, which is likely an adaptation for arboreal life.In order to test the arboreal interpretation, the team analysed K. antipollicatus and other pterosaurs using a set of anatomical characters related to arboreal adaptation. The results support K. antipollicatus as an arboreal species, but not the other pterosaurs from the same ecosystem. This suggests niche-partitioning among these pterosaurs and provides the first quantitative evidence that at least some darwinopteran pterosaurs were arboreal.Fion Waisum Ma, co-author of the study and PhD researcher at the University of Birmingham, said: "The fingers of 'Monkeydactyl' are tiny and partly embedded in the slab. Thanks to micro-CT scanning, we could see through the rocks, create digital models and tell how the opposed thumb articulates with the other finger bones."This is an interesting discovery. It provides the earliest evidence of a true opposed thumb, and it is from a pterosaur -- which wasn't known for having an opposed thumb."Xuanyu Zhou from China University of Geosciences who led the study commented: "Tiaojishan palaeoforest is home to many organisms, including three genera of darwinopteran pterosaurs. Our results show that K. antipollicatus has occupied a different niche from Darwinopterus and Wukongopterus, which has likely minimized competition among these pterosaurs."Rodrigo V. Pêgas from Federal University of ABC, in Sao Bernardo, Brazil, said: "Darwinopterans are a group of pterosaurs from the Jurassic of China and Europe, named after Darwin due to their unique transitional anatomy that has revealed how evolution affected the anatomy of pterosaurs throughout time."On top of that, a particular darwinopteran fossil has been preserved with two associated eggs, revealing clues to pterosaur reproduction. They've always been considered precious fossils for these reasons and it is impressive that new darwinopteran species continue to surprise us!"
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Biology
| 2,021 |
April 12, 2021
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https://www.sciencedaily.com/releases/2021/04/210412084533.htm
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Rapid evolution in foxgloves pollinated by hummingbirds
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Researchers have found common foxgloves brought to the Americas have rapidly evolved to change flower length in the presence of a new pollinator group, hummingbirds. The findings are published in the British Ecological Society's
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Researchers from the University of Sussex, Universidad de Los Andes (Colombia) and Universidad de Costa Rica, studying the common foxglove Digitalis purpurea, a bumblebee pollinated species native to Europe, have shown for the first time how rapid physical changes can occur in flowers following a change in environment and the presence of a new pollinator.The researchers compared foxgloves in the UK, which are pollinated by bumblebees, with foxgloves introduced in two independent events to Costa Rica and Colombia around 200 years ago, which are pollinated by different species of bumblebees and also hummingbirds. They found the base of the cone structure of the flowers, called the proximal corolla tube, was 13-26% larger in populations in the Americas.Foxgloves have long, narrow proximal corolla tubes. This part of the flower holds the nectar and by being this shape, they restrict floral visitors to those with long mouthparts such as long-tongued bumblebees."We found foxglove populations in Costa Rica and Colombia now have flowers with longer tubes at the base, when compared to native populations. There is also substantial natural selection on this floral characteristic in the naturalised populations." said Dr Maria Clara Castellanos at the University of Sussex and one of the authors of the study."Long corollas are a common feature in many hummingbird-pollinated plants, likely because this improves the precision of pollen transfer during the pollination interaction. It is also possible that long corolla tubes exclude other pollinators that are less effective."Because foxgloves are biennial (meaning each generation takes two years) these changes have occurred in around 85 generations, indicating a rapid evolutionary change.In the study the researchers also confirmed that hummingbirds are effective foxglove pollinators. "We counted pollen grains deposited in flowers and found that after a single visit they can bring in more pollen than a bumblebee." said Dr Castellanos.The study also confirms how invasions can be used to understand evolution of floral structures. The researchers say that scenarios like this are likely to happen often as humans influence the range of plants and pollinators.Dr Castellanos said: "Our research shows how rapid evolutionary change in a new environment can be an important force behind the extraordinary diversity of flowers."Foxgloves are now naturalised in many areas of the world. They were introduced to Colombia and Costa Rica in the 19th Century, most likely by English architects and engineers. In these new tropical environments, foxgloves grow at high altitudes above 2,200 meters where temperatures are broadly similar to those in their native European range. Because there are no seasons, populations flower at different times of the year.In the study, the researchers looked at both native UK foxglove populations and populations in mountainous areas in Colombia and Costa Rica. They compared the shape of the flowers and the reproductive success of the plants. They also recorded the pollinators in each location and how effective each pollinator was at transferring pollen.The authors caution that although the changes they observed are consistent with natural selection hummingbirds have imposed during the evolution of native plants they pollinate, the study doesn't prove the changes to foxgloves have been directly caused by hummingbirds.To do this, the researchers are planning to experimentally exclude pollinators from foxgloves in the field and record the consequences for the plants. They are also studying the genetic basis of the traits both in the greenhouse and using genomic approaches.The researchers emphasise the importance of studying other plant groups in this context. "Plants around the world are experiencing changes in their pollinators and it is important to understand the evolutionary implications of this" said Dr Castellanos.
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Biology
| 2,021 |
April 12, 2021
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https://www.sciencedaily.com/releases/2021/04/210412101905.htm
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Auxin visualized for the first time
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A team of scientists at the Max Planck Institute for Developmental Biology in Tübingen and the University of Bayreuth have created a novel tool that provides a real-time visualization of the growth-regulating hormone auxin in living plant cells. This new biosensor enables them to observe spatial and temporal redistribution dynamics of the plant hormone, for example in conjunction with changing environmental conditions.
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Auxin plays a central role in plant life. The hormone regulates various processes, from embryonic development to the formation of roots and the directional growth in response to light and gravity. Auxin binds to specific receptors in the nucleus of a cell, leading to an activation of signaling cascades that coordinate the plant's response to external stimuli.Although the molecular action of auxin is well understood mechanistically, it has not been feasible so far to directly observe auxin in individual cells. Instead it was only possible to determine the overall response to, and the general presence of auxin. With the new biosensor, it is now possible to visualize auxin directly in individual plant cells. This way, the rapid and dynamic redistribution of auxin, e.g. upon changing the directional root growth, could be viewed for the first time, almost 100 years after the physiological effects of auxin in plants were first described.The development of this biosensor, in short AuxSen, is the result of an interdisciplinary collaboration between two teams that built strong synergies in plant biology and protein biochemistry. The goal was easily phrased: Plants should produce a protein that glows when auxin is present, allowing the team to visualize auxin distribution with an optical method. However, the implementation was a bit more complex.The researchers chose a protein from the bacterium E. coli that binds specifically to the amino acid tryptophan and rather poorly to the chemically related auxin. This protein was coupled to two other proteins that fluoresce when excited with light of a specific wavelength. When these two fluorescent proteins come close to each other, for example due to binding another molecule, the excitation energy of one is transferred to the other protein, and a so-called fluorescence resonance energy transfer (FRET) occurs.The goal of the engineering process was that this FRET effect should only occur when AuxSen is bound to auxin. For this purpose, the starting protein had to be substantially altered in order to bind strongly to auxin but no longer to tryptophan. Biochemistry became crucial in this experimental phase. Crystal structures of the protein complex with tryptophan or auxin were generated, and the team was able to derive predictions about the effects of amino acid exchanges on the binding to auxin. "For us, it was amazing to see that tryptophan and auxin, two closely related molecules, are oriented very differently in the binding pocket," said co-first author Andre C. Stiel. "This made it easier to improve binding to auxin at the expense of tryptophan." In total, about 2,000 variants were generated in an iterative process and these were tested for their specific binding to auxin, finally leading to AuxSen.Transferring the AuxSen biosensor from the test tube to transgenic plants posed another challenge of finding the right conditions for AuxSen expression. There was a dilemma. On the one hand, a protein with a high binding affinity to auxin was needed in order to detect auxin with high sensitivity, and this protein should be present in sufficient quantity in all cells; on the other hand, the researchers worried about a disruption of normal auxin activity and that plants might suffer. After some testing, a compromise was found. AuxSen is ubiquitously and strongly expressed, but only after induction with a chemical agent and then for a relatively short time, so that the plants would not be harmed.What are the key findings? One unexpected finding is the rapid uptake of auxin into the cells, reflecting their ability to respond fast to changing conditions -- after addition of auxin, the team observed a maximum response of AuxSen in the cell nucleus within one to two minutes. Auxin export from the cell appears to be slower, taking about ten minutes for the AuxSen signal to disappear. This difference between fast uptake and slower export might facilitate the directional transport of auxin, for example towards the root tip.Of particular interest was the rapid auxin redistribution after rotating the plant such that the root tip pointed no longer downward but diagonally upward. Just after one minute, auxin accumulated on the new bottom side of the root tip, and after turning back the root, the former distribution of auxin was restored. "This completely amazed us," commented co-first authors Ole Herud-Sikimic and Martina Kolb. This rapid and reversible response had not been expected. Nor had it been possible to measure this.The publication of AuxSen is first and foremost a technological breakthrough that has enormous application potential. The conclusion of the two senior authors Birte Höcker from the University of Bayreuth and Gerd Jürgens from the Max Planck Institute for Developmental Biology: "We have shown that both increases and decreases of auxin concentration can be visualized in tissue in real time, which was not possible before. In addition, AuxSen reveals auxin in subcellular areas to which other, indirect auxin reporters have no access. The goal now is to improve the possible applications to other biological problems by optimizing expression systems and using fluorescent proteins with different characteristics. We are now providing the necessary material to the scientific community." AuxSen might well be the starting point to elucidate in the near future how rapid redistribution, in time and space, of auxin in diverse biological contexts mediates the multitude of physiological effects attributed to this remarkable small molecule over the past 100 years.
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Biology
| 2,021 |
April 9, 2021
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https://www.sciencedaily.com/releases/2021/04/210409145852.htm
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Brain disease transmitted by tick bites may be treatable
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Tick-borne encephalitis is a disease just as nasty as it sounds. Once bitten by an infected tick, some people develop flu-like symptoms that resolve quietly but leave behind rampant neurological disease -- brain swelling, memory loss, and cognitive decline. Cases are on the rise in Central Europe and Russia with some 10,000 incidents reported each year. Vaccines can provide protection, but only for a limited time. There is no cure.
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Now a new study describes antibodies capable of neutralizing the virus transmitted by tick bites. These so-called broadly neutralizing antibodies have shown promise in preventing TBE in mice and could inform the development of better vaccines for humans. Further, preliminary results suggest that the antibodies may not only prevent tick-borne encephalitis but even treat the condition, as well as the related Powassan virus emerging in the United States.Lead author Marianna Agudelo and colleagues in the laboratory of Rockefeller's Michel C. Nussenzweig examined nearly 800 antibodies obtained from individuals who had recovered from TBE or had been vaccinated to prevent infection. The most potent antibodies, designated VH3-48, turned out to be best suited to fend off future infections. They found that VH3-48 neutralized lab-grown varieties of the TBE virus, as well other tick-borne illnesses including the Langat, Louping ill, Omsk hemorrhagic fever, Kyasanur forest disease, and Powassan viruses.The researchers also showed that these powerful antibodies are not common; in fact, most of the antibodies produced by humans exposed to TBE virus are of inferior quality, with the coveted VH3-48 antibodies making only occasional appearances. Moreover, vaccinated patients in the study did not manage to develop any VH3-48 antibodies at all. "You'd expect the most prevalent antibodies to be the absolute best, but that is not what we found in TBE," Agudelo says. "This may explain how the virus tricks the immune system, misdirecting it into producing inferior antibodies."The discovery of VH3-48 provides hope for a more effective TBE vaccine. Current vaccines require three doses spaced over two years and only provide about five years of protection before a booster shot is required. Next-generation vaccines built around coaxing the body into producing the rare VH3-48 antibody could be more potent, require fewer booster shots, and also prove protective against a number of tick-borne viruses."A vaccine like this would not just be more elegant, but also better focused," says Michel C. Nussenzweig, the Zanvil A. Cohn and Ralph M. Steinman Professor and head of the Laboratory of Molecular Immunology at Rockefeller. "Now that we have the structures of these antibodies, we know what to target in order to design more effective vaccines."Broadly neutralizing antibodies may also provide the first specific treatment for TBE. Nussenzweig, Agudelo, and colleagues found that mice infected with TBE recover after receiving antibody therapy, although it remains to be seen if this finding will translate to humans."The next step is a clinical trial with the antibodies," Nussenzweig says, "perhaps in Europe where there are many cases, to see whether we can ameliorate the symptoms of those suffering from encephalitis."
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Biology
| 2,021 |
April 9, 2021
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https://www.sciencedaily.com/releases/2021/04/210409104457.htm
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Metabolic changes in fat tissue in obesity associated with adverse health effects
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Researchers at the Obesity Research Unit of the University of Helsinki have found that obesity clearly reduces mitochondrial gene expression in fat tissue, or adipose tissue. Mitochondria are important cellular powerplants which process all of our energy intake. If the pathways associated with breaking down nutrients are lazy, the changes can often have health-related consequences.
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A total of 49 pairs of identical twins discordant for body weight participated in the study conducted at the University of Helsinki: their body composition and metabolism were studied in detail, and biopsies from adipose and muscle tissue were collected. Multiple techniques for analysing the genome-wide gene expression, the proteome and the metabolome were used in the study.The study was recently published in the journal According to the findings, the pathways responsible for mitochondrial metabolism in adipose tissue were greatly reduced by obesity. Since mitochondria are key to cellular energy production, their reduced function can maintain obesity. For the first time, the study also compared the effects of obesity specifically on the mitochondria in muscle tissue in these identical twin pairs: muscle mitochondria too were found to be out of tune, but the change was less distinct than in adipose tissue.The study provided strong evidence of a connection between the low performance of adipose tissue mitochondria and a proinflammatory state. Furthermore, the findings indicate that metabolic changes in adipose tissue are associated with increased accumulation of fat in the liver, prediabetic disorders of glucose and insulin metabolism as well as cholesterol."If mitochondria, the cellular powerplants, are compared to the engine of a car, you could say that the power output decreases as weight increases. A low-powered mitochondrial engine may also generate toxic exhaust fumes, which can cause a proinflammatory state in adipose tissue and, consequently, the onset of diseases associated with obesity," says Professor Kirsi Pietiläinen from the Obesity Research Unit, University of Helsinki."What was surprising was that the mitochondrial pathways in muscle had no association with these adverse health effects," Pietiläinen adds.In the study, changes in mitochondrial function were also seen in amino acid metabolism. The metabolism of branched-chain amino acids, which are essential to humans, was weakened in the mitochondria of both adipose tissue and muscle tissue."This finding was of particular significance because the reduced breakdown of these amino acids and the resulting heightened concentration in blood have also been directly linked with prediabetic changes and the accumulation of liver fat in prior twin studies," says Pietiläinen.Obesity, with its numerous associated diseases, is a common phenomenon that is continuously increasing in prevalence. While lifestyle influence the onset of obesity, genes also have a significant role."Identical twins have the same genes, and their weight is usually fairly similar. In fact, studying twins is the best way to investigate the interplay between genes and lifestyle. In spite of their identical genome, the genes and even mitochondria of twins can function on different activity levels. We utilised this characteristic in our study when looking into the effects of weight on tissue function," Pietiläinen says.
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Biology
| 2,021 |
April 9, 2021
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https://www.sciencedaily.com/releases/2021/04/210409104447.htm
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A sulfosugar from green vegetables promotes the growth of important gut bacteria
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A team of scientists has analyzed how microbes in the gut process the plant-based, sulfur-containing sugar sulfoquinovose. Their study discovered that specialized bacteria cooperate in the utilization of the sulfosugar, producing hydrogen sulfide. This gas has disparate effects on human health: at low concentrations, it has an anti-inflammatory effect, while increased amounts of hydrogen sulfide in the intestine, in turn, are associated with diseases such as cancer.
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With the consumption of a single type of vegetable such as spinach, hundreds of chemical components enter our digestive tract. There, they are further metabolized by the gut microbiome, a unique collection of hundreds of microbial species. The gut microbiome thus plays a major role in determining how nutrition affects our health. "So far, however, the metabolic capabilities of many of these microorganisms in the microbiome are still unknown. That means we don't know what substances they feed on and how they process them," explains Buck Hanson, lead author of the study and a microbiologist at the Center for Microbiology and Environmental Systems Science (CMESS) at the University of Vienna. "By exploring the microbial metabolism of the sulfosugar sulfoquinovose in the gut for the first time, we have shed some light into this black box," he adds. The study thus generates knowledge that is necessary to therapeutically target the interactions between nutrition and the microbiome in the future.Sulfoquinovose is a sulfonic acid derivative of glucose and is found as a chemical building block primarily in green vegetables such as spinach, lettuce, and in algae. From previous studies by the research group led by microbiologist David Schleheck at the University of Konstanz, it was known that other microorganisms can in principle use the sulfosugar as a nutrient. In their current study, the researchers from the Universities of Konstanz and Vienna used analyses of stool samples to determine how these processes specifically take place in the human intestine. "We have now been able to show that, unlike glucose, for example, which feeds a large number of microorganisms in the gut, sulfoquinovose stimulates the growth of very specific key organisms in the gut microbiome," says David Schleheck. These key organisms include the bacterium of the species Eubacterium rectale, which is one of the ten most common gut microbes in healthy people. "The E. rectale bacteria ferment sulfoquinovose via a metabolic pathway that we have only recently deciphered, producing, among other things, a sulfur compound, dihydroxypropane sulfonate or DHPS for short, which in turn serves as an energy source for other intestinal bacteria such as Bilophila wadsworthia. Bilophila wadsworthia ultimately produces hydrogen sulfide from DHPS via a metabolic pathway that was also only recently discovered," explains the microbiologist.Hydrogen sulfide is produced in the intestine by our own body cells as well as by specialized microorganisms and has a variety of effects on our body. "This gas is a Janus-faced metabolic product," explains Alexander Loy, head of the research group at the University of Vienna. "According to current knowledge, it can have a positive but also a negative effect on intestinal health." A decisive factor, he says, is the dose: in low amounts, hydrogen sulfide can have an anti-inflammatory effect on the intestinal mucosa, among other things. Increased hydrogen sulfide production by gut microbes, on the other hand, is associated with chronic inflammatory diseases and cancer. Until now, mainly sulfate and taurine, which are found in increased amounts in the intestine as a result of a diet rich in meat or fat, were known to be sources of hydrogen sulfide for microorganisms. The discovery that sulfoquinovose from green foods such as spinach and algae also contribute to the production of the gas in the gut therefore comes as a surprise."We have shown that we can use sulfoquinovose to promote the growth of very specific gut bacteria that are an important component of our gut microbiome. We now also know that these bacteria in turn produce the contradictory hydrogen sulfide from it," Loy sums up. Further studies by the scientists from Konstanz and Vienna will now clarify whether and how the intake of the plant-based sulfosugar can have a health-promoting effect. "It is also possible that sulfoquinovose could be used as a so-called prebiotic," adds Schleheck. Prebiotics are food ingredients or additives that are metabolized by specific microorganisms and used to explicitly support the intestinal microbiome.
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Biology
| 2,021 |
April 9, 2021
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https://www.sciencedaily.com/releases/2021/04/210409104242.htm
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Bird blood is a heating system in winter
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Researchers at Lund University in Sweden have discovered that bird blood produces more heat in winter, when it is colder, than in autumn. The study is published in
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The secret lies in the energy factories of cells, the mitochondria. Mammals have no mitochondria in their red blood cells, but birds do, and according to the research team from Lund and Glasgow this means that the blood can function as a central heating system when it is cold."In winter, the mitochondria seem to prioritize producing more heat instead of more energy. The blood becomes a type of radiator that they can turn up when it gets colder," says Andreas Nord, researcher in evolutionary ecology at Lund University who led the study.Until now, the common perception has been that birds keep warm by shivering with their large pectoral muscles and fluffing up their feathers. Less is known about other heat-regulating processes inside birds.To investigate the function of mitochondria, the researchers examined great tits, coal tits and blue tits on two different occasions: early autumn and late winter. The researchers took blood samples from the birds and isolated the red blood cells. By using a so-called cell respirometer, a highly sensitive instrument that can measure how much oxygen the mitochondria consume, the researchers were able to calculate how much of the oxygen consumption was spent on producing energy and how much was spent on creating heat. Finally, they also measured the amount of mitochondria in each blood sample.The results show that the blood samples taken in winter contained more mitochondria and that the mitochondria worked harder. However, the work was not to produce more energy, something the researchers had assumed since birds have a much higher metabolism in winter."We had no idea that the birds could regulate their blood as a heating system in this way, so we were surprised," says Andreas Nord.The researchers will now investigate whether cold weather is the whole explanation for the birds' blood producing more heat in winter. Among other things, they will study whether the food that the birds eat in winter affects the mitochondria.
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Biology
| 2,021 |
April 8, 2021
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https://www.sciencedaily.com/releases/2021/04/210408163439.htm
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Rewriting evolutionary history and shape future health studies
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The network of nerves connecting our eyes to our brains is sophisticated and researchers have now shown that it evolved much earlier than previously thought, thanks to an unexpected source: the gar fish.
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Michigan State University's Ingo Braasch has helped an international research team show that this connection scheme was already present in ancient fish at least 450 million years ago. That makes it about 100 million years older than previously believed."It's the first time for me that one of our publications literally changes the textbook that I am teaching with," said Braasch, as assistant professor in the Department of Integrative Biology in the College of Natural Science.This work, published in the journal And this work, which was led by researchers at France's Inserm public research organization, does more than reshape our understanding of the past. It also has implications for future health research.Studying animal models is an invaluable way for researchers to learn about health and disease, but drawing connections to human conditions from these models can be challenging.Zebrafish are a popular model animal, for example, but their eye-brain wiring is very distinct from a human's. In fact, that helps explain why scientists thought the human connection first evolved in four-limbed terrestrial creatures, or tetrapods."Modern fish, they don't have this type of eye-brain connection," Braasch said. "That's one of the reasons that people thought it was a new thing in tetrapods."Braasch is one of the world's leading experts in a different type of fish known as gar. Gar have evolved more slowly than zebrafish, meaning gar are more similar to the last common ancestor shared by fish and humans. These similarities could make gar a powerful animal model for health studies, which is why Braasch and his team are working to better understand gar biology and genetics.That, in turn, is why Inserm's researchers sought out Braasch for this study."Without his help, this project wouldn't have been possible," said Alain Chédotal, director of research at Inserm and a group leader of the Vision Institute in Paris. "We did not have access to spotted gar, a fish that does not exist in Europe and occupies a key position in the tree of life."To do the study, Chédotal and his colleague, Filippo Del Bene, used a groundbreaking technique to see the nerves connecting eyes to brains in several different fish species. This included the well-studied zebrafish, but also rarer specimens such as Braasch's gar and Australian lungfish provided by a collaborator at the University of Queensland.In a zebrafish, each eye has one nerve connecting it to the opposite side of the fish's brain. That is, one nerve connects the left eye to the brain's right hemisphere and another nerve connects its right eye to the left side of its brain.The other, more "ancient" fish do things differently. They have what's called ipsilateral or bilateral visual projections. Here, each eye has two nerve connections, one going to either side of the brain, which is also what humans have.Armed with an understanding of genetics and evolution, the team could look back in time to estimate when these bilateral projections first appeared. Looking forward, the team is excited to build on this work to better understand and explore the biology of visual systems."What we found in this study was just the tip of the iceberg," Chédotal said. "It was highly motivating to see Ingo's enthusiastic reaction and warm support when we presented him the first results. We can't wait to continue the project with him."Both Braasch and Chédotal noted how powerful this study was thanks to a robust collaboration that allowed the team to examine so many different animals, which Braasch said is a growing trend in the field.The study also reminded Braasch of another trend."We're finding more and more that many things that we thought evolved relatively late are actually very old," Braasch said, which actually makes him feel a little more connected to nature. "I learn something about myself when looking at these weird fish and understanding how old parts of our own bodies are. I'm excited to tell the story of eye evolution with a new twist this semester in our Comparative Anatomy class."
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Biology
| 2,021 |
April 8, 2021
|
https://www.sciencedaily.com/releases/2021/04/210408153644.htm
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Scientists discover 'jumping' genes that can protect against blood cancers
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New research has uncovered a surprising role for so-called "jumping" genes that are a source of genetic mutations responsible for a number of human diseases. In the new study from Children's Medical Center Research Institute at UT Southwestern (CRI), scientists made the unexpected discovery that these DNA sequences, also known as transposons, can protect against certain blood cancers.
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These findings, published in Transposons are DNA sequences that can move, or jump, from one location in the genome to another when activated. Though many different classes of transposons exist, scientists in the Xu laboratory focused on a type known as long interspersed element-1 (L1) retrotransposons. L1 sequences work by copying and then pasting themselves into different locations in the genome, which often leads to mutations that can cause diseases such as cancer. Nearly half of all cancers contain mutations caused by L1 insertion into other genes, particularly lung, colorectal, and head-and-neck cancers. The incidence of L1 mutations in blood cancers such as AML is extremely low, but the reasons why are poorly understood.When researchers screened human AML cells to identify genes essential for cancer cell survival, they found MPP8, a known regulator of L1, to be selectively required by AML cells. Curious to understand the underlying basis of this connection, scientists in the Xu lab studied how L1 sequences were regulated in human and mouse leukemia cells. They made two key discoveries. The first was that MPP8 blocked the copying of L1 sequences in the cells that initiate AML. The second was that when the activity of L1 was turned on, it could impair the growth or survival of AML cells."Our initial finding was a surprise because it's been long thought that activated transposons promote cancer development by generating genetic mutations. We found it was the opposite for blood cancers, and that decreased L1 activity was associated with worse clinical outcomes and therapy resistance in patients," says Jian Xu, Ph.D., associate professor in CRI and senior author of the study.MPP8 thus suppressed L1 in order to safeguard the cancer cell genome and allow AML-initiating cells to survive and proliferate. Cancer cells, just like healthy cells, need to maintain a stable genome to replicate. Too many mutations, like those created by L1 activity, can impair the replication of cancer cells. Researchers found L1 activation led to genome instability, which in turn activated a DNA damage response that triggered cell death or eliminated the cell's ability to replicate itself. Xu believes this discovery may provide a mechanistic explanation for the unusual sensitivity of myeloid leukemia cells to DNA damage-inducing therapies that are currently used to treat patients."Our discovery that L1 activation can suppress the survival of certain blood cancers opens up the possibility of using it as a prognostic biomarker, and possibly leveraging its activity to target cancer cells without affecting normal cells," says Xu.
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Biology
| 2,021 |
April 8, 2021
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https://www.sciencedaily.com/releases/2021/04/210408153628.htm
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Green chemistry and biofuel: The mechanism of a key photoenzyme decrypted
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The functioning of the enzyme FAP, useful for producing biofuels and for green chemistry, has been decrypted. This result mobilized an international team of scientists, including many French researchers from the CEA, CNRS, Inserm, École Polytechnique, the universities of Grenoble Alpes, Paris-Saclay and Aix Marseille, as well as the European Synchrotron (ESRF) and synchrotron SOLEIL. The study is published in
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The researchers decrypted the operating mechanisms of FAP (Fatty Acid Photodecarboxylase), which is naturally present in microscopic algae such as Chlorella. The enzyme had been identified in 2017 as able to use light energy to form hydrocarbons from fatty acids produced by these microalgae. To achieve this new result, research teams used a complete experimental and theoretical toolkit.Understanding how FAP works is essential because this photoenzyme opens up a new opportunity for sustainable biofuel production from fatty acids naturally produced by living organisms. FAP is also very promising for producing high added-value compounds for fine chemistry, cosmetics and pharmaceutics.In addition, due to their light-induced reaction, photoenzymes give access to ultrarapid phenomena that occur during enzymatic reactions. FAP therefore offers a unique opportunity to understand in detail a chemical reaction taking place in living organisms.More specifically, in this work, researchers show that when FAP is illuminated and absorbs a photon, an electron is stripped in 300 picoseconds from the fatty acid produced by the algae. This fatty acid is then dissociated into a hydrocarbon precursor and carbon dioxide (CO2). Most of the CO2 generated is then turned in 100 nanoseconds into bicarbonate (HCO3-) within the enzyme. This activity uses light but does not prevent photosynthesis: the flavin molecule within the FAP, which absorbs the photon, is bent. This conformation shifts the molecule's absorption spectrum towards the red, so that it uses photons not used for the microalgae's photosynthetic activity.It is the combined interpretation of the results of various experimental and theoretical approaches by the international consortium that yields the detailed, atomic-scale picture of FAP at work. This multidisciplinary study combined bioengineering work, optical and vibrational spectroscopy, static and kinetic crystallography performed with synchrotrons or an X-ray free electron laser, as well as quantum chemistry calculations.The study involved a strong collaboration of French researchers from the Biosciences and Biotechnologies Institute of Aix-Marseille (CEA/CNRS/Aix-Marseille University), the Institute of Structural Biology (CEA/CNRS/Grenoble Alpes University), the Laboratory for Optics and Biosciences (CNRS/École Polytechnique-Institut Polytechnique de Paris/Inserm), the Advanced Spectroscopy Laboratory for Interactions, Reactivity and the Environment (CNRS/University of Lille), the Institute for Integrative Biology of the Cell (CEA/CNRS/Paris-Saclay University), the SOLEIL synchrotron and also from the European Synchrotron (ESRF) and the Laue Langevin Institute (ILL), two major European instruments based in Grenoble, France. It received funding from the French National Research Agency. The study also involved researchers from the Max Planck Institute in Heidelberg (Germany), Moscow State University (Russia) and the SLAC National Accelerator Laboratory (USA).
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Biology
| 2,021 |
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