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February 26, 2021
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https://www.sciencedaily.com/releases/2021/02/210226140455.htm
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Measuring the tRNA world
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Transfer RNAs (tRNAs) deliver specific amino acids to ribosomes during translation of messenger RNA into proteins. The abundance of tRNAs can therefore have a profound impact on cell physiology, but measuring the amount of each tRNA in cells has been limited by technical challenges. Researchers at the Max Planck Institute of Biochemistry have now overcome these limitations with mim-tRNAseq, a method that can be used to quantify tRNAs in any organism and will help improve our understanding of tRNA regulation in health and disease.
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A cell contains several hundred thousand tRNA molecules, each of which consists of only 70 to 90 nucleotides folded into a cloverleaf-like pattern. At one end, tRNAs carry one of the twenty amino acids that serve as protein building blocks, while the opposite end pairs with the codon specifying this amino acid in messenger RNA during translation. Although there are only 61 codons for the twenty amino acids, cells from different organisms can contain hundreds of unique tRNA molecules, some of which differ from each other by only a single nucleotide. Many nucleotides in tRNAs are also decorated with chemical modifications, which help tRNAs fold or bind the correct codon.The levels of individual tRNAs are dynamically regulated in different tissues and during development, and tRNA defects are linked to neurogical diseases and cancer. The molecular origins of these links remain unclear, because quantifying the abundance and modifications of tRNAs in cells has long remained a challenge. The team of Danny Nedialkova at the MPI of Biochemistry has now developed mim-tRNAseq, a method that accurately measures the abundance and modification status of different tRNAs in cells.To measure the levels of multiple RNAs simultaneously, scientists use an enzyme called reverse transcriptase to first rewrite RNA into DNA. Millions of these DNA copies can then be quantified in parallel by high-throughput sequencing. Rewriting tRNAs into DNA has been tremendously hard since many tRNA modifications block the reverse transcriptase, causing it to stop synthesizing DNA."Many researches have proposed elegant solutions to this problem, but all of them relieve only a fraction of the modification roadblocks in tRNAs," explains Danny Nedialkova, Max Planck Research Group Leader at the Max Planck Institute of Biochemistry. "We noticed that one specific reverse transcriptase seemed to be much better at reading through modified tRNA sites. By optimizing the reaction conditions, we could significantly improve the enzyme's efficiency, enabling it to read through nearly all tRNA modification roadblocks," adds Nedialkova. This made it possible to construct DNA libraries from full-length tRNA copies and use them for high-throughput sequencing.The analysis of the resulting sequencing data also presented significant challenges. "We identified two major issues: the first one is the extensive sequence similarity between different tRNA transcripts," explains Andrew Behrens, PhD student in Nedialkova's group and first author of the paper. "The second one comes from the fact that an incorrect nucleotide (a misincorporation) is introduced at many modified sites during reverse transcription. Both make it extremely challenging to assign each DNA read to the tRNA molecule it originated from," adds Behrens.The team tackled these issues with novel computational approaches, including the use of modification annotation to guide accurate read alignment. The resulting comprehensive toolkit is packaged into a freely available pipeline for alignment, analysis and visualization of tRNA-derived sequencing data . Researchers can use mim-tRNAseq to not only measure tRNA abundance, but also to map and quantify tRNA modifications that induce nucleotide misincorporations by the reverse transcriptase. "mim-tRNAseq opens up myriad possibilities moving forward," says Nedialkova. "We expect it will help us and others to tackle many outstanding questions about tRNA biology in health and disease."
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Biology
| 2,021 |
February 26, 2021
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https://www.sciencedaily.com/releases/2021/02/210226121249.htm
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Bioinformatics tool accurately tracks synthetic DNA
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Tracking the origin of synthetic genetic code has never been simple, but it can be done through bioinformatic or, increasingly, deep learning computational approaches.
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Though the latter gets the lion's share of attention, new research by computer scientist Todd Treangen of Rice University's Brown School of Engineering is focused on whether sequence alignment and pan-genome-based methods can outperform recent deep learning approaches in this area."This is, in a sense, against the grain given that deep learning approaches have recently outperformed traditional approaches, such as BLAST," he said. "My goal with this study is to start a conversation about how to combine the expertise of both domains to achieve further improvements for this important computational challenge."Treangen, who specializes in developing computational solutions for biosecurity and microbial forensics applications, and his team at Rice have introduced PlasmidHawk, a bioinformatics approach that analyzes DNA sequences to help identify the source of engineered plasmids of interest."We show that a sequence alignment-based approach can outperform a convolutional neural network (CNN) deep learning method for the specific task of lab-of-origin prediction," he said.The researchers led by Treangen and lead author Qi Wang, a Rice graduate student, reported their results in an open-access paper in The program may be useful not only for tracking potentially harmful engineered sequences but also for protecting intellectual property."The goal is either to help protect intellectual property rights of the contributors of the sequences or help trace the origin of a synthetic sequence if something bad does happen," Treangen said.Treangen noted a recent high-profile paper describing a recurrent neural network (RNN) deep learning technique to trace the originating lab of a sequence. That method achieved 70% accuracy in predicting the single lab of origin. "Despite this important advance over the previous deep learning approach, PlasmidHawk offers improved performance over both methods," he said.The Rice program directly aligns unknown strings of code from genome data sets and matches them to pan-genomic regions that are common or unique to synthetic biology research labs"To predict the lab-of-origin, PlasmidHawk scores each lab based on matching regions between an unclassified sequence and the plasmid pan-genome, and then assigns the unknown sequence to a lab with the minimum score," Wang said.In the new study, using the same dataset as one of the deep learning experiments, the researchers reported the successful prediction of "unknown sequences' depositing labs" 76% of the time. They found that 85% of the time the correct lab was in the top 10 candidates.Unlike the deep learning approaches, they said PlasmidHawk requires reduced pre-processing of data and does not need retraining when adding new sequences to an existing project. It also differs by offering a detailed explanation for its lab-of-origin predictions in contrast to the previous deep learning approaches."The goal is to fill your computational toolbox with as many tools as possible," said co-author Ryan Leo Elworth, a postdoctoral researcher at Rice. "Ultimately, I believe the best results will combine machine learning, more traditional computational techniques and a deep understanding of the specific biological problem you are tackling."
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Biology
| 2,021 |
February 26, 2021
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https://www.sciencedaily.com/releases/2021/02/210226103822.htm
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Dinosaur species: 'Everyone's unique'
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"Everyone's unique" is a popular maxim. All people are equal, but there are of course individual differences. This was no different with dinosaurs. A study by researchers at the University of Bonn and the Dinosaur Museum Frick in Switzerland has now revealed that the variability of
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The first bones of Dinosaurs have been preserved for posterity mainly through bones. Paleontologists rely on anatomical details to distinguish different species. "A perpetual difficulty with this is that such anatomical differences can also occur within a species, as natural variation between individuals," Lallensack reports. Researchers at the University of Bonn and the Dinosaur Museum Frick (Switzerland) have now been able to show that Can all these fossils from Germany and Switzerland really be assigned to a single species? Answering this question has become all the more urgent since Martin Sander and Nicole Klein of the University of Bonn published in "Science" in 2005. According to this, The researchers have now carefully documented the variations in skulls of different sizes. A significant portion of the differences can be attributed to bone deformation during fossilization deep below the Earth's surface. Individual variations must be distinguished from this: The posterior branch of the zygomatic bone, which is sometimes bifurcated and sometimes not, appeared most striking to the researchers. A strongly sculptured bone bridge over the eye was also present only in some skulls. The relative size of the nasal opening also varies."It becomes apparent that each skull has a unique combination of features," Lallensack notes, emphasizing the distinct individuality of these dinosaurs. The uniquely large number of skulls studied made it possible to show that the differences in characteristics were variations within a species and not different species. "Only if as many finds as possible are excavated and secured will we obtain the high quantities needed to prove species affiliation and answer fundamental questions of biology" says Sander.
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Biology
| 2,021 |
February 25, 2021
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https://www.sciencedaily.com/releases/2021/02/210225190945.htm
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Signal transduction without signal: Receptor clusters can direct cell movement
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Our body consists of 100 trillion cells that communicate with each other, receive signals from the outside world and react to them. A central role in this communication network is attributed to receiver proteins, called receptors, which are anchored at the cell membrane. There, they receive and transmit signals to the inside of the cell, where a cell reaction is triggered.
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In humans, G protein-coupled receptors (GPC receptors) represent the largest group of these receptor molecules, with around 700 different types. The research of the Frankfurt and Leipzig scientists focused on a GPC receptor that serves as a receptor for the neuropeptide Y in cells and is accordingly called the Y2 receptor. Neuropeptide Y is a messenger substance that primarily mediates signals between nerve cells, which is why Y2 receptors are mainly present in nerve cells and among other activities trigger the formation of new cell connections.In the laboratory, the researchers engineered cells, which had approx. 300,000 Y2 receptors on their surface and were grown on specifically developed, light-sensitive matrices. Each of the Y2 receptors was provided with a small molecular "label." Once the scientists created a spot of light with a fine laser beam on the cell surface, the Y2 receptor under this spot were trapped via the molecular label to the exposed matrix in such a way that the Y2 receptors moved closely together to form an assembly known as a cluster. The whole reaction could be immediately observed at the defined spot and within a few seconds.Professor Robert Tampé from the Institute of Biochemistry at Goethe University Frankfurt explains: "The serendipity about this experiment is that the clustering of receptors triggers a signal that is similar to that of neuropeptide Y. Solely by the clustering, we were able to trigger cell movement as a reaction of the cell. The laser spots even allowed us to control the direction of the cell movement." As the light-sensitive lock-and-key pairs utilized are very small compared to the receptors, the organization of the receptors in the cell membrane can be controlled with high precision using the laser spot. "This non-invasive method is thus particularly well suited to study the effects of receptor clustering in living cells," Tampé continues. "Our method can be used to investigate exciting scientific questions, such as how receptors are organized in networks and how new circuits are formed in the brain."
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Biology
| 2,021 |
February 25, 2021
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https://www.sciencedaily.com/releases/2021/02/210225171648.htm
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First complete coronavirus model shows cooperation
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The COVID-19 virus holds some mysteries. Scientists remain in the dark on aspects of how it fuses and enters the host cell; how it assembles itself; and how it buds off the host cell.
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Computational modeling combined with experimental data provides insights into these behaviors. But modeling over meaningful timescales of the pandemic-causing SARS-CoV-2 virus has so far been limited to just its pieces like the spike protein, a target for the current round of vaccines.A new multiscale coarse-grained model of the complete SARS-CoV-2 virion, its core genetic material and virion shell, has been developed for the first time using supercomputers. The model offers scientists the potential for new ways to exploit the virus's vulnerabilities."We wanted to understand how SARS-CoV-2 works holistically as a whole particle," said Gregory Voth, the Haig P. Papazian Distinguished Service Professor at the University of Chicago. Voth is the corresponding author of the study that developed the first whole virus model, published November 2020 in the "We developed a bottom-up coarse-grained model," said Voth, "where we took information from atomistic-level molecular dynamics simulations and from experiments." He explained that a coarse-grained model resolves only groups of atoms, versus all-atom simulations, where every single atomic interaction is resolved. "If you do that well, which is always a challenge, you maintain the physics in the model."The early results of the study show how the spike proteins on the surface of the virus move cooperatively."They don't move independently like a bunch of random, uncorrelated motions," Voth said. "They work together."This cooperative motion of the spike proteins is informative of how the coronavirus explores and detects the ACE2 receptors of a potential host cell."The paper we published shows the beginnings of how the modes of motion in the spike proteins are correlated," Voth said. He added that the spikes are coupled to each other. When one protein moves another one also moves in response."The ultimate goal of the model would be, as a first step, to study the initial virion attractions and interactions with ACE2 receptors on cells and to understand the origins of that attraction and how those proteins work together to go on to the virus fusion process," Voth said.Voth and his group have been developing coarse-grained modeling methods on viruses such as HIV and influenza for more than 20 years. They 'coarsen' the data to make it simpler and more computationally tractable, while staying true to the dynamics of the system."The benefit of the coarse-grained model is that it can be hundreds to thousands of times more computationally efficient than the all-atom model," Voth explained. The computational savings allowed the team to build a much larger model of the coronavirus than ever before, at longer time-scales than what has been done with all-atom models."What you're left with are the much slower, collective motions. The effects of the higher frequency, all-atom motions are folded into those interactions if you do it well. That's the idea of systematic coarse-graining."The holistic model developed by Voth started with atomic models of the four main structural elements of the SARS-CoV-2 virion: the spike, membrane, nucleocapsid, and envelope proteins. These atomic models were then simulated and simplified to generate the complete course-grained model.The all-atom molecular dynamics simulations of the spike protein component of the virion system, about 1.7 million atoms, were generated by study co-author Rommie Amaro, a professor of chemistry and biochemistry at the University of California, San Diego."Their model basically ingests our data, and it can learn from the data that we have at these more detailed scales and then go beyond where we went," Amaro said. "This method that Voth has developed will allow us and others to simulate over the longer time scales that are needed to actually simulate the virus infecting a cell."Amaro elaborated on the behavior observed from the coarse-grained simulations of the spike proteins."What he saw very clearly was the beginning of the dissociation of the S1 subunit of the spike. The whole top part of the spike peels off during fusion," Amaro said.One of the first steps of viral fusion with the host cell is this dissociation, where it binds to the ACE2 receptor of the host cell."The larger S1 opening movements that they saw with this coarse-grained model was something we hadn't seen yet in the all-atom molecular dynamics, and in fact it would be very difficult for us to see," Amaro said. "It's a critical part of the function of this protein and the infection process with the host cell. That was an interesting finding."Voth and his team used the all-atom dynamical information on the open and closed states of the spike protein generated by the Amaro Lab on the Frontera supercomputer, as well as other data. The National Science Foundation (NSF)-funded Frontera system is operated by the Texas Advanced Computing Center (TACC) at The University of Texas at Austin."Frontera has shown how important it is for these studies of the virus, at multiple scales. It was critical at the atomic level to understand the underlying dynamics of the spike with all of its atoms. There's still a lot to learn there. But now this information can be used a second time to develop new methods that allow us to go out longer and farther, like the coarse-graining method," Amaro said."Frontera has been especially useful in providing the molecular dynamics data at the atomistic level for feeding into this model. It's very valuable," Voth said.The Voth Group initially used the Midway2 computing cluster at the University of Chicago Research Computing Center to develop the coarse-grained model.The membrane and envelope protein all-atom simulations were generated on the Anton 2 system. Operated by the Pittsburgh Supercomputing Center (PSC) with support from National Institutes of Health, Anton 2 is a special-purpose supercomputer for molecular dynamics simulations developed and provided without cost by D. E. Shaw Research."Frontera and Anton 2 provided the key molecular level input data into this model," Voth said."A really fantastic thing about Frontera and these types of methods is that we can give people much more accurate views of how these viruses are moving and carrying about their work," Amaro said."There are parts of the virus that are invisible even to experiment," she continued. "And through these types of methods that we use on Frontera, we can give scientists the first and important views into what these systems really look like with all of their complexity and how they're interacting with antibodies or drugs or with parts of the host cell."The type of information that Frontera is giving researchers helps to understand the basic mechanisms of viral infection. It is also useful for the design of safer and better medicines to treat the disease and to prevent it, Amaro added.Said Voth: "One thing that we're concerned about right now are the UK and the South African SARS-CoV-2 variants. Presumably, with a computational platform like we have developed here, we can rapidly assess those variances, which are changes of the amino acids. We can hopefully rather quickly understand the changes these mutations cause to the virus and then hopefully help in the design of new modified vaccines going forward."The study, "A multiscale coarse-grained model of the SARS-CoV-2 virion," was published on November 27, 2020 in the Biophysical Journal. The study co-authors are Alvin Yu, Alexander J. Pak, Peng He, Viviana Monje-Galvan, Gregory A. Voth of the University of Chicago; and Lorenzo Casalino, Zied Gaieb, Abigail C. Dommer, and Rommie E. Amaro of the University of California, San Diego. Funding was provided by the NSF through NSF RAPID grant CHE-2029092, NSF RAPID MCB-2032054, the National Institute of General Medical Sciences of the National Institutes of Health through grant R01 GM063796, National Institutes of Health GM132826, and a UC San Diego Moore's Cancer Center 2020 SARS-COV-2 seed grant. Computational resources were provided by the Research Computing Center at the University of Chicago, Frontera at the Texas Advanced Computer Center funded by the NSF grant (OAC-1818253), and the Pittsburgh Super Computing Center (PSC) through the Anton 2 machine. Anton 2 computer time was allocated by the COVID-19 HPC Consortium and provided by the PSC through Grant R01GM116961 from the National Institutes of Health. The Anton 2 machine at PSC was generously made available by D. E. Shaw Research."
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Biology
| 2,021 |
February 25, 2021
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https://www.sciencedaily.com/releases/2021/02/210225171639.htm
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Scientists use Doppler to peer inside cells
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Doppler radar improves lives by peeking inside air masses to predict the weather. A Purdue University team is using similar technology to look inside living cells, introducing a method to detect pathogens and treat infections in ways that scientists never have before.
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In a new study, the team used Doppler to sneak a peek inside cells and track their metabolic activity in real time, without having to wait for cultures to grow. Using this ability, the researchers can test microbes found in food, water, and other environments to see if they are pathogens, or help them identify the right medicine to treat antibiotic-resistant bacteria.David Nolte, Purdue's Edward M. Purcell Distinguished Professor of Physics and Astronomy; John Turek, professor of basic medical sciences; Eduardo Ximenes, research scientist in the Department of Agricultural and Biological Engineering; and Michael Ladisch, Distinguished Professor of Agricultural and Biological Engineering, adapted this technique from their previous study on cancer cells in a paper released this month in Using funding from the National Science Foundation as well as Purdue's Discovery Park Big Idea Challenge, the team worked with immortalized cell lines -- cells that will live forever unless you kill them. They exposed the cells to different known pathogens, in this case salmonella and E. coli. They then used the Doppler effect to spy out how the cells reacted. These living cells are called "sentinels," and observing their reactions is called a biodynamic assay."First we did biodynamic imaging applied to cancer, and now we're applying it to other kinds cells," Nolte said. "This research is unique. No one else is doing anything like it. That's why it's so intriguing."This strategy is broadly applicable when scientists have isolated an unknown microbe and want to know if it is pathogenic -- harmful to living tissues -- or not. Such cells may show up in food supply, water sources or even in recently melted glaciers."This directly measures whether a cell is pathogenic," Ladisch said. "If the cells are not pathogenic, the Doppler signal doesn't change. If they are, the Doppler signal changes quite significantly. Then you can use other methods to identify what the pathogen is. This is a quick way to tell friend from foe."Being able to quickly discern whether a cell is harmful is incredibly helpful in situations where people encounter a living unknown microorganism, allowing scientists to know what precautions to take. Once it is known that a microbe is harmful, they can begin established protocols that allow them to determine the specific identity of the cell and determine an effective antibiotic against the microorganism.Another benefit is the ability to quickly and directly diagnose which bacteria respond to which antibiotics. Antibiotic resistance can be a devastating problem in hospitals and other environments where individuals with already compromised bodies and immune systems may be exposed to and infected by increasingly high amounts of antibiotic resistant bacteria. Sometimes this results in a potentially fatal condition called bacterial sepsis, or septicemia. This is different from the viral sepsis that has been discussed in connection with COVID-19, though the scientists say their next steps will include investigating viral sepsis.Treating sepsis is challenging. Giving the patient broad-spectrum antibiotics, which sounds like a good idea, might not help and could make the situation worse for the next patient. Letting bacteria come into close contact with antibiotics that do not kill them only makes them more resistant to that antibiotic and more difficult to fight next time.Culturing the patient's tissues and homing in on the correct antibiotic to use can take time the patient does not have, usually eight to 10 hours. This new biodynamic process allows scientists to put the patient's bacterial samples in an array of tiny petri dishes containing the tissue sentinels and treat each sample with a different antibiotic. Using Doppler, they can quickly notice which bacterial samples have dramatic metabolic changes. The samples that do are the ones that have reacted to the antibiotic -- the bacteria are dying, being defeated and beaten back by antibiotics."When we treat with antibiotics, the bacteria don't have to multiply much before they start to affect the tissue sentinels," Nolte explained. "There are still too few bacteria to see or to measure directly, but they start to affect how the tissues behaves, which we can detect with Doppler."In less than half the time a traditional culture and diagnosis takes, doctors could tell which antibiotic to administer, bolstering the patient's chances for recovery. The researchers worked closely with the Purdue Research Foundation Office of Technology Commercialization to patent and license their technologies. They plan to further explore whether this method would work for tissue samples exposed to nonliving pathogenic cells or dried spores, and to test for and treat viral sepsis.
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Biology
| 2,021 |
February 25, 2021
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https://www.sciencedaily.com/releases/2021/02/210225143835.htm
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Tiny crustaceans' show fastest repeatable movements ever seen in marine animals
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A group of crustaceans called amphipods can accelerate as fast as a bullet -- literally, according to a new study by biologists at the University of Alberta and Duke University.
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This study shows that a tiny and unusual species is responsible for making the fastest repeatable movements yet known for any animal in water."The high speeds of these repeatable movements reach nearly 30 metres per second or more than 100 kilometres per hour," explained Richard Palmer, professor emeritus in the Department of Biological Sciences and co-author on the study."They have the highest accelerations of any animal in water, reaching more than 0.5 million metres per second squared, which is close to the acceleration of a bullet."Amphipods are a type of crustacean related to marine beach hoppers and freshwater scuds. Male amphipods use their large claws to make ultra-fast, repeatable snapping motions. The snaps make a popping sound and create rapid water jets that may be used to defend their territory."Each new discovery of extreme movements in a novel group of organisms raises fascinating questions about how such extreme adaptations are achieved in terms of biomechanics and functional behaviour, and how they evolved from more common, slower-moving relatives," said Palmer.Though faster movements have been seen in other creatures, these movements only happen once and cannot be repeated. As Palmer noted, the mechanism that allows amphipods to create such high-speed movements repeatedly could inspire human engineering efforts."This may suggest novel engineering solutions to design and build small structures that can move extremely fast over and over."This research was led by Sarah Longo and Sheila Patek at Duke University, in collaboration with Palmer in the U of A's Faculty of Science. Funding was provided by the Natural Sciences and Engineering Research Council of Canada.The study, "Tiny snaps of an amphipod push the boundary of ultrafast, repeatable movement," was published in
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Biology
| 2,021 |
February 25, 2021
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https://www.sciencedaily.com/releases/2021/02/210225143811.htm
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Harnessing the power of proteins in our cells to combat disease
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Over many decades now, traditional drug discovery methods have steadily improved at keeping diseases at bay and cancer in remission. And for the most part, it's worked well.
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But it hasn't worked perfectly.A lab on UNLV's campus has been a hub of activity in recent years, playing a significant role in a new realm of drug discovery -- one that could potentially provide a solution for patients who have run out of options."It's starting to get to the point where we've kind of taken traditional drug discovery as far as we can, and we really need something new," said UNLV biochemist Gary Kleiger.Traditional drug discovery involves what is called the small molecule approach. To attack a protein that's causing disease in a cancer cell, for instance, a traditional drug has to -- in a very targeted way -- find that protein and shut down its activities.It'd be like filling a baseball player's glove with a bunch of cement."The glove gives a baseball player the ability to do his job and catch a baseball," Kleiger said. "But if we were to take cement, and fill the pocket of the baseball glove with that cement, it would effectively shut down the ability of that baseball player to function on the team. That's what traditional drugs do."There's a big but, however. Up until this point, traditional drugs have only had the capability to target proteins that are participating in the disease that also have activities that are amenable to the small molecule approach, or, like the baseball player, actively engaging in the sport on the field.These proteins make up a seemingly small percentage of the disease-causing proteins in our bodies.So, as you can imagine, Kleiger said, while this model has helped effectively treat HIV and cancer, and helped treat everyday diseases through the use of antibiotics, it has some major setbacks."Cancer cells are clever," Kleiger said. "They can evolve very, very quickly. So, a drug might be working at first -- targeting an enzyme and telling that enzyme, 'stop doing your activity,' which can stop the cancer cells from growing. Those cancer cells appear to lie dormant, but all the while there are still little things that happen that eventually enable those cancer cells to bypass that drug." The upshot is that, to stay ahead of cancer's capacity to evolve drug resistance, we need to be able to target many additional disease-causing proteins, and thus, limiting the landscape of druggable proteins is a serious disadvantage.There might be a better way, and recent research published in the journal The new approach uses a family of human enzymes called ubiquitin ligases that exist in human cells. Enzymes are proteins in the cells of the body that speed up chemical reactions occurring at the cellular level and which help your body perform essential functions. There are roughly 20,000 known proteins in the human body, and perhaps some 5-10% are enzymes.Kleiger first became interested in the ubiquitin protein as a postdoctoral fellow at the California Institute of Technology in the 2000s. At the time, Kleiger heard of a researcher who was working in what was then already appreciated to be an important field but that had yet to fully blossom."I didn't have any idea that the field was going to become this important. I just thought it sounded really cool, and something I wanted to explore," he said.Now, nearly 20 years later, Kleiger and colleagues are helping to uncover how ubiquitin ligases work in molecular detail. And this has become especially important, considering that these enzymes are now being employed in a totally novel type of drug discovery modality.Instead of targeting enzymes that have an active role in the disease -- like the baseball player on the field -- there might be a way to target practically any protein that has a role in making a person sick. Think of a baseball team manager or the owner, Kleiger said."They're not a part of the team on the field, but they nevertheless can have a huge role to play in making the baseball team work," he said. "If I want to get rid of that protein, I can't use the traditional approach."That's where the ubiquitin ligase comes in. In the presence of special new drugs first envisioned by Kleiger's post-doctoral mentor Dr. Ray Deshaies and his collaborator Dr. Craig Crews, the ubiquitin ligase is now guided to the disease-causing protein to strategically target that protein for degradation, essentially killing it."People believe in this new modality, this new therapy so much that every major pharmaceutical company is now at various stages of developing this," Kleiger said. Indeed, a phase two clinical trial led by the pharmaceutical company Arvinas is already testing the approach in patients for the treatment of prostate cancer. "This would be like the equivalent of you stepping into a batting cage for the old modality, to now being inside of Allegiant Stadium -- this is an unbelievable new playing field."To do this work effectively, scientists needed to understand the biology of ubiquitin ligases -- work that has been going on for less than 30 years, which is a short time in the grand scheme of science and discovery, Kleiger said. And in that time, the technology has gotten sharper and more efficient.So efficient that for the first time, Kleiger's collaborators are using new, state-of-the-art cryo electron microscopes to be able to take pictures of what the ubiquitin ligases look like when they're at work."It's enabling us for the first time to really be able to see how they work, which is going to have huge impacts on the pharmaceutical industry's ability to make new drug therapies," Kleiger said. "It's truly a sea change moment."The microscope is able to photograph these enzymes, and in his lab on UNLV's campus, Kleiger and collaborators use the photographs to hypothesize how the enzymes are working. He then measures the activity of 'mutated' enzymes that should now be defective in their activities if their hypothesis is correct.The work would be similar to a 50,000-year old society being given a picture of a bicycle, and asked to explain how it works."They might hypothesize that it's a bicycle, and that you would use it to ride from point A to point B, or if there was a cart attached, you would use it to transport stuff," Kleiger said. "You'd then have to test that hypothesis, and that's what we do at UNLV."Kleiger examines the picture, and if it were the bicycle, uncovers that a gear on the bike is very important to its operational ability."If you were to bend that gear, now the bike's not going to work -- the chain will just fall off," Kleiger said. "We can do that at the molecular level with the enzymes."His work, in collaboration with colleagues at the Max Planck Institute of Biochemistry and published in the journal "These are diseases that millions of people around the world suffer from, so that's one of the reasons why this is such great news," Kleiger said. "For the first time ever, we're seeing atomic resolution pictures of the ubiquitin ligase at work, and that's undoubtedly going to be synergistic with pharmaceutical companies that are creating drugs harnessing the power of the ubiquitin ligase. It really could be a game changer."
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Biology
| 2,021 |
February 25, 2021
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https://www.sciencedaily.com/releases/2021/02/210225143731.htm
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Drive-thru type test to detect viral infections in bacteria
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The pandemic has made clear the threat that some viruses pose to people. But viruses can also infect life-sustaining bacteria and a Johns Hopkins University-led team has developed a test to determine if bacteria are sick, similar to the one used to test humans for COVID-19.
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"If there was a COVID-like pandemic occurring in important bacterial populations it would be difficult to tell, because before this study, we lacked the affordable and accurate tools necessary to study viral infections in uncultured bacterial populations," said study corresponding author Sarah Preheim, a Johns Hopkins assistant professor of environmental health and engineering.The findings were published today in Sick bacteria are stymied in their function as decomposers and as part of the foundation of the food web in the Chesapeake Bay and other waterways. Determining viral infections in bacteria traditionally relies on culturing both bacteria and virus, which misses 99% of bacteria found in the environment because they cannot be grown in culture, Preheim says, adding that tests of viral infections in uncultured bacteria are expensive and difficult to apply widely, not unlike the early stages of COVID-19 testing.The key to making a test of viral infections for uncultured bacteria faster and more affordable was to isolate single bacterial cells in a small bubble (i.e. an emulsion droplet) and fuse the genes of the virus and bacteria together once inside."The fused genes act like name tags for the bacteria and viruses," said lead author Eric Sakowski, a former postdoctoral researcher in Preheim's laboratory who is now an assistant professor at Mount St. Mary's University. "By fusing the genes together, we are able to identify which bacteria are infected, as well as the variant of the virus that is causing the infection."The resulting test provides a novel way to screen for viral infections in a subset of bacterial populations. The test allows researchers to identify a link between environmental conditions and infections in Actinobacteria, one of the most abundant bacterial groups in the Chesapeake Bay and one that plays a crucial role in decomposing organic matter, making nutrients available to plants and photosynthetic algae.Though the researchers developed this tool studying the Chesapeake Bay, they say their approach could be widely applied across aquatic ecosystems, shedding light on viral ecology and helping predict -- and even prevent -- devastating environmental impacts."This testing tool allows us to track viral infections more easily, so we can monitor these infections to see when they are most likely to have important environmental consequences," Preheim said.Sakowski said the new test could someday also affect how we treat bacterial infections."Viruses show potential for treating infections caused by antibiotic-resistant bacteria," he said. "Knowing which viruses most effectively infect bacteria will be critical to this type of treatment."Preheim's team also included Johns Hopkins doctoral student Keith Arora-Williams, and Funing Tian, Ahmed A. Zayed, Olivier Zablocki, and Matthew B. Sullivan, all from the Ohio State University.Support was provided by the National Science Foundation and the Gordon E. and Betty I. Moore Foundation.
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Biology
| 2,021 |
February 25, 2021
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https://www.sciencedaily.com/releases/2021/02/210225143651.htm
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Male superb lyrebirds imitate alarm calls of a 'mobbing flock' while mating
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When birds see a predator in their midst, one defensive strategy is to call out loudly, attracting other birds of the same or different species to do the same. Sometimes individuals within this "mobbing flock" will fly over or at the predator or attack it directly. Now, researchers reporting in the journal
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"Our paper shows that male superb lyrebirds regularly create a remarkable acoustic illusion of a flock of mobbing birds and, in so doing, create a complex but potent cue of a hidden predator," says Anastasia Dalziell of the Cornell Lab of Ornithology. "Astonishingly, males only mimic a mobbing flock in two contexts: when a potential mate tries to leave a displaying male without copulating, or during copulation itself. These two moments are key to male reproductive success, suggesting that mimicking a mobbing flock is a crucial sexual behavior for males."Male superb lyrebirds already are world famous for their extraordinary ability to mimic complex sounds of human origin such as chainsaws. But the reasons for their impressive mimicking skills have been somewhat mysterious, Dalziell says.Dalziell and her colleagues didn't set out initially to study the mobbing mimicry at all. They were expecting to capture instead the male's loud, flamboyant, and musical mimetic recital song. But, to their surprise, they began hearing the male lyrebirds mimicking a sound that's much less melodious at the end of each mating dance display: the panicked alarm calls of a mixed-species flock of birds. "It was a superb piece of mimicry, if you will excuse the pun," Dalziell says.The second surprise was watching and recording a male lyrebird mimicking a mixed-species mobbing flock during copulation."That seemed remarkable -- indeed it seemed absurd," Dalziell says. "We gradually realized that mimicking a mobbing flock during copulation seemed to be the rule for lyrebirds," although she noted that it's very hard to observe copulations in lyrebirds. "It was such a strange and complex behavior that we thought that we really needed audio-video footage to show everyone, and we were lucky enough to eventually film several events."She says it's not clear exactly how males benefit from their extraordinary mimicry. But the evidence suggests a likely explanation is that males set a kind of "sensory trap" for females. The males may gain a reproductive advantage by tricking the female into responding as if she may be at risk of a predator. Because females have to watch out for predators all the time, the sound of the mob is tough to tune out. Dalziell says, "It's a bit like saying, 'Baby, it's dangerous out there. Stay here with me.'" The stalling tactic might allow for copulation to happen in the first place or last longer, preventing females from leaving before sperm has been successfully transferred. In addition to being intriguing, the findings also extend scientists' traditional understanding of mimicry."In the past, biologists have specified that mimicry involves three protagonists: a mimic, a signal receiver, and a model. But here we have an example of one individual -- a male lyrebird -- mimicking an entire ecological scene comprising multiple individuals and multiple species calling simultaneously," she says.The findings also suggest that elaborate bird songs aren't always an honest signal. They can be driven by sexual conflict and deception, which represents an important departure from conventional explanations for song evolution that rely on females' preferences for male extravagance, the researchers say. In future studies, the researchers plan to explore the females' reactions to actual mobbing flocks versus mimetic ones. They also want to understand exactly how the mimetic song benefits males.They've got lots of other questions, too. For example, Dalziell says, another odd behavior that they've observed is that during copulation, the male holds his wings over the female's head. "Are males 'blindfolding' females to prevent females from detecting the male's deception?" she asks.This work was supported by Australian National University, the Cornell Lab of Ornithology Rose Postdoctoral Fellowship Program (AHD), an Australian Postgraduate Award (AHD), a University of Wollongong VC Postdoctoral Fellowship (AHD), an ARC Discovery Project (RDM), an NSF grant, the Hawkesbury Institute for the Environment (JAW), BirdLife Australia's Stuart Leslie Award program (AHD), and the Australian Geographic Society (AHD).
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Biology
| 2,021 |
February 25, 2021
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https://www.sciencedaily.com/releases/2021/02/210225143648.htm
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Bacterial toxin is found in patients with urinary tract infections
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A DNA-damaging bacterial toxin called colibactin is produced in patients with urinary tract infections (UTIs), according to a study published February 25th in the open-access journal
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UTIs are among the most common bacterial infections, affecting approximately 150 million individuals each year. UTIs occur most frequently in women, with more than 60% of females diagnosed with a UTI during their lifetime. In addition to their consequences in terms of illness, mortality, and economic losses, UTIs are also a major reason for antibiotic treatments and thus strongly contribute to the global issue of antibiotic resistance. Uropathogenic E. coli (UPEC) cause approximately 80% of all UTIs. In the new study, the researchers show that colibactin, which is suspected of being involved in cancer, is produced in UPEC-infected patients with UTIs.The researchers analyzed urine samples from 223 patients with community-acquired UTIs, and detected evidence of colibactin synthesis in 55 of the samples examined. Moreover, UPEC strains isolated from these patients produced colibactin. In a mouse model of UTI, colibactin-producing bacteria induced extensive DNA damage in bladder cells. According to the authors, the findings support the idea that UTIs may play a role in bladder cancer.The authors conclude, "Our work suggests that there should be a more specific follow-up of patients regularly suffering from urinary tract infections, with a systematic search for colibactin markers in their urine, but also more proactive, by proposing therapeutic approaches aimed at modulating the composition of their intestinal microbiota, which represents the main reservoir of the E. coli bacteria involved in these urinary tract infections."
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Biology
| 2,021 |
February 25, 2021
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https://www.sciencedaily.com/releases/2021/02/210225143638.htm
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How plant stem cells renew themselves -- a cytokinin story
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The mechanism by which the plant hormone cytokinin controls cell division has been discovered -- a breakthrough that significantly improves our understanding of how plants grow.
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Cell division is fundamental for all forms of life -- all multi-cellular organisms, including plants and animals, develop from a single cell that divides billions of times to build a complex organism. Undifferentiated stem cells in plants function as a reservoir of new cells from which the plant can grow and develop specialised tissues. New stems, new leaves, new roots and new flowers all originate from small clusters of stem cells in growth regions called apical meristems.The cells in these growth regions are continually dividing in a process called mitosis, which build the plant's architecture. Scientists have long known that cytokinin is central to these acts of cell division, but without knowing exactly how it stimulates cell proliferation.In a paper published in the journal Using Arabidopsis thaliana -- a member of the mustard family commonly used as a model plant in plant science research -- they show cytokinin directly promotes the transport of the transcription factor MYB3R4 from the cytoplasm to the nucleus where it activates the expression of key cell cycle genes.Dr Weibing Yang, lead author of the paper and now a group leader at the Centre of Excellence for Plant and Microbial Science (CEPAMS) said: "Understanding how stem cell self-renewal is controlled is crucial for understanding plant growth and development. We knew the plant hormone cytokinin was important, and our research now explains the mechanism by which cytokinin regulates stem cell division -- It does this by shuttling proteins into the nucleus where they activate genes involved in mitosis."In mitotic cell division (mitosis), chromosomes replicate and then are segregated equally into two daughter cells. "Using time-lapse confocal microscopy of live plants, we were able to capture cellular dynamics of proteins that were found to be important for triggering mitosis," added Dr Raymond Wightman, Imaging Core Facility Manager at the Sainsbury Laboratory."Time lapse observation of individual cells revealed rapid changes in MYB3R4 protein location," Dr Yang explained. "Prior to cell division the protein was predominantly in the cytoplasm, and at the onset of mitosis, there was a rapid accumulation of MYB3R4 in the nucleus, followed by the protein being exported back into the cytoplasm at the completion of cell division. It has been known for more than 40 years that plant endogenous cytokinin level fluctuates during the cell cycle, and peaks at the G2/M transition. We now show that a direct response of this cytokinin peak is MYB3R4 nuclear trafficking."Further experiments revealed that cytokinin functions as a 'molecular switch' that triggers a positive feedback loop -- it promotes MYB3R4 nuclear localisation to activate the transcription of importin genes IMPA3 and IMPA6, which in turn act to facilitate MYB3R4 nuclear import. "With mathematical modelling, we demonstrate that this positive feedback can cause MYB3R4 nuclear trafficking to become both faster and stronger," said Professor Henrik Jönsson."Our findings may have practical applications," Dr Yang added, "through mutating the nuclear export signal, we were able to engineer a constitutively nuclear localised MYB3R4 protein, and found that it could greatly enhance stem cell proliferation and meristem growth, partially mimicking the effect of cytokinin treatment.""Increased cytokinin in the shoot meristem is one of the results of increasing nitrogen nutrition at the roots. Being able to increase the cytokinin cell division response in the meristem may provide a way to have plants grow as if they were well-fertilized, even when nitrogen levels in the soil are suboptimal," said Professor and Howard Hughes Medical Institute Investigator Elliot Meyerowitz.By enabling a deeper understanding of how plant cells divide in growth, fundamental plant science like this research could help identify new ways to enhance plant growth and sets a foundation for future work that can impact on plant health and agricultural yield.
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Biology
| 2,021 |
February 25, 2021
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https://www.sciencedaily.com/releases/2021/02/210225113308.htm
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Super-resolution RNA imaging in live cells
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Ribonucleic acid (RNA) is key to various fundamental biological processes. It transfers genetic information, translates it into proteins or supports gene regulation. To achieve a more detailed understanding of the precise functions it performs, researchers based at Heidelberg University and at the Karlsruhe Institute of Technology (KIT) have devised a new fluorescence imaging method which enables live-cell RNA imaging with unprecedented resolution.
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The method is based on a novel molecular marker called Rhodamine-Binding Aptamer for Super-Resolution Imaging Techniques (RhoBAST). This RNA-based fluorescence marker is used in combination with the dye rhodamine. Due to their distinctive properties, marker and dye interact in a very specific way, which makes individual RNA molecules glow. They can then be made visible using single-molecule localisation microscopy (SMLM), a super-resolution imaging technique. Due to a lack of suitable fluorescence markers, direct observation of RNA via optical fluorescence microscopy has been severely limited to date.RhoBAST was developed by researchers from the Institute of Pharmacy and Molecular Biotechnology (IPMB) at Heidelberg University and the Institute of Applied Physics (APH) at KIT. The marker created by them is genetically encodable, which means that it can be fused to the gene of any RNA produced by a cell. RhoBAST itself is non-fluorescent, but lights up a cell-permeable rhodamine dye by binding to it in a very specific way. "This leads to a dramatic increase in fluorescence achieved by the RhoBAST-dye complex, which is a key requirement for obtaining excellent fluorescence images," explains Dr Murat Sunbul from the IPMB, adding: "However, for super-resolution RNA imaging the marker needs additional properties."The researchers discovered that each rhodamine dye molecule remains bound to RhoBAST for approximately one second only before becoming detached again. Within seconds, this procedure repeats itself with a new dye molecule. "It is quite rare to find strong interactions -- as between RhoBAST and rhodamine -- combined with exceptionally fast exchange kinetics," says Prof. Dr Gerd Ulrich Nienhaus from the APH. Since rhodamine only lights up after binding to RhoBAST, the constant string of newly emerging interactions between marker and dye results in incessant "blinking." "This 'on-off switching' is exactly what we need for SMLM imaging," continues Prof. Nienhaus.At the same time, the RhoBAST system solves yet another important problem. Fluorescence images are collected under laser light irradiation, which destroys the dye molecules over time. The fast dye exchange ensures that photobleached dyes are replaced by fresh ones. This means that individual RNA molecules can be observed for longer periods of time, which can greatly improve image resolution, as Prof. Dr Andres Jaeschke, a scientist at the IPMB, explains.The researchers from Heidelberg and Karlsruhe were able to demonstrate the superb properties of RhoBAST as an RNA marker by visualising RNA structures inside gut bacteria (Escherichia coli) and cultured human cells with excellent localisation precision. "We can reveal details of previously invisible subcellular structures and molecular interactions involving RNA using super-resolution fluorescence microscopy. This will enable a fundamentally new understanding of biological processes," says Prof. Jaeschke.The research carried out by Murat Sunbul and Andres Jaeschke in the context of the study was supported by the German Research Foundation (DFG) and the work performed by Gerd Ulrich Nienhaus was supported by the DFG and the Helmholtz Association. The results were published in the journal
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Biology
| 2,021 |
February 25, 2021
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https://www.sciencedaily.com/releases/2021/02/210225082429.htm
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Scientists reveal details of antibodies that work against Zika virus
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The Zika outbreak of 2015 and 2016 is having lasting impacts on children whose mothers became infected with the virus while they were pregnant. Though the numbers of Zika virus infections have dropped, which scientists speculate may be due to herd immunity in some areas, there is still potential for future outbreaks. To prevent such outbreaks, scientists want to understand how the immune system recognizes Zika virus, in hopes of developing vaccines against it. Shannon Esswein, a graduate student, and Pamela Bjorkman, a professor, at the California Institute of Technology, have new insights on how the body's antibodies attach to Zika virus. Esswein will present the work, which was published in PNAS, on Thursday, February 25 at the 65th Biophysical Society Annual Meeting.
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Zika virus is a kind of flavivirus, and other flavivirus family members include dengue, West Nile, and yellow fever virus. To protect against these and other pathogens, "we have the ability to make a huge diversity of antibodies, and if we get infected or vaccinated, those antibodies recognize the pathogen," Esswein said. But sometimes when the body mounts an immune response against a flavivirus, there is concern that this response could make the person sicker if they get infected a second time. Called antibody-dependent enhancement (ADE), this happens when the antibodies stick to the outside of the virus without blocking its ability to infect cells, which can inadvertently help the virus infect more cells by allowing it enter cells that the antibodies stick to.In order to prevent ADE when creating a vaccine, it's crucial for scientists to have a detailed understanding of how antibodies stick to a specific virus. This is especially important for flaviviruses, because antibodies that protect against one flavivirus may also stick to, but not protect against other flavivirus, increasing the risk of ADE. There is a concern that antibodies generated in response to a Zika virus vaccine could trigger ADE if someone were to be later infected with dengue or other flaviviruses.To study the antibody response to Zika and other flavivirus, Esswein and Bjorkman looked at several antibodies from the blood of patients from Mexico and Brazil. To find antibodies that recognize flaviviruses, they used a piece of the outside of the virus, called the envelope domain III protein. Previous studies have shown the envelope domain III is an important target of protective antibodies that fight flavivirus infections.The researchers studied how those antibodies changed over time as they mature and become better able to stick to Zika virus, and also how the antibodies cross-react with other flaviviruses, including the four types of dengue viruses. They found that the Zika antibodies also tightly stick to and defend against dengue type 1, and weakly stick to West Nile and dengue types 2 and 4. "The weak cross-reactivity of these antibodies doesn't seem to defend against those flaviviruses, but also doesn't induce ADE," Esswein said, suggesting envelope domain III may be useful to make a vaccine that is safe. They also determined structures showing how two antibodies recognize Zika and West Nile envelope domain III.Together, the team's experiments show how the body mounts "a potent immune response to Zika virus," says Esswein. Their insights into the antibodies involved in this immune response will help inform vaccine design strategy.
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Biology
| 2,021 |
February 25, 2021
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https://www.sciencedaily.com/releases/2021/02/210225082527.htm
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'Miracle poison' for novel therapeutics
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When people hear botulinum toxin, they often think one of two things: a cosmetic that makes frown lines disappear or a deadly poison.
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But the "miracle poison," as it's also known, has been approved by the F.D.A. to treat a suite of maladies like chronic migraines, uncontrolled blinking, and certain muscle spasms. And now, a team of researchers from Harvard University and the Broad Institute have, for the first time, proved they could rapidly evolve the toxin in the laboratory to target a variety of different proteins, creating a suite of bespoke, super-selective proteins called proteases with the potential to aid in neuroregeneration, regulate growth hormones, calm rampant inflammation, or dampen the life-threatening immune response called cytokine storm."In theory, there is a really high ceiling for the number and type of conditions where you could intervene," said Travis Blum, a postdoctoral researcher in the Department of Chemistry and Chemical Biology and first author on the study published in Together, the team achieved two firsts: They successfully reprogrammed proteases -- enzymes that cut proteins to either activate or deactivate them -- to cut entirely new protein targets, even some with little or no similarity to the native targets of the starting proteases, and to simultaneously avoid engaging their original targets. They also started to address what Blum called a "classical challenge in biology": designing treatments that can cross into a cell. Unlike most large proteins, botulinum toxin proteases can enter neurons in large numbers, giving them a wider reach that makes them all the more appealing as potential therapeutics.Now, the team's technology can evolve custom proteases with tailor-made instructions for which protein to cut. "Such a capability could make 'editing the proteome' feasible," said Liu, "in ways that complement the recent development of technologies to edit the genome."Current gene-editing technologies often target chronic diseases like sickle cell anemia, caused by an underlying genetic error. Correct the error, and the symptoms fade. But some acute illnesses, like neurological damage following a stroke, aren't caused by a genetic mistake. That's where protease-based therapies come in: The proteins can help boost the body's ability to heal something like nerve damage through a temporary or even one-time treatment.Scientists have been eager to use proteases to treat disease for decades. Unlike antibodies, which can only attack specific alien substances in the body, proteases can find and attach to any number of proteins, and, once bound, can do more than just destroy their target. They could, for example, reactivate dormant proteins."Despite these important features, proteases have not been widely adopted as human therapeutics," said Liu, "primarily because of the lack of a technology to generate proteases that cleave protein targets of our choosing."But Liu has a technological ace in his pocket: PACE (which stands for phage-assisted continuous evolution). A Liu lab invention, the platform rapidly evolves novel proteins with valuable features. PACE, Liu said, can evolve dozens of generations of proteins a day with minimal human intervention. Using PACE, the team first taught so-called "promiscuous" proteases -- those that naturally target a wide swath of proteins -- to stop cutting certain targets and become far more selective. When that worked, they moved on to the bigger challenge: Teaching a protease to only recognize an entirely new target, one outside its natural wheelhouse."At the outset," said Blum, "we didn't know if it was even feasible to take this unique class of proteases and evolve them or teach them to cleave something new because that had never been done before." ("It was a moonshot to begin with," said Michael Packer, a previous Liu lab member and an author on the paper). But the proteases outperformed the team's expectations. With PACE, they evolved four proteases from three families of botulinum toxin; all four had no detected activity on their original targets and cut their new targets with a high level of specificity (ranging from 218- to more than 11,000,000-fold). The proteases also retained their valuable ability to enter cells. "You end up with a powerful tool to do intracellular therapy," said Blum. "In theory.""In theory" because, while this work provides a strong foundation for the rapid generation of many new proteases with new capabilities, far more work needs to be done before such proteases can be used to treat humans. There are other limitations, too: The proteins are not ideal as treatments for chronic diseases because, over time, the body's immune system will recognize them as alien substances and attack and defuse them. While botulinum toxin lasts longer than most proteins in cells (up to three months as opposed to the typical protein lifecycle of hours or days), the team's evolved proteins might end up with shorter lifetimes, which could diminish their effectiveness.Still, since the immune system takes time to identify foreign substances, the proteases could be effective for temporary treatments. And, to side-step the immune response, the team is also looking to evolve other classes of mammalian proteases since the human body is less likely to attack proteins that resemble their own. Because their work on botulinum toxin proteases proved so successful, the team plans to continue to tinker with those, too, which means continuing their fruitful collaboration with Min Dong, who not only has the required permission from the Centers for Disease Control (CDC) to work with botulinum toxin but provides critical perspective on the potential medical applications and targets for the proteases."We're still trying to understand the system's limitations, but in an ideal world," said Blum, "we can think about using these toxins to theoretically cleave any protein of interest." They just have to choose which proteins to go after next.
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Biology
| 2,021 |
February 25, 2021
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https://www.sciencedaily.com/releases/2021/02/210225082505.htm
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After Hurricane Irma, soundscape reveals resilient reef ecosystem
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A new study from North Carolina State University reveals that the soundscapes of coral reef ecosystems can recover quickly from severe weather events such as hurricanes. The work also demonstrates that non-invasive monitoring is an important tool in shedding further light on these key ecosystems.
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Soundscape ecology is a relatively new way for researchers to keep tabs on a variety of habitats without direct interference. In underwater habitats like coral reefs, soundscapes allow continual monitoring of an ecosystem that is difficult to access. By deploying underwater microphones, or hydrophones, researchers can get an acoustic picture of the types of animals in the ecosystem, as well as their behavior patterns.Kayelyn Simmons, a Ph.D. student at NC State, used soundscapes and underwater mapping to monitor two different reef sites in the Florida Keys from February to December 2017. She deployed and collected eight hydrophones every three months between the two sites: a pristine reef located at Eastern Sambo, and a fishing site located at Western Dry Rocks.Hurricane Irma struck the Florida Keys as a Category 4 storm in September 2017. Simmons was able to retrieve two of the hydrophones -- one from each site -- in December. Unfortunately, the hydrophone retrieved from Western Dry Rocks had been compromised by the storm, rendering its post-storm data unusable."Prior to the hurricane, we were able to determine what the 'normal' sound patterns were in each habitat, so we knew what the baselines were in terms of species and behavior," Simmons says. "You can tell which species are present based on where their sounds are on the frequency band. Similarly, the amount of noise from each species can give you an idea of their numbers. So the soundscape is a good way to measure abundance and diversity."Each study site had the same species present. For example, snapping shrimp, with their high frequency "Rice Krispies in milk" popping noises, were active in the periods between dusk and dawn; while grunts, grouper and snapper, with sounds in the lower frequency bands, were mainly active during the day. The hydrophones also captured spawning activity during the full moon.Simmons analyzed the sound captured by the surviving Eastern Sambo hydrophone and discovered that even though the reef suffered physical damage from the hurricane, the residents and their activity levels began returning to normal approximately 24 to 48 hours after the storm passed."The acoustic energy exposure for the reef was as loud as a small boat circling in one spot for two weeks," Simmons says. "So we didn't record any fish noises during the four-day period that Irma came through due to acoustic masking from the storm. However, the snapping shrimp were back to pre-storm sound levels within 24 hours. The fish noises on the lower frequency were back within 72. And on the next full moon we heard normal spawning behavior."Overall, the research shows that the coral reef soundscape was resilient and able to recover from the storm quickly."
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Biology
| 2,021 |
February 25, 2021
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https://www.sciencedaily.com/releases/2021/02/210225082451.htm
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Scientists achieve breakthrough in culturing corals and sea anemones cells
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Researchers have perfected the recipe for keeping sea anemone and coral cells alive in a petri dish for up to 12 days. The new study, led by scientists at the University of Miami (UM) Rosenstiel School of Marine and Atmospheric Science, has important applications to study everything from evolutionary biology to human health.
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Cnidarians are emerging model organisms for cell and molecular biology research. Yet, successfully keeping their cells in a laboratory setting has proved challenging due to contamination from the many microorganisms that live within these marine organisms or because the whole tissue survive in a culture environment.UM cell biologist Nikki Traylor-Knowles and her team used two emerging model organisms in developmental and evolutionary biology -- the starlet sea anemone (James Nowotny, a recent UM graduate mentored by Traylor-Knowles at the time, tested 175 cell cultures from the two organisms and found that their cells can survive for on average 12 days if they receive an antibiotic treatment before being cultured."This is a real breakthrough," said Traylor Knowles, an assistant professor of marine biology and ecology at the UM Rosenstiel School. "We showed that if you treat the animals beforehand and prime their tissues, you will get a longer and more robust culture to study the cell biology of these organisms.""This is the first time that individual cells from all tissues of coral or sea anemones were shown to survive in cell culture for over 12 days," said Nowotny, who is currently a graduate student at the University of Maryland.There are over 9,000 species in the phylum Cnidaria, which includes jellyfish, sea anemones, corals, Hydra, and sea fans. Due to several special unique attributes such as radial symmetry, a stinging cell known as a nematocyte and two-dermal cell layer, there is growing interest in using these animals to study key aspects of animal development."We can also now grow coral cells and use them in experiments that will help improve our understanding of their health in a very targeted way," said Traylor-Knowles.
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Biology
| 2,021 |
February 25, 2021
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https://www.sciencedaily.com/releases/2021/02/210225082443.htm
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New shape-changing 4D materials hold promise for morphodynamic tissue engineering
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New hydrogel-based materials that can change shape in response to psychological stimuli, such as water, could be the next generation of materials used to bioengineer tissues and organs, according to a team of researchers at the University of Illinois Chicago.
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In a new paper published in the journal In nature, embryonic development and tissue healing often involve a high concentration of cells and complex architectural and organizational changes that ultimately give rise to final tissue morphology and structure.For tissue engineering, traditional techniques have involved, for example, culturing biodegradable polymer scaffolds with cells in biochambers filled with liquid nutrients that keep the cells alive. Over time, when provided with appropriate signals, the cells multiply in number and produce new tissue that takes on the shape of the scaffold as the scaffold degrades. For example, a scaffold in the shape of an ear seeded with cells capable of producing cartilage and skin tissue may eventually become a transplantable ear.However, a geometrically static scaffold cannot enable the formation of tissues that dynamically change shape over time or facilitate interactions with neighboring tissues that change shape. A high density of cells is also typically not used and/or supported by the scaffolds."Using a high density of cells can be advantageous in tissue engineering as this enables increased cell-cell interactions that can promote tissue development," said Alsberg, who also is professor of orthopaedics, pharmacology and mechanical and industrial engineering at UIC.Enter 4D materials, which are like 3D materials, but they change shape when they are exposed to specific environmental cues, such as light or water. These materials have been eyed by biomedical engineers as potential new structural substrates for tissue engineering, but most currently available 4D materials are not biodegradable or compatible with cells.To take advantage of the promise of 4D materials for bioengineering applications, Alsberg and colleagues developed novel 4D materials based on gelatin-like hydrogels that change shape over time in response to the addition of water and are cell-compatible and biodegradable, making them excellent candidates for advanced tissue engineering. The hydrogels also support very high cell densities, so they can be heavily seeded with cells.In the paper, the researchers describe how exposure to water causes the hydrogel scaffolds to swell as the water is absorbed. The amount of swelling can be tuned by, for example, changing aspects of the hydrogel material such as its degradation rate or the concentration of cross-linked polymers -- strands of protein or polysaccharide in this case -- that comprise the hydrogels. The higher the polymer concentration and crosslinking, the less and more slowly a given hydrogel will absorb water to induce a change in shape.The researchers found that by layering hydrogels with different properties like a stack of paper, the difference in water absorption between the layers will cause the hydrogel stack to bend into a 'C' shaped conformation. If the stack bends enough, a tubular shape is formed, which resembles structures like blood vessels and other tubular organs.They also found that it is possible to calibrate the system to control the timing and the extent of shape change that occurred. The researchers were able to embed bone marrow stem cells into the hydrogel at very high density -- the highest density of cells ever recorded for 4D materials -- and keep them alive, a significant advance in bioengineering that has practical applications.In the paper, the researchers described how the shape-changing cell-laden hydrogel could be induced to become bone- and cartilage-like tissues. 4D bioprinting of this hydrogel was also implemented to obtain unique configurations to achieve more complex 4D architectures."Using our bilayer hydrogels, we can not only control how much bending the material undergoes and its temporal progression, but because the hydrogels can support high cell densities, they more closely mimic how many tissues form or heal naturally," said Yu Bin Lee, a biomedical engineering postdoctoral researcher and first author on the paper. "This system holds promise for tissue engineering, but may also be used to study the biological processes involved in early development."This research was supported by grants from the National Institutes of Health's National Institute of Arthritis And Musculoskeletal and Skin Diseases (R01AR069564, R01AR066193) and the National Institute of Biomedical Imaging and Bioengineering (R01EB023907).
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Biology
| 2,021 |
February 25, 2021
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https://www.sciencedaily.com/releases/2021/02/210225081939.htm
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Baby mice have a skill that humans want, and this microchip might help us learn it
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Baby mice might be small, but they're tough, too.
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For their first seven days of life, they have the special ability to regenerate damaged heart tissue.Humans, on the other hand, aren't so lucky: any heart injuries we suffer could lead to permanent damage. But what if we could learn to repair our hearts, just like baby mice?A team of researchers led by UNSW Sydney have developed a microchip that can help scientists study the regenerative potential of mice heart cells. This microchip -- which combines microengineering with biomedicine -- could help pave the way for new regenerative heart medicine research."We've developed a simple, reliable, cheap and fast way to identify and separate these important mouse heart cells," says lead author Dr Hossein Tavassoli, a biomedical engineer and stem cell researcher at UNSW Medicine & Health who conducted this work as part of his doctoral thesis."Our method uses a microchip that's easy to fabricate and can be made in any laboratory in the world."The process for identifying and separating mice heart cells is rather complex.First, scientists need to separate the Their next challenge is keeping the cells alive."Newborn mice heart cells (called proliferative cardiomyocytes) are very sensitive," says Dr Vashe Chandrakanthan, a senior research fellow at UNSW Medicine & Health and co-senior author of the study."Only about 20 per cent usually survive the conventional isolation and separation process. If we want to study these cells, we need to isolate them before they undergo cell death."Dr Tavassoli says that this new method is much more efficient."We reduced the stress applied on these cells by minimising the isolation and processing time," he says. "Our method can purify millions of cells in less than 10 minutes."Almost all of the cells survived when we used our microfluidic chip -- over 90 per cent."The spiral-shaped device is a microfluidic chip -- that is, a chip designed to handle liquids on tiny scale. It filters cells according to their size, separating the cardiomyocytes from other cells. The chip costs less than $500 to produce, making it cheaper than other isolation and separation methods.This tool will make it easier for researchers to study how baby mice repair their hearts -- and whether humans might be able to use the same technique."Heart disease is the number one killer in the world," says Dr Tavassoli. "In Australia, someone dies of heart disease every 12 minutes, and every four hours a baby is born with a heart defect."We hope that our device will help accelerate heart disease research."Once the heart cells were separated from other cells with the help of their chip, the researchers seized the opportunity to study the cells' physico-mechanical properties -- that is, the way they respond to force.This involved asking questions like 'How do these individual heart cells beat?', 'Do the cells have distinct features?' and 'What are their differences in size, shape and elasticity?'.The findings could provide new insights for developing materials that repair heart tissue, like cardiac patches, scaffolds and hydrogels."The fast, large-scale characterisation of cells' physico-mechanical features is a relatively new field of research," says Dr Tavassoli, who originally trained as an engineer before specialising in medicine."This is the first time microfluidic technology has been used to study mechanical properties of baby mouse heart cells."Dr Chandrakanthan says that even though the microchip was created for baby mouse heart cells, it could potentially be adapted for use in other types of cell applications."The principles are compatible with isolating cardiomyocytes from mouse heart cells of all ages," he says."We could potentially also use this method to separate not only the heart cells, but all sorts of cells from different organs."Dr Tavassoli says this method could also help other areas of medical research, including cardiac biology, drug discovery and nanoengineering. He is currently conducting research at the Garvan Institute and Lowy Cancer Research Centre on how this method could help cancer diagnosis."This microchip opens up the opportunity for new discoveries by researchers all over the world," he says.
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Biology
| 2,021 |
February 24, 2021
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https://www.sciencedaily.com/releases/2021/02/210224143527.htm
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Sulfur metabolism may have paved the way for evolution of multicellularity
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The transition from single-celled organisms to multicellular ones was a major step in the evolution of complex life forms. Multicellular organisms arose hundreds of millions of years ago, but the forces underlying this event remain mysterious. To investigate the origins of multicellularity, Erika Pearce's group at the MPI of Immunobiology and Epigenetics in Freiburg turned to the slime mold Dictyostelium discoideum, which can exist in both a unicellular and a multicellular state, lying on the cusp of this key evolutionary step. These dramatically different states depend on just one thing -- food.
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A core question of Pearce's lab is to answer how changes in metabolism drive cell function and differentiation. Usually, they study immune cells to answer this question, however, when first author Beth Kelly joined the group they decided to shift focus. "We figured that if we were interested in how nutrient availability induces changes in how cells function, there was no better organism to study than Dicty, where starvation causes cells to go from existing on their own to forming a multicellular organism. This is an immense shift in biology," Erika Pearce said.Simply by depriving D. discoideum of its food supply, they could turn this organism from single cells into a multicellular aggregate, allowing them to examine the factors driving this multicellularity. The aggregate behaves as a complex, multicellular organism, with individual cells specializing to having different functions, and moving as a whole. Multicellular D. discoideum eventually form a protective spore, allowing the population to survive starvation.Starving D. discoideum induce a rapid burst of reactive oxygen species (ROS) production. ROS are small molecules that are made by our cells, but were also used for signaling early in evolution, before more complex, receptor-based systems existed. However, when ROS levels are too high, they become damaging, oxidizing proteins and nucleic acids, eventually causing cells to die. So, an increase in ROS is generally accompanied by the production of antioxidants to control these ROS. Beth Kelly noted, "in our case, production of the antioxidant glutathione increased to counter the massive ROS burst upon starvation. If we gave the starving slime mold extra glutathione, we were able to block this increase in ROS and, importantly, stop the formation of the multicellular aggregate, keeping the cells in a single-celled state."In turn, when they blocked glutathione production using an inhibitor, they found that instead of promoting an even faster aggregation, this reversed it, maintaining the single-celled state for longer. This suggested that some function of supplemented glutathione, other than antioxidant activity, was reversing the aggregation process. They carefully considered how glutathione is made. It consists of only three amino acids, cysteine, glycine, and glutamine. Kelly added each of these components individually back to starving cells and she found that only cysteine alone could reverse multicellular aggregation upon starvation.What is unique about the biology of cysteine? It is one of only two amino acids that contain sulfur, and this sulfur is critical for a wide variety of processes in proliferating cells. It is used for making new proteins, is vital for enzyme activity, and supports metabolic processes for energy production. Limiting cysteine therefore limits sulfur supply, slowing growth and proliferation, and indicating that there are insufficient nutrients for these processes to continue. For Dictyostelium, this means that they should transition to a multicellular state, to form a spore that can survive this period of nutrient limitation, preserving the population.It turned out that the loss of sulfur was the important process underlying this multicellularity, and that increasing ROS was a clever means for D. discoideum to achieve this end. By increasing ROS, starving Dictyostelium consequently increase glutathione production. "This in effect pulls cysteine in the cells into glutathione, limiting the use of its sulfur for proliferation and protein production. By artificially blocking glutathione production, or by providing extra cysteine to the starving cells, we could restore this sulfur supply, recovering proliferation and the single-celled state," Beth Kelly said. "Thus, we revealed how sulfur dictates a switch between the single-celled and multicellular states." Sulfur and oxygen were common, small elements in an ancient world, and this work reveals how they may have played a role in the origins of multicellularity."Beyond this, we think that our work has therapeutic implications for more complex organisms. Cancer cells are highly proliferative, and some cancer cells specifically preserve sulfur metabolism. Restricting or targeting sulfur metabolic processes in these cells may enhance anti-tumor immunity," Pearce said. Immune cells traffic through environments containing distinct nutrient mixtures, and immune cell function depends on metabolic pathway activity. Manipulating sulfur metabolism may be a means to modulate immune cell function. Overall, examining such conserved nutrient signaling pathways in the early eukaryote Dictyostelium will likely be highly informative for mammalian cell function.
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Biology
| 2,021 |
February 24, 2021
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https://www.sciencedaily.com/releases/2021/02/210224143525.htm
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Scientists capture the choreography of a developing brain
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The formation of a brain is one of nature's most staggeringly complex accomplishments. The intricate intermingling of neurons and a labyrinth of connections also make it a particularly difficult feat for scientists to study.
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Now, Yale researchers and collaborators have devised a strategy that allows them to see this previously impenetrable process unfold in a living animal -- the worm Caenorhabditis elegans, they report February 24 in the journal "Before, we were able to study single cells, or small groups of cells, in the context of the living C. elegans, and for relatively short periods of time," said Mark Moyle, an associate research scientist in neuroscience at Yale School of Medicine and first author of the study. "It has been a breathtaking experience to now be able to watch development unfold for hours, across the entire brain of the organism, and visualize this highly orchestrated dance."The researchers describe the choreography of a developing brain in this video.Moyle works in the lab headed by corresponding author Daniel Colón-Ramos, the Dorys McConnell Duberg Professor of Neuroscience and Cell Biology and senior author of the study.The lab collaborated with computational and microscopy scientists to develop novel network algorithms and imaging technologies that allowed them to study complex webs of interconnected neurons in living C. elegans, a common type of roundworm often used in research. Despite its simplicity, it shares key molecular and genetic characteristics with human biology.The researchers found that interconnected neurons, densely packed into units called neuropils, are organized to sort signals which dictate many functions and behaviors in the organisms. The study details architectural principles in the neuropil structure that determines how functional brain circuits are developed and assembled.The authors found that neuronal processes and connections in the worm's brain are organized into layers, each containing modular components of functional circuits that are linked to distinct behaviors.Then, using high-resolution light sheet microscopy, the researchers were able to track single cells over the course of the organism's development, providing insights into how these cells help choreograph the assembly of the brain."When you see the architecture, you realize that all this knowledge that was out there about the animal's behaviors has a home in the structure of the brain," Colón-Ramos said.For instance, researchers can trace reflex behavior in animals to circuits leading to muscles and how these same circuits integrate with still others to regulate the animal's movement.He said the brain is organized like a city such as New York, with areas like Wall Street or Broadway organized to carry out the specific functions of finance and entertainment, respectively."Suddenly you see how the city fits together and you understand the relationships between the neighborhoods," Colon-Ramos said.The work is the result of a decade long collaboration between the labs of Colón-Ramos and Smita Krishnaswamy of Yale; Hari Shroff of the National Institutes of Health; Zhirong Bao of the Sloan Kettering Institute; and William A. Mohler of the University of Connecticut Health Center. The Colón-Ramos, Shroff, Bao, and Mohler labs are part of the consortium WormGUIDES.Video:
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Biology
| 2,021 |
February 24, 2021
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https://www.sciencedaily.com/releases/2021/02/210224143512.htm
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Mechanism by which exercise strengthens bones and immunity
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Scientists at the Children's Medical Center Research Institute at UT Southwestern (CRI) have identified the specialized environment, known as a niche, in the bone marrow where new bone and immune cells are produced. The study, published in
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Researchers from the Morrison laboratory discovered that forces created from walking or running are transmitted from bone surfaces along arteriolar blood vessels into the marrow inside bones. Bone-forming cells that line the outside of the arterioles sense these forces and are induced to proliferate. This not only allows the formation of new bone cells, which helps to thicken bones, but the bone-forming cells also secrete a growth factor that increases the frequency of cells that form lymphocytes around the arterioles. Lymphocytes are the B and T cells that allow the immune system to fight infections.When the ability of the bone-forming cells to sense pressure caused by movement, also known as mechanical forces, was inactivated, it reduced the formation of new bone cells and lymphocytes, causing bones to become thinner and reducing the ability of mice to clear a bacterial infection."As we age, the environment in our bone marrow changes and the cells responsible for maintaining skeletal bone mass and immune function become depleted. We know very little about how this environment changes or why these cells decrease with age," says Sean Morrison, Ph.D., the director of CRI and a Howard Hughes Medical Institute Investigator. "Past research has shown exercise can improve bone strength and immune function, and our study discovered a new mechanism by which this occurs."Previous work from the Morrison laboratory discovered the skeletal stem cells that give rise to most of the new bone cells that form during adulthood in the bone marrow. They are Leptin Receptor+ (LepR+) cells. They line the outside of blood vessels in the bone marrow and form critical growth factors for the maintenance of blood-forming cells. The Morrison lab also found that a subset of LepR+ cells synthesize a previously undiscovered bone-forming growth factor called Osteolectin. Osteolectin promotes the maintenance of the adult skeleton by causing LepR+ to form new bone cells.In the current study, Bo Shen, Ph.D., a postdoctoral fellow in the Morrison laboratory, looked more carefully at the subset of LepR+ cells that make Osteolectin. He discovered that these cells reside exclusively around arteriolar blood vessels in the bone marrow and that they maintain nearby lymphoid progenitors by synthesizing stem cell factor (SCF) -- a growth factor on which those cells depend. Deleting SCF from Osteolectin-positive cells depleted lymphoid progenitors and undermined the ability of mice to mount an immune response to bacterial infection."Together with our previous work, the findings in this study show Osteolectin-positive cells create a specialized niche for bone-forming and lymphoid progenitors around the arterioles. Therapeutic interventions that expand the number of Osteolectin-positive cells could increase bone formation and immune responses, particularly in the elderly," says Shen.Shen found that the number of Osteolectin-positive cells and lymphoid progenitors decreased with age. Curious if he could reverse this trend, Shen put running wheels in the cages so that the mice could exercise. He found the bones of these mice became stronger with exercise, while the number of Osteolectin-positive cells and lymphoid progenitors around the arterioles increased. This was the first indication that mechanical stimulation regulates a niche in the bone marrow.Shen found that Osteolectin-positive cells expressed a receptor on their surfaces -- known as Piezo1 -- that signals inside the cell in response to mechanical forces. When Piezo1 was deleted from Osteolectin-positive cells of mice, these cells and the lymphoid progenitors they support became depleted, weakening bones and impairing immune responses."We think we've found an important mechanism by which exercise promotes immunity and strengthens bones, on top of other mechanisms previously identified by others," says Morrison.
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Biology
| 2,021 |
February 24, 2021
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https://www.sciencedaily.com/releases/2021/02/210224120355.htm
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How single celled algae rotate as they swim towards the light
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Scientists have made a pivotal breakthrough in the quest to understand how single-cell green algae are able to keep track of the light as they swim.
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A team of researchers from the University of Exeter's flagship Living Systems Institute has discovered how the model alga Chlamydomonas is seemingly able to scan the environment by constantly spinning around its own body axis in a corkscrewing movement. This helps it respond to light, which it needs for photosynthesis.The tiny alga, which is found abundantly in fresh-water ponds across the world, swims by beating its two flagella, hair-like structures that adopt a whip-like movement to move the cell. These flagella beat in much the same way as the cilia in the human respiratory system.Chlamydomonas cells are able to sense light through a red eye spot and can react to it, known as phototaxis. The cell rotates steadily as it propels itself forwards using a sort of breaststroke, at a rate of about once or twice a second, so that its single eye can scan the local environment.However, the intricate mechanism that allows the alga to achieve this helical swimming has been previously unclear.IN the new study, the researchers first performed experiments which revealed that the two flagella in fact beat in planes that are slightly skewed away from each other.Then, creating a sophisticated computer model of Chlamydomonas, they were able to simulate the flagella movement and reproduce the observed swimming behaviour.The researchers discovered that the flagella were able to move the Chlamydomonas in a clockwise fashion with each power stroke, and then anticlockwise on the reverse stroke -- akin to how a swimmer rocks back and forth when switching from one arm to another. Except here the cell feels no inertia.Furthermore, they also deduced how simply by exerting slightly different forces on the two flagella, the alga can even steer, rather than just move in a straight line.The researchers were able to show that by adding in an additional influence, such as light, the alga can navigate left or right by knowing which flagellum to stroke harder than the other.Dr Kirsty Wan, who led the study said: "The question of how a cell makes these types of precise decisions can be a matter of life or death. It's quite a remarkable feat of both physics and biology, that a single cell with no nervous system to speak of is able to do this...It's an age-old mystery that my group is currently working hard to solve."For the study, the researchers were able to test various scenarios to determine which variables were influencing the trajectory. Their study showed that by varying different parameters, such as if one flagella is slightly stronger than another, the tilt plane of the flagella or its beat pattern, the algae can manipulate its own movement.Team member Dr Dario Cortese added: "The agreement of our model with the experiments is surprising really, that we could effectively capture the complex 3D beat of the flagella with a very simple movement of a bead going around in circles."
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Biology
| 2,021 |
February 24, 2021
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https://www.sciencedaily.com/releases/2021/02/210224120344.htm
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Cancer research to gain from identification of 300 proteins that regulate cell division
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With the hope of contributing to the fight against cancer, researchers in Sweden have published a new molecular mapping of proteins that regulate the cell division process -- identifying 300 such proteins.
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The release of the data, which was published today in the scientific journal, Identifying and understanding what characterizes these proteins is important, says co-author Emma Lundberg, a professor at KTH Royal Institute of Technology whose research group at Science for Life Laboratory (SciLifeLab) in Stockholm contributed to the mapping of these proteins. The long-term hope is that doing so will lead to progress in development of tailor-made cancer drugs and treatments, adapted to the specific anatomical condition of the individual patient in relation to the underlying disease, Lundberg says.In addition to the 300 newly-identified proteins, the researchers report that 20 percent of the human proteome (all protein molecules that the genome encodes for) indicates cell-to-cell variation, that is, fluctuation in gene expression within otherwise identical cells.This information presents medical research with new insights into the cell cycle, in which a balance is moderated between those proteins which promote cell proliferation and those which inhibit it.Lundberg says the work is now incorporated into the open-access research database, the Human Protein Atlas."Our hope is that this provides a valuable resource for a better understanding of, among other things: cell-to-cell variation, the human cell cycle, and the newly-identified proteins in the cell cycle and their role in the formation of tumors," she says.In order to identify the cell cycle-specific proteins, the researchers used so-called immunofluorescent microscopy. The researchers then combined the collected data with RNA sequencing of individual cells to describe the temporal presence of RNA and proteins throughout the cell cycle.
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Biology
| 2,021 |
February 24, 2021
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https://www.sciencedaily.com/releases/2021/02/210224100849.htm
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New fossil discovery illuminates the lives of the earliest primates
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Graduate Center, CUNY/Brooklyn College professor was part of a discovery of the first fossil evidence of any primate, illustrating the earliest steps of primates 66 million years ago following the mass extinction that wiped out all dinosaurs and led to the rise of mammals.
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Stephen Chester, an assistant professor of anthropology and paleontologist at the Graduate Center, CUNY and Brooklyn College, was part of a team of 10 researchers from across the United States who analyzed several fossils of Purgatorius, the oldest genus in a group of the earliest-known primates called plesiadapiforms. These ancient mammals were small-bodied and ate specialized diets of insects and fruits that varied across species.This discovery is central to primate ancestry and adds to our understanding of how life on land recovered after the Cretaceous-Paleogene extinction event 66 million years ago that wiped out all dinosaurs, except for birds. This study was documented in a paper published in the journal "This discovery is exciting because it represents the oldest dated occurrence of archaic primates in the fossil record," Chester said. "It adds to our understanding of how the earliest primates separated themselves from their competitors following the demise of the dinosaurs."Chester and Gregory Wilson Mantilla, Burke Museum Curator of Vertebrate Paleontology and University of Washington biology professor, were co-leads on this study, where the team analyzed fossilized teeth found in the Hell Creek area of northeastern Montana. The fossils, now part of the collections at the University of California Museum of Paleontology, Berkeley, are estimated to be 65.9 million years old, about 105,000 to 139,000 years after the mass extinction event.Based on the age of the fossils, the team estimates that the ancestor of all primates (the group including plesiadapiforms and today's primates such as lemurs, monkeys, and apes) likely emerged by the Late Cretaceous -- and lived alongside large dinosaurs."Stephen Chester's high-caliber impactful research in this area with Brooklyn College students has significantly contributed to our understanding of the environmental, biological, and social dependencies that ultimately led to the evolution of primates," said Peter Tolias, dean of the School of Natural and Behavioral Sciences.This is not the first big find Chester has been involved with. While this latest discovery is unique in that it focused on one group of mammals -- primates -- in 2019, Chester, along with current collaborator Wilson Mantilla, was a key member of a groundbreaking discovery that revealed in striking detail how many life forms -- including mammals, turtles, crocodiles, and plants -- recovered after the asteroid impact that wiped out the dinosaurs. Chester, who specializes in the early evolutionary history of primates and other placental mammals, was also a co-author of that peer-reviewed scientific paper in Science magazine with Denver Museum of Nature & Science researchers.In 2015, while at Brooklyn College, Chester was also the lead author on a paper published in the Proceedings of the National Academy of Sciences on this same genus of primate, Purgatorius. His co-authored paper described the ankle bones of Purgatorius, which is still the oldest fossil evidence that primates lived in the trees shortly after the extinction of the dinosaurs.Chester did some of the research for this project at his Evolutionary Morphology Laboratory, where he trains undergraduate students in all aspects of paleontological research at Brooklyn College. While students were not directly involved in this latest discovery and subsequent paper, Chester has brought many lucky students from his paleoanthropological fieldwork classes to Wyoming, Montana, and North Dakota to a region essentially known as the "paleontological mecca of the West" to dig for primate fossils from 66 million years ago. These trips connected Brooklyn College students with Chester's scientific collaborators and other students from the Denver Museum of Nature & Science, the Smithsonian's National Museum of Natural History, the Yale Peabody Museum, the Royal Ontario Museum, and the Marmarth Research Foundation.The team of researchers who collaborated alongside Chester and Wilson Mantilla in this latest discovery includes William Clemens, University of California Museum of Paleontology; Jason Moore, University of New Mexico; Courtney Sprain, University of Florida and University of California, Berkeley; Brody Hovatter, University of Washington; William Mitchell, Minnesota IT Services; Wade Mans, University of New Mexico; Roland Mundil, Berkeley Geochronology Center; and Paul Renne, University of California, Berkeley.
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Biology
| 2,021 |
February 24, 2021
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https://www.sciencedaily.com/releases/2021/02/210224100840.htm
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Exposure to superbacteria among visitors to the tropics proved more extensive than thought
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Before the corona pandemic, tens of millions international travellers annually headed to the tropics, getting exposed to local intestinal bacteria. A total of 20-70% of those returning from the tropics carry -- for the most unknowingly -- ESBL-producing bacteria resistant to multiple antibiotics. The likelihood of acquiring such superbacteria depends on destination and health behaviour abroad. The risk is greatest in South and Southeast Asia, and a substantial increase is associated with contracting travellers' diarrhea and taking antibiotics while abroad.
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An investigation led by professor of Infectious diseases Anu Kantele at Helsinki University together with MD Esther Kuenzli from Swiss Tropical and Public Health Institute involved a real-time scrutiny of superbacteria acquisition among a group of 20 Europeans over a three-week visit to Laos. The participants' daily stool samples were initially screened on site in Vientiane, Laos, and later, in Europe, the superbacteria strains isolated were analysed in detail by whole-genome sequencing.The study was recently published in the "Our study revealed that travellers to the tropics are much more predisposed to acquiring superbacteria than previously thought. In conventional studies, stool samples are only collected before and after travel, not while abroad as we did now. Travellers to the tropics are known to be exposed to superbacteria, but the extent of the risk revealed by our real-time sampling was unexpected," Kantele says.In Laos, daily stool samples from the participants were analysed locally in the Lao-Oxford-Mahosot Hospital-Wellcome Trust -Research laboratory. Had samples only been collected before and after travel, the proportion of superbacteria carriers had been approximately 70%. Daily real-time scrutiny already while abroad revealed, however, that all travellers had contracted a superbacter within a week after arrival.The findings varied day by day. While some participants carried superbacteria for several days, others had a couple of days' breaks after which superbacteria were found again. Part of the travellers acquired several strains."It became evident that acquisition of superbacteria is a dynamic process: bacteria come and go, some strains persisting for a lengthy period of time," Kantele says.After returning home, to explore the isolated superbacteria strains in more detail, the researchers established a collaboration with Jukka Corander, professor of Statistics at the Universities of Helsinki and Oslo, and Alan McNally, professor of Microbial genetics at the University of Birmingham, England. Whole-genome sequencing and analyses proved colonization to be a dynamic process involving constant switches between the various strains. Indeed, all the travellers had been exposed to a much wider range of superbacteria than generally thought. Applying the traditional approach, about 20 new strains would have been detected after travel, but daily sampling abroad and whole-genome sequencing enabled the researchers to unravel that the participants acquired 83 different strains altogether.Only in four cases did two travellers share the same strains, indicating that the bacteria were not in general transmitted from one to another.None of the participants developed a clinical infection caused by the superbacteria. Had they not been delivered their screening results on a daily basis, the study participants would have remained totally unaware of them carrying superbugs."It was wonderful to see how our intestinal bacteria stand up to the incomers: the great majority of all alien strains disappeared already before the end of the journey," Kantele rejoices.Professor Jukka Corander points out that the study provides a completely new perspective to the bacterial colonization diversity in geographic regions where superbugs are endemic."We have earlier obtained robust modelling results concerning the stability of E. coli colonization in populations with low levels of antibiotic resistance, however, the new study conducted in Laos implies that we need to start building the model anew, so that we gain thorough understanding about the role of superbugs also in those circumstances where they colonize the majority of the people," Corander says.The worldwide growth of antibiotic resistance is particularly alarming in tropical regions with inadequate hygiene and uncontrolled use of antibiotics. Multidrug-resistant bacteria are carried both by animals and local inhabitants. Returning from such environments, many visitors carry superbacteria to their home countries.Increasing resistance is also being witnessed by research: the proportion of travellers carrying these bacteria is growing. Usually acquisition of ESBL or other superbacteria does not cause any symptoms. After travellers return home, the strains usually disappear over time. Carriers can, however, pass these bacteria on to others. Among a small proportion, the superbacteria cause a symptomatic infection, most typically a urinary tract infection. Treatment of infections caused by superbacteria is more challenging than of those caused by sensitive bacteria. In some cases, the infection may even turn out life-threatening.Antibiotic use during travel further adds to the risk of carriage: favouring the resistant bacteria, antibiotic treatment makes space for newcomers.Kantele stresses the grave threat increasing resistance poses to healthcare worldwide."Antibiotics are not only needed to treat infections, but they also enable high-risk operations such as major surgery and organ transplants, where they are given to prevent infections," she says.
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Biology
| 2,021 |
February 24, 2021
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https://www.sciencedaily.com/releases/2021/02/210224090646.htm
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Evidence that Earth's first cells could have made specialized compartments
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New research by the University of Oslo provides evidence that the "protocells" that formed around 3.8 billion years ago, before bacteria and single-celled organisms, could have had specialized bubble-like compartments that formed spontaneously, encapsulated small molecules, and formed "daughter" protocells.
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Scientists have long speculated about the features that our long-ago single-celled ancestors might have had, and the order in which those features came about. Bubble-like compartments are a hallmark of the superkingdom to which we, and many other species including yeast, belong. But the cells in today's superkingdom have a host of specialized molecules that help make and shape these bubbles inside our cells. Scientists wondered what came first: the bubbles or the shaping molecules? New research by Karolina Spustova, a graduate student, and colleagues in the lab of Irep Gözen at the University of Oslo, shows that with just a few key pieces these little bubbles can form on their own, encapsulate molecules, and divide without help. Spustova will present her research, which was published in January, on Wednesday, February 24 at the 65th Annual Meeting of the Biophysical Society.3.8 billion years ago is about when our long ago single-cell ancestor came to be. It would have preceded not only complex organisms in our superkingdom, but also the more basic bacteria. Whether this "protocell" had bubble-like compartments is a mystery. For a long time, scientists thought that these lipid-bubbles were something that set our superkingdom apart from other organisms, like bacteria. Because of this, scientists thought that these compartments might have formed after bacteria came to exist. But recent research has shown that bacteria have specialized compartments too, which led Gözen's research team to wonder--could the protocell that came before bacteria and our ancestors have them? And if so, how could they have formed?The research team mixed the lipids that form modern cell compartments, called phospholipids, with water and put the mix on a mineral-like surface. They found that large bubbles spontaneously formed, and inside those bubbles, were smaller ones. To test whether those compartments could encapsulate small molecules, as they would need to do to have specialized functions, the team added fluorescent dyes. They observed that these bubbles were able to take up and hold onto the dyes. They also saw instances where the bubbles split, leaving smaller "daughter" bubbles, which is "something like simple division of the first cells," Spustova says. All of this occurred without any molecular machines, like those we have in our cells, and without added energy.The idea that this could have happened on Earth 3.8 billion years ago is not inconceivable. Gözen explained that water would have been plentiful, plus "silica and aluminum, which we used in our study, are present in natural rocks." Research shows that the phospholipid molecules could have been synthesized under early Earth conditions or reached Earth with meteorites. Gözen says, "these molecules are believed to have reached sufficient concentrations to form phospholipid compartments." So, it is possible that the ancient "protocell" that came before all the organisms currently on Earth, had everything it needed for bubble-like compartments to form spontaneously.
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Biology
| 2,021 |
February 24, 2021
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https://www.sciencedaily.com/releases/2021/02/210224100858.htm
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Using landscape connectivity to control deadly mosquito-borne viruses
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The yellow fever mosquito (
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In a study recently published in "Connectivity maps allow managers to make informed decisions based on how mosquitoes are likely to move through a landscape," says Evlyn Pless, a postdoctoral researcher at the University of California, Davis and a PhD graduate of Yale's Department of Ecology and Evolutionary Biology. "Our results suggest that in the southern U.S., Plessco-authored the paper with Giuseppe Amatulli, a research scientist with the Center for Research Computing and the Yale School of the Environment; Norah Saarman, assistant professor of biology at Utah State University; and Jeffrey Powell and Adalgisa Caccone from the Department of Ecology and Evolutionary Biology at Yale.Now, the most common method for controlling invasive, disease-carrying species like "This creates a challenge that can only be solved by more information on where mosquitoes live and how they get around."One cutting-edge method of control is releasing genetically-modified mosquitoes into existing populations, in an effort to stunt reproduction and spread of the disease. The authors say they expect connectivity maps like those they've created to be useful in designing more strategic releases of modified mosquitoes."By integrating machine learning with an optimization process, our approach overcomes constraints of previous methods and should be helpful for more precise planning of vector control actions," says Amatulli.The authors also believe this novel advance could have broader applications, including in conservation and environmental protection."Connectivity maps can also be essential for the protection of endangered native species,'' says Pless, "for example, in designing corridors to connect fragmented populations."
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Biology
| 2,021 |
February 23, 2021
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https://www.sciencedaily.com/releases/2021/02/210223150847.htm
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New gene-editing tool allows for programming of sequential edits over time
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Researchers from the University of Illinois Chicago have discovered a new gene-editing technique that allows for the programming of sequential cuts -- or edits -- over time.
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CRISPR is a gene-editing tool that allows scientists to change the DNA sequences in cells and sometimes add a desired sequence or genes. CRISPR uses an enzyme called Cas9 that acts like scissors to make a cut precisely at a desired location in the DNA. Once a cut is made, the ways in which cells repair the DNA break can be influenced to result in different changes or edits to the DNA sequence.The discovery of the gene-editing capabilities of the CRISPR system was described in the early 2010s. In only a few years, scientists became enamored with the ease of guiding CRISPR to target almost any DNA sequence in a cell or to target many different sites in a cell in a single experiment."A drawback of currently available CRISPR-based editing systems is that all the edits or cuts are made all at once. There is no way to guide them so that they take place in a sequential fashion, one after the other," said UIC's Bradley Merrill, associate professor of biochemistry and molecular genetics at the College of Medicine and lead author of the paper.Merrill and colleagues' new process involves the use of special molecules called guide RNA that ferry the Cas9 enzyme within the cell and determine the precise DNA sequence at which Cas9 will cut. They call their specially engineered guide RNA molecules "proGuides," and the molecules allow for the programmed sequential editing of DNA using Cas9.Their findings are published in the journal While proGuide is still in the prototype phase, Merrill and colleagues plan to further develop their concept and hope that researchers will be able to use the technique soon."The ability to preprogram the sequential activation of Cas9 at multiple sites introduces a new tool for biological research and genetic engineering," Merrill said. "The time factor is a critical component of human development and also disease progression, but current methods to genetically investigate these processes don't work effectively with the time element. Our system allows for gene editing in a pre-programmed fashion, enabling researchers to better investigate time-sensitive processes like how cancer develops from a few gene mutations and how the order in which those mutations occur may affect the disease."This research was supported by grants from the National Institutes of Health (R21OD027080, F30CA225058 and F30HD090938) and by the UIC Center for Clinical and Translational Sciences.
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Biology
| 2,021 |
February 23, 2021
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https://www.sciencedaily.com/releases/2021/02/210223110457.htm
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New features of a gene defect that affects muzzle length and caudal vertebrae in dogs
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A recent genetic study at the University of Helsinki provides new information on the occurrence of a DVL2 gene defect associated with a screw tail and its relevance to canine constitution and health. The variant was found in several Bulldog and Pit Bull type breeds, and it was shown to result in caudal vertebral anomalies and shortening of the muzzle. The DLV2 variant may also affect the development of the heart.
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Dog breeding is often focused on appearance. In some breeds, the ideal body shape is bulky, with a broad head and short muzzle, short legs and a very short and kinked tail, also known as a "screw tail." In a previous study in the United States, screw tail was linked to a variant in the DVL2 gene. The variant has become enriched in English Bulldogs, French Bulldogs and Boston Terriers due to inbreeding. In addition to the shape of the tail, the DVL2 variant was suggested to contribute to other features typical of the above breeds, as well as what is known as the Robinow-like syndrome. However, its specific effects on body shape and health remained unclear at the time."In this study, we wanted to further investigate the frequency of the DVL2 variant in different dog breeds and determine its effects on skeletal development. The variant was identified in several Bulldog and Pit Bull type breeds, some of which had both the normal form and the genetic variant. This made it possible to investigate the consequences of the variant," says doctoral researcher Julia Niskanen from the University of Helsinki and the Folkhälsan Research Center.The prevalence of the DVL2 variant varied greatly between breeds. All of the English Bulldogs, French Bulldogs and Boston Terriers in the study were homozygous for the variant, that is, they had inherited the variant from both parents. In other words, the normal form of the gene was not found in these breeds. Both the variant and the normal form were found in the American Staffordshire Terriers, Staffordshire Bull Terriers, Dogues de Bordeaux, Olde English Bulldogges and American Bulldogs.To determine the effect of the variant on body shape, the researchers analysed the skeletal anatomy of American Staffordshire Bull Terriers of different genotypes through computed tomography scans carried out at the Veterinary Teaching Hospital. The results clearly showed that the DVL2 gene defect results in caudal vertebrae anomalies in homozygous state."However, tail abnormalities in the American Staffordshire Terriers were less severe than the screw tails typically seen in English Bulldogs, French Bulldogs and Boston Terriers. In contrast to the previous study, we did not find an association between the DVL2 variant and thoracic vertebral anomalies," says veterinarian and Clinical Instructor Vilma Reunanen from the Faculty of Veterinary Medicine, University of Helsinki.Another main finding in the study was that the gene defect affects muzzle length in varying degrees. In homozygous dogs, the muzzle is significantly shorter than in heterozygous dogs, who only carry one copy of the gene defect. Similarly, heterozygous dogs have shorter muzzles than dogs that don't have any copies of the gene defect."In addition to the effects on the skeletal system, we discovered that several dogs homozygous for the DVL2 variant had a congenital heart defect. However, this is a preliminary finding that requires further study. If confirmed, it could partially explain the prevalence of congenital heart defects in certain breeds," doctoral researcher Niskanen adds."Besides the DVL2 gene defect, many breeds also have other genetic variants that affect body shape. Their combined effects may result in serious health problems. For example, a short muzzle predisposes dogs to brachycephalic obstructive airway syndrome (BOAS), whose symptoms include breathing difficulties and low exercise tolerance. The prevalence of the gene defect demonstrates that in certain breeds, DVL2-related health problems can be prevented with gene tests. In some breeds, there is no longer any variation, which makes it impossible to improve the situation with current breeding programmes," explains Docent Marjo Hytönen from the University of Helsinki and the Folkhälsan Research Center.
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Biology
| 2,021 |
February 23, 2021
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https://www.sciencedaily.com/releases/2021/02/210223110420.htm
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Scientists use DNA origami to monitor CRISPR gene targeting
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The remarkable genetic scissors called CRISPR/Cas9, the discovery that won the 2020 Nobel Prize in Chemistry, sometimes cut in places that they are not designed to target. Though CRISPR has completely changed the pace of basic research by allowing scientists to quickly edit genetic sequences, it works so fast that it is hard for scientists to see what sometimes goes wrong and figure out how to improve it. Julene Madariaga Marcos, a Humboldt postdoctoral fellow, and colleagues in the lab of Professor Ralf Seidel at Leipzig University in Germany, found a way to analyze the ultra-fast movements of CRISPR enzymes, which will help researchers understand how they recognize their target sequences in hopes of improving the specificity. Madariaga Marcos will present the research on Tuesday, February 23 at the 65th Annual Meeting of the Biophysical Society.
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To use CRISPR enzymes to edit gene sequences, scientists can tailor them to target a specific sequence within the three billion DNA base pairs in the human genome. During target recognition CRISPR enzymes untwist the DNA strands to find a sequence that is complementary to CRISPR's attached RNA sequence. But sometimes the RNA matches to DNA sequences that are not quite complementary. To troubleshoot this unintended match, scientists need to be able to observe how CRISPR is acting along individual DNA base pairs, but the process is fast and difficult to observe.To measure CRISPR's actions on an ultra-fast timescale, Madariaga Marcos and colleagues turned to DNA origami, which uses special DNA sequences to form complex three-dimensional nanostructures instead of a simple double helix. DNA origami has applications in drug delivery, nanoelectronics, and even art. Using DNA origami, they built rotor arms out of DNA so that they could watch with a high-speed camera on a microscope the untwisting of the DNA by CRISPR enzymes, causing the rotor arm to spin like helicopter blades. With this system, they were able to measure the different responds to matches and mismatches within the DNA sequence. "We are able to directly measure the energy landscape of CRISPR/Cascade when it interacts with DNA for the first time," said Madariaga Marcos.This technique will help scientists better understand CRISPR enzymes, and how they ultimately land on their match. That way, they can figure out how to optimize CRISPR so it makes fewer off-target matches. In the future, Madariaga Marcos is interested in "developing more tools and methods for studying these gene editing processes in new ways and at a more detailed level."
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Biology
| 2,021 |
February 23, 2021
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https://www.sciencedaily.com/releases/2021/02/210223110433.htm
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Don't focus on genetic diversity to save our species
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Scientists at the University of Adelaide have challenged the common assumption that genetic diversity of a species is a key indicator of extinction risk.
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Published in the journal "Nature is being destroyed by humans at a rate never seen before," says computational biologist Dr Huber. "We burn forests, over-fish our seas and destroy wild areas and it's estimated that about one million species are threatened with extinction, some within decades."Although researchers agree that this rapid decline of species numbers has to be stopped, how that's best tackled is still open to debate."Conservation geneticists consider genetic diversity as an important way to assess if a species is threatened by extinction. The view is that as long as individuals are genetically different from each other (having high genetic diversity), there will always be individuals with the right genetic makeup to survive under adverse conditions. On the other hand, if a species shows little genetic diversity, it's believed that the species is fragile and likely to become extinct."Dr Teixeira and Dr Huber have compiled a wide range of evidence from laboratory experiments, field studies, and evolutionary theory which suggests a need for re-evaluation on the measurement and interpretation of genetic diversity for conservation."In this paper, we've shown that this simple relationship between genetic diversity and survival is often wrong," says population geneticist Dr Teixeira. "Most of the genetic diversity within a genome is 'neutral', meaning that it neither improves nor diminishes an individual's ability to survive or produce offspring. On the other hand, the genetic diversity that does affect survival is found in very specific regions of the genome and is not at all correlated with genome-wide genetic diversity."Researchers need to investigate for each species individually which genetic mutations allow the species to thrive and which mutations lead to diseases that can threaten the species. There is certainly no simple 'one-size-fits-all' measure of extinction risk."The authors finally warn that, although genetics can play an important role in certain cases, fixating on genetic diversity shifts much-needed focus away from the much bigger problem: habitat destruction."Since the year 2000, wildlife habitat about eight times the area of the UK has been lost," says Dr Huber. "Without habitat, there is no wildlife. And without wildlife and the ecosystem services that humans rely on, we are ultimately risking our own security and survival here on Earth."
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Biology
| 2,021 |
February 22, 2021
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https://www.sciencedaily.com/releases/2021/02/210222164213.htm
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Scientists use machine-learning approach to track disease-carrying mosquitoes
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You might not like mosquitoes, but they like you, says Utah State University biologist Norah Saarman. And where you lead, they will follow.
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In addition to annoying bites and buzzing, some mosquitoes carry harmful diseases. "With Evlyn Pless of the University of California, Davis and Jeffrey Powell, Andalgisa Caccone and Giuseppe Amatulli of Yale University, Saarman published findings from a machine-learning approach to mapping landscape connectivity in the February 22, 2021 issue of the The team's research was supported by the National Institutes of Health."We're excited about this approach, which uses a random forest algorithm that allows us to overcome some of the constraints of classical spatial models," Saarman says. "Our approach combines the advantages of a machine-learning framework and an iterative optimization process that integrates genetic and environmental data."In its native Africa, "Using our machine-learning model and NASA-supplied satellite imagery, we can combine this spatial data with the genetic data we have already collected to drill down into very specific movement of these mosquitoes," Saarman says. "For example, our data reveal their attraction to human transportation networks, indicating that activities such as plant nurseries are inadvertently transporting these insects to new areas."Public officials and land managers once relied on pesticides, including DDT, to keep the pesky mosquitoes at bay."As we now know, those pesticides caused environmental harm, including harm to humans," she says. "At the same time, mosquitos are evolving resistance to the pesticides that we have found to be safe for the environment. This creates a challenge that can only be solved by more information on where mosquitos live and how they get around."Saarman adds the rugged survivors are not only adapting to different food sources and resisting pesticides, they're also adapting to varied temperatures, which allows them to expand into colder ranges.Current methods to curb disease-carrying mosquitoes focus on biotechnological solutions, including cutting-edge genetic modification."We hope the tools we're developing can help managers identify effective methods of keeping mosquito populations small enough to avoid disease transmission," Saarman says. "While native species play an important role in the food chain, invasive species, such as
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Biology
| 2,021 |
February 22, 2021
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https://www.sciencedaily.com/releases/2021/02/210222164201.htm
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Salmon scales reveal substantial decline in wild salmon population and diversity
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The diversity and numbers of wild salmon in Northern B.C. have declined approximately 70 per cent over the past century, according to a new Simon Fraser University study.
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Researchers drawing on 100-year-old salmon scales report that recent numbers of wild adult sockeye salmon returning to the Skeena River are 70 per cent lower than 100 years ago. Wild salmon diversity in the Skeena watershed has similarly declined by 70 per cent over the last century.The research undertaken by Simon Fraser University (SFU) and Fisheries and Oceans Canada was published today in the The research team applied modern genetic tools to salmon scales collected from commercial fisheries during 1913-1947 to reconstruct historical abundance and diversity of populations for comparison with recent information.The analysis revealed that Canada's second largest salmon watershed -- the Skeena River -- once hosted a diverse sockeye salmon portfolio composed of many populations that fluctuated from year to year, yet overall remained relatively stable. However, the Skeena sockeye portfolio has largely eroded over the last century, such that it now is dominated by a single population that primarily is supported by artificial production from spawning channels."Our study provides a rare example of the extent of erosion of within-species biodiversity over the last century of human influence," says Michael Price, an SFU PhD candidate and lead author. "That loss in abundance and diversity from wild populations has weakened the adaptive potential for salmon to survive and thrive in an increasingly variable environment influenced by climate change."Life-cycle diversity also has shifted: populations are migrating from freshwater at an earlier age, and spending more time in the ocean."Rebuilding a diversity of abundant wild populations -- that is, maintaining functioning portfolios -- should help ensure that important salmon watersheds like the Skeena are robust to global change," says John Reynolds, co-author, SFU professor, and Tom Buell BC Leadership Chair in Aquatic Conservation.This research can help inform status assessments and rebuilding plan discussions for threatened salmon populations by expanding our understanding of historical diversity and production potential.
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Biology
| 2,021 |
February 22, 2021
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https://www.sciencedaily.com/releases/2021/02/210222164147.htm
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Impacts of climate warming on microbial network interactions
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Climate change impacts are broad and far reaching. A new study by University of Oklahoma researchers from the Institute for Environmental Genomics explores the impacts of climate warming on microbial network complexity and stability, providing critical insights to ecosystem management and for projecting ecological consequences of future climate warming.
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"Global climate change is one of the most profound anthropogenic disturbances to our planet," said Jizhong Zhou, IEG's director, a George Lynn Cross Research Professor in the College of Arts and Sciences and an adjunct professor in the Gallogly College of Engineering. "Climate warming can alter soil microbial community diversity, structure and activities, but it remains uncertain whether and how it impacts network complexity and its relationships to stability in microbial communities."To understand whether and how climate warming affects the complexity and stability of ecological networks in soil microbial communities, the research team examined temporal dynamics of soil microbial communities in a long-term experiment carried out in a tallgrass prairie ecosystem in central Oklahoma."Our study provides explicit evidence that network complexity begets stability in microbial ecology," Zhou said. "Molecular ecological networks under warming became significantly more robust, with network stability strongly correlated with network complexity, supporting the central ecological belief that complexity begets stability.""Furthermore, these results suggest that preserving microbial 'interactions' is critical for ecosystem management and for projecting ecological consequences of future climate warming," he added.The study's findings have implications for projecting ecological consequences of future climate warming and for ecosystem management. Although climate warming has impacted decreased biodiversity and associated ecosystem functioning, this study suggests that the microbial community stability in the grassland ecosystem and the linked ecosystem functions could be less vulnerable in the warmer world.
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Biology
| 2,021 |
February 22, 2021
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https://www.sciencedaily.com/releases/2021/02/210222124653.htm
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Dozens of new lichen species discovered in East African mountain forests
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The species diversity and relationships of lichens in the genus Leptogium, which are often very difficult to identify to species, were assessed on the basis of DNA analyses using a large dataset collected during more than 10 years from East Africa. "The lengthy groundwork is finally complete," says Jouko Rikkinen, Professor of Botany at the University of Helsinki, Finland, giving a sigh of relief.
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The research article just published focuses on species diversity in the genus DNA analyses revealed that the dataset on "The morphological differences between species are often subtle and open to interpretation, and the outer appearances of individual species can also vary greatly depending on environmental factors. Even chemical characteristics cannot be used as an aid for identification to the extent to which they are used with many other groups of lichens," Rikkinen notes.Due to problems in species delimitation and identification, "Similar results have also been obtained from many other genera of lichens whose diversity has been recently studied with DNA analysis methods," says Docent Ulla Kaasalainen, who leads a research project on tropical lichens at the University of Göttingen.
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Biology
| 2,021 |
February 22, 2021
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https://www.sciencedaily.com/releases/2021/02/210222124608.htm
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Study could explain tuberculosis bacteria paradox
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Tuberculosis bacteria have evolved to remember stressful encounters and react quickly to future stress, according to a study by computational bioengineers at Rice University and infectious disease experts at Rutgers New Jersey Medical School (NJMS).
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Published online in the open-access journal Researchers have long suspected that the ability of TB bacteria to remain dormant, sometimes for decades, stems from their ability to behave based upon past experience.Latent TB is an enormous global problem. While TB kills about 1.5 million people each year, the World Health Organization estimates that 2-3 billion people are infected with a dormant form of the TB bacterium."There's some sort of peace treaty between the immune system and bacteria," Igoshin said. "The bacteria don't grow, and the immune system doesn't kill them. But if people get immunocompromised due to malnutrition or AIDS, the bacteria can be reactivated."One of the most likely candidates for a genetic switch that can toggle TB bacteria into a dormant state is a regulatory network that is activated by the stress caused by immune cell attacks. The network responds by activating several dozen genes the bacteria use to survive the stress. Based on a Rice computational model, Igoshin and his longtime Rutgers NJMS collaborator Maria Laura Gennaro and colleagues predicted just such a switch in 2010. According to the theory, the switch contained an ultrasensitive control mechanism that worked in combination with multiple feedback loops to allow hysteresis, or history-dependent behavior."The idea is that if we expose cells to intermediate values of stress, starting from their happy state, they don't have that much of a response," Igoshin explained. "But if you stress them enough to stop their growth, and then reduce the stress level back to an intermediate level, they remain stressed. And even if you fully remove the stress, the gene expression pathway stays active, maintaining a base level of activity in case the stress comes back."In later experiments, Gennaro's team found no evidence of the predicted control mechanism in Mycobacterium smegmatis, a close relative of the TB bacterium. Since both organisms use the same regulatory network, it looked like the prediction was wrong. Finding out why took years of follow-up studies. Gennaro and Igoshin's teams found that the TB bacterium, unlike their noninfectious cousins, had the hysteresis control mechanism, but it didn't behave as expected."Hysteretic switches are known to be very slow, and this wasn't," Igoshin said. "There was hysteresis, a history-dependent response, to intermediate levels of stress. But when stress went from low to high or from high to low, the response was relatively fast. For this paper, we were trying to understand these somewhat contradictory results. "Igoshin and study co-author Satyajit Rao, a Rice doctoral student who graduated last year, revisited the 2010 model and considered how it might be modified to explain the paradox. Studies within the past decade had found a protein called DnaK played a role in activating the stress-response network. Based on what was known about DnaK, Igoshin and Rao added it to their model of the dormant-active switch."We didn't discover it, but we proposed a particular mechanism for it that could explain the rapid, history-dependent switching we'd observed," Igoshin said. "What happens is, when cells are stressed, their membranes get damaged, and they start accumulating unfolded proteins. Those unfolded proteins start competing for DnaK."DnaK was known to play the role of chaperone in helping rid cells of unfolded proteins, but it plays an additional role in the stress-response network by keeping its sensor protein in an inactive state."When there are too many unfolded proteins, DnaK has to let go of the sensor protein, which is an activation input for our network," Igoshin said. "So once there are enough unfolded proteins to 'distract' DnaK, the organism responds to the stress."Gennaro and co-author Pratik Datta conducted experiments at NJMS to confirm DnaK behaved as predicted. But Igoshin said it is not clear how the findings might impact TB treatment or control strategies. For example, the switch responds to short-term biochemical changes inside the cell, and it's unclear what connection, if any, it may have with long-term behaviors like TB latency, he said."The immediate first step is to really try and see whether this hysteresis is important during the infection," Igoshin said. "Is it just a peculiar thing we see in our experiments, or is it really important for patient outcomes? Given that it is not seen in the noninfectious cousin of the TB bacterium, it is tempting to speculate it is related to survival inside the host."
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Biology
| 2,021 |
February 22, 2021
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https://www.sciencedaily.com/releases/2021/02/210222095038.htm
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Can bacteria make stronger cars, airplanes and armor?
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Biological systems can harness their living cells for growth and regeneration, but engineering systems cannot. Until now.
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Qiming Wang and researchers at the USC Viterbi School of Engineering are harnessing living bacteria to create engineering materials that are strong, tolerant, and resilient. The research is published in "The materials we are making are living and self-growing," said Wang, the Stephen Schrank Early Career Chair in Civil and Environmental Engineering and assistant professor of civil and environmental engineering in the Sonny Astani Department of Civil and Environmental Engineering (CEE). "We have been amazed by the sophisticated microstructures of natural materials for centuries, especially after microscopes were invented to observe these tiny structures. Now we take an important step forward: We use living bacteria as a tool to directly grow amazing structures that cannot be made on our own."The researchers work with specific bacteria -- S. pasteurii -- known for secreting an enzyme called urease. When urease is exposed to urea and calcium ions, it produces calcium carbonate, a fundamental and strong mineral compound found in bones or teeth. "The key innovation in our research," said Wang, "is that we guide the bacteria to grow calcium carbonate minerals to achieve ordered microstructures which are similar to those in the natural mineralized composites."Wang added: "Bacteria know how to save time and energy to do things. They have their own intelligence, and we can harness their smartness to design hybrid materials that are superior to fully synthetic options.Borrowing inspiration from nature is not new in engineering. As one would suspect, nature has great examples of complex mineralized composites that are strong, fracture resistant, and energy damping -- for example nacre or the hard shell surrounding a mollusk.Wang said: "Although microorganisms such as bacteria, fungi and viri are sometimes detrimental in causing diseases -- like COVID-19 -- they can also be beneficial. We have a long history of using microorganisms as factories -- for example, using yeast to make beer. But there is limited research on using microorganisms to manufacture engineering materials."Combining living bacteria and synthetic materials, Wang said this new living material demonstrates mechanical properties superior to that of any natural or synthetic material currently in use. This is largely due to the material's bouligand structure, which is characterized by multiple layers of minerals laid at varying angles from each other to form a sort of "twist" or helicoidal shape. This structure is difficult to create synthetically.Wang worked in collaboration with USC Viterbi researchers An Xin, Yipin Su, Minliang Yan, Kunhao Yu, Zhangzhengrong Feng, and Kyung Hoon Lee. Additional support was provided by Lizhi Sun, professor of civil engineering at the University of California, Irvine, and his student Shengwei Feng.One of the key properties of a mineralized composite, Wang said, is that it can be manipulated to follow different structures or patterns. Researchers long ago observed the ability of a mantis shrimp to use his "hammer" to break open a muscle shell. Looking at his "hammer" -- a club-like structure or hand -- more closely, they found it was arranged in a bouligand structure. This structure offers superior strength to one arranged at more homogenous angles -- for example alternating the lattice structure of the material at 90 degrees with each layer."Creating this structure synthetically is very challenging in the field," Wang said. "So we proposed using bacteria to achieve it instead."In order to build the material, the researchers 3-D printed a lattice structure or scaffolding. This structure has empty squares within it and the lattice layers are laid at varying angles to create scaffolding in line with the helicoidal shape.The bacteria are then introduced to this structure. Bacteria intrinsically like to attach to surfaces and will gravitate to the scaffolding, grabbing on to the material with their "legs." There the bacteria will secrete urease, the enzyme which triggers formations of calcium carbonate crystals. These grow from the surface up, eventually filling in the tiny squares or voids in the 3-D printed lattice structure. Bacteria like porous surfaces, Wang said, allowing them to create different patterns with the minerals."We did mechanical testing that demonstrated the strength of such structures to be very high. They also were able to resist crack propagation -- fractures -- and help dampen or dissipate energy within the material," said An Xin, a CEE doctoral student.Existing materials have shown exceptional strength, fracture resistance, and energy dissipation but the combination of all three elements has not been demonstrated to work as well as in the living materials Wang and his team created."We fabricated something very stiff and strong," Wang said. "The immediate implications are for use in infrastructures like aerospace panels and vehicle frames."The living materials are relatively lightweight, also offering options for defense applications like body armor or vehicle armor. "This material could resist bullet penetration and dissipate energy from its release to avoid damage," said Yipin Su, a postdoc working with Wang.There's even potential for these materials to be reintroduced to bacteria when repairs are needed."An interesting vision is that these living materials still possess self-growing properties," Wang said. "When there is damage to these materials, we can introduce bacteria to grow the materials back. For example, if we use them in a bridge, we can repair damages when needed."
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Biology
| 2,021 |
February 22, 2021
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https://www.sciencedaily.com/releases/2021/02/210222082631.htm
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Rapid evolution may help species adapt to climate change and competition
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Loss of biodiversity in the face of climate change is a growing worldwide concern. Another major factor driving the loss of biodiversity is the establishment of invasive species, which often displace native species. A new study shows that species can adapt rapidly to an invader and that this evolutionary change can affect how they deal with a stressful climate.
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"Our results demonstrate that interactions with competitors, including invasive species, can shape a species' evolution in response to climatic change," said co-author Seth Rudman, a WSU Vancouver adjunct professor who will join the faculty as an assistant professor of biological sciences in the fall.Results were published in the Scientists have increasingly recognized that evolution is not necessarily slow and often occurs quickly enough to be observed in real time. These rapid evolutionary changes can have major consequences for things like species' persistence and responses to climatic change. The investigators chose to examine this topic in fruit flies, which reproduce quickly, allowing change to be observed over several generations in a matter of months. The team focused on two species: one naturalized in North American orchards (Drosophila melanogaster) and one that has recently started to invade North America (Zaprionus indianus).The experiment first tested whether the naturalized species can evolve rapidly in response to exposure to the invasive species over the summer, then tested how adaptation in the summer affects the naturalized species' ability to deal with and adapt to the colder fall conditions."A cool thing about the way we conducted this study is that while most experiments that look at rapid evolution use controlled lab systems, we used an outdoor experimental orchard that mimics the natural habitat of our focal species," said Tess Grainger of the Biodiversity Centre at the University of British Columbia and the lead author on the paper. "This gives our experiment a sense of realism and makes our findings more applicable to understanding natural systems."Over the course of just a few months, the naturalized species adapted to the presence of the invasive species. This rapid evolution then affected how the flies evolved when the cold weather hit. Flies that had been previously exposed to the invasive species evolved in the fall to be larger, lay fewer eggs and develop faster than flies that had never been exposed.The study marks the beginning of research that may ultimately hold implications for other threatened species that are more difficult to study. "In the era of global environmental change in which species are increasingly faced with new climates and new competitors, these dynamics are becoming essential to understand and predict," Grainger said.Rudman summarized the next big question: "As biodiversity changes, as climate changes and invaders become more common, what can rapid evolution do to affect outcomes of those things over the next century or two? It may be that rapid evolution will help biodiversity be maintained in the face of these changes."In addition to Rudman and Grainger, the paper's co-authors are Jonathan M. Levine, Ecology and Evolutionary Biology Department, Princeton University (where Grainger was a postdoctoral fellow); and Paul Schmidt, Department of Biology, University of Pennsylvania (where Rudman was a postdoctoral fellow). The research was conducted in an outdoor field site near the University of Pennsylvania.
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Biology
| 2,021 |
February 21, 2021
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https://www.sciencedaily.com/releases/2021/02/210221195711.htm
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Bioengineered hybrid muscle fiber for regenerative medicine
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Muscle is the largest organ that accounts for 40% of body mass and plays an essential role in maintaining our lives. Muscle tissue is notable for its unique ability for spontaneous regeneration. However, in serious injuries such as those sustained in car accidents or tumor resection which results in a volumetric muscle loss (VML), the muscle's ability to recover is greatly diminished. Currently, VML treatments comprise surgical interventions with autologous muscle flaps or grafts accompanied by physical therapy. However, surgical procedures often lead to a reduced muscular function, and in some cases result in a complete graft failure. Thus, there is a demand for additional therapeutic options to improve muscle loss recovery.
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A promising strategy to improve the functional capacity of the damaged muscle is to induce de novo regeneration of skeletal muscle via the integration of transplanted cells. Diverse types of cells, including satellite cells (muscle stem cells), myoblasts, and mesenchymal stem cells, have been used to treat muscle loss. However, invasive muscle biopsies, poor cell availability, and limited long-term maintenance impede clinical translation, where millions to billions of mature cells may be needed to provide therapeutic benefits.Another important issue is controlling the three-dimensional microenvironment at the injury site to ensure that the transplanted cells properly differentiate into muscle tissues with desirable structures. A variety of natural and synthetic biomaterials have been used to enhance the survival and maturation of transplanted cells while recruiting host cells for muscle regeneration. However, there are unsolved, long-lasting dilemmas in tissue scaffold development. Natural scaffolds exhibit high cell recognition and cell binding affinity, but often fail to provide mechanical robustness in large lesions or load-bearing tissues that require long-term mechanical support. In contrast, synthetic scaffolds provide a precisely engineered alternative with tunable mechanical and physical properties, as well as tailored structures and biochemical compositions, but are often hampered by lack of cell recruitment and poor integration with host tissue.To overcome these challenges, a research team at the Center for Nanomedicine within the Institute for Basic Science (IBS) in Seoul, South Korea, Yonsei University, and the Massachusetts Institute of Technology (MIT) devised a novel protocol for artificial muscle regeneration. The team achieved effective treatment of VML in a mouse model by employing direct cell reprogramming technology in combination with a natural-synthetic hybrid scaffold.Direct cell reprogramming, also called direct conversion, is an efficient strategy that provides effective cell therapy because it allows the rapid generation of patient-specific target cells using autologous cells from the tissue biopsy. Fibroblasts are the cells that are commonly found within the connective tissues, and they are extensively involved in wound healing. As the fibroblasts are not terminally differentiated cells, it is possible to turn them into induced myogenic progenitor cells (iMPCs) using several different transcription factors. Herein, this strategy was applied to provide iMPC for muscle tissue engineering.In order to provide structural support for the proliferating muscle cells, polycaprolactone (PCL), was chosen as a material for the fabrication of a porous scaffold due to its high biocompatibility. While salt-leaching is a widely used method to create porous materials, it is mostly limited to producing closed porous structures. To overcome this limitation, the researchers augmented the conventional salt leaching method with thermal drawing to produce customized PCL fiber scaffolds. This technique facilitated high-throughput fabrication of porous fibers with controlled stiffness, porosity, and dimensions that enable precise tailoring of the scaffolds to the injury sites.However, the synthetic PCL fiber scaffolds alone do not provide optimal biochemical and local mechanical cues that mimic muscle-specific microenvironment. Hence the construction of a hybrid scaffold was completed through the incorporation of decellularized muscle extracellular matrix (MEM) hydrogel into the PCL structure. Currently, MEM is one of the most widely used natural biomaterials for the treatment of VML in clinical practice. Thus, the researchers believe that hybrid scaffolds engineered with MEM have a huge potential in clinical applications.The resultant bioengineered muscle fiber constructs showed mechanical stiffness similar to that of muscle tissues and exhibited enhanced muscle differentiation and elongated muscle alignment in vitro. Furthermore, implantation of bioengineered muscle constructs in the VML mouse model not only promoted muscle regeneration with increased innervation and angiogenesis but also facilitated the functional recovery of damaged muscles. The research team notes: "The hybrid muscle construct might have guided the responses of exogenously added reprogrammed muscle cells and infiltrating host cell populations to enhance functional muscle regeneration by orchestrating differentiation, paracrine effect, and constructive tissue remodeling."Prof. CHO Seung-Woo from the IBS Center for Nanomedicine and Yonsei University College of Life Science and Biotechnology who led this study notes: "Further studies are required to elucidate the mechanisms of muscle regeneration by our hybrid constructs and to empower the clinical translation of cell-instructive delivery platforms."
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Biology
| 2,021 |
February 19, 2021
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https://www.sciencedaily.com/releases/2021/02/210219190942.htm
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Direct cloning method CAPTUREs novel microbial natural products
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Microorganisms possess natural product biosynthetic gene clusters (BGCs) that may harbor unique bioactivities for use in drug development and agricultural applications. However, many uncharacterized microbial BGCs remain inaccessible. Researchers at University of Illinois Urbana-Champaign previously demonstrated a technique using transcription factor decoys to activate large, silent BGCs in bacteria to aid in natural product discovery.
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Now, they have developed a direct cloning method that aims to accelerate large-scale discovery of novel natural products. Their findings are reported in the journal Named Cas12a assisted precise targeted cloning using in vivo Cre-lox recombination (CAPTURE), the method allows for direct cloning of large genomic fragments, including those with high-GC content or sequence repeats. Where existing direct cloning methods fail to effectively clone natural product BGCs of this nature, CAPTURE excels."Using CAPTURE, microbial natural product BGCs can be directly cloned and heterologously expressed at an unprecedented rate," said study leader and Steven L. Miller Chair professor of chemical and biomolecular engineering Huimin Zhao, also a member of the Carl R. Woese Institute for Genomic Biology at Illinois. "As a result, CAPTURE allows large-scale cloning of natural product BGCs from various organisms, which can lead to discovery of numerous novel natural products."Researchers first characterized the efficiency and robustness of CAPTURE by cloning 47 natural product BGCs from both Actinomycetes and Bacilli. After demonstrating nearly 100% efficiency of CAPTURE, 43 uncharacterized natural product BGCs from 14 Streptomyces and three Bacillus species were cloned and heterologously expressed by researchers. The produced compounds were purified and determined as 15 novel natural products, including six unprecedented compounds designated as bipentaromycins. Four of the bipentaromycins exhibited antimicrobial activity against methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus, and Bacillus anthracis."Addressing the current antimicrobial resistance crisis requires discovery of novel molecules capable of treating drug-resistant infections," said Zhao. "Discovery of bipentaromycins not only demonstrates the possibility of discovering novel antimicrobials, but it also provides an example on how this strategy can be applied for discovery of unique bioactive compounds for use in drug development and agricultural applications."The researchers plan next to characterize these compounds for other bioactivities such as anticancer, antiparasitic and anticancer properties. Preliminary results are already showing anticancer properties for some of the compounds."Due to its exceptional robustness and efficiency, CAPTURE will likely become the method of choice for direct cloning of large DNA molecules such as natural product BGCs from genomic or metagenomic DNA for various basic and applied biological applications," said Zhao.
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Biology
| 2,021 |
February 19, 2021
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https://www.sciencedaily.com/releases/2021/02/210219155928.htm
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Mitochondrial function can play significant part in serious disease
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Disorders of the cells' energy supply can cause a number of serious diseases, but also seem to be connected to ageing. More research is needed on mitochondrial function to find future treatments. A new study involving researchers at Karolinska Institutet shows how an important molecule inside the mitochondria affects their function in mice and fruit flies. The study, which is published in
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In each cell of the body is an organ called the mitochondrion, which converts nutrients in our food to energy. Mitochondria are an essential part of the metabolism, and when things go wrong we can develop serious diseases.Mitochondrial dysfunction is the hallmark of a group of rare genetic disorders but can also be observed in common diseases such as diabetes, heart disease, neurodegenerative diseases and the normal ageing process.More research is needed on mitochondria and how they communicate with the rest of the cell if scientists are to find new therapeutic approaches to improve mitochondrial function.Researchers at Karolinska Institutet, the Max-Planck Institute for Biology of Ageing in Cologne and the University of California San Diego have now studied how the methylation of proteins affects different mitochondrial processes.Methylation is a chemical modification in which a methyl group (CH3) is added to a molecule, thereby potentially affecting its function. S-Adenosylmethionine (SAM), also known as AdoMet, is the main methyl group donor within the cell, including inside of mitochondria."We're interested in studying this particular molecule since the production of SAM changes in cancer and when we age," says Anna Wredenberg, researcher at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet.By completely removing SAM from the mitochondria of fruit flies and mice, the researchers have been able to study which processes in the mitochondria are dependent on methylation."Earlier studies have shown that both SAM and cellular energy levels drop during ageing. Our study suggests a link between these two pathways by demonstrating that low SAM levels can influence mitochondrial energy production."The study has identified which of the mitochondrial proteins are methylated and how methylation affects them, and how these modifications might affect mitochondrial function. The researchers also demonstrate the physiological consequences of the lack of such changes. However, several questions still need answering."Our study has provided an indication that some modifications can be modulated by diet, but we need to continue examining if we can change the pathological process for the better," says Anna Wredenberg. "So far we've only looked at protein changes, but other molecules can also be modified by intra-mitochondrial SAM. We have to study these modifications to get a better understanding of the role it plays."The study was financed by the Swedish Research Council, the European Research Council, the Knut and Alice Wallenberg Foundation, the Max Planck Society and the Ragnar Söderberg Foundation. There are no reported conflicts of interest.
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Biology
| 2,021 |
February 19, 2021
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https://www.sciencedaily.com/releases/2021/02/210219155923.htm
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New technology enables predictive design of engineered human cells
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Northwestern University synthetic biologist Joshua Leonard used to build devices when he was a child using electronic kits. Now he and his team have developed a design-driven process that uses parts from a very different kind of toolkit to build complex genetic circuits for cellular engineering.
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One of the most exciting frontiers in medicine is the use of living cells as therapies. Using this approach to treat cancer, for example, many patients have been cured of previously untreatable disease. These advances employ the approaches of synthetic biology, a growing field that blends tools and concepts from biology and engineering.The new Northwestern technology uses computational modeling to more efficiently identify useful genetic designs before building them in the lab. Faced with myriad possibilities, modeling points researchers to designs that offer real opportunity."To engineer a cell, we first encode a desired biological function in a piece of DNA, and that DNA program is then delivered to a human cell to guide its execution of the desired function, such as activating a gene only in response to certain signals in the cell's environment," Leonard said. He led a team of researchers from Northwestern in collaboration with Neda Bagheri from the University of Washington for this study.Leonard is an associate professor of chemical and biological engineering in the McCormick School of Engineering and a leading faculty member within Northwestern's Center for Synthetic Biology. His lab is focused on using this kind of programming capability to build therapies such as engineered cells that activate the immune system, to treat cancer.Bagheri is an associate professor of biology and chemical engineering and a Washington Research Foundation Investigator at the University of Washington Seattle. Her lab uses computational models to better understand -- and subsequently control -- cell decisions. Leonard and Bagheri co-advised Joseph Muldoon, a recent doctoral student and the paper's first author."Model-guided design has been explored in cell types such as bacteria and yeast, but this approach is relatively new in mammalian cells," Muldoon said.The study, in which dozens of genetic circuits were designed and tested, will be published Feb. 19 in the journal To date, it remains difficult and time-consuming to develop genetic programs when relying upon trial and error. It is also challenging to implement biological functions beyond relatively simple ones. The research team used a "toolkit" of genetic parts invented in Leonard's lab and paired these parts with computational tools for simulating many potential genetic programs before conducting experiments. They found that a wide variety of genetic programs, each of which carries out a desired and useful function in a human cell, can be constructed such that each program works as predicted. Not only that, but the designs worked the first time."In my experience, nothing works like that in science; nothing works the first time. We usually spend a lot of time debugging and refining any new genetic design before it works as desired," Leonard said. "If each design works as expected, we are no longer limited to building by trial and error. Instead, we can spend our time evaluating ideas that might be useful in order to hone in on the really great ideas.""Robust representative models can have disruptive scientific and translational impact," Bagheri added. "This development is just the tip of the iceberg."The genetic circuits developed and implemented in this study are also more complex than the previous state of the art. This advance creates the opportunity to engineer cells to perform more sophisticated functions and to make therapies safer and more effective."With this new capability, we have taken a big step in being able to truly engineer biology," Leonard said.The research was supported by the National Institute of Biomedical Imaging and Bioengineering (award number 1R01EB026510), the National Institute of General Medical Sciences (award number T32GM008152) and the National Cancer Institute (award number F30CA203325).
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Biology
| 2,021 |
February 19, 2021
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https://www.sciencedaily.com/releases/2021/02/210219111317.htm
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Origin of life: Did Darwinian evolution begin before life itself?
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A study done by physicists demonstrates that fundamental characteristics of polymeric molecules, such as their subunit composition, are sufficient to trigger selection processes in a plausible prebiotic setting.
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Before life emerged on Earth, many physicochemical processes on our planet were highly chaotic. A plethora of small compounds, and polymers of varying lengths, made up of subunits (such as the bases found in DNA and RNA), were present in every conceivable combination. Before life-like chemical processes could emerge, the level of chaos in these systems had to be reduced. In a new study, LMU physicists led by Dieter Braun show that basic features of simple polymers, together with certain aspects of the prebiotic environment, can give rise to selection processes that reduce disorder.In previous publications, Braun's research group explored how spatial order could have developed in narrow, water-filled chambers within porous volcanic rocks on the sea bottom. These studies showed that, in the presence of temperature differences and a convective phenomenon known as the Soret effect, RNA strands could locally be accumulated by several orders of magnitude in a length-dependent manner. "The problem is that the base sequences of the longer molecules that one obtains are totally chaotic," says Braun.Evolved ribozymes (RNA-based enzymes) have a very specific base sequence that enable the molecules to fold into particular shapes, while the vast majority of oligomers formed on the Early Earth most probably had random sequences. "The total number of possible base sequences, known as the 'sequence space', is incredibly large," says Patrick Kudella, first author of the new report. "This makes it practically impossible to assemble the complex structures characteristic of functional ribozymes or comparable molecules by a purely random process." This led the LMU team to suspect that the extension of molecules to form larger 'oligomers' was subject to some sort of preselection mechanism.Since at the time of the Origin of Life there were only a few, very simple physical and chemical processes compared to the sophisticated replication mechanisms of cells, the selection of sequences must be based on the environment and the properties of the oligomers. This is where the research of Braun's group comes in. For catalytic function and stability of oligomers, it is important that they form double strands like the well-known helical structure of DNA. This is an elementary property of many polymers and enables complexes with both double- and single-stranded parts. The single-stranded parts can be reconstructed by two processes. First, by so-called polymerization, in which strands are completed by single bases to form complete double strands. The other is by what is known as ligation. In this process, longer oligomers are joined together. Here, both double-stranded and single-stranded parts are formed, which enable further growth of the oligomer."Our experiment starts off with a large number of short DNA strands, and in our model system for early oligomers we use only two complementary bases, adenine and thymine," says Braun. "We assume that ligation of strands with random sequences leads to the formation of longer strands, whose base sequences are less chaotic." Braun's group then analyzed the sequence mixtures produced in these experiments using a method that is also used in analyzing the human genome. The test confirmed that the sequence entropy, i.e. the degree of disorder or randomness within the sequences recovered, was in fact reduced in these experiments.The researchers were also able to identify the causes of this 'self-generated' order. They found that the majority of sequences obtained fell into two classes -- with base compositions of either 70 % adenine and 30 % thymine, or vice versa. "With a significantly larger proportion of one of the two bases, the strand cannot fold onto itself and remains as a reaction partner for the ligation," Braun explains. Thus, hardly any strands with half of each of the two bases are formed in the reaction. "We also see how small distortions in the composition of the short DNA pool leave distinct position-dependent motif patterns, especially in long product strands," Braun says. The result surprised the researchers, because a strand of just two different bases with a specific base ratio has limited ways to differentiate from each other. "Only special algorithms can detect such amazing details," says Annalena Salditt, co-author of the study.The experiments show that the simplest and most fundamental characteristics of oligomers and their environment can provide the basis for selective processes. Even in a simplified model system, various selection mechanisms can come into play, which have an impact on strand growth at different length scales, and are the results of different combinations of factors. According to Braun, these selection mechanisms were a prerequisite for the formation of catalytically active complexes such as ribozymes, and therefore played an important role in the emergence of life from chaos.
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Biology
| 2,021 |
February 18, 2021
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https://www.sciencedaily.com/releases/2021/02/210218160357.htm
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Researchers eavesdrop on cellular conversations
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An interdisciplinary team of biologists and mathematicians at the University of California, Irvine has developed a new tool to help decipher the language cells use to communicate with one another.
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In a paper published today in "To properly understand why cells do certain things, and to predict their future actions, we need to be able to listen to what they are saying to one another; mathematical and machine learning tools enable the translation of such messages," said co-senior author Qing Nie, UCI Chancellor's Professor of mathematics and developmental & cell biology."Just like in our world, where we are constantly bombarded with information, all cells experience a lot of molecular words coming at them simultaneously," added co-senior author Maksim Plikus, UCI professor of developmental & cell biology, "What they choose to do is dependent on this steady flow of molecular information and on what words and sentences are being heard the loudest."To use CellChat to translate molecular messages between cells, researchers feed in a single-cell gene expression, and out comes a detailed report on signaling communication features of a given tissue or organ."For each distinct group of cells, CellChat shows what significant signals are being sent to their neighbors and what signals they have the ability to receive," Plikus said. "As an interpreter of cellular language, CellChat provides scientists with a valuable insight into signaling patterns that guide function of the entire organ."In developing CellChat, the researchers in UCI's NSF-Simons Center for Multiscale Cell Fate Research -- including postdoctoral fellows Suoqin Jin, Christian F. Guerrero-Juarez, Raul Ramos and Lihua Zhang -- borrowed heavily from machine learning tools and social network theory, which allows the platform to predict a higher level meaning of cellular language and identify contextual similarities that are otherwise not obvious. It breaks down the immense complexity of cellular communication patterns.Cells produce modifier molecules to add emphasis to a certain command, transforming "do this" to "do this now." CellChat automatically calibrates the strength of signaling communication between cells by considering all significantly present modifier molecules. As a result, its translation becomes more nuanced and helps to minimize inaccuracies that plague other similar yet less sophisticated computational tools.Beyond the purely fundamental research enterprise of interpreting these biological messages, Nie said CellChat can also be used to compare communication networks in different states of an organ, such as sickness and health. Calling it a "Google Translator for the lexicon of cells," Nie said one of tool's most significant capabilities is that it can be used to uncover molecular drivers in a broad spectrum of maladies including cancer and autoimmune disorders."In our paper, we showcase the power of CellChat using atopic dermatitis, a human skin condition, but the tool can be used on any tissue with the same success," Plikus added.
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Biology
| 2,021 |
February 18, 2021
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https://www.sciencedaily.com/releases/2021/02/210218151139.htm
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In dueling ants vying to become queen, behavioral and molecular cues quickly determine who will win
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In one species of ants, workers duel to establish new leadership after the death of their queen. While these sparring matches stretch for more than a month, changes in behavior and gene expression in the first three days of dueling can accurately predict who will triumph, according to a New York University study published in the journal
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"Despite prolonged social upheaval in ant colonies following the loss of the queen, the winners of these dueling tournaments are rapidly determined," said Claude Desplan, Silver Professor of Biology at NYU. "Our findings may provide clues on adaptability in reproduction and aging, given that the workers who win the duel, or 'pseudoqueens,' gain the ability to lay eggs and live much longer than the average worker ant. This suggests that changes in the environment are able to dramatically affect the structure of a society."The caste system in social insects creates a division of labor, with insects specialized to perform particular tasks. The queen is responsible for reproduction, while workers maintain the colony -- caring for the young, foraging and hunting for food, cleaning, and defending the nest.In many insect societies, when the queen dies, the entire colony dies along with her due to the lack of reproduction. However, in Indian jumping ants (Harpegnathos saltator), "caste switching" occurs after the queen's death. While the queen is alive, she secretes pheromones that prevent female worker ants from laying eggs, but when she dies, the workers sense the lack of pheromones and begin fighting each other to take on the top role.The ants engage in dueling tournaments, striking each other with their antennae in matches that can last more than a month. While most ants quickly return to their usual work during the tournament, the winners become pseudoqueens -- also known as gamergates -- and acquire new behaviors and roles. Through this transition, their life expectancy dramatically increases (from seven months to four years) and they begin laying eggs, allowing the colony to survive.In their study in They found that, as early as after three days of dueling, the winners can be accurately predicted solely based on the dueling behavior. The workers who triumphed and became pseudoqueens had much higher levels of dueling -- sparring roughly twice as much in the first five days -- while the others who remained workers dueled less and went back to performing other tasks such as cleaning and hunting."Despite the fact that dueling tournaments last for several weeks, we were able to anticipate which ants would become pseudoqueens in only three days," said Comzit Opachaloemphan, a doctoral student in the Department of Biochemistry and Molecular Pharmacology at NYU Grossman School of Medicine and one of the study's lead authors.Comparing biological samples and gene expression from dueling versus non-dueling ants, the researchers then determined the changes associated with the worker-to-pseudoqueen transition. Molecular analyses revealed that the brain may be driving the dueling and early caste determination in the ants, with other tissues taking cues from the brain.The researchers found that the first genes to respond to the loss of the queen were in the brain, suggesting that the lack of queen pheromones perceived by the olfactory system affects brain neurohormonal factors. These changes in the brain then lead to altered social behavior and hormone-mediated physiological changes in other parts of the body, including the ovaries."Both behavioral and molecular data -- especially changes in gene expression in the brain -- show us that new pseudoqueens are quickly determined after a colony's social structure has been disrupted by the loss of the queen," said study author Danny Reinberg, the Terry and Mel Karmazin Professor in the Department of Biochemistry and Molecular Pharmacology at NYU Grossman School of Medicine, as well as an investigator for the Howard Hughes Medical Institute.Additional study authors include co-first authors Giacomo Mancini and Nikos Konstantinides, as well as Apurva Parikh, Jakub Mlejnek, and Hua Yan. The research was supported by a Howard Hughes Medical Institute Collaborative Innovation Award (#2009005), the National Institutes of Health (R21-GM114457, R01-EY13010, R01-AG058762, and F32AG044971), EMBO (365-2014), and the Human Frontier Science Program (LT000122/2015-L).
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Biology
| 2,021 |
February 18, 2021
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https://www.sciencedaily.com/releases/2021/02/210218151102.htm
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Explainable AI for decoding genome biology
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Researchers at the Stowers Institute for Medical Research, in collaboration with colleagues at Stanford University and Technical University of Munich have developed advanced explainable artificial intelligence (AI) in a technical tour de force to decipher regulatory instructions encoded in DNA. In a report published online February 18, 2021, in
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Neural networks are powerful AI models that can learn complex patterns from diverse types of data such as images, speech signals, or text to predict associated properties with impressive high accuracy. However, many see these models as uninterpretable since the learned predictive patterns are hard to extract from the model. This black-box nature has hindered the wide application of neural networks to biology, where interpretation of predictive patterns is paramount.One of the big unsolved problems in biology is the genome's second code -- its regulatory code. DNA bases (commonly represented by letters A, C, G, and T) encode not only the instructions for how to build proteins, but also when and where to make these proteins in an organism. The regulatory code is read by proteins called transcription factors that bind to short stretches of DNA called motifs. However, how particular combinations and arrangements of motifs specify regulatory activity is an extremely complex problem that has been hard to pin down.Now, an interdisciplinary team of biologists and computational researchers led by Stowers Investigator Julia Zeitlinger, PhD, and Anshul Kundaje, PhD, from Stanford University, have designed a neural network -- named BPNet for Base Pair Network -- that can be interpreted to reveal regulatory code by predicting transcription factor binding from DNA sequences with unprecedented accuracy. The key was to perform transcription factor-DNA binding experiments and computational modeling at the highest possible resolution, down to the level of individual DNA bases. This increased resolution allowed them to develop new interpretation tools to extract the key elemental sequence patterns such as transcription factor binding motifs and the combinatorial rules by which motifs function together as a regulatory code."This was extremely satisfying," says Zeitlinger, "as the results fit beautifully with existing experimental results, and also revealed novel insights that surprised us."For example, the neural network models enabled the researchers to discover a striking rule that governs binding of the well-studied transcription factor called Nanog. They found that Nanog binds cooperatively to DNA when multiples of its motif are present in a periodic fashion such that they appear on the same side of the spiraling DNA helix."There has been a long trail of experimental evidence that such motif periodicity sometimes exists in the regulatory code," Zeitlinger says. "However, the exact circumstances were elusive, and Nanog had not been a suspect. Discovering that Nanog has such a pattern, and seeing additional details of its interactions, was surprising because we did not specifically search for this pattern.""This is the key advantage of using neural networks for this task," says ?iga Avsec, PhD, first author of the paper. Avsec and Kundaje created the first version of the model when Avsec visited Stanford during his doctoral studies in the lab of Julien Gagneur, PhD, at the Technical University in Munich, Germany."More traditional bioinformatics approaches model data using pre-defined rigid rules that are based on existing knowledge. However, biology is extremely rich and complicated," says Avsec. "By using neural networks, we can train much more flexible and nuanced models that learn complex patterns from scratch without previous knowledge, thereby allowing novel discoveries."BPNet's network architecture is similar to that of neural networks used for facial recognition in images. For instance, the neural network first detects edges in the pixels, then learns how edges form facial elements like the eye, nose, or mouth, and finally detects how facial elements together form a face. Instead of learning from pixels, BPNet learns from the raw DNA sequence and learns to detect sequence motifs and eventually the higher-order rules by which the elements predict the base-resolution binding data.Once the model is trained to be highly accurate, the learned patterns are extracted with interpretation tools. The output signal is traced back to the input sequences to reveal sequence motifs. The final step is to use the model as an oracle and systematically query it with specific DNA sequence designs, similar to what one would do to test hypotheses experimentally, to reveal the rules by which sequence motifs function in a combinatorial manner."The beauty is that the model can predict way more sequence designs that we could test experimentally," Zeitlinger says. "Furthermore, by predicting the outcome of experimental perturbations, we can identify the experiments that are most informative to validate the model." Indeed, with the help of CRISPR gene editing techniques, the researchers confirmed experimentally that the model's predictions were highly accurate.Since the approach is flexible and applicable to a variety of different data types and cell types, it promises to lead to a rapidly growing understanding of the regulatory code and how genetic variation impacts gene regulation. Both the Zeitlinger Lab and the Kundaje Lab are already using BPNet to reliably identify binding motifs for other cell types, relate motifs to biophysical parameters, and learn other structural features in the genome such as those associated with DNA packaging. To enable other scientists to use BPNet and adapt it for their own needs, the researchers have made the entire software framework available with documentation and tutorials.
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Biology
| 2,021 |
February 18, 2021
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https://www.sciencedaily.com/releases/2021/02/210218142803.htm
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New data sheds light on genesis of our body's powerhouses
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Scientists uncover for the first time how the body's energy makers are made using Cryo-Electron Microscopy (cryo-EM) at eBIC within Diamond which is based in Oxfordshire.
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A new paper published in Mitochondria are intracellular organelles which serve as tiny but potent powerhouses in our body. They use oxygen which we inhale and derivatives from food we eat to produce more than 90% of our energy, and therefore effectively support our life. Mitochondria are particularly important in high-energy demanding organs such as heart, liver, muscles and brain. For example, almost 40% of each heart muscle cell is made up of mitochondria.The bulk of energy production in mitochondria takes place in naturally evolved nano-factories incorporated in specialised membranes. These nano-factories consist of proteins cooperatively transporting ions and electrons to generate the chemical energy currency of our bodies which have to be constantly maintained, replaced and duplicated during cell division. To address this, mitochondria have their own protein making machine called the mitoribosome. The first fundamental understanding of how the mitoribosome looks was achieved in 2014."7 years ago, our work on the mitoribosome from yeast was termed the Resolution Revolution. The current study represents an additional advance on the original breakthrough. Not only does it reveal how the human mitoribosome is designed at an unprecedented level of detail, but it also explains the molecular mechanism that drives the process of bioenergetics to fuel life," says lead author, Alexey Amunts, Head of the program for Biology of Molecular Interactions, at SciLifeLab in Sweden.The term Resolution Revolution was coined at "Our study exposed the dynamic molecular mechanism that explains how the mitoribosome actually works to form the cellular powerhouse and reveals that the mitoribosome is much more flexible and active than previously thought. The discovery of intrinsic conformational changes represents a gating mechanism of the mitoribosome without similarity in bacterial and cytosolic systems. Together, the data offer a molecular insight into how proteins are synthesized in human mitochondria," adds Alexey Amunts.Yuriy Chaban, Principal Electron Microscopy Scientist at eBIC, Diamond comments; "At Diamond, we are pushing the boundaries of what can be measured in the physical and life sciences and this latest development is tribute to the team involved in what can now be routinely achieved.The most important aspect of Alexey's work is the interaction between mitoribosome and OXA1L and the associated flexibility. The fact that mitoribosome is flexible as such is not novel, but the particular flexibility associated with OXA1L interaction is. This is important for synthesis of membrane proteins, including respiratory chain proteins. Overall, this work significantly widens our understanding how mitoribosome functions. The work by Alexey Amunts lab resolves another mystery about basic biological processes necessary for creating life as we know it."The sequencing of the human mitochondrial genome 40 years ago was a turning point in mitochondrial research, postulating a putative specialized mechanism for the synthesis of the mitochondrial transmembrane proteins. Indeed, the discovered gating mechanism of the human mitoribosome represents a unique occurrence. Therefore, the structural data offer a fundamental understanding into how bioenergetic proteins are synthesized in our body.
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Biology
| 2,021 |
February 18, 2021
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https://www.sciencedaily.com/releases/2021/02/210218142742.htm
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Metabolic mutations help bacteria resist drug treatment
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Bacteria have many ways to evade the antibiotics that we use against them. Each year, at least 2.8 million people in the United States develop an antibiotic-resistant infection, and more than 35,000 people die from such infections, according to the U.S. Centers for Disease Control.
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Most of the mutations known to confer resistance occur in the genes targeted by a particular antibiotic. Other resistance mutations allow bacteria to break down antibiotics or pump them out through their cell membranes.MIT researchers have now identified another class of mutations that helps bacteria develop resistance. In a study of E. coli, they discovered that mutations to genes involved in metabolism can also help bacteria to evade the toxic effects of several different antibiotics. The findings shed light on a fundamental facet of how antibiotics work, and suggest potential new avenues for developing drugs that could enhance the effectiveness of existing antibiotics, the researchers say."This study gives us insights into how we can boost the effectiveness of existing antibiotics because it emphasizes that downstream metabolism plays an important role. Specifically, our work indicates that the killing efficacy of an antibiotic can be enhanced if one can elevate the metabolic response of the treated pathogen," says James Collins, the Termeer Professor of Medical Engineering and Science in MIT's Institute for Medical Engineering and Science (IMES) and Department of Biological Engineering.Collins is the senior author of the study, which appears today in The new study builds on previous work from Collins' lab showing that when treated with antibiotics, many bacteria are forced to ramp up their metabolism, leading to an accumulation of toxic byproducts. These byproducts damage the cells and contribute to their death.However, despite the role of overactive metabolism in cell death, scientists had not found any evidence that this metabolic pressure leads to mutations that help bacteria evade the drugs. Collins and Lopatkin set out to see if they could find such mutations.First, they performed a study similar to those normally used to look for antibiotic resistance mutations. In this type of screen, known as adaptive evolution, researchers begin with a laboratory strain of E. coli and then treat the cells with gradually increasing doses of a particular antibiotic. Researchers then sequence the cells' genomes to see what kinds of mutations arose during the course of the treatment. This approach has not previously yielded mutations to genes involved in metabolism, because of limitations in the number of genes that could be sequenced."Many of the studies before now have looked at a few individual evolved clones, or they sequence maybe a couple of the genes where we expect to see mutations because they're related to how the drug acts," Lopatkin says. "That gives us a very accurate picture of those resistance genes, but it limits our view of anything else that's there."For example, the antibiotic ciprofloxacin targets DNA gyrase, an enzyme involved in DNA replication, and forces the enzyme to damage cells' DNA. When treated with ciprofloxacin, cells often develop mutations in the gene for DNA gyrase that allow them to evade this mechanism.In their first adaptive evolution screen, the MIT team analyzed more E. coli cells and many more genes than had been studied before. This allowed them to identify mutations in 24 metabolic genes, including genes related to amino acid metabolism and the carbon cycle -- the set of chemical reactions that allows cells to extract energy from sugar, releasing carbon dioxide as a byproduct.To tease out even more metabolism-related mutations, the researchers ran a second screen in which they forced the cells into a heightened metabolic state. In these studies, E. coli were treated with a high concentration of an antibiotic every day, at incrementally increasing temperatures. The temperature changes gradually drove the cells into a very active metabolic state, and at the same time, they also gradually evolved resistance to the drug.The researchers then sequenced the genomes of those bacteria and found some of the same metabolism-related mutations they saw in the first screen, plus additional mutations to metabolism genes. These included genes involved in synthesis of amino acids, especially glutamate, in addition to the carbon cycle genes. They then compared their results to a library of genomes of resistant bacteria isolated from patients, and found many of the same mutations.The researchers then engineered some of these mutations into typical E. coli strains and found that their rates of cellular respiration were significantly reduced. When they treated these cells with antibiotics, much larger doses were required to kill the bacteria. This suggests that by turning down their metabolism after drug treatment, bacteria can prevent the buildup of harmful byproducts.The findings raise the possibility that forcing bacteria into a heightened metabolic state could increase the effectiveness of existing antibiotics, the researchers say. They now plan to further investigate how these metabolic mutations help bacteria evade antibiotics, in hopes of discovering more specific targets for new adjuvant drugs."I think these results are really exciting because it unleashes gene targets that could improve antibiotic efficacy, that are not being currently investigated," Lopatkin says. "New resistance mechanisms are really exciting because they give many new avenues of research to follow up on and to see to what extent is this going to improve the efficacy for treating clinical strains."The research was funded by the Defense Threat Reduction Agency, the National Institutes of Health, the National Science Foundation Graduate Research Fellowship Program, the Broad Institute of MIT and Harvard, and a gift from Anita and Josh Bekenstein.
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Biology
| 2,021 |
February 18, 2021
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https://www.sciencedaily.com/releases/2021/02/210218142739.htm
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Scientists identify more than 140,000 virus species in the human gut
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Viruses are the most numerous biological entities on the planet. Now researchers at the Wellcome Sanger Institute and EMBL's European Bioinformatics Institute (EMBL-EBI) have identified over 140,000 viral species living in the human gut, more than half of which have never been seen before.
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The paper, published today (18 February 2021) in The human gut is an incredibly biodiverse environment. In addition to bacteria, hundreds of thousands of viruses called bacteriophages, which can infect bacteria, also live there.It is known that imbalances in our gut microbiome can contribute to diseases and complex conditions such as Inflammatory Bowel Disease, allergies and obesity. But relatively little is known about the role our gut bacteria, and the bacteriophages that infect them, play in human health and disease.Using a DNA-sequencing method called metagenomics, researchers at the Wellcome Sanger Institute and EMBL's European Bioinformatics Institute (EMBL-EBI) explored and catalogued the biodiversity of the viral species found in 28,060 public human gut metagenomes and 2,898 bacterial isolate genomes cultured from the human gut.The analysis identified over 140,000 viral species living in the human gut, more than half of which have never been seen before.Dr Alexandre Almeida, Postdoctoral Fellow at EMBL-EBI and the Wellcome Sanger Institute, said: "It's important to remember that not all viruses are harmful, but represent an integral component of the gut ecosystem. For one thing, most of the viruses we found have DNA as their genetic material, which is different from the pathogens most people know, such as SARS-CoV-2 or Zika, which are RNA viruses. Secondly, these samples came mainly from healthy individuals who didn't share any specific diseases. It's fascinating to see how many unknown species live in our gut, and to try and unravel the link between them and human health."Among the tens of thousands of viruses discovered, a new highly prevalent clade -- a group of viruses believed to have a common ancestor -- was identified, which the authors refer to as the Gubaphage. This was found to be the second most prevalent virus clade in the human gut, after the crAssphage, which was discovered in 2014.Both of these viruses seem to infect similar types of human gut bacteria, but without further research it is difficult to know the exact functions of the newly discovered Gubaphage.Dr Luis F. Camarillo-Guerrero, first author of the study from the Wellcome Sanger Institute, said: "An important aspect of our work was to ensure that the reconstructed viral genomes were of the highest quality. A stringent quality control pipeline coupled with a machine learning approach enabled us to mitigate contamination and obtain highly complete viral genomes. High-quality viral genomes pave the way to better understand what role viruses play in our gut microbiome, including the discovery of new treatments such as antimicrobials from bacteriophage origin."The results of the study form the basis of the Gut Phage Database (GPD), a highly curated database containing 142,809 non-redundant phage genomes that will be an invaluable resource for those studying bacteriophages and the role they play on regulating the health of both our gut bacteria and ourselves.Dr Trevor Lawley, senior author of the study from the Wellcome Sanger Institute, said: "Bacteriophage research is currently experiencing a renaissance. This high-quality, large-scale catalogue of human gut viruses comes at the right time to serve as a blueprint to guide ecological and evolutionary analysis in future virome studies."
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Biology
| 2,021 |
February 18, 2021
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https://www.sciencedaily.com/releases/2021/02/210218140056.htm
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New study examines leeches for role in major disease of sea turtles in Florida
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University of Central Florida researchers are homing in on the cause of a major disease of sea turtles, with some of their latest findings implicating saltwater leeches as a possible factor.
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The disease, known as fibropapillomatosis, or FP, causes sea turtles to develop tumors on their bodies, which can limit their mobility and also their health by interfering with their ability to catch and eat prey.While the cause of FP isn't known, saltwater leeches have been suspected to play a role due to their frequent presence on areas of sea turtles where FP tumors often develop, such as on their eyes, mouths and flippers.The results, which were published recently in the journal "Florida is one of the areas most heavily impacted by FP," says Anna Savage, an associate professor in UCF's Department of Biology and study co-author. "Over the past three decades, approximately half of the green turtle juveniles encountered in the Indian River Lagoon have FP tumors, which is one of the highest rates documented," she says.Sea turtle health is important because the ancient marine reptiles contribute to healthy oceans and coastlines by grazing and maintaining sea grass beds.All sea turtles are categorized as threatened or endangered because of threats from pollution, coastal development and fishing, in addition to infectious diseases.Central Florida's Atlantic coastline hosts about one-third of all green turtle nests in the state and is one of the most important nesting areas in the world for loggerheads.Knowing if leeches play a role in the disease transmission can help researchers better understand and predict its spread, as well as inform conservation actions, such as leech removal in sea turtle rehabilitation centers.The ProcessThe study's lead author and a recent undergraduate alumna of UCF's Biology Department, Leah Rittenburg, spearheaded the research and was responsible for the genetic analyses.To find out a possible connection between leeches and FP, the researchers documented the presence of leeches on green and loggerhead turtles captured from the Indian River Lagoon and also used genetic analyses to determine if leeches collected from the turtles contained chelonid alphaherpesvirus 5, or ChHV5, the virus most likely responsible for disease development in an individual turtle."Our historical data, collected by the UCF Marine Turtle Research Group between 2006 and 2018, revealed that leech parasitism was significantly associated with FP in green turtles but not in loggerhead turtles," Rittenburg says."For the genetic analysis, about one-fifth of the leeches we collected were positive for ChHV5, and one leech species trended towards coming from FP-positive turtles, further supporting the hypothesis that leeches may act as ChHV5 transmitters," she says.Now that the researchers have demonstrated a relationship between FP and leeches, they want to evaluate more specifically if leeches transmit the turtle herpesvirus, which would provide stronger evidence that the virus in an underlying cause of FP.
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Biology
| 2,021 |
February 18, 2021
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https://www.sciencedaily.com/releases/2021/02/210218113958.htm
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A new piece of the HIV infection puzzle explored
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Scientists at EMBL Heidelberg and at the Zentrum für Infektiologie at Heidelberg University Hospital have succeeded for the first time in imaging HIV during transport into the nucleus of an infected cell. The electron tomographic images show the protein envelope of the virus passing through one of the nuclear pores -- the openings in the membrane around the nucleus that allow molecules in and out. The scientists found that the virus passes through the nuclear pore intact, only breaking apart inside the nucleus, where it releases its genetic information. This clarifies an important mechanism by which the virus's genetic material is integrated into the genome of the infected cell.
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The human immunodeficiency virus type 1 (HIV-1) -- which was the focus of this study -- primarily infects certain cells of the immune system, and in this way massively weakens the body's own defence against diseases. The genetic material of the virus is securely packaged in a cone-shaped protein capsule known as the capsid, which is composed of individual hexagonal parts. Scientists knew how the capsid passes through the cell membrane into the interior of the cell during infection, but not how the virus's genetic material gets from the capsid into the cell nucleus, where it triggers the formation of new viruses.This is where the work of the Heidelberg collaboration comes in. Using newly developed methods for 3D imaging of molecular complexes in virus-infected cells, the scientists succeeded in imaging the viral capsid directly during transport into the nucleus. "Until now, it was assumed that the capsid does not fit through the pores," explains Hans-Georg Kräusslich, Medical Director of the Zentrum für Infektiologie. "However, the question of how the viral genome gets into the cell nucleus is essential for its reproduction. Our results therefore support the search for new targets for future therapeutic approaches." Although current treatment options can suppress multiplication of the virus in the body, a true cure that eliminates the virus is not yet possible.To get a detailed look at the inner workings of infected immune cells in the laboratory, the scientists used high-resolution imaging techniques. With the help of the Electron Microscopy Core Facility at Heidelberg University and the Cryo-Electron Microscopy Service Platform at EMBL Heidelberg, they combined light and electron microscopy methods. They were able to reconstruct 3D images of the molecular structures from their data. This allowed them to visualise the composition and architecture of the viral complexes and their interaction with cellular structures in high resolution. "The fruitful collaboration between our two institutions and the combination of specialised technology has helped to fit another piece of the HIV infection puzzle into the overall picture," says Martin Beck, a visiting group leader at EMBL and, since 2019, a Director and Scientific Member of the Max Planck Institute of Biophysics.
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Biology
| 2,021 |
February 18, 2021
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https://www.sciencedaily.com/releases/2021/02/210218094534.htm
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Cone snail venom shows potential for treating severe malaria
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Severe forms of malaria such as
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Using venom from the Results, published in the "Molecular stability, small size, solubility, intravenous delivery, and no immunogenic response make conotoxins excellent blockade-therapy candidates," said Andrew V. Oleinikov, Ph.D., corresponding author and a professor of biomedical science, FAU's Schmidt College of Medicine. "Conotoxins have been vigorously studied for decades as molecular probes and drug leads targeting the central nervous systems. They also should be explored for novel applications aimed to thwart amiss cellular responses or foil host parasite interactions through their binding with endogenous and exogenous proteins. Further investigation is likely to yield breakthroughs in fields continuously toiling for more efficient therapeutic approaches such as cancer, autoimmune diseases, novel emerging viral diseases as well as malaria where venom-based peptidic natural products can be put into practice."The disruption of protein-protein interactions by conotoxins is an extension of their well known inhibitory action in many ion channels and receptors. Disabling prey by specifically modulating their central nervous system is a ruling principle in the mode of action of venoms."Among the more than 850 species of cone snails there are hundreds of thousands of diverse venom exopeptides that have been selected throughout several million years of evolution to capture their prey and deter predators," said Frank Marí, Ph.D., corresponding author and senior advisor for biochemical sciences at the National Institute of Standards and Technology. "They do so by targeting several surface proteins present in target excitable cells. This immense biomolecular library of conopeptides can be explored for potential use as therapeutic leads against persistent and emerging diseases affecting non-excitable systems."For the study, researchers used high-throughput assays to study The results are noteworthy as each of these six venom fractions, which contain a mostly single or a very limited set of peptides, affected binding of domains with different receptor specificity to their corresponding receptors, which are proteins (CD36 and ICAM-1), and polysaccharide. This activity profile suggests that the peptides in these conotoxin fractions either bind to common structural elements in the different PfEMP1 domains, or that a few different peptides in the fraction may interact efficiently (concentration of each is lower proportionally to the complexity) with different domains.Study co-authors are Alberto Padilla, Ph.D., first author and a former graduate student, FAU's Schmidt College of Medicine; Sanaz Dovell, Ph.D., a former student in FAU's Charles E. Schmidt College of Science; Olga Chesnokov, Ph.D., research associate, FAU's Schmidt College of Medicine; and Mickelene Hoggard, Ph.D., Chemical Sciences Division, National Institute of Standards and Technology.This research is supported in part by the National Institute of Allergy and Infectious Diseases (grants R21A137721 and R01AI092120) awarded to Oleinikov.
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Biology
| 2,021 |
February 18, 2021
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https://www.sciencedaily.com/releases/2021/02/210218094507.htm
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Long-term, heavy coffee consumption and CVD risk
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Long black, espresso, or latte, whatever your coffee preference, drink too much and you could be in hot water, especially when it comes to heart health.
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In a world first genetic study, researchers from the Australian Centre for Precision Health at the University of South Australia found that that long-term, heavy coffee consumption -- six or more cups a day -- can increase the amount of lipids (fats) in your blood to significantly heighten your risk of cardiovascular disease (CVD).Importantly, this correlation is both positive and dose-dependent, meaning that the more coffee you drink, the greater the risk of CVD.It's a bitter pill, especially for lovers of coffee, but according to UniSA researcher, Professor Elina Hyppönen, it's one we must swallow if we want keep our hearts healthy."There's certainly a lot of scientific debate about the pros and cons of coffee, but while it may seem like we're going over old ground, it's essential to fully understand how one of the world's most widely consumed drinks can impact our health," Prof Hyppönen says."In this study we looked at genetic and phenotypic associations between coffee intake and plasma lipid profiles -- the cholesterols and fats in your blood -- finding causal evidence that habitual coffee consumption contributes to an adverse lipid profile which can increase your risk of heart disease."High levels of blood lipids are a known risk factor for heart disease, and interestingly, as coffee beans contain a very potent cholesterol-elevating compound (cafestol), it was valuable to examine them together."Cafestol is mainly present in unfiltered brews, such as French press, Turkish and Greek coffees, but it's also in espressos, which is the base for most barista-made coffees, including lattes and cappuccinos."There is no, or very little cafestol in filtered and instant coffee, so with respect to effects on lipids, those are good coffee choices."The implications of this study are potentially broad-reaching. In my opinion it is especially important for people with high cholesterol or who are worried about getting heart disease to carefully choose what type of coffee they drink."Importantly, the coffee-lipid association is dose-dependent -- the more you drink unfiltered coffee the more it raises your blood lipids, putting you at greater risk of heart disease."Globally, an estimated 3 billion cups of coffee are consumed every day. Cardiovascular diseases are the number one cause of death globally, taking an estimated 17.9 million lives each year.The study used data from 362,571 UK Biobank participants, aged 37-73 years, using a triangulation of phenotypic and genetic approaches to conduct comprehensive analyses.While the jury still may be out on the health impacts of coffee, Prof Hyppönen says it is always wise to choose filtered coffee when possible and be wary of overindulging, especially when it comes to a stimulant such as coffee."With coffee being close to the heart for many people, it's always going to be a controversial subject," Prof Hyppönen says."Our research shows, excess coffee is clearly not good for cardiovascular health, which certainly has implications for those already at risk."Of course, unless we know otherwise, the well-worn adage usually fares well -- everything in moderation -- when it comes to health, this is generally good advice."
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Biology
| 2,021 |
February 17, 2021
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https://www.sciencedaily.com/releases/2021/02/210217151057.htm
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Mimicking a chronic immune response changes the brain
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As March comes around, many people experience hay fever. As excessive immune responses go, most would admit that hay fever really isn't that bad. At the other end of the spectrum are severely debilitating autoimmune diseases like rheumatoid arthritis and multiple sclerosis. A common thread in all these conditions are cytokines, molecules that cause inflammation. Recent research by the University of Tsukuba sheds light on the effect of excessive cytokines on neuronal and glial cells in the brain.
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Researchers led by Professor Yosuke Takei and Assistant Professor Tetsuya Sasaki at the University of Tsukuba in Japan have been studying an important cytokine called interleukin (IL)-17A. Their recent study shows that chronic increases in the levels of IL-17A circulating in mouse blood can reduce the microglia activity in one part of the brain's hippocampus. This might explain why it's related to several neurological diseases.The researchers focused on IL-17A because it is known to be involved in neurological autoimmune disorders as well as disorders of the mind. "In addition to being linked to multiple sclerosis," explains Sasaki, "recent reports show that IL-17A is also a factor in Alzheimer's disease, schizophrenia, and autism spectrum disorder." To study how chronically high levels of IL-17A can affect the brain, the team used their knowledge of how IL-17A is made naturally in the body.The researchers focused on immune cells called helper T-cells. Helper T-cells come in many varieties, each one making its own cytokine, and each one created from a generic helper T-cell. "Our strategy," says Sasaki, "was to induce more generic helper T-cells to become the kind that produce IL-17A." With more of these helper T-cells, called Th17, the mutant mice did indeed produce more IL-17A in the gut, which spread throughout the body in the blood.IL-17A is known to interact with two kinds of glial cells in the nervous system, astrocytes and microglia. The researchers found that chronically high IL-17A led to reduced activity and density of microglia in one region of the hippocampus, a part of the brain that is needed for learning and forming memories. In contrast, astrocytes in the brain did not differ between the mutant and control mice. Thus, there was reason to believe that chronic IL-17A inflammation would affect cognition, specifically memory. Surprisingly, spatial memory seemed to be just as good in the mutant mice as in the control mice."These mutant mice can be used in future studies as a model for chronic IL-17A-related inflammation," says Takei. "Further neuronal and behavioral testing will help us begin to understand IL-17A's role in a range of debilitating neurological disorders."
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Biology
| 2,021 |
February 16, 2021
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https://www.sciencedaily.com/releases/2021/02/210216133457.htm
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Secret to how cholera adapts to temperature revealed
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Scientists have discovered an essential protein in cholera-causing bacteria that allows them to adapt to changes in temperature, according to a study published today in eLife.
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The protein, BipA, is conserved across bacterial species, which suggests it could hold the key to how other types of bacteria change their biology and growth to survive at suboptimal temperatures.Vibrio cholerae (V. cholerae) is the bacteria responsible for the severe diarrheal disease cholera. As with other species, V. cholerae forms biofilms -- communities of bacteria enclosed in a structure made up of sugars and proteins -- to protect against predators and stress conditions. V. cholerae forms these biofilms both in their aquatic environment and in the human intestine. There is evidence to suggest that biofilm formation is crucial to V. cholerae's ability to colonise in the intestine and might enhance its infectivity."V. cholerae experiences a wide range of temperatures, and adapting to them is not only important for survival in the environment but also for the infection process," explains lead author Teresa del Peso Santos, a postdoctoral researcher at the Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, Sweden. "We know that at 37 degrees Celsius, V. cholerae grows as rough colonies that form a biofilm. However, at lower temperatures these colonies are completely smooth. We wanted to understand how it does this."The researchers screened the microbes for genes known to be linked with biofilm formation. They found a marked increase in the expression of biofilm-related genes in colonies grown at 37C compared with 22C.To find out how these biofilm genes are controlled at lower temperatures, they generated random mutations in V. cholerae and then identified which mutants developed rough instead of smooth colonies at 22C. They then isolated the colonies to determine which genes are essential for switching off biofilm genes at low temperatures.The most common gene they found is associated with a protein called BipA. As anticipated, when they intentionally deleted BipA from V. cholerae, the resulting microbes formed rough colonies typical of biofilms rather than smooth colonies. This confirmed BipA's role in controlling biofilm formation at lower temperatures.To explore how BipA achieves this, the researchers compared the proteins produced by normal V. cholerae with those produced by microbes lacking BipA, at 22 and 37 degrees Celsius. They found that BipA alters the levels of more than 300 proteins in V. cholerae grown at suboptimal temperatures, increasing the levels of 250 proteins including virtually all known biofilm-related proteins. They also showed that at 37 degrees Celsius, BipA adopts a conformation that may make it more likely to be degraded. In BipA's absence, the production of key biofilm regulatory proteins increases, leading to the expression of genes responsible for biofilm formation.These results provide new insights into how V. cholerae adapts to temperature and will help understand -- and ideally prevent -- its survival in different environments and transmission into humans."We have shown that BipA is critical for temperature-dependent changes in the production of biofilm components and alters colony shape in some V. cholerae strains," concludes senior author Felipe Cava, Associate Professor at the Department of Molecular Biology, and MIMS Group Leader and Wallenberg Academy Fellow, Umeå University. "Future research will address the effect of temperature- and BipA-dependent regulation on V. cholerae during host infection and the consequences for cholera transmission and outbreaks."
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Biology
| 2,021 |
February 16, 2021
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https://www.sciencedaily.com/releases/2021/02/210216133434.htm
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A boost for plant research
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It is almost ten years since the scientific journal Science called optogenetics the "breakthrough of the decade." Put simply, the technique makes it possible to control the electrical activity of cells with pulses of light. With its help, scientists can gain new insights into the functioning of nerve cells, for example, and thus better understand neurological and psychiatric diseases such as depression and schizophrenia.
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In research on animal cells, optogenetics is now an established technique used in many fields. The picture is different in plant research: transferring the principle to plant cells and applying it widely has not been possible until now.However, this has now changed: Scientists at the Julius Maximilians University of Würzburg (JMU) have succeeded in applying optogenetic methods in tobacco plants. They present the results of their work in the current issue of the journal "Optogenetics is the manipulation of cells or living organisms by light after a 'light sensor' has been introduced into them using genetic engineering methods. In particular, the light-controlled cation channel channelrhodopsin-2 has helped optogenetics achieve a breakthrough," says Nagel, describing the method he co-developed. With the help of channelrhodopsin, the activity of cells can be switched on and off as if with a light switch.In plant cells, however, this has so far only worked to a limited extent. There are two main reasons for this: "It is difficult to genetically modify plants so that they functionally produce rhodopsins. In addition, they lack a crucial cofactor without which rhodopsins cannot function: all-trans retinal, also known as vitamin A," explains Dr. Gao.Prof. Nagel, Dr. Gao, Dr. Konrad, and colleagues have now been able to solve both problems. They have succeeded in producing vitamin A in tobacco plants by means of an introduced enzyme from a marine bacterium, thus enabling improved incorporation of rhodopsin into the cell membrane. This allows, for the first time, non-invasive manipulation of intact plants or selected cells by light via the so-called anion channel rhodopsin GtACR1.In an earlier approach, plant physiologists from Botany I had artificially added the much-needed cofactor vitamin A to cells to allow a light-gated cation channel to become active in plant cells (Reyer et al., 2020, PNAS). Using the genetic trick now presented, Prof. Nagel and colleagues have generated plants that produce a special enzyme in addition to a rhodopsin, called dioxygenase. These plants are then able to produce vitamin A -- which is normally not present in plants -- from provitamin A which is abundant in the plant chloroplast. The combination of vitamin A production and optimization of rhodopsins for plant application ultimately led the researchers led by Prof. Nagel, Dr. Konrad and Dr. Gao to success."If you irradiate these cells with green light, the permeability of the cell membrane for negatively charged particles increases sharply, and the membrane potential changes significantly," explains Dr. Konrad. In this way, he says, it is possible to specifically manipulate the growth of pollen tubes and the development of leaves, for example, and thus to study the molecular mechanisms of plant growth processes in detail. The Würzburg researchers are confident that this novel optogenetic approach to plant research will greatly facilitate the analysis of previously misunderstood signaling pathways in the future.Rhodopsin is a naturally light-sensitive pigment that forms the basis of vision in many living organisms. The fact that a light-sensitive ion pump from archaebacteria (bacteriorhodopsin) can be incorporated into vertebrate cells and function there was first demonstrated by Georg Nagel in 1995 together with Ernst Bamberg at the Max Planck Institute for Biophysics in Frankfurt. In 2002/2003, this proof was then also achieved with light-sensitive ion channels from algae.Together with Peter Hegemann, Nagel demonstrated the existence of two light-sensitive channel proteins, channelrhodopsin-1 and channelrhodopsin- 2 (ChR1/ChR2), in two papers published in 2002 and 2003. Crucially, the researchers discovered that ChR2 elicits an extremely rapid, light-induced change in membrane current and membrane voltage when the gene is expressed in vertebrate cells. In addition, ChR2's small size makes it very easy to use.Nagel has since then received numerous awards for this discovery, most recently in 2020 -- together with two other pioneers of optogenetics -- the $1.2 million Shaw Prize for Life Sciences.
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Biology
| 2,021 |
February 16, 2021
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https://www.sciencedaily.com/releases/2021/02/210216133409.htm
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Breakthrough in the fight against spruce bark beetles
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For the first time, a research team led by Lund University in Sweden has mapped out exactly what happens when spruce bark beetles use their sense of smell to find trees and partners to reproduce with. The hope is that the results will lead to better pest control and protection of the forest in the future.
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The Eurasian spruce bark beetle uses its sense of smell to locate trees and partners. The odours are captured via odorant receptors (proteins) in their antennae. Researchers have long understood the connection, but so far they have not known exactly which receptors bind to what pheromones. This is key knowledge for the long-term development of more effective and environmentally friendly pesticides and bark beetle traps used to protect the forest.The research team were able to characterize the response of odorant receptors in bark beetles for the first time. They identified 73 different receptors in the antennae of the Eurasian spruce bark beetle (Ips typographus), and succeeded in characterizing the odour response in two of the receptors. One responds to the pheromone ipsenol, the other to ipsdienol."A large number of different bark beetle species use these pheromones when communicating with scents, so the fact that we have been able to to characterize them is a breakthrough," says Martin N Andersson who led the research group consisting of researchers in Lund, Germany and the Czech Republic.The two receptors are thus the first ever to be characterized in bark beetles. To put the result into context, Martin N Andersson says that within the entire insect order Coleoptera beetles, with more than 300,000 species on Earth, only three odour receptors had been characterized previously."Our results indicate that the pheromone receptors of different beetle species are evolutionarily unrelated, at least in the few species that have been studied. We also show that the odour response in these receptors is very specific, and we are the first in the world to be able to show exactly where in the receptors the pheromones are likely to bind," he says.The results could make it possible to develop better and more environmentally friendly pest control methods. One approach is to try to find other odours that bind even better to the two receptors than ipsenol and ipsdienol. If such odours can be found, they can hopefully be used to disrupt the pheromone communication of spruce bark beetles -- either by a stronger activation of the receptor compared with the natural pheromone, or by blocking the receptor.Another way could be to use the two characterized receptors in a biosensor that is under development. This would quickly locate spruce bark beetles and thus be able to identify infested trees before the bark beetles spread.According to Martin N Andersson, the practical applications are a few years away."Screening for better substances can begin in 2021. If we find something, the results must be confirmed in the lab and then evaluated in the field, and that would take two or three years. Using it in biosensors for monitoring and detection will probably take longer than that. However, our discovery means that the process can now begin," he concludes.
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Biology
| 2,021 |
February 16, 2021
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https://www.sciencedaily.com/releases/2021/02/210216094314.htm
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Photosynthetic bacteria-based cancer optotheranostics
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Cancer is one of the most thought-provoking healthcare problems throughout the world. The development of therapeutic agents with highly selective anti-cancer activities is increasingly attractive due to the lack of tumor selectivity of conventional treatments.
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Scientists at Japan Advanced Institute of Science and Technology (JAIST) have created a photosynthetic bacteria-based cancer optotheranostics.Discovered by Associate Professor Eijiro Miyako and his team from JAIST, natural purple photosynthetic bacteria (PPSB) can play a key role as a highly active cancer immunotheranostics agent that uses the bio-optical-window I and II near-infrared (NIR) light thanks to the light harvesting nanocomplexes in microbial membrane. The NIR light-driven PPSB would serve as an effective "all-in-one" theranostic material for use in deep tumor treatments.At least, the present work has the following great advantages in comparison with other cancer treatments such as anticancer drug, nanomedicine, antibody, and conventional microbial therapies. 1) PPSB have high tumor specificity and non-pathogenicity; 2) Sufficient active cancer efficacy and multifunction such as NIR-I-to-NIR-II fluorescence (FL), photothermal conversion, reactive oxygen species (ROS) generation, and contrasty photoacoustic (PA) effect, can be simultaneously expressed using NIR light exposure without chemical functionalizations and genetic manipulations; 3) Complicated and expensive procedures for their production are unnecessary because they can be spontaneously proliferated by simple culturing in cheap medium.The present experiments warrant further consideration of this novel theranostic approach for the treatment of refractory cancers. The team believes that the developed technology would advance cancer treatment for creating more effective medicine.The work was supported by the Japan Society for the Promotion of Science KAKENHI Grant-in-Aid for Scientific Research (A) and the KAKENHI Fund for the Promotion of Joint International Research.
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Biology
| 2,021 |
February 16, 2021
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https://www.sciencedaily.com/releases/2021/02/210216092830.htm
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TB study reveals potential targets to treat and control infection
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Researchers at the Southwest National Primate Research Center (SNPRC) at Texas Biomedical Research Institute (Texas Biomed) may have found a new pathway to treat and control tuberculosis (TB), the disease caused by Mycobacterium tuberculosis (Mtb). Using single-cell RNA sequencing (scRNAseq), a next-generation sequencing technology, scientists were able to further define the mechanisms that lead to TB infection and latency. Co-led by Deepak Kaushal, Ph.D., Director of the SNPRC, this is the first study that used scRNAseq to study TB in macaques in depth. Results from the study were published in
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"Single-cell RNAseq is a novel approach that has developed in the past three or four years. It's an approach that allows us to look at the immune response more granularly, in higher resolution," Dr. Kaushal explained. "We were able to identify an immune response to Mtb infection in single lung cells as the infection progressed to disease, in some cases, or was controlled in others."The number of TB related deaths has decreased by 30% globally. However, according to the World Health Organization, 1.4 million people died from TB in 2019; the disease continues to be one of the top communicable diseases plaguing low-income countries. It's one of several diseases negatively impacted by COVID-19 due to the virus's impact on health systems worldwide. TB is primarily spread by a cough or sneeze from someone who is infected with the disease; however, people with latent TB are not contagious. The disease is both preventable and treatable, but latent TB can become active if disrupted by another invading infection, such as Human Immunodeficiency Virus (HIV) and drug resistance continues to be a major impediment.The study highlighted that plasmacytoid dendritic cells, which sense infection in the body, overproduce Type I interferons. Plasmacytoid dendritic cells are immune cells sent out to stop a bacteria or virus from replicating or causing disease. However, an overproduction of interferons can also cause harm. In this study, scientists observed that the interferon response correlated with disease instead of control. This information is important to scientists developing TB therapeutics and vaccines. Modifications to therapeutic/vaccine formulas may be needed to address interferon signaling."When we have a more precise understanding of how an infection develops, that knowledge can lead us to identify new drugs or therapies to treat disease and improve vaccines," Dr. Kaushal said. "Although our findings decreased the gap in knowledge of TB disease and latent infection, there's still more we need to learn."
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Biology
| 2,021 |
February 16, 2021
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https://www.sciencedaily.com/releases/2021/02/210216083059.htm
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Evolution's game of rock-paper-scissors
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If B is better than A, and C is better than B, it follows by the transitive property that C is better than A. And, yet, this is not always the case. Every kid is familiar with the Rock-Paper-Scissors game -- the epitome of nontransitivity in which there is no clear hierarchy among the three choices, despite each two-way interaction having a clear winner: Paper beats Rock, Scissors beats Paper, and Rock beats Scissors.
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Evolution may be teeming with nontransitive interactions as well. While natural selection -- the process by which organisms better adapted to their environments are more likely to survive and pass on their genes -- can be observed over shorter time intervals, there is still debate about whether fitness gains accumulate over long evolutionary time scales. In other words, one might expect that successive adaptive events (like the two-way interactions of Rock-Paper-Scissors) would translate into a cumulative increase in fitness, resulting in the very latest generation always being more fit than its all of its genealogical ancestors. However, this turns out to not be true in every case.The evolutionary process, then, includes what are known as nontransitive interactions, sometimes producing organisms that are less fit than its ancestors. Experimental demonstrations of such nontransitivity, however, have been lacking.Until now. A group of scientists at Lehigh University led by Gregory Lang, associate professor in the Department of Biological Sciences, has recently provided empirical evidence that evolution can be nontransitive. Lang and his team identify a nontransitive evolutionary sequence through a 1,000-generation yeast evolution experiment. In the experiment, an evolved clone outcompetes a recent ancestor but loses in direct competition with a distant ancestor.The nontransitivity in this case arose as a result of multilevel selection that involved adaptive changes in both the yeast nuclear genome and the genome of an intracellular RNA virus. The results, which provide experimental evidence that the continuous action of selection can give rise to organisms that are less fit compared to a distant ancestor, are described in an article published in This study confronts two common misconceptions about evolution, according to Lang. The first, he says, is that evolution is a linear "march of progress" where each organism along a line of descent is more fit than all those that came before it.Lang and his colleagues set out to determine how nontransitivity arose along a particular line of genealogical descent. In their 1,000-generation yeast experiment, nontransitivity arose due to adaptation in the yeast nuclear genome combined with the stepwise deterioration of an intracellular virus. Initially the population produced a virally encoded toxin and was immune to the toxin. As the population adapted, it fixed the beneficial nuclear mutations as well as mutations within the intracellular viral population that resulted in loss of toxin production. Over time the more beneficial nuclear mutations fix, and selection in the viral population resulted in a loss of toxin immunity -- since the toxin was no longer produced. When placed in competition against its distant ancestor, the 1,000-generation evolved population lost due to the toxin produced by the ancestor."Another misconception is that there is a single locus of selection," says Lang. "Multilevel selection -- as its name implies -- states that selection can act simultaneously on multiple levels of biological organization."In the context of this experiment, multilevel selection was common, says Lang. "Selection acts across multiple levels of biological organization, from genes within a cell to individuals within a population. Selection at one level can impact fitness at another."In fact, when we expanded our study of host-virus genome evolution to additional populations, we found that nearly half of the approximately 140 populations we studied experienced multilevel selection, fixing adaptive mutations in both the nuclear and viral genomes," he adds."Laboratory evolution experiments have proven highly effective for studying evolutionary principles, yet this work is the first to document a non-transitive interaction and provide a mechanistic explanation," says co-author Sean W. Buskirk, an assistant professor at West Chester University who collaborated on the research when a postdoctoral student in Lang's lab. "Ultimately, the presence of a virus in the ancestor drastically impacts how the evolved yeast populations compete and interact with one another."The work of co-author Alecia B. Rokes, at the time an undergraduate biology major at Lehigh, focused on competing two intracellular viruses inside yeast cells in what she terms her very own "virus fight club.""I worked on competing two viruses within the yeast cells to see if either virus variant had an advantage over the other, thus leading to higher frequency and one virus outcompeting the other," says Rokes, now a graduate student in microbiology at the University of Pittsburgh. "It was amazing to be part of the process of elimination, persistence, and pure curiosity that went into figuring out what was actually going on in these populations."By showing that nontransitive interactions can arise along a line of genealogical succession, the team's work has broad implications for the scientific community's understanding of evolutionary processes."It resolves what evolutionary biologist Stephen Jay Gould referred to as 'the paradox of the first tier,' which is the failure to identify broad patterns of progress over long evolutionary time scales, despite clear evidence of selection acting over successive short time intervals," says Lang. "In addition, it calls into doubt whether true fitness maxima exist and, more broadly, it implies that directionality and progress in evolution may be illusory."
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Biology
| 2,021 |
February 16, 2021
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https://www.sciencedaily.com/releases/2021/02/210216115125.htm
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Can evolution be predicted?
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Scientists created a framework to test the predictions of biological optimality theories, including evolution.
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Evolution adapts and optimizes organisms to their ecological niche. This could be used to predict how an organism evolves, but how can such predictions be rigorously tested? The Biophysics and Computational Neuroscience group led by professor Gašper Tkačik at the Institute of Science and Technology (IST) Austria has now created a mathematical framework to do exactly that.Evolutionary adaptation often finds clever solutions to challenges posed by different environments, from how to survive in the dark depths of the oceans to creating intricate organs such as an eye or an ear. But can we mathematically predict these outcomes?This is the key question that motivates the Tkačik research group. Working at the intersection of biology, physics, and mathematics, they apply theoretical concepts to complex biological systems, or as Tkačik puts it: "We simply want to show that it is sometimes possible to predict change in biological systems, even when dealing with such a complex beast as evolution."In a joint work by the postdoctoral fellow Wiktor Młynarski and PhD student Michal Hledík, assisted by group alumnus Thomas Sokolowski, who is now working at the Frankfurt Institute for Advanced Studies, the scientists spearheaded an essential advance towards their goal. They developed a statistical framework that uses experimental data from complex biological systems to rigorously test and quantify how well such a system is adapted to its environment. An example of such an adaptation is the design of the eye's retina that optimally collects light to form a sharp image, or the wiring diagram of a worm's nervous system that ensures all the muscles and sensors are connected efficiently, using the least amount of neural wiring.The established model the scientists base their results on represents adaptation as movement on a landscape with mountains and valleys. The features of an organism determine where it is located on this landscape. As evolution progresses and the organism adapts to its ecological niche, it climbs towards the peak of one of the mountains. Better adaptation results in a better performance in the environment -- for example producing more offspring -- which in turn is reflected in a higher elevation on this landscape. Therefore, a falcon with its sharp eyesight is located at a higher point than the bird's ancestor whose vision was worse in the same environment.The new framework by Młynarski, Hledík, and colleagues allows them to quantify how well the organisms are adapted to their niche. On a two-dimensional landscape with mountains and valleys, calculating the elevation appears trivial, but real biological systems are much more complex. There are many more factors influencing it, which results in landscapes with many more dimensions. Here, intuition breaks down and the researchers need rigorous statistical tools to quantify adaptation and test its predictions against experimental data. This is what the new framework delivers.IST Austria provides a fertile ground for interdisciplinary collaborations. Wiktor Młynarski, originally coming from computer science, is interested in applying mathematical concepts to biological systems. "This paper is a synthesis of many of my scientific interests, bringing together different biological systems and conceptual approaches," he describes this most recent study. In his interdisciplinary research, Michal Hledík works with both the Tkačik group and the research group led by Nicholas Barton in the field of evolutionary genetics at IST Austria. Gašper Tkačik himself was inspired to study complex biological systems through the lens of physics by his PhD advisor William Bialek at Princeton University. "There, I learned that the living world is not always messy, complex, and unapproachable by physical theories. In contrast, it can drive completely new developments in applied and fundamental physics," he explains."Our legacy should be the ability to point a finger at selected biological systems and predict, from first principles, why these systems are as they are, rather than being limited to describing how they work," Tkačik describes his motivation. Prediction should be possible in a controlled environment, such as with the relatively simple E. coli bacteria growing under optimal conditions. Another avenue for prediction are systems that operate under hard physical limits, which strongly constrain evolution. One example are our eyes that need to convey high-resolution images to the brain while using the minimal amount of energy. Tkačik summarizes, "Theoretically deriving even a bit of an organism's complexity would be the ultimate answer to the 'Why?' question that humans have grappled with throughout the ages. Our recent work creates a tool to approach this question, by building a bridge between mathematics and biology."
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Biology
| 2,021 |
February 16, 2021
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https://www.sciencedaily.com/releases/2021/02/210216115118.htm
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Let the immune cell see the virus: Scientists discover unique way to target common virus
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Scientists at Cardiff University have discovered a unique way to target a common virus that affects one in 200 newborn babies in the UK but for which there is only limited treatments available.
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Human cytomegalovirus (HCMV) is a master at "hiding" from the body's immune system so antibodies and T-cells cannot attack it as they do in other viruses, like the current coronavirus.The researchers have now discovered a new type of antibody in the lab which -- instead of killing the virus directly -- marks infected cells so the immune system can "see" them.Once the immune system can see the infected cells it is able to kill the virus.The team have submitted a patent for the unique immunotherapeutic and hope it can help to treat HCMV, which can leave newborn babies severely disabled or even kill them.Further work is needed to make sure it is safe and effective in humans -- but the researchers hope the technique could eventually be used to fight other infectious diseases and the method they used to find the new antibody could be applied to cancer.The study is published today in the Lead author Dr Richard Stanton, a virologist from Cardiff University's Division of Infection and Immunity, said: "HCMV is a major challenge because it has evolved a range of different techniques to avoid the body's own immune response."We have developed a really unique way of letting the immune system see the virus so it can get on with its task of killing it."HCMV causes lifelong infection in humans and is a significant cause of severe disease or death in immunocompromised individuals, such as those undergoing transplants or people with HIV.A vaccine is paramount to fighting the virus, particularly for tackling congenital disease, however there is currently no vaccine and only limited treatment options are available.In this study, the researchers looked at whether antibody-dependent cellular cytotoxicity (ADCC) -- a particular type of immune response in which a target cell is coated with antibodies and killed by immune cells -- could be exploited for therapeutic use.They used a special technique (proteomics) to characterise the molecules found on the surface of the infected cell and combined this with immunological screening to identify targets for ADCC.They found a unique target expressed early in the virus's lifecycle and were then able to develop human antibodies for use against this target.In the lab, this brought about a potent activation of ADCC, killing the infected cells."The identification of novel ADCC targets not only opens up a fuller understanding of natural immunity against HCMV that can be exploited for therapeutic benefit, but this could also now be applied to other infectious diseases -- and the mechanism we used to pinpoint the new antibody could potentially also work in cancer," said Dr Stanton."Further work is now needed to demonstrate both safety and efficacy in humans."
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Biology
| 2,021 |
February 16, 2021
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https://www.sciencedaily.com/releases/2021/02/210216115104.htm
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Mathematical modeling to identify factors that determine adaptive therapy success
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One of the most challenging issues in cancer therapy is the development of drug resistance and subsequent disease progression. In a new article featured on this month's cover of
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Cancer treatment options have increased substantially over the past few decades; however, many patients eventually develop drug resistance. Physicians strive to overcome resistance by either trying to target cancer cells through an alternative approach or targeting the resistance mechanism itself, but success with these approaches is often limited, as additional resistance mechanisms can arise.Researchers in Moffitt's Integrated Mathematical Oncology Department and Center of Excellence for Evolutionary Therapy believe that resistance may partly develop because of the high doses of drugs that are commonly used during treatment. Patients are typically administered a maximum tolerated dose of therapy that kills as many cancer cells as possible with the fewest side effects. However, according to evolutionary theories, this maximum tolerated dose approach could lead to drug resistance because of the existence of drug resistant cells before treatment even begins. Once sensitive cells are killed by anti-cancer therapies, these drug resistant cells are given free rein to divide and multiply. Moffitt researchers believe an alternative treatment strategy called adaptive therapy may be a better approach to kill cancer cells and minimize the development of drug resistance."Adaptive therapy aims not to eradicate the tumor, but to control it. Therapy is applied to reduce tumor burden to a tolerable level but is subsequently modulated or withdrawn to maintain a pool of drug-sensitive cancer cells," said Alexander Anderson, Ph.D., chair of the Integrated Mathematical Oncology Department and founding director of the Center of Excellence for Evolutionary Therapy.Previous laboratory studies have shown that adaptive therapy can prolong the time to cancer progression for several different tumor types, including ovarian, breast and melanoma. Additionally, a clinical trial in prostate cancer patients at Moffitt has shown that compared to standard treatment, adaptive therapy increased the time to cancer progression by approximately 10 months and reduced the cumulative drug usage by 53%.Despite these encouraging results, it is unclear which tumor types will respond best to adaptive therapy in the clinic. Recent studies have shown that the success of adaptive therapy is dependent on different factors, including levels of spatial constraint, the fitness of the resistant cell population, the initial number of resistant cells and the mechanisms of resistance. However, it is unclear how the cost of resistance factors into a tumor's response to adaptive therapy.The cost of resistance refers to the idea that cells that become resistant have a fitness advantage over non-resistant cells when a drug is present, but this may come at a cost, such as a slower growth rate. However, drug resistance is not always associated with a cost and it is unclear whether a cost of resistance is necessary for the success of adaptive therapy.The research team at Moffitt used mathematical modeling to determine how the cost of resistance is associated with adaptive therapy. They modeled the growth of drug sensitive and resistant cell populations under both continuous therapy and adaptive therapy conditions and compared their time to disease progression in the presence and absence of a cost of resistance.The researchers showed that tumors with higher cell density and those with smaller levels of pre-existing resistance did better under adaptive therapy conditions. They also showed that cell turnover is a key factor that impacts the cost of resistance and outcomes to adaptive therapy by increasing competition between sensitive and resistance cells. To do so, they made use of phase plane techniques, which provide a visual way to dissect the dynamics of mathematical models."I'm a very visual person and find that phase planes make it easy to gain an intuition for a model. You don't need to manipulate equations, which makes them great for communicating with experimental and clinical collaborators. We are honored that To confirm their models, the researchers analyzed data from 67 prostate cancer patients undergoing intermittent therapy treatment, a predecessor of adaptive therapy."We find that even though our model was constructed as a conceptual tool, it can recapitulate individual patient dynamics for a majority of patients, and that it can describe patients who continuously respond, as well as those who eventually relapse," said Anderson.While more studies are needed to understand how adaptive therapies may benefit patients, researchers are hopeful their data will lead to better indicators of which tumors will respond to adaptive therapy."With better understanding of tumor growth, resistance costs, and turnover rates, adaptive therapy can be more carefully tailored to patients who stand to benefit from it the most and, more importantly, highlight which patients may benefit from multi-drug approaches," said Anderson.
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Biology
| 2,021 |
February 16, 2021
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https://www.sciencedaily.com/releases/2021/02/210216115043.htm
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Evolution of cereal spikes
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In plants, the "meristem" refers to a type of tissue comprising undifferentiated cells from which various other plant organs can develop through cell division and differentiation. These "plant stem cells" give rise to shoots, leaves and roots, but also spikes and flowers.
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The research team including members of the Cluster of Excellence on Plant Sciences CEPLAS investigated the function of a gene responsible for the different spike forms of wheat and barley. This gene controls the activity of the spike and floret meristems and thus the number of spikelet and kernels per spike.The closely related cool-season cereals, barley and wheat, produce variable and defined number of spikelets on their spikes, respectively. It is from these spikelets, that florets and the grains develop. The plant researchers have identified two barley mutants named "intermedium-m" and "double seed 1," which form a wheat-like spike with a terminal floret that consumes the spike meristem thereby reducing the number of lateral spikelets per spike. The INT-M/DUB1 gene maintains meristem identity and suppresses meristem differentiation. The ability of spike meristem to form lateral spikelets thus remains intact.Prof. Dr. Maria von Korff Schmising, Head of the HHU Institute for Plant Genetics, about possible applications of the research findings: "These key regulators can be used to extend meristem activities. This may allow barley, wheat and other cereals to be modified to produce a higher grain yield."
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Biology
| 2,021 |
February 16, 2021
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https://www.sciencedaily.com/releases/2021/02/210216100137.htm
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Regular caffeine consumption affects brain structure
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Coffee, cola or an energy drink: caffeine is the world's most widely consumed psychoactive substance. Researchers from the University of Basel have now shown in a study that regular caffeine intake can change the gray matter of the brain. However, the effect appears to be temporary.
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No question -- caffeine helps most of us to feel more alert. However, it can disrupt our sleep if consumed in the evening. Sleep deprivation can in turn affect the gray matter of the brain, as previous studies have shown. So can regular caffeine consumption affect brain structure due to poor sleep? A research team led by Dr. Carolin Reichert and Professor Christian Cajochen of the University of Basel and UPK (the Psychiatric Hospital of the University of Basel) investigated this question in a study.The result was surprising: the caffeine consumed as part of the study did not result in poor sleep. However, the researchers observed changes in the gray matter, as they report in the journal A group of 20 healthy young individuals, all of whom regularly drink coffee on a daily basis, took part in the study. They were given tablets to take over two 10-day periods, and were asked not to consume any other caffeine during this time. During one study period, they received tablets with caffeine; in the other, tablets with no active ingredient (placebo). At the end of each 10-day period, the researchers examined the volume of the subjects' gray matter by means of brain scans. They also investigated the participants' sleep quality in the sleep laboratory by recording the electrical activity of the brain (EEG).Data comparison revealed that the participants' depth of sleep was equal, regardless of whether they had taken the caffeine or the placebo capsules. But they saw a significant difference in the gray matter, depending on whether the subject had received caffeine or the placebo. After 10 days of placebo -- i.e. "caffeine abstinence" -- the volume of gray matter was greater than following the same period of time with caffeine capsules.The difference was particularly striking in the right medial temporal lobe, including the hippocampus, a region of the brain that is essential to memory consolidation. "Our results do not necessarily mean that caffeine consumption has a negative impact on the brain," emphasizes Reichert. "But daily caffeine consumption evidently affects our cognitive hardware, which in itself should give rise to further studies." She adds that in the past, the health effects of caffeine have been investigated primarily in patients, but there is also a need for research on healthy subjects.Although caffeine appears to reduce the volume of gray matter, after just 10 days of coffee abstinence it had significantly regenerated in the test subjects. "The changes in brain morphology seem to be temporary, but systematic comparisons between coffee drinkers and those who usually consume little or no caffeine have so far been lacking," says Reichert.
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Biology
| 2,021 |
February 16, 2021
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https://www.sciencedaily.com/releases/2021/02/210216093007.htm
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New microscopy analysis allows discovery of central adhesion complex
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Researchers at University of Münster and the Max Planck Institute of Biochemistry have developed a method for determining the arrangement and density of individual proteins in cells. In this way, they were able to prove the existence of an adhesion complex consisting of three proteins.
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Cells of organisms are organized in subcellular compartments that consist of many individual molecules. How these single proteins are organized on the molecular level remains unclear, because suitable analytical methods are still missing. Researchers at the University of Münster together with colleagues from the Max Planck Institute of Biochemistry (Munich, Germany) have established a new technique that enables quantifying molecular densities and nanoscale organizations of individual proteins inside cells. The first application of this approach reveals a complex of three adhesion proteins that appears to be crucial for the ability of cells to adhere to the surrounding tissue. The research results have been published in the journal The attachment of cells is mediated by multi-molecular adhesion complexes that are built by hundreds of different proteins. The development of super-resolution microscopy, which was honoured with the Nobel Prize in 2014, allowed the identification of basic structural elements within such complexes. However, it remained unclear how individual proteins assemble and co-organize to form functional units. The laboratories of Prof. Dr. Carsten Grashoff at the Institute of Molecular Cell Biology (University of Münster) and Prof. Dr. Ralf Jungmann at the Max Planck Institute of Biochemistry (Munich) now developed a novel approach that allows the visualization and quantification of such molecular processes even in highly crowded subcellular structures."A substantial limitation even of the best super-resolution microscopy techniques is that many molecules remain undetected. It is therefore nearly impossible to make quantitative statements about processes of molecular complex formation in cells," explains Lisa Fischer, PhD student in the Grashoff group and first author of the study. This difficulty could now be circumvented with a combination of experimental controls and theoretical considerations."By applying our new analytical method, we were able to provide evidence for the existence of a long suspected ternary adhesion complex. We knew already before that each of these three molecules is very important for cell adhesion," explains Fischer. "However, it was not clear whether all three proteins come together to form a functional unit." As the method is broadly applicable, the researchers believe that many other cellular processes will be studied with the new analysis procedure.
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Biology
| 2,021 |
February 15, 2021
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https://www.sciencedaily.com/releases/2021/02/210215110323.htm
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Cheap, potent pathway to pandemic therapeutics
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By capitalizing on a convergence of chemical, biological and artificial intelligence advances, University of Pittsburgh School of Medicine scientists have developed an unusually fast and efficient method for discovering tiny antibody fragments with big potential for development into therapeutics against deadly diseases.
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The technique, published today in the journal "Most of the vaccines and treatments against SARS-CoV-2 target the spike protein, but if that part of the virus mutates, which we know it is, those vaccines and treatments may be less effective," said senior author Yi Shi, Ph.D., assistant professor of cell biology at Pitt. "Our approach is an efficient way to develop therapeutic cocktails consisting of multiple nanobodies that can launch a multipronged attack to neutralize the pathogen."Shi and his team specialize in finding nanobodies -- which are small, highly specific fragments of antibodies produced by llamas and other camelids. Nanobodies are particularly attractive for development into therapeutics because they are easy to produce and bioengineer. In addition, they feature high stability and solubility, and can be aerosolized and inhaled, rather than administered through intravenous infusion, like traditional antibodies.By immunizing a llama with a piece of a pathogen, the animal's immune system produces a plethora of mature nanobodies in about two months. Then it's a matter of teasing out which nanobodies are best at neutralizing the pathogen -- and most promising for development into therapies for humans.That's where Shi's "high-throughput proteomics strategy" comes into play."Using this new technique, in a matter of days we're typically able to identify tens of thousands of distinct, highly potent nanobodies from the immunized llama serum and survey them for certain characteristics, such as where they bind to the pathogen," Shi said. "Prior to this approach, it has been extremely challenging to identify high-affinity nanobodies."After drawing a llama blood sample rich in mature nanobodies, the researchers isolate those nanobodies that bind specifically to the target of interest on the pathogen. The nanobodies are then broken down to release small "fingerprint" peptides that are unique to each nanobody. These fingerprint peptides are placed into a mass spectrometer, which is a machine that measures their mass. By knowing their mass, the scientists can figure out their amino acid sequence -- the protein building blocks that determine the nanobody's structure. Then, from the amino acids, the researchers can work backward to DNA -- the directions for building more nanobodies.Simultaneously, the amino acid sequence is uploaded to a computer outfitted with artificial intelligence software. By rapidly sifting through mountains of data, the program "learns" which nanobodies bind the tightest to the pathogen and where on the pathogen they bind. In the case of most of the currently available COVID-19 therapeutics, this is the spike protein, but recently it has become clear that some sites on the spike are prone to mutations that change its shape and allow for antibody "escape." Shi's approach can select for binding sites on the spike that are evolutionarily stable, and therefore less likely to allow new variants to slip past.Finally, the directions for building the most potent and diverse nanobodies can then be fed into vats of bacterial cells, which act as mini factories, churning out orders of magnitude more nanobodies compared to the human cells required to produce traditional antibodies. Bacterial cells double in 10 minutes, effectively doubling the nanobodies with them, whereas human cells take 24 hours to do the same."This drastically reduces the cost of producing these therapeutics," said Shi.Shi and his team believe their technology could be beneficial for more than just developing therapeutics against COVID-19 -- or even the next pandemic."The possible uses of highly potent and specific nanobodies that can be identified quickly and inexpensively are tremendous," said Shi. "We're exploring their use in treating cancer and neurodegenerative diseases. Our technique could even be used in personalized medicine, developing specific treatments for mutated superbugs for which every other antibiotic has failed."Additional researchers on this publication are Yufei Xiang and Jianquan Xu, Ph.D., both of Pitt; Zhe Sang of Pitt and Carnegie Mellon University; and Lirane Bitton and Dina Schneidman-Duhovny, Ph.D., both of the Hebrew University of Jerusalem.This research was supported by the UPMC Aging Institute, National Institutes of Health grant 1R35GM137905-01, Israel Science Foundation grant 1466/18, the Ministry of Science and Technology of Israel and the Hebrew University of Jerusalem Center for Interdisciplinary Data Science Research.
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Biology
| 2,021 |
February 15, 2021
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https://www.sciencedaily.com/releases/2021/02/210215092416.htm
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Membrane building blocks play decisive role in controlling cell growth
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Lipids are the building blocks of a cell's envelope -- the cell membrane. In addition to their structural function, some lipids also play a regulatory role and decisively influence cell growth. This has been investigated in a new study by scientists at Martin Luther University Halle-Wittenberg (MLU). The impact of the lipids depends on how they are distributed over the plasma membrane. The study was published in "
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If plant cells want to move, they need to grow. One notable example of this is the pollen tube. When pollen lands on a flower, the pollen tube grows directionally into the female reproductive organs. This allows the male gametes to be delivered, so fertilisation can occur. The pollen tube is special in that it is made up of a single cell that continues to extend and, in extreme cases, can become several centimetres long. "This makes pollen tubes an exciting object for research on directional growth processes," says Professor Ingo Heilmann, head of the Department of Plant Biochemistry at MLU.For the current study, Heilmann's team focused on the phospholipids of pollen tubes, which, as the main component of the plasma membrane, are responsible for separating the cell's interior from its surroundings. "Lipids are generally known to have this structuring function," says Dr Marta Fratini, first author of the study. It has only recently come to light that some phospholipids can also regulate cellular processes. The scientists from Halle have now been able to show that a specific phospholipid called phosphatidylinositol 4,5-bisphosphate ("PIP2") can control various aspects of cell growth in pollen tubes -- depending on its position at the plasma membrane. They did this by labelling the lipid with a fluorescent marker. "We found it is either distributed diffusely over the entire tip of the pollen tube without a recognisable pattern, or is concentrated in small dynamic nanodomains," Fratini explains. One can imagine a group of people on a square: either individuals remain 1.5 metres apart as currently prescribed, or they form small groups.It appears that different enzymes are responsible for the varying distribution of PIP2. "Plant cells have several enzymes that can produce this one phospholipid," explains Heilmann. Like the lipids, some of these enzymes are widely distributed over the membrane and others are concentrated in nanodomains, as shown by the current study. Depending on which of the enzymes the researchers artificially increased, either the cytoskeleton -- a structure important for directed growth -- stabilised and the pollen tube swelled at the tip, or more pectin -- an important building material for plant cell walls -- was secreted. This made the cell branch out at the tip. To make sure that the distribution of the lipids was indeed responsible for these growth effects, the biochemists artificially changed the arrangement of the enzymes at the plasma membrane -- from clusters to a wide scattering or vice versa. It turns out they were able to control the respective effects on cell growth."As far as I know, our study is the first to trace the regulatory function of a lipid back to its spatial distribution in the membrane," says Heilmann. Further research is now needed to clarify exactly how the membrane nanodomains assemble and how the distribution of PIP2 at the membrane can have such varying effects.
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Biology
| 2,021 |
February 15, 2021
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https://www.sciencedaily.com/releases/2021/02/210215092413.htm
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Managing crab and lobster catches could offer long-term benefits
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The UK's commercial fishing industry is currently experiencing a number of serious challenges.
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However, a study by the University of Plymouth has found that managing the density of crab and lobster pots at an optimum level increases the quality of catch, benefits the marine environment and makes the industry more sustainable in the long term.Published today in Over a sustained period, researchers exposed sections of the seabed to differing densities of pot fishing and monitored any impacts using a combination of underwater videos and catch analysis.They found that in areas of higher pot density, fishermen caught 19% less brown crab and 35% less European lobster, and their catches of brown crab were on average 35 grams per individual (7%) lighter.The effect on marine species was also significant with two ecologically important reef species, Ross coral (Pentapora foliacea) and Neptune's Heart sea squirt (Phallusia mammillata), 83% and 74% less abundant respectively where pot density was higher.Researchers say the study provides evidence of a pot fishing intensity 'threshold' and highlights that commercial pot fisheries are likely to be compatible with marine conservation when managed correctly at low, sustainable levels.The study was carried out by academics from the University's School of Biological and Marine Sciences, with funding from Defra and the Blue Marine Foundation and working with the Lyme Bay Consultative Committee.It builds on an interim report published by Defra in 2019, and research published in October 2020 which used previously unseen footage to show the environmental impacts of pot fishing.Dr Adam Rees, Post-Doctoral researcher and lead author on the current research, said: "The effects of bottom-towed fishing have been clearly shown as part of the University's long-term monitoring project in Lyme Bay. But before we started this research, very little was known about the precise impacts of pot fishing over a prolonged period. We have shown that -- if left unchecked -- it can pose threats but that changing ways of working can have benefits for species on the seabed and the quality and quantity of catches."The study focussed on the Lyme Bay Reserve, a 206 km² area that has been protected from all bottom-towed fishing since 2008. It is part of the Lyme Bay and Torbay Special Area of Conservation, a 312 km² section of the English Channel that is predominantly fished by small boats operating out of towns and villages.The University has been assessing the seabed recovery since 2008 and has previously demonstrated that several species have returned to the area since the MPA was introduced. Recommendations from this work have been included within the Government's 25-year Environment Plan, and a major UK government report into Highly Protected Marine Areas (HPMAs), led by former Defra Fisheries Minister Richard Benyon.This latest study comes just days after the Marine Management Organisation (MMO) signalled its intent to ban bottom trawling at various offshore MPAs around the UK.Dr Emma Sheehan, Associate Professor of Marine Ecology and one of the study's co-authors, said: "Over a decade ago, the fishing community in Lyme Bay realised that changing the way they fish was essential to the sustainability of their industry. We have worked closely with them ever since to take their concerns into account and attempt to provide them with solutions. This study is the latest part of our ongoing work to establish the best ways to both preserve their traditions and enhance the environment they work in."Martin Attrill, Professor of Marine Ecology and senior author on the research, added: "The fishing industry is currently facing huge uncertainty. And we of course know that every fishing community is different. But with the drive to further enhance marine protection around the UK, some of the lessons we have learned in Lyme Bay could help other fleets make changes that can secure their long-term future."
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Biology
| 2,021 |
February 12, 2021
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https://www.sciencedaily.com/releases/2021/02/210212101844.htm
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Researchers have broken the code for cell communication
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Knowledge on how cells communicate is an important key to understanding many biological systems and diseases. A research team led by researchers at the University of Gothenburg has now used a unique combination of methods to map the mechanism behind cellular communication. Their findings can potentially improve understanding of the underlying mechanism behind type 2 diabetes.
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We know that human communication is important, but communication between the cells in our bodies is just as vital. The processes where cells synchronize and coordinate their behaviour is required for an organism to function and for human organs to be able to perform their functions."How do cells go from monologues to dialogues? How do cells transit from acting as individuals to acting as a community? We need to better understand this complex and difficult-to-study behaviour," says Caroline Beck Adiels, senior lecturer at the Department of Physics at the University of Gothenburg.She is responsible for the study now published in the scientific journal The researchers chose to study yeast cells, since they are similar to human cells, and their focus is on glycolytic oscillations -- a series of chemical reactions during metabolism where the concentration of substances can pulse or oscillate. The study showed how cells that initially oscillated independent of each other shifted to being more synchronized, creating partially synchronized populations of cells."One of the unique things with this study is that we have been able to study individual cells instead of simply entire cell populations. This has allowed us to really be able to see how the cells transition from their individual behaviour to coordinating with their neighbours. We have been able to map their behaviour both temporally and spatially, that is to say, when something occurs and in which cell," says Beck Adiels.According to Beck Adiels, this knowledge can be applied in many other biological systems and more complex cells where coordinated cell behaviour plays an important role. This type of behaviour is also found in cells such as heart muscle cells and in pancreatic cells, which can be an important piece of the puzzle in diabetes research."The study can contribute to understanding how pancreatic cells are regulated and how they secrete insulin, which can help us understand the underlying mechanism behind type 2 diabetes. Eventually, this could contribute to developing new medicines for treating the disease."The study is a collaboration between eight researchers at Swedish and international universities, and Caroline Beck Adiels emphasizes that this interdisciplinary collaboration has been fundamental in studying the complex behaviour of cells from multiple perspectives."I am very proud of this work, which had not been possible to complete if we had not collaborated across disciplines," she says.
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Biology
| 2,021 |
March 4, 2021
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https://www.sciencedaily.com/releases/2021/03/210304161111.htm
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Less inflammation with a traditional Tanzanian diet than with a Western diet
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Urban Tanzanians have a more activated immune system compared to their rural counterparts. The difference in diet appears to explain this difference: in the cities, people eat a more western style diet, while in rural areas a traditional diet is more common. A team of researchers from Radboud university medical center in the Netherlands, the LIMES Institute at the University of Bonn in Germany and the Kilimanjaro Clinic Research Center in Tanzania believe that this increased activity of the immune system contributes to the rapid increase in non-communicable diseases in urban areas in Africa.
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The survey was conducted among more than 300 Tanzanians, some of whom live in the city of Moshi and some in the countryside. The team found that immune cells from participants from Moshi produced more inflammatory proteins. The people surveyed had no health problems and were not ill, but an activated immune system may increase the risk for lifestyle diseases, such as cardiovascular disease.The researchers used new techniques to investigate the function of the immune system and the factors that influence its activity. Quirijn de Mast, internist-infectious diseases specialist at Radboud university medical center explains: "We looked at active RNA molecules in the blood -- known as the transcriptome -- and the composition of metabolic products in the blood."These analyses showed that metabolites derived from food had an effect on the immune system. Participants from rural areas had higher levels of flavonoids and other anti-inflammatory substances in their blood. The traditional rural Tanzanian diet, which is rich in whole grains, fibre, fruits and vegetables, contains high amounts of these substances. In people with an urban diet, which contains more saturated fats and processed foods, increased levels of metabolites that are involved in cholesterol metabolism were found. The team also found a seasonal change in the activity of the immune system. In the dry season, which is the time of harvest in the study area, the urban people had a less activated immune system.It has been known for some time that a Western lifestyle and eating habits lead to chronic diseases. According to de Mast, two important findings have emerged from this study. "First of all, we showed that a traditional Tanzanian diet has a beneficial effect on inflammation and the functioning of the immune system. This is important because rapid urbanization is ongoing, not only in Tanzania, but also in other parts of Africa. The migration from the countryside to the city is leading to dietary changes and is accompanied by a rapid increase in the number of lifestyle diseases, which puts a heavy burden on the local healthcare systems. That is why prevention is essential, and diet can be very important for this."Western countries can learn from the results Second, these findings from Africa are also relevant for Western countries. Urbanization took place a long time ago in most western countries. By studying populations at different stages of urbanization, researchers therefore have unique opportunities to improve their understanding of how diet and lifestyle affect the human immune system.
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Biology
| 2,021 |
February 11, 2021
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https://www.sciencedaily.com/releases/2021/02/210211144252.htm
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A plant's nutrient-sensing abilities can modulate its response to environmental stress
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Understanding how plants respond to stressful environmental conditions is crucial to developing effective strategies for protecting important agricultural crops from a changing climate. New research led by Carnegie's Zhiyong Wang, Shouling, Xu, and Yang Bi reveals an important process by which plants switch between amplified and dampened stress responses. Their work is published by
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To survive in a changing environment, plants must choose between different response strategies, which are based on both external environmental factors and internal nutritional and energy demands. For example, a plant might either delay or accelerate its lifecycle, depending on the availability of the stored sugars that make up its energy supply."We know plants are able to modulate their response to environmental stresses based on whether or not nutrients are available," Wang explained. "But the molecular mechanisms by which they accomplish this fine tuning are poorly understood."For years, Carnegie plant biologists have been building a treasure trove of research on a system by which plants sense available nutrients. It is a sugar molecule that gets tacked onto proteins and alters their activities. Called O-linked N-Acetylglucosamine, or O-GlcNAc, this sugar tag is associated with changes in gene expression, cellular growth, and cell differentiation in both animals and plants.The functions of O-GlcNAc are well studied in the context of human diseases, such as obesity, cancer, and neurodegeneration, but are much less understood in plants. In 2017, the Carnegie-led team identified for the first time hundreds of plant proteins modified by O-GlcNAc, providing a framework for fully parsing the nutrient-sensing network it controls.In this most recent report, researchers from Wang's lab -- lead author Bi, Zhiping Deng, Dasha Savage, Thomas Hartwig, and Sunita Patil -- and Xu's lab -- Ruben Shrestha and Su Hyun Hong -- revealed that one of the proteins modified by an O-GlcNAc tag provides a cellular physiological link between sugar availability and stress response. It is an evolutionarily conserved protein named Apoptotic Chromatin Condensation Inducer in the Nucleus, or Acinus, which is known in mammals to play numerous roles in the storage and processing of a cell's genetic material.Through a comprehensive set of genetic, genomic, and proteomic experiments, the Carnegie team demonstrated that in plants Acinus forms a similar protein complex as its mammalian counterpart and plays a unique role in regulating stress responses and key developmental transitions, such as seed germination and flowering. The work further demonstrates that sugar modification of the Acinus protein allows nutrient availability to modulate a plant's sensitivity to environmental stresses and to control seed germination and flowering time."Our research illustrates how plants use the sugar sensing mechanisms to fine tune stress responses," Xu explained. "Our findings suggest that plants choose different stress response strategies based on nutrient availability to maximize their survival in different stress conditions."Looking forward, the researchers want to study more proteins that are tagged by O-GlcNAc and better understand how this important system could be harnessed to fight hunger."Understanding how plants make cellular decisions by integrating environmental and internal information is important for improving plant resilience and productivity in a changing climate," Wang concluded. "Considering that many parts of the molecular circuit are conserved in plant and human cells, our research findings can lead to improvement of not only agriculture and ecosystems, but also of human health."This work was supported by the U.S. National Institutes of Health and the Carnegie Institution for Science endowment.
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Biology
| 2,021 |
February 11, 2021
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https://www.sciencedaily.com/releases/2021/02/210211144244.htm
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Ebola is a master of disguise
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It was once thought that Ebola and related filoviruses were more or less contained to Central Africa. After a West African outbreak and the discovery of Reston ebolavirus in the Philippines, cuevavirus in Spain and various bat filoviruses in China, researchers now understand that this viral family -- causing hemorrhagic fevers with up to 90% case fatality rates -- has been widespread around the world for millions of years.
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Our defenses against it are more embryonic, and though we have a vaccine against one species of Ebola and some therapeutic antibodies on the horizon, both have production or distribution issues. What doctors have been hoping for is a regular drug that can treat Ebola as soon as it rears its terrifying head. A study published today in the journal Ebola is so pernicious because it pulls a fast one on the body, disguising itself as a dying cell."It's cloaking itself in a lipid that is normally not exposed at the surface of a cell. It's only exposed when the cell is undergoing apoptosis," says Dr. Marceline Côté, an associate professor in the department of Biochemistry, Microbiology and Immunology, Canada Research Chair in Molecular Virology and Antiviral Therapeutics and the primary investigator on this study. Dr. Côté is a leading global expert on how viruses get into us, an understanding that is key to any effort to keep them out.The malingering virus is then taken up by immune system cells that unwittingly carry the virus to other parts of the body, disseminating the infection. Virtually all organs become active sites of replication, and the result is a vicious, multi-system disease. Once it tricks its way into the cell, the virus needs to find a specific receptor that serves as the lock for its glycoprotein key, kicking off the process that will allow it to multiply. A drug that prevents it from any one step in turning that key could defeat the disease.Dr. Côté's team, in particular PhD student Corina Stewart, tested a library of drugs against a virus in cell cultures. It's not safe to work with a replicating Ebola virus in a regular lab, so the uOttawa team used a surrogate system."We use a safe virus disguised as an Ebola virus. They will enter just the same way as an Ebola virus, but actually the inside core when they uncoat is all safe stuff," says Dr. Coté. "It's murine leukemia virus or engineered retroviruses, so nothing to worry about."Once they found a collection of drugs that seemed to work, they passed the data to collaborator Dr. Darwyn Kobasa at the National Microbiology Laboratory in Winnipeg, where a biosafety level 4 rating allows researchers to handle the bona fide virus. Dr. Kobasa confirmed that a small number of cancer chemotherapy drugs were effective in preventing Ebola from gaining a foothold in the cells.Though these types of drugs can be tough on the body, an Ebola infection carries a high risk of death. What's more, the infection doesn't last long, so any unpleasant treatment can be similarly brief.Knowing which drugs worked against Ebola also tells the team more about how the virus gets in. In particular, this study shows that Ebola virus has evolved ways to be active in its invasion of a cell. Previously, it was thought that viral entry was left mostly up to chance, with many particles being left behind while a random few were taken up into the cell. Dr. Côté's study shows the virus has evolved to get in very efficiently, rather than just going along for the ride."They are not passive passengers," says Dr. Côté. "They have their hands on the steering wheel."
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Biology
| 2,021 |
February 11, 2021
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https://www.sciencedaily.com/releases/2021/02/210211144239.htm
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Once bitten, twice shy: the neurology of why one bad curry could put us off for life
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A negative experience with food usually leaves us unable to stomach the thought of eating that particular dish again. Using sugar-loving snails as models, researchers at the University of Sussex believe these bad experiences could be causing a switch in our brains, which impacts our future eating habits.
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Like many other animals, snails like sugar and usually start feeding on it as soon as it is presented to them. But through aversive training which involved tapping the snails gently on the head when sugar appeared, the snails' behaviour was altered and they refused to feed on the sugar, even when hungry.When the team of Sussex Neuroscience researchers led by Dr Ildiko Kemenes looked a little closer, they discovered a neuronal mechanism that effectively reversed the snails' usual response to sugar after the conditioning training had taken place.Dr Ildiko Kemenes, Reader in Neuroscience in the University of Sussex's School of Life Sciences, explained: "There's a neuron in the snail's brain which normally suppresses the feeding circuit. This is important, as the network is prone to becoming spontaneously activated, even in the absence of any food. By suppressing the feeding circuit, it ensures that the snail doesn't just eat everything and anything. But when sugar or other food stimulus is present, this neuron becomes inhibited so that feeding can commence."After the aversive training, we found that this neuron reverses its electrical response to sugar and becomes excited instead of inhibited by it. Effectively, a switch has been flipped in the brain which means the snail no longer eats the sugar when presented with it, because sugar now suppresses rather than activates feeding."When researchers presented the trained snails with a piece of cucumber instead, they found that the animal was still happy to eat the healthy option -- showing that the taps were associated with only the particular type of food they were trained to reject.George Kemenes, Professor of Neuroscience at the University of Sussex and a senior member of the investigator team, added: "Snails provide us with a similar yet exceptionally basic model of how human brains work."The effect of the inhibitory neuron which suppresses the feeding circuit in the snail is quite similar to how, in the human brain, cortical networks are under inhibitory control to avoid 'runaway' activation which may lead to overeating resulting in obesity."In our research, the negative experience the snail had with the sugar could be likened to eating a bad takeaway curry which then puts us off that particular dish in future."We believe that in a human brain, a similar switch could be happening where particular groups of neurons reverse their activity in line with the negative association of a particular food. "The research, funded by the Biotechnology and Biological Sciences Research Council (BBSRC) and published in Dr Ildiko Kemenes said: "This suggests that the neuron is necessary for the expression of the learned behaviour and for altering the response to sugar."However, we cannot rule out that the sugar-activated sensory pathway also undergoes some changes, so we don't make the assumption that this is all that's happening in the brain."
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Biology
| 2,021 |
February 11, 2021
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https://www.sciencedaily.com/releases/2021/02/210211113859.htm
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New study suggests better approach in search for COVID-19 drugs
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Research from the University of Kent, Goethe-University in Frankfurt am Main, and the Philipps-University in Marburg has provided crucial insights into the biological composition of SARS-CoV-2, the cause of COVID-19, revealing vital clues for the discovery of antiviral drugs.
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Researchers compared SARS-CoV-2 and the closely related virus SARS-CoV, the cause of the 2002/03 SARS outbreak. Despite being 80% biologically identical, the viruses differ in crucial properties. SARS-CoV-2 is more contagious and less deadly, with a fatality rate of 2% compared to SARS-CoV's 10%. Moreover, SARS-CoV-2 can be spread by asymptomatic individuals, whereas SARS-CoV was only transmitted by those who were already ill.Most functions in cells are carried out by proteins; large molecules made up of amino acids. The amino acid sequence determines the function of a protein. Viruses encode proteins that reprogramme infected cells to produce more viruses. Despite the proteins of SARS-CoV-2 and SARS-CoV having largely the same amino acid sequences, the study identifies a small subset of amino acid sequence positions that differ between them and are responsible for the observed changes in the behaviour of both viruses.Crucially, these dissimilarities between SARS-CoV-2 and SARS-CoV also result in different sensitivities to drugs for the treatment of COVID-19. This is vitally important, as many attempts to identify COVID-19 drugs are based on drug response data from other coronaviruses like SARS-CoV. However, the study findings show that the effectiveness of drugs against SARS-CoV or other coronaviruses does not indicate their effectiveness against SARS-CoV-2.Martin Michaelis, Professor of Molecular Medicine at Kent's School of Biosciences, said: "We have now a much better idea how the small differences between SARS-CoV and SARS-CoV-2 can have such a massive impact on the behaviour of these viruses and the diseases that they cause. Our data also show that we must be more careful with the experimental systems that are used for the discovery of drugs for COVID-19. Only research using SARS-CoV-2 produces reliable results."Professor Jindrich Cinatl, Goethe-University, said: "Since the COVID-19 pandemic started, I have been amazed that two so similar viruses can behave so differently. Now we start to understand this. This also includes a better idea of what we have to do to get better at finding drugs for COVID-19."
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Biology
| 2,021 |
February 11, 2021
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https://www.sciencedaily.com/releases/2021/02/210211113827.htm
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Combination of pine scent and ozone as super source of particulate emissions
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Scientists have managed to figure out why conifer forests release so many fine particles into the atmosphere. Aerosol particles are particularly abundant when a-pinene, the molecule responsible for the characteristic scent of pine trees, reacts with atmospheric ozone.
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Atmospheric aerosol particles affect the Earth's climate by forming clouds, but at the same time they also pollute the air, thereby increasing mortality.Aerosol particles in the atmosphere have their origins in many sources. The significant amount of aerosol particles in the atmosphere is caused by the oxidation of hydrocarbon molecules produced by trees and other plants. One of the most important hydrocarbons forming particles is a-pinene, that is, the molecule that causes the characteristic smell of pine trees."Especially efficiently aerosols are produced when a-pinene reacts with ozone, which in turn smells "like electricity"," explains Theo Kurtén, university lecturer in Department of Chemistry at the University of Helsinki.The chemical details of this particle formation have been studied for decades, but only recently research groups at Tampere University, the University of Helsinki, and the University of Washington (in Seattle, USA) have established the blueprints for the conversion of a-pinene into products that lead to aerosol. They managed to solve the problem by using a combination of modelling based on quantum mechanics and targeted mass spectrometric experiments."The key issue, unaccounted for in previous studies, is the vast excess energy released in the initial reaction of ozone with the a-pinene molecule. Our research reveals how this energy can break certain chemical bonds inside the a-pinene molecule, which would otherwise slow down the formation of aerosol-forming products to the point of irrelevance. In contrast, the reaction mechanism discovered by us allows these products to form within less than one second," says Siddharth Iyer, postdoctoral researcher in Aerosol Physics Laboratory at Tampere University."This is an extremely important finding for aerosol scientists as we are finally able to bridge the gap between theory and observation concerning the formation of aerosols from hydrocarbons emitted by trees," adds Matti Rissanen, assistant professor in Experimental Aerosol Science at Tampere University.The study helps demystify some of the complexity of atmospheric reactions in the aerosol context. It also provides a methodological framework for studying other similar reactions where excess energy can lead to hitherto unexplored reaction channels.The research has been published in
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Biology
| 2,021 |
February 10, 2021
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https://www.sciencedaily.com/releases/2021/02/210210170145.htm
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Novel protein could reverse severe muscle wasting in disease, aging and trauma
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When we tear a muscle " stem cells within it repair the problem. We can see this occurring not only in severe muscle wasting diseases such as muscular dystrophy and in war veterans who survive catastrophic limb injuries, but also in our day to day lives when we pull a muscle.
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Also when we age and become frail we lose much of our muscle and our stem cells don't seem to be able to work as well as we age.These muscle stem cells are invisible engines that drive the tissue's growth and repair after such injuries. But growing these cells in the lab and then using them to therapeutically replace damaged muscle has been frustratingly difficult.Researchers at the Australian Regenerative Medicine Institute at Monash University in Melbourne, Australia have discovered a factor that triggers these muscle stem cells to proliferate and heal. In a mouse model of severe muscle damage, injections of this naturally occurring protein led to the complete regeneration of muscle and the return of normal movement after severe muscle trauma.The research led by Professor Peter Currie, Director of Monash University's Australian Regenerative Medicine Institute, is published today in The scientists studied the regeneration of skeletal muscle in zebrafish, fast becoming the go-to animal model for the study of stem cell regeneration because but fish are quick to reproduce, easier to experimentally manipulate, and share at least 70 percent of its genes with humans. It is also transparent which allows the scientists to witness the actual regeneration in living muscle.By studying the cells that migrated to a muscle injury in these fish the scientists identified a group of immune cells, called macrophages, which appeared to have a role in triggering the muscle stem cells to regenerate. "What we saw were macrophages literally cuddling the muscle stem cells, which then started to divide and proliferate. Once they started this process, the macrophage would move on and cuddle then next muscle stem cell, and pretty soon the wound would heal,"? Professor Currie saidMacrophages are the cells that flock to any injury or infection site in the body, removing debris and promoting healing. "They are the clean up crew of the immune system," Professor Currie said.It has long been thought that two types of macrophages exist in the body: those that move to the injury rapidly and remove debris, and those that come in slower and stick around doing the longer term clean-up.The research team, however, found that there were in fact eight genetically different types of macrophages in the injury site, and that one type, in particular, was the "cuddler." Further investigation revealed that this affectionate macrophage released a substance called NAMPT.By removing these macrophages from the zebrafish and adding the NAMPT to the aquarium water the scientists found they could stimulate the muscle stem cells to grow and heal " effectively replacing the need for the macrophages."Importantly recent experiments placing a hydrogel patch containing NAPMT into a mouse model of severe muscle wasting led to what Professor Currie called significant replacement of the damaged muscle. The researchers are now in discussions with a number of biotech companies about taking NAMPT to clinical trials for the use of this compound in the treatment of muscle disease and injury.
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Biology
| 2,021 |
February 10, 2021
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https://www.sciencedaily.com/releases/2021/02/210210170137.htm
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Earliest signs of an immune response found in developing embryos
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Researchers at the Centre for Genomic Regulation (CRG) reveal that newly formed embryos clear dying cells to maximise their chances of survival. It is the earliest display of an innate immune response found in vertebrate animals to date.
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The findings, which are published today in the journal An embryo is fragile in the first hours after its formation. Rapid cell division and environmental stress make them prone to cellular errors, which in turn cause the sporadic death of embryonic stem cells. This is assumed to be one of the major causes of embryonic developmental failure before implantation.Living organisms can remove cellular errors using immune cells which are dedicated to carry out this function, but a newly-formed embryo cannot create these specialised cells. To find out whether embryos can remove dying cells before the formation of an immune system, the researchers used high resolution time-lapse imaging technology to monitor zebrafish and mouse embryos, two established scientific models used to study vertebrate development.They found that epithelial cells -- which collectively form the first tissue on the surface of an embryo -- can recognise, ingest and destroy defective cells. It is the first time this biological process, known as epithelial phagocytosis, has been shown to clear cellular errors in newly formed vertebrate embryos."Long before the formation of the organs, one of the first tasks performed by a developing embryo is to create a protective tissue," says Dr. Esteban Hoijman, first and co-corresponding author of the paper.According to Dr. Hoijman, epithelial phagocytosis was a surprisingly efficient process thanks to the presence of arm-like protrusions on the surface of epithelial cells. "The cells cooperate mechanically; like people distributing food around the dining table before tucking into their meal, we found that epithelial cells push defective cells towards other epithelial cells, speeding up the removal of dying cells," he adds."Here we propose a new evolutionarily conserved function for epithelia as efficient scavengers of dying cells in the earliest stages of vertebrate embryogenesis," says Dr. Verena Ruprecht, group Leader in the Cell & Developmental Biology program at the CRG and senior author of the paper. "Our work may have important clinical applications by one day leading to improved screening methods and embryo quality assessment standards used in fertility clinics."According to the authors, the discovery that embryos exhibit an immune response earlier than previously thought warrants further exploration on the role of mechanical cooperation as a physiological tissue function, which remains poorly understood, in other important biological processes such as homeostasis and tissue inflammation.The study is published today in the journal
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Biology
| 2,021 |
February 10, 2021
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https://www.sciencedaily.com/releases/2021/02/210210170104.htm
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How cells drop the stress
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Under stress conditions, cells switch quickly from the normal to the crisis mode to prevent themselves from being damaged. This so-called heat shock response is associated with a rapid downregulation of gene activity to release capacities to cope with the threat. Researchers at the Max Planck Institute of Immunobiology and Epigenetics in Freiburg have now discovered how exactly a stress-induced molecular droplet formation of the transcription regulator NELF downregulates transcription to promote cell survival upon stress.
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All life on earth evolved multiple layers and networks of ensuring survival upon catastrophic events. Even cells have their emergency plan: the heat shock response. Triggered by multiple stress stimuli such as heat, toxins, or radiation, this cellular safety program tries to prevent permanent damage to the organism. The response resembles an overall adopted "lockdown" strategy witnessed during the global corona virus pandemic. During a lockdown, only essential activities are permitted and resources were diverted towards measures ensuring minimizing the impact of a pandemic.Under normal conditions, RNA polymerase II rushes down the DNA. At the correct places, the DNA is transcribed into mRNA, which is then translated into proteins. In a crisis, however, this transcription activity must come to a standstill, for the most part, to shut down or minimize the production of proteins not essential during stress conditions. "This move releases necessary capacities to ramp-up the production of RNA and proteins called molecular chaperones, which help to cope with the threat and effects of stress. The question remains, how to place an entire cell under lockdown?" says Ritwick Sawarkar, group leader at the Max Planck Institute of Immunobiology and Epigenetics and the University of Cambridge.Earlier studies by the Sawarkar lab gave first insights what happens in the cells, when they switch from normal to emergency. Stress causes the accumulation of the negative elongation factor (NELF) in the nucleus and stops the transcription at a vast number of genes. But how exactly the transcriptional regulator NELF executes the so-called Stress-Induced Transcriptional Attenuation (SITA) remained unknown."At the start of this project, we tried to visualize the NELF protein with live-cell imaging to understand its role and regulation better. Surprisingly, we discovered that NELF forms puncta or droplets upon stress whereas the same protein remains diffused under no stress conditions. We called these droplets NELF condensates," says Prashant Rawat, first-author of the study. Together with the Lab of Patrick Cramer at the Max Planck Institute for Biophysical Chemistry who could recapitulate the same NELF droplets in vitro with recombinant purified proteins, the teams propose that the stress induced biomolecular condensation facilitates an enhanced recruitment of NELF to the promoter regions of genes. Here, the NELF droplets presumably block the activity of the polymerase and drive the downregulation of gene expression.NELF subunits contain so-called Intrinsically disordered regions (IDRs). IDRs are the parts of proteins with no fixed structure and act as tentacles. The Max Planck scientists were able to show that interactions between the NELF tentacles are essential for condensation. "Many individual NELF molecules come together and their tentacles engage strongly together to form the droplet just like holding each other's hands. But what puzzled us the most was that NELF always contains IDRs as part of their structure but only undergoes condensation upon stress," says Prashant Rawat.Using genome and proteome-wide molecular and biochemical approaches, the team identified specific Post-translational Modifications (PTMs) that are essential for NELF condensation. PTMs are changes of proteins after their synthesis and are often used by cells to answer environmental stimuli. The results show that two different modifications make NELF condensates possible. "We found that stress -contingent changes in NELF phosphorylation and further SUMOylation governs NELF condensation," says Ritwick Sawarkar.Cells failing to form the NELF droplets because of impaired IDR or SUMOylation deficiency also fail to downregulate the genes and transcription upon stress. "If cells fail to go under lockdown by NELF condensation and transcriptional downregulation they risk their fitness. Our data shows significantly higher death rates of cells lacking a proper NELF condensation during stress," says Prashant Rawat.For Ritwick Sawarkar, these results also highlight the collaborative aspects of life at Max Planck Institutes. "This research only became possible because of close cooperations. Andrea Pichler's lab at the Max Planck Institute of Immunobiology and Epigenetics was key to understanding the SUMO machinery's role, while another collaboration with Patrick Cramer's lab at the Max Planck Institute for Biophysical Chemistry in Göttingen could recapitulate the same NELF droplets in vitro with recombinant purified proteins," says Ritwick Sawarkar, lead author of the study.Stress-induced transcriptional downregulation is already speculated to be associated with neurological disorders like Huntington. "We have already generated mouse models at the institute to extend our findings in vivo and to relevant disease models," says Prashant Rawat. The possibility of exploring the role of NELF condensates in different diseases seems to be an exciting avenue for future research in the lab.
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Biology
| 2,021 |
February 10, 2021
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https://www.sciencedaily.com/releases/2021/02/210210170003.htm
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HIV research yields potential drug target
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Humans possess a formidable multi-layered defense system that protects us against viral infections. Better understanding of these defenses and the tricks that viruses use to evade them could open novel avenues for treating viral infections and possibly other diseases.
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For example, a human protein called SAMHD1 impedes replication of the human immunodeficiency virus (HIV) and other viruses by depleting deoxynucleotides -- building blocks needed for the replication of the viral genome. It has long remained a mystery whether and how this protein is activated in response to infection.Now researchers from The University of Texas Health Science Center at San Antonio (UT Health San Antonio) have discovered that SAMHD1 recognizes a unique molecular pattern in nucleic acids. This pattern, called "phosphorothioation," may act as a signal for action. It's like a sentinel atop a palace wall who sees an invading horde in the distance and calls the troops to battle stations.Understanding the mechanism of SAMHD1 activation could be a step forward in the fight against HIV/AIDS."If we are able to increase SAMHD1 activity using a specific drug, that could potentially have anti-HIV activity," said Corey H. Yu, PhD, postdoctoral fellow in the laboratory of Dmitri Ivanov, PhD, at UT Health San Antonio.Today's antivirals target the viral proteins. If, in addition, therapies could unleash the power of our existing immune defenses on the virus to help eliminate it from the body, that could be a game-changer."It's a different way to look at antiviral drugs," Dr. Yu said. "We want to know if we can try to target a protein to hopefully boost its activity against HIV."
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Biology
| 2,021 |
February 10, 2021
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https://www.sciencedaily.com/releases/2021/02/210210133405.htm
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How the 3-D structure of eye-lens proteins is formed
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The lens of the human eye gets its transparency and refractive power from the fact that certain proteins are densely packed in its cells. These are mainly crystallines. If this dense packing cannot be maintained, for example due to hereditary changes in the crystallines, the result is lens opacities, known as cataracts, which are the most common cause of vision loss worldwide.
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In order for crystallins to be packed tightly in lens fibre cells, they must be folded stably and correctly. Protein folding already begins during the biosynthesis of proteins in the ribosomes, which are large protein complexes. Ribosomes help translate the genetic code into a sequence of amino acids. In the process, ribosomes form a protective tunnel around the new amino acid chain, which takes on three-dimensional structures with different elements such as helices or folded structures immediately after the tunnel's formation. The gamma-B crystallines studied in Frankfurt and Grenoble also exhibit many bonds between two sulphur-containing amino acids, so-called disulphide bridges.The production of these disulphide bridges is not easy for the cell, since biochemical conditions prevail in the cell environment that prevent or dissolve such disulphide bridges. In the finished gamma-B crystalline protein, the disulphide bridges are therefore shielded from the outside by other parts of the protein. However, as long as the protein is in the process of formation, this is not yet possible.But because the ribosomal tunnel was considered too narrow, it was assumed -- also on the basis of other studies -- that the disulphide bridges of the gamma-B crystallins are formed only after the proteins have been completed. To test this assumption, the researchers from Frankfurt and Grenoble used genetically modified bacterial cells as a model system, stopped the synthesis of the gamma-B crystallins at different points in time and examined the intermediate products with mass spectrometric, nuclear magnetic resonance spectroscopic and electron microscopic methods, and supplemented these with theoretical simulation calculations. The result: The disulphide bridges are already formed on the not yet finished protein during the synthesis of the amino acid chain."We were thus able to show that disulphide bridges can already form in the ribosomal tunnel, which offers sufficient space for this and shields the disulphide bridges from the cellular milieu," says Prof. Harald Schwalbe from the Institute of Organic Chemistry and Chemical Biology at Goethe University. "Surprisingly, however, these are not the same disulphide bridges that are later present in the finished gamma-B crystallin. We conclude that at least some of the disulphide bridges are later dissolved again and linked differently. The reason for this probably lies in the optimal timing of protein production: the 'preliminary' disulphide bridges accelerate the formation of the 'final' disulphide bridges when the gamma-B crystallin is released from the ribosome."In further studies, the researchers now want to test whether the synthesis processes in the slightly different ribosomes of higher cells are similar to those in the bacterial model system.
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Biology
| 2,021 |
February 10, 2021
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https://www.sciencedaily.com/releases/2021/02/210210133345.htm
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Cell biology: Overseers of cell death
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A new study shows that proteins called IAPs, which can trigger programmed cell death, are inhibited by a specific chemical modification, and reveals that they play a wider role in protein quality control than previously assumed.
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N-terminal acetylation -- the attachment of an acetyl group (CH3-COO-) directly to the N-terminus of a protein -- is one of the most common modifications found in the protein complements of higher organisms. The chemical tag has been linked to a wide variety of cellular signaling pathways. Now researchers led by Tanja Bange (Institute of Medical Psychology, Ludwig-Maximilians-Universitaet (LMU) in Munich) have shown that N-terminal acetylation shields certain proteins from degradation, and inhibits programmed cell death ('apoptosis'). In their unacetylated state, these same proteins can induce apoptosis by interacting with proteins called IAPs. While the acronym refers to the function of IAPs as inhibitors of apoptosis, the new study suggests that they actually have a more general role in protein quality control. The work demonstrates for the first time that two fundamental cellular processes -- N-terminal protein acetylation and programmed cell death -- are functionally linked. This finding could open up new approaches to cancer therapy. The paper appears in the journal As their name implies, IAPs are known to participate in the regulation of programmed cell death. They inhibit the process by binding to particular target proteins, and it was previously shown that IAPs can only do so as long as the N-termini of these targets are not acetylated. "In our experiments, we observed that a protein which is not involved in the control of apoptosis also binds exclusively to IAPs in its non-acetylated form," Bange explains. "This prompted us to explore the role of acetylation in the binding of proteins to IAPs in general."In experiments on cultured cells, Bange and her colleagues were able to show that, as a general rule, IAPs indeed bind to proteins whose N-termini are unacetylated. It is also known that IAPs are able to induce their own destruction as well as the degradation of their binding partners. The authors therefore assume that IAPs have a hitherto unrecognized and general function in the quality control of newly synthesized proteins. "N-terminal acetylation protects proteins from degradation," says Bange. "If its N-terminus is not 'capped' in this way, a protein is recognized as defective by IAPs and destroyed. Conversely, if proteins that lack the modification accumulate in sufficient numbers, apoptosis is triggered."These results could have therapeutic implications for the treatment of cancer. In many types of cancer, the signaling relays that trigger apoptosis are defective owing to mutation. This closes off one possible treatment option. According to the authors, inhibiting N-terminal acetylation pathways might provide a means of activating IAP function and sensitizing tumor cells to apoptosis.
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Biology
| 2,021 |
February 10, 2021
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https://www.sciencedaily.com/releases/2021/02/210210133325.htm
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Why overfishing leads to smaller cod
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Overfishing, hunting and intensive agriculture and forestry can sometimes contribute to plants and animals becoming endangered. New research from Lund University in Sweden and University of Toronto can now show why this leads to entire populations becoming smaller in size, as well as reproducing earlier. The study is published in the journal
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Researchers from Lund and Toronto are behind the study conducted on five different species of damselflies. They have studied how different environmental factors affect when and at what size the damselflies begin to reproduce. In the study, the researchers also shed light on how overfishing off the coast of Newfoundland has had direct consequences for the reproduction size and age of cod, which is similar to what they have found in damselflies."Overfishing has resulted in the cod now reproducing earlier and at a smaller size, something it has been forced to do to survive. If it had not evolved in this way, it might have completely disappeared from the waters off southeastern Canada," says Viktor Nilsson-Örtman, a researcher at Lund University.The classic explanation for the smaller reproductive size is that it is a direct consequence of a higher mortality rate due to overfishing. But that might not be the case, according to Viktor Nilsson-Örtman and his colleague Locke Rowe at the University of Toronto. In support of their thesis, the two researchers point out that the cod should then have returned to a larger reproductive size when the overfishing stopped. However, that has not happened.Instead, they point to another explanation. Overfishing off Newfoundland may have led to a rapid, evolutionary change in the species' threshold size (the smallest size at which an organism can begin to reproduce). The smaller threshold size was maintained when overfishing ceased. Evolution has thus made a permanent change, and the cod have continued to reproduce earlier and at a smaller size."Our results show that future fishing quotas may need to be changed so that species avoid developing smaller threshold sizes only to get stuck there," says Viktor Nilsson-Örtman.The theory of threshold sizes was put forth over 40 years ago and applies to all living organisms, but has remained a theory until now.The unique aspect of the current study is that the researchers prove that threshold sizes exist in reality and that they control how organisms react to various environmental factors, such as access to food. The study also shows that threshold sizes can change via evolution."It is important to understand that both animals and plants that we use for our food supply can undergo evolutionary changes in size if they are exploited too harshly. Cod stocks outside Newfoundland are one example, but this could apply to crops that are harvested at frequent intervals or huntable game," concludes Viktor Nilsson-Örtman.
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Biology
| 2,021 |
February 10, 2021
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https://www.sciencedaily.com/releases/2021/02/210210133315.htm
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New weapon against resistant bacteria
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Every day, people die from simple infections even though they have been treated with antibiotics. This is because more and more bacteria have become resistant to the types of antibiotics that doctors can prescribe.
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"It's a huge societal problem and a crisis that we must solve. For example, by developing new antibiotics that can defeat the resistant bacteria," says professor of chemistry at the Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Poul Nielsen.Resistant bacteria are not only known from pig farms, where it is becoming increasingly difficult to keep the pigsties disease-free. Hospitals are also experiencing with increasing regularity that, for example, infectious diseases cannot be controlled in patients. Thus, an infection in a surgical wound can become life-threatening even if the operation went well.According to Poul Nielsen, it is important to be at the forefront of the development because the list of resistant bacteria will only grow, which means that the treatment options will be reduced. It is therefore important to develop alternatives that can be used when the current antibiotics no longer work."Resistance can occur very quickly, and then it's essential that we're ready," he says.Together with his research assistant Christoffer Heidtmann and associate professor Janne Kudsk Klitgaard from the Department of Biochemistry and Molecular Biology as well as Clinical Microbiology, he has developed a substance that has the potential to become a new effective antibiotic, and SDU has now taken out a patent for it.Unlike traditional antibiotics such as penicillin, sulfonamides and tetracyclines, this antibiotic is from the pleuromutilin class.The substance is developed in a medicinal chemistry project and recently published in the The substance fights both resistant enterococcus, streptococcus and staphylococcus bacteria. The substance and the pleuromutilin class do this via a unique mechanism of action, which also causes resistance to develop at a very slow pace.So far, the substance has been tested on bacteria and human cells. The next step towards becoming an approved drug is animal studies and then clinical studies in humans."If this substance is to reach doctors and patients as a drug, comprehensive and cost-intensive further development efforts are needed, which we can only initiate under the auspices of the university."The big pharmaceutical companies have that kind of money, but they are traditionally not interested in this kind of tasks, because they are not financially attractive," says Poul Nielsen.According to Poul Nielsen, there are several reasons why it is not financially attractive to develop new antibiotics:Antibiotics are only taken for days or weeks. There is more money in drugs for chronically ill people, such as antidepressants or blood pressure medicine.Newly developed antibiotics will be backups and not used until the current antibiotics no longer work. So earnings are not just around the corner.The bacteria can also become resistant to a new antibiotic, and then it has to be taken off the market again."However, this doesn't change the fact that the world community is in dire need of new effective drugs against antibiotic resistance. Maybe we should consider this a societal task, rather than a task that will only be solved if it's financially attractive," says Poul Nielsen.He and his colleagues hope that the work of further developing their new antibiotic can continue. Whether it will happen, and whether it will be in a public or private context, only time will tell.MRSA (Methicillin-resistant Staphylococcus aureus) comes from pigs, among others. May cause wound infection, abscesses, impetigo, infection of bones and joints as well as blood poisoning.ESBL (Extended-spectrum beta-lactamase) is an enzyme that causes resistant intestinal bacteria from especially poultry, which can cause inflammation of the bladder, inflammation of the renal pelvis and blood poisoning.Clostridium difficile is an intestinal bacterium that causes diarrhoea and is transmitted through faeces. It forms spores, which means that water, soap and alcohol have no effect.VRE (Vancomycin-resistant enterococci) are bacteria that are born resistant to a wide range of antibiotics. VRE typically causes inflammation of the bladder but can also cause inflammation of the heart valves (endocarditis).The WHO has presented an action plan to stop the spread of resistance. According to the organisation, we are heading towards a 'post-antibiotic era, in which common infections and minor injuries can once again kill'.
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Biology
| 2,021 |
February 10, 2021
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https://www.sciencedaily.com/releases/2021/02/210210122015.htm
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A recipe for regenerating bioengineered hair
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Researchers at the RIKEN Center for Biosystems Dynamics Research in Japan have discovered a recipe for continuous cyclical regeneration of cultured hair follicles from hair follicle stem cells.
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Scientists have been making waves in recent years by developing ways to grow a variety of useful items in laboratories, from meat and diamonds to retinas and other organoids. At the RIKEN Center for Biosystems Dynamics Research in Japan, a team led by Takashi Tsuji has been working on ways to regenerate lost hair from stem cells. In an important step, a new study identifies a population of hair follicle stem cells in the skin and a recipe for normal cyclical regeneration in the lab.The researchers took fur and whisker cells from mice and cultured them in the laboratory with other biological "ingredients." They used 220 combinations of ingredients, and found that combining a type of collagen with five factors -- the NFFSE medium -- led to the highest rate of stem cell amplification in the shortest period of time..Hair growth in mammals is a continuous cyclical process in which hair grows, falls out, and is grown again. Growth occurs in the anagen phase and hair falls out in the telogen phase. Thus, a successful hair-regeneration treatment must produce hair that recycles. To test whether stem cells cultured in the NFFSE medium produce hair that cycles, the researchers placed bioengineered hair follicle stem cells in NFFSE medium or in medium missing one of the ingredients and observed the regenerated hair for several weeks. They found 81% of hair follicles generated in NFFSE medium went through at least three hair cycles and produced normal hair. In contrast, 79% of follicles grown in the other medium produced only one hair cycle.Knowing that stem-cell renewal can depend on what is attached to the outside of the cells, the researchers next looked for markers on the surface of cells cultured in the NFFSE medium. In addition to the expected CD34 and CD49f markers, they found the best hair cycling was related to the addition of Itgβ5. "We found almost 80% of follicles reached three hair cycles when Itgβ5 was also bioengineered into the hair follicle germ," explains first author Makoto Takeo. "In contrast, only 13% reached three cycles when it was not present." Analysis showed that these important cells are naturally located in the upper part of the hair follicle's bulge region."Our culture system establishes a method for cyclical regeneration of hair follicles from hair follicle stem cells," says Tsuji, "and will help make hair follicle regeneration therapy a reality in the near future." As preclinical animal-safety tests using these cultured cells were completed in 2019, the next step in the process is clinical trials.
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Biology
| 2,021 |
February 10, 2021
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https://www.sciencedaily.com/releases/2021/02/210210091153.htm
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New improved dog reference genome will aid a new generation of investigation
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Researchers at Uppsala University and the Swedish University of Agricultural Sciences have used new methods for DNA sequencing and annotation to build a new, and more complete, dog reference genome. This tool will serve as the foundation for a new era of research, helping scientists to better understand the link between DNA and disease, in dogs and in their human friends. The research is presented in the journal
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The dog has been aiding our understanding of the human genome since both genomes were released in the early 2000s. At that time, a comparison of both genomes, and two others, revealed that the human genome contained circa 20,000 genes, down from the around 100,000 predicted earlier. In the new study, researchers led by Dr Jennifer Meadows and Professor Kerstin Lindblad-Toh, have greatly improved the dog genome, identifying missing genes and highlighting regions of the genome that regulate when these genes are on or off.A key factor was the move from short- to long-read technology, reducing the number of genome gaps from over 23,000 to a mere 585."We can think of the genome as a book," says Meadows. "In the previous assembly, many words and sometimes whole sentences were in the wrong order or even missing. Long-read technology allowed us to read whole paragraphs at once, greatly improving our comprehension of the genome.""Additional tools which measure the DNA's 3D structure allowed us to place the paragraphs in order," adds Dr Chao Wang, first author of the study.A better reference genome also helps disease research. Domestic dogs have lived alongside humans for tens of thousands of years and suffer from similar diseases to humans, including neurological and immunological diseases as well as cancer. Studying dog disease genetics can provide precise clues to the causes of corresponding human diseases."The improved canine genome assembly will be of great importance and use in canine comparative medicine, where we study diseases in dogs, for example osteosarcoma, systemic lupus erythematosus (SLE) and amyotrophic lateral sclerosis (ALS), with the goal of helping both canine and human health," says Lindblad-Toh.The new dog reference genome and annotation, GSD_1.0, is available publicly for download (DDBJ/ENA/GenBank: JAAHUQ000000000) or for online browsing via UCSC and Ensembl. Major financial support was provided by the National Cancer Institute (USA), with additional contributions from the laboratories of individual co-authors.
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Biology
| 2,021 |
February 10, 2021
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https://www.sciencedaily.com/releases/2021/02/210210091139.htm
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The chemistry lab inside cells
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Investigators from the Institute of Scientific and Industrial Research at Osaka University, together with Hiroshima Institute of Technology, have announced the discovery of a new protein that allows an organism to conduct an initial and essential step in converting amino acid residues on a crosslinked polypeptide into an enzyme cofactor. This research may lead to a better understanding of the biochemistry underlying catalysis in cells.
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Every living cell is constantly pulsing with an array of biochemical reactions. The rates of these reactions are controlled by special proteins called enzymes, which catalyze specific processes that would otherwise take much longer. A number of enzymes require specialized molecules called "cofactors," which can help shuttle electrons back and forth during oxidation-reduction reactions. But these cofactors themselves must be produced by the organisms, and often require the assistance of previously existing proteins.Now, a team of scientists at Osaka University has identified a novel protein called QhpG that is essential for the biogenesis of the enzyme cofactor cysteine tryptophylquinone (CTQ). By analyzing the mass of the reaction products and determining its crystal structure, they were able to deduce the catalytic function of QhpG, which is adding two hydroxyl groups to a specific tryptophan residue within an active-site subunit QhpC of quinoheme protein amine dehydrogenase, the bacterial enzyme catalyzing the oxidation of various primary amines. The resulting dihydroxylated tryptophan and an adjacent cysteine residue are finally converted to cofactor CTQ.However, the action of QhpG is somewhat unusual compared with other protein-modifying enzymes in that it reacts with the tryptophan residue on the QhC triply crosslinked by another enzyme QhpD in a process call post-translation modification. Tryptophan, which naturally contains rings with conjugated bonds, needs the fewest changes to become a quinone cofactor. "Although several enzymes are known to contain a quinone cofactor derived from a tryptophan residue, the mechanism involved in post-translational modification, as well as the structures of the enzymes involved in their biogenesis, remains poorly understood," lead author Toshinori Oozeki says.The proteins were obtained by introducing plasmids with the corresponding genes into
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Biology
| 2,021 |
February 9, 2021
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https://www.sciencedaily.com/releases/2021/02/210209204136.htm
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Friends matter: Giraffes that group with others live longer
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A research team led by Monica Bond, research associate at the Department of Evolutionary Biology and Environmental Studies of the University of Zurich (UZH), studied giraffes in Tanzania for five years. The biologists examined the relative effects of sociability, the natural environment, and human factors on survival of the mega-herbivore. They have now shown that adult female giraffes living in larger groups have higher survival chances than more socially isolated individuals.
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Giraffe group formations are dynamic and change throughout the day, but adult females maintain many specific friendships over the long term. "Grouping with more females, called gregariousness, is correlated with better survival of female giraffes, even as group membership is frequently changing," says Bond. "This aspect of giraffe sociability is even more important than attributes of their non-social environment such as vegetation and nearness to human settlements."Aside from poaching, the main causes of adult female giraffe mortality are likely to be disease, stress or malnutrition, all of which are interconnected stressors. "Social relationships can improve foraging efficiency, and help manage intraspecific competition, predation, disease risk and psychosocial stress," says UZH professor Barbara König, senior author of the study. Female giraffes may seek out and join together with an optimal number of other females in order to share and obtain information about the highest-quality food sources. Other benefits to living in larger groups might be lowering stress levels by reducing harassment from males, cooperating in caring for young, or simply experiencing physiological benefits by being around familiar females. The study also finds that females living closer to towns had lower survival rates, possibly due to poaching.The team documented the social behaviors of the wild free-ranging giraffes using network analysis algorithms similar to those used by big-data social media platforms. According to the results, the giraffes are surprisingly similar in their social habits to humans and other primates, for whom greater social connectedness offers more opportunities. Chimpanzees and gorillas, for example, live in communities where ties between many individuals facilitate the flexibility of feeding strategies. "It seems to be beneficial for female giraffes to connect with a greater number of others and develop a sense of larger community, but without a strong sense of exclusive subgroup affiliation," adds Monica Bond.For the past decade the research team has been conducting the largest study to date of a giraffe population. The vast scale of their study area in the Tarangire region of Tanzania spans more than a thousand square kilometers and includes multiple social communities, each with about 60 to 90 adult female members. Thus, the study was able to disentangle individual from community-level influences on survival. The study is also unique in combining social network analysis and modeling of vital rates such as survival in a sample of hundreds of individuals.
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Biology
| 2,021 |
February 9, 2021
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https://www.sciencedaily.com/releases/2021/02/210209151853.htm
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New CRISPR tech targets human genome's complex code
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Finding a needle in a haystack is hard enough. But try finding a specific molecule on the needle.
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Rice University researchers have achieved something of the sort with a new genome editing tool that targets the supporting players in a cell's nucleus that package DNA and aid gene expression. Their work opens the door to new therapies for cancer and other diseases.Rice bioengineer Isaac Hilton, postdoctoral researcher and lead author Jing Li and their colleagues programmed a modified CRISPR/Cas9 complex to target specific histones, ubiquitous epigenetic proteins that keep DNA in order, with pinpoint accuracy.The open-access research appears in Histones help regulate many cellular processes. There are four in each nucleosome (the basic "beads on a string" in DNA) that help control the structure and function of our genomes by exposing genes for activation."Nucleosomes serve as architectural substrates to fit our DNA inside of our cells, and can also control access to key parts of our genomes," Hilton said.Like other proteins, histones can be triggered by phosphorylation, the addition of a phosphoryl group that can control protein-protein or protein-DNA interactions."Histones can display an exquisitely diverse spectrum of chemical modifications that serve as beacons or regulatory markers and tell which genes to turn on, and when, and how much to do so," Hilton said. "One of these mysterious modifications is phosphorylation, and we aimed to better illuminate the mechanism by which it can rapidly turn human genes on and off."No other epigenome editing technique has enabled site-specific control over histone phosphorylation, he said. The programmable Rice tool, called dCas9-dMSK1, fuses a deactivated "dCas9" protein and a "hyperactive" human histone kinase, an enzyme that catalyzes phosphorylation.CRISPR/Cas9 typically employs guide RNAs and Cas9 "scissors" to target and cut sequences in DNA. The new tool programs deactivated dCas9 to target without cutting sequences, instead using the recruited dMSK1 enzyme to phosphorylate the targeted histone and turn on nearby genes.The researchers used dCas9-dMSK1 to uncover novel genes and pathways that are pivotal for drug resistance. Li used it to identify three genes previously linked to melanoma drug resistance. "And then she identified seven new genes linked to melanoma resistance," Hilton said. "It's an exciting finding that we are following up on."Histone proteins that wrap up DNA can have all sorts of chemical marks and combinations on them," he said. "This results in what has been dubbed a histone code, and one of our goals is to work to decipher it."Li's tool also confirms how specific histone marks communicate with one another. "It tells us that chemical modifications on histones talk to each other, and we can show it happening at specific spots in the human genome," Li said. "And that's linked to a gene turning on, so this allows us to synthetically control them."Li said a long-term goal is to target a range of other histone marks. "It's a complicated story," she said. "There are a lot of different positions and features of histones that we want to study.""Getting these technologies into patients is a long process," Hilton added. "But tools like this are the first step and can pave the way towards understanding how normal cellular processes unfortunately go awry in human diseases."
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Biology
| 2,021 |
February 9, 2021
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https://www.sciencedaily.com/releases/2021/02/210209151831.htm
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Collective worm and robot 'blobs' protect individuals, swarm together
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Individually, California blackworms live an unremarkable life eating microorganisms in ponds and serving as tropical fish food for aquarium enthusiasts. But together, tens, hundreds, or thousands of the centimeter-long creatures can collaborate to form a "worm blob," a shape-shifting living liquid that collectively protects its members from drying out and helps them escape threats such as excessive heat.
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While other organisms form collective flocks, schools, or swarms for such purposes as mating, predation, and protection, the Lumbriculus variegatus worms are unusual in their ability to braid themselves together to accomplish tasks that unconnected individuals cannot. A new study reported by researchers at the Georgia Institute of Technology describes how the worms self-organize to act as entangled "active matter," creating surprising collective behaviors whose principles have been applied to help blobs of simple robots evolve their own locomotion.The research, supported by the National Science Foundation and the Army Research Office, was reported Feb. 5 in the journal The spark for the research came several years ago in California, where Saad Bhamla was intrigued by blobs of the worms he saw in a backyard pond."We were curious about why these worms would form these living blobs," said Bhamla, an assistant professor in Georgia Tech's School of Chemical and Biomolecular Engineering. "We have now shown through mathematical models and biological experiments that forming the blobs confers a kind of collective decision-making that enables worms in a larger blob to survive longer against desiccation. We also showed that they can move together, a collective behavior that's not done by any other organisms we know of at the macro scale."Such collective behavior in living systems is of interest to researchers exploring ways to apply the principles of living systems to human-designed systems such as swarm robots, in which individuals must also work together to create complex behaviors."The worm blob collective turns out to have capabilities that are more than what the individuals have, a wonderful example of biological emergence," said Daniel Goldman, a Dunn Family Professor in Georgia Tech's School of Physics, who studies the physics of living systems.The worm blob system was studied extensively by Yasemin Ozkan-Aydin, a research associate in Goldman's lab. Using bundles of worms she originally ordered from a California aquarium supply company -- and now raises in Georgia Tech labs -- Ozkan-Aydin put the worms through several experiments. Those included development of a "worm gymnasium" that allowed her to measure the strength of individual worms, knowledge important to understanding how small numbers of the creatures can move an entire blob.She started by taking the aquatic worms out of the water and watching their behavior. First, they individually began searching for water. When that search failed, they formed a ball-shaped blob in which individuals took turns on the outer surface exposed to the air where evaporation was taking place -- behavior she theorized would reduce the effect of evaporation on the collective. By studying the blobs, she learned that worms in a blob could survive out of water 10 times longer than individual worms could."They would certainly want to reduce desiccation, but the way in which they would do this is not obvious and points to a kind of collective intelligence in the system," said Goldman. "They are not just surface-minimizing machines. They are looking to exploit good conditions and resources."Ozkan-Aydin also studied how worm blobs responded to both temperature gradients and intense light. The worms need a specific range of temperatures to survive and dislike intense light. When a blob was placed on a heated plate, it slowly moved away from the hotter portion of the plate to the cooler portion and under intense light formed tightly entangled blobs. The worms appeared to divide responsibilities for the movement, with some individuals pulling the blob while others helped lift the aggregation to reduce friction.As with evaporation, the collective activity improves the chances of survival for the entire group, which can range from 10 worms up to as many as 50,000."For an individual worm going from hot to cold, survival depends on chance," said Bhamla. "When they move as a blob, they move more slowly because they have to coordinate the mechanics. But if they move as a blob, 95% of them get to the cold side, so being part of the blob confers many survival advantages."The researchers noted that only two or three "puller" worms were needed to drag a 15-worm blob. That led them to wonder just how strong the creatures were, so Ozkan-Aydin created a series of poles and cantilevers in which she could measure the forces exerted by individual worms. This "worm gymnasium" allowed her to appreciate how the pullers managed to do their jobs."When the worms are happy and cool, they stretch out and grab onto one of the poles with their heads and they pull onto it," Bhamla said. "When they are pulling, you can see the deflection of the cantilever to which their tails were attached. Yasemin was able to use known weights to calibrate the forces the worms create. The force measurement shows the individual worms are packing a lot of power."Some worms were stronger than others, and as the temperature increased, their willingness to work out at the gym declined.Ozkan-Aydin also applied the principles observed in the worms to small robotic blobs composed of "smart active particles," six 3D-printed robots with two arms and two sensors allowing them to sense light. She added a mesh enclosure and pins to arms that allowed these "smarticles" to be entangled like the worms and tested a variety of gaits and movements that could be programmed into them."Depending on the intensity, the robots try to move away from the light," Ozkan-Aydin said. "They generate emergent behavior that is similar to what we saw in the worms."She noted that there was no communication among the robots. "Each robot is doing its own thing in a decentralized way," she said. "Using just the mechanical interaction and the attraction each robot had for light intensity, we could control the robot blob."By measuring the energy consumption of an individual robot when it performed different gaits (wiggle and crawl), she determined that the wiggle gait uses less power than the crawl gait. The researchers anticipate that by exploiting gait differentiation, future entangled robotic swarms could improve their energy efficiency.The researchers hope to continue their study of the collective dynamics of the worm blobs and apply what they learn to swarm robots, which must work together with little communication to accomplish tasks that they could not do alone. But those systems must be able to work in the real world."Often people want to make robot swarms do specific things, but they tend to be operating in pristine environments with simple situations," said Goldman. "With these blobs, the whole point is that they work only because of physical interaction among the individuals. That's an interesting factor to bring into robotics."Among the challenges ahead are recruiting graduate students willing to work with the worm blobs, which have the consistency of bread dough."The worms are very nice to work with," said Ozkan-Aydin. "We can play with them and they are very friendly. But it takes a person who is very comfortable working with living systems."The project shows how the biological world can provide insights beneficial to the field of robotics, said Kathryn Dickson, program director of the Physiological Mechanisms and Biomechanics Program at the National Science Foundation."This discovery shows that observations of animal behavior in natural settings, along with biological experiments and modeling, can offer new insights, and how new knowledge gained from interdisciplinary research can help humans, for example, in the robotic control applications arising from this work," she said.
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Biology
| 2,021 |
February 9, 2021
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https://www.sciencedaily.com/releases/2021/02/210209121031.htm
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Unusual DNA folding increases the rates of mutations
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DNA sequences that can fold into shapes other than the classic double helix tend to have higher mutation rates than other regions in the human genome. New research shows that the elevated mutation rate in these sequences plays a major role in determining regional variation in mutation rates across the genome. Deciphering the patterns and causes of regional variation in mutation rates is important both for understanding evolution and for predicting sites of new mutations that could lead to disease.
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A paper describing the research by a team of Penn State scientists is available online in the journal "Most of the time we think about DNA as the classic double helix; this basic form is referred to as 'B-DNA,'" said Wilfried Guiblet, co-first author of the paper, a graduate student at Penn State at the time of research and now a postdoctoral scholar at the National Cancer Institute. "But, as much as 13% of the human genome can fold into different conformations called 'non-B DNA.' We wanted to explore what role, if any, this non-B DNA played in variation that we see in mutation rates among different regions of the genome."Non-B DNA can fold into a number of different conformations depending on the underlying DNA sequence. Examples include G-quadruplexes, Z-DNA, H-DNA, slipped strands, and various other conformations. Recent research has revealed that non-B DNA plays critical roles in cellular processes, including the replication of the genome and the transcription of DNA into RNA, and that mutations in non-B sequences are associated with genetic diseases."In a previous study, we showed that in the artificial system of a DNA sequencing instrument, which uses similar DNA copying processes as in the cell, error rates were higher in non-B DNA during polymerization," said Kateryna Makova, Verne M. Willaman Chair of Life Sciences at Penn State and one of the leaders of the research team. "We think that this is because the enzyme that copies DNA during sequencing has a harder time reading through non-B DNA. Here we wanted to see if a similar phenomenon exists in living cells."The team compared mutation rates between B- and non-B DNA at two different timescales. To look at relatively recent changes, they used an existing database of human DNA sequences to identify individual nucleotides -- letters in the DNA alphabet -- that varied among humans. These 'single nucleotide polymorphisms' (SNPs) represent places in the human genome where at some point in the past a mutation occurred in at least one individual. To look at more ancient changes, the team also compared the human genome sequence to the genome of the orangutan.They also investigated multiple spatial scales along the human genome, to test whether non-B DNA influenced mutation rates at nucleotides adjacent to it and further away."To identify differences in mutation rates between B- and non-B DNA we used statistical tools from 'functional data analysis' in which we compare the data as curves rather than looking at individual data points," said Marzia A. Cremona, co-first author of the paper, a postdoctoral researcher at Penn State at the time of the research and now an assistant professor at Université Laval in Quebec, Canada. "These methods give us the statistical power to contrast mutation rates for the various types of non-B DNA against B-DNA controls."For most types of non-B DNA, the team found increased mutation rates. The differences were enough that non-B DNA mutation rates impacted regional variation in their immediate surroundings. These differences also helped explain a large portion of the variation that can be seen along the genome at the scale of millions of nucleotides."When we look at all the known factors that influence regional variation in mutation rates across the genome, non-B DNA is the largest contributor," said Francesca Chiaromonte, Huck Chair in Statistics for the Life Sciences at Penn State and one of the leaders of the research team. "We've been studying regional variation in mutation rates for a long time from a lot of different angles. The fact that non-B DNA is such a major contributor to this variation is an important discovery.""Our results have critical medical implications," said Kristin Eckert, professor of pathology and biochemistry and molecular biology at Penn State College of Medicine, Penn State Cancer Institute Researcher, an author on the paper, and the team's long-time collaborator. "For example, human geneticists should consider the potential of a locus to form non-B DNA when evaluating candidate genetic variants for human genetic diseases. Our current and future research is focused on unraveling the mechanistic basis behind the elevated mutation rates at non-B DNA."The results also have evolutionary implications."We know that natural selection can impact variation in the genome, so for this study we only looked at regions of the genome that we think are not under the influence of selection," said Yi-Fei Huang, assistant professor of biology at Penn State and one of the leaders of the research team. "This allows us to establish a baseline mutation rate for each type of non-B DNA that in the future we could potentially use to help identify signatures of natural selection in these sequences."Because of their increased mutation rates, non-B DNA sequences could be an important source of genetic variation, which is the ultimate source of evolutionary change."Mutations are usually thought to be so rare, that when we see the same mutation in different individuals, the assumption is that those individuals shared an ancestor who passed the mutation to them both," said Makova, a Penn State Cancer Institute researcher. "But it's possible that the mutation rate is so high in some of these non-B DNA regions that the same mutation could occur independently in several different individuals. If this is true, it would change how we think about evolution."
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Biology
| 2,021 |
February 9, 2021
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https://www.sciencedaily.com/releases/2021/02/210209113902.htm
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Biomaterials could mean better vaccines, virus-fighting surfaces
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Advances in the fields of biomaterials and nanotechnology could lead to big breakthroughs in the fight against dangerous viruses like the novel coronavirus that causes COVID-19.
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In "It is important not just in terms of COVID," said author Kaushik Chatterjee. "We've seen SARS, and MERS, and Ebola, and a lot of other viral infections that have come and gone. COVID has, of course, taken a different turn altogether. Here, we wanted to see how biomaterials could be useful."Biomaterials are materials engineered to interact with other biological systems in some way. Examples include joint replacements, dental implants, surgical mesh, and drug delivery systems.Nanotechnology, meanwhile, focuses on building tiny structures and devices at the microscopic level. It has been used in the medical field to target specific cells or tissues.It is the combination of the two that could lead to more effective vaccines against viruses. While some current vaccines are already effective, the authors said biomaterials-based nanoparticles could one day be used to make them even stronger."It is a means of stimulating the immune cells which produce antibodies during the vaccination," said author Sushma Kumari. "It is like a helper, like priming the cells. Now, the moment they see the protein, the cells are more responsive to it and would be secreting more antibodies."At the same time, researchers are studying ways the technology could be used to curb the spread of viruses in the world around us. Currently, the techniques used to disinfect surfaces in public places, from conventional cleaning to aerosols to ultraviolet light, can require lots of time and effort.Emerging bioengineering technologies would create antiviral surfaces that could disinfect themselves."As viruses end up as droplets on various surfaces, the next person touching that could be picking up the disease," Chatterjee said.By putting a natural charge on the surface or designing it at the nano-level in an unfriendly pattern for the virus, masks, PPE suits, hospital beds, doorknobs, and other items could be created that automatically damage or destroy a virus.The authors note this research is in its infancy. Much work remains to be done to learn which of many biomaterials may be most effective at fighting viruses, and an answer for one disease likely will not be the same for others."Hopefully, this review and this kind of discussion will get researchers to think about how to use the knowledge that's out there," said Chatterjee.
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Biology
| 2,021 |
February 9, 2021
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https://www.sciencedaily.com/releases/2021/02/210209113840.htm
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How cells recycle the machinery that drives their motility?
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Research groups at University of Helsinki and Institut Jacques Monod, Paris, discovered a new molecular mechanism that promotes cell migration. The discovery sheds light on the mechanisms that drive uncontrolled movement of cancer cells, and also revises the 'text book view' of cell migration.
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The ability of cells to move within our bodies is critical in wound healing, as well as for immune cells to patrol in our tissues to hunt bacterial and viral pathogens. On the flip-side, uncontrolled movement of cells is a hallmark of cancer invasion and metastasis.The machinery that drives cell migration is a complex network of dynamic filaments composed of a protein actin. Actin exists in monomeric form, but like Lego bricks, different types of filamentous structures can be built from actin monomers in cells. Actin filaments are organized in cells in a way that their rapidly elongating plus-ends face the plasma membrane, whereas their minus-ends are oriented away from the plasma membrane. Elongation of actin filaments at their plus-ends against the plasma membrane generates the force to push the leading edge of cell forward during cell migration. To maintain a sufficient supply of monomeric actin subunits for filament elongation, actin filaments must be rapidly disassembled in cells, and this is believed to occur at their minus-ends. An important factor that limits actin filament disassembly to their minus-ends is Capping Protein, which binds very tightly to filament plus-ends to block filament elongation and shortening.A new study published in "Our results suggest that Twinfilin and Capping Protein make together a 'molecular clock', which ensures that the 'productive' actin filaments pushing the plasma membrane have a sufficient supply of actin monomers, whereas the 'aged' actin filaments that no longer push the plasma membrane are disassembled," says Lappalainen."This study highlights the need of several proteins with different functions to act in synergistic manner to maintain the normal morphology and functions of actin networks in cells," continues Dr. Markku Hakala who is the main author of this study.Despite extensive studies, the precise mechanisms by which actin monomers are recycled in cells has remained elusive. The new study adds an important piece in this puzzle by reveling how Capping Protein is removed from actin filament plus-ends to enable their rapid disassembly. These findings also create a basis for further studies to understand how irregularities in actin disassembly machinery cause severe diseases and developmental disorders."Uncontrolled expression of Twinfilin is linked to many diseases, such as breast cancer invasion and lymphoma progression. Our work, therefore, also sheds light on the molecular mechanisms that drive uncontrolled movement of cancer cells," concludes Lappalainen.
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Biology
| 2,021 |
February 9, 2021
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https://www.sciencedaily.com/releases/2021/02/210209091334.htm
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All in the head? Brains adapt to support new species
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Scientists studying forest dwelling butterflies in Central and South America have discovered that changes in the way animals perceive and process information from their environment can support the emergence of new species. The study led by the University of Bristol, and published today [9 February] in the
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The international team, led by Dr Stephen Montgomery from the School of Biological Sciences at the University of Bristol, compared the brain morphology of two distinct but closely related lineages of butterfly that occur in distinct tropical forest habitats. The first, including the species Heliconius cydno, lives in deeper forests, where the canopy light levels are low. Its sister lineage, including a species called Heliconius melpomene, lives around the forest edges, where light is much more abundant. Despite their ecological differences, these species are very closely related and can still produce viable offspring, suggesting they sit right at the brink of being new species.The team found substantial differences in the brains of forest edge and deep forest species, with the latter investing more in parts of the brain that process visual information. By collecting butterflies across south and central America, as well as rearing captive individuals under controlled conditions at the Smithsonian Tropical Research Institute in Panama, the researchers showed that differences in brain morphology have accumulated in a way consistent with natural selection.Dr Stephen Montgomery, Senior Research Fellow at Bristol, said: "These butterflies aren't separated by huge distances, nor are they distantly related, but their brain structure is finely tuned to the specific habitats they occupy, and we think this process helps keep the two lineages apart, allowing them to become distinct species."Similar differences were seen when the team examined the how highly different genes were expressed in the brain.Matteo Rossi, a PhD student at LMU Munich, explained: "Based on the pattern of gene expression in brain tissue we can accurately cluster individuals into the correct species. The expression of genes driving these differences evolve fast, and seem to be located in regions of the genome that are most distinct between the two species."To further explore these effects the team produced hybrid offspring between forest edge and deep forest species. They found these hybrids showed intermediate brain morphologies and patterns of gene expression in the brain.Dr Richard Merrill, also from LMU Munich, said: "Our study is exciting because it suggests that hybrids in the wild might be behavioural misfits in both habitats, and suffer the consequences."The researchers believe that the work may imply adaptations in the brain play an underappreciated role in speciation across environments."We're used to thinking about behaviour being important in speciation, but behavioural evolution must have a neural basis, but we're only just beginning to unpick this kind of process" added Dr Stephen Montgomery.The team also hope their work illustrates how important it is to protect habitat complexity in tropical forests."The forest is a tapestry of different conditions, with different structures, resources and cues. This work illustrates how closely species evolve to occupy these different micro-habitats, supporting high numbers of species in seemingly small areas" said Dr Owen McMillan, a co-author from the Smithsonian Tropical Research Institute in Panama, "if we want to protect the diversity of species in these areas, we have to protect the forests in a way that supports their natural variability."The study was funded with support from the Royal Commission for the Great Exhibition of 1851, The Leverhulme Trust, British Ecological Society, the Natural Environment Research Council, the DFG and the Smithsonian Tropical Research Institute.
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Biology
| 2,021 |
February 8, 2021
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https://www.sciencedaily.com/releases/2021/02/210208161924.htm
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Scientists discover how a group of caterpillars became poisonous
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The Atala butterfly (
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Because they are filled with poison, Eumaeus are big, gaudily iridescent and flap about like they have no place to go. Even their caterpillars are conspicuous, congregating in groups to munch cycad plants all while sporting flashy red and gold coloration. Their ostentatious qualities all signal to predators that they are a not a good meal; in nature, being toxic protects organisms from being attacked if their predators know it.Now, new research led by the Smithsonian's National Museum of Natural History butterfly curator Bob Robbins tells the evolutionary tale of how these six poisonous butterflies gained their toxin-laced defenses as well as the bold colors and behaviors that tell all would-be predators to steer clear."Butterflies don't have teeth or claws to defend themselves," Robbins said. "But they use their wing color and flight behavior as a signal of their unsavory qualities to predators, sometimes deceptively and in others truthfully, as in the case of Eumaeus. With the newfound ability to sequence genomes with relative ease, we have the opportunity to look at that in great detail for the first time."The paper, published in the Feb. 8 issue of the journal the Hairstreaks occur widely in North and South America, and almost all of them are small, evasive and nondescript. Their caterpillars, which typically eat a varied diet of flowering plants, usually are well camouflaged and do not congregate in groups. Eumaeus' ranks are notable exceptions; so much so that for years some researchers suggested that Eumaeus might not even be hairstreaks at all. In addition, because of cycads' ancient evolutionary history, most scientists had assumed that the six members of Eumaeus developed their tolerance for cycasin and their conspicuousness a very long time ago in their evolutionary history.To settle the matter, Robbins and his colleagues set about sequencing the genomes of Eumaeus' six members and a bevy of other hairstreaks around three years ago, drawing on the wealth of diverse specimens held in the museum's collections as well as some samples from wild butterflies. Those results definitively showed that Eumaeus butterflies were not an ancient evolutionary departure from the rest of the hairstreaks. In fact, they are closely related to a pair of rather typical genera called Theorema and Mithras.The results also showed that the ability to eat poisonous cycads was such a boon to Eumaeus that it spurred a frenzy of rapid evolutionary change that outpaced all other hairstreaks. The team also learned that Eumaeus had split in two evolutionary lines after they began to eat cycads, so they were able to analyze the evolutionary dash twice, including the marked genetic similarities the two lineages had in responding to their new poisonous diet.When the team started analyzing the Eumaeus genomes, they saw a striking amount of genetic change to parts of these butterflies' genomes related to building various types of proteins. To narrow down whether these proteins might be related to eating cycads, the researchers compared the Eumaeus genomes to butterflies in Theorema, their closest non-toxic relatives, which have camouflaged, solitary caterpillars that eat a standard range of flowering plants.Theorema also had some regions of fast evolving DNA that coded the construction of various proteins. When Robbins and his co-authors compared the two genomes they discarded any regions of rapid change that overlapped between the two to hopefully isolate the genetic changes involved in coping with the cycad's toxins."Sure enough, there was a core group of proteins that had gone through a lot of rapid change in Eumaeus but not in the hairstreaks that don't eat cycads," Robbins said. "When we looked at the function of the proteins that changed quickly, it was very strong on the proteins that would destroy cells, proteins that would remove dead cell debris and proteins to create new cells."Robbins said these proteins are exactly what an organism would need if it had to find a way to safely ingest cycasin-type toxin. "If the cycad toxins were killing cells at high rates, the organism would need to break those cells down, clean them out and then very rapidly make new ones to avoid any ill effects," he said.This research details the evolution of a toxic defense mechanism in these six butterfly species and the genetic consequences that result. Though the emergence of warning coloration and lazy flight might not be as easy to pick out in Eumaeus' genes, it appeared in parallel with the change in diet.Numerous butterfly species have evolved to make themselves less attractive to predators by eating toxic substances, and Robbins said this evolutionary accounting of how Eumaeus honed its defense could offer an evolutionary model for how species adapt to living with these toxins inside their bodies.Funding and support for this research were provided by the Smithsonian.
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Biology
| 2,021 |
February 8, 2021
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https://www.sciencedaily.com/releases/2021/02/210208134421.htm
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New drug target for Ebola, Marburg viruses
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Ebola and Marburg are among the most deadly viruses, with mortality rates from these infections ranging from 25% to 90%. While no drugs currently are available on the market to prevent infection from these viruses -- they belong to a category of viruses called filoviruses, which are known to cause hemorrhagic fever -- researchers have identified a few small drug molecules that can block filoviruses from infecting cells by occupying a single site on a glycoprotein in the virus.
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Now, researchers at the University of Illinois Chicago have identified a second site on the filovirus glycoprotein to which small drug molecules can bind and prevent infection. The researchers say that small drug molecules that block both glycoprotein sites may be more effective and reduce the risk of side effects.These findings are reported in the journal "We need to identify how these filoviruses get into cells as a means to help us identify or develop drugs that can prevent infection," said Lijun Rong, UIC professor of microbiology and immunology at the College of Medicine and a corresponding author of the paper. "Even though at the moment Ebola and Marburg are not in the news that often, having drugs in our arsenal in case of a flare-up is invaluable. These viruses also mutate constantly, so having a better understanding of how they work will let us develop next-generation viral inhibitors."Rong's group and his collaborators, led by Rui Xiong, UIC research assistant professor of pharmaceutical sciences at the College of Pharmacy, identified the second glycoprotein binding site by pairing the virus with hundreds of different small drug molecules thought to possibly have an effect on viral entry into cells. Several of the drugs were able to prevent viral entry.Through a series of experiments using molecular, biophysical and structural experimental techniques, they were able to look more closely at how these drugs were interacting with the virus. They found that the drugs were binding to a previously unknown site on the viral surface glycoprotein required for cell infection."The good news is that there are already drugs approved by the FDA that can bind to the new site we identified," Rong said. "If we can give drugs that bind to the site we newly identified and the site previously identified, it can help prevent viral infection with lower doses of each drug. Interfering with both sites on the viral surface glycoprotein, it also reduces the chances of the glycoprotein mutating to the point that it escapes the effect of the drug combination and is able to infect cells once again."This research was partially supported by grant awards from the National Institutes of Health (R41AI12697, R42AI126971).
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Biology
| 2,021 |
February 8, 2021
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https://www.sciencedaily.com/releases/2021/02/210208125335.htm
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Brain changed by caffeine in utero
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New research finds caffeine consumed during pregnancy can change important brain pathways that could lead to behavioral problems later in life. Researchers in the Del Monte Institute for Neuroscience at the University of Rochester Medical Center (URMC) analyzed thousands of brain scans of nine and ten-year-olds, and revealed changes in the brain structure in children who were exposed to caffeine in utero.
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"These are sort of small effects and it's not causing horrendous psychiatric conditions, but it is causing minimal but noticeable behavioral issues that should make us consider long term effects of caffeine intake during pregnancy," said John Foxe, Ph.D., director of the Del Monte Institute for Neuroscience, and principal investigator of the Adolescent Brain Cognitive Development or ABCD Study at the University of Rochester. "I suppose the outcome of this study will be a recommendation that any caffeine during pregnancy is probably not such a good idea."Elevated behavioral issues, attention difficulties, and hyperactivity are all symptoms that researchers observed in these children. "What makes this unique is that we have a biological pathway that looks different when you consume caffeine through pregnancy," said Zachary Christensen, a M.D/Ph.D. candidate in the Medical Science Training Program and first author on the paper published in the journal Investigators analyzed brain scans of more than 9,000 nine and ten-year-old participants in the ABCD study. They found clear changes in how the white matter tracks -- which form connections between brain regions -- were organized in children whose mothers reported they consumed caffeine during pregnancy.URMC is one of 21-sites across the country collecting data for the ABCD study, the largest long-term study of brain development and child health. The study is funded by the National Institutes of Health. Ed Freedman, Ph.D., is the principal investigator of the ABCD study in Rochester and a co-author of the study."It is important to point out this is a retrospective study," said Foxe. "We are relying on mothers to remember how much caffeine they took in while they were pregnant."Previous studies have found caffeine can have a negative effect on pregnancy. It is also known that a fetus does not have the enzyme necessary to breakdown caffeine when it crosses the placenta. This new study reveals that caffeine could also leave a lasting impact on neurodevelopment.The researchers point out that it is unclear if the impact of the caffeine on the fetal brain varies from one trimester to the next, or when during gestation these structural changes occur."Current clinical guidelines already suggest limiting caffeine intake during pregnancy -- no more than two normal cups of coffee a day," Christensen said. "In the long term, we hope to develop better guidance for mothers, but in the meantime, they should ask their doctor as concerns arise."
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Biology
| 2,021 |
February 8, 2021
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https://www.sciencedaily.com/releases/2021/02/210208114240.htm
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Cells are collective thinkers
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Cells, like humans, cast votes to make decisions as a group. But how do they know what to vote for? Researchers at the Francis Crick Institute and King's College London have uncovered how cells actively seek information in order to make faster and better collective decisions to coordinate the growth of new blood vessels. This provides a new basis for understanding intelligence in cells.
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The process of how cells precisely and quickly coordinate action when they create new tissue is complex. They must collectively decide which cells should take on specific jobs and ensure that not too many or too few cells are fulfilling each role.In their study, published in The researchers compare this to entering a dark, unfamiliar room and extending your arms to feel around the wall for a light switch. In the case of the cells, they reach out long 'fingers' and feel their way in the environment. This allows them to quickly choose the cell that senses the most signal from the surroundings to become their leader. This leader, called a tip cell, drives the new blood vessel forward.Katie Bentley, senior author and group leader of the Cellular Adaptive Behaviour Laboratory at the Crick and senior lecturer at King's College London says: "In most biology textbooks, processes are set out step by step in a certain order. Molecule A binds to receptor B and causes movement C. In the case of this important collective cell decision, steps happen alongside each other rather than consecutively, as cells simultaneously move about while 'deciding' how to form new tissue."This ability to use feedback from moving through the world while making a choice is something we usually associate with 'higher-organisms' so recognising how these processes also play a role in more basic living systems could reveal fundamental aspects of biological function driving them to behave as they do."And in cases where this process has gone wrong, it could even unlock new therapies and treatments that impact these feedback processes."In their proof of concept work, the researchers focussed on blood vessel formation, which is vital to healthy tissue development and repair, and is often dysregulated in disease.At the start of this process, some endothelial cells along the outside of an existing blood vessel turn into tip cells. These tip cells have long finger-like protrusions on their surface, called filopodia, and are the first to move out from the existing vessel to form the head of the new, sprouting vessel.Many aspects of the timing and cell interactions involved in this process, including how the endothelial cells decide which of them should become tip cells, are not yet understood.Using computer simulations and studies of zebrafish embryos, the researchers found that the filopodia start forming on the cell surface before it has committed to becoming a tip cell. The filopodia then extend out into the surrounding tissue and detect signals which can either trigger the cell to become a tip cell or inhibit it. This process of filopodia movement and sensing constitutes an active perception feedback loop.Importantly, to stop all the cells becoming tip cells, neighbouring cells send signals to each other so that only every other cell specialises.Bahti Zakirov, author and researcher at the Crick and King's College London says: "It was exciting to find that the creation of filopodia was taking place before the cells had fully become tip cells. Until now these protrusions have been considered as merely the end product of the cell decision making process. We've flipped this on its head and shown that the cells use filopodia to better sense their environment and inform their decision -- highlighting the feedback between movement and sensing as an important player in the decision-making process."When the researchers disrupted the filopodia in their computer models and in zebrafish embryos, fewer tip cells were selected and this selection happened more slowly. This delayed process has previously been shown to lead to the formation of less dense blood vessel networks.Zakirov continues: "If tip cell selection goes wrong or is slowed down this can lead to poorly branched or abnormal vessel networks, limiting blood flow. This in turn, can contribute to diseases such as cancer, retinopathy and HHT- hereditary haemorrhagic telangiectasia. A greater understanding of how to speed up or alter the branching tempo could therefore lead to new therapies which can regulate blood vessel density. This could also help in the creation of artificial organs or tissues as these also need dense blood vessel networks."Bentley adds: "This work has not only given us a a fresh perspective on the tip cell selection process, revealing a hidden, yet vital time-keeping role for filopodia, but also opened the door to a myriad of new and exciting research directions. We will be exploring some of these important questions in future work, with a view to better interpreting and understanding cell behaviour."
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Biology
| 2,021 |
February 8, 2021
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https://www.sciencedaily.com/releases/2021/02/210208114222.htm
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Halt cell recycling to treat cancer
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Recycling cans and bottles is a good practice. It helps keep the planet clean.
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The same is true for recycling within cells in the body. Each cell has a way of cleaning out waste in order to regenerate newer, healthier cells. This "cell recycling" is called autophagy.Targeting and changing this process has been linked to helping control or diminish certain cancers. Now, University of Cincinnati researchers have shown that completely halting this process in a very aggressive form of breast cancer may improve outcomes for patients one day.These results are published in the Feb. 8 print edition of the journal "Autophagy is sort of like cell cannibalism," says corresponding author Jun-Lin Guan, PhD, Francis Brunning Professor and Chair of UC's Department of Cancer Biology. "They eat the nasty components of themselves and come out strong and undamaged; however, we do not want cancer cells doing this to create stronger, healthier versions of themselves. Previous studies found that disabling this process slowed down the growth of another type of breast cancer, but it was unknown whether blocking autophagy could be beneficial for a particularly aggressive type of breast cancer, known as HER2-positive breast cancer."This type of breast cancer grows rapidly, and while there are effective treatments, unfortunately, these particular cancer cells find a way to become resistant to therapy, leading to relapse and a higher death rate in patients.Researchers in this study used animal models to show that blocking autophagy eliminated the development and growth of this type of breast cancer "even to a greater extent than our previous studies in other types of breast cancer," says Guan, also a member of the UC Cancer Center.He adds that researchers also uncovered that by blocking this activity, they were able to impact the other activities and mechanisms within the cancer cells completely, changing their roles and reactions."It altered trafficking patterns of the HER2 protein after it is produced by the cancer cells," he continues. "Instead of being put in its 'normal' location on the cell surface to cause cancer development, it is incorporated into some small fluid-filled pouches, known as vesicles, and secreted out of the tumor cells."Guan says these findings are particularly important as they show a completely different way to potentially treat this type of breast cancer and may work as a combination therapy with current treatments to prevent resistance and relapse."It would be harder for the cancer cells to develop ways to evade two different ways to be blocked," he adds. "Future clinical studies will be needed to validate the treatment in human patients. Also, the HER2 protein plays a role in several other cancers including lung, gastric [stomach] and prostate cancers, so future studies will need to examine whether this new mechanism may also be beneficial in treating those cancers as well."This study really shows the value of basic research in beating cancer in the future. Breakthroughs, like this one, are sometimes made from curiosity-driven research that result in surprising findings that could one day help people."Lead author on the study Mingang Hao, PhD, who is a postdoctoral fellow in Guan's lab, says he was handling two separate cancer research projects at the same time, but this study inspired findings for the other, which also involved vesicles or "bubbles" in cancer spread."Cancer research has so many intricate twists and turns, but so much of it can be interconnected, even in tiny ways," Hao says. "Working with the teams at UC has shown me some really innovative ways to tackle this disease, and I'm able to apply things I'm learning in one lab to research in another, to ultimately help find solutions for this terrible disease."Co-author Kevin Turner, MD, a resident in the Department of Surgery at UC, says his work with this science helps him understand more about cancer development and spread to better treat patients."As a surgical resident planning to pursue a career in surgical oncology, having the opportunity to work in a science lab with Dr. Guan and his team has allowed me to develop a deeper understanding of the workings of a disease I have seen in my patients," he says. "I hope to continue studies on this as we work toward clinical trials and applying it in patients."
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Biology
| 2,021 |
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