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36897919 | Naturally-occurring serotype 3 Streptococcus pneumoniae strains that lack functional pneumolysin and autolysin have attenuated virulence but induce localized protective immune responses. | Streptococcus pneumoniae is an important cause of fatal pneumonia in humans. These bacteria express virulence factors, such as the toxins pneumolysin and autolysin, that drive host inflammatory responses. In this study we confirm loss of pneumolysin and autolysin function in a group of clonal pneumococci that have a chromosomal deletion resulting in a pneumolysin-autolysin fusion gene Δ(lytA'-ply')593. The Δ(lytA'-ply')593 pneumococci strains naturally occur in horses and infection is associated with mild clinical signs. Here we use immortalized and primary macrophage in vitro models, which include pattern recognition receptor knock-out cells, and a murine acute pneumonia model to show that a Δ(lytA'-ply')593 strain induces cytokine production by cultured macrophages, however, unlike the serotype-matched ply+lytA+ strain, it induces less tumour necrosis factor α (TNFα) and no interleukin-1β production. The TNFα induced by the Δ(lytA'-ply')593 strain requires MyD88 but, in contrast to the ply+lytA+ strain, is not reduced in cells lacking TLR2, 4 or 9. parison to the ply+lytA+ strain in a mouse model of acute pneumonia, infection with the Δ(lytA'-ply')593 strain resulted in less severe lung parable levels of interleukin-1α, but minimal release of other pro-inflammatory cytokines, including interferon-γ, interleukin-6 and TNFα. These results suggest a mechanism by which a naturally occurring Δ(lytA'-ply')593 mutant strain of S. pneumoniae that resides in a non-human host has reduced inflammatory and invasive pared to a human S. pneumoniae strain. These data probably explain the relatively mild clinical disease in response to S. pneumoniae infection seen in horses parison to humans. |
36897921 | Real-time emotion detection by quantitative facial motion analysis. | Research into mood and emotion has often depended on slow and subjective self-report, highlighting a need for rapid, accurate, and objective assessment tools. |
36897922 | Evaluating combined effects of pesticide and crop nutrition (with N, P, K and Si) on weevil damage in East African Highland Bananas. | Banana weevil (Cosmopolites sordidus, Germar) is a major pest in East African Highland Banana. The influence of crop nutritional status on weevil damage is poorly understood. Nutrient availability affects the nutritional quality of plants for weevils and may affect weevil damage. Here, we evaluate the effect of insecticides alone and bination with fertilisers (N, P, K and Si) on weevil damage using data from two experiments in central and southwest Uganda. In the first experiment, we varied chlorpyrifos and application rates of N, P and K. In the second experiment, we varied the application rates of K and Si. Treatment effects were analysed using generalised linear mixed models with a negative binomial distribution. In the first experiment, chlorpyrifos reduced and N increased weevil damage, while P and K had no significant effect. In the K or Si application rates reduced weevil pared with the control. We conclude that bined application of chlorpyrifos with K and Si fertilisers can contribute to weevil damage control on sites with low nutrient availability and should form part of integrated weevil management in bananas. Future studies should assess how much reduction in insecticide use is possible in EAHB with judicious input rates. |
36897923 | Evolution of highly pathogenic H5N1 influenza A virus in the central nervous system of ferrets. | Central nervous system (CNS) disease is the mon extra-respiratory plication of influenza A virus infections in humans. Remarkably, zoonotic highly pathogenic avian influenza (HPAI) H5N1 virus infections are more often associated with CNS disease than infections with seasonal influenza viruses. Evolution of avian influenza viruses has been extensively studied in the context of respiratory infections, but evolutionary processes in CNS infections remain poorly understood. We have previously observed that the ability of HPAI A/Indonesia/5/2005 (H5N1) virus to replicate in and spread throughout the CNS varies widely between individual ferrets. Based on these observations, we sought to understand the impact of entrance into and replication within the CNS on the evolutionary dynamics of virus populations. First, we identified and characterized three substitutions-PB1 E177G and A652T and NP I119M - detected in the CNS of a ferret infected with influenza A/Indonesia/5/2005 (H5N1) virus that developed a severe meningo-encephalitis. We found that some of these substitutions, individually or collectively, resulted in increased polymerase activity in vitro. Nevertheless, in vivo, the virus bearing the CNS-associated mutations retained its capacity to infect the CNS but showed reduced dispersion to other anatomical sites. Analyses of viral diversity in the nasal turbinate and olfactory bulb revealed the lack of a genetic bottleneck acting on virus populations accessing the CNS via this route. Furthermore, virus populations bearing the CNS-associated mutations showed signs of positive selection in the brainstem. These features of dispersion to the CNS are consistent with the action of selective processes, underlining the potential for H5N1 viruses to adapt to the CNS. |
36897924 | Prevalence of lung cancer in Colombia and a new diagnostic algorithm using health administrative databases: A real-world evidence study. | Reliable, timely and detailed information on lung cancer prevalence, mortality and costs from e countries is essential to policy design. Thus, we aimed to develop an electronic algorithm to identify lung cancer prevalent patients in Colombia by using administrative claims databases, as well as to estimate prevalence rates by age, sex and geographic region. We performed a cross-sectional study based on national claim databases in Colombia (Base de datos de suficiencia de la Unidad de Pago por Capitación and Base de Datos Única de Afiliados) to identify lung cancer prevalent patients in 2017, 2018 and 2019. Several algorithms based on the presence or absence of oncological procedures (chemotherapy, radiotherapy and surgery) and a minimum number of months that each individual had lung cancer ICD-10 codes were developed. After testing 16 algorithms, those with the closest prevalence rates to those rates reported by aggregated official sources (Global Cancer Observatory and Cuenta de Alto Costo) were selected. We estimated prevalence rates by age, sex and geographic region. Two algorithms were selected: i) one algorithm that was defined as the presence of ICD-10 codes for 4 months or more (the sensitive algorithm); and ii) one algorithm that was defined by adding the presence of at least one oncological procedure (the specific algorithm). The estimated prevalence rates per 100,000 inhabitants ranged between 11.14 and 18.05 for both, the contributory and subsidized regimes over years 2017, 2018 and 2019. These rates in the contributory regime were higher in women (15.43, 15.61 and 17.03 per 100,000 for years 2017, 2018 and 2019), over 65-years-old (63.45, 56.92 and 61.79 per 100,000 for years 2017, 2018 and 2019) who lived in Central, Bogota and Pacific regions. Selected algorithms showed similar aggregated prevalence estimations to those rates reported by official sources and allowed us to estimate prevalence rates in specific aging, regional and gender groups for Colombia by using national claims databases. These findings could be useful to identify clinical and economical es related to lung cancer patients by using national individual-level databases. |
36897925 | Humans peeing: Justice-involved women's access to toilets in public spaces. | Justice-involved women face myriad challenges as they negotiate the terms munity supervision and manage the long-term implications and stigma of living with a criminal record. Major tasks that women juggle include securing safe, affordable housing, finding and retaining employment, accessing physical and mental health care (including substance use treatment), and handling relationships with family, friends, children, and intimate partners. In addition to these responsibilities, women must meet their basic physiological needs to eat, sleep, and use the toilet. Women's ability to safely meet their personal care needs may impact their capacity to manage their criminal-legal challenges. This study uses qualitative methods to understand justice-involved women's lived experiences related to urination. Specifically, the study reports on a thematic analysis of 8 focus groups conducted with justice-involved women (n = 58) and the results of a toilet audit conducted in the downtown areas of the small city in the United States where the focus group participants were living. Findings suggest that women had limited access to restrooms and reported urinating outside. Lack of restroom access impacted their engagement with social services support and employment and their ability to travel through public spaces. Women perceived their public toilet options as unsafe, increasing their sense of vulnerability and reinforcing the idea that they did not have full access to citizenship in munity because of their criminal-legal involvement. The exclusion and denial of women's humanity that is perpetuated by a lack of public toilet access impacts women's psychosocial es. City governments, social service agencies, and employers are encouraged to consider how lack of toilet access may impact their public safety and criminal-legal objectives and expand opportunities for people to access safe restroom facilities. |
36897926 | Host Cell Rap1b mediates cAMP-dependent invasion by Trypanosoma cruzi. | Trypanosoma cruzi cAMP-mediated invasion has long been described, however, the detailed mechanism of action of the pathway activated by this cyclic nucleotide still remains unknown. We have recently demonstrated a crucial role for Epac in the cAMP-mediated invasion of the host cell. In this work, we gathered evidence indicating that the cAMP/Epac pathway is activated in different cells lines. In accordance, data collected from pull-down experiments designed to identify only the active form of Rap1b (Rap1b-GTP), and infection assays using cells transfected with a constitutively active mutant of Rap1b (Rap1b-G12V), strongly suggest the participation of Rap1b as mediator of the pathway. In addition to the activation of this small GTPase, fluorescence microscopy allowed us to demonstrate the relocalization of Rap1b to the entry site of the parasite. Moreover, phospho-mimetic and non-phosphorylable mutants of Rap1b were used to demonstrate a PKA-dependent antagonistic effect on the pathway, by phosphorylation of Rap1b, and potentially of Epac. Finally, Western Blot analysis was used to determine the involvement of the MEK/ERK signalling downstream of cAMP/Epac/Rap1b-mediated invasion. |
36897928 | Building an explanatory model for snakebite envenoming care in the Brazilian Amazon from the indigenous caregivers' perspective. | In the Brazilian Amazon, snakebite envenomings (SBE) disproportionately affect indigenous peoples. Communication between indigenous and biomedical health sectors in regards to SBEs has never been explored in this region. This study aims to build an explanatory model (EM) of the indigenous healthcare domain for SBE patients from the perspective of the indigenous caregivers. |
36897927 | Constitutive expression and distinct properties of IFN-epsilon protect the female reproductive tract from Zika virus infection. | The immunological surveillance factors controlling vulnerability of the female reproductive tract (FRT) to sexually transmitted viral infections are not well understood. Interferon-epsilon (IFNɛ) is a distinct, immunoregulatory type-I IFN that is constitutively expressed by FRT epithelium and is not induced by pathogens like other antiviral IFNs α, β and λ. We show the necessity of IFNɛ for Zika Virus (ZIKV) protection by: increased susceptibility of IFNɛ-/- mice; their "rescue" by intravaginal binant IFNɛ treatment and blockade of protective endogenous IFNɛ by neutralising antibody. Complementary studies in human FRT cell lines showed IFNɛ had potent anti-ZIKV activity, associated with transcriptome responses similar to IFNλ but lacking the proinflammatory gene signature of IFNα. IFNɛ activated STAT1/2 pathways similar to IFNα and λ that were inhibited by ZIKV-encoded non-structural (NS) proteins, but not if IFNε exposure preceded infection. This scenario is provided by the constitutive expression of endogenous IFNε. However, the IFNɛ expression was not inhibited by ZIKV NS proteins despite their ability to antagonise the expression of IFNβ or λ. Thus, the constitutive expression of IFNɛ provides cellular resistance to viral strategies of antagonism and maximises the antiviral activity of the FRT. These results show that the unique spatiotemporal properties of IFNε provides an innate immune surveillance network in the FRT that is a significant barrier to viral infection with important implications for prevention and therapy. |
36897929 | MAdCAM-1 costimulation in the presence of retinoic acid and TGF-β promotes HIV infection and differentiation of CD4+ T cells into CCR5+ TRM-like cells. | CD4+ tissue resident memory T cells (TRMs) are implicated in the formation of persistent HIV reservoirs that are established during the very early stages of infection. The tissue-specific factors that direct T cells to establish tissue residency are not well defined, nor are the factors that establish viral latency. We report that costimulation via MAdCAM-1 and retinoic acid (RA), two constituents of gut tissues, together with TGF-β, promote the differentiation of CD4+ T cells into a distinct subset α4β7+CD69+CD103+ TRM-like cells. Among the costimulatory ligands we evaluated, MAdCAM-1 was unique in its capacity to upregulate both CCR5 and CCR9. MAdCAM-1 costimulation rendered cells susceptible to HIV infection. Differentiation of TRM-like cells was reduced by MAdCAM-1 antagonists developed to treat inflammatory bowel diseases. These finding provide a framework to better understand the contribution of CD4+ TRMs to persistent viral reservoirs and HIV pathogenesis. |
36897931 | Retrolental Bullous Retinal Detachment as the Presenting Feature of Vogt-Koyanagi-Harada Disease in an Elderly Indian Female: Diagnostic and Therapeutic Challenge. | To report an atypical case of Vogt-Koyanagi-Harada (VKH) disease with retrolental bullous retinal detachment (RD). |
36897932 | Discovery of a Potent, Cooperative, and Selective SOS1 PROTAC ZZ151 with In Vivo Antitumor Efficacy in KRAS-Mutant Cancers. | The linker moiety of a proteolysis-targeting chimera (PROTAC) molecule plays a critical role in modulating the degradation activity, target selectivity, and physico-chemical properties. However, the basics and underlying mechanisms of chemical modifications of the linker structure causing dramatic changes in the PROTAC degradation activity warrant further investigation. Herein, we report the design and characterization of a highly potent and selective SOS1 PROTAC ZZ151. After systematically modifying the linker length position, we observed that subtle modification of just one atom of the linker moiety of ZZ151 resulted in remarkable changes in the formation of the plex and thus dramatically affected the degradation activities. ZZ151 quickly, specifically, and effectively induced SOS1 degradation; displayed potent antiproliferation activities against a broad panel of KRAS mutant-driven cancer cells; and showed superior anticancer activities in the KRAS |
36897933 | Nanopore Detection Using Supercharged Polypeptide Molecular Carriers. | The analysis at the single-molecule level of proteins and their interactions can provide critical information for understanding biological processes and diseases, particularly for proteins present in biological samples with low copy numbers. Nanopore sensing is an analytical technique that allows label-free detection of single proteins in solution and is ideally suited to applications, such as studying protein-protein interactions, biomarker screening, drug discovery, and even protein sequencing. However, given the current spatiotemporal limitations in protein nanopore sensing, challenges remain in controlling protein translocation through a nanopore and relating protein structures and functions with nanopore readouts. Here, we demonstrate that supercharged unstructured polypeptides (SUPs) can be genetically fused with proteins of interest and used as molecular carriers to facilitate nanopore detection of proteins. We show that cationic SUPs can substantially slow down the translocation of target proteins due to their electrostatic interactions with the nanopore surface. This approach enables the differentiation of individual proteins with different sizes and shapes via characteristic subpeaks in the nanopore current, thus facilitating a viable route to use polypeptide molecular carriers to control molecular transport and as a potential system to study protein-protein interactions at the single-molecule level. |
36897934 | Machine Learning-Assisted Sensor Based on CsPbBr | Methanol is a respiratory biomarker for pulmonary diseases, including COVID-19, and is mon chemical that may harm people if they are accidentally exposed to it. It is significant to effectively identify methanol plex environments, yet few sensors can do so. In this work, the strategy of coating perovskites with metal oxides is proposed to synthesize core-shell CsPbBr |
36897935 | Palidis: fast discovery of novel insertion sequences. | The diversity of microbial insertion sequences, crucial mobile genetic elements in generating diversity in microbial genomes, needs to be better represented in current microbial databases. Identification of these sequences in munities presents some significant problems that have led to their underrepresentation. Here, we present a bioinformatics pipeline called Palidis that recognizes insertion sequences in metagenomic sequence data rapidly by identifying inverted terminal repeat regions from mixed munity genomes. Applying Palidis to 264 human metagenomes identifies 879 unique insertion sequences, with 519 being novel and not previously characterized. Querying this catalogue against a large database of isolate genomes reveals evidence of horizontal gene transfer events across bacterial classes. We will continue to apply this tool more widely, building the Insertion Sequence Catalogue, a valuable resource for researchers wishing to query their microbial genomes for insertion sequences. |
36897936 | Stimulated Raman Scattering Imaging Sheds New Light on Lipid Droplet Biology. | A lipid droplet (LD) is a dynamic organelle closely associated with cellular functions and energy homeostasis. Dysregulated LD biology underlies an increasing number of human diseases, including metabolic disease, cancer, and neurodegenerative disorder. Commonly used lipid staining and analytical tools have difficulty providing the information regarding LD distribution position at the same time. To address this problem, stimulated Raman scattering (SRS) microscopy uses the intrinsic chemical contrast of biomolecules to achieve both direct visualization of LD dynamics and quantitative analysis of position with high molecular selectivity at the subcellular level. Recent developments of Raman tags have further enhanced sensitivity and specificity of SRS imaging without perturbing molecular activity. With these advantages, SRS microscopy has offered great promise for deciphering LD metabolism in single live cells. This article overviews and discusses the latest applications of SRS microscopy as an emerging platform to dissect LD biology in health and disease. |
36897938 | Integration of reconfigurable microchannels into aligned three-dimensional neural networks for spatially controllable neuromodulation. | Anisotropically organized neural networks are indispensable routes for functional connectivity in the brain, which remains largely unknown. While prevailing animal models require additional preparation and stimulation-applying devices and have exhibited limited capabilities regarding localized stimulation, no in vitro platform exists that permits spatiotemporal control of chemo-stimulation in anisotropic three-dimensional (3D) neural networks. We present the integration of microchannels seamlessly into a fibril-aligned 3D scaffold by adapting a single fabrication principle. We investigated the underlying physics of elastic microchannels' ridges and interfacial sol-gel transition of collagen pression to determine a critical window of geometry and strain. We demonstrated the spatiotemporally resolved neuromodulation in an aligned 3D neural network by local deliveries of KCl and Ca |
36897939 | High-throughput genetic engineering of nonmodel and undomesticated bacteria via iterative site-specific genome integration. | Efficient genome engineering is critical to understand and use microbial functions. Despite recent development of tools such as CRISPR-Cas gene editing, efficient integration of exogenous DNA with well-characterized functions remains limited to model bacteria. Here, we describe serine binase-assisted genome engineering, or SAGE, an easy-to-use, highly efficient, and extensible technology that enables selection marker-free, site-specific genome integration of up to 10 DNA constructs, often with efficiency on par with or superior to replicating plasmids. SAGE uses no replicating plasmids and thus lacks the host range limitations of other genome engineering technologies. We demonstrate the value of SAGE by characterizing genome integration efficiency in five bacteria that span multiple taxonomy groups and biotechnology applications and by identifying more than 95 heterologous promoters in each host with consistent transcription across environmental and genetic contexts. We anticipate that SAGE will rapidly expand the number of industrial and environmental patible with high-throughput genetics and synthetic biology. |
36897940 | Molecular origin of the two-step mechanism of gellan aggregation. | Among hydrocolloids, gellan is one of the most studied polysaccharides due to its ability to form mechanically stable gels. Despite its long-standing use, the gellan aggregation mechanism is still not understood because of the lack of atomistic information. Here, we fill this gap by developing a new gellan force field. Our simulations offer the first microscopic overview of gellan aggregation, detecting the coil to single-helix transition at dilute conditions and the formation of higher-order aggregates at high concentration through a two-step process: first, the formation of double helices and then their assembly into superstructures. For both steps, we also assess the role of monovalent and divalent plementing simulations with rheology and atomic force microscopy experiments and highlighting the leading role of divalent cations. These results pave the way for future use of gellan-based systems in a variety of applications, from food science to art restoration. |
36897944 | Wild macaques challenge the origin of intentional tool production. | Intentionally produced sharp-edged stone flakes and flaked pieces are our primary evidence for the emergence of technology in our lineage. This evidence is used to decipher the earliest hominin behavior, cognition, and subsistence strategies. Here, we report on the largest lithic assemblage associated with a primate foraging behavior undertaken by long-tailed macaques ( |
36897943 | Gas-phase detection of oxirene. | Oxirenes-highly strained 4π Hückel antiaromatic organics-have been recognized as key reactive intermediates in the Wolff rearrangement and in interstellar environments. Predicting short lifetimes and tendency toward ring opening, oxirenes are one of the most mysterious classes of organic transients, with the isolation of oxirene ( |
36897942 | Structure-guided engineering of a receptor-agonist pair for inducible activation of the ABA adaptive response to drought. | Strategies to activate abscisic acid (ABA) receptors and boost ABA signaling by small molecules that act as ABA receptor agonists are promising biotechnological tools to enhance plant drought tolerance. Protein structures of crop ABA receptors might require modifications to improve recognition of chemical ligands, which in turn can be optimized by structural information. Through structure-based targeted design, we bined chemical and genetic approaches to generate an ABA receptor agonist molecule (iSB09) and engineer a CsPYL1 ABA receptor, named CsPYL1 |
36897941 | Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice. | Pathogenic variants in |
36897945 | Dopamine error signal to actively cope with lack of expected reward. | To obtain more of a particular uncertain reward, animals must learn to actively e the lack of reward and adjust behavior to obtain it again. The neural mechanisms underlying such coping with reward omission remain unclear. Here, we developed a task in rats to monitor active behavioral switch toward the next reward after no reward. We found that some dopamine neurons in the ventral tegmental area exhibited increased responses to unexpected reward omission and decreased responses to unexpected reward, following the opposite responses of the well-known dopamine neurons that signal reward prediction error (RPE). The dopamine increase reflected in the nucleus accumbens correlated with behavioral adjustment to actively e unexpected no reward. We propose that these responses signal error to actively cope with lack of expected reward. The dopamine error signal thus cooperates with the RPE signal, enabling adaptive and robust pursuit of uncertain reward to ultimately obtain more reward. |
36897946 | Global concurrent climate extremes exacerbated by anthropogenic climate change. | Increases in concurrent climate extremes in different parts of the world threaten the ecosystem and our society. However, spatial patterns of these extremes and their past and future changes remain unclear. Here, we develop a statistical framework to test for spatial dependence and show widespread dependence of temperature and precipitation extremes in observations and model simulations, with more frequent than expected concurrence of extremes around the world. Historical anthropogenic forcing has strengthened the concurrence of temperature extremes over 56% of 946 global paired regions, particularly in the tropics, but has not yet significantly affected concurrent precipitation extremes during 1901-2020. The future high-emissions pathway of SSP585 will substantially amplify the concurrence strength, intensity, and spatial extent for both temperature and precipitation extremes, especially over tropical and boreal regions, while the mitigation pathway of SSP126 can ameliorate the increase in concurrent climate extremes for these high-risk regions. Our findings will inform adaptation strategies to alleviate the impact of future climate extremes. |
36897947 | In situ amplification of spin echoes within a kinetic inductance parametric amplifier. | The use of superconducting microresonators together with quantum-limited Josephson parametric amplifiers has enhanced the sensitivity of pulsed electron spin resonance (ESR) measurements by more than four orders of magnitude. So far, the microwave resonators and amplifiers have been designed as ponents due to the patibility of Josephson junction-based devices with magnetic fields. This has plex spectrometers and raised technical barriers toward adoption of the technique. Here, we circumvent this issue by coupling an ensemble of spins directly to a weakly nonlinear and magnetic field-resilient superconducting microwave resonator. We perform pulsed ESR measurements with a 1-pL mode volume containing 6 × 10 |
36897948 | FERONIA and wall-associated kinases coordinate defense induced by lignin modification in plant cell walls. | Altering the content position of the cell wall polymer lignin is a favored approach to valorize lignin toward biomaterial and chemical production in the biorefinery. However, modifying lignin or cellulose in transgenic plants can induce expression of defense responses and negatively affect growth. Through genetic screening for suppressors of defense gene induction in the low lignin |
36897949 | Effects of culling vampire bats on the spatial spread and spillover of rabies virus. | Controlling pathogen circulation in wildlife reservoirs is notoriously challenging. In Latin America, vampire bats have been culled for decades in hopes of mitigating lethal rabies infections in humans and livestock. Whether culls reduce or exacerbate rabies transmission remains controversial. Using Bayesian state-space models, we show that a 2-year, spatially extensive bat cull in an area of exceptional rabies incidence in Peru failed to reduce spillover to livestock, despite reducing bat population density. Viral whole genome sequencing and phylogeographic analyses further demonstrated that culling before virus arrival slowed viral spatial spread, but reactive culling accelerated spread, suggesting that culling-induced changes in bat dispersal promoted viral invasions. Our findings question the core assumptions of density-dependent transmission and localized viral maintenance that underlie culling bats as a rabies prevention strategy and provide an epidemiological and evolutionary framework to understand the es of interventions plex wildlife disease systems. |
36897951 | Spectral imaging enables contrast agent-free real-time ischemia monitoring in laparoscopic surgery. | Laparoscopic surgery has evolved as a key technique for cancer diagnosis and therapy. While characterization of the tissue perfusion is crucial in various procedures, such as partial nephrectomy, doing so by means of visual inspection remains highly challenging. We developed a laparoscopic real-time multispectral imaging system featuring pact and lightweight multispectral camera and the possibility plement the conventional surgical view of the patient with functional information at a video rate of 25 Hz. To enable contrast agent-free ischemia monitoring during laparoscopic partial nephrectomy, we phrase the problem of ischemia detection as an out-of-distribution detection problem that does not rely on data from any other patient and uses an ensemble of invertible neural networks at its core. An in-human trial demonstrates the feasibility of our approach and highlights the potential of spectral bined with advanced deep learning-based analysis tools for fast, efficient, reliable, and safe functional laparoscopic imaging. |
36897950 | Silicon flexoelectronic transistors. | It is extraordinarily challenging to implement adaptive and seamless interactions between mechanical triggering and current silicon technology for tunable electronics, human-machine interfaces, and micro/nanoelectromechanical systems. Here, we report Si flexoelectronic transistors (SFTs) that can innovatively convert applied mechanical actuations into electrical control signals and achieve directly electromechanical function. Using the strain gradient-induced flexoelectric polarization field in Si as a "gate," the metal-semiconductor interfacial Schottky barriers' heights and the channel width of SFT can be substantially modulated, resulting in tunable electronic transports with specific characteristics. Such SFTs and corresponding perception system can not only create a high strain sensitivity but also identify where the mechanical force is applied. These findings provide an in-depth understanding about the mechanism of interface gating and channel width gating in flexoelectronics and develop highly sensitive silicon-based strain sensors, which has great potential to construct the next-generation silicon electromechanical nanodevices and nanosystems. |
36897952 | Fishing through the cracks: The unregulated nature of global squid fisheries. | While most research has focused on the legality of global industrial fishing, unregulated fishing has largely escaped scrutiny. Here, we evaluate the unregulated nature of global squid fisheries using AIS data and nighttime imagery of the globalized fleet of light-luring squid vessels. We find that this fishery is extensive, fishing 149,000 to 251,000 vessel days annually, and that effort increased 68% over the study period 2017-2020. Most vessels are highly mobile and fish in multiple regions, largely (86%) in unregulated areas. While scientists and policymakers express concerns over the declining abundance of squid stocks globally and regionally, we find a net increase in vessels fishing squid globally and spatial expansion of effort to novel areas. Since fishing effort is static in areas with increasing management, and rising in unmanaged areas, we suggest actors may take advantage of fragmented regulations to maximize resource extraction. Our findings highlight a profitable, but largely unregulated fishery, with strong potential for improved management. |
36897953 | The evolution of the Galápagos mantle plume. | The lavas associated with mantle plumes may sample domains throughout Earth's mantle and probe its dynamics. However, plume studies are often only able to take snapshots in time, usually of the most recent plume activity, leaving the chemical and geodynamic evolution of major convective upwellings in Earth's mantle poorly constrained. Here, we report the geodynamically key information of how the lithology and density of a plume change from plume head phase to tail. We use iron stable isotopes and thermodynamic modeling to show that the Galápagos plume has contained small, nearly constant, amounts of dense recycled crust over its 90-million-year history. Despite a temporal evolution in the amount of recycled crust-derived melt in Galápagos-related lavas, we show that this can be explained by plume cooling alone, without associated changes in the plume's mantle source; results are also consistent with a plume rooted in a lower mantle low-velocity zone also sampling ponents. |
36897954 | Design of a minimal di-nickel hydrogenase peptide. | Ancestral metabolic processes involve the reversible oxidation of molecular hydrogen by hydrogenase. Extant hydrogenase enzymes prising hundreds of amino acids and multiple cofactors. We designed a 13-amino acid nickel-binding peptide capable of robustly producing molecular hydrogen from protons under a wide variety of conditions. The peptide forms a di-nickel cluster structurally analogous to a Ni-Fe cluster in [NiFe] hydrogenase and the Ni-Ni cluster in acetyl-CoA synthase, two ancient, extant proteins central to metabolism. These experimental results demonstrate that modern enzymes, despite their plexity, likely evolved from simple peptide precursors on early Earth. |
36897957 | Targeting the chromatin effector Pygo2 promotes cytotoxic T cell responses and overcomes immunotherapy resistance in prostate cancer. | The noninflamed microenvironment in prostate cancer represents a barrier to immunotherapy. Genetic alterations underlying cancer cell-intrinsic oncogenic signaling are increasingly appreciated for their role in shaping the immune landscape. Recently, we identified Pygopus 2 ( |
36897956 | A tale of two paths: The evolution of mitochondrial recombination in bivalves with doubly uniparental inheritance. | In most animals, mitochondrial DNA is strictly maternally inherited and bining. One exception to this pattern is called doubly uniparental inheritance (DUI), a phenomenon involving the independent transmission of female and male mitochondrial genomes. DUI is known only from the molluskan class Bivalvia. The phylogenetic distribution of male-transmitted mitochondrial DNA (M mtDNA) in bivalves is consistent with several evolutionary scenarios, including multiple independent gains, losses, and varying degrees of bination with female-transmitted mitochondrial DNA (F mtDNA). In this study, we use phylogenetic methods to test M mtDNA origination hypotheses and infer the prevalence of mitochondrial bination in bivalves with DUI. Phylogenetic modeling using site concordance factors supported a single origin of M mtDNA in bivalves coupled with bination acting over long evolutionary timescales. Ongoing mitochondrial bination is present in Mytilida and Venerida, which results in a pattern of concerted evolution of F mtDNA and M mtDNA. Mitochondrial bination could be favored to offset the deleterious effects of asexual inheritance and maintain patibility across tissues. Cardiida and Unionida have gone without recent bination, possibly due to an extension of the COX2 gene in male mitochondrial DNA. The loss of bination could be connected to the role of M mtDNA in sex determination or sexual development. Our results support that bination events may occur throughout the mitochondrial genomes of DUI species. Future investigations may reveal plex patterns of inheritance of binants, which could explain the retention of signal for a single origination of M mtDNA in protein-coding genes. |
36897958 | An XBP1s-PIM-2 positive feedback loop controls IL-15-mediated survival of natural killer cells. | Spliced X-box-binding protein 1 (XBP1s) is an essential transcription factor downstream of interleukin-15 (IL-15) and AKT signaling, which controls cell survival and effector functions of human natural killer (NK) cells. However, the precise mechanisms, especially the downstream targets of XBP1s, remain unknown. In this study, by using XBP1 conditional knockout mice, we found that XBP1s is critical for IL-15-mediated NK cell survival but not proliferation in vitro and in vivo. Mechanistically, XBP1s regulates homeostatic NK cell survival by targeting PIM-2, a critical anti-apoptotic gene, which in turn stabilizes XBP1s protein by phosphorylating it at Thr |
36897960 | The Arthroplasty Surgeon Growth Indicator: A Tool for Monitoring Supply and Demand Trends in the Orthopaedic Surgeon Workforce from 2020 to 2050. | Orthopaedic practices in the U.S. face a growing demand for total joint arthroplasties (TJAs), while the orthopaedic workforce size has been stagnant for decades. This study aimed to estimate annual TJA demand and orthopaedic surgeon workforce supply from 2020 to 2050, and to develop an arthroplasty surgeon growth indicator (ASGI), based on the arthroplasty-to-surgeon ratio (ASR), to gauge nationwide supply and demand trends. |
36897959 | Penicillin Responsive Presumed Seronegative Ocular Syphilis in a Patient with Human Immunodeficiency Virus: A Case Report and Review of the Literature. | Ocular and systemic syphilis are well known to mimic other clinical entities making them challenging to diagnose in many cases. Syphilis testing plays an important role in diagnosis and timely treatment. Here we describe a patient with untreated human immunodeficiency virus (HIV) infection who presented with bilateral panuveitis with repeatedly negative syphilis serologies. In light of worsening retinitis while on aggressive anti-viral treatment and in consideration of the clinical suspicion for syphilitic uveitis, intravenous penicillin was initiated empirically. The patient demonstrated significant improvement subjectively and objectively after treatment. We also review and discuss syphilis testing reliability generally and in HIV co-infected patients in particular. Empiric intravenous penicillin should be considered in patients with clinical features of ocular syphilis despite negative serologic testing, especially in those with HIV co-infection. |
36897961 | Chemical Vapor Deposition Growth of Few-Layer β | Borophene has drawn tremendous attention in the past decade for a wide range of potential applications owing to its unique structural, optical, and electronic properties. However, applications of borophene toward next-generation nanodevices are mostly theoretical predictions, while experimental realization is still lacking due to rapid oxidation of intrinsic borophene in an air environment. Here, we have successfully prepared structurally stable and transferrable few-layer β |
36897963 | Bifunctional Electron-Transporting Agent for Red Colloidal Quantum Dot Light-Emitting Diodes. | Indium phosphide (InP) quantum dots have enabled light-emitting diodes (LEDs) that are heavy-metal-free, narrow in emission linewidth, and physically flexible. However, ZnO/ZnMgO, the electron-transporting layer (ETL) in high-performance red InP/ZnSe/ZnS LEDs, suffers from high defect densities, quenches luminescence when deposited on InP, and induces performance degradation that arises due to trap migration from the ETL to the InP emitting layer. We posited that the formation of Zn |
36897964 | Parental Perspectives on Life-Altering News in Emergency Settings: A Qualitative Evaluation. | Delivering life-altering news is a difficult task that is frequently the responsibility of emergency physicians. However, the existing frameworks for guiding such interactions fail to address the physician-parent-patient dynamic of pediatric emergency encounters. To date, no study has investigated the parental perspective, limiting the ability to provide evidence-based mendations. This study describes how parents experience receiving life-altering news about their child in emergency settings. |
36897965 | When, how, and why the path of an air bubble rising in pure water becomes unstable. | Recently, [Herrada, M. A. and Eggers, J. G., Proc. Natl. Acad. Sci. U.S.A. 120, e2216830120 (2023)] reported predictions for the onset of the path instability of an air bubble rising in water and put forward a physical scenario to explain this intriguing phenomenon. In this Brief Report, we review a series of previously established results, some of which were overlooked or misinterpreted by the authors. We show that this set of findings provides an accurate prediction and a consistent explanation of the phenomenon that invalidates the suggested scenario. The instability mechanism actually at play results from the hydrodynamic fluid-body coupling made possible by the unconstrained motion of the bubble which behaves essentially, in the relevant size range, as a rigid, nearly spheroidal body on the surface of which water slips freely. |
36897962 | State of the art in epitope mapping and opportunities in COVID-19. | The understanding of any disease calls for studying specific biological structures called epitopes. One important tool recently drawing attention and proving efficiency in both diagnosis and vaccine development is epitope mapping. Several techniques have been developed with the urge to provide precise epitope mapping for use in designing sensitive diagnostic tools and developing rpitope-based vaccines (EBVs) as well as therapeutics. In this review, we will discuss the state of the art in epitope mapping with a special emphasis on plishments and opportunities bating COVID-19. prise SARS-CoV-2 variant analysis versus the currently available immune-based diagnostic tools and vaccines, immunological profile-based patient stratification, and finally, exploring novel epitope targets for potential prophylactic, therapeutic or diagnostic agents for COVID-19. |
36897967 | Low-distortion information propagation with noise suppression in swarm networks. | A method for low-distortion (low-dissipation, low-dispersion) information propagation in swarm-type networks with suppression of high-frequency noise is presented. Information propagation in current neighbor-based networks, where each agent seeks to achieve a consensus with its neighbors, is diffusion-like, dissipative, and dispersive and does not reflect the wave-like (superfluidic) behavior seen in nature. However, pure wave-like neighbor-based networks have two challenges: i) It requires munication for sharing information about time derivatives and ii) it can lead to information decoherence through noise at high frequencies. The main contribution of this work is to show that delayed self-reinforcement (DSR) by the agents using prior information (e.g., using short-term memory) can lead to the wave-like information propagation at low-frequencies as seen in nature without the need for additional information sharing between the agents. Moreover, it is shown that the DSR can be designed to enable suppression of high-frequency noise transmission while limiting the dissipation and dispersion of (lower-frequency) information content leading to similar (cohesive) behavior of agents. In addition to explaining noise-suppressed wave-like information transfer in natural systems, the result impacts the design of noise-suppressing cohesive algorithms for engineered networks. |
36897966 | Quantifying heterogeneity to drug response in cancer-stroma kinetics. | A crucial challenge in medicine is choosing which drug bination) will be the most advantageous for a particular patient. Usually, drug response rates differ substantially, and the reasons for this response unpredictability remain ambiguous. Consequently, it is central to classify features that contribute to the observed drug response variability. Pancreatic cancer is one of the deadliest cancers with limited therapeutic achievements due to the massive presence of stroma that generates an environment that enables tumor growth, metastasis, and drug resistance. To understand the cancer-stroma cross talk within the tumor microenvironment and to develop personalized adjuvant therapies, there is a necessity for effective approaches that offer measurable data to monitor the effect of drugs at the single-cell level. Here, we develop putational approach, based on cell imaging, that quantifies the cellular cross talk between pancreatic tumor cells (L3.6pl or AsPC1) and pancreatic stellate cells (PSCs), coordinating their kinetics in presence of the chemotherapeutic agent gemcitabine. We report significant heterogeneity in the organization of cellular interactions in response to the drug. For L3.6pl cells, gemcitabine sensibly decreases stroma-stroma interactions but increases stroma-cancer interactions, overall enhancing motility and crowding. In the AsPC1 case, gemcitabine promotes the interactions among tumor cells, but it does not affect stroma-cancer interplay, possibly suggesting a milder effect of the drug on cell dynamics. |
36897968 | Genes and sites under adaptation at the phylogenetic scale also exhibit adaptation at the population-genetic scale. | Adaptation in protein-coding sequences can be detected from multiple sequence alignments across species or alternatively by leveraging polymorphism data within a population. Across species, quantification of the adaptive rate relies on phylogenetic codon models, classically formulated in terms of the ratio of nonsynonymous over synonymous substitution rates. Evidence of an accelerated nonsynonymous substitution rate is considered a signature of pervasive adaptation. However, because of the background of purifying selection, these models are potentially limited in their sensitivity. Recent developments have led to more sophisticated mutation-selection codon models aimed at making a more detailed quantitative assessment of the interplay between mutation, purifying, and positive selection. In this study, we conducted a large-scale exome-wide analysis of placental mammals with mutation-selection models, assessing their performance at detecting proteins and sites under adaptation. Importantly, mutation-selection codon models are based on a population-genetic formalism and thus are parable to the McDonald and Kreitman test at the population level to quantify adaptation. Taking advantage of this relationship between phylogenetic and population genetics analyses, we integrated divergence and polymorphism data across the entire exome for 29 populations across 7 genera and showed that proteins and sites detected to be under adaptation at the phylogenetic scale are also under adaptation at the population-genetic scale. Altogether, our exome-wide analysis shows that phylogenetic mutation-selection codon models and the population-genetic test of adaptation can be reconciled and are congruent, paving the way for integrative models and analyses across individuals and populations. |
36897969 | Transcription shapes 3D chromatin organization by interacting with loop extrusion. | Cohesin folds mammalian interphase chromosomes by extruding the chromatin fiber into numerous loops. "Loop extrusion" can be impeded by chromatin-bound factors, such as CTCF, which generates characteristic and functional chromatin organization patterns. It has been proposed that transcription relocalizes or interferes with cohesin and that active promoters are cohesin loading sites. However, the effects of transcription on cohesin have not been reconciled with observations of active extrusion by cohesin. To determine how transcription modulates extrusion, we studied mouse cells in which we could alter cohesin abundance, dynamics, and localization by genetic "knockouts" of the cohesin regulators CTCF and Wapl. Through Hi-C experiments, we discovered intricate, cohesin-dependent contact patterns near active genes. Chromatin organization around active genes exhibited hallmarks of interactions between transcribing RNA polymerases (RNAPs) and extruding cohesins. These observations could be reproduced by polymer simulations in which RNAPs were moving barriers to extrusion that obstructed, slowed, and pushed cohesins. The simulations predicted that preferential loading of cohesin at promoters is inconsistent with our experimental data. Additional ChIP-seq experiments showed that the putative cohesin loader Nipbl is not predominantly enriched at promoters. Therefore, we propose that cohesin is not preferentially loaded at promoters and that the barrier function of RNAP accounts for cohesin accumulation at active promoters. Altogether, we find that RNAP is an extrusion barrier that is not stationary, but rather, translocates and relocalizes cohesin. Loop extrusion and transcription might interact to dynamically generate and maintain gene interactions with regulatory elements and shape functional genomic organization. |
36897970 | Growth produces coordination trade-offs in | How collectives remain coordinated as they grow in size is a fundamental challenge affecting systems ranging from biofilms to governments. This challenge is particularly apparent in multicellular organisms, where coordination among a vast number of cells is vital for coherent animal behavior. However, the earliest multicellular organisms were decentralized, with indeterminate sizes and morphologies, as exemplified by |
36897971 | Diamagnetic response and phase stiffness for interacting isolated narrow bands. | Superconductivity is a macroscopic manifestation of a quantum phenomenon where pairs of electrons delocalize and develop phase coherence over a long distance. A long-standing quest has been to address the underlying microscopic mechanisms that fundamentally limit the superconducting transition temperature, |
36897972 | Propofol disrupts alpha dynamics in functionally distinct thalamocortical networks during loss of consciousness. | During propofol-induced general anesthesia, alpha rhythms measured using electroencephalography undergo a striking shift from posterior to anterior, termed anteriorization, where the ubiquitous waking alpha is lost and a frontal alpha emerges. The functional significance of alpha anteriorization and the precise brain regions contributing to the phenomenon are a mystery. While posterior alpha is thought to be generated by thalamocortical circuits connecting nuclei of the sensory thalamus with their cortical partners, the thalamic origins of the propofol-induced alpha remain poorly understood. Here, we used human intracranial recordings to identify regions in sensory cortices where propofol attenuates a coherent alpha network, distinct from those in the frontal cortex where it amplifies coherent alpha and beta activities. We then performed diffusion tractography between these identified regions and individual thalamic nuclei to show that the opposing dynamics of anteriorization occur within two distinct thalamocortical networks. We found that propofol disrupted a posterior alpha network structurally connected with nuclei in the sensory and sensory associational regions of the thalamus. At the same time, propofol induced a coherent alpha oscillation within prefrontal cortical areas that were connected with thalamic nuclei involved in cognition, such as the mediodorsal nucleus. The cortical and thalamic anatomy involved, as well as their known functional roles, suggests multiple means by which propofol dismantles sensory and cognitive processes to achieve loss of consciousness. |
36897973 | Inflammation differentially controls transport of depolarizing Nav versus hyperpolarizing Kv channels to drive rat nociceptor activity. | Inflammation causes pain by shifting the balance of ionic currents in nociceptors toward depolarization, leading to hyperexcitability. The ensemble of ion channels within the plasma membrane is regulated by processes including biogenesis, transport, and degradation. Thus, alterations in ion channel trafficking may influence excitability. Sodium channel Na |
36897974 | Light-dependent signal transduction in the marine diatom | Unlike most higher plants, unicellular algae can acclimate to changes in irradiance on time scales of hours to a few days. The process involves an enigmatic signaling pathway originating in the plastid that leads to coordinated changes in plastid and nuclear gene expression. To deepen our understanding of this process, we conducted functional studies to examine how the model diatom, |
36897975 | Endoplasmic reticulum-bound ANAC013 factor is cleaved by RHOMBOID-LIKE 2 during the initial response to hypoxia in | Aerobic reactions are essential to sustain plant growth and development. Impaired oxygen availability due to excessive water availability, e.g., during waterlogging or flooding, reduces plant productivity and survival. Consequently, plants monitor oxygen availability to adjust growth and metabolism accordingly. Despite the identification of ponents in hypoxia adaptation in recent years, molecular pathways involved in the very early activation of low-oxygen responses are insufficiently understood. Here, we characterized three endoplasmic reticulum (ER)-anchored |
36897976 | Convergence of Ras- and Rac-regulated formin pathways is pivotal for phagosome formation and particle uptake in | prising phagocytosis and macropinocytosis is an actin-driven process regulated by small GTPases that depend on the dynamic reorganization of the membrane that protrudes and internalizes extracellular material by cup-shaped structures. To effectively capture, enwrap, and internalize their targets, these cups are arranged into a peripheral ring or ruffle of protruding actin sheets emerging from an actin-rich, nonprotrusive zone at its base. Despite extensive knowledge of the mechanism driving actin assembly of the branched network at the protrusive cup edge, which is initiated by the actin-related protein (Arp) plex downstream of Rac signaling, our understanding of actin assembly in the base is still plete. In the |
36897978 | Self-propulsion via slipping: Frictional swimming in multilegged locomotors. | otion is typically studied either in continuous media where bodies and legs experience forces generated by the flowing medium or on solid substrates dominated by friction. In the former, centralized whole-body coordination is believed to facilitate appropriate slipping through the medium for propulsion. In the latter, slip is often assumed minimal and thus avoided via decentralized control schemes. We find in laboratory experiments that terrestrial otion of a meter-scale multisegmented/legged robophysical model resembles undulatory fluid swimming. Experiments varying waves of leg stepping and body bending reveal how these parameters result in effective terrestrial otion despite seemingly ineffective isotropic frictional contacts. Dissipation dominates over inertial effects in this macroscopic-scaled regime, resulting in essentially geometric otion on land akin to microscopic-scale swimming in fluids. Theoretical analysis demonstrates that the high-dimensional multisegmented/legged dynamics can be simplified to a centralized low-dimensional model, which reveals an effective resistive force theory with an acquired viscous drag anisotropy. We extend our low-dimensional, geometric analysis to illustrate how body undulation can aid performance in non-flat obstacle-rich terrains and also use the scheme to quantitatively model how body undulation affects performance of biological centipede otion (the desert centipede |
36897979 | A pan-sarbecovirus vaccine based on RBD of SARS-CoV-2 original strain elicits potent neutralizing antibodies against XBB in non-human primates. | The recently emerged Omicron subvariants XBB and BQ.1.1 have presented striking immune evasion against most monoclonal neutralizing antibodies and convalescent plasma. Therefore, it is essential to develop broad-spectrum COVID-19 vaccines bat current and future emerging variants. Here, we found that the human IgG Fc-conjugated RBD of the original SARS-CoV-2 strain (WA1) plus a novel STING agonist-based adjuvant CF501 (CF501/RBD-Fc) could induce highly potent and durable broad-neutralizing antibody (bnAb) responses against Omicron subvariants, including BQ.1.1 and XBB in rhesus macaques with NT50s ranging from 2,118 to 61,742 after three doses. A decline of 0.9- to 4.7-fold was observed in the neutralization activity of sera in the CF501/RBD-Fc group against BA.2.2, BA.2.9, BA.5, BA.2.75, and BF.7 relative to D614G after three doses, while a significant decline of NT50 against BQ.1.1 (26.9-fold) and XBB (22.5-fold) relative to D614G. However, the bnAbs were still effective in neutralizing BQ.1.1 and XBB infection. These results suggest that the conservative but nondominant epitopes in RBD could be stimulated by CF501 to generate bnAbs, providing a proof-of-concept for using "nonchangeable against changeables" strategy to develop pan-sarbecovirus vaccines against sarbecoviruses, including SARS-CoV-2 and its variants. |
36897980 | Proprioceptive feedback amplification restores effective locomotion in a neuromechanical model of lampreys with spinal injuries. | Spinal injuries in many vertebrates can result in partial plete loss of otor ability. While mammals often experience permanent loss, some nonmammals, such as lampreys, can regain swimming function, though the exact mechanism is not well understood. One hypothesis is that amplified proprioceptive (body-sensing) feedback can allow an injured lamprey to regain functional swimming even if the descending signal is lost. This study employs a multiscale, putational model of an anguilliform swimmer fully coupled to a viscous, pressible fluid and examines the effects of amplified feedback on swimming behavior. This represents a model that analyzes spinal injury recovery bining a closed-loop neuromechanical model with sensory feedback coupled to a full Navier-Stokes model. Our results show that in some cases, feedback amplification below a spinal lesion is sufficient to partially or entirely restore effective swimming behavior. |
36897981 | Using conditional independence tests to elucidate causal links in cell cycle regulation in | How cells regulate their cell cycles is a central question for cell biology. Models of cell size homeostasis have been proposed for bacteria, archaea, yeast, plant, and mammalian cells. New experiments bring forth high volumes of data suitable for testing existing models of cell size regulation and proposing new mechanisms. In this paper, we use conditional independence tests in conjunction with data of cell size at key cell cycle events (birth, initiation of DNA replication, and constriction) in the model bacterium |
36897983 | Model misspecification misleads inference of the spatial dynamics of disease outbreaks. | Epidemiology has been transformed by the advent of Bayesian phylodynamic models that allow researchers to infer the geographic history of pathogen dispersal over a set of discrete geographic areas [1, 2]. These models provide powerful tools for understanding the spatial dynamics of disease outbreaks, but contain many parameters that are inferred from minimal geographic information (i.e., the single area in which each pathogen was sampled). Consequently, inferences under these models are inherently sensitive to our prior assumptions about the model parameters. Here, we demonstrate that the default priors used in empirical phylodynamic studies make strong and biologically unrealistic assumptions about the underlying geographic process. We provide empirical evidence that these unrealistic priors strongly (and adversely) monly reported aspects of epidemiological studies, including: 1) the relative rates of dispersal between areas; 2) the importance of dispersal routes for the spread of pathogens among areas; 3) the number of dispersal events between areas, and; 4) the ancestral area in which a given outbreak originated. We offer strategies to avoid these problems, and develop tools to help researchers specify more biologically reasonable prior models that will realize the full potential of phylodynamic methods to elucidate pathogen biology and, ultimately, inform surveillance and monitoring policies to mitigate the impacts of disease outbreaks. |
36897982 | A complete biomechanical model of | How does neural activity drive muscles to produce behavior? The recent development of genetic lines in |
36897984 | A quantum information processing machine for computing by observables. | A quantum machine that accepts an input and processes it in parallel is described. The logic variables of the machine are not wavefunctions (qubits) but observables (i.e., operators) and its operation is described in the Heisenberg picture. The active core is a solid-state assembly of small nanosized colloidal quantum dots (QDs) or dimers of dots. The size dispersion of the QDs that causes fluctuations in their discrete electronic energies is a limiting factor. The input to the machine is provided by a train of very brief laser pulses, at least four in number. The coherent band width of each ultrashort pulse needs to span at least several and preferably all the single electron excited states of the dots. The spectrum of the QD assembly is measured as a function of the time delays between the input laser pulses. The dependence of the spectrum on the time delays can be Fourier transformed to a frequency spectrum. This spectrum of a finite range in time is made up of discrete pixels. These are the visible, raw, basic logic variables. The spectrum is analyzed to determine a possibly smaller number of ponents. A Lie-algebraic point of view is used to explore the use of the machine to emulate the dynamics of other quantum systems. An explicit example demonstrates the considerable quantum advantage of our scheme. |
36897985 | Cross-sections of doubly curved sheets as confined elastica. | Although thin films are typically manufactured in planar sheets or rolls, they are often forced into three-dimensional (3D) shapes, producing a plethora of structures across multiple length scales. To understand plex response, previous studies have either focused on the overall gross shape or the small-scale buckling that decorates it. A geometric model, which considers the sheet as inextensible yet free press, has been shown to capture the gross shape of the sheet. However, the precise meaning of such predictions, and how the gross shape constrains the fine features, remains unclear. Here, we study a thin-membraned balloon as a prototypical system that involves a doubly curved gross shape with large amplitude undulations. By probing its side profiles and horizontal cross-sections, we discover that the mean behavior of the film is the physical observable that is predicted by the geometric model, even when the buckled structures atop it are large. We then propose a minimal model for the horizontal cross-sections of the balloon, as independent elastic filaments subjected to an effective pinning potential around the mean shape. Despite the simplicity of our model, it reproduces a broad range of phenomena seen in the experiments, from how the morphology changes with pressure to the detailed shape of the wrinkles and folds. Our results establish a route bine global and local features consistently over an enclosed surface, which could aid the design of inflatable structures, or provide insight into biological patterns. |
36897986 | Immune cells use active tugging forces to distinguish affinity and accelerate evolution. | Cells are known to exert forces to sense their physical surroundings for guidance of motion and fate decisions. Here, we propose that cells might do mechanical work to drive their own evolution, taking inspiration from the adaptive immune system. Growing evidence indicates that immune B cells-capable of rapid Darwinian evolution-use cytoskeletal forces to actively extract antigens from other cells' surfaces. To elucidate the evolutionary significance of force usage, we develop a theory of tug-of-war antigen extraction that maps receptor binding characteristics to clonal reproductive fitness, revealing physical determinants of selection strength. This framework unifies mechanosensing and affinity-discrimination capabilities of evolving cells: Pulling against stiff antigen tethers enhances discrimination stringency at the expense of absolute extraction. As a consequence, active force usage can accelerate adaptation but may also cause extinction of cell populations, resulting in an optimal range of pulling strength that matches molecular rupture forces observed in cells. Our work suggests that nonequilibrium, physical extraction of environmental signals can make biological systems more evolvable at a moderate energy cost. |
36897987 | De novo design of small beta barrel proteins. | Small beta barrel proteins are attractive targets putational design because of their considerable functional diversity despite their very small size (<70 amino acids). However, there are considerable challenges to designing such structures, and there has been little success thus far. Because of the small size, the hydrophobic core stabilizing the fold is necessarily very small, and the conformational strain of barrel closure can oppose folding; also intermolecular aggregation through free beta strand edges pete with proper monomer folding. Here, we explore the de novo design of small beta barrel topologies using both Rosetta energy-based methods and deep learning approaches to design four small beta barrel folds: Src homology 3 (SH3) and oligonucleotide/oligosaccharide-binding (OB) topologies found in nature and five and six up-and-down-stranded barrels rarely if ever seen in nature. Both approaches yielded successful designs with high thermal stability and experimentally determined structures with less than 2.4 Å rmsd from the designed models. Using deep learning for backbone generation and Rosetta for sequence design yielded higher design success rates and increased structural diversity than Rosetta alone. The ability to design a large and structurally diverse set of small beta barrel proteins greatly increases the protein shape space available for designing binders to protein targets of interest. |
36897989 | Dissecting the energetic architecture within an RNA tertiary structural motif via high-throughput thermodynamic measurements. | Structured RNAs and plexes perform critical cellular functions. They often contain structurally conserved tertiary contact "motifs," whose occurrence simplifies the RNA folding landscape. Prior studies have focused on the conformational and energetic modularity of intact motifs. Here, we turn to the dissection of mon motif, the 11nt receptor (11ntR), using quantitative analysis of RNA on a massively parallel array to measure the binding of all single and double 11ntR mutants to GAAA and GUAA tetraloops, thereby probing the energetic architecture of the motif. While the 11ntR behaves as a motif, its cooperativity is not absolute. Instead, we uncovered a gradient from high cooperativity amongst base-paired and neighboring residues to additivity between distant residues. As expected, substitutions at residues in direct contact with the GAAA tetraloop resulted in the largest decreases to binding, and energetic penalties of mutations were substantially smaller for binding to the alternate GUAA tetraloop, which lacks tertiary contacts present with the canonical GAAA tetraloop. However, we found that the energetic consequences of base partner substitutions are not, in general, simply described by base pair type or isostericity. We also found exceptions to the previously established stability-abundance relationship for 11ntR sequence variants. These findings of "exceptions to the rule" highlight the power of systematic high-throughput approaches to uncover novel variants for future study in addition to providing an energetic map of a functional RNA. |
36897988 | MYC-driven synthesis of Siglec ligands is a glycoimmune checkpoint. | The Siglecs (sialic acid-binding immunoglobulin-like lectins) are glycoimmune checkpoint receptors that suppress immune cell activation upon engagement of cognate sialoglycan ligands. The cellular drivers underlying Siglec ligand production on cancer cells are poorly understood. We find the |
36897991 | Palladium-Catalyzed Enantioselective Isodesmic C-H Iodination of Phenylacetic Weinreb Amides. | Isodesmic reactions represent mild alternatives to other chemical transformations that require harsh oxidizing agents or highly reactive intermediates. However, enantioselective isodesmic C-H functionalization is unknown and enantioselective direct iodination of inert C-H bond is very rare. Rapid synthesis of chiral aromatic iodides is of significant importance for synthetic chemistry. Herein, we report an unprecedented highly enantioselective isodesmic C-H functionalization to access chiral iodinated phenylacetic Weinreb amides via desymmetrization and kinetic resolution with Pd |
36897992 | Clinical Features, Long-Term Outcomes, and Prognostic Factors of Eales' Disease in Korean Patients. | We studied Korean patients with Eales' disease to document clinical features, long-term es, and explore its association with TB, given South Korea's high TB burden. |
36897994 | Protein Conformational Exchanges Modulated by the Environment of Outer Membrane Vesicles. | Protein function, in many cases, is strongly coupled to the dynamics and conformational equilibria of the protein. The environment surrounding proteins is critical for their dynamics and can dramatically affect the conformational equilibria and subsequently the activities of proteins. However, it is unclear how protein conformational equilibria are modulated by their crowded native environments. Here we reveal that outer membrane vesicle (OMV) environments modulate the conformational exchanges of Im7 protein at its local frustrated sites and shift the conformation toward its ground state. Further experiments show both macromolecular crowding and quinary interactions with the ponents stabilize the ground state of Im7. Our study highlights the key role that the OMV environment plays in the protein conformational equilibria and subsequently the conformation-related protein functions. Furthermore, the long-lasting nuclear magnetic resonance measurement time of proteins within OMVs indicates that they could serve as a promising system for investigating protein structures and dynamics |
36897995 | Nonadiabatic Coupling in Trajectory Surface Hopping: How Approximations Impact Excited-State Reaction Dynamics. | Photochemical reactions are widely modeled using the popular trajectory surface hopping (TSH) method, an affordable mixed quantum-classical approximation to the full quantum dynamics of the system. TSH is able to account for nonadiabatic effects using an ensemble of trajectories, which are propagated on a single potential energy surface at a time and which can hop from one electronic state to another. The occurrences and locations of these hops are typically determined using the nonadiabatic coupling between electronic states, which can be assessed in a number of ways. In this work, we benchmark the impact of some approximations to the coupling term on the TSH dynamics for several typical isomerization and ring-opening reactions. We have identified that two of the schemes tested, the popular local diabatization scheme and a scheme based on biorthonormal wave function overlap implemented in the OpenMOLCAS code as part of this work, reproduce at a much reduced cost the dynamics obtained using the explicitly calculated nonadiabatic coupling vectors. The other two schemes tested can give different results, and in some cases, even entirely incorrect dynamics. Of these two, the scheme based on configuration interaction vectors gives unpredictable failures, while the other scheme based on the Baeck-An approximation systematically overestimates hopping to the ground state pared to the reference approaches. |
36897997 | Engineering Metal-Organic Frameworks for Selective Separation of Hexane Isomers Using 3-Dimensional Linkers. | Metal-organic frameworks (MOFs) are highly tunable materials with potential for use as porous media in non-thermal adsorption or membrane-based separations. However, many separations target molecules with sub-angstrom differences in size, requiring precise control over the pore size. Herein, we demonstrate that this precise control can be achieved by installing a three-dimensional linker in an MOF with one-dimensional channels. Specifically, we synthesized single crystals and bulk powder of |
36897998 | Clinical Significance of Anti-U1 Ribonucleoprotein Antibody Is Analyte Dependent: Implications for Laboratory Reporting, Interpretation, and Interassay Correlations. | Antibodies to U1 ribonucleoprotein (U1RNP) were first described more than 50 years ago, and although clinically relevant for antinuclear antibody-associated connective tissue disease (ANA-CTD), test results are challenging to interpret. |
36897996 | Selecting High-Dimensional Representations of Physical Systems by Reweighted Diffusion Maps. | Constructing reduced representations of high-dimensional systems is a fundamental problem in physical chemistry. Many unsupervised machine learning methods can automatically find such low-dimensional representations. However, an often overlooked problem is what high-dimensional representation should be used to describe systems before dimensionality reduction. Here, we address this issue using a recently developed method called the reweighted diffusion map [ |
36897999 | TERT Promoter Mutation c.-124C>T Commonly Occurs in Low-Grade Fibromatosis-like Metaplastic Breast Carcinoma. | Low-grade fibromatosis-like metaplastic carcinoma (FLMC) is a very rare subtype of triple-negative metaplastic (spindle cell) breast carcinoma. It is characterized by the proliferation of spindle cells closely resembling fibromatosis, which represents a benign fibroblastic/myofibroblastic breast proliferation. Unlike most triple-negative and basal-like breast cancers, FLMC has a very low potential for metastases, but demonstrates frequent local recurrences. |
36898001 | Adsorbed Enolate as the Precursor for the C-C Bond Splitting during Ethanol Electrooxidation on Pt. | Ethanol is a promising alternative fuel to methanol for direct alcohol fuel cells. However, plete electrooxidation of ethanol to CO |
36898000 | Elucidating the Multimodal Anticancer Mechanism of an Organometallic Terpyridine Platinum(II) N-Heterocyclic Carbene Complex against Triple-Negative Breast Cancer In Vitro and In Vivo. | Treatment of triple-negative breast cancer (TNBC) has long been a medical challenge because of the lack of effective therapeutic targets. Targeting lipid, carbohydrate, and nucleotide metabolism pathways has recently been proven as a promising option in view of three heterogeneous metabolic-pathway-based TNBC subtypes. Here, we present a multimodal anticancer plex, named Pt(II)caffeine, with a novel mode of action involving simultaneous mitochondrial damage, inhibition of lipid, carbohydrate, and nucleotide metabolic pathways, and promotion of autophagy. All these biological processes eventually result in a strong suppression of TNBC MDA-MB-231 cell proliferation both |
36898002 | Density Functional Tight-Binding Model for Lithium-Silicon Alloys. | The predictive power of molecular dynamic simulations is mainly restricted by the time scale and model accuracy. Many systems of current relevance are of plexity that they require addressing both issues simultaneously. This is the case of silicon electrodes in Li-ion batteries, where different Li |
36898003 | Modeling the Infrared Spectroscopy of Oligonucleotides with | The carbonyl stretching modes have been widely used in linear and two-dimensional infrared (IR) spectroscopy to probe the conformation, interaction, and biological functions of nucleic acids. However, due to their universal appearance in nucleobases, the IR absorption bands of nucleic acids are often highly congested in the 1600-1800 cm |
36898005 | Microhydration of the Pyrrole Cation (Py | Microhydration of heterocyclic aromatic molecules can be an appropriate fundamental model to shed light on intermolecular interactions and functions of macromolecules and biomolecules. We characterize herein the microhydration process of the pyrrole cation (Py |
36898006 | Surgical Glaucoma Treatment in Patients with Juvenile Idiopathic Arthritis-Associated Uveitis: Results after Trabeculectomy or Ahmed Glaucoma Valve Implantation. | Patients with juvenile idiopathic arthritis (JIA) associated uveitis (JIAU) are at risk for secondary a, frequently requiring surgical management. pared the success rates for trabeculectomy (TE) and Ahmed a valve (AGV) implantation. |
36898007 | TERT Promoter Mutational Analysis as an Ancillary Diagnostic Tool for Diagnostically Challenging Melanocytic Neoplasms. | Telomerase reverse transcriptase promoter mutations (TPMs) have been shown to mon in melanoma and mon in benign nevi. To assess the use of TPMs as an ancillary diagnostic tool, we report the concordance of the TPM status with the final diagnosis in clinical cases with distinct differential diagnostic scenarios: dysplastic nevus versus melanoma, atypical Spitz nevus versus melanoma, atypical deep penetrating nevus (DPN) versus melanoma, and atypical blue nevus versus malignant blue nevus. In a control cohort, we found a positive TPM in 51/70 (73%) of the total melanomas with the highest frequency in vertical growth phase melanoma cases. Conversely, only 2/35 (6%) dysplastic nevi in our control cases were TPM-positive and b were severely atypical dysplastic nevi. Our clinical cohort of 257 cases had a positive TPM in 24% of cases diagnosed as melanoma and in 1% of cases with a benign diagnosis. The overall concordance of the TPM status with the final diagnosis was 86%. The TPM status had the greatest concordance (95%) with the final diagnosis in the atypical DPN versus melanoma group, with the rest of the groups ranging between 50% and 88%. Overall, our results suggest that TPMs are most useful in the differential diagnosis of atypical DPN versus melanoma. It also has some value in the differential diagnosis of atypical Spitz tumor versus melanoma and dysplastic nevus versus melanoma, whereas in our cohort, it did not contribute meaningfully to differentiating malignant blue nevus and atypical blue nevus. |
36898009 | Custodiol cardioplegia for temporary mechanical circulatory support. | Several patients requiring biventricular mechanical circulatory support in the acute setting will not be candidates for less invasive advanced heart failure therapies not requiring median sternotomy. Temporary biventricular assist device may provide reliable short term support bridging patients to recovery or further advanced treatments. However, this exposes patients to increased risk of reoperation due to bleeding and further exposure to blood products. This article outlines the practical details necessary in performing this technique while minimizing plications. |
36898010 | Double Hook Perylene Diimide as a New Receptor for PAHs: An Experimental and Theoretical Study. | In a one-step reaction, we prepared a dibenzylamine perylene diimide derivative (PDI). Its double hook structure allows for self-association with a constant of K |
36898011 | HDAC3 Inhibition Promotes Antitumor Immunity by Enhancing CXCL10-Mediated Chemotaxis and Recruiting of Immune Cells. | It is generally believed that histone deacetylase (HDAC) inhibitors, which represent a new class of anticancer agents, exert their antitumor activity by directly causing cell-cycle arrest and apoptosis of tumor cells. However, in this study, we demonstrated that class I HDAC inhibitors, such as Entinostat and Panobinostat, effectively suppressed tumor growth in petent but not immunodeficient mice. Further studies with Hdac1, 2, or 3 knockout tumor cells indicated that tumor-specific inactivation of HDAC3 suppressed tumor growth by activating antitumor immunity. Specifically, we found that HDAC3 could directly bind to promotor regions and inhibit the expression of CXCL9, 10, and 11 chemokines. Hdac3-deficient tumor cells expressed high levels of these chemokines, which suppressed tumor growth in petent mice by recruiting CXCR3+ T cells into the tumor microenvironment (TME). Furthermore, the inverse correlation between HDAC3 and CXCL10 expression in hepatocellular carcinoma tumor tissues also suggested HDAC3 might be involved in antitumor immune regulation and patient survival. Thus, our studies have illustrated that HDAC3 inhibition suppresses tumor growth by enhancing immune cell infiltration into the TME. This antitumor mechanism may be helpful in guiding HDAC3 inhibitor-based treatment. |
36898013 | Urinary Biomarkers for the Assessment of Acute Kidney Injury of Pediatric Sickle Cell Anemia Patients Admitted for Severe Vaso-occlusive Crises. | Sickle cell nephropathy is a progressive morbidity, beginning in childhood, which is pletely understood partially due to insensitive measures. We performed a prospective pilot study of pediatric and young adult patients with sickle cell anemia (SCA) to assess urinary biomarkers during acute pain crises. Four biomarkers were analyzed with elevations potentially suggesting acute kidney injury: (1) neutrophil gelatinase-associated lipocalin (NGAL), (2) kidney injury molecule-1, (3) albumin, and (4) nephrin. Fourteen unique patients were admitted for severe pain crises and were found to be representative of a larger SCA population. Urine samples were collected at the time of admission, during admission, and at follow-up after discharge. Exploratory pared cohort values to the best available population values; individuals were pared against themselves at various time points. Albumin was found to be moderately elevated for an individual during pared with follow-up ( P = 0.006, Hedge g : 0.67). Albumin was not found to be pared with population values. Neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, and nephrin were not found to be significantly pared with population values paring admission to follow-up. Though albumin was found to be minimally elevated, further research should focus on alternative markers in efforts to further understand kidney disease in patients with SCA. |
36898015 | The Association Between Caregiver Coping and Youth Clinic Attendance and Health-related Quality of Life in Pediatric Sickle Cell Disease. | Caregivers of youth with sickle cell disease (SCD) influence the youth disease management and psychosocial es. Effective caregiver coping is important for improving disease management and es since caregivers often report high disease-related parenting stress. This study characterizes caregiver coping and examines its relation to youth clinic nonattendance and health-related quality of life (HRQOL). Participants were 63 youth with SCD and their caregivers. pleted the Responses to Stress Questionnaire-SCD module to assess primary control engagement (PCE; attempts to change stressors or reactions to stress), secondary control engagement (SCE; strategies to adapt to stress), and disengagement (avoidance) coping. Youth with pleted the Pediatric Quality of Life Inventory-SCD module. Medical records were reviewed for the hematology appointment nonattendance rates. Coping factors were significantly different ( F [1.837, 113.924]=86.071, P <0.001); caregivers reported more PCE ( M =2.75, SD =0.66) and SCE ( M =2.78, SD =0.66) than disengagement ( M =1.75, SD =0.54) coping. Responses to short-answer questions corroborated this pattern. Greater caregiver PCE coping was associated with lower youth nonattendance (β=-0.28, P =0.050), and greater caregiver SCE coping was related to higher youth HRQOL (β=0.28, P =0.045). Caregiver coping is related to improved clinic attendance and HRQOL in pediatric SCD. Providers should assess caregiver coping styles and consider encouraging engagement coping. |
36898018 | Resistance Risk Assessment for the New OSBP Inhibitor Y18501 in | Y18501 is a new oxysterol-binding protein inhibitor (OSBPI) that shows strong inhibitory activity against |
36898017 | Hopping as an Indicator of Chemotoxicity: Gait Analysis in Patients With Leukemia and Lymphoma. | Survivors of acute lymphoblastic leukemia (ALL) can experience chemotherapy-related changes in neuromuscular function, which can persist and impact the quality of life. Clinically, neuromuscular changes are assessed by observing gait. The primary aims of this study were pare observational gait/functional movement analysis to matched electronic gait analysis in children with ALL and lymphoblastic lymphoma at specific time points during and after treatment. |
36898019 | Extreme Emission Reduction Requirements for China to Achieve World Health Organization Global Air Quality Guidelines. | A big gap exists between current air quality in China and the World Health Organization (WHO) global air quality guidelines (AQG) released in 2021. Previous studies on air pollution control have focused on emission reduction demand in China but ignored the influence of transboundary pollution, which has been proven to have a significant impact on air quality in China. Here, we develop an emission-concentration response surface model coupled with transboundary pollution to quantify the emission reduction demand for China to achieve WHO AQG. China cannot achieve WHO AQG by its own emission reduction for high transboundary pollution of both PM |
36898020 | Juvenile Hemochromatosis With Non-transfused Hemolytic Anemia Caused by a De Novo PIEZO1 Gene Mutation. | Differential diagnosis of juvenile hemochromatosis along with hemolytic anemia is often difficult. We report a 23-year-old woman with macrocytic hemolytic anemia with iron overload. The patient showed high serum ferritin and transferrin saturation and low serum transferrin and ceruloplasmin. We also noticed stomatocytes in her blood smear, which was confirmed by scanning electron microscopy. Target gene sequencing identified a mutation in PIEZO1 (heterozygous c.6008C>A: p.A2003D). This mutation was reported previously in a family with dehydrated hereditary stomatocytosis (DHS1, [OMIM 194380]), but in the current case, it was identified to be a de novo mutation. We underscore DHS1 in the differential diagnosis of iron overload associated with non-transfused hemolytic anemia in children and young adults. |
36898021 | Double-Enzyme Active Vanadium Nanospheres-Mediated Ratiometric Multicolor Immunosensors for Sensitive Detection of the T-2 Toxin. | Owing to its high throughput, simplicity, and rapidity, enzyme-linked immunosorbent assay (ELISA) has attracted much attention in the field of immunoassays. However, the traditional ELISA usually affords a single signal readout and the labeling ability of the enzyme used is poor, resulting in low accuracy and a limited detection range. Herein, a vanadium nanospheres petitive ratio nanozymes-linked immunosorbent assay (VNSs-RNLISA) was created for the sensitive detection of the T-2 toxin (T-2). As the key to the biosensor, the VNSs with superoxide dismutase-like and peroxidase-like dual-enzyme mimetic activities were synthesized by a one-step hydrothermal method, which oxidized 1,1-diphenyl-2-picryl-hydrazyl fading and catalyzed 3,3',5,5'-tetramethylbenzidine (TMB) color development. Therefore, T-2 could not only be qualitatively measured with the naked eye but also be quantitatively evaluated by monitoring the ratio of absorbance at 450 and 517 nm wavelengths. Moreover, the characterization of a VNSs-labeled antibody probe showed strong dual-enzymatic activity, excellent stability, and high affinity with T-2 [the affinity constant ( |
36898022 | Cardiovascular and Thyroid Late Effects in Pediatric Patients With Hodgkin Lymphoma Treated With ABVD Protocol. | Hodgkin lymphoma (HL) survivors are at risk of developing a range of plications. The goal of this study is to investigate therapy-related late-effects in HL survivors. |
36898023 | Electrochemical Stability of Thiolate Self-Assembled Monolayers on Au, Pt, and Cu. | Self-assembled monolayers (SAMs) of thiolates have increasingly been used for modification of metal surfaces in electrochemical applications including selective catalysis (e.g., CO |
36898032 | Prognostic Factors and Long-term Outcomes in 41 Children With Primary Hemophagocytic Lymphohistiocytosis: Report of a Single-center Experience and Review of the Literature. | Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening hyperinflammatory syndrome with diverse clinical manifestations leading to major diagnostic and therapeutic difficulties. This study aimed to evaluate clinical manifestations, prognostic factors, and long-term es in children with primary HLH. Forty-one patients diagnosed with primary HLH were retrospectively evaluated for patient characteristics, HLH gene mutations, clinical and laboratory manifestations, prognostic factors, and long-term es. The median age of the patients at the time of diagnosis was 3 months (minimum to maximum: 1 to 144 mo). There were 23 patients who had HLH mutation analysis performed, 10 patients with PRF1 mutation, 6 with STX11 mutation, and 7 with UNC13D mutation. Thirteen patients (31.7%) had central nervous system involvement. No correlation was found between overall survival and central nervous system involvement. The estimated 5-year overall survival for the patient who had hematopoietic stem cell transplantation was 9.4 times better than the patients who did not receive hematopoietic stem cell transplantation (81.3% vs 16.7%; P = 0.001). Median serum sodium and blood urea nitrogen levels were significantly higher in deceased HLH pared with surviving HLH patients ( P = 0.043, and P = 0.017, respectively). Primary HLH has a poor e with high mortality, which necessitates well-designed and international clinical trials to improve diagnosis, therapy, and long-term es. |
36898033 | A Rare Report of the Coexistence of Sickle Cell Disease, Neurofibromatosis Type 1, and Intracranial Hypertension in a Pediatric Patient. | A pediatric female with sickle cell disease (SCD) and neurofibromatosis type 1 was noted to have incidental papilledema, with subsequent workup showing an elevated opening pressure. She was diagnosed with intracranial hypertension and began treatment with acetazolamide. Hydroxyurea was also discontinued. Acetazolamide was tapered off, and hydroxyurea was restarted with no worsening in her ophthalmologic exam. We report this case due to the rare occurrence of all 3 conditions, and while intracranial hypertension has been reported in SCD, the diagnostic workup for papilledema in hemoglobinopathies is not well defined. This case helps delineate the presentation and diagnostic workup of papilledema in SCD. |
36898034 | A Cross-sectional Survey to Review Food Safety Practices Within Pediatric Oncology and Stem Cell Transplant Centers in the United Kingdom. | Neutropenia is plication of chemotherapy, which poses a high risk of infection and mortality. Neutropenic diet has historically been mended for those undergoing chemotherapy. The rationale is to reduce the risk of foodborne infection by avoiding foods considered to be of high microbial risk. However, evidence for this diet is limited, and there is a lack of national consensus guidelines. |
36898038 | Description of a Colocated Comprehensive Care Model for People With Sickle Cell and Comorbid Pulmonary Disease. | Comorbid plications in people with sickle cell disease (pwSCD) are associated with high rates of morbidity and mortality, and poor access to care contributes to poor es among this particularly high-risk pwSCD. Our purpose was to describe the population served and the resources required for hematology, pulmonary, nursing, respiratory therapy, social work, genetics, psychology, and school liaison providers to see these patients in an integrated clinic. We abstracted demographic, medication, clinical, and diagnostics data of the pwSCD seen at least once in this clinic from February 1, 2014 to December 10, 2020 from the electronic medical record and identified 145 unique pwSCD. Abnormal lung function and bronchodilator responsiveness were detected in 31% and 42% of participants respectively. Sleep abnormalities were found in over two-thirds of those screened and 65% had ≥1 previous acute chest syndrome episode. This clinic also allowed for direct munication and required relatively limited resources to serve a large number of severely affected pwSCD. Given the degree of abnormal respiratory variables detected and the limited resources required to implement this model, studies are warranted to evaluate whether it has the potential to improve es in high-risk populations. |
36898037 | Addressing Barriers to Career Development Awards for Early Career Women in Pediatric Psychology. | To provide person and system-level mendations for supporting early career women in the field of pediatric psychology in writing and submitting National Institutes of Health (NIH) Career Development Award (K award) applications. mendations are provided in the context mon barriers, with a focus on practical solutions. |
36898039 | Construction of Monophosphine-Metal Complexes in Privileged Diphosphine-Based Covalent Organic Frameworks for Catalytic Asymmetric Hydrogenation. | Privileged diphosphine ligands that chelate many transition metals to form stable plexes are essential in a variety of catalytic processes. However, the exact identity of the catalytically active moieties remains ambiguous because the chelated metal catalysts may undergo rearrangement during catalysis to produce plexes, which are hard to isolate and evaluate the activities. By taking advantage of the isolation of two phosphorus atoms, we demonstrate here the successful construction of chiral plexes of diphosphine ligands in covalent organic frameworks (COFs) for enantioselective hydrogenation. By condensation of the tetraaldehyde of enantiopure MeO-BIPHEP and linear aromatic diamines, we prepare two homochiral two-dimensional COFs with ABC stacking, in which the two P atoms of each diphosphine are separated and fixed far apart. Post-synthetic metalations of the COFs thus afford the single-site Ir/Ru-monophosphine catalysts, in contrast to the homogeneous chelated analogues, that demonstrated excellent catalytic and recyclable performance in the asymmetric hydrogenation of quinolines and β-ketoesters, affording up to 99.9% enantiomeric excess. Owing to the fact that the porous catalyst is capable of adsorbing and concentrating hydrogen, the catalytic reactions are promoted under ambient/medium pressure, which are typically performed under high pressure for homogeneous catalysis. This work not only shows that plexes of diphosphines can be catalytically active centers for asymmetric hydrogenation reactions but also provides a new strategy to prepare new types of privileged phosphine-based heterogeneous catalysts. |
36898041 | Mass Spectrometry Imaging Reveals Early Metabolic Priming of Cell Lineage in Differentiating Human-Induced Pluripotent Stem Cells. | Induced pluripotent stem cells (iPSCs) hold great promise in regenerative medicine; however, few algorithms of quality control at the earliest stages of differentiation have been established. Despite lipids having known functions in cell signaling, their role in pluripotency maintenance and lineage specification is underexplored. We investigated the changes in iPSC lipid profiles during the initial loss of pluripotency over the course of spontaneous differentiation using the co-registration of confocal microscopy and matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging. We identified phosphatidylethanolamine (PE) and phosphatidylinositol (PI) species that are highly informative of the temporal stage of differentiation and can reveal iPS cell lineage bifurcation occurring metabolically. Several PI species emerged from the machine learning analysis of MS data as the early metabolic markers of pluripotency loss, preceding changes in the pluripotency transcription factor Oct4. The manipulation of phospholipids via PI 3-kinase inhibition during differentiation manifested in the spatial reorganization of the iPS cell colony and elevated expression of NCAM-1. In addition, the continuous inhibition of phosphatidylethanolamine |
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