bluuebunny/crossref_metadata_2025 huggingface dataset:
RPRH: a web-based tool for the inference of potential roles of plant microRNAs in human body
Authors: Gao Yuanxu , Cui Chunmei , Jia Kaiwen , Zhou Yuan , Cui Qinghua
Published: June 2020

Recently, increasing studies reported that plant microRNAs (miRNAs) from food could be absorbed through gastrointestinal tract to regulate the physiological processes of animals. These novel cross-kingdom regulatory roles of plant miRNAs open a new field in miRNA study and drug discovery, but the lack of corresponding bioinformatics tools limit the development of this field. In this study, we built a web-based tool, RPRH (Role of Plant microRNA in Human), to infer the potential roles of plant miRNAs in human and to profile the landscape of all documented plant miRNAs regulatory functions in human. Totally, RPRH included 10414 miRNAs from 82 plant species and 18062 annotation terms like diseases, pathway, gene ontology (GO), and drugs. RPRH represents a bioinformatics resource for further investigation of cross-kingdom regulations of plant miRNAs.

Availability

http://www.rnanut.net/rprh/
A two-locus system with strong epistasis underlies rapid parasite-mediated evolution of host resistance
Authors: Ameline Camille , Bourgeois Yann , Vögtli Felix , Savola Eevi , Andras Jason , Engelstädter Jan , Ebert Dieter
Published: June 2020

Parasites are a major evolutionary force, driving adaptive responses in host populations. Although the link between phenotypic response to parasite-mediated natural selection and the underlying genetic architecture often remains obscure, this link is crucial for understanding the evolution of resistance and predicting associated allele frequency changes in the population. To close this gap, we monitored the response to selection during epidemics of a virulent bacterial pathogen,Pasteuria ramosa, in a natural host population ofDaphnia magna. Across two epidemics, we observed a strong increase in the proportion of resistant phenotypes as the epidemics progressed. Field and laboratory experiments confirmed that this increase in resistance was caused by selection from the local parasite. Using a genome wide association study (GWAS), we obtained a genetic model in which two genomic regions with dominance and epistasis control resistance polymorphism in the host. We verified this model by selfing host genotypes with different resistance phenotypes and scoring their F1 for segregation of resistance and associated genetic markers. Applying the model to the dynamics of the field population revealed moderate changes in allele frequencies at the two resistance loci relative to the profound changes observed at the phenotypic level. This apparent discrepancy is explained by strong epistasis and dominance at the two resistance loci, which reduces the effect of selection on alleles at both loci. Such epistatic effects with strong fitness consequences in host-parasite coevolution are believed to be crucial in the Red Queen model for the evolution of genetic recombination.
Machine Learning Maps Research Needs in COVID-19 Literature
Authors: Doanvo Anhvinh , Qian Xiaolu , Ramjee Divya , Piontkivska Helen , Desai Angel , Majumder Maimuna
Published: June 2020

Manually assessing the scope of the thousands of publications on the COVID-19 (coronavirus disease 2019) pandemic is an overwhelming task. Shortcuts through metadata analysis (e.g., keywords) assume that studies are properly tagged. However, machine learning approaches can rapidly survey the actual text of coronavirus abstracts to identify research overlap between COVID-19 and other coronavirus diseases, research hotspots, and areas warranting exploration. We propose a fast, scalable, and reusable framework to parse novel disease literature. When applied to the COVID-19 Open Research Dataset (CORD-19), dimensionality reduction suggested that COVID-19 studies to date are primarily clinical-, modeling- or field-based, in contrast to the vast quantity of laboratory-driven research for other (non-COVID-19) coronavirus diseases. Topic modeling also indicated that COVID-19 publications have thus far focused primarily on public health, outbreak reporting, clinical care, and testing for coronaviruses, as opposed to the more limited number focused on basic microbiology, including pathogenesis and transmission.
Eco-evolutionary feedbacks and the maintenance of metacommunity diversity in a changing environment
Authors: Fielding Aidan P. , Pantel Jelena H.
Published: June 2020

The presence and strength of resource competition can influence how organisms adaptively respond to environmental change. Selection may thus reflect a balance between two forces, adaptation to an environmental optimum and evolution to avoid strong competition. While this phenomenon has previously been explored for single communities, its implications for eco-evolutionary dynamics at the metacommunity scale are unknown. We developed a simulation model for the evolution of a quantitative trait that influences both an organism’s carrying capacity and its intra- and interspecific competitive ability. In the model, multiple species inhabit a variable three-patch landscape, and we varied the connectivity level of the species among patches, the presence and pace of directional environmental change, and the strength of competition between the species. Our results reflect some patterns previously observed in evolving metacommunity models, such as species sorting and community monopolization. However species sorting was more likely to occur in evolving communities without dispersal, and monopolization was observed only when environmental change was very rapid. We also detected an eco-evolutionary feedback loop between local phenotypic evolution at one site and competition at another site, which maintains species diversity in some conditions. The existence of a feedback loop maintained by dispersal indicates that eco-evolutionary dynamics in communities operate at a landscape scale.
A new inference approach for training shallow and deep generalized linear models of noisy interacting neurons
Authors: Mahuas Gabriel , Isacchini Giulio , Marre Olivier , Ferrari Ulisse , Mora Thierry
Published: June 2020

Generalized linear models are one of the most efficient paradigms for predicting the correlated stochastic activity of neuronal networks in response to external stimuli, with applications in many brain areas. However, when dealing with complex stimuli, the inferred coupling parameters often do not generalize across different stimulus statistics, leading to degraded performance and blowup instabilities. Here, we develop a two-step inference strategy that allows us to train robust generalized linear models of interacting neurons, by explicitly separating the effects of correlations in the stimulus from network interactions in each training step. Applying this approach to the responses of retinal ganglion cells to complex visual stimuli, we show that, compared to classical methods, the models trained in this way exhibit improved performance, are more stable, yield robust interaction networks, and generalize well across complex visual statistics. The method can be extended to deep convolutional neural networks, leading to models with high predictive accuracy for both the neuron firing rates and their correlations.
Temporal dynamics of QTL effects on vegetative growth inArabidopsis thaliana
Authors: Meyer Rhonda C. , Weigelt-Fischer Kathleen , Knoch Dominic , Heuermann Marc , Zhao Yusheng , Altmann Thomas
Published: June 2020

We assessed early vegetative growth in a population of 382 accessions ofArabidopsis thalianausing automated non-invasive high-throughput phenotyping. All accessions were imaged daily from seven to 18 days after sowing in three independent experiments and genotyped using the Affymetrix 250k SNP array. Projected leaf area (PLA) was derived from image analysis and used to calculate relative growth rates (RGR). In addition, initial seed size was determined. The generated data sets were used jointly for a genome-wide association study that identified 238 marker-trait associations (MTAs) individually explaining up to 8 % of the total phenotypic variation. Co-localisation of MTAs occurred at 33 genomic positions. At 21 of these positions, sequential co-localisation of MTAs for two to nine consecutive days was observed. The detected MTAs for PLA and RGR could be grouped according to their temporal expression patterns, emphasising that temporal variation of MTA action can be observed even during the vegetative growth phase, a period of continuous formation and enlargement of seemingly similar rosette leaves. This indicates that causal genes may be differentially expressed in successive periods. Analyses of the temporal dynamics of biological processes are needed to gain important insight into the molecular mechanisms of growth-controlling processes in plants.

Highlight

A genome-wide association study including the factor time highlighted that early plant growth in Arabidopsis is governed by several medium and many small effect loci, most of which act only during short phases of two to nine days.
Dissociable control of unconditioned responses and associative fear learning by parabrachial CGRP neurons
Authors: Bowen Anna J. , Chen Jane Y. , Huang Y. Waterlily , Baertsch Nathan A. , Park Sekun , Palmiter Richard D.
Published: June 2020

Parabrachial CGRP neurons receive diverse threat-related signals and contribute to multiple phases of adaptive threat responses, with their inactivation attenuating both unconditioned behavioral responses to somatic pain and fear-memory formation. Because CGRPPBNneurons respond broadly to multi-modal threats, it remains unknown how these distinct adaptive processes are individually engaged. We show that while three partially separable subsets of CGRPPBNneurons broadly collateralize to their respective downstream partners, individual projections accomplish distinct functions: hypothalamic and extended amygdalar projections elicit assorted unconditioned threat responses including autonomic arousal, anxiety, and freezing behavior, while thalamic and basal forebrain projections generate freezing behavior and, unexpectedly, contribute to associative fear learning. Moreover, the unconditioned responses generated by individual projections are complementary, with simultaneous activation of multiple sites driving profound freezing behavior and bradycardia that are not elicited by any individual projection. This semi-parallel, scalable connectivity schema likely contributes to flexible control of threat responses in unpredictable environments.
Tabula-rasa exploration decreases during youth and is linked to ADHD symptoms
Authors: Dubois M , Bowler A , Moses-Payne ME , Habicht J , Steinbeis N , Hauser TU
Published: June 2020

During childhood and adolescence, exploring the unknown is important to build a better model of the world. This means that youths have to regularly solve the exploration-exploitation trade-off, a dilemma in which adults are known to deploy a mixture of computationally light and heavy exploration strategies. In this developmental study, we investigated how youths (aged 8 to 17) performed an exploration task that allows us to dissociate these different exploration strategies. Using computational modelling, we demonstrate that tabula-rasa exploration, a computationally light exploration heuristic, is used to a higher degree in children and younger adolescents compared to older adolescents. Additionally, we show that this tabula-rasa exploration is more extensively used by youths with high attention-deficit/hyperactivity disorder (ADHD) traits. In the light of ongoing brain development, our findings show that children and younger adolescents use computationally less burdensome strategies, but that an excessive use thereof might be a risk for mental health conditions.
Selection on phenotypic plasticity favors thermal canalization
Authors: Svensson Erik I. , Gomez-Llano Miguel , Waller John T.
Published: June 2020

Climate change affects organisms worldwide with profound ecological and evolutionary consequences, often increasing population extinction risk. Climatic factors can increase the strength, variability or direction of natural selection on phenotypic traits, potentially driving adaptive evolution. Phenotypic plasticity in relation to temperature can allow organisms to maintain fitness in response to increasing temperatures, thereby “buying time” for subsequent genetic adaptation and promoting evolutionary rescue. Although many studies have shown that organisms respond plastically to increasing temperatures, it is unclear if such thermal plasticity is adaptive. Moreover, we know little about how natural and sexual selection operate on thermal reaction norms reflecting such plasticity. Here, we investigate how natural and sexual selection shape phenotypic plasticity in two congeneric and phenotypically similar sympatric insect species. We show that the thermal optima for longevity and mating success differ, suggesting temperature-dependent trade-offs between survival and reproduction. Males in these species have similar thermal reaction norm slopes but have diverged in baseline body temperature (intercepts), being higher for the more northern species. Natural selection favoured reduced thermal reaction norm slopes at high ambient temperatures, suggesting that the current level of thermal plasticity is maladaptive in the context of anthropogenic climate change and that selection now promotes thermal canalization and robustness. Our results show that ectothermic animals also at high latitudes can suffer from overheating and challenge the common view of phenotypic plasticity as being beneficial in harsh and novel environments.

Significance Statement

Organisms are increasingly challenged by increasing temperatures due to climate change. In insects, body temperatures are strongly affected by ambient temperatures, and insects are therefore expected to suffer increasingly from heat stress, potentially reducing survival and reproductive success leading to elevated extinction risks. We investigated how ambient temperature affected fitness in two insect species in the temperate zone. Male and female survivorship benefitted more from low temperatures than did reproductive success, which increased with higher temperatures, revealing a thermal conflict between fitness components. Male body temperature plasticity reduced survival, and natural and sexual selection operated on such thermal plasticity. Our results reveal the negative consequences of thermal plasticity and show that these insects have limited ability to buffer heat stress.
Identification of pathogenic missense mutations using protein stability predictors
Authors: Gerasimavicius Lukas , Liu Xin , Marsh Joseph A
Published: June 2020

Attempts at using protein structures to identify disease-causing mutations have been dominated by the idea that most pathogenic mutations are disruptive at a structural level. Therefore, computational stability predictors, which assess whether a mutation is likely to be stabilising or destabilising to protein structure, have been commonly used when evaluating new candidate disease variants, despite not having been developed specifically for this purpose. We therefore tested 12 different stability predictors for their ability to discriminate between pathogenic and putatively benign missense variants. We find that one method, FoldX, considerably outperforms all others in the identification of disease variants. Moreover, we demonstrate that employing absolute energy change scores improves performance of nearly all predictors. Importantly, however, we observe that the utility of computational stability predictors is highly heterogeneous across different proteins, and that they are all are inferior to the best performing variant effect predictors for identifying pathogenic mutations. We suggest that this is largely due to alternate molecular mechanisms other than protein destabilisation underlying many pathogenic mutations. Thus, better ways of incorporating protein structural information and molecular mechanisms into computational variant effect predictors will be required for improved disease variant prioritisation.
Gene expression variability in human and chimpanzee populations share common determinants
Authors: Fair Benjamin J. , Blake Lauren E. , Sarkar Abhishek , Pavlovic Bryan J. , Cuevas Claudia , Gilad Yoav
Published: June 2020

Inter-individual variation in gene expression has been shown to be heritable and it is often associated with differences in disease susceptibility between individuals. Many studies focused on mapping associations between genetic and gene regulatory variation, yet much less attention has been paid to the evolutionary processes that shape the observed differences in gene regulation between individuals in humans or any other primate. To begin addressing this gap, we performed a comparative analysis of gene expression variability and expression quantitative trait loci (eQTLs) in humans and chimpanzees, using gene expression data from primary heart samples. We found that expression variability in both species is often determined by non-genetic sources, such as cell-type heterogeneity. However, we also provide evidence that inter-individual variation in gene regulation can be genetically controlled, and that the degree of such variability is generally conserved in humans and chimpanzees. In particular, we found a significant overlap of orthologous genes associated with eQTLs in both species. We conclude that gene expression variability in humans and chimpanzees often evolves under similar evolutionary pressures.
The transposable elements of theDrosophila serratareference panel
Authors: Tiedeman Zachary , Signor Sarah
Published: June 2020

Transposable elements are an important element of the complex genomic ecosystem, proving to be both adaptive and deleterious - repressed by the piRNA system and fixed by selection. Transposable element insertion also appears to be bursty – either due to invasion of new transposable elements that are not yet repressed, de-repression due to instability of organismal defense systems, stress, or genetic variation in hosts. Here, we characterize the transposable element landscape in an important modelDrosophila, D. serrata, and investigate variation in transposable element copy number between genotypes and in the population at large. We find that a subset of transposable elements are clearly related to elements annotated inD. melanogasterandD. simulans, suggesting they spread between species more recently than other transposable elements. We also find that transposable elements do proliferate in particular genotypes, and that often if an individual is host to a proliferating transposable element, it is host to more than one proliferating transposable element. In addition, if a transposable element is active in a genotype, it is often active in more than one genotype. This suggests that there is an interaction between the host and the transposable element, such as a permissive genetic background and the presence of potentially active transposable element copies. In natural populations an active transposable element and a permissive background would not be held in association as in inbred lines, suggesting the magnitude of the burst would be much lower. Yet many of the inbred lines have actively proliferating transposable elements suggesting this is an important mechanism by which transposable elements maintain themselves in populations.
Healthy cells functionally present TAP-independent SSR1 peptides: implications for selection of clinically relevant antigens
Authors: de Waard Antonius A. , Verkerk Tamara , Hoefakker Kelly , van der Steen Dirk M. , Jongsma Marlieke L.M. , Bliss Sophie , de Ru Arnoud H. , van Veelen Peter A. , Griffioen Marieke , Heemskerk Mirjam H.M. , Spaapen Robbert M.
Published: June 2020

Tumors with an impaired transporter associated with antigen processing (TAP) present several ER-derived self-antigens on HLA class I (HLA-I) which are absent on healthy cells. Selection of such TAP-independent antigens for T cell-based immunotherapy should include analysis of their expression on healthy cells to prevent therapy-induced adverse toxicities. However, it is unknown how the absence of clinically relevant antigens on healthy cells needs to be validated. Here we monitored TAP-independent antigen presentation on various healthy cells using a new toolbox consisting of a T cell clone recognizing a TAP-independent SSR1-derived antigen. We found that most but not all healthy cells present this antigen under normal and inflammatory conditions, indicating that TAP-independent antigen presentation is a variable phenomenon. Our data emphasize the necessity of extensive testing of a wide variety of healthy cell types to define clinically relevant TAP-independent antigens that can be safely targeted by immunotherapy.
Bacterial H-NS contacts DNA at the same irregularly spaced sites in both bridged and hemi-sequestered linear filaments
Authors: Shen Beth A. , Hustmyer Christine M. , Roston Daniel , Wolfe Michael B. , Landick Robert
Published: June 2020

Gene silencing in bacteria is mediated by chromatin proteins, of whichEscherichia coliH-NS is a paradigmatic example. H-NS forms nucleoprotein filaments with either one or two DNA duplexes. However, the structures, arrangements of DNA-binding domains (DBDs), and positions of DBD–DNA contacts in linear and bridged filaments are uncertain. To characterize the contacts that silence transcription by RNA polymerase, we combined ·OH footprinting, molecular dynamics, statistical modeling, and DBD mapping using a chemical nuclease (Fe2+-EDTA) tethered to the DBDs (TEN-map). We find that H-NS DBDs contact DNA at indistinguishable locations in bridged or linear filaments and that the DBDs vary in orientation and position with ~10-bp average spacing. Our results support a hemi-sequestration model of linear-to-bridged H-NS switching in which linear filaments able to inhibit only transcription initiation switch to bridged filaments able to inhibit both initiation and elongation using the same irregularly spaced DNA contact sites.

Highlights

Tethered-nuclease mapping (TEN-map) of H-NS DNA-binding domains detects DNA contacts

Bridged and linear H-NS filaments use the same DNA contact sites

H-NS–DNA contacts are unevenly spaced with ~10 bp average separation

AT-steps, minor groove width, and electrostatic potential best predict contact sites
A strain-specific inhibitor of receptor-bound HIV-1 targets a pocket near the fusion peptide and offers a template for drug design
Authors: Ozorowski Gabriel , Torres Jonathan L. , Santos-Martins Diogo , Forli Stefano , Ward Andrew B.
Published: June 2020

Disruption of viral fusion represents a viable, albeit under-explored, target for HIV therapeutics. While studying the receptor-bound envelope glycoprotein conformation by cryo-EM, we identified a pocket near the base of the trimer containing a bound detergent molecule and performedin silicodrug screening using a library of drug-like and commercially available molecules. After down-selection, we solved cryo-EM structures that validated binding of two small molecule hits in very similar manners to the predicted binding poses, including interactions with aromatic residues within the fusion peptide. One of the molecules demonstrated low micromolar inhibition of the autologous virus by utilizing a very rare phenylalanine in the fusion peptide and stabilizing the surrounding region. This work demonstrates that small molecules can target the fusion process, providing a new target for anti-HIV therapeutics, and highlights the need to explore how fusion peptide sequence variations affect receptor-mediated conformational states across diverse HIV strains.
Bridging scales in scattering tissues via multifocal two-photon microscopy
Authors: Chen David , Segovia-Miranda Fabian , Walker Noreen , Valenzuela Jose I. , Zerial Marino , Myers Eugene W.
Published: June 2020

Imaging biological systems at subcellular resolution and across scales is essential to under-standing how cells form tissues, organs, and organisms. However, existing large-scale optical techniques often require harsh tissue-clearing methods that cause significant morphological changes, compromise the integrity of cell membranes, and reduce the signal of fluorescent proteins. Here, we demonstrate multifocal two-photon microscopy that enables imaging mesoscopic scattering samples in their native tissue environment at high resolution and high speed.
Neuroscience Cloud Analysis As a Service
Authors: Abe Taiga , Kinsella Ian , Saxena Shreya , Buchanan E. Kelly , Couto Joao , Briggs John , Kitt Sian Lee , Glassman Ryan , Zhou John , Paninski Liam , Cunningham John P.
Published: June 2020

A major goal of computational neuroscience is the development of powerful data analyses that operate on large datasets. These analyses form an essential toolset to derive scientific insights from new experiments. Unfortunately, a major obstacle currently impedes progress: novel data analyses have a hidden dependence upon complex computing infrastructure (e.g. software dependencies, hardware), acting as an unaddressed deterrent to potential analysis users. While existing analyses are increasingly shared as open source software, the infrastructure needed to deploy these analyses – at scale, reproducibly, cheaply, and quickly – remains totally inaccessible to all but a minority of expert users. In this work we develop Neuroscience Cloud Analysis As a Service (NeuroCAAS): a fully automated analysis platform that makes state-of-the-art data analysis tools accessible to the neuroscience community. Based on modern large-scale computing advances, NeuroCAAS is an open source platform with a drag-and-drop interface, entirely removing the burden of infrastructure purchase, configuration, deployment, and maintenance from analysis users and developers alike. NeuroCAAS offers two major scientific benefits to any data analysis. First, NeuroCAAS provides automatic reproducibility of analyses at no extra effort to the analysis developer or user. Second, NeuroCAAS cleanly separates tool implementation from usage, allowing for immediate use of arbitrarily complex analyses, at scale. We show how these benefits drive the design of simpler, more powerful data analyses. Furthermore, we show that many popular data analysis tools offered through NeuroCAAS outperform typical analysis solutions (in terms of speed and cost) while improving ease of use, dispelling the myth that cloud compute is prohibitively expensive and technically inaccessible. By removing barriers to fast, efficient cloud computation, NeuroCAAS can dramatically accelerate both the dissemination and the effective use of cutting-edge analysis tools for neuroscientific discovery.
Cohesin residency determines chromatin loop patterns
Authors: Costantino Lorenzo , Hsieh Tsung-Han S. , Lamothe Rebecca , Darzacq Xavier , Koshland Douglas
Published: June 2020

The organization of chromatin into higher-order structures is essential for chromosome segregation, the repair of DNA-damage, and the regulation of gene expression. Using Micro-C XL to detect chromosomal interactions, we observed the pervasive presence of cohesin-dependent loops with defined positions throughout the genome of budding yeast, as seen in mammalian cells. In early S phase, cohesin stably binds to cohesin associated regions (CARs) genome-wide. Subsequently, positioned loops accumulate with CARs at the bases of the loops. Cohesin regulators Wpl1 and Pds5 alter the levels and distribution of cohesin at CARs, changing the pattern of positioned loops. From these observations, we propose that cohesin with loop extrusion activity is stopped by preexisting CAR-bound cohesins, generating positioned loops. The patterns of loops observed in a population of wild-type and mutant cells can be explained by this mechanism, coupled with a heterogeneous residency of cohesin at CARs in individual cells.
Activity Dependent Stimulation Increases Synaptic Efficacy In Spared Pathways In An Anesthetized Rat Model Of Spinal Cord Contusion Injury
Authors: Borrell Jordan A. , Krizsan-Agbas Dora , Nudo Randolph J. , Frost Shawn B.
Published: June 2020

The purpose of this study was to assess the ability of intraspinal microstimulation (ISMS), triggered by action potentials (spikes) recorded in motor cortex, to alter synaptic efficacy in descending motor pathways in an anesthetized rat model of spinal cord injury (SCI). Experiments were carried out in adult, male, Sprague Dawley rats with a moderate contusion injury at T8. For activity-dependent stimulation (ADS) sessions, a recording microelectrode was used to detect neuronal spikes in motor cortex that triggered ISMS in the spinal cord grey matter. SCI rats were randomly assigned to one of four experimental groups differing by: a) cortical spike-ISMS stimulus delay (10 or 25 ms) and b) number of ISMS pulses (1 or 3). Four weeks after SCI, ADS sessions were conducted in three consecutive 1-hour conditioning bouts for a total of 3 hours. At the end of each conditioning bout, changes in synaptic efficacy were assessed using intracortical microstimulation (ICMS) to examine the number of spikes evoked in spinal cord neurons during 5-minute test bouts. A multichannel microelectrode recording array was used to record cortically-evoked spike activity from multiple layers of the spinal cord. The results showed that ADS resulted in an increase in cortically-evoked spikes in spinal cord neurons at specific combinations of spike-ISMS delays and numbers of pulses. Efficacy in descending motor pathways was increased throughout all dorsoventral depths of the hindlimb spinal cord. These results show that after an SCI, ADS can increase synaptic efficacy in spared pathways between motor cortex and spinal cord. This study provides further support for ADS as an effective therapeutic approach for enhancing descending motor control after SCI.
Capturing brain dynamics: latent spatiotemporal patterns predict stimuli and individual differences
Authors: Venkatesh Manasij , JaJa Joseph , Pessoa Luiz
Published: June 2020

Insights from functional Magnetic Resonance Imaging (fMRI), and more recently from recordings of large numbers of neurons through calcium imaging, reveal that many cognitive, emotional, and motor functions depend on the multivariate interactions of neuronal populations. To capture and characterize spatiotemporal properties of brain events, we propose an architecture based on long short-term memory (LSTM) networks to uncover distributed spatiotemporal signatures during dynamic experimental conditions1. We demonstrate the potential of the approach using naturalistic movie-watching fMRI data. We show that movie clips result in complex but distinct spatiotemporal patterns in brain data that can be classified using LSTMs (≈ 90% for 15-way classification), demonstrating that learned representations generalized to unseen participants. LSTMs were also superior to existing methods in predicting behavior and personality traits of individuals. We propose a dimensionality reduction approach that uncovers low-dimensional trajectories and captures essential informational properties of brain dynamics. Finally, we employed saliency maps to characterize spatiotemporally-varying brain-region importance. The spatiotemporal saliency maps revealed dynamic but consistent changes in fMRI activation data. We believe our approach provides a powerful framework for visualizing, analyzing, and discovering dynamic spatially distributed brain representations during naturalistic conditions.
Specific viral RNA drives the SARS CoV-2 nucleocapsid to phase separate
Authors: Iserman Christiane , Roden Christine , Boerneke Mark , Sealfon Rachel , McLaughlin Grace , Jungreis Irwin , Park Chris , Boppana Avinash , Fritch Ethan , Hou Yixuan J. , Theesfeld Chandra , Troyanskaya Olga G , Baric Ralph S. , Sheahan Timothy P. , Weeks Kevin , Gladfelter Amy S.
Published: June 2020

A mechanistic understanding of the SARS-CoV-2 viral replication cycle is essential to develop new therapies for the COVID-19 global health crisis. In this study, we show that the SARS-CoV-2 nucleocapsid protein (N-protein) undergoes liquid-liquid phase separation (LLPS) with the viral genome, and propose a model of viral packaging through LLPS. N-protein condenses with specific RNA sequences in the first 1000 nts (5’-End) under physiological conditions and is enhanced at human upper airway temperatures. N-protein condensates exclude non-packaged RNA sequences. We comprehensively map sites bound by N-protein in the 5’-End and find preferences for single-stranded RNA flanked by stable structured elements. Liquid-like N-protein condensates form in mammalian cells in a concentration-dependent manner and can be altered by small molecules. Condensation of N-protein is sequence and structure specific, sensitive to human body temperature, and manipulatable with small molecules thus presenting screenable processes for identifying antiviral compounds effective against SARS-CoV-2.
Responsiveness to perturbations is a hallmark of transcription factors that maintain cell identity
Authors: Mellis Ian A. , Edelstein Hailey I. , Truitt Rachel , Beck Lauren E. , Symmons Orsolya , Goyal Yogesh , Dunagin Margaret C. , Saldana Ricardo A. Linares , Shah Parisha P. , Yang Wenli , Jain Rajan , Raj Arjun
Published: June 2020

Our ability to identify the particular transcription factors that maintain cell type is limited. Identification of factors by their cell type-specific expression or their participation in developmental regulation has been only modestly successful. We hypothesized that because cell type is often resilient to perturbations, the transcriptional response to perturbations would identify identity-maintaining factors. We developed Perturbation Panel Profiling (P3) as a framework for perturbing cells in dozens of conditions and measuring gene expression responsiveness transcriptome-wide. Applying P3to human iPSC-derived cardiac myocytes showed that transcription factors known to function in cardiac differentiation and maintenance were among the most frequently up-regulated (most responsive). We reasoned that one potential function of responsive genes may be to maintain cellular identity. We identified responsive transcription factors in fibroblasts using P3and found that suppressing their expression led to enhanced reprogramming efficiency. We propose that responsiveness to perturbations is a property of factors that help maintain cellular identity.
Right lateralized posterior parietal theta-gamma coupling during sustained attention in mice
Authors: Yang Ryan , Dunbar Corrinne , Sonesra Alina , Park Suhyeorn , Pham Timothy , Samaco Rodney C. , Foster Brett L. , Maheshwari Atul
Published: June 2020

Sustained attention is supported by circuits in the frontoparietal attention network. In human and primate studies, the right posterior parietal cortex (PPC) shows dominance for sustained attention, and phase-amplitude coupling (PAC) throughout the frontoparietal network correlates with performance on attention tasks. Here we evaluate oscillatory dynamics of bilateral PPC in mice during the 5-Choice Serial Reaction Time Task (5-CSRTT). Right PPC theta-gamma PAC (TG-PAC) and gamma power were independently elevated to a greater degree than the left PPC during the period prior to a correct response and were significantly correlated with accuracy in both simple and difficult tasks. Greater task difficulty was also associated with greater hemispheric asymmetry in TG-PAC, favoring the right PPC. These findings highlight the engagement of PPC with sustained attention in mice, reflected by increases in TG-PAC and gamma power, with maximal expression in the right hemisphere.
A Platform Incorporating Trimeric Antigens into Self-Assembling Nanoparticles Reveals SARS-CoV-2-Spike Nanoparticles to Elicit Substantially Higher Neutralizing Responses than Spike Alone
Authors: Zhang Baoshan , Chao Cara W. , Tsybovsky Yaroslav , Abiona Olubukola M. , Hutchinson Geoffrey B. , Moliva Juan I. , Olia Adam S. , Pegu Amarendra , Phung Emily , Stewart-Jones Guillaume , Verardi Raffaello , Wang Lingshu , Wang Shuishu , Werner Anne , Yang Eun Sung , Yap Christina , Zhou Tongqing , Mascola John R. , Sullivan Nancy J. , Graham Barney S. , Corbett Kizzmekia S. , Kwong Peter D.
Published: June 2020

Antigens displayed on self-assembling nanoparticles can stimulate strong immune responses and have been playing an increasingly prominent role in structure-based vaccines. However, the development of such immunogens is often complicated by inefficiencies in their production. To alleviate this issue, we developed a plug-and-play platform using the spontaneous isopeptide-bond formation of the SpyTag:SpyCatcher system to display trimeric antigens on self-assembling nanoparticles, including the 60-subunitAquifex aeolicuslumazine synthase (LuS) and the 24-subunitHelicobacter pyloriferritin. LuS and ferritin coupled to SpyTag expressed well in a mammalian expression system when anN-linked glycan was added to the nanoparticle surface. The respiratory syncytial virus fusion (F) glycoprotein trimer – stabilized in the prefusion conformation and fused with SpyCatcher – could be efficiently conjugated to LuS-SpyTag or ferritin-SpyTag, enabling multivalent display of F trimers with prefusion antigenicity. Similarly, F-glycoprotein trimers from human parainfluenza virus-type 3 and spike-glycoprotein trimers from SARS-CoV-2 could be displayed on LuS nanoparticles with decent yield and antigenicity. Notably, murine vaccination with the SARS-CoV-2 spike-LuS nanoparticles elicited ~25-fold higher neutralizing responses, weight-per-weight relative to spike alone. The versatile platform described here thus allows for multivalent plug-and-play presentation on self-assembling nanoparticles of trimeric viral antigens, with SARS-CoV-2 spike-LuS nanoparticles inducing particularly potent neutralizing responses.
How far Covid19 virus spread can be curbed by relaxing lockdown in different stages? -A study in Indian scenario
Authors: Chakraborty Arindom , Das Kalyan
Published: June 2020

After the emergence of the first cases in Wuhan, China, the novel coronavirus (2019-nCoV) infection has rapidly spread out to other provinces, neighboring countries and finally has become a global terror. It is indeed a matter of serious concern to study the transmission dynamics of this virus. The potential and severity of an outbreak and providing critical information for identifying the type of disease interventions and intensity can be well understood by the unknown basic reproduction number. A stochastic model can be used to estimate this number with possible safeguard on uncertainties. It is essential to assess how the expensive, resource-intensive measures can contribute to the prevention and control of the 2019-nCoV infection and how long they should be maintained. A short-term forecast of incidences are often of high priority. The challenge is to forecast unseen “future” simulated data for three different scenarios at some time points. We estimate current levels of transmissibility, over variable time points under different levels of interventions and use that to forecast near-future incidence. The forecasted values of incidence can be used for determining the near future mortality also.
Room Temperature Isothermal Colorimetric Padlock Probe Rolling Circle Amplification for Viral DNA and RNA Detection
Authors: Huang Wilson , Ting Joyce , Fang Matthew , Hsu Hannah , Su Jimmy , Misaki Tsuyoshi , Chan Derek , Yang Justin , Yeh Ting-Yu , Yang Kelly , Chien Vera , Huang Tiffany , Chen Andrew , Wei Claire , Hsu Jonathan , Clapper Jude C.
Published: June 2020

Seasonal flu and pandemics, which account for millions of infections and hundreds of thousands of deaths, require rapid and reliable detection mechanisms to implement preventive and therapeutic measures. Current detection methods of viral infections have limitations in speed, accuracy, accessibility, and usability. This project presents a novel, widely applicable viral diagnostic test that uses a modified version of rolling circle amplification (RCA) to be sensitive, specific, direct RNA targeted, colorimetric and operable at room temperature. We are specifically detecting the following high-impact viruses: SARS-CoV-2, Influenza A (H1N1pdm09), and Influenza B (Victoria Lineage), although our test can be adapted to any viral infection. Results using synthetic viral DNA and RNA sequences show that our diagnostic test takes approximately one hour, detects femtomolar concentrations of RNA strands, and differentiates between virus strains. We believe implementing our diagnostic test will provide faster responses to future viral-related outbreaks for quicker societal recovery.
Systematic analysis of protein targets associated with adverse events of drugs from clinical trials and post-marketing reports
Authors: Smit Ines A. , Afzal Avid M. , Allen Chad H. G. , Svensson Fredrik , Hanser Thierry , Bender Andreas
Published: June 2020

Adverse drug reactions (ADRs) are undesired effects of medicines that can harm patients and are a significant source of attrition in drug development. ADRs are anticipated by routinely screening drugs against secondary pharmacology protein panels. However, there is still a lack of quantitative information on the links between these off-target proteins and the risk of ADRs in humans. Here, we present a systematic analysis of associations between measured and predictedin vitrobioactivities of drugs, and adverse events (AEs) in humans from two sources of data: the Side Effect Resource (SIDER), derived from clinical trials, and the Food and Drug Administration Adverse Event Reporting System (FAERS), derived from post-marketing surveillance. The ratio of a drug’sin vitropotency against a given protein relative to its therapeutic unbound drug plasma concentration was used to select proteins most likely to be relevant toin vivoeffects. In examining individual target bioactivities as predictors of AEs, we found a trade-off between the Positive Predictive Value and the fraction of drugs with AEs that can be detected, however considering sets of multiple targets for the same AE can help identify a greater fraction of AE-associated drugs. Of the 45 targets with statistically significant associations to AEs, 30 are included on existing safety target panels. The remaining 15 targets include 8 carbonic anhydrases, of which CA5B was significantly associated with cholestatic jaundice. We include the full quantitative data on associations betweenin vitrobioactivities and AEs in humans in this work, which can be used to make a more informed selection of safety profiling targets.
Feed restriction in mid-lactation dairy cows. I: Effects on milk production and energy metabolism-related blood metabolites
Authors: Ansia I. , Ohta Y. , Fujieda T. , Drackley J. K.
Published: June 2020

The aim of the study was to describe the metabolic responses on energy metabolism to a period of negative nutrient balance induced by feed restriction (FR). Seven multiparous Holstein cows (93 ± 15 days in milk) were randomly assigned to 7 treatments in a 7 × 4 Youden square design. Daily intake was restricted to provide 60% of energy requirements during 5 d except for one treatment with ad libitum (AL) feeding. While 5 out of 7 experimental treatments involved abomasal supplementation of amino acids or glucose, in this article we evaluated only the effects of a negative nutrient balance by comparing both control treatments (AL and FR). Data of 2 cows within the AL group were removed due to sickness and therefore it had n = 2. Milk and energy corrected milk yield were reduced by FR. Yields of milk protein and lactose were lower during FR than during AL but the yield of milk fat only had a tendency (P> 0.06) to be lower with FR. Milk protein concentration was lower with FR than with AL but concentration of milk lactose and fat were not different between diets. The FR induced a decrease in plasma insulin and glucose concentrations, with quadratic decreasing trends both reaching nadirs on d 3. Simultaneously, non-esterified fatty acids (NEFA) concentration was greater and increased quadratically, peaking at d 3 during FR. There were no differences in daily β-hydroxybutyrate concentration, but it increased linearly until d 4 with FR. Comparison of the variation in concentration after feeding of insulin, NEFA and glucose could indicate a likely increased insulin sensitivity for peripheral NEFA uptake and a resistance for glucose uptake. This mechanism would contribute to decrease NEFA in circulation and sparing of glucose for lactose synthesis, respectively. Metabolic adaptations to a short-term reduction in dry matter intake include lipid mobilization, as well as modulation of peripheral tissue endocrine sensitivity in order to maintain yield of milk components production but prioritizing milk fat and lactose over milk protein.

Implications

The short-term feed restriction model described in this article can serve as an alternative to study metabolic adaptations during the transition period. The response of energy metabolism observed sets the baseline to measure the effect of nutrients supplementation and identify those candidates that will improve milk production and overall health after calving.
State-dependent signatures of Anti-NMDA Receptor Encephalitis: a dynamic functional connectivity study
Authors: von Schwanenflug Nina , Krohn Stephan , Heine Josephine , Paul Friedemann , Prüss Harald , Finke Carsten
Published: June 2020

Objective

Traditional static functional connectivity (FC) analyses have shown functional network alterations in patients with anti-NMDA receptor encephalitis (NMDARE). Here, we use a dynamic FC approach that increases the temporal resolution of connectivity analyses from minutes to seconds. We hereby explore the spatiotemporal variability of large-scale brain network activity in NMDARE and assess the discriminatory power of functional brain states in a supervised classification approach.

Methods

We included resting-state fMRI data from 57 patients and 61 controls to extract four discrete connectivity states and assess state-wise group differences in FC, dwell time, transition frequency, fraction time and occurrence rate. Additionally, for each state, logistic regression models with embedded feature selection were trained to predict group status in a leave-one-out cross-validation scheme.

Results

Compared to controls, patients exhibited diverging dynamic FC patterns in three out of four states mainly encompassing the default-mode network and frontal areas. This was accompanied by a characteristic shift in the dwell time pattern and higher volatility of state transitions in patients. Moreover, dynamic FC measures were associated with disease severity, disease duration and positive and negative schizophrenia-like symptoms. Predictive power was highest in dynamic FC models and outperformed static analyses, reaching up to 78.6% classification accuracy.

Conclusions

By applying time-resolved analyses, we disentangle state-specific FC impairments and characteristic changes in temporal dynamics not detected in static analyses, offering new perspectives on functional reorganization underlying NMDARE. Correlation of dynamic FC measures with disease symptoms and severity indicates their clinical relevance and potential as prognostic biomarkers in NMDARE.