bluuebunny/crossref_metadata_2025_split huggingface dataset:
Controlling for background genetic effects using polygenic scores improves the power of genome-wide association studies
Authors: Bennett Declan , O’Shea Donal , Ferguson John , Morris Derek , Seoighe Cathal 
Published: May 2020

ABSTRACTOngoing increases in the size of human genotype and phenotype collections offer the promise of improved understanding of the genetics of complex diseases. In addition to the biological insights that can be gained from the nature of the variants that contribute to the genetic component of complex trait variability, these data bring forward the prospect of predicting complex traits and the risk of complex genetic diseases from genotype data. Here we show that advances in phenotype prediction can be applied to improve the power of genome-wide association studies. We demonstrate a simple and efficient method to model genetic background effects using polygenic scores derived from SNPs that are not on the same chromosome as the target SNP. Using simulated and real data we found that this can result in a substantial increase in the number of variants passing genome-wide significance thresholds. This increase in power to detect trait-associated variants also translates into an increase in the accuracy with which the resulting polygenic score predicts the phenotype from genotype data. Our results suggest that advances in methods for phenotype prediction can be exploited to improve the control of background genetic effects, leading to more accurate GWAS results and further improvements in phenotype prediction.
3D bioprinting of high cell-density heterogeneous tissue models through spheroid fusion within self-healing hydrogels
Authors: Daly Andrew C. , Davidson Matthew D. , Burdick Jason A. 
Published: May 2020

AbstractCellular models are needed to study human development and diseasein vitro, including the screening of drugs for toxicity and efficacy. However, current approaches are limited in the engineering of functional tissue models with requisite cell densities and heterogeneity to appropriately model cell and tissue behaviors. Here, we develop a new bioprinting approach to transfer spheroids into self-healing support hydrogels at high resolution, which enables their patterning and fusion into high-cell density microtissues of prescribed spatial organization. As an example application, we bioprint induced pluripotent stem cell-derived cardiac microtissue models with spatially controlled cardiomyocyte and fibroblast cell ratios to replicate the structural and functional features of scarred cardiac tissue that arise following myocardial infarction, including reduced contractility and irregular electrical activity. The bioprintedin vitromodel is combined with functional readouts to probe how various pro-regenerative microRNA treatment regimes influence tissue regeneration and recovery of function as a result of cardiomyocyte proliferation. This method is useful for a range of biomedical applications, including the development of precision models to mimic diseases and for the screening of drugs, particularly where high cell densities and heterogeneity are important.
Electron microscopic observation of infected CCB and whole genome analysis of Koi herpesvirus isolate GY01
Authors: Duan Hongan , Xu Ye , Zhou Yi , Wang Fengzhi , Ding Chao , Cao Jie 
Published: May 2020

AbstractBackgroundCyprinid herpesvirus-3 (CyHV-3), commonly known as Koi herpesvirus (KHV) can induce infectious and acute viremia in common/koi carp (Cyprinus carpio). In an earlier study in this laboratory a KHV isolate GY1506 (KHV GY01 in GeneBank) was isolated from diseased common carp, replicated on CCB cells and identified by PCR targeted on and phylogenetic analysis of thymidine kinase (TK) gene. Electron microscopy examination of GY01 infected CCB cell line and whole genome analysis was studied for further characteristics and epidemiological features of this strain.ResultsElectron microscopy examination of CCB infected with KHV GY01 strain revealed destruct of infected cells including incomplete nuclear membranes, deformed nucleus, marginalized nuclear chromosome, and the virus of different development stages and morphologies in the cytoplasm and nucleus, which resembles the herpesvirus. MEGA X and phyML were used for multiple alignment and phylogenetic analysis of whole genomes of GY01 and other 21 KHV strains available in GeneBank. analysis showed that GY01 was more close to E and KHV-I and was predicted it originated from the same ancestor as the E and KHV-I. Pairwise alignment of strain GY01 and strain E by Geneious software and YASS online version revealed that two strains had high identity(99.1%) at the nucleotide sequence level although variations and disagreement existed. The number and structure arrangement of open reading frames (orfs) or protein-encoding genes of GY01 is very similar to KHV E, and also to KHV-U but different from KHV-I. The characteristics and function of each orf need further study in the future.ConclusionsPathogenic changes of infected CCB cells and morphologies of KHV GY01 resembles the herpesvirus. Pairwise, multiple alignment and phylogenetic analysis of whole genomes of GY01 and other 21 KHV strains available in GeneBank demonstrated that the GY01 is closely related to strain KHV E and KHV-I and suggested it originated from the same ancestor as the E and KHV-I.
Viscoelasticity of single macromolecules using Atomic Force Microscopy
Authors: Rajput Shatruhan Singh , Deopa Surya Pratap S , Yadav Jyoti , Ahlawat Vikhyaat , Talele Saurabh , Patil Shivprasad 
Published: May 2020

We measured viscoelasticity of single protein molecules using two types of Atomic Force Microscopes (AFM) which employ different detection schemes to measure the cantilever response. We used a commonly available deflection detection scheme in commercial AFMs which measures cantilever bending and a fibre-interferometer based home-built AFM which measures cantilever displacement. For both methods, the dissipation coefficient of a single macromolecule is immeasurably low. The upper bound on the dissipation coefficient is 5 × 10−7kg/s whereas the entropic stiffness of single unfolded domains of protein measured using both methods is in the range of 10 mN/m. We show that in a conventional deflection detection measurement, the phase of bending signal can be a primary source of artefacts in the dissipation estimates. It is recognized that the measurement of cantilever displacement, which does not have phase lag due to hydrodynamics of the cantilever, is better suited for ensuring artefact-free measurement of viscoelasticty compared to the measurement of the cantilever bending. We confirmed that the dissipation coefficient in single macromolecules is below the detection limit of AFM by measuring dissipation in water layers confined between the tip and the substrate using similar experimental parameters. Further, we experimentally determined the limits in which the simple point-mass approximation of the cantilever works in off-resonance operation.Significance StatementSingle Macromolecules, including unfolded proteins bear rubber-like entropic elasticity and internal friction characterized by finite dissipation coefficient. Direct measurement of this viscoelastic response is important since it plays a significant role, both in polymer physics as well as protein folding dynamics. The viscoelastic response of single polymer chain is difficult and prone to artefacts owing to the complications of hydrodynamics of macroscopic probe itself in the liquid environment. Using a special atomic force microscope, which allows quantitative estimate of viscoelasticity in liquid environments, we measured viscoelastic response of single molecule of Titin. We report here that the dissipation coefficient is below the detection limit of our experiments - with upper bound which is less than reported values in the literature.
Bioinformatic analysis based genome-wide identification, characterization, diversification and regulatory transcription components of RNA silencing machinery genes in wheat (Triticum aestivumL.)
Authors: Akond Zobaer , Rahman Hafizur , Ahsan Md. Asif , Mosharaf Md. Parvez , Alam Munirul , Mollah Md. Nurul Haque 
Published: May 2020

AbstractDicer-Like (DCL), Argonaute (AGO), and RNA-dependent RNA polymerase (RDR) gene families are known as RNA silencing machinery genes or RNAi genes. They have important activities at post-transcriptional and chromatin modification levels. They regulate gene expression relating to different stresses, growth, and development in eukaryotes. A complete cycle of gene silencing is occurred by the collaboration of these three families. However, these gene families are not yet rigorously studied in the economically important wheat genome. Our bioinformatic analysis based genome-wide identification, characterization, diversification and regulatory components of these gene families identified 7 TaDCL, 39 TaAGO and 16 TaRDR genes from wheat genome against RNAi genes ofArabidopsis thaliana. Phylogenetic analysis of wheat genome withArabidopsisand rice RNAi genes showed that TaDCL, TaAGO and TaRDR proteins are clustered into four, eight and four subgroups respectively. Domain, motif and exon-intron structure analyses showed that the TaDCL, TaAGO and TaRDR proteins conserve identical characteristics within groups while retain diverse differences between groups. GO annotations implied that a number of biological and molecular pathways are linked to RNAi mechanism in wheat. Gene networking between transcription factors and RNAi proteins indicates that ERF is the leading family linked to maximum RNAi genes followed by MIKC-MADS, C2H2, BBR-BPC, MYB, and Dof.Cis-regulatory elements associated to RNAi genes are predicted to act as regulatory components against various environmental conditions. Expressed sequence tag analysis showed that larger numbers of RNAi genes are expressed in different tissues and organs predicted to play roles for healthy plants and grains. Expression analysis of 7 TaDCL genes using qRT-PCR showed that only TaDCL3a and TaDCL3b had root specific significant expression (p-value<0.05) with no expression in leaf validated EST results. Besides, TaDCL3b and TaDCL4 significantly prompted in drought condition indicating their potential role in drought stress tolerance. Overall results would however help researchers for in-depth biological investigation of these RNAi genes in wheat crop improvement.
Laminin N-terminus α31 protein distribution in adult human tissues
Authors: Troughton Lee D. , Reuten Raphael , Sugden Conor J. , Hamill Kevin J. 
Published: May 2020

AbstractLaminin N terminus α31 (LaNt α31) is a netrin-like protein derived from alternative splicing of the laminin α3 gene. Although LaNt α31 has been demonstrated to influence corneal and skin epithelial cell function, its expression has not been investigated beyond these tissues. In this study, we used immunohistochemistry to characterise the distribution of this protein in a wide-array of human tissue sections in comparison to laminin α3. These data revealed widespread LaNt α31 expression. In epithelial tissue, LaNt α31 was present in the basal layer of the epidermis, throughout the epithelium of the digestive tract, and much of the epithelium of the reproductive system. LaNt α31 was also found throughout the vasculature of most tissues, with enrichment in reticular-like fibres in the extracellular matrix surrounding large vessels. A similar matrix pattern was observed around the terminal ducts in the breast and around the alveolar epithelium in the lung, where basement membrane staining was also evident. Specific enrichment of LaNt α31 was identified in sub-populations of cells of the kidney, liver, pancreas, and spleen, with variations in intensity between different cell types in the collecting ducts and glomeruli of the kidney being of particular note. Intriguingly, LaNt α31 immunoreactivity was also evident in neurons of the central nervous system, in the cerebellum, cerebral cortex, and spinal cord. Together these findings suggest that LaNt α31 may be functionally relevant in a wider range of tissue contexts than previously thought, and provides a valuable basis for investigation into this interesting protein.
Multiple stressors in multiple species: effects of different RDX soil concentrations and differential water-resourcing on RDX fate, plant health, and plant survival
Authors: Lance Richard F. , Butler Afrachanna D. , Jung Carina M. , Lindsay Denise L. 
Published: May 2020

AbstractResponse to simultaneous stressors is an important facet of plant ecology and land management. In a greenhouse trial, we studied how eight plant species responded to single and combined effects of three RDX soil concentrations and two levels of water-resourcing. In an outdoor trial, we studied the effects of high RDX soil concentration and two levels of water-resourcing in three plant species. Multiple endpoints related to RDX fate, plant health, and plant survival were evaluated in both trials. Starting RDX concentration was the most frequent factor influencing all endpoints. Water-resourcing also had significant impacts, but in fewer cases. For most endpoints, significant interaction effects between RDX concentration and water-resourcing were observed for some species and treatments. Main and interaction effects were typically variable (significant in one treatment, but not in another; associated with increasing endpoint values for one treatment and/or with decreasing endpoint values in another). This complexity has implications for understanding how RDX and water-availability combine to impact plants, as well as for applications like phytoremediation. Two plant species native to the southeastern United States,Ruellia caroliniensis and Salvia coccinea, exhibited treatment responses that suggest they may be useful for phytoremediation, even within complex and changing environments.
Too attractive to self: How pollinators can interfere with the evolution of selfing
Authors: Spigler RB , Smith-Ramesh LM , Kalisz S 
Published: May 2020

ABSTRACTPollinators are widely invoked to explain the evolution of selfing despite genetic conditions favoring outcrossing. But their role in maintaining outcrossing despite genetic conditions favoring selfing remains unexplored. We use consumer-resource models to explicitly consider the how the plant-pollinator mutualism can constrain the evolution of selfing. We model outcrossing as a function of attractiveness and account for the cost of attractiveness as a saturating, linear, or exponential function alongside the costs of selfing: inbreeding depression and pollen discounting. We show specific, clear combinations of ecological and genetic conditions where pure selfing can invade a resident population of partial selfers. Complete selfing can evolve in the face of pollen discounting so long as there is a cost to pollinator attraction and reward. However, we also predict conditions under which mixed mating is maintained even when inbreeding depression is low. Our model highlights how under some scenarios mixed mating represents the worst of both worlds, leaving plants to pay the costs of both inbreeding depression and attraction and even leading to extinction. By linking pollinator attraction to the selfing rate, our models provide a likely common mechanism to explain pollen discounting and an alternative evolutionary pathway to the selfing syndrome.
SSRIs modulate asymmetric learning from reward and punishment
Authors: Michely Jochen , Eldar Eran , Erdman Alon , Martin Ingrid M. , Dolan Raymond J. 
Published: May 2020

AbstractHuman instrumental learning is driven by a history of outcome success and failure. We demonstrate that week-long treatment with a serotonergic antidepressant modulates a valence-dependent asymmetry in learning from reinforcement. In particular, we show that prolonged boosting of central serotonin reduces reward learning, and enhances punishment learning. This treatment induced learning asymmetry can result in lowered positive and enhanced negative expectations. A consequential effect is more rewarding, and less disappointing, experiences and this may, in part, explain the slow temporal evolution of serotonin’s well-established antidepressant effects.
Trimeric SARS-CoV-2 Spike interacts with dimeric ACE2 with limited intra-Spike avidity
Authors: Lui Irene , Zhou Xin X. , Lim Shion A. , Elledge Susanna K. , Solomon Paige , Rettko Nicholas J. , Zha Beth Shoshana , Kirkemo Lisa L. , Gramespacher Josef A. , Liu Jia , Muecksch Frauke , Lorenzi Julio Cesar Cetrulo , Schmidt Fabian , Weisblum Yiska , Robbiani Davide F. , Nussenzweig Michel C. , Hatziioannou Theodora , Bieniasz Paul D. , Rosenburg Oren S. , Leung Kevin K. , Wells James A. 
Published: May 2020

AbstractA serious public health crisis is currently unfolding due to the SARS-CoV-2 pandemic. SARS-CoV-2 viral entry depends on an interaction between the receptor binding domain of the trimeric viral Spike protein (Spike-RBD) and the dimeric human angiotensin converting enzyme 2 (ACE2) receptor. While it is clear that strategies to block the Spike/ACE2 interaction are promising as anti-SARS-CoV-2 therapeutics, our current understanding is insufficient for the rational design of maximally effective therapeutic molecules. Here, we investigated the mechanism of Spike/ACE2 interaction by characterizing the binding affinity and kinetics of different multimeric forms of recombinant ACE2 and Spike-RBD domain. We also engineered ACE2 into a split Nanoluciferase-based reporter system to probe the conformational landscape of Spike-RBDs in the context of the Spike trimer. Interestingly, a dimeric form of ACE2, but not monomeric ACE2, binds with high affinity to Spike and blocks viral entry in pseudotyped virus and live SARS-CoV-2 virus neutralization assays. We show that dimeric ACE2 interacts with an RBD on Spike with limited intra-Spike avidity, which nonetheless contributes to the affinity of this interaction. Additionally, we demonstrate that a proportion of Spike can simultaneously interact with multiple ACE2 dimers, indicating that more than one RBD domain in a Spike trimer can adopt an ACE2-accessible “up” conformation. Our findings have significant implications on the design strategies of therapeutic molecules that block the Spike/ACE2 interaction. The constructs we describe are freely available to the research community as molecular tools to further our understanding of SARS-CoV-2 biology.
Chemogenetic manipulation of microglia inhibits neuroinflammation and neuropathic pain in mice
Authors: Yi Min-Hee , Liu Yong U. , Liu Kevin , Chen Tingjun , Bosco Dale B. , Zheng Jiaying , Xie Manling , Zhou Lijun , Qu Wenchun , Wu Long-Jun 
Published: May 2020

AbstractMicroglia play an important role in the central sensitization and chronic pain. However, a direct connection between microglial function and the development of neuropathic painin vivoremains incompletely understood. To address this issue, we applied chemogenetic approach by using CX3CR1creER/+:R26LSL-hM4Di/+transgenic mice to enable expression of inhibitory Designer Receptors Exclusively Activated by Designer Drugs (Gi DREADD) exclusively in microglia. We found that microglial Gi DREADD activation inhibited spinal nerve transection (SNT)-induced microglial reactivity as well as chronic pain initiation and maintenance. Gi DREADD activation downregulated the transcription factor interferon regulatory factor 8 (IRF8) and its downstream target pro-inflammatory cytokine interleukin 1 beta (IL-1β). Usingin vivospinal cord recording, we found that activation of microglial Gi DREADD attenuated synaptic transmission following SNT. Our results demonstrate that microglial Gi DREADD reduces neuroinflammation, synaptic function and neuropathic pain after peripheral nerve injury. Thus, chemogenetic approaches provide a potential opportunity for interrogating microglial function and neuropathic pain treatment.
Sweet taste of heavy water
Authors: Abu Natalie Ben , Mason Philip E. , Klein Hadar , Dubovski Nitzan , Shoshan-Galeczki Yaron Ben , Malach Einav , Pražienková Veronika , Maletínská Lenka , Tempra Carmelo , Chamorro Victor Cruces , Cvačka Josef , Behrens Maik , Niv Masha Y. , Jungwirth Pavel 
Published: May 2020

AbstractHydrogen to deuterium isotopic substitution has only a minor effect on physical and chemical properties of water and, as such, is not supposed to influence its neutral taste. Here we conclusively demonstrate that humans are, nevertheless, able to distinguish D2O from H2O by taste. Indeed, highly purified heavy water has a distinctly sweeter taste than same-purity normal water and adds to perceived sweetness of sweeteners. In contrast, mice do not prefer D2O over H2O, indicating that they are not likely to perceive heavy water as sweet. HEK 293T cells transfected with the TAS1R2/TAS1R3 heterodimer and chimeric G-proteins are activated by D2O but not by H2O. Lactisole, which is a known sweetness inhibitor acting via the TAS1R3 monomer of the TAS1R2/TAS1R3, suppresses the sweetness of D2O in human sensory tests, as well as the calcium release elicited by D2O in sweet taste receptor-expressing cells. The present multifaceted experimental study, complemented by homology modelling and molecular dynamics simulations, resolves a long-standing controversy about the taste of heavy water, shows that its sweet taste is mediated by the human TAS1R2/TAS1R3 taste receptor, and opens way to future studies of the detailed mechanism of action.One sentence summaryHeavy water elicits sweet taste for humans via the TAS1R2/TAS1R3 taste receptor.
Bulk polarity of 3,5,7-trinitro-1-azaadamantane mediated by asymmetric NO2(lone pair)...NO2(π-hole) supramolecular bonding
Authors: Domasevitch Kostiantyn V. , Senchyk Ganna A. , Krautscheid Harald 
Published: May 2020

Molecular crystals exhibiting polar symmetry are important paradigms for developing new electrooptical materials. Though accessing bulk polarity still presents a significant challenge, in some cases it may be rationalized as being associated with the specific molecular shapes and symmetries and subtle features of supramolecular interactions. In the crystal structure of 3,5,7-trinitro-1-azaadamantane, C9H12N4O6, the polar symmetry of the molecular arrangement is a result of complementary prerequisites, namely the C
3v
symmetry of the molecules is suited to the generation of polar stacks and the inherent asymmetry of the principal supramolecular bonding, as is provided by NO2(lone pair)...NO2(π-hole) interactions. These bonds arrange the molecules into a trigonal network. In spite of the apparent simplicity, the structure comprises three unique molecules (Z′ = 1 \over 3 + 1 \over 3 + 1 \over 3), two of which are donors and acceptors of three N...O interactions and the third being primarily important for weak C—H...O hydrogen bonding. These distinct structural roles agree with the results of Hirshfeld surface analysis. A set of weak C—H...O and C—H...N hydrogen bonds yields three kinds of stacks. The orientation of the stacks is identical and therefore the polarity of each molecule contributes additively to the net dipole moment of the crystal. This suggests a special potential of asymmetric NO2(lone pair)...NO2(π-hole) interactions for the supramolecular synthesis of acentric materials.