bluuebunny/crossref_metadata_2025_split huggingface dataset:
HRWR: Predicting Potential Efficacious Drug Combination Based on Hypergraph Random Walk with Restart
Authors: Wang Qi , Yan Guiying 
Published: December 2020

AbstractSome studies have shown that efficacious drug combination can increase the therapeutic effect, and decrease drug toxicity and side-effects. Thus, drug combinations have been widely used in the treatment of complex diseases, especially cancer. However, experiment-based methods are extremely costly in time and money. Computational models can greatly reduce the cost, but most of the models do not use the data of more than two drugs and lose a lot of useful information. Here, we used high-order drug combination information and developed a hypergraph random walk with restart model (HRWR) for efficacious drug combination prediction.As a result, compared with the other methods by leave-one-out cross-validation (LOOCV), the Area Under Receiver Operating Characteristic Curve (AUROC) of the HRWR algorithm were higher than others. Moreover, the case studies of lung cancer, breast cancer, and colorectal cancer showed that HRWR had a powerful ability to predict potential efficacious combinations, which provides new prospects for cancer treatment. The code and dataset of HRWR are freely available athttps://github.com/wangqi27/HRWR.
SPEAQeasy: a Scalable Pipeline for Expression Analysis and Quantification for R/Bioconductor-powered RNA-seq analyses
Authors: Eagles Nicholas J. , Burke Emily E. , Leonard Jacob , Barry Brianna K. , Stolz Joshua M. , Huuki Louise , Phan BaDoi N. , Serrato Violeta Larios , Gutiérrez-Millán Everardo , Aguilar-Ordoñez Israel , Jaffe Andrew E. , Collado-Torres Leonardo 
Published: December 2020

AbstractRNA sequencing (RNA-seq) is a common and widespread biological assay, and an increasing amount of data is generated with it. In practice, there are a large number of individual steps a researcher must perform before raw RNA-seq reads yield directly valuable information, such as differential gene expression data. Existing software tools are typically specialized, only performing one step-- such as alignment of reads to a reference genome-- of a larger workflow. The demand for a more comprehensive and reproducible workflow has led to the production of a number of publicly available RNA-seq pipelines. However, we have found that most require computational expertise to set up or share among several users, are not actively maintained, or lack features we have found to be important in our own analyses. In response to these concerns, we have developed a Scalable Pipeline for Expression Analysis and Quantification (SPEAQeasy), which is easy to install and share, and provides a bridge towards R/Bioconductor downstream analysis solutions. SPEAQeasy is user-friendly and lowers the computational-domain entry barrier for biologists and clinicians to RNA-seq data processing as the main input file is a table with sample names and their corresponding FASTQ files. SPEAQeasy is portable across computational frameworks (SGE, SLURM, local, docker integration) and different configuration files are provided.
The effect of acidic pH on the interaction and lytic activity of MP1 and its H-MP1 analog in anionic lipid membrane: a biophysical study by Molecular Dynamics and Spectroscopy
Authors: Martins Ingrid Bernardes Santana , Viegas Taisa Giordano , de Souza Bibiana Monson , Palma Mário Sérgio , Neto João Ruggiero , de Araujo Alexandre Suman 
Published: December 2020

AbstractAntimicrobial peptides (AMPs) are part of the innate immune system of many species and are compounds with potential application against the development of resistant bacterial strains promoted by conventional antibiotics. The AMPs are rich in cationic and hydrophobic residues and act directly on the lipidic phase of the cell membranes. The MP1 has a broad-spectrum bactericide activity in both Gram-negative and positive bacteria, not being hemolytic or cytotoxic. H-MP1 is a synthetic analog of MP1 with lysines replaced by histidines so that its net charge could be responsive to changes in solution pH. In the present work, we investigated the effect of the solution pH on the structural properties, in the adsorption and insertion, and on the lytic activity of these peptides in lipid bilayers mimicking the cell membrane of Gram-negative bacteria, using experimental and computational biophysical techniques. The results indicate that the lytic activity of H-MP1 is sensitive to pH, increasing to an acidic environment, matching that of MP1, which is not influenced by solution pH. Molecular Dynamic simulations indicated that the adsorption process of both peptides started by the interaction of the N-terminus with the bilayer, followed by the complete adsorption of the peptide laying parallel to the bilayer plane, inducing an increase in the peptide’s helical content enhancing peptides contact with the bilayer hydrophobic phase.
Genetic variation in aneuploidy prevalence and tolerance across theSaccharomyces cerevisiaephylogeny
Authors: Scopel Eduardo F.C. , Hose James , Bensasson Douda , Gasch Audrey P. 
Published: December 2020

ABSTRACTIndividuals carrying an aberrant number of chromosomes can vary widely in their expression of aneuploidy phenotypes. A major unanswered question is the degree to which an individual’s genetic makeup influences its tolerance of karyotypic imbalance. Here we took a population genetics perspective to investigate the selective forces influencing aneuploidy prevalence inSaccharomyces cerevisiaepopulations as a model for eukaryotic biology. We analyzed genotypic and phenotypic variation recently published for over 1,000S. cerevisiaestrains spanning dozens of genetically defined clades and ecological associations. Our results show that the prevalence of chromosome gain and loss varies by clade and can be better explained by differences in genetic background than ecology. The phylogenetic context of lineages showing high aneuploidy rates suggests that increased aneuploidy frequency arose multiple times inS. cerevisiaeevolution. Separate from aneuploidy frequency, analyzing growth phenotypes reveals that some backgrounds – such as European Wine strains – show fitness costs upon chromosome duplication, whereas other clades with high aneuploidy rates show little evidence of major deleterious effects. Our analysis confirms that chromosome amplification can produce phenotypic benefits that can influence evolutionary trajectories. These results have important implications for understanding genetic variation in aneuploidy prevalence in health, disease, and evolution.ARTICLE SUMMARYAneuploidy, an imbalance in the normal chromosome copy number, is detrimental during human development; yet individuals show substantial variability in their aneuploidy susceptibility, suggesting the influence of genetic background on aneuploidy tolerance. Scopelet al.employed a population genetic approach to address this question, analyzing over 1,000 publishedSaccharomyces cerevisiaegenomes. The results demonstrate that genetic background has a substantial effect on aneuploidy frequency and cellular tolerance of aneuploidy stress, presenting important new information on the forces that contribute to aneuploidy prevalence.
Chronic deep brain stimulation of the human nucleus accumbens region disrupts the stability of inter-temporal preferences
Authors: Wagner Ben J. , Schüller Canan B. , Schüller Thomas , Baldermann Juan C. , Kohl Sina , Visser-Vandewalle Veerle , Huys Daniel , Marx Milena , Kuhn Jens , Peters Jan 
Published: December 2020

AbstractWhen choosing between rewards that differ in temporal proximity (inter-temporal choice), human preferences are typically stable, constituting a clinically-relevant transdiagnostic trait. Here we show in patients undergoing deep brain stimulation (DBS) of the anterior limb of the internal capsule / nucleus accumbens region for treatment-resistant obsessivecompulsive disorder (OCD), that long-term chronic (but not phasic) DBS disrupts inter-temporal preferences. Hierarchical Bayesian modeling accounting for temporal discounting behavior across multiple time points allowed us to assess both short-term and long-term reliability of inter-temporal choice. In controls, temporal discounting was highly reliable, both long-term (6 months) and short-term (1 week). In contrast, in patients undergoing DBS, short-term reliability was high, but long-term reliability (6 months) was severely disrupted. Control analyses confirmed that this effect was not due to range restriction, the presence of OCD symptoms or group differences in choice stochasticity. Model-agnostic between- and within-subject analyses confirmed this effect. These findings provide initial evidence for long-term modulation of cognitive function via DBS and highlight a potential contribution of the human nucleus accumbens region to inter-temporal preference stability over time.Significance StatementChoosing between rewards that differ in temporal proximity is in part a stable trait with relevance for many mental disorders, and depends on prefrontal regions and regions of the dopamine system. Here we show that chronic deep brain stimulation (DBS) of the human anterior limb of the internal capsule / nucleus accumbens region for treatment-resistant obsessive compulsive disorder disrupts the stability of inter-temporal preferences. These findings show that chronic stimulation of one of the brain’s central motivational hubs can disrupt preferences thought to depend on this circuit.
Functional crosstalk between phosphorylation and disease-causing mutations in the cardiac sodium channel Nav1.5
Authors: Galleano Iacopo , Harms Hendrik , Choudhury Koushik , Khoo Keith , Delemotte Lucie , Pless Stephan Alexander 
Published: December 2020

AbstractThe voltage-gated sodium channel Nav1.5 initiates the cardiac action potential. Alterations of its activation and inactivation properties due to mutations can cause severe, life-threatening arrhythmias. Yet despite intensive research efforts, many functional aspects of this cardiac channel remain poorly understood. For instance, Nav1.5 undergoes extensive post-translational modificationin vivo, but the functional significance of these modifications is largely unexplored, especially under pathological conditions. This is because most conventional approaches are unable to insert metabolically stable post-translational modification mimics, thus preventing a precise elucidation of the contribution by these modifications to channel function. Here, we overcome this limitation by using protein semi-synthesis of Nav1.5 in live cells and carry out complementary molecular dynamics simulations. We introduce metabolically stable phosphorylation mimics on both WT and two pathogenic long-QT mutant channel backgrounds and decipher functional and pharmacological effects with unique precision. We elucidate the mechanism by which phosphorylation of Y1495 impairs steady-state inactivation in WT Nav1.5. Surprisingly, we find that while the Q1476R patient mutation does not affect inactivation on its own, it enhances the impairment of steady-state inactivation caused by phosphorylation of Y1495 through enhanced unbinding of the inactivation particle. We also show that both phosphorylation and patient mutations can impact Nav1.5 sensitivity towards the clinically used anti-arrhythmic drugs quinidine and ranolazine, but not flecainide. The data highlight that functional effects of Nav1.5 phosphorylation can be dramatically amplified by patient mutations. Our work is thus likely to have implications for the interpretation of mutational phenotypes and the design of future drug regimens.Significance statementThe cardiac sodium channel (Nav1.5) is crucial for generating a regular heartbeat. It is thus not surprising that mutations in its sequence have been linked to life-threatening arrhythmias. Interestingly, Nav1.5 activity can also be altered by posttranslational modifications, such as tyrosine phosphorylation. Our combination of protein engineering and molecular modeling studies has revealed that the detrimental effect of a long QT3 patient mutation is only exposed when a proximal tyrosine is phosphorylated. This suggests a dynamic crosstalk between the genetic mutation and a neighboring phosphorylation, a phenomenon that could be important in other classes of proteins. Additionally, we show that phosphorylation can affect the channel’s sensitivity towards clinically-relevant drugs, a finding that may prove important when devising patient-specific treatment plans.
Phagocytosis by stroma confounds co-culture studies
Authors: Herbst Sophie A. , Stolarczyk Marta , Becirovic Tina , Liu Yi , Kolb Carolin , Herling Marco , Müller-Tidow Carsten , Dietrich Sascha 
Published: December 2020

AbstractSignals provided by the microenvironment can modify and circumvent pathway activities that are therapeutically targeted by drugs. Bone marrow stromal cell co-culture models are frequently used to study the influence of the bone marrow niche on ex-vivo drug response. Here we show that mesenchymal stromal cells from selected donors and NKTert, a stromal cell line which is commonly used for co-culture studies with primary leukemia cells, extensively phagocytose apoptotic cells. This could lead to misinterpretation of the results, especially if the viability readout of the target cells in such co-culture models is based on the relative proportions of dead and alive cells. Future co-culture studies which aim to investigate the impact of bone marrow stromal cells on drug response should take into account that stromal cells have the capacity to phagocytose apoptotic cells.
Effects of early life adversity on maternal effort and glucocorticoids in wild olive baboons
Authors: Patterson Sam K. , Hinde Katie , Bond Angela B. , Trumble Benjamin C. , Strum Shirley C. , Silk Joan B. 
Published: December 2020

AbstractAdverse experiences during early life exert important effects on development, health, reproduction, and social bonds, with consequences often persisting across generations. A mother’s early life experiences can impact her offspring’s development through a number of pathways, such as maternal care, physiological signaling through glucocorticoids, or even intergenerational effects like epigenetic inheritance. Early life adversity in female yellow baboons (Papio cynocephalus) predicts elevated glucocorticoids, reduced sociality, shortened lifespan, and higher offspring mortality. If baboon mothers with more early life adversity, experience poorer condition and struggle to provide for their offspring, this could contribute to the persisting transgenerational effects of adversity. Here, we examined the effects of mothers’ early life adversity on their maternal effort, physiology, and offspring survivability in a population of olive baboons,Papio anubis.Mothers who experienced more adversity in their own early development exerted greater maternal effort (i.e., spent more time nursing and carrying) and had higher glucocorticoid metabolites than mothers with less early life adversity. Offspring of mothers with more early life adversity had reduced survivability compared to offspring of mothers with less early life adversity. There was no evidence that high maternal social rank buffered against the effects of early life adversity. Our data suggest early life experiences can have lasting consequences on maternal effort and physiology, which may function as proximate mechanisms for intergenerational effects of maternal experience.
TCRMatch: Predicting T-cell receptor specificity based on sequence similarity to previously characterized receptors
Authors: Chronister William D. , Crinklaw Austin , Mahajan Swapnil , Vita Randi , Kosaloglu-Yalcin Zeynep , Yan Zhen , Greenbaum Jason A. , Jessen Leon E. , Nielsen Morten , Christley Scott , Cowell Lindsay G. , Sette Alessandro , Peters Bjoern 
Published: December 2020

ABSTRACTThe adaptive immune system in vertebrates has evolved to recognize non-self-antigens, such as proteins expressed by infectious agents and mutated cancer cells. T cells play an important role in antigen recognition by expressing a diverse repertoire of antigen-specific receptors, which bind epitopes to mount targeted immune responses. Recent advances in high-throughput sequencing have enabled the routine generation of T-cell receptor (TCR) repertoire data. Identifying the specific epitopes targeted by different TCRs in these data would be valuable. To accomplish that, we took advantage of the ever-increasing number of TCRs with known epitope specificity curated in the Immune Epitope Database (IEDB) since 2004. We compared six metrics of sequence similarity to determine their power to predict if two TCRs have the same epitope specificity. We found that a comprehensivek-mer matching approach produced the best results, which we have implemented into TCRMatch, an openly accessible tool (http://tools.iedb.org/tcrmatch/) that takes TCR β-chain CDR3 sequences as an input, identifies TCRs with a match in the IEDB, and reports the specificity of each match. We anticipate that this tool will provide new insights into T cell responses captured in receptor repertoire and single cell sequencing experiments and will facilitate the development of new strategies for monitoring and treatment of infectious, allergic, and autoimmune diseases, as well as cancer.
Single-cell RNA sequencing reveals distinct tumor microenvironmental patterns in lung adenocarcinoma
Authors: Bischoff Philip , Trinks Alexandra , Obermayer Benedikt , Pett Jan Patrick , Lehmann Annika , Jurmeister Philipp , Elsner Aron , Dziodzio Tomasz , Rückert Jens-Carsten , Neudecker Jens , Falk Christine , Beule Dieter , Sers Christine , Morkel Markus , Horst David , Blüthgen Nils , Klauschen Frederick 
Published: December 2020

AbstractRecent developments in immuno-oncology demonstrate that not only cancer cells, but also features of the tumor microenvironment guide precision medicine. Still, the relationship between tumor and microenvironment remains poorly understood. To overcome this limitation and identify clinically relevant microenvironmental and cancer features, we applied single-cell RNA sequencing to lung adenocarcinomas. While the highly heterogeneous carcinoma cell transcriptomes reflected histological grade and activity of relevant oncogenic pathways, our analysis revealed two distinct microenvironmental patterns. We identified a prognostically unfavorable group of tumors with a microenvironment composed of cancer-associated myofibroblasts, exhausted CD8+ T cells, proinflammatory monocyte-derived macrophages and plasmacytoid dendritic cells (CEP2pattern) and a prognostically favorable group characterized by myeloid dendritic cells, anti-inflammatory monocyte-derived macrophages, normal-like myofibroblasts, NK cells and conventional T cells (MAN2C pattern). Our results show that single-cell gene expression profiling allows to identify patient subgroups based on the tumor microenvironment beyond cancer cell-centric profiling.
Highly multiplexed imaging of biosensors in live cells
Authors: Yang Jr-Ming , Chi Wei-Yu , Liang Jessica , Iglesias Pablo , Huang Chuan-Hsiang 
Published: December 2020

AbstractFluorescent biosensors allow for real-time monitoring of biochemical activities in cells, but their multiplexing capacity is severely limited by the availability of spectral space. We overcome this problem by developing a set of barcoding proteins that are spectrally separable from commonly used FRET (fluorescence resonance energy transfer)-based and single-fluorophore biosensors. Mixed populations of barcoded cells expressing different biosensors can be concurrently imaged and computationally unmixed to achieve highly multiplexed tracking of biochemical activities in live cells.
Hippocampal cells multiplex positive and negative engrams
Authors: Shpokayte Monika , McKissick Olivia , Guan Xiaonan , Yuan Bingbing , Rahsepar Bahar , Fernandez Fernando R. , Ruesch Evan , Grella Stephanie L. , White John A. , Liu X. Shawn , Ramirez Steve 
Published: December 2020

AbstractThe hippocampus is involved in processing a variety of mnemonic computations specifically the spatiotemporal components and emotional dimensions of contextual memory.1–3Recent studies have demonstrated vast structural and functional heterogeneity along the dorsal-ventral axis1, 5of the hippocampus. The ventral hippocampus has been shown to be important in the processing of emotion and valence.6–9Here, we combine transgenic and all-virus based activity-dependent tagging strategies to visualize multiple valence-specific engrams in the vHPC and demonstrate two partially segregated cell populations and projections that respond to appetitive and aversive experiences. Next, using RNA sequencing and DNA methylation sequencing approaches, we find that vHPC appetitive and aversive engram cells display distinct transcriptional programs and DNA methylation landscapes compared to a neutral engram population. Additionally, while optogenetic manipulation of tagged cell bodies in vHPC is not sufficient to drive appetitive or aversive behavior in real-time place preference, stimulation of tagged vHPC terminals projecting to the amygdala and nucleus accumbens (NAc), but not the prefrontal cortex (PFC), had the capacity drive preference and avoidance. These terminals can also undergo a “switch” or “reset” in their capacity to drive either, thereby demonstrating their adaptable contributions to behavior. We conclude that the vHPC contains genetically, cellularly, and behaviorally distinct populations of cells processing appetitive and aversive memory engrams. Together, our findings provide a novel means by which to visualize multiple engrams within the same brain and point to their unique genetic signatures as reference maps for the future development of new therapeutic strategies.One sentence summaryThe hippocampus contains neurons that correspond to positive and negative engrams, which are segregated by their molecular, cellular, and projection-specific features.
Individual variation in tolerance of human activity by urban dark-eyed juncos (Junco hyemalis)
Authors: Stansell Hayley M. , Blumstein Daniel T. , Yeh Pamela J. , Nonacs Peter 
Published: December 2020

ABSTRACTAn important goal of urban ecology is determining what differentiates urban-tolerant populations of birds from their non-urban ancestors and urban-intolerant species. One key to urban success may be reacting appropriately to human activity, and the degree to which birds view humans as threats can be quantified by their escape behavior. Understanding individual-level plasticity, however, requires the tracking of known individuals. We compared flight-initiation distances (FID) and distances fled (DF) from approaches by a human across urban and non-urban populations of individually-marked Dark-eyed Juncos (Junco hyemalis) in southern California. The urban population is more tolerant to people as evidenced by attenuated FIDs and DFs relative to non-urban birds. Although individual urban birds either habituated or sensitized to repeated approaches, there was no significant pattern at the population level. Overall, the behavioral patterns exhibited by urban juncos are more supportive ofin situevolution than either being a biased sample from an ancestral non-urban population or intrinsic behavioral plasticity that produces a uniform adjustment to urban life.