bluuebunny/crossref_metadata_2025_split huggingface dataset:
Utilizing Computational Machine Learning Tools to Understand Immunogenic Breadth in the Context of a CD8 T-Cell Mediated HIV Response
Authors: McGowan Ed , Rosenthal Rachel , Fiore-Gartland Andrew , Macharia Gladys , Balinda Sheila , Kapaata Anne , Umviligihozo Gisele , Muok Erick , Dalel Jama , Streatfield Claire , Coutinho Helen , Monaco Daniela C. , Morrison David , Yue Ling , Hunter Eric , Nielsen Morten , Gilmour Jill , Hare Jonathan 
Published: August 2020

ABSTRACTPredictive models are becoming more and more commonplace as tools for candidate antigen discovery to meet the challenges of enabling epitope mapping of cohorts with diverse HLA properties. Here we build on the concept of using two key parameters, diversity metric of the HLA profile of individuals within a population and consideration of sequence diversity in the context of an individual’s CD8 T-cell immune repertoire to assess the HIV proteome for defined regions of immunogenicity. Using this approach, Analysis of HLA adaptation and functional immunogenicity data enabled the identification of regions within the proteome that offer significant conservation, HLA recognition within a population, low prevalence of HLA adaptation and demonstrated immunogenicity. We believe this unique and novel approach to vaccine design that, in combination with in vitro functional assays, offers a bespoke pipeline for expedited and rational CD8 T-cell vaccine design for HIV and potentially other pathogens with the potential for both global and local coverage.
Fibroblasts close a void in free space by a purse-string mechanism
Authors: Da Costa Avelino Dos Santos , Subbiah Ramesh , Oh Seung Ja , Jeong Hyun Tae , Na Jung-Im , Park Kwideok , Shin Jennifer Hyunjong , Choi In-Suk 
Published: August 2020

AbstractHow stromal cells fill voids in wounded tissue remains one of the most fundamental questions in regenerative medicine. Fibroblasts are known to fill voids by depositing extracellular matrix (ECM) proteins while migrating towards the wound site; however, their ability to adopt an epithelial-like purse-string behaviour remains unexplored. Here, we fabricated an artificial wound with a deep void space to investigate fibroblasts’ behaviour during gap closure. We found that fibroblasts can form a free-standing bridge on deep microvoids and consequently close the void through the purse-string contraction, which was previously believed to be exclusively an epithelial wound closure mechanism. The results also revealed that the fibroblast gap closure in our fabricated 3D artificial wound depends on myosin II-mediated contractility and intercellular adherent junctions. Our study reveals that stromal cells can gain the structural features of epithelial cells, namely, intercellular contractile rings, to fulfil their functions under the specific microenvironmental conditions of tissue repair. Furthermore, fibroblasts can close artificial wounds with gap widths up to 300 μm, approximately twice as large as the critical epithelial gap closure size on non-adherent substrates. Fibroblasts exhibited a zip-up gap closure mechanism with a geometrical size effect. These findings reveal a new mechanism for gap closure by stromal cells during wound healing and pave a way to groundbreaking therapeutic strategies for tissue repair.
TISCH: a comprehensive web resource enabling interactive single-cell transcriptome visualization of tumor microenvironment
Authors: Sun Dongqing , Wang Jin , Han Ya , Dong Xin , Zheng Rongbin , Ge Jun , Shi Xiaoying , Wang Binbin , Li Ziyi , Ren Pengfei , Sun Liangdong , Yan Yilv , Zhang Peng , Zhang Fan , Li Taiwen , Wang Chenfei 
Published: August 2020

AbstractCancer immunotherapy targeting co-inhibitory pathways by checkpoint blockade shows remarkable efficacy in a variety of cancer types. However, only a minority of patients respond to treatment due to the stochastic heterogeneity of tumor microenvironment (TME). Recent advances in single-cell RNA-seq technologies enabled comprehensive characterization of the immune system heterogeneity in tumors, but also posed computational challenges on how to integrate and utilize the massive published datasets to inform immunotherapy. Here, we present Tumor Immune Single Cell Hub (TISCH,http://tisch.comp-genomics.org), a large-scale curated database that integrates single-cell transcriptomic profiles of nearly two million cells from 76 high-quality tumor datasets across 28 cancer types. All the data were uniformly processed with a standardized workflow, including quality control, batch effect removal, malignant cell classification, cell clustering, cell-type annotation, differential expression analysis, and functional enrichment analysis. TISCH provides interactive gene expression visualization across multiple datasets at the single-cell level or cluster level, allowing systematic comparison between different cell-types, patients, tissue origins, treatment and response groups, and even different cancer-types. In summary, TISCH provides a user-friendly interface for systematically visualizing, searching, and downloading gene expression atlas in the TME from multiple cancer types, enabling fast, flexible and comprehensive exploration of the TME.
Antioxidant nanozyme counteracts HIV-1 by modulating intracellular redox potential
Authors: Singh Shalini , Ghosh Sourav , Pal Virender Kumar , Munshi MohamedHusen , Rajmani Raju S , Mugesh Govindasamy , Singh Amit 
Published: August 2020

AbstractReactive oxygen species (ROS) regulates the proliferation of human immunodeficiency virus (HIV-1) andMycobacterium tuberculosis(Mtb) inside the infected immune cells. However, the application of this knowledge to develop therapeutic strategies remained unsuccessful due to unfavorable consequences of manipulating cellular antioxidant systems that respond to ROS. Here, we show that vanadium pentoxide (V2O5) nanosheets functionally mimic the activity of natural glutathione peroxidase (GPX) to mitigate ROS associated with HIV-1 infection without triggering detrimental changes in cellular physiology. Using genetic reporters of glutathione (GSH) redox potential (EGSH; Grx1-roGFP2) and H2O2(Orp1-roGFP2), we showed that V2O5-nanosheets catalyze GSH-dependent neutralization of ROS in HIV-1 infected cells. Notably, V2O5-nanosheets uniformly blocked HIV-1 reactivation, multiplication, and impaired survival of drug-resistantMtbduring HIV-TB co-infection. Mechanistically, V2O5-nanosheets suppressed HIV-1 by affecting the expression of pathways coordinating redox balance, virus transactivation (e.g.,NF-κB and FOS), inflammation, and apoptosis. Importantly, a combination of V2O5-nanosheets with a pharmacological inhibitor of NF-κB (BAY11-7082) abrogated activation of HIV-1 from latency. Lastly, V2O5-nanosheets counteracted ROS, disease pathophysiology, and virus expression in HIV-1 transgenic mice. Our data successfully revealed the usefulness of V2O5-nanosheets against human pathogens and suggest nanozymes as future platforms to develop interventions against infectious diseases.Significance StatementRedox stress, such as those caused by the deregulation of the antioxidant glutathione, promotes the multiplication of human immunodeficiency virus-1 (HIV-1) andMycobacterium tuberculosis(Mtb). Here we present a vanadium pentoxide (V2O5)-based antioxidant nanozyme that targets cells infected with HIV-1. The nanozyme, by mimicking the activity of glutathione peroxidase, reprograms redox signaling to subvert HIV-1 from monocytes, lymphocytes, and HIV-1 transgenic mice. Treatment with nanozyme bolsters the antiviral potential of immune cells by reducing the expression of genes involved in virus activation, inflammation, and apoptosis. The nanozyme also inhibited the proliferation ofMtb, which is a major cause of lethality in HIV patients. These V2O5-based nanozymes may be applied to numerous human pathogens where redox signaling contributes to disease progression.
Structural evolution of the tissue-specific U2AF2 paralog and alternative splicing factor LS2
Authors: Kawale Ashish Ashok , Taliaferro J. Matthew , Kang Hyun-Seo , Hartmüller Christoph , Geerlof Arie , Stehle Ralf , Burge Christopher , Rio Donald C. , Sattler Michael 
Published: August 2020

AbstractTheDrosophila melanogasterLS2 protein is a tissue-specific paralog of U2AF2 that mediates testis-specific alternative splicing. In order to understand the structural mechanisms underlying the distinct RNA binding specificity we determined the solution structures of the LS2 RNA recognition motif (RRM) domains and characterized their interaction withcis-regulatory guanosine-rich RNA motifs found in intron regions upstream of alternatively spliced exons. We show that the guanosine-rich RNA adopts a G quadruplex (G4) foldin vitro. The LS2 tandem RRMs adopt canonical RRM folds that are connected by a 38-residue linker that harbors a small helical motif α0. The LS2 RRM2 domain and the α0helix in the interdomain linker mediate interactions with the G4 RNA. The functional importance of these unique molecular features in LS2 is validated by mutational analysisin vitroand RNA splicing assaysin vivo. RNA sequencing data confirm the enrichment of G4-forming LS2 target motifs near LS2-affected exons. Our data indicate a role of G quadruplex structures ascis-regulatory motifs in introns for the regulation of alternative splicing, that engage non-canonical interactions with a tandem RRM protein. These results highlight the intriguing molecular evolution of a tissue-specific splicing factor from its conserved U2AF2 paralog as a result of (retro-) gene duplication inD. melanogaster.
A universal formula for avian egg shape
Authors: Narushin Valeriy G. , Romanov Michael N. , Griffin Darren K. 
Published: August 2020

AbstractThe bird’s oomorphology has far escaped mathematical formulation universally applicable. All bird egg shapes can be laid in four basic geometric figures: sphere, ellipsoid, ovoid, and pyriform (conical/pear-shaped). The first three have a clear mathematical definition, each derived from expression of the previous, but a formula for the pyriform profile has yet to be inferred. To rectify this, we introduced an additional function into the ovoid formula. The subsequent mathematical model fits a completely novel geometric shape that can be characterized as the last stage in the evolution of the sphere—ellipsoid—Hügelschäffer’s ovoid transformation applicable to any avian egg shape geometry. Required measurements are the egg length, maximum breadth, and diameter at the terminus from the pointed end. This mathematical description is invariably a significant step in understanding not only the egg shape itself, but how and why it evolved, thus making widespread biological and technological applications theoretically possible.
Climate change and the migration of a pastoralist people c.3500 cal. years BP inferred from palaeofire and lipid biomarker records in the montane Western Ghats, India
Authors: Kavil Sarath Pullyottum , Ramya Bala Prabhakaran , Kumar Pankaj , Ghosh Devanita , Sukumar Raman 
Published: August 2020

AbstractHuman migration in response to climate change during the Holocene has been recorded in many regions of the world. The Todas are a pastoralist people who are believed to have colonized the higher elevations (>2000 m asl) of the Nilgiris in the Western Ghats, India, not earlier than about 2000 cal. yr BP. Vegetation shifts in response to changing climate in tropical montane forest-grassland mosaic of the Ghats have been well documented using stable carbon isotopes and pollen profiles; however, there have been no corresponding investigations of human presence and activity at the highest elevations. We used a number of other proxies to infer the human ecology of this montane region. Radiocarbon dated (~22,000 cal. BP to the present) peat samples from the Sandynallah basin (2200m asl, Nilgiri hills, Tamil Nadu State) were used to reconstruct fire history, animal abundance, and human presence since the Last Glacial Maximum (LGM). While the macro-charcoal record indicates fires at the LGM, macro- and micro-charcoal counts indicate intense fire at ~3500 cal. yr BP, coprophilous fungal spores indicate a large population of herbivorous mammals, and steroid biomarkers indicate human faecal remains for the first time. This period is also characterized by dry arid conditions and dominant grassy vegetation as inferred from n-alkane signatures. We thus infer that a pastoralist people, most likely the Todas, migrated to the highest elevations of the Western Ghats along with their buffalo herds in response to prolonged or abrupt climate change in peninsular India, about 3500 cal. yr BP or at least 1500 years prior to what historical accounts assume.
Comparative morphology of the corpus callosum across the adult lifespan in chimpanzees (Pan troglodytes) and humans
Authors: Westerhausen René , Fjell Anders M. , Kompus Kristiina , Schapiro Steven J. , Sherwood Chet , Walhovd Kristine B. , Hopkins William D. 
Published: August 2020

AbstractThe human corpus callosum exhibits substantial atrophy in old age, which is stronger than what would be predicted from parallel changes in overall brain anatomy. To date, however, it has not been conclusively established whether this accentuated decline represents a common feature of brain aging across species, or whether it is a specific characteristic of the aging human brain. In the present cross-sectional study, we address this question by comparing age-related difference in corpus callosum morphology of chimpanzees and humans. For this purpose, we measured total midsagittal area and regional thickness of the corpus callosum from T1-weighted MRI data from 213 chimpanzees, aged between 9 and 54 years. The results were compared with data drawn from a large-scale human samples which was age-range matched using two strategies: (a) matching by chronological age (human sample size: n = 562), or (b) matching by accounting for differences in longevity and various maturational events between the species (i.e., adjusted human age range: 13.6 to 80.9 years; n = 664). Using generalized additive modelling to fit and compare aging trajectories, we found significant differences between the two species. The chimpanzee aging trajectory compared to the human trajectory was characterized by a slower increase from adolescence to middle adulthood, and by a lack of substantial decline from middle to old adulthood, which, however, was present in humans. Thus, the accentuated decline of the corpus callosum found in aging humans, is not an universal characteristic of the aging brain, and appears to be human-specific.
Wavelet coherence phases decode the universal switching mechanism of Ras GTPase superfamily
Authors: Motiwala Zenia , Sandholu Anand S. , Sengupta Durba , Kulkarni Kiran 
Published: August 2020

AbstractRas superfamily GTPases are molecular switches which regulate critical cellular processes. Extensive structural and computational studies on these G proteins have established a general framework for their switching mechanism, which involves conformational changes in their two loops, Switch I and Switch II, upon GTP binding and hydrolysis. Since the extent of these conformational changes is not uniform amongst the members of the Ras superfamily, there is no genericmodus operandidefining their switching mechanism. Here, we have developed a novel approach employing wavelet coherence analysis to correlate the structural changes with their functional states. Our analysis shows that the structural coupling between the Switch I and Switch II regions is manifested in terms of conserved wavelet coherence phases, which could serve as useful parameters to define functional states of the GTPases. In oncogenic GTPases mutants, this phase coupling gets disentangled, which perhaps provides an alternative explanation for their aberrant function. We have tested the statistical significance of the observed phase angle correlations on multiple switch region conformers, generated through MD simulations.
Bixafen, a succinate dehydrogenase inhibitor fungicide, causes microcephaly and motor neuron axon defects during development
Authors: Brenet Alexandre , Hassan-Abdi Rahma , Soussi-Yanicostas Nadia 
Published: August 2020

AbstractSuccinate dehydrogenase inhibitors (SDHIs), the most widely used fungicides in agriculture today, act by blocking succinate dehydrogenase (SDH), an essential and evolutionarily conserved component of mitochondrial respiratory chain. Recent results showed that several SDHIs used as fungicides not only inhibit the SDH activity of target fungi but also block this activity in human cells inin vitromodels, revealing a lack of specificity and thus a possible health risk for exposed organisms, including humans. Despite the frequent detection of SDHIs in the environment and on harvested products and their increasing use in modern agriculture, their potential toxic effectsin vivo, especially on neurodevelopment, are still under-evaluated. Here we assessed the neurotoxicity of bixafen, one of the latest-generation SDHIs, which had never been tested during neurodevelopment. For this purpose, we used a well-known vertebrate model for toxicity testing, namely zebrafish transparent embryos, and live imaging using transgenic lines labelling the brain and spinal cord. Here we show that bixafen causes microcephaly and defects on motor neuron axon outgrowth and their branching during development. Our findings show that the central nervous system is highly sensitive to bixafen, thus demonstratingin vivothat bixafen is neurotoxic in vertebrates and causes neurodevelopmental defects. This work adds to our knowledge of the toxic effect of SDHIs on neurodevelopment and may help us take appropriate precautions to ensure protection against the neurotoxicity of these substances.
Evidence-based gene expression modulation correlates with transposable element knock-down
Authors: Hernandes-Lopes José , Quintanilha Danielle M. , de Jesus Erika M. , Lopes Fabrício M. , Parmigiani Raphael B. , Karolski Bruno , Dias Henrique M. , Jacobs Thomas B. , Camargo Anamaria A. , Kitajima João P. , Van Sluys Marie-Anne 
Published: August 2020

ABSTRACTBackgroundTransposable elements (TEs) are major components of plant genomes. Despite being regarded as “junk DNA” at first, TEs play important roles for the organisms they are found in. The most obvious and easily recognizable effects caused by TEs result from their mobility, which can disrupt coding sequences or promoter regions. However, with the recent advances in transcriptomics, it is becoming increasingly evident that TEs can act as an additional layer of gene expression regulation through a number of processes, which can involve production of non-coding RNAs. Here, we describe how Tnt1, a stress-responsive LTR-retrotransposon, interferes with gene expression and modulate a number of developmental aspects in tobacco.ResultsThrough an RNAi approach, we generated tobacco (HP) lines knocked-down for Tnt1 expression. Quantitative RT-PCR experiments confirm that Tnt1 is downregulated in HP lines after ethylene exposure. A RNA-seq experiment was performed and through two independent bioinformatic approaches (with different stringencies) we found 932 and 97 differentially expressed genes in HP lines. A number of phenotypes were observed in such lines, namely lesion mimicry in leaves, underdevelopment of the root system, overproduction of root hairs and early loss of seed viability. Folding prediction of part of the Tnt1 mRNA reveals putative stem-loop secondary structures containing transcriptional regulation sequences, suggesting it could be a source of small RNAs. We also propose a model to explain the Tnt1 expression in both homeostatic and stress conditions, and how it could interact with stress-responsive genes.ConclusionsOur results are consistent that interferences with Tnt1 transcript levels correlate with transcriptomic and phenotypic changes, suggesting a functional role for this element during plant development and stress response.
Ligand Effects on Phase Separation of Multivalent Macromolecules
Authors: Ruff Kiersten M. , Dar Furqan , Pappu Rohit V. 
Published: August 2020

AbstractBiomolecular condensates enable spatial and temporal control over cellular processes by concentrating biomolecules into non-stoichiometric assemblies. Many condensates form via reversible phase transitions of condensate-specific multivalent macromolecules known as scaffolds. Phase transitions of scaffolds can be regulated by changing the concentrations of ligands, which are defined as non-scaffold molecules that bind to specific sites on scaffolds. Here, we use theory and computation to uncover rules that underlie ligand-mediated control over scaffold phase behavior. We use thestickers-and-spacersmodel wherein reversible non-covalent crosslinks among stickers drive phase transitions of scaffolds, and spacers modulate the driving forces for phase transitions. We find that the modulatory effects of ligands are governed by: the valence of ligands; whether they bind directly to stickers versus spacers; and the relative affinities of ligand-scaffold versus scaffold-scaffold interactions. In general, all ligands have a diluting effect on the concentration of scaffolds within condensates. Whereas monovalent ligands destabilize condensates, multivalent ligands can stabilize condensates by binding directly to spacers or destabilize condensates by binding directly to stickers. Bipartite ligands that bind to stickers and spacers can alter the structural organization of scaffold molecules within condensates even when they have a null effect on condensate stability. Our work highlights the importance of measuring dilute phase concentrations of scaffolds as a function of ligand concentration in cells. This can reveal whether ligands modulate scaffold phase behavior by enabling or suppressing phase separation at endogeneous levels thereby regulating the formation and dissolution of condensatesin vivo.SignificancePhase transitions of multivalent macromolecules known as scaffolds help drive the formation of functional biomolecular condensates in cells. The formation and dissolution of condensates is tightly regulated, as aberrant phase behavior is associated with disease. Here, we show that distinct types of ligands can exert control over the formation and dissolution of condensates by binding to distinct sites on scaffold molecules. We further show that the extent and direction of regulation can be inferred through direct measurements of how ligands impact scaffold phase boundaries. Our findings have broad implications for understanding and modeling ligand-mediated regulation of condensates in cells, and for designing novel molecules that exert regulatory control over condensates.
Evolution of multicellularity and unicellularity in yeastS. cerevisiaeto study reversibility of evolutionary trajectories
Authors: Alugoju Phaniendra , Mahilkar Anjali , Saini Supreet 
Published: August 2020

AbstractAdaptive trajectories of populations have been focus of number of studies. However, adaptive trajectories have not been studied in the context of reverse evolution. By reverse evolution, we mean a scenario where selection is reversed. In this work, we use evolution (and reversal from) of multicellularity inS. cerevisiaeas a model to answer this question. When selected for fast-settling variants, multicellularity evolves rapidly in the organism. On reversing selection, unicellularity evolves from the multicellular clusters. However, the dynamic trajectories of the two processes are different. In this context, evolution is not reversed dynamically at a phenotypic level. The phenotypic reversal is not driven by reversal of the original mutations during the forward evolution. Overall, our results show that the dynamics of molecular and phenotypic trajectories of evolution are distinct, and reversal of selection leads to unique trajectories of phenotypic reversal.