bluuebunny/crossref_metadata_2025_split huggingface dataset:
Distinct cellular origins and differentiation process account for distinct oncogenic and clinical behaviors of leiomyosarcomas
Authors: Darbo Elodie , Pérot Gaëlle , Darmusey Lucie , Guellec Sophie Le , Leroy Laura , Gaston Laëtitia , Desplat Nelly , Thébault Noémie , Merle Candice , Rochaix Philippe , Valentin Thibaud , Ferron Gwenaël , Chevreau Christine , Bui Binh , Stoeckle Eberhard , Ranchere-Vince Dominique , Méeus Pierre , Terrier Philippe , Piperno-Neumann Sophie , Collin Françoise , Pinieux Gonzague De , Duffaud Florence , Coindre Jean-Michel , Blay Jean-Yves , Chibon Frédéric 
Published: October 2020

AbstractIn leiomyosarcoma (LMS), a very aggressive disease, a relatively transcriptionally uniform subgroup of well differentiated tumors has been described and is associated with poor survival. The question raised how differentiation and tumor progression, two apparently antagonist processes, coexist and allow tumor malignancy. We first identified the most transcriptionally homogeneous LMS subgroup in three independent cohorts, which we named ‘hLMS’. The integration of multi-omics data and functional analysis suggests that hLMS originate from vascular smooth muscle cells and show that hLMS transcriptional program reflects both modulation of smooth muscle contraction activity controlled by MYOCD/SRF regulatory network and activation of the cell cycle activity controlled by E2F/RB1 pathway. We propose that the phenotypic plasticity of vascular smooth muscle cells coupled with MYOCD/SRF pathway amplification, essential for hLMS survival, concomitant with PTEN absence andRB1alteration, could explain how hLMS balance this uncommon interplay between differentiation and aggressiveness.
Learning sparse codes from compressed representations with biologically plausible local wiring constraints
Authors: Fallah Kion , Willats Adam A. , Liu Ninghao , Rozell Christopher J. 
Published: October 2020

AbstractSparse coding is an important method for unsupervised learning of task-independent features in theoretical neuroscience models of neural coding. While a number of algorithms exist to learn these representations from the statistics of a dataset, they largely ignore the information bottlenecks present in fiber pathways connecting cortical areas. For example, the visual pathway has many fewer neurons transmitting visual information to cortex than the number of photoreceptors. Both empirical and analytic results have recently shown that sparse representations can be learned effectively after performing dimensionality reduction with randomized linear operators, producing latent coefficients that preserve information. Unfortunately, current proposals for sparse coding in the compressed space require a centralized compression process (i.e., dense random matrix) that is biologically unrealistic due to local wiring constraints observed in neural circuits. The main contribution of this paper is to leverage recent results on structured random matrices to propose a theoretical neuroscience model of randomized projections for communication between cortical areas that is consistent with the local wiring constraints observed in neuroanatomy. We show analytically and empirically that unsupervised learning of sparse representations can be performed in the compressed space despite significant local wiring constraints in compression matrices of varying forms (corresponding to different local wiring patterns). Our analysis verifies that even with significant local wiring constraints, the learned representations remain qualitatively similar, have similar quantitative performance in both training and generalization error, and are consistent across many measures with measured macaque V1 receptive fields.
Epigenetics and expression of key genes associated with cardiac fibrosis:NLRP3, MMP2, MMP9, CCN2/CTGF, andAGT
Authors: Chandra Sruti , Ehrlich Kenneth C. , Lacey Michelle , Baribault Carl , Ehrlich Melanie 
Published: October 2020

AbstractExcessive inflammatory signaling and pathological remodeling of the extracellular matrix are important contributors to cardiac fibrosis and involve major changes in gene expression. We examined the relationships between tissue-specific expression and the epigenetics of five genes involved in these pathways,NLRP3, MMP2, MMP9, CCN2/CTGF,andAGT.The proteins encoded by these genes play major fibrosis-related roles in inflammasome formation, degradation of extracellular matrix proteins and remodeling of the extracellular matrix and vasculature, autocrine regulation of fibrosis, or cell signaling. Our analyses showed that the first four of these genes had super-enhancers (unusually strong enhancer clusters) that correlate with their very high expression in monocytes, neutrophils, fibroblasts, or venous cells. Expression of the gene encoding miR-223, a micro-RNA that plays an important role in downregulating NLRP3 protein levels, is also probably driven by the super-enhancer in which it is embedded. Enhancer chromatin for all these genes was inside as well as outside the gene body. WhileAGT,which encodes precursors of angiotensin II, lacked a super-enhancer, its tissue-specific expression profile correlates with the tissue-specific enhancer chromatin extending into its distant silent gene neighbor (CAPN9). Tissue-specific peaks of DNA hypomethylation, open chromatin (DNaseI hypersensitivity), and transcription factor binding were detected in subregions of these super-enhancers/enhancers that are likely to be the main drivers of expression of their associated gene. We found thatCCN2/CTGFis co-expressed with its far-upstream neighborLINC01013, a noncoding RNA gene, specifically in vein endothelial cells (HUVEC) and chondrocytes. Evidence from chromatin looping profiling (Hi-C) suggests coregulation of these genes in HUVEC. Our findings indicate the importance of understanding the often-overlooked roles of enhancers and their hypomethylated, transcription factor-binding subregions in the regulation of expression of fibrosis-related genes in normal and fibrotic tissue.
A derivative of the D5 monoclonal antibody that targets the gp41 N-heptad repeat of HIV-1 with broad tier-2 neutralizing activity
Authors: Rubio Adonis A. , Filsinger Interrante Maria V. , Bell Benjamin N. , Brown Clayton L. , LaBranche Celia C. , Montefiori David C. , Kim Peter S. 
Published: October 2020

AbstractHIV-1 infection is initiated by the viral glycoprotein Env, which, after interaction with cellular coreceptors, adopts a transient conformation known as the pre-hairpin intermediate (PHI). The N-heptad repeat (NHR) is a highly conserved region of gp41 exposed in the PHI; it is the target of the FDA-approved drug enfuvirtide and of neutralizing monoclonal antibodies (mAbs). However, to date these mAbs have only been weakly effective against tier-1 HIV-1 strains, which are most sensitive to neutralizing antibodies. Here, we engineered and tested 11 IgG variants of D5, an anti-NHR mAb, by recombining previously described mutations in four of D5’s six antibody complementarity-determining regions. One variant, D5_AR, demonstrated 6-fold enhancement in ID50against lentivirus pseudotyped with HXB2 Env. Importantly, D5_AR exhibited weak cross-clade neutralizing activity against a diverse set of tier-2 HIV-1 viruses, which are less sensitive to neutralizing antibodies than tier-1 viruses and are the target of current antibody-based vaccine efforts. In addition, the neutralization potency of D5_AR IgG was greatly enhanced in target cells expressing FcγRI with ID50values below 0.1 μg/mL; this immunoglobulin receptor is expressed on macrophages and dendritic cells, which are implicated in the early stages of HIV-1 infection of mucosal surfaces. D5 and D5_AR have equivalent neutralization potency in IgG, Fab, and scFv formats, indicating that neutralization is not impacted by steric hindrance. Taken together, these results provide support for vaccine strategies that target the PHI by eliciting antibodies against the gp41 NHR.ImportanceDespite advances in anti-retroviral therapy, HIV remains a global epidemic and has claimed more than 32 million lives. Accordingly, developing an effective vaccine remains an urgent public health need. The gp41 N-heptad repeat (NHR) of the HIV-1 pre-hairpin intermediate (PHI) is highly conserved (>90%) and is inhibited by the FDA-approved drug enfuvirtide, making it an attractive vaccine target. However, to date NHR antibodies have not been potent. Here, we engineered D5_AR, a more potent variant of the anti-NHR antibody D5, and established its ability to inhibit HIV-1 strains that are more difficult to neutralize and are more representative of circulating strains (tier-2 strains). The neutralizing activity of D5_AR was greatly potentiated in cells expressing FcγRI; FcγRI is expressed on cells that are implicated at the earliest stages of sexual HIV-1 transmission. Taken together, these results bolster efforts to target the gp41 NHR and the PHI for vaccine development.
CSF-1 maintains pathogenic but not homeostatic myeloid cells in the central nervous system during autoimmune neuroinflammation
Authors: Hwang Daniel , Seyedsadr Maryam S. , Ishikawa Larissa Lumi Watanabe , Boehm Alexandra , Sahin Ziver , Casella Giacomo , Jang Soohwa , Gonzalez Michael V. , Garifallou James P. , Hakonarson Hakon , Zhang Weifeng , Xiao Dan , Rostami Abdolmohamad , Zhang Guang-Xian , Ciric Bogoljub 
Published: October 2020

ABSTRACTThe receptor for colony stimulating factor 1 (CSF-1R) is important for the survival and function of myeloid cells that mediate pathology during experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). CSF-1 and IL-34, the ligands of CSF-1R, have similar bioactivities but distinct tissue and context-dependent expression patterns, suggesting that they have different roles. This could be the case in EAE, given that CSF-1 expression is upregulated in the CNS, while IL-34 remains constitutively expressed. We found that targeting CSF-1 with neutralizing mAb halted ongoing EAE, with efficacy superior to CSF-1R inhibitor BLZ945, whereas IL-34 neutralization had no effect, suggesting that pathogenic myeloid cells were maintained by CSF-1, not IL-34. Both anti-CSF-1- and BLZ945-treatment greatly reduced numbers of monocyte-derived cells and microglia in the CNS. However, anti-CSF-1 selectively depleted inflammatory microglia and monocytes in inflamed CNS areas, whereas BLZ945 depleted virtually all myeloid cells, including quiescent microglia, throughout the CNS. Anti-CSF-1 treatments reduced the size of demyelinated lesions, and microglial activation in the grey matter. Lastly, we found that bone marrow-derived immune cells were the major mediators of CSF-1R-dependent pathology, while microglia played a lesser role. Our findings suggest that targeting CSF-1 could be effective in ameliorating MS pathology, while preserving the homeostatic functions of myeloid cells, thereby minimizing risks associated with total ablation of CSF-1R-dependent cells.Significance StatementMultiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are autoimmune diseases characterized by accumulation of myeloid immune cells into the central nervous system (CNS). Both harmful and beneficial myeloid cells are present in EAE/MS, and a goal of MS therapy is to preferentially remove harmful myeloid cells. The receptor for CSF-1 (CSF-1R) is found on myeloid cells and it is important for their survival. CSF-1R can bind two ligands, CSF-1 and IL-34, but is unknown whether their functions in EAE/MS differ. We found that blocking CSF-1 depleted only harmful myeloid cells in the CNS and suppressed EAE, whereas blocking IL-34 had no effect. Thus, we propose that blocking CSF-1 could be a novel therapy for MS.
Emergent robustness of bacterial quorum sensing in fluid flow
Authors: Dalwadi Mohit P. , Pearce Philip 
Published: October 2020

AbstractBacteria use intercellular signaling, or quorum sensing (QS), to share information and respond collectively to aspects of their surroundings. The autoinducers that carry this information are exposed to the external environment; consequently, they are affected by factors such as removal through fluid flow, a ubiquitous feature of bacterial habitats ranging from the gut and lungs to lakes and oceans. To understand how QS genetic architectures in cells promote appropriate populationlevel phenotypes throughout the bacterial life cycle requires knowledge of how these architectures determine the QS response in realistic spatiotemporally varying flow conditions. Here, we develop and apply a general theory that identifies and quantifies the conditions required for QS activation in fluid flow by systematically linking cell- and population-level genetic and physical processes. We predict that, when a subset of the population meets these conditions, cell-level positive feedback promotes a robust collective response by overcoming flow-induced autoinducer concentration gradients. By accounting for a dynamic flow in our theory, we predict that positive feedback in cells acts as a low-pass filter at the population level in oscillatory flow, allowing a population to respond only to changes in flow that occur over slow enough timescales. Our theory is readily extendable, and provides a framework for assessing the functional roles of diverse QS network architectures in realistic flow conditions.
Spaceflight decelerates the epigenetic clock orchestrated with a global alteration in DNA methylome and transcriptome in the mouse retina
Authors: Chen Zhong , Stanbouly Seta , Nishiyama Nina C. , Chen Xin , Delp Michael D. , Qiu Hongyu , Mao Xiao W. , Wang Charles 
Published: October 2020

AbstractAstronauts exhibit an assortment of clinical abnormalities in their eyes during long-duration spaceflight. The purpose of this study was to determine whether spaceflight induces epigenomic and transcriptomic reprogramming in the retina or alters the epigenetic clock. The mice were flown for 37 days in animal enclosure modules on the International Space Station; ground-based control animals were maintained under similar housing conditions. Mouse retinas were isolated and both DNA methylome and transcriptome were determined by deep sequencing. We found that a large number of genes were differentially methylated with spaceflight, whereas there were fewer differentially expressed genes at the transcriptome level. Several biological pathways involved in retinal diseases such as macular degeneration were significantly altered. Our results indicated that spaceflight decelerated the retinal epigenetic clock. This study demonstrates that spaceflight impacts the retina at the epigenomic and transcriptomic levels, and such changes could be involved in the etiology of eye-related disorders among astronauts.
FloridaDrosophila melanogastergenomes sampled 13 years apart show increases in warm-associated SNP alleles
Authors: Veeramah Krishna R. , Brud Evgeny , Eanes Walter F. 
Published: October 2020

ABSTRACTWe studied genetic change inDrosophila melanogasterusing whole-genome SNP data from samples taken 13 years apart in Homestead, FL. This population is at the southern tip of a well-studied US latitudinal cline. On the non-inversion-carrying chromosome arms, 11-16% of SNPs show significant frequency changes. These are enriched for latitudinal clines and genic sites. For clinal SNPs each allele is either the northern- or southern-favored. Seventy-eight to 95 percent with significant frequency increase are southern-favored. Five to seven percent of SNPs also show significant seasonal change and involve increases in the northern-favored allele during the season. On the 2L and 3R chromosome arms there are significant seasonal shifts for common inversions. We identify regions and genes that are candidates for selection. These regions also show correspondence with those associated with soft sweeps in Raleigh, NC. This shift towards southern-favored alleles may be caused by climate shifts or increased African-European admixture.
Pharmacological but not physiological GDF15 suppresses feeding and the motivation to exercise
Authors: Klein Anders B. , Nicolaisen Trine S. , Ørtenblad Niels , Gejl Kasper D. , Jensen Rasmus , Fritzen Andreas M. , Larsen Emil L. , Karstoft Kristian , Poulsen Henrik E. , Morville Thomas , Sahl Ronni E. , Helge Jørn W. , Lund Jens , Falk Sarah , Lyngbæk Mark , Ellingsgaard Helga , Pedersen Bente K. , Lu Wei , Finan Brian , Jørgensen Sebastian B. , Seeley Randy J. , Kleinert Maximilian , Kiens Bente , Richter Erik A. , Clemmensen Christoffer 
Published: October 2020

AbstractGrowing evidence supports that pharmacological application of growth differentiation factor 15 (GDF15) suppresses appetite but also promotes sickness-like behaviors in rodents via GDNF family receptor α-like (GFRAL)-dependent mechanisms1,2. Conversely, the endogenous regulation and secretion of GDF15 and its physiological effects on energy homeostasis and behavior remain elusive. Here we show, in four independent studies that prolonged, moderate- to high-intensity endurance exercise substantially increases circulating GDF15, in a time-dependent and reversible fashion, to peak levels otherwise only observed in pathophysiological conditions. This exercise-induced increase can be recapitulated in mice following forced treadmill running and is accompanied by increasedGdf15expression in the liver, skeletal muscle, and heart muscle. Compared to other metabolic stressors, like fasting, acute high-fat diet feeding, severe caloric excess and temperature changes, exercise has a greater impact on circulating GDF15 levels. However, whereas pharmacological GDF15 inhibits appetite and suppresses wheel running activity via GFRAL, in response to exercise, the physiological induction of GDF15 does not. In summary, exercise-induced circulating GDF15 correlates with the duration of endurance exercise. However, higher GDF15 levels after exercise are not sufficient to evoke canonical pharmacological GDF15 effects on appetite or responsible for exercise aversion/fatigue. Thus, the physiological effects of GDF15 as an exerkine remain elusive.
Analysis of the Immune Response to Sciatic Nerve Injury Identifies Efferocytosis as a Key Mechanism of Nerve Debridement
Authors: Kalinski Ashley L. , Yoon Choya , Huffman Lucas D. , Duncker Patrick C. , Kohen Rafi , Passino Ryan , Hafner Hannah , Johnson Craig , Kawaguchi Riki , Carbajal Kevin S. , Jara Juan Sebastián , Hollis Edmund , Geschwind Daniel H. , Segal Benjamin M. , Giger Roman J. 
Published: October 2020

AbstractSciatic nerve crush injury triggers sterile inflammation within the distal nerve and axotomized dorsal root ganglia (DRGs). Granulocytes and pro-inflammatory Ly6Chighmonocytes infiltrate the nerve first, and rapidly give way to Ly6Cnegativeinflammation-resolving macrophages. In axotomized DRGs, few hematogenous leukocytes are detected and resident macrophages acquire a ramified morphology. Single-cell RNA-sequencing of injured sciatic nerve identifies five macrophage subpopulations, repair Schwann cells, and mesenchymal precursor cells. Macrophages at the nerve crush site are molecularly distinct from macrophages associated with Wallerian degeneration. In the injured nerve, macrophages “eat” apoptotic leukocytes, a process called efferocytosis, and thereby promote an anti-inflammatory milieu. Myeloid cells in the injured nerve, but not axotomized DRGs, strongly express receptors for the cytokine GM-CSF. In GM-CSF deficient (Csf2-/-) mice, inflammation resolution is delayed and conditioning-lesion induced regeneration of DRG neuron central axons is abolished. Thus, carefully orchestrated inflammation resolution in the nerve is required for conditioning-lesion induced neurorepair.
Rapid evolution of enhanced Zika virus virulence during direct vertebrate transmission chains
Authors: Riemersma Kasen K. , Jaeger Anna S. , Crooks Chelsea M. , Braun Katarina M. , Weger-Lucarelli James , Ebel Gregory D. , Friedrich Thomas C. , Aliota Matthew T. 
Published: October 2020

AbstractZika virus (ZIKV) has the unusual capacity to circumvent natural alternating mosquito-human transmission and be directly transmitted human-to-human via sexual and vertical routes. The impact of direct transmission on ZIKV evolution and adaptation to vertebrate hosts is unknown. Here we show that molecularly barcoded ZIKV rapidly adapted to a mammalian host during direct transmission chains in mice, coincident with the emergence of an amino acid substitution previously shown to enhance virulence. In contrast, little to no adaptation of ZIKV to mice was observed following chains of direct transmission in mosquitoes or alternating host transmission. Detailed genetic analyses revealed that ZIKV evolution in mice was generally more convergent and subjected to more relaxed purifying selection than in mosquitoes or alternate passages. These findings suggest that prevention of direct human transmission chains may be paramount to resist gains in ZIKV virulence.
Bifidobacteria-mediated immune system imprinting early in life
Authors: Henrick Bethany M. , Rodriguez Lucie , Lakshmikanth Tadepally , Pou Christian , Henckel Ewa , Olin Axel , Wang Jun , Mikes Jaromir , Tan Ziyang , Chen Yang , Ehrlich Amy M. , Bernhardsson Anna Karin , Mugabo Constantin Habimana , Ambrosiani Ylva , Gustafsson Anna , Chew Stephanie , Brown Heather K. , Prambs Johann , Bohlin Kajsa , Mitchell Ryan D. , Underwood Mark A. , Smilowitz Jennifer T. , German J. Bruce , Frese Steven A. , Brodin Petter 
Published: October 2020

SUMMARYImmune-microbe interactions early in life influence an individual’s risk of developing allergies, asthma and some autoimmune disorders. Breastfeeding helps guide the development of healthy immune-microbe relationships, in part by providing nutrients to specialized microbes that in turn benefit the host and its developing immune system. Such bacteria having co-evolved with humans are associated with reduced risks of immune mediated diseases but are increasingly rare in modern societies. Here we map an immunological sequence of events, triggered by microbial colonization that distinguish children with different gut bacterial composition. Lack of bifidobacterial species is associated with elevated markers of intestinal inflammation and immune dysregulation and in a randomized trial of breastfed infants, the infant-adaptedBifidobacterium infantisEVC001 silenced intestinal Th2 and Th17 immune responses, while inducing IFNβ, and its metabolites skew T-cell polarizationin vitro, from Th2 towards Th1, suggesting a healthier immune imprinting during the first critical months of life.HIGHLIGHTSAn ordered sequence of immune changes after birth, driven by microbial interactionsLow gutBifidobacteriumabundance is associated with markers of intestinal inflammationFeedingB. infantisEVC001 silenced intestinal Th2 and Th17 but upregulates IFNβB. infantisEVC001 metabolites and/or enteric cytokines skew naïve T-cell polarization towards Th1 and away from Th2