bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single-cell sequencing reveals clonally expanded plasma cells during chronic viral infection produce virus-specific and cross-reactive antibodies
Authors: Neumeier Daniel , Pedrioli Alessandro , Genovese Alessandro , Sandu Ioana , Ehling Roy , Hong Kai-Lin , Papadopoulou Chrysa , Agrafiotis Andreas , Kuhn Raphael , Robbiani Damiano , Han Jiami , Hauri Laura , Csepregi Lucia , Greiff Victor , Merkler Doron , Reddy Sai T. , Oxenius Annette , Yermanos Alexander 
Published: February 2021

AbstractPlasma cells and their secreted antibodies play a central role in the long-term protection against chronic viral infection. However, due to experimental limitations, a comprehensive description of linked genotypic, phenotypic, and antibody repertoire features of plasma cells (gene expression, clonal frequency, virus specificity, and affinity) has been challenging to obtain. To address this, we performed single-cell transcriptome and antibody repertoire sequencing of the murine bone marrow plasma cell population following chronic lymphocytic choriomeningitis virus infection. Our single-cell sequencing approach recovered full-length and paired heavy and light chain sequence information for thousands of plasma cells and enabled us to perform recombinant antibody expression and specificity screening. Antibody repertoire analysis revealed that, relative to protein immunization, chronic infection led to increased levels of clonal expansion, class-switching, and somatic variants. Furthermore, antibodies from the highly expanded and class-switched (IgG) plasma cells were found to be specific for multiple viral antigens and a subset of clones exhibited cross-reactivity to non-viral- and auto-antigens. Integrating single-cell transcriptome data with antibody specificity suggested that plasma cell transcriptional phenotype was correlated to viral antigen specificity. Our findings demonstrate that chronic viral infection can induce and sustain plasma cell clonal expansion, combined with significant somatic hypermutation, and can generate cross-reactive antibodies.Graphical abstract.Single-cell sequencing reveals clonally expanded plasma cells during chronic viral infection produce virus-specific and cross-reactive antibodies.
DIAmeter: Matching peptides to data-independent acquisition mass spectrometry data
Authors: Lu Yang Young , Bilmes Jeff , Rodriguez-Mias Ricard A , Villén Judit , Noble William Stafford 
Published: February 2021

AbstractTandem mass spectrometry data acquired using data independent acquisition (DIA) is challenging to interpret because the data exhibits complex structure along both the mass-to-charge (m/z) and time axes. The most common approach to analyzing this type of data makes use of a library of previously observed DIA data patterns (a “spectral library”), but this approach is expensive because the libraries do not typically generalize well across laboratories. Here we propose DIAmeter, a search engine that detects peptides in DIA data using only a peptide sequence database. Unlike other library-free DIA analysis methods, DIAmeter supports data generated using both wide and narrow isolation windows, can readily detect peptides containing post-translational modifications, can analyze data from a variety of instrument platforms, and is capable of detecting peptides even in the absence of detectable signal in the survey (MS1) scan.
Quantitative prediction of conditional vulnerabilities in regulatory and metabolic networks ofMycobacterium tuberculosis
Authors: Immanuel Selva Rupa Christinal , Arrieta-Ortiz Mario L. , Ruiz Rene A. , Pan Min , de Lomana Adrian Lopez Garcia , Peterson Eliza J. R. , Baliga Nitin S. 
Published: February 2021

AbstractThe ability ofMycobacterium tuberculosis(Mtb) to adopt heterogeneous physiological states, underlies its success in evading the immune system and tolerating antibiotic killing. Drug tolerant phenotypes are a major reason why the tuberculosis (TB) mortality rate is so high, with over 1.8 million deaths annually. To develop new TB therapeutics that better treat the infection (faster and more completely), a systems-level approach is needed to reveal the complexity of network-based adaptations of Mtb. Here, we report a new predictive model called PRIME (Phenotype ofRegulatory influencesIntegrated withMetabolism andEnvironment) to uncover environment-specific vulnerabilities within the regulatory and metabolic networks of Mtb. Through extensive performance evaluations using genome-wide fitness screens, we demonstrate that PRIME makes mechanistically accurate predictions of context-specific vulnerabilities within the integrated regulatory and metabolic networks of Mtb, accurately rank-ordering targets for potentiating treatment with frontline drugs.
Dysregulation of PAX5 causes uncommitted B cell development and tumorigenesis in mice
Authors: Boast Brigette , Helian Kaiyue , Andrews T. Daniel , Li Xi , Cho Vicky , Closa Adria , Sutton Henry J. , Reed Joanne H. , Bergmann Hannes , Roots Carla M. , Yabas Mehmet , Barthel Nadine , Omari Sofia A. , Young Clara , Miosge Lisa A. , Eyras Eduardo , Nutt Stephen L. , Hein Nadine , Hannan Katherine M. , Cockburn Ian A. , Goodnow Christopher C. , Enders Anselm 
Published: February 2021

AbstractPAX5 is the master transcription factor controlling B cell identity. In humans, mutations inPAX5account for 30% of B cell acute lymphoblastic leukemia (B-ALL) cases. Investigating the causal effects ofPAX5mutations has however been difficult due to the premature lethality ofPax5−/−mice. Here we describe a novel mouse strain with a premature STOP mutation inPax5(Y351*) that produces a truncated protein and reduction in protein function, yet still allows for some B cell development to occur. A population of uncommitted and multipotent CD19+B220−B cells develops in the bone marrow of homozygous mice leading to the development of B-ALL. We show that the tumors frequently acquire secondary mutations inJak3, andPtpn11highlighting key pathways interacting with PAX5 during malignant transformation. Analysis of the PAX5Y351*mice provide insight not only into the functional consequence of reduced PAX5 activity on B cell development and identity, but also provides an avenue in which to study PAX5-driven B-ALL in mice.One Sentence SummaryReduction in PAX5 function in mice induces the development of uncommitted B cells that have multipotent and malignant potential.
Non cell-autonomous effect of astrocytes on cerebral cavernous malformations
Authors: Lopez-Ramirez Miguel Alejandro , Soliman Shady Ibrahim , Hale Preston , Lai Catherine Chinhchu , Pham Angela , Estrada Esau , McCurdy Sara , Girard Romuald , Verma Riya , Moore Thomas , Lightle Rhonda , Hobson Nicholas , Shenkar Robert , Poulsen Orit , Haddad Gabriel G. , Daneman Richard , Gongol Brendan , Sun Hao , Lagarrigue Frederic , Awad Issam A. , Ginsberg Mark H. 
Published: February 2021

AbstractCerebral cavernous malformations (CCMs) are common neurovascular lesions caused by loss-of-function mutations in one of three genes, includingKRIT1(CCM1),CCM2, andPDCD10(CCM3), and generally regarded as an endothelial cell-autonomous disease. Here we report that proliferative astrocytes play a critical role in CCM pathogenesis by serving as a major source of VEGF during CCM lesion formation. An increase in astrocyte VEGF synthesis is driven by endothelial nitric oxide (NO) generated as a consequence of KLF2 and KLF4-dependent elevation of eNOS in CCM endothelium. The increased brain endothelial production of NO stabilizes HIF-1α in astrocytes, resulting in increased VEGF production and expression of a “hypoxic” program under normoxic conditions. We show that the upregulation of cyclooxygenase-2 (COX-2), a direct HIF-1α target gene and a known component of the hypoxic program, contributes to the development of CCM lesions because the administration of a COX-2 inhibitor significantly prevents progression of CCM lesions. Thus, non-cell-autonomous crosstalk between CCM endothelium and astrocytes propels vascular lesion development, and components of the hypoxic program represent potential therapeutic targets for CCMs.
A Mixture Model Incorporating Individual Heterogeneity in Human Lifetimes
Authors: Huang Fei , Maller Ross , Milholland Brandon , Ning Xu 
Published: February 2021

AbstractAnalysis of some extensive individual-record data using a demographically informed model suggests constructing a general population model in which the lifetime of a person, beyond a certain threshold age, follows an extreme value distribution with a finite upper bound, and with that upper bound randomized over the population. The resulting population model incorporates heterogeneity in life-lengths, with lifetimes being finite individually, but with extremely long lifespans having negligible probability. Our findings are compared in detail with those of related studies in the literature, and used to reconcile contradictions between previous studies of extreme longevity. While being consistent with currently reported analyses of human lifetimes, we nevertheless differ with those who conclude in favour of unbounded human lifetimes.
Trial-by-trial modulation of express visuomotor responses induced by symbolic or barely detectable cues
Authors: Contemori Samuele , Loeb Gerald E. , Corneil Brian D. , Wallis Guy , Carroll Timothy J. 
Published: February 2021

ABSTRACTHuman cerebral cortex can produce visuomotor responses that are modulated by contextual and task-specific constraints. However, the distributed cortical network for visuomotor transformations limits the minimal response time of that pathway. Notably, humans can generate express visuomotor responses that are inflexibly tuned to the target location and occur 80-120ms from stimulus presentation (stimulus-locked responses, SLRs). This suggests a subcortical pathway for visuomotor transformations involving the superior colliculus and its downstream reticulo-spinal projections. Here we investigated whether cognitive expectations can modulate the SLR. In one experiment, we recorded surface EMG from shoulder muscles as participants reached toward a visual target whose location was unpredictable in control conditions, and partially predictable in cue conditions by extrapolating a symbolic cue (75% validity). Valid symbolic cues led to faster and larger SLRs than control conditions; invalid symbolic cues produced slower and smaller SLRs than control conditions. This is consistent with a cortical top-down modulation of the putative subcortical SLR-network. In a second experiment, we presented high-contrast targets in isolation (control) or ~24ms after low-contrast stimuli, which could appear at the same (valid cue) or opposite (invalid cue) location as the target, and with equal probability (50% cue validity). We observed faster SLRs than control with the valid low-contrast cues, whereas the invalid cues led to the opposite results. These findings may reflect exogenous priming mechanisms of the SLR network, potentially evolving subcortically via the superior colliculus. Overall, our results support both top-down and bottom-up modulations of the putative subcortical SLR network in humans.NEW & NOTEWORTHYExpress visuomotor responses in humans appear to reflect subcortical sensorimotor transformation of visual inputs, potentially conveyed via the tecto-reticulo-spinal pathway. Here we show that the express responses are influenced both by symbolic and barely detectable spatial cues about stimulus location. The symbolic cue-induced effects suggest cortical top-down modulation of the putative subcortical visuomotor network. The effects of barely detectable cues may reflect exogenous priming mechanisms of the tecto-reticulo-spinal pathway.
Multicellular immune hubs and their organization in MMRd and MMRp colorectal cancer
Authors: Pelka Karin , Hofree Matan , Chen Jonathan , Sarkizova Siranush , Pirl Joshua D. , Jorgji Vjola , Bejnood Alborz , Dionne Danielle , Ge William H. , Xu Katherine H. , Chao Sherry X. , Zollinger Daniel R. , Lieb David J. , Reeves Jason W. , Fuhrman Christopher A. , Hoang Margaret L. , Delorey Toni , Nguyen Lan T. , Waldman Julia , Klapholz Max , Wakiro Isaac , Cohen Ofir , Smillie Christopher S. , Cuoco Michael S. , Wu Jingyi , Su Mei-ju , Yeung Jason , Vijaykumar Brinda , Magnuson Angela M. , Asinovski Natasha , Moll Tabea , Goder-Reiser Max N. , Applebaum Anise S. , Brais Lauren K. , DelloStritto Laura K. , Denning Sarah L. , Phillips Susannah T. , Hill Emma K. , Meehan Julia K. , Frederick Dennie T. , Sharova Tatyana , Kanodia Abhay , Todres Ellen Z. , Jané-Valbuena Judit , Biton Moshe , Izar Benjamin , Lambden Conner D. , Clancy Thomas E. , Bleday Ronald , Melnitchouk Nelya , Irani Jennifer , Kunitake Hiroko , Berger David L. , Srivastava Amitabh , Hornick Jason L. , Ogino Shuji , Rotem Asaf , Vigneau Sébastien , Johnson Bruce E. , Corcoran Ryan , Sharpe Arlene H. , Kuchroo Vijay K. , Ng Kimmie , Giannakis Marios , Nieman Linda T. , Boland Genevieve M. , Aguirre Andrew J. , Anderson Ana C. , Rozenblatt-Rosen Orit , Regev Aviv , Hacohen Nir 
Published: February 2021

AbstractImmune responses to cancer are highly variable, with mismatch repair-deficient (MMRd) tumors exhibiting more anti-tumor immunity than mismatch repair-proficient (MMRp) tumors. To understand the rules governing these varied responses, we transcriptionally profiled 371,223 cells from colorectal tumors and adjacent normal tissues of 28 MMRp and 34 MMRd patients. Analysis of 88 cell subsets and their 204 associated gene expression programs revealed extensive transcriptional and spatial remodeling across tumors. To discover hubs of interacting malignant and immune cells, we identified expression programs in different cell types that co-varied across patient tumors and used spatial profiling to localize coordinated programs. We discovered a myeloid cell-attracting hub at the tumor-luminal interface associated with tissue damage, and an MMRd-enriched immune hub within the tumor, with activated T cells together with malignant and myeloid cells expressing T-cell-attracting chemokines. By identifying interacting cellular programs, we thus reveal the logic underlying spatially organized immune-malignant cell networks.
Intermittent KHz-frequency electrical stimulation selectively engages small unmyelinated vagal afferents
Authors: Chang Yao-Chuan , Ahmed Umair , Jayaprakash Naveen , Mughrabi Ibrahim , Lin Qihang , Wu Yi-Chen , Gerber Michael , Abbas Adam , Daytz Anna , Gabalski Arielle H. , Ashville Jason , Dokos Socrates , Rieth Loren , Datta-Chaudhury Timir , Tracey Kevin , Guo Tianruo , Al-Abed Yousef , Zanos Stavros 
Published: February 2021

AbstractAfferent and efferent vagal fibers mediate bidirectional communication between the brain and visceral organs. Small, unmyelinated C-afferents constitute the majority of vagal fibers, play critical roles in numerous interoceptive circuits and autonomic reflexes in health and disease and may contribute to the efficacy and safety of vagus nerve stimulation (VNS). Selective engagement of C-afferents with electrical stimuli has not been feasible, due to the default fiber recruitment order: larger fibers first, smaller fibers last. Here, we determine and optimize an electrical stimulus that selectively engages vagal C-afferents. Intermittent KHz-frequency electrical stimulation (KES) activates motor and, preferentially, sensory vagal neurons in the brainstem. During KES, asynchronous activity of C-afferents increases, while that of larger fibers remains largely unchanged. In parallel, KES effectively blocks excitability of larger fibers while moderately suppressing excitability of C-afferents. By compiling selectivity indices in individual animals, we find that optimal KES parameters for C-afferents are >5KHz frequency and 7-10 times engagement threshold (×T) intensity in rats, 15-25×T in mice. These effects can be explained in computational models by how sodium channel responses to KES are shaped by axonal size and myelin. Our results indicate that selective engagement of vagal C-afferents is attainable by intermittent KES.
Small Intestinal Resident Eosinophils Maintain Gut Homeostasis Following Microbial Colonisation
Authors: Shah K. , Ignacio A. , Bernier-Latmani J. , Köller Y. , Coakley G. , Moyat M. , Hamelin R. , Armand F. , Wong N. C. , Ramay H. , Thomson C.A. , Burkhard R. , Dufour A. , Petrova T.V. , Harris N.L. , McCoy K. D. 
Published: February 2021

SUMMARYIntestinal homeostasis following postnatal microbial colonization requires the coordination of multiple processes including the activation of immune cells, cell-cell communication, the controlled deposition of extracellular matrix, and epithelial cell turnover and differentiation. The intestine harbors the largest frequency of resident eosinophils of all homeostatic organs, yet the functional significance of eosinophil recruitment to this organ has long remained enigmatic. Eosinophils are equipped to both respond to, and modify, their local tissue environment and thus are able to regulate the adaption of tissues to environmental changes. We report a critical role for eosinophils in regulating villous structure, barrier integrity and motility in the small intestine. Notably, the microbiota was identified as a key driver of small intestinal eosinophil activation and function. Collectively our findings demonstrate a critical role for eosinophils in facilitating mutualistic interactions between host and microbiota and provide a rationale for the functional significance of their early life recruitment in the small intestine.HIGHLIGHTSThe microbiota is a critical regulator of eosinophil activation and turnoverEosinophils uphold intestinal barrier integrity following microbial colonizationLoss of eosinophils at steady-state results in increased villous blunting and altered intestinal motility
PalaCell2D: A framework for detailed tissue morphogenesis
Authors: Conradin Raphaël , Coreixas Christophe , Latt Jonas , Chopard Bastien 
Published: February 2021

AbstractIn silico, cell based approaches for modeling biological morphogenesis are used to test and validate our understanding of the biological and mechanical process that are at work during the growth and the organization of multi-cell tissues. As compared to in vivo experiments, computer based frameworks dedicated to tissue modeling allow us to easily test different hypotheses, and to quantify the impact of various biophysically relevant parameters.Here, we propose a formalism based on a detailed, yet simple, description of cells that accounts for intra-, inter- and extra-cellular mechanisms. More precisely, the cell growth and division is described through the space and time evolution of the membrane vertices. These vertices follow a Newtonian dynamics, meaning that their evolution is con-trolled by different types of forces: a membrane force (spring and bending), an adherence force (inter-cellular spring), external and internal pressure forces. Different evolution laws can be applied on the internal pressure, depending on the intra-cellular mechanism of interest. In addition to the cells dynamics, our formalism further relies on a lattice Boltzmann method, using the Palabos library, to simulate the diffusion of chemical signals. The latter aims at driving the growth and migration of a tissue by simply changing the state of the cells.All of this leads to an accurate description of the growth and division of cells, with realistic cell shapes and where membranes can have different properties. While this work is mainly of methodological nature, we also propose to validate our framework through simple, yet biologically relevant benchmark tests at both single-cell and full tissue scales. This includes free and chemically controlled cell tissue growth in an unbounded domain. The ability of our framework to simulate cell migration, cell compression and morphogenesis under external constraints is also investigated in a qualitative manner.
Thermodynamic modeling reveals widespread multivalent binding by RNA-binding proteins
Authors: Sohrabi-Jahromi Salma , Söding Johannes 
Published: February 2021

AbstractMotivationUnderstanding how proteins recognize their RNA targets is essential to elucidate regulatory processes in the cell. Many RNA-binding proteins (RBPs) form complexes or have multiple domains that allow them to bind to RNA in a multivalent, cooperative manner. They can thereby achieve higher specificity and affinity than proteins with a single RNA-binding domain. However, current approaches to de-novo discovery of RNA binding motifs do not take multivalent binding into account.ResultsWe present Bipartite Motif Finder (BMF), which is based on a thermodynamic model of RBPs with two cooperatively binding RNA-binding domains. We show that bivalent binding is a common strategy among RBPs, yielding higher affinity and sequence specificity. We furthermore illustrate that the spatial geometry between the binding sites can be learned from bound RNA sequences. These discovered bipartite motifs are consistent with previously known motifs and binding behaviors. Our results demonstrate the importance of multivalent binding for RNA-binding proteins and highlight the value of bipartite motif models in representing the multivalency of protein-RNA interactions.AvailabilityBMF source code is available athttps://github.com/soedinglab/bipartite_motif_finderunder a GPL license. The BMF web server is accessible athttps://bmf.soedinglab.org.
Is energetics or competition a stronger driver of male smallmouth bass seasonal reproductive timing?
Authors: Laroche Robert A.S. , Weinersmith Kelly L. , Angeloni Lisa , Baylis Jeffrey R. , Newman Steven P. , Egan Scott P. , Wiegmann Daniel D. 
Published: February 2021

ABSTRACTIntraspecific competitive ability is often associated with body size and has been shown to influence reproductive timing in many species. However, energetic constraints provide an alternative explanation for size-related differences of reproductive timing. In temperate fishes that experience a winter starvation period, for instance, a negative allometric relationship between body size and winter energy loss might explain why larger males spawn earlier in a season than smaller males, especially in fishes that exhibit paternal care, which is energetically costly and limits parental foraging opportunities. Male smallmouth bass,Micropterus dolomieu, defend nesting territories in which they care for offspring over an extended period. In northern populations, males rely on energy reserves over a winter starvation period and in spring must recoup energy losses before initiating reproduction, making them ideal systems in which to study contributions of competition and energetic allometry on differences of reproductive timing. Here, we harness data on parental maleM. dolomieufrom a 10-year study and show that larger males required fewer degree days-a measure of thermal energy experienced-in spring before they spawned each year and that the time of peak seasonal reproduction in the population was negatively related to the number of degree days accumulated before reproduction started. Furthermore, we found that growth of individual males between seasons better predicted changes in timing of reproduction than changes in size relative to competitors. Together, these results suggest that timing of reproduction in this population is more strongly influenced by energetic constraints than size-based competition amongst males.