bluuebunny/crossref_metadata_2025_split huggingface dataset:
Germinal center activity and B cell maturation promote protective antibody responses against Plasmodium pre-erythrocytic infection
Authors: Visweswaran Ganesh Ram R. , Vijayan Kamalakannan , Chandrasekaran Ramyavardhanee , Trakhimets Olesya , Whiteside Samantha L. , Vigdorovich Vladimir , Yang Ashton , Raappana Andrew , Watson Alex , Selman William , Zuck Meghan , Dambrauskas Nicholas , Kaushansky Alexis , Sather D. Noah 
Published: September 2021

AbstractBlocking Plasmodium, the causative agent of malaria, at the asymptomatic pre-erythrocytic stage would abrogate disease pathology and prevent transmission. Rodent-infectious species of Plasmodium such as P. yoelii (Py) serve as key tools to study vaccine efficacy and disease biology in immune-competent experimental animals. Here we evaluated the differences in vaccine-elicited humoral immunity in two widely used, and vastly diverged, inbred mouse strains, BALB/cJ and C57BL/6J, and identified immunological factors associated with protection. We vaccinated with Py circumsporozoite protein (CSP), the major surface antigen on the sporozoite, and evaluated protective efficacy after mosquito bite challenge. Vaccination achieved 60% sterile protection and otherwise delayed blood stage patency in BALB/cJ mice, whereas; all C57BL/6J mice were infected similar to controls. Interestingly, protection was mediated by antibodies, and could be passively transferred from immunized BALB/cJ mice into naïve C57BL/6J. Dissection of the underlying immunological features of protection revealed early deficits in antibody titers and polyclonal avidity in C57BL/6J mice. Additionally, PyCSP-vaccination in BALB/cJ induced a significantly higher proportion of antigen-specific B-cells and class-switched memory B-cell (MBCs) populations than in C57BL/6J mice. Strikingly, C57BL/6J mice also had markedly fewer germinal center experienced, CSP-specific class-switched MBCs compared to BALB/cJ mice. Analysis of the IgG γ chain repertoires by next generation sequencing in PyCSP-specific memory B-cell repertoires also revealed higher somatic hypermutation rates in BALB/cJ mice than in C57BL/6J mice. These findings indicate that BALB/cJ mice achieved higher levels of B cell maturation in response to vaccination with PyCSP, which likely enabled the development of protective antibody responses. Overall, our study indicates that germinal center activity and B cell maturation are key processes in the development of vaccine-elicited protective antibodies against CSP.
How biological cells including platelets and megakaryocytes decide complex problems fast but risky
Authors: Prada Juan , Balkenhol Johannes , Kaltdorf Martin , Osmanoglu Özge , Stoerkle Martin , Heinze Katrin , Manukjan Georgi , Schulze Harald , Dandekar Thomas 
Published: September 2021

Short AbstractMathematical decision processes are accurate but sometimes take very long time or simply do not happen. Decisions in biology happen fast and driven by evolution, optimizing survival chances. This results in stochastic decisions with on average good adaptation to the environment but an inherent risk of individual errors e.g. developing cancer during cell regeneration. We calculate and show in platelets and megakaryocytes how cellular decision processes increases risk for errors and inflammation. Short cut solutions adapted from nature improve computer strategies for protein folding and network decision processes. Complex problems are not always solved in foreseeable time, instead the fast solutions in biology speed up errors everywhere including biochemical aging of blood vessels, misfolded proteins, mis-programmed cells, cancer and heart failure.One sentence abstractWe investigate in biological networks how complex decision problems are mastered not by an accurate but unforeseeable long mathematical search but rather pragmatic and fast, with an inherent risk of error, a basis for inflammation and cancer.
A model-guided pipeline for drug cardiotoxicity screening with human stem-cell derived cardiomyocytes
Authors: Clark Alexander P. , Wei Siyu , Krogh-Madsen Trine , Christini David J. 
Published: September 2021

ABSTRACTNew therapeutic compounds go through a preclinical drug cardiotoxicity screening process that is overly conservative and provides limited mechanistic insight, leading to the misclassification of potentially beneficial drugs as proarrhythmic. There is a need to develop a screening paradigm that maintains this high sensitivity, while ensuring non-cardiotoxic compounds pass this phase of the drug approval process. In this study, we develop an in vitro-in silico pipeline using human induced stem-cell derived cardiomyocytes (iPSC-CMs) to address this problem. The pipeline includes a model-guided optimization that produces a voltage-clamp (VC) protocol to determine drug block of seven cardiac ion channels. Such VC data, along with action potential (AP) recordings, were acquired from iPSC-CMs before and after treatment with a control solution or a low-, intermediate-, or high-risk drug. We identified significant AP prolongation (a proarrhythmia indicator) in two high-risk drugs and, from the VC data, determined strong ion channel blocks that led to the AP changes. The VC data also uncovered an undocumented funny current (If) block by quinine, which we confirmed with experiments using a HEK-293 expression line. We present a new approach to cardiotoxicity screening that simultaneously evaluates proarrhythmia risk (e.g. AP prolongation) and mechanism (e.g. channel block) from iPSC-CMs.
Long-term effects of wildfire smoke exposure during early-life on the nasal epigenome in rhesus macaques
Authors: Brown Anthony P. , Cai Lucy , Laufer Benjamin I. , Miller Lisa A. , LaSalle Janine M. , Ji Hong 
Published: September 2021

ABSTRACTBackgroundWildfire smoke is responsible for around 20% of all particulate emissions in the U.S. and affects millions of people worldwide. Children are especially vulnerable, as ambient air pollution exposure during early childhood is associated with reduced lung function. Most studies, however, have focused on the short-term impacts of wildfire smoke exposures. We aimed to identify long-term baseline epigenetic changes associated with early-life exposure to wildfire smoke. We collected nasal epithelium samples for whole genome bisulfite sequencing (WGBS) from two groups of adult female rhesus macaques: one group born just before the 2008 California wildfire season and exposed to wildfire smoke during early-life (n = 8), and the other group born in 2009 with no wildfire smoke exposure during early-life (n = 14). RNA-sequencing was also performed on a subset of these samples.ResultsWe identified 3370 differentially methylated regions (DMRs) (difference in methylation ≥ 5% empirical p < 0.05) and 1 differentially expressed gene (FLOT2) (FDR< 0.05, fold of change ≥ 1.2). The DMRs were annotated to genes significantly enriched for synaptogenesis signaling, protein kinase A signaling, and a variety of immune processes, and some DMRs significantly correlated with gene expression differences. DMRs were also significantly enriched within regions of bivalent chromatin (top odds ratio = 1.46, q-value < 3 x 10-6) that often silence key developmental genes while keeping them poised for activation in pluripotent cells.ConclusionsThese data suggest that early-life exposure to wildfire smoke leads to long-term changes in the methylome over genes impacting the nervous and immune systems, but follow-up studies will be required to test whether these changes influence transcription following an immune/respiratory challenge.
Social hosts evade predation but have deadlier parasites
Authors: Walsman Jason C. , Janecka Mary J. , Clark David R. , Kramp Rachael D. , Rovenolt Faith , Patrick Regina , Mohammed Ryan S. , Konczal Mateusz , Cressler Clayton E. , Stephenson Jessica F. 
Published: September 2021

AbstractParasites exploit hosts to replicate and transmit, but overexploitation kills host and parasite (1): predators may shift this cost-benefit balance by consuming hosts (2–4) or changing host behavior, but the strength of these effects remains unclear. Modeling both, we find a primary, strong effect: hosts group to defend against predators (5), increasing parasite transmission, thus multiple infections, and therefore favoring more exploitative, virulent, parasites (6). Indeed, among 18 TrinidadianGyrodactyusspp. parasite lines, those collected from high predation guppy populations were more virulent in common garden than those from low predation populations. Our model accurately predicted this result when parametrized with our experimentally demonstrated virulence-transmission trade-off, implicating the behavioral effects of predation. Broadly, our results indicate that reduced social contact selects against parasite virulence.One-Sentence SummaryOur theory and data show predators cause increased host social grouping; the resulting transmission favors parasite virulence.
Dense cortical input to the rostromedial tegmental nucleus mediates aversive signaling
Authors: Glover Elizabeth J , Starr E Margaret , Gascon Andres , Clayton-Stiglbauer Kacey , Amegashie Christen L , Selchick Alyson H , Vaughan Dylan T , Wayman Wesley N , Woodward John J , Chandler L Judson 
Published: September 2021

AbstractThe rostromedial tegmental nucleus (RMTg) encodes negative reward prediction error (RPE) and plays an important role in guiding behavioral responding to aversive stimuli. While initial studies describing the RMTg revealed the presence of cortical afferents, the density and distribution of this input has not been explored in detail. In addition, the functional consequences of cortical modulation of RMTg signaling are only just beginning to be investigated. The current study anatomically and functionally characterizes cortical input to the RMTg in rats. Findings from this work reveal dense input spanning the entire medial prefrontal cortex (PFC) as well as the orbitofrontal cortex and anterior insular cortex. Afferents were most dense in the dorsomedial subregion of the PFC (dmPFC), an area which has also been implicated in both RPE signaling and aversive responding. RMTg-projecting dmPFC neurons originate in layer V and collateralize extensively throughout the brain. In-situ mRNA hybridization further revealed that neurons in this circuit are predominantly D1 receptor-expressing with a high degree of D2 receptor colocalization. Optogenetic stimulation of dmPFC terminals in the RMTg drives avoidance, and cFos expression is enhanced in this neural circuit during exposure to aversive stimuli. Exposure to such aversive stimuli results in significant physiological and structural plasticity suggestive of a loss of top-down modulation of RMTg-mediated signaling. Altogether, these data reveal the presence of a prominent cortico-subcortical projection involved in adaptive behavioral responding and provide a foundation for future work aimed at exploring alterations in circuit function in diseases characterized by deficits in cognitive control over the balance between reward and aversion.
A well conserved archaeal B-family polymerase functions as a mismatch and lesion extender
Authors: Feng Xu , Zhang Baochang , Gao Zhe , Xu Ruyi , Liu Xiaotong , Ishino Sonoko , Feng Mingxia , Shen Yulong , Ishino Yoshizumi , She Qunxin 
Published: September 2021

ABSTRACTB-family DNA polymerases (PolBs) of different groups are widespread in Archaea and different PolBs often coexist in the same organism. Many of these PolB enzymes remain to be investigated. One of the main groups that are poorly characterized is PolB2 whose members occur in many archaea but are predicted as an inactivated form of DNA polymerase. Herein,Sulfolobus islandicusDNA polymerase 2 (Dpo2), a PolB2 enzyme was expressed in its native host and purified. Characterization of the purified enzyme revealed that the polymerase harbors a robust nucleotide incorporation activity, but devoid of the 3’-5’ exonuclease activity. Enzyme kinetics analyses showed that Dpo2 replicates undamaged DNA templates with high fidelity, which is consistent with its inefficient nucleotide insertion activity opposite different DNA lesions. Strikingly, the polymerase is highly efficient in extending mismatches and mispaired primer termini once a nucleotide is placed opposite a damaged site. Together, these data suggested Dpo2 functions as a mismatch and lesion extender, representing a novel type of PolB that is primarily involved in DNA damage repair in Archaea. Insights were also gained into the functional adaptation of the motif C in the mismatch extension of the B-family DNA polymerases.
Genomic estimation of quantitative genetic parameters in wild admixed populations
Authors: Aase Kenneth , Jensen Henrik , Muff Stefanie 
Published: September 2021

AbstractHeritable genetic variation among free-living animals or plants is essential for populations to respond to selection and adapt. It is therefore important to be able to estimate additive genetic variance VA, which can be obtained using a generalized linear mixed model known as the animal model. An underlying assumption of the standard animal model is that the study population is genetically unstructured, which is often unrealistic. In fact, admixture might be the norm rather than the exception in the wild, like in geographically structured populations, in the presence of (im)migration, or in re-introduction and conservation contexts. Unfortunately, animal model estimators may be biased in such cases. So-called genetic group animal models that account for genetically differentiated subpopulations have recently become popular, but methodology is currently only available for cases where relatedness among individuals can be estimated from pedigrees.To ensure that genetic group animal models with heterogeneous VA remain applicable to populations with genomic data but no pedigrees, there is a clear need to generalize these models to the case when exclusively genomic data is available. We therefore introduce such methodology for wild admixed systems by extending methods that were recently suggested in the context of plant breeding. Our extension relaxes the limiting assumptions that currently restrict their use to artificial breeding setups.We illustrate the usefulness of the extended genomic genetic groups animal model on a wild admixed population of house sparrows resident in an island system in Northern Norway, where genome-wide data on more than 180 000 single nucleotide polymorphisms (SNPs) is available to derive genomic relatedness. We compare our estimates of quantitative genetic parameters to those derived from a corresponding pedigree-based genetic groups animal model. The satisfactory agreement indicates that the new method works as expected.Our extension of the very popular animal model ensures that the upcoming challenges with increasing availability of genomic data for quantitative genetic studies of wild admixed populations can be handled. To make the method widely available to the scientific community, we offer guidance in the form of a tutorial including step-by-step instructions to facilitate implementation.
MetaCoAG: Binning Metagenomic Contigs via Composition, Coverage and Assembly Graphs
Authors: Mallawaarachchi Vijini , Lin Yu 
Published: September 2021

ABSTRACTMetagenomics binning has allowed us to study and characterize various genetic material of different species and gain insights into microbial communities. While existing binning tools bin metagenomics de novo assemblies, they do not make use of the assembly graphs that produce such assemblies. Here we propose MetaCoAG, a tool that utilizes assembly graphs with the composition and coverage information to bin metagenomic contigs. MetaCoAG uses single-copy marker genes to estimate the number of initial bins, assigns contigs into bins iteratively and adjusts the number of bins dynamically throughout the binning process. Experimental results on simulated and real datasets demonstrate that MetaCoAG significantly outperforms state-of-the-art binning tools, producing more high-quality bins than the second-best tool, with an average median F1-score of 88.40%. To the best of our knowledge, MetaCoAG is the first stand-alone binning tool to make direct use of the assembly graph information. MetaCoAG is available at https://github.com/Vini2/MetaCoAG.
Optimal strategies to protect a sub-population at risk due to an established epidemic
Authors: Bussell Elliott H. , Cunniffe Nik J. 
Published: September 2021

AbstractEpidemics can particularly threaten certain sub-populations. For example, for SARS-CoV-2, the elderly are often preferentially protected. For diseases of plants and animals, certain sub-populations can drive mitigation because they are intrinsically more valuable for ecological, economic, socio-cultural or political reasons. Here we use optimal control theory to identify strategies to optimally protect a “high value” sub-population when there is a limited budget and epidemiological uncertainty. We use protection of the Redwood National Park in California in the face of the large ongoing state-wide epidemic of sudden oak death (caused by Phytophthora ramorum) as a case study. We concentrate on whether control should be focused entirely within the National Park itself, or whether treatment of the growing epidemic in the surrounding “buffer region” can instead be more profitable. We find that, depending on rates of infection and the size of the ongoing epidemic, focusing control on the high value region is often optimal. However, priority should sometimes switch from the buffer region to the high value region only as the local outbreak grows. We characterise how the timing of any switch depends on epidemiological and logistic parameters, and test robustness to systematic misspecification of these factors due to imperfect prior knowledge.
Horizontal connectivity in V1 : Prediction of coherence in contour and motion integration
Authors: Le Bec Benoit , Troncoso Xoana G. , Desbois Christophe , Passarelli Yannick , Baudot Pierre , Monier Cyril , Pananceau Marc , Frégnac Yves 
Published: September 2021

AbstractThis study demonstrates the functional importance of the Surround context relayed laterally in V1 by the horizontal connectivity, in controlling the latency and the gain of the cortical response to the feedforward visual drive. We report here four main findings : 1) a centripetal apparent motion sequence results in a shortening of the spiking latency of V1 cells, when the orientation of the local inducer and the global motion axis are both co-aligned with the RF orientation preference; 2) this contextual effects grows with visual flow speed, peaking at 150-250°/s when it matches the propagation speed of horizontal connectivity (0.15-0.25 mm/ms); 3) For this speed range, the axial sensitivity of V1 cells is tilted by 90° to become co-aligned with the orientation preference axis; 4) the strength of modulation by the surround context correlates with the spatiotemporal coherence of the apparent motion flow. Our results suggest an internally-generated binding process, linking local (orientation /position) and global (motion/direction) features as early as V1. This long-range diffusion process constitutes a plausible substrate in V1 of the human psychophysical bias in speed estimation for collinear motion. Since it is demonstrated in the anesthetized cat, this novel form of contextual control of the cortical gain and phase is a built-in property in V1, whose expression does not require behavioral attention and top-down control from higher cortical areas. We propose that horizontal connectivity participates in the propagation of an internal “prediction” wave, shaped by visual experience, which links contour co-alignment and global axial motion at an apparent speed in the range of saccade-like eye-movements.
Clonal evolution and specificity of the human T follicular helper cell response toPlasmodium falciparumcircumsporozoite protein
Authors: Wahl Ilka , Obraztsova Anna , Puchan Julia , Hundsdorfer Rebecca , Chakravarty Sumana , Lee Sim B. Kim , Hoffman Stephen L. , Kremsner Peter G. , Mordmüller Benjamin , Wardemann Hedda 
Published: September 2021

ABSTRACTT follicular helper (TFH) cells play a crucial role in the development of long-lived, quality-improved B cell responses after infection and vaccination. However, little is known about their clonal evolution. Here we assessed the cell phenotype, clonal dynamics, and TCR specificity of human circulating TFH(cTFH) cells at monoclonal level during successive malaria immunizations with radiation-attenuatedPlasmodium falciparum(Pf) sporozoites. Repeated parasite exposures induced a dynamic, polyclonal cTFHresponse with high frequency of cells specific to thePfcircumsporozoite protein (PfCSP), the main surface protein of sporozoites and a validated vaccine target. Repeated immunizations were required to induce detectable PfCSP-reactive cTFHcell responses to a small number of epitopes. HLA-restrictions and differences in TCR generation probability explain the high targeting frequency of the polymorphic Th2R/T* region over the conserved T1 epitope. The vast majority of anti-Th2R/T* TCRs failed to tolerate natural polymorphisms in their target peptide sequence suggesting that parasite diversity limits natural boosting of the cTFHcell response in endemic areas and protection from non-vaccine strains. Among convergent anti-Th2R/T* TCRs with high sequence similarity, subtle differences in CDR3 composition discriminated cross-reactive from non-cross-reactive cTFHcells. Thus, our study provides deep molecular and cellular insights into the kinetics, fine specificity and HLA-restrictions of the anti-cTFHcell response that are of direct relevance for the design of PfCSP-based malaria vaccines by guiding the selection of PfCSP peptides that induce optimal B cell help.
Protein-lipid interaction at low pH induces oligomerisation of the MakA cytotoxin from Vibrio cholerae
Authors: Nadeem Aftab , Berg Alexandra , Pace Hudson , Alam Athar , Toh Eric , Ådén Jörgen , Zlatkov Nikola , Myint Si Lhyam , Persson Karina , Gröbner Gerhard , Sjöstedt Anders , Bally Marta , Barandun Jonas , Uhlin Bernt Eric , Wai Sun Nyunt 
Published: September 2021

AbstractMany pathogenic bacteria produce protein toxins that target and perturb host cell membranes. The secreted α-pore-forming toxins (α-PFTs) cause membrane damage via pore formation. This study demonstrates a remarkable, hitherto unknown mechanism by an α-PFT protein from Vibrio cholerae. As part of the MakA/B/E tripartite toxin, MakA is involved in membrane pore formation similar to other α-PFTs. In contrast, MakA protein alone induces tube-like structures in the acidic lysosomal host cell compartment. In vitro studies unravel the dynamics of tubular growth, which occur in a pH-, lipid- and concentration-dependent manner. A 3.7-Å cryo-electron microscopy structure of MakA filaments reveals a unique protein-lipid superstructure. In its active α-PFT conformation, MakA embeds its transmembrane helices into a thin annular lipid bilayer and spirals around a central cavity. Our study provides molecular insights into a novel tubulation mechanism of an α-PFT protein, revealing a new mode of action by a secreted bacterial toxin.