bluuebunny/crossref_metadata_2025_split huggingface dataset:
RUNX1 is required in granulocyte-monocyte progenitors to attenuate inflammatory cytokine production by neutrophils
Authors: Zezulin Alexandra U. , Ye Darwin , Howell Elizabeth , Yen Daniel , Bresciani Erica , Diemer Jamie , Ren Jian-gang , Ahmad Mohd Hafiz , Castilla Lucio H. , Touw Ivo P. , Minn Andy J. , Tong Wei , Liu P. Paul , Tan Kai , Yu Wenbao , Speck Nancy A. 
Published: January 2023

ABSTRACTThe transcription factor RUNX1 is mutated in familial platelet disorder with associated myeloid malignancies (FPDMM) and in sporadic myelodysplastic syndrome and leukemia. RUNX1 regulates inflammation in multiple cell types. Here we show that RUNX1 is required in granulocyte-monocyte progenitors (GMPs) to restrict the inflammatory response of neutrophils to toll-like receptor 4 (TLR4) signaling. Loss of RUNX1 in GMPs increased the TLR4 coreceptor CD14 on neutrophils, which contributed to neutrophils’ increased inflammatory cytokine production in response to the TLR4 ligand lipopolysaccharide. RUNX1 loss increased the chromatin accessibility of retrotransposons in GMPs and neutrophils and induced a type I interferon signature characterized by enriched footprints for signal transducer and activator of transcription (STAT1::STAT2) and interferon regulatory factors (IRF) in opened chromatin, and increased expression of interferon-stimulated genes. The overproduction of inflammatory cytokines by neutrophils was reversed by inhibitors of type I IFN signaling. We conclude that RUNX1 restrains the chromatin accessibility of retrotransposons in GMPs and neutrophils, and that loss of RUNX1 increases proinflammatory cytokine production by elevating tonic type I interferon signaling.
scGREAT: Graph-based regulatory element analysis tool for single-cell multi-omics data
Authors: Liu Chaozhong , Wang Linhua , Liu Zhandong 
Published: January 2023

AbstractMotivationWith the development in single-cell multi-omics sequencing technology and data integration algorithms, we have entered the single-cell multi-omics era. Current multi-omics analysis algorithms failed to systematically dissect the heterogeneity within the datasets when inferring cis-regulatory events. Thus, there is a need for cis-regulatory element inferring algorithms that considers the cellular heterogeneity.ResultsHere, we propose scGREAT, a single-cell multi-omics regulatory state analysis Python package with a rapid graph-based correlation measurementL. The graph-based correlation method assigns each cell a localLindex, pinpointing specific cell groups of certain regulatory states. Such single-cell resolved regulatory state information enables the heterogeneity analysis equipped in the package. Applying scGREAT to the 10X Multiome PBMC dataset, we demonstrated how it could help subcluster cell types, infer regulation-based pseudo-time trajectory, discover feature modules, and find cluster-specific regulatory gene-peak pairs. Besides, we showed that global L index, which is the average of all local L values, is a better replacement for Pearson’s r in ruling out confounding regulatory relationships that are not of research interests.Availabilityhttps://github.com/ChaozhongLiu/scGREAT
The aftermath of a trophic cascade: Increased anoxia following species invasion of a eutrophic lake
Authors: Rohwer Robin R. , Ladwig Robert , Dugan Hilary A. , Hanson Paul C. , Walsh Jake R. , Zanden M. Jake Vander 
Published: January 2023

Species invasions can disrupt aquatic ecosystems by re-wiring food webs. A trophic cascade triggered by the invasion of the predatory zooplankter spiny water flea (Bythotrephes cederströmii) resulted in increased phytoplankton due to decreased zooplankton grazing. Here, we show that increased phytoplankton biomass led to an increase in lake anoxia. The temporal and spatial extent of anoxia experienced a step change increase coincident with the invasion. Anoxia was driven by phytoplankton biomass and stratification changes, and anoxic factor increased by 10 days. In particular, anoxia established more quickly following spring stratification. A shift in spring phytoplankton phenology encompassed both abundance and community composition. Diatoms (Bacillaryophyta) drove the increase in spring phytoplankton biomass, but not all phytoplankton community members increased, shifting the community composition. We infer that increased phytoplankton biomass increased labile organic matter and drove hypolimnetic oxygen consumption. These results demonstrate how a species invasion can shift lake phenology and biogeochemistry.Scientific significance statementInvasive species can affect aquatic ecosystems, often by disrupting food webs. We investigated whether the invasive predatory zooplankton spiny water flea could additionally impact the biogeochemistry of a lake, specifically hypolimnetic anoxia dynamics. Using 24 years of observations spanning a spiny water flea invasion that triggered a food web-mediated increase in phytoplankton, we found that increased spring phytoplankton coincided with an earlier onset of anoxia, thereby drawing a connection between a species invasion and a shift in lake oxygen dynamics.Data availability statementAll data is publicly available through the Environmental Data Initiative via identifiers referenced in the methods. Scripts and data to reproduce the results are available on GitHub (https://github.com/robertladwig/spinyAnoxia) and in Rohwer et al. (2023).Author contributionsRRR and RL co-led the entire manuscript effort and contributed equally. RL and RRR came up with the research question and conducted the statistical and numerical analyses: RL analysed the anoxia dynamics and related water quality variables, RRR analysed the phytoplankton community dynamics. RL, RRR, and HAD created figures and visualizations. PCH, JW and JVZ provided essential feedback to the analyses and the discussion of ecosystem implications. RRR and RL co-wrote the paper.
Structure and dynamics of the essential endogenous mycobacterial polyketide synthase Pks13
Authors: Kim Sun Kyung , Dickinson Miles Sasha , Finer-Moore Janet , Guan Ziqiang , Kaake Robyn M. , Echeverria Ignacia , Chen Jen , Pulido Ernst H. , Sali Andrej , Krogan Nevan J. , Rosenberg Oren S. , Stroud Robert M. 
Published: January 2023

SummaryMycobacterium tuberculosisis currently the leading cause of death by any bacterial infection1. The mycolic acid layer of the cell wall is essential for viability and virulence, and the enzymes responsible for its synthesis are therefore front line targets for antimycobacterial drug development2,3. Polyketide synthase 13 (Pks13) is a module comprised of a closely symmetric parallel dimer of chains, each encoding several enzymatic and transport functions, that carries out the condensation of two different very long chain fatty acids to produce mycolic acids that are essential components of the mycobacterial cell wall. Consequently individual enzymatic domains of Pks13 are targets for antimycobacterial drug development4. To understand this machinery, we sought to determine the structure and domain trajectories of the dimeric multi-enzyme Pks13, a 2×198,426 Dalton complex, from protein purified endogenously from mycobacteria under normal growth conditions, to capture it with normal substrates bound trapped ‘in action’.Structures of the multi-domain assembly revealed by cryogenic electron microscopy (cryoEM) define the ketosynthase (KS), linker, and acyltransferase (AT) domains, each at atomic resolution (1.8Å), with bound substrates defined at 2.4Å and 2.9Å resolution. Image classification reveals two distinct structures with alternate locations of the N-terminal acyl carrier protein (termed ACP1a, ACP1b) seen at 3.6Å and 4.6Å resolution respectively. These two structures suggest plausible intermediate states, related by a ~60Å movement of ACP1, on the pathway for substrate delivery from the fatty acyl-ACP ligase (FadD32) to the ketosynthase domain. The linking sequence between ACP1 and the KS includes an 11 amino acid sequence with 6 negatively charged side chains that lies in different positively charged grooves on the KS in ACP1a versus ACP1b structures. This charge complementarity between the extended chain and the grooves suggests some stabilization of these two distinct orientations. Other domains are visible at lower resolution and indicate flexibility relative to the KS-AT core. The chemical structures of three bound endogenous long chain fatty acid substrates with their proximal regions defined in the structures were determined by electrospray ionization mass spectrometry.The domain proximities were probed by chemical cross-linking and identified by mass spectrometry. These were incorporated into integrative structure modeling to define multiple domain configurations that transport the very long fatty acid chains throughout the multistep Pks13 mediated synthetic pathway.
The nuclear receptor LRH-1 discriminates between ligands using distinct allosteric signaling circuits
Authors: Mays Suzanne G. , Hercules David , Ortlund Eric A. , Okafor C. Denise 
Published: January 2023

AbstractNuclear receptors (NRs) are transcription factors that regulate essential biological processes in response to cognate ligands. An important part of NR function involves ligand-induced conformational changes that recruit coregulator proteins to the activation function surface (AFS), ~15 Å away from the ligand binding pocket. Ligands must communicate with the AFS to recruit appropriate coregulators and elicit different transcriptional outcomes, but this communication is poorly understood. These studies illuminate allosteric communication networks underlying activation of liver receptor homolog-1 (LRH-1), a NR that regulates development, metabolism, cancer progression and intestinal inflammation. Using >100 microseconds of all-atom molecular dynamics simulations involving 69 LRH-1 complexes, we identify distinct signaling circuits used by active and inactive ligands for AFS communication. Inactive ligands communicate via strong, coordinated motions along paths through the receptor to the AFS. Activating ligands disrupt the “inactive” circuit by inducing connectivity elsewhere. Ligand-contacting residues in helix 7 help mediate the switch between circuits, suggesting new avenues for developing LRH-1-targeted therapeutics. We also elucidate aspects of coregulator signaling, showing that localized, destabilizing fluctuations are induced by inappropriate ligand-coregulator pairings. These studies have uncovered novel features of LRH-1 allostery, and the quantitative approach used to analyze many simulations provides a framework to study allosteric signaling in other receptors.
pA regulator: a system for controlling mammalian gene expression via the modulation of polyA signal cleavage
Authors: Luo Liming , Jea Jocelyn Duen-Ya , Wang Yan , Chao Pei-Wen , Yen Laising 
Published: January 2023

AbstractThe ability to control the expression of a therapeutic gene or a transgene in mammalian cells is crucial for safe and efficacious gene and cell therapy, as well as for elucidating the function of a specific gene product. Yet current mammalian gene regulation systems either evoke harmful immune responses in hosts or lack the required regulatory efficiency. Here we describe a highly responsive RNA-based molecular switch, the pA regulator, that harnesses the power of polyA signal cleavage within the 5’ UTR to control mammalian gene expression. The pA regulator is governed by a ‘dual mechanism’ to ensure maximal control of gene expression: (1) aptamer clamping of polyA signal via drug binding and (2) drug-induced alternative splicing that removes the polyA signal. The metholology achieves an induction efficiency up to 900-fold with an EC50of 0.5μg/ml Tetracycline, a drug concentration that falls well within the FDA-approved dose range. The pA regulator circumvents the immune responses that plague other systems by eliminating the use of a regulatory foreign protein and the need to change transgene coding sequences. Furthermore, it is not dependent on any specific promoter, therefore the system is simple to implement in a single non-viral or viral vector. In a mouse study using AAV-mediated gene transfer, we showed that the pA regulator controlled transgene expression in a “dose-dependent’ and “reversible” manner and exhibited long-term stabilityin vivo, in which both features are crucial for effective therapeutics. The pA regulator is the first non-immunogenic system that demonstrates an EC50at a drug concentration approved by FDA, making it a clinically relevant gene regulation system that could open a new window of opportunity in clinical applications as well as biological studies.
Social Isolation Causes Cortical and Trabecular Bone Loss in Adult Male, but not Female, C57BL/6J Mice
Authors: Mountain Rebecca V. , Langlais Audrie L. , Hu Dorothy , Baron Roland , Lary Christine W. , Motyl Katherine J. 
Published: January 2023

AbstractSocial isolation is a potent form of psychosocial stress and is a growing public health concern, particularly among older adults. Even prior to the onset of the COVID-19 pandemic, which has significantly increased the prevalence of isolation and loneliness, researchers have been concerned about a rising “epidemic” of loneliness. Isolation is associated with an increased risk for many physical and mental health disorders and increased overall mortality risk. In addition to social isolation, older adults are also at greater risk for osteoporosis and related fractures. While researchers have investigated the negative effects of other forms of psychosocial stress on bone, including depression and PTSD, the effects of social isolation on bone have not been thoroughly investigated. The aim of this study was to test the hypothesis that social isolation would lead to bone loss in male and female C57BL/6J mice. 16-week-old mice were randomized into social isolation (1 mouse/cage) or grouped housing (4 mice/cage) for four weeks (N=16/group). Social isolation significantly decreased trabecular (BV/TV, BMD, Tb. N., Tb. Th.) and cortical bone (Ct.Th., Ct.Ar., Ct.Ar./Tt.Ar., pMOI, Ct.Por.) parameters in male, but not female mice. Isolated male mice had signs of reduced bone remodeling represented by reduced osteoblast numbers, osteoblast-related gene expression and osteoclast-related gene expression. However, isolated females had increased bone resorption-related gene expression, without any change in bone mass. Overall, our data suggest that social isolation has negative effects on bone in males, but not females, although females showed suggestive effects on bone resorption. These results provide critical insight into the effects of isolation on bone and have key clinical implications as we grapple with the long-term health impacts of the rise in social isolation related to the COVID-19 pandemic.
HAT:de novovariant calling for highly accurate short-read and long-read sequencing data
Authors: Ng Jeffrey K. , Turner Tychele N. 
Published: January 2023

AbstractMotivationde novovariant (DNV) calling is challenging from parent-child sequenced trio data. We developedHareAndTortoise (HAT) to work as an automated workflow to detect DNVs in highly accurate short-read and long-read sequencing data. Reliable detection of DNVs is important for human genetics studies (e.g., autism, epilepsy).ResultsHAT is a workflow to detect DNVs from short-read and long read sequencing data. This workflow begins with aligned read data (i.e., CRAM or BAM) from a parent-child sequenced trio and outputs DNVs. HAT detects high-quality DNVs from short-read whole-exome sequencing, short-read wholegenome sequencing, and highly accurate long-read sequencing data.Availabilityhttps://github.com/TNTurnerLab/HATContacttychele@wustl.eduSupplementary informationSupplementary data are available at bioRxiv.
Identification of potent and selectiveN-myristoyltransferase inhibitors ofPlasmodium vivaxliver stage hypnozoites and schizonts
Authors: Rodríguez-Hernández Diego , Vijayan Kamalakannan , Zigweid Rachael , Fenwick Michael K. , Sankaran Banumathi , Roobsoong Wanlapa , Sattabongkot Jetsumon , Glennon Elizabeth K.K. , Myler Peter J. , Sunnerhagen Per , Staker Bart L. , Kaushansky Alexis , Grøtli Morten 
Published: January 2023

ABSTRACTNew drugs targeting multiple stages of the malaria-causing parasite,Plasmodium, are needed to reduce and eliminate malaria worldwide.N-Myristoyltransferase (NMT) is an essential eukaryotic enzyme, and a validated chemically tractable drug target for malaria. Previous efforts have failed to target NMT owing to the low selectivity for thePlasmodiumenzyme compared with human NMTs. Herein, we applied a structure-guided approach using previously reported NMT inhibitors as scaffolds to develop a new generation ofPlasmodium vivaxNMT (PvNMT) targeting compounds. We report a series of compounds with IC50values in the nM range and an order of magnitude improved selectivity toPlasmodiumNMT over human NMT (HsNMT). X-ray co-crystallization ofPvNMT with a representative lead compound,12b, supported the prevailing hypothesis that a conformational difference in a key tyrosine residue ofPvNMT andHsNMT drives the selectivity between these enzymes. The compounds were triaged based on their selectivity forPvNMT. They significantly decreasedP. falciparumblood-stage parasite load, with IC50values ranging from 0.36 μM to 1.25 μM. The compounds exhibited a dose-dependent inhibition ofP. vivaxliver stage schizont and hypnozoite infection, consistently, in three differentP. vivaxisolates with IC50values ranging from 2.2 μM to 6 μM and from 1.2 μM to 12 μM. Our data provide evidence that NMT inhibitors could be multistage antimalarials, targeting both dormant and developing liver stage parasites, which is essential for malaria elimination.One Sentence SummaryPotent and selectiveN-myristoyltransferase inhibitors ofPlasmodium vivaxhypnozoites and schizonts were synthesized and tested.
Humans adaptively select different computational strategies in different learning environments
Authors: Verbeke Pieter , Verguts Tom 
Published: January 2023

AbstractThe Rescorla-Wagner rule remains the most popular tool to describe human behavior in reinforcement learning tasks. Nevertheless, it cannot fit human learning in complex environments. Previous work proposed several hierarchical extensions of this learning rule. However, it remains unclear when a flat (non-hierarchical) versus a hierarchical strategy is adaptive, or when it is implemented by humans. To address this question, current work applies a nested modelling approach to evaluate multiple models in multiple reinforcement learning environments both computationally (which approach performs best) and empirically (which approach fits human data best). We consider ten empirical datasets (N= 407) divided over three reinforcement learning environments. Our results demonstrate that different environments are best solved with different learning strategies; and that humans adaptively select the learning strategy that allows best performance. Specifically, while flat learning fitted best in less complex stable learning environments, humans employed more hierarchically complex models in more complex environments.
Accumulation of TCR signaling from self-antigens in naive CD8 T cells mitigates early responsiveness
Authors: Eggert Joel , Zinzow-Kramer Wendy M. , Hu Yuesong , Tsai Yuan-Li , Weiss Arthur , Salaita Khalid , Scharer Christopher D. , Au-Yeung Byron B. 
Published: January 2023

AbstractThe cumulative effects of T cell receptor (TCR) signal transduction over extended periods of time influences T cell biology, such as the positive selection of immature thymocytes or the proliferative responses of naive T cells. Naive T cells experience recurrent TCR signaling in response to self-antigens in the steady state. However, how these signals influence the responsiveness of naive CD8+T cells to subsequent agonist TCR stimulation remains incompletely understood. We investigated how naive CD8+T cells that experienced relatively low or high levels of TCR signaling in response to self-antigens respond to stimulation with foreign antigens. A transcriptional reporter ofNr4a1(Nur77-GFP) revealed substantial heterogeneity of the amount of TCR signaling naive CD8+T cells accumulate in the steady state. Nur77-GFPHIcells exhibited diminished T cell activation and secretion of IFNγ and IL-2 relative to Nur77-GFPLOcells in response to agonist TCR stimulation. Differential gene expression analyses revealed upregulation of genes associated with acutely stimulated T cells in Nur77-GFPHIcells but also increased expression of negative regulators such as the phosphatase Sts1. Responsiveness of Nur77-GFPHIcells to TCR stimulation was partially restored at the level of IFNγ secretion by deficiency of Sts1 or the ubiquitin ligase Cbl-b. Our data suggest that extensive accumulation of TCR signaling during steady state conditions induces a recalibration of the responsiveness of naive CD8+T cells through gene expression changes and negative regulation, at least in part, dependent on Sts1 and Cbl-b. This cell-intrinsic negative feedback loop may allow the immune system to limit the autoreactive potential of highly self-reactive naive CD8+T cells.
Perturbation Variability Does Not Influence Implicit Sensorimotor Adaptation
Authors: Wang Tianhe , Avraham Guy , Tsay Jonathan S. , Abram Sabrina J. , Ivry Richard B. 
Published: January 2023

AbstractCerebellar-dependent implicit adaptation has been regarded as a rigid process that automatically operates in response to movement errors in order to keep the sensorimotor system calibrated. This hypothesis has been challenged by recent evidence suggesting flexibility in this learning process. One compelling line of evidence comes from work suggesting that this form of learning is context-dependent, with the rate of learning modulated by error history. Specifically, learning was attenuated in the presence of perturbations exhibiting high variance compared to when the perturbation is fixed. However, these findings are confounded by the fact that the adaptation system corrects for errors of different magnitudes in a non-linear manner, with the adaptive response increasing in a proportional manner to small errors and saturating to large errors. Through simulations, we show that this non-linear motor correction function is sufficient to explain the effect of perturbation variance without referring to an experience-dependent change in error sensitivity. Moreover, by controlling the distribution of errors experienced during training, we provide empirical evidence showing that there is no measurable effect of perturbation variance on implicit adaptation. As such, we argue that the evidence to date remains consistent with the rigidity assumption.