bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evolutionarily divergentMycobacterium tuberculosisCTP synthase filaments are under selective pressure
Authors: Lynch Eric M. , Lu Yao , Park Jin Ho , Shao Lin , Kollman Justin , Rego E. Hesper 
Published: July 2024

ABSTRACTThe final and rate-limiting enzyme in pyrimidine biosynthesis, CTP synthase (CTPS), is essential for the viability ofMycobacterium tuberculosisand other mycobacteria. Its product, CTP, is critical for RNA, DNA, lipid and cell wall synthesis, and is involved in chromosome segregation. In various organisms across the tree of life, CTPS assembles into higher-order filaments, leading us to hypothesize thatM. tuberculosisCTPS (mtCTPS) also forms higher-order structures. Here, we show that mtCTPS does assemble into filaments but with an unusual architecture not seen in other organisms. Through a combination of structural, biochemical, and cellular techniques, we show that polymerization stabilizes the active conformation of the enzyme and resists product inhibition, potentially allowing for the highly localized production of CTP within the cell. Indeed, CTPS filaments localize near the CTP-dependent complex needed for chromosome segregation, and cells expressing mutant enzymes unable to polymerize are altered in their ability to robustly form this complex. Intriguingly, mutants that alter filament formation are under positive selection in clinical isolates ofM. tuberculosis, pointing to a critical role needed to withstand pressures imposed by the host and/or antibiotics. Taken together, our data reveal an unexpected mechanism for the spatially organized production of a critical nucleotide inM. tuberculosis, which may represent a vulnerability of the pathogen that can be exploited with chemotherapy.
Alleviation of salt stress in strawberries by hydrogen-rich water: physiological, transcriptomic and metabolomic responses
Authors: Wang Renyuan , Chu Shaohua , Zhang Dan , Zhang Xia , Chi Yaowei , Ma Xianzhong , Chen Xunfeng , Yang Haiyan , Ding Wenjiang , Zhao Ting , Ren Yongfeng , Yang Xijia , Zhou Pei 
Published: July 2024

AbstractAbstract FigureWith the continuous advancement of climate change and human activities, cultivable land is becoming increasingly susceptible to the influence of salt ions. Therefore, it is crucial to mitigate the salt stress on plants through various approaches. In this study, strawberry seedlings were selected as the experimental plants, and a comprehensive transcriptomic and metabolomic analysis was conducted to elucidate the effects of hydrogen-rich water (HRW) on strawberries under salt stress. The results indicated that HRW significantly promoted plant growth, particularly increasing root biomass by 49.50%. Additionally, HRW regulated the levels of soluble sugars, malondialdehyde (MDA), and antioxidant enzymes, enhancing the cellular uptake of potassium ions and the expulsion of sodium ions. The levels of Ca2+and Mg2+in organelles increased by 2.06 and 2.45-fold, respectively. Transcriptomic analysis revealed that HRW substantially altered gene expression in strawberry roots; under salt stress, HRW up-regulated beneficial biological processes. Furthermore, genes related to ion absorption and transport, antioxidant enzymes, and cell wall biosynthesis were screened. Meanwhile, key common pathways were identified in differentially expressed metabolites (DEMs) and differentially expressed genes (DEGs) related to phenylpropane biosynthesis, alanine, aspartate, and glutamate metabolism, amino and nucleotide sugar metabolism, and galactose metabolism. A molecular mechanism for mitigating salt stress in strawberry seedlings by HRW was provided by the integrated approaches in this research, reflecting the potential applications of hydrogen gas in agriculture.
Spatially variable competition contributes to mismatched responses of plant fitness and occurrence to environmental gradients
Authors: Hayashi Kenji T. , Kraft Nathan J. B. 
Published: July 2024

AbstractSpecies distributions have long been understood to depend on the complex interplay between the abiotic environment and biotic interactions. Empirical work in ecological communities has increasingly revealed how competition can mediate species’ demographic responses to environmental variation, but understanding how the demographic consequences of spatially variable competition manifest in observed distribution patterns remains an important challenge.Here, we describe a conceptual framework for characterizing competition-driven mismatches between responses of fitness and occurrence to environmental gradients. We then explore these mismatches for eight annual plant species in an edaphically variable California grassland landscape.We experimentally quantified how species’ demographic rates (germination rate, fecundity) and fitness respond to spatial variation in the soil environment, either in the presence or absence of naturally occurring neighbors. We also surveyed species’ occurrence across the study landscape. Combining these demographic and occurrence data, we asked whether observed occurrence patterns are congruent with responses of intrinsic fitness (i.e., fitness in the absence of competitors) to soil gradients.We found that competition altered responses of fitness to the primary soil gradient (soil texture) for many (4/8) species. In turn, occurrence patterns were often poorly or even inversely related to responses of intrinsic fitness to this environmental axis. In contrast, we found that competition had relatively little effect on responses of fitness and occurrence to a secondary soil gradient (soil Ca:Mg).Synthesis. We demonstrate that spatially variable competition can contribute to mismatched responses of fitness and occurrence to environmental variation. Importantly, these quantitative mismatches depend on the species and environmental gradient in question. Our results caution against assuming that variation in occurrence implies variation in intrinsic fitness (or vice versa) without first disentangling how the abiotic environment and competition impact the demographic processes that underlie species distributions.
Genetic variance in the murine defensin locus modulates glucose homeostasis
Authors: Masson Stewart W.C. , Simpson Rebecca C. , Cutler Harry B. , Carlos Patrick W. , Marian Oana C. , Potter Meg , Madsen Søren , Cooke Kristen C. , Craw Niamh R. , Fuller Oliver K. , Harney Dylan J. , Larance Mark , Cooney Gregory J. , Morahan Grant , Shanahan Erin R. , Hodgkins Christopher , Payne Richard J. , Stöckli Jacqueline , James David E. 
Published: July 2024

AbstractInsulin resistance is a heritable risk factor for many chronic diseases; however, the genetic drivers remain elusive. In seeking these, we performed genetic mapping of insulin sensitivity in 670 chow-fed Diversity Outbred in Australia (DOz) mice and identified a genome-wide significant locus (QTL) on chromosome 8 encompassing 17 defensin genes. By taking a systems genetics approach, we ultimately identified alpha-defensin 26 (Defa26) as the causal gene in this region. To validate these findings, we synthesized Defa26 and performed diet supplementation experiments in two mouse strains with distinct endogenous Defa26 expression levels. In the strain with relatively lower endogenous expression (C57BL/6J) supplementation improved insulin sensitivity and reduced gut permeability, while in the strain with higher endogenous expression (A/J) it caused hypoinsulinemia, glucose intolerance and muscle wasting. Based on gut microbiome and plasma bile acid profiling this appeared to be the result of disrupted microbial bile acid metabolism. These data illustrate the danger of single strain over-reliance and provide the first evidence of a link between host-genetics and insulin sensitivity which is mediated by the microbiome.
Decoding RNA Metabolism by RNA-linked CRISPR Screening in Human Cells
Authors: Nugent Patrick J. , Park Heungwon , Wladyka Cynthia L. , Chen Katharine Y. , Bynum Christine , Quarterman Grace , Hsieh Andrew C. , Subramaniam Arvind Rasi 
Published: July 2024

AbstractRNAs undergo a complex choreography of metabolic processes in human cells that are regulated by thousands of RNA-associated proteins. While the effects of individual RNA-associated proteins on RNA metabolism have been extensively characterized, the full complement of regulators for most RNA metabolic events remain unknown. Here we present a massively parallel RNA-linked CRISPR (ReLiC) screening approach to measure the responses of diverse RNA metabolic events to knockout of 2,092 human genes encoding all known RNA-associated proteins. ReLiC screens highlight modular interactions between gene networks regulating splicing, translation, and decay of mRNAs. When combined with biochemical fractionation of polysomes, ReLiC reveals striking pathway-specific coupling between growth fitness and mRNA translation. Perturbing different components of the translation and proteostasis machineries have distinct effects on ribosome occupancy, while perturbing mRNA transcription leaves ribosome occupancy largely intact. Isoform-selective ReLiC screens capture differential regulation of intron retention and exon skipping by SF3b complex subunits. Chemogenomic screens using ReLiC decipher translational regulators upstream of mRNA decay and uncover a role for the ribosome collision sensor GCN1 during treatment with the anti-leukemic drug homoharringtonine. Our work demonstrates ReLiC as a versatile platform for discovering and dissecting regulatory principles of human RNA metabolism.
Transfer RNA acetylation regulates in vivo mammalian stress signaling
Authors: Thalalla Gamage Supuni , Khoogar Roxane , Howpay Manage Shereen , Crawford McKenna C. , Georgeson Joe , Polevoda Bogdan V. , Sanders Chelsea , Lee Kendall A. , Nance Kellie D. , Iyer Vinithra , Kustanovich Anatoly , Perez Minervo , Thu Chu T. , Nance Sam R. , Amin Ruhul , Miller Christine N. , Holewinski Ronald J. , Meyer Thomas , Koparde Vishal , Yang Acong , Jailwala Parthav , Nguyen Joe T. , Andresson Thorkell , Hunter Kent , Gu Shuo , Mock Beverly A. , Edmondson Elijah F. , Difilippantonio Simone , Chari Raj , Schwartz Schraga , O’Connell Mitchell R. , Wu Colin Chih-Chien , Meier Jordan L. 
Published: July 2024

ABSTRACTTransfer RNA (tRNA) modifications are crucial for protein synthesis, but their position-specific physiological roles remain poorly understood. Here we investigate the impact of N4-acetylcytidine (ac4C), a highly conserved tRNA modification, using a Thumpd1 knockout mouse model. We find that loss of Thumpd1-dependent tRNA acetylation leads to reduced levels of tRNALeu, increased ribosome stalling, and activation of eIF2α phosphorylation. Thumpd1 knockout mice exhibit growth defects and sterility. Remarkably, concurrent knockout of Thumpd1 and the stress-sensing kinase Gcn2 causes penetrant postnatal lethality, indicating a critical genetic interaction. Our findings demonstrate that a modification restricted to a single position within type II cytosolic tRNAs can regulate ribosome-mediated stress signaling in mammalian organisms, with implications for our understanding of translation control as well as therapeutic interventions.
A new regulator of sporulation sheds light on spore morphogenesis and ballistospory in mushroom-forming fungi
Authors: Hou Zhihao , Merényi Zsolt , Yang Yashu , Zhang Yan , Csernetics Árpád , Bálint Balázs , Hegedüs Botond , Földi Csenge , Wu Hongli , Kristóffy Zsolt , Ábrahám Edit , Miklovics Nikolett , Virágh Máté , Liu Xiao-Bin , Zsibrita Nikolett , Lipinszki Zoltán , Karcagi Ildiko , Gao Wei , Nagy László G. 
Published: July 2024

AbstractSporulation is the most widespread means of reproduction and dispersal in fungi. In the Basidiomycota, sexual spores are produced on specialised cells known as basidia, from which they are discharged forcibly by a powered process called ballistospory, the highest known acceleration in nature. However, the genetics of sporulation, in particular postmeiotic events related to spore morphogenesis and ballistospory, remain poorly known. Here, we explore the genetics of these processes, based on a new, highly conserved transcription factor, Sporulation-Related Regulator 1 (SRR1), and its putative downstream regulatory network. Reverse genetics ofSrr1in the model mushroomCoprinopsis cinereaand commercially produced oyster mushroom indicated a conserved role ofSrr1in sporulation across Agaricomycetes. RNA-Seq analysis and motif-based inference of a hypothetical SRR1 gene regulatory network allowed delimiting putative targets regulated by SRR1 in a direct and indirect manner. Using this network and comparative genomics, we identified genes associated with ballistospory, including a putative SRR1-target chitinase, which was found to be required for normal spore production and morphology. Overall, our study offers new insights into the genetic mechanisms governing postmeiotic spore morphogenesis and ballistospory in the Agaricomycetes.
A finite set of content-free pointers in visual working memory: MEG evidence
Authors: Yu Xinchi , Lau Ellen 
Published: July 2024

AbstractHuman visual working memory (VWM) is known to be capacity-limited, but the nature of this limit continues to be debated. Recent work has proposed that VWM is supported by a finite (∼ 3) set of content-free pointers, acting as stand-ins for individual objects and binding features together. Here, based on two visual working memory experiments (N=20 each) examining memory for simple and complex objects, we report a sustained MEG response over right posterior cortex whose magnitude tracks the core hypothesized properties of this system: load-dependent, capacity-limited and content-free. These results provide novel evidence for a finite set of content-free pointers underlying VWM.
PLK-1 regulates MEX-1 polarization in theC. eleganszygote
Authors: Kim Amelia J. , Miller Stephanie I. , Greiner Elora C. , Kettenbach Arminja N. , Griffin Erik E. 
Published: July 2024

AbstractThe one-cellC. elegansembryo undergoes an asymmetric cell division during which germline factors such as the RNA-binding proteins POS-1 and MEX-1 segregate to the posterior cytoplasm, leading to their asymmetric inheritance to the posterior germline daughter cell. Previous studies found that the RNA-binding protein MEX-5 recruits polo-like kinase PLK-1 to the anterior cytoplasm where PLK-1 inhibits the retention of its substrate POS-1, leading to POS-1 segregation to the posterior. In this study, we tested whether PLK-1 similarly regulates MEX-1 polarization. We find that both the retention of MEX-1 in the anterior and the segregation of MEX-1 to the posterior depend on PLK kinase activity and on the interaction between MEX-5 and PLK-1. Human PLK1 directly phosphorylates recombinant MEX-1 on 9 predicted PLK-1 sites in vitro, four of which were identified in previous phosphoproteomic analysis ofC. elegansembryos. The introduction of alanine substitutions at these four PLK-1 phosphorylation sites (MEX-1(4A)) significantly weakened the inhibition of MEX-1 retention in the anterior, thereby weakening MEX-1 segregation to the posterior. In contrast, mutation of a predicted CDK1 phosphorylation site had no effect on MEX-1 retention or on MEX-1 segregation. MEX-1(4A) mutants are viable and fertile but display significant sterility and fecundity defects at elevated temperatures. Taken together with our previous findings, these findings suggest PLK-1 phosphorylation drives both MEX-1 and POS-1 polarization during the asymmetric division of the zygote.
Adaptive resistance to FLT3 inhibitors is potentiated by ROS-driven DNA repair signalling
Authors: Staudt Dilana E. , Germon Zacary P. , Mannan Abdul , McLachlan Tabitha , Murray Heather C. , Duchatel Ryan J. , Thomas Bryce C. , Beitaki Tyrone , McEwen Holly P. , Persson Mika L. , Calvert Leah , Findlay Izac J. , Jackson Evangeline R. , Smith Nathan D. , Skerrett-Byrne David A. , Mossman David , Nixon Brett , De Iullis Geoffry , Douglas Alicia M. , Enjeti Anoop K. , Sillar Jonathan R. , Chamberlain Janis , Alvaro Frank , Wei Andrew H. , Connerty Patrick , Verrills Nicole , Dun Matthew D. 
Published: July 2024

ABSTRACTAlterations in the FMS-like tyrosine kinase 3 (FLT3) gene are the most frequent driver mutations in acute myeloid leukaemia (AML), linked to a high risk of relapse in patients with internal tandem duplications (FLT3-ITD). Tyrosine kinase inhibitors (TKIs) targeting the FLT3 protein are approved for clinical use, yet resistance often emerges. This resistance is mainly seen following the acquisition of additional point mutations in the tyrosine kinase domain (TKD), resulting in a double mutant FLT3-ITD/TKD, which sustains cell signalling and survival despite the presence of FLT3 inhibitors. Here, we developed a FLT3-mutant AML model with adaptive resistance to type II TKIs, sorafenib, and quizartinib byin vitrodrug selection. Through global multiomic profiling, we identified upregulation of proteins involved in reactive oxygen species (ROS) production, particularly NADPH-oxidases, driving cellular ’ROS-addiction’, with resistant cells relying on ROS for survival, and genome fidelity preserved by ATM-driven DNA repair. Transcriptomic analysis of adult and paediatric AML (pAML) patients identified high ATM expression as a biomarker for shorter median overall survival in both the de novo and relapsed settings. Inhibition of ATM with clinically relevant therapy WSD-0628 effectively killed TKI- and chemotherapy-resistant AML cellsin vitroand significantly extended the survival of mice with sorafenib- and quizartinib-resistant FLT3-ITD AMLin vivo. We propose a new treatment strategy to improve survival of patients who develop resistance to sorafenib and quizartinib, as well as relapsed and refractory pAML, exploiting resistance mechanisms to precision therapies and cell-intrinsic features of high-risk cases, highlighting a clinically relevant salvage strategy.
Optimized reporters for multiplexed detection of transcription factor activity
Authors: Trauernicht Max , Filipovska Teodora , Rastogi Chaitanya , van Steensel Bas 
Published: July 2024

SUMMARYIn any given cell type, dozens of transcription factors (TFs) act in concert to control the activity of the genome by binding to specific DNA sequences in regulatory elements. Despite their considerable importance in determining cell identity and their pivotal role in numerous disorders, we currently lack simple tools to directly measure the activity of many TFs in parallel. Massively parallel reporter assays (MPRAs) allow the detection of TF activities in a multiplexed fashion; however, we lack basic understanding to rationally design sensitive reporters for many TFs. Here, we use an MPRA to systematically optimize transcriptional reporters for 86 TFs and evaluate the specificity of all reporters across a wide array of TF perturbation conditions. We thus identified critical TF reporter design features and obtained highly sensitive and specific reporters for 60 TFs, many of which outperform available reporters. The resulting collection of “prime” TF reporters can be used to uncover TF regulatory networks and to illuminate signaling pathways.HIGHLIGHTSSystematic design and optimization of transcriptional reporters for 86 TFsCharacterization of TF-specific reporter design optimization rulesEvaluation of reporter TF-specificity across a wide array of TF perturbationsIdentification of a collection of 60 “prime” TF reporters with optimized performance
Learning cell fate landscapes from spatial transcriptomics using Fused Gromov-Wasserstein
Authors: Huizing Geert-Jan , Peyré Gabriel , Cantini Laura 
Published: July 2024

AbstractIn dynamic biological processes such as development, spatial transcriptomics is revolutionizing the study of the mechanisms underlying spatial organization within tissues. Inferring cell fate trajectories from spatial transcriptomics profiled at several time points has thus emerged as a critical goal, requiring novel computational methods. Wasserstein gradient flow learning is a promising framework for analyzing sequencing data across time, built around a neural network representing the differentiation potential. However, existing gradient flow learning methods cannot analyze spatially resolved transcriptomic data.Here, we propose STORIES, a method that employs an extension of Optimal Transport to learn a spatially informed potential. We benchmark our approach using three large Stereo-seq spatiotemporal atlases and demonstrate superior spatial coherence compared to existing approaches. Finally, we provide an in-depth analysis of axolotl neural regeneration and mouse gliogenesis, recovering gene trends for known markers asNptx1in neuron regeneration andAldh1l1in gliogenesis and additional putative drivers.
Emissions of climate-altering species from open vegetation fires in the Mediterranean region - A review on methods and data
Authors: Hundal Rabia Ali , Annadate Saurabh , Cesari Rita , Collalti Alessio , Maione Michela , Cristofanelli Paolo 
Published: July 2024

AbstractThe climate change over the Mediterranean region poses serious concerns about the role of open vegetation fires in the emissions of climate-altering species. The aim of this work is to review the current methodologies for quantifying the emissions of greenhouse gases and black carbon from open vegetation fires, as well as the data provided by four state-of-the-art inventories of emissions of carbon dioxide (CO2), methane (CH4), nitrous oxide (N2O) and black carbon (BC) in the Mediterranean region for the period 2003 - 2020. A limited number of studies specifically addressed the quantification of emissions from open fires in the Mediterranean region. Our data review of fire emissions in the Mediterranean region, where “top-down” methods have not yet implemented, reveals discrepancies across the four inventories examined (GFED v4.1s, GFAS v1.2, FINN v2.5, and EDGAR v8.0). Among these, FINN v2.5 consistently reported the highest emissions, while GFED v4.1s reported the lowest. We observed that the relative ranking of total emissions between the inventories varied for the species considered (e.g. CO2vs. CH4) and that different proportions of emissions were attributed to the individual countries included in the Mediterranean domain. We argued that these differences were related to the different spatial resolutions of the input data used to detect the occurrence of fires, the different approaches to calculating the amount of fuel available, and the emission factors used.The three inventories reporting wildfire emissions were consistent in identifying the occurrence of peaks in the emissions for the years 2007, 2012 and 2017. We hypothesized that La Niña events could partially contribute to triggering the occurrence of these emission peaks.To increase the accuracy and consistency of climate-altering emission data related to open vegetation fires in the Mediterranean region, we recommend to integrate bottom-up approaches with top-down inversion methods based on satellite and in-situ atmospheric observations.