bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cold, but not for long enough: first insights into the tolerance to subzero temperatures of the invasive amphipodDikerogammarus villosus
Authors: Mucciolo Serena , Podwysocki Krzysztof , Desiderato Andrea 
Published: November 2023

AbstractDikerogammarus villosusis an invasive Ponto-Caspian amphipod, known to have colonized most of the major European freshwater bodies in the last few decades. Several studies assessing its tolerance related to higher temperatures have been performed; however, no records are present about its response to subzero temperatures. Therefore, in this study, we wanted to experimentally assess for the first time the tolerance ofD. villosusto temperatures below 0°C. The animals were exposed to 0°C, -8°C, and room temperature for 2 and 24 hours, tracking their possible movements during the ice melting. Only long exposures at -8°C appeared to be fatal. These results provide new insights for more accurate predictive models regarding the future expansion of this invader.
Deciphering histone mark-specific fine-scale chromatin organization at high resolution with Micro-C-ChIP
Authors: Metelova Mariia , Krietenstein Nils 
Published: November 2023

AbstractThe regulation of cell-type-specific transcription programs is a highly controlled and complex process that needs to be fully understood. The gene regulation is often influenced by distal regulatory elements and their interactions with promoters in three-dimensional space. Although proximity ligation techniques like Hi-C have revolutionized our understanding of genome organization, the genomic resolution for many of these methods is limited by both experimental and financial constraints. Here, we introduce Micro-C-ChIP to provide extremely high-resolution views of chromosome architecture at genomic loci marked by specific covalent histone modifications. This is achieved by chromatin immunoprecipitation of specific chromatin states to target chromosome folding libraries to focus on chromatin domains (regulatory elements, heterochromatin, etc.) of interest, yielding extremely high sequencing depth at these loci. We applied Micro-C-ChIP to mouse embryonic stem cells (mESC) and hTERT-immortalized human retinal epithelial cells (hTERT-RPE1), revealing architectural features of genome organization with comparable or higher resolution than Micro-C datasets sequenced with higher depth. We discovered extensive promoter-promoter networks in both cell types and characterized the specific architecture of bivalently marked promoters in mESC. Together, these data highlight Micro-C-ChIP as a cost-effective approach to exploring the landscape of genome folding at extraordinarily high resolution.
Loss of Nkd1 is epistatic to loss of Axin2 in regulating Wnt signaling
Authors: Bell Ian , Khan Haider , Stutt Nathan , Horn Matthew , Hydzik Teesha , Lum Whitney , Rea Victoria , Clapham Emma , Hoeg Lisa , Van Raay Terence J. 
Published: November 2023

AbstractWnt signaling is a crucial developmental pathway involved in early development as well as stem cell maintenance in adults and its misregulation leads to numerous diseases. Thus, understanding the regulation of this pathway becomes vitally important. Axin2 and Nkd1 are widely utilized negative feedback regulators in Wnt signaling where Axin2 functions to destabilize cytoplasmic β-catenin, and Nkd1 functions to inhibit the nuclear localization of β-catenin. Here, we set out to further understand how Axin2 and Nkd1 regulate Wnt signaling by creatingaxin2-/-,nkd1-/-single mutants andaxin2-/-;nkd1-/-double mutant zebrafish using sgRNA/Cas9. All three Wnt regulator mutants were viable and had impaired heart looping, neuromast migration defects, and behavior abnormalities in common, but there were no signs of synergy in theaxin2-/-;nkd1-/-double mutants. Further, Wnt target gene expression by qRT-PCR, and RNA-seq analysis and protein expression by mass spectrometry demonstrated that the doubleaxin2-/-;nkd1-/-mutant resembled thenkd1-/-phenotype demonstrating that Axin2 functions upstream of Nkd1 and that loss of Nkd1 is epistatic to the loss of Axin2. In support of this, the data further demonstrates that Axin2 uniquely alters the properties of β-catenin-dependent transcription having novel readouts of Wnt activity compared tonkd1-/-or theaxin2-/-;nkd1-/-double mutant. We also tested the sensitivity of the Wnt regulator mutants to exacerbated Wnt signaling, where the single mutants displayed characteristic heightened Wnt sensitivity, resulting in an eyeless phenotype. Surprisingly, this phenotype was rescued in the double mutant, where we speculate that cross-talk between Wnt/β-catenin and Wnt/Planar Cell Polarity pathways could lead to altered Wnt signaling in some scenarios. Collectively, the data emphasizes both the commonality and the complexity in the feedback regulation of Wnt signaling.
Pervasive aggregation and depletion of host and viral proteins in response to cysteine-reactive electrophilic compounds
Authors: Julio Ashley R. , Shikwana Flowreen , Truong Cindy , Burton Nikolas R. , Dominguez Emil , Turmon Alexandra C. , Cao Jian , Backus Keriann 
Published: November 2023

ABSTRACTProtein homeostasis is tightly regulated, with damaged or misfolded proteins quickly eliminated by the proteasome and autophagosome pathways. By co-opting these processes, targeted protein degradation technologies enable pharmacological manipulation of protein abundance. Recently, cysteine-reactive molecules have been added to the degrader toolbox, which offer the benefit of unlocking the therapeutic potential of ‘undruggable’ protein targets. The proteome-wide impact of these molecules remains to be fully understood and given the general reactivity of many classes of cysteine-reactive electrophiles, on- and off-target effects are likely. Using chemical proteomics, we identified a cysteine-reactive small molecule degrader of the SARS-CoV-2 non- structural protein 14 (nsp14), which effects degradation through direct modification of cysteines in both nsp14 and in host chaperones together with activation of global cell stress response pathways. We find that cysteine-reactive electrophiles increase global protein ubiquitylation, trigger proteasome activation, and result in widespread aggregation and depletion of host proteins, including components of the nuclear pore complex. Formation of stress granules was also found to be a remarkably ubiquitous cellular response to nearly all cysteine-reactive compounds and degraders. Collectively, our study sheds light on complexities of covalent target protein degradation and highlights untapped opportunities in manipulating and characterizing proteostasis processes via deciphering the cysteine-centric regulation of stress response pathways.
Patient phenotypes and their relation to TNFα signaling and immune cell composition in critical illness and autoimmune disease
Authors: Krishna Vinod , Banie Homayon , Conceição-Neto Nádia , Murata Yoshihiko , Verbrugge Inge , Trifonov Vladimir , Martinez Roxana , Murali Vasumathy , Lee Yu-Chi , May Richard D , Nájera Isabel , Fowler Andrew , Li Chris Ka Fai 
Published: November 2023

AbstractRationaleTNFα inhibitors have shown promise in reducing mortality in hospitalized COVID-19 patients; one hypothesis explaining the limited clinical efficacy is patient heterogeneity in the TNFα pathway.MethodsWe evaluated the effect of TNFα inhibitors in a mouse model of LPS-induced acute lung injury. Using machine learning we attempted predictive enrichment of TNFα signaling in patients with either ARDS or sepsis. We examined biological factors that drive heterogeneity in host responses to critical infection and their relation to clinical outcomes.ResultsIn mice, LPS induced TNFα–dependent neutrophilia, alveolar permeability and endothelial injury. In humans, TNFα pathway activation was significantly increased in peripheral blood of patients with critical illnesses and associated with the presence of mature neutrophils across critical illnesses and several autoimmune conditions. Machine learning using a gene signature separated patients into 5 phenotypes; one was a hyper-inflammatory, interferon-associated phenotype enriched for increased TNFα pathway activation and conserved across critical illnesses and autoimmune diseases. Cell subset profiles segregated severely ill patients into neutrophil-subset-dependent groups that were enriched for disease severity, demonstrating the importance of neutrophils in the immune response in critical illness.ConclusionsTNFα signaling and mature neutrophils are associated with a hyper-inflammatory phenotype of patients, shared across critical illness and autoimmune disease. This phenotyping provides a personalized medicine hypothesis to test anti-TNFα therapy in severe respiratory illness.Graphical abstract
From sequence to molecules: Feature sequence-based genome mining uncovers the hidden diversity of bacterial siderophore pathways
Authors: Gu Shaohua , Shao Yuanzhe , Rehm Karoline , Bigler Laurent , Zhang Di , He Ruolin , Xu Ruichen , Shao Jiqi , Jousset Alexandre , Friman Ville-Petri , Bian Xiaoying , Wei Zhong , Kümmerli Rolf , Li Zhiyuan 
Published: November 2023

AbstractMicrobial secondary metabolites are a rich source for pharmaceutical discoveries and play crucial ecological functions. While tools exist to identify secondary metabolite clusters in genomes, precise sequence-to-function mapping remains challenging because neither function nor substrate specificity of biosynthesis enzymes can accurately be predicted. Here we developed a knowledge-guided bioinformatic pipeline to solve these issues. We analyzed 1928 genomes ofPseudomonasbacteria and focused on iron-scavenging pyoverdines as model metabolites. Our pipeline predicted 188 chemically different pyoverdines with nearly 100% structural accuracy and the presence of 94 distinct receptor groups required for the uptake of iron-loaded pyoverdines. Our pipeline unveils an enormous yet overlooked diversity of siderophores (151 new structures) and receptors (91 new groups). Our approach, combining feature sequence with phylogenetic approaches, is extendable to other metabolites and microbial genera, and thus emerges as powerful tool to reconstruct bacterial secondary metabolism pathways based on sequence data.Abstract Figure
Understanding the dynamics of complexin-situenzyme-catalyzed reactions undergoing mechanical stress
Authors: Tikader Baishakhi , Kar Sandip 
Published: November 2023

AbstractUnderstanding the diversity in the enzymatic mechanism have utmost importance as it can temporally control the catalytic efficiency. Recent literature suggests that by influencing mechanical properties of hybrid materials, the catalytic efficiency of the enzymatic reactions can be altered significantly. Here, taking a computational and experimental approach, we have dig out the fate of the kinetics of enzyme reaction systems exhibiting relatively complex mechanism than usual Michaelis Menten kinetics involving multiple substrate/enzyme/enzyme-substrate complex. We have developed a numerical recipe improvising stochastic reaction-diffusion approach to explore the role of mechanical stress like compression-decompression cycle (C-D) on modulating the output of enzymatic reaction. The proposed methodology can be used as a theoretical tool to understand how to enhance the catalytic activity and setup appropriate reaction conditions by efficiently using the catalytic cycles. Hence, our methodology will be crucial to identify the most effective strategy to efficiently convert substrate into product in this type of mechanoresponsive materials, which will enable future development of cost-effective biomaterials. In future, the insights gained from this work may find enormous application in drug delivery, tissue engineering, bio-sensing and bio-catalysis.
Breast cancer risk SNPs converge on estrogen receptor binding sites commonly shared between breast tumors to locally alter estrogen signalling output
Authors: Joosten Stacey EP. , Gregoricchio Sebastian , Stelloo Suzan , Yapıcı Elif , Huang Chia-Chi Flora , Collier Maria Donaldson , Morova Tunc , Altintas Berkay , Kim Yongsoo , Canisius Sander , Korkmaz Gozde , Lack Nathan , Vermeulen Michiel , Linn Sabine C. , Zwart Wilbert 
Published: November 2023

ABSTRACTEstrogen Receptor alpha (ERα) is the main driver and prime drug target in luminal breast. ERα chromatin binding is extensively studied in cell lines and a limited number of human tumors, using consensi of peaks shared among samples. However, little is known about inter-tumor heterogeneity of ERα chromatin action, along with its biological implications.Here, we use a large set of ERα ChIP-seq data from 70 ERα+ breast cancers to explore inter-patient heterogeneity in ERα DNA binding, to reveal a striking inter-tumor heterogeneity of ERα action. Interestingly, commonly-shared ERα sites showed the highest estrogen-driven enhancer activity and were most-engaged in long-range chromatin interactions. In addition, the most-commonly shared ERα-occupied enhancers were enriched for breast cancer risk SNP loci. We experimentally confirm SNVs to impact chromatin binding potential for ERα and its pioneer factor FOXA1. Finally, in the TCGA breast cancer cohort, we could confirm these variations to associate with differences in expression for the target gene. Cumulatively, we reveal a natural hierarchy of ERα-chromatin interactions in breast cancers within a highly heterogeneous inter-tumor ERα landscape, with the most-common shared regions being most active and affected by germline functional risk SNPs for breast cancer development.
Attenuating amyloid-beta pathology in mice with in situ programmed astrocytes
Authors: Zhang Lun , Lu Shuai , Jia Ying-bo , Hou Sheng-jie , Zhu Jie , Liu Xiao-ge , Sun Xiao-ying , Huang Ya-ru , Zhao Yu-xuan , Ren Hongan , Liu Chun-yu , Cui Fang , Liu Dong-qun , Du Xiao-yu , Niu Xiao-yun , Li Ling-jie , Wang Ke , Liang Shi-yu , Yang Jin-ju , Ji Shao-yang , Sun Le , Zhou Wei-wei , Xie Xi-xiu , Yu Xiao-lin , Wang Xiaoqun , Liu Rui-tian 
Published: November 2023

AbstractAstrocytes are abundant cells in the central nervous system that provide trophic support for neurons and clear detrimental factors, such as Aβ oligomers (AβOs). However, in the brains of Alzheimer’s disease (AD) patients, astrocytes lose these physiological functions. Here, we genetically engineered astrocytes with an anti-AβO chimeric antigen receptor (CAR), constructed by replacing the antigen-binding domain of MerTK with an AβO-specific single-chain variable fragment, to direct their phagocytic activity against AβOs. CAR-engineered astrocytes (CAR-As) showed significantly enhanced phagocytosis of AβOs due to effective activation of Rac1, Cdc42 and RhoA and markedly decreased release of pro-inflammatory cytokines due to inhibition of the NF-κB and cytokine receptor signalling pathways. Consistently, in situ CAR-As markedly ameliorated the cognitive deficits of APP/PS1 transgenic mice possibly by clearing AβOs and creating a non-inflammatory microenvironment for neuronal survival and the restoration of microglia to a healthy phenotype. Our present study is the first to introduce a CAR-A-based therapy, validate its feasibility and effectiveness, and highlight its potential application for the treatment of AD and other brain disorders.
Enabling population protein dynamics through Bayesian modeling
Authors: Lehmann Sylvain , Vialaret Jérôme , Gabelle Audrey , Bauchet Luc , Villemin Jean-Philippe , Hirtz Christophe , Colinge Jacques 
Published: November 2023

ABSTRACTThe knowledge of protein dynamics or turnover in patients provides invaluable information related to certain diseases, drug efficacy, or biological processes. A great corpus of experimental and computational methods has been developed, including by us, in the case of human patients followedin vivo. Moving one step further, we propose here a new modeling approach to capture the highly relevant notion of population protein dynamics. Using two data sets, we show that models inspired by population pharmacokinetics can accurately capture protein turnover within a cohort of individuals, even in presence of substantial inter-individual variability. Such models pave the way for comparative studies searching for altered dynamics or biomarkers in diseases.
Moderate Diversity of activation thresholds promotes cooperation in the Threshold Public Good Games
Authors: Boza Gergely , Számadó Szabolcs 
Published: November 2023

AbstractSocieties face various collective actions which posits social dilemmas, in which a certain number of group members must act cooperatively in order to reach a collective goal. Such social dilemmas are often modelled as Threshold Public Good Games, in which the collective goal is reached successfully if the number of cooperative decisions reaches a threshold. Because cooperation is often a costly act, to coordinate such actions actors can attempt to communicate, to ensure that cooperative decisions are only made once the chances of reaching the goal, thus meeting the threshold is secured. Here we focus on the distribution of activation thresholds in societies, which captures the dynamics of peer pressure and the interaction between different levels of selfish and cooperative behaviours. Here we show that moderate diversity of activation thresholds favours cooperation under wide range of parameters.
AssessingArthrospira platensisGrowth Rates in three Jeju Local Medium, Including Jeju Magma Seawater
Authors: Jang Huey 
Published: November 2023

ABSTRACTJeju Magma Seawater (JMS), naturally formed beneath the bedrocks of Jeju island, consists of high micronutrient concentrations such as Zinc (Z, 0.019 mg/L), Iron (F, 0.015 mg/L), Manganese (M, 0.008 mg/L), Vanadium (V, 0.015 mg/L), Selenium (S, 0.013 mg/L) and Germanium (G, 0.002 mg/L). Despite the extensive research conducted upon the conventional Zarrouk medium used in Arthrospira platensis culture industry, the commercial potential of JMS on the growth of Arthrospira platensis has been poorly investigated. With respect to growth rate and cost efficiency, the purpose of the study is to discern and compare the growth of Arthrospira platensis in JMS with other accessible mediums on Jeju island. This study investigated the effects of three different growth mediums: Jeju Magma Seawater (JMS), Jeju seawater (JS), and Artificial seawater (AS) to assess their impact on the growth of Arthrospira platensis measured by biomass concentration (g L-1). The ANOVA results showed that JMS exhibited higher growth levels compared to JS ((p = 0.001) < 0.05) and AS (p=0.001). The results of the t-test revealed a statistically significant disparity between mean mass growth in JMS micronutrient-present environment and JMS micronutrient-absent environment (T = 7.94, p (= 4.57e-05) < 0.05). However, based on the growth rate over this experiment, it is estimated that the cost of cultivation required to obtain the same amount of mass is more than seven times higher in JMS compared to conventional Zarrouk medium. Therefore, it is believed that there are limitations to immediate commercialization.
Differential Activity of MAPK signalling Defines Fibroblast Subtypes in Pancreatic Cancer
Authors: Veghini Lisa , Pasini Davide , Delfino Pietro , Fang Rui , Filippini Dea , Neander Christian , Vicentini Caterina , Fiorini Elena , Lupo Francesca , D’Agosto Sabrina L. , Carbone Carmine , Bevere Michele , Behrens Diana , Luchini Claudio , Lawlor Rita T. , Scarpa Aldo , Biffi Giulia , Cheung Phyllis F. , Siveke Jens T. , Corbo Vincenzo 
Published: November 2023

ABSTRACTFibroblast heterogeneity is increasingly recognised across cancer conditions. Given their important contribution to disease progression, mapping out fibroblasts’ heterogeneity is critical to devise effective anti-cancer therapies. Cancer-associated fibroblasts (CAFs) represent the most abundant cell population in pancreatic ductal adenocarcinoma (PDAC). Whether CAF phenotypes are differently specified by PDAC cell lineages remains to be elucidated. Here, we reveal an important role for the MAPK signalling pathway in the definition of PDAC CAF phenotypes. We identify the myCAF transcriptional phenotype as uniquely dependent on proficient MAPK signalling. In addition, CAFs displaying elevated MAPK activity are specifically anchored to basal-like/squamous PDAC cells and define tumour subdomains with reduced frequency of CD8+ T cells. We characterize the single-cell transcriptome of mouse PDAC tumours in response to MAPK inhibition and identify gene expression signatures of MAPKhighCAFs, which suggest immunoregulatory functions. Accordingly, a gene expression signature of MAPKhighCAFs correlates with poor prognosis in several human cancer conditions, including PDAC, and with reduced response to immune checkpoint inhibition in immune-reactive solid tumours. Altogether, our data expand our knowledge on CAF phenotype heterogeneity and reveal a new strategy for targeting of myofibroblastic CAFsin vivo.
A statistical framework for powerful multi-trait rare variant analysis in large-scale whole-genome sequencing studies
Authors: Li Xihao , Chen Han , Selvaraj Margaret Sunitha , Van Buren Eric , Zhou Hufeng , Wang Yuxuan , Sun Ryan , McCaw Zachary R. , Yu Zhi , Arnett Donna K. , Bis Joshua C. , Blangero John , Boerwinkle Eric , Bowden Donald W. , Brody Jennifer A. , Cade Brian E. , Carson April P. , Carlson Jenna C. , Chami Nathalie , Chen Yii-Der Ida , Curran Joanne E. , de Vries Paul S. , Fornage Myriam , Franceschini Nora , Freedman Barry I. , Gu Charles , Heard-Costa Nancy L. , He Jiang , Hou Lifang , Hung Yi-Jen , Irvin Marguerite R. , Kaplan Robert C. , Kardia Sharon L.R. , Kelly Tanika , Konigsberg Iain , Kooperberg Charles , Kral Brian G. , Li Changwei , Loos Ruth J.F. , Mahaney Michael C. , Martin Lisa W. , Mathias Rasika A. , Minster Ryan L. , Mitchell Braxton D. , Montasser May E. , Morrison Alanna C. , Palmer Nicholette D. , Peyser Patricia A. , Psaty Bruce M. , Raffield Laura M. , Redline Susan , Reiner Alexander P. , Rich Stephen S. , Sitlani Colleen M. , Smith Jennifer A. , Taylor Kent D. , Tiwari Hemant , Vasan Ramachandran S. , Wang Zhe , Yanek Lisa R. , Yu Bing ,   NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Rice Kenneth M. , Rotter Jerome I. , Peloso Gina M. , Natarajan Pradeep , Li Zilin , Liu Zhonghua , Lin Xihong 
Published: November 2023

AbstractLarge-scale whole-genome sequencing (WGS) studies have improved our understanding of the contributions of coding and noncoding rare variants to complex human traits. Leveraging association effect sizes across multiple traits in WGS rare variant association analysis can improve statistical power over single-trait analysis, and also detect pleiotropic genes and regions. Existing multi-trait methods have limited ability to perform rare variant analysis of large-scale WGS data. We propose MultiSTAAR, a statistical framework and computationally-scalable analytical pipeline for functionally-informed multi-trait rare variant analysis in large-scale WGS studies. MultiSTAAR accounts for relatedness, population structure and correlation among phenotypes by jointly analyzing multiple traits, and further empowers rare variant association analysis by incorporating multiple functional annotations. We applied MultiSTAAR to jointly analyze three lipid traits (low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides) in 61,861 multi-ethnic samples from the Trans-Omics for Precision Medicine (TOPMed) Program. We discovered new associations with lipid traits missed by single-trait analysis, including rare variants within an enhancer ofNIPSNAP3Aand an intergenic region on chromosome 1.