bluuebunny/crossref_metadata_2025_split huggingface dataset:
Unraveling COVID-19 Relationship with Anxiety Disorders and Symptoms
Authors: Asgel Zeynep , Kouakou Manuela R. , Koller Dora , Pathak Gita A. , Cabrera-Mendoza Brenda , Polimanti Renato 
Published: July 2023

AbstractBackgroundWhile COVID-19 outcomes are associated with increased anxiety, individuals affected by anxiety disorders are more likely to develop severe COVID-19 outcomes.MethodsWe used genome-wide data from UK Biobank (up to 420,531 participants), FinnGen Project (up to 329,077 participants), Million Veteran Program (175,163 participants), and COVID-19 Host Genetics Initiative (up to 122,616 cases and 2,475,240 controls) to investigate possible causal effects and shared genetic mechanisms linking COVID-19 outcomes to anxiety disorders and symptoms.ResultsWe observed a strong genetic correlation of anxiety disorder with COVID-19 positive status (rg=0.35, p=2 × 10-4) and COVID-19 hospitalization (rg=0.31, p=7.2 × 10-4). Among anxiety symptoms, “Tense, sore, or aching muscles during worst period of anxiety” was genetically correlated with COVID-19 positive status (rg=0.33, p=0.001), while “Frequent trouble falling or staying asleep during worst period of anxiety” was genetically correlated with COVID-19 hospitalization (rg=0.24, p=0.004). Through a latent causal variable analysis, we observed that COVID-19 outcomes have statistically significant genetic causality proportion (gcp) on anxiety symptoms (e.g., COVID-19 positive status→“Recent easy annoyance or irritability” │gcp│=0.18, p=6.72 × 10-17). Conversely, anxiety disorders appear to have a possible causal effect on COVID-19 (│gcp│=0.38, p=3.17 × 10-9). Additionally, we also identified multiple loci with evidence of local genetic correlation between anxiety and COVID-19. These appear to be related to genetic effects shared with lung function, brain morphology, alcohol and tobacco use, and hematologic parameters.ConclusionsThis study provided important insights into the relationship between COVID-19 and mental health, differentiating the dynamics linking anxiety disorders to COVID-19 from the effect of COVID-19 on anxiety symptoms.
Testis morphogenesis and fetal Leydig cell development are mediated through ERK signaling activated by platelet derived growth factor receptor alpha
Authors: Li Shu-Yun , Matsuyama Satoko , Whiteside Sarah , Gu Xiaowei , Cool Jonah , Capel Blanche , DeFalco Tony 
Published: July 2023

AbstractPlatelet derived growth factor receptor alpha(Pdgfra) plays a crucial role in the morphogenesis and differentiation of the fetal testis, but the molecular signaling involved in these processes remains unclear. Here, we use XYPdgfra-null knock-in (KI) gonads to investigate the molecular mechanisms underlyingPdgfra-mediated testis cord formation and development of fetal Leydig cells (FLCs). The extracellular signal-regulated kinase (ERK) pathway, a well-known mitogen-activated protein kinase signaling pathway, was significantly inhibited in XYPdgfraKI gonads, suggesting that ERK signaling is activated downstream of PDGFRA. Usingex vivowhole-organ culture, small interfering RNA (siRNA) cell culture methods, transwell assays and a genetic mouse model to disrupt ERK signaling in gonadal cells, we found that the ERK pathway promoted testis cord formation viaearly growth response 1(Egr1)-mediated cell migration and regulated the expression of steroidogenic enzymes in FLCs via activating the transcription factor cAMP responsive element binding protein 1 (CREB; official name CREB1). These findings highlight the significance of PDGFRA and its downstream signaling in fetal testis morphogenesis and cellular differentiation, thus providing insights into the etiology of and potential therapeutic targets for disorders related to gonadal development.
Methods for cell isolation and analysis of the highly regenerative tunicatePolycarpa mytiligera
Authors: gordon Tal , Hendin Noam , Wurtzel Omri 
Published: July 2023

AbstractPolycarpa mytiligerais the only molecularly characterized solitary ascidian capable of regenerating all organs and tissue types. The cellular basis for regeneration inP. mytiligerais largely unknown, and methods for isolating live cells from this species for functional analyses are unavailable. Here, we developed a method for isolating live cells fromP. mytiligera, overcoming major experimental challenges, including the dissociation of its thick body wall and native cellular autofluorescence. We demonstrated the applicability of our approach for tissue dissociation and cell analysis using three flow cytometry platforms, and by using broadly used non-species-specific cell labeling reagents. In addition to live cell isolation, proof-of-concept experiments showed that this approach was compatible with gene expression analysis of RNA extracted from the isolated cells, and with ex vivo analysis of phagocytosis. The ability to purify live cells will promote future studies of cell function inP. mytiligeraregeneration.
Neuron-specific RNA-sequencing reveals different responses in peripheral neurons after nerve injury
Authors: Bolívar S , Sanz E , Ovelleiro D , Zochodne DW , Udina E 
Published: July 2023

AbstractPeripheral neurons are heterogeneous and functionally diverse, but all share the capability to switch to a pro-regenerative state after nerve injury. Despite the assumption that the injury response is similar among neuronal subtypes, functional recovery may differ. Understanding the distinct intrinsic regenerative properties between neurons may help to improve the quality of regeneration, prioritizing the growth of axon subpopulations to their targets. Here, we present a comparative analysis of regeneration across four key peripheral neuron populations: motoneurons, proprioceptors, cutaneous mechanoreceptors, and nociceptors. Using Cre/Ai9 mice that allow fluorescent labelling of neuronal subtypes, we found that nociceptors showed the greater regeneration after a sciatic crush, followed by motoneurons, mechanoreceptors and, finally, proprioceptors. By breeding these Cre mice with Ribotag mice, we isolated specific translatomes and defined the regenerative response of these neuronal subtypes after axotomy. Only 20% of the regulated genes were common, revealing a diverse response to injury among neurons, which was also supported by the differential influence of neurotrophins among neuron subtypes. Among differentially regulated genes, we proposed MED12 as a specific regulator of the regeneration of proprioceptors. Altogether, we demonstrate that the intrinsic regenerative capacity differs between peripheral neuron subtypes, opening the door to selectively modulate these responses.
Diallel panel reveals a significant impact of low-frequency genetic variants on gene expression variation in yeast
Authors: Tsouris Andreas , Brach Gauthier , Friedrich Anne , Hou Jing , Schacherer Joseph 
Published: July 2023

AbstractUnraveling the genetic sources of gene expression variation is essential to better understand the origins of phenotypic diversity in natural populations. Genome-wide association studies identified thousands of variants involved in gene expression variation, however, variants detected only explain part of the heritability. In fact, variants such as low-frequency and structural variants (SVs) are poorly captured in association studies. To assess the impact of these variants on gene expression variation, we explored a half-diallel panel composed of 323 hybrids originated from pairwise crosses of 26 naturalSaccharomyces cerevisiaeisolates. Using short- and long-read sequencing strategies, we established an exhaustive catalog of single nucleotide polymorphisms (SNPs) and SVs for this panel. Combining this dataset with the transcriptomes of all hybrids, we comprehensively mapped SNPs and SVs associated with gene expression variation. While SVs impact gene expression variation, SNPs exhibit a higher effect size with an overrepresentation of low-frequency variants compared to common ones. These results reinforce the importance of dissecting the heritability of complex traits with a comprehensive catalog of genetic variants at the population level.
Five inhibitory receptors display distinct vesicular distributions in T cells
Authors: Lu Jiahe , Veler Alisa , Simonetti Boris , Raj Timsse , Chou Po Han , Cross Stephen J. , Phillips Alexander M. , Ruan Xiongtao , Huynh Lan , Dowsey Andrew W. , Ye Dingwei , Murphy Robert F. , Verkade Paul , Cullen Peter J. , Wülfing Christoph 
Published: July 2023

AbstractT cells can express multiple inhibitory receptors. Upon induction of T cell exhaustion in response to persistent antigen, prominently in the anti-tumor immune response, many are expressed simultaneously. Key inhibitory receptors are CTLA-4, PD-1, LAG3, TIM3 and TIGIT, as investigated here. These receptors are important as central therapeutic targets in cancer immunotherapy. Inhibitory receptors are not constitutively expressed on the cell surface, but substantial fractions reside in intracellular vesicular structures. It remains unresolved to which extent the subcellular localization of different inhibitory receptors is distinct. Using quantitative imaging of subcellular distributions and plasma membrane insertion as complemented by proximity proteomics and a biochemical analysis of the association of the inhibitory receptors with trafficking adaptors, the subcellular distributions of the five inhibitory receptors were discrete. The distribution of CTLA-4 was most distinct with preferential association with lysosomal-derived vesicles and the sorting nexin 1/2/5/6 transport machinery. With a lack of evidence for the existence of specific vesicle subtypes to explain divergent inhibitory receptor distributions, we suggest that such distributions are driven by divergent trafficking through an overlapping joint set of vesicular structures. This extensive characterization of the subcellular localization of five inhibitory receptors in relation to each other lays the foundation for the molecular investigation of their trafficking and its therapeutic exploitation.
The density of regulatory information is a major determinant of evolutionary constraint on non-coding DNA inDrosophila
Authors: Sabarís Gonzalo , Ortíz Daniela M. , Laiker Ian , Mayansky Ignacio , Naik Sujay , Cavalli Giacomo , Stern David L. , Noon Ella Preger-Ben , Frankel Nicolás 
Published: July 2023

AbstractThe density and distribution of regulatory information in non-coding DNA of eukaryotic genomes is largely unknown. Evolutionary analyses have estimated that ∼60% of nucleotides in intergenic regions of theD. melanogastergenome is functionally relevant. This estimate is difficult to reconcile with the commonly accepted idea that enhancers are compact regulatory elements that generally encompass less than 1 kilobase of DNA. Here, we approached this issue through a functional dissection of the regulatory region of the geneshavenbaby(svb). Most of the ∼90 kilobases of this large regulatory region is highly conserved in the genusDrosophila, though characterized enhancers occupy a small fraction of this region. By analyzing the regulation ofsvbin different contexts ofDrosophiladevelopment, we found that the regulatory architecture that drivessvbexpression in the abdominal pupal epidermis is organized in a dramatically different way than the information that drivessvbexpression in the embryonic epidermis. While in the embryonic epidermissvbis activated by compact and dispersed enhancers,svbexpression in the pupal epidermis is driven by large regions with enhancer activity, which occupy a great portion of thesvb cis-regulatory DNA. We observed that other developmental genes also display a dense distribution of putative regulatory elements in their regulatory regions. Furthermore, we found that a large percentage of conserved non-coding DNA of theDrosophilagenome is contained within putative regulatory DNA. These results suggest that part of the evolutionary constraint on non-coding DNA ofDrosophilais explained by the density of regulatory information.
Guided Differentiation of Pluripotent Stem Cells into Heterogeneously Differentiating Cultures of Cardiac Cells
Authors: McIntire Erik , Barr Kenneth A. , Gonzales Natalia M. , Allen Olivia L. , Gilad Yoav 
Published: July 2023

SummaryIn principle, induced pluripotent stem cells (iPSCs) can differentiate into any cell type in the body. The challenge is to find a way to rapidly expand the dimensionality of cell types and cell states we can characterize. To address this, we developed a guided differentiation protocol to produce heterogeneous differentiating cultures of cardiac cell types (cardiac HDCs) in 16 days. Cardiac HDCs are three-dimensional, rhythmically contracting cell aggregates that harbor a temporally and functionally diverse range of cardiac-relevant cell types. We characterize cardiac HDCs from 47 iPSC lines using single-cell RNA-sequencing to identify cardiomyocytes, epicardial cells, cardiac fibroblasts, endothelial cells, and hematopoietic cells, along with both ectodermal and endodermal derivatives. This guided differentiation approach prioritizes simplicity by minimizing the reagents and steps required, thereby enabling rapid and cost-effective experimental throughput. We expect cardiac HDCs to provide a scalable cardiac model for population-level studies of gene regulatory variation and gene-by-environment interactions.
Cross-transmission of resistant gastrointestinal nematodes between wildlife and transhumant sheep
Authors: Beaumelle Camille , Toïgo Carole , Papet Rodolphe , Benabed Slimania , Beurier Mathieu , Bordes Léa , Brignone Anaïs , Curt-Grand-Gaudin Nadine , Garel Mathieu , Ginot Justine , Jacquiet Philippe , Miquel Christian , Poirel Marie-Thérèse , Serafino Anna , Vannard Eric , Bourgoin Gilles , Yannic Glenn 
Published: July 2023

ABSTRACTWild and domestic ungulates can be infected with the same species of gastrointestinal parasitic nematodes. These parasites have free-living stages in the environment that contribute to the ease of transmission among different host species. In addition, gastrointestinal nematodes have developed resistance to anthelmintics which is now considered a major problem for the livestock sector. In a context where wild and domestic ungulates share the same pastures, the maintenance and circulation of resistant gastrointestinal nematodes between species have rarely been explored.In the European Alps, domestic sheep are driven to high-altitude summer pastures and live in sympatry with wild ungulates for several months each year. In this study, we investigated the nemabiome of domestic sheep and Alpine ibex,Capra ibex, in three different areas of the French Alps to evaluate parasite circulation between the two host species. The Alpine ibex is a protected mountain ungulate that is phylogenetically related to sheep and hosts nematode species common to sheep.Using internal transcribed spacer 2 (ITS-2) nemabiome metabarcoding, we found sheep and ibex share similar gastrointestinal nematodes, except for a few species such asMarshallagia marshalliandTrichostrongylus axei. This suggests that the long-term co-occurrence of sheep and ibex on mountain pastures has promoted the exchange of gastrointestinal nematodes between the two hosts. Based on the sequencing of the isotype 1 of the beta tubulin gene, associated with benzimidazole resistance, we found resistant nematodes in all sheep flocks and in all ibex populations. Our results demonstrated that ibex can host and shed resistant strains before transhumant sheep arrive on pastures, and thus could act as a refuge or even contribute to maintaining resistant gastrointestinal nematodes. The relative role of ibex in the maintenance and circulation of resistant strains in sheep remain to be determined.
Allelic variations in a serine protease effector withinClavibacter michiganensispopulations determine pathogen host range
Authors: Verma Raj Kumar , Roman-Reyna Veronica , Coaker Gitta L. , Jacobs Jonathan M. , Teper Doron 
Published: July 2023

AbstractPlant pathogenic bacteria often have a narrow host range, which can vary among different isolates within a population. Here we investigated the host range of the tomato pathogenClavibacter michiganensis(Cm). We determined the genome sequences of 40 tomato Cm isolates and screened them for pathogenicity on tomato and eggplant. Our screen revealed that out of the tested isolates, five were unable to cause disease on any of the hosts, 33 were exclusively pathogenic on tomato, and two were capable of infecting both tomato and eggplant. Through comparative genomic analyses, we identified that the five non-pathogenic isolates lacked thechp/tomApathogenicity island, which has previously been associated with virulence in tomato. In addition, we found that the two eggplant-pathogenic isolates encode a unique allelic variant of the serine proteasechpG(chpGC), an effector that is recognized in eggplant. Introduction ofchpGCinto achpGinactivation mutant in the eggplant-non-pathogenic strain Cm101, failed to complement the mutant, which retained its ability to cause disease in eggplant and failed to elicit hypersensitive response (HR). Conversely, introduction of thechpGvariant from Cm101 into an eggplant pathogenic isolate (CmC48), eliminated its pathogenicity on eggplant, and enabled CmC48 to elicit HR. Our study demonstrates that allelic variation in thechpGeffector gene is a key determinant of host range plasticity within Cm populations.
Chromosome organization shapes replisome dynamics inCaulobacter crescentus
Authors: Zhang Chen , Joseph Asha Mary , Casini Laurent , Collier Justine , Badrinarayanan Anjana , Manley Suliana 
Published: July 2023

AbstractDNA replication in bacteria takes place on highly compacted chromosomes, where segregation, transcription, and repair must occur simultaneously. Within this dynamic environment, colocalization of sister replisomes has been observed in many bacterial species, driving the hypothesis that a physical linker may tether them together. However, replisome splitting has also been reported in many of the same species, leaving the principles behind replisome organization a long-standing puzzle. Here, by tracking the replisome β-clamp subunit in liveCaulobacter crescentus, we find that rapid DNA segregation can give rise to a second focus which resembles a replisome, but does not replicate DNA. Sister replisomes can remain colocalized, or split apart to travel along DNA separately upon disruption of chromosome inter-arm alignment. Furthermore, chromosome arm-specific replication-transcription conflicts differentially modify replication speed on the two arms, facilitate the decoupling of the two replisomes. With these observations, we conclude that the dynamic chromosome organization flexibly shapes the organization of sister replisomes, and we outline principles which can help to reconcile previously conflicting models of replisome architecture.
Shared etiology of Mendelian and complex disease supports drug discovery
Authors: Lalagkas Panagiotis N. , Melamed Rachel D. 
Published: July 2023

AbstractDrugs targeting disease causal genes are more likely to succeed for that disease. However, complex disease causal genes are not always clear. In contrast, Mendelian disease causal genes are well-known and druggable. Here, we seek an approach to exploit the well characterized biology of Mendelian diseases for complex disease drug discovery, by leveraging evidence of pathogenic processes shared between monogenic and complex disease. One way to find shared disease etiology is clinical association: some Mendelian diseases are known to predispose patients to specific complex diseases (comorbidity). Previous studies link this comorbidity to pleiotropic effects of the Mendelian disease causal genes on the complex disease. In previous work studying incidence of 90 Mendelian and 65 complex diseases, we found 2,908 pairs of clinically associated (comorbid) diseases. Using this clinical signal, we can match each complex disease to a set of Mendelian disease causal genes. We hypothesize that the drugs targeting these genes are potential candidate drugs for the complex disease. Our analysis shows that the candidate drugs are enriched among currently investigated or indicated drugs for the relevant complex diseases (odds ratio=1.84, p=5.98e-22). By combining comorbidity with genetic similarity, we recommend drugs further enriched for those investigated or indicated. Our findings suggest a novel way to take advantage of the rich knowledge about Mendelian disease biology to improve treatment of complex diseases.
Assessing the effect of innovation diffusion and technology readiness theories on attitude, behavioral intention and implementation of smart learning
Authors: Alhammadi Khadija , Marashdeh Hazem , Hussain Matloub 
Published: July 2023

PurposeThis study assesses the impact of innovation diffusion theory (IDT), technology readiness index (TRI) and technology acceptance model (TAM) on the actual use of smart learning. This impact also accounts for the country-digital culture by moderating the effects of resistance to change (RTC) and mediating the role of attitude.Design/methodology/approachThe authors gather data from 301 respondents from various academic institutions in the United Arab Emirates (UAE) by operationalizing established theoretical constructs. The authors adopt a covariance-based structural equation modeling (SEM) approach.FindingsThe results reveal that IDT and TRI significantly and positively affect attitudes toward implementing smart learning. Besides, the attitude fully mediates the relationship between IDT, TRI constructs and behavioral intention (BI). Moreover, this study proves that RTC plays a major role in converging BI to place smart learning into actual use.Research limitations/implicationsThe major limitation of the authors' work is that this work employs cross-sectional data from UAE only, and the data were gathered during the coronavirus disease 2019 (COVID-19) pandemic.Practical implicationsThe stakeholders and administrators in government can benefit from the study findings to improve the efficiency and effectiveness of the implementation of smart learning, which will contribute to achieving stakeholders and administrators' strategic objectives.Originality/valueThe originality of this work stems from the incorporation of IDT, TRI and TAM constructs in the case of smart learning in UAE in post-COVID-19 scenarios.