bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deep-mining of vertebrate genomes reveals an unexpected diversity of endogenous viral elements
Authors: Barreat Jose Gabriel Nino , Katzourakis Aris 
Published: October 2023

AbstractEndogenous viral elements (EVEs) are key to our understanding of the diversity, host range and evolutionary history of viruses. Given the increasing amounts of virus and host sequence data, a systematic search for EVEs is becoming computationally challenging. We used ElasticBLAST on the Google Cloud Platform to perform a comprehensive search for EVEs (kingdomsShotokuviraeandOrthornavirae) across vertebrates. We provide evidence for the first EVEs belonging to the familiesChuviridae,Paramyxoviridae,NairoviridaeandBenyviridaein vertebrate genomes. We also find an EVE from theHepacivirusgenus of flaviviruses with orthology across murine rodents. Phylogenetic analysis of hits closely related to reptarenavirus and filovirus ectodomains suggest three independent captures from a retroviral source. Our findings increase the family-level diversity of non-retroviral EVEs in vertebrates by 44%. In particular, our results shed light on key aspects of the natural history and evolution of viruses in the phylaNegarnaviricotaandKitrinoviricota.
Natural variation in oxytocin receptor signaling causes widespread changes in brain transcription: a link to the natural killer gene complex
Authors: Boender Arjen J. , Johnson Zachary V. , Gruenhagen George W. , Horie Kengo , Hegarty Brianna E. , Streelman Jeffrey T. , Walum Hasse , Young Larry J. 
Published: October 2023

AbstractOxytocin (OXT) is a highly conserved neuropeptide that modulates social cognition, and variation in its receptor gene (Oxtr) is associated with divergent social phenotypes. The cellular mechanisms connectingOxtrgenotype to social phenotype remain obscure. We exploit an association betweenOxtrpolymorphisms and striatal-specific OXTR density in prairie voles to investigate how OXTR signaling influences the brain transcriptome. We discover widespread, OXTR signaling- dependent transcriptomic changes. Interestingly, OXTR signaling robustly modulates gene expression of C-type lectin-like receptors (CTLRs) in the natural killer gene complex, a genomic region associated with immune function. CTLRs are positioned to control microglial synaptic pruning; a process important for shaping neural circuits. Similar relationships betweenOXTRRNA and CTLR gene expression were found in human striatum. These data suggest a potential molecular mechanism by which variation in OXTR signaling due to genetic background and/or life-long social experiences, including nurturing/neglect, may affect circuit connectivity and social behavior.
Impact of repeated cryopreservation on embryo health and implantation potential
Authors: Li Tong , Li Shan , Chow Darren J.X. , Rose Ryan D. , Tan Tiffany C.Y. , Dunning Kylie R. 
Published: October 2023

AbstractIn IVF clinics, preimplantation genetic testing (PGT) is a common practice that involves a biopsy and cryopreservation of embryos for genetic evaluation. When testing fails – or is required for already cryopreserved embryos – multiple freeze-thaw cycles occur. Though known to impact live birth rates, the exclusive influence of cryopreservation has not been elucidated. Here, we evaluate the effect of repeated cryopreservation on embryo health and implantation potential.Blastocyst-stage murine embryos were subjected to one, two or three freeze-thaw cycles with fresh embryos serving as a control. Outcomes assessed included post-thaw survival rate, allocation of cells to the inner cell mass (ICM)vs. trophectoderm cell lineages, implantation potential and offspring health.Post-thawing, embryos that were subjected to three freeze-thaw cycles had a significantly lower survival rates compared to embryos that had undergone one cycle (P<0.001). Additionally, the number of ICM cells was significantly reduced in embryos subjected to two or three freeze-thaw cycles compared to fresh or single-cycle embryos (P<0.001). No statistically significant differences were found for pregnancy rate, number of implantations, viable fetuses or resorption sites between treatment groups. We did however, find a non-significant yet interesting trend: three freeze-thaw cycles were associated with a 20% decrease in viable fetuses and a 20% increase in resorption sites compared to one freeze-thaw cycle group.These findings demonstrate that repeated cryopreservation adversely affects embryo health and may decrease implantation potential. Consequently, caution is advised regarding the repeated application of cryopreservation in IVF clinics, underscoring the need for further research to optimise cryopreservation protocols.
Atypical Protein Kinase C Promotes its own Asymmetric Localisation by Phosphorylating Cdc42 in theC. eleganszygote
Authors: Packer John , Gubieda Alicia G. , Brooks Aaron , Deutz Lars N. , Squires Iolo , Ellison Shona , Schneider Claudia , Naganathan Sundar Ram , Wollman Adam J.M. , Dickinson Daniel J. , Rodriguez Josana 
Published: October 2023

SUMMARYAtypical protein kinase C (aPKC) is a major regulator of cell polarity. Acting in conjunction with Par6, Par3 and the small GTPase Cdc42, aPKC becomes asymmetrically localised and drives the polarisation of cells. aPKC activity is crucial for its own asymmetric localisation, suggesting a hitherto unknown feedback mechanism contributing to polarisation. Here we show in theC. eleganszygote that the feedback relies on aPKC phosphorylation of Cdc42 at serine 71. The turnover of CDC-42 phosphorylation ensures optimal aPKC asymmetry and activity throughout polarisation by tuning Par6/aPKC association with Par3 and Cdc42. Moreover, turnover of Cdc42 phosphorylation regulates actomyosin cortex dynamics that are known to drive aPKC asymmetry. Given the widespread role of aPKC and Cdc42 in cell polarity, this form of self-regulation of aPKC may be vital for the robust control of polarisation in many cell types.Key findings/graphical abstract- Phosphorylation of CDC-42 by aPKC accelerates aPKC dissociation from CDC-42, limiting aPKC activity- CDC-42/aPKC dissociation promotes aPKC association with PAR-3 and, thereby, aPKC asymmetry due to actomyosin flow- Cycling of CDC-42 phosphorylation fuels the exchange of aPKC between anteriorly transported PAR-3 and aPKC-active CDC-42 complexes- Turnover of CDC-42 phosphorylation alternates its association with effectors, aPKC and MRCK-1, ensuring proper actomyosin dynamics
ATR promotes mTORC1 activity viade novocholesterol synthesis
Authors: Tangudu Naveen Kumar , Grumet Alexandra N. , Fang Richard , Buj Raquel , Cole Aidan R. , Uboveja Apoorva , Amalric Amandine , Yang Baixue , Huang Zhentai , Happe Cassandra , Sun Mai , Gelhaus Stacy L. , MacDonald Matthew L. , Hempel Nadine , Snyder Nathaniel W. , Kedziora Katarzyna M. , Valvezan Alexander J. , Aird Katherine M. 
Published: October 2023

ABSTRACTDNA damage and cellular metabolism exhibit a complex interplay characterized by bidirectional feedback mechanisms. Key mediators of the DNA damage response and cellular metabolic regulation include Ataxia Telangiectasia and Rad3-related protein (ATR) and the mechanistic Target of Rapamycin Complex 1 (mTORC1), respectively. Previous studies have established ATR as a regulatory upstream factor of mTORC1 during replication stress; however, the precise mechanisms by which mTORC1 is activated in this context remain poorly defined. Additionally, the activity of this signaling axis in unperturbed cells has not been extensively investigated. Here, we demonstrate that ATR promotes mTORC1 activity across various cellular models under basal conditions. This effect is particularly enhanced in cells following the loss of p16, which we have previously associated with hyperactivation of mTORC1 signaling and here found have increased ATR activity. Mechanistically, we found that ATR promotesde novocholesterol synthesis and mTORC1 activation through the upregulation of lanosterol synthase (LSS), independently of both CHK1 and the TSC complex. Furthermore, the attenuation of mTORC1 activity resulting from ATR inhibition was rescued by supplementation with lanosterol or cholesterol in multiple cellular contexts. This restoration corresponded with enhanced localization of mTOR to the lysosome. Collectively, our findings demonstrate a novel connection linking ATR and mTORC1 signaling through the modulation of cholesterol metabolism.
Trait selection strategy in multi-trait GWAS: Boosting SNPs discoverability
Authors: Suzuki Yuka , Ménager Hervé , Brancotte Bryan , Vernet Raphaël , Nerin Cyril , Boetto Christophe , Auvergne Antoine , Linhard Christophe , Torchet Rachel , Lechat Pierre , Troubat Lucie , Cho Michael H. , Bouzigon Emmanuelle , Aschard Hugues , Julienne Hanna 
Published: October 2023

AbstractSince the first Genome-Wide Association Studies (GWAS), thousands of variant-trait associations have been discovered. However, the sample size required to detect additional variants using standard univariate association screening is increasingly prohibitive. Multi-trait GWAS offers a relevant alternative: it can improve statistical power and lead to new insights about gene function and the joint genetic architecture of human phenotypes. Although many methodological hurdles of multi-trait testing have been discussed, the strategy to select trait, among overwhelming possibilities, has been overlooked. In this study, we conducted extensive multi-trait tests using JASS (Joint Analysis of Summary Statistics) and assessed which genetic features of the analysed sets were associated with anincreased detection of variants as compared to univariate screening. Our analyses identified multiple factors associated with the gain in the association detection in multi-trait tests. Together, these factors of the analysed sets are predictive of the gain of the multi-trait test (Pearson’s ρ equal to 0.43 between the observed and predicted gain,P< 1.6 × 10-60). Applying an alternative multi-trait approach (MTAG, multi-trait analysis of GWAS), we found that in most scenarios but particularly those with larger numbers of traits, JASS outperformed MTAG. Finally, we benchmark several strategies to select set of traits including the prevalent strategy of selecting clinically similar traits, which systematically underperformed selecting clinically heterogenous traits or selecting sets that issued from our data-driven models. This work provides a unique picture of the determinant of multi-trait GWAS statistical power and outline practical strategies for multi-trait testing.
Pervasive relaxed selection on spermatogenesis genes coincident with the evolution of polygyny in gorillas
Authors: Bowman Jacob D. , Silva Neide , Schüftan Erik , Almeida Joana M. , Brattig-Correia Rion , Oliveira Raquel A. , Tüttelmann Frank , Enard David , Navarro-Costa Paulo , Lynch Vincent J. 
Published: October 2023

AbstractGorillas have a polygynous social system in which the highest-ranking male has almost exclusive access to females and sires most of the offspring in the troop. Such behavior results in a dramatic reduction of sperm competition, which is ultimately associated with numerous traits that cause low efficacy of gorilla spermatogenesis. However, the molecular basis behind the remarkable erosion of the gorilla male reproductive system remains unknown. Here, we explored the genetic consequences of the polygynous social system in gorillas by testing for altered selection intensity across 13,310 orthologous protein-coding genes from 261 Eutherian mammals. We identified 578 genes with relaxed purifying selection in the gorilla lineage, compared with only 96 that were positively selected. Genes under relaxed purifying selection in gorillas have accumulated numerous deleterious amino acid substitutions, their expression is biased towards male germ cells, and are enriched in functions related to meiosis and sperm biology. We tested the function of gorilla relaxed genes previously not implicated in sperm biology using theDrosophilamodel system and identified 41 novel spermatogenesis genes required for normal fertility. Furthermore, by exploring exome/genome sequencing data of infertile men with severe spermatogenic impairment, we found that the human orthologs of the gorilla relaxed genes are enriched for loss-of-function variants in infertile men. These data provide compelling evidence that reduced sperm competition in gorillas is associated with relaxed purifying selection on genes related to male reproductive function. The accumulation of deleterious mutations in these genes likely provides the mechanistic basis behind the low efficacy of gorilla spermatogenesis and uncovers new candidate genes for human male infertility.
Engineered Reversible Inhibition of SpyCatcher Reactivity Enables Rapid Generation of Bispecific Antibodies
Authors: Hentrich Christian , Putyrski Mateusz , Hanuschka Hanh , Preis Waldemar , Kellmann Sarah-Jane , Wich Melissa , Cavada Manuel , Hanselka Sarah , Ylera Francisco 
Published: October 2023

AbstractThe precise regulation of protein function is essential in biological systems, and achieving such control is a fundamental objective in the fields of chemical biology and protein engineering. Here, we describe a straightforward method to engineer functional control into the isopeptide bond-forming SpyTag/SpyCatcher protein ligation system. First, we performed a cysteine scan of SpyCatcher, exchanging each amino acid in the structured region against cysteine. Except for the two known reactive and catalytic residues, none of these mutations abolished reactivity. In a second screening step, we modified the cysteines with disulfide bond-forming small molecules and screened for reactivity again. Here we found 8 positions that, when modified, strongly inhibited reactivity. This inhibition could be reversed by treatment with reducing agents. We call such a reversibly inhibitable SpyCatcher “SpyLock”.We then used “BiLock”, a fusion of SpyLock and wildtype SpyCatcher, in combination with SpyTagged antibody fragments to generate bispecific antibodies. A first antibody was reacted with the regular SpyCatcher moiety, followed by unlocking of the SpyLock through reduction and its reaction with a second antibody. This method to generate bispecific antibodies requires only a single antibody format and is readily scalable, facilitating the screening of a large number of antibody combinations. We demonstrate the utility of this approach to screen anti-PD-1/anti-PD-L1 bispecific antibodies using a cellular reporter assay.
The molecular architecture of the kidney slit diaphragm
Authors: Birtasu Alexandra N. , Wieland Konstantin , Ermel Utz H. , Rahm Johanna V. , Scheffer Margot P. , Flottmann Benjamin , Heilemann Mike , Grahammer Florian , Frangakis Achilleas S. 
Published: October 2023

AbstractVertebrate life depends on renal function to filter excess fluid and remove low-molecular-weight waste products. An essential component of the kidney filtration barrier is the slit diaphragm (SD), a specialized cell-cell junction between podocytes. Although the constituents of the SD are largely known, its molecular organization remains elusive. Here, we use super-resolution correlative light and electron microscopy to quantify a linear rate of reduction in albumin concentration across the filtration barrier. Next, we use cryo-electron tomography of vitreous lamellae from high-pressure frozen native glomeruli to analyze the molecular architecture of the SD. The resulting densities resemble a fishnet pattern. Fitting of Nephrin and Neph1, the main constituents of the SD, results in a complex interaction pattern with multiple contact sites between the molecules. Using molecular dynamics flexible fitting, we construct a blueprint of the SD, where we describe all interactions. Our architectural understanding of the SD reconciles previous findings and provides a mechanistic framework for the development of novel therapies to treat kidney dysfunction.
Drosophilamodels of PIGA-CDG mirror patient phenotypes
Authors: Thorpe Holly J. , Owings Katie G. , Aziz Miriam C. , Haller Madelyn , Coelho Emily , Chow Clement Y. 
Published: October 2023

AbstractMutations in the phosphatidylinositol glycan biosynthesis class A (PIGA) gene cause a rare, X-linked recessive congenital disorder of glycosylation (CDG). PIGA-CDG is characterized by seizures, intellectual and developmental delay, and congenital malformations. ThePIGAgene encodes an enzyme involved in the first step of GPI anchor biosynthesis. There are over 100 GPI anchored proteins that attach to the cell surface and are involved in cell signaling, immunity, and adhesion. Little is known about the pathophysiology of PIGA-CDG. Here we describe the firstDrosophilamodel of PIGA-CDG and demonstrate that loss ofPIG-Afunction inDrosophilaaccurately models the human disease. As expected, complete loss ofPIG-Afunction is larval lethal. Heterozygous null animals appear healthy, but when challenged, have a seizure phenotype similar to what is observed in patients. To identify the cell-type specific contributions to disease, we generated neuron- and glia-specific knockdown ofPIG-A. Neuron-specific knockdown resulted in reduced lifespan and a number of neurological phenotypes, but no seizure phenotype. Glia-knockdown also reduced lifespan and, notably, resulted in a very strong seizure phenotype. RNAseq analyses demonstrated that there are fundamentally different molecular processes that are disrupted whenPIG-Afunction is eliminated in different cell types. In particular, loss ofPIG-Ain neurons resulted in upregulation of glycolysis, but loss ofPIG-Ain glia resulted in upregulation of protein translation machinery. Here we demonstrate thatDrosophilais a good model of PIGA-CDG and provide new data resources for future study of PIGA-CDG and other GPI anchor disorders.Article SummaryPIGA-CDG is a rare genetic disorder. In order to study this rare disease, we generated and characterized several Drosophila models of PIGA-CDG. These models faithfully recapitulate different patient phenotypes, including movement disorder and seizures. Drosophila is a good model for PIGA-CDG and other GPI anchor disorders.
Overexpression of Alpha-1 Antitrypsin Increases the Proliferation of Mesenchymal Stem Cells by Upregulation of Cyclin D1 and is Independent of the Wnt Signaling Pathway
Authors: Wolf Bryan , Muralidharan Prasanth , Lee Michael , Hua Wei , Green Erica , Wang Hongjun , Strange Charlie 
Published: October 2023

ABSTRACTAlaph-1 antitrypsin overexpressing mesenchymal stromal/stem cells (AAT-MSCs) showed improved innate properties with a faster proliferation rate when studied for their protective effects in mouse models of diseases. Here, we investigated the potential mechanism(s) by which AAT gene insertion increases MSC proliferation. Human bone marrow-derived primary or immortalized MSCs (iMSCs) or AAT-MSCs (iAAT-MSCs) were used in the study. Cell proliferation was measured by cell counting and cell cycle analysis. Possible pathways involved in the pro-proliferation effect of AAT were investigated by measuring mRNA and protein expression of key cell cycle genes. Interval cell counting showed increased proliferation in AAT-MSCs or iAAT-MSCs compared to their corresponding MSC controls. Cell cycle analysis revealed more cells progressing into the S and G2/M phases in iAAT-MSCs, with a notable increase in the cell cycle protein, Cyclin D1. Moreover, treatment with Cyclin D1 inhibitors showed that the increase in proliferation is due to Cyclin D1 and that the AAT protein is upstream and a positive regulator of Cyclin D1. Furthermore, AAT’s effect on Cyclin D1 is independent of the Wnt signaling pathway as there were no differences in the expression of regulatory proteins, including GSK3β and β-Catenin in iMSC and iAAT-MSCs. In summary, our results indicate that AAT gene insertion in an immortalized MSC cell line increases cell proliferation and growth by increasing Cyclin D1 expression and consequently causing cells to progress through the cell cycle at a significantly faster rate.
“Safety and security are everything”: a qualitative study on the quality of life of Syrian refugees living in Za’atari camp
Authors: Momani Aaliyah M. , Alduraidi Hamza , Zaghmouri Abeer 
Published: October 2023

Purpose
Many refugees around the world are forced to leave their counties seeking safety and security. Millions of Syrian refugees fled their country since the conflict started in Syria. Jordan is one of the host countries for refugees from different countries including Syria. Health-related quality of life of individuals influences both the individual and the community, and how these two interact with one another. This study aims to explore the four domains – physical health, psychological health, social relationships and environment domains – of health-related quality of life of adults residing in Za’atari camp in the North of Jordan.

Design/methodology/approach
A constructivist grounded theory approach was used. Data were collected using semi-structured, face-to-face, audio-recorded interviews. Data were analysed using different levels of coding, constant comparative analysis and writing reflective memos.

Findings
Pursuing safety and security emerged as a core theme in this study. Participants were pursuing safety and security since the conflict started in Syria. Lack of safety and security led them to flee Syria. For participants, safety and security were among the most important aspects of their lives. The meaning of safety and security for Syrian refugees is presented in this paper.

Originality/value
To the best of the authors’ knowledge, this is the first study exploring the health-related quality of life of Syrian refugees residing in Za’atari camp using a qualitative approach.
The effects of supply chain governance on supply chain resilience based on information processing theory
Authors: Lu Qiang , Jiang Yu , Wang Yu 
Published: October 2023

PurposeThis study investigates the impact of supply chain governance (SCG, which includes relational governance and contractual governance) on supply chain resilience (SCR) using the information processing theory. Moreover, the study also examines the mediating role of information processing capability and the moderating role of digital technology (DT) deployment.Design/methodology/approachA total of 288 questionnaires were collected from the Chinese manufacturing industry, and hierarchical regression was used to empirically test the proposed model.FindingsThis study reveals that SCG positively impacts SCR. Moreover, information processing capability plays a mediating role between SCG and SCR. Furthermore, the breadth of DT deployment positively moderates the effect of relational governance on information processing capability, and the depth of DT deployment positively moderates the effects of both relational governance and contractual governance on information processing capability.Originality/valueThis study offers a novel perspective that helps to understand the importance of the supply chain-wide information acquired by SCG in respect of improving SCR. Furthermore, this article extends the application of information processing theory by providing empirical evidence of the mediating role of information processing capability and elucidating the moderating role of DT deployment.