bluuebunny/crossref_metadata_2025_split huggingface dataset:
Partial sex linkage and linkage disequilibrium on the guppy sex chromosome
Authors: Qiu Suo , Yong Lengxob , Wilson Alastair , Croft Darren P. , Graham Chay , Charlesworth Deborah 
Published: January 2022

AbstractThe guppy Y chromosome has been considered a model system for the evolution of suppressed recombination between sex chromosomes, and it has been proposed that complete sex-linkage has evolved across about 3 Mb surrounding this fish’s sex-determining locus, followed by recombination suppression across a further 7 Mb of the 23 Mb XY pair, forming younger “evolutionary strata”. Sequences of the guppy genome show that Y is very similar to the X chromosome, making it important to understand which parts of the Y are completely non-recombining, and whether there is indeed a large completely non-recombining region. Here, we describe new evidence that supports a different interpretation of the data that suggested the presence of such a region. We analysed PoolSeq data in samples from multiple natural populations from Trinidad. This yields evidence for linkage disequilibrium (LD) between sequence variants and the sex-determining locus. Downstream populations have higher diversity than upstream ones (which display the expected signs of bottlenecks). The associations we observe conform to predictions for a genome region with infrequent recombination that carries one or more sexually antagonistic polymorphisms. They also suggest the region in which the sex-determining locus must be located. However, no consistently male-specific variants were found, supporting the suggestion that any completely sex-linked region may be very small.
Contrast-enhanced microCT evaluation of degeneration following partial and full width injuries to mouse lumbar intervertebral disc
Authors: Walk Remy E. , Moon Hong Joo , Tang Simon Y. , Gupta Munish C. 
Published: January 2022

AbstractStudy DesignPreclinical animal studyObjectiveEvaluation of the degenerative progression resulting from either a partial- or full- width injury to the mouse lumbar intervertebral disc (IVD) using contrast-enhanced micro-computed tomography and histological analyses. We utilized a lateral-retroperitoneal surgical approach to access the lumbar IVD, and the injuries to the IVD were induced by either incising one side of the annulus fibrosus or puncturing both sides of the annulus fibrosus. The full-width injury caused dramatic reduction in nucleus pulposus hydration and significant degeneration. A partial-width injury produces localized deterioration around the annulus fibrosus that resulted in local tissue remodeling without gross degeneration to the IVD.MethodsFemale C57BL/6J mice of 3-4 months age were used in this study. They were divided into three groups to undergo partial-width, full-width, or sham injuries. The L5/L6 and L6/S1 lumbar IVDs were surgically exposed using a lateral-retroperitoneal approach. The L6/S1 IVDs were injured using either a surgical scalpel (partial-width) or a 33G needle (full-width), with the L5/L6 serving as an internal control. These animals were allowed to recover and then sacrificed at 2-, 4-, or 8-weeks post-surgery. The IVDs were assessed for degeneration using contrast-enhanced microCT (CEµCT) and histological analysis.ResultsThe high-resolution 3D evaluation of the IVD confirmed that the respective injuries localized within one side of the annulus fibrosus or spanned the full width of the IVD. The full-width injury caused deteriorations in the nucleus pulposus after 2 weeks and progressed to significant degeneration at 8 weeks, while the partial width injury caused localized disruptions that remained limited to the annulus fibrosus.ConclusionThe use of CEµCT revealed distinct IVD degeneration profiles resulting from partial- and full- width injuries. The partial width injury may serve as an alternative for IVD degeneration resulting from localized annulus fibrosus injuries in humans.
Temporal control of late replication and coordination of origin firing by self-stabilizing Rif1-PP1 hubs in Drosophila
Authors: Cho Chun-Yi , Seller Charles A. , O’Farrell Patrick H. 
Published: January 2022

ABSTRACTIn the metazoan S phase, coordinated firing of clusters of origins replicates different parts of the genome in a temporal program. Despite advances, neither the mechanism controlling timing nor that coordinating firing of multiple origins is fully understood. Rif1, an evolutionarily conserved inhibitor of DNA replication, recruits protein phosphatase 1 (PP1) and counteracts firing of origins by S-phase kinases. During the mid-blastula transition (MBT) in Drosophila embryos, Rif1 forms subnuclear hubs at each of the large blocks of satellite sequences and delays their replication. Each Rif1 hub disperses abruptly just prior to the replication of the associated satellite sequences. Here, we show that the level of activity of the S-phase kinase, DDK, accelerated this dispersal program, and that the level of Rif1-recruited PP1 retarded it. Further, Rif1-recruited PP1 supported chromatin association of nearby Rif1. This influence of nearby Rif1 can create a “community effect” counteracting kinase-induced dissociation such that an entire hub of Rif1 undergoes switch-like dispersal at characteristic times that shift in response to the balance of Rif1-PP1 and DDK activities. We propose a model in which the spatiotemporal program of late replication in the MBT embryo is controlled by self-stabilizing Rif1-PP1 hubs, whose abrupt dispersal synchronizes firing of associated late origins.SIGNIFICANCESeventy years ago, it was discovered that large domains of the eukaryotic genome replicate at different times. Detailed descriptions left significant questions unresolved. How are the many origins in the large domains coordinated to fire in unison? What distinguishes different domains and gives rise to a temporal program? When Drosophila embryos first establish late replication, an inhibitor of DNA replication, Rif1, forms hubs over domains of late replicating DNA. Rif1 recruits protein phosphatase 1 (PP1), which prevents kinases from dispersing Rif1 hubs or activating associated origins. When kinase activity eventually exceeds a hub-specific threshold, the self-stabilization of Rif1-PP1 breaks down, hubs disperse abruptly, and all associated origins are free to initiate.
Somatodendritic release of cholecystokinin potentiates GABAergic synapses onto ventral tegmental area dopamine cells
Authors: Damonte Valentina Martinez , Pomrenze Matthew B. , Casper Caroline , Wolfden Annie M. , Malenka Robert C. , Kauer Julie A. 
Published: January 2022

SUMMARYNeuropeptides are contained in nearly every neuron in the central nervous system and can be released from somatodendritic sites as well as from nerve terminals. Cholecystokinin (CCK), among the most abundant neuropeptides in the brain, is expressed in the majority of midbrain dopamine neurons. Here we report that ventral tegmental area (VTA) dopamine neurons release CCK from somatodendritic regions, where it triggers long-term potentiation of GABAergic synapses. The somatodendritic release occurs with trains of action potentials or prolonged but modest depolarization and is dependent on synaptotagmin 7 and T-type Ca2+ channels. Depolarization-induced LTP is blocked by the CCK2R antagonist, LY225910, and mimicked by exogenously added CCK. To test the behavioral role of CCK, we infused it into the mouse VTA. Ca2+ imaging in vivo demonstrated that infused CCK reduced dopamine cell signals during fasted food consumption. Moreover, local infusion of CCK also inhibited food consumption and decreased distance traveled in an open field test. Together our experiments introduce somatodendritic neuropeptide release as a previously unknown feedback regulator of VTA dopamine cell excitability and dopamine-related behaviors.
conST: an interpretable multi-modal contrastive learning framework for spatial transcriptomics
Authors: Zong Yongshuo , Yu Tingyang , Wang Xuesong , Wang Yixuan , Hu Zhihang , Li Yu 
Published: January 2022

AbstractMotivationSpatially resolved transcriptomics (SRT) shows its impressive power in yielding biological insights into neuroscience, disease study, and even plant biology. However, current methods do not sufficiently explore the expressiveness of the multi-modal SRT data, leaving a large room for improvement of performance. Moreover, the current deep learning based methods lack interpretability due to the “black box” nature, impeding its further applications in the areas that require explanation.ResultsWe propose conST, a powerful and flexible SRT data analysis framework utilizing contrastive learning techniques. conST can learn low-dimensional embeddings by effectively integrating multi-modal SRT data, i.e. gene expression, spatial information, and morphology (if applicable). The learned embeddings can be then used for various downstream tasks, including clustering, trajectory and pseudotime inference, cell-to-cell interaction, etc. Extensive experiments in various datasets have been conducted to demonstrate the effectiveness and robustness of the proposed conST, achieving up to 10% improvement in clustering ARI in the commonly used benchmark dataset. We also show that the learned embedding can be used in complicated scenarios, such as predicting cancer progression by analyzing the tumour microenvironment and cell-to-cell interaction (CCI) of breast cancer. Our framework is interpretable in that it is able to find the correlated spots that support the clustering, which matches the CCI interaction pairs as well, providing more confidence to clinicians when making clinical decisions.
Structural Insights into Sphingosine-1-phosphate Receptor Activation
Authors: Yu Leiye , He Licong , Gan Bing , Ti Rujuan , Xiao Qingjie , Hu Hongli , Zhu Lizhe , Wang Sheng , Ren Ruobing 
Published: January 2022

AbstractAs a critical sphingolipid metabolite, sphingosine-1-phosphate (S1P) plays an essential role in immune and vascular systems. There are five S1P receptors, designated as S1PR1-5, encoded in the human genome, and their activities are governed by endogenous S1P, lipid-like S1P mimics, or non-lipid-like therapeutic molecules. Among S1PRs, S1PR1 stands out due to its non-redundant functions, such as the egress of T and B cells from the thymus and secondary lymphoid tissues, making it a potential therapeutic target. However, the structural basis of S1PR1 activation and regulation by various agonists remains unclear. Here we reported four atomic resolution cryo-EM structures of Gi-coupled human S1PR1 complexes: bound to endogenous agonist d18:1 S1P, benchmark lipid-like S1P mimic phosphorylated Fingolimod ((S)-FTY720-P), or non-lipid-like therapeutic molecule CBP-307 in two binding modes. Our results revealed the similarities and differences of activation of S1PR1 through distinct ligands binding to the amphiphilic orthosteric pocket. We also proposed a two-step “shallow to deep” transition process of CBP-307 for S1PR1 activation. Both binding modes of CBP-307 could activate S1PR1, but from shallow to deep transition may trigger the rotation of the N-terminal helix of Gαi and further stabilize the complex by increasing the Gαi interaction with the cell membrane. We combine with extensive biochemical analysis and molecular dynamic simulations to suggest key steps of S1P binding and receptor activation. The above results decipher the common feature of the S1PR1 agonist recognition and activation mechanism and will firmly promote the development of therapeutics targeting S1P receptors.
The Cif proteins from Wolbachia prophage WO modify sperm genome integrity to establish cytoplasmic incompatibility
Authors: Kaur Rupinder , Leigh Brittany A. , Ritchie Isabella T. , Bordenstein Seth R. 
Published: January 2022

AbstractInherited microorganisms can selfishly manipulate host reproduction to drive through populations. In Drosophila melanogaster, germline expression of the native Wolbachia prophage WO proteins CifA and CifB cause cytoplasmic incompatibility (CI) in which embryos from infected males and uninfected females suffer catastrophic mitotic defects and lethality; however, in infected females, CifA expression rescues the embryonic lethality and thus imparts a fitness advantage to the maternally-transmitted Wolbachia. Despite widespread relevance to sex determination, evolution, and vector control, the mechanisms underlying when and how CI impairs male reproduction remain unknown and a topic of debate. Here we use cytochemical, microscopic, and transgenic assays in D. melanogaster to demonstrate that CifA and CifB proteins of wMel localize to nuclear DNA throughout the process of spermatogenesis. Cif proteins cause abnormal histone retention in elongating spermatids and protamine deficiency in mature sperms that travel to the female reproductive tract with Cif proteins. Notably, protamine gene knockouts enhance wild type CI. In ovaries, CifA localizes to germ cell nuclei and cytoplasm of early-stage egg chambers, however Cifs are absent in late-stage oocytes and subsequently in fertilized embryos. Finally, CI and rescue are contingent upon a newly annotated CifA bipartite nuclear localization sequence. Together, our results strongly support the Host Modification model of CI in which Cifs initially modify the paternal and maternal gametes to bestow CI-defining embryonic lethality and rescue.
Metal-binding propensity in the mitochondrial dynamin-related protein 1
Authors: Roy Krishnendu , Pucadyil Thomas J. 
Published: January 2022

AbstractDynamin-related protein1 (Drp1) functions to divide mitochondria and peroxisomes by binding specific adaptor proteins and lipids, both of which are integral to the limiting organellar membrane. In efforts to understand how such multivalent interactions regulate Drp1 functions,in vitroreconstitution schemes rely on recruiting soluble portions of the adaptors appended with genetically encoded polyhistidine tags onto membranes containing Ni2+-bound chelator lipids. These strategies are facile and circumvent the challenge in working with membrane proteins but assume that binding is specific to proteins carrying the polyhistidine tag. Here, we find using chelator lipids and chelator beads that both native and recombinant Drp1 directly bind Ni2+ions. Metal-binding therefore represents a potential strategy to deplete or purify Drp1 from native tissue lysates. Importantly, high concentrations of the metal in solution inhibit GTP hydrolysis and renders Drp1 inactive in membrane fission. Together, our results emphasize a metal-binding propensity, which could significantly impact Drp1 functions.
Cryo-EM reconstruction of the human 40S ribosomal subunit at 2.15 Å resolution
Authors: Pellegrino Simone , Dent Kyle C. , Spikes Tobias , Warren Alan J. 
Published: January 2022

ABSTRACTThe chemical modification of ribosomal RNA and proteins is critical for ribosome assembly, for protein synthesis and may drive ribosome specialization in development and disease. However, the inability to accurately visualize these modifications has limited mechanistic understanding of the role of these modifications in ribosome function. Here we report the 2.15 Å resolution cryo-EM reconstruction of the human 40S ribosomal subunit. We directly visualize post-transcriptional modifications within the 18S rRNA and post-translational modifications at the N-termini of two ribosomal proteins. Additionally, we interpret the solvation shells in the core regions of the 40S ribosomal subunit and reveal how potassium and magnesium ions establish both universally conserved and eukaryote-specific coordination to promote the stabilization and folding of key ribosomal elements. This work provides unprecedented structural details for the human 40S ribosomal subunit that will serve as an important reference for unraveling the functional role of ribosomal RNA modifications.
Outer membrane protein A (OmpA) deficient Salmonella Typhimurium displays enhanced susceptibility towards β-lactam antibiotics: third-generation cephalosporins (ceftazidime) and carbapenems (meropenem)
Authors: Chowdhury Atish Roy , Mukherjee Debapriya , Singh Ashish Kumar , Chakravortty Dipshikha 
Published: January 2022

AbstractThe invasive non-typhoidal serovar of Salmonella enterica, namely Salmonella Typhimurium ST313, causes bloodstream infection in sub-Saharan Africa. Like other bacterial pathogens, the development of antimicrobial resistance is a severe problem in curing non-typhoidal Salmonella infection. In this work, we have investigated the role of four prominent outer membrane porins of S. Typhimurium, namely OmpA, OmpC, OmpD, and OmpF, in resistance against broad-spectrum β-lactam antibiotics-ceftazidime and meropenem. We found that deleting OmpA from Salmonella makes the bacteria susceptible to β-lactam drugs. The MIC for both the antibiotics reduced significantly for STM ΔompA compared to the wild-type and the ompA complemented strains. Despite the presence of antibiotics, the uninterrupted growth of STM ΔompC, ΔompD, and ΔompF endorsed the dispensability of these three porins in antimicrobial resistance. The β-lactam antibiotics caused massive depolarization in the outer membrane of the bacteria in the absence of OmpA. We have proved that none of the extracellular loops but the complete structure of perfectly folded OmpA is required by the bacteria for developing antimicrobial resistance. Our data revealed that STM ΔompA consumed more antibiotics than the wild-type and the complemented strain, resulting in severe damage of the bacterial outer membrane and subsequent killing of the pathogen by antibiotic-mediated oxidative stress. Upon deleting ompA, the steady decrease in the relative proportion of antibiotic-resistant persisters and the clearance of the STM ΔompA from the liver and spleen of C57BL/6 mice upon treatment with ceftazidime proved the role of OmpA in rendering protection against β-lactam antibiotics.
EFCAB4B (CRACR2A) genetic variants associated with COVID-19 fatality
Authors: Wang Dapeng , Wiktor Sabina D , Cheng Chew W , Simmons Katie J , Money Ashley , Pedicini Lucia , Carlton Asya , Breeze Alexander L , McKeown Lynn 
Published: January 2022

AbstractThe coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in more than 235 million cases worldwide and 4.8 million deaths (October 2021). Severe COVID-19 is characterised in part by vascular thrombosis and a cytokine storm due to increased plasma concentrations of factors secreted from endothelial and T-cells. Here, using patient data recorded in the UK Biobank, we demonstrate the importance of variations in Rab46 (CRACR2A) with clinical outcomes. Using logistic regression analysis, we determined that three single nucleotide polymorphisms (SNPs) in the gene EFCAB4B cause missense mutations in Rab46, which are associated with COVID-19 fatality independently of risk factors. All three SNPs cause changes in amino acid residues that are highly conserved across species, indicating their importance in protein structure and function. Two SNPs, rs17836273 (A98T) and rs36030417 (H212Q), cause amino acid substitutions in important functional domains: the EF-hand and coiled-coil domain respectively. By using molecular modelling, we suggest that the substitution of threonine at position 98 causes structural changes in the EF-hand calcium binding domain. Since Rab46 is a Rab GTPase that regulates both endothelial cell secretion and T-cell signalling, these missense variations may play a role in the molecular mechanisms underlying the thrombotic and inflammatory characteristics observed in patients with severe COVID-19 outcomes.
The language of profit warnings: a case of denial, defiance, desperation and defeat
Authors: Edgar Victoria C. , Brennan Niamh M. , Power Sean Bradley 
Published: January 2022

PurposeTaking a communication perspective, the paper explores management's rhetoric in profit warnings, whose sole purpose is to disclose unexpected bad news.Design/methodology/approachAdopting a close-reading approach to text analysis, the authors analyse three profit warnings of the now-collapsed Carillion, contrasting the rhetoric with contemporaneous investor conference calls to discuss the profit warnings and board minutes recording boardroom discussions of the case company's precarious financial circumstances. The analysis applies an Aristotelian framework, focussing on logos (appealing to logic and reason), ethos (appealing to authority) and pathos (appealing to emotion) to examine how Carillion's board and management used language to persuade shareholders concerning the company's adverse circumstances.FindingsAs non-routine communications, the language in profit warnings displays and mimics characteristics of routine communications by appealing primarily to logos (logic and reason). The rhetorical profiles of investor conference calls and board meeting minutes differ from profit warnings, suggesting a different version of the story behind the scenes. The authors frame the three profit warnings as representing three stages of communication as follows: denial, defiance and desperation and, for our case company, ultimately, culminating in defeat.Research limitations/implicationsThe research is limited to the study of profit warnings in one case company.Originality/valueThe paper views profit warnings as a communication artefact and examines the rhetoric in these corporate documents to elucidate their key features. The paper provides novel insights into the role of profit warnings as a corporate communication vehicle/genre delivering bad news.
Designing interpretive communities toward justice: indexicality in classroom discourse
Authors: Storm Scott , Jones Karis , Beck Sarah W. 
Published: January 2022

PurposeThis study aims to investigate how, through text-based classroom talk, youth collaboratively draw on and remix discourses and practices from multiple socially indexed traditions.Design/methodology/approachDrawing on data from a year-long social design experiment, this study uses qualitative coding and traces discoursal markers of indexicality.FindingsThe youth sustained, remixed and evaluated interpretive communities in their navigation across disciplinary and fandom discourses to construct a hybrid classroom interpretive community.Originality/valueThis research contributes to scholarship that supports using popular texts in classrooms as the focus of a scholarly inquiry by demonstrating how youth in one high school English classroom discursively index interpretive communities aligned with popular fandoms and literary scholarship. This study adds to understandings about the social nature of literary reading, interpretive whole-class text-based talk and literary literacies with multimodal texts in diverse, high school classrooms.