bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomized controlled trial of gut decontamination in pediatric patients undergoing allogeneic hematopoietic cell transplantation
Authors: Severyn Christopher J. , Siranosian Benjamin A. , Kong Sandra Tian-Jiao , Moreno Angel , Li Michelle M. , Chen Nan , Duncan Christine N. , Margossian Steven P. , Lehmann Leslie E. , Sun Shan , Andermann Tessa M. , Birbrayer Olga , Silverstein Sophie , Kim Soomin , Banaei Niaz , Ritz Jerome , Fodor Anthony A. , London Wendy B. , Bhatt Ami S. , Whangbo Jennifer S. 
Published: December 2021

ABSTRACTBackgroundGut decontamination (GD) can decrease the incidence and severity of acute graft- versus-host-disease (aGVHD) in murine models of allogeneic hematopoietic cell transplantation (HCT). Several HCT centers standardly practice GD with different antibiotic regimens. In this pilot study, we examined the impact of GD on the gut microbiome composition and incidence of aGVHD in HCT patients.MethodsWe randomized 20 pediatric patients undergoing allogeneic HCT to receive (GD) or not receive (no-GD) oral vancomycin-polymyxin B from day -5 through neutrophil engraftment. We evaluated shotgun metagenomic sequencing of serial stool samples to compare the composition and diversity of the gut microbiome between study arms. We assessed clinical outcomes in the 2 arms and performed strain-specific analyses of pathogens that caused bloodstream infections (BSI).ResultsThe two arms did not differ in Shannon diversity of the gut microbiota at two weeks post- HCT (Genus,p=0.8; Species,p=0.44) or aGVHD incidence (p=0.58). Immune reconstitution of T- cell subsets was similar, but absolute CD19+ B-cell counts were higher in the GD arm at 12 months post-HCT (p=0.02). Five patients in the no-GD arm had eight BSI episodes vs one episode in the GD arm (p=0.09). The BSI-causing pathogens were traceable to the gut in seven of eight BSI episodes in the no-GD arm, including the genusStaphylococcus.ConclusionsWhile GD did not differentially impact Shannon diversity or clinical outcomes, our findings suggest that GD may protect against gut-derived BSI in HCT patients by decreasing the prevalence or abundance of gut microbial pathogens.Key points:–In this phase 2 randomized study of gut decontamination (GD) in 20 pediatric HCT patients, neither two-week post-HCT Shannon diversity of the gut microbiome nor incidence of aGVHD differ between the GD and no-GD arms.–All bloodstream infections (BSIs) caused by pathogens traceable to the gut either temporally or via strain-specific analysis (concomitant gut colonization) occurred in patients in the no-GD arm; this suggests that GD with vancomycin-polymyxin B may decrease the incidence of gut-derived BSI in allo-HCT patients.–In contrast to prior studies, we find that non-mucosal barrier injury (MBI) pathogens, such asStaphylococcus aureus,can be found in the gut microbiome of HCT patients.
Lower infant mortality and access to contraception reduce fertility in low- and middle-income nations
Authors: Bradshaw Corey J A , Perry Claire , Saraswati Chitra Maharani , Judge Melinda , Heyworth Jane , Le Souëf Peter N 
Published: December 2021

ABSTRACTAlthough average contraceptive use has increased globally in recent decades, an estimated 222 million (26%) of women of child-bearing age worldwide face an unmet need for family planning — defined as a discrepancy between fertility preferences and contraception practice, or failing to translate desires to avoid pregnancy into preventative behaviours and practices.While many studies have reported relationships between availability of contraception, infant mortality, and fertility, these relationships have not been evaluated quantitatively across a broad range of low- and middle-income countries. Using publicly available data from 46 low- and middle-income countries, we collated test and control variables in six themes: (i) availability of family planning, (ii) quality of family planning, (iii) maternal education, (iv) religion, (v) mortality, and (vi) socio-economic conditions. We predicted that higher nation-level availability/quality of family-planning services, maternal education, and wealth reduce average fertility, whereas higher infant mortality and religious adherence increase it. Given the sample size, we first constructed general linear models to test for relationships between fertility and the variables from each theme, from which we retained those with the highest explanatory power within a final general linear model set to determine the partial correlation of dominant test variables. We also applied boosted regression trees, generalised least-squares models, and a generalised linear mixed-effects models to account for non-linearity and spatial autocorrelation. On average among all countries, we found an association between all main variables and fertility, with reduced infant mortality having the strongest relationship with reduced fertility. Access to contraception was the next-highest correlate with reduced fertility, with female secondary education, home health visitations, and adherence to Catholicism having weak, if any, explanatory power. Our models suggest that decreasing infant mortality and increasing access to contraception will have the greatest effect on decreasing global fertility. We thus provide new evidence that progressing the United Nation’s Sustainable Development Goals for reducing infant mortality can be accelerated by increasing access to any form of family planning.
Transcription factor lineages in plant-pathogenic fungi, connecting diversity with fungal virulence
Authors: John Evan , Singh Karam B. , Oliver Richard P. , Tan Kar-Chun 
Published: December 2021

AbstractPlant-pathogenic fungi span diverse taxonomic lineages. Their host-infection strategies are often specialised and require the coordinated regulation of molecular virulence factors. Transcription factors (TFs) are fundamental regulators of gene expression, controlling development and virulence in plant pathogenic fungi. Recent research has established regulatory roles for several taxonomically conserved fungal TFs, but the evolution of specific virulence regulators is not well understood. This study sought to explore the representation of TFs across a taxonomically-diverse range of fungi, with a focus on plant pathogens. A significant trend was observed among the obligate, host-associated pathogens, which possess a reduced overall TF repertoire, alluding to a lack of pressure for maintaining diversity. A novel orthology-based analysis is then presented that refined TF classifications, traditionally based on the nature of the DNA-binding domains. Using this analysis, cases of TF over/underrepresentation across fungal pathogen lineages are systematically highlighted. Specific examples are then explored and discussed that included the TF orthologues of Ste12, Pf2 and EBR1, plus phytotoxic secondary-metabolite cluster regulators, which all presented novel and distinct evolutionary insights. Ultimately, as the examples presented demonstrate, this resource can be interrogated to guide functional studies that seek to characterise virulence-specific regulators and shed light on the factors underpinning plant pathogenicity.
Emergence of compensatory mutations reveal the importance of electrostatic interactions between HIV-1 integrase and genomic RNA
Authors: Mugisha Christian Shema , Dinh Tung , Kumar Abhishek , Tenneti Kasyap , Eschbach Jenna E. , Davis Keanu , Gifford Robert , Kvaratskhelia Mamuka , Kutluay Sebla B. 
Published: December 2021

ABSTRACTHIV-1 integrase (IN) has a non-catalytic function in virion maturation through its binding to the viral RNA genome (gRNA). Allosteric integrase inhibitors (ALLINIs) and class II IN substitutions inhibit IN-gRNA binding and result in non-infectious viruses marked by mislocalization of the gRNA within virions. HIV-1 IN utilizes basic residues within its C-terminal domain (CTD) to bind to the gRNA. However, the molecular nature of how these residues mediate gRNA binding and whether other regions of IN are involved remain unknown. To address this, we have isolated compensatory substitutions in the background of a class II IN mutant virus bearing R269A/K273A substitutions within the IN-CTD. We found that the nearby D256N and D270N compensatory substitutions restored the ability of IN to bind gRNA and led to the formation of mature infectious virions. Reinstating the local positive charge of the IN-CTD through individual D256R, D256K, D278R and D279R substitutions was sufficient to restore IN-RNA binding and infectivity for the IN R269A/K273A as well as the IN R262A/R263A class II mutants. Structural modeling suggested that compensatory substitutions in the D256 residue created an additional interaction interface for gRNA binding. Finally, HIV-1 IN R269A/K273A, but not IN R262A/R263A, bearing compensatory mutations was more sensitive to ALLINIs providing key genetic evidence that specific IN residues required for RNA binding also influence ALLINI activity. Taken together, our findings highlight the essential role of CTD in gRNA binding and ALLINI sensitivity, and reveal the importance of pliable electrostatic interactions between the IN- CTD and the gRNA.IMPORTANCEIn addition to its catalytic function, HIV-1 integrase (IN) binds to the viral RNA genome (gRNA) through positively charged residues within its C-terminal domain (CTD) and regulates proper virion maturation. Here we show that compensatory mutations in nearby acidic residues (i.e. D256N and D270N) restore the ability to bind gRNA for IN variants bearing substitutions in these positively charged CTD residues. Similarly, charge reversals through individual D-to-R and D-to-K substitutions at these positions enabled the respective IN mutants to bind gRNA and restore virion infectivity. Further, we show that specific residues within the IN-CTD required for RNA binding also influence sensitivity to allosteric integrase inhibitors, a class of novel IN- targeting compounds that target the non-catalytic function of IN. Taken together, our findings reveal the importance of electrostatic interactions in IN-gRNA binding and provide key evidence for a crucial role of the IN-CTD in allosteric integrase inhibitor mechanism of action.
Divergent clonal differentiation trajectories of T cell exhaustion
Authors: Daniel Bence , Yost Kathryn E. , Sandor Katalin , Xia Yu , Qi Yanyan , Hiam-Galvez Kamir J. , Meier Stefanie L. , Belk Julia A. , Giles Josephine R. , Wherry E. John , Chang Howard Y. , Egawa Takeshi , Satpathy Ansuman T. 
Published: December 2021

SUMMARYT cells activated by chronic antigen exposure in the setting of viral infections or cancer can adopt an exhausted T cell (Tex) state, characterized by reduced effector function and proliferative capacity, and the upregulation of inhibitory receptors. However, whether all antigen-specific T cell clones follow the same molecular and cellular Tex differentiation trajectory remains unclear. Here, we generate a single-cell multi-omic atlas of T cell exhaustion that redefines the phenotypic diversity and molecular regulation of Tex phenotypes. Longitudinal analysis during chronic viral infection identifies an early effector phenotype that is epigenetically primed for Tex differentiation and two late-stage Tex cell states with either a terminal exhaustion or a killer cell lectin-like receptor (KLR)-expressing cytotoxic gene signature. We define clonal trajectories of antigen-specific T cells using paired single-cell RNA and T cell receptor sequencing and reveal distinct differentiation trajectories resulting in terminal Tex-biased, KLR Tex-biased, or divergent clones that differentiate into both phenotypes. Comparison of Tex phenotypes among shared T cell clones that traffic to multiple organs reveals that clonal differentiation trajectories are maintained across tissues. Finally, we show that differences in clonal differentiation trajectory are driven by TCR signal strength, whereby high-affinity T cell clones preferentially adopt a terminal Tex fate, while low-affinity clones adopt an effector-like KLR Tex fate that is detectable long-term but depleted in high antigen settings. These findings reveal clonal heterogeneity in the T cell response to chronic antigen and genomic programs that underlie Tex fates and persistence.HighlightsA single-cell atlas of T cell exhaustion identifies novel early effector and KLR Tex states.Clonal T cell analysis defines divergent differentiation trajectories during chronic viral infection leading to terminal and KLR Tex fates.The heterogeneity of the Tex pool arises from three primary differentiation patterns and are differentially persistent in the setting of high antigen.Clonal Tex differentiation patterns are conserved across organ sites and driven by TCR signal strength.
The genome sequence of the lesser marbled fritillary, Brenthis ino, and evidence for a segregating neo-Z chromosome
Authors: Mackintosh Alexander , Laetsch Dominik R. , Baril Tobias , Foster Robert , Dincă Vlad , Vila Roger , Hayward Alexander , Lohse Konrad 
Published: December 2021

AbstractThe lesser marbled fritillary, Brenthis ino (Rottemburg, 1775), is a species of Palearctic butterfly. Male B. ino individuals have been reported to have between 12 and 14 pairs of chromosomes, a much reduced chromosome number than is typical in butterflies. Here we present a chromosome-level genome assembly for B. ino, as well as gene and transposable element annotations. The assembly is 411.8 Mb in span with contig and scaffold N50s of 9.6 and 29.5 Mb respectively. We also show evidence that the male individual from which we generated HiC data was heterozygous for a neo-Z chromosome, consistent with inheriting 14 chromosomes from one parent and 13 from the other. This genome assembly will be a valuable resource for studying chromosome evolution in Lepidoptera, as well as for comparative and population genomics more generally.
4D reconstruction of developmental trajectories using spherical harmonics
Authors: Dalmasso Giovanni , Musy Marco , Niksic Martina , Robert-Moreno Alexandre , Badía-Careaga Claudio , Sanz-Ezquerro Juan J. , Sharpe James 
Published: December 2021

SummaryAlthough the full embryonic development of species such as Drosophila and zebrafish can be 3D imaged in real time, this is not true for mammalian organs, as normal organogenesis cannot be recapitulated in vitro. Currently available 3D data is therefore ex vivo images which provide only a snap shot of development at discrete moments in time. Here we propose a computer-based approach to recreate the continuous evolution in time and space of developmental stages from 3D volumetric images. Our method uses the mathematical approach of spherical harmonics to re-map discrete shape data into a space in which facilitates a smooth interpolation over time. We tested our approach on mouse limb buds (from E10 to E12.5) and embryonic hearts (from 10 to 29 somites). A key advantage of the method is that the resulting 4D trajectory takes advantage of all the available data (i.e. it is not dominated by the choice of a few “ideal” images), while also being able to interpolate well through time intervals for which there is little or no data. This method not only provides a quantitative basis for validating predictive models, but it also increases our understanding of morphogenetic processes. We believe this is the first data-driven quantitative 4D description of limb morphogenesis.
Prolonged nicotine exposure reduces aversion to the drug in mice by altering nicotinic transmission in the interpeduncular nucleus
Authors: Mondoloni Sarah , Nguyen Claire , Vicq Eléonore , Jehl Joachim , Durand-de Cuttoli Romain , Torquet Nicolas , Tolu Stefania , Pons Stéphanie , Maskos Uwe , Marti Fabio , Faure Philippe , Mourot Alexandre 
Published: December 2021

AbstractNicotine intake is likely to result from a balance between the rewarding and aversive properties of the drug, yet the individual differences in neural activity that control aversion to nicotine and their adaptation during the addiction process remain largely unknown. Using a two-bottle choice experiment, we observed a high heterogeneity in nicotine-drinking profiles in isogenic adult male mice, with about half of the mice persisting in consuming nicotine even at high concentrations, whereas the other half stopped consuming. We found that nicotine intake was negatively correlated with nicotine-evoked currents in the interpeduncular nucleus (IPN), and that prolonged exposure to nicotine, by weakening this response, decreased aversion to the drug, and hence boosted consumption. Lastly, using knock-out mice and local gene re-expression, we identified β4-containing nicotinic acetylcholine receptors of IPN neurons as the molecular and cellular correlates of nicotine aversion. Collectively, our results identify the IPN as a substrate of individual variabilities and adaptations in nicotine consumption.
Computational modelling and near-complete kinetochore tracking reveal how chromosome dynamics during cell division are co-ordinated in space and time
Authors: Harrison Jonathan U. , Sen Onur , McAinsh Andrew D. , Burroughs Nigel J. 
Published: December 2021

AbstractMitotic chromosome segregation is a self-organising process that achieves high fidelity separation of 46 duplicated chromosomes into two daughter cells. Chromosomes must be captured by the microtubule-based spindle, aligned at the spindle equator where they undergo oscillatory motion (metaphase) and then pulled to opposite spindle poles (anaphase). These large and small-scale chromosome movements are driven by kinetochores, multi-protein machines, that link chromosomes to microtubules and generate directional forces. Through automated near-complete tracking of kinetochores at fine spatio-temporal resolution over long timescales, we produce a detailed atlas of kinetochore dynamics throughout metaphase and anaphase in human cells. We develop a hierarchical biophysical model of kinetochore dynamics and fit this model to 4D lattice light sheet experimental data using Bayesian inference. We demonstrate that location in the metaphase plate is the largest factor in the variation in kinetochore dynamics, exceeding the variation between cells, whilst within the spindle there is local spatio-temporal coordination between neighbouring kinetochores of directional switching events, kinetochore-fibre (K-fibre) polymerization/depolymerization state and the segregation of chromosomes. Thus, metaphase oscillations are robust to variation in the mechanical forces throughout the spindle, whilst the spindle environment couples kinetochore dynamics across the plate. Our methods provide a framework for detailed quantification of chromosome dynamics during mitosis in human cells.
Systematic simulation of the interactions of Pleckstrin homology domains with membranes
Authors: Le Huray Kyle I.P. , Wang He , Sobott Frank , Kalli Antreas C. 
Published: December 2021

AbstractPleckstrin homology (PH) domains can recruit proteins to membranes by recognition of phosphatidylinositol phosphates (PIPs). Here we report the systematic simulation of the interactions of 100 mammalian PH domains with PIP containing model membranes. Comparison with crystal structures of PH domains bound to PIP analogues demonstrates that our method correctly identifies interactions at known canonical and non-canonical sites, while revealing additional functionally important sites for interaction not observed in the crystal structure, such as for P-Rex1 and Akt1. At the family level, we find that the β1 and β2 strands and their connecting loop constitute the primary PIP interaction site for the majority of PH domains, but we highlight interesting exceptional cases. Simultaneous interaction with multiple PIPs and clustering of PIPs induced by PH domain binding are also observed. Our findings support a general paradigm for PH domain membrane association involving multivalent interactions with anionic lipids.TeaserSimulating the binding of 100 Pleckstrin homology domains to cell membranes reveals patterns in their lipid interactions.
Menopause modulates the circulating metabolome: evidence from a prospective cohort study
Authors: Karppinen Jari E. , Törmäkangas Timo , Kujala Urho M. , Sipilä Sarianna , Laukkanen Jari , Aukee Pauliina , Kovanen Vuokko , Laakkonen Eija K. 
Published: December 2021

AbstractAimsWe studied the changes in the circulating metabolome and their relation to the menopausal hormonal shift in 17β-oestradiol and follicle-stimulating hormone levels among women transitioning from perimenopause to early postmenopause.Methods and ResultsWe analysed longitudinal data from 218 Finnish women, 35 of whom started menopausal hormone therapy during the study. The menopausal transition was monitored with menstrual diaries and serum hormone measurements. The median follow-up was 14 months (interquartile range: 8–20). Serum metabolites were quantified with targeted nuclear magnetic resonance metabolomics. The model results were adjusted for age, follow-up duration, education, lifestyle, and multiple comparisons. Menopause was associated with 84 metabolite measures. The concentration of apoB (0.17 standard deviation [SD], 99.5% confidence interval [CI] 0.03–0.31), VLDL triglycerides (0.25 SD, CI 0.05–0.45) and particles (0.21 SD, CI 0.05–0.36), LDL cholesterol (0.17 SD, CI 0.01–0.34) and particles (0.17 SD, CI 0.03–0.31), HDL triglycerides (0.24 SD, CI 0.02–0.46), glycerol (0.32 SD, CI 0.07–0.58) and leucine increased (0.25 SD, CI 0.02–0.49). Citrate (−0.36 SD, CI -0.57 to - 0.14) and 3-hydroxybutyrate concentrations decreased (−0.46 SD, CI -0.75 to -0.17). Most metabolite changes were associated with the menopausal hormonal shift. This explained 10% and 9% of the LDL cholesterol and particle concentration increase, respectively. Menopausal hormone therapy was associated with increased medium-to-large HDL particle count and decreased small-to-medium LDL particle and glycine concentration.ConclusionsMenopause is associated with proatherogenic circulating metabolome alterations. Female sex hormones levels are connected to the alterations, highlighting their impact on women’s cardiovascular health.‘One-sentence Summary’Female sex hormone alterations induced by menopause altered the levels of circulating metabolites, leading to a higher risk profile for cardiovascular diseases.
Triangulating evidence for the causal impact of single-dose zinc supplement on glycemic control for type-2 diabetes
Authors: Wang Zhiyang , Ronsmans Carine , Woolf Benjamin 
Published: December 2021

AbstractBackgroundAlthough previous studies suggested the protective effect of zinc for type-2 diabetes, the unitary causal effect remains inconclusive.ObjectiveWe investigated the causal effect of zinc as a single intervention on glycemic control in type-2 diabetes patients, using a systematic review of RCTs and two-sample Mendelian randomization (MR).MethodsFour outcomes were identified: fasting blood glucose/fasting glucose, hemoglobin A1c (HbA1c), homeostasis model assessment of insulin resistance (HOMA-IR), and serum insulin/fasting insulin level. In the systematic review, four databases were searched up to June 2021. Results were synthesized through the random-effects meta-analysis. Single nucleotide polymorphisms (SNPs) that are independent and are strongly related to zinc supplements were selected from MR-base to perform the two-sample MR with inverse-variance weighted (IVW) coefficient.ResultsIn the systematic review, 14 trials were included. The zinc supplement led to a significant reduction in the post-trial mean of fasting blood glucose (mean difference (MD): - 26.52, 95%CI: -35.13, -17.91), HbA1C (MD: -0.52, 95%CI: -0.90, -0.13), and HOMA-IR (MD: -1.65, 95%CI: -2.62, -0.68), compared to the control group. In the two-sample MR, zinc supplement with 2 SNPs associated with lower fasting glucose (IVW coefficient: -2.04, 95%CI: -3.26, -0.83), but not specified type-2 diabetes.ConclusionAlthough the study was limited by the few trials (review) and SNPs (two-sample MR), we demonstrated that the single zinc supplementary improved glycemic control among type-2 diabetes patients with causal evidence to a certain extent.