bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical phenotypes in acute and chronic infarction explained through human ventricular electromechanical modelling and simulations
Authors: Zhou Xin , Wang Zhinuo Jenny , Camps Julia , Tomek Jakub , Santiago Alfonso , Quintanas Adria , Vazquez Mariano , Vaseghi Marmar , Rodriguez Blanca 
Published: February 2022

ABSTRACTAimsSudden death after myocardial infarction (MI) is associated with electrophysiological heterogeneities and ionic remodelling, which are reflected as variable phenotypes. Low ejection fraction (EF) is used in risk stratification, but its mechanistic links with the post-MI pro-arrhythmic heterogeneities are unknown. We aim to provide a mechanistic explanation of clinical phenotypes in acute and chronic MI, from ionic remodeling to ECG and EF, using human electromechanical modelling and simulation to augment experimental and clinical investigations.Methods and ResultsA human ventricular electromechanical modelling and simulation framework is constructed and validated with rich experimental and clinical datasets. Abnormalities caused by scar and border zone ionic remodeling are introduced in varying degrees as reported in experimental data obtained in acute and chronic infarction. Simulations enabled reproducing and explaining clinical phenotypes post-MI, from ionic remodelling to ECGs and pressure-volume loops. In acute MI, T-wave inversion and Brugada phenocopy were explained by up to 57 ms of local APD prolongation and activation failure due to the inhibition of potassium, sodium and calcium channels in the border zone. In chronic MI, upright tall T-waves highlight large repolarisation dispersion caused by uneven potassium channel expression in border and remote zones, which promoted ectopic propagation at fast pacing. Post-MI ionic remodelling reduced EF by up to 10% through inhibition of calcium transient amplitude due to weaker calcium currents or SERCA activity, but the EF at resting heart rate was not sensitive to the extent of repolarisation heterogeneity and the risk of repolarisation abnormalities at fast pacing.ConclusionsMulti-scale modelling and simulation coherently integrates experimental and clinical data at subcellular, tissue, and organ scales to unravel electromechanical disease mechanisms in MI. In acute post-MI, ionic remodelling and its effect on refractoriness and propagation failure in the BZ have a strong impact on phenotypic ECG variability, whereas in chronic post-MI, the repolarisation dispersion across the BZ is crucial. T-wave and QT abnormalities are better indicators of repolarisation heterogeneities than EF in post-MI.
Age and spatio-temporal variations in food resources modulate stress-immunity relationships in three populations of wild roe deer
Authors: Carbillet Jeffrey , Hollain Marine , Rey Benjamin , Palme Rupert , Pellerin Maryline , Regis Corinne , Geffré Anne , Duhayer Jeanne , Pardonnet Sylvia , Debias François , Merlet Joël , Lemaître Jean-François , Verheyden Hélène , Gilot-Fromont Emmanuelle 
Published: February 2022

AbstractLiving in variable and unpredictable environments, organisms face recurrent stressful situations. The endocrine stress response, which includes the secretion of glucocorticoids, helps organisms to cope with these perturbations. Although short-term elevations of glucocorticoid levels are often associated with immediate beneficial consequences for individuals, long-term glucocorticoid elevation can compromise key physiological functions such as immunity. While laboratory works highlighted the immunosuppressive effect of long-term elevated glucocorticoids, it remains largely unknown, especially in wild animals, whether this relationship is modulated by individual and environmental characteristics. In this study, we explored the co-variation between baseline cortisol levels, assessed non-invasively using faecal cortisol metabolites (FCMs), and 12 constitutive indices of innate, inflammatory, and adaptive immune functions, in wild roe deer living in three populations with contrasting environmental conditions. Using longitudinal data on 564 individuals, we further investigated whether age and spatio-temporal variations in the quantity and quality of food resources affect the relationship between FCMs and immunity. Negative covariation with glucocorticoids was evident only for innate and inflammatory markers of immunity, while adaptive immunity appeared to be positively or not linked to glucocorticoids. In addition, the negative covariations were generally exacerbated, or revealed, in individuals facing harsh environmental constraints and in old individuals. Therefore, our results highlight the importance of measuring multiple immune markers of immunity in individuals from contrasted environments to unravel the complex relationships between glucocorticoids and immunity in wild animals. Our results also help explain conflicting results found in the literature and could improve our understanding of the long-term consequences of elevated glucocorticoid levels on disease spread and population dynamics.
Arbidol inhibits esophageal squamous cell carcinoma growth in vitro and in vivo through suppressing ataxia telangiectasia and Rad3-related protein kinase
Authors: Yang Ning , Lu Xuebo , Jiang Yanan , Zhao Lili , Wang Donghao , Wei Yaxing , Yu Yin , Kim Myoung Ok , Laster Kyle Vaughn , Li Xin , Yuan Baoyin , Dong Zigang , Liu Kangdong 
Published: February 2022

AbstractBackgroundEsophageal cancer has a global impact on human health due to its high incidence and mortality. Therefore, there is an urgent need to develop new drugs to treat or prevent the prominent pathological subtype of esophageal cancer, esophageal squamous cell carcinoma. Based upon a screening of drugs approved by the Food and Drug Administration, we discovered that Arbidol could effectively inhibit the proliferation of esophageal squamous cell carcinoma in vitro and in vivo.MethodWe first conducted a series of cell-based assays and found that Arbidol treatment inhibited the proliferation and colony formation ability of ESCC cells and promoted G1 phase cell cycle arrest. Phospho-proteomics experiments and in vitro kinase assays were subsequently performed using cell lysates derived from Arbidol-treated cells in order to identify the underlying growth inhibitory mechanism. Finally, a PDX model was used to verify the inhibitory effect of Arbidol in vivo.FindingArbidol inhibits proliferation of ESCC in vitro and in vivo through the DNA replication pathway and is associated with the cell cycle.InterpretationArbidol is a potential ATR inhibitor via binding to ATR kinase to reduce the phosphorylation and activation of MCM2 at Ser108.FundingThis research was supported by the National Natural Science Foundation of China (grant number 81872335), the National Natural Science Youth Foundation (grant number 81902486), and the Natural Science Foundation of Henan (grant number 161100510300).
Depletion of Sun1/2 induces heterochromatin accrual in mesenchymal stem cells during adipogenesis
Authors: Goelzer Matthew , Howard Sean , Zavala Anamaria , Conway Daniel , Rubin Janet , van Wijnen Andre J , Uzer Gunes 
Published: February 2022

AbstractCritical to the mechano-regulation of mesenchymal stem cells (MSC), Linker of the Nucleoskeleton and Cytoskeleton (LINC) complex transduces cytoskeletal forces to the nuclei. The LINC complex contains outer nuclear membrane Nesprin proteins that associate with the cytoskeleton and their inner nuclear membrane couplers, Sun proteins. In addition to coupling Nesprin-associated cytoskeletal elements to inner nuclear membrane, Sun proteins also function in regulating nuclear mechanics and chromatin tethering to inner nuclear membrane. This suggests that release of LINC-mediated cytoskeletal connections from cell nuclei may have different effects on chromatin organization and MSC differentiation than those due to ablation of intra-nuclear Sun proteins. To test this hypothesis we compared Sun1/2 depletion with expression of the dominant-negative KASH domain (dnKASH) that inhibits Nesprin-Sun association. In cells cultured under adipogenic conditions, disconnecting LINC from the cytoskeleton through dnKASH expression, increased adipogenic gene expression and fat droplet formation; heterochromatin H3K27 and H3K9 methylation was unaltered. In contrast, Sun1/2 depletion inhibited adipogenic gene expression and fat droplet formation; as well the anti-adipogenic effect of Sun1/2 depletion was accompanied by increased H3K9me3, which was enriched on Adipoq, silencing this fat locus. We conclude that releasing the nucleus from cytoskeletal constraints via dnKASH accelerates adipogenesis while depletion of Sun1/2 increases heterochromatin accrual on adipogenic genes in a fashion independent of LINC complex function. Therefore, while these two approaches both disable LINC functions, their divergent effects on the epigenetic landscape indicate they cannot be used interchangeably to study mechanical regulation of cell differentiation.
Gene Drive Mosquitoes Can Aid Malaria Elimination by Retarding Plasmodium Sporogonic Development
Authors: Hoermann Astrid , Habtewold Tibebu , Selvaraj Prashanth , Del Corsano Giuseppe , Capriotti Paolo , Inghilterra Maria G. , Kebede Temesgen M. , Christophides George K. , Windbichler Nikolai 
Published: February 2022

AbstractGene drives hold promise for the genetic control of malaria vectors. The development of vector population modification strategies hinges on the availability of effector mechanisms impeding parasite development in transgenic mosquitoes. We augmented a midgut gene of the malaria mosquito Anopheles gambiae to secrete two exogenous antimicrobial peptides, Magainin 2 and Melittin. This small genetic modification, capable of efficient non-autonomous gene drive, hampers oocyst development in both Plasmodium falciparum and Plasmodium berghei. It delays the release of infectious sporozoites while it simultaneously reduces the lifespan of homozygous female transgenic mosquitoes. Modeling the spread of this modification using a large-scale agent-based model of malaria epidemiology reveals that it can break the cycle of disease transmission across a range of endemic settings.One sentence summaryWe developed a gene drive effector that retards Plasmodium development in transgenic Anopheles gambiae mosquitoes via the expression of antimicrobial peptides in the midgut and which is predicted to eliminate malaria under a range of transmission scenarios.
Leishmania amazonensisinfection induces PD-L1 expression on dendritic cells in an mTor-dependent manner and impairs Th1 responsesin vitroandin vivo
Authors: Matos Guedes Herbert L. de , Fonseca-Martins Alessandra M. da , Liang Yuejin , Carlsen Eric D. , Henard Calvin A. , Pinchuk Irina V. , Soong Lynn 
Published: February 2022

AbstractLeishmania amazonensisis one of the etiological agents of diffuse cutaneous leishmaniasis in South America. In murine models of this infection, dysregulated expansion of effector T cells or exhaustion of Th1 responses are known to be related to pathogenesis, while the induction of regulatory T cells (Tregs) promotes lesion resolution. Recent research has identified several important co-stimulator/receptor pairs, including PD-1/PD-L1, for modulating Th1 responses and Treg induction. In this study, we examined the roles of these molecules inL. amazonensis-infected C57BL/6 mice. We found a significant and selective increase in the expression of PD-1 and PD-L1 (20-fold and 5-fold, respectively), in infected footpad tissues, which correlated with an increased percentage of PD-L1+CD11c+dendritic cells (DCs) and PD-1+CD4+T cells in the draining lymph nodes. To evaluate the mechanism of parasite-induced PD-L1 expression, we infected bone marrow-derived DCs (BMDCs) with promastigotes and amastigotesin vitroin the presence of small molecular inhibitors of critical signaling pathways. WhileL. amazonensisinfection decreased PD-L2 expression on the surface of BMDCs, infection-mediated PD-L1 up-regulation was consistently detected, which was dependent on mTOR and partially dependent on STAT3, PI3K, and MAPK. Infected BMDCs also significantly inhibited the expansion of Th1 cells, but were more competent in inducing CD25+FoxP3+Tregsin vitrothan the non-infected BMDCs; such effects were PD-L1-dependent, as BMDCs from PD-L1−/−mice failed to do the same.In vivoexperiments revealed that infected PD-L1−/−mouse tissues showed increased Th1 responses and IFN-γ production, as well as reduced lesion sizes and parasite loads, without affecting Tregs cell expansion. Together, these results support a protective role for PD-1/PD-L1 signaling in regulating local immune responses duringL. amazonensisinfection. This study provides new insights on immune regulation in New World cutaneous leishmaniasis.
Ethnic inequities in multimorbidity among people with psychosis: A retrospective cohort study
Authors: de Freitas Daniela Fonseca , Pritchard Megan , Shetty Hitesh , Khondoker Mizanur , Nazroo James , Hayes Richard D. , Bhui Kamaldeep 
Published: February 2022

ABSTRACTBackgroundResearch shows persistent ethnic inequities in mental health experiences and outcomes, with a higher incidence of illnesses among minoritised ethnic groups. People with psychosis have a higher risk of multiple long-term conditions (MLTC; multimorbidity). However, there is limited research regarding ethnic inequalities in multimorbidity in people with a schizophrenia spectrum disorder. This study investigates ethnic disparities in physical health multimorbidity in a cohort of people with psychosis.MethodsIn this retrospective cohort study, using the Clinical Records Interactive Search (CRIS) system, we identified service-users of the South London and Maudsley NHS Trust with a schizophrenia spectrum disorder, and then additional diagnoses of diabetes, hypertension, low blood pressure, overweight or obesity, and rheumatoid arthritis. Multinomial logistic regression was then used to investigate ethnic inequities in odds of multimorbidity (psychosis plus one physical health condition), as well as multimorbidity severity (having one or two physical health conditions, or three or more conditions), compared with no additional health conditions (no multimorbidity). The regression models adjusted for age and duration of care and investigated the influence of gender and area-level deprivation.ResultsOn a sample of 20,800 service-users with psychosis, aged 13-65, ethnic differences were observed in the odds for multimorbidity. Compared to White British people, higher odds of multimorbidity were found for people of Black African [aOR=1.41, 95%CI (1.23 - 1.56)], Black Caribbean [aOR=1.79, 95%CI (1.58 – 2.03)], and Black British [aOR=1.64, 95%CI (1.49 - 1.81)] ethnicity. Reduced odds were observed among people of Chinese [aOR=0.61, 95%CI (0.43 – 0.88)] and Other ethnicities [aOR=0.67, 95%CI (0.59 – 0.76)]. Increased odds for severe multimorbidity (three or more physical health conditions) were also observed for people of any Black background.ConclusionsEthnic inequities are observed for multimorbidity among people with psychosis. Further research is needed to understand the aetiology and impact of these inequities. These findings support the provision of integrated health care interventions and public health preventive policies and actions.
A centimeter-long bacterium with DNA compartmentalized in membrane-bound organelles
Authors: Volland Jean-Marie , Gonzalez-Rizzo Silvina , Gros Olivier , Tyml Tomáš , Ivanova Natalia , Schulz Frederik , Goudeau Danielle , Elisabeth Nathalie H , Nath Nandita , Udwary Daniel , Malmstrom Rex R , Guidi-Rontani Chantal , Bolte-Kluge Susanne , Davies Karen M , Jean Maïtena R , Mansot Jean-Louis , Mouncey Nigel J , Angert Esther , Woyke Tanja , Date Shailesh V 
Published: February 2022

AbstractCells of most bacterial species are around 2 µm in length, with some of the largest specimens reaching 750 µm. Using fluorescence, x-ray, and electron microscopy in conjunction with genome sequencing, we characterized Ca. Thiomargarita magnifica, a bacterium with an average cell length greater than 9,000 µm that is visible to the naked eye. We found that these cells grow orders of magnitude over theoretical limits for bacterial cell size through unique biology, display unprecedented polyploidy of more than half a million copies of a very large genome, and undergo a dimorphic life cycle with asymmetric segregation of chromosomes in daughter cells. These features, along with compartmentalization of genomic material and protein synthesis in membrane-bound organelles, indicate gain of complexity in the Thiomargarita lineage, and challenge traditional concepts of bacterial cells.One Sentence SummaryCa. T. magnifica are compartmentalized centimeter-long bacteria
FAM21 is critical for TLR2-CLEC4E-mediated dendritic cell function againstCandida albicans
Authors: Kulkarni Rakesh , Kasani Siti Khadijah , Tsai Ching-Yen , Tung Shu-Yun , Yeh Kun-Hai , Yu Chen-Hsin Albert , Chang Wen 
Published: February 2022

AbstractFAM21 (family with sequence similarity 21) is a component of the Wiskott–Aldrich syndrome protein and SCAR homologue (WASH) protein complex that mediates actin polymerization at endosomal membranes to facilitate sorting of cargo-containing vesicles out of endosomes. To study the function of FAM21in vivo, we generated conditional knockout (cKO) mice in the C57BL/6 background in which FAM21 was specifically knocked out of CD11c-positive dendritic cells. Bone marrow-derived dendritic cells (BMDC) from those mice displayed enlarged early endosomes, and altered cell migration and morphology relative to wildtype (WT) cells. FAM21-cKO cells were less competent in phagocytosis and antigen processingin vitro, though antigen presentation was not affected. More importantly, we identified the TLR2/CLEC4E signaling pathway as being downregulated in FAM21-cKO BMDCs when challenged with its specific ligandCandida albicans. Moreover, FAM21-cKO mice were more susceptible toC. albicansinfection than WT mice. Reconstitution of WT BMDCs in FAM21-cKO mice rescued them from lethalC. albicansinfection. Thus, our study highlights the importance of FAM21 in a host immune response against a significant pathogen.
Genome-widein vivoCRISPR screens identify GATOR1 as a potent tumor suppressor in MYC-driven lymphomagenesis
Authors: Potts Margaret A. , Mizutani Shinsuke , Deng Yexuan , Vaidyanathan Srimayee , Ting Keziah E. , Giner Göknur , Sridhar Shruti , Liao Yang , Diepstraten Sarah , Kueh Andrew J. , Pal Martin , Healey Geraldine , Tai Lin , Wang Zilu , König Christina , Kaloni Deeksha , Whelan Lauren , Milevskiy Michael , Coughlan Hannah , Pomilio Giovanna , Wei Andrew H. , Visvader Jane E. , Papenfuss Anthony T. , Wilcox Stephen , Jeyasekharan Anand D. , Shi Wei , Lelliott Emily J. , Kelly Gemma L. , Brown Kristin K. , Strasser Andreas , Herold Marco J. 
Published: February 2022

AbstractIdentifying tumor suppressor genes is predicted to inform on the development of novel strategies for cancer therapy. To identify new lymphoma driving processes that cooperate with oncogenic MYC (which is abnormally highly expressed in ∼70% of human cancers) we have used a genome-wide CRISPR knockout screen inEµ-Myc;Cas9transgenic hematopoietic stem and progenitor cellsin vivo. We discovered that loss of any of the GATOR1 complex components - NPRL3, DEPDC5, NPRL2 - significantly accelerated c-MYC-driven lymphoma development in mice. Low expression of the GATOR1 complex genes correlated with poor survival outcomes for human patients with high MYC- expressing cancers. Murine lymphomas lacking GATOR1 were highly sensitive to mTOR inhibitors as a single agent therapy, bothin vitroandin vivo. These findings identify inhibition of mTORC1 as a potent tumor suppressive mechanism in c-MYC-driven lymphomagenesis and suggest a new avenue for therapeutic intervention in GATOR1-deficient lymphomas through mTOR inhibition.Key PointsIn vivoCRISPR/Cas9 whole genome knockout screens identified the GATOR1 complex as a potent suppressor of c-MYC-driven lymphomagenesis.GATOR1 deficiency in MYC-driven lymphomas confers sensitivity to mTOR inhibition, suggesting a novel therapeutic approach.
Autophagy promotes programmed cell death and corpse clearance in specific cell types of the Arabidopsis root cap
Authors: Feng Qiangnan , De Rycke Riet , Dagdas Yasin , Nowack Moritz K. 
Published: February 2022

SummaryAutophagy is a conserved quality control pathway that mediates the degradation of unnecessary or dysfunctional cellular components by targeting them to the lysosomes or central vacuoles. Autophagy has been implicated in the regulation or execution of regulated cell death processes in a wide range of eukaryotes. However, its function in developmentally controlled programmed cell death (dPCD) in plants remains little studied and controversial. Here, we investigated the role of autophagy in dPCD using the Arabidopsis root cap as an accessible and genetically tractable model system. We show that autophagic flux is induced prior to dPCD execution in both root cap tissues, the columella and the lateral root cap (LRC), and impaired in autophagy-deficient mutants. These mutants show a strongly delayed cell death and an absence of corpse clearance in the columella during and after their shedding into the rhizosphere. However, autophagy deficiency does not affect dPCD execution or corpse clearance in LRC cells at the distal end of the root cap. Our results demonstrate that autophagy promotes dPCD in a highly cell-type specific manner, and present the root cap as a powerful model system to study organ-specific autophagy in vivo.
Tensor decomposition reveals coordinated multicellular patterns of transcriptional variation that distinguish and stratify disease individuals
Authors: Mitchel Jonathan , Gordon M. Grace , Perez Richard K. , Biederstedt Evan , Bueno Raymund , Ye Chun Jimmie , Kharchenko Peter V. 
Published: February 2022

SummaryTissue- and organism-level biological processes often involve coordinated action of multiple distinct cell types. Current computational methods for the analysis of single-cell RNA-sequencing (scRNA-seq) data, however, are not designed to capture co-variation of cell states across samples, in part due to the low number of biological samples in most scRNA-seq datasets. Recent advances in sample multiplexing have enabled population-scale scRNA-seq measurements of tens to hundreds of samples. To take advantage of such datasets, here we introduce a computational approach called single-cell Interpretable Tensor Decomposition (scITD). This method extracts “multicellular gene expression patterns” that capture how sample-specific expression states of a cell type are correlated with the expression states of other cell types. Such multicellular patterns can reveal molecular mechanisms underlying coordinated changes of different cell types within the tissue, and can be used to stratify individuals in a clinically-relevant and reproducible manner. We first validated the performance of scITD usingin vitroexperimental data and simulations. We then applied scITD to scRNA-seq data on peripheral blood mononuclear cells (PBMCs) from 115 patients with systemic lupus erythematosus and 56 healthy controls. We recapitulated a well-established pan-cell-type signature of interferon-signaling that was associated with the presence of anti-dsDNA autoantibodies and a disease activity index. We further identified a novel multicellular pattern linked to nephritis, which was characterized by an expansion of activated memory B cells along with helper T cell activation. Our approach also sheds light on ligand-receptor interactions potentially mediating these multicellular patterns. As validation, we demonstrated that these expression patterns also stratified donors from a pediatric SLE dataset by the same phenotypic attributes. Lastly, we found the interferon multicellular pattern and others to be conserved in a COVID-19 dataset, pointing to the presence of both general and disease-specific patterns of inter-individual immune variation. Overall, scITD is a flexible method for exploring co-variation of cell states in multi-sample single-cell datasets, which can yield new insights into complex non-cell-autonomous dependencies that define and stratify disease.