bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antigen presentation by clonally diverse CXCR5+ B cells to CD4 and CD8 T cells is associated with durable response to immune checkpoint inhibitors
Authors: Ding Lizhong , Sun Lu , Bu Melissa T. , Zhang Yanjun , Scott Lauren N. , Prins Robert M. , Su Maureen A. , Lechner Melissa G. , Hugo Willy 
Published: December 2022

AbstractThe mechanism by which ICI (immune checkpoint inhibitor) induce durable antitumor T cell activity remains inadequately defined. Tumors from melanoma patients who responded to ICI or MAPK pathway inhibitors (MAPKi) therapy generally displayed increased T cell infiltration and interferon gamma (IFNγ) pathway activation. Yet, the rate of durable tumor control after ICI is almost twice that of MAPKi. Comparing the transcriptome of cohorts of melanoma patients treated with ICI or MAPKi therapy, we discovered that response to ICI is associated with CXCL13-driven recruitment of CXCR5+ B cells with higher clonal diversity than MAPKi. Higher B cell receptor (BCR) diversity allows presentation of diverse tumor antigens by B cells, resulting in robust increases of IFNγ pathway activity and CXCL13 expression in tumor reactive CD8 T cells after ICI therapy. Accordingly, ICI-treated melanoma patients, but not MAPKi, whose tumors displayed higher BCR diversity and IFNγ pathway score, survived significantly longer than those with either one or none. Thus, response to ICI, but not to MAPKi therapy, induces the recruitment of clonally diverse antigen presenting B cells that activate tumor specific, cytotoxic CD8 T cells to effect a durable antitumor immune response. Our result suggests that enhancing B cells’ tumor antigen presentation to intratumoral CD8 T cells can increase the rate of long-term response to ICI therapy.
Commensal Microbiota Regulate Renal Gene Expression
Authors: Moore Brittni N. , Pluznick Jennifer L. 
Published: December 2022

ABSTRACTThe gut microbiome impacts host gene expression not only in the colon, but also at distal sites including liver, white adipose tissue, and spleen. The gut microbiome also influences the kidney and is associated with renal diseases and pathologies; however, a role for the gut microbiome to modulate renal gene expression has not been examined. To determine if microbes modulate renal gene expression, we used whole-organ RNA sequencing (RNA-Seq) to compare gene expression in C57Bl/6 mice that are germ-free (lacking gut microbiota) versus conventionalized (with gut microbiota). 16S sequencing showed that males and females were similarly conventionalized, although Verrucomicrobia was higher in male mice. We find that renal gene expression is differentially regulated in the presence versus absence of microbiota, and that these changes are largely sex-specific. Although microbes also influence gene expression in the liver and large intestine, most differentially expressed genes (DEGs) in the kidney are not similarly regulated in the liver or large intestine. This demonstrates that the influence of the gut microbiota on gene expression is tissue specific. However, a minority of genes (n=4 in males, n=6 in females) were similarly regulated in all three tissues examined, including genes associated with circadian rhythm (Per1in males andPer2in females) and metal binding (Mt1 and Mt2in both males and females). Finally, using a previously published single cell RNA-Seq (scRNA-Seq) dataset, we assigned a subset of DEGs to specific kidney cell types, revealing clustering of DEGs by cell type and/or sex.NEW & NOTEWORTHYIt is unknown whether the microbiome influences host gene expression in the kidney. Here, we utilize an unbiased, bulk RNA-Seq approach to compare gene expression in the kidneys of male and female mice with or without gut microbiota, as well as in liver and large intestine. This report demonstrates that renal gene expression is modulated by the microbiome in a sex- and tissue-specific manner.
Taxonomy of interventions at academic institutions to improve research quality
Authors: Davidson Alexandra R , Barbour Ginny , Nakagawa Shinichi , Holcombe Alex O. , Fidler Fiona , Glasziou Paul P 
Published: December 2022

AbstractResearch institutions and researchers have become increasingly concerned about poor research reproducibility and replicability, and research waste more broadly. Research institutions play an important role and understanding their intervention options is important. This review aims to identify and classify possible interventions to improve research quality, reduce waste, and improve reproducibility and replicability within research-performing institutions.Taxonomy development steps: 1) use of an exemplar paper of journal-level research quality improvement interventions, 2) 2-stage search in PubMed using seed and exemplar articles, and forward and backward citation searching to identify articles evaluating or describing research quality improvement, 3) elicited draft taxonomy feedback from researchers at an open-sciences conference workshop, and 4) cycles of revisions from the research team.The search identified 11 peer-reviewed articles on relevant interventions. Overall, 93 interventions were identified from peer-review literature and researcher reporting. Interventions covered before, during, and after study conduct research stages and whole of institution. Types of intervention included: Tools, Education & Training, Incentives, Modelling & Mentoring, Review & Feedback, Expert involvement, and Policies & Procedures. Identified areas for research institutions to focus on to improve research quality and for further research includes improving incentives to implement quality research practices, evaluating current interventions, encourage no- or low-cost/high-benefit interventions, examine institution research culture, and encourage mentor-mentee relationships.
Multiomic Profiling Reveals Metabolic Alterations Mediating Aberrant Platelet Activity and Inflammation in Myeloproliferative Neoplasms
Authors: He Fan , Laranjeira Angelo B. A. , Kong Tim , Liu Alice , Ashworth Katrina J. , Lasky Nina M. , Fisher Daniel A. C. , Cox Maggie J. , Fulbright Mary C. , Heck Lilian A. , Yu LaYow , Sykes Stephen M. , D’Alessandro Angelo , Di Paola Jorge , Oh Stephen T. 
Published: December 2022

AbstractPlatelets from patients with myeloproliferative neoplasms (MPNs) exhibit a hyperreactive phenotype. Here, we found elevated P-selectin exposure and platelet-leukocyte aggregates indicating activation of platelets from essential thrombocythemia (ET) patients. Single cell RNA-seq analysis of primary samples revealed significant enrichment of transcripts related to platelet activation, mTOR and oxidative phosphorylation (OXPHOS) in ET patient platelets. These observations were validated via proteomic profiling. Platelet metabolomics revealed distinct metabolic phenotypes consisting of elevated ATP generation, accompanied by increases in the levels of multiple intermediates of the tricarboxylic acid (TCA) cycle, but lower alpha-ketoglutarate (α-KG) in MPN patients. Inhibition of PI3K/AKT/mTOR signaling significantly reduced metabolic responses and hyperreactivity in MPN patient platelets, while α-KG supplementation markedly reduced oxygen consumption and ATP generation.Ex vivoincubation of platelets from both MPN patients andJak2 V617Fmice with α-KG significantly reduced platelet activation responses. Oral α-KG supplementation ofJak2 V617Fmice decreased splenomegaly and reduced hematocrit, monocyte and platelet counts. Finally, α-KG incubation significantly decreased proinflammatory cytokine secretion from MPN CD14+ monocytes. Our results reveal a previously unrecognized metabolic disorder in conjunction with aberrant PI3K/AKT/mTOR signaling, contributing to platelet hyperreactivity in MPN patients.
Lipid remodeling by hypoxia aggravates migratory potential in pancreatic cancer while maintaining membrane homeostasis
Authors: Agarwala Prema Kumari , Nie Shuai , Reid Gavin E. , Kapoor Shobhna 
Published: December 2022

AbstractMembranes are crucial cell components underlying optimal cellular functioning under diverse conditions including cancer. The membrane physiology requires acute maintenance of biophysical properties and a regulation of cellular lipidome. Homeostatic adaptation of membranes to temperature, pressure and anti-cancer drugs is a well-recognized. However, how the same is regulated under the influence of oxygen deprivation in pancreatic cancers-highly hypoxic cancer- is not known. Here, we report robust lipidomic remodelling in response to HIF-1α induction in pancreatic cancer cells and significant accumulation of lipid droplets. The lipidome rewiring span changes across various lipid classes, levels of unsaturation and acyl chain lengths. Interestingly, despite extensive lipidome alteration, cellular membrane homeostatic response ensures no major modulation of membrane biophysical properties underlying enhanced migratory potential. The correlation of lipidome changes, with pathway analysis and proteomics provide the basis for mutually exclusive regulation of lipidome and membrane properties. These findings help to understand the hypoxic regulation of pancreatic membrane homeostasis.
Maternal Mental Health and Engagement in Developmental Care Activities with Preterm Infants in the NICU
Authors: Dubner Sarah E. , Morales Maya Chan , Marchman Virginia A. , Shaw Richard J. , Travis Katherine E. , Scala Melissa 
Published: December 2022

AbstractObjectiveTo examine associations between maternal mental health and involvement in developmental care in the NICU.Study DesignMothers of infants born at <32 weeks gestation (n=55) were screened for anxiety, depression, and post traumatic stress disorder two weeks after admission. Mothers’ frequency, rate, and duration of developmental care activities were documented in the electronic health record. Group differences between unscreened mothers, and mothers with and without elevated screener scores and developmental care measures were assessed retrospectively.Results35% of screened mothers scored above the cutoff for clinical concern on ≥1 measure. No significant group differences were identified for rates, frequency, or amount of overall developmental care, kangaroo care, or holding.ConclusionMaternal mental health ratings did not relate to developmental care. Maternal developmental care engagement may not indicate mental health status. Universal screening for psychological distress is required to accurately detect symptoms in mothers of hospitalized preterm infants.
The Changing Global Epidemiology of Re-emerging Human Monkeypox Virus Infection: A Systematic Review
Authors: Sham Sunder , Sapna FNU , Anjali FNU , Kumar Sanjay , Podder Vivek , Jaladi Soumya , Bendari Ahmed , Al-Refai Reham , Baloch Manal Mohammad , Abdelwahed Mohammed , Kiran FNU , Laharwani Hansini 
Published: December 2022

AbstractBackgroundHuman monkeypox (MPXV) virus infection, an emerging zoonotic disease caused by an orthopoxvirus, leads to smallpox-like disease. Human MPXV infection was first reported in 1970 in the Democratic Republic of Congo (DRC). Before April 2022, MPXV cases were endemic and seldom reported outside African regions; but recent global outbreaks of MPXV are concerning. We aimed to investigate the epidemiology of emerging human monkeypox virus infection including the number of suspected, confirmed, and fatal cases as well as risk factors for contracting monkeypox infection.DesignWe performed a systematic review of peer-reviewed literature by following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. An electronic database search (PubMed, online Willey library, science direct) was undertaken. For monkeypox related studies, we included 25 peer-reviewed articles from 2018 and 2022 and data were extracted to inform current evidence on the cases and public health risk factors for developing infection, and public health advice.ResultsOur reports show a rapid rise of MPVX cases in highly endemic African regions after the 1970s, spread to other countries, and increased median age from young children to young adults. Cessation of smallpox vaccination might be one of the factors responsible for the findings. Till 2022 genomic sequences of ten MPXV strains, associated with the recent countrywide outbreak, have been determined. While West African Clade is mostly implicated in the recent viral surge, data were insufficient to determine which mutation contributed to increased transmissibility. In DRC, sleeping on the floor was significantly (odds ratio [OR] 6.1, 95% confidence interval [CI] 1.2-31.6) associated with contracting MPVXwhile eating or processing animal foods was not a significant risk factor. In the United States, cleaning cages, bedding sick animals (OR 5.3, 95% CI 1.4-20.7), or touching infected animals (OR 4.0, 95% CI 1.2-13.4), daily sick animal exposure (OR 4.0, 95% CI 1.2-13.4) were associated with contracting MPVX infection.ConclusionRecent global outbreaks, the rising incidence in young adults and endemic zones might result from smallpox vaccine cessation. Increased risk with sick animal exposure or sleeping on the floor suggests high infectivity from animal excretions. Increasing awareness, strict surveillance, and contact tracing can contain global outbreaks. Ring vaccination approach to exposed people can also be a strategy. Future studies should investigate to determine measures for rapid laboratory diagnosis, maintaining lab safety, and also transmissibility.
User and Usability Testing of a web-basedGBAandLRRK2genetics education tool
Authors: Han Noah , Paul Rachel A. , Bardakjian Tanya , Kargilis Daniel , Bradbury Angela R. , Chen-Plotkin Alice , Tropea Thomas F. 
Published: December 2022

AbstractBackgroundGenetic testing is essential to identify research participants for clinical trials enrolling people with Parkinson’s disease (PD) carrying a variant in theGBAorLRRK2genes. Limited availability of professionals trained in genetic counseling is a major barrier to increased testing.ObjectiveAs an alternative to pre-test genetic counseling, we developed a web-based genetics education tool focused onGBAandLRRK2testing for PD called the Interactive Multimedia Approach to Genetic counseling to INform and Educate in PD (IMAGINE-PD) and conducted user testing and usability testing.MethodsGenetic counselors and PD and neurogenetics subject matter experts developed content for IMAGINE-PD, specifically focused onGBAandLRRK2genetic testing. User testing to review content was conducted with thirteen patients with PD and eleven movement disorder specialists (MDS). Twelve PD patients were enrolled in usability testing of a high-fidelity prototype in accordance with national guidelines. Qualitative data analysis was used in both phases.ResultsQualitative analysis conducted by three evaluators identified themes emerging from MDS and PD patient feedback in user testing in three content areas: content, function, and appearance. Similarly, qualitative analysis of usability testing feedback identified additional themes in these three content areas. Refinements were made to IMAGINE-PD based on consensus recommendation by evaluators.ConclusionsUser testing for content review and usability testing have informed refinements to IMAGINE-PD to develop this alternative to standard pre-test genetic counseling. Comparison of this stakeholder-informed intervention to standard telegenetic counseling approaches is ongoing.
Molecular determinants of inhibition of UCP1-mediated respiratory uncoupling
Authors: Gagelin Antoine , Largeau Corentin , Masscheleyn Sandrine , Piel Mathilde S. , Calderon-Mora Daniel , Bouillaud Frédéric , Hénin Jérôme , Miroux Bruno 
Published: December 2022

AbstractBrown adipose tissue expresses uncoupling protein 1 (UCP1), a mitochondrial transporter that uncouples respiration from ATP synthesis and dissipates energy as heat, making it a target for treating obesity and related metabolic disorders. Here, we combine molecular dynamics simulations with mitochondrial respiration assays to investigate how purine nucleotides inhibit respiration uncoupling by UCP1. Simulations predict that GDP binds UCP1 in the common substrate binding site in an upright orientation, where the base moiety interacts with a pair of charged residues (R92/E191) that are specifically conserved in the subfamily of UCPs. E191, among others, interacts with purine but not pyrimidine bases, suggesting a rationale for nucleotide specificity in UCP1 inhibition. We also identify a triplet of uncharged residues involved in hydrophobic contacts with GDP. Site-directed mutagenesis of either I187 or W281 to alanine increases lauric acid-induced uncoupling activity of UCP1 and partially suppresses inhibition of UCP1 activity by GDP in yeast spheroplasts. The triple mutant (F88, I187, W281) to alanine is overactivated by lauric acid even in a high concentration of purine nucleotides. Variants at these positions may help increase energy expenditure in a cellular and therapeutic context.
Novel porcine model reveals two distinct LGR5 cell types during lung development and homeostasis
Authors: Polkoff Kathryn M. , Lampe Ross , Gupta Nithin K. , Murphy Yanet , Chung Jaewook , Carter Amber , Simon Jeremy M. , Gleason Katherine , Moatti Adele , Murthy Preetish K. , Edwards Laura , Greenbaum Alon , Tata Aleksandra , Tata Purushothama Rao , Piedrahita Jorge A. 
Published: December 2022

ABSTRACTCells expressing LGR5 play a pivotal role in homeostasis, repair, and regeneration in multiple organs including skin and gastrointestinal tract, yet little is known about their role in the lung. Findings from mice, a widely used animal model, suggest that lung LGR5 expression differs from that of humans. In this work, using a new transgenic pig model, we identify two main populations of LGR5+cells in the lung that are conserved in human, but not mouse lungs. Using RNA sequencing, 3D imaging and organoid models, we determine that in the fetal lung, epithelial LGR5 expression is transient in a subpopulation of SOX9+/ETV+/SFTPC+progenitor lung tip cells. In contrast, epithelial LGR5 expression is absent from postnatal lung, but is reactivated in bronchioalveolar organoids derived from basal airway cells. We also describe a separate population of mesenchymal LGR5+cells that surrounds developing and mature airways, lies adjacent to airway basal cells, and is closely associated with nerve fibers. Transcriptionally, mesenchymal LGR5+cells include a subset of peribronchial fibroblasts (PBF) that express unique patterns ofSHH, FGF, WNTandTGF-β signaling pathway genes. These results support distinct roles for LGR5+cells in the lung and describe a physiologically relevant animal model for further studies on the function of these cells in repair and regeneration.
METTL3 drives telomere targeting of TERRA lncRNA through m6A-dependent R-loop formation: a therapeutic target for ALT-positive neuroblastoma
Authors: Vaid Roshan , Thombare Ketan , Mendez Akram , Burgos-Panadero Rebeca , Djos Anna , Jachimowicz Daniel , Lundberg Kristina Ihrmark , Bartenhagen Christoph , Kumar Navinder , Tümmler Conny , Sihlbom Carina , Fransson Susanne , Johnsen John Inge , Kogner Per , Martinsson Tommy , Fischer Matthias , Mondal Tanmoy 
Published: December 2022

AbstractTelomerase-negative tumors maintain telomere length by alternative lengthening of telomeres (ALT), but the underlying mechanism behind ALT remains poorly understood. A proportion of aggressive neuroblastoma (NB), particularly relapsed tumors, are positive for ALT (ALT+), suggesting that a better dissection of the ALT mechanism could lead to novel therapeutic opportunities. TERRA, a long non-coding RNA (lncRNA) derived from telomere ends, localizes to telomeres in a R-loop-dependent manner and plays a crucial role in telomere maintenance. Here we present evidence that RNA modification at theN6position of internal adenosine (m6A) in TERRA by the methyltransferase METTL3 is essential for telomere maintenance in ALT+ cells, and the loss of TERRA m6A/METTL3 results in telomere damage. We observed that m6A modification is abundant in R-loop enriched TERRA, and the m6A-mediated recruitment of hnRNPA2B1 to TERRA is critical for R-loop formation. Our findings suggest that m6A drives telomere targeting of TERRA via R-loops, and this m6A-mediated R-loop formation could be a widespread mechanism employed by other chromatin-interacting lncRNAs. Furthermore, treatment of ALT+ NB cells with a METTL3 inhibitor resulted in compromised telomere targeting of TERRA and accumulation of DNA damage at telomeres, indicating that METTL3 inhibition may represent a therapeutic approach for ALT+ NB.
Random genetic drift sets an upper limit on mRNA splicing accuracy in metazoans
Authors: Bénitière Florian , Necsulea Anamaria , Duret Laurent 
Published: December 2022

AbstractMost eukaryotic genes undergo alternative splicing (AS), but the overall functional significance of this process remains a controversial issue. It has been noticed that the complexity of organisms (assayed by the number of distinct cell types) correlates positively with their genome-wide AS rate. This has been interpreted as evidence that AS plays an important role in adaptive evolution by increasing the functional repertoires of genomes. However, this observation also fits with a totally opposite interpretation: given that ‘complex’ organisms tend to have small effective population sizes (Ne), they are expected to be more affected by genetic drift, and hence more prone to accumulate deleterious mutations that decrease splicing accuracy. Thus, according to this “drift barrier” theory, the elevated AS rate in complex organisms might simply result from a higher splicing error rate. To test this hypothesis, we analyzed 3,496 transcriptome sequencing samples to quantify AS in 53 metazoan species spanning a wide range ofNevalues. Our results show a negative correlation betweenNeproxies and the genome-wide AS rates among species, consistent with the drift barrier hypothesis. This pattern is dominated by low abundance isoforms, which represent the vast majority of the splice variant repertoire. We show that these low abundance isoforms are depleted in functional AS events, and most likely correspond to errors. Conversely, the AS rate of abundant isoforms, which are relatively enriched in functional AS events, tends to be lower in more complex species. All these observations are consistent with the hypothesis that variation in AS rates across metazoans reflects the limits set by drift on the capacity of selection to prevent gene expression errors.
Positions of pivot points in quadrupedal locomotion: limbs and trunk global control in four different dog breeds
Authors: Andrada Emanuel , Hildebrandt Gregor , Witte Hartmut , Fischer Martin S. 
Published: December 2022

AbstractDogs (Canis familiaris) prefer the walk at lower speeds and the more economical trot at speeds ranging from 0.5 Fr up to 3 Fr. Important works were carried out to understand these gaits at the levels of center of mass, joint mechanics, and muscular control. However, less is known about the global control goals for limbs and overall locomotion, and of whether these global control goals are gait or breed specific. For walk and trot, we analyzed dog global dynamics based on motion capture and single leg kinetic data recorded from treadmill locomotion of French Bulldog (N = 4), Whippet (N = 5), Malinois (N = 4) and Beagle (N = 5). Dogs displayed two virtual pivot points (VPP) during walk and trot each. One resembles control of both thoracic (fore) limbs and is roughly located above and caudally to the scapular pivot, while the second is located roughly above and cranially to the hip and mirrors the control of the pelvic (hind-) limbs. The positions of VPPs and the patterns of the legs‘ axial and tangential functions were gait and breed related. However, breed related changes were mainly exposed by the French Bulldog. The position of VPPs relative to the proximal pivots explains the propulsive and breaking forces observed in quadrupedal locomotion and may help to reduce limb work. In combination with former work, from the present study the VPP template emerges as the expression of a simple and general global control rule for both bipeds and quadrupeds.