bluuebunny/crossref_metadata_2025_split huggingface dataset:
Synaptotagmin-9 and Tomosyn-1 molecular complex regulates Stx1A SNAREs to inhibit insulin secretion from pancreatic β-cells
Authors: Rahman Md Mostafizur , Pathak Asmita , Schueler Kathryn L , Al Sharif Haifa , Michl Ava , Alexander Justin , Kim Jeonga-a , Chapman Edwin , Bhatnagar Sushant 
Published: October 2022

SummaryStimulus-coupled insulin secretion from β-cells involves the fusion of insulin granules to the plasma membrane (PM) via SNARE complex formation—a cellular process key for maintaining whole-body glucose homeostasis. Optimal insulin secretion depends on how the clamping of SNAREs is released, rendering granules fusogenic. We show that an insulin granule protein synaptotagmin-9 (Syt9) deletion in lean mice increased glucose clearance, random-fed plasma insulin levels, and insulin secretion (in vivo and ex vivo islets) without affecting insulin sensitivity. These outcomes demonstrate that Syt9 has an inhibitory function in insulin secretion. Moreover, Syt9 interacts with PM-Stx1A and soluble Tomosyn-1 proteins to form non-fusogenic complexes between PM and insulin granules, preventing Stx1A-SNARE formation and insulin secretion. Furthermore, Syt9 inhibits SNARE-complex formation by posttranscriptional regulation of Tomosyn-1. We conclude that Syt9 and Tomosyn-1 are endogenous inhibitors that modulate Stx1A availability to determine β-cell secretory capacity.HighlightsSynaptotagmin-9 inhibits biphasic insulin secretion from β-cells.Synaptotagmin-9, syntaxin-1A, and Tomosyn-1 forms a molecular complex that decreases the availability of syntaxin-1A to form SNARE complexes in insulin secretion.Synaptotagmin-9–mediated inhibition of insulin secretion occurs through post-transcriptional regulation of Tomosyn-1.
Additivity predicts the efficacy of most approved combination therapies for advanced cancer
Authors: Hwangbo Haeun , Patterson Sarah , Dai Andy , Plana Deborah , Palmer Adam C. 
Published: October 2022

ABSTRACTMost advanced cancers are treated with drug combinations. Rational designs aim to identify synergistic drug interactions to produce superior treatments. However, metrics of drug interaction (i.e., synergy, additivity, antagonism) apply to pre-clinical experiments, and there has been no established method to quantify synergy versus additivity in clinical settings. Here, we propose and apply a model of drug additivity for progression-free survival (PFS) to assess if the clinical efficacies of approved drug combinations are more than, or equal to, the sum of their parts. This model accounts for the benefit from patient-to-patient variability in the best single drug response, plus the added benefit of the weaker drug per patient. Among FDA approvals for advanced cancers between 1995-2020, we identified 37 combinations across 13 cancer types where monotherapies and combination therapy could be compared. 95% of combination therapies exhibited progression-free survival times that were additive, or less than additive. Among a set of phase III trials with either positive or negative results published between 2014 and 2018, every combination that did improve PFS was expected to succeed by additivity (100% sensitivity) and most failures were expected to fail (78% specificity). This study has two key findings. First, a synergistic effect (more than additive) is neither a necessary nor even a common property of clinically effective drug combinations. Second, the predictable efficacy of many of the best drug combinations established over the past 25 years suggests that additivity can be used as a design principle for novel drug combinations and clinical trials.
Design of effective outpatient sentinel surveillance for COVID-19 decision-making: a modeling study
Authors: Toh Kok Ben , Runge Manuela , Richardson Reese AK , Hladish Thomas J , Gerardin Jaline 
Published: October 2022

AbstractBackgroundDecision-makers impose COVID-19 mitigations based on public health indicators such as reported cases, which are sensitive to fluctuations in supply and demand for diagnostic testing, and hospital admissions, which lag infections by up to two weeks. Imposing mitigations too early has unnecessary economic costs, while imposing too late leads to uncontrolled epidemics with unnecessary cases and deaths. Sentinel surveillance of recently-symptomatic individuals in outpatient testing sites may overcome biases and lags in conventional indicators, but the minimal outpatient sentinel surveillance system needed for reliable trend estimation remains unknown.MethodsWe used a stochastic, compartmental transmission model to evaluate the performance of various surveillance indicators at reliably triggering an alarm in response to, but not before, a step increase in transmission of SARS-CoV-2. The surveillance indicators included hospital admissions, hospital occupancy, and sentinel cases with varying levels of sampling effort capturing 5, 10, 20, 50 or 100% of incident mild cases. We tested 3 levels of transmission increase, 3 population sizes, and condition of either simultaneous transmission increase, or lagged increase in older population. We compared the indicators’ performance at triggering alarm soon after, but not prior, to the transmission increase.ResultsCompared to surveillance based on hospital admissions, outpatient sentinel surveillance that captured at least 20% of incident mild cases could trigger alarm 2 to 5 days earlier for a mild increase in transmission and 6 days earlier for moderate or strong increase. Sentinel surveillance triggered fewer false alarms and averted more deaths per day spent in mitigation. When transmission increase in older populations lagged increase in younger populations by 14 days, sentinel surveillance extended its lead time over hospital admissions by an additional 2 days.ConclusionsSentinel surveillance of mild symptomatic cases can provide more timely and reliable information on changes in transmission to inform decision-makers in an epidemic like COVID-19.
Potential Misrepresentation of Inherited Breast Cancer Risk by Common Germline Alleles
Authors: Letsou William , Wang Fan , Moon Wonjong , Im Cindy , Sapkota Yadav , Robison Leslie L. , Yasui Yutaka 
Published: October 2022

AbstractHundreds of common variants have been found to confer small but significant differences in breast cancer risk, supporting the polygenic additive model of inherited risk. This widely accepted model is at odds with twin data indicating highly elevated risk in a subgroup of women. Using a novel closed-pattern-mining algorithm, we provide evidence that rare variants or haplotypes may underlie the association of breast cancer risk with common germline alleles. Our method, called Chromosome Overlap, consists in iteratively pairing chromosomes from affected individuals and looking for noncontiguous patterns of shared alleles without exhaustive enumeration. We applied Chromosome Overlap to haplotypes of genotyped SNPs from 9,011 female breast cancer cases from the UK Biobank (UKBB) at three topologically associating domains containing well-established common-allele “hits” for breast cancer. A total of 181,034 UKBB women of “white British” ancestry were used to assess the discovered haplotypes, and 55,346 cases and controls of European ancestry in the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) case-control study were used for replication. Out of twenty rare (frequency < ∼0.1%) risk haplotypes of large effect identified in UKBB atP< 1.0 × 10−5, four (hazard ratio: 4.22–20.2) were subsequently replicated in DRIVE (odds ratio: 2.13–11.9) atP< 0.05. Our results support the genetic heterogeneity and rare-variant/haplotype basis of breast cancer risk and suggest a novel type of “synthetic association” wherein common risk alleles on a rare risk haplotype may misrepresent disease risk through their tagging of many “false positive” haplotypes.SignificanceChromosome Overlap reveals that common alleles identified by GWAS may be poor surrogates for underlying high-risk haplotypes, necessitating a reappraisal of the polygenic model of disease risk.
Career Self-Efficacy Disparities in Underrepresented Biomedical Scientist Trainees
Authors: Chatterjee Deepshikha , Jacob Gabrielle A. , Varvayanis Susi Sturzenegger , Wefes Inge , Chalkley Roger , Nogueira Ana T. , Fuhrmann Cynthia N. , Varadarajan Janani , Hubbard Nisan M. , Gaines Christiann H. , Layton Rebekah L. , Chaudhary Sunita 
Published: October 2022

AbstractThe present study examines racial, ethnic, and gender disparities in career self-efficacy amongst 6077 US citizens and US naturalized graduate and postdoctoral trainees. Respondents from biomedical fields completed surveys administered by the National Institutes of Health Broadening Experiences in Scientific Training (NIH BEST) programs across 17 US institutional sites. Graduate and postdoctoral demographic and survey response data were examined to evaluate the impact of intersectional identities on trainee career self-efficacy. The study hypothesized that race, ethnicity and gender, and the relations between these identities, would impact trainee career self-efficacy. The analysis demonstrated that racial and ethnic group, gender, specific career interests (academic principal investigator vs. other careers), and seniority (junior vs. senior trainee level) were, to various degrees, all associated with trainee career self-efficacy and the effects were consistent across graduate and postdoctoral respondents. Implications for differing levels of self-efficacy are discussed, including factors and events during training that may contribute to (or undermine) career self-efficacy. The importance of mentorship for building research and career self-efficacy of trainees is discussed, especially with respect to those identifying as women and belonging to racial/ethnic populations underrepresented in biomedical sciences. The results underscore the need for change in the biomedical academic research community in order to retain a diverse biomedical workforce.
Zebrafish Rif1 impacts zygotic genome activation, replication timing, and sex determination
Authors: Masser Emily A. , Noble Tyler D. , Siefert Joseph C. , Goins Duane , Sansam Courtney G. , Sansam Christopher L. 
Published: October 2022

AbstractDeregulated DNA replication causes human developmental disorders and cancer, but we know little about how DNA replication is coordinated with changes in transcription and chromatin structure. The initiation of replication forks follows a spatiotemporal pattern called the replication timing program. We have developed the zebrafish into a model system to study the mechanisms by which the replication timing program changes during the extensive changes in the cell cycle, transcription, chromatin organization, and nuclear structure that occur during development. Our previous studies identified changes in DNA replication timing patterns occurring from the onset of zygotic transcription through gastrulation in zebrafish embryos. Rif1 is required for DNA replication timing in a wide range of eukaryotes. The broader role of Rif1 in establishing the replication timing program and chromatin structure during early vertebrate development remains unknown. We have generated Rif1 mutant zebrafish and have performed RNA sequencing and whole-genome replication timing analyses on multiple developmental stages. Rif1 mutants were viable but had a defect in female sex determination. Surprisingly, Rif1 loss predominantly affected DNA replication timing after gastrulation, while its impacts on transcription were more substantial during zygotic genome activation. Our results indicate that Rif1 has distinct roles in DNA replication and transcription control that manifest at different stages of development.
Barley MLA3 recognizes the host-specificity determinant PWL2 from rice blast (M. oryzae)
Authors: Brabham Helen J. , De La Cruz Diana Gómez , Were Vincent , Shimizu Motoki , Saitoh Hiromasa , Hernández-Pinzón Inmaculada , Green Phon , Lorang Jennifer , Fujisaki Koki , Sato Kazuhiro , Molnár István , Šimková Hana , Doležel Jaroslav , Russell James , Taylor Jodie , Smoker Matthew , Gupta Yogesh Kumar , Wolpert Tom , Talbot Nicholas J. , Terauchi Ryohei , Moscou Matthew J. 
Published: October 2022

AbstractPlant nucleotide-binding leucine-rich repeat immune receptors (NLRs) directly or indirectly recognize pathogen-secreted effector molecules to initiate plant defense. Recognition of multiple pathogens by a single NLR is rare and usually occurs via monitoring for changes to host proteins; few characterized NLRs have been shown to recognize multiple effectors. The barley NLRMlahas undergone functional diversification andMlaalleles recognize host-adapted isolates of barley powdery mildew (Blumeria graminisf. sp.hordei; Bgh). Here, we show thatMla3also confers resistance to rice blast (Magnaporthe oryzae) in a dosage dependent manner. Using a forward genetic screen, we discovered that the recognized effector fromM. oryzaeisPWL2, a host range determinant factor that preventsM. oryzaefrom infecting weeping lovegrass (Eragrostis curvula).Mla3has therefore convergently evolved the capacity to recognize effectors from diverse pathogens.
Lineage plasticity in SCLC generates non-neuroendocrine cells primed for vasculogenic mimicry
Authors: Pearsall Sarah M , Williamson Stuart C , García Marqués Fernando J , Humphrey Sam , Hughes Ellyn , Shue Yan Ting , Bermudez Abel , Frese Kristopher K , Galvin Melanie , Carter Mathew , Priest Lynsey , Kerr Alastair , Zhou Cong , Oliver Trudy G. , Humphries Jonathan D , Humphries Martin J. , Blackhall Fiona , Cannell Ian G , Pitteri Sharon J , Hannon Gregory J , Sage Julien , Simpson Kathryn L , Dive Caroline 
Published: October 2022

AbstractIntroductionVasculogenic mimicry (VM), the process of tumor cell trans-differentiation to endow endothelial-like characteristics supportingde novovessel formation, is associated with poor prognosis in several tumor types, including small cell lung cancer (SCLC). In genetically engineered mouse models (GEMMs) of SCLC, NOTCH and MYC co-operate to drive a neuroendocrine (NE) to non-NE phenotypic switch and co-operation between NE and non-NE cells is required for metastasis. Here, we define the phenotype of VM-competent cells and molecular mechanisms underpinning SCLC VM using circulating tumor cell-derived explant (CDX) models and GEMMs.MethodsWe analysed perfusion within VM vessels and their association with NE and non-NE phenotypes using multiplex immunohistochemistry in CDX and GEMMs. VM-proficient cell subpopulations inex vivocultures were molecularly profiled by RNA sequencing and mass spectrometry. We evaluated their 3D structure and defined collagen-integrin interactions.ResultsWe show that VM vessels are present in 23/25 CDX models and in 2 GEMMs. Perfused VM vessels support tumor growth and only Notch-active non-NE cells are VM-competentin vivoandex vivo, expressing pseudohypoxia, blood vessel development and extracellular matrix (ECM) organization signatures. On Matrigel, VM-primed non-NE cells re-model ECM into hollow tubules in an integrin β1-dependent process.ConclusionsWe identify VM as an exemplar of functional heterogeneity and plasticity in SCLC and these findings take significant steps towards understanding the molecular events that enable VM. These results support therapeutic co-targeting of both NE and non-NE cells to curtail SCLC progression and to improve SCLC patient outcomes in future.
Brain DNA methylomic analysis of frontotemporal lobar degeneration revealsOTUD4in shared dysregulated signatures across pathological subtypes
Authors: Fodder Katherine , Murthy Megha , Rizzu Patrizia , Toomey Christina E. , Hasan Rahat , Humphrey Jack , Raj Towfique , Lunnon Katie , Mill Jonathan , Heutink Peter , Lashley Tammaryn , Bettencourt Conceição 
Published: October 2022

ABSTRACTFrontotemporal lobar degeneration (FTLD) is an umbrella term describing the neuropathology of a clinically, genetically and pathologically heterogeneous group of diseases, including frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP). Among the major FTLD pathological subgroups, FTLD with TDP-43 positive inclusions (FTLD-TDP) and FTLD with tau positive inclusions (FTLD-tau) are the most common, representing about 90% of the cases. Although alterations in DNA methylation have been consistently associated with neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease, little is known for FTLD and its heterogeneous subgroups and subtypes. The main goal of this study was to investigate DNA methylation variation in FTLD-TDP and FTLD-tau. We used frontal cortex genome-wide DNA methylation profiles from three FTLD cohorts (234 individuals), generated using the Illumina 450K or EPIC microarray. We performed epigenome-wide association studies (EWAS) for each cohort followed by meta-analysis to identify shared differential methylated loci across FTLD subgroups/subtypes. Additionally, we used weighted gene correlation network analysis to identify co-methylation signatures associated with FTLD and other disease-related traits. Wherever possible, we also incorporated relevant gene/protein expression data. After accounting for a conservative Bonferroni multiple testing correction, the EWAS meta-analysis revealed two differentially methylated loci in FTLD, one annotated to OTUD4 (5’UTR-shore) and the other to NFATC1 (gene body-island). Of these loci, OTUD4 showed consistent upregulation of mRNA and protein expression in FTLD. Additionally, in the three independent co-methylation networks,OTUD4-containing modules were enriched for EWAS meta-analysis top loci and were strongly associated with the FTLD status. These co-methylation modules were enriched for genes implicated in the ubiquitin system, RNA/stress granule formation and glutamatergic synaptic signalling. Altogether, our findings identified novel FTLD-associated loci, and support a role for DNA methylation as a mechanism involved in the dysregulation of biological processes relevant to FTLD, highlighting novel potential avenues for therapeutic development.
Targeting the Human Papillomavirus 16 E6 Oncoprotein with Antibodies
Authors: Dayer Guillem , Faulkner Ashley , Talwar Tanu , Togtema Melissa , Zehbe Ingeborg 
Published: October 2022

AbstractThe human papillomavirus (HPV) 16 genome encodes two oncoproteins, E6 and E7, which are essential for viral carcinogenesis. While E7 promotes cell proliferation, E6 abolishes the resulting p53-dependent apoptotic response. Due to this specific function, E6 is considered a suitable target for the development of a variety of therapeutic agents such as antibodies. Here, we review anti-E6 antibodies/antibody fragments generated by us and others, as well as present our latest results withCamelidae-derived single-domain antibodies (sdAbs). We had previously isolated a pool of anti-E6 sdAbs to identify E6 binders with the potential to be used clinically and in research. While our previous work has focused on recombinant E6 proteins, here we evaluated these sdAbs’ binding capacity to the endogenous E6 protein using co-immunoprecipitation and immunofluorescence. We obtained reproducible results in these applications with two sdAbs, filling a gap in HPV research. Despite their apparent E6 binding ability, these sdAbs do not raise p53 levels or induce apoptosis. Thus, while these reagents are valuable diagnostic and detection tools, identifying their therapeutic potential will require further development and testing.
Improving fine-mapping by modeling infinitesimal effects
Authors: Cui Ran , Elzur Roy A , Kanai Masahiro , Ulirsch Jacob C , Weissbrod Omer , Daly Mark J , Neale Benjamin M , Fan Zhou , Finucane Hilary K 
Published: October 2022

AbstractFine-mapping aims to identify causal variants for phenotypes. Bayesian fine-mapping algorithms (e.g.: SuSiE, FINEMAP, ABF, and COJO-ABF) are widely used, but assessing posterior probability calibration remains challenging in real data, where model misspecification likely exists, and true causal variants are unknown. We introduce Replication Failure Rate (RFR), a metric to assess fine-mapping consistency by down-sampling. SuSiE, FINEMAP and COJO-ABF show high RFR, indicating potential under-conservative mis-calibration. Simulations reveal that non-sparse genetic architecture can lead to miscalibration, while imputation noise, non-uniform distribution of causal variants, and QC filters have minimal impact. We present SuSiE-inf and FINEMAP-inf, novel fine-mapping methods modeling infinitesimal effects alongside fewer larger causal effects. Our methods exhibit improved calibration, RFR and functional enrichment, competitive recall and computational efficiency. Notably, using our methods’ posterior effect sizes substantially increases PRS accuracy over SuSiE and FINEMAP. Our work improves causal variants identification for complex traits, a fundamental goal of human genetics.
Rapamycin rescues loss-of-function in blood-brain barrier-interacting regulatory T cells
Authors: Baeten Paulien , Hamad Ibrahim , Hoeks Cindy , Hiltensperger Michael , Van Wijmeersch Bart , Popescu Veronica , Aly Lilian , Somers Veerle , Korn Thomas , Kleinewietfeld Markus , Hellings Niels , Broux Bieke 
Published: October 2022

AbstractIn many autoimmune diseases, FOXP3+regulatory T cells (Tregs) skew towards a pro-inflammatory and non-suppressive phenotype and are therefore unable to control the exaggerated autoimmune response. This may largely impact the success of autologous Treg therapy which is currently under investigation for treatment of autoimmune diseases, including multiple sclerosis (MS). Thus, there is a need to ensurein vivostability of Tregs before successful Treg therapy can be applied. Using a murine genetic fate-mapping model, we demonstrate that inflammatory exFOXP3 T cells accumulate in the central nervous system (CNS) during experimental autoimmune encephalomyelitis (EAE). In a humanin vitroBBB model, we discovered that interaction with inflamed blood-brain barrier (BBB)-endothelial cells induces loss of suppressive function in Tregs. Transcriptome analysis further revealed that Tregs which migrated across inflamed BBB-endothelial cellsin vitrohave a pro-inflammatory Th1/17 signature and upregulate the mTORC1 signaling pathway compared to non-migrated Tregs. These findings suggest that interaction with BBB-endothelial cells is sufficient to affect Treg function, and that transmigration triggers an additive pro-inflammatory phenotype switch, which was also seen in CNS-derived exFOXP3 T cells of EAE mice.In vitrotreatment of migrated human Tregs with the clinically-approved mTORC1 inhibitor rapamycin completely restored the loss of suppressive function. Finally, flow cytometric analysis indicated an enrichment of inflammatory, less suppressive CD49d+Tregs in the cerebrospinal fluid of MS patients, thereby underscoring the relevance of our findings for human disease. In sum, our findings provide firm evidence that the inflamed BBB affects human Treg stability, which can be restored using a mTORC1 inhibitor. These insights can help in significantly improving the efficacy of autologous Treg therapy of MS.