bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic ascertainment ofCHEK2-related cancer predisposition
Authors: Kim Sun Young , Kim Jung , Ramos Mark , Haley Jeremy , Smelser Diane , Rao H. Shanker , Mirshahi Uyenlinh L. ,   Geisinger-Regeneron DiscovEHR Collaboration, Graubard Barry I. , Katki Hormuzd A. , Carey David , Stewart Douglas R. 
Published: August 2024

AbstractPurposeThere is clear evidence that deleterious germline variants inCHEK2increases risk for breast and prostate cancers; there is limited or conflicting evidence for other cancers. Genomic ascertainment was used to quantify cancer risk inCHEK2germline pathogenic variant heterozygotes.Patients and MethodsGermlineCHEK2variants were extracted from two exome-sequenced biobanks linked to the electronic health record: UK Biobank (n= 469,765)and Geisinger MyCode (n=170,503). Variants were classified as per American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) criteria. Heterozygotes harbored aCHEK2pathogenic/likely pathogenic (P/LP) variant; controls harbored benign/likely benignCHEK2variation or wildtypeCHEK2. Tumor phenotype and demographic data were retrieved; to adjust for relatedness, association analysis was performed with SAIGE-GENE+ with Bonferroni correction.ResultsInCHEK2heterozygotes in both MyCode and UK Biobank, there was a significant excess risk of all cancers tested, including breast cancer (C50; OR=1.54 and 1.84, respectively), male genital organ cancer (C60-C63; OR=1.61 and 1.77 respectively), urinary tract cancer (C64-C68; OR=1.56 and 1.75, respectively) and lymphoid, hematopoietic, and related tissue cancer (C81-C96; OR=1.42 and 2.11, respectively). Compared to controls, age-dependent cancer penetrance inCHEK2heterozygotes was significantly younger in both cohorts; no significant difference was observed between the penetrance of truncating and missense variants for cancer in either cohort. Overall survival was significantly decreased inCHEK2heterozygotes in UK Biobank but there was no statistical difference in MyCode.ConclusionUsing genomic ascertainment in two population-scale cohorts, this investigation quantified the prevalence, penetrance, cancer phenotype and survival inCHEK2heterozygotes. Tailored treatment options and surveillance strategies to manage those risks are warranted.
Persistent PTSD symptoms are associated with plasma metabolic alterations relevant to long-term health: A metabolome-wide investigation in women
Authors: Zhu Yiwen , Shutta Katherine H. , Huang Tianyi , Balasubramanian Raji , Zeleznik Oana A. , Clish Clary B. , Ávila-Pacheco Julián , Hankinson Susan E. , Kubzansky Laura D. 
Published: August 2024

AbstractBackgroundPosttraumatic stress disorder (PTSD) is characterized by severe distress and associated with cardiometabolic diseases. Studies in military and clinical populations suggest dysregulated metabolomic processes may be a key mechanism. Prior work identified and validated a metabolite-based distress score (MDS) linked with depression and anxiety and subsequent cardiometabolic diseases. Here, we assessed whether PTSD shares metabolic alterations with depression and anxiety and also if additional metabolites are related to PTSD.MethodsWe leveraged plasma metabolomics data from three subsamples nested within the Nurses’ Health Study II, including 2835 women with 2950 blood samples collected across three timepoints (1996-2014) and 339 known metabolites consistently assayed by mass spectrometry-based techniques. Trauma and PTSD exposures were assessed in 2008 and characterized as follows: lifetime trauma without PTSD, lifetime PTSD in remission, and persistent PTSD symptoms. Associations between the exposures and the MDS or individual metabolites were estimated within each subsample adjusting for potential confounders and combined in random-effects meta-analyses.ResultsPersistent PTSD symptoms were associated with higher levels of the previously developed MDS for depression and anxiety. Out of 339 metabolites, we identified nine metabolites (primarily elevated glycerophospholipids) associated with persistent symptoms (false discovery rate<0.05). No metabolite associations were found with the other PTSD-related exposures.ConclusionsAs the first large-scale, population-based metabolomics analysis of PTSD, our study highlighted shared and distinct metabolic differences linked to PTSD versus depression or anxiety. We identified novel metabolite markers associated with PTSD symptom persistence, suggesting further connections with metabolic dysregulation that may have downstream consequences for health.
Associations of Serum GDF-15 Levels with Physical Performance, Mobility Disability, Cognition, Cardiovascular Disease, and Mortality in Older Adults
Authors: Webber Katey , Patel Sheena , Kizer Jorge R. , Eastell Richard , Psaty Bruce M. , Newman Anne B. , Cummings Steven R. 
Published: August 2024

ABSTRACTBackgroundGrowth differentiation factor 15 (GDF-15) is a member of the TGFβ superfamily secreted by many cell types and found at higher blood concentrations as chronological age increases (1). Given the emergence of GDF-15 as a key protein associated with aging, it is important to understand the multitude of conditions with which circulating GDF-15 is associated.MethodsWe pooled data from 1,174 randomly selected Health ABC Study (Health ABC) participants and 1,503 Cardiovascular Health Study (CHS) participants to evaluate the risk of various conditions and age-related outcomes across levels of GDF-15. The primary outcomes were (1) risk of mobility disability and falls; (2) impaired cognitive function; (3) and increased risk of cardiovascular disease and total mortality.ResultsThe pooled study cohort had a mean age of 75.4 +/−4.4 years. Using a Bonferroni-corrected threshold, our analyses show that high levels of GDF-15 were associated with a higher risk of severe mobility disability (HR: 2.13 [1.64, 2.77]), coronary heart disease (HR: 1.47 [1.17, 1.83]), atherosclerotic cardiovascular disease (HR: 1.56 [1.22, 1.98]), heart failure (HR: 2.09 [1.66, 2.64]), and mortality (HR: 1.81 [1.53, 2.15]) when comparing the highest and lowest quartiles. For CHS participants, analysis of extreme quartiles in fully adjusted models revealed a 3.5-fold higher risk of dementia (HR: 3.50 [1.97, 6.22]).ConclusionsGDF-15 is associated with several age-related outcomes and diseases, including mobility disability, impaired physical and cognitive performance, dementia, cardiovascular disease, and mortality. Each of these findings demonstrates the importance of GDF-15 as a potential biomarker for many aging-related conditions.
cGAS Expression is Enhanced in Systemic Sclerosis Associated Interstitial Lung Disease and Stimulates Inflammatory Myofibroblast Activation
Authors: Yu Sheeline , Hu Buqu , Sun Ying , Peng Xue Yan , Lee Chris J. , Woo Samuel , McGovern John , Zielonka Jana , Saber Tina , Ghincea Alexander , Gandhi Shifa , Walia Anjali , Pivarnik Taylor , Ishikawa Genta , Shuai Shao , Sun Huanxing , Gunes Baran Ilayda , Kujawski Sophia , Perez Stephanie , Odell William , Hinchcliff Monique , Varga John , Bostwick Carol Feghali- , Sauler Maor , Gomez Jose L. , Ryu Changwan , Herzog Erica L. 
Published: August 2024

ABSTRACTObjectiveThe lungs of patients with Systemic Sclerosis Associated Interstitial Lung Disease (SSc-ILD) contain inflammatory myofibroblasts arising in association with fibrotic stimuli and perturbed innate immunity. The innate immune DNA binding receptor Cyclic GMP-AMP synthase (cGAS) is implicated in inflammation and fibrosis, but its involvement in SSc-ILD remains unknown. We examined cGAS expression, activity, and therapeutic potential in SSc-ILD using cultured fibroblasts, precision cut lung slices (PCLS), and a well-accepted animal model.MethodsExpression and localization of cGAS, cytokines, and type 1 interferons were evaluated in SSc-ILD lung tissues, bronchoalveolar lavage (BAL), and isolated lung fibroblasts.CGASactivation was assessed in a publicly available SSc-ILD single cell RNA sequencing dataset. Production of cytokines, type 1 interferons, and αSMA elicited by TGFβ1 or local substrate stiffness were measured in normal human lung fibroblasts (NHLFs) via qRT-PCR, ELISA, and immunofluorescence. Small molecule cGAS inhibition was tested in cultured fibroblasts, human PCLS, and the bleomycin pulmonary fibrosis model.ResultsSSc-ILD lung tissue and BAL are enriched for cGAS, cytokines, and type 1 interferons. The cGAS pathway shows constitutive activation in SSc-ILD fibroblasts and is inducible in NHLFs by TGFβ1 or mechanical stimuli. In these settings, and in human PCLS, cGAS expression is paralleled by the production of cytokines, type 1 interferons, and αSMA that are mitigated by a small molecule cGAS inhibitor. These findings are recapitulated in the bleomycin mouse model.ConclusioncGAS signaling contributes to pathogenic inflammatory myofibroblast phenotypes in SSc-ILD. Inhibiting cGAS or its downstream effectors represents a novel therapeutic approach.
Country Level Incidence of Alzheimer Disease and Related Dementias is Associated with Increased Omega6 PUFA Consumption
Authors: Ciesielski Timothy H. , Tosto Giuseppe , Durodoye Razaq O. , Rajabali Farid , Akinyemi Rufus O. , Byrd Goldie S. , Bush William S. , Kunkle Brian W. , Reitz Christiane , Vance Jeffery M. , Pericak-Vance Margaret A. , Haines Jonathan L. , Williams Scott M. 
Published: August 2024

AbstractINTRODUCTIONClinical and genetic studies have implicated lipid dysfunction in Alzheimer Disease (AD) pathogenesis. However, lipid consumption at the individual-level does not vary greatly within most cohorts, and multiple lipids are rarely measured in any one study.METHODSMean country-level lipid intakes were compared to Age-Standardized Alzheimer-Disease-Incidence-Rates(ASAIR) in 183 countries across all inhabited continents. Penalized spline regression and multivariable-adjusted linear regression, including a lag between intake and incidence, were used to assess the relationships between five lipid intakes and ASAIR. Validation was conducted using longitudinal within-country changes between 1990 and 2019.RESULTSOmega6 Polyunsaturated-Fatty-Acid(PUFA) intake exhibited a positive linear relationship with ASAIR(multivariable-adjusted model: β=2.44; 95%CI: 1.70, 3.19; p=1.38×10-9). ASAIR also increased with saturated-fat, trans-fat, and dietary-cholesterol up to a threshold. The association between Omega6-PUFA and ASAIR was confirmed using longitudinal intake changes.DISCUSSIONDecreasing Omega6-PUFA consumption on the country-level may have substantial benefits in reducing the country-level burden of AD.
Combining short and long read sequencing technologies to identify SARS-CoV-2 variants in wastewater
Authors: Jayme Gabrielle , Liu Ju-Ling , Galvez Jose Hector , Reiling Sarah Julia , Aydin Sukriye Celikkol , N’Guessan Arnaud , Lee Sally , Chen Shu-Huang , Tsitouras Alexandra , Sanchez-Quete Fernando , Maere Thomas , Goitom Eyerusalem , Hachad Mounia , Mercier Elisabeth , Loeb Stephanie Katharine , Vanrolleghem Peter , Dorner Sarah , Delatolla Robert , Shapiro B. Jesse , Frigon Dominic , Ragoussis Jiannis , Snutch Terrance P. 
Published: August 2024

AbstractDuring the COVID-19 pandemic, the monitoring of SARS-COV-2 RNA in wastewater was used to track the evolution and emergence of variant lineages and gauge infection levels in the community, informing appropriate public health responses without relying solely on clinical testing. As more sublineages were discovered, it increased the difficulty in identifying distinct variants in a mixed population sample, particularly those without a known lineage. Here, we compare two next-generation sequencing technologies, Illumina and Nanopore, in order to determine their efficacy at detecting variants of differing abundance, using 248 wastewater samples from various Quebec and Ontario cities. Our study used two analytical approaches to identify main variants in the samples: the presence of signature and marker mutations, and the co-occurrence of signature mutations within the same amplicon. We observed that each sequencing method detected certain variants at different frequencies as each method preferentially detects mutations of distinct variants. Illumina sequencing detected more mutations with a predominant lineage that is in low abundance across the population or unknown for that time period, while Nanopore sequencing had a higher detection rate of mutations that are predominantly found in the high abundance B.1.1.7 (Alpha) lineage as well as a higher sequencing rate of co-occurring mutations in the same amplicon. We present a workflow that integrates short read and long read sequencing to improve the detection of SARS-CoV-2 variant lineages in mixed population samples, such as wastewater.
NF-κB Mediated Disruption of Pancreatic Signaling Pathways and its Implications for the Risk of Pancreatic Adenocarcinoma: a systematic review
Authors: Shafi Ovais , Rajpar Rahimeen , Aakash  , Waqas Muhammad , Haseeb Madiha , Raveena  , Kumari Madhurta , Kumar Ajay , Kumari Muskan , Yaqub Muhammad Danial 
Published: August 2024

AbstractObjectiveThe objective of this study is to determine how NF-κB-mediated inflammation disrupts pancreatic signaling pathways and the resultant increase in the risk of Pancreatic Adenocarcinoma.BackgroundPancreatic adenocarcinoma’s severity and poor prognosis underscore the critical role of NF-κB-mediated inflammation in disease progression. NF-κB activation disrupts key pancreatic signaling pathways by promoting cell proliferation, inhibiting differentiation, and facilitating oncogenic transformation. Understanding these mechanisms is essential for developing targeted therapies that mitigate NF-κB-induced damage, improve early detection through biomarkers, and enhance treatment outcomes for pancreatic cancer patients.MethodsDatabases, including PubMed, MEDLINE, Google Scholar, and open access/ subscription-based journals were searched for published articles without any date restrictions, to investigate how NF-κB-mediated inflammation disrupts pancreatic signaling pathways and the resultant increase in the risk of Pancreatic Adenocarcinoma. Based on the criteria mentioned in the methods section, studies were systematically reviewed to investigate the research question. This study adheres to relevant PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses).ResultsNF-κB-mediated inflammation significantly disrupts several critical pancreatic signaling pathways, leading to oncogenic transformations and increased risk of pancreatic adenocarcinoma. Specifically, NF-κB activation alters Notch signaling, causing abnormal cell differentiation; disrupts Wnt and Shh pathways, enhancing cellular proliferation; and perturbs FGF and TGF-β pathways, leading to impaired cellular homeostasis. Additionally, NF-κB interferes with BMP signaling, contributing to dysregulated cell growth; modulates the PI3K/Akt/mTOR pathway, promoting cell survival and tumor growth; affects JAK/STAT signaling, resulting in enhanced inflammatory responses and tumor progression; and disrupts Hippo pathway components, which normally regulate organ size and inhibit tumorigenesis.ConclusionNF-κB-mediated inflammation disrupts critical pancreas signaling pathways—Notch, Wnt, Hippo, JAK/STAT, and others—promoting cell survival, proliferation, and oncogenic transformation. This dysregulation, seen in chronic inflammation, elevates pancreatic adenocarcinoma risk by fostering a tumorigenic microenvironment. These interactions highlight NF-κB as a central player in pancreatic cancer pathogenesis. Targeting NF-κB and associated pathways emerges as crucial for therapeutic strategies aimed at mitigating inflammatory damage and improving outcomes in pancreatic adenocarcinoma treatment.
Stochastic Wiring of Cell Types Enhances Fitness by Generating Phenotypic Variability
Authors: Lachi Divyansha , Huang Ann , Mavor-Parker Augustine N. , Ghosh Arna , Richards Blake , Zador Anthony 
Published: August 2024

AbstractThe development of neural connectivity is a crucial biological process that gives rise to diverse brain circuits and behaviors. Neural development is a stochastic process, but this stochasticity is often treated as a nuisance to overcome rather than as a functional advantage. Here we use a computational model, in which connection probabilities between discrete cell types are genetically specified, to investigate the benefits of stochasticity in the development of neural wiring. We show that this model can be viewed as a generalization of a powerful class of artificial neural networks—Bayesian neural networks—where each network parameter is a sample from a distribution. Our results reveal that stochasticity confers a greater benefit in large networks and variable environments, which may explain its role in organisms with larger brains. Surprisingly, we find that the average fitness over a population of agents is higher than a single agent defined by the average connection probability. Our model reveals how developmental stochasticity, by inducing a form of non-heritable phenotypic variability, can increase the probability that at least some individuals will survive in rapidly changing, unpredictable environments. Our results suggest how stochasticity may be an important feature rather than a bug in neural development.
Cell wall composition in relation to photosynthesis across land plants’ phylogeny: crops as outliers
Authors: Roig-Oliver Margalida , Flexas Jaume , Clemente-Moreno María José , Carriquí Marc 
Published: August 2024

SummaryIn the present study, we combine published and novel data on cell wall composition and photosynthesis limitations, including data for all the major land plant’s phylogenetic groups. We provide novel evidence on the importance of cell wall composition in determining mesophyll conductance to CO2diffusion (gm) across land plants’ phylogeny. We address the hypothesis that the pectin fraction of total major cell wall compounds is positively related togmand, consequently, to photosynthesis, when pooling species from across the entire phylogeny.The role of cell wall composition in photosynthesis has only recently been proposed. Apparently contradictory results have been reported, but previous studies were often limited to single or closely related species. This is the very first report to show general relationships by considering species spanning the entire phylogeny of land plants.This study identifies a clear biochemical basis—one that can be traced back to specific genes— for a large component of mesophyll conductance and, thus, photosynthetic capacity. It opens new avenues for improving the photosynthesis of terrestrial plants. Additionally, it suggests that current crops are already optimized and even uncoupled from these general relationships, raising questions about the regulation ofgmin crop species.
The novel ECM protein SNED1 mediates cell adhesion via the RGD-binding integrins α5β1 and αvβ3
Authors: Pally Dharma , Kapoor Nandini , Naba Alexandra 
Published: August 2024

ABSTRACTThe extracellular matrix (ECM) is a complex meshwork comprising over 100 proteins. It serves as an adhesive substrate for cells and, hence, plays critical roles in health and disease. We have recently identified a novel ECM protein, SNED1, and have found that it is required for neural crest cell migration and craniofacial morphogenesis during development and in breast cancer, where it is necessary for the metastatic dissemination of tumor cells. Interestingly, both processes involve the dynamic remodeling of cell-ECM adhesions via cell surface receptors. Sequence analysis revealed that SNED1 contains two amino acid motifs, RGD and LDV, known to bind integrins, the largest class of ECM receptors. We thus sought to investigate the role of SNED1 in cell adhesion. Here, we report that SNED1 mediates breast cancer and neural crest cell adhesion via its RGD motif. We further demonstrate that cell adhesion to SNED1 is mediated by the RGD integrins α5β1 and αvβ3. These findings are a first step toward identifying the signaling pathways activated downstream of the SNED1-integrin interactions guiding craniofacial morphogenesis and breast cancer metastasis.SUMMARY STATEMENTWe report that the novel extracellular matrix protein SNED1 promotes the adhesion of breast cancer cells and neural crest cells via interaction with α5β1 and αvβ3 integrins, the first SNED1 receptors identified to date.
In vitrobio-activity of three potential antagonistic fungi against selected plant pathogens in Ghana
Authors: Dwamena Elvis , Awuah Richard Tuyee , Agbetiameh Daniel , Aidoo Atta Kwesi 
Published: August 2024

AbstractIn the quest of developing sustainable strategies for the management of diseases affecting major crop species, this study screened three antagonists,viz. Trichoderma asperellum.,Penicillium citrinum. andMyxotrichum stipitatum., for inhibitory activity against seven plant pathogens,viz. Pestalotia heterocornis, Curvularia eragrostidis, Lasiodiplodia theobromae, Sclerotium rolfsii, Colletotrichum gloeosporioides, Aspergillus flavus,andA. parasiticuson Potato Dextrose Agar (PDA) plates using the dual culture method. For each potential antagonistic fungus-pathogen combination, four replicated dual culture plates were prepared and laid out in a completely randomized design (CRD). Control plates with only the pathogens and no antagonistic fungi were also established. All assay plates were incubated at 28 ℃ (approx.) and the diameters of the pathogen in both the dual culture and control plates were measured at 6, 10 and 14 days. Percentage inhibition of fungal pathogens were calculated and used to draw a colony reduction curve for each antagonist-pathogen interaction. Areas Under the Colony Reduction Curves (AUCRC’s) were calculated. Of the three antagonistic fungi tested,Trichoderma asperellum. was the most effective in inhibiting colony diameters of all seven pathogens with an average AUCRC of 813.19 % days, followed by thePenicillium citrinum. (519.25 % days). The weakest antagonist wasMyxotrichum stipitatumsp. with an AUCRC of 440.6. % days. The results of the study suggest thatT.asperellumandP.citrinumcould be exploited for plant disease biocontrol.
Peripheral membrane protein endophilin B1 probes, perturbs and permeabilizes lipid bilayers
Authors: Thorlacius Arni , Rulev Maksim , Sundberg Oscar , Sundborger-Lunna Anna 
Published: August 2024

AbstractBin/Amphiphysin/Rvs (BAR) domain containing proteins are cytosolic, peripheral membrane proteins that regulate the curvature of membranes in eukaryotic cells. BAR protein endophilin B1 plays a key role in multiple cellular processes critical for oncogenesis, including autophagy and apoptosis. Amphipathic regions in endophilin B1 drive membrane association and tubulation through membrane scaffolding. Our understanding of exactly how BAR proteins like endophilin B1 promote highly diverse intracellular membrane remodeling events in the cell is severely limited due to lack of high-resolution structural information. Here we present the highest resolution cryo-EM structure of a BAR protein to date and the first structures of a BAR protein bound to nanodiscs. Using neural networks, we can effectively sort particle species of different stoichiometries, revealing the tremendous flexibility of post-membrane binding, pre-polymer BAR dimer organization and membrane deformation. We also show that endophilin B1 efficiently permeabilizes negatively charged liposomes that contain mitochondria-specific lipid cardiolipin and propose a new model for Bax-mediated cell death.