bluuebunny/crossref_metadata_2025_split huggingface dataset:
Allium Vegetables Intake and Digestive System Cancer Risk: A Study Based on Mendelian Randomization, Network Pharmacology and Molecular Docking
Authors: Li Shuhao , Lou Jingwen , Mulatihan Yelina , Xiong Yuhang , Li Yao , Xu Qi 
Published: September 2024

AbstractBackgroundAllium vegetables (garlic and onion) are one of the flavorings in people’s daily diets. Observational studies suggest that intake of allium vegetables may be correlated with a lower incidence of digestive system cancers. However, the existence of a causal relationship is still controversial due to confounding factors and reverse causation. Therefore, we explored the causal relationship between intake of allium vegetables and digestive system cancers using Mendelian randomization approach.MethodsFirst, we performed Mendelian randomization analyses using inverse variance weighting (IVW), weighted median, and MR-Egger approaches, and demonstrated the reliability of the results in the sensitivity step. Second, Multivariable Mendelian randomization was applied to adjust for smoking and alcohol consumption. Third, we explored the molecular mechanisms behind the positive results through network pharmacology and molecular docking methods.ResultsThe study suggests that increased intake of garlic reduced gastric cancer risk. However, onion intake was not statistically associated with digestive system cancer.ConclusionGarlic may have a protective effect against gastric cancer.
Efficacy and Safety of Beta Blockers for Patients with Myocardial Infarction in the Percutaneous Coronary Intervention Era: A Systematic Review and Meta-Analysis
Authors: Irtaza Ahmed , Junaid Muhammad , Saqlain Muhammad , Akram Ayesha , Khan Ayesha , Sarwari Areeba Shams , Ali Hussain , Ahsan Salman , Ahmed Tayyab , Talib Tuba , Ebad Ur Rehman Mohammad , Ahmad Cheema Huzaifa , Ahmad Adeel , Ur Rehman Wajeeh , Wahab Arif Abdul , Dani Sourbha S. 
Published: September 2024

AbstractBackgroundBeta-blockers are commonly prescribed to patients after MI. However, the evidence is based on studies conducted before the widespread use of PCI for treating MI. We conducted this meta-analysis to evaluate beta-blockers’ efficacy post-MI in the modern day and age.MethodsWe conducted our search using and one clinical trial registry to get RCTs and propensity-matched observational studies comparing the use of beta-blockers after MI to control in post-MI patients. The primary outcome of our analysis was the likelihood of all-cause mortality.ResultsOur analysis included 3 RCTs and 12 propensity-matched observational studies with a total study population of 102,794. Our results showed a statistically significant decrease in all-cause mortality in the beta-blocker group compared to the non-beta-blocker group (RR 0.63, 95% CI 0.47-0.83; p= 0.001). However, this decrease was not observed when only RCTs were considered (RR 0.91). Beta-blockers were also found to reduce the risk of MI and heart failure with RR of 0.86 (95% CI 0.75-1.00; p=0.05) and 0.84 (95% CI 0.73-0.97; p=0.02), respectively.ConclusionBeta-blockers effectively reduce mortality and decrease the risk of MI and heart failure without a significant increase in adverse effects. Thus, our findings support the contemporary use of beta blockers in post-MI patients. However, more long-term studies need to be done to determine the sustained benefits of beta blockers in the context of evolving cardiac care.
Family income is associated with regional brain glucose metabolism in middle-aged adults
Authors: Pak Kyoungjune , Shin Seunghyeon , Nam Hyun-Yeol , Kim Keunyoung , Kim Jihyun , Lee Myung Jun 
Published: September 2024

ABSTRACTSocioeconomic status is a multifaceted construct that plays a prominent role in shaping our environment by defining our access to healthcare, nutrition, and enrichment, as well as represents social standing. Therefore, to address the effects of family income, and education level on brain glucose metabolism, we analyzed a large cohort of healthy middle-aged adults who underwent brain18F-FDG PET, and survey of family income and education level. We retrospectively analyzed data of healthy males who underwent health check-up program. Health check-up program included 1) Brain18F-FDG PET, 2) anthropometric measurements, 3) survey of family income and education level, and 4) measures of stress, anxiety, and depression. The effects of family income and education level on regional SUVR were investigated using Bayesian hierarchical modelling. A total of 233 healthy males were included in this study. Family income was positively correlated with education level. There was no significant indirect effect of family income or education level via stress, anxiety, or depression on regional brain glucose metabolism. Family income is positively associated with brain glucose metabolism in caudate, putamen, anterior cingulate, hippocampus, and amygdala, while education level does not show any significant association with brain glucose metabolism in middle-aged adults. In conclusion, family income is positively associated with brain glucose metabolism in caudate, putamen, anterior cingulate, hippocampus, and amygdala, while education level does not show any significant association with brain glucose metabolism. This finding might reflect the link between family income, and reward sensitivity, stress in middle-aged adults.
Tracing SARS-CoV-2 Clusters Across Local Scales Using Genomic Data
Authors: Lyu Leke , Gill Mandev , Stott Guppy , Subedi Sachin , Dailey Cody , Veytsel Gabriella , Alabady Magdy , Fujimoto Kayo , Penn Ryker , Brown Pamela , Sealy Roger , Bahl Justin 
Published: September 2024

AbstractQuantitatively understanding local transmission dynamics is essential for designing effective prevention strategies. In this study, we developed a novel algorithm to identify introductions and trace locally circulating clusters. We analyzed over 26,000 SARS-CoV-2 genomes and their associated metadata, collected between January and October 2021, to explore introduction and dispersal patterns in Greater Houston, a major metropolitan area known for its demographic diversity. Our analysis identified more than 1,000 independent introduction events, resulting in clusters of varying sizes. Earlier clusters were generally larger and posed greater challenges for control efforts. Characterization of introduction sources revealed that domestic origins were more significant than international ones. Additionally, analysis of locally circulating clusters highlighted age-structured transmission dynamics. Geographic reconstruction of cluster spread identified Harris County as the primary viral source for surrounding counties. Harris county sustained the local epidemic with a smaller proportion of new cases driven by external importations and longer persistence times of circulating lineages. Overall, our high-resolution spatiotemporal reconstruction of the epidemic in Greater Houston provides critical insights into the heterogeneous transmission landscape, supporting regional response strategies and public health planning.Significance StatementThe growing recognition of genome sequencing as a critical tool for outbreak response has driven a rapid increase in the availability of sequence data. Here, we present an analytical workflow to trace imported SARS-CoV-2 clusters using large-scale genome datasets. Our approach pinpoints when, where, and how many introductions occurred, while also tracking the circulation of resulting clusters. By incorporating metrics such as the Source Sink Score, Local Import Score, and Persistence Time, our analysis reveals transmission heterogeneity between subregions of the focal area. These insights are essential for monitoring viral introductions and guiding targeted control measures, enhancing the ability of local responders to address the challenges of current and future pandemics as new variants emerge.
Role of Forkhead box F1 in the Pathobiology of Pulmonary Arterial Hypertension
Authors: Gomez-Arroyo Jose , Houweling Arjan C. , Bogaard Harm Jan , Aman Jurjan , Kitzmiller Joseph A. , Porollo Aleksey , Dooijes Dennis , Meijboom Lilian J. , Hale Phillip , Pauciulo Michael W. , Hong Jason , Zhu Na , Welch Carrie , Shen Yufeng , Zacharias William J. , McCormack Francis X. , Aldred Micheala A. , Weirauch Matthew T. , Graf Stefan , Rhodes Christopher , Chung Wendy K. , Whitsett Jeffrey A. , Martin Lisa J. , Kalinichenko Vladimir V. , Nichols William C. 
Published: September 2024

AbstractRationaleApproximately 80% of patients with non-familial pulmonary arterial hypertension (PAH) lack identifiable pathogenic genetic variants. While most genetic studies of PAH have focused on predicted loss-of-function variants, recent approaches have identified ultra-rare missense variants associated with the disease.FOXF1encodes a highly conserved transcription factor, essential for angiogenesis and vasculogenesis in human and mouse lungs.ObjectivesWe identified a rareFOXF1missense coding variant in two unrelated probands with PAH.FOXF1is an evolutionarily conserved transcription factor required for lung vascular development and vascular integrity. Our aims were to determine the frequency ofFOXF1variants in larger PAH cohorts compared to the general population, studyFOXF1expression in explanted lung tissue from PAH patients versus control (failed-donor) lungs, and define potential downstream targets linked to PAH development.MethodsThree independent, international, multicenter cohorts were analyzed to evaluate the frequency ofFOXF1rare variants. Various composite prediction models assessed the deleteriousness of individual variants. Bulk RNA sequencing datasets from human explanted lung tissues were compared to failed-donor controls to determineFOXF1expression. Bioinformatic tools identified putativeFOXF1binding targets, which were orthogonally validated using mouse ChIP-seq datasets.Measurements and Main ResultsSeven novel or ultra-rare missense coding variants were identified across three patient cohorts in different regions of theFOXF1gene, including the DNA binding domain.FOXF1expression was dysregulated in PAH lungs, correlating with disease severity. Histological analysis showed heterogeneousFOXF1expression, with the lowest levels in phenotypically abnormal endothelial cells within complex vascular lesions in PAH samples. A hybrid bioinformatic approach identified FOXF1 downstream targets potentially involved in PAH pathogenesis, includingBMPR2.ConclusionsLarge genomic and transcriptomic datasets suggest that decreasedFOXF1expression or predicted dysfunction is associated with PAH.
Increased cGMP improves microvascular exercise training adaptations independent of endothelial nitric oxide synthase
Authors: Winn Nathan C. , Cappel David A. , Pollock Ethan D. , Lantier Louise , Riveros Jillian K. , Debrow Payton , Bracy Deanna P. , Beckman Joshua A. , Wasserman David H. 
Published: September 2024

AbstractImpaired microvascular function is a hallmark of pre-diabetes. With development of atherosclerosis this impaired microvascular function can result in diminished capacity for ambulation and is a risk factor for Type 2 Diabetes. Dynamic changes in vascular tone are determined, in large part, by the eNOS/NO/cGMP axis. We used gain of function of the eNOS/NO/cGMP axis in diet-induced obese (DIO) mice and reduced function in lean mice to test the hypothesis that functionality of this vascular control mechanism parallels the benefits of an exercise training regimen. DIO mice have lower exercise capacity than lean mice and were used for pharmacological gain of function. The PDE-5a inhibitor – sildenafil – increases cGMP and was administered to DIO mice daily. In sedentary mice, we find that sildenafil does not improve exercise capacity. In contrast, it amplifies the microcirculatory effects of exercise training. Sildenafil synergizes with exercise training to improve performance during an incremental exercise test. Improved exercise performance was accompanied by increased skeletal muscle capillary flow velocity and capillary density measured via intravital microscopy. Loss of function was tested in lean mice hemizygous for endothelial cell (EC) specific eNOS creating an EC-eNOS knockdown (KD). EC-eNOS KD decreases capillary density and exercise tolerance in sedentary mice; however, it did not prevent exercise-training induced improvements in endurance capacity. These data show that 1) increasing cGMP with sildenafil enhances microcirculatory function and exercise work tolerance that results from training; 2) eNOS KD does not prevent the microcirculatory or improvements in exercise tolerance with training. PDE-5a inhibitors combined with physical exercise are a potential mechanism for improving ambulation in patients with circulatory limitations.
Monocyte-derived cells but not Microglia cause Oxidative Tissue Damage in Neuroinflammation
Authors: Villar-Vesga Juan , De Feo Donatella , Clément Pauline , Ingelfinger Florian , Ulutekin Can , Kim Jeanne , Pena-Francesch Maria , Schmidt Katarina Wendy , Meuffels Elèni , Bugada Viola , Greis Deborah , Costa-Pereira Sara , Oberbichler Laura , Seehusen Frauke , Prisco Francesco , Dalvi Urvashi , Münz Christian , Saab Aiman S. , Becher Burkhard , Mundt Sarah 
Published: September 2024

AbstractMultiple sclerosis (MS) is characterized by neuroinflammation, oxidative stress, iron toxicity and mitochondrial dysfunction. Reactive oxygen species (ROS) produced by mononuclear phagocytes (MPs) are widely held to drive tissue damage, yet the specific roles of central nervous system (CNS)- resident versus CNS-invading MPs remain unclear. Here, by combining single-cell profiling with conditional gene targeting, we systematically dissected and interfered with ROS production across CNS MPs in a preclinical model for neuroinflammation. We show that CNS-invading monocyte derived cells (MdCs) exhibit a higher oxidative stress gene signature and produce more ROS compared to CNS-resident microglia. While NADPH oxidase 2 (NOX2), a phagocytic source of ROS, proved redundant, our findings underscore the critical role of mitochondrial ROS (mtROS) in driving oxidative tissue damage. Quenching mtROS through mitocatalase overexpression in MdCs, but not microglia, significantly alleviated neuroinflammation in mice. Thus, our study resolves a longstanding controversy, identifying MdCs as the primary driver of ROS-mediated neuropathology.
Overcoming immune evasion from post-translational modification of a mutant KRAS epitope to achieve TCR-T cell-mediated antitumor activity
Authors: Lee Jihoon William , Chen Emily Y. , Hu Taylor , Perret Rachel , Chaffee Mary E. , Martinov Tijana , Mureli Shwetha , McCurdy Clara L. , Jones Lisa A. , Gafken Philip R. , Chanana Pritha , Su Yapeng , Chapuis Aude G. , Bradley Philip , Schmitt Thomas M. , Greenberg Philip D. 
Published: September 2024

AbstractT cell receptor (TCR)-T cell immunotherapy, in which T cells are engineered to express a TCR targeting a tumor epitope, is a form of adoptive cell therapy (ACT) that has exhibited promise against various tumor types. Mutants of oncoprotein KRAS, particularly at glycine-12 (G12), are frequent drivers of tumorigenicity, making them attractive targets for TCR-T cell therapy. However, class I-restricted TCRs specifically targeting G12-mutant KRAS epitopes in the context of tumors expressing HLA-A2, the most common human HLA-A allele, have remained elusive despite evidence an epitope encompassing such mutations can bind HLA-A2 and induce T cell responses. We report post-translational modifications (PTMs) on this epitope may allow tumor cells to evade immunologic pressure from TCR-T cells. A lysine side chain-methylated KRASG12Vpeptide, rather than the unmodified epitope, may be presented in HLA-A2 by tumor cells and impact TCR recognition. Using a novel computationally guided approach, we developed by mutagenesis TCRs that recognize this methylated peptide, enhancing tumor recognition and destruction. Additionally, we identified TCRs with similar functional activity in normal repertoires from primary T cells by stimulation with modified peptide, clonal expansion, and selection. Mechanistically, a gene knockout screen to identify mechanism(s) by which tumor cells methylate/demethylate this epitope unveiled SPT6 as a demethylating protein that could be targeted to improve effectiveness of these new TCRs. Our findings highlight the role of PTMs in immune evasion and suggest identifying and targeting such modifications should make effective ACTs available for a substantially greater range of tumors than the current therapeutic landscape.One-sentence summaryTumor cell methylation of KRASG12Vepitope in HLA-A2 permits immune evasion, and new TCRs were generated to overcome this with engineered cell therapy.
Development of a small-molecule epigenetic regenerative therapy. Subcutaneous administration of alginate formulations with high loads of zebularine and retinoic acid promotes tissue growth, vascularization and innervation and induces extensive epigenetic repatterning
Authors: Słonimska Paulina , Baczyński-Keller Jakub , Płatek Rafał , Deptuła Milena , Dzierżyńska Maria , Sawicka Justyna , Król Oliwia , Sosnowski Paweł , Koczkowska Magdalena , Kostecka Anna , Crossman David K. , Crowley Michael R. , Sass Piotr , Smoleński Ryszard Tomasz , Skowron Piotr M. , Piotrowski Arkadiusz , Pikuła Michał , Rodziewicz-Motowidło Sylwia , Sachadyn Paweł 
Published: September 2024

AbstractRecently, zebularine, a small-molecule epigenetic inhibitor and retinoic acid, acting as a transcriptional activator, have been found to induce tissue regeneration. In this study, the pro-regenerative properties of zebularine and retinoic acid were combined with the potential of the alginate carrier to expand its therapeutic possibilities.Alginate formulations of zebularine and retinoic acid were developed for subcutaneous administration to mice. Hydrophilic zebularine formed a homogenous formulation with extreme drug loadings reaching 240 mg of zebularine per 1 ml of 2% sodium alginate, while hydrophobic retinoic acid, 0.8 mg/ml, dispersed as fine crystals. Cell culture tests exhibited no significant cytotoxicity of the alginate formulations.Subcutaneous administration of zebularine and retinoic acid in 2% sodium alginate promoted regenerative responses in a mouse model of ear pinna punch wound mice involving the restoration of tissue architecture, nerve and vessel growth, and extensive epigenetic and transcriptional repatterning with no adverse effects observed in the animals. Significant trancriptomic responses to the epigenetic treatment included the induction of epithelium development genes contrasted with the downregulation of muscle development genes on day 7 post-injury. Among the remarkable changes in global gene methylation are those in neurodevelopmental genes.In vitrostudies showed rapid zebularine but no retinoic acid discharge from the alginate formulations. Live ultrasound imaging demonstrated gradual absorption of the subcutaneously injected alginate formulations, which may explain thein vivoactivity of retinoic acid following subcutaneous administration.Effective induction of tissue regeneration together with a high safety profile and of the subcutaneously administered pro-regenerative alginate formulations opens the way to testing further regenerative therapies for hard-to-reach lesions.
The Unified Phenotype Ontology (uPheno): A framework for cross-species integrative phenomics
Authors: Matentzoglu Nicolas , Bello Susan M , Stefancsik Ray , Alghamdi Sarah M. , Anagnostopoulos Anna V. , Balhoff James P. , Balk Meghan A. , Bradford Yvonne M. , Bridges Yasemin , Callahan Tiffany J. , Caufield Harry , Cuzick Alayne , Carmody Leigh C , Caron Anita R. , de Souza Vinicius , Engel Stacia R. , Fey Petra , Fisher Malcolm , Gehrke Sarah , Grove Christian , Hansen Peter , Harris Nomi L. , Harris Midori A. , Harris Laura , Ibrahim Arwa , Jacobsen Julius O.B. , Köhler Sebastian , McMurry Julie A. , Munoz-Fuentes Violeta , Munoz-Torres Monica C. , Parkinson Helen , Pendlington Zoë M , Pilgrim Clare , Robb Sofia MC , Robinson Peter N. , Seager James , Segerdell Erik , Smedley Damian , Sollis Elliot , Toro Sabrina , Vasilevsky Nicole , Wood Valerie , Haendel Melissa A. , Mungall Christopher J. , McLaughlin James A. , Osumi-Sutherland David 
Published: September 2024

AbstractPhenotypic data are critical for understanding biological mechanisms and consequences of genomic variation, and are pivotal for clinical use cases such as disease diagnostics and treatment development. For over a century, vast quantities of phenotype data have been collected in many different contexts covering a variety of organisms. The emerging field of phenomics focuses on integrating and interpreting these data to inform biological hypotheses.A major impediment in phenomics is the wide range of distinct and disconnected approaches to recording the observable characteristics of an organism. Phenotype data are collected and curated using free text, single terms or combinations of terms, using multiple vocabularies, terminologies, or ontologies. Integrating these heterogeneous and often siloed data enables the application of biological knowledge both within and across species. Existing integration efforts are typically limited to mappings between pairs of terminologies; a generic knowledge representation that captures the full range of cross-species phenomics data is much needed.We have developed the Unified Phenotype Ontology (uPheno) framework, a community effort to provide an integration layer over domain-specific phenotype ontologies, as a single, unified, logical representation. uPheno comprises (1) a system for consistent computational definition of phenotype terms using ontology design patterns, maintained as a community library; (2) a hierarchical vocabulary of species-neutral phenotype terms under which their species-specific counterparts are grouped; and (3) mapping tables between species-specific ontologies. This harmonized representation supports use cases such as cross-species integration of genotype-phenotype associations from different organisms and cross-species informed variant prioritization.
Widespread selection relaxation in aquatic mammals
Authors: Farina B.M. , Latrille T. , Salamin N. , Silvestro D. , Faurby S. 
Published: September 2024

AbstractWhile mammals are predominantly terrestrial, several lineages within them have independently transitioned to aquatic environments and exhibit a great variety of evolutionary changes, which ultimately lead to irreversible transitions to aquatic lifestyle. Such changes should also be detectable at the molecular level and, for instance, olfactory genes have been found to evolve under reduced selection and functionality in whales. However, the presence of a molecular signature related to aquatic transitions across other genes remains unknown as is the degree to which this affects only fully aquatic groups or also semiaquatic ones. Here, we use a Bayesian framework to investigate differences in the strength of purifying selection among terrestrial, semiaquatic and fully aquatic mammals using a set of 1000 orthologous genes, while accounting for shared ancestry, and controlling for body mass and effective population size. We found that selection relaxation linked to aquatic transitions is not only occurring in olfactory genes, but also detected across 20% of the other genes analysed here. This consistent trend of genes under weaker selection is inferred in both semi- and fully aquatic mammals although the pattern is stronger in the latter. While most of the genes analysed here likely remain functional in all mammals, their evolution is inferred to be neutral in a substantial number of aquatic species, consistently with genes that might be losing their functionality. The inferred widespread relaxation of selection among genes is consistent with a macroevolutionary scenario where secondary transitions to aquatic environment eventually become irreversible.