bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mutation of two intronic nucleotides alters RNA structure and dynamics inhibiting MBNL1 and RBFOX1 regulated splicing of the Insulin Receptor
Authors: Nowzari Zohreh R. , Hale Melissa , Ellis Joseph , Biaesch Samantha , Vangaveti Sweta , Reddy Kaalak , Chen Alan A. , Berglund J. Andrew 
Published: January 2024

ABSTRACTAlternative splicing (AS) of Exon 11 of the Insulin Receptor (INSR) is highly regulated and disrupted in several human disorders. To better understandINSRexon 11 AS regulation, splicing activity of anINSRexon 11 minigene reporter was measured across a gradient of the AS regulator muscleblind-like 1 protein (MBNL1). The RNA-binding protein Fox-1 (RBFOX1) was added to determine its impact on MBNL1-regulated splicing. The role of the RBFOX1 UGCAUG binding site within intron 11 was assessed across the MBNL1 gradient. Mutating the UGCAUG motif inhibited RBFOX1 regulation of exon 11 and had the unexpected effect of reducing MBNL1 regulation of this exon. Molecular dynamics simulations showed that exon 11 and the adjacent RNA adopts a dynamically stable conformation. Mutation of the RBFOX1 binding site altered RNA structure and dynamics, while a mutation that created an optimal MBNL1 binding site at the RBFOX1 site shifted the RNA back to wild type. An antisense oligonucleotide (ASO) was used to confirm the structure in this region of the pre-mRNA. This example of intronic mutations shifting pre-mRNA structure and dynamics to modulate splicing suggests RNA structure and dynamics should be taken into consideration for AS regulation and therapeutic interventions targeting pre-mRNA.Abstract figure:Model forINSRexon 11 splicing regulation through the UGCAUG motif. We propose that the UGCAUG motif, MBNL1, and RBFOX1 cooperatively regulateINSRexon 11 splicing. Mutating this UGCAUG motif is sufficient to alter RNA structural dynamics to disrupt this regulation.
Activity ofSalmonellaSPI-1 inhibits the TLR4-dependent transcriptional but not translational response during macrophage infection
Authors: Wood George , Johnson Rebecca , Brember Matt , Lastovka Filip , Tourlomousis Pani , Bryant Clare , Chung Betty Y-W 
Published: January 2024

AbstractChanges in gene expression during bacterial infection are the combined result of altered transcription and translation, with the latter comparatively understudied. Gram-negative bacteria rapidly trigger cytokine gene transcription in macrophages through the activation of pathogen associated molecular pattern receptors, for example detection ofSalmonellalipopolysaccharide (LPS) from the bacterial cell envelope by Toll-like receptor 4 (TLR4). Here, through time-resolved parallel translatomic and transcriptomic profiling, we now show temporal TLR4-specific translational upregulation of cell signalling proteins in macrophages induced bySalmonella. While transcriptional upregulation of these genes is dampened through the activity of theSalmonellaSPI-1 type three secretion system, a robust translational response remains. These data reveal an important host-pathogen translational regulatory network that modifies the innate immune response of macrophages to infection.
Intrinsic and extrinsic determinants of conditional localization of Mms6 to magnetosome organelles inMagnetospirillum magneticumAMB-1
Authors: Bickley Carson D. , Komeili Arash 
Published: January 2024

AbstractMagnetotactic bacteria are a diverse group of microbes that use magnetic particles housed within intracellular lipid-bounded magnetosome organelles to guide navigation along geomagnetic fields. Development of magnetosomes and their magnetic crystals inMagnetospirillum magneticumAMB-1 requires the coordinated action of numerous proteins. Most proteins are thought to localize to magnetosomes during the initial stages of organelle biogenesis regardless of environmental conditions. However, magnetite-shaping protein Mms6 is only found in magnetosomes that contain magnetic particles, suggesting that it might conditionally localize after the formation of magnetosome membranes. The mechanisms for this unusual mode of localization to magnetosomes are unclear. Here, using pulse-chase labeling, we show that Mms6 translated under non-biomineralization conditions translocates to pre-formed magnetosomes when cells are shifted to biomineralizing conditions. Genes essential for magnetite production, namelymamE, mamM,andmamOare necessary for Mms6 localization, whereasmamNinhibits Mms6 localization. MamD localization is also investigated and found to be controlled by similar cellular factors. The membrane localization of Mms6 is dependent on a glycine-leucine repeat region, while the N-terminal domain of Mms6 is necessary for retention in the cytosol and impacts conditional localization to magnetosomes. The N-terminal domain is also sufficient to impart conditional magnetosome localization to MmsF, altering its native constitutive magnetosome localization. Our work illuminates an alternative mode of protein localization to magnetosomes in which Mms6 and MamD are kept in the cytosol by MamN until biomineralization initiates, whereupon they translocate into magnetosome membranes to control the development of growing magnetite crystals.ImportanceMagnetotactic bacteria (MTB) are a diverse group of bacteria that form magnetic nanoparticles surrounded by membranous organelles. MTB are widespread and serve as a model for bacterial organelle formation and biomineralization. Magnetosomes require a specific cohort of proteins to enable magnetite formation, but how those proteins are localized to magnetosome membranes is unclear. Here, we investigate protein localization using pulse-chase microscopy and find a system of protein coordination dependent on biomineralization permissible conditions. In addition, our findings highlight a protein domain that alters the localization behavior of magnetosome proteins. Utilization of this protein domain may provide a synthetic route for conditional functionalization of magnetosomes for biotechnological applications.
Activating A1 adenosine receptor signaling boosts early pulmonary neutrophil recruitment in aged mice in response toStreptococcus pneumoniaeinfection
Authors: Simmons Shaunna R. , Herring Sydney E. , Tchalla Essi Y.I , Lenhard Alexsandra P. , Bhalla Manmeet , Bou Ghanem Elsa N. 
Published: January 2024

ABSTRACTBackground:Streptococcus pneumoniae(pneumococcus) is a leading cause of pneumonia in older adults. Successful control of pneumococci requires robust pulmonary neutrophil influx early in infection. However, aging is associated with aberrant neutrophil recruitment and the mechanisms behind that are not understood. Here we explored how neutrophil recruitment following pneumococcal infection changes with age and the host pathways regulating this.Results:Following pneumococcal infection there was a significant delay in early neutrophil recruitment to the lungs of aged mice. Neutrophils from aged mice showed defects in trans-endothelial migrationin vitrocompared to young controls. To understand the pathways involved, we examined immune modulatory extracellular adenosine (EAD) signaling, that is activated upon cellular damage. Signaling through the lower affinity A2A and A2B adenosine receptors had no effect on neutrophil recruitment to infected lungs. In contrast, inhibition of the high affinity A1 receptor in young mice blunted neutrophil recruitment to the lungs following infection. A1 receptor inhibition decreased expression of CXCR2 on circulating neutrophils, which is required for transendothelial migration. Indeed, A1 receptor signaling on neutrophils was required for their ability to migrate across endothelial cells in response to infection. Aging was not associated with defects in EAD production or receptor expression on neutrophils. However, agonism of A1 receptor in aged mice rescued the early defect in neutrophil migration to the lungs and improved control of bacterial burden.Conclusions:This study suggests age-driven defects in EAD damage signaling can be targeted to rescue the delay in pulmonary neutrophil migration in response to bacterial pneumonia.
Evolution of plant cell-type-specificcis-regulatory elements
Authors: Yan Haidong , Mendieta John P. , Zhang Xuan , Marand Alexandre P. , Liang Yan , Luo Ziliang , Minow Mark A.A. , Jang Hosung , Li Xiang , Roulé Thomas , Wagner Doris , Tu Xiaoyu , Wang Yonghong , Jiang Daiquan , Zhong Silin , Huang Linkai , Wessler Susan R. , Schmitz Robert J. 
Published: January 2024

AbstractCis-regulatory elements (CREs) are critical in regulating gene expression, and yet understanding of CRE evolution remains challenging. Here, we constructed a comprehensive single-cell atlas of chromatin accessibility inOryza sativa, integrating data from 103,911 nuclei representing 126 discrete cell states across nine distinct organs. We used comparative genomics to compare cell-type resolved chromatin accessibility betweenO. sativaand 57,552 nuclei from four additional grass species (Zea mays, Sorghum bicolor, Panicum miliaceum, andUrochloa fusca). Accessible chromatin regions (ACRs) had different levels of conservation depending on the degree of cell-type specificity. We found a complex relationship between ACRs with conserved noncoding sequences, cell-type specificity, conservation, and tissue-specific switching. Additionally, we found that epidermal ACRs were less conserved compared to other cell types, potentially indicating that more rapid regulatory evolution has occurred in the L1-derived epidermal layer of these species. Finally, we identified and characterized a conserved subset of ACRs that overlapped the repressive histone modification H3K27me3, implicating them as potentially silencer-like CREs maintained by evolution. Collectively, this comparative genomics approach highlights the dynamics of plant cell-type-specific CRE evolution.
Cardiovascular disease and Osteoporosis : A Mendelian randomization study
Authors: Wang Zhao , Zhang Shuyi , Gong Hongyang , Zhao Guoxu , Xiao Hong , Yuan Shuai , Wu Wenhao , Xu Pai , Chen Yihong , Yang Mei , Kang Chan 
Published: January 2024

I.AbstractBackgroundCardiovascular disease (CVD) may have some association with osteoporosis (OP). This Mendelian randomization (MR) investigation aimed to explore the potential causal linkage between CVD and OP.MethodsUtilizing genome-wide association study data from individuals of European descent, we pinpointed Single Nucleotide Polymorphisms (SNPs) relevant to CVD, including those for coronary heart disease (CHD) with 64,762 cases and 22,233 controls, heart failure (HF) comprising 47,309 cases against 930,014 controls, and stroke with a case-control tally of 3,611 to 18,084, to serve as the instrumental variables. Later, we searched for total body bone mineral density (BMD) statistics which were used as phenotypes for OP(sample size = 56,284). In this paper, the traditional inverse variance weighting (IVW) method, the weighted median estimation method, and the MR-Egger method are used to estimate different results. The MR-Egger intercept test, outlier (Mr-PRESSO) test and Cochran-Q statistic are used to detect potential directional pleiotropy and heterogeneity, while we also draw the scatter plot, funnel plot and forest plot. Additionally, a reverse-direction MR analysis was performed to explore the potential for reverse causation.ResultsThe IVW analysis showed that CHD could significantly impact total body BMD levels, and every higher standard deviation in the risk of CHD decreased the average total body BMD by 0.0459 units in the IVW analysis(Beta = -0.0459; 95%CI = -0.0815 –-0.0104, P = 0.0113). Reverse MR analysis showed no significant correlation of the change of total body BMD on the prevalence effect of CHD. No particular relationship exists between HF and total body BMD. There was no significant effect between the changes in total body BMD induced by stroke. Reverse MR analysis revealed no significant correlation between alterations in total body BMD on stroke.ConclusionOur analysis points to a substantial causative link between CHD and the vulnerability to OP, potentially paving the way for innovative approaches in treating and preventing OP.
Effect of testosterone therapy on breast tissue composition and mammographic breast density in trans masculine individuals
Authors: Heng Yujing J , Baker Gabrielle M , Fein-Zachary Valerie J , Guzman-Arocho Yaileen D , Bret-Mounet Vanessa C , Massicott Erica S , Gitin Sy , Russo Paul , Tobias Adam M , Bartlett Richard A , Varma Gopal , Kontos Despina , Yaghjyan Lusine , Irwig Michael S , Potter Jennifer E , Wulf Gerburg M 
Published: January 2024

AbstractObjectiveDetermine the association between TT and breast tissue composition and breast tissue density in trans masculine individuals (TMIs).DesignThis is a cross-sectional study.SettingTMIs (n=444) underwent chest-contouring surgeries to treat their gender dysphoria between 2013 and 2019 at an urban medical center.ParticipantsOf the 444 TMIs, 425 had pathology images analyzed by our deep-learning algorithm to extract breast tissue composition. A subset of 42/444 TMIs had mammography prior to surgery; mammography files were available for 25/42 TMIs and analyzed using a breast density software, LIBRA.Main Outcome(s) and Measure(s)The first outcome was the association of duration of TT and breast tissue composition assessed by pathologists (categories of lobular atrophy and stromal composition) or by our algorithm (% epithelium, % fibrous stroma, and % fat). The second outcome is the association of TT and breast density as assessed by a radiologist (categorical variable) or by LIBRA (percent density, absolute dense area, and absolute non-dense area).ResultsLength of TT was associated with increasing degrees of lobular atrophy (p<0.001) but not fibrous content (p=0.821) when assessed by the pathologists. Every six months of TT was associated with decreased amounts of both epithelium (exp(β)=0.97, 95% CI 0.95-0.98, adjp=0.005) and stroma (exp(β)=0.99, 95% CI 0.98-1.00, adjp=0.051), but not fat (exp(β)=1.01, 95%CI 0.98-1.05,p=0.394) in fully adjusted models. There was no association between TT and radiologist’s breast density assessment (p=0.575) or LIBRA measurements (p>0.05).ConclusionsTT decreases breast epithelium and fibrous stroma, thus potentially reducing the breast cancer risk of TMIs. Further studies are warranted to elucidate the effect of TT on breast density and breast cancer risk.Summary BoxVery little is known about the effect of gender-affirming testosterone therapy on cancer risks, such as breast cancer.Epidemiological studies had different conclusions about the association between testosterone and breast cancer in cisgender women (positive association) and trans masculine individuals (inverse association).More laboratory-based research are needed to understand the effect of testosterone on breast cancer risk in the understudied trans masculine population.Our study provides quantitative histological evidence to support prior epidemiological reports that testosterone may reduce breast cancer risk in trans masculine individuals.
Prevalence of Substance Use and related Behaviors among Tertiary Students: A Cross-sectional Survey in Yaoundé, Cameroon
Authors: Edzamba Michel Franck , Lekeumo Cheuyem Fabrice Zobel , Amani Adidja , Mossus Tatiana 
Published: January 2024

AbstractBackgroundThe use of psychoactive substances is a major global public health problem. People aged 15-24 years are more likely to abuse psychoactive substances than the general population. Substances use among youth, especially students in higher education is increasing rapidly worldwide. This study aimed to assess the prevalence of substances use among university students and to describe their behavioral profiles.MethodsAn institutional-based descriptive and cross-sectional study was conducted from September to October 2023 at the Yaoundé 1 University in Cameroon. A convenience non probabilistic sampling method were used to recruit consenting students. The data collectors were medical students who were trained for 2 days and given appropriate instructions before the survey. The data collected were reviewed and checked for completeness before being entered. All data were coded and entered into Microsoft Excel 2016. Descriptive statistics were performed using R Statistics 4.3.1. Qualitative data were collected from all participants through interviews.ResultsA total of 191 university students were enrolled in the study. The median age was 20 years. They were predominantly male (66.5%) and aged between 20-25. The prevalence of substance use was 66% for alcohol consumption, 33.5% for smoking habits and 26.7% for drug use. The main motivations for substance use were companionship, thrill-seeking and curiosity. More than a third of students were polysubstance users (35.1%). Most participants were aware of the academic consequence (85.9%) and almost all (93.7%) acknowledged the physical and psycho-social consequences of substance use.ConclusionThere is a high rate of psychoactive substance use among university students. Therefore, effective campus-based counseling, peer education, and national surveillance systems that can monitor risky behaviors among university students should be implemented.
A One-Shot Lossless Algorithm for Cross-Cohort Learning in Mixed-Outcomes Analysis
Authors: Li Ruowang , Benz Luke , Duan Rui , Denny Joshua C. , Hakonarson Hakon , Mosley Jonathan D. , Smoller Jordan W. , Wei Wei-Qi , Lumley Thomas , Ritchie Marylyn D. , Moore Jason H. , Chen Yong 
Published: January 2024

AbstractIn cross-cohort studies, integrating diverse datasets, such as electronic health records (EHRs), is both essential and challenging due to cohort-specific variations, distributed data storage, and data privacy concerns. Traditional methods often require data pooling or complex data harmonization, which can reduce efficiency and limit the scope of cross-cohort learning. We introduce mixWAS, a one-shot, lossless algorithm that efficiently integrates distributed EHR datasets via summary statistics. Unlike existing approaches, mixWAS preserves cohort-specific covariate associations and supports simultaneous mixed-outcome analyses. Simulations demonstrate that mixWAS outperforms conventional methods in accuracy and efficiency across various scenarios. Applied to EHR data from seven cohorts in the US, mixWAS identified 4,534 significant cross-cohort genetic associations among traits such as blood lipids, BMI, and circulatory diseases. Validation with an independent UK EHR dataset confirmed 97.7% of these associations, underscoring the algorithm’s robustness. By enabling lossless cross-cohort integration, mixWAS improves the precision of multi-outcome analyses and expands the potential for actionable insights in healthcare research.
From Chest Pain to Coronary Functional Testing: Clinical and Economic Impact of Coronary Microvascular Dysfunction
Authors: Merdler Ilan , Wallace Ryan , Hill Andrew , Medranda Giorgio A. , Reddy Pavan , Zhang Cheng , Ozturk Sevket Tolga , Sawant Vaishnavi , Weintraub William S. , Lopez Kassandra , Ben-Dor Itsik , Waksman Ron , Hashim Hayder D. , Case Brian C. 
Published: January 2024

AbstractBackgroundCoronary functional testing to formally diagnose coronary microvascular dysfunction (CMD) reduces cardiovascular events and alleviates angina. This study aims to investigate the extensive and complex journey that patients with CMD undergo, from the onset of chest pain to eventual diagnosis.MethodsData from the Coronary Microvascular Disease Registry (CMDR) were analyzed, including information on the date of first documentation of chest pain, number of non-invasive and invasive tests the patient underwent, emergency department visits, and hospitalizations. In addition, we estimated the total cost per patient. A total of 61 patients with CMD diagnosis were included in this analysis.ResultsThe cohort had an average age of 65.6±9.9 years. The median time from initial chest pain symptoms to diagnosis was 0.62 (interquartile range [IQR]: 0.06-2.96) years. During this period, patients visited the emergency department a median of 1.0 (IQR: 0.0-2.0) times. Diagnostic tests included 3.0 (IQR: 2.0-6.0) electrocardiograms, 3.0 (IQR: 0.0-6.0) high-sensitivity troponin tests, and 1.0 (IQR: 1.0-2.0) echocardiograms. Prior to diagnosis of CMD, 13 (21.3%) patients had left heart catheterization without coronary functional testing. Non-invasive testing for ischemia was conducted in 43 (70.5%) patients. Alternative non-cardiac diagnoses were given to 11 (18.0%) patients during the diagnostic process, with referrals made to gastroenterology for 16 (26.2%) and pulmonology for 10 (16.4%) patients. The cost averaged $1,790±2,506 per patient.ConclusionTimely identification of CMD offers promising opportunities for prompt symptom alleviation, accompanied by reduced visits to the emergency department, cardiovascular testing, invasive medical procedures, and consequently reduced healthcare expenses.Clinical Trial RegistryCoronary Microvascular Disease Registry (CMDR),clinicaltrials.gov,NCT05960474What is Known; What the Study AddsWhat is Known- Angina pectoris is a major global health concern, impacting millions of individuals around the world.- Coronary microvascular dysfunction (CMD) is a known etiology to cause angina.What the Study Adds- This study reveals the challenging journey of CMD patients from chest pain to diagnosis, showing the complexity, and overlapping symptoms of CMD, leading to under/misdiagnosis or delay in definitive diagnosis.- Healthcare providers must improve CMD awareness and understanding to ensure timely and accurate diagnosis, minimizing patient burden and unnecessary expenses.- Further research and awareness campaigns are crucial to optimize CMD management, leading to better healthcare outcomes and reduced economic strain.