bluuebunny/crossref_metadata_2025_split huggingface dataset:
Linking acetylated α-Tubulin redistribution to α-Synuclein pathology in brain of Parkinson’s disease patients
Authors: Mazzetti Samanta , Giampietro Federica , Isilgan Huseyin Berkcan , Calogero Alessandra Maria , Gagliardi Gloria , Rolando Chiara , Cantele Francesca , Ascagni Miriam , Bramerio Manuela , Giaccone Giorgio , Isaias Ioannis Ugo , Pezzoli Gianni , Cappelletti Graziella 
Published: December 2022

AbstractHighly specialized microtubules in neurons are crucial to the health and disease of the nervous system, and their properties are strictly regulated by different post-translational modifications, including α-Tubulin acetylation. An imbalance in the levels of acetylated α-Tubulin has been reported in experimental models of Parkinson’s disease (PD) whereas pharmacological or genetic modulation that leads to increased acetylated α-Tubulin successfully rescues axonal transport defects and inhibits α-Synuclein aggregation. However, the role of acetylation of α-Tubulin in the human nervous system is largely unknown as most studies are based onin vitroevidence.To capture the complexity of the pathological processesin vivo, we analysedpost-mortemhuman brain of PD patients and control subjects. In the brain of PD patients at Braak stage 6, we found a redistribution of acetylated α-Tubulin, which accumulates in the neuronal cell bodies in subcortical structures but not in the cerebral cortex, and decreases in the axonal compartment, both in the central and peripheral nervous system. High-resolution and 3D reconstruction analysis linked acetylated α-Tubulin redistribution to α-Synuclein oligomerization, leading us to propose a model for Lewy body (LB) morphogenesis. Finally, for the first time inpost-mortemhuman brain, we observed threadlike structures, resembling tunnelling nanotubes that contain α-Synuclein oligomers and are associated with acetylated α-Tubulin enriched neurons.In conclusion, we disclose a novel aspect of LB morphogenesis, indicating the role of acetylated α-Tubulin in PD, that may provide clues to design novel therapeutic interventions.
Predicting regulators of epithelial cell state through regularized regression analysis of single cell multiomic sequencing
Authors: Ledru Nicolas , Wilson Parker C. , Muto Yoshiharu , Yoshimura Yasuhiro , Wu Haojia , Asthana Amish , Tullius Stefan G. , Waikar Sushrut S. , Orlando Giuseppe , Humphreys Benjamin D. 
Published: December 2022

AbstractChronic disease processes are marked by cell-specific transcriptomic and epigenomic changes. Single nucleus joint RNA- and ATAC-seq offers an opportunity to study the gene regulatory networks underpinning these changes in order to identify key regulatory drivers. We developed a regularized regression approach, RENIN, (RegulatoryNetworkInference) to construct genome-wide parametric gene regulatory networks using multiomic datasets. We generated a single nucleus multiomic dataset from seven adult human kidney biopsies and applied RENIN to study drivers of a failed injury response associated with kidney disease. We demonstrate that RENIN is highly effective tool at predicting keycis-andtrans-regulatory elements.
MicroRNA-205 promotes hair regeneration by modulating mechanical properties of hair follicle stem cells
Authors: Wang Jingjing , Fu Yuheng , Huang Wenmao , Biswas Ritusree , Banerjee Avinanda , Broussard Joshua A. , Zhao Zhihai , Wang Dongmei , Bjerke Glen , Raghavan Srikala , Yan Jie , Green Kathleen J. , Yi Rui 
Published: December 2022

AbstractStiffness and actomyosin contractility are intrinsic mechanical properties of animal cells required for the shaping of tissues. However, whether tissue stem cells (SCs) and progenitors located within SC niche have different mechanical properties that govern their size and functions remains unclear. We show that hair follicle SCs in the bulge are stiff with high actomyosin contractility and resistant to size change, whereas hair germ (HG) progenitors are soft and periodically enlarge and contract during quiescence. During activation, HGs reduce contraction and more frequently enlarge, a process that is associated with weakening of the actomyosin network, nuclear YAP accumulation and cell cycle re-entry. Induction of miR-205, a novel regulator of the actomyosin cytoskeleton, reduces actin contractility, decreases the stiffness of the bulge and HG, and activates hair regeneration in young and old mice. This study reveals the control of tissue SC size and activities by spatiotemporally compartmentalized mechanical properties and demonstrates the possibility to stimulate tissue regeneration by fine-tuning cell mechanics.
dcSBM: A federated constrained source-based morphometry approach for multivariate brain structure mapping
Authors: Saha Debbrata K. , Silva Rogers F. , Baker Bradley T. , Saha Rekha , Calhoun Vince D. 
Published: December 2022

AbstractThe examination of multivariate brain morphometry patterns has gained attention in recent years, especially for their powerful exploratory capabilities in the study of differences between patients and controls. Among many existing methods and tools for analysis of brain anatomy based on structural magnetic resonance imaging (sMRI) data, data-driven source based morphometry (SBM) focuses on the exploratory detection of such patterns. Constrained source-based morphometry (constrained SBM) is a widely used semi-blind extension of SBM that enables extracting maximally independent reference-alike sources using the constrained independent component analysis (ICA) approach. In order to operate, constrained SBM needs the data to be locally accessible. However, there exist many reasons (e.g., the concerns of revealing identifiable rare disease information, or violating strict IRB policies) that may preclude access to data from different sites. In this scenario, constrained SBM fails to leverage the benefits of decentralized data. To mitigate this problem, we present a novel approach: decentralized constrained source-based morphometry (dcSBM). In dcSBM, the original data never leaves the local site. Each site operates constrained ICA on their private local data while using a common distributed computation platform. Then, an aggregator/master node aggregates the results estimated from each local site and applies statistical analysis to find out the significant sources. In our approach, we first use UK Biobank sMRI data to investigate the reliability of our dcSBM algorithm. Finally, we utilize two additional multi-site patient datasets to validate our model by comparing the resulting group difference estimates from both centralized and decentralized constrained SBM.
Polygenic prediction across populations is influenced by ancestry, genetic architecture, and methodology
Authors: Wang Ying , Kanai Masahiro , Tan Taotao , Kamariza Mireille , Tsuo Kristin , Yuan Kai , Zhou Wei , Okada Yukinori ,   the BioBank Japan Project, Huang Hailiang , Turley Patrick , Atkinson Elizabeth G. , Martin Alicia R. 
Published: December 2022

SummaryPolygenic risk scores (PRS) developed from multi-ancestry genome-wide association studies (GWAS), PRSmulti, hold promise for improving PRS accuracy and generalizability across populations. To establish best practices for leveraging the increasing diversity of genomic studies, we investigated how various factors affect the performance of PRSmulticompared to PRS constructed from single-ancestry GWAS (PRSsingle). Through extensive simulations and empirical analyses, we showed that PRSmultioverall outperformed PRSsinglein understudied populations, except when the understudied population represented a small proportion of the multi-ancestry GWAS. Notably, for traits with large-effect ancestry-enriched variants, such as mean corpuscular volume, using substantially fewer samples from Biobank Japan achieved comparable accuracies to a much larger European cohort. Furthermore, integrating PRS based on local ancestry-informed GWAS and large-scale European-based PRS improved predictive performance in understudied African populations, especially for less polygenic traits with large ancestry-enriched variants. Our work highlights the importance of diversifying genomic studies to achieve equitable PRS performance across ancestral populations and provides guidance for developing PRS from multiple studies.
Association between obesity, brain atrophy and accelerated brain aging and their genetic mechanisms
Authors: Kang Jujiao , Jia Tianye , Linli Zeqiang , Li Yuzhu , Cheng Wei , Guo Shuixia , Feng Jianfeng 
Published: December 2022

AbstractObjectiveTo investigate the causal relationship and the underlying biological mechanisms between body mass index (BMI) and grey matter volume (GMV).MethodsWe applied Mendelian randomization analyses utilizing 33,6514 individuals from the UK Biobank cohort to establish the causal relationship between BMI and GMV. We also quantified obesity-related accelerated brain aging using an XGBoost prediction paradigm. Then, mediation analyses were performed to test the association between BMI, brain atrophy, brain aging and cognitive function. Finally, the gene expression data from the Allen Human Brain Atlas were used to identify genes contributing to the BMI-GMV association.ResultsA causal effect of increased BMI on decreased GMV was established using multiple Mendelian randomization methods. The brain age prediction paradigm achieved appreciable performance in both training (R = 0.725, mean-absolute-error (MAE) = 4.130) and test data (R= 0.71, MAE = 4.239). On average, overweight and obese individuals exhibited significantly accelerated brain aging by +0.59 years and +1.7 years, respectively. Further, the accelerated brain age and total GMV mediated 18% of the association of higher BMI with poorer cognitive function. BMI-associated lower GMVs were related to the over-expression of gene TRIM27 and other genes involved in the autophagy biological process.ConclusionObesity led to GMV decline and accelerated brain aging. Genes including TRIM27 and biological process pathways involved in autophagy may contribute to the BMI-GMV association.
Mood symptoms and chronic fatigue syndrome due to relapsing remitting multiple sclerosis are associated with immune activation and aberrations in the erythron
Authors: Almulla Abbas F. , Abdul Jaleel Al-Karrar Kais , Abo Algon Ali Abbas , Tunvirachaisakul Chavit , Hassoun Hayder K. , Al-Hakeim Hussein K. , Maes Michael 
Published: December 2022

AbstractBackgroundMultiple sclerosis (MS) is a chronic autoimmune and neuroinflammatory disease of the central nervous system characterized by peripheral activation of immune-inflammatory pathways which culminate in neurotoxicity causing demyelination of central neurons. Nonetheless, the pathophysiology of relapsing-remitting MS (RRMS)-related chronic fatigue, depression, anxiety, cognitive impairments, and autonomic disturbances is not well understood.ObjectivesThe current study aims to delineate whether the remitted phase of RRMS is accompanied by activated immune-inflammatory pathways and if the latter, coupled with erythron variables, explain the chronic fatigue and mood symptoms due to RRMS.Material and MethodsWe recruited 63 MS patients, 55 in the remitted phase of RRMS and 8 with secondary progressive MS, and 30 healthy controls and assessed erythron variables and used a bio-plex assay to measure 27 serum cytokines.ResultsA significant part of the MS patients (46%) displayed activation of the immune-inflammatory response (IRS) and compensatory immune response (CIRS) systems, T helper (Th)1 and Th-17 cytokine profiles. Remitted RRMS patients showed increased chronic fatigue, depression, anxiety, physiosomatic, autonomic, and insomnia scores, which could partly be explained by M1 macrophage, Th1, Th-17, growth factor, and CIRS activation, as well as aberrations in the erythron including lowered hematocrit and hemoglobin levels.ConclusionsAround 50% of remitted RRMS patients show activation of immune-inflammatory pathways in association with mood and chronic-fatigue-like symptoms. IRS and CIRS activation as well as the aberrations in the erythron are new drug targets to treat chronic fatigue and affective symptoms due to MS.
Epigenetics ofPNLIPRP1in human pancreas reveals a molecular path between type 2 diabetes and pancreatic cancer
Authors: Maurin Lucas , Marselli Lorella , Ning Lijiao , Boissel Mathilde , Boutry Raphael , Suleiman Mara , Leloire Audrey , Pascat Vincent , Maina Jared , Toussaint Bénédicte , Amanzougarene Souhila , Badreddine Alaa , Derhourhi Mehdi , Prokopenko Inga , Jörns Anne , Lenzen Sigurd , Pattou François , Kerr-Conte Julie , Canouil Mickaël , Bonnefond Amélie , Marchetti Piero , Froguel Philippe , Khamis Amna 
Published: December 2022

AbstractBackgroundType 2 diabetes (T2D) increases the risk of pancreatic ductal adenocarcinoma (PDAC), which could be due to an epigenetic mechanism.MethodsWe explored the association between T2D and whole pancreas methylation in 141 individuals, of which 28 had T2D, using Illumina MethylationEPIC 850K BeadChip arrays. We performed downstream functional assessment in the rat acinar pancreas cell line AR42J. To further understand the role of our candidate gene in humans, we tested whether null variants were associated with T2D and related traits using the UK biobank.ResultsMethylation analysis identified one significant CpG associated with T2D: hypermethylation in an enhancer inPNLIPRP1, an acinar-specific gene.PNLIPRP1expression was decreased in T2D individuals. Using a rat acinar cell line, we 1/ confirmed decreasedPnliprp1in response to a diabetogenic treatment, and 2/ inPnliprp1knockdown, an up-regulation of cholesterol biosynthesis, cell cycle down-regulation, decreased expression of acinar markers and increased expression of ductal markers pointing towards acinar-to-ductal metaplasia (ADM), a hallmark of PDAC initiation. Using exome data from UK Biobank, we show that rarePNLIPRP1null variants associated with increased glucose, BMI and LDL-cholesterol.Conclusions/interpretationWe present evidence that an epigenetically-regulated gene associates with T2D risk, and might promote ADM and PDAC progression, opening new insights into early prevention of PDAC.
Effectiveness of Sotrovimab in Preventing COVID-19-related Hospitalizations or Deaths Among U.S. Veterans
Authors: Young-Xu Yinong , Korves Caroline , Zwain Gabrielle , Satram Sacha , Drysdale Myriam , Reyes Carolina , Cheng Mindy M. , Epstein Lauren , Marconi Vincent C. , Ginde Adit 
Published: December 2022

ABSTRACTBackgroundData on effectiveness of sotrovimab preventing COVID-19-related hospitalization or mortality, particularly after the emergence of the Omicron variant, are limited.MethodDetermine the real-world clinical effectiveness of sotrovimab for prevention of 30-day COVID-19 related hospitalization or mortality using a retrospective cohort within the U.S. Department of Veterans Affairs (VA) healthcare system.Veterans aged ≥18 years, diagnosed with COVID-19 between December 1, 2021, and April 4, 2022, were included. Sotrovimab recipients (n=2,816) were exactly matched to untreated controls (n=11,250) on date of diagnosis, vaccination status, and region.The primary outcome was COVID-19-related hospitalization or all-cause mortality within 30 days from diagnosis. Cox proportional hazards modeling estimated the hazard ratios (HR) and 95% Confidence Interval (CI) for the association between receipt of sotrovimab and outcomes.ResultsDuring BA.1 dominance, compared to matched controls, sotrovimab-treated patients had a 70% lower risk hospitalization within 30 days or mortality (HR 0.30; 95%CI, 0.23-0.40), a 66% lower risk of 30-day hospitalization (HR 0.34; 95%CI, 0.25-0.46), and a 77% lower risk of 30-day all-cause mortality (HR 0.23; 95%CI, 0.14-0.38). During BA.2 dominance sotrovimab-treated patients had a 71% (HR .29; 95%CI, 0.08-0.98) lower risk of 30-day COVID-19-related-hospitalization, emergency, or urgent care. Limitations include confounding by indication.ConclusionsUsing national real-world data from high risk and predominantly vaccinated Veterans, administration of sotrovimab, compared with no treatment, was associated with reduced risk of 30-day COVID-19-related hospitalization or all-cause mortality during the Omicron BA.1 period and reduced risk of progression to severe COVID-19 during the BA.2 dominant period.SummaryExamination of national real-world evidence demonstrates sotrovimab is effective in preventing at risk positive COVID-19 cases from progressing to severe SARS-CoV-2 infections compared to matched untreated cases during Delta and early Omicron variant waves in the U.S. Veteran population.
A Randomized, Double-Blind Trial of the Analgesic and Anti-Inflammatory Effects of Naproxen Sodium and Acetaminophen Following Implant Placement Surgery
Authors: Theken Katherine N. , Chen Mengxiang , Wall D. Lucas , Pham Truongan , Secreto Stacey A. , Yoo Thomas H. , Rascon Allison N. , Chang Yu-Cheng , Korostoff Jonathan M. , Mitchell Claire H. , Hersh Elliot V. 
Published: December 2022

AbstractObjectivesThe objectives of this study were to compare the analgesic and anti-inflammatory effects of naproxen sodium and acetaminophen after implant placement surgery.Materials and MethodsAdult patients who received one or two dental implants were treated with naproxen sodium (440 mg loading dose + 220 mg q8h, n=15) or acetaminophen (1000 mg q6h - max daily dose 3000 mg, n=15) for three days after implant placement in a randomized, double-blind design. Pain was assessed on a 0-10 scale every 20 minutes for 6 h. Tramadol (50 mg) was available as a rescue medication. Plasma and gingival crevicular fluid (GCF) were collected prior to the surgery and 0, 1, 2, 4, 6, 24, and 72h after surgery for quantification of interleukin (IL)-6, IL-8, and IL-1β levels.ResultsPain scores were significantly lower in patients treated with naproxen sodium compared to those treated with acetaminophen. Inflammatory mediator levels in plasma and GCF increased after surgery and returned to near baseline levels by 72h. Plasma IL-6 levels were significantly lower 6h after surgery in patients treated with naproxen sodium compared to acetaminophen. No differences in inflammatory mediator concentrations in GCF were observed between the treatment groups.ConclusionsNaproxen sodium was more effective than acetaminophen in reducing post-operative pain and systemic inflammation following surgical placement of one or two dental implants. Further studies are needed to determine whether these findings are applicable to more complex implant cases and how they affect clinical outcomes following implant placement.
Effects of counteracting measures on muscle contraction determinants in CKD: what muscle biopsy studies tell us?
Authors: Mitrou Georgia I. 
Published: December 2022

AbstractChronic kidney disease (CKD) is characterized by muscle atrophy, fatigue intolerance and other indicators of muscle dysfunction, collectively termed uremic myopathy, with devastating consequences in overall health status and mortality rates. Although many factors such as metabolic acidosis, substrate availability and neuropathy have been implicated, the mechanisms underlying uremic myopathy have not yet been fully understood. However, there is clear evidence that muscle specific factors such as fiber atrophy, fiber type alterations and mitochondrial abnormalities are presented in muscle biopsies of CKD patients and can negatively affect muscle contraction. Counteracting measures such as exercise and nutritional interventions have been shown to improve muscle performance, health indices and overall quality of life of CKD patients. However, little is known about their effects on factors affecting muscle contraction at the muscle biopsy level and therefore on the mechanisms underlying uremic myopathy. The current systematic review aims to summarize the effects of recent interventional studies on muscle contraction determinants based on muscle biopsies of human patients.
Exploring the Efficacy and Feasibility of using Biomarkers for Early Screening of Lung Cancer and their Potential Reverberation on Mortality Rate: A Review
Authors: Safari Vejin T , OLeary J , Singh L , Sullivan T , Aziague S , Akbariansaravi A 
Published: December 2022

AbstractIntroductionLung cancer patients often have a poor prognosis, due to various factors that play into the diagnosis, such as timeframe, early detection, and progression. The rate of patients with advanced-stage lung cancer is often high due to the inability to be diagnosed early. The lack of screening, therefore, increases the mortality rate of lung cancer. High mortality rate is also attributed to advanced lung cancer cases that are undiagnosed due to the lack of symptoms in patients early in disease acquisition.MethodsThis review explores lung cancer screening methods adopted around the world and those with the most promising standardizations. Criteria used to filter articles included lung cancer methods using biomarkers, research conducted in the United States within the past 10 years, screening methods observed in a clinical setting, and patients with primary lung cancer. Some practices that can be utilized to improve screening for lung cancer may involve using genetic markers to identify patients possessing genetic makeup associated with lung cancer.ResultsOur study included 32 articles in our review calculating the sensitivity and specificity for a variety of potential biomarkers including: 1) Volatile organic compounds has a specificity of 80% and sensitivity of 80% 2) Circulating tumor DNA has a sensitivity of 80% and specificity of 96% 3) miRNA molecules (miR-146-5p, miR-324-5p, miR-223-3p, and miR-223-5p) displayed sensitivities of 93%, 94%, 96%, and 95% respectively, with specificities of 33%, 23%, 27%, and 26% respectively 4) methylation beads specific genomic sequences (SOX17, TAC1, HOXA7, CDO1, HOXA9, and ZFP42) with sensitivities of 84%, 86%, 63%, 78%, 93%, and 87% respectively when found in sputum and 73%, 76%, 34%, 65%, 86%, and 84% respectively when found in serum. Specificities were calculated at 88%, 75%, 92%, 67%, 8%, and 63% respectively when found in sputum, and 84%, 78%, 92%, 74%, 46%, and 54% respectively in serum 5) Ga-Alfatide II scans were found to have a sensitivity of 86% and a specificity of 85% 6) Combined score had a sensitivity of 78% and specificity of 50% 7) WT-IDH had a sensitivity of 63% and specificity of 93%.DiscussionIn such a high-risk patient population, cautious preventative measures can be used such as lifestyle choices and environmental exposures that are known risk factors. Informed physicians will be able to provide care directed toward minimizing patient’s modifiable risk factors to lower incidence rate and routine imaging offered when there is an index of suspicion to minimize mortality rate in high-risk populations. This review highlighted practices such as circulating tumor DNA and a Ga-Alfatide II CT/PET scan that can be utilized to improve screening in the future and further dissected errors made in lung cancer diagnosis.