bluuebunny/crossref_metadata_2025_split huggingface dataset:
Valvular Prostaglandins are Elevated in Severe Human Aortic Valve Stenosis
Authors: Cayer Lucien G.J. , Surendran Arun , Karakach Tobias , Aukema Harold M. , Ravandi Amir 
Published: August 2023

AbstractIntroductionAortic valve stenosis (AVS) is the most common valvular disease in the developed world. AVS involves the progressive fibro-calcific remodeling of the aortic valve (AV), which impairs function and can ultimately lead to heart failure. Due to gaps in our understanding of the underlying mechanisms of AVS, there are no pharmacological treatments nor dietary interventions known to slow AVS progression. Recent studies have begun to suggest oxylipins, a class of bioactive lipid, may be dysregulated in the valves of AVS-patients.MethodologyWe utilized HPLC-MS/MS to conduct a targeted oxylipin analysis on human AV tissue and plasma from a cohort of 110 patients undergoing AV surgery.ResultsWe identified 36 oxylipins in human AV tissue with all showing significant increase in patients with severe AVS. A multivariate model including patient characteristics and valvular oxylipins identified arachidonic acid-cyclooxygenase (COX) pathway derived prostanoids to be the most associated with AVS severity. Plasma oxylipin levels were measured in a subset of aortic surgery patients and compared to a control group of healthy participants, showing distinct oxylipin profiles between control and disease.ConclusionOur comprehensive analysis of oxylipins in the human AV to date and identified the inflammatory and osteogenic regulating prostanoids to be positively correlated with AVS severity. This elucidation of prostanoid dysregulation warrants further research into COX inhibition to mitigate AVS.
Effects of high-intensity interval training and moderate-intensity continuous training on non-motor symptoms in patients with Parkinson’s disease: a randomized pilot trial
Authors: Kim Ryul , Choi Seohee , Kang Nyeonju , Park Kiwon , Shin Heehyun , Lee Hanall , Lee Hyungwoo , Jun Jin-Sun , Jeon Beomseok , Byun Kyeongho 
Published: August 2023

AbstractObjectiveTo explore whether high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) have different effects on non-motor symptoms in patients with Parkinson’s disease (PD).MethodsIn this 24-week, randomized, controlled, investigator–blinded pilot trial, 33 participants with PD (Hoehn and Yahr stages 1–2; aged 50–80 years) were allocated to HIIT (3 days/week, 60% maximum aerobic power for 30–50 seconds with 1 minute rest intervals), MICT (3 days/week, 50% peak oxygen consumption), or control (usual care) groups. The primary clinical outcome was a 24-week change in the Non-Motor Symptoms Scale (NMSS) score. The secondary clinical outcomes were 24-week changes in the scores of specific non-motor questionnaires covering neuropsychiatric, sleep-related, autonomic, and sensory symptoms.ResultsNMSS score changes did not differ significantly among the three groups (Bonferroni-adjustedp>0.6 in all). In the secondary clinical outcome analyses, the MICT group showed a greater improvement in Beck Depression Inventory scores (median difference, 3.5 points; 95% confidence interval [CI], 1.4 to 6.0; Bonferroni-adjustedp=0.016) and, to a lesser extent, Beck Anxiety Inventory scores (median difference, 2.0 points; 95% CI, 0.0 to 10.8; Bonferroni-adjustedp=0.054) compared with those of the control group. However, these trends were not observed in the HIIT group when compared with the control group (Bonferroni-adjustedp>0.9 in all). There were no significant differences in the other secondary outcomes between the groups.ConclusionThis trial did not show the potential benefits of HIIT or MICT on overall non-motor symptoms in patients with PD. However, MICT may be more effective than HIIT in alleviating mood symptoms, which requires further large-scale investigation.Trial registrationCRIS (cris.nih.go.kr) identifier: KCT0007130
Modelling the risk ecosystem of depression using machine learning in a population of young adults
Authors: Fraser H. , Kwong A.S.F. , Brooks M. , Davidson B.I. , McConville R. , Pearson R. M. 
Published: August 2023

AbstractUnderstanding what is predictive of early adulthood depression could help inform resource targeting and direction of approaches aiming to alleviate the personal, cultural, and economic burden of depression and similar disorders. This work uses multivariate longitudinal data (n=3487) measured from conception to adulthood from a UK based birth cohort of young adults (Avon Longitudinal Study of Parents and Children (ALSPAC)) and a machine learning approach to a) investigate whether episodes of early adulthood depression can be predicted from various risk factors across early life and adolescence, and b) interpret which factors are most important for predicting episodes of early adulthood depression. Here, we build four models to predict participants having an episode of early adulthood depression and show that the highest performing model can predict if people experienced symptoms of depression with an F1-score of 0.66, using a range of biological, behavioural, and early life experience related risk factors.
PCSK9genetic variants and risk of vascular and non-vascular diseases in Chinese and UK populations
Authors: Holmes Michael V , Kartsonaki Christiana , Boxall Ruth , Lin Kuang , Reeve Nicola , Yu Canqing , Lv Jun , Bennett Derrick A , Hill Michael R , Yang Ling , Chen Yiping , Du Huaidong , Turnbull Iain , Collins Rory , Clarke Robert J , Tobin Martin D , Li Liming , Millwood Iona Y , Chen Zhengming , Walters Robin G 
Published: August 2023

AbstractBackgroundLowering low-density lipoprotein cholesterol (LDL-C) through PCSK9 inhibition represents a new therapeutic approach to preventing and treating cardiovascular disease (CVD). Phenome-wide analyses ofPCSK9genetic variants in large prospective biobanks can help to identify unexpected effects of PCSK9 inhibition.MethodsThe prospective China Kadoorie Biobank genotyped >100,000 participants with follow-up for fatal and non-fatal disease events. APCSK9genetic score (PCSK9-GS) was constructed using three single nucleotide polypmorphisms at thePCSK9locus associated with directly-measured LDL-C, including a loss-of-function variant (rs151193009). Logistic regression gave estimated odds ratios (ORs) forPCSK9-GS associations with CVD and non-CVD outcomes, scaled to 1-standard deviation (SD) lower LDL-C.ResultsPCSK9-GS was associated with lower apolipoprotein B, and with lower risks of carotid plaque (n=8340 cases; OR=0.61 [95%CI: 0.45-0.83]; P=0.0015), major occlusive vascular events (n=15,752; 0.80 [0.67-0.95]; P=0.011), and ischaemic stroke (n=11,467; 0.80 [0.66-0.98]; P=0.029). However,PCSK9-GS was also associated with higher risk of hospitalisation with chronic obstructive pulmonary disease (COPD: n=6836; 1.38 [1.08-1.76]; P=0.0089), and with even higher risk of fatal exacerbations among individuals with pre-existing COPD (n=730; 3.61 [1.71-7.60]; P=7.3×10−4). Risk of acute upper respiratory tract infection (URTI) was also increased (n=1,095; 2.18 [1.34-3.53]; P=0.0016), as previously reported in UK Biobank, with a pooled OR after meta-analysis of 1.87 ([1.38-2.54]; P=5.4×10−5). We also replicated a previously-reported association with self-reported asthma (pooled OR 1.17 ([1.04-1.30]; P=0.0071). There was heterogeneity between the associations ofPCSK9-GS and a polygenic LDL-C score for each of COPD hospitalisation (P-het=0.015), fatal COPD exacerbation (P-het=0.0012), and URTI (P-het=0.013).ConclusionsLDL-C-loweringPCSK9genetic variants are associated with lower risk of subclinical and clinical atherosclerotic vascular disease, but higher risks of respiratory diseases which appear unrelated to LDL-C. Pharmacovigilance studies may be required to monitor patients treated with therapeutic PCSK9 inhibitors for exacerbations of respiratory diseases or respiratory tract infections.
Cervicovaginal and anal self-sampling for HPV testing in a transgender and gender diverse population assigned female at birth: comfort, difficulty, and willingness to use
Authors: Welsh Erin F , Andrus Emily C. , Sandler Claire B. , Moravek Molly B. , Stroumsa Daphna , Kattari Shanna K. , Walline Heather M. , Goudsmit Christine M. , Brouwer Andrew F. 
Published: August 2023

AbstractBackgroundTransgender and gender diverse (TGD) people assigned female at birth (AFAB) face numerous barriers to preventive care, including for HPV and cervical cancer screening. Self-sampling options may expand access to HPV testing for TGD people AFAB.MethodsWe recruited TGD individuals AFAB to collect cervicovaginal and anal specimens at-home using self-sampling for HPV testing, and individuals reported their perceptions of self-sampling. Associations between demographic and health characteristics and each of comfort of use, ease of use, and willingness to use self-sampling were estimated using robust Poisson regression.ResultsThe majority of the 101 participants who completed the study reported that the cervicovaginal self-swab was not uncomfortable (68.3%) and not difficult to use (86.1%), and nearly all (96.0%) were willing to use the swab in the future. Fewer participants found the anal swab to not be uncomfortable (47.5%), but most participants still found the anal swab to not be difficult to use (70.2%) and were willing to use the swab in the future (89.1%). Participants were more willing to use either swab if they had not seen a medical professional in the past year. About 70% of participants who reported negative experiences with either self-swab were still willing to use that swab in the future.ConclusionsTGD AFAB individuals were willing to use and preferred self-sampling methods for cervicovaginal and anal HPV testing. Developing clinically approved self-sampling options for cancer screening could expand access to HPV screening for TGD AFAB populations.
Machine learning for the prediction of in-hospital mortality in patients with spontaneous intracerebral hemorrhage
Authors: Mao Baojie , Zhang Rui , Pan Yuhang , Zheng Ruzi , Shen Yanfei , Lu Wei , Lu Yuning , Xu Shanhu , Wu Jiong , Wang Ming , Wan Shu 
Published: August 2023

BackgroundsEarly and accurate identification of patients with spontaneous intracerebral hemorrhage(sICH) who are at high risk of in-hospital death can help intensive care unit (ICU) physicians make optimal clinical decisions. The aim of this study was to develop a machine learning(ML)-based tool to predict the risk of in-hospital death in patients with sICH in ICU.MethodsWe conducted a retrospective administrative database study using the MIMIC-IV and Zhejiang Hospital database. The outcome of the study was in-hospital mortality. To develop and validate the final model, we employed the LASSO regression to screen and select relevant variables. Five algorithms, namely Logistic Regression (LR), K-Nearest Neighbors (KNN), Adaptive Boosting (AdaBoost), Random Forest (RF), and eXtreme Gradient Boosting (XGBoost), were utilized. The selection of the best model was based on the area under the curve (AUC) in the validation cohort. Furthermore, we employ the SHapley Additive exPlanations (SHAP) methodology to elucidate the contributions of individual features to the model and analyze their impact on the model’s outputs. To facilitate accessibility, we also created a visual online calculation page for the model.ResultsIn the final cohort comprising 1596 patients from MIMIC-IV and Zhejiang Hospital, 367 individuals (23%) experienced in-hospital mortality during the inpatient follow-up period. After extracting 46 variables from the database, LASSO regression identified 14 predictor variables for further analysis. Among the five evaluated models, the XGBoost model demonstrated superior discriminative power in both the internal validation set (AUC = 0.907) and the external validation set (AUC = 0.787). Furthermore, through the SHAP technique, we identified the top 5 predictors in the feature importance rankings: Glasgow Coma Scale (GCS), Sequential Organ Failure Assessment (SOFA), anticoagulant medication, mannitol medication and oxygen saturation.ConclusionsAmong the five models, the XGBoost model exhibited superior performance in predicting mortality for patients with sICH in the ICU, indicating its potential significance in the development of early warning systems.
Detection of regularities in auditory sequences before and at term-age in human neonates
Authors: Panzani Marine , Mahmoudzadeh Mahdi , Wallois Fabrice , Dehaene-Lambertz Ghislaine 
Published: August 2023

AbstractDuring the last trimester of gestation, fetuses and preterm neonates begin to respond to sensory stimulation and to discover the structure of their environment. Yet, neuronal migration is still ongoing. This late migration notably concerns the supra-granular layers neurons, which are believed to play a critical role in encoding predictions and detecting regularities. In order to gain a deeper understanding of how the brain processes and perceives regularities during this stage of development, we conducted a study in which we recorded event-related potentials (ERP) in 31-wGA preterm and full-term neonates exposed to alternating auditory sequences (e.g. “ba ga baga ba”), when the regularity of these sequences was violated by a repetition (e.g., "ba ga baga ga"). We compared the ERPs in this case to those obtained when violating a simple repetition pattern (“ga ga gaga ga” vs “ga ga gaga ba”). Our results indicated that both preterm and full-term neonates were able to detect violations of regularity in both types of sequences, indicating that as early as 31 weeks gestational age, human neonates are sensitive to the conditional statistics between successive auditory elements. Full-term neonates showed an early and similar mismatch response (MMR) in the repetition and alternating sequences. In contrast, 31-wGA neonates exhibited a two-component MMR. The first component which was only observed for simple sequences with repetition, corresponded to sensory adaptation. It was followed much later by a deviance-detection component that was observed for both alternation and repetition sequences. This pattern confirms that MMRs detected at the scalp may correspond to a dual cortical process and shows that deviance detection computed by higher-level regions accelerates dramatically with brain maturation during the last weeks of gestation to become indistinguishable from bottom-up sensory adaptation at term.HighlightsStarting at 31 wGA, neonates are sensitive to conditional statistics between successive events.The MisMatch Response detected at the scalp may correspond to a dual cortical processThe prediction error signal accelerates during the third trimester of gestationIt overlaps with the phenomenon of sensory adaptation at term age
Osteoclast-Cancer Cell Metabolic Symbiosis Renders PARP Inhibitor Therapy Resistance in Bone Metastasis
Authors: Fan Huijuan , Xu Zhanao , Yao Ke , Zheng Bingxin , Zhang Yuan , Wang Xuxiang , Zhang Tengjiang , Li Xuan , Hu Haitian , Yue Bin , Hu Zeping , Zheng Hanqiu 
Published: August 2023

ABSTRACTSeventy percent of patients with late-stage breast cancer develop distal bone metastases; however, the mechanism by which the metabolic microenvironment affects resistance to therapy remains unknown. We investigated the metabolic bone microenvironment and identified glutathione metabolism as the top pathway in osteoclasts, which provides feedback to tumor cells to help neutralize oxidative stress and generate PARP inhibitor (PARPi) therapy resistance. GPX4, the critical enzyme responsible for glutathione oxidation, was upregulated during PARPi therapy through stress-induced ATF4-dependent transcriptional programming. The increased absorption of glutamine and the upregulation of GPX4 expression work in concert to enhance glutathione metabolism in cancer cells. Human clinical sample analysis of paired primary breast tumor and bone metastasis samples revealed that GPX4 was significantly induced in bone metastases. Combination therapy utilizing PARPi and zoledronate, which blocks osteoclast activity and thereby reduces the microenvironmental glutamine supply, generates a synergistic effect in reducing bone metastasis. Thus, our results identified an essential metabolic symbiosis between bone-resident cells and metastatic cancer cells during PARPi therapy.SIGNIFICANCEOsteoclast-derived glutamine is taken up by tumor cells to synthesize glutathione and neutralize the ROS generated by PARPi. This is the first example of “metabolic symbiosis” in therapeutic resistance of bone metastasis.
Development and characterization of pFluor50, a fluorogenic-based kinetic assay system for high-throughput inhibition screening and characterization of time-dependent inhibition and inhibition type for six human CYPs
Authors: Shriwas Pratik , Revnew Andre , Roo Sarah , Bender Alex , Lane Thomas R. , Ekins Sean , McElroy Craig A. 
Published: August 2023

1AbstractCytochrome P450 enzymes (CYPs) play an integral role in drug and xenobiotic metabolism in humans and thus understanding CYP inhibition or activation by new therapeutic candidates is an important step in the drug development process. Ideally, CYP inhibition/activation assays should be high-throughput, use commercially available components, allow for analysis of metabolism by the majority of human CYPs, and allow for kinetic analysis of inhibition type and time-dependent inhibition. Here, we developed pFluor50, a 384-well microtiter plate-based fluorogenic kinetic enzyme assay system using substrates metabolized by six human CYPs to generate fluorescent products and determined the Michaelis-Menten kinetics constant (KM) and product formation rate (Vmax) for each substrate-CYP pair. The substrate-CYP pairs were as follows: resorufin ethyl ether for CYP1A2 (KM= 0.8 μM), CYP2C9 (KM= 0.6 μM), and CYP2D6 (KM= 2.7 μM); resorufin benzyl ether for CYP2B6 (KM= 46 μM); 3-O-methyl fluorescein for CYP2C19 (KM= 3.0 μM); and dibenzyl fluorescein for CYP3A4 (KM= 2.9 μM). We then validated each assay using known inhibitors: α-naphthoflavone for CYP1A2 (IC50= 13.5 nM); sertraline for CYP2B6 (IC50= 410 nM) and CYP2D6 (IC50= 2.4 μM); sulfaphenazole for CYP2C9 (IC50= 1 μM); ticlopidine for CYP2C19 (IC50= 1.2 μM); and CYP3cide for CYP3A4 (IC50= 56 nM). pFluor50 was also used to elucidate inhibition type and time-dependent inhibition for some inhibitors demonstrating its utility for characterizing the observed inhibition, even mechanism-based inhibition. The pFluor50 assay system developed in this study using commercially available components should be very useful for high-throughput screening and further characterization of potential therapeutic candidates for inhibition/activation with the most prevalent human CYPs.
A robust ultrasensitive transcriptional switch in noisy cellular environments
Authors: Jeong Eui Min , Kim Jae Kyoung 
Published: August 2023

ABSTRACTUltrasensitive transcriptional switches enable sharp transitions between on and off states of transcription and are essential for cells to respond to environmental cues precisely. However, conventional switches, relying on direct repressor-DNA binding, are extremely sensitive to noise. Here, we discovered an alternative design combining three indirect transcriptional repression mechanisms, sequestration, blocking, and displacement, to generate a noise-resilient ultrasensitive switch. Although sequestration alone can generate an ultrasensitive switch, it remains sensitive to noise because the unintended transcriptional state induced by noise can persist for long periods. However, by jointly utilizing blocking and displacement, these noise-induced transitions can be rapidly restored to the original transcriptional state. Because this transcriptional switch is effective in noisy cellular contexts, it goes beyond previous synthetic transcriptional switches utilizing direct repression mechanisms, making it particularly valuable for robust synthetic system design. Our findings also provide insights into the evolution of robust ultrasensitive switches in real cells. Specifically, the concurrent use of seemingly redundant indirect repression mechanisms in diverse biological systems appears to be a strategy to achieve noise-resilience of ultrasensitive switches.GRAPHICAL ABSTRACT
The BCKDK inhibitor BT2 is a chemical uncoupler that lowers mitochondrial ROS production andde novolipogenesis
Authors: Acevedo Aracely , Jones Anthony E. , Danna Bezawit T. , Turner Rory , Montales Katrina P. , Benincá Cristiane , Reue Karen , Shirihai Orian S. , Stiles Linsey , Wallace Martina , Wang Yibin , Bertholet Ambre M. , Divakaruni Ajit S. 
Published: August 2023

ABSTRACTElevated levels of branched chain amino acids (BCAAs) and branched-chain α-ketoacids (BCKAs) are associated with cardiovascular and metabolic disease, but the molecular mechanisms underlying a putative causal relationship remain unclear. The branched-chain ketoacid dehydrogenase kinase (BCKDK) inhibitor BT2 is often used in preclinical models to increase BCAA oxidation and restore steady-state BCAA and BCKA levels. BT2 administration is protective in various rodent models of heart failure and metabolic disease, but confoundingly, targeted ablation ofBckdkin specific tissues does not reproduce the beneficial effects conferred by pharmacologic inhibition. Here we demonstrate that BT2, a lipophilic weak acid, can act as a mitochondrial uncoupler. Measurements of oxygen consumption, mitochondrial membrane potential, and patch-clamp electrophysiology show BT2 increases proton conductance across the mitochondrial inner membrane independently of its inhibitory effect on BCKDK. BT2 is roughly five-fold less potent than the prototypical uncoupler 2,4-dinitrophenol (DNP), and phenocopies DNP in loweringde novolipogenesis and mitochondrial superoxide production. The data suggest the therapeutic efficacy of BT2 may be attributable to the well-documented effects of mitochondrial uncoupling in alleviating cardiovascular and metabolic disease.