bluuebunny/crossref_metadata_2025_split huggingface dataset:
The association between body mass index and metabolite response to a liquid mixed meal challenge
Authors: Hughes David A. , Li-Gao Ruifang , Bull Caroline J. , de Mutsert Renée , Rosendaal Frits R. , Mook-Kanamori Dennis O. , Willems van Dijk Ko , Timpson Nicholas J. 
Published: August 2023

AbstractBackgroundMetabolite abundance is a dynamic trait that is not only variable in a fasting state, but also varies in response to environmental stimuli, such as food consumption. Postprandial abundance and response to a meal are emergent traits in studies of disease and which themselves may be subject to specific risk factors. We investigated body mass index (BMI) as a recognized risk factor for numerous health outcomes that may influence metabolite response to feeding. Here we use the Netherlands Epidemiology of Obesity (NEO) study to examine associations between BMI and metabolite response to a liquid meal and extend this by using Mendelian randomization (MR) to estimate potential causal effects.Methods and findingsThe NEO study conducted a liquid meal challenge and collected metabolite profiles using the Nightingale metabolomics platform in 5744 study participants. Observational and one-sample MR analysis were conducted to estimate the effect of BMI on metabolites and ratios of metabolites (n = 229) in the fasting, postprandial and response (or change in abundance) states. After an appropriate multiple testing correction, we observed 473 associations with BMI (175 fasting, 188 postprandial, 110 response) in observational analyses. In MR analyses, we observed 20 metabolite traits (5 fasting, 12 postprandial, 3 response) to be associated with BMI. In both the fasting and postprandial state, this included citrate and the ratios of linoleic acid, omega-6 fatty acid and polyunsaturated fatty acids to total fatty acids. In addition, the glucogenic amino acid alanine was inversely associated with BMI in the response state, suggesting that as alanine increased in postprandial abundance, that increase was attenuated with increasing BMI.ConclusionsOverall, MR estimates were strongly correlated with observational effect estimates suggesting that the broad associations seen between BMI and metabolite variation in fasting, postprandial and response states have a causal underpinning. Specific effects in previously unassessed postprandial and response states were detected and these may likely mark novel life course risk exposures driven by regular nutrition.
Bidirectional association and shared risk factors between atrial fibrillation and heart failure: a Mendelian Randomization study
Authors: Lu Haibin , Gao Ziting , Wei Hongye , Wei Yajing , Qiu Ziyi , Xiao Jun , Huang Wuqing 
Published: August 2023

AbstractBackgroundAtrial fibrillation and heart failure are closely related and share multiple risk factors. We aimed to apply the mendelian randomization (MR) analysis to explore the bidirectional causal link between atrial fibrillation and heart failure, and the independent effect of potential risk factors on the risk of both conditions.MethodsThis is a two-sample MR study using publicly available summary-level statistics of genome-wide association studies (GWAS). Bidirectional MR was performed to explore the relation between atrial fibrillation and heart failure. A total of 14 factors were selected as potential risk factors, univariable MR analyses were used to identify shared risk factors, and then the multivariable MR analyses were further used to investigate the independent effect of these factors on both conditions. Inverse-variance-weighted MR (IVW-MR) were used to obtain the effect estimates.ResultsMR analysis found evidence of causal relationship between atrial fibrillation and heart failure (odds ratio [OR], 1.24; 95% confidence interval [CI], 1.19–1.29), as well as between heart failure and atrial fibrillation (OR, 3.88; 95% CI, 1.45–10.37). Univariable MR analyses identified several shared risk factors for both conditions, including body mass index (BMI), blood pressure, smoking, coronary heart disease and myocardial infarction. After adjusting for atrial fibrillation, the observed associations between shared factors and heart failure kept stable, such as BMI, smoking, coronary heart disease and myocardial infarction. However, after adjusting for heart failure, the relationships between most risk factors and atrial fibrillation attenuated to null.ConclusionsThis two-sample MR study found a bidirectional relationship between atrial fibrillation and heart failure, and identified several shared risk factors of both conditions, which had an independent effect on the risk of heart failure while probably affected the risk of atrial fibrillation via cardiac impairment.FundingStart-up Fund for high-level talents of Fujian Medical University (grant no.XRCZX2021026) and Natural Science Foundation of Fujian Province (grant no. 2022J01706).
Discovery of a first-in-class small molecule ligand for WDR91 using DNA-encoded chemical library selection followed by machine learning
Authors: Ahmad Shabbir , Xu Jin , Feng Jianwen A , Hutchinson Ashley , Zeng Hong , Ghiabi Pegah , Dong Aiping , Centrella Paolo A , Clark Matthew A , Guié Marie-Aude , Guilinger John P , Keefe Anthony D , Zhang Ying , Cerruti Thomas , Cuozzo John W. , Rechenberg Moritz von , Bolotokova Albina , Li Yanjun , Loppnau Peter , Seitova Alma , Li Yen-Yen , Santhakumar Vijayaratnam , Brown Peter J. , Ackloo Suzanne , Halabelian Levon 
Published: August 2023

AbstractWD40 repeat-containing protein 91 regulates endosomal phosphatidylinositol 3-phosphate levels at the critical stage of endosome maturation and plays vital roles in endosome fusion, recycling, and transport by mediating protein-protein interactions. Due to its various roles in endocytic pathways, WDR91 has recently been identified as a potential host factor responsible for viral infection. We employed DNA-Encoded Chemical Library (DEL) selection against the WDR domain of WDR91, followed by machine learning to generate a model that was then used to predict ligands from the synthetically accessible Enamine REAL database. Screening of predicted compounds enabled us to identify the hit compound1, which binds selectively to WDR91 with a KDof 6 ± 2 μM by surface plasmon resonance. The co-crystal structure confirmed the binding of1to the WDR91 side pocket, in proximity to cysteine 487. Machine learning-assisted structure activity relationship-by-catalog validated the chemotype of1and led to the discovery of covalent analogs18and19. Intact mass LC-MS and differential scanning fluorimetry confirmed the formation of a covalent adduct, and thermal stabilization, respectively. The discovery of1, 18, 19, accompanying SAR, and co-crystal structures will provide valuable insights for designing more potent and selective compounds against WDR91, thus accelerating the development of novel chemical tools to evaluate the therapeutic potential of WDR91 in disease.
Post-ischemic ubiquitination at the postsynaptic density reversibly influences the activity of ischemia-relevant kinases
Authors: Dhawka Luvna , Palfini Victoria , Hambright Emma , Blanco Ismary , Poon Carrie , Kahl Anja , Resch Ulrike , Bhawal Ruchika , Benakis Corinne , Balachandran Vaishali , Zhang Sheng , Iadecola Costantino , Hochrainer Karin 
Published: August 2023

ABSTRACTUbiquitin modifications alter protein function and stability, thereby regulating cell homeostasis and viability, particularly under stress. Ischemic stroke induces protein ubiquitination at the ischemic periphery, wherein cells remain viable, however the identity of ubiquitinated proteins is unknown. Here, we employed a proteomics approach to identify these proteins in mice undergoing ischemic stroke. The data are available in a searchable web interface (https://hochrainerlab.shinyapps.io/StrokeUbiOmics/). We detected increased ubiquitination of 198 proteins, many of which localize to the postsynaptic density (PSD) of glutamatergic neurons. Among these were proteins essential for maintaining PSD architecture, such as PSD95, as well as NMDA and AMPA receptor subunits. The largest enzymatic group at the PSD with elevated post-ischemic ubiquitination were kinases, such as CaMKII, PKC, Cdk5, and Pyk2, whose aberrant activities are well-known to contribute to post-ischemic neuronal death. Concurrent phospho-proteomics revealed altered PSD-associated phosphorylation patterns, indicative of modified kinase activities following stroke. PSD-located CaMKII, PKC, and Cdk5 activities were decreased while Pyk2 activity was increased after stroke. Removal of ubiquitin restored kinase activities to pre-stroke levels, identifying ubiquitination as the responsible molecular mechanism for post-ischemic kinase regulation. These findings unveil a previously unrecognized role of ubiquitination in the regulation of essential kinases involved in ischemic injury.
Cortical representations of languages during natural dialogue
Authors: Yamashita Masahiro , Kubo Rieko , Nishimoto Shinji 
Published: August 2023

AbstractIndividuals integrate their own words, their partner’s words, and the context of dialogue into coherent meanings. Research suggests that mutual understanding between speakers and listeners is supported by a shared representation between language production and comprehension1,2. However, it remains unknown how languages are represented in the brain during dialogue, which is characterized by dynamic, adaptive behaviours such as turn-taking3,4. Here, we used functional magnetic resonance imaging (fMRI) to compare language production and comprehension maps obtained from natural dialogue in the same participants to show that separate representations exist for language production and comprehension. While production showed selectivity towards the motor system and comprehension towards the auditory system, both production and comprehension were represented in broadly distributed regions. These separate representations were similar in amodal brain regions that integrate semantic5,6and pragmatic information7,8, and provide a common ground for mutual understanding1,2, reflecting dynamic, complementary roles in interactive language use, including turn-taking3,4,9, backchannels10, and fillers11. Our findings suggest that separate and analogous linguistic representations for production and comprehension are interwoven in the same networks that underlie complementary interactions and making sense in dialogue.
Reverse engineering morphogenesis through Bayesian optimization of physics-based models
Authors: Kumar Nilay , Dowling Alexander , Zartman Jeremiah 
Published: August 2023

AbstractMorphogenetic programs direct the cell signaling and nonlinear mechanical interactions between multiple cell types and tissue layers to define organ shape and size. A key challenge for systems and synthetic biology is determining optimal combinations of intra- and inter-cellular interactions to predict an organ’s shape, size, and function. Physics-based mechanistic models that define the subcellular force distribution facilitate this, but it is extremely challenging to calibrate parameters in these models from data. To solve this inverse problem, we created a Bayesian optimization framework to determine the optimal cellular force distribution such that the predicted organ shapes match the desired organ shapes observed within the experimental imaging data. This integrative framework employs Gaussian Process Regression (GPR), a non-parametric kernel-based probabilistic machine learning modeling paradigm, to learn the mapping functions relating to the morphogenetic programs that generate and maintain the final organ shape. We calibrated and tested the method on cross-sections ofDrosophilawing imaginal discs, a highly informative model organ system, to study mechanisms that regulate epithelial processes that range from development to cancer. As a specific test case, the parameter estimation framework successfully infers the underlying changes in core parameters needed to match simulation data with time series imaging data of wing discs perturbed with collagenase. Unexpectedly, the framework also identifies multiple distinct parameter sets that generate shapes similar to wild-type organ shapes. This platform enables an efficient, global sensitivity analysis to support the necessity of both actomyosin contractility and basal ECM stiffness to generate and maintain the curved shape of the wing imaginal disc. The optimization framework, combined with fixed tissue imaging, identified that Piezo, a mechanosensitive ion channel, impacts fold formation by regulating the apical-basal balance of actomyosin contractility and elasticity of ECM. This framework is extensible toward reverse-engineering the morphogenesis of any organ system and can be utilized in real-time control of complex multicellular systems.
In-silicoanalysis reveals hub genes and enriched pathways in Type 2 Diabetes Mellitus
Authors: Gandham Prasad , Sharathchandra RG 
Published: August 2023

AbstractThe worldwide prevalence of diabetes mellitus poses a significant hazard to human health and a substantial economic burden for modern society. Multiple genes and gene-environment interactions make up the complicated genetic landscape of type 2 diabetes (T2D). The majority of genetic studies concentrated on separate genes, while some put an excessive amount of emphasis on SNPs. The objective of this work was to analyze all known T2D-associated genes in a collective manner in order to identify candidate genes and assess their possible functional role using bioinformatic tools. Interactome networks, enrichment clustering, hub genes, enriched biological pathways, and miRNAs targeting hub genes were analyzed. From the pool of 490 genes implicated in type 2 diabetes, the 25 most prominent hub genes were identified using measures of betweenness centrality and degree of each node. From the interactome analysis 8 different MCODE clusters was observed with a highest number of 63 genes in cluster one. GO analyses revealed that candidate genes were significantly enriched in glucose homeostasis, carbohydrate homeostasis, regulation of type B pancreatic cell apoptotic process, and regulation of hormone secretion biological process. Insulin resistance, PI3K-Akt signaling pathway, AMPK signaling pathway, Neuroactive ligand-receptor interaction, and Adipocytokine signaling pathway were among the notable enriched pathways. Subsequently we found 54 miRNAs targeting 25 hub genes out of which IRS1 and IGF1 hub genes were targeted by seven different miRNA. This study contributes to a thorough bioinformatics investigation of genes, functions, and pathways that are relevant to the etiology of T2DM and may be useful in the development of precision medicine-based treatments.
Thermoplasmonic modulation of cardiomyocytes activity with local temperature read-out
Authors: Guo Fanglei , Yu Wei , Deschaume Olivier , Jooken Stijn , Liu Liwang , Wei Qi , Thielemans Wim , Bartic Carmen 
Published: August 2023

ABSTRACTCardiomyocyte beating rate modulation is required in multiplein vitroassays and it is usually done by electrical or optogenetic methods. In this work, we develop and characterize a light-based strategy to modulate the cardiomyocyte beating rate by near-infrared (NIR) controlled plasmonic stimulation. For this purpose, gold nanorods (GNRs) acting as plasmonic heaters and silica-coated quantum dots (QDs) as nanothermometers are attached to surfaces used for cardiomyocyte cultures, while the cell electrophysiological activity is visualized by monitoring calcium transients via calcium imaging. This system is capable of modulating cardiac activity with near infrared-controllable plasmonic heating while measuring local temperature changes owing to the temperature-dependent fluorescence of silica-coated QDs.Table of Contents (TOC)
High-level prediction errors in low-level visual cortex
Authors: Richter David , Kietzmann Tim C , de Lange Floris P 
Published: August 2023

AbstractPerception and behaviour are significantly moulded by expectations derived from our prior knowledge. Hierarchical predictive processing theories provide a principled account of the neural mechanisms underpinning these processes, casting perception as a hierarchical inference process. While numerous studies have shown stronger neural activity for surprising inputs, in line with this account, it is unclear what predictions are made across the cortical hierarchy, and therefore what kind of surprise drives this upregulation of activity. Here we leveraged fMRI and visual dissimilarity metrics derived from a deep neural network to arbitrate between two hypotheses: prediction errors may signal a local mismatch between input and expectation at each level of the cortical hierarchy, or prediction errors may incorporate feedback signals and thereby inherit complex tuning properties from higher areas. Our results are in line with this second hypothesis. Prediction errors in both low- and high-level visual cortex primarily scaled with high-level, but not low-level, visual surprise. This scaling with high-level surprise in early visual cortex strongly diverges from feedforward tuning, indicating a shift induced by predictive contexts. Mechanistically, our results suggest that high-level predictions may help constrain perceptual interpretations in earlier areas thereby aiding perceptual inference. Combined, our results elucidate the feature tuning of visual prediction errors and bolster a core hypothesis of hierarchical predictive processing theories, that predictions are relayed top-down to facilitate perception.
Computational Insights into Colonic Motility: Mechanical Role of Mucus in Homeostasis and Inflammation
Authors: Erbay I.H. , Alexiadis A. , Rochev Y. 
Published: August 2023

AbstractColonic motility plays a vital role in maintaining proper digestive function. The rhythmic contractions and relaxations facilitate various types of motor functions that generate both propulsive and non-propulsive motility modes which in turn generate shear stresses on the epithelial surface. However, the interplay between colonic mucus, shear stress, and epithelium remains poorly characterized. Here, we present a colonic computational model that describes the potential roles of mucus and shear stress in both homeostasis and ulcerative colitis (UC). Our model integrates several key features, including the properties of the mucus bilayer and lumen contents, colonic pressure, and crypt characteristics to predict the time-space mosaic of shear stress. We show that the mucus thickness which could vary based on the severity of UC, may significantly reduce the amount of shear stress applied to the colonic crypts and effect colonic content velocity. Our model also reveals an important spatial shear stress variance in homeostatic colonic crypts that suggests shear stress may have a modulatory role in epithelial cell migration, differentiation, apoptosis, and immune surveillance. Together, our study uncovers the rather neglected roles of mucus and shear stress in intestinal cellular processes during homeostasis and inflammation.
Exploring the interaction of inhibitor ‘YM-1’ withPlasmodium falciparumHSP70s throughin silicomethods
Authors: Singh Bikramjit , Kaur Satinder , Nainani Chanchal , Sandhu Komalpreet Kaur , Upadhyay Vipul , Hora Rachna , Mishra Prakash Chandra 
Published: August 2023

AbstractYM-1 belongs to the rhodacyanine class of the 70kDa heat shock protein (Hsp70) inhibitors. It antagonizes nucleotide exchange factor (NEF) ‘BAG3’ to block the critical ATPase cycle of HSP70 chaperones thereby disabling them. The anti-cancer potential of this small molecule derivative of MKT-077 is attributed to its improved solubility and stability over its parent. In the current study, we have used bioinformatics tools including molecular docking to study the binding strength of YM-1 forPlasmodium falciparum(Pf) HSP70s. Of the four PfHSP70 homologs, the mitochondrial counterpart was predicted to bind most efficiently with YM-1 at a previously reported inhibitor binding site. The interaction of YM-1 with mitochondrial PfHSP70 was significantly better than with any of the other Pf homologs. Further analysis of this PfHSP70-YM-1 complex helped us to predict not just the types of interactions, but also specific residues of the protein involved in inhibitor engagement. Information reported in this article is important from the standpoint of design and development of newer rhodacyanine based drugs against malaria.
EZH2 specifically regulatesISL1during embryonic urinary tract formation
Authors: Mingardo Enrico , Kalanithy Jeshurun C. , Dworschak Gabriel , Ishorst Nina , Yilmaz Öznur , Lindenberg Tobias , Hollstein Ronja , Felger Tim , Angrand Pierre-Olivier , Reutter Heiko , Odermatt Benjamin 
Published: August 2023

AbstractIsl1has been described as an embryonic master control gene expressed in the pericloacal mesenchyme. Deletion ofIsl1from the genital mesenchyme in mice leads to an ectopic urethral opening and epispadias-like phenotype. Using genome wide association methods, we identifiedISL1as the key susceptibility gene for classic bladder exstrophy (CBE), comprising epispadias and exstrophy of the urinary bladder. The most significant marker (rs6874700) identified in our recent GWAS meta-analysis achieved apvalue of 1.48 × 10-24within theISL1region. In silico analysis of rs6874700 and all other genome-wide significant markers in Linkage Disequilibrium (LD) with rs6874700 (D’ = 1.0; R2> 0.90) revealed marker rs2303751 (pvalue 8.12 x 10-20) as the marker with the highest regulatory effect predicted. Here, we describe a novel 1.2 kb intragenic promoter residing between 6.2 and 7.4 kb downstream of theISL1transcription starting site, which is located in the reverse DNA strand and harbors a binding side for EZH2 at the exact region of marker rs2303751. We show, that EZH2 silencing in HEK cells reducesISL1expression. We show thatezh2-/-ko zebrafish larvae display tissues specificity of ISL1 regulation with reduced expression of Isl1 in the pronephric region of zebrafish larvae. In addition, a shorter and malformed nephric duct is observed inezh2-/-ko zebrafishTg(wt1ß:eGFP)reporter lines. Our study shows, that Ezh2 is a key regulator ofIsl1during urinary tract formation and suggests tissue specificISL1dysregulation as an underlying mechanism for CBE formation.
Brain asymmetries from mid- to late life and hemispheric brain age
Authors: Korbmacher Max , van der Meer Dennis , Beck Dani , de Lange Ann-Marie , Eikefjord Eli , Lundervold Arvid , Andreassen Ole A. , Westlye Lars T. , Maximov Ivan I. 
Published: August 2023

ABSTRACTThe human brain demonstrates structural and functional asymmetries which have implications for ageing and mental and neurological disease development. We used a set of magnetic resonance imaging (MRI) metrics derived from structural and diffusion MRI data inN=48,040 UK Biobank participants to evaluate age-related differences in brain asymmetry. Most regional grey and white matter metrics presented asymmetry, which were higher later in life. Informed by these results, we conductedhemispheric brain age(HBA) predictions from left/right multimodal MRI metrics. HBA was concordant to conventional brain age predictions, using metrics from both hemispheres, but offers a supplemental general marker of brain asymmetry when setting left/right HBA into relationship with each other. In contrast to WM brain asymmetries, left/right discrepancies in HBA are lower at higher ages. Our findings outline various sex-specific differences, particularly important for brain age estimates, and the value of further investigating the role of brain asymmetries in brain ageing and disease development.