bluuebunny/crossref_metadata_2025_split huggingface dataset:
Influence of Response Criterion on Nociceptive Detection Thresholds and Evoked Potentials
Authors: van den Berg Boudewijn , Vanwinsen L. , Pezzali G. , Buitenweg Jan R. 
Published: November 2021

AbstractPain scientists and clinicians search for objective measures of altered nociceptive processing to study and stratify chronic pain patients. Nociceptive processing can be studied by observing a combination of nociceptive detection thresholds and evoked potentials. However, it is unknown whether the nociceptive detection threshold measured using a Go-/No-Go (GN) procedure can be biased by a response criterion. In this study, we compared nociceptive detection thresholds, psychometric slopes and central evoked potentials obtained during a GN procedure with those obtained during a 2-interval forced choice (2IFC) procedure to determine 1) if the nociceptive detection threshold during a GN procedure is biased by a criterion and 2) to determine if nociceptive evoked potentials observed in response to stimuli around the detection threshold are biased by a criterion. We found that the detection threshold can be higher when assessed using a GN procedure in comparison with the 2IFC procedure. The average P2 component in the central evoked potential showed on-off behavior with respect to stimulus detection and increased proportionally with the detection probability during a GN procedure. These data suggest that nociceptive detection thresholds estimated using a GN procedure are subject to a response criterion.
Unbiased Proteomics, Histochemistry, and Mitochondrial DNA Copy Number Reveal Better Mitochondrial Health in Muscle of High Functioning Octogenarians
Authors: Ubaida-Mohien Ceereena , Spendiff Sally , Lyashkov Alexey , Moaddel Ruin , MacMillan Norah J. , Filion Marie-Eve , Morais Jose A. , Taivassalo Tanja , Ferrucci Luigi , Hepple Russell T. 
Published: November 2021

AbstractBackgroundMaster athletes prove that preserving a high level of physical function up to very late in life is possible, but the mechanisms responsible for their high function remain unclear.MethodsWe performed muscle biopsies in 15 octogenarian world class track and field masters athletes (MA) and 14 non-athlete age/sex-matched controls (NA) to provide insights into mechanisms for preserving function in advanced age. Muscle samples were assessed for respiratory compromised fibers, mtDNA copy number, and proteomics by liquid-chromatography mass spectrometry.ResultsMost of the ∼800 differentially represented proteins in MA versus NA pertained to mitochondria structure/function such as electron transport capacity (ETC), cristae formation, mitochondrial biogenesis, and mtDNA-encoded proteins. In contrast, proteins from the spliceosome complex and nuclear pore were downregulated in MA. Consistent with proteomics data, MA had fewer respiratory compromised fibers, higher mtDNA copy number, and an increased protein ratio of the cristae-bound ETC subunits relative to the outer mitochondrial membrane protein voltage dependent anion channel. There was a substantial overlap of proteins overrepresented in MA versus NA with proteins that decline with aging and which are higher in physically active than sedentary individuals. However, we also found 176 proteins related to mitochondria that are uniquely differentially expressed in MA.DiscussionWe conclude that high function in advanced age is associated with preserving mitochondrial structure/function proteins, with under-representation of proteins involved in the spliceosome and nuclear pore complex. Whereas many of these differences in MA appear related to their physical activity habits, others may reflect unique biological (e.g., gene, environment) mechanisms that preserve muscle integrity and function with aging.
Structure Determination of Inactive-State GPCRs with a Universal Nanobody
Authors: Robertson Michael J. , Papasergi-Scott Makaía , He Feng , Seven Alpay B. , Meyerowitz Justin G. , Panova Ouliana , Peroto Maria Claudia , Che Tao , Skiniotis Georgios 
Published: November 2021

SummaryCryogenic electron microscopy (cryo-EM) has widened the field of structure-based drug discovery by allowing for routine determination of membrane protein structures previously intractable. However, despite representing one of the largest classes of therapeutic targets, most inactive-state G protein-coupled receptors (GPCRs) have remained inaccessible for cryo-EM because their small size and membrane-embedded nature impedes projection alignment for high-resolution map reconstructions. Here we demonstrate that the same single-chain camelid antibody (nanobody) recognizing a grafted intracellular loop can be used to obtain cryo-EM structures of different inactive-state GPCRs at resolutions comparable or better than those obtained by X-ray crystallography. Using this approach, we obtained the structure of human neurotensin 1 receptor (NTSR1) bound to antagonist SR48692, of µ-opioid receptor (MOR) bound to the clinical antagonist alvimopan, as well as the structures of the previously uncharacterized somatostatin receptor 2 (SSTR2) in the apo state and histamine receptor 2 (H2R) bound to the H2 blocker famotidine. Each of these structures yields novel insights into ligand binding and specificity. We expect this rapid, straightforward approach to facilitate the broad structural exploration of GPCR inactive states without the need for extensive engineering and crystallization.
Wound-like tumor periphery in human breast cancer predicts a convergent drug nonresponse
Authors: Li Lianhuang , Liao Xiaoxia , Fu Fangmeng , Xi Gangqin , Kang Deyong , He Jiajia , Guo Wenhui , Qiu Lida , Han Zhonghua , Wang Xingfu , Zhan Qingyuan , You Sixian , Chen Jianxin , Wang Chuan , Boppart Stephen A. , Tu Haohua 
Published: November 2021

AbstractA significant portion of breast cancer patients are nonresponsive to well-established drugs and destined for a poor outcome regardless of molecular subtype. Although several (multiparameter) molecular markers have predicted their resistance to some of these drugs, profound uniparameter markers predictive of a convergent nonresponse to all these drugs remain elusive. We employ co-registered standard-multiphoton histology to representatively sample a few peripheral niches of the primary tumor, so that hundreds of patients can be stratified with either a wound-like or non-wound tumor periphery. With no fitting variable, this simple uniparameter morphological marker is: (a) highly sensitive and specific to predict a multidrug-nonresponsive phenotype that accounts for the majority of recurrence or death, independent of the molecular subtype or related adjuvant drug selection, clinical endpoint (disease-free versus overall survival), and hosting medical center; (b) robust against intratumor heterogeneity and valid at the earliest clinicopathological stage; and (c) dominant in predicting prognosis in the context of routine clinicopathological markers. Considering the mechanistic link between a wound-like extracellular matrix and a microenvironment supporting migratory or mesenchymal tumor cells, we attribute these unusual capabilities to an epithelial-mesenchymal transition nature of the morphological marker long sought after by pathologists.
A multivariate to multivariate approach for voxel-wise genome-wide association analysis
Authors: Wu Qiong , Zhang Yuan , Huang Xiaoqi , Ma Tianzhou , Hong L. Elliot , Kochunov Peter , Chen Shuo 
Published: November 2021

AbstractThe joint analysis of imaging-genetics data facilitates the systematic investigation of genetic effects on brain structures and functions with spatial specificity. We focus on voxel-wise genome-wide association analysis, which may involve trillions of single nucleotide polymorphism (SNP)-voxel pairs. We attempt to identify underlying organized association patterns of SNP-voxel pairs and understand the polygenic and pleiotropic networks on brain imaging traits. We propose a bi-clique graph structure (i.e., a set of SNPs highly correlated with a cluster of voxels) for the systematic association pattern. Next, we develop computational strategies to detect latent SNP-voxel bi-cliques and inference model for statistical testing. We further provide theoretical results to guarantee the accuracy of our computational algorithms and statistical inference. We validate our method by extensive simulation studies, and then apply it to the whole genome genetic and voxel-level white matter integrity data collected from 1052 participants of the human connectome project (HCP). The results demonstrate multiple genetic loci influencing white matter integrity measures on splenium and genu of the corpus callosum.
SPCS: A Spatial and Pattern Combined Smoothing Method for Spatial Transcriptomic Expression
Authors: Liu Yusong , Wang Tongxin , Duggan Ben , Sharpnack Michael , Huang Kun , Zhang Jie , Ye Xiufen , Johnson Travis S. 
Published: November 2021

AbstractHigh dimensional, localized RNA sequencing is now possible owing to recent developments in spatial transcriptomics (ST). ST is based on highly multiplexed sequence analysis and uses barcodes to match the sequenced reads to their respective tissue locations. ST expression data suffers from high noise and drop-out events; however, smoothing techniques have the promise to improve the data interpretability prior to performing downstream analyses. Single cell RNA sequencing (scRNA-seq) data similarly suffer from these limitations, and smoothing methods developed for scRNA-seq can only utilize associations in transcriptome space (also known as one-factor smoothing methods). Since they do not account for spatial relationships, these one-factor smoothing methods cannot take full advantage ST data. In this study, we present a novel two-factor smoothing technique, Spatial and Pattern Combined Smoothing (SPCS), that employs k-nearest neighbor technique to utilize information from transcriptome and spatial relationships. By performing SPCS on multiple ST slides from pancreatic ductal adenocarcinoma (PDAC), dorsolateral prefrontal cortex (DLPFC), and simulated high-grade serous ovarian cancer (HGSOC) datasets, smoothed ST slides have better separability, partition accuracy, and biological interpretability than the ones smoothed by pre-existing one-factor methods. Source code of SPCS is provided in Github (https://github.com/Usos/SPCS).
Whole-Blood DNA Methylation Analysis Reveals Respiratory Environmental Traits Involved in COVID-19 Severity Following SARS-CoV-2 Infection
Authors: Barturen Guillermo , Carnero-Montoro Elena , Martínez-Bueno Manuel , Rojo-Rello Silvia , Sobrino Beatriz , Alcántara-Domínguez Clara , Bernardo David , Alarcón-Riquelme Marta E. 
Published: November 2021

AbstractSARS-CoV-2 causes a severe inflammatory syndrome (COVID-19) leading, in many cases, to bilateral pneumonia, severe dyspnea and in ∼5% of these, death. DNA methylation is known to play an important role in the regulation of the immune processes behind COVID-19 progression, however it has not been studied in depth, yet. In this study, we aim to evaluate the implication of DNA methylation in COVID-19 progression by means of a genome-wide DNA methylation analysis combined with DNA genotyping.The results reveal the existence of epigenomic regulation of functional pathways associated with COVID-19 progression and mediated by genetic loci. We found an environmental trait-related signature that discriminates mild from severe cases, and regulates IL-6 expression via the transcription factor CEBP. The analyses suggest that an interaction between environmental contribution, genetics and epigenetics might be playing a role in triggering the cytokine storm described in the most severe cases.
Exploring new EEG-parameters in electroconvulsive therapy
Authors: Schreiner J , Kessler U , Oedegaard KJ , Mardal KA , Oltedal L 
Published: November 2021

AbstractBackgroundElectroconvulsive therapy (ECT) is an effective treatment against severe depressive episodes, which has been shown to induce volume changes in the hippocampus. The power spectrum of the electroencephalogram (EEG) follows a characteristic power-law relation but its utility as a metric of ECT-induced seizures has not been explored.ObjectiveThis study aims to evaluate a novel metric based on the power spectrum of the EEG recordings from ECT-induced seizures; its association to volume changes in the hippocampus following ECT and improvement in depression rating scores.MethodsDepressed patients treated with ECT underwent brain MRI before- and after treatment and the EEG from each seizure was recorded (N=29). Hippocampal volume changes and EEG parameters were recorded in addition to clinician-rated and self-reported measures of depressive symptoms. The slope of the power-law in the power spectral density of the EEG was calculated. Multivariate linear models relating seizure parameters to volume change or clinical outcome was systematically and successively simplified. The best models were selected according to Akaike’s information criterion.ResultsThe slope of the power-law was steeper in the right than the left hemisphere (p < 0.001). EEG measures were included in the best models of volume change for both hippocampi as well as in the models explaining clinical outcome (p = 0.014, p = 0.004).ConclusionsA novel EEG measures was explored and contributed in models explaining the variation in volume change in the hippocampus and in clinical outcome following ECT.
A brain structural connectivity biomarker for diagnosis of autism spectrum disorder in early childhood
Authors: Jiang Xi , Shou Xiao-Jing , Zhao Zhongbo , Meng Fanchao , Le Jiao , Song Tianjia , Xu Xinjie , Ke Xiaoyan , Chen Yuzhong , Cai Xiaoe , Zhao Weihua , Kou Juan , Huo Ran , Liu Ying , Yuan Huishu , Xing Yan , Han Jisheng , Han Songping , Li Yun , Lai Hua , Zhang Lan , Jia Meixiang , Liu Jing , Kendrick Keith M. , Zhang Rong 
Published: November 2021

AbstractObjectiveAutism spectrum disorder (ASD) is associated with altered brain development, but it is unclear which specific structural changes may serve as potential diagnostic markers. This study aimed to identify and model brain-wide differences in structural connectivity using MRI diffusion tensor imaging (DTI) in young ASD and typically developing (TD) children (3·5-6 years old).MethodsNinety-three ASD and 26 TD children were included in a discovery dataset and 12 ASD and 9 TD children from different sites included as independent validation datasets. Brain-wide (294 regions) structural connectivity was measured using DTI (fractional anisotropy, FA) under sedation together with symptom severity and behavioral and cognitive development. A connection matrix was constructed for each child for comparisons between ASD and TD groups. Pattern classification was performed and the resulting model tested on two independent datasets.ResultsThirty-three structural connections showed increased FA in ASD compared to TD children and associated with both symptom severity and general cognitive development. The majority (29/33) involved the frontal lobe and comprised five different networks with functional relevance to default mode, motor control, social recognition, language and reward. Overall, classification accuracy is very high in the discovery dataset 96.77%, and 91·67% and 88·89% in the two independent validation datasets.ConclusionsIdentified structural connectivity differences primarily involving the frontal cortex can very accurately distinguish individual ASD from TD children and may therefore represent a robust early brain biomarker.
Obesity and accelerated epigenetic aging in a high-risk cohort of children
Authors: Etzel Laura , Hastings Waylon J. , Hall Molly A. , Heim Christine , Meaney Michael J. , Noll Jennie G. , O’Donnell Kieran J. , Pokhvisneva Irina , Rose Emma Jane , Schreier Hannah M. C. , Shenk Chad , Shalev Idan 
Published: November 2021

AbstractBackgroundNew insights into mechanisms linking obesity to poor health outcomes suggest a role for cellular aging pathways, casting obesity as a disease of accelerated biological aging. Although obesity has been linked to accelerated epigenetic aging in middle-aged adults, the impact during childhood remains unclear. We tested the association between body mass index (BMI) and accelerated epigenetic aging in a cohort of high-risk children. Participants were children (N=273, aged 8 to 14 years, 82% investigated for maltreatment) recruited to the Child Health Study, an ongoing prospective study of youth investigated for maltreatment and a comparison youth. BMI was measured as a continuous variable. Accelerated epigenetic aging of blood leukocytes was defined as the age-adjusted residuals of several established epigenetic aging clocks (Horvath, Hannum, GrimAge, PhenoAge) along with a newer algorithm, the DunedinPoAm, developed to quantify the pace-of-aging. Hypotheses were tested with generalized linear models.ResultsHigher BMI was significantly correlated with older chronological age, maltreatment status, household income, blood cell counts, and three of the accelerated epigenetic aging measures: GrimAge (r=0.29,P<.0001), PhenoAge (r=0.25,P<.0001), and DunedinPoAm (r=0.37,P<.0001). In fully adjusted models, GrimAge (b=.06;P=.007) and DunedinPoAm (b=.0017;P<.0001) remained significantly associated with higher BMI. Maltreatment-status was not independently associated with accelerated epigenetic aging after accounting for other factors.ConclusionIn a high-risk cohort of children, higher BMI predicted epigenetic aging as assessed by two epigenetic aging clocks. These results suggest the association between obesity and accelerated epigenetic aging begins in early life, with implications for future morbidity and mortality risk.
Investigating the relationship between interventions, contact patterns, and SARS-CoV-2 transmissibility
Authors: Trentini Filippo , Manna Adriana , Balbo Nicoletta , Marziano Valentina , Guzzetta Giorgio , Merler Stefano , Ajelli Marco , Poletti Piero , Melegaro Alessia 
Published: November 2021

ABSTRACTBackgroundAfter a rapid upsurge of COVID-19 cases in Italy during the fall of 2020, the government introduced a three-tiered restriction system aimed at increasing physical distancing. The Ministry of Health, after periodic epidemiological risk assessments, assigned a tier to each of the 21 Italian regions and autonomous provinces (AP). It is still unclear to what extent these different measures altered mixing patterns and how quickly the population adapted their social interactions to continuous changes in restrictions.Methods and findingsWe conducted a survey between July 2020 and March 2021 to monitor changes in social contact patterns among individuals in the metropolitan city of Milan, Italy, which was hardly hit by the second wave of COVID-19 pandemic. The number of contacts during periods characterized by different levels of restrictions was analyzed through negative binomial regression models and age-specific contact matrices were estimated under the different tiers. Relying on the empirically estimated mixing patterns, we quantified relative changes in SARS-CoV-2 transmission potential associated with the different tiers.As tighter restrictions were implemented during the fall of 2020, a progressive reduction in the mean number of contacts recorded by study participants was observed: from 16.4% under mild restrictions (yellow tier), to 45.6% under strong restrictions (red tier). Higher restrictions levels were also found to increase the relative contribution of contacts occurring within the household. The SARS-CoV-2 reproduction number was estimated to decrease by 18.7% (95%CI: 4.6-30.8), 33.4% (95%CI: 22.7-43.2), and 50.2% (95%CI: 40.9-57.7) under the yellow, orange, and red tiers, respectively.ConclusionsOur results give an important quantification of the expected contribution of different restriction levels in shaping social contacts and decreasing the transmission potential of SARS-CoV-2. These estimates can find an operational use in anticipating the effect that the implementation of these tiered restriction can have on SARS-CoV-2 reproduction number under an evolving epidemiological situation.
Emergent dynamics of a three-node regulatory network explain phenotypic switching and heterogeneity: a case study of Th1/Th2/Th17 cell differentiation
Authors: Duddu Atchuta Srinivas , Majumdar Sauma Suvra , Sahoo Sarthak , Jhunjhunwala Siddharth , Jolly Mohit Kumar 
Published: November 2021

AbstractNaïve helper (CD4+) T-cells can differentiate into distinct functional subsets including Th1, Th2, and Th17 phenotypes. Each of these phenotypes has a ‘master regulator’ – T-bet (Th1), GATA3 (Th2) and RORγT (Th17) – that inhibits the other two master regulators. Such mutual repression among them at a transcriptional level can enable multistability, giving rise to six experimentally observed phenotypes – Th1, Th2, Th17, hybrid Th/Th2, hybrid Th2/Th17 and hybrid Th1/Th17. However, the dynamics of switching among these phenotypes, particularly in the case of epigenetic influence, remains unclear. Here, through mathematical modeling, we investigated the coupled transcription-epigenetic dynamics in a three-node mutually repressing network to elucidate how epigenetic changes mediated by any ‘master regulator’ can influence the transition rates among different cellular phenotypes. We show that the degree of plasticity exhibited by one phenotype depends on relative strength and duration of mutual epigenetic repression mediated among the master regulators in a three-node network. Further, our model predictions can offer putative mechanisms underlying relatively higher plasticity of Th17 phenotype as observedin vitroandin vivo. Together, our modeling framework characterizes phenotypic plasticity and heterogeneity as an outcome of emergent dynamics of a three-node regulatory network, such as the one mediated by T-bet/GATA3/RORγT.
CryoEM of endogenous mammalian V-ATPase interacting with the TLDc protein mEAK-7
Authors: Tan Yong Zi , Abbas Yazan M. , Wu Jing Ze , Wu Di , Hesketh Geoffrey G. , Bueler Stephanie A. , Gingras Anne-Claude , Robinson Carol V. , Grinstein Sergio , Rubinstein John L. 
Published: November 2021

AbstractV-ATPases are rotary proton pumps that serve as signaling hubs with numerous proposed binding partners in cells. We used cryoEM combined with exhaustive focused classification to detect endogenous proteins that associate with V-ATPase from porcine kidney. A super-stoichiometric copy of subunit C was found in ~3% of complexes, while an additional ~1.6% of complexes bound mEAK-7, a protein with proposed roles in dauer formation in nematodes and mTOR signaling in mammals. High-resolution cryoEM of porcine kidney V-ATPase with recombinant mEAK-7 shows that mEAK-7’s TLDc domain interacts with V-ATPase’s stator while its C-terminal α helix binds V-ATPase’s rotor. This crosslink would be expected to inhibit rotary catalysis. However, unlike inhibition of yeast V-ATPase by the TLDc protein Oxr1p, exogenous mEAK-7 does not inhibit V-ATPase and mEAK-7 overexpression in cells does not alter lysosomal or phagosomal pH. Instead, cryoEM suggests that interaction of mEAK-7 with V-ATPase is disrupted by ATP-induced rotation of the rotor. Comparison of Oxr1p and mEAK-7 binding explains this difference. Together, these results show that differences in V-ATPase binding by TLDc domain-containing proteins can lead to effects ranging from strong inhibition to formation of labile interactions that are sensitive to the enzyme’s activity.