bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ventral pallidum GABA neurons bidirectionally control opioid relapse across rat behavioral models
Authors: Farrell Mitchell R. , Ye Qiying , Xie Yiyan , Esteban Jeanine Sandra D. , Mahler Stephen V. 
Published: February 2022

AbstractOpioid addiction is a chronic, relapsing disorder. Whether addicted individuals are forced to abstain or they decide themselves to quit using drugs, relapse rates are high—especially upon encountering contexts and stimuli associated with prior opioid use. Rodents similarly show context- and cue-induced reinstatement of drug seeking following abstinence, and intriguingly, the neural circuits underlying these relapse-like behaviors differ when abstinence is involuntarily imposed, versus when animals decide themselves to cease taking drug. Here, we employ two complementary rat behavioral models of relapse-like behavior for the highly reinforcing opioid drug remifentanil, and asked whether GABAergic neurons in the ventral pallidum (VPGABA) control opioid seeking under these behavioral conditions. Specifically, we asked how chemogenetically stimulating VPGABA neurons with clozapine-N-oxide (CNO) influences the ability of contextual or discrete remifentanil-paired cues to reinstate drug seeking following either voluntary (punishment-induced; GroupPunish), or experimenter-imposed (extinction training; GroupExt) abstinence. In GroupPunish rats, we also chemogenetically inhibited VPGABA neurons, and examined spontaneous VP activity (Fos) during cued-reinstatement. In both GroupPunish and GroupExt rats, stimulating Gq-signaling in VPGABA neurons augmented remifentanil reinstatement in a cue- and context-dependent manner. Conversely, engaging inhibitory Gi-signaling in VPGABA neurons in GroupPunish suppressed cue-induced reinstatement, and additionally cue-triggered seeking was correlated with Fos in rostral, but not caudal VP. In contrast, neither stimulating nor inhibiting VPGABA neurons influenced unpunished remifentanil self-administration. We conclude that VPGABA neurons bidirectionally control opioid seeking regardless of the specific relapse model employed, highlighting their fundamental role in opioid relapse-like behavior across behavioral models, and potentially across species.HighlightsWe acutely inhibit or stimulate VP GABA neurons during opioid seekingVP GABA neurons mediate relapse-like behavior across behavioral modelsBehavioral context impacts DREADD stimulation of behavior, not VP activityRostral, not caudal VP Fos correlates with opioid reinstatement
Analysis of altered pre-mRNA splicing patterns caused by a mutation in the RNA binding protein hnRNPA1 linked to amyotrophic lateral sclerosis
Authors: Lee Yeon J. , Rio Donald C. 
Published: February 2022

AbstractAmyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disease characterized by loss of motor neurons. Human genetic studies have linked mutations in RNA binding proteins as causative for this disease. The hnRNPA1 protein, a known pre-mRNA splicing factor, is mutated in a number of ALS patients. Here, we generate two cell models to investigate how a mutation in the C-terminal low complexity domain of hnRNPA1 affects global pre-mRNA splicing patterns and RNA binding. We show that a single amino acid change in the C-terminal low complexity domain (D262V) leads to changes in splicing of thousands of transcripts whose genes are linked to the DNA damage response, cilia organization and translation. We also show that there are changes in RNA binding of the mutant hnRNPA1 protein to transcripts whose splicing patterns change. Finally, we show that cells expressing the hnRNPA1 D262V mutation exhibit an aggregation phenotype, markedly reduced growth rates and changes in stress granules. This study shows that global changes in pre-mRNA splicing patterns caused by a single mutation in the hnRNPA1 protein lead to phenotypes related to ALS and that specific cellular pathways are affected.
Towards Effective and Generalizable Fine-tuning for Pre-trained Molecular Graph Models
Authors: Xia Jun , Zheng Jiangbin , Tan Cheng , Wang Ge , Li Stan Z. 
Published: February 2022

AbstractGraph Neural Networks (GNNs) and Transformer have emerged as dominant tools for AI-driven drug discovery. Many state-of-the-art methods first pre-train GNNs or the hybrid of GNNs and Transformer on a large molecular database and then fine-tune on downstream tasks. However, different from other domains such as computer vision (CV) or natural language processing (NLP), getting labels for molecular data of downstream tasks often requires resource-intensive wet-lab experiments. Besides, the pre-trained models are often of extremely high complexity with huge parameters. These often cause the fine-tuned model to over-fit the training data of downstream tasks and significantly deteriorate the performance. To alleviate these critical yet under-explored issues, we propose two straightforward yet effective strategies to attain better generalization performance: 1. MolAug, which enriches the molecular datasets of down-stream tasks with chemical homologies and enantiomers; 2. WordReg, which controls the complexity of the pre-trained models with a smoothness-inducing regularization built on dropout. Extensive experiments demonstrate that our proposed strategies achieve notable and consistent improvements over vanilla fine-tuning and yield multiple state-of-the-art results. Also, these strategies are model-agnostic and readily pluggable into fine-tuning of various pre-trained molecular graph models. We will release the code and the fine-tuned models.
CDMAP/CDVIS: Context-dependent Mutation Analysis Package and Visualization Software
Authors: Patton David L. , Cardenas Thomas , Mele Perrin , Navarro Jon , Sung Way 
Published: February 2022

AbstractThe Context-dependent Mutation Analysis Package and Visualization Software (CDMAP/CDVIS) is an automated, modular toolkit used for analysis and visualization of context-dependent mutation patterns (site-specific variation in mutation rate from neighboring-nucleotide effects). The CDMAP algorithm calculates context-dependent mutation rates in chromosomes or replichores, and can generate high-resolution figures to analyze variation in mutation rate across spatiotemporal scales. Output from CDMAP can be integrated into CDVIS, an interactive database for visualizing mutation patterns across multiple taxa simultaneously.
Circulatory exosomes from COVID-19 patients trigger NLRP3 inflammasome in endothelial cells
Authors: Sur Subhayan , Steele Robert , Isbell T. Scott , Ray Ranjit , Ray Ratna B. 
Published: February 2022

AbstractSARS-CoV-2 infection induces inflammatory response, cytokine storm, venous thromboembolism, coagulopathy, and multiple organ damage. Resting endothelial cells prevent coagulation, control blood flow and inhibit inflammation. However, it remains unknown how SARS-CoV-2 induces strong molecular signals in distant cells for immunopathogenesis. In this study, we examined the consequence of human endothelial cells (microvascular endothelial cells (HMEC-1) and liver endothelial cells (TMNK-1)) to exosomes from plasma of severe COVID-19 patients. We observed a significant induction of NLRP3, caspase-1 and IL-1β mRNA expression in the endothelial cells following exposure to exosomes from plasma of COVID-19 patients as compared to that of healthy donors. Activation of caspase-1 was noted in the endothelial cell culture medium following exposure to the COVID-19 exosomes. Further, COVID-19 exosomes significantly induced mature IL-1β secretion in the endothelial cell culture medium. Thus, our results demonstrated for the first time that exosomes from COVID-19 plasma trigger NLRP3 inflammasome in endothelial cells of distant organs.
A PRACTICAL MODEL FOR EARLY IDENTIFICATION OF PROSPECTIVE HIGH NEED HIGH COST PATIENTS
Authors: Cohen Avivit Golan , Vinker Shlomo , Isaacson Adi , Avramovich Eva , Merzon Eugene 
Published: February 2022

ABSTRACTBackgroundHigh Need-High Cost (HNHC) patients are those who experience poor health outcomes and high health care costs. Early identification may improve outcomes and lower costs.AimDevelopment of a model using retrospective data to identify patients at risk for becoming HNHC patients, in order to efficaciously plan interventions.MethodsData from a large Israeli Health Maintenance Organization (HMO) that includes 488,615 clients above the age of 21 were examined. Multivariate linear regression models were developed using 2012–2016 health expenditure as a dependent variable.ResultsThe number of yearly purchases of medications for chronic disorders, yearly outpatient visits, yearly emergency department and hospital admissions and the last measured HgA1c level were highly predictive of increased expenditure over a five-year period. Each of these indicators has a different coefficient of influence.ConclusionsWe developed a predictive model, based on easily obtained data from electronic medical records that enabled us to identify a population at risk for becoming HNHC in the next five years, a time window allows for intervention. Further research is needed to evaluate whether this is an early enough stage to implement pro-active intervention in the primary care setting.Trial registrationretrospectively registered.HIGHLIGHTSIn this study, we developed a numerical point system calculator, to indicate a risk score for health deterioration within 5 years of patients, by using numerical indicators existing in standard EMR data.The indicators introduced into this calculated risk can guide healthcare providers to the needed areas of intervention. The display of indicators also promotes optimization of care management and continuity of care.This risk score is expected to focus the attention of primary care teams on the population that will benefit most from it, as well as to evaluate the effectiveness of specific interventions.
Emulation of a target trial from observational data to compare effectiveness of Casirivimab/Imdevimab and Bamlanivimab/Etesevimab for early treatment of non-hospitalized patients with COVID-19
Authors: Mazzotta V , Cozzi Lepri A , Colavita F , Lanini S , Rosati R , Lalle E , Mastrorosa I , Cimaglia C , Vergori A , Bevilacqua Nazario , Daniele Lapa , Andrea Mariano , Bettini Aurora , Agrati C , Piselli P , Girardi E , Castilletti C , Garbuglia AR , Vaia F , Nicastri E , Antinori A 
Published: February 2022

AbstractObjectivesComparative analysis between different monoclonal antibodies (mAbs) against SARS-CoV-2 are lacking. We present an emulation trial from observational data to compare effectiveness of Bamlanivimab/Etesevimab (BAM/ETE) and Casirivimab/Imdevimab (CAS/IMD) in outpatients with early mild-to-moderate COVID-19 in a real-world scenario of variants of concern (VoCs) from Alpha to Delta.MethodsAllocation to treatment was subject to mAbs availability, and the measured factors were not used to determine which combination to use. Patients were followed through day 30. Viral load was measured by cycle threshold (CT) on D1 (baseline) and D7.Primary outcome was time to COVID-19-related hospitalization or death from any cause over days 0-30. Weighted pooled logistic regression and marginal structural Cox model by inverse probability weights were used to compare BAM/ETE vs. CAS/IMD. ANCOVA was used to compare mean D7 CT values by intervention. Models were adjusted for calendar month, MASS score and VoCs. We evaluated effect measure modification by VoCs, vaccination, D1 CT levels and enrolment period.ResultsCOVID19-related hospitalization or death from any cause occurred in 15 of 237 patients in the BAM/ETE group (6.3%) and in 4 of 196 patients in the CAS/IMD group (2.0%) (relative risk reduction [1 minus the relative risk] 72%; p=0.024). Subset analysis carried no evidence that the effect of the intervention was different across stratification factors. There was no evidence in viral load reduction from baseline through day 7 across the two groups (+0.17, 95% −1.41;+1.74, p=0.83). Among patients who experienced primary outcome, none showed a negative RT-PCR test in nasopharingeal swab (p=0.009) and 82.4% showed still high viral load (p<0.001) on D7.ConclusionsIn a pre-Omicron epidemiologic scenario, CAS/IMD reduced risk of clinical progression of COVID-19 compared to BAM/ETE. This effect was not associated with a concomitant difference in virological response.
The Relevance of Lactate Levels in Acute Seizure
Authors: Sop Jessica , Rogers Jessica , Opara Nnennaya , Tager Alfred , Dean Scott , Gustafson Mark L 
Published: February 2022

IntroductionSeizures can result in profound elevations of serum lactate. A paucity of investigation into whether lactate levels in these patients is associated with increased mortality. We sought to evaluate the significance in patients presenting with a seizure and elevated lactate.MethodsThis is a retrospective study involving patients presenting to the Emergency Department (ED) with a diagnosis of seizure from September 1st, 2016 until March 31st, 2018. Those with normal serum lactate (< 2mmol/L) were compared with patients that had an elevated serum lactate (≥ 2mmol/L).ResultsPatients with normal serum lactate levels had a significantly longer length of stay in the ED (60 minutes p = 0.04) when compared to those with elevated serum lactate levels. Additionally, a higher percentage of patients with elevated serum lactate received intravenous fluids in the ED (54.69% vs. 35.4%, P=0.01). There was no significant difference in other measured variables.ConclusionThis study illustrates that serum lactate levels do not directly correlate with indicators of disease severity or outcomes when elevated secondary to seizure. However, patients with normal serum lactate levels had a longer length of stay in the ED.
Optimal Deployment of Automated External Defibrillators in a Long and Narrow Environment
Authors: Lin Chih-Hao , Chu Kuan-Chao , Lee Jung-Ting , Kao Chung-Yao 
Published: February 2022

AbstractAim of the studyPublic access to automated external defibrillators (AEDs) plays a key role in increasing survival outcomes for patients with out-of-hospital cardiac arrest. Based on the concept of maximizing “rescue benefit” of AEDs, we aimed to develop strategies for optimal deployment of AEDs for long and narrow spaces.MethodsWe classified the effective coverage of an AED in hot, warm, and cold zones. The AEDs were categorized, according to their accessibility, as fixed, summonable, or patrolling types. The overall rescue benefit of the AEDs were evaluated by the weighted size of their collective hot zones. The optimal strategies for the deployment of AEDs were derived mathematically and numerically verified by computer programs.ResultsTo maximize the overall rescue benefit of the AEDs, the AEDs should avoid overlapping with each other’s coverage as much as possible. Specific rules for optimally deploying one, two, or multiple AEDs, and various types of AEDs are summarized and presented.ConclusionA methodology for assessing the rescue benefit of deployed AEDs was proposed, and deployment strategies for maximizing the rescue benefit of AEDs along a long, narrow, corridor-like, finite space were derived. The strategies are simple and readily implementable. Our methodology can be easily generalized to search for optimal deployment of AEDs in planar areas or three-dimensional spaces.
Polycomb-mediated repression of paternal chromosomes maintains haploid dosage in diploid embryos of Marchantia
Authors: Montgomery Sean A. , Hisanaga Tetsuya , Wang Nan , Axelsson Elin , Akimcheva Svetlana , Sramek Milos , Liu Chang , Berger Frédéric 
Published: February 2022

AbstractComplex mechanisms regulate gene dosage throughout eukaryotic life cycles. Mechanisms controlling gene dosage have been extensively studied in animals, however it is unknown how generalizable these mechanisms are to diverse eukaryotes. Here, we use the haploid plant Marchantia polymorpha to assess gene dosage control in its short-lived diploid embryo. We show that throughout embryogenesis, paternal chromosomes are repressed resulting in functional haploidy. The paternal genome is targeted for genomic imprinting by the Polycomb mark H3K27me3 starting at fertilization, rendering the maternal genome in control of embryogenesis. Maintaining haploid gene dosage by this new form of imprinting is essential for embryonic development. Our findings illustrate how haploid-dominant species can regulate gene dosage through paternal chromosome inactivation and initiates the exploration of the link between life cycle history and gene dosage in a broader range of organisms.
Quantitative modeling of pentose phosphate pathway response to oxidative stress reveals a cooperative regulatory strategy
Authors: Hurbain Julien , Thommen Quentin , Anquez Francois , Pfeuty Benjamin 
Published: February 2022

AbstractLiving cells use signaling and regulatory mechanisms to adapt to environmental stresses. In the case of oxidative stress due for instance to hydrogen peroxide exposure, the adaptation response relies on co-regulation of enzymes in both glycolysis and pentose phosphate pathways (PPP), so as to support PPP-dependentNADPHand redox homeostasis. To understand the regulatory logic underlying early oxidative stress response, available metabolomics and13C fluxomics dataset are used to infer a probabilistic ensemble of kinetic models. Model ensemble properties of parameter distributions, transient dynamics, dose-response curves and loss-of-function phenotypes all highlights significant and cooperative effects of allosteric regulations of G6PD, PGI and GAPD in early oxidative response. Indeed, efficient flux rerouting into PPP is shown to require dose-dependent coordination between upregulated G6PD enzyme and increased G6P metabolite, the latter requiring fine-tuned inhibition of upper and lower glycolytic enzymes. This set of allosteric regulation also combines negative and positive feedback loops in a subtle manner prone to generate paradoxical perturbation phenotypes for instance related to 6PGD modulation.
Mechanical control of the mammalian circadian clock via YAP/TAZ and TEAD
Authors: Abenza Juan F. , Rossetti Leone , Mouelhi Malèke , Burgués Javier , Andreu Ion , Kennedy Keith , Roca-Cusachs Pere , Marco Santiago , García-Ojalvo Jordi , Trepat Xavier 
Published: February 2022

SummaryCircadian rhythms are a key survival mechanism that dictates biological activity according to the day-night cycle. In animals, cell-autonomous circadian clocks can be found in nearly every cell type and are subjected to multi-layered regulation. Although these peripheral clocks are remotely controlled by the master clock in the brain, they are also sensitive to their immediate mechano-chemical microenvironment. Whereas the mechanisms by which biochemical signalling controls the circadian clock at the single cell level are increasingly well understood, mechanisms underlying regulation by mechanical cues are still unknown. Here we show that the circadian clock in fibroblasts is regulated mechanically through YAP/TAZ and TEAD. We use high-throughput analysis of single-cell circadian rhythms and apply controlled mechanical, biochemical, and genetic perturbations to study the expression of the clock gene Rev-erbα. We observe that Rev-erbα circadian oscillations are disrupted concomitantly with the translocation of YAP/TAZ to the nucleus. By targeted mutations and tuning expression levels of YAP we identify TEAD as the transcriptional effector of this mechanosensitive regulatory pathway. Our findings establish a mechanism that links cell mechanobiology and the circadian clock, which could contribute to explain the circadian impairment observed in cancer and ageing, where the regulation of the mechanical environment and YAP/TAZ is lost.
ZNF598 responds to mitochondrial stress to abort stalled translation on mitochondrial outer membrane and maintain tissue homeostasis
Authors: Geng Ji , Li Yu , Wu Zhihao , Ohja Rani , Li Shuangxi , Lu Bingwei 
Published: February 2022

AbstractTranslational control exerts immediate effect on the composition, abundance, and integrity of the proteome. Ribosome-associated quality control (RQC) handles ribosomes stalled at the elongation and termination steps of translation, with ZNF598 in mammals and Hel2 in yeast serving as key sensors of translation stalling and coordinators of downstream resolution of collided ribosomes, termination of stalled translation, and removal of faulty translation products. The physiological regulation of RQC in general and ZNF598 in particular in multicellular settings is underexplored. Here we show that ZNF598 undergoes regulatory K63-linked ubiquitination and its level is upregulated upon mitochondrial stress in mammalian cells andDrosophila. Overexpression of ZNF598 protects against mitochondrial stress. InDrosophilamodels of neurodegenerative diseases and patient cells, ZNF598 overexpression aborted stalled translation of mitochondrial outer membrane-associated mRNAs and removed faulty translation products causal of disease. These results shed lights on the regulation of ZNF598 and its important role in mitochondrial homeostasis.
Effect of compound Tinglizi Decoction on non-classical pathway of pyroptosis in rats with chronic obstructive pulmonary disease related pulmonary hypertension
Authors: Wang Qizhi , Liu Min , Liu Yu , Bai Zhengping 
Published: February 2022

AbstractObjectiveTo observe the effect of compound Tinglizi Decoction on non-classical pathway of cell death in rats with pulmonary hypertension, and to explore its mechanism of action in the treatment of COPD-related pulmonary hypertension.Methods60 male SD rats were randomly divided into Western group, normal group, model group, high-dose group, medium dose group and low-dose group, with 10 rats per group. We detected the protein expression levels of caspase-11, GSDMD and IL-6 by Western blot, detected serum TNF-α by ELISA, and observed the morphology of lung tissue by hematoxylin and eosin (HE) staining.ResultsIn the expression of caspase11, GSDMD, IL-6 mRNA and protein in lung tissue, the model group was significantly higher than the normal group (P < 0.01), and the high-dose group, middledose group, low-dose group and western medicine group were significantly lower than the model group (P < 0.01). The levels of serum TNF-α and serum creatinine in the model group were significantly higher than those in the normal group (P < 0.01); and those in the high-dose group, middle-dose group, low-dose group and western medicine group were significantly lower than those in the model group (P < 0.05).ConclusionThe mechanism of compound Tinglizi Decoction in the intervention of COPD-related pulmonary hypertension rats is related to the inhibition of non-classical pathway of cell death.