bluuebunny/crossref_metadata_2025_split huggingface dataset:
The systemic inflammatory response and clinicopathological characteristics in patients admitted to hospital with COVID-19 infection: Comparison of 2 consecutive cohorts
Authors: Maguire Donogh , Richards Conor , Woods Marylynne , Dolan Ross , Veitch Jesse Wilson , Sim Wei MJ , Kemmett Olivia EH , Milton David C , Randall Sophie LW , Bui Ly D , Goldmann Nicola , Brown Amy , Gillen Eilidh , Cameron Allan , Laird Barry , Talwar Dinesh , Godber Ian M , Wadsworth John , Catchpole Anthony , Davidson Alan , McMillan Donald C 
Published: February 2021

AbstractBackgroundIn order to manage the COVID-19 systemic inflammatory response, it is important to identify clinicopathological characteristics across multiple cohorts.MethodsElectronic patient records for 2 consecutive cohorts of patients admitted to two urban teaching hospitals with COVID-19 during two 7-week periods of the COVID-19 pandemic in Glasgow, U.K. (cohort 1: 17th March 2020 – 1st May 2020) and (cohort 2: 18th May 2020 – 6th July 2020) were examined for routine clinical, laboratory and clinical outcome data.ResultsCompared with cohort 1, cohort 2 were older (p<0.001), more likely to be female (p<0.05) and have less independent living circumstances (p<0.001). More patients in cohort 2 were PCR positive, CXR negative (both p<0.001) and had low serum albumin concentrations (p<0.001). 30-day mortality was similar between both cohorts (23% and 22%). Over the 2 cohorts, age ≥70 (p<0.001), male gender (p<0.05), hypertension (p<0.01), heart failure (p<0.05), cognitive impairment (p<0.001), frailty (p<0.001), COPD (p<0.05), delirium (p<0.001), elevated perioperative Glasgow Prognostic Score (p≤0.001), elevated neutrophil-lymphocyte ratio (p<0.001), low haematocrit (p<0.01), elevated urea (p<0.001), creatinine (p<0.001), glucose (p<0.05) and lactate (p<0.01); and the 4C score were associated with 30-day mortality. When compared with the 4C score, greater frailty (OR 10.2, 95% C.I. 3.4 – 30.6, p<0.01) and low albumin (OR 5.6, 95% C.I. 2.0 – 15.6, p<0.01) were strongly independently associated with 30-day mortality.ConclusionIn addition to the 4C mortality score, frailty score and a low albumin were strongly independently associated with 30-day mortality in two consecutive cohorts of patients admitted to hospital with COVID-19.Article summaryIn two consecutive cohorts of patients with COVID-19 infection admitted to two urban teaching hospitals in Glasgow, UK, there were variations in a number of clinicopathological characteristics despite similar mortality (23 and 22%).In these two cohorts, in a multivariate analysis that included the 4C mortality score, clinical frailty score >3, low serum albumin concentration (<35 g/L), high neutrophil-lymphocyte ratio (≥5), and abnormal serum sodium concentration (<133/>145 mmol/L) remained independently associated with 30-day mortality.
Comprehensive Study of Germline Mutations and Double-Hit Events in Esophageal Squamous Cell Cancer
Authors: Zeng Bing , Huang Peide , Du Peina , Sun Xiaohui , Huang Xuanlin , Fang Xiaodong , Li Lin 
Published: February 2021

AbstractEsophageal squamous cell cancer (ESCC) is the eighth most common cancer around the world. Several reports have focused on somatic mutations and common germline mutations in ESCC. However, the contributions of pathogenic germline alterations in cancer susceptibility genes (CSGs), highly frequently mutated CSGs, and pathogenically mutated CSG-related pathways in ESCC remain unclear. We obtained data on 571 ESCC cases from public databases and East Asian from the 1000 Genomes Project database and the China Metabolic Analytics Project database to characterize pathogenic mutations. We detected 157 mutations in 75 CSGs, accounting for 25.0% (143/571) of ESCC cases. Six genes had more than five mutations: TP53 (n = 15 mutations), GJB2 (n = 8), BRCA2 (n = 6), RECQL4 (n = 6), MUTYH (n = 6), and PMS2 (n = 5). Our results identified significant differences in pathogenic germline mutations of TP53, BRCA2, and RECQL4 between the ESCC and control cohorts. Moreover, we identified 84 double-hit events (16 germline/somatic double-hit events and 68 somatic/somatic double-hit events) occurring in 18 tumor suppressor genes from 83 patients. Patients who had ESCC with germline/somatic double-hit events were diagnosed at younger ages than patients with the somatic/somatic double-hit events, although the correlation was not significant. Fanconi anemia was the most enriched pathway of pathogenically mutated CSGs, and it appeared to be a primary pathway for ESCC predisposition. The results of this study identified the underlying roles that pathogenic germline mutations in CSGs play in ESCC pathogenesis; increased our awareness about the genetic basis of ESCC; and provided suggestions for using highly mutated CSGs and double-hit features in the early discovery, prevention, and genetic counseling of ESCC.
Assessing the performance of a serological point-of-care test in measuring detectable antibodies against SARS-CoV-2
Authors: Coyle Peter V. , Kahlout Reham Awni El , Dargham Soha R. , Chemaitelly Hiam , Kacem Mohamed Ali Ben Hadj , Al-Mawlawi Naema Hassan Abdulla , Gilliani Imtiaz , Younes Nourah , Kanaani Zaina Al , Khal Abdullatif Al , Kuwari Einas Al , Jeremijenko Andrew , Kaleeckal Anvar Hassan , Latif Ali Nizar , Shaik Riyazuddin Mohammad , Rahim Hanan F. Abdul , Nasrallah Gheyath K. , Yassine Hadi M. , Kuwari Mohamed G. Al , Al Romaihi Hamad Eid , Tang Patrick , Bertollini Roberto , Al-Thani Mohamed H. , Abu-Raddad Laith J. 
Published: February 2021

AbstractObjectiveTo investigate the performance of a rapid point-of-care antibody test, the BioMedomics COVID-19 IgM/IgG Rapid Test, in comparison with a high-quality, validated, laboratory-based platform, the Roche Elecsys Anti-SARS-CoV-2 assay.MethodsSerological testing was conducted on 708 individuals. Concordance metrics were estimated. Logistic regression was used to assess associations with seropositivity.ResultsSARS-CoV-2 seroprevalence was 63.4% (449/708; 95% CI 59.8%-66.9%) using the BioMedomics assay and 71.9% (509/708; 95% CI 68.5%-75.1%) using the Elecsys assay. There were 62 discordant results between the two assays. One specimen was seropositive in the BioMedomics assay, but seronegative in the Elecsys assay, while 61 specimens were seropositive in the Elecsys assay, but seronegative in the BioMedomics assay. Positive, negative, and overall percent agreements between the two assays were 88.0% (95% CI 84.9%-90.6%), 99.5% (95% CI 97.2%-99.9%), and 91.2% (95% CI 88.9%-93.1%), respectively, with a Cohen’s kappa of 0.80 (95% CI 0.77-0.83), indicating excellent agreement. Excluding specimens with lower antibody titers, the agreement improved with positive, negative, and overall percent concordance of 91.2% (95% CI 88.2%-93.6%), 99.5% (95% CI 97.2%-99.9%), and 93.9% (95% CI 91.7%-95.5%), respectively, and a Cohen’s kappa of 0.87 (95% CI 0.84-0.89). Logistic regression confirmed better agreement with higher antibody titers.ConclusionThe BioMedomics COVID-19 IgM/IgG Rapid Test demonstrated excellent performance in measuring detectable antibodies against SARS-CoV-2, supporting the utility of such rapid point-of-care serological testing to guide the public health responses and possible vaccine prioritization.
Epigenome-wide scan identifies differentially methylated regions for lung cancer using pre-diagnostic peripheral blood
Authors: Zhao Naisi , Ruan Mengyuan , Koestler Devin C. , Lu Jiayun , Marsit Carmen J. , Kelsey Karl T. , Platz Elizabeth A. , Michaud Dominique S. 
Published: February 2021

AbstractBackgroundTo reduce lung cancer burden in the US, a better understanding of biological mechanisms in early disease development could provide new opportunities for risk stratification.MethodsIn a nested case-control study, we measured blood leukocyte DNA methylation levels in pre-diagnostic samples collected from 430 men and women in the 1989 CLUE II cohort. Median time from blood drawn to diagnosis was 14 years for all participants. We compared DNA methylation levels by case/control status to identify novel genomic regions, both single CpG sites and differentially methylated regions (DMRs), while controlling for known DNA methylation changes associated with smoking using a previously described pack-years based smoking methylation score. Stratification analyses were conducted by time from blood draw to diagnosis, histology, and smoking status.ResultsWe identified sixteen single CpG sites and forty DMRs significantly associated with lung cancer risk (q < 0.05). The identified genomic regions were associated with genes includingH19, HOXA4, RUNX3, BRICD5, PLXNB2, andRP13. For the single CpG sites, the strongest association was noted for cg09736286 in theDIABLOgene (OR [for 1 SD] = 2.99, 95% CI: 1.95-4.59, P-value = 4.81 × 10−7). For the DMRs, we found that CpG sites in theHOXA4region were hypermethylated in cases compared to controls.ConclusionThe single CpG sites and DMRs that we identified represented significant measurable differences in lung cancer risk, providing new insights into the biological processes of early lung cancer development and potential biomarkers for lung cancer risk stratification.
A Quantitative Data-Driven Analysis (QDA) Framework for Resting-state fMRI: a Study of the Impact of Adult Age
Authors: Li Xia , Fischer Håkan , Manzouri Amirhossein , Månsson Kristoffer N.T. , Li Tie-Qiang 
Published: February 2021

AbstractPurposeThe objective of this study is to introduce a new quantitative data-driven analysis (QDA) framework for the analysis of resting-state fMRI (R-fMRI) and use it to investigate the effect of adult age on resting-state functional connectivity (RFC).MethodsWhole-brain R-fMRI measurements were conducted on a 3T clinical MRI scanner in 227 healthy adult volunteers (N=227, aged 18-74 years old, male/female=99/128). With the proposed QDA framework we derived two types of voxel-wise RFC metrics: the connectivity strength index (CSI) and connectivity density index (CDI) utilizing the convolutions of the cross-correlation (CC) histogram with different kernels. Furthermore, we assessed the negative and positive portions of these metrics separately.ResultsWith the QDA framework we found age-related declines of RFC metrics in the superior and middle frontal gyrus (MFG), posterior cingulate cortex (PCC), right insula and inferior parietal lobule (IPL) of the default mode network (DMN), which resembles previously reported results using other types of RFC data processing methods. Importantly, our new findings complement previously undocumented results in the following aspects: 1) the PCC and right insula are anti-correlated and tend to manifest simultaneously declines of both the negative and positive connectivity strength with subjects’ age; 2) separate assessment of the negative and positive RFC metrics provides enhanced sensitivity to the aging effect; 3) the sensorimotor network depicts enhanced negative connectivity strength with the adult age.ConclusionThe proposed QDA framework can produce threshold-free, voxel-wise analysis of R-fMRI data the RFC metrics. The detected adult age effect is largely consistent with previously reported studies using different R-fMRI analysis approaches. Moreover, the separate assessment of the negative and positive contributions to the RFC metrics can enhance the RFC sensitivity and clarify some of the mixed results in the literature regarding to the DMN and sensorimotor network involvement in adult aging.HighlightsA quantitative data-driven analysis (QDA) framework was proposed to analysis resting-state fMRI data.Threshold-free resting-state functional connectivity (RFC) metrics were derived to assess brain changes with adult age.Separate assessment of the positive and negative correlations improve sensitivity of the RFC metrics.The posterior cingulate and right insula cortices are anti-correlated and tend to manifest declines in both the negative and positive connectivity strength with adult age.Negative connectivity strength enhances with adult age in sensorimotor network.
Interleukin-33 regulates metabolic reprogramming of the retinal pigment epithelium in response to immune stressors
Authors: Scott Louis M , Vincent Emma E , Hudson Natalie , Neal Chris , Jones Nicholas , Lavelle Ed , Campbell Matthew , Halestrap Andrew P , Dick Andrew D , Theodoropoulou Sofia 
Published: February 2021

SummaryIt remains unresolved how retinal pigment epithelial (RPE) cell metabolism is regulated following immune activation to maintain retinal homeostasis and retinal function. We exposed RPE to several stress signals, particularly toll-like receptor stimulation, and uncovered an ability of RPE to adapt their metabolic preference on aerobic glycolysis or oxidative glucose metabolism in response to different immune stimuli. We have identified interleukin-33 (IL-33) as a key metabolic checkpoint that antagonises the Warburg effect to ensure the functional stability of the RPE. The identification of IL-33 as a key regulator of mitochondrial metabolism suggests roles for the cytokine that go beyond its extracellular “alarmin” activities. IL-33 exerts control over mitochondrial respiration in RPE by facilitating oxidative pyruvate catabolism. We have also revealed that in the absence of IL-33, mitochondrial function declines and resultant bioenergetic switching is aligned with altered mitochondrial morphology. Our data not only sheds new light in the molecular pathway of activation of mitochondrial respiration in RPE in response to immune stressors, but also uncovers a novel role of nuclear intrinsic IL-33 as a metabolic checkpoint regulator.
Fentanyl binds to the μ-opioid receptor via the lipid membrane and transmembrane helices
Authors: Sutcliffe Katy J , Corey Robin A , Charlton Steven J , Sessions Richard B , Henderson Graeme , Kelly Eamonn 
Published: February 2021

AbstractOverdose deaths from synthetic opioids, such as fentanyl, have reached epidemic proportions in the USA and are increasing worldwide. Fentanyl is a potent opioid agonist, that is less well reversed by naloxone than morphine. Due to fentanyl’s high lipophilicity and elongated structure we hypothesised that its unusual pharmacology may be explained by a novel binding mode to the μ-opioid receptor (MOPr).By employing coarse-grained molecular dynamics simulations and free energy calculations, we determined the routes by which fentanyl and morphine access the orthosteric pocket of MOPr.Morphine accesses MOPr via the aqueous pathway; first binding to an extracellular vestibule, then diffusing into the orthosteric pocket. In contrast, fentanyl takes a novel route; first partitioning into the membrane, before accessing the orthosteric site by diffusing through a ligand-induced gap between the transmembrane helices.This novel lipophilic route may explain the high potency and lower susceptibility of fentanyl to reversal by naloxone.
Differentiation of human adult-derived stem cells towards a neural lineage involves a de-differentiation event prior to re-differentiation to neural phenotypes
Authors: Bueno Carlos , Martínez-Morga Marta , García-Bernal David , Moraleda José M , Martínez Salvador 
Published: February 2021

AbstractAlthough it has been reported that mesenchymal stem cells isolated from adult tissues can be induced to overcome their mesenchymal fate and transdifferentiate into neural cells, the findings and their interpretation have been challenged. The main argument against this process is that the cells rapidly adopt neuron-like morphologies through retraction of the cytoplasm rather than active neurite extension.In this study, we examined the sequence of biological events during neural differentiation of human periodontal ligament-derived stem cells (hPDLSCs), human bone marrow-derived stem cells (hBMSCs) and human dental pulp-derived stem cells (hDPSCs) by time-lapse microscopy.We have demonstrated that hPDLSCs, hBMSCs and hDPSCs can directly differentiate into neuron-like cells without passing through a mitotic stage and that they shrink dramatically and change their morphology to that of neuron-like cells through active neurite extension. Furthermore, we observed micronuclei movement and transient cell nuclei lobulation concurrent to in vitro neurogenesis from hBMSCs and hDPSCs.Our results demonstrate that the differentiation of hPDLSCs, hBMSCs and hDPSCs towards a neural lineage occurs through a de-differentiation step followed by re-differentiation to neural phenotypes, and therefore we definitively confirm that the rapid acquisition of the neural phenotype is via a differentiation trait.
The molecular clockwork of the suprachiasmatic nucleus is sufficient to co-ordinate phasing and stabilisation of sleep-wake cycles and enhance memory deficits in a clockless mouse
Authors: Maywood Elizabeth S. , Chesham Johanna E. , Winsky-Sommerer Raphaelle , Hastings Michael H. 
Published: February 2021

AbstractThe timing and quality of sleep-wake cycles are regulated by interacting circadian and homeostatic mechanisms. Although the suprachiasmatic nucleus (SCN) is the principal circadian clock, local clocks are active across the brain and the respective sleep-regulatory roles of SCN and extra-SCN clocks are unclear. To determine the specific contribution(s) of the SCN, we used virally mediated genetic complementation, expressing Cryptochrome1 (Cry1) to restore circadian molecular competence to the SCN of globally clocklessCry1/Cry2-null mice. Under free-running conditions, the rest/activity behaviour ofCry1/Cry2-null controls which received EGFP (SCNCon) was arrhythmic, whereas Cry1-complemented mice (SCNCry1) had circadian behaviour comparable to that of Cry1,2-competent wild-types (WT). In SCNConmice, sleep-wakefulness, assessed by electroencephalography/electromyography, also lacked circadian organisation. In SCNCry1mice, however, it was comparable to WT, with consolidated vigilance states (wake, REM and NREM sleep) and rhythms in NREMS delta power and expression of REMS within total sleep. Wakefulness in SCNConmice was more fragmented than in WT, with more wake-NREMS-wake transitions. This disruption was corrected in SCNCry1mice. Following sleep deprivation, all mice showed an initial homeostatic increase in NREMS delta power. The SCNConmice, however, had reduced, non-consolidated NREMS during the inactive phase of the recovery period. In contrast, the dynamics of homeostatic responses in the SCNCry1mice were equivalent to WT. Finally, SCNConmice exhibited poor sleep-dependent memory but this was corrected in SCNCry1mice. Therefore, the SCN clock is sufficient for circadian control of sleep-wake, facilitating initiation and maintenance of wake, promoting sleep consolidation, homeostatic dynamics, and sleep-dependent memory.Significance statementThe circadian timing system regulates sleep-wake cycles. The hypothalamic suprachiasmatic nucleus (SCN) is the principal circadian clock, but local clocks are also active across the brain and the respective roles of SCN and local clocks in regulating sleep are unclear. To determine, explicitly, the contribution of the SCN, we used virally mediated genetic complementation to restore SCN molecular circadian functions in otherwise genetically clockless mice. This initiated circadian activity-rest cycles, accompanied by circadian sleep-wake cycles, circadian patterning to the intensity of NREM sleep and circadian control of REM sleep as a proportion of total sleep. Consolidation of sleep-wake established normal dynamics of sleep homeostasis and enhanced sleep-dependent memory. Thus, the SCN is the principal and sufficient circadian regulator of sleep-wake.
Interaction between decision-making and interoceptive representations of bodily arousal in frontal cortex
Authors: Fujimoto Atsushi , Murray Elisabeth A. , Rudebeck Peter H. 
Published: February 2021

AbstractDecision-making and representations of arousal are intimately linked. Behavioral investigations have classically shown that either too little or too much bodily arousal is detrimental to decision-making, indicating that there is an inverted ‘U’ relationship between bodily arousal and performance. How these processes interact at the level of single neurons as well as the neural circuits involved are unclear. Here we recorded neural activity from orbitofrontal cortex (OFC) and dorsal anterior cingulate cortex (dACC) of macaque monkeys while they made reward-guided decisions. Heart rate (HR) was also recorded and used as a proxy for bodily arousal. Recordings were made both before and after subjects received excitotoxic lesions of the bilateral amygdala. In intact monkeys, higher HR facilitated reaction times (RTs). Concurrently, a set of neurons in OFC and dACC selectively encoded trial-by-trial variations in HR independent of reward value. After amygdala lesions, HR increased and the relationship between HR and RTs was reversed. Concurrent with this change, there was an increase in the proportion of dACC neurons encoding HR. Applying a novel population-coding analysis, we show that after bilateral amygdala lesions the balance of encoding in dACC is skewed away from signaling either reward value or choice direction towards HR coding around the time that choices are made. Taken together, the present results provide insight into how bodily arousal and decision-making are signaled in frontal cortex.Significance statementHow bodily arousal states influence decision-making has been a central question in psychology, but the neural mechanisms are unclear. We recorded heart rate, a measure of bodily arousal, while simultaneously monitoring neural activity in orbitofrontal cortex (OFC) and dorsal anterior cingulate cortex (dACC) of macaques making reward-guided decisions. In intact macaques higher HR was associated with shorter reaction times. Concurrently, the activity of a set of neurons in OFC and dACC selectively encoded HR. Following amygdala lesions, HR generally increased and now the relationship between HR and reaction times was reversed. At the neural level, the balance of encoding in dACC shifted towards signaling HR, suggesting a specific mechanism through which bodily arousal influences decision-making.
Multi-task deep learning for concurrent prediction of protein structural properties
Authors: Zhang Buzhong , Li Jinyan , Quan Lijun , Lyu Qiang 
Published: February 2021

AbstractProtein structural properties are diverse and have the characteristics of spatial hierarchy, such as secondary structures, solvent accessibility and backbone angles. Protein tertiary structures are formed in close association with these features. Separate prediction of these structural properties has been improved with the increasing number of samples of protein structures and with advances in machine learning techniques, but concurrent prediction of these tightly related structural features is more useful to understand the overall protein structure and functions. We introduce a multi-task deep learning method for concurrent prediction of protein secondary structures, solvent accessibility and backbone angles (ϕ, ψ). The new method has main two deep network modules: the first one is designed as a DenseNet architecture a using bidirectional simplified GRU (GRU2) network, and the second module is designed as an updated Google Inception network. The new method is named CRRNN2.CRRNN2 is trained on 14,100 protein sequences and its prediction performance is evaluated by testing on public benchmark datasets: CB513, CASP10, CASP11, CASP12 and TS1199. Compared with state-of-the-art methods, CRRNN2 achieves similar, or better performance on the prediction of 3- and 8-state secondary structures, solvent accessibility and backbone angles (ϕ, ψ). Online CRRN-N2 applications, datasets and standalone software are available athttp://qianglab.scst.suda.edu.cn/crrnn2/.