bluuebunny/crossref_metadata_2025_split huggingface dataset:
Etiological Group Analysis of Cytokine Response To Influenza-Like Illnesses
Authors: Plotnikova Marina A. , Klotchenko Sergey A. , Lozhkov Alexey A. , Lebedev Kirill I , Taraskin Alexander S. , Baranovskaya Irina L. , Egorova Maria A , Ramsay Edward S. , Vasin Andrey V. 
Published: December 2020

AbstractRespiratory infections, collectively, are one of the world’s most common and serious illness groups. As recent observations have shown, the most severe courses of acute respiratory infection, often leading to death, are due to uncontrolled cytokine production (hypercytokinemia). The research presented is devoted to assessment of mRNA expression of specific cytokines (IL-1b, IL-2, IL-4, IL-6, IL-8, IL-10, IL-18, TNF-α, IFN-λ) and MxA in whole blood leukocytes, by means of real-time PCR. This study involved 364 patients with respiratory illness being treated in clinics in St. Petersburg (Russia) in 2018-2019 and 30 healthy subjects. In 70% of patients, bacterial or viral pathogens were identified, with influenza viral infections (types A, B) prevailing. Cytokine analysis was carried out in the acute phase of illness (2-3 days from onset of initial symptoms) and in the stage of recovery (days 9-10). Significant increases in the expression of IL-18, TNF, and IL-10 were observed, relative to controls, only with influenza viral infections. We have shown a difference in IL-6 mRNA expression in patients with bacterial or viral pathogens. No significant difference was found in WBC IL-4 expression levels between patients and healthy subjects. Investigation of the nuances of systemic cytokine production, in response to specific viral and bacterial pathogens, makes it possible to: assess the risks of developing hypercytokinemia during respiratory infection with agents circulating in the human population; and to predict the pathogenicity and virulence of circulating threats.
Cerebrospinal fluid Aβ42 and fractalkine are associated with Parkinson’s disease with freezing of gait
Authors: Hatcher-Martin J. M. , McKay J.L. , Sommerfeld B. , Howell J.C. , Goldstein F. C. , Hu W.T. , Factor S.A. 
Published: December 2020

AbstractObjectiveTo evaluate the association of Alzheimer’s disease-related and inflammation-related cerebrospinal fluid (CSF) markers with freezing of gait (FOG) in patients with Parkinson’s disease (PD).MethodThe study population included well-characterized PD patients with FOG (PD-FOG), without FOG (PD-NoFOG) and healthy controls (HC). CSF was collected using standard protocols. Three Alzheimer’s disease-related markers and 10 inflammation-related markers were measured in a Luminex 200 platform. Differences in marker expression across groups were evaluated with multivariate linear models.ResultsCSF was collected from PD-FOG (N=12), PD-NoFOG (N=20) and HC (N=11) for analysis. Age was not significantly different between the three groups. Duration of PD was not significantly different between the two PD groups. After adjusting for covariates and multiple comparisons, the anti-inflammatory marker, fractalkine, was significantly decreased in the PD groups compared to HC (P=0.022), and further decreased in PD-FOG compared to PD-NoFOG or HC (P=0.032). The Alzheimer’s disease-related protein, Aβ42, was increased in PD-FOG compared to PD-NoFOG or HC (P=0.004). p-Tau181 was also decreased in both PD groups compared to HC (P=0.010).ConclusionsWe found high levels of Aβ42 in PD-FOG patients and cross-sectional data which supports an increase over time from early to advanced state. We also found low levels of fractalkine which might suggest anti-inflammatory effect. This is the first time an association between fractalkine and FOG has been shown. Whether these changes are specific to FOG requires further exploration.
DNA demethylation switches the drivers of Foxp3 expression to maintain regulatory T cell identity
Authors: Li Jun , Xu Beisi , Zong Xinying , He Minghong , Fan Yiping , Cross Richard , Hanna Jacob H. , Feng Yongqiang 
Published: December 2020

ABSTRACTMaintenance of differentiated cellular states is crucial for numerous biological processes, yet its molecular basis remains unclear. Here, we investigate how mechanistically regulatory T (Treg) cell fate is “locked in” during lineage commitment via transcriptional regulation of its lineage-specifying factor Foxp3. Tet-mediated DNA demethylation ofFoxp3enhancer CNS2 was proposed to be a key mechanism maintaining Foxp3 transcription. However, this model has not been directly tested. Therefore, we integrated genetic, pharmacological, and epigenetic approaches to examine the function and mechanism of DNA demethylation in Treglineage maintenance. We observed an abrupt switch of the transcriptional drivers of Foxp3 upon DNA demethylation, which was abolished by CNS2 deficiency. Demethylation of CNS2 increased chromatin accessibility and protein binding, conferring on Tregfate substantial resistance to adverse environments. Thus, our study consolidated the role of DNA demethylation in stabilizing Foxp3 expression incisand revealed a novel regulatory mode governing Tregidentity.
Master Transcription Factors Regulate the DNA Methylation Landscape During Hepatocyte Differentiation
Authors: Suzuki Takahiro , Furuhata Erina , Maeda Shiori , Kishima Mami , Miyajima Yurina , Tanaka Yuki , Lim Joanne , Nishimura Hajime , Nakanish Yuri , Shojima Aiko , Suzuki Harukazu 
Published: December 2020

BackgroundHepatocytes are the dominant cell type of the human liver, with functions in metabolism, detoxification, and in producing secreted proteins. During the process of hepatocyte differentiation, gene regulation and master transcription factors have been extensively investigated, whereas little is known about how the epigenome is regulated, particularly the dynamics of DNA methylation, and the upstream factors that have critical roles.ResultsBy examining changes in the transcriptome and the methylome duringin vitrohepatocyte differentiation, we identified putative DNA methylation-regulating transcription factors, which are likely involved in DNA demethylation and maintenance of hypo-methylation in a differentiation stage-specific manner. Of these factors, we further reveal that GATA6 induces DNA demethylation together with chromatin activation at a binding-site-specific manner during endoderm differentiation.ConclusionsThese results provide an insight into the spatiotemporal regulatory mechanisms exerted on the DNA methylation landscape by transcription factors, and uncover a new role for transcription factors in early liver development.
Maximum Antigen Diversification in a Lyme Bacterial Population and Evolutionary Strategies to Overcome Pathogen Diversity
Authors: Di Lia , Akther Saymon , Bezrucenkovas Edgaras , Ivanova Larisa , Sulkow Brian , Wu Bing , Gomes-Solecki Maria , Qiu Wei-Gang 
Published: December 2020

AbstractNatural populations of microbes and their hosts are engaged in an arms race in which microbes diversify to escape host immunity while hosts evolve novel immunity. This co-evolutionary process, known as the “Red Queen” hypothesis, poses a fundamental challenge to the development of broadly effective vaccines and diagnostics against a diversifying pathogen. Based on surveys of natural allele frequencies and experimental immunization of mice, we show minimal antigenic cross-reactivity among natural variants of the outer surface protein C (OspC), a dominant antigen of a Lyme Disease-causing bacterium (Borrelia burgdorferi). To overcome the challenge of OspC antigenic diversity to clinical development of preventive measures, we implemented a number of evolution-based strategies to broaden OspC immunological cross-reactivity. In particular, the centroid algorithm – a genetic algorithm to minimize sequence differences with natural variants – generated synthetic OspC analogs with the greatest promise as diagnostic and vaccine candidates against diverse Lyme pathogen strains coexisting in the Northeast United States. Mechanistically, we propose a model of runaway maximum antigen di-versification (MAD) mediated by amino-acid variations distributed across hypervariable regions on the OspC molecule. Under the MAD model, evolutionary centroids display high cross-reactivity by occupying the central void in the antigenic space excavated by diversifying natural variants. In contrast to the vaccine design based on concatenated epitopes, the centroid algorithm generates analogs of native antigens and is automated. The MAD model and evolution-inspired antigen designs have broad implications for combating diversifying pathogens driven by pathogen-host coevolution.ImportanceMicrobial pathogens rely on molecular diversity of cell surface antigens to escape host immunity. Vaccines based on one antigen variant often fail to protect the host against pathogens carrying other variants. Here we show evolution-based designs of synthetic antigens that are broadly reactive to all natural variants. The evolutionary analogs of a major surface antigen of a Lyme disease bacterium (Borrelia burgdorferi) showed promise as vaccine candidates against diverse pathogen strains coexisting in the endemic areas of Lyme disease in Northeast United States. Our evolution-based computational design is automated, generates molecular analogs of natural antigens, and opens a novel path to combating fast-evolving microbial pathogens.
CRISPR-cas13 enzymology rapidly detects SARS-CoV-2 fragments in a clinical setting
Authors: Khan Wahab A. , Barney Rachael E. , Tsongalis Gregory J. 
Published: December 2020

ABSTRACTThe well-recognized genome editing ability of the CRISPR-Cas system has triggered significant advances in CRISPR diagnostics. This has prompted an interest in developing new biosensing applications for nucleic acid detection. Recently, such applications have been engineered for detection of SARS-CoV-2. Increased demand for testing and consumables of RT-qPCR assays has led to the use of alternate testing options in some cases. Here we evaluate the accuracy and performance of a novel fluorescence based assay that received EUA authorization from the FDA for detecting SARS-CoV-2 in clinical samples. The Specific High-Sensitivity Enzymatic Reporter UnLOCKing (SHERLOCK) technology forms the basis of the Sherlock CRISPR SARS-CoV-2 kit using the CRISPR-Cas13a system. Our experimental strategy included selection of COVID-19 patient samples from previously validated RT-qPCR assays. Positive samples were selected based on a broad range of cycle thresholds. A total of 50 COVID-19 patient samples were correctly diagnosed with 100% accuracy (relative fluorescence ratios: N gene 95% CI 23.2-36.3, ORF1ab gene 95% CI 27.6-45.4). All controls, including RNase P, showed expected findings. Overall ratios were robustly distinct between positive and negative cases relative to the pre-established 5-fold change in fluorescence read output. We have evaluated the accuracy of detecting conserved targets of SARS-CoV-2 across a range of viral loads using the SHERLOCK CRISPR collateral detection reaction in a clinical setting. These findings demonstrate encouraging results, especially at a time when COVID-19 clinical diagnosis is in high demand; often with limited resources. This approach highlights new thinking in infectious disease identification and can be expanded to measure nucleic acids in other clinical isolates.
An Efficient and Accurate Distributed Learning Algorithm for Modeling Multi-Site Zero- Inflated Count Outcomes
Authors: Edmondson Mackenzie J. , Luo Chongliang , Duan Rui , Maltenfort Mitchell , Chen Zhaoyi , Locke Kenneth , Shults Justine , Bian Jiang , Ryan Patrick B. , Forrest Christopher B. , Chen Yong 
Published: December 2020

AbstractClinical research networks (CRNs), made up of multiple healthcare systems each with patient data from several care sites, are beneficial for studying rare outcomes and increasing generalizability of results. While CRNs encourage sharing aggregate data across healthcare systems, individual systems within CRNs often cannot share patient-level data due to privacy regulations, prohibiting multi-site regression which requires an analyst to access all individual patient data pooled together. Meta-analysis is commonly used to model data stored at multiple institutions within a CRN; while relatively simple to implement, meta-analysis can result in biased estimation, notably in rare-event contexts. We present a communication-efficient, privacy-preserving algorithm for modeling multi-site zero-inflated count outcomes within a CRN. Our method, a one-shot distributed algorithm for performing hurdle regression (ODAH), models zero-inflated count data stored in multiple sites without sharing patient-level data across sites, resulting in estimates closely approximating those that would be obtained in a pooled patient-level data analysis. We evaluate our method through extensive simulations and two realworld data applications using electronic health records (EHRs): examining risk factors associated with pediatric avoidable hospitalization and modeling serious adverse event frequency associated with a colorectal cancer therapy. Relative to existing methods for distributed data analysis, ODAH offers a highly accurate, computationally efficient method for modeling multi-site zero-inflated count data.
History of premorbid depression is a risk factor for COVID-related mortality: Analysis of 1,387 COVID+ patients
Authors: Clouston Sean A. P. , Luft Benjamin J. , Sun Edward 
Published: December 2020

AbstractBackgroundThe goal of the present work was to examine risk factors for mortality in a 1,387 COVID+ patients admitted to a hospital in Suffolk County, NY.MethodsData were collated by the hospital epidemiological service for patients admitted from 3/7/2020-9/1/2020. Time until final discharge or death was the outcome. Cox proportional hazards models were used to estimate time until death among admitted patients.FindingsIn total, 99.06% of cases had resolved leading to 1,179 discharges and 211 deaths. Length of stay was significantly longer in those who died as compared to those who did not p=0.007). Of patients who had been discharged (n=1,179), 54 were readmitted and 9 subsequently died. Multivariable-adjusted Cox proportional hazards regression revealed that in addition to older age, male sex, and heart failure that a history of premorbid depression was a risk factors for COVI-19 mortality (HR = 2.64 [1.54-4.54] P<0.001), and that this association remained after adjusting for age and for neuropsychiatric conditions as well as medical comorbidities including cardiovascular disease and pulmonary conditions. Sex-stratified analyses revealed that associations between mortality and depression was strongest in males (aHR = 4.45 [2.04-9.72], P<0.001), and that the association between heart failure and mortality was strongest in participants aged <65 years old (aHR = 30.50 [9.17-101.48], P<0.001).InterpretationWhile an increasing number of studies have identified a number of comorbid medical conditions and age of patient as risk factors for mortality in COVID+ patients, this study reports that history of depression is a risk factor for COVID mortality.FundingNo funding was received for this study.
SARS-CoV-2 RNAemia with higher nasopharyngeal viral load is strongly associated with severity and mortality in patients with COVID-19
Authors: Kawasuji Hitoshi , Morinaga Yoshitomo , Tani Hideki , Yoshida Yoshihiro , Taekgoshi Yusuke , Kaneda Makito , Murai Yushi , Kimoto Kou , Ueno Akitoshi , Miyajima Yuki , Kawago Koyomi , Fukui Yasutaka , Kimura Miyuki , Yamada Hiroshi , Sakamaki Ippei , Yamamoto Yoshihiro 
Published: December 2020

AbstractObjectiveThis study aimed to determine the frequency of SARS-CoV-2 RNA in serum and its association with the clinical severity of COVID-19.MethodsAn analytical cross-sectional study was performed in a single tertiary care hospital and included consecutive patients with confirmed COVID-19. The prevalence of SARS-CoV-2 RNAemia and the strength of its association with clinical severity variables, including required oxygen supplementation, ICU admission, invasive mechanical ventilation, and in-hospital mortality, were examined.ResultsFifty-six patients were included in the study. The median age was 54.5 years, and individuals with RNAemia were older than those without detectable SARS-CoV-2 RNA in serum (78 vs. 50 years; P = .0013). RNAemia was detected in 19.6% of patients (11/56) and in 1.0% (1/25), 50.0% (6/12), and 100.0% (4/4) of moderate, severe, and critically ill cases, respectively. Patients with RNAemia required more frequent oxygen supplementation (90.0% vs. 13.3%; P < .0001) and ICU admission (81.8% vs. 6.7%; P < .0001) and required invasive mechanical ventilation (27.3% vs. 0.0%; P < .0001). Among patients with RNAemia, the median viral loads of NP swabs that were collected around the same time as the serum were significantly higher in critically ill cases (5.4 Log10 copies/μL [IQR: 4.2–6.3]) than in moderate–severe cases (2.6 Log10 copies/μL [1.1–4.5]; P =.030) and were significantly higher in nonsurvivor cases (6.2 Log10 copies/μL [IQR: 6.0–6.5]) than in survivor cases (3.9 Log10 copies/μL [1.6–4.6]; P =.045).ConclusionsThis study demonstrated a relatively high proportion of SARS-CoV-2 RNAemia and an association between RNAemia and clinical severity. Moreover, among the patients with RNAemia, the viral loads of NP swabs were correlated with severity and mortality, thus suggesting the potential utility of combining serum testing with NP tests as a prognostic indicator for COVID-19 with a higher quality than each separate test.
Longitudinal analysis of COVID-19 patients shows age-associated T cell changes independent of ongoing ill-health
Authors: Townsend Liam , Dyer Adam H , Naughton Aifric , Kiersey Rachel , Holden Dean , Gardiner Mary , Dowds Joanne , O’Brien Kate , Bannan Ciaran , Nadarajan Parthiban , Dunne Jean , Martin-Loeches Ignacio , Fallon Padraic G , Bergin Colm , O’Farrelly Cliona , Ni Cheallaigh Cliona , Bourke Nollaig M , Conlon Niall 
Published: December 2020

AbstractThe trajectory of immunological and inflammatory changes following acute COVID-19 infection are unclear. We investigate immunological changes in convalescent COVID-19 and interrogate their potential relationships with persistent symptoms, termed long COVID.We performed paired immunophenotyping at initial SARS-CoV-2 infection and convalescence (n=40, median 68 days) and validated findings in 71 further patients at median 101 days convalescence. Results were compared to 40 pre-pandemic controls. Fatigue and exercise tolerance were assessed and investigated their relationship with convalescent results.We demonstrate persistent expansion of intermediate monocytes, effector CD8+, activated CD4+ and CD8+ T cells, and reduced naïve CD4+ and CD8+ T cells at 68 days, with activated CD8+ T cells remaining increased at 101 days. Patients >60 years also demonstrate reduced naïve CD4+ and CD8+ T cells and expanded activated CD4+ T cells at 101 days. Ill-health, fatigue, and reduced exercise tolerance were common but were not associated with immunological changes.Graphical Abstract
Case finding of early pregnancies at risk of preeclampsia using maternal blood leptin/ceramide ratio: multi-omics discovery and validation from a longitudinal study
Authors: Huang Qianyang , Hao Shiying , You Jin , Yao Xiaoming , Li Zhen , Schilling James , Li Zhen , Thyparambil Sheeno , Liao Wei-li , Zhou Xin , Mo Lihong , Ladella Subhashini , Fan David , Whitin John C. , Cohen Harvey J. , McElhinney Doff B. , Wong Ronald J. , Shaw Gary M. , Stevenson David K. , Sylvester Karl G. , Ling Xuefeng B. 
Published: December 2020

AbstractObjectiveTo evaluate whether longitudinal measurements of serological adipokines and sphingolipids can predict preeclampsia early in gestation.DesignRetrospective multi-omics discovery and longitudinal validation.SettingMaternity units in two US hospitals.MethodsA multi-omics approach integrating genomic and lipidomic discoveries was employed to identify leptin (Lep) and ceramide (Cer) as novel PE early gestational biomarkers. The levels of placental growth factor (PlGF), soluble fms-like tyrosine kinase (sFlt-1), Lep, and Cer in maternal sera were then determined by enzyme-linked immunosorbent (ELISA) and liquid chromatography-tandem mass spectrometric (LC/MS/MS) assays.Main outcome measuresInterval from positive prediction to confirmative diagnosis.ResultsGenomic meta-analysis compiled six PE placental cohorts with 78 PE and 95 non-PE control placentas. The Testing Cohort included sera from 7 non-PE and 8 PE women collected at confirmatory diagnosis. The Validation Cohort included sera from 20 non-PE and 20 PE women collected longitudinally through gestation. Our findings revealed a marked elevation of maternal serum Leptin/Ceramide (d18:1/25:0) ratio from early gestation (a median of 23 weeks) when comparing later PE-complicated with uncomplicated pregnancies. The maternal Lep/Cer (d18:1/25:0) ratio significantly outperformed the established sFlt-1/PlGF ratio in predicting PE for sensitivity (85% vs. 40%), positive predictive value (89% vs. 42%), and AUC (0.92 vs. 0.52) from 5 to 25 weeks of gestation.ConclusionsNon-invasive longitudinal assessment by serological evaluation of Lep/Cer (d18:1/25:0) ratio can case find early pregnancies at risk of preeclampsia, outperforming sFlt-1/PlGF ratio test.Tweetable abstractNon-invasive longitudinal assessment by serological evaluation of Lep and Cer ratio can predict preeclampsia early in gestation.
Temporally specific patterns of neural activity in interconnected corticolimbic structures during reward anticipation
Authors: Young Megan E. , Spencer-Salmon Camille , Mosher Clayton , Tamang Sarita , Rajan Kanaka , Rudebeck Peter H. 
Published: December 2020

ABSTRACTFunctional neuroimaging studies indicate that interconnected parts of the subcallosal anterior cingulate cortex (ACC), striatum, and amygdala play a fundamental role in affect in health and disease. Yet, while the patterns of neural activity engaged in striatum and amygdala during affective processing are well established, especially during reward anticipation, little is known about subcallosal ACC. Here we recorded neural activity in non-human primate subcallosal ACC and compared this to interconnected parts of basolateral amygdala and rostromedial striatum while macaque monkeys performed reward-based tasks. Applying multiple analysis approaches, we found that neurons in subcallosal ACC and rostromedial striatum preferentially signal anticipated reward using short bursts of activity that form temporally specific patterns. By contrast, basolateral amygdala uses a mixture of both temporally specific and more sustained patterns of activity to signal anticipated reward. Thus, dynamic patterns of neural activity across populations of neurons are engaged in affect, especially in subcallosal ACC.HIGHLIGHTSSustained changes in neural activity signal anticipated reward in basolateral amygdalaTemporally specific patterns signal anticipated reward in all areas recordedNeurons exhibit more punctate encoding when tasks become more complexTemporally specific patterns of neural activity signal different anticipated rewards in BLA