bluuebunny/crossref_metadata_2025_split huggingface dataset:
Simultaneous Control of Infection and Inflammation by Keratin-Derived Antibacterial Peptides (KAMPs) Targeting TLRs and Co-Receptors
Authors: Sun Yan , Chan Jonathan , Bose Karthikeyan , Tam Connie 
Published: January 2021

ABSTRACTThe use and the timing of initiation of steroids for controlling unwanted infectious inflammation are major clinical dilemmas due to their possible adverse effects including delayed microbial clearance and wound healing. Compounding this difficulty is the continued emergence of drug-resistant bacteria; yet anti-infective strategies aiming at augmenting inflammatory responses to facilitate bacterial killing cannot be used to treat infections involving vulnerable tissues. As is the case with bacterial keratitis, excessive inflammation jeopardizes corneal transparency leading to devastating vision loss. Hence, a two-pronged remedy possessing both anti-infective and anti-inflammatory properties would be helpful for tackling antibiotic resistance and enabling prompt inflammation control at once. Using murine primary neutrophils, macrophages and sterile corneal inflammation models, we found that non-toxic and pro-healing human keratin 6a-derived antimicrobial peptides (KAMPs) with a native 10-or 18-amino-acid sequence suppress LTA- and LPS-induced NF-кB and IRF3 activation, proinflammatory cytokine production, as well as phagocyte recruitment, independently of their bactericidal function. Mechanistically, direct binding of KAMPs to cell surface TLR2 and TLR co-receptors CD14 and MD-2 not only blocks their bacterial ligand docking sites, but also reduces cell surface availability of TLR2 and TLR4 through promotion of receptor endocytosis. Benefitting from the dual functions of topical KAMPs, experimental bacterial keratitis caused was effectively prevented or controlled, as evidenced by significant reductions of corneal opacification and inflammatory cell infiltration in addition to enhanced bacterial clearance. These findings reveal multiple TLR-targeting activities of KAMPs and demonstrate their therapeutic potential as a multifunctional drug for managing sterile and infectious inflammatory diseases.One Sentence SummaryBifunctional native keratin peptides allow concurrent alleviation of inflammation and infection to avoid functional damages in vulnerable tissues.
Inflammatory Cytokines Regulate T-Cell Development from Blood Progenitor Cells in a Stage and Dose-Specifc Manner
Authors: Edgar John M. , Zandstra Peter W. 
Published: January 2021

ABSTRACTT-cell development from hematopoietic stem and progenitor cells (HSPCs) is tightly regulated through Notch pathway activation by the Notch ligands Delta-like (DL) 1 and 4 and Jagged-2. Other molecules, such as stem cell factor (SCF), FMS-like tyrosine kinase 3 ligand (Flt3L) and interleukin (IL)-7, play a supportive role in regulating the survival, differentiation, and proliferation of developing progenitor (pro)T-cells. Numerous other signaling molecules are known to instruct T-lineage developmentin vivo, but little work has been done to optimize their use for T-cell productionin vitro. Using a defined T-lineage differentiation assay consisting of plates coated with the Notch ligand DL4 and adhesion molecule VCAM-1, we performed a cytokine screen that identified IL-3 and tumor necrosis factor α (TNFα) as enhancers of proT-cell differentiation and expansion. Mechanistically, we found that TNFα induced T-lineage differentiation through the positive regulation of T-lineage genesGATA3, TCF7, andBCL11b. TNFα also synergized with IL-3 to induce proliferation by upregulating the expression of the IL-3 receptor on CD34+HSPCs, yielding 753.2 (532.4-1026.9; 5-95 percentile)-fold expansion of total cells after 14 days compared to 8.9 (4.3-21.5)-fold expansion in conditions without IL-3 and TNFα. We then optimized cytokine concentrations for T-cell maturation. Focusing on T-cell maturation, we used quantitative models to optimize dynamically changing cytokine requirements and used these to construct a three-stage assay for generating CD3+CD4+CD8+and CD3+CD4−CD8+T-cells. Our work provides new insight into T-cell development and a robustin vitroassay for generating T-cells to enable clinical therapies for treating cancer and immune disorders.
Sodium channel Nav1.2-L1342P variant displaying complex biophysical properties renders hyperexcitability of cortical neurons derived from human iPSCs
Authors: Que Zhefu , Olivero-Acosta Maria I. , Zhang Jingliang , Eaton Muriel , Skarnes William C. , Yang Yang 
Published: January 2021

AbstractWith the wide adoption of whole-exome sequencing in children having seizures, an increasing number ofSCN2Avariants has been revealed as possible genetic causes of epilepsy. Voltage-gated sodium channel Nav1.2, encoded by geneSCN2A, is strongly expressed in the pyramidal excitatory neurons and supports action potential firing. One recurrentSCN2Avariant is L1342P, which was identified in multiple patients with early-onset encephalopathy and intractable seizures. Our biophysical analysis and computational modeling predicted gain-of-function features of this epilepsy-associated Nav1.2 variant. However, the mechanism underlying L1342P mediated seizures and the pharmacogenetics of this variant in human neurons remain unknown. To understand the core phenotypes of the L1342P variant in human neurons, we took advantage of a reference human induced pluripotent stem cell (hiPSC) line, in which L1342P was engineered by CRISPR/Cas9 mediated genome-editing. Using patch-clamping and micro-electrode array (MEA) recording, we found that the cortical neurons derived from hiPSCs carrying heterozygous L1342P variant presented significantly increased intrinsic excitability, higher sodium current density, and enhanced bursting and synchronous network firing, showing clear hyperexcitability phenotypes. Interestingly, the L1342P neuronal culture displayed a degree of resistance to the anti-seizure medication (phenytoin), which likely recapitulated aspects of clinical observation of patients carrying the L1342P variant. In contrast, phrixotoxin-3 (PTx3), a Nav1.2 isoform-specific blocker, was able to potently alleviate spontaneous and chemical-induced hyperexcitability of neurons carrying the L1342P variant. Our results reveal a possible pathogenic underpinning of Nav1.2-L1342P mediated epileptic seizures, and demonstrate the utility of genome-edited hiPSCs as anin vitroplatform to advance personalized phenotyping and drug discovery.
Factors associated with COVID-19 related hospitalisation, critical care admission and mortality using linked primary and secondary care data
Authors: Cummins Lisa , Ebyarimpa Irene , Cheetham Nathan , Brown Victoria Tzortziou , Brennan Katie , Panovska-Griffiths Jasmina 
Published: January 2021

AbstractBackgroundTo identify risk factors associated with increased risk of hospitalisation, intensive care unit (ICU) admission and mortality in inner North East London (NEL) during the first UK COVID-19 wave.MethodsMultivariate logistic regression analysis on linked primary and secondary care data from people aged 16 or older with confirmed COVID-19 infection between 01/02/2020-30/06/2020 determined odds ratios (OR), 95% confidence intervals (CI) and p-values for the association between demographic, deprivation and clinical factors with COVID-19 hospitalisation, ICU admission and mortality.ResultsOver the study period 1,781 people were diagnosed with COVID-19, of whom 1,195 (67%) were hospitalised, 152 (9%) admitted to ICU and 400 (23%) died. Results confirm previously identified risk factors: being male, or of Black or Asian ethnicity, or aged over 50. Obesity, type 2 diabetes and chronic kidney disease (CKD) increased the risk of hospitalisation. Obesity increased the risk of being admitted to ICU. Underlying CKD, stroke and dementia in-creased the risk of death. Having learning disabilities was strongly associated with increased risk of death (OR=4.75, 95%CI=(1.91,11.84), p=0.001). Having three or four co-morbidities increased the risk of hospitalisation (OR=2.34,95%CI=(1.55,3.54),p<0.001;OR=2.40, 95%CI=(1.55,3.73), p<0.001 respectively) and death (OR=2.61, 95%CI=(1.59,4.28), p<0.001;OR=4.07, 95% CI= (2.48,6.69), p<0.001 respectively).ConclusionsWe confirm that age, sex, ethnicity, obesity, CKD and diabetes are important determinants of risk of COVID-19 hospitalisation or death. For the first time, we also identify people with learning disabilities and multi-morbidity as additional patient cohorts that need to be actively protected during COVID-19 waves.
Safety and immunogenicity of SARS-CoV-2 recombinant protein vaccine formulations in healthy adults: a randomised, placebo-controlled, dose-ranging study
Authors: Goepfert Paul A , Fu Bo , Chabanon Anne-Laure , Bonaparte Matthew I , Davis Matthew G , Essink Brandon J , Frank Ian , Haney Owen , Janosczyk Helene , Keefer Michael C , Koutsoukos Marguerite , Kimmel Murray A , Masotti Roger , Savarino Stephen J , Schuerman Lode , Schwartz Howard , Sher Lawrence D , Smith Jon , Tavares-Da-Silva Fernanda , Gurunathan Sanjay , DiazGranados Carlos A , De Bruyn Guy 
Published: January 2021

AbstractBackgroundEffective vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are urgently needed. CoV2 preS dTM is a stabilised pre-fusion S protein vaccine produced in a baculovirus expression system. We present interim safety and immunogenicity results of the first-in-human study of the CoV2 preS dTM vaccine with two different adjuvant formulations.MethodsThis Phase I/II, randomised, double-blind study (NCT04537208) is being conducted in healthy, SARS-CoV-2-seronegative adults in the USA. Participants were stratified by age (18–49 and ≥50 years) and randomised to receive one (on Day[D]1) or two doses (D1, D22) of placebo or candidate vaccine, containing: low-dose (LD, effective dose 1.3 µg) or high-dose (HD, 2.6 µg) antigen with adjuvant AF03 (Sanofi Pasteur) or AS03 (GlaxoSmithKline); or unadjuvanted HD (18–49 years only). Safety was assessed up to D43. SARS-CoV-2 neutralising and binding antibody profiles were assessed in D1, D22 and D36 serum samples.FindingsThe interim safety analyses included 439/441 randomised participants. There were no related unsolicited immediate AEs, serious AEs, medically attended AEs classified as severe, or AE of special interest. More grade 3 solicited reactions were reported than expected after the second dose in the adjuvanted vaccine groups. Neutralising and binding antibody responses after two vaccine doses were higher in adjuvanted versus unadjuvanted groups, in AS03-versus AF03-adjuvanted groups, in HD versus LD groups, and in younger versus older age strata.InterpretationThe lower than expected immune responses, especially in the older age stratum, and the higher than anticipated reactogenicity post dose 2 were likely due to a higher than anticipated host cell protein content and lower than planned antigen dose in the clinical material. Further development of the AS03-adjuvanted candidate vaccine will focus on identifying the optimal antigen formulation and dose.
RPE65-related retinal dystrophy: mutational and phenotypic spectrum in 45 affected patients
Authors: Lopez-Rodriguez R , Lantero E , Blanco-Kelly F , Avila-Fernandez A , Martin Merida I , del Pozo-Valero M , Perea-Romero I , Zurita O , Jiménez-Rolando B , Swafiri ST , Riveiro-Alvarez R , Trujillo-Tiebas MJ , Carreño Salas E , García-Sandoval B , Corton M , Ayuso C 
Published: January 2021

ABSTRACTBackgroundBiallelic pathogenicRPE65variants are related to a spectrum of clinically overlapping inherited retinal dystrophies (IRD). Most affected individuals show a severe progression, with 50% of patients legally blind by 20 years of age. A better knowledge of the mutational spectrum and the phenotype-genotype correlation inRPE65-related IRD is needed.MethodsForty-five affected subjects from 27 unrelated families with a clinical diagnosis ofRPE65-related IRD were included. Clinical evaluation consisted on self-reported ophthalmological history and objective ophthalmological examination. Patients’ genotype was classified accordingly to variant class (truncating or missense) or to variant location at different protein domains. Main phenotypic outcome was age at onset (AAO) of the symptomatic disease and a Kaplan–Meier analysis of disease symptom event-free survival was performed.ResultsTwenty-nine differentRPE65variants were identified in our cohort, 7 of them novel. Most frequent variants were p.(Ile98Hisfs*26), p.(Pro111Ser) and p.(Gly187Glu) accounting for the 24% of the detected alleles. Patients carrying two missense alleles showed a later disease onset than those with 1 or 2 truncating variants (Log Rank test p<0.05). While the 60% of patients carrying a missense/missense genotype presented symptoms before or at the first year of life, almost all patients with at least 1 truncating allele (91%) had an AAO ≤1 year (p<0.05).ConclusionOur findings suggest an association between the type of theRPE65carried variant and the AAO. Thus, our results provide useful data onRPE65-associated IRD phenotypes which may help to improve clinical and therapeutic management of these patients.
Economic Burden of Periodontal Disease in Europe and the United States of America – An updated forecast
Authors: Botelho João , Proença Luís , Leira Yago , Chambrone Leandro , Mendes José João , Machado Vanessa 
Published: January 2021

AbstractIntroductionPeriodontal disease is a pandemic condition and its severe form affects approximately 10% of the global population. Here, we present a forecast for the economic burden of periodontal disease in 32 European countries and in the United States of America (USA).Material and methodsIn an aggregate population-based cost analysis, taken as reference the most recent available data, we estimated the cost of periodontal disease. Under this, global health, dental and periodontal expenditures were estimated. Additionally, indirect estimates accounted for Disability-Adjusted Life Years (DALY) valued at per capita Gross Domestic Product (GDP), to estimate productivity losses, including periodontal disease, edentulism due to periodontal disease and caries due to periodontal disease.ResultsIn 2018 the aggregate cost in Europe was estimated at €17.00B and €2.35B more in the USA (€19.35B). Indirect costs due to periodontal disease amounted to €132.52B in European countries and €103.30B in the USA. The majority of the projected indirect costs were due to edentulism related to periodontal disease and periodontal disease. Indirect costs were the major portion of the estimated economic impact with an average of 0.66% of GDP in Europe and 0.50% in the USA. For the overall costs (direct and indirect), the value amounted to 0.75% of GDP in Europe and 0.60% in the USA.ConclusionPeriodontal disease caused a €149.52B loss in Europe and €122.65B in the USA, in 2018. These results show that the economic burden of periodontal disease is increasing.CLINICAL RELEVANCEScientific rationale for the studyConsidering the pandemic pattern of periodontal diseases we present a forecast for the economic burden of periodontal disease in 32 European countries and in the United States of America (USA).Principal findingsPeriodontal disease caused a €149.52B loss in Europe and €122.65B in the USA, in 2018. For the overall costs (direct and indirect), the value amounted to 0.75% of GDP in Europe and 0.60% in the USA.Practical implicationsThese results show that the economic burden of periodontal disease is increasing.
The Impact of U.S. County-Level Factors on COVID-19 Morbidity and Mortality
Authors: Itzhak Nevo , Shahar Tomer , Moskovich Robert , Shahar Yuval 
Published: January 2021

AbstractBackgroundThe effect of socioeconomic factors, ethnicity, and other variables, on the frequency of COVID-19 cases [morbidity] and induced deaths [mortality] atsub-population, rather than atindividuallevels, is only partially understood.ObjectiveTo determine which county-level features best predict COVID-19 morbidity and mortality for a given county in the U.S.DesignA Machine-Learning model that predicts COVID-19 mortality and morbidity using county-level features, followed by a SHAP-values-based importance analysis of the predictive features.SettingPublicly available data from various American government and news websites.Participants3,071 U.S. counties, from which 53 county-level features, as well as morbidity and mortality numbers, were collected.MeasurementsFor each county: Ethnicity, socioeconomic factors, educational attainment, mask usage, population density, age distribution, COVID-19 morbidity and mortality, air quality indicators, presidential election results, ICU beds.ResultsA Random Forest classifier produced an AUROC of 0.863 for morbidity prediction and an AUROC of 0.812 for mortality prediction. A SHAP-values-based analysis indicated that poverty rate, obesity rate, mean commute time to work, and proportion of people that wear masks significantly affected morbidity rates, while ethnicity, median income, poverty rate, and education levels, heavily influenced mortality rates. The correlation between several of these factors and COVID-19 morbidity and mortality, from 4/2020 to 11/2020 shifted, probably due to COVID-19 being initially associated with more urbanized areas, then with less urbanized ones.LimitationsData are still coming in.ConclusionsEthnicity, education, and economic disparity measures are major factors in predicting the COVID-19 mortality rate in a county. Between-counties low-variance factors (e.g., age), are not meaningful predictors.Differing correlations can be explained by the COVID-19 spread from metropolitan to less metropolitan areas.Primary Funding SourceNone.
Adipocyte deletion of the RNA binding protein HuR induces cardiac hypertrophy and fibrosis
Authors: Guarnieri Adrienne R. , Anthony Sarah R. , Gozdiff Anamarie , Green Lisa C. , Slone Sam , Nieman Michelle L. , Alam Perwez , Benoit Joshua B. , Kanisicak Onur , Tranter Michael 
Published: January 2021

ABSTRACTAdipose tissue continues to gain appreciation for its broad role as an endocrine organ, and disruptions in adipose tissue homeostasis plays a central role in cardiovascular physiology. We have previously shown that expression of the RNA binding protein HuR in adipose tissue mediates energy expenditure, but the potential cardiovascular impacts of this finding have not been explored. We show here that adipose tissue-specific deletion of HuR (Adipo-HuR-/-) is sufficient to induce the spontaneous development of cardiac hypertrophy and fibrosis. Hearts from Adipo-HuR-/-mice have increased left ventricular (LV) ejection fraction, rate of pressure generation, and LV posterior wall thickness that is accompanied by an increase in LV/body weight ratio and hypertrophic gene expression. Furthermore, Adipo-HuR-/-hearts display increased fibrosis by picrosirius red staining and periostin expression. To identify underlying mechanisms, we applied both RNA-seq and weighted gene co-expression network analysis (WGCNA) to define HuR-dependent changes in gene expression as well as significant relationships between adipose tissue gene expression and LV mass. RNA-seq results demonstrate a significant increase in pro-inflammatory gene expression in the subcutaneous white adipose tissue (scWAT) from Adipo-HuR-/-mice that is accompanied by an increase in serum levels of both TNF-α and IL-6. WGCNA identified a significant enrichment in inflammation, apoptosis/cell death, and vesicle-mediated transport genes among those whose expression most significantly associated with CVD in Adipo-HuR-/-. In conclusion, we demonstrate that the loss of HuR expression in adipose tissue promotes the development of cardiac hypertrophy and fibrosis, potentially through modulation of inflammation and vesicle-mediated transport in scWAT.NEW AND NOTEWORTHYThis work demonstrates the spontaneous development of cardiac hypertrophy and fibrosis upon adipose tissue-specific deletion of the RNA binding protein HuR that appears to be mechanistically driven by HuR-dependent changes in inflammatory and extracellular vesicle transport mediating genes in the subcutaneous white adipose tissue. These results suggest that loss of HuR expression in adipose tissue in obesity, as demonstrated in mouse and humans by our group and others, may contribute to obesity-mediated CVD.
In VivoSubcellular Mass Spectrometry Enables Proteo-Metabolomic Single-cell Systems Biology in a Chordate Embryo Developing to a Normally Behaving Tadpole (X. laevis)
Authors: Lombard-Banek Camille , Li Jie , Portero Erika P. , Onjiko Rosemary M. , Singer Chase D. , Plotnick David , Al Shabeeb Reem Q. , Nemes Peter 
Published: January 2021

ABSTRACTWe present the first example ofin vivohigh-resolution mass spectrometry (HRMS) for subcellular molecular systems biology of proteins and metabolites. With light microscopy, we identified the left-dorsal and left-ventral animal cells in cleavage-stage non-sentientXenopus laevisembryos. Using precision-translated fabricated microcapillaries, the subcellular content of each cell was double-probed, each time collecting <5% of cell volume (~10 nL) swiftly (<5 s/event). The proteins and metabolites were analyzed by custom-built ultrasensitive capillary electrophoresis electrospray ionization employing Orbitrap and time-of-flight HRMS. Label-free detection of ~150 metabolites (57 identified) and 738 proteins found proteo-metabolomic networks with differential quantitative activities between the cell types. Spatially and temporally scalable sampling the technology preserved the integrity of the analyzed cells, the neighboring cells, and the embryo. 95% of the analyzed embryos developed into sentient tadpoles that were indistinguishable from their wild-type siblings based on anatomy and visual function in a background color preference assay.
Dissecting the localization ofTilapia tilapinevirusin the brain of the experimentally infected Nile tilapia (Oreochromis niloticus)
Authors: Dinh-Hung Nguyen , Sangpo Pattiya , Kruangkum Thanapong , Kayansamruaj Pattanapon , Rung-ruangkijkrai Tilladit , Senapin Saengchan , Rodkhum Channarong , Dong Ha Thanh 
Published: January 2021

AbstractTilapia tilapinevirusor tilapia lake virus (TiLV) is an emerging virus that inflicts significant mortality on farmed tilapia globally. Previous studies reported detection of the virus in multiple organs of the infected fish; however, little is known about the in-depth localization of the virus in the central nervous system. Herein, we determined the distribution of TiLV in the entire brain of experimentally infected Nile tilapia.In situhybridization (ISH) using TiLV-specific probes revealed that the virus was broadly distributed throughout the brain. The strongest positive signals were dominantly detected in the forebrain (responsible for learning, appetitive behavior, and attention) and the hindbrain (involved in controlling locomotion and basal physiology). The permissive cell zones for viral infection were observed mostly to be along the blood vessels and the ventricles. This indicates that the virus may productively enter into the brain through the circulatory system and widen broad regions, possibly through the cerebrospinal fluid along the ventricles, and subsequently induce the brain dysfunction. Understanding the pattern of viral localization in the brain may help elucidate the neurological disorders of the diseased fish. This study revealed the distribution of TiLV in the whole infected brain, providing new insights into fish-virus interactions and neuropathogenesis.