bluuebunny/crossref_metadata_2025_split huggingface dataset:
Synthesize Heterogeneous Biological Knowledge via Representation Learning for Alzheimer’s Disease Drug Repurposing
Authors: Hsieh Kang-Lin , Plascencia-Villa German , Lin Ko-Hong , Perry George , Jiang Xiaoqian , Kim Yejin 
Published: December 2021

SummaryDeveloping drugs for treating Alzheimer’s disease (AD) has been extremely challenging and costly due to limited knowledge on underlying biological mechanisms and therapeutic targets. Repurposing drugs or their combination has shown potential in accelerating drug development due to the reduced drug toxicity while targeting multiple pathologies. To address the challenge in AD drug development, we developed a multi-task deep learning pipeline to integrate a comprehensive knowledge graph on biological/pharmacological interactions and multi-level evidence on drug efficacy, to identify repurposable drugs and their combination candidates. We developed and computationally validated a heterogeneous graph representation model with transfer learning from universal biomedical databases and joint optimization with AD risk genes. Using the drug embedding from the heterogeneous graph representation model, we ranked drug candidates based on evidence from post-treatment transcriptomic patterns, mechanistic efficacy in preclinical models, population-based treatment effect, and Phase II/III clinical trials. We mechanistically validated the top-ranked candidates in neuronal cells, identifying drug combinations with efficacy in reducing oxidative stress and safety in maintaining neuronal viability and morphology. Our neuronal response experiments confirmed several biologically efficacious drug combinations. This pipeline showed that harmonizing heterogeneous and complementary data/knowledge, including human interactome, transcriptome patterns, experimental efficacy, and real-world patient data shed light on the drug development of complex diseases.One-Sentence SummaryA novel multitask deep learning method that synthesize heterogeneous biological knowledge to identify repurposable drugs for Alzheimer’s Disease.
A novel disease mechanism leading to the expression of a disallowed gene in the pancreatic beta-cell identified by non-coding, regulatory mutations controlling HK1
Authors: Wakeling Matthew N. , Owens Nick D. L. , Hopkinson Jessica R. , Johnson Matthew B. , Houghton Jayne A.L. , Dastamani Antonia , Flaxman Christine S. , Wyatt Rebecca C. , Hewat Thomas I. , Hopkins Jasmin J. , Laver Thomas W. , Van Heugten Rachel , Weedon Michael N. , De Franco Elisa , Patel Kashyap A. , Ellard Sian , Morgan Noel G. , Cheesman Edmund , Banerjee Indraneel , Hattersley Andrew T. , Dunne Mark J. ,   International Congenital Hyperinsulinism Consortium, Richardson Sarah J. , Flanagan Sarah E. 
Published: December 2021

AbstractGene expression is tightly regulated with many genes exhibiting cell-specific silencing when their protein product would disrupt normal cellular function. This silencing is largely controlled by non-coding elements and their disruption might cause human disease. We performed gene-agnostic screening of the non-coding regions to discover new molecular causes of congenital hyperinsulinism. This identified 14 non-coding de novo mutations affecting a 42bp conserved region encompassed by a regulatory element in intron 2 of Hexokinase 1 (HK1), a pancreatic beta-cell disallowed gene. We demonstrated that these mutations resulted in expression of HK1 in the pancreatic beta-cells causing inappropriate insulin secretion and congenital hyperinsulinism. These mutations identify a regulatory region critical for cell-specific silencing. Importantly, this has revealed a new disease mechanism for non-coding mutations that cause inappropriate expression of a disallowed gene.
Identification of ATP2B4 regulatory element containing functional genetic variants associated with severe malaria
Authors: Nisar Samia , Torres Magali , Thiam Alassane , Pouvelle Bruno , Rosier Florian , Gallardo Frederic , Ka Oumar , Mbengue Babacar , Diallo Rokhaya Ndiaye , Brosseau Laura , Spicuglia Salvatore , Dieye Alioune , Marquet Sandrine , Rihet Pascal 
Published: December 2021

AbstractGenome-wide association studies (GWAS) for severe malaria have identified 30 genetic variants that are mostly located in non-coding regions, with only a few associations replicated in independent populations. In this study, we aimed at identifying potential causal genetic variants located in these loci and demonstrate their functional activity. We systematically investigated the regulatory effect of the SNPs in linkage disequilibrium with the tagSNPs associated with severe malaria in several populations. Annotating and prioritizing genetic variants led to the identification of a regulatory region containing 5 ATP2B4 SNPs in linkage disequilibrium with the tagSNP rs10900585. We confirmed the association of rs10900585 and also found significant associations of severe malaria with our candidate SNPs (rs11240734, rs1541252, rs1541253, rs1541254, and rs1541255) in a Senegalese population. Then, we showed that this region had both promoter and enhancer activities and that both individual SNPs and the combination of SNPs had regulatory effects using luciferase reporter assays. Moreover, CRISPR/Cas9-mediated deletion of this region decreased ATP2B4 transcript and protein levels and increased Ca2+ intracellular concentration in the K562 cell line. Taken together, our data show that severe malaria-associated genetic variants alter the activity of a promoter with enhancer function. We showed that this regulatory element controls the expression of ATP2B4 that encodes a plasma membrane calcium-transporting ATPase 4 (PMCA4), which is the major calcium pump on red blood cells. Altering the activity of this regulatory element affects the risk of severe malaria probably through calcium concentration effect on parasitaemia.
The relationship between visually evoked effects and concussion in youth
Authors: Gentile Carlyn Patterson , Aguirre Geoffrey K , Arbogast Kristy B. , Master Christina L. 
Published: December 2021

ABSTRACTIncreased sensitivity to light is common following concussion. Viewing a flickering light can also produce uncomfortable somatic sensations like nausea or headache. Here we examined effects evoked by viewing a patterned, flickering screen in a cohort of 81 uninjured youth athletes and 84 youth with concussion. We used exploratory factor analysis and identified two primary dimensions of variation: the presence or absence of visually evoked effects, and variation in the tendency to manifest effects that localized to the eyes (e.g., eye watering), versus more generalized neurologic symptoms (e.g., headache). Based on these two primary dimensions, we grouped participants into three categories of evoked symptomatology: no effects, eye-predominant effects, and brain-predominant effects. A similar proportion of participants reported eye-predominant effects in the uninjured (33.3%) and concussion (32.1%) groups. By contrast, participants who experienced brain-predominant effects were almost entirely from the concussion group (1.2% of uninjured, 35.7% of concussed). The presence of brain-predominant effects was associated with a higher concussion symptom burden and reduced performance on visio-vestibular tasks. Our findings indicate that the experience of negative constitutional, somatic sensations in response to a dynamic visual stimulus is a salient marker of concussion and is indicative of more severe concussion symptomatology. We speculate that differences in visually evoked effects reflect varying levels of activation of the trigeminal nociceptive system.
Cellular and humoral responses to SARS-CoV-2 vaccination in immunosuppressed patients
Authors: Mohanraj Dinesh , Baldwin Samuel , Singh Satbeer , Gordon Alun , Whitelegg Alison 
Published: December 2021

ABSTRACTObjectiveSARS-CoV-2 vaccinations have demonstrated vaccine immunogenicity in healthy volunteers, however, efficacy in immunosuppressed patients is less well characterised. Subsequently, there is an urgent need to address the impact of immunosuppression on vaccine immunogenicity.MethodsSerological, T-cell ELISpot, cytokines and immunophenotyping investigations were used to assess vaccine responses (either BNT162b2 mRNA or ChAdOx1 nCoV-19) in double-vaccinated patients receiving immunosuppression for renal transplants or haematological malignancies (n=13). Immunological responses in immunosuppressed patients (VACC-IS) were compared to immunocompetent vaccinated (VACC-IC, n=12), unvaccinated (UNVACC, n=11) and infection-naïve unvaccinated (HC, n=3) cohorts. All participants, except HC, had prior COVID-19 infection.ResultsT-cell responses were identical between VACC-IS and VACC-IC (92%) to spike-peptide (S) stimulation. UNVACC had the highest T-cell non-responders (n=3), whereas VACC-IC and VACC-IS both had one T-cell non-responder. No significant differences in humoral responses were observed between VACC-IC and VACC-IS, with 92% (12/13) of VACC-IS patients demonstrating seropositivity. One VACC-IS failed to seroconvert, however had detectable T-cell responses. All VACC-IC participants were seropositive for anti-spike antibodies. Furthermore, both VACC-IS and VACC-IC participants elicited strong Th1 cytokine response with immunodominance towards S-peptide. Differences in T-cell immunophenotyping were seen between VACC-IS and VACC-IC, with lower CD8+ activation and T-effector memory phenotype observed in VACC-IS.ConclusionSARS-CoV-2 vaccines are immunogenic in patients receiving immunosuppressive therapy, with responses comparable to vaccinated immunocompetent participants. Lower humoral responses were seen in patients treated with B-cell depleting therapeutics, but with preserved T-cell responses. We suggest further work to correlate both protective immunity and longevity of these responses in both healthy and immunosuppressed patients.
A multiplex protein panel assay determines disease severity and is prognostic about outcome in COVID-19 patients
Authors: Wang Ziyue , Cryar Adam , Lemke Oliver , Ludwig Daniela , Tober-Lau Pinkus , Helbig Elisa Theresa , Blake Daniel , Lane Catherine S , Sayers Rebekah L , Mueller Christoph , Zeiser Johannes , Townsend StJohn , Demichev Vadim , Mülleder Michael , Kurth Florian , Sirka Ernestas , Hartl Johannes , Ralser Markus 
Published: December 2021

AbstractGlobal healthcare systems continue to be challenged by the COVID-19 pandemic, and there is a need for clinical assays that can both help to optimize resource allocation and accelerate the development and evaluation of new therapies. Here, we present a multiplex proteomic panel assay for the assessment of disease severity and outcome prediction in COVID-19. The assay quantifies 50 peptides derived from 30 COVID-19 severity markers in a single measurement using analytical flow rate liquid chromatography and multiple reaction monitoring (LC-MRM), on equipment that is broadly available in routine and regulated analytical laboratories. We demonstrate accurate classification of COVID-19 severity in patients from two cohorts. Furthermore, the assay outperforms established risk assessments such as SOFA and APACHE II in predicting survival in a longitudinal COVID-19 cohort. The prognostic value implies its use for support of clinical decisions in settings with overstrained healthcare resources e.g. to optimally allocate resources to severely ill individuals with high chance of survival. It can furthermore be helpful for monitoring of novel therapies in clinical trials.
Using an electronic frailty index to predict adverse outcomes in geriatric COVID-19 patients: data from the Stockholm GeroCovid study
Authors: Mak Jonathan K. L. , Eriksdotter Maria , Annetorp Martin , Kuja-Halkola Ralf , Kananen Laura , Boström Anne-Marie , Kivipelto Miia , Metzner Carina , Jerlardtz Viktoria Bäck , Engström Malin , Johnson Peter , Lundberg Lars Göran , Åkesson Elisabet , Öberg Carina Sühl , Olsson Maria , Cederholm Tommy , Hägg Sara , Religa Dorota , Jylhävä Juulia 
Published: December 2021

ABSTRACTBackgroundThe Clinical Frailty Scale (CFS) is a strong predictor for worse outcomes in geriatric COVID-19 patients, but it is less clear whether an electronic frailty index (eFI) constructed from routinely collected electronic health records (EHRs) provides similar predictive value. This study aimed to investigate the predictive ability of an eFI in comparison to other frailty and comorbidity measures, using mortality, readmission, and the length of stay as outcomes in geriatric COVID-19 patients.MethodsWe conducted a retrospective cohort study using EHRs from nine geriatric clinics in Stockholm, Sweden, comprising 3,405 COVID-19 patients (mean age 81.9 years) between 1/3/2020 and 31/10/2021. Frailty was assessed using a 48-item eFI developed for Swedish geriatric patients, the CFS, and Hospital Frailty Risk Score (HFRS). Comorbidity was measured using the Charlson Comorbidity Index (CCI). We analyzed in-hospital mortality and 30-day readmission using logistic regression and area under receiver operating characteristic curve (AUC). 30-day and 6-month mortality were modelled by Cox regression, and the length of stay by linear regression.ResultsControlling for age and sex, a 10% increase in the eFI was associated with higher risks of in-hospital mortality (odds ratio [OR]=2.84; 95% confidence interval=2.31-3.51), 30-day mortality (hazard ratio [HR]=2.30; 1.99-2.65), 6-month mortality (HR=2.33; 2.07-2.62), 30-day readmission (OR=1.34; 1.06-1.68), and longer length of stay (β=2.28; 1.90-2.66).The CFS, HFRS and CCI similarly predicted these outcomes, but the eFI had the best predictive accuracy for in-hospital mortality (AUC=0.775).ConclusionsAn eFI based on routinely collected EHRs can be applied in identifying high-risk geriatric COVID-19 patients.
Risk assessment of banknotes as a fomite of SARS-CoV-2 in cash payment transactions
Authors: Schijven Jack , Wind Mark , Todt Daniel , Howes John , Tamele Barbora , Steinmann Eike 
Published: December 2021

AbstractBackgroundThe COVID 19 pandemic has triggered concerns and assumptions globally about transmission of the SARS-CoV-2 virus via cash transactions.ObjectivesAssess the risk of contracting COVID-19 through exposure to SARS-CoV-2 via cash acting as a fomite in payment transactions.MethodsA quantitative microbial risk assessment was conducted for a worst-case scenario assuming an infectious person at the onset of symptoms, when virion concentrations in coughed droplets are at their highest. This person then contaminates a banknote by coughing on it and immediately hands it over to another person, who might then be infected by transferring the virions with a finger from the contaminated banknote to a facial mucous membrane. The scenario considered transfer efficiency of virions on the banknote to fingertips when droplets were still wet and after having dried up and subsequently being touched by finger printing or rubbing the object.ResultsAccounting for the likelihood of the worst-case scenario to occur by considering 1) a local prevalence of 100 COVID-19 cases/100,000 persons, 2) a maximum of about 1/5th of infected persons transmit high virus loads and 3) the numbers of cash transactions/person/day, the risk of contracting COVID-19 via person-to-person cash transactions was estimated to be much lower than once per 39,000 days (107 years) for a single person. In the general populace, there will be a maximum of 2.6 expected cases/100,000 persons/day. The risk for a cashier at an average point of sale was estimated to be much less than once per 430 working days (21 months).DiscussionThe worst-case scenario is a rare event, therefore, for a single person, the risk of contracting COVID-19 via person-to-person cash transactions is very low. At a point of sale, the risk to the cashier proportionally increases but it is still low.
A practical guideline of genomics-driven drug discovery in the era of global biobank meta-analysis
Authors: Namba Shinichi , Konuma Takahiro , Wu Kuan-Han , Zhou Wei ,   Global Biobank Meta-analysis Initiative, Okada Yukinori 
Published: December 2021

SummaryGenomics-driven drug discovery is indispensable for accelerating the development of novel therapeutic targets. However, the drug discovery framework based on evidence from genome-wide association studies (GWAS) has not been established, especially for cross-population GWAS meta-analysis. Here, we introduce a practical guideline for genomics-driven drug discovery for cross-population meta-analysis, as lessons from the Global Biobank Meta-analysis Initiative (GBMI). Our drug discovery framework encompassed three methodologies and was applied to the 13 common diseases targeted by GBMI (Nmean= 1,329,242). First, we evaluated the overlap enrichment between disease risk genes and the drug-target genes of the disease-relevant medication categories. An omnibus approach integrating the four gene prioritization tools yielded twice the enrichment in the disease-relevant medication categories compared with any single tool, and identified drugs with approved indications for asthma, gout, and venous thromboembolism. Second, we performed an endophenotype Mendelian randomization analysis using protein quantitative trait loci as instrumental variables. After the application of quality controls, including a colocalization analysis, significant causal relationships were estimated for 18 protein–disease pairs, including MAP2K inhibitors for heart failure. Third, we conducted anin silicoscreening for negative correlations between genetically determined disease case–control gene expression profiles and compound-regulated ones. Significant negative correlations were observed for 31 compound–disease pairs, including a histone deacetylase inhibitor for asthma. Integration of the three methodologies provided a comprehensive catalog of candidate drugs for repositioning, nominating promising drug candidates targeting the genes involved in the coagulation process for venous thromboembolism. Our study highlighted key factors for successful genomics-driven drug discovery using cross-population meta-analysis.
Safety and immunogenicity of the third booster dose with inactivated, viral vector, and mRNA COVID-19 vaccines in fully immunized healthy adults with inactivated vaccine
Authors: Kanokudom Sitthichai , Assawakosri Suvichada , Suntronwong Nungruthai , Auphimai Chompoonut , Nilyanimit Pornjarim , Vichaiwattana Preeyaporn , Thongmee Thanunrat , Yorsaeng Ritthideach , Srimuan Donchida , Thatsanatorn Thaksaporn , Klinfueng Sirapa , Sudhinaraset Natthinee , Wanlapakorn Nasamon , Honsawek Sittisak , Poovorawan Yong 
Published: December 2021

AbstractThe coronavirus disease-2019 (COVID-19) pandemic has become a severe healthcare problem worldwide since the first outbreak in late December 2019. Currently, the COVID-19 vaccine has been used in many countries, but it is still unable to control the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection despite patients receiving full vaccination doses. Therefore, we aimed to appraise the booster effect of the different platforms of vaccines, including inactivated vaccine (BBIBP), viral vector vaccine (AZD122), and mRNA vaccine (BNT162b2) in healthy adults who received the full dose of inactivated vaccine (CoronaVac). The booster dose was safe with no serious adverse events. Moreover, the immunogenicity indicated that the booster dose with viral vector and mRNA vaccine achieved a significant proportion of Ig anti-receptor binding domain (RBD), IgG anti-RBD, and IgA anti-S1 booster response. In contrast, inactivated vaccine achieved a lower booster response than others. Consequently, the neutralization activity of vaccinated serum had a high inhibition of over 90% against SARS-CoV-2 wild-type and their variants (B.1.1.7–alpha, B.1.351–beta, and B.1.617.2–delta). In addition, IgG anti-nucleocapsid was observed only among the group that received the BBIBP booster. Our study found a significant increase in levels of interferon gamma-secreting T-cell response after the additional viral vector or mRNA booster vaccination. This study showed that administration with either viral vector (AZD1222) or mRNA (BNT162b2) boosters in individuals with a history of two doses of inactivated vaccine (CoronaVac) obtained great immunogenicity with acceptable adverse events.
Underlying co morbidity reveals unique immune signatures in Type II diabetes patients infected with SARS-CoV2
Authors: Sengupta Soumya , Bhattacharya Gargee , Chatterjee Sanchari , Datey Ankita , Shaw Shubham K , Suranjika Sandhya , Nath Paritosh , Barik Prakash K , Prasad Punit , Chattopadhyay Soma , Swain Rajeeb K , Parida Ajay , Devadas Satish 
Published: December 2021

AbstractBackgroundSARS-CoV2 infection in patients with comorbidities, particularly T2DM has been a major challenge globally. Here, we did whole blood immunophenotyping along with plasma cytokine, chemokine, antibody isotyping and viral load determination from oropharyngeal swab to understand the immune pathology in the T2DM patients infected with SARS-CoV2.MethodsBlood samples from 25 Covid-19 positive patients having T2DM, 10 Covid-19 positive patients not having T2DM and 10 Covid-19 negative, non-diabetic healthy controls were assessed for various immune cells by analyzing for their signature surface proteins in mass cytometry. Circulating cytokines, chemokines and antibody isotypes were determined from plasma. Viral copy number was determined from oropharyngeal swabs. All our representative data corroborated with laboratory findings.ResultsOur observations encompass T2DM patients having elevated levels of both type I and type II cytokines and higher levels of circulating IgA, IgM, IgG1 and IgG2 as compared to NDM and healthy volunteers. They also displayed higher percentages of granulocytes, mDCs, plasmablasts, Th2-like cells, CD4+ EM cells, CD8+ TE cells as compared to healthy volunteers. T2DM patients also displayed lower percentages of pDCs, lymphocytes, CD8+ TE cells, CD4+, CD8+ EM.ConclusionOur study demonstrated that patients with T2DM displayed higher inflammatory markers and a dysregulated anti-viral and anti-inflammatory response when compared to NDM and healthy controls.Contribution to the fieldCovid-19 infection in people with comorbidities, particularly T2DM has been a cause of mortality in several nations and they represent an extremely vulnerable population to Covid-19. This study is one of the most comprehensive study from India, to understand the interplay between immune response and viremia occurring in these T2DM patients infected with SARS-CoV2 and will help in designing public health response and vaccination priorities.