bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modelling fatality curves of COVID-19 and the effectiveness of intervention strategies
Authors: Vasconcelos Giovani L. , Macêdo Antônio M. S. , Ospina Raydonal , Almeida Francisco A. G. , Duarte-Filho Gerson C. , Brum Arthur A. , Souza Inês C. L. 
Published: April 2020

ABSTRACTThe main objective of the present paper is twofold: first, to model the fatality curves of the COVID-19 disease, as represented by the cumulative number of deaths as a function of time; and second, to use the corresponding mathematical model to study the effectiveness of possible intervention strategies. We applied the Richards growth model (RGM) to the COVID-19 fatality curves from several countries, where we used the data from the Johns Hopkins University database up to May 8, 2020. Countries selected for analysis with the RGM were China, France, Germany, Iran, Italy, South Korea, and Spain. The RGM was shown to describe very well the fatality curves of China, which is in a late stage of the COVID-19 outbreak, as well as of the other above countries, which supposedly are in the middle or towards the end of the outbreak at the time of this writing. We also analysed the case of Brazil, which is in an initial sub-exponential growth regime, and so we used the generalised growth model which is more appropriate for such cases. An analytic formula for the efficiency of intervention strategies within the context of the RGM is derived. Our findings show that there is only a narrow window of opportunity, after the onset of the epidemic, during which effective countermeasures can be taken. We applied our intervention model to the COVID-19 fatality curve of Italy of the outbreak to illustrate the effect of several possible interventions.
COVID-19 pandemic: Power law spread and flattening of the curve
Authors: Verma Mahendra K. , Asad Ali , Chatterjee Soumyadeep 
Published: April 2020

AbstractIn this paper, we analyze the real-time infection data of COVID-19 epidemic for nine nations. Our analysis is up to 7 April 2020. For China and South Korea, who have already flattened their infection curves, the number of infected individuals (I(t)) exhibits power-law behavior before flattening of the curve. Italy has transitioned to the power-law regime for some time. For the other six nations—USA, Spain, Germany, France, Japan, and India—a power-law regime is beginning to appear after exponential growth. We argue that the transition from an exponential regime to a power-law regime may act as an indicator for flattening of the epidemic curve. We also argue that long-term community transmission and/or the transmission by asymptomatic carriers traveling long distances may be inducing the power-law growth of the epidemic.
Prediction and Evolution of B Cell Epitopes of Surface Protein in SARS-CoV-2
Authors: Lon Jerome R , Bai Yunmeng , Zhong Bingxu , Cai Fuqaing , Du Hongli 
Published: April 2020

AbstractThe discovery of epitopes is helpful to the development of SARS-CoV-2 vaccine. The sequences of the surface protein of SARS-CoV-2 and its proximal sequences were obtained by BLAST, the sequences of the whole genome of SARS-CoV-2 were obtained from the GenBank. Based on the NCBI Reference Sequence: NC_045512.2, the conformational and linear B cell epitopes of the surface protein were predicted separately by various prediction methods. Furthermore, the conservation of the epitopes, the adaptability and other evolutionary characteristics were also analyzed. 7 epitopes were predicted, including 5 linear epitopes and 2 conformational epitopes, one of the linear and one of the conformational were coincide. The epitope D mutated easily, but the other epitopes were very conservative and the epitope C was the most conservative. It is worth mentioning that all of the 6 dominated epitopes were absolutely conservative in nearly 1000 SARS-CoV-2 genomes, and they deserved further study. The findings would facilitate the vaccine development, had the potential to be directly applied on the treatment in this disease, but also have the potential to prevent the possible threats caused by other types of coronavirus.
Triphosphates of the Two Components in DESCOVY and TRUVADA are Inhibitors of the SARS-CoV-2 Polymerase
Authors: Jockusch Steffen , Tao Chuanjuan , Li Xiaoxu , Anderson Thomas K. , Chien Minchen , Kumar Shiv , Russo James J. , Kirchdoerfer Robert N. , Ju Jingyue 
Published: April 2020

AbstractSARS-CoV-2, a member of the coronavirus family, is responsible for the current COVID-19 pandemic. We previously demonstrated that four nucleotide analogues (specifically, the active triphosphate forms of Sofosbuvir, Alovudine, AZT and Tenofovir alafenamide) inhibit the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). Tenofovir and emtricitabine are the two components in DESCOVY and TRUVADA, the two FDA-approved medications for use as pre-exposure prophylaxis (PrEP) to prevent HIV infection. This is a preventative method in which individuals who are HIV negative (but at high-risk of contracting the virus) take the combination drug daily to reduce the chance of becoming infected with HIV. PrEP can stop HIV from replicating and spreading throughout the body. We report here that the triphosphates of tenofovir and emtricitabine, the two components in DESCOVY and TRUVADA, act as terminators for the SARS-CoV-2 RdRp catalyzed reaction. These results provide a molecular basis to evaluate the potential of DESCOVY and TRUVADA as PrEP for COVID-19.
Genomic evaluation of circulating proteins for drug target characterisation and precision medicine
Authors: Folkersen Lasse , Gustafsson Stefan , Wang Qin , Hansen Daniel Hvidberg , Hedman Åsa K , Schork Andrew , Page Karen , Zhernakova Daria V , Wu Yang , Peters James , Ericsson Niclas , Bergen Sarah E , Boutin Thibaud , Bretherick Andrew D , Enroth Stefan , Kalnapenkis Anettne , Gådin Jesper R , Suur Bianca , Chen Yan , Matic Ljubica , Gale Jeremy D , Lee Julie , Zhang Weidong , Quazi Amira , Ala-Korpela Mika , Choi Seung Hoan , Claringbould Annique , Danesh John , Davey-Smith George , de Masi Federico , Elmståhl Sölve , Engström Gunnar , Fauman Eric , Fernandez Celine , Franke Lude , Franks Paul , Giedraitis Vilmantas , Haley Chris , Hamsten Anders , Ingason Andres , Johansson Åsa , Joshi Peter K , Lind Lars , Lindgren Cecilia M. , Lubitz Steven , Palmer Tom , Macdonald-Dunlop Erin , Magnusson Martin , Melander Olle , Michaelsson Karl , Morris Andrew P. , Mägi Reedik , Nagle Michael , Nilsson Peter M , Nilsson Jan , Orho-Melander Marju , Polasek Ozren , Prins Bram , Pålsson Erik , Qi Ting , Sjögren Marketa , Sundström Johan , Surendran Praveen , Võsa Urmo , Werge Thomas , Wernersson Rasmus , Westra Harm-Jan , Yang Jian , Zhernakova Alexandra , Ärnlöv Johan , Fu Jingyuan , Smith Gustav , Esko Tonu , Hayward Caroline , Gyllensten Ulf , Landen Mikael , Siegbahn Agneta , Wilson Jim F , Wallentin Lars , Butterworth Adam S , Holmes Michael V , Ingelsson Erik , Mälarstig Anders 
Published: April 2020

AbstractCirculating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. By mapping and replicating protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, we identified 467 pQTLs for 85 proteins. The pQTLs were used in combination with other sources of information to evaluate known drug targets, and suggest new target candidates or repositioning opportunities, underpinned by a) causality assessment using Mendelian randomization, b) pathway mapping usingtrans-pQTL gene assignments, and c) protein-centric polygenic risk scores enabling matching of plausible target mechanisms to sub-groups of individuals enabling precision medicine.
TMEM70 forms oligomeric scaffolds within mitochondrial cristae promotingin situassembly of mammalian ATP synthase proton channel
Authors: Bahri Hela , Buratto Jérémie , Rojo Manuel , Dompierre Jim , Salin Bénédicte , Blancard Corinne , Cuvellier Sylvain , Rose Marie , Elgaaied Amel Ben Ammar , Tetaud Emmanuel , di Rago Jean-Paul , Devin Anne , Duvezin-Caubet Stéphane 
Published: April 2020

AbstractMitochondrial ATP-synthesis is catalyzed by a F1Fo-ATP synthase, an enzyme of dual genetic origin enriched at the edge of cristae where it plays a key role in their structure/stability. The enzyme’s biogenesis remains poorly understood, both from a mechanistic and a compartmentalization point of view. The present study provides novel molecular insights into this process through investigations on a human protein called TMEM70 with an unclear role in the assembly of ATP synthase. A recent study has revealed the existence of physical interactions between TMEM70 and the subunit c (Su.c), a protein present in 8 identical copies forming a transmembrane oligomeric ring (c-ring) within the ATP synthase proton translocating domain (FO). Herein we analyzed the ATP-synthase assembly in cells lacking TMEM70, mitochondrial DNA or F1 subunits and observe a reciprocal dependence of TMEM70 and Su.c levels, regardless of the status of other ATP synthase subunits or of mitochondrial bioenergetics. Immunoprecipitation and two-dimensional blue-native/SDS-PAGE reveal that TMEM70 forms large oligomers composed of 8 TMEM70 dimers and that TMEM70 oligomers interact with Su.c not yet incorporated into ATP synthase complexes. Moreover, discrete TMEM70-Su.c complexes with increasing Su.c contents can be detected, suggesting a role for TMEM70 oligomers in the gradual assembly of the c-ring. Furthermore, we demonstrate using expansion super-resolution microscopy the specific localization of TMEM70 at the inner cristae membrane, distinct from the MICOS component MIC60. Taken together, our results show that TMEM70 oligomers provide a scaffold for c-ring assembly and that mammalian ATP synthase is assembled within inner cristae membranes.
Deep whole genome sequencing of multiple proband tissues and parental blood reveals the complex genetic etiology of congenital diaphragmatic hernias
Authors: Bogenschutz EL , Fox ZD , Farrell A , Wynn J , Moore B , Yu L , Aspelund G , Marth G , Yandell MY , Shen Y , Chung WK , Kardon G 
Published: April 2020

ABSTRACTThe diaphragm is a mammalian muscle critical for respiration and separation of the thoracic and abdominal cavities. Defects in the development of the diaphragm are the cause of congenital diaphragmatic hernia (CDH), a common birth defect. In CDH, weaknesses in the developing diaphragm allow abdominal contents to herniate into the thoracic cavity and impair lung development, leading to a high neonatal mortality. The genetic etiology of CDH is complex. Single nucleotide variants (SNVs), insertion/deletions (indels), and structural/copy number variants in more than 150 genes have been associated with CDH, although few genes are recurrently mutated in multiple patients and recurrently mutated genes can be incompletely penetrant. This suggests that multiple genetic variants in combination, other not yet investigated classes of variants, and/or nongenetic factors contribute to CDH susceptibility. However, to date no studies have comprehensively investigated the contribution of all possible classes of variants throughout the genome to the etiology of CDH. In our study, we used a unique cohort of four patients with isolated CDH with samples from blood, skin, and diaphragm connective tissue and parental blood samples and deep whole genome sequencing to assess germline and somaticde novoand inherited variants of various sizes (SNVs, indels, and structural variants) in exons, introns, UTRs, and intergenic regions. In each patient we found a different mutational landscape that included germlinede novo,and inherited SNVs and indels in multiple genes. We also found in two patients an inherited 343 bp deletion interrupting an annotated enhancer of the CDH associated gene,GATA4, and we hypothesize that this common deletion (found in 1-2% of the population) acts as a sensitizing allele for CDH. Overall, our comprehensive reconstruction of the genetic architecture of four CDH individuals demonstrates that the etiology of CDH is heterogeneous and multifactorial.AUTHOR SUMMARYDeep whole genome sequencing of family trios shows that etiology of congenital diaphragmatic hernias is heterogeneous and multifactorial.
Genome wide analysis of gene dosage in 24,092 individuals shows that 10,000 genes modulate cognitive ability
Authors: Huguet Guillaume , Schramm Catherine , Douard Elise , Petra Tamer , Main Antoine , Monin Pauline , England Jade , Jizi Khadije , Renne Thomas , Poirier Myriam , Nowak Sabrina , Martin Charles-Olivier , Younis Nadine , Knoth Inga Sophia , Jean-Louis Martineau , Saci Zohra , Auger Maude , Tihy Frédérique , Mathonnet Géraldine , Maftei Catalina , Léveillé France , Porteous David , Davies Gail , Redmond Paul , Harris Sarah E. , Hill W. David , Lemyre Emmanuelle , Schumann Gunter , Bourgeron Thomas , Pausova Zdenka , Paus Tomas , Karama Sherif , Lippe Sarah , Deary Ian J. , Almasy Laura , Labbe Aurélie , Glahn David , Greenwood Celia M.T. , Jacquemont Sébastien 
Published: April 2020

ABSTRACTGenomic Copy Number Variants (CNVs) are routinely identified and reported back to patients with neuropsychiatric disorders, but their quantitative effects on essential traits such as cognitive ability are poorly documented. We have recently shown that the effect-size of deletions on cognitive ability can be statistically predicted using measures of intolerance to haploinsufficiency. However, the effect-sizes of duplications remain unknown. It is also unknown if the effect of multigenic CNVs are driven by a few genes intolerant to haploinsufficiency or distributed across tolerant genes as well.Here, we identified all CNVs >50 kilobases in 24,092 individuals from unselected and autism cohorts with assessments of general intelligence. Statistical models used measures of intolerance to haploinsufficiency of genes included in CNVs to predict their effect-size on intelligence. Intolerant genes decrease general intelligence by 0.8 and 2.6 points of IQ when duplicated or deleted, respectively. Effect-sizes showed no heterogeneity across cohorts. Validation analyses demonstrated that models could predict CNV effect-sizes with 78% accuracy. Data on the inheritance of 27,766 CNVs showed that deletions and duplications with the same effect-size on intelligence occurde novoat the same frequency.We estimated that around 10,000 intolerant and tolerant genes negatively affect intelligence when deleted, and less than 2% have large effect-sizes. Genes encompassed in CNVs were not enriched in any GOterms but gene regulation and brain expression were GOterms overrepresented in the intolerant subgroup. Such pervasive effects on cognition may be related to emergent properties of the genome not restricted to a limited number of biological pathways.
RIPK2 dictates insulin responses to tyrosine kinase inhibitors in obese mice
Authors: Duggan Brittany M. , Cavallari Joseph F. , Foley Kevin P. , Barra Nicole G. , Schertzer Jonathan D. 
Published: April 2020

ABSTRACTTyrosine kinase inhibitors (TKIs) used in cancer are also being investigated in diabetes. TKIs can improve blood glucose control in diabetic cancer patients, but the specific kinases that alter blood glucose or insulin are not clear. We sought to define the role of Receptor Interacting Serine/Threonine Kinase 2 (RIPK2) in mouse models of insulin resistance. We tested the TKI gefitinib, which inhibits RIPK2 activity, in WT,Nod1-/-, Nod2-/-andRipk2-/-mice fed an obesogenic high fat diet. Gefitinib lowered blood glucose during a glucose tolerance test (GTT) in a NOD-RIPK2-independent manner in all obese mice. However, gefitinib lowered glucose-stimulated insulin secretion only in obeseRipk2-/-mice. Gefitinib had no effect on insulin secretion in obese WT,Nodi-/-, orNod2-/-mice. Hence, genetic deletion ofRipk2promoted the insulin sensitizing potential of gefitinib, since this TKI lowered both blood glucose and insulin only inRipk2-/-mice. Gefitinib did not alter the inflammatory profile of pancreas, adipose, liver or muscle tissues in obeseRipk2-/-mice compared to obese WT mice. We also tested imatinib, a TKI which does not inhibit RIPK2 activity, in obese WT mice. Imatinib lowered blood glucose during a GTT, consistent with TKIs lowering blood glucose independently of RIPK2. However, imatinib increased glucose-stimulated insulin secretion during the glucose challenge. These data show that multiple TKIs lower blood glucose, where actions of TKIs on RIPK2 dictate divergent insulin responses, independent of tissue inflammation. Our data shows that RIPK2 limits the insulin sensitizing effect of gefitinib, whereas imatinib increased insulin secretion.
Detecting fine and elaborate movements with piezo sensors, from heartbeat to the temporal organization of behavior
Authors: Carreño-Muñoz Maria Isabel , Medrano Maria Carmen , Leinekugel Thomas , Bompart Maelys , Martins Fabienne , Subashi Enejda , Aby Franck , Frick Andreas , Landry Marc , Grana Manuel , Leinekugel Xavier 
Published: April 2020

AbstractBehavioral phenotyping devices have been successfully used to build ethograms, but studying the temporal dynamics of individual movements during spontaneous, ongoing behavior, remains a challenge. We now report on a novel device, the Phenotypix, which consists in an open-field platform resting on highly sensitive piezoelectric (electro-mechanical) pressure-sensors, with which we could detect the slightest movements from freely moving rats and mice. The combination with video recordings and signal analysis based on time-frequency decomposition, clustering and machine learning algorithms allowed to quantify various behavioral components with unprecedented accuracy, such as individual heartbeats and breathing cycles during rest, shaking in response to pain or fear, and the dynamics of balance within individual footsteps during spontaneous locomotion. We believe that this device represents a significant progress and offers new opportunities for the awaited advance of behavioral phenotyping.
Intralaboratory evaluation of luminescence based high-throughput Serum Bactericidal Assay (L-SBA) to determine bactericidal activity of human sera againstShigella
Authors: Rossi O. , Molesti E. , Saul A. , Giannelli C. , Micoli F. , Necchi F. 
Published: April 2020

ABSTRACTDespite the huge decrease in deaths caused byShigellaworldwide in the last decades, shigellosis is still causing over 200,000 deaths every year. No vaccine is currently available, and the morbidity of disease coupled with the rise of antimicrobial resistance renders the introduction of an effective vaccine extremely urgent. Although a clear immune correlate of protection against shigellosis has not been established yet, the demonstration of bactericidal activity of antibodies induced upon vaccination may provide one means of functionality of antibodies induced on protecting againstShigella.The method of choice to evaluate the complement-mediated functional activity of vaccine-induced antibodies is the Serum Bactericidal Assay (SBA).Here we present the development and intra-laboratory characterisation of a high-throughput luminescence-based SBA (L-SBA) method, based on the detection of ATP as a proxy of surviving bacteria, to evaluate the complement-mediated killing of human sera. We demonstrated the high specificity of the assay against homologous strain without any heterologous aspecificity detected against species-related and not species-related strains. We assessed linearity, repeatability and reproducibility of L-SBA on human sera.This work will guide the bactericidal activity assessment of clinical sera raised againstS. sonnei.The method has the potential of being applicable with similar performances to determine bactericidal activity of any non-clinical and clinical sera that rely on complement mediated killing.IMPORTANCEShigellais an important cause of diarrhoea worldwide and antimicrobial resistance is on rise, thus efforts by several groups are ongoing to produce a safe and effective vaccine against shigellosis. Although a clear immune correlate of protection has not been established, demonstration of bactericidal capacity of sera from patients immunised withShigellavaccines may provide one means of protecting against shigellosis. We have developed and fully characterised a novel high-throughput L-SBA method for evaluation of functionality of antibodies raised againstS. sonneiin human sera. This work will allow the clinical testing of human sera raised against GMMA-based and potentially all vaccines producing antibodies than can workviacomplement mediated manner.
ACE2gene variants may underlie interindividual variability and susceptibility to COVID-19 in the Italian population
Authors: Elisa Benetti , Rossella Tita , Ottavia Spiga , Andrea Ciolfi , Giovanni Birolo , Alessandro Bruselles , Gabriella Doddato , Annarita Giliberti , Caterina Marconi , Francesco Musacchia , Tommaso Pippucci , Annalaura Torella , Alfonso Trezza , Floriana Valentino , Margherita Baldassarri , Alfredo Brusco , Rosanna Asselta , Mirella Bruttini , Simone Furini , Marco Seri , Vincenzo Nigro , Giuseppe Matullo , Marco Tartaglia , Francesca Mari , Alessandra Renieri , Maria Pinto Anna 
Published: April 2020

ABSTRACTIn December 2019, an initial cluster of interstitial bilateral pneumonia emerged in Wuhan, China. A human-to-human transmission was assumed and a previously unrecognized entity, termed coronavirus-disease-19 (COVID-19) due to a novel coronavirus (SARS-CoV-2) was described. The infection has rapidly spread out all over the world and Italy has been the first European country experiencing the endemic wave with unexpected clinical severity in comparison with Asian countries.It has been shown that SARS-CoV-2 utilizes angiotensin converting enzyme 2 (ACE2) as host receptor and host proteases for cell surface binding and internalization. Thus, a predisposing genetic background can give reason for inter-individual disease susceptibility and/or severity. Taking advantage of the Network of Italian Genomes (NIG), here we mined whole-exome-sequencing data of 6930 Italian control individuals from five different centers looking forACE2variants. A number of variants with a potential impact on protein stability were identified. Among these, three more common missense changes, p.(Asn720Asp), p.(Lys26Arg), p.(Gly211Arg) were predicted to interfere with protein structure and stabilization. Rare variants likely interfering with the internalization process, namely p.(Leu351Val) and p.(Pro389His), predicted to interfere with SARS-CoV-2 spike protein binding, were also observed. Comparison ofACE2WES data between a cohort of 131 patients and 258 controls allowed identifying a statistically significant (P value <0,029) higher allelic variability in controls compared to patients. These findings suggest that a predisposing genetic background may contribute to the observed inter-individual clinical variability associated with COVID-19, allowing an evidence-based risk assessment leading to personalized preventive measures and therapeutic options.