bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic susceptibility to pneumonia: A GWAS meta-analysis between UK Biobank and FinnGen
Authors: Campos Adrian I. , Kho Pik Fang , Vazquez-Prada Karla X. , García-Marín Luis M. , Martin Nicholas G. , Cuéllar-Partida Gabriel , Rentería Miguel E. 
Published: June 2020

ABSTRACTRationalePneumonia is a respiratory condition with complex aetiology. Host genetic variation is thought to contribute to individual differences in susceptibility and symptom manifestation.MethodsWe analysed pneumonia data from the UK Biobank (14,780 cases and 439,096 controls) and FinnGen (9,980 cases and 86,519 controls). We perform genome-wide association study (GWAS) meta-analysis, gene-based test, colocalisation, genetic correlation, latent causal variable and polygenic prediction in an independent Australian sample (N=5,595) to draw insights into the genetic aetiology of pneumonia risk.ResultsWe identify two independent loci on chromosome 15 (lead SNPs rs2009746 and rs76474922) to be associated with pneumonia(p<5e-8). Gene-based tests revealed eighteen genes in chromosomes 15,16 and 9, includingIL127, PBX3, APOBRand smoking related genesCHRNA3/5, associated with pneumonia. Evidence ofHYKKandPBX3involvement in pneumonia risk was supported by eQTL colocalisation analysis. We observed genetic correlations between pneumonia and cardiorespiratory, psychiatric and inflammatory related traits. Latent causal variable analysis suggests a strong genetic causal relationship cardiovascular health phenotypes and pneumonia risk. Polygenic risk scores (PRS) for pneumonia significantly predicted self-reported pneumonia history in an independent Australian sample, albeit with a small effect size (OR=1.11 95%CI=[1.04-1.19], p<0.05). Sensitivity analyses suggested the associations in chromosome 15 are mediated by smoking history, but the association of genes in chromosome 16 and 9, and polygenic prediction were robust to adjustment for smoking.ConclusionsAltogether, our results highlight common genetic variants, genes and potential pathways that contribute to individual differences in susceptibility to pneumonia, and advance our understanding of the genetic factors underlying heterogeneity in respiratory medical outcomes.
An urgent need for a paradigm shift in HIV testing for older children: A sine qua non condition to achieve an AIDS-free generation
Authors: Yumo H.A. , Ndenkeh J.J.N. , Sieleunou I. , Nsame D.N. , Kuwoh P.B. , Beissner M. , Kuaban C. 
Published: June 2020

AbstractBackgroundAchieving an AIDS-free generation requires effective pediatric testing and treatment services. While pediatric HIV testing has been more focused on children below 18 months through PMTCT, the yield of this approach remains unclear comparatively to testing children above 18 months through routine PITC. This study aimed at bridging this evidence gap and provide knowledge to guide pediatric HIV testing investments.Materials and MethodsParents visiting or receiving HIV care in three hospitals in Cameroon were invited to test their children for HIV. HIV testing was done using PCR and antibody rapid tests for children < 18 months and those ≥18 months, respectively. We compared HIV case detection and ART initiation between the two subgroups of children and this using Chi-square test at 5% significant level.ResultsA total of 4079 children aged 6 weeks-15 years were included in the analysis. Compared to children < 18 months, children group ≥18 months was 4-fold higher among those who enrolled in the study (80.3% vs 19.7%, p<0.001); 3.5-fold higher among those who tested for HIV (77.6% vs 22.4%, p<0.001); 6-fold higher among those who tested HIV+ (85.7% vs 14.3%, p=0.241) and 11-fold higher among those who enrolled on ART (91.7% vs 8.3%, p< 0.028).ConclusionsOur results show that 4 out of 5 children who tested HIV+ and over 90% of ART enrolled cases were children ≥ 18 months. Thus, while rolling out PCR HIV testing technology for neonates and infants, committing adequate and proportionate resources in antibody rapid testing for older children is a sine quo none condition to achieve an AIDS-free generation.
Qualitative forecast and temporal evolution of the disease spreading using a simplified model and COVID-19 data for Italy
Authors: Simeone Roberto 
Published: June 2020

AbstractIn a previous paper [1] a simplified SEIR model applied to COVID-19 cases detected in Italy, including the lockdown period, has shown a good fitting to the time evolution of the disease during the observed period.In this paper that model is applied to the initial data available for Italy in order to forecast, in a qualitative way, the time evolution of the disease spreading. The values obtained are to be considered indicative.The same model has been applied both to the data relating to Italy and to some italian regions generally finding good qualitative results.The only tuning parameter in the model is the ‘incubation period’ τ.In this modelization the tuning parameter, together with the calculated growth rate of the exponential curve used to approximate the early stage data, are in strong relationship with the compartments’ transfer rates.The relationships between the parameters simplify modeling by allowing a rough (not supported by statistical considerations) forecast of the time evolution, starting from the first period of growth of the diffusion.ConclusionsA simplified compartmental model that uses only the incubation period and the exponential growth rate as parameters is applied to the COVID-19 data for Italy in several periods of the initial growth of the diffusion showing the different stages of the spread evolution. The simplification is based on the strong protection measures that were in place in Italy during the lockdown period after the initial free diffusion.
Cost-effectiveness and return on investment of protecting health workers in low- and middle-income countries during the COVID-19 pandemic
Authors: Risko Nicholas , Werner Kalin , Offorjebe O. Agatha , Vecino-Ortiz Andres I. , Wallis Lee A. , Razzak Junaid 
Published: June 2020

AbstractBackgroundIn this paper, we predict the health and economic consequences of immediate investment in personal protective equipment (PPE) for health care workers (HCWs) in low- and middle-income countries (LMICs).MethodsTo account for health consequences, we estimated mortality for health care workers (HCW), and present a cost-effectiveness and return on investment (ROI) analysis using a decision-analytic model with Bayesian multivariate sensitivity analysis and Monte Carlo simulation. Inputs were used from the World Health Organization Essential Supplies Forecasting Tool and the Imperial College of London epidemiologic model.ResultsAn investment of $9.6 billion USD would adequately protect HCWs in all LMICs. This intervention saves 2,299,543 lives across LMICs, costing $59 USD per HCW case averted and $4,309 USD per HCW life saved. The societal ROI is $755.3 billion USD, the equivalent of a 7,932% return. Regional and national estimates are also presented. In scenarios where PPE remains scarce, 70-100% of HCWs will get infected, irrespective of nationwide social distancing policies. Maintaining HCW infection rates below 10% and mortality below 1% requires inclusion of a PPE scale-up strategy as part of the pandemic response.DiscussionIn conclusion, wide-scale procurement and distribution of PPE for LMICs is an essential strategy to prevent widespread HCW morbidity and mortality. It is cost-effective and yields a large downstream return on investment.
An agent based modelling approach to study lockdown efficacy for infectious disease spreads
Authors: Pathak Anagh , Mohan Varun Madan , Banerjee Arpan 
Published: June 2020

AbstractWe sought to simulate lockdown scenarios using an Agent Based Modelling (ABM) strategy, which is a new modelling paradigm that seeks to simulate the actions and interactions of autonomous agents within an environment. The spread of infectious viral diseases occur over a connected social network. Specifically, the goal was to understand the effect of network topology and lockdown strategies on disease spreading dynamics. To explore the effect of topology we assumed the social network over which the disease spreads to have small-world or scale-free properties characterized by a rewiring probability and degree distribution respectively. Lockdowns were simulated as intervention strategies that modified the spreading dynamics of infection over a given graph structure through changes in properties of agent interaction. Lockdown efficacy was assessed by the maximum number of infections recorded during a simulation run. Thereafter, lockdown efficacy was evaluated as a function of lockdown start times and duration. Thus, we propose that ABM approach can be used to assess various lockdown strategies that aim to prevent breakdown of medical infrastructure while accounting for realistic social network configurations specific to a local population.Notation
Decoding the microstructural properties of white matter using realistic models
Authors: Hédouin Renaud , Metere Riccardo , Chan Kwok-Shing , Licht Christian , Mollink Jeroen , van Walsum Anne-Marievan Cappellen , Marques José P. 
Published: June 2020

AbstractMulti-echo gradient echo (ME-GRE) magnetic resonance signal evolution in white matter has a strong dependence on the orientation of myelinated axons with respect to the main static field. Although analytical solutions have been able to predict some of the white matter (WM) signal behaviour of the hollow cylinder model, it has been shown that realistic models of WM offer a better description of the signal behaviour observed.In this work, we present a pipeline to (i) generate realistic 2D WM models with their microstructure based on real axon morphology with adjustable fiber volume fraction (FVF) and g-ratio. We (ii) simulate their interaction with the static magnetic field to be able to simulate their MR signal. For the first time, we (iii) demonstrate that realistic 2D WM models can be used to simulate a MR signal that provides a good approximation of the signal obtained from a real 3D WM model derived from electron microscopy. We then (iv) demonstratein silicothat 2D WM models can be used to predict microstructural parameters in a robust way if ME-GRE multi-orientation data is available and the main fiber orientation in each pixel is known using DTI. A deep learning network was trained and characterized in its ability to recover the desired microstructural parameters such as FVF, g-ratio, free and bound water transverse relaxation and magnetic susceptibility. Finally, the network was trained to recover these micro-structural parameters from anex vivodataset acquired in 9 orientations with respect to the magnetic field and 12 echo times. We demonstrate that this is an overdetermined problem and that as few as 3 orientations can already provide comparable results for some of the decoded metrics.[Highlights] - A pipeline to generate realistic white models of arbitrary fiber volume fraction and g-ratio is presented; - We present a methodology to simulated the gradient echo signal from segmented 2D and 3D models of white matter, which takes into account the interaction of the static magnetic field with the anisotropic susceptibility of the myelin phospholipids; - Deep Learning Networks can be used to decode microstructural white matter parameters from the signal of multi-echo multi-orientation data;
Interspecific introgression and natural selection in the evolution of Japanese apricot (Prunus mume)
Authors: Numaguchi Koji , Akagi Takashi , Kitamura Yuto , Ishikawa Ryo , Ishii Takashige 
Published: June 2020

SummaryDomestication and population differentiation in crops involve considerable phenotypic changes. The logs of these evolutionary paths, including natural/artificial selection, can be found in the genomes of the current populations. However, these profiles have been little studied in tree crops, which have specific characters, such as long generation time and clonal propagation, maintaining high levels of heterozygosity.We conducted exon-targeted resequencing of 129 genomes in the genusPrunus, mainly Japanese apricot (Prunus mume), and apricot (P. armeniaca), plum (P. salicina), and peach (P. persica). Based on their genome-wide single nucleotide polymorphisms merged with published resequencing data of 79 ChineseP. mumecultivars, we inferred complete and ongoing population differentiation inP. mume.Sliding window characterization of the indexes for genetic differentiation identified interspecific fragment introgressions betweenP. mumeand related species (plum and apricot). These regions often exhibited strong selective sweeps formed in the paths of establishment or formation of substructures ofP. mume, suggesting thatP. mumehas frequently imported advantageous genes from other species in the subgenusPrunusas adaptive evolution.These findings shed light on the complicated nature of adaptive evolution in a tree crop that has undergone interspecific exchange of genome fragments with natural/artificial selection.
Expression ofAce2, Tmprss2, andFurinin mouse ear tissue
Authors: Uranaka Tsukasa , Kashio Akinori , Ueha Rumi , Sato Taku , Bing Han , Ying Gao , Kinoshita Makoto , Kondo Kenji , Yamasoba Tatsuya 
Published: June 2020

AbstractObjectivesIntracellular entry of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) depends on the interaction between its spike protein to a cellular receptor named angiotensin-converting enzyme 2 (ACE2) and depends on Furin-mediated spike 23 protein cleavage and spike protein priming by host cell proteases including 24 transmembrane protease serine 2 (TMPRSS2).Tmprss1, Tmprss3,andTmprss5are expressed in the spiral ganglion neurons and the organ of Corti in the inner ear; however,Ace2, Tmprss2,andFurinexpression profiles in the middle ear remain unclear. Therefore, this study aimed to analyzeAce2, Tmprss2,andFurinexpression in the middle and inner ear of mice.Study DesignAnimal research.SettingDepartment of Otolaryngology and Head and Neck Surgery, University of Tokyo.MethodsWe performed immunohistochemical analysis to examine the distribution of Ace2, Tmprss2, and Furin in the eustachian tube, middle ear space, and cochlea of mice.ResultsAce2 was expressed in the cytoplasm in the middle ear epithelium, eustachian tube epithelium, stria vascularis, and spiral ganglion. Tmprss2 and Furin were widely expressed in the middle ear spaces and the cochlea.ConclusionCo-expression of Ace2, Tmprss2, and Furin in the middle ear indicates that the middle ear is susceptible to SARS-CoV-2 infections, thus warranting the use of personal protective equipment during mastoidectomy for coronavirus disease (COVID-19) patients.
Spinal Column Architecture of the Flexible SPP1 Bacteriophage Tail Tube
Authors: Zinke Maximilian , Sachowsky Katrin A. A. , Öster Carl , Zinn-Justin Sophie , Ravelli Raimond B.G. , Schröder Gunnar F. , Habeck Michael , Lange Adam 
Published: June 2020

AbstractPhage therapy has recently regained attention at combating multidrug-resistant bacteria. In 2019, tailed bacteriophages of theSiphoviridaefamily were engineered to successfully treat a disseminated bacterial infection after all other drugs had failed.(1) This family of phages features a long, flexible, non-contractile tail that has been difficult to characterize structurally. Here, we present the atomic structure of the tail-tube of the bacteriophage SPP1 – a member of this family. Our hybrid structure is based on the integration of structural restraints from solid-state NMR and a density map from cryo-EM. We show that the tail tube protein (TTP) gp17.1 organizes into hexameric rings that are stacked by flexible linker domains and, thus, form a hollow flexible tube with a negatively charged lumen suitable for the transport of DNA.One sentence summaryIntegrative structural biology by solid-state NMR and cryo-EM enables structure determination of the flexible tail of the bacteriophage SPP1.
DGAT1 is a lipid metabolism oncoprotein that enables cancer cells to accumulate fatty acid while avoiding lipotoxicity
Authors: Wilcock Daniel J. , Badrock Andrew P. , Owen Rhys , Guerin Melissa , Southam Andrew D. , Johnston Hannah , Ogden Samuel , Fullwood Paul , Watson Joanne , Ferguson Harriet , Ferguson Jennifer , Richardson Daniel A. , Lloyd Gavin R. , Jankevics Andris , Dunn Warwick B. , Wellbrock Claudia , Lorigan Paul , Ceol Craig , Francavilla Chiara , Smith Michael P. , Hurlstone Adam F. L. 
Published: June 2020

ABSTRACTDysregulated cellular metabolism is a hallmark of cancer. As yet, few druggable oncoproteins directly responsible for this hallmark have been identified. Increased fatty acid acquisition allows cancer cells to meet their membrane biogenesis, ATP, and signaling needs. Excess fatty acids suppress growth factor signaling and cause oxidative stress in non-transformed cells, but surprisingly not in cancer cells. Molecules underlying this cancer adaptation may provide new drug targets. Here, we identify Diacylglycerol O-acyltransferase 1 (DGAT1), an enzyme integral to triacylglyceride synthesis and lipid droplet formation, as a frequently up-regulated oncoprotein allowing cancer cells to tolerate excess fatty acids. DGAT1 over-expression alone induced melanoma in zebrafish melanocytes, and co-operated with oncogenic BRAF or NRAS for more rapid melanoma formation. Mechanistically, DGAT1 stimulated melanoma cell growth through sustaining mTOR kinase–S6 kinase signaling and suppressed cell death by tempering fatty acid oxidation, thereby preventing accumulation of reactive oxygen species including lipid peroxides.SIGNIFICANCEWe show that DGAT1 is abona fideoncoprotein capable of inducing melanoma formation and co-operating with other known drivers of melanoma. DGAT1 facilitates enhanced fatty acid acquisition by melanoma cells through suppressing lipototoxicity. DGAT1 is also critical for maintaining S6K activity required for melanoma cell growth.
The ketogenic diet is not effective in preclinical models of IDH1 wild-type and IDH1 mutant glioma
Authors: Javier Rodrigo , Horbinski Craig 
Published: June 2020

ABSTRACTInfiltrative gliomas are the most common neoplasms arising in the brain, and remain largely incurable despite decades of research. A subset of these gliomas contains mutations inisocitrate dehydrogenase 1(IDH1mut). This mutation disrupts cellular biochemistry, and IDH1mutgliomas are generally less aggressive than IDH1 wild-type (IDH1wt) gliomas. Some preclinical studies and clinical trials have suggested that a ketogenic diet (KD), characterized by low-carbohydrate and high-fat content, may be beneficial in slowing glioma progression. However, not all studies have shown promising results, and to date, no study has addressed whether IDH1mutgliomas might be more sensitive to KD. The aim of the current study was to compare the effects of KD in preclinical models of IDH1wtversus IDH1mutgliomas.In vitro, simulating KD by treatment with the ketone body β-hydroxybutyrate had no effect on the proliferation of patient-derived IDH1wtor IDH1mutglioma cells. Likewise, KD had no effect on thein vivogrowth of these patient-derived gliomas. Furthermore, mice engrafted with Sleeping-Beauty transposase-engineered IDH1wtand IDH1mutglioma showed no difference in survival while on KD. These data suggest that IDH1mutgliomas are not more responsive to KD, and that clinical trials further exploring KD in this subset of glioma patients may not be warranted.
Quantifying synergy in the bioassay-guided fractionation of natural product extracts
Authors: Dettweiler Micah , Marquez Lewis , Bao Max , Quave Cassandra L. 
Published: June 2020

AbstractMixtures of drugs often have greater therapeutic value than any of their constituent drugs alone, and such combination therapies are widely used to treat diseases such as cancer, malaria, and viral infections. However, developing useful drug mixtures is challenging due to complex interactions between drugs. Natural substances can be fruitful sources of useful drug mixtures because secondary metabolites produced by living organisms do not often act in isolationin vivo. In order to facilitate the study of interactions within natural substances, a new analytical method to quantify interactions using data generated in the process of bioassay-guided fractionation is presented here: the extract fractional inhibitory concentration index (EFICI). The EFICI method uses the framework of Loewe additivity to calculate fractional inhibitory concentration values by which interactions can be determined for any combination of fractions that make up a parent extract. The EFICI method was applied to data on the bioassay-guided fractionation ofLechea mucronataandSchinus terebinthifoliafor growth inhibition of the pathogenic bacteriumAcinetobacter baumannii. TheL. mucronataextract contained synergistic interactions (EFICI = 0.4181) and theS. terebinthifoliaextract was non-interactive overall (EFICI = 0.9129). Quantifying interactions in the bioassay-guided fractionation of natural substances does not require additional experiments and can be useful to guide the experimental process and to support the development of standardized extracts as botanical drugs.
Macrovesicular steatosis in nonalcoholic fatty liver disease is a consequence of purine nucleotide cycle driven fumarate accumulation
Authors: Sinton Matthew C. , Lucendo Villarin Baltasar , Meseguer Ripolles Jose , Wernig-Zorc Sara , Thomson John P. , Walker Paul D. , Thakker Alpesh , Lavery Gareth G. , Ludwig Christian , Tennant Daniel A. , Hay David C. , Drake Amanda J. 
Published: June 2020

SummaryNonalcoholic fatty liver disease (NAFLD) affects ~88% of obese individuals and is characterised by hepatic lipid accumulation. Mitochondrial metabolic dysfunction is a feature of NAFLD. We used a human pluripotent stem cell-based system to determine how mitochondrial dysfunction is linked to hepatic lipid accumulation. We induced lipid accumulation in hepatocyte-like cells (HLCs) using lactate, pyruvate and octanoate (LPO). Transcriptomic analysis revealed perturbation of mitochondrial respiratory pathways in LPO exposed cells. Using13C isotopic tracing, we identified truncation of the TCA cycle in steatotic HLCs. We show that increased purine nucleotide cycle (PNC) activity fuels fumarate accumulation and drives lipid accumulation in steatotic cells. These findings provide new insights into the pathogenesis of hepatic steatosis and may lead to an improved understanding of the metabolic and transcriptional rewiring associated with NAFLD.