bluuebunny/crossref_metadata_2025_split huggingface dataset:
Zika virus-like particles bearing covalent dimer of envelope protein protect mice from lethal challenge
Authors: De Lorenzo Giuditta , Tandavanitj Rapeepat , Doig Jennifer , Setthapramote Chayanee , Poggianella Monica , Velazquez Ricardo Sanchez , Scales Hannah E. , Edgar Julia M. , Kohl Alain , Brewer James , Burrone Oscar R. , Patel Arvind H. 
Published: July 2020

AbstractZika virus (ZIKV) envelope (E) protein is the major target of neutralizing antibodies in infected host, and thus represents a candidate of interest for vaccine design. However, a major concern in the development of vaccines against ZIKV and the related dengue virus is the induction of cross-reactive poorly neutralizing antibodies that can cause antibody-dependent enhancement (ADE) of infection. This risk necessitates particular care in vaccine design. Specifically, the engineered immunogens should have their cross-reactive epitopes masked, and they should be optimized for eliciting virus-specific strongly neutralizing antibodies upon vaccination. Here, we developed ZIKV subunit- and virus-like particle (VLP)-based vaccines displaying E in its wild type form, or E locked in a covalently linked dimeric (cvD) conformation to enhance the exposure of E dimers to the immune system. Compared with their wild-type derivatives, cvD immunogens elicited antibody with higher capacity of neutralizing virus infection of cultured cells. More importantly, these immunogens protected animals from lethal challenge with both the African and Asian lineages of ZIKV, impairing virus dissemination to brain and sexual organs. Moreover, the locked conformation of E reduced the exposure of epitopes recognized by cross-reactive antibodies and therefore showed a lower potential to induce ADEin vitro. Our data demonstrated a higher efficacy of the VLPs in comparison with the soluble dimer and support VLP-cvD as a promising ZIKV vaccine.Author SummaryInfection with Zika virus (ZIKV) leads to the production by host of antibodies that target the viral surface envelope (E) protein. A subset of these antibodies can inhibit virus infection, thus making E as a suitable candidate for the development of vaccine against the virus. However, the anti-ZIKV E antibodies can cross-react with the E protein of the related dengue virus on account of the high level of similarity exhibited by the two viral proteins. Such a scenario may lead to severe dengue disease. Therefore, the design of a ZIKV vaccine requires particular care. Here, we tested two candidate vaccines containing a recombinant form of the ZIKV E protein that is forced in a covalently stable dimeric conformation (cvD). They were generated with an explicit aim to reduce the exposure of the cross-reactive epitopes. One vaccine is composed of a soluble form of the E protein (sE-cvD), the other is a more complex virus-like particle (VLP-cvD). We used the two candidate vaccines to immunize mice and later infected with ZIKV. The animals produced high level of inhibitory antibodies and were protected from the infection. The VLP-cvD was the most effective and we believe it represents a promising ZIKV vaccine candidate.
Transmission dynamics and control measures of COVID-19 outbreak in China: a modelling study
Authors: Zhang Xu-Sheng , Vynnycky Emilia , Charlett Andre , de Angelis Daniela , Chen Zhengji ,   PHE COVID-19 modelling group, Liu Wei 
Published: July 2020

AbstractCOVID-19 is reported to have been effectively brought under control in China at its initial start place. To understand the COVID-19 outbreak in China and provide potential lessons for other parts of the world, in this study we combine a mathematical modelling with multiple datasets to estimate its transmissibility and severity and how it was affected by the unprecedented control measures. Our analyses show that before 29thJanuary 2020, the ascertainment rate is 6.9%(95%CI: 3.5 – 14.6%); then it increased to 41.5%(95%CI: 30.6 – 65.1%). The basic reproduction number (R0) was 2.23(95%CI: 1.86 – 3.22) before 8thFebruary 2020; then it dropped to 0.04(95%CI: 0.01 – 0.10). This estimation also indicates that the effect on transmissibility of control measures taken since 23rdJanuary 2020 emerged about two weeks late. The confirmed case fatality rate is estimated at 4.41%(95%CI: 3.65 – 5.30%). This shows that SARS-CoV-2 virus is highly transmissible but less severe than SARS-CoV-1 and MERS-CoV. We found that at the early stage, the majority ofR0comes from the undetected infected people. This implies that the successful control in China was achieved through decreasing the contact rates among people in general populations and increasing the rate of detection and quarantine of the infected cases.
“An exploratory Integrated Moving Average Time Series Model of the initial outbreak of COVID-19 in six (6) significantly impacted Countries”
Authors: Pascarella Joseph E. , Pascarella Elaina 
Published: July 2020

AbstractThe 2019 Novel Coronavirus SARS-CoV-2 (COVID-19) is a single-stranded RNA virus that has threatened the lives of humans all over the globe. Government officials, policy makers and public health officials have been scrambling and struggling to “flatten the curve” to decelerate the prevalence and spread of COVID-19 given the significant economic destruction of the spread of the virus. Most “flatten the curve” models are based on Compartmental Models. This preliminary research is based on six (6) selected countries significantly impacted by COVID-19 and endeavors to build a new model based on moving averages lagged at different time periods to better hone in on the time the COVID-19 begins to decelerate using the date of first reported case and date of first reported death. This new model, the Consistent Deceleration Model (CDM) is based on each individual country’s date of Peak Increase in Mortality Rate (PINC MR) and the Moving Average since the peak increase in mortality rate (MA POSTINC). The CDM can be utilized of one of many quantitative tools to determine the strength of the deceleration of an infectious outbreak.
A minimal model for household effects in epidemics
Authors: Huber Greg , Kamb Mason , Kawagoe Kyle , Li Lucy M. , Veytsman Boris , Yllanes David , Zigmond Dan 
Published: July 2020

AbstractShelter-in-place and other confinement strategies implemented in the current COVID-19 pandemic have created stratified patterns of contacts between people: close contacts within households and more distant contacts between the households. The epidemic transmission dynamics is significantly modified as a consequence.We introduce a minimal model that incorporates these household effects in the framework of mean-field theory and numerical simulations. We show that the reproduction number R0 depends on the household size in a surprising way: linearly for relatively small households, and as a square root of size for larger households. We discuss the implications of the findings for the lockdown, test, tracing, and isolation policies.
Analysis of exome-sequenced UK Biobank subjects implicates genes affecting risk of hyperlipidaemia
Authors: Curtis David 
Published: July 2020

AbstractRare genetic variants in LDLR, APOB and PCSK9 are known causes of familial hypercholesterolaemia and it is expected that rare variants in other genes will also have effects on hyperlipidaemia risk although such genes remain to be identified. The UK Biobank consists of a sample of 500,000 volunteers and exome sequence data is available for 50,000 of them. 11,490 of these were classified as hyperlipidaemia cases on the basis of having a relevant diagnosis recorded and/or taking lipid-lowering medication while the remaining 38,463 were treated as controls. Variants in each gene were assigned weights according to rarity and predicted impact and overall weighted burden scores were compared between cases and controls, including population principal components as covariates. One biologically plausible gene, HUWE1, produced statistically significant evidence for association after correction for testing 22,028 genes with a signed log10 p value (SLP) of −6.15, suggesting a protective effect of variants in this gene. Other genes with uncorrected p<0.001 are arguably also of interest, including LDLR (SLP=3.67), RBP2 (SLP=3.14), NPFFR1 (SLP=3.02) and ACOT9 (SLP=-3.19). Gene set analysis indicated that rare variants in genes involved in metabolism and energy can influence hyperlipidaemia risk. Overall, the results provide some leads which might be followed up with functional studies and which could be tested in additional data sets as these become available. This research has been conducted using the UK Biobank Resource.
Intelligent Pneumonia Identification from Chest X-Rays: A Systematic Literature Review
Authors: Khan Wasif , Zaki Nazar , Ali Luqman 
Published: July 2020

ABSTRACTChest radiography is an important diagnostic tool for chest-related diseases. Medical imaging research is currently embracing the automatic detection techniques used in computer vision. Over the past decade, Deep Learning techniques have shown an enormous breakthrough in the field of medical diagnostics. Various automated systems have been proposed for the rapid detection of pneumonia on chest x-rays images Although such detection algorithms are many and varied, they have not been summarized into a review that would assist practitioners in selecting the best methods from a real-time perspective, perceiving the available datasets, and understanding the currently achieved results in this domain. This paper overviews the current literature on pneumonia identification from chest x-ray images. After summarizing the topic, the review analyzes the usability, goodness factors, and computational complexities of the algorithms that implement these techniques. It also discusses the quality, usability, and size of the available datasets, and ways of coping with unbalanced datasets.
Identification of bioactive metabolites in human iPSC-derived dopaminergic neurons with PARK2 mutation: altered mitochondrial and energy metabolism
Authors: Okarmus Justyna , Havelund Jesper F. , Ryding Matias , Schmidt Sissel I. , Bogetofte Helle , Færgeman Nils J. , Hyttel Poul , Meyer Morten 
Published: July 2020

AbstractPARK2(parkin) mutations cause early onset of autosomal recessively inherited Parkinson’s disease (PD). Parkin is an ubiquitin E3 ligase and has been reported to participate in several cellular functions, including mitochondrial homeostasis. However, the specific metabolomic changes caused by parkin depletion remain largely unknown. Human induced pluripotent stem cells (iPSCs) withPARK2knockout (KO) provide a valuable model for studying parkin dysfunction in dopaminergic neurons. In the current study, we used isogenic iPSCs to investigate the effect of parkin loss-of-function by comparative metabolomics analysis. The metabolomic profile of thePARK2KO neurons differed substantially from that of healthy controls. We found increased tricarboxylic acid (TCA) cycle activity, perturbed mitochondrial ultrastructure connected with ATP depletion, glycolysis dysregulation with lactate accumulation, and elevated levels of short- and long-chain carnitines. These mitochondrial and energy perturbations in thePARK2KO neurons were combined with increased levels of oxidative stress and a decreased anti-oxidative response. In conclusion, our data describe a unique metabolomic profile associated with parkin dysfunction, demonstrating several PD-related cellular defects. Our findings support and expand previously described PD phenotypic features and show that combining metabolomic analysis with an iPSC-derived dopaminergic neuronal model of PD is a valuable approach to obtain novel insight into the disease pathogenesis.
Panton Valentine leucocidin enhances community-acquired methicillin-resistantStaphylococcus aureuscolonisation of the gut
Authors: Couzon Florence , Bourgeois-Nicolaos Nadège , Benito Yvonne , Larroude Macarena , Tristan Anne , Rasigade Jean-Philippe , Diep Binh An , Doucet-Populaire Florence , Vandenesch François 
Published: July 2020

AbstractObjectiveCommunity-acquired methicillin resistantStaphylococcus aureus(CA-MRSA) independently emerged and became epidemic at the end of the 20thcentury. Since gut carriage was reported for CA-MRSA and since the common feature of historical CA-MRSA is to harbour Panton Valentine leucocidin (PVL), the question of the possible involvement of this toxin in gut carriage was investigated in mice and cellular models.MethodsCA-MRSA of three lineages (USA300, USA1100, and ST80) and their isogenic Δpvlderivatives, were tested in competition for gut colonisation in mice and in a model of bacterial adhesion to mucus-producing intestinal epithelial cells.ResultsMice inoculated with CA-MRSA and their Δpvlderivatives had their gut successfully colonised by the three lineages regardless of the presence of PVL; however, the wild type (WT) CA-MRSA outcompeted the Δpvlderivatives by at least 3 log after 40 days for all lineages tested.In vitrocompetition of CA-MRSA with their Δpvlderivatives showed no fitness disequilibrium after 6 weeks, ensuring that the results obtained in mice did not result from direct bacterial interference. Direct fluorescence assay of mice intestine showedS. aureuslocalised at the mucosal surface of the intestine and within the intestinal crypts, but not within epithelial cells, suggesting a bacterial tropism for the mucus layer. Significant difference in adhesion to intestinal epithelial cells between WT andpvlknockout was only observed on mucus-producing cells, and not on non-producing ones.ConclusionPVL enhances CA-MRSA gut colonisation in mice by a mechanism involving adhesion-colonisation of the mucus layer.
Optimization of On-Bead Emulsion Polymerase Chain Reaction Based on Single Particle Analysis
Authors: Siu Ryan H.P. , Liu Yang A. , Chan Kaitlin H. Y. , Ridzewski Clara , Slaughter Liane Siu , Wu Angela R. 
Published: July 2020

AbstractEmulsion polymerase chain reaction (ePCR) enables parallel amplification of millions of different DNA molecules while avoiding bias and chimeric byproducts, essential criteria for applications including next generation sequencing, aptamer selection, and protein-DNA interaction studies. Despite these advantages, ePCR remains underused due to the lack of optimal starting conditions, straightforward methods to evaluate success, and guidelines for tuning the reaction. This knowledge has been elusive for bulk emulsion generation methods, such as stirring, the only methods that can emulsify libraries of ≥108sequences within minutes, because these emulsions have not been characterized in ways that preserve the heterogeneity that defines successful ePCR. Our study systematically quantifies the influence of tuning individual ePCR parameters by single particle analysis, which preserves this heterogeneity. We combine ePCR with magnetic microbeads and quantify the amplification yield via qPCR and the proportion of clonal and saturated beads via flow cytometry. Our single particle level analysis of thousands of beads resolves two key criteria that define the success of ePCR: 1) whether the target fraction of 20% clonal beads predicted by the Poisson distribution is achieved, and 2) whether those beads are partially or maximally covered by amplified DNA. We found that increasing the polymerase concentration 20-fold in ePCR over recommended concentrations for conventional PCR was necessary to obtain sufficient PCR products. Surprisingly, dramatical increases in the concentrations of reverse primer and nucleotides recommended in literature gave no measurable change in outcome. We thus provide evidence-based starting conditions for effective and economical ePCR for real DNA libraries and a straightforward workflow for evaluating the success of tuning ePCR prior to downstream applications.
Analysis of neuronal Ca2+handling properties by combining perforated patch clamp recordings and the added buffer approach
Authors: Hess Simon , Pouzat Christophe , Paeger Lars , Pippow Andreas , Kloppenburg Peter 
Published: July 2020

AbstractCa2+functions as an important intracellular signal for a wide range of cellular processes. These processes are selectively activated by controlled spatiotemporal dynamics of the free cytosolic Ca2+. Intracellular Ca2+dynamics are regulated by numerous cellular parameters. Here, we established a new way to determine neuronal Ca2+handling properties by combining the ‘added buffer’ approach (Neher and Augustine, 1992) with perforated patch-clamp recordings (Horn and Marty, 1988). Since the added buffer approach typically employs the standard whole-cell configuration for concentration-controlled Ca2+indicator loading, it only allows for the reliable estimation of the immobile fraction of intracellular Ca2+buffers. Furthermore, crucial components of intracellular signaling pathways are being washed out during prolonged whole-cell recordings, leading to cellular deterioration. By combining the added buffer approach with perforated patch-clamp recordings, these issues are circumvented, allowing the precise quantification of the cellular Ca2+handling properties, including immobile as well as mobile Ca2+buffers.
Widespread retention of ohnologs in key developmental gene families following whole genome duplication in arachnopulmonates
Authors: Harper Amber , Gonzalez Luis Baudouin , Schönauer Anna , Janssen Ralf , Seiter Michael , Holzem Michaela , Arif Saad , McGregor Alistair P. , Sumner-Rooney Lauren 
Published: July 2020

ABSTRACTWhole genome duplications have occurred multiple times during animal evolution, including in lineages leading to vertebrates, teleosts, horseshoe crabs and arachnopulmonates. These dramatic events initially produce a wealth of new genetic material, generally followed by extensive gene loss. It appears, however, that developmental genes such as homeobox genes, signalling pathway components and microRNAs are frequently retained as duplicates (so called ohnologs) following whole-genome duplication. These not only provide the best evidence for whole-genome duplication, but an opportunity to study its evolutionary consequences. Although these genes are well studied in the context of vertebrate whole-genome duplication, similar comparisons across the extant arachnopulmonate orders are patchy. We sequenced embryonic transcriptomes from two spider species and two amblypygid species and surveyed three important gene families, Hox, Wnt and frizzled, across these and twelve existing transcriptomic and genomic resources for chelicerates. We report extensive retention of putative ohnologs, including amblypygids, further supporting the ancestral arachnopulmonate whole-genome duplication. We also find evidence of consistent evolutionary trajectories in Hox and Wnt gene repertoires across three of the five arachnopulmonate orders, with inter-order variation in the retention of specific paralogs. We identify variation between major clades in spiders and are better able to reconstruct the chronology of gene duplications and losses in spiders, amblypygids, and scorpions. These insights shed light on the evolution of the developmental toolkit in arachnopulmonates, highlight the importance of the comparative approach within lineages, and provide substantial new transcriptomic data for future study.
A Model of the Transition to Behavioral and Cognitive Modernity using Reflexively Autocatalytic Networks
Authors: Gabora Liane , Steel Mike 
Published: July 2020

AbstractThis paper proposes a model of the cognitive mechanisms underlying the transition to behavioral and cognitive modernity in the Upper Paleolithic using autocatalytic networks. These networks have been used to model life’s origins. More recently, they have been applied to the emergence ofcognitivestructure capable of undergoingculturalevolution. Mental representations of knowledge and experiences play the role of catalytic molecules, the interactions among them (e.g., the forging of new associations or affordances) play the role of reactions, and thought processes are modeled as chains of these interactions. We posit that one or more genetic mutations may have allowed thought to be spontaneously tailored to the situation by modulating the degree of (1) divergence (versus convergence), (2) abstractness (versus concreteness), and (3) context-specificity. This culminated in persistent, unified autocatalytic semantic networks that bridged previously compartmentalized knowledge and experience. We explain the model using one of the oldest-known uncontested examples of figurative art: the carving of the Hohlenstein-Stadel Löwenmensch, or lion-man. The approach keeps track of where in a cultural lineage each innovation appears, and models cumulative change step by step. It paves the way for a broad scientific framework for the origins of both biological and cultural evolutionary processes.
Functional and structural characterization of allosteric activation of Phospholipase Cε by Rap1A
Authors: Sieng Monita , Selvia Arielle F. , Garland-Kuntz Elisabeth E. , Hopkins Jesse B. , Fisher Isaac J. , Marti Andrea T. , Lyon Angeline M. 
Published: July 2020

ABSTRACTPhospholipase Cε (PLCε) is activated downstream of G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs) through direct interactions with small GTPases, including Rap1A and Ras. While Ras has been reported to allosterically activate the lipase, it is not known whether Rap1A has the same ability, or what its molecular mechanism might be. Rap1A activates PLCε in response to the stimulation of β-adrenergic receptors (β-ARs), translocating the complex to the perinuclear membrane. Because the C-terminal Ras association (RA2) domain of PLCε was proposed to the primary binding site for Rap1A, we first confirmed using purified proteins that the RA2 domain is indeed essential for activation by Rap1A. However, we also showed that the PLCε pleckstrin homology (PH) domain and first two EF hands (EF1/2) are required for Rap1A activation, and identified hydrophobic residues on the surface of the RA2 domain that are also necessary for activation by the GTPase. Finally, small angle X-ray scattering (SAXS) showed that Rap1A binding induces and stabilizes discrete conformational states in PLCε variants that can be activated by the GTPase. This data, together with the recent structure of a catalytically active fragment of PLCε, provide the first evidence that Rap1A, and by extension Ras, allosterically activate the lipase by promoting and stabilizing interactions between the RA2 domain and the PLC core.
Selective cross-linking of coinciding protein assemblies by in-gel cross-linking mass-spectrometry
Authors: Hevler Johannes F. , Lukassen Marie V. , Cabrera-Orefice Alfredo , Arnold Susanne , Pronker Matti F. , Franc Vojtech , Heck Albert J.R. 
Published: July 2020

AbstractCross-linking mass spectrometry has developed into an important method to study protein structures and interactions. The in-solution cross-linking workflows involve time and sample consuming steps and do not provide sensible solutions for differentiating cross-links obtained from co-occurring protein oligomers, complexes, or conformers. Here we developed a cross-linking workflow combining blue native PAGE with in-gel cross-linking mass spectrometry (IGX-MS). This workflow circumvents steps, such as buffer exchange and cross-linker concentration optimization. Additionally, IGX-MS enables the parallel analysis of co-occurring protein complexes using only small amounts of sample. Another benefit of IGX-MS observed by experiments on GroEL and purified bovine heart mitochondria, is the substantial reduction of artificial over-length cross-links when compared to in-solution cross-linking. We next used IGX-MS to investigate the complement components C5, C6, and their hetero-dimeric C5b6 complex. The obtained cross-links were used to generate a refined structural model of the complement component C6, resembling C6 in its inactivated state. This finding shows that IGX-MS can be used to provide new insights into the initial stages of the terminal complement pathway.