bluuebunny/crossref_metadata_2025_split huggingface dataset:
Disrupting the ArcA regulatory network increases tetracycline susceptibility of TetREscherichia coli
Authors: Arrieta-Ortiz Mario L. , Pan Min , Kaur Amardeep , Srinivas Vivek , Dash Ananya , Immanuel Selva Rupa Christinal , Baliga Nitin S. 
Published: September 2020

ABSTRACTThere is an urgent need for strategies to discover secondary drugs to prevent or disrupt antimicrobial resistance (AMR), which is causing >700,000 deaths annually. Here, we demonstrate that tetracycline resistant (TetR)Escherichia coliundergoes global transcriptional and metabolic remodeling, including down-regulation of tricarboxylic acid cycle and disruption of redox homeostasis, to support consumption of the proton motive force for tetracycline efflux. Targeted knockout of ArcA, identified by network analysis as a master regulator among 25 transcription factors of this new compensatory physiological state, significantly increased the susceptibility of TetRE. colito tetracycline treatment. A drug, sertraline, which generated a similar metabolome profile as thearcAknockout strain also synergistically re-sensitized TetRE. colito tetracycline. The potentiating effect of sertraline was eliminated upon knocking outarcA, demonstrating that the mechanism of synergy was through action of sertraline on the tetracycline-induced ArcA network in the TetRstrain. Our findings demonstrate that targeting mechanistic drivers of compensatory physiological states could be a generalizable strategy to re-sensitize AMR pathogens to lost antibiotics.
Immunogenicity studies of various experimental vaccines in chickens
Authors: Vaillant Angel Justiz , Akpaka Patrick E. 
Published: September 2020

AbstractIn this paper, the main objective was to raise chickens’ antibodies against three crucial public health microorganisms: the human immunodeficiency virus-1,Salmonellaspp, andStaphylococcus aureus. Immunogens were prepared from the said microorganisms. Chickens were vaccinated either orally or intramuscularly. After a booster immunization, mostly eggs were collected and assess for the presence of specific antibodies. The most important results were the production of a large amount of anti-HIV antibodies in chicken’s eggs, and also the synthesis of anti-protein A antibodies with the ability to inhibit the growth ofS. aureus in vitroand to serve as anti-anti-idiotypic antibodies with the capacity of neutralizing the original antigen. Enzyme-linked immune absorbent assays detected the presence of these antibodies as anti-Salmonella antibodies that were critical in reducing the bacterial load in the stomach and caeca compared with a control group. The vaccines were effective and safe, but more laboratory work, and economics have to be carried out to start a human trial.
PyClone-VI: Scalable inference of clonal population structures using whole genome data
Authors: Gillis Sierra , Roth Andrew 
Published: September 2020

AbstractWe describe PyClone-VI, a computationally efficient Bayesian statistical method for inferring the clonal population structure of cancers. Our proposed method is 10-100x times faster than existing methods, while providing results which are as accurate. We demonstrate the utility of the method by analyzing data from 1717 patients from PCAWG study and 100 patients from the TRACERx study. Software implementing our method is freely availablehttps://github.com/Roth-Lab/pyclone-vi.
PhosR enables processing and functional analysis of phosphoproteomic data
Authors: Kim Hani Jieun , Kim Taiyun , Hoffman Nolan J , Xiao Di , James David E , Humphrey Sean J , Yang Pengyi 
Published: September 2020

SUMMARYMass spectrometry (MS)-based phosphoproteomics has revolutionised our ability to profile phosphorylation-based signalling in cells and tissues on a global scale. To infer the action of kinases and signalling pathways in phosphoproteomic experiments, we present PhosR, a set of tools and methodologies implemented in a suite of R packages facilitating comprehensive analysis of phosphoproteomic data. By applying PhosR to both published and new phosphoproteomic datasets, we demonstrate capabilities in data imputation and normalisation using a novel set of ‘stably phosphorylated sites’, and in functional analysis for inferring active kinases and signalling pathways. In particular, we introduce a ‘signalome’ construction method for identifying a collection of signalling modules to summarise and visualise the interaction of kinases and their collective actions on signal transduction. Together, our data and findings demonstrate the utility of PhosR in processing and generating novel biological knowledge from MS-based phosphoproteomic data.
Adaptation of codon and amino acid use for translational functions in highly expressed cricket genes
Authors: Whittle Carrie A. , Kulkarni Arpita , Chung Nina , Extavour Cassandra G. 
Published: September 2020

AbstractBackgroundFor multicellular organisms, much remains unknown about the dynamics of synonymous codon and amino acid use in highly expressed genes, including whether their use varies with expression in different tissue types and sexes. Moreover, specific codons and amino acids may have translational functions in highly transcribed genes, that largely depend on their relationships to tRNA gene copies in the genome. However, these relationships and putative functions are poorly understood, particularly in multicellular systems.ResultsHere, we rigorously studied codon and amino acid use in highly expressed genes from reproductive and nervous system tissues (male and female gonad, somatic reproductive system, brain, ventral nerve cord, and male accessory glands) in the cricket Gryllus bimaculatus. We report an optimal codon, defined as the codon preferentially used in highly expressed genes, for each of the 18 amino acids with synonymous codons in this organism. The optimal codons were largely shaped by selection, and their identities were mostly shared among tissue types and both sexes. However, the frequency of optimal codons was highest in gonadal genes. Concordant with translational selection, a majority of the optimal codons had abundant matching tRNA gene copies in the genome, but sometimes obligately required wobble tRNAs. We suggest the latter may comprise a mechanism for slowing translation of abundant transcripts, particularly for cell-cycle genes. Non-optimal codons, defined as those least commonly used in highly transcribed genes, intriguingly often had abundant tRNAs, and had elevated use in a subset of genes with specialized functions (gametic and apoptosis genes), suggesting their use promotes the upregulation of particular mRNAs. In terms of amino acids, we found evidence suggesting that amino acid frequency, tRNA gene copy number, and amino acid biosynthetic costs (size/complexity) had all interdependently evolved in this insect model, potentially for translational optimization.ConclusionsCollectively, the results strongly suggest that codon use in highly expressed genes, including optimal, wobble, and non-optimal codons, and their tRNAs abundances, as well as amino acid use, have been adapted for various functional roles in translation within this cricket. The effects of expression in different tissue types and the two sexes are discussed.
Comparative metagenomics evidence distinct trends of genome evolution between sponge-dwelling bacteria and their pelagic counterparts
Authors: Kelly Joseph B. , Carlson David , Low Jun Siong , Thacker Robert W. 
Published: September 2020

AbstractProkaryotic associations with sponges are among the oldest host-microbiome relationships on Earth. In this study, we investigated how bacteria from several phyla have independently adapted to the sponge interior by comparing metagenome-assembled genomes of sponge-dwelling and pelagic bacteria sourced from broad phylogenetic and geographic samplings. We discovered that sponge-dwelling bacteria have more energetically expensive genomes and share patterns of depletion and enrichment for functional categories of genes that evidence evolution towards lower pathogenicity. We also identified a new defining genomic characteristic of sponge-dwelling bacteria that is virtually absent from pelagic bacteria, the presence of cassettes that contain eukaryotic steroid biosynthesis genes. Collectively, these results illuminate the trends in genome evolution that are associated with a sponge-dwelling life history strategy and have implications for furthering our understanding of how sponge-microbial symbioses have persisted through deep evolutionary time.ImportanceMuch attention has recently been devoted to investigating the evolution of microbes that live in symbiosis with sponge hosts using microbial metagenomic data. However, several biological questions regarding this symbiosis remain unanswered. Two questions that we address here are: 1) what are the long-term consequences of the symbiosis on the evolution of microbial symbiont genome size, protein content, and nucleotide content, and 2) how is the evolution of virulence in sponge-dwelling microbial symbionts, which generally undergo a mixed transmission modes (e.g. horizontal and vertical), related to long-term stability of the symbiosis? By employing the largest comparative metagenomic analysis to date in terms of host sponge species and geographic representation, we address these questions and provide further resolution into the evolutionary processes that are involved in mediating the crosstalk between sponge hosts and their microbial symbionts.
Characterization of neutralizing versus binding antibodies and memory B cells in COVID-19 recovered individuals from India
Authors: Nayak Kaustuv , Gottimukkala Kamalvishnu , Kumar Sanjeev , Reddy Elluri Seetharami , Edara Venkata Viswanadh , Kauffman Robert , Floyd Katharine , Mantus Grace , Savargaonkar Deepali , Goel Pawan Kumar , Arora Satyam , Rahi Manju , Davis Carl W , Linderman Susanne , Wrammert Jens , Suthar Mehul S , Ahmed Rafi , Sharma Amit , Murali-Krishna Kaja , Chandele Anmol 
Published: September 2020

AbstractIndia is one of the countries most affected by the recent COVID-19 pandemic. Characterization of humoral responses to SARS-CoV-2 infection, including immunoglobulin isotype usage, neutralizing activity and memory B cell generation, is necessary to provide critical insights on the formation of immune memory in Indian subjects. In this study, we evaluated SARS-CoV-2 receptor-binding domain (RBD)-specific IgG, IgM, and IgA antibody responses, neutralization of live virus, and RBD-specific memory B cell responses in pre-pandemic healthy versus convalescent COVID-19 individuals from India. We observed substantial heterogeneity in the formation of humoral and B cell memory post COVID-19 recovery. While a vast majority (38/42, 90.47%) of COVID-19 recovered individuals developed SARS-CoV-2 RBD-specific IgG responses, only half of them had appreciable neutralizing antibody titers. RBD-specific IgG titers correlated with these neutralizing antibody titers as well as with RBD-specific memory B cell frequencies. In contrast, IgG titers measured against SARS-CoV-2 whole virus preparation, which includes responses to additional viral proteins besides RBD, did not show robust correlation. Our results suggest that assessing RBD-specific IgG titers can serve as a surrogate assay to determine the neutralizing antibody response. These observations have timely implications for identifying potential plasma therapy donors based on RBD-specific IgG in resource-limited settings where routine performance of neutralization assays remains a challenge.ImportanceOur study provides an understanding of SARS-CoV-2-specific neutralizing antibodies, binding antibodies and memory B cells in COVID-19 convalescent subjects from India. Our study highlights that PCR-confirmed convalescent COVID-19 individuals develop SARS-CoV-2 RBD-specific IgG antibodies, which correlate strongly with their neutralizing antibody titers. RBD-specific IgG titers, thus, can serve as a valuable surrogate measurement for neutralizing antibody responses. These finding have timely significance for selection of appropriate individuals as donors for plasma intervention strategies, as well as determining vaccine efficacy.
A versatile reporter system to monitor virus infected cells and its application to dengue virus and SARS-CoV-2
Authors: Pahmeier Felix , Neufeldt Christoper J , Cerikan Berati , Prasad Vibhu , Pape Costantin , Laketa Vibor , Ruggieri Alessia , Bartenschlager Ralf , Cortese Mirko 
Published: September 2020

ABSTRACTPositive-strand RNA viruses have been the etiological agents in several major disease outbreaks over the last few decades. Examples of that are flaviviruses, such as dengue virus and Zika virus that cause millions of yearly infections and spread around the globe, and coronaviruses, such as SARS-CoV-2, which is the cause of the current pandemic. The severity of outbreaks caused by these viruses stresses the importance of virology research in determining mechanisms to limit virus spread and to curb disease severity. Such studies require molecular tools to decipher virus-host interactions and to develop effective interventions. Here, we describe the generation and characterization of a reporter system to visualize dengue virus and SARS-CoV-2 replication in live cells. The system is based on viral protease activity causing cleavage and nuclear translocation of an engineered fluorescent protein that is expressed in the infected cells. We show the suitability of the system for live cell imaging and visualization of single infected cells as well as for screening and testing of antiviral compounds. Given the modular building blocks, the system is easy to manipulate and can be adapted to any virus encoding a protease, thus offering a high degree of flexibility.IMPORTANCEReporter systems are useful tools for fast and quantitative visualization of viral replication and spread within a host cell population. Here we describe a reporter system that takes advantage of virus-encoded proteases that are expressed in infected cells to cleave an ER-anchored fluorescent protein fused to a nuclear localization sequence. Upon cleavage, the fluorescent protein translocates to the nucleus, allowing for rapid detection of the infected cells. Using this system, we demonstrate reliable reporting activity for two major human pathogens from theFlaviviridaeand theCoronaviridaefamilies: dengue virus and SARS-CoV-2. We apply this reporter system to live cell imaging and use it for proof-of-concept to validate antiviral activity of a nucleoside analogue. This reporter system is not only an invaluable tool for the characterization of viral replication, but also for the discovery and development of antivirals that are urgently needed to halt the spread of these viruses.
SARS-CoV-2 causes severe alveolar inflammation and barrier dysfunction
Authors: Deinhardt-Emmer Stefanie , Böttcher Sarah , Häring Clio , Giebeler Liane , Henke Andreas , Zell Roland , Hornung Franziska , Brandt Christian , Marquet Mike , Mosig Alexander S. , Pletz Mathias W. , Schacke Michael , Rödel Jürgen , Heller Regine , Nietzsche Sandor , Löffler Bettina , Ehrhardt Christina 
Published: September 2020

ABSTRACTInfections with SARS-CoV-2 lead to mild to severe coronavirus disease-19 (COVID-19) with systemic symptoms. Although the viral infection originates in the respiratory system, it is unclear how the virus can overcome the alveolar barrier, which is observed in severe COVID-19 disease courses.To elucidate the viral effects on the barrier integrity and immune reactions, we used mono-cell culture systems and a complex human alveolus-on-a-chip model composed of epithelial, endothelial, and mononuclear cells.Our data show that SARS-CoV-2 efficiently infected epithelial cells with high viral loads and inflammatory response, including the interferon expression. By contrast, the adjacent endothelial layer was no infected and did neither show productive virus replication or interferon release. With prolonged infection, both cell types are damaged, and the barrier function is deteriorated, allowing the viral particles to overbear.In our study, we demonstrate that although SARS-CoV-2 is dependent on the epithelium for efficient replication, the neighboring endothelial cells are affected, e.g., by the epithelial cytokine release, which results in the damage of the alveolar barrier function and viral dissemination.
Remote Vision Testing: Validation Of A Simple Home-Printable Vision Screening Test for Telemedicine
Authors: Crossland Michael D , Dekker Tessa M , Hancox Joanne , Lisi Matteo , Wemyss Thomas A , Thomas Peter BM 
Published: September 2020

AbstractImportanceHundreds of thousands of ophthalmology clinic appointments have been converted to telemedicine assessments. Here we validate a simple paper vision test (the Home Acuity Test) for ophthalmology telemedicine appointments, which can be used by people who are digitally excluded.ObjectiveTo determine the repeatability of vision measured on the Home Acuity Test, and the agreement between the Home Acuity Test and the last in-clinic visual acuity.DesignBland-Altman analysis of the Home Acuity Test chart, compared to the last measured visual acuity on a standard clinical test.SettingRoutine outpatient ophthalmology telemedicine clinics in a large specialist eye hospital.Participants50 control subjects with no eye disease and 100 consecutive adult ophthalmology outpatients from strabismus and low vision telemedicine clinics. Participants were excluded if they reported subjective changes in their vision.Main outcomes and measuresFor control participants, test/retest variability of the HAT and agreement with standard logMAR visual acuity measurement. For ophthalmology outpatients, agreement with the last recorded clinic visual acuity and with ICD-11 visual impairment category.Results50 control subjects and 100 ophthalmology patients with a wide range of disease were recruited. For control participants, Home Acuity Test test/retest variability was -0.012 logMAR (95% CI: -0.25 to 0.11 logMAR). Agreement with standard vision charts was -0.14 logMAR, with a 95% confidence interval of -0.39 to +0.12 logMAR. For ophthalmology outpatients, agreement in visual acuity was -0.10 logMAR (one line on a conventional logMAR sight chart), with the Home Acuity Test indicating poorer vision than the previous in-clinic test. The 95% confidence interval for difference was –0.44 to +0.24 logMAR. Agreement in visual impairment category was good for patients (Cohen’s k test, k = 0.77 (95% CI, 0.74 to 0.81), and control participants (Cohen’s k test, k = 0.88 (95% CI, 0.88 to 0.88).Conclusions and relevanceThe Home Acuity Test can be used to measure vision by telephone for a wide range of ophthalmology outpatients with diverse conditions, including those who are severely visually impaired. Test/retest variability is low and agreement in visual impairment category is good.
A neutrophil activation signature predicts critical illness and mortality in COVID-19
Authors: Meizlish Matthew L. , Pine Alexander B. , Bishai Jason D. , Goshua George , Nadelmann Emily R. , Simonov Michael , Chang C-Hong , Zhang Hanming , Shallow Marcus , Bahel Parveen , Owusu Kent , Yamamoto Yu , Arora Tanima , Atri Deepak S. , Patel Amisha , Gbyli Rana , Kwan Jennifer , Won Christine H. , Cruz Charles Dela , Price Christina , Koff Jonathan , King Brett A. , Rinder Henry M. , Wilson F. Perry , Hwa John , Halene Stephanie , Damsky William , Dijk David van , Lee Alfred I. , Chun Hyung J. 
Published: September 2020

AbstractPathologic immune hyperactivation is emerging as a key feature of critical illness in COVID-19, but the mechanisms involved remain poorly understood. We carried out proteomic profiling of plasma from cross-sectional and longitudinal cohorts of hospitalized patients with COVID-19 and analyzed clinical data from our health system database of over 3,300 patients. Using a machine learning algorithm, we identified a prominent signature of neutrophil activation, including resistin, lipocalin-2, HGF, IL-8, and G-CSF, as the strongest predictors of critical illness. Neutrophil activation was present on the first day of hospitalization in patients who would only later require transfer to the intensive care unit, thus preceding the onset of critical illness and predicting increased mortality. In the health system database, early elevations in developing and mature neutrophil counts also predicted higher mortality rates. Altogether, we define an essential role for neutrophil activation in the pathogenesis of severe COVID-19 and identify molecular neutrophil markers that distinguish patients at risk of future clinical decompensation.
Convalescent plasma as potential therapy for severe COVID-19 pneumonia
Authors: Valentini Ricardo , Fernández José , Riveros Dardo , Pálizas Fernando , Solimano Jorge , Saúl Pablo , Medina Juan , Falasco Viviana , Dupont María Laura , Laviano Julia , Fornillo Florencia , Maymó Daniela , Gotta Daniel , Martinez Alfredo , Bonvehí Pablo , Dupont Juan 
Published: September 2020

AbstractAt the beginning of the COVID-19 pandemic, there was high mortality and a lack of effective treatment for critically ill patients. Build on the experience in argentine hemorrhagic fever with convalescent plasma, we incorporated 90 patients into a multicenter study, and 87 were evaluable. We collected 397 donations from 278 convalescent donors. Patients received plasma with an IgG concentration of 0.7-0.8 (measured by Abbott chemiluminescence) for every 10 kg of body weight. Survival during the first 28 days was the primary objective. 77% were male, age 54 ± 15.6 y/o (range 27-85); body mass index 29.7 ± 4,4; hypertension 39% and diabetes 20%; 19.5% had an immunosuppression condition; 23% were healthcare workers. Plasma was administered to 55 patients (63%) on spontaneous breathing with oxygen supplementation (mainly oxygen mask with reservoir bag in 80%), and 32 patients (37%) were infused on mechanical ventilation. The 28-day survival rate was 80%, with 91% in patients infused on spontaneous breathing and 63% in those infused on mechanical ventilation (p = 0.0002). There was a significant improvement in the WHO pneumonia clinical scale at 7 and 14 days, and in PaO2 / FiO2, ferritin and LDH, in the week post-infusion. We observed an episode of circulatory volume overload and a febrile reaction, both mild. Convalescent plasma infusions are feasible, safe, and potentially effective, especially before requiring mechanical ventilation, and are an attractive clinical option for treating severe forms of COVID-19 until other effective therapies become available.