bluuebunny/crossref_metadata_2025_split huggingface dataset:
Geospatial analysis reveals distinct hotspots of severe mental illness
Authors: Song Janet , Ramírez Mauricio Castaño , Okano Justin , Service Susan K. , de la Hoz Juan , Díaz-Zuluaga Ana M , Upegui Cristian Vargas , Gallago Cristian , Arias Alejandro , Sánchez Alexandra Valderrama , Teshiba Terri , Sabatti Chiara , Gur Ruben C. , Bearden Carrie E. , Escobar Javier I. , Reus Victor I. , Jaramillo Carlos Lopez , Freimer Nelson B. , Olde Loohuis Loes M. , Blower Sally 
Published: March 2022

AbstractBackgroundThe identification of geographic variation in incidence can be an important step in the delineation of disease risk factors, but has mostly been undertaken in upper-income countries. Here, we use Electronic Health Records (EHR) from a middle-income country, Colombia, to characterize geographic variation in major mental disorders.MethodWe leveraged geolocated EHRs of 16,295 patients at a psychiatric hospital serving the entire state of Caldas, all of whom received a primary diagnosis of bipolar disorder, schizophrenia, or major depressive disorder at their first visit. To identify the relationship between travel time and incidence of mental illness we used a zero-inflated negative binomial regression model. We used spatial scan statistics to identify clusters of patients, stratified by diagnosis and severity: mild (outpatients) or severe (inpatients).ResultsWe observed a significant association between incidence and travel time for outpatients (N = 11,077, relative risk (RR) = 0.80, 95% confidence interval (0.71, 0.89)), but not inpatients (N = 5,218). We found seven clusters of severe mental illness: the cluster with the most extreme overrepresentation of bipolar disorder (RR = 5.83, p < 0.001) has an average annual incidence of 8.7 inpatients per 10,000 residents, among the highest frequencies worldwide.ConclusionsThe hospital database reflects the geographic distribution of severe, but not mild, mental illness within Caldas. Each hotspot is a candidate location for further research to identify genetic or environmental risk factors for severe mental illness. Our analyses highlight how existing infrastructure from middle-income countries can be extraordinary resources for population studies.
Estimated Incidence of Respiratory Hospitalizations Attributable to RSV Infections across Age and Socioeconomic Groups
Authors: Zheng Zhe , Warren Joshua L. , Shapiro Eugene D. , Pitzer Virginia E. , Weinberger Daniel M. 
Published: March 2022

AbstractBackgroundSurveillance for respiratory syncytial virus (RSV) likely captures just a fraction of the burden of disease. Understanding the burden of hospitalizations and disparities between populations can help to inform upcoming RSV vaccine programs and to improve surveillance.MethodsWe obtained monthly age-, ZIP code- and cause-specific hospitalizations in New York, New Jersey, and Washington from the US State Inpatient Databases (2005-2014). We estimated the incidence of respiratory hospitalizations attributable to RSV by age and by socioeconomic status using regression models. We compared the estimated incidence and the recorded incidence (based on ICD9-CM) of RSV hospitalizations to estimate the under-recorded rate in the different sub-populations.ResultsThe estimated annual incidence of respiratory hospitalizations due to RSV was highest among infants <1 year of age with low socioeconomic status, (2700 per 100,000 people, 95% CrI [2600, 2900]) and were considerable in older adults that are ≥65 years of age across socioeconomic status, ranging from 130 to 970 per 100,000 people. The incidence of hospitalization recorded as being due to RSV represented a significant undercount, particularly in adults. Only <5% of the estimated RSV hospitalizations were captured for the older adults that are ≥65 years of age.ConclusionsRSV causes a considerable burden of hospitalization in young children and in older adults in the U.S, with variation by socioeconomic group. Estimates of the incidence of hospitalizations due to RSV in older adults based on the recorded diagnoses likely represent an underestimate.Key messagesWhat is already known on this topic?Previous study suggested that the incidence of hospitalization for bronchiolitis (often caused by RSV) in infants varies greatly between communities of different socioeconomic levels. However, it is unclear whether these differences are associated with the admission criteria or the risk of RSV infection.What this study adds?The estimated annual incidence of respiratory hospitalizations due to RSV in infants residing in low socioeconomic areas was about twice as high as the incidence in infants residing in high socioeconomic areas. In older adults, a small fraction of the hospitalizations estimated to be caused by RSV were recorded as such in the inpatient database.How this study might affect research, practice or policy?With several vaccines and extended half-life monoclonal antibodies against RSV under active development, these estimates can help anticipate the impact of RSV prevention strategies in populations of different demographic characteristics.
Cell size and shape regulation of E. coli determines surface area scaling with volume
Authors: Kale Tanvi , Khatri Dhruv , Athale Chaitanya A. 
Published: March 2022

AbstractThe scaling of surface area and volume of cells has widespread consequences for cell physiology, growth and adaptation. While the surface area increases with volume as SA ~ Vγ the scaling exponent for proportional growth maintaining the shape and aspect is γ ~ 2/3 or 0.66. However most well-studied cellular systems deviate from this standard exponent. At the same time, a mechanism that could predict the biological or physical basis of these scaling relations remains unclear. Here, we quantify the surface area scaling with volume of Escherichia coli cells with varying growth rates and under different conditions and find the scaling exponent varies from γ ~ 0.7 to 0.9. A model of uncorrelated statistical variation of cell lengths and widths can reproduce the exponent observed in experiment. Average values of length and width on the other hand results in an impression of ‘ideal’ geometric scaling, as reported in some studies. Experimental data however suggests that E. coli cell width is strongly correlated with length and a model of saturation best explains the observations. We hypothesize this model of cell size and shape regulation could serve the function of optimizing flux of nutrients, within the constraints of the cell division machinery.
A novel oral GyrB/ParE dual binding inhibitor effective against multidrug resistant Neisseria gonorrhoeae and other high-threat pathogens
Authors: Park Steven , Russo Riccardo , Westfall Landon , Shrestha Riju , Zimmerman Matthew , Dartois Veronique , Kurepina Natalia , Kreiswirth Barry , Singleton Eric , Li Shao-Gang , Mittal Nisha , Ahn Yong-Mo , Bilotta Joseph , Connolly Kristie L. , Jerse Ann E. , Freundlich Joel S. , Perlin David S. 
Published: March 2022

ABSTRACTDrug resistant Neisseria gonorrhoeae is a serious global health concern. New drugs are needed that can overcome existing drug resistance, as well as limit development of new resistance. We describe the small molecule tricyclic pyrimidoindole JSF-2414 [8-(6- fluoro-8-(methylamino)-2-((2-methylpyrimidin-5-yl)oxy)-9H-pyrimido[4,5-b]indol-4-yl)-2- oxa-8-azaspiro[4.5]decan-3-yl)methanol], which simultaneously binds to ATP binding regions of DNA gyrase (GyrB) and topoisomerase (ParE). JSF-2414 displays potent activity against N. gonorrhoeae including drug-resistant strains. A phosphate prodrug JSF-2659 was developed to facilitate oral dosing. In two different animal models of Neisseria gonorrhoeae vaginal infection, JSF-2659 was highly efficacious in reducing microbial burdens to the limit of detection. The parent molecule also showed potent in vitro activity against high-threat Gram positive organisms, and JSF-2659 was shown in a deep tissue model of VRSA and a model of C. difficile-induced colitis to be highly efficacious and protective. JSF-2659 is a novel drug candidate against high-threat multidrug resistant organisms with low potential to develop new resistance.
Discovery of a Novel Inhibitor for Chikungunya Virus
Authors: Puhl Ana C. , Fernandes Rafaela S. , Godoy Andre S. , Gil Laura H. V. G. , Oliva Glaucius , Ekins Sean 
Published: March 2022

AbstractChikungunya virus (CHIKV) is the etiological agent of chikungunya fever, a (re)emerging arbovirus infection, that causes severe and often persistent arthritis, representing a serious health problem worldwide for which no antivirals are currently available. Despite the efforts over the last decade to identify and optimize new inhibitors or to reposition existing drugs, no compound has progressed to clinical trials and prophylaxis is based on vector control, which has shown limited success in containing the virus. Herein, we screened 36 compounds using a replicon system and ultimately identified 3-methyltoxoflavin with activity against CHIKV using cell assays (EC50 200 nM). We have additionally screened 3-methyltoxoflavin against a panel of viruses and showed that it also inhibits yellow fever virus (IC50 370 nM, SI=3.2 in Huh-7 cells). 3-methyltoxoflavin is a known protein disulfide isomerase (PDI) inhibitor, and inhibitor of alphaviruses which likely depends on this host protein to aid in facilitating disulfide bond formation and isomerization, since alphaviruses require conserved cysteine residues for proper folding and assembly of the E1 and E2 envelope glycoproteins. In summary we demonstrate that 3-methyltoxoflavin has activity against CHIKV and may represent a starting point for optimization to develop inhibitors to this and other viruses.
Urinary F plasmids reduce permissivity to coliphage infection
Authors: Hernandez Cesar Montelongo , Putonti Catherine , Wolfe Alan J. 
Published: March 2022

AbstractThe microbial community of the urinary tract (urinary microbiota or urobiota) has been associated with human health. Bacteriophages (phages) and plasmids present in the urinary tract, like in other niches, may shape urinary bacteria dynamics. While urinary E. coli, often associated with urinary tract infection (UTI), and their phages have been catalogued for the urobiome, the dynamics of their interactions have yet to be explored. In this study, we characterized urinary E. coli F plasmids and their ability to decrease permissivity to E. coli phage (coliphage) infection. Putative F plasmids were present in 47 of 67 urinary E. coli isolates, and most of these plasmids carry genes that encode for toxin-antitoxin (TA) modules, antibiotic resistance, and/or virulence. Two urinary E. coli F plasmids, from urinary microbiota (UMB) 0928 and 1284, were conjugated into E. coli K-12 strains; plasmids included genes for antibiotic resistance and virulence. These plasmids, pU0928 and pU1284, decreased permissivity to coliphage infection by the laboratory phage P1vir and the urinary phages Greed and Lust. Furthermore, pU0928 could be maintained in E. coli K-12 for up to ten days in the absence of antibiotic resistance selection; this included maintenance of the antibiotic resistance phenotype and decreased permissivity to phage. Finally, we discuss how F plasmids present in urinary E. coli could play a role in coliphage dynamics and maintenance of antibiotic resistance in urinary E. coli.ImportanceThe microbial community of the urinary tract (urinary microbiota or urobiota) has been associated with human health. Bacteriophages (phages) and plasmids present in the urinary tract, like in other niches, may shape urinary bacteria dynamics. While urinary E. coli, often associated with urinary tract infection, and their phages have been catalogued for the urobiome, the dynamics of their interactions have yet to be explored. In this study, we characterized urinary E. coli F plasmids and their ability to decrease permissivity to E. coli phage (coliphage) infection. Two urinary E. coli F plasmids, each encoding antibiotic resistance and transferred by conjugation into naïve laboratory E. coli K-12 strains decreased permissivity to coliphage infection. We propose a model by which F plasmids present in urinary E. coli could help to maintain antibiotic resistance of urinary E. coli.
Prognostic factors for mortality, ICU and hospital admission due to SARS-CoV-2: A systematic review and meta-analysis of cohort studies in Europe
Authors: Vardavas Constantine I. , Mathioudakis Alexander G. , Nikitara Katerina , Stamatelopoulos Kimon , Georgiopoulos Georgios , Phalkey Revati , Leonardi-Bee Jo , Fernandez Esteve , Carnicer-Pont Dolors , Vestbo Jørgen , Semenza Jan C. , Deogan Charlotte , Suk Jonathan E. , Kramarz Piotr , Lamb Favelle , Penttinen Pasi 
Published: March 2022

ABSTRACTBackgroundAs mortality from COVID-19 is strongly age-dependent, we aimed to identify population subgroups at an elevated risk for adverse outcomes from COVID-19 using age/gender-adjusted data from European cohort studies with the aim to identify populations that could potentially benefit from booster vaccinations.MethodsWe performed a systematic literature review and meta-analysis to investigate the role of underlying medical conditions as prognostic factors for adverse outcomes due to SARS-CoV-2, including death, hospitalisation, Intensive Care Unit (ICU) admission, and mechanical ventilation within three separate settings (community, hospital and ICU). Cohort studies that reported at least age and gender-adjusted data from Europe were identified through a search of peer-reviewed articles published until 11thJune 2021 in Ovid Medline and Embase. Results are presented as Odds Ratios (ORs) with 95% confidence intervals (95%C.I.) and absolute risk differences (RD) in deaths per 1,000 COVID-19 patients.FindingsWe included 88 cohort studies with age/gender adjusted data from 6,653,207 SARS-CoV-2 patients from Europe. Hospital-based mortality was associated with high and moderate certainty evidence for solid organ tumours, diabetes mellitus, renal disease, arrhythmia, ischemic heart disease, liver disease, and obesity, while a higher risk, albeit with low certainty, was noted for chronic obstructive pulmonary disease and heart failure. Community-based mortality was associated with a history of heart failure, stroke, diabetes, and end-stage renal disease. Evidence of high/moderate certainty revealed a strong association between hospitalisation for COVID-19 and solid organ transplant recipients, sleep apnoea, diabetes, stroke, and liver disease.InterpretationThe results confirmed the strong association between specific prognostic factors and mortality and hospital admission. Prioritisation of booster vaccinations and the implementation of non-pharmaceutical protective measures for these populations may contribute to a reduction in COVID-19 mortality, ICU and hospital admissions.FundingEuropean Centre for Disease Prevention and Control (ECDC) under specific contract No. 10 ECD.11843 within Framework contract ECDC/2019/001 Lot 1B.
A Computational Pipeline to Identify and Characterize Binding Sites and Interacting Chemotypes in SARS-CoV-2
Authors: Sandholtz Sarah H. , Drocco Jeffrey A. , Zemla Adam T. , Torres Marisa W. , Silva Mary S. , Allen Jonathan E. 
Published: March 2022

1AbstractMinimizing the human and economic costs of the COVID-19 pandemic and of future pandemics requires the ability to develop and deploy effective treatments for novel pathogens as soon as possible after they emerge. To this end, we introduce a unique, computational pipeline for the rapid identification and characterization of binding sites in the proteins of novel viruses as well as the core chemical components with which these sites interact. We combine molecular-level structural modeling of proteins with clustering and cheminformatic techniques in a computationally efficient manner. Similarities between our results, experimental data, and other computational studies provide support for the effectiveness of our predictive framework. While we present here a demonstration of our tool on SARS-CoV-2, our process is generalizable and can be applied to any new virus, as long as either experimentally solved structures for its proteins are available or sufficiently accurate homology models can be constructed.
Reaction-diffusion patterning of DNA-based artificial cells
Authors: Leathers Adrian , Walczak Michal , Brady Ryan A. , Al Samad Assala , Kotar Jurij , Booth Michael J. , Cicuta Pietro , Di Michele Lorenzo 
Published: March 2022

AbstractBiological cells display complex internal architectures, with distinct micro environments that establish the chemical heterogeneity needed to sustain cellular functions. The continued efforts to create advanced cell mimics –artificial cells– demands strategies to construct similarly heterogeneous structures with localized functionalities. Here, we introduce a platform for constructing membrane-less artificial cells from the self-assembly of synthetic DNA nanostructures, in which internal domains can be established thanks to prescribed reaction-diffusion waves. The method, rationalized through numerical modeling, enables the formation of up to five distinct, concentric environments, in which functional moieties can be localized. As a proof-of-concept, we apply this platform to build DNA-based artificial cells in which a prototypical nucleus synthesizes fluorescent RNA aptamers, which then accumulate in a surrounding storage shell, thus demonstrating spatial segregation of functionalities reminiscent of that observed in biological cells.
Growth Condition Dependent Differences in Methylation Implies Transiently Differentiated DNA Methylation States in E. coli
Authors: Breckell Georgia L , Silander Olin K 
Published: March 2022

AbstractDNA methylation in bacteria frequently serves as a simple immune system, allowing recognition of DNA from foreign sources, such as phages or selfish genetic elements. It is not well established whether methylation also frequently serves a more general epigenetic function, modifying bacterial phenotypes in a heritable manner. To address this question, here we use Oxford Nanopore sequencing to profile DNA modification marks in three natural isolates of E. coli. We first identify the DNA sequence motifs targeted by the methyltransferases in each strain. We then quantify the frequency of methylation at each of these motifs across the genome in different growth conditions. We find that motifs in specific regions of the genome consistently exhibit high or low levels of methylation. Furthermore, we show that there are replicable and consistent differences in methylated regions across different growth conditions. This suggests that during growth, E. coli transiently differentiates into distinct methylation states that depend on the growth state, raising the possibility that measuring DNA methylation alone can be used to infer bacterial growth states without additional information such as transcriptome or proteome data. These results provide new insights into the dynamics of methylation during bacterial growth, and provide evidence of differentiated cell states, a transient analogue to what is observed in the differentiation of cell types in multicellular organisms.
Human Elp3/Kat9 is a mitochondrial tRNA modifying enzyme
Authors: Boutoual Rachid , Jo Hyunsun , Heckenbach Indra , Tiwari Ritesh , Kasler Herbert , Lerner Chad A. , Shah Samah , Schilling Birgit , Calvanese Vincenzo , Rardin Matthew J. , Scheibye-Knudsen Morten , Verdin Eric 
Published: March 2022

AbstractPost-translational modifications, such as lysine acetylation, regulate the activity of diverse proteins across many cellular compartments. Protein deacetylation in mitochondria is catalyzed by the enzymatic activity of the NAD+-dependent deacetylase sirtuin 3 (SIRT3), however it remains unclear whether corresponding mitochondrial acetyltransferases exist. We used a bioinformatics approach to search for mitochondrial proteins with an acetyltransferase catalytic domain, and identified a novel splice variant of ELP3 (mt-ELP3) of the elongator complex, which localizes to the mitochondrial matrix in mammalian cells. Unexpectedly, mt-ELP3 does not mediate mitochondrial protein acetylation but instead induces a post-transcriptional modification of mitochondrial-transfer RNAs (mt-tRNAs). Overexpression of mt-ELP3 leads to the protection of mt-tRNAs against the tRNA-specific RNase angiogenin, increases mitochondrial translation, and furthermore increases expression of OXPHOS complexes. This study thus identifies mt-ELP3 as a non-canonical mt-tRNA modifying enzyme.
A microbiota membrane disrupter disseminates to the pancreas and increases β-cell mass
Authors: Hill Jennifer Hampton , Massaquoi Michelle Sconce , Sweeney Emily Goers , Wall Elena S. , Jahl Philip , Bell Rickesha , Kallio Karen , Derrick Daniel , Murtaugh L. Charles , Parthasarathy Raghuveer , Remington S. James , Round June L. , Guillemin Karen 
Published: March 2022

SummaryMicrobiome dysbiosis is a feature of diabetes, but how microbial products influence insulin production is poorly understood. Here we report the mechanism of BefA, a microbiome-derived protein that increases proliferation of insulin-producing β-cells during pancreatic development in gnotobiotic zebrafish and mice. BefA disseminates systemically via multiple anatomic routes to act directly on pancreatic islets. We report the structure of BefA, containing a lipid-binding SYLF domain, and demonstrate that it permeabilizes synthetic liposomes and bacterial membranes. A BefA mutant impaired in membrane disruption fails to expand β-cells whereas the pore-forming host defense protein, Reg3, stimulates β-cell proliferation. Our work demonstrates that membrane permeabilization by microbiome-derived and host defense proteins is necessary and sufficient for β-cell expansion during pancreas development, thereby connecting microbiome composition with diabetes risk.