bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of natural induced antibodies against select Group B streptococcus surface proteins and invasive disease in early infancy
Authors: Dzanibe Sonwabile , Izu Alane , Dangor Ziyaad , Kwatra Gaurav , Adrian Peter V. , Kimaro Mlacha Sheila Z. , Madhi Shabir A. 
Published: July 2024

AbstractBackgroundGroup Bstreptococcus(GBS) surface protein epitopes are potential targets for development of vaccines that could confer protection against invasive GBS disease (IGbsD) irrespective of the capsular serotype. The aim of this study was to determine the association of natural acquired mother-newborn GBS surface proteins specific serum IgG and IGbsD during early infancy (<90 days age).MethodsClinical GBS isolates from 81 women who delivered either infant with IGbsD (n=38) and healthy controls (n=43) were assessed for surface expression of proteins Sip, GBS0393 and GBS206 using flow cytometry. Serum IgG titres to Sip, GBS0393 and GBS206 surface proteins were measured in paired maternal-infant sera on multiplex Luminex platform to determine IgG titres associated with reduce risk of IGbsD caused by GBS strains expressing homotypic protein.ResultsInfant sera IgG GMT in IGbsD cases caused by strains expressing Sip and GBS2016 were lower (64 and 61 U/ml, respectively) compared to healthy controls born to women colonized by strains expressing the respective proteins (145 and 151 U/mL, respectively, p<0.01). Moreover, increasing infant antibody titres against Sip and GBS2016 were associated with ≥80% adjusted disease risk (ADR) reduction to GBS isolates expressing homotypic proteins. Among women colonized with GBS isolates expressing GBS2106, mothers of cases had lower GBS2016-specific IgG GMT (249 U/mL) compared to mothers of controls (163 U/mL, adj-p=0.023).ConclusionIncreasing infant IgG titres to GBS2106 and Sip was associated with reduced IGbsD risk and therefore warranting further investigations as potential GBS vaccines and/or protein conjugants.
Impact analysis of infant antibiotic exposure on the burden of asthma: a simulation modeling study
Authors: Lee Tae Yoon , Petkau John , Saatchi Ariana , Marra Fawziah , Turvey Stuart E , Lishman Hannah , Patrick David M , Cragg Jacquelyn J , Johnson Kate M , Sadatsafavi Mohsen 
Published: July 2024

AbstractBackgroundInfant antibiotic use is associated with increased risk of asthma. We examined the population impact of antibiotic exposure in the first year of life on the burden of pediatric asthma in British Columbia, Canada, using simulation modeling.MethodsWe performed a Bayesian meta-analysis of empirical studies to construct dose-response equations between antibiotic exposure in the first year of life and pediatric (<19 years of age) asthma. We used administrative health data to document trends in infant (< 1 year of age) antibiotic use in British Columbia during 2001 and 2018 (the study period). An independently developed microsimulation model of asthma was utilized to estimate asthma-related outcomes under three scenarios pertaining to the trends in antibiotic use during the study period: 1) observed trends, 2) flat trend in which the prescription rate remained at the 2001 value, and 3) intermediate trends midway between these two. We reported cumulative person-years with asthma, cumulative asthma incidence, and cumulative asthma exacerbations among the pediatric population during the study period.ResultsThere were 773,160 live births during the study period, with an average antibiotic prescription rate of 523 per 1,000 infants in the first year of life. The prescription rate decreased by 71.5% during the study period. In Scenario 1, there were 1,982,861 person-years with asthma, 183,392 asthma incident cases, and 383,072 exacerbations. Had the antibiotic exposure remained at the 2001 values (Scenario 2), there would have been additional 37,213 person-years with asthma, 10,053 asthma incident cases, and 23,280 exacerbations. Had the decline been half of the observed trend (Scenario 3), there would have been additional 20,318 person-years with asthma, 5,486 asthma incident cases, and 12,728 exacerbations. At least 80% of the excess burden in each outcome was attributable to the younger pediatric population of <10 years of age.ConclusionsThe decline in infant antibiotic exposure has resulted in a substantial reduction in the burden of asthma in British Columbia. Such benefits should be considered when evaluating the value proposition of initiatives aimed at reducing unnecessary antibiotic exposure in early life.
Exposome-wide association study of cognition among older adults in the National Health and Nutrition Examination Survey
Authors: Middleton Lauren Y. M. , Walker Erika , Cockell Scarlet , Dou John , Nguyen Vy K. , Schrank Mitchell , Patel Chirag J. , Ware Erin B. , Colacino Justin A. , Park Sung Kyun , Bakulski Kelly M. 
Published: July 2024

AbstractCognitive impairment among older adults is a growing public health challenge and environmental chemicals may be modifiable risk factors. A wide array of chemicals has not yet been tested for association with cognition in an environment-wide association framework. In the US National Health and Nutrition Examination Survey (NHANES) 1999-2000 and 2011-2014 cross-sectional cycles, cognition was assessed using the Digit Symbol Substitution Test (DSST, scores 0-117) among participants aged 60 years and older. Concentrations of environmental chemicals measured in blood or urine were log2transformed and standardized. Chemicals with at least 50% of measures above the lower limit of detection were included (nchemicals=147, nclasses=14). We tested for associations between chemical concentrations and cognition using parallel survey-weighted multivariable linear regression models adjusted for age, sex, race/ethnicity, education, smoking status, fish consumption, cycle year, urinary creatinine, and cotinine. Participants with at least one chemical measurement (n=4,982) were mean age 69.8 years, 55.0% female, 78.2% non-Hispanic White, and 77.0% at least high school educated. The mean DSST score was 50.4 (standard deviation (SD)=17.4). In adjusted analyses, 5 of 147 exposures were associated with DSST at p-value<0.01. Notably, a SD increase in log2-scaled cotinine concentration was associated with 2.71 points lower DSST score (95% CI -3.69, -1.73). A SD increase in log2-scaled urinary tungsten concentration was associated with 1.34 points lower DSST score (95% CI -2.11, -0.56). Exposure to environmental chemicals, particularly heavy metals and tobacco smoke, may be modifiable factors for cognition among older adults.
Multicellular immune ecotypes within solid tumors predict real-world therapeutic benefits with immune checkpoint inhibitors
Authors: Wang Xuefeng , Li Tingyi , Eljilany Islam , Sukrithan Vineeth , Ratan Aakrosh , McCarter Martin , Carpten John , Colman Howard , Ikeguchi Alexandra P. , Puzanov Igor , Arnold Susanne , Churchman Michelle , Hwu Patrick , Rodriguez Paulo C. , Dalton William S. , Weiner George J. , Tarhini Ahmad A. 
Published: July 2024

ABSTRACTBackgroundCancer initiation, progression, and immune evasion depend on the tumor microenvironment (TME). Thus, understanding the TME immune architecture is essential for understanding tumor metastasis and therapy response. This study aimed to create an immune cell states (CSs) atlas using bulk RNA-seq data enriched by eco-type analyses to resolve the complex immune architectures in the TME.MethodsWe employed EcoTyper, a machine-learning (ML) framework, to study the real-world prognostic significance of immune CSs and multicellular ecosystems, utilizing molecular data from 1,610 patients with multiple malignancies who underwent immune checkpoint inhibitor (ICI) therapy within the ORIEN Avatar cohort, a well-annotated real-world dataset.ResultsOur analysis revealed consistent ICI-specific prognostic TME carcinoma ecotypes (CEs) (including CE1, CE9, CE10) across our pan-cancer dataset, where CE1 being more lymphocyte-deficient and CE10 being more proinflammatory. Also, the analysis of specific immune CSs across different cancers showed consistent CD8+ and CD4+ T cell CS distribution patterns. Furthermore, survival analysis of the ORIEN ICI cohort demonstrated that ecotype CE9 is associated with the most favorable survival outcomes, while CE2 is linked to the least favorable outcomes. Notably, the melanoma-specific prognostic EcoTyper model confirmed that lower predicted risk scores are associated with improved survival and better response to immunotherapy. Finally, de novo discovery of ecotypes in the ORIEN ICI dataset identified Ecotype E3 as significantly associated with poorer survival outcomes.ConclusionOur findings offer important insights into refining the patient selection process for immunotherapy in real-world practice and guiding the creation of novel therapeutic strategies to target specific ecotypes within the TME.Trial Registration:NCT04526730
Autoinhibition of cMyBP-C by its middle domains
Authors: Greenman A.C. , Sadler R.L. , Harris S.P. 
Published: July 2024

AbstractCardiac myosin binding protein-C (cMyBP-C) is a sarcomere regulatory protein consisting of 11 well-folded immunoglobulin-like (Ig-like) and fibronectin type-III domains with the individual domains numbered C0-C10. Despite progress in understanding the functions of the N’ and C’-terminal ends of the protein, our understanding of the functional effects of the middle domains (C3-C4-C5-C6-C7) is still limited. Here we aimed to determine the functional significance of the middle domains by replacing endogenous cMyBP-C with recombinant proteins with and without the middle domains using our “cut and paste” SpyC3 mouse model. Specifically, we deleted domains C3-C7 or substituted these domains with unrelated Ig-like domains from titin to behave as inert “spacer” domains. Replacement with the spacer constructs resulted in a significant increase in myofilament calcium sensitivity, an almost instantaneous redevelopment of tension after a slack re-stretch protocol, and altered stretch activation responses, suggesting that the middle domains are functionally relevant and normally exert inhibitory effects on force development. We also investigated the significance of a flexible linker between domains C4 and C5 and a unique 28 amino acid loop insertion in C5. Whereas deletion of the C5 loop had no effect on force, deletion of the linker between C4 and C5 had comparable effects to deletion of domains C3-C7. Taken together, these data indicate that the middle domains play an important role in limiting the activating effects of the C0-C2 domains and that the C4C5 linker contributes to these effects.Significance StatementThe functional role of the middle domains of cardiac myosin binding protein-C (cMyBP-C) are poorly understood, in part due to technical challenges inherent toin vitromethods that have mainly been used to study recombinant N’-terminal domains in the absence of the whole protein. Here we overcome this barrier by using a “cut and paste” approach, selectively removing and replacing the middle domains of cMyBP-C in permeabilized cardiomyocytes. Substituting the middle domains with titin Ig-like domains resulted in a large increase in myofilament calcium sensitivity, almost instantaneous redevelopment of force, and altered response to rapid stretch. Deletion of only the C4-C5 linker (11 amino acids) qualitatively resulted in the same alterations in force mechanics, albeit to a lesser magnitude. We suggest that the middle domains directly affect the regulation of cardiac muscle function by inhibiting the activating effects of the N’-terminal domains of cMyBP-C.
AliMarko: A Novel Tool for Eukaryotic Virus Identification Using Expert-Guided Approach
Authors: Popov Nikolay , Evdokimova Anastasia , Sonets Ignat , Molchanova Maria , Panova Vera , Korneenko Elena , Manolov Alexander , Ilina Elena 
Published: July 2024

AbstractMetagenomic sequencing is a valuable tool for studying viral diversity in biological samples. Analyzing this data is complex due to the high variability of viral genomes and their low representation in databases. We present the Alimarko pipeline, designed to streamline virus identification in metagenomic data. A key feature of our tool is the focus on the interpretability of findings: results are provided with tabular and visual information to help determine the confidence level in the identified viral sequences.The pipeline employs two approaches for identifying viral sequences: mapping to reference genomes and de novo assembly followed by the application of Hidden Markov Models (HMM). Additionally, it includes a step for phylogenetic analysis, which constructs a phylogenetic tree to determine the evolutionary relationships with reference sequences. We also emphasize reducing false-positive results. Reads related to cellular organisms are computationally depleted, and the identified viral sequences are checked against a list of potential contaminants. The output is an HTML document containing visualizations and tabular information designed to assist researchers in making informed decisions about the presence of viruses. Using our pipeline for total RNA sequencing of bat feces, we identified a range of viruses and rapidly determined the validity and phylogenetic relationships of the findings to known sequences with the aid of reports generated by AliMarko.
Multiple cell types support productive infection and dynamic translocation of infectious Ebola virus to the surface of human skin
Authors: Messingham Kelly N. , Richards Paige T. , Fleck Anthony , Patel Radhika A. , Djurkovic Marija , Elliff Jonah , Connell Samuel , Crowe Tyler P. , Gonzalez J. Pablo Munoz , Gourronc Francoise , Dillard Jacob A. , Davey Robert A. , Klingelhutz Al , Shtanko Olena , Maury Wendy 
Published: July 2024

AbstractEbola virus (EBOV) within theFiloviridaefamily causes severe human disease. At late stages of infection, EBOV virions are found on the surface of patients’ skin; however, the permissive cell types within the skin and how infectious virus translocates to the apical skin surfaces is not known. Here, we describe a human transwell skin explant culture model and show that EBOV infection of human skin tissues via the basal media results in a time- and dose-dependent increase in infectious virus in dermal and epidermal tissue. Infectious virus was detected on the apical epidermal surface within 3 days, indicating that the virus propagates within and traffics through the tissue. In the dermis, EBOV-infected cells were of myeloid, endothelial and fibroblast origins, whereas keratinocytes harbored virus in the epidermis. Complementary studies showed that both purified skin fibroblasts and keratinocytes supported EBOV infection ex vivo and that both cell types required the phosphatidylserine receptor, Axl, and the endosomal protein, NPC1, for virus entry. Our experimental platform identified new susceptible cell types and demonstrated dynamic trafficking of EBOV virions that resulted in infectious virus on the skin surface; findings that may explain person-to-person transmission via skin contact.TeaserUsing a human skin explant model, these studies identify and characterize skin cell populations that support Ebola virus infection.
Disentangling the regulatory response ofAgrobacterium tumefaciensCHLDO to glyphosate for engineering whole-cell phosphonate biosensors
Authors: Masotti Fiorella , Krink Nicolas , Lencina Nicolas , Gottig Natalia , Ottado Jorgelina , Nikel Pablo I. 
Published: July 2024

AbstractPhosphonates (PHTs), organic compounds with a stable C—P bond, are widely distributed in nature. Glyphosate (GP), a synthetic PHT, is extensively used in agriculture and has been linked to various human health issues and environmental damage. Given the prevalence of GP, developing cost-effective, on-site methods for GP detection is key for assessing pollution and reducing exposure risks. We adoptedAgrobacterium tumefaciensCHLDO, a natural GP degrader, as the source of genetic parts for constructing PHT biosensors. In this species, thephngene cluster, encoding the C—P lyase pathway, is regulated by the PhnF transcriptional repressor and is part of the Pho regulon. We selected thephnGpromoter, which displays a dose-dependent response to GP, to build a set of whole-cell biosensors. Through stepwise optimization of the transcriptional cascade, we created a biosensor capable of detecting GP in the 0.25-50 μM range in various samples, including soil and water.
Resolving DJ-1 Glyoxalase Catalysis Using Mix-and-Inject Serial Crystallography at a Synchrotron
Authors: Zielinski Kara A. , Dolamore Cole , Dalton Kevin M. , Smith Nathan , Termini John , Henning Robert , Srajer Vukica , Hekstra Doeke R. , Pollack Lois , Wilson Mark A. 
Published: July 2024

AbstractDJ-1 (PARK7) is an intensively studied protein whose cytoprotective activities are dysregulated in multiple diseases. DJ-1 has been reported as having two distinct enzymatic activities in defense against reactive carbonyl species that are difficult to distinguish in conventional biochemical experiments. Here, we establish the mechanism of DJ-1 using a synchrotron-compatible version of mix-and-inject-serial crystallography (MISC), which was previously performed only at XFELs, to directly observe DJ-1 catalysis. We designed and used new diffusive mixers to collect time-resolved Laue diffraction data of DJ-1 catalysis at a pink beam synchrotron beamline. Analysis of structurally similar methylglyoxal-derived intermediates formed through the DJ-1 catalytic cycle shows that the enzyme catalyzes nearly two turnovers in the crystal and defines key aspects of its glyoxalase mechanism. In addition, DJ-1 shows allosteric communication between a distal site at the dimer interface and the active site that changes during catalysis. Our results rule out the widely cited deglycase mechanism for DJ-1 action and provide an explanation for how DJ-1 produces L-lactate with high chiral purity.
Preparation of oxygen-sensitive proteins for high-resolution cryoEM structure determination using (an)aerobic blot-free vitrification
Authors: Cook Brian D. , Narehood Sarah M. , McGuire Kelly L. , Li Yizhou , Tezcan F. Akif , Herzik Mark A. 
Published: July 2024

AbstractHigh-quality grid preparation for single-particle cryogenic electron microscopy (cryoEM) remains a bottleneck for routinely obtaining high-resolution structures. The issues that arise from traditional grid preparation workflows are particularly exacerbated for oxygen-sensitive proteins, including metalloproteins, whereby oxygen-induced damage and alteration of oxidation states can result in protein inactivation, denaturation, and/or aggregation. Indeed, 99% of the current structures in the EMBD were prepared aerobically and limited successes for anaerobic cryoEM grid preparation exist. Current practices for anaerobic grid preparation involve a vitrification device located in an anoxic chamber, which presents significant challenges including temperature and humidity control, optimization of freezing conditions, costs for purchase and operation, as well as accessibility. Here, we present a streamlined approach that allows for the (an)aerobic vitrification of oxygen-sensitive proteins using an automated aerobic blot-free grid vitrification device – the SPT Labtech chameleon. This robust workflow allows for high-resolution structure determination of dynamic, oxygen-sensitive proteins, of varying complexity and molecular weight.
Power Outages: An Underappreciated Risk Factor for Children’s Carbon Monoxide Poisoning
Authors: Northrop Alexander J. , Do Vivian , Flores Nina M. , Wilner Lauren Blair , Sheffield Perry E. , Casey Joan A. 
Published: July 2024

ABSTRACTChildren’s risk of exposure to carbon monoxide (CO) increases after disasters, likely due to improper generator use during power outages. Here, we evaluate the impact of outages on children’s CO-related emergency department (ED) visits in New York State (NYS). We leveraged power outage data spanning 2017-2020 from the NYS Department of Public Service for 1,865 power operating localities (i.e., communities) and defined all-size and large-scale power outage hours. All-size outage hours affected ≥1% of customers, and large-scale outage hours affected ≥20%. We identified CO poisoning using diagnostic codes among those aged <18 between 2017 and 2020 using the Statewide Planning and Research Cooperative System (SPARCS), an all-payer reporting system in NYS. We linked community power outage exposure to patients using the population-weighted centroid of their block group of residence. We estimated the impact of power outages on CO poisoning using a time-stratified case-crossover study design with conditional logistic regression, controlling for daily relative humidity, mean temperature, and total precipitation. Analyses were stratified by urban and rural communities. From 2017-2020, there were 917 pediatric CO poisoning ED visits in NYS. Most cases (83%) occurred in urban region of the state. We observed an association statewide between all-size and large-scale outages and CO ED visits on the index day and the following two days before a return to baseline on lag day 3. Four hours without power increased the odds of a pediatric CO poisoning ED visit by ≥50% for small-scale and ≥150% for large-scale outages, and associations were stronger in urban versus rural areas. While CO poisoning is a relatively rare cause of pediatric ED visits in NYS, it can be deadly and is also preventable. Expanded analyses of the health impacts of outages and advocacy for reliable energy access are needed to support children’s health in a changing climate
Estimating the impact of the RTS,S/AS01 malaria vaccine in Benin: A mathematical modelling study
Authors: Alohoutade Sena , Hounsell Rachel , Silal Sheetal 
Published: July 2024

AbstractBackgroundMalaria constitutes a major public health burden in sub-Saharan Africa. It remains the primary health concern in health care institutions and the leading cause of death in children under five years of age. Since October 2021, the World Health Organization (WHO) has recommended the RTS,S/AS01 malaria vaccine in children in sub-Saharan Africa and other high burden areas wherePlasmodium falciparumtransmission is moderate to high. However, with the exception of Ghana, there is a scarcity of studies modelling the potential impact of the RTS,S/AS01 vaccine in the context of West Africa. This study addresses a gap in research by modelling the additional impact of malaria childhood vaccination onPlasmodium falciparummalaria transmission in Benin.MethodsA compartmental mathematical model has been developed to estimate clinical and severe malaria cases averted in children under the age of five with the primary series (3 doses) of the RTS,S/AS01 malaria vaccine in Benin. Key features of the model include seasonality and the use of insecticide-treated bed nets. Over a period of 10 years, a number of scenarios of vaccine, coverage are simulated. These scenarios included vaccination introduction at different coverage levels to supplement the use of Insecticide-treated bed nets to assess the impact of the RTS,S/AS01 vaccine on malaria transmission in Benin.ResultsThe model projected outcomes in terms of malaria burden alleviation by childhood vaccination in Benin. The combination of malaria childhood vaccination at a coverage equivalent to the national DTP3 and the current uptake of insecticide-treated bed nets is projected to lead to a 45% reduction in malaria cases and deaths among children under five years old in the country from 2025 to 2034. However, a decrease in the use of ITN is projected to lead to an increase in malaria burden, surpassing baseline levels despite vaccine introduction.ConclusionChild vaccination is expected to avert clinical and severe cases of malaria and is an additional tool to advance malaria control efforts in Benin.