bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structural characterization of stem cell factors Oct4, Sox2, Nanog and Esrrb disordered domains, and a method to identify their phospho-dependent binding partners
Authors: Chafiaa Bouguechtouli , Ghouil Rania , Alik Ania , Florent Dingli , Damarys Loew , Francois-Xavier Theillet 
Published: March 2023

AbstractThe combined expression of a handful of pluripotency transcription factors (PluriTFs) in somatic cells can generate induced pluripotent stem cells (iPSCs). Here, we report the structural characterization of disordered regions contained in four important PluriTFs, namely Oct4, Sox2, Nanog and Esrrb. Moreover, many post-translational modifications (PTMs) have been detected on PluriTFs, whose roles are not yet characterized. To help in their study, we also present a method i) to produce well-characterized phosphorylation states of PluriTFs, using NMR analysis, and ii) to use them for pull-downs in stem cell extracts analyzed by quantitative proteomics to identify of Sox2 binders.
Vaccine induction of CD4-mimicking broadly neutralizing antibody precursors in macaques
Authors: Saunders Kevin O. , Counts James , Stalls Victoria , Edwards Robert , Manne Kartik , Lu Xiaozhi , Thakur Bhishem , Mansouri Katayoun , Chen Yue , Parks Rob , Barr Maggie , Sutherland Laura , Bal Joena , Havill Nicholas , Chen Haiyan , Machiele Emily , Jamieson Nolan , Hora Bhavna , Kopp Megan , Janowska Katarzyna , Anasti Kara , Jiang Chuancang , Venkatayogi Sravani , Eaton Amanda , Henderson Rory , Barbosa Christopher , Alam S. Munir , Santra Sampa , Weissman Drew , Moody M. Anthony , Cain Derek W. , Tam Ying , Lewis Mark , Williams Wilton B. , Wiehe Kevin , Montefiori David , Acharya Priyamvada , Haynes Barton F. 
Published: March 2023

SUMMARYThe CD4 binding site (CD4bs) is a conserved epitope on HIV-1 envelope (Env) that can be targeted by protective broadly neutralizing antibodies (bnAbs). HIV-1 vaccines have not elicited CD4bs bnAbs for many reasons, including the CD4bs is occluded by glycans, immunogen expansion of appropriate naïve B cells, and selection of functional antibody mutations. Here, we demonstrate immunization of macaques with a CD4bs-targeting immunogen elicits neutralizing bnAb precursors with structural and genetic features of CD4-mimicking bnAbs. Structures of the CD4bs nAbs bound to HIV-1 Env demonstrated binding angles similar to human bnAbs and heavy chain second complementarity determining region-dependent binding characteristic of all known human CD4-mimicking bnAbs. Macaque nAbs were derived from variable and joining gene segments orthologous to the genes of human VH1-46-class bnAbs. This vaccine study initiated the B cells from which derive CD4bs bnAbs in primates, accomplishing the key first step in development of an effective HIV-1 vaccine.
Nanopore sequencing of antibiotic-resistantKlebsiella pneumoniaeJRCGR1 isolate from Pakistan and country scale pan-genomics
Authors: Basharat Zarrin , Nisa Zaib un , Irfan Muhammad , Khan Rao Muhammad Abid , Karim Asad , Aurongzeb Muhammad , Hassan Syed Shah 
Published: March 2023

AbstractKlebsiella pneumoniaeis a gram-negative, encapsulated, non-motile bacterium that can cause damage to human lungs. Antibiotic resistance of this strain requires constant monitoring and for this purpose, Oxford nanopore mediated whole genome sequencing was done for a strain acquired from the pleural fluid of a diabetic patient suffering from chronic kidney disease. A genome of 5.98 MB was obtained, with 8,869 CDSs and 110 RNAs. Around 96 proteins were seen as involved in virulence, disease or defense, while 25 antibiotic resistance genes were identified. Pan-genome was inferred as open, with 12,857 and 1,303 CDSs forming respective accessory and core genome of antibiotic resistant Pakistani strains (n=168) of this species. Apart from notable antimicrobial resistance genes like beta-lactamases, a gene conferring resistance to colistin was also mined. To the best of our knowledge, this is first report of nanopore mediated long read sequencing of a hypermucoviscous virulentK. pneumoniaefrom Pakistan.
Oceanographic drivers of legal-sized male Dungeness crab in the California Current System
Authors: Bani Ridouan , Punt André E. , Holland Daniel S. , Tolimieri Nick , Richerson Kate , Haltuch Melissa A. , Mantua Nathan J. , Oken Kiva L. 
Published: March 2023

AbstractWe investigate environmental drivers of pre-season abundance of US West Coast legal-sized male Dungeness crab (Cancer magister), with the goal of developing an environmental index that can be used to forecast crab abundance in advance of the fishery. A conceptual life history approach is used to generate life-stage-specific and spatio-temporally-specific mechanistic hypotheses regarding oceanographic variables that influence survival at each life stage. Linear models are fit using the logarithms of pre-season abundance estimates of the coastal population of legal-sized male Dungeness crab as the dependent variable and environmental drivers from outputs developed using a regional oceanographic model for the California Current System as the independent environmental variables. Using different model selection methods, we show that the so-called ‘best’ models differ substantially among model selection approaches, illustrating the need to carefully choose performance metrics for model selection. Since our goal was to forecast crab abundance, we selected the ‘best’ model using a cross-validation metric that accounts for the time-series nature of the data. The resulting ‘best’ models suggest that the mechanisms that drive preseason abundance differ among regions widely recognized for spatially and seasonally varying dominant physical processes. We found that the processes determining pre-season abundance of legal-sized male Dungeness crab could be identified with sufficient precision to enable a predictive skill, suggesting that the predictions may be useful for management purposes. Moreover, we found that transport (within and between regions), as well as temperature were likely drivers of pre-season abundance, highlighting that future studies should focus on multiple processes.
Validation of a multiplex microsphere immunoassay for detection ofTrypanosoma cruziantibodies in dogs
Authors: Rodriguez Carlos A. , Busselman Rachel E. , Shen Huifeng , Saunders Ashley B. , Tarleton Rick , Hamer Sarah A. 
Published: March 2023

AbstractThe vector-borne protozoan parasiteTrypanosoma cruzicauses Chagas disease in humans, dogs, and many other mammalian hosts. Canine Chagas disease is increasingly diagnosed in dogs of the southern US where triatomine insect vectors occur, and there are limited veterinary diagnostic options; currently, only the indirect fluorescent antibody (IFA) test is offered at a single accredited diagnostic laboratory. This study evaluated a multiplex microsphere immunoassay (MIA) for detecting antibodies againstT. cruziin dogs and compared with existing serological methods to establish cut-off values and relative sensitivity/specificity. Dog sera (n=135) which were previously characterized using the IFA and off-label use of two commercial rapid assays were tested on the multiplex MIA against 12 different antigens: nineT. cruziantigens, a negative control recombinant protein (green fluorescent protein), aLeishmaniaantigen, and a canine parvovirus antigen (used as an antibody control given near-ubiquitous parvovirus vaccination). For each sample, the ratio of median fluorescence intensity (MFI) for eachT. cruziantigen to that of GFP was calculated. Samples with an antigen/GFP ratio greater than 4 standard deviations above the mean of 25 known negative sera were considered positive on that antigen. Samples testing positive on 2 or more antigens were considered positive forT. cruziantibodies. Compared to the IFA, the multiplex MIA demonstrated a relative sensitivity of 100% and specificity of 96.97%. Given its precision, high-throughput format, potential for automation, and lack of subjective interpretation, the multiplex MIA should be considered a valid and improved assay forT. cruziantibodies in dogs.
Predicting the feasibility of targeting a conserved region on the S2 domain of the SARS-CoV-2 spike protein
Authors: Garg Pranav , Hsueh Shawn C. C. , Plotkin Steven S. 
Published: March 2023

AbstractThe efficacy of vaccines against the SARS-CoV-2 virus significantly declines with the emergence of mutant strains, prompting investigation into the feasibility of targeting highly conserved but often cryptic regions on the S2 domain of spike protein. Using tools from molecular dynamics, we find that this conserved S2 epitope located in the central helices below the receptor binding domains is unlikely to be exposed by dynamic fluctuations without any external facilitating factors, in spite of previous computational evidence suggesting transient exposure of this region. Furthermore, glycans inhibit opening dynamics, and thus stabilize spike in addition to immunologically shielding the protein surface, again in contrast to previous computational findings. Though the S2 epitope region examined here is central to large scale conformational changes during viral entry, free energy landscape analysis obtained using the path coordinate formalism reveals no inherent “loaded spring” effect, suggesting that a vaccine immunogen would tend to present the epitope in a pre-fusion-like conformation and may be effective in neutralization. These findings contribute to a deeper understanding of the dynamic origins of the function of the spike protein, as well as further characterizing the feasibility of the S2 epitope as a therapeutic target.
Opportunities to sustain a multi-country quality of care network: lessons on the actions of four countries Bangladesh, Ethiopia, Malawi, and Uganda
Authors: Lemma Seblewengel , Daniels-Howell Callie , Tufa Asebe Amenu , Sarker Mithun , Akter Kohenour , Nakidde Catherine , Seruwagi Gloria , Dube Albert , Mwandira Kondwani ,   The QCN Evaluation group, Taye Desalegn Bekele , English Mike , Shawar Yusra Ribhi , Mwaba Kasonde , Djellouli Nehla , Colbourn Tim , Marchant Tanya 
Published: March 2023

AbstractThe Quality of Care Network (QCN) is a global initiative that was established in 2017 under the leadership of WHO in 11 low-and-middle income countries to improve maternal, newborn, and child health. The vision was that the Quality of Care Network would be embedded within member countries and continued beyond the initial implementation period: that the Network would be sustained. This paper investigated the experience of actions taken to sustain QCN in four Network countries (Bangladesh, Ethiopia, Malawi, and Uganda) and reports on lessons learned. Multiple iterative rounds of data collection were conducted through qualitative interviews with global and national stakeholders, and non-participatory observation of health facilities and meetings. A total of 241 interviews, 42 facility and four meeting observations were carried out. We conducted a thematic analysis of all data using a framework approach that defined six critical actions that can be taken to promote sustainability. The analysis revealed that these critical actions were present with varying degrees in each of the four countries. Although vulnerabilities were observed, there was good evidence to support that actions were taken to institutionalize the innovation within the health system, to motivate micro-level actors, plan opportunities for reflection and adaptation from the outset, and to support strong government ownership. Two actions were largely absent and weakened confidence in future sustainability: managing financial uncertainties and fostering community ownership.Evidence from four countries suggested that the QCN model would not be sustained in its original format, largely because of financial vulnerability and insufficient time to embed the innovation at the sub-national level. But especially the efforts made to institutionalize the innovation in existing systems meant that some characteristics of QCN may be carried forward within broader government quality improvement initiatives.
A hybrid approach to scalable real-world data curation by machine learning and human experts
Authors: Waskom Michael L. , Tan Katherine , Wiberg Holly , Cohen Aaron B. , Wittmershaus Brett , Shapiro Will 
Published: March 2023

AbstractObjectiveMachine learning has the potential to increase the scale of real-world data curated from electronic health records, but maintaining a high standard of data quality is important to avoid biasing downstream analyses. To increase scale without compromising quality, we propose a hybrid data curation methodology that employs both manual abstraction by clinical experts and automated extraction by machine learning models.Materials and MethodsOur methodology makes the determination about when to employ manual abstraction using a confidence score associated with each model output. We describe a process for selecting confidence thresholds based on simulations validated against a reference-standard labeled dataset. To establish the fitness of our methodology for retrospective research, we apply it to a multi-variable cohort selection task on a large real-world oncology database.ResultsOnly small amounts of manual abstraction are required for hybrid curation to achieve expert-level error rates. In fact, the hybrid methodology can even reduce error rates relative to manual abstraction in some cases. We further demonstrate that demographic characteristics of a research cohort defined using hybrid variables are comparable to one curated with conventional methods.DiscussionOur methodology is general and makes few assumptions about the clinical variable or machine learning model. A key requirement is the availability of reference standard labels for calibrating the tradeoff between abstraction effort and data quality.ConclusionIncorporating machine learning into real-world data curation using hybrid methodology holds the promise to scale practicable cohort sizes while maintaining data fitness for research purposes.
Systemic inflammation and subsequent risk of amyotrophic lateral sclerosis: prospective cohort study
Authors: Batty G. David , Kivimäki Mika , Frank Philipp , Gale Catharine R. , Wright Liam 
Published: March 2023

AbstractImportanceWhile systemic inflammation has been implicated in the aetiology of selected neurodegenerative disorders, its role in the development of amyotrophic lateral sclerosis (ALS) is untested.ObjectiveTo quantify the relationship of C-reactive protein (CRP), an acute-phase reactant and marker of systemic inflammation, with ALS occurrence.Design, Setting, ParticipantsUK Biobank, a prospective cohort study of 502,649 participants who were aged 37 to 73 years when examined at research centres between 2006 and 2010.ExposureVenous blood was collected at baseline in the full cohort and assayed for CRP. Repeat measurement was made 3-7 years later in a representative subgroup (N=14,514) enabling correction for regression dilution.Main Outcome(s) and Measure(s)ALS as ascertained via national hospitalisation and mortality registries. We computed multi-variable hazard ratios with accompanying 95% confidence intervals for log-transformed CRP expressed as standard deviation and tertiles.ResultsIn an analytical sample of 400,884 individuals (218,203 women), a mean follow-up of 12 years gave rise to 231 hospitalisations and 223 deaths ascribed to ALS. After adjustment for covariates which included health behaviours, comorbidity, and socio-economic status, a one standard deviation higher log-CRP was associated with elevated rates of both ALS mortality (hazard ratios; 95% confidence intervals: 1.32; 1.13, 1.53) and hospitalisations (1.20; 1.00, 1.39). There was evidence of dose-response effects across tertiles of CRP for both outcomes (p for trend≤0.05). Correction for regression dilution led to a strengthening of the relationship with CRP for both mortality (1.62; 1.27, 2.08) and hospitalisations (1.37; 1.05, 1.76) ascribed to ALS.Conclusions and RelevanceHigher levels of CRP, a blood-based biomarker widely captured in clinical practice, were associated with a higher subsequent risk of ALS.Key PointsQuestionIs C-reactive protein (CRP), a marker of systemic inflammation widely used in clinical practice, associated with later risk of amyotrophic lateral sclerosis (ALS)?FindingsFollowing 11 years disease surveillance in 400,884 individuals (218,203 women), after adjustment for covariates and correction for regression dilution, a one standard deviation higher CRP levels were associations with both mortality (hazard ratio; 95% confidence interval: 1.62; 1.27, 2.08) and hospitalisations (1.37; 1.05, 1.76) ascribed to ALS.MeaningIn the present study, CRP has a dose-response relationship with the risk of later ALS.
An Explainable Host Genetic Severity Predictor Model for COVID-19 Patients
Authors: Onoja Anthony , Raimondi Francesco , Nanni Mirco 
Published: March 2023

AbstractUnderstanding the COVID-19 severity and why it differs significantly among patients is a thing of concern to the scientific community. The major contribution of this study arises from the use of a voting ensemble host genetic severity predictor (HGSP) model we developed by combining several state-of-the-art machine learning algorithms (decision tree-based models: Random Forest and XGBoost classifiers). These models were trained using a genetic Whole Exome Sequencing (WES) dataset and clinical covariates (age and gender) formulated from a 5-fold stratified cross-validation computational strategy to randomly split the dataset to overcome model instability. Our study validated the HGSP model based on the 18 features (i.e., 16 identified candidate genetic variants and 2 covariates) identified from a prior study. We provided post-hoc model explanations through the ExplainerDashboard - an open-source python library framework, allowing for deeper insight into the prediction results. We applied the Enrichr and OpenTarget genetics bioinformatic interactive tools to associate the genetic variants for plausible biological insights, and domain interpretations such as pathways, ontologies, and disease/drugs. Through an unsupervised clustering of the SHAP feature importance values, we visualized the complex genetic mechanisms. Our findings show that while age and gender mainly influence COVID-19 severity, a specific group of patients experiences severity due to complex genetic interactions.
Quantitative analysis of insecticides in long-lasting insecticidal nets using liquid chromatography mass spectrometry (LC-MS) and X-ray fluorescence (XRF) spectroscopy
Authors: Koinari Melanie , Bubun Nakei , Wilson David , Anetul Evodia , Timinao Lincoln , Johnson Petrina , Daly Norelle , Laman Moses , Freeman Tim , Karl Stephan 
Published: March 2023

AbstractBackgroundLong lasting insecticidal nets (LLIN) are a key vector control tool used for the prevention of malaria. Active ingredient (AI) measurements in LLIN are essential for evaluating their quality and effectiveness. The main aim of the present study was to determine the utility of X-ray fluorescence (XRF) spectroscopy as a suitable in-field tool for total AI quantification in LLINs.MethodsNew and unused LLIN samples containing deltamethrin (PermaNet® 2.0, n = 35) and alpha-cypermethrin (SafeNet®, n = 43) were obtained from batches delivered to PNG for mass distribution. Insecticides were extracted from the LLINs using a simple extraction technique and quantified using liquid chromatography mass spectrometry (LC-MS). The LC-MS results were correlated with in-field XRF spectroscopy measurements on the same nets. Operators were blinded towards the identity of the nets. Bioefficacy of the LLIN samples was tested using WHO cone bioassays and test results were correlated with total AI content.ResultsThe results indicate a close agreement between the quantitative XRF and LC-MS. Interestingly, the total AI content was negatively correlated with bioefficacy in PermaNet® 2.0 (especially, in recently manufactured nets). In contrast, AI content was positively correlated with bioefficacy in SafeNet®. These results indicate that the chemical content analysis in predelivery inspections does not always predict bioefficacy well.ConclusionXRF is a promising in-field method for quantification of both deltamethrin and alpha-cypermethrin coated LLINs. Since total AI content is not always a predictor of the efficacy of LLINs to kill mosquitoes, bioefficacy measurements should be included in predelivery inspections.
Genome wide association study based on clustering by obesity-related variables shed light on a genetic architecture of obesity in Japanese and UK population
Authors: Takahashi Ippei , Ohseto Hisashi , Ueno Fumihiko , Onuma Tomomi , Narita Akira , Obara Taku , Ishikuro Mami , Murakami Keiko , Noda Aoi , Hozawa Atsushi , Sugawara Junichi , Tamiya Gen , Kuriyama Shinichi 
Published: March 2023

AbstractBackgroundMany loci associated with obesity have been reported in previous genome-wide association studies (GWASs). However, it remains unclear whether variants at all these loci contributed to onset of obesity or whether one or a few variants cause obesity when obesity is a genetically heterogeneous population.ObjectiveTo investigate the genetic architecture of obesity by clustering a population with obesity into clusters using obesity-related factors.MethodsThis study was based on the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study and the Community-Based Cohort Study. As the Step-1, a GWAS with body mass index (BMI) as an outcome was performed for all 48,365 eligible participants. As the Step-2, we then assigned the 13,067/48,365 participants with obesity (BMI ≥ 25 kg/m2) using the k-prototype to 5 clusters. Obesity-related factors (such as age, nutrient intake, physical activity, sleep duration, difference between weight at age 20 and current weight, smoking, alcohol drinking, psychological distress, and birth weight) were used for clustering. Subsequently, participants in each cluster and those with a BMI < 25 kg/m2were combined, and GWASs were performed according to the 5 clusters. Additionally, a sub-analysis using data from the UK Biobank was conducted to compare the results.ResultsThe Step-1 detected 18 genes, most of which were reportedly associated with obesity or obesity-related topics in previous studies. The result of Step-2, of the 18 genes detected in Step-1,LINC01741, CRYZL2P-SEC16B, andSEC16Bwere significantly related to Cluster 2,FTO, PMAIP1, andMC4Rto Cluster 3, andBDNF, BDNF-AS, LINC00678, andKIF18Ato Clusters 4 and 5. In the sub-analysis, a similar phenomenon was observed in which separate obesity-related genes were detected for each cluster.ConclusionsOur data support the notion that a decreased sample size with increased homogeneity may reveal insights into the genetic architecture of obesity.