bluuebunny/crossref_metadata_2025_split huggingface dataset:
The biosynthetic pathway of ubiquinone contributes to pathogenicity ofFrancisella
Authors: Kazemzadeh Katayoun , Chehade Mahmoud Hajj , Hourdoir Gautier , Brunet Camille , Caspar Yvan , Loiseau Laurent , Barras Frederic , Pierrel Fabien , Pelosi Ludovic 
Published: August 2021

AbstractFrancisella tularensisis the causative agent of tularemia. Because of its extreme infectivity and high mortality rate, this pathogen was classified as a biothreat agent.Francisellaspp are strict aerobe and ubiquinone (UQ) has been previously identified in these bacteria. While the UQ biosynthetic pathways were extensively studied inEscherichia coliallowing the identification of fifteen Ubi-proteins to date, little is known aboutFrancisellaspp. In this study, and usingFrancisella novicidaas a surrogate organism, we first identified UQ8as the major quinone found in the membranes of this bacterium. Then, we characterized the UQ biosynthetic pathway inF. novicidausing a combination of bioinformatics, genetics and biochemical approaches. Our analysis disclosed the presence inFrancisellaof ten putative Ubi-proteins and we confirmed eight of them by heterologous complementation inE. coli. The UQ biosynthetic pathways fromF. novicidaandE. colishare a similar pattern. However, differences were highlighted: the decarboxylase remains unidentified inFrancisellaspp and homologs of the Ubi-proteins involved in the O2-independent UQ pathway are not present. This is in agreement with the strictly aerobic niche of this bacterium. Then,viatwo approaches, i.e. the use of an inhibitor (3-amino-4-hydroxybenzoic acid) and a transposon mutant, which both strongly impair the synthesis of UQ, we demonstrated that UQ is essential for the growth ofF. novicidain a respiratory medium and contributes to its pathogenicity inGalleria mellonellaused as an alternative animal model.ImportanceFrancisella tularensisis the causative bacterium of tularemia and is classified as a biothreat agent. Using multidisciplinary approaches, we investigated the ubiquinone (UQ) biosynthetic pathway that operates inF. novicidaused as a surrogate. We showed that UQ8is the major quinone identified in the membranes ofFrancisella novicida. We identified a new competitive inhibitor, which strongly decreased the biosynthesis of UQ. Our demonstration of the crucial role of UQ for the respiratory metabolism ofF. novicidaand for the involving in its pathogenicity in theGalleria mellonellamodel should stimulate the search for selective inhibitors of bacterial UQ biosynthesis.
DEVELOPMENT AND VALIDATION OF A MODEL FOR THE PREDICTION OF MORTALITY IN CHILDREN UNDER FIVE YEARS WITH CLINICAL PNEUMONIA IN RURAL GAMBIA
Authors: Jarde Alexander , Jeffries David J. , Mackenzie Grant A. 
Published: August 2021

ABSTRACTBackgroundPneumonia is the leading cause of death in children aged 1-59 months. Prediction models for child pneumonia mortality have been developed using regression methods but their performance is insufficient for clinical use.MethodsWe used a variety of machine learning methods to develop a predictive model for mortality in children with clinical pneumonia enrolled in population-based surveillance in the Basse Health and Demographic Surveillance System in rural Gambia (n=11,012). Four machine learning algorithms (support vector machine, random forest, artifical neural network, and regularized logistic regression) were implemented, fitting all possible combinations of two or more of 16 selected features. Models were shortlisted based on their training set performance, the number of included features, and the reliability of feature measurement. The final model was selected considering its clinical interpretability.ResultsWhen we applied the final model to the test set (55 deaths), the area under the Receiver Operating Characteristic Curve was 0.88 (95% confidence interval: 0.84, 0.91), sensitivity was 0.78 and specificity was 0.77.ConclusionsOur evaluation of multiple machine learning methods combined with minimal and pragmatic feature selection led to a predictive model with very good performance. We plan further validation of our model in different populations.
Association between anticholinergic burden and dementia in UK Biobank
Authors: Mur J. , Russ T.C. , Cox S. R. , Marioni R. E. , Muniz-Terrera G. 
Published: August 2021

AbstractPrevious studies on the association between the long-term use of anticholinergic drugs and dementia report heterogenous results. This variability could be due to, among other factors, different anticholinergic scales used, and differential effects of distinct classes of anticholinergic drugs. Here, we use 171,775 participants of UK Biobank with linked GP prescription records to calculate the cumulative annual anticholinergic burden (ACB) and ascertain dementia diagnoses through GP- and inpatient records. We then compare 13 anticholinergic scales and anticholinergic burden (ACB) due to different classes of drugs in their association with dementia. We find dementia to be more strongly predicted by ACB than by polypharmacy across most anticholinergic scales (standardised ORs range: 1.027-1.125). Furthermore, not only the baseline ACB, but the slope of the longitudinal trajectory of ACB (HR=1.094; 95% CI: 1.068-1.119) is predictive of dementia. However, the association between ACB and dementia holds only for some classes of drugs – especially antidepressants, antiepileptics, and high-ceiling antidiuretics. Moreover, we do not find a clear relationship between reported anticholinergic potency and dementia risk. The heterogeneity in findings on the association between ACB and dementia may in part be due to different effects for different classes of drugs. Future studies should establish such differences in more detail and further examine the practicality of using a general measure of anticholinergic potency as it relates to the risk of dementia.
Learning about COVID-19 across borders: Public health information and adherence among international travellers to the UK
Authors: Cai Shenghan , Zhang Tingting , Robin Charlotte , Sawyer Clare , Rice Wendy , Smith Louise E. , Amlôt Richard , Rubin G. James , Yardley Lucy , Hickman Matthew , Oliver Isabel , Lambert Helen 
Published: August 2021

AbstractObjectivePublic health control measures at borders have long been central to national strategies for the prevention and containment of infectious diseases. Travel was inevitably associated with the rapid global transmission of COVID-19. In the UK, public health authorities took action to reduce risks of travel-associated spread by providing public health information at ports of entry. This study aims to understand individual risk assessment processes, decision making, and adherence to official advice among international travellers; to provide evidence to inform future policy on the presentation of public health information to facilitate safer international travel.Study designThis study is a qualitative study evaluation.MethodSemi-structured interviews were conducted to investigate risk assessment processes, decision making, and adherence to official Public Health England (PHE) advice among travellers.ResultsParticipants regarded official advice as adequate at the time, despite observing differences between the intervention measures implemented in the countries of departure. Participants however also described adopting precautionary measures including self-isolation and the use of face coverings that went beyond official advice, and variability in the extent to which they adhered to guidance on contacting health authorities. Adherence to official guidance was informed by the perceived salience of specific transmission possibilities and containment measures assessed in relation to participants’ social and institutional environments.ConclusionAnalysis of travellers’ reported motivations demonstrates that responses to public health advice constitute a proactive process of risk assessment and rationalised decision-making that incorporates consideration of living situation, trust in information sources, correspondence with cultural logics, and willingness to accept potential risk to self and significant others in guiding preventive action. Our findings concerning international passengers’ understanding of, and compliance with, official advice and mitigation measures provide valuable evidence to inform future policy and we provide recommendations on the presentation of public health information to facilitate safer international travel. Access to a central source of regularly updated official information would help minimise confusion between different national guidelines. Greater attention to the differentiated information needs of diverse groups in creating future public-facing guidance would help to minimise the uncertainties generated by receipt of generic information.
Association between obesity and hospitalization in mild COVID-19 young adult outpatients in Brazil: a prospective cohort study
Authors: Sartor Ivaine Tais Sauthier , de David Caroline Nespolo , Telo Gabriela Heiden , Zavaglia Gabriela Oliveira , Fernandes Ingrid Rodrigues , Kern Luciane Beatriz , Polese-Bonatto Márcia , Azevedo Thaís Raupp , Santos Amanda Paz , de Almeida Walquiria Aparecida Ferreira , Porto Victor Bertollo Gomes , Varela Fernanda Hammes , Scotta Marcelo Comerlato , Rosa Regis Goulart , Stein Renato T. ,   COVIDa study group
Published: August 2021

AbstractBackground/ObjectivesThe aim of this study was to evaluate the association between obesity and hospitalization in mild COVID-19 adult outpatients in Brazil.Subjects/MethodsAdults with signs and symptoms suggestive of acute SARS-CoV-2 infection who sought two hospitals (one public and one private) emergency department (ED) were prospectively enrolled. Patients with confirmed COVID-19 at inclusion were followed by phone calls at day (D) D7, D14 and D28. Multivariable logistic regression models were employed to explore the association between obesity and other potential predictors for hospitalization.ResultsA total of 1,050 participants were screened, 310 were diagnosed with COVID-19 by RT-PCR. Median age was 37.4 (IQR 29.8-45.0) years, and 186 (60.0%) were female. Duration of symptoms was 3.0 (IQR 2.0-5.0) days, and 10.0 (IQR 8.0-12.0) was the median number of symptoms at inclusion. A total of 98 (31.6%) were obese, and 243 (78.4%) had no previous medical conditions. Twenty three participants (23/310, 7.4%) required hospitalization during the period. After adjusting, obesity (BMI≥30.0 kg/m2) (OR=2.69, 95%CI 1.63-4.83, P<0.001) and older age (OR=1.05, 95%CI 1.01-1.09, P<0.001), were significantly associated with higher risks of hospitalization.ConclusionsObesity, followed by aging, was the main factor associated with hospital admission for COVID-19 in a young population in a low-middle income country. Our findings highlighted the need for actions to promote additional protection for obese population, such as vaccination, and to encourage lifestyle changes.
More rapid, robust and sustainable antibody responses to mRNA COVID-19 vaccine in convalescent COVID-19 individuals
Authors: Racine-Brzostek Sabrina E. , Yee Jim , Sukhu Ashley , Qiu Yuqing , Rand Sophie , Barone Paul , Hao Ying , Yang He S. , Meng Qing H , Apple Fred S , Shi Yuanyuan , Chadburn Amy , Golden Encouse , Formenti Silvia C. , Cushing Melissa M. , Zhao Zhen 
Published: August 2021

AbstractLongitudinal studies are needed to evaluate the SARS-CoV-2 mRNA vaccine antibody response under “real-world” conditions. This longitudinal study investigated the quantity and quality of SARS-CoV-2 antibody response in 846 specimens from 350 subjects: comparing BNT162b2-vaccinated individuals (19 previously diagnosed with COVID-19 [RecoVax]; 49 never been diagnosed [NaïveVax]) to 122 hospitalized unvaccinated (HospNoVax) and 160 outpatient unvaccinated (OutPtNoVax) COVID-19 patients.NaïveVax experienced a delay in generating SARS-CoV-2 total antibody levels (TAb) and neutralizing antibodies (SNAb) after the 1st vaccine dose (D1), but a rapid increase in antibody levels was observed after the 2nddose (D2). However, these never reached the robust levels observed in RecoVax. In fact, NaïveVax TAb and SNAb levels decreased 4-weeks post-D2 (p=0.003;p<0.001). For the most part, RecoVax TAb persisted throughout this study, after reaching maximal levels 2-weeks post-D2; but SNAb decreased significantly ∼6-months post-D1 (p=0.002). Although NaïveVax avidity lagged behind that of RecoVax for most of the follow-up periods, NaïveVax did reach similar avidity by ∼6-months post-D1. These data suggest that one vaccine dose elicits maximal antibody response in RecoVax and may be sufficient. Also, despite decreasing levels in TAb and SNAb overtime, long-term avidity maybe a measure worth evaluating and possibly correlating to vaccine efficacy.
Better together – relative retention time plus spectral matching improves automated glycan characterization using PGC-nLC-IT-ESI-MS/MS
Authors: Alagesan Kathirvel , Schirmeister Falko , Möginger Uwe , Everest-Dass Arun , Altmann Friedrich , Seeberger Peter H , von Itzstein Mark , Packer Nicolle H , Kolarich Daniel 
Published: August 2021

ABSTRACTPorous Graphitized Carbon nano-liquid chromatography tandem mass spectrometry (PGC-nLC-MS/MS) is a glycomics technique with the unique capacity to differentiate isobaric glycans. The lack of suitable software tools integrating chromatography and MS-information delivered by PGC-nLC-MS/MS has been limiting fast and robust glycan identification and quantitation. We report a LC-system-independent strategy called GlycoRRT that combines relative retention time (RRT) and negative ion fragment spectra analyses for isobaric structure-specific glycomics of PGC-nLC-MS/MS data. The GlycoRRT toolset is fully customizable and easily adaptable enabling semi-automated high-throughput structural assignments. The current library contains over 200 entries and their individual meta-data (MS instrumentation, experimental conditions, retention times, fragmentation profiles and glycan structural diagnostic ion features) relevant for reliable data analyses. The GlycoRRT workflow was employed to map the N- and O-glycome in blood group matched human plasma and urine as well as decipher Immunoglobulin (IgG) glycosylation features from 13 different animal species. We have also developed visualization tools to enable a consistent, reliable, and reproducible analysis of large sets of multidimensional PGC-nLC-MS/MS glycomics data. This comprehensive glycan resource provides the glycan map of human and animal species, will serve as a reference in dissecting the role of glycans in host pathogen interaction and zoonotic disease transmission.
Are members of the Anopheles fluviatilis complex conspecific?
Authors: Singh Om P , Sindhania Ankita , Sharma Gunjan , Mishra Shobhna , Sharma Surya K , Singh Piyoosh K , Das Manoj K. 
Published: August 2021

AbstractAnopheles fluviatilis sensu lato, a primary malaria vector in India, was identified to be comprised of four cryptic species, provisionally designated as species S, T, U and V. However, Kumar et al. (Mol Ecol Resour, 2013;13:354-61) considered all of the then known three members of this species complex (S, T and U) conspecific. The specific status of species S and T was refuted based on the lack of sufficient barcode gap in mitochondrial-CO1 and the perceived presence of heterozygotes in populations as detected through one of the two species-specific PCR assays employed for the cryptic species identification. The existence of species U was refuted claiming that earlier investigations have already refuted their existence. This conclusion is concerning because of the differential public health implications of members of the Fluviatilis Complex. Here we discuss problems associated with the CO1-based barcode approach for delimitation of cryptic species, the perceived heterozygosity between species S and T based on a species-specific PCR assay, and interpretation of published reports. We demonstrated that fixed differences do exist in the ITS2-rDNA sequence of species S and T with no evidence of heterozygotes in sympatric populations and, that the observed heterozygosity by Kumar et al. in the ITS2-based species diagnostic PCR is due to the high mispriming tendency of the T-specific primer with species S. We infer that mitochondrial DNA-based ‘barcoding gap’, an arbitrary threshold recommended for species delimitation, alone, is inadequate to delimit the members of An. fluviatilis complex.
Sequence dependence of transient Hoogsteen base-pairing in DNA
Authors: de Alba Ortíz Alberto Pérez , Vreede Jocelyne , Ensing Bernd 
Published: August 2021

AbstractHoogsteen (HG) base-pairing is characterized by a 180° rotation of the purine base with respect to the Watson-Crick-Franklin (WCF) motif. Recently, it has been found that both conformations coexist in a dynamical equilibrium and that several biological functions require HG pairs. This relevance has motivated experimental and computational investigations of the base-pairing transition. However, a systematic simulation of sequence variations has remained out of reach. Here, we employ advanced path-based methods to perform unprecedented free-energy calculations. Our methodology enables us to study the different mechanisms of purine rotation, either remaining inside or after flipping outside of the double helix. We study seven different sequences, which are neighbor variations of a well-studied A·T pair in A6-DNA. We observe the known effect of A·T steps favoring HG stability, and find evidence of triple-hydrogen-bonded neighbors hindering the inside transition. More importantly, we identify a dominant factor: the direction of the A rotation, with the 6-ring pointing either towards the longer or shorter segment of the chain, respectively relating to a lower or higher barrier. This highlights the role of DNA’s relative flexibility as a modulator of the WCF/HG dynamic equilibrium. Additionally, we provide a robust methodology for future HG proclivity studies.
Biophysical network models of phase-synchronization in MEG resting-state
Authors: Williams N , Toselli B , Siebenhühner F , Palva S , Arnulfo G , Kaski S , Palva JM 
Published: August 2021

AbstractMagnetoencephalography (MEG) is used extensively to study functional connectivity (FC) networks of phase-synchronization, but the relationship of these networks to their biophysical substrates is poorly understood. Biophysical Network Models (BNMs) have been used to produce networks corresponding to MEG-derived networks of phase-synchronization, but the roles of inter-regional conduction delays, the structural connectome and dynamics of model of individual brain regions, in obtaining this correspondence remain unknown. In this study, we investigated the roles of conduction delays, the structural connectome, and dynamics of models of individual regions, in obtaining a correspondence between model-generated and MEG-derived networks between left-hemispheric regions. To do this, we compared three BNMs, respectively comprising Wilson-Cowan oscillators interacting with diffusion Magnetic Resonance Imaging (MRI)-based patterns of structural connections through zero delays, constant delays and distance-dependent delays respectively. For the BNM whose networks corresponded most closely to the MEG-derived network, we used comparisons against null models to identify specific features of each model component, e.g. the pattern of connections in the structure connectome, that contributed to the observed correspondence. The Wilson-Cowan zero delays model produced networks with a closer correspondence to the MEG-derived network than those produced by the constant delays model, and the same as those produced by the distance-dependent delays model. Hence, there is no evidence that including conduction delays improves the correspondence between model-generated and MEG-derived networks. Given this, we chose the Wilson-Cowan zero delays model for further investigation. Comparing the Wilson-Cowan zero delays model against null models revealed that both the pattern of structural connections and Wilson-Cowan oscillatory dynamics contribute to the correspondence between model-generated and MEG-derived networks. Our investigations yield insight into the roles of conduction delays, the structural connectome and dynamics of models of individual brain regions, in obtaining a correspondence between model-generated and MEG-derived networks. These findings result in a parsimonious BNM that produces networks corresponding closely to MEG-derived networks of phase-synchronization.HighlightsSimple biophysical model produces close match (ρ=0.49) between model and MEG networksNo evidence for conduction delays improving match between model and MEG networksPattern of structural connections contributes to match between model and MEG networksWilson-Cowan oscillatory dynamics contribute to match between model and MEG networks
Membrane remodeling and matrix dispersal intermediates during mammalian acrosomal exocytosis
Authors: Leung Miguel Ricardo , Ravi Ravi Teja , Gadella Bart M. , Zeev-Ben-Mordehai Tzviya 
Published: August 2021

SummaryTo become fertilization-competent, mammalian sperm must undergo a complex series of biochemical and morphological changes in the female reproductive tract. These changes, collectively called capacitation, culminate in the exocytosis of the acrosome, a large vesicle overlying the nucleus. Acrosomal exocytosis is not an all-or-nothing event, but rather a regulated process in which vesicle cargo disperses gradually. However, the structural mechanisms underlying this controlled release remain undefined. In addition, unlike other exocytotic events, fusing membranes are shed as vesicles; the cell thus loses the entire anterior two-thirds of its plasma membrane and yet remains intact while the remaining non-vesiculated plasma membrane becomes fusogenic. Precisely how cell integrity is maintained through-out this drastic vesiculation process is unclear, as is how it ultimately leads to the acquisition of fusion competence. Here, we use cryo-electron tomography to visualize these processes in unfixed, unstained, fully-hydrated sperm. We show that crystalline structures within the acrosome disassemble during capacitation and acrosomal exocytosis, representing a plausible mechanism for gradual dispersal of the acrosomal matrix. We find that the architecture of the sperm head supports an atypical membrane fission-fusion pathway that maintains cell integrity. Finally, we detail how the acrosome reaction transforms both the micron-scale topography and the nano-scale protein landscape of the sperm surface, thus priming the sperm for fertilization.SignificanceMammalian sperm must undergo a complex series of biochemical and morphological changes in the female reproductive tract in order to become fertilization-competent. These changes culminate in acrosomal exocytosis, during which multiple membrane fusions destabilize the acrosomal vesicle and liberate its contents, which include proteins implicated in penetrating and binding to the egg vestments. Here, we use cryo-electron tomography to visualize acrosomal exocytosis intermediates in unfixed, unstained sperm. Our results suggest structural bases for how gradual dispersal of acrosome contents is regulated, as well as for how the cell remains intact after losing much of its plasma membrane, We also show that acrosomal exocytosis transforms both the micron-scale topography and the nano-scale molecular landscape of the sperm surface, thus priming it for interaction and fusion with the egg. These findings yield important insights into sperm physiology and contribute to our understanding of the fundamental yet enigmatic process of mammalian fertilization.