bluuebunny/crossref_metadata_2025_split huggingface dataset:
MRI: an algorithm to identify metabolic reprogramming during adaptive laboratory evolution using gene expression data
Authors: Yazdanpanah Shaghayegh , Motamedian Ehsan , Shojaosadati Seyed Abbas 
Published: October 2022

AbstractThe development of a method for identifying latent reprogramming in gene expression data resulting from evolution has been a challenge. In this study, a method called Metabolic Reprogramming Identifier (MRI), based on the integration of expression data to a genome-scale metabolic model, has been developed. To identify key genes playing the main role in reprogramming, a MILP problem is presented and maximum utilization of gene expression resources is defined as an objective function. Then, genes with complete expression usage and significant expression difference between wild-type and evolved strains were selected as key genes for reprogramming. This score is also applied to evaluate compatibility of expression pattern with maximal use of key genes. The method was implemented to investigate the reprogramming ofE. coliduring adaptive evolution caused by changing carbon sources. The results indicate the importance of inner membrane in reprogramming ofE. colito adapt to the new environment. The method predicts no reprogramming occurs when switching from glucose to glycerol.
Beyond consensus sequence: a quantitative scheme for inferring transmission using deep sequencing in a bacterial transmission model
Authors: Senghore Madikay , Read Hannah , Oza Priyali , Johnson Sarah , Passarelli-Araujo Hemanoel , Taylor Bradford P , Ashley Stephen , Grey Alex , Callendrello Alanna , Lee Robyn , Goddard Matthew R , Lumley Thomas , Hanage William P , Wiles Siouxsie 
Published: October 2022

AbstractGenomic surveillance provides a data source complementary to contact tracing to resolve putative transmission chains. However, the role of within-host diversity in transmission is understudied due to a lack of experimental and clinical datasets that capture within-host diversity in both donors and recipients. Here, we assess the utility of deep-sequenced genomic surveillance within a mouse transmission model where the gastrointestinal pathogenCitrobacter rodentiumwas controllably spread during co-housing of infected and naïve animals. We observed that within-host variants were maintained over multiple transmission steps until fixation or elimination. We present a model for inferring the likelihood that a given pair of samples are linked by transmission, by comparing the allelic frequency at variant genomicloci. Our data affirm that within-host single nucleotide variants (iSNVs) can repeatedly pass from donor to recipient along the transmission chain, and the mere sharing of iSNVs between different transmission pairs offers limited confidence in identifying a transmission pair. Beyond the presence and absence of within-host variants, we show that differences arising in the relative abundance of iSNVs can infer transmission pairs with high precision. An important component of our approach is that the inference is based solely on sequence data, without incorporating epidemiological or demographic data for context. Our model, which substantially reduces the number of comparisons a contact tracer needs to consider, may enhance the accuracy of contact tracing and other epidemiological processes, including early detection of emerging transmission clusters.
VACS: VAccination disComfort Scale
Authors: Wallace Manolis , Antonopoulos Stavros , Poulopoulos Vassilis 
Published: October 2022

AbstractIn this article we focus on the discomfort experienced by children during vaccination and ask ourselves how this discomfort could be quantified. We develop VACS, a tool to measure this discomfort as a number in the range 0-25 and apply it to 40 vaccinations of children aged 2 to 12. Our findings show that approximately 40% of the children do not face discomfort during vaccination, but for the rest discomfort of varying degrees is observed. We also find that doctors are content with their patients facing considerably higher discomfort levels that what the children themselves are willing to withstand. Surprisingly, characteristics such as a) gender, b) whether the state’s recommended vaccination program has been implemented in full and even c) prior negative vaccination experiences are found to be poor predictors of vaccination discomfort. Age may be a factor, with younger children experiencing discomfort more often and more intensely, but more research is required in order to validate this. The formulation of VACS opens the door for more systematic work towards the minimization of vaccination discomfort for children.
Alternative splicing in the lung influences COVID-19 severity and respiratory diseases
Authors: Nakanishi Tomoko , Farjoun Yossi , Willett Julian , Allen Richard J. , Guillen-Guio Beatriz , Zhou Sirui , Richards J. Brent 
Published: October 2022

AbstractHospital admission for COVID-19 remains common despite the successful development of vaccines and treatments. Thus, there is an ongoing need to identify targets for new COVID-19 therapies. Alternative splicing is an essential mechanism for generating functional diversity in protein isoforms and influences immune response to infection. However, the causal role of alternative splicing in COVID-19 severity and its potential therapeutic relevance is not fully understood. In this study, we evaluated the causal role of alternative splicing in COVID-19 severity and susceptibility using Mendelian randomization (MR). To do so, we performed two-sample MR to assess whethercis-sQTLs spanning 8,172 gene splicing in 5,295 genes were associated with COVID-19 outcomes in the COVID-19 Host Genetics Initiative, including up to 158,840 COVID-19 cases and 2,782,977 population controls. We identified that alternative splicing in lungs, rather than total RNA expression ofOAS1, ATP11A, DPP9andNPNT, was associated with COVID-19 severity.MUC1splicing was associated with COVID-19 susceptibility. Further colocalization analyses supported a shared genetic mechanism between COVID-19 severity with idiopathic pulmonary fibrosis atATP11AandDPP9loci, and with chronic obstructive lung diseases atNPNT. We lastly showed thatATP11A, DPP9, NPNT, andMUC1were highly expressed in lung alveolar epithelial cells, both in COVID-19 uninfected and infected samples. Taken together, these findings clarify the importance of alternative splicing of proteins in the lung for COVID-19 and other respiratory diseases, providing isoform-based targets for drug discovery.
Prefrontal hemodynamics during forward and backward walking, with and without a cognitive task, in people with MS: An fNIRS study
Authors: Kupchenko Yana , Dreyer-Alster Sapir , Broscheid Kim-Charline , Kalron Alon 
Published: October 2022

AbstractObjectiveTo investigate the prefrontal cortex (PFC) hemodynamics during forward and as well as backward walking, with and without a cognitive task, in people with MS (pwMS) and healthy controls.MethodsThe observational functional near-infrared spectroscopy (fNIRS) study comprised 18 pwMS and 17 healthy controls. Each subject completed four walking trials: Single task (ST) forward walking, dual task (DT) forward walking, ST backward walking, DT backward walking. PFC activity for all trials was recorded using functional near-infrared spectroscopy (fNIRS). The PFC was subdivided in the frontal eye field (FEF), frontopolar cortex (FPC) and the dorsolateral PFC (DLPFC).ResultsThe relative oxygenated hemoglobin (HbO) concentration was higher during the DT forward walking in all PFC subareas compared with the ST forward walking for both groups. The relative HbO concentration was higher during ST backward walking compared with ST forward walking in pwMS (DLPFC, FEF) and the healthy controls (FEF, FPC), specifically during the initial part of the trial. There was no distinct difference in the relative HbO concentration between ST backward walking with DT backward walking in pwMS. In contrast, the relative HbO concentration in the FEF and the FPC increased in healthy controls during DT backward walking compared with ST backward walking, specifically during the second half of the trial.ConclusionsST backward walking and DT forward walking impact the hemodynamics at the PFC, although, the difference between pwMS and healthy adults requires further clarification. Future RCT’s are encouraged to examine the impact of an intervention program based on DT forward and backward walking on PFC activity in pwMS.ImpactThe present study demonstrated that backward walking increases activity in the PFC region. Similarly, when performing a cognitive task while walking forward. This information should be considered by PT’s for training, particularly pwMS.
ALCOHOLIC LIVER BIOMARKERS: DETERMINANTS FOR ADMISSION TO REHABILITATION CENTRES DURING THE COVID 19 PERIOD IN KENYA
Authors: Njoroge George , Mwenda Catherine , Mecha Ezekiel , Waithaka Stanley 
Published: October 2022

AbstractConsumption of alcohol is a practice world over that dates back to 10,000 Before Christ. Evaluation on the damages caused by the alcohol on the human organs such as the liver is paramount. There is no direct evaluation to liver parenchyma before admission rather blood samples are evaluated to show damage or no damage to the liver cells. The outcome of the blood samples denote the health status of the liver cells before admission. Alcohol biomarkers are usually elevated when there is damage to the liver parenchyma. This was a quantitative descriptive cross sectional study. Purpose sampling was used to select two Counties with the highest number of alcohol consumers. Simple Random sampling method was used to select participants for liver biomarkers. Participants were requested to consent for blood donation and confidentiality was maintained. Blood samples collected were separated for serum and cells using centrifuge within one hour after donation. The samples were transported for storage using cool boxes and temperature was maintained between −8 and +8 degrees during transportation. The blood samples were stored at −8 and +8 degrees in the deep freezer. Majority (97%) of the participants had alanine aminotransferase levels of 41 to 80 IU/L. Eighty eight percent of the participants had aspartate aminotransferase elevated to between 35 and 68 IU/L. Gamma Glutamyl aminotransferase was elevated in all of the participants while alanine phosphatase was elevated in 99% of the participants. Most participants had elevated liver biomarkers before admission to rehabilitation centre.
Extreme mito-nuclear discordance within Anthozoa, with notes on unique properties of their mitochondrial genomes
Authors: Quattrini Andrea M. , Snyder Karen , Purow-Ruderman Risa , Seiblitz Isabela G.L. , Hoang Johnson , Floerke Natasha , Ramos Nina I. , Wirshing Herman H. , Rodriguez Estefanía , McFadden Catherine S. 
Published: October 2022

AbstractWhole mitochondrial genomes are often used in phylogenetic reconstruction. However, discordant patterns in species relationships between mitochondrial and nuclear phylogenies are commonly observed. Within Anthozoa (Phylum Cnidaria), mitochondrial-nuclear discordance has not yet been examined using a large and comparable dataset. Here, we used data obtained from target-capture enrichment sequencing to assemble and annotate mitochondrial genomes and reconstruct phylogenies for comparisons to phylogenies inferred from 100s of nuclear loci obtained from the same samples. The datasets comprised 108 hexacorals and 94 octocorals representing all orders and >50% of extant families. Results indicated rampant discordance between datasets at every taxonomic level. This discordance is not attributable to substitution saturation, but rather likely caused by recent and ancient introgressive hybridization and selection. We also found strong purifying selection across the mitochondrial genomes, cautioning their use in analyses that rely on assumptions of neutrality. Furthermore, unique properties of the mitochondrial genomes were noted, including genome rearrangements and the presence ofnad5introns. Specifically, we note the presence of the homing endonuclease in ceriantharians. This large dataset of mitochondrial genomes further demonstrates the utility of off-target reads generated from target-capture data for mitochondrial genome assembly and adds to the growing knowledge of anthozoan evolution.
Intra-host viral populations of SARS-CoV-2 in immunosuppressed patients with hematologic cancers
Authors: Fournelle Dominique , Mostefai Fatima , Brunet-Ratnasingham Elsa , Poujol Raphael , Grenier Jean-Christophe , Gálvez José Héctor , Pagliuzza Amélie , Levade Inès , Moreira Sandrine , Lapierre Simon Grandjean , Chomont Nicolas , Kaufmann Daniel E. , Craig Morgan , Hussin Julie G. 
Published: October 2022

AbstractThroughout the SARS-CoV-2 pandemic, several variants of concern (VOC) have been identified, many of which share recurrent mutations in the spike protein’s receptor binding domain (RBD). This region coincides with known epitopes and can therefore have an impact on immune escape. Protracted infections in immunosuppressed patients have been hypothesized to lead to an enrichment of such mutations and therefore drive evolution towards VOCs. Here, we show that immunosuppressed patients with hematologic cancers develop distinct populations with immune escape mutations throughout the course of their infection. Notably, by investigating the co-occurrence of substitutions on individual sequencing reads in the RBD, we found quasispecies harboring mutations that confer resistance to known monoclonal antibodies (mAbs) such as S:E484K and S:E484A. Furthermore, we provide the first evidence for a viral reservoir based on intra-host phylogenetics. Our results on viral reservoirs can shed light on protracted infections interspersed with periods where the virus is undetectable as well as an alternative explanation for some long-COVID cases. Our findings also highlight that protracted infections should be treated with combination therapies rather than by a single mAbs to clear pre-existing resistant mutations.
Forecasting of a complex microbial community using meta-omics
Authors: Delogu F. , Kunath B. J. , Queirós P. M. , Halder R. , Lebrun L. A. , Pope P. B. , May P. , Widder S. , Muller E. E. L. , Wilmes P. 
Published: October 2022

ABSTRACTMicrobial communities are complex assemblages whose dynamics are shaped by abiotic and biotic factors. A major challenge concerns correctly forecasting the community behaviour in the future. In this context, communities in biological wastewater treatment plants (BWWTPs) represent excellent model systems, because forecasting them is required to ultimately control and operate the plants in a sustainable manner. Here, we forecast the microbial community from the water-air interface of the anaerobic tank of a BWWTP via longitudinal meta-omics (metagenomics, metatranscriptomics and metaproteomics) data covering 14 months at weekly intervals. We extracted all the available time-dependent information, summarised it in 17 temporal signals (explaining 91.1% of the temporal variance) and linked them over time to rebuild the sequence of ecological phenomena behind the community dynamics. We forecasted the signals over the following five years and tested the predictions with 21 extra samples. We were able to correctly forecast five signals accounting for 22.5% of the time-dependent information in the system and generate mechanistic predictions on the ecological events in the community (e.g. a predation cycle involving bacteria, viruses and amoebas). Through the forecasting of the 17 signals and the environmental variables readings we reconstructed the gene abundance and expression for the following 5 years, showing a nearly perfect trend prediction (coefficient of determination ≥ 0.97) for the first 2 years. The study demonstrates the maturity of microbial ecology to forecast composition and gene expression of open microbial ecosystems using year-spanning interactions between community cycles and environmental parameters.
Engineered synthetic one-carbon fixation exceeds yield of the Calvin Cycle
Authors: Dronsella Beau , Orsi Enrico , Benito-Vaquerizo Sara , Glatter Timo , Bar-Even Arren , Erb Tobias. J. , Claassens Nico J. 
Published: October 2022

AbstractOne-carbon (C1) feedstocks derived from CO2and renewable electricity, such as formate, are promising substrates for sustainable production of chemicals, food and fuels. Energetically more efficient, engineered C1-fixation pathways were proposed to increase biomass yields above their natural counterparts, but have so far not been shown to achieve this. Here, we replace the native ‘energy-inefficient’ Calvin-Benson-Bassham (CBB) cycle inCupriavidus necatorby genomic integration of the synthetic reductive glycine pathway for growth on formate. Our final engineered strain reaches a higher biomass yield than the CBB-cycle-utilizing wild type, showing for the first time that efficiencies found in natural metabolism can be exceeded via a synthetic pathway. This yield increase demonstrates the potential of synthetic metabolism and is an important step towards realizing truly sustainable, economically feasible bio-based production.
Structure of human TRPM8 channel
Authors: Palchevskyi Sergii , Czarnocki-Cieciura Mariusz , Vistoli Giulio , Gervasoni Silvia , Nowak Elżbieta , Beccari Andrea R. , Nowotny Marcin , Talarico Carmine 
Published: October 2022

SUMMARYTRPM8 is a calcium ion channel that is activated by multiple factors, such as temperature, voltage, pressure, and osmolality. It is a therapeutic target for anticancer drug development, and its modulators can be utilized for several pathological conditions. Here, we present a cryo-electron microscopy structure of a human TRPM8 channel in the closed state that was solved at 2.7 Å resolution. Based on our reconstruction, we built the most complete model of the N-terminal pre-melastatin homology region. We also visualized several ligands that are bound by the protein and modeled how the human channel interacts with icilin. Analyses of pore helices showed that all available TRPM8 structures can be grouped into closed and desensitized states based on the register of pore helix S6 and the resulting positioning of particular amino acid residues at the channel constriction.
Broadly neutralizing SARS-CoV-2 antibodies through epitope-based selection from convalescent patients
Authors: Rouet Romain , Henry Jake Y. , Johansen Matt D. , Sobti Meghna , Balachandran Harikrishnan , Langley David B. , Walker Gregory , Lenthall Helen , Jackson Jennifer , Ubiparipovic Stephanie , Mazigi Ohan , Schofield Peter , Burnett Deborah L. , Brown Simon H. J. , Martinello Marianne , Hudson Bernard , Gilroy Nicole , Post Jeffrey J. , Kelleher Anthony , Jäck Hans-Martin , Goodnow Christopher C. , Turville Stuart G. , Rawlinson William D. , Bull Rowena A. , Stewart Alastair G. , Hansbro Philip M. , Christ Daniel 
Published: October 2022

SUMMARYEmerging variants of concern (VOCs) are threatening to limit the effectiveness of SARS-CoV-2 monoclonal antibodies and vaccines currently used in clinical practice; broadly neutralizing antibodies and strategies for their identification are therefore urgently required. Here we demonstrate that broadly neutralizing antibodies can be isolated from peripheral blood mononuclear cells (PBMCs) of convalescent patients using SARS-CoV-2 receptor binding domains (RBDs) carrying epitope-specific mutations. This is exemplified by two human antibodies, GAR05, binding to epitope class 1, and GAR12, binding to a new epitope class 6 (located between class 3 and class 5). Both antibodies broadly neutralize VOCs, exceeding the potency of the clinical monoclonal sotrovimab (mAb S309) by orders of magnitude. They also provide potent prophylactic and therapeuticin vivoprotection of hACE2 mice against viral challenge. Our results indicate that exposure to Wuhan SARS-CoV-2 induces antibodies that maintain potent and broad neutralization against emerging VOCs using two unique strategies: either by targeting the divergent class 1 epitope in a manner resistant to VOCs (ACE2 mimicry, as illustrated by GAR05 and mAbs P2C-1F11/S2K14); or alternatively, by targeting rare and highly conserved epitopes, such as the new class 6 epitope identified here (as illustrated by GAR12). Our results provide guidance for next generation monoclonal antibody development and vaccine design.
Glycogen degrading activities of catalytic domains of α-amylase and α-amylase-pullulanase enzymes conserved inGardnerellaspp. from the vaginal microbiome
Authors: Bhandari Pashupati , Tingley Jeffrey , Abbott D. Wade , Hill Janet E. 
Published: October 2022

AbstractGardnerellaspp. are associated with bacterial vaginosis, in which normally dominant lactobacilli are replaced with facultative and anaerobic bacteria includingGardnerellaspp. Co-occurrence of multiple species ofGardnerellais common in the vagina and competition for nutrients such as glycogen likely contributes to the differential abundances ofGardnerellaspp. Glycogen must be digested into smaller components for uptake; a process that depends on the combined action of glycogen degrading enzymes. In this study, the ability of culture supernatants of 15 isolates ofGardnerellaspp. to produce glucose, maltose, maltotriose and maltotetraose from glycogen was demonstrated. Carbohydrate active enzymes were identified bioinformatically inGardnerellaproteomes using dbCAN2. Identified proteins included a single domain α-amylase (EC 3.2.1.1) (encoded by all 15 isolates) and an α-amylase-pullulanase (EC 3.2.1.41) containing amylase, carbohydrate binding modules and pullulanase domains (14/15 isolates). To verify the sequence-based functional predictions, the amylase and pullulanase domains of the α-amylase-pullulanase, and the single domain α-amylase were each produced inE. coli. The α-amylase domain from the α-amylase-pullulanase released maltose, maltotriose and maltotetraose from glycogen, and the pullulanase domain released maltotriose from pullulan and maltose from glycogen, demonstrating that theGardnerellaα-amylase-pullulanase is capable of hydrolyzing α-1,4 and α-1,6 glycosidic bonds. Similarly, the single domain α-amylase protein also produced maltose, maltotriose and maltotetraose from glycogen. Our findings show thatGardnerellaspp. produce extracellular amylase enzymes as ‘public goods’ that can digest glycogen into maltose, maltotriose and maltotetraose that can be used by the vaginal microbiota.ImportanceIncreased abundance ofGardnerellaspp. is a diagnostic characteristic of bacterial vaginosis, an imbalance in the human vaginal microbiome associated with troubling symptoms, and negative reproductive health outcomes, including increased transmission of sexually transmitted infections and preterm birth. Competition for nutrients is likely an important factor in causing dramatic shifts in the vaginal microbial community but little is known about the contribution of bacterial enzymes to the metabolism of glycogen, a major food source available to vaginal bacteria. The significance of our research is characterizing the activity of enzymes conserved inGardnerellaspecies that contribute to the ability of these bacteria to utilize glycogen.