bluuebunny/crossref_metadata_2025_split huggingface dataset:
Elevated binding and functional antibody responses to SARS-CoV-2 in infants versus mothers
Authors: Stoddard Caitlin I. , Sung Kevin , Yaffe Zak A. , Weight Haidyn , Beaudoin-Bussières Guillaume , Galloway Jared , Gantt Soren , Adhiambo Judith , Begnel Emily R. , Ojee Ednah , Slyker Jennifer , Wamalwa Dalton , Kinuthia John , Finzi Andrés , Matsen Frederick A. , Lehman Dara A. , Overbaugh Julie 
Published: February 2023

SummaryInfant antibody responses to viral infection can differ from those in adults. However, data on the specificity and function of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in infants, and direct comparisons between infants and adults are limited. We characterized antibody binding and functionality in convalescent plasma from postpartum women and their infants infected with SARS-CoV-2 from a vaccine-naïve prospective cohort in Nairobi, Kenya. Antibody titers against SARS-CoV-2 Spike, receptor binding domain and N-terminal domain, and Spike-expressing cell-surface staining levels were significantly higher in infants than in mothers. Plasma antibodies from mothers and infants bound to similar regions of the Spike S2 subunit, including the fusion peptide (FP) and stem helix-heptad repeat 2. However, infants displayed higher antibody levels and more consistent antibody escape pathways in the FP region compared to mothers. Finally, infants had significantly higher levels of antibody-dependent cellular cytotoxicity (ADCC), though, surprisingly, neutralization titers between infants and mothers were similar. These results suggest infants develop distinct SARS-CoV-2 binding and functional antibody repertoires and reveal age-related differences in humoral immunity to SARS-CoV-2 infection that could be relevant to protection and COVID-19 disease outcomes.
Coevolutionary Stability of Host-Symbiont Systems with Mixed-mode Transmission
Authors: Krishnan Nandakishor , Rózsa Lajos , Szilágyi András , Garay József 
Published: February 2023

AbstractThe coevolution of hosts and symbionts based on virulence and mode of transmission is a complex and diverse biological phenomenon. We introduce a conceptual model to study the stable coexistence of an obligate symbiont (mutualist or parasite) with mixed-mode transmission and its host. The existence of evolutionarily and ecologically stable coexistence is analyzed in the framework of coevolutionary dynamics. Using an age-structured Leslie model for the host, we demonstrate how the obligate symbiont can modify the host’s life history parameters (survival and fecundity) and the long-term growth rate of the infected lineage. The evolutionary success of the symbionts is given by the long-term growth rate of the infected population (multi-level selection). When the symbiont is vertically transmitted, we find that the host and its symbiont can maximize the long-term growth rate of the infected lineage. Moreover, we provide conditions for the ecological and evolutionary stability of the resident host-symbiont pair in the coevolutionary model, which does not allow invasion by any rare mutants (each mutant dies out by ecological selection). We observed that ecological competition, clearing of infection, and density-dependent interactions could play a role in determining the criteria for evolutionary stability.
Systematically testing human HMBS missense variants to reveal mechanism and pathogenic variation
Authors: van Loggerenberg Warren , Sowlati-Hashjin Shahin , Weile Jochen , Hamilton Rayna , Chawla Aditya , Gebbia Marinella , Kishore Nishka , Frésard Laure , Mustajoki Sami , Pischik Elena , Pierro Elena Di , Barbaro Michela , Floderus Ylva , Schmitt Caroline , Gouya Laurent , Colavin Alexandre , Nussbaum Robert , Friesema Edith C. H. , Kauppinen Raili , To-Figueras Jordi , Aarsand Aasne K. , Desnick Robert J. , Garton Michael , Roth Frederick P. 
Published: February 2023

AbstractDefects in hydroxymethylbilane synthase (HMBS) can cause Acute Intermittent Porphyria (AIP), an acute neurological disease. Although sequencing-based diagnosis can be definitive, ~⅓ of clinical HMBS variants are missense variants, and most clinically-reported HMBS missense variants are designated as “variants of uncertain significance” (VUS). Using saturation mutagenesis,en masseselection, and sequencing, we applied a multiplexed validated assay to both the erythroid-specific and ubiquitous isoforms of HMBS, obtaining confident functional impact scores for >84% of all possible amino-acid substitutions. The resulting variant effect maps generally agreed with biochemical expectation. However, the maps showed variants at the dimerization interface to be unexpectedly well tolerated, and suggested residue roles in active site dynamics that were supported by molecular dynamics simulations. Most importantly, these HMBS variant effect maps can help discriminate pathogenic from benign variants, proactively providing evidence even for yet-to-be-observed clinical missense variants.
A remarkable transformation catalyzed by a domain-of-unknown-function 692 during the biosynthesis of a new RiPP natural product
Authors: Ayikpoe Richard S. , Zhu Lingyang , Chen Jeff Y. , Ting Chi P. , van der Donk Wilfred A. 
Published: February 2023

AbstractThe domain of unknown function 692 (DUF692) is an emerging family of posttranslational modification enzymes involved in the biosynthesis of ribosomally-synthesized and posttranslationally modified peptide (RiPP) natural products. Members of this family are multinuclear iron-containing enzymes and only two members have been functionally characterized to date: MbnB and TglH. Here, we used bioinformatics to select another member of the DUF692 family, ChrH, that is ubiquitously encoded in the genomes of theChryseobacteriumgenus along with a partner protein ChrI. We structurally characterized the ChrH reaction product and show that the enzyme catalyzes an unprecedented chemical transformation that results in the formation of a macrocycle, an imidazolidinedione heterocycle, two thioaminals, and a thiomethylation. Based on isotopic labeling studies, we propose a mechanism for the four-electron oxidation and methylation of the substrate peptide. This work identifies the first SAM-dependent DUF692 enzyme, further expanding the repertoire of remarkable reactions catalyzed by these enzymes.
Profiling the impact of the promoters on CRISPR-Cas12a system in human cells
Authors: Li Jinhe , Liang Qinchun , Zhou HuaPing , Zhou Ming , Huang Hongxin 
Published: February 2023

AbstractThe plasmid vector platform is the most commonly used for the expression of the versatile CRISPR-Cas technique and the promoter is a crucial element for the expression vector, thus profiling the impact of the promoters on CRISPR editors provides the basic information for the gene-editing toolkits and can be a guideline for its design. Herein, we made a parallel comparison among four commonly used promoters (CAG,∼1700bp; EF1a core, ∼210bp; CMV, ∼500bp; and PGK, ∼500bp) in CRISPR-Cas12a system in mammalian cells to explore the impact of promoters on this powerful tool. We found that without badly damaging targeting specificity, the CAG promoter-driving Cas12a editor exhibited the most active (efficiency takes as 100%, specificity index= ∼75%) in genomic cleavage, multiplex editing, transcriptional activation, and base editing, followed by promoter CMV (efficiency=70∼90% (vs CAG), specificity index= ∼78%), and then EF1a core and PGK (both efficiency=40∼60%, vs CAG) but with higher specificity (specificity index= ∼84% and ∼82%, respectively). Therefore, CAG is recommended in the CRISPR-Cas12a system for the applications that need a robust editing activity but without size limitation, CMV mostly can be an alternative for CAG when requiring a smaller space, EF1a is similar to PGK with relatively high specificity, but has a smaller size, thus is more suitable forin vivotherapeutic applications. The data outlined the properties of the widely used promoters in the CRISPR-Cas12a system, which can be a guide for its applications and can be a useful resource for the gene-editing field.
The influence of heteroresistance on minimum inhibitory concentration (MIC), investigated using weak-acid stress in food spoilage yeasts
Authors: Violet Joseph , Smid Joost , Pielaat Annemarie , Sanders Jan-Willem , Avery Simon V. 
Published: February 2023

AbstractPopulations of microbial cells may resist environmental stress by maintaining a high population-median resistance (IC50) or, potentially, a high variability in resistance between individual cells (heteroresistance); where heteroresistance would allow certain cells to resist high stress, provided the population was sufficiently large to include resistant cells. This study sets out to test the hypothesis that both IC50and heteroresistance may contribute to conventional minimal-inhibitory-concentration (MIC) determinations, using the example of spoilage-yeast resistance to the preservative sorbic acid. Across a panel of 26 diverse yeast species, both heteroresistance and particularly IC50were positively correlated with predicted MIC. A focused panel of 29 different isolates of a particular spoilage yeast was also examined (isolates previously recorded asZygosaccharomyces bailii, but genome resequencing revealing that several were in fact hybrid species,Z. parabailii and Z. pseudobailii). Applying a novel high-throughput assay for heteroresistance, it was found that IC50but not heteroresistance was positively correlated with predicted MIC when considered across all isolates of this panel, but the heteroresistance-MIC interaction differed for the individualZygosaccharomycessubspecies.Z. pseudobailiiexhibited higher heteroresistance thanZ. parabailiiwhereas the reverse was true for IC50, suggesting possible alternative strategies for achieving high MIC between subspecies. This work highlights the limitations of conventional MIC measurements due to the effect of heteroresistance in certain organisms, as the measured resistance can vary markedly with population (inoculum) size.ImportanceFood spoilage by fungi is a leading cause of food waste, with specialised food spoilage yeasts capable of growth at preservative concentrations above the legal limit, in part due to heteroresistance allowing small subpopulations of cells to exhibit extreme preservative resistance. Whereas heteroresistance has been characterised in numerous ecological contexts, measuring this phenotype systematically and assessing its importance are not encompassed by conventional assay methods. The development here of a high-throughput method for measuring heteroresistance, amenable to automation, addresses this issue and has enabled characterisation of the contribution that heteroresistance may make to conventional MIC measurements. We used the example of sorbic acid heteroresistance in spoilage yeasts likeZygosaccharomycesspp, but the approach is relevant to other fungi and other inhibitors, including antifungals. The work shows how median resistance, heteroresistance and inoculum size should all be considered when selecting appropriate inhibitor doses in real-world antimicrobial applications such as food preservation.
T-toxin virulence genes: unconnected dots in a sea of repeats
Authors: Haridas Sajeet , González Jennifer B. , Riley Robert , Koriabine Maxim , Yan Mi , Ng Vivian , Rightmyer Adriana , Grigoriev Igor V. , Baker Scott E. , Turgeon B. Gillian 
Published: February 2023

AbstractIn 1970, the Southern Corn Leaf Blight epidemic ravaged US fields to great economic loss. The outbreak was caused by never-before-seen, super-virulent, Race T of the fungusCochliobolus heterostrophus. The functional difference between Race T and O, the previously known, far less aggressive strain, is production of T-toxin, a host-selective polyketide. Super-virulence is associated with ∼1 Mb of Race T- specific DNA; only a fraction encodes T-toxin biosynthetic genes (Tox1).Tox1is genetically and physically complex, with unlinked loci (Tox1A, Tox1B) genetically inseparable from breakpoints of a Race O reciprocal translocation that generated hybrid Race T chromosomes. Previously, we identified ten genes for T-toxin biosynthesis. Unfortunately, high depth, short-read sequencing placed these genes on four small, unconnected scaffolds surrounded by repeated A+T rich sequence, concealing context. To sort outTox1topology and pinpoint the hypothetical Race O translocation breakpoints corresponding to Race T-specific insertions, we undertook PacBio long-read sequencing which revealedTox1gene arrangement and the breakpoints. SixTox1Agenes are arranged as three small islands in a Race T-specific sea (∼634 kb) of repeats. FourTox1Bgenes are linked, on a large loop of Race T-specific DNA (∼210 kb). The race O breakpoints are short sequences of race O-specific DNA; corresponding positions in race T are large insertions of race T-specific, A+T rich DNA, often with similarity to transposable (predominantly Gypsy) elements. Nearby, are ‘Voyager Starship’ elements and DUF proteins. These elements may have facilitatedTox1integration into progenitor Race O and promoted large scale recombination resulting in race T.ImportanceIn 1970 a corn disease epidemic ravaged fields in the US to great economic loss. The outbreak was caused by a never-before seen, super-virulent strain of the fungal pathogenCochliobolus heterostrophus. This was a plant disease epidemic, however, the current COVID-19 pandemic of humans is a stark reminder that novel, highly virulent, pathogens evolve with devastating consequences, no matter what the host-animal, plant, or other organism. Long read DNA sequencing technology allowed in depth structural comparisons between the sole, previously known, much less aggressive, version of the pathogen and the super-virulent version and revealed, in meticulous detail, the structure of the unique virulence-causing DNA. These data are foundational for future analysis of mechanisms of DNA acquisition from a foreign source.
Proteomic insight into human directed evolution of the domesticated chickenGallus gallus
Authors: Schmidt Carl J , Kim Dong Kyun , Pendarvis G Ken , Abasht Behnam , McCarthy Fiona M 
Published: February 2023

AbstractChicken domestication began at least 3,500 years ago for purposes of divination, cockfighting, and food. Prior to industrial scale chicken production, domestication selected larger birds with increased egg production. In the mid-20thcentury companies began intensive selection with the broiler (meat) industry focusing on improved feed conversion, rapid growth, and breast muscle yield. Here we present proteomic analysis comparing the Ross 708 modern broiler line with the UIUC legacy line. Comparing the breast muscle proteome between modern broilers and legacy lines not selected for these growth traits identifies cellular processes that have responded to human directed evolution. Mass spectrometry was used to identify differences in protein levels in the breast muscle of 6-day old chicks from Modern and Legacy lines. The results highlighted elevated levels of stress proteins, ribosomal proteins, and proteins that participate in the innate immune pathway in the Modern chickens. Furthermore, the comparative analyses indicated differences in the levels of proteins involved in multiple biochemical pathways. In particular, the Modern line had elevated levels of proteins affecting the pentose phosphate pathway, TCA cycle, and fatty acid oxidation and reduced protein levels of the first phase of glycolysis. These analyses provide hypotheses linking the morphometric changes driven by human directed selection to biochemical pathways. The results also have implications for the onset of Wooden Breast disease that arose due to selection for rapid breast muscle growth and is a major problem in the poultry industry.
Aminobisphosphonates reactivate the latent reservoir in people living with HIV-1
Authors: Sanz Marta , Weideman Ann Marie K. , Ward Adam R. , Clohosey Matthew L. , Garcia-Recio Susana , Selitsky Sara R. , Mann Brendan T. , Iannone Marie Anne , Whitworth Chloe P. , Chitrakar Alisha , Garrido Carolina , Kirchherr Jennifer , Coffey Alisha R. , Tsai Yi-Hsuan , Samir Shahryar , Xu Yinyan , Copertino Dennis , Bosque Alberto , Jones Brad R. , Parker Joel S. , Hudgens Michael G. , Goonetilleke Nilu , Soriano-Sarabia Natalia 
Published: February 2023

ABSTRACTAntiretroviral therapy (ART) is not curative due to the existence of cellular reservoirs of latent HIV-1 that persist during therapy. Current research efforts to cure HIV-1 infection include “shock and kill” strategies to disrupt latency using small molecules or latency-reversing agents (LRAs) to induce expression of HIV-1 enabling cytotoxic immune cells to eliminate infected cells. The modest success of current LRAs urges the field to identify novel drugs with increased clinical efficacy. Aminobisphosphonates (N-BPs) that include pamidronate, zoledronate, or alendronate, are the first-line treatment of bone-related diseases including osteoporosis and bone malignancies. Here, we show the use of N-BPs as a novel class of LRA: we found inex vivoassays using primary cells from ART-suppressed people living with HIV-1 that N-BPs induce HIV-1 from latency to levels that are comparable to the T cell activator phytohemagglutinin (PHA). RNA sequencing and mechanistic data suggested that reactivation may occur through activation of the activator protein 1 signaling pathway. Stored samples from a prior clinical trial aimed at analyzing the effect of alendronate on bone mineral density, provided further evidence of alendronate-mediated latency reversal and activation of immune effector cells. Decay of the reservoir measured by IPDA was however not detected. Our results demonstrate the novel use of N-BPs to reverse HIV-1 latency while inducing immune effector functions. This preliminary evidence merits further investigation in a controlled clinical setting possibly in combination with therapeutic vaccination.
Selecting Covariates for Genome-Wide Association Studies
Authors: Dor Erez , Margaliot Ido , Brandes Nadav , Zuk Or , Linial Michal , Rappoport Nadav 
Published: February 2023

AbstractThe choice of which covariates to include in a Genome-Wide Association Study (GWAS) is important since it affects the ability to detect true association signal of variants, to correct for confounders and avoid false positives, and the running time of the analysis. Commonly used covariates include age, sex, genotyping batches, genotyping array type, as well as an arbitrary number of Principal Components (PCs) used to adjust for population structure. Despite the importance of this issue, there is no consensus or clear guidelines for the right choice of covariates. Therefore, studies typically employ heuristics for their choice with no clear justification. Here, we explore the dependence of the GWAS analysis results on the choice of covariates for a wide range of quantitative and binary human phenotypes. We propose guidelines for covariates choice based on the phenotype’s type (quantitative vs. disease), the heritability, and the disease prevalence, with the goal of maximizing the statistical power to detect true associations and fit accurate polygenic scores while avoiding spurious associations and minimizing computation time. We analyze 36 traits in the UK-Biobank dataset. We show that the genotype batch and assessment center can be safely removed as covariates, thus significantly reducing the GWAS computational burden for these traits.
A new inverse probability of selection weighted Cox model to deal with outcome-dependent sampling in survival analysis
Authors: Arntzen Vera H. , Fiocco Marta , Lakeman Inge M.M. , Nielsen Maartje , Rodríguez-Girondo Mar 
Published: February 2023

AbstractMotivated by the study of genetic effect modifiers of cancer, we examined weighting approaches to correct for ascertainment bias in survival analysis. Family-based outcome-dependent sampling is common in genetic epidemiology leading to study samples with too many events in comparison to the population and an overrepresentation of young, affected subjects. A usual approach to correct for ascertainment bias in this setting is to use an inverse probability-weighted Cox model, using weights based on external available population-based age-specific incidence rates of the type of cancer under investigation. However, the current approach is not general enough leading to invalid weights in relevant practical settings if oversampling of cases is not observed in all age groups. Based on the same principle of weighting observations by their inverse probability of selection, we propose a new, more general approach. We show the advantage of our new method using simulations and two real datasets. In both applications the goal is to assess the association between common susceptibility loci identified in Genome Wide Association Studies (GWAS) and cancer (colorectal and breast) using data collected through genetic testing in clinical genetics centers.
Shift in vacuolar to cytosolic regime of infectingSalmonellafrom a dual proteome perspective
Authors: Fels Ursula , Willems Patrick , De Meyer Margaux , Gevaert Kris , Van Damme Petra 
Published: February 2023

AbstractBy applying dual proteome profiling toSalmonella entericaserovar Typhimurium (S. Typhimurium) encounters with its epithelial host (here,S. Typhimurium infected human HeLa cells), a detailed interdependent and holistic proteomic perspective on host-pathogen interactions over a time course of infection was obtained. Data-independent acquisition (DIA)-based proteomics was found to outperform data-dependent acquisition (DDA) workflows, especially in identifying the downregulated bacterial proteome response during infection progression infection by permitting quantification of low abundant bacterial proteins at early times of infection at low bacterial infection load.S. Typhimurium invasion and replication specific proteomic signatures in epithelial cells revealed interdependent host/pathogen specific responses besides pointing to putative novel infection markers and signalling responses.