bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chance favors the prepared genomes: horizontal transfer shapes the emergence of antibiotic resistance mutations in core genes
Authors: Coluzzi Charles , Guillemet Martin , Mazzamurro Fanny , Touchon Marie , Godfroid Maxime , Achaz Guillaume , Glaser Philippe , Rocha Eduardo PC 
Published: June 2023

AbstractBacterial lineages vary in the frequency with which they acquire novel traits, like antibiotic resistance or virulence. While previous studies have highlighted the impact of the genetic background on the successful acquisition of novel traits through horizontal gene transfer, the impact of the latter on the subsequent evolution of bacterial genomes by point mutations remains poorly understood. Here, we studied the evolution of resistance to quinolones in thousands ofEscherichia coligenomes. Resistance-conferring point mutations in the core genes are frequent and accumulate very quickly. We searched for gene gains and losses significantly associated with the subsequent acquisition of these resistance mutations. This revealed 60 groups of genes in genetic linkage whose gain or loss induced a change in the probability of subsequently becoming resistant to quinolones by point mutations ingyrAandparC. Although some of these chronologies may reflect epidemiological trends, most of these groups encoded functions that were previously associated with antibiotic resistance, tolerance, or persistence, often specifically under quinolone treatment. A lot of the largest groups were found in prophages or plasmids, and they usually increased the likelihood of subsequent resistance mutations. Conversely groups of lost genes were typically small and chromosomal. Quinolone resistance was among the first resistances acquired in the extant lineages ofE. coliand its acquisition was associated with an increased likelihood of acquiring other types of resistances, including to aminoglycosides and beta-lactams. Our findings suggest that gene flow shapes the subsequent fixation rate of adaptive mutations in core genes. Given the substantial gene flow within bacterial genomes, interactions between horizontal transfer and point mutations in core genes may be key to the success of adaptation processes.
Use of Recommended Real-World Methods for Electronic Health Record Data Analysis Has Not Improved Over 10 Years
Authors: Li Chenyu , Alsheikh Abdulrahman M. , Robinson Karen A. , Lehmann Harold P. 
Published: June 2023

ABSTRACTBackground and PurposeTo document the use of recommended Real-World Methods (RWM) in Electronic Health Record (EHR)-based analysis in biomedical research over 10 years.MethodsSampled-article scoping review of methods used in EHR-based biomedical research. We developed a search strategy to identify reports of biomedical research based on EHR data and systematically sampled articles from different ranges of years (epochs) between 2010 and 2019 to establish a trajectory of use of recommended RWM. Methods were classified by 3 phases of research: pre-analytic (missing data), analytic (specific methods), and post-analytic (sensitivity analysis). The primary outcome was the proportion of studies using recommended RWM within each epoch. Meta-regressions were performed to examine trends.Data SynthesisFive epochs were defined between 2010 and 2019 with 35 studies selected per epoch as pre-defined by a sample size calculation. Of the 175 articles reviewed, 70 (40.%) reported recommended RWM in any of the 3 phases of research. The breakdown for the most recent year in the dataset, 2019, was 14.% (95% confidence interval 2.7%, 26.%), 14.% (2.7%, 26.%), and 11.% (0.89%, 22.%), for assessing missing data, using specific methods, and performing sensitivity analysis, respectively. Only 3.4 % of studies used appropriate methods for each phase of research. Meta-regression slopes for each of the three phases were statistically 0.Limitation and ConclusionsThe underuse of recommended Real-World Methods (RWM) in EHR-based biomedical research remains a concern, with less than 50% of reports using these methods in any phase of research over the last decade. This lack of use indicates a continued risk of bias in the EHR-based literature.
Intrinsically disordered regions in the transcription factor MYC:MAX modulate DNA binding via intramolecular interactions
Authors: Schütz Stefan , Bergsdorf Christian , Hänni-Holzinger Sandra , Lingel Andreas , Renatus Martin , Gossert Alvar D. , Jahnke Wolfgang 
Published: June 2023

ABSTRACTThe basic helix-loop-helix leucine zipper (bHLH-LZ) transcription factor (TF) MYC is in large parts an intrinsically disordered oncoprotein. In complex with its obligate heterodimerization partner MAX, MYC preferentially binds E-Box DNA sequences (CANNTG). At promotors containing these sequence motifs, MYC controls fundamental cellular processes such as cell cycle progression, metabolism, and apoptosis. A vast network of proteins controls MYC function via intermolecular interactions. In this work, we establish another layer of MYC regulation by intramolecular interactions. We use Nuclear Magnetic Resonance (NMR) spectroscopy to identify and map multiple binding sites for the C-terminal MYC:MAX DNA binding domain (DBD) on the intrinsically disordered regions (IDRs) in the MYC N-terminus. We find that these binding events intransare driven by electrostatic attraction, that they have distinct affinities, and that they are competitive with DNA binding. Thereby, we observe the strongest effects for the N-terminal MYC box 0 (Mb0), a conserved motif involved in MYC transactivation and target gene induction. We prepared recombinant full-length MYC:MAX complex and demonstrate that the interactions identified in this work are also relevant incis, i.e. as intramolecular interactions. These findings are supported by Surface Plasmon Resonance (SPR) experiments, which revealed that intramolecular IDR:DBD interactions in MYC decelerate the association of MYC:MAX complexes to DNA. Our work offers new insights how bHLH-LZ TFs are regulated by intramolecular interactions, which opens up new possibilities for drug discovery.
The widespread influence of ZSWIM8 on microRNAs during mouse embryonic development
Authors: Shi Charlie Y. , Elcavage Lara E. , Chivukula Raghu R. , Stefano Joanna , Kleaveland Benjamin , Bartel David P. 
Published: June 2023

AbstractMicroRNAs (miRNAs) pair to sites in mRNAs to direct the degradation of these RNA transcripts. Conversely, certain RNA transcripts can direct the degradation of particular miRNAs. This target-directed miRNA degradation (TDMD) requires the ZSWIM8 E3 ubiquitin ligase. Here, we report the function of ZSWIM8 in the mouse embryo.Zswim8−/−embryos were smaller than their littermates and died near the time of birth. This highly penetrant perinatal lethality was apparently caused by a lung sacculation defect attributed to failed maturation of alveolar epithelial cells. Some mutant individuals also had heart ventricular septal defects. These developmental abnormalities were accompanied by aberrant accumulation of >50 miRNAs observed across 12 tissues, which often led to enhanced repression of their mRNA targets. These ZSWIM8-sensitive miRNAs were preferentially produced from genomic miRNA clusters, and in some cases, ZSWIM8 caused a switch in the dominant strand that accumulated from a miRNA hairpin—observations suggesting that TDMD provides a mechanism to uncouple co-produced miRNAs from each other. Overall, our findings indicate that the regulatory influence of TDMD in mammalian biology is widespread and posit the existence of many yet-unidentified transcripts that trigger miRNA degradation.
Revisiting annotation ofSchistosoma mansoniMicro-Exon Gene (MEG) family
Authors: Nedvedova Stepanka , De Stefano Davide , Walker Olivier , Hologne Maggy , Miele Adriana Erica 
Published: June 2023

AbstractGenome sequencing of the human parasiteSchistosoma mansonirevealed an interesting gene superfamily calledmicro-exon gene(MEG) that encodes MEG secreted proteins. The genes are composed of short exons (3-81 base pairs) with symmetrically inserted long introns (up to 5 kbp). This article recollects 35S. mansonispecificmeggenes that are distributed over 7 autosomes and one pair of sex chromosomes and that code for at least 87 verified MEG proteins. We used various bioinformatics tools to produce an optimal alignment, propose a phylogenetic analysis and highlight intriguing conserved patterns/motifs in the sequences of these MEG proteins. Based on the analyses, we were able to classify the MEG proteins into two subfamilies and to hypothesize their duplication and colonization of all the chromosomes. Together with motif identification, we also proposed to revisit MEGs’ common names and annotation in order to avoid duplication, to help reproducibility of research results and to avoid possible misunderstandings.Author AbstractSchistosoma mansoniis a parasitic worm, the etiological agent of schistosomiasis or bilharzia, a chronic tropical disease. It is a vector-borne parasite with a complex life cycle and an equally complex genome, assembled in 7 autosomes and a pair of sexual chromosomes. Within the gene products, one superfamily is particularly interesting, since it is specific toSchistosomatidae, highly variable and redundant: the micro-exon gene (MEG) family. As the name implies, these genes are made by short coding exons (3 to 81 base pairs), symmetrically interspersed by long introns (from 0.2 to 5 kbp). There are 35megsallover the chromosomes, which code for at least 87 MEG proteins. We have aligned all of them, constructed a phylogenetic tree and proposed a theory for their duplication and genome colonization. Based on that, we propose a rational nomenclature to help the community to study MEG’s elusive role. We also propose to help WormBaseParaSite to adopt this new nomenclature to avoid giving the same acronym to different protein sequences.
Kinetics of zoospores approaching a root using a microfluidic device
Authors: Cohen C , Gauci FX , Noblin X , Galiana E , Attard A , Thomen P 
Published: June 2023

AbstractPhytophthoraspecies are plant pathogens that cause considerable damage to agrosystems and ecosystems, and have a major impact on the economy. Infection occurs when their biflagellate zoospores move and reach a root on which they aggregate. However, the communication between the plant and the zoospores and how this communication modifies the behavior of the swimming zoospores is not yet well characterized. Here we show that using a microfluidic device comprising a growingArabidopsis thalianaroot, we are able to study the kinetics ofPhytophthora parasiticazoospores approaching the root and aggregating on a specific area, in real time. We show that the kinetics of zoospores is modified only below a distance of about 300μm from the center of aggregation, with a decrease in the speed coupled with an increase in the number of turns made. In addition, we show that the rate of aggregation is constant throughout the experiment, approximately one hour, and depends on the density of zoospores. The rate is consistent with a random encounter of zoospores with the root, indicating that no long range signal is evidenced in our set-up.
The Limits of Haplotype-Based Approaches: Exploring the Applicability of the Li and Stephens Haplotype-Copying Model to Ancient Samples
Authors: Cort Isabel Díaz-Pinés , Rubin Joshua Daniel , Sackett Peter Wad , Renaud Gabriel 
Published: June 2023

AbstractThe Li and Stephens (LS) haplotype-copying model is a seminal framework that represents a target haplotype as an imperfect mosaic of a set of reference haplotypes. Using a hidden Markov model, it can switch from different source haplotypes to model recombinations. This model has been used in several applications in modern populations including phasing and inference of ancestry. However, recent publications have looked at the applicability of the model to using ancient individuals as targets and modern reference panels as source data. Previous research exploring the impact of time separation between the modern references and the ancient target on the model’s behavior relied on coalescent simulation to generate genetic variation data, which could lead to an underestimation of the ancient population’s genetic diversity. Further, these simulations were restricted to a relatively short time period of anatomically modern human history. To overcome these limitations, our study evaluates the robustness of the LS model using forward-simulated data enabling us to sample haplotypes that do not have direct descendants among the modern population. Additionally, we evaluate the model under the simple demographic scenario of a constant-sized continuous population starting 1.5M years ago to isolate the effect of time separation. Results indicate good performance for target haplotypes up to 900,000 years old, suggesting potential applicability to ancient DNA (aDNA) from anatomically modern humans. Although more complex demographic scenarios should be considered for a definitive answer, this research serves as a starting point for evaluating the haplotype-copying framework in aDNA data analysis.
Major patterns in the introgression history ofHeliconiusbutterflies
Authors: Thawornwattana Yuttapong , Seixas Fernando A. , Yang Ziheng , Mallet James 
Published: June 2023

AbstractGene flow between species is an important evolutionary process that can facilitate adaptation and lead to species diversification. It also makes reconstruction of species relationships difficult. Here, we use the full-likelihood multispecies coalescent (MSC) approach to estimate species phylogeny and major introgression events inHeliconiusbutterflies from whole-genome sequence data. We obtain a robust estimate of species branching order among major clades in the genus, including the “melpomene-silvaniform” group, which shows extensive historical and on-going gene flow. We obtain chromosome-level estimates of key parameters in the species phylogeny, including species divergence times, present-day and ancestral population sizes as well as the direction, timing, and intensity of gene flow. Our analysis leads to a phylogeny with introgression events that differ from those obtained in previous studies. We find thatH. aoedemost likely represents the earliest-branching lineage of the genus and that “silvaniform” species are paraphyletic within the melpomene-silvaniform group. Our phylogeny provides new, parsimonious histories for the origins of key traits inHeliconius, including pollen feeding and an inversion involved in wing pattern mimicry. Our results demonstrate the power and feasibility of the full-likelihood MSC approach for estimating species phylogeny and key population parameters despite extensive gene flow. The methods used here should be useful for analysis of other difficult species groups with high rates of introgression.
UVA hyperspectral light-sheet microscopy for volumetric metabolic imaging: application to pre-implantation embryo development
Authors: Morizet J. , Chow D. , Wijesinghe P. , Schartner E. , Dwapanyin G. , Dubost N. , Bruce G. D. , Anckaert E. , Dunning K. , Dholakia K. 
Published: June 2023

AbstractCellular metabolism is a key regulator of energetics, cell growth, regeneration and homeostasis. Spatially mapping the heterogeneity of cellular metabolic activity is of great importance for unraveling the overall cell and tissue health. In this regard, imaging the endogenous metabolic co-factors NAD(P)H and FAD with sub-cellular resolution and in a non-invasive manner would be useful to determine tissue and cell viability in a clinical environment, but practical use is limited by current imaging techniques. In this article, we demonstrate the use of phasor-based hyperspectral light-sheet (HS-LS) microscopy using a single UVA excitation wavelength as a route to mapping metabolism in three dimensions. We show that excitation solely at a UVA wavelength of 375 nm can simultaneously excite NAD(P)H and FAD autofluorescence, while their relative contributions can be readily quantified using a hardware-based spectral phasor analysis. We demonstrate the potential of our HS-LS system by capturing dynamic changes in metabolic activity during pre-implantation embryo development. To validate our approach, we delineate metabolic changes during pre-implantation embryo development from volumetric maps of metabolic activity. Importantly, our approach overcomes the need for multiple excitation wavelengths, two-photon imaging or significant post-processing of data, paving the way towards clinical translation, such as in situ, non-invasive assessment of embryo viability.
The impact of within-host coinfection interactions on between-host parasite transmission dynamics varies with spatial scale
Authors: Keegan Shaun P. , Pedersen Amy B. , Fenton Andy 
Published: June 2023

AbstractWithin-host interactions among coinfecting parasites can have major consequences for individual infection risk and disease severity. However, the impact of these within-host interactions on between-host parasite transmission, and the spatial scales over which they occur, remain unknown. We developed and apply a novel spatially-explicit analysis to parasite infection data from a wild wood mouse (Apodemus sylvaticus) population. We previously demonstrated a strong negative interaction within individual hosts gastrointestinal parasites, the nematodeHeligmosomoides polygyrusand the coccidiaEimeria hungaryensis, using drug-treatment experiments. Here, we find that this negative within-host interaction can significantly alter the between-host transmission dynamics ofE. hungaryensis, but only within spatially-restricted neighbourhoods around each host. However, for the closely-related speciesE. apionodes, which experiments show does not interact strongly withH. polygyrus, we did not find any effect on transmission over any spatial scale. Our results demonstrate that the effects of within-host coinfection interactions can ripple out beyond each host to alter the transmission dynamics of the parasites, but only over local scales that likely reflect the spatial dimension of transmission. Hence there may be knock-on consequences of drug treatments impacting the transmission of non-target parasites, altering infection risks even for non-treated individuals in the wider neighbourhood.
Hip thrust and back squat training elicit similar gluteus muscle hypertrophy and transfer similarly to the deadlift
Authors: Plotkin Daniel L. , Rodas Merlina A. , Vigotsky Andrew D. , McIntosh Mason C. , Breeze Emma , Ubrik Rachel , Robitzsch Cole , Agyin-Birikorang Anthony , Mattingly Madison L. , Michel J. Max , Kontos Nicholas J. , Frugé Andrew D. , Wilburn Christopher M. , Weimar Wendi H. , Bashir Adil , Beyers Ronald J. , Henselmans Menno , Contreras Bret M. , Roberts Michael D. 
Published: June 2023

ABSTRACTPurposeWe examined how set-volume equated resistance training using either the back squat (SQ) or hip thrust (HT) affected hypertrophy and various strength outcomes.MethodsUntrained college-aged participants were randomized into HT or SQ groups. Surface electromyograms (sEMG) from the right gluteus maximus and medius muscles were obtained during the first training session. Participants completed nine weeks of supervised training (15–17 sessions), before and after which we assessed muscle cross-sectional area (mCSA) via magnetic resonance imaging and strength via three-repetition maximum (3RM) testing and an isometric wall push test.ResultsGlutei mCSA growth was similar across both groups. Estimates [(−) favors HT; (+) favors SQ] modestly favored the HT compared to SQ for lower [effect ± SE, −1.6 ± 2.1 cm2], mid [−0.5 ± 1.7 cm2], and upper [−0.5 ± 2.6 cm2], but with appreciable variance. Gluteus medius+minimus [−1.8 ± 1.5 cm2] and hamstrings [0.1 ± 0.6 cm2] mCSA demonstrated little to no growth with small differences between groups. Thigh mCSA changes were greater in SQ for the quadriceps [3.6 ± 1.5 cm2] and adductors [2.5 ± 0.7 cm2]. Squat 3RM increases favored SQ [14 ± 2.5 kg] and hip thrust 3RM favored HT [−26 ± 5 kg]. 3RM deadlift [0 ± 2 kg] and wall push strength [−7 ± 13 N] similarly improved. All measured gluteal sites showed greater mean sEMG amplitudes during the first bout hip thrust versus squat set, but this did not consistently predict gluteal hypertrophy outcomes.ConclusionNine weeks of squat versus hip thrust training elicited similar gluteal hypertrophy, greater thigh hypertrophy in SQ, strength increases that favored exercise allocation, and similar strength transfers to the deadlift and wall push.
Site-specific acetylation of polynucleotide kinase 3’-phosphatase (PNKP) regulates its distinct role in DNA repair pathways
Authors: Islam Azharul , Chakraborty Anirban , Sarker Altaf H , Aryal Uma K , Sharma Gulshan , Boldogh Istvan , Hazra Tapas 
Published: June 2023

AbstractMammalian polynucleotide kinase 3’-phosphatase (PNKP) is a dual-function DNA end-processing enzyme with 3’-phosphatase and 5’-kinase activities, which generate 3’-OH and 5’-phosphate termini respectively, as substrates for DNA polymerase and DNA ligase to complete DNA repair. PNKP is thus involved in multiple DNA repair pathways, including base excision (BER), single-strand break (SSBR), and double-strand break repair (DSBR). However, little is known as to how PNKP functions in such diverse repair processes, which involve distinct sets of proteins. In this study, we report that PNKP is acetylated at two lysine (K142 and K226) residues. While K142 (AcK142) is constitutively acetylated by p300, CBP acetylates K226 (AcK226) only after DSB induction. Co-immunoprecipitation analysis using antibodies specific for PNKP peptides containing AcK142 or AcK226 of PNKP showed that AcK142-PNKP associates only with BER/SSBR, and AcK226 PNKP only with DSBR proteins. Although acetylation at these residues did not significantly affect the enzymatic activity of PNKPin vitro, cells expressing non-acetylable PNKP (K142R or K226R) accumulated DNA damage, specifically in transcribed genes. Intriguingly, in striatal neuronal cells of a Huntington’s Disease (HD)-based mouse model, K142, but not K226, was acetylated. This observation is consistent with the reported degradation of CBP but not p300 in HD cells. Moreover, genomes of HD cells progressively accumulated DSBs specifically in the transcribed genes. Chromatin-immunoprecipitation analysis using anti-AcK142 or anti-AcK226 antibodies demonstrated an association of Ac-PNKP with the transcribed genes, consistent with PNKP’s role in transcription-coupled repair. Thus, our findings collectively demonstrate that acetylation at two lysine residues located in different domains of PNKP regulates its functionally distinct role in BER/SSBR vs. DSBR.
Lineage-specific intolerance to oncogenic drivers restricts histological transformation
Authors: Gardner Eric E. , Earlie Ethan M. , Li Kate , Thomas Jerin , Hubisz Melissa J. , Stein Benjamin D. , Zhang Chen , Cantley Lewis C. , Laughney Ashley M. , Varmus Harold 
Published: June 2023

AbstractLung adenocarcinoma (LUAD) and small cell lung cancer (SCLC) are thought to originate from different epithelial cell types in the lung. Intriguingly, LUAD can histologically transform into SCLC following treatment with targeted therapies. Here we designed models to follow the conversion of LUAD to SCLC and found the barrier to histological transformation converges on tolerance to Myc, which we implicate as a lineage-specific driver of the pulmonary neuroendocrine cell. Histological transformations are frequently accompanied by activation of the Akt pathway. Manipulating this pathway permitted tolerance to Myc as an oncogenic driver, producing rare, stem-like cells, transcriptionally resembling the pulmonary basal lineage. These findings suggest histological transformation may require the plasticity inherent to the basal stem cell, enabling tolerance to previously incompatible oncogenic driver programs.One-Sentence SummaryBy modeling histological transformation of lung cancer, we uncover neuroendocrine-specific tolerance to Myc as an oncogenic driver.