bluuebunny/crossref_metadata_2025_split huggingface dataset:
PhenoMultiOmics: an enzymatic reaction inferred multi-omics network visualization web server
Authors: Shi Yuying , Xu Botao , Chai Jie , Wang Cheng 
Published: April 2024

AbstractEnzymatic reactions play a pivotal role in regulating cellular processes with a high degree of specificity to biological functions. When enzymatic reactions are disrupted by gene, protein, or metabolite dysfunctions in diseases, it becomes crucial to visualize the resulting perturbed enzymatic reaction-induced multi-omics network. Multi-omics network visualization aids in gaining a comprehensive understanding of the functionality and regulatory mechanisms within biological systems. In this study, we designed PhenoMultiOmics, an enzymatic reaction-based multi-omics web server designed to explore the scope of the multi-omics network across various cancer types. We first curated the PhenoMultiOmics Database (PMODB), which enables the retrieval of cancer-gene-protein-metabolite relationships based on the enzymatic reactions. We then developed the MultiOmics network visualization module to depict the interplay between genes, proteins, and metabolites in response to specific cancer-related enzymatic reactions. The biomarker discovery module facilitates functional analysis through differential omic feature expression and pathway enrichment analysis. PhenoMultiOmics has been applied to analyze transcriptomics data of gastric cancer and metabolomics data of lung cancer, providing insights into interrupted enzymatic reactions and the associated multi-omics network. PhenoMultiOmics is freely accessed athttps://phenomultiomics.shinyapps.io/cancer/with a user-friendly and interactive web interface.
Revealing the ArabidopsisAtGRP7mRNA binding proteome by specific enhanced RNA interactome capture
Authors: Reichel Marlene , Schmidt Olga , Rettel Mandy , Stein Frank , Köster Tino , Butter Falk , Staiger Dorothee 
Published: April 2024

AbstractBackgroundThe interaction of proteins with RNA in the cell is crucial to orchestrate all steps of RNA processing. RNA interactome capture (RIC) techniques have been implemented to catalogue RNA-binding proteins in the cell. In RIC, RNA-protein complexes are stabilized by UV crosslinkingin vivo. Polyadenylated RNAs and associated proteins are pulled down from cell lysates using oligo(dT) beads and the RNA-binding proteome is identified by quantitative mass spectrometry. However, insights into the RNA-binding proteome of a single RNA that would yield mechanistic information on how RNA expression patterns are orchestrated, are scarce.ResultsHere, we explored RIC in Arabidopsis to identify proteins interacting with a single mRNA, using the circadian clock-regulatedArabidopsis thalianaGLYCINE-RICH RNA-BINDING PROTEIN 7 (AtGRP7) transcript, one of the most abundant transcripts in Arabidopsis, as a showcase. Seedlings were treated with UV light to covalently crosslink RNA and proteins. TheAtGRP7transcript was captured from cell lysates with antisense oligonucleotides directed against the 5’untranslated region (UTR). The efficiency of RNA capture was greatly enhanced by using locked nucleic acid (LNA)/DNA oligonucleotides, as done in the enhanced RIC protocol. Furthermore, performing a tandem capture with two rounds of pulldown with the 5’UTR oligonucleotide increased the yield. In total, we identified 356 proteins enriched relative to a pulldown fromatgrp7mutant plants. These were benchmarked against proteins pulled down from nuclear lysates byAtGRP7 in vitrotranscripts immobilized on beads. Among the proteins validated byin vitrointeraction we found the family of Acetylation Lowers Binding Affinity (ALBA) proteins. Interaction of ALBA4 with theAtGRP7RNA was independently validated via individual-nucleotide resolution crosslinking and immunoprecipitation (iCLIP). The expression of theAtGRP7transcript in analbaloss-of-function mutant was slightly changed compared to wild-type, demonstrating the functional relevance of the interaction.ConclusionWe adapted specific RNA interactome capture with LNA/DNA oligonucleotides for use in plants usingAtGRP7as a showcase. We anticipate that with further optimization and up-scaling the protocol should be applicable for less abundant transcripts.
Three-photon excited fluorescence microscopy enables imaging of blood flow, neural structure and inflammatory response deep into mouse spinal cordin vivo
Authors: Cheng Yu-Ting , Lett Kawasi M. , Xu Chris , Schaffer Chris B. 
Published: April 2024

AbstractNonlinear optical microscopy enables non-invasive imaging in scattering samples with cellular resolution. The spinal cord connects the brain with the periphery and governs fundamental behaviors such as locomotion and somatosensation. Because of dense myelination on the dorsal surface, imaging to the spinal grey matter is challenging, even with two-photon microscopy. Here we show that three-photon excited fluorescence (3PEF) microscopy enables multicolor imaging at depths of up to ~550 μm into the mouse spinal cord,in vivo. We quantified blood flow across vessel types along the spinal vascular network. We then followed the response of neurites and microglia after occlusion of a surface venule, where we observed depth-dependent structural changes in neurites and interactions of perivascular microglia with vessel branches upstream from the clot. This work establishes that 3PEF imaging enables studies of functional dynamics and cell type interactions in the top 550 μm of the murine spinal cord,in vivo.
Proteasome hyperactivation rewires the proteome enhancing stress resistance, proteostasis, lipid metabolism and ERAD inC. elegans
Authors: Salcedo-Tacuma David , Asad Nadeeem , Howells Giovanni , Anderson Raymond , Smith David M. 
Published: April 2024

AbstractProteasome dysfunction is implicated in the pathogenesis of neurodegenerative diseases and age-related proteinopathies. Using aC. elegansmodel, we demonstrate that 20S proteasome hyperactivation, facilitated by 20S gate-opening, accelerates the targeting of intrinsically disordered proteins. This leads to increased protein synthesis, extensive rewiring of the proteome and transcriptome, enhanced oxidative stress defense, accelerated lipid metabolism, and peroxisome proliferation. It also promotes ER-associated degradation (ERAD) of aggregation-prone proteins, such as alpha-1 antitrypsin (ATZ) and various lipoproteins. Notably, our results reveal that 20S proteasome hyperactivation suggests a novel role in ERAD with broad implications for proteostasis-related disorders, simultaneously affecting lipid homeostasis and peroxisome proliferation. Furthermore, the enhanced cellular capacity to mitigate proteostasis challenges, alongside unanticipated acceleration of lipid metabolism is expected to contribute to the longevity phenotype of this mutant. Remarkably, the mechanism of longevity induced by 20S gate opening appears unique, independent of known longevity and stress-resistance pathways. These results support the therapeutic potential of 20S proteasome activation in mitigating proteostasis-related disorders broadly and provide new insights into the complex interplay between proteasome activity, cellular health, and aging.
Pervasive loss of regulated necrotic cell death genes in elephants, hyraxes, and sea cows (Paenungualta)
Authors: Birkemeier Meaghan , Swindle Arianna , Bowman Jacob , Lynch Vincent J. 
Published: April 2024

AbstractGene loss can promote phenotypic differences between species, for example, if a gene constrains phenotypic variation in a trait, its loss allows for the evolution of a greater range of variation or even new phenotypes. Here, we explore the contribution of gene loss to the evolution of large bodies and augmented cancer resistance in elephants. We used genomes from 17 Afrotherian and Xenarthran species to identify lost genes, i.e., genes that have pseudogenized or been completely lost, and Dollo parsimony to reconstruct the evolutionary history of gene loss across species. We unexpectedly discovered a burst of gene losses in the Afrotherian stem lineage and found that the loss of genes with functions in regulated necrotic cell death modes was pervasive in elephants, hyraxes, and sea cows (Paenungulata). Among the lost genes areMLKLandRIPK3, which mediate necroptosis, and sensors that activate inflammasomes to induce pyroptosis, includingAIM2,MEFV,NLRC4,NLRP1, andNLRP6. These data suggest that the mechanisms that regulate necrosis and pyroptosis are either extremely derived or potentially lost in these lineages, which may contribute to the repeated evolution of large bodies and cancer resistance in Paenungulates as well as susceptibility to pathogen infection.
Circulating, cell-free methylated DNA indicates cellular sources of allograft injury after liver transplant
Authors: McNamara Megan E. , Jain Sidharth S. , Oza Kesha , Muralidaran Vinona , Kiliti Amber J. , McDeed A. Patrick , Patil Digvijay , Cui Yuki , Schmidt Marcel O. , Riegel Anna T. , Kroemer Alexander H.K. , Wellstein Anton 
Published: April 2024

AbstractPost-transplant complications reduce allograft and recipient survival. Current approaches for detecting allograft injury non-invasively are limited and do not differentiate between cellular mechanisms. Here, we monitor cellular damages after liver transplants from cell-free DNA (cfDNA) fragments released from dying cells into the circulation. We analyzed 130 blood samples collected from 44 patients at different time points after transplant. Sequence-based methylation of cfDNA fragments were mapped to patterns established to identify cell types in different organs. For liver cell types DNA methylation patterns and multi-omic data integration show distinct enrichment in open chromatin and regulatory regions functionally important for the respective cell types. We find that multi-tissue cellular damages post-transplant recover in patients without allograft injury during the first post-operative week. However, sustained elevation of hepatocyte and biliary epithelial cfDNA beyond the first week indicates early-onset allograft injury. Further, cfDNA composition differentiates amongst causes of allograft injury indicating the potential for non-invasive monitoring and timely intervention.
Multiplexed transcriptomic analyses of the plant embryonic hourglass
Authors: Wu Hao , Zhang Ruqiang , Niklas Karl J. , Scanlon Michael J. 
Published: April 2024

Zoologists have adduced morphological convergence among embryonic stages of closely related taxa, which has been called the phylotypic stage of embryogenesis. Transcriptomic analyses reveal a phylotypic hourglass pattern of gene expression during plant as well as animal embryogenesis, characterized by the accumulation of evolutionarily older and conserved transcripts during mid-embryogenesis, whereas younger less-conserved transcripts predominate at earlier and later embryonic stages. However, widespread comparisons of embryonic gene expression across animal phyla describe an inverse hourglass pattern, where gene expression is correlated during early and late stages but not during mid-development. Here, multiplexed spatial-transcriptomic analyses is used to investigate embryo ontogeny and homology in maize, which has novel, grass-specific morphology. An embryonic-organ genetic network is identified, replete for ancient/conserved genes manifesting a phylotypic hourglass during mid-embryogenesis. Transcriptomic comparisons of grass embryo ontogeny with that of a mossPhyscomitrium patensidentify a conserved, inverse hourglass pattern across plant phyla, as in animals.The data indicate that the plant phylotypic stage and that of animals is characterized by ancient gene network expression during early histo– and morphogenesis and polarized embryonic development. The data reveal an ancient, convergent mechanism for the evolution of morphological novelty.
Plk1 inhibition delays mitotic entry revealing prophase-specific changes to the phosphoproteome
Authors: Gobran Monica , Welp Luisa , Jakobi Jasmin , Politi Antonio , Urlaub Henning , Lenart Peter 
Published: April 2024

AbstractPolo-like kinase 1 (plk1) is a conserved regulator of cell division. During prophase, plk1 phosphorylates direct substrates and is involved in activation of the cyclin-dependent kinase 1 (cdk1). However, the exact functions of plk1 in prophase remain incompletely understood. By testing several cell lines and small-molecule inhibitors, we confirm that plk1 inhibition causes a delay in mitotic entry. We show that cells are delayed in a prophase-like state displaying progressively condensing chromosomes, increased microtubule dynamics, reorganization of the actin cortex, while the nuclear envelope remains intact. We show that during this prolonged prophase cdk1 activity increases gradually over several hours with individual cells stochastically reaching the entry threshold, explaining the highly variable timing of mitotic entry. We then use phosphoproteomics to characterize this prolonged prophase state revealing for the first time phosphosites specific to prophase including several regulators of chromatin organization and the cytoskeleton. Together, we show that plk1 functions as a catalyst of prophase to prometaphase transition, and by using plk1 inhibition as a tool, we identify early changes in the phosphoproteome as the cell prepares for division.
Evolving impact of the COVID-19 pandemic in chronic dialysis recipients over the course of pandemic waves and COVID-19 vaccination rollout: a French national study
Authors: Leye Elhadji , El Karoui Khalil , Delory Tristan , Espagnacq Maude , Khlat Myriam , Le Coeur Sophie , Lapidus Nathanaël , Hejblum Gilles 
Published: April 2024

SummaryBackgroundThis observational study aims to assess the impact of the pandemic on the evolving of kidney transplantations, survival, and vaccination in chronic dialysis recipients (CDR) over the COVID-19 pandemic subperiods.MethodsUsing the French national health claims database, incident persons with end stage kidney disease in years 2015 to 2021 treated with dialysis were followed-up until December 31, 2022. Kidney transplantion and survival over pandemic subperiods versus the prepandemic period were investigated using longitudinal models with time-dependent covariates. Moreover, the impact of cumulative doses of COVID-19 vaccine on hospitalization and survival were compared between CDR and matched-control individuals.FindingsFollow-up of the 71,583 CDR and 143,166 controls totalized 639,341 person-years (CDR: 184,909; controls: 454,432). The likelihood of receiving a kidney transplant decreased during all pandemic subperiods except one. Mortality in CDR increased during the 3 wave subperiods (hazard ratio (HR [95% confidence interval]): 1.19 [1.13–1.27], 1.19 [1.15–1.23], and 1.12 [1.07–1.17], respectively). While vaccine coverage declined with each booster dose, receiving such doses was associated with lower risks of COVID-19-related hospitalization (0.66 [0.56–0.77], 0.83 [0.72–0.94] for 1stbooster versus 2nddose and 2ndbooster versus 1stbooster, respectively) and death (corresponding HR: 0.55 [0.51–0.59], 0.88 [0.83–0.95]). Evolving patterns in mortality and vaccination outcomes were similar in CDR and controls.InterpretationThe impact of the pandemic in CDR was not specific of the kidney diseaseper se. Study results also suggest future research aimed at increasing adherence to vaccine booster doses.FundingInitiative Économie de la Santé de Sorbonne Université (Idex Sorbonne Université, programmes Investissements d’Avenir) ; Ministère de la Solidarité et de la Santé (PREPS 20-0163).
Impact of the 2013 WHO guidelines for screening and treatment of cervical precancerous lesions on women’s screening rates, by HIV-status, in East and Southern Africa: A regression discontinuity design analysis
Authors: Chipanta David , Osborne Connie , Bohlius Julia , Shakarishvilia Ani , Amo-Agyei Silas , Nyondo-Mipando Alinane Linda , Estill Janne Anton Markus , Keiser Olivia 
Published: April 2024

AbstractIntroductionIn 2013, the World Health Organization (WHO) issued guidelines for cervical pre-cancer screening. It recommended screening women aged 30–49, and younger women once they tested HIV-positive. Subsequent WHO guidelines recommended screening women living with HIV (WLHIV) starting at age 25. However, the impact of 2013 guidelines and age to start screening on screening has not been studied.MethodsWe used a regression discontinuity design (RDD) analysis of population-based data to assess the impact of the 2013 WHO guidelines on the screening rates for women according to HIV status and age group in Ethiopia, Malawi, Rwanda, Tanzania, Zambia, and Zimbabwe. The outcome was self-reported ever having been screened for cervical pre-cancer between 2008 and 2018. We compared the screening rates according to HIV status and age group, before and after age 25 years. And before and after 2014, the year countries adopted the 2013 guidelines. We then used a data-driven optimal bandwidth selection procedure to estimate the guidelines’ average treatment effect (ATE), with a local polynomial regression discontinuity and robust bias-corrected confidence intervals. We validated the RDD methodology overall and for women with a significant ATE at the country-level analysis.ResultsWe included 73179 women: 6680 (9.1%) living with HIV, 4328 (5.9%) with unknown HIV status, and 62171 (85.0) with a negative HIV status. 5726 (7.9%) reported having ever been screened; 4022 (6.5%) with unknown HIV status, 525 (12.1%) with a negative HIV status and 1179 (17.7%) living with HIV. Adolescent girls and young women living with HIV (AGYWLHIV) aged 15–24 reported screening less often (917 (13.7%)) than their peers with unknown (1677 (38.8%)) or positive HIV status (27278 (43.9%)) (P<0.001), or older women. The ATE of screening was 0 for women with unknown or positive HIV status, for whom the RDD was valid.ConclusionWe found no evidence the 2013 WHO guidelines increased or reduced women’s cervical pre- cancer screening. However, AGYWLHIV reported screening less often. Policy makers should lower the age to start screening WLHIV from 25 to 15 to screen more AGYWLHIV. Studies are required to examine the impact of the guidelines on cervical pre-cancer screening in more countries.
Blood pressure, cardiometabolic traits and cardiovascular events in women with uterine fibroids: a genetic correlation and Mendelian randomization study
Authors: Henry Joséphine , Berrandou Takiy , Brewster Lizzy M. , Bouatia-Naji Nabila 
Published: April 2024

AbstractBackgroundUterine fibroids (UFs) are under-studied uterus neoplasms, affecting women of reproductive age and often leading to hysterectomy. Clinical series suggest impaired cardiometabolic features including hypertension in UFs. We investigated potential genetic links between blood pressure (BP), several cardiometabolic traits and events and UFs.MethodsWe used summary statistics of genome-wide association studies (GWAS) for UFs and 18 traits related to BP and cardio-metabolism. We applied linkage disequilibrium score regression to estimate genetic correlations and GCTA-mtCOJO for adjusted correlations. Univariate and bi-directional Mendelian randomization (MR) were used to test causal associations with UFs. We computed inverse variance-weighted. Weighted median estimation and MR-Egger regression were computed for sensitivity analyses. Multiple testing was addressed by Bonferroni correction.ResultsUFs significantly correlated with systolic (rg=0.08,P=8.7×10−5) and diastolic (rg=0.12,P=8.2×10−8) BP, including after adjustment on body mass index (BMI). UFs positively corelated with BMI (rg=0.11,P=4.1×10−4), waist-to-hip ratio (WHR) (rg=0.09,P=7.3×10−3), diabetes (rg=0.15,P=1.9×10−5) and triglycerides (TG) (rg=0.17,P=7.6×10−7). We identified a negative correlation with sex hormone-binding globulin (SHBG) (rg=-0.16,P=3×10−4), a marker of bio-availability of sex-steroids. We found no evidence for shared genetics with vascular diseases, except migraine (rg=0.08,P=5.8×10−7). MR analyses supported BMI, WHR, TG and SHBG, to causally associate with increased risk for UFs.ConclusionsOur study shows that UFs share substantial genetic basis with traits related to BP, obesity, diabetes, in addition to migraine, a predominantly female vascular condition. We provide MR-based evidence for central obesity, visceral fat traits and sex-steroids bio-availability as relevant genetic risk factors for UFs.
The Current State & Sentiment of Artificial Intelligence in North American Anesthesiology Residency Programs
Authors: Elliott Tyler V , Goldstein Joseph C , Goldstein Heidi V 
Published: April 2024

PurposeThis study aims to investigate the current state and sentiment of artificial intelligence (AI) training in North American anesthesiology residency programs, assessing existing AI education landscapes, identifying barriers to implementation, and understanding program directors’ expectations for AI’s impact on the field.MethodsA cross-sectional survey targeted anesthesiology program directors across North America. The survey, conducted anonymously via Qualtrics, gauged their AI training offerings, sentiments towards AI’s influence, and familiarity with AI educational policies. Information on questionnaire development, administration, and data analysis was included.ResultsOf the 163 programs surveyed, 32 responded, yielding a response rate of 19.6%. A substantial 81% of responding program directors reported no current AI training. Despite this, 67% anticipate AI’s transformative impact. Only 19% currently offer AI/ML training. Standardized presentation of results with accompanying numerators and denominators were employed.ConclusionThe findings reveal a significant gap between the recognition of AI’s importance and the current offering of training in anesthesiology residency programs. Barriers to implementation include resource constraints and time limitations, exacerbated by the pandemic. Overcoming these barriers and aligning positive sentiments with educational offerings is crucial for preparing future physicians for the AI-driven healthcare landscape.Implication StatementThis study exposes a substantial gap between the positive anticipation of AI’s impact on anesthesiology and the current lack of training in North American residency programs. Recognizing this disparity is crucial for swiftly implementing comprehensive AI education, ensuring future anesthesiologists navigate healthcare’s evolving landscape adeptly.DisclosuresThe authors have no competing interests or financial interests to disclose. There was no funding associated with the completion of this study.