bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bivalent BNT162b2mRNA original/Omicron BA.4-5 booster vaccination: adverse reactions and inability to work compared to the monovalent COVID-19 booster
Authors: Wagenhäuser Isabell , Reusch Julia , Gabel Alexander , Krone Lukas B. , Kurzai Oliver , Petri Nils , Krone Manuel 
Published: November 2022

AbstractIn the light of emerging SARS-CoV-2 variants of concern (VOC), bivalent COVID-19 vaccines combining the wild-type spike mRNA with an Omicron VOC BA.1 or BA.4-5 spike mRNA became available. This non-randomized controlled study examined adverse reactions, PRN (pro re nata) medication intake and inability to work after a fourth COVID-19 vaccination among 76 healthcare workers. As fourth dose either the original, monovalent BNT162b2mRNA (48.7%) or the bivalent BNT162b2mRNA original/Omicron BA.4-5 vaccine (51.3%) was administered. The rate of adverse reactions for the second booster dose was significantly higher among participants receiving the bivalent 84.6% (95% CI 70.3%-92.8%; 33/39) compared to the monovalent 51.4% (95% CI 35.9-66.6%; 19/37) vaccine (p=0.0028). Also, there was a trend towards an increased rate of inability to work and intake of PRN medication following bivalent vaccination. In view of preprints reporting inconclusive results in neutralizing antibody levels between the compared vaccines, our results and further studies on safety and reactogenicity of bivalent COVID-19 booster vaccines are highly important to aid clinical decision making in the choice between bivalent and monovalent vaccinations.
Patient Clustering and Classification for Vital Organ Failure Using ICD Code with Graph Attention
Authors: Liu Zhangdaihong , Hu Ying , Mertes Gert , Yang Yang , Clifton David A. 
Published: November 2022

AbstractObjectiveHeart failure, respiratory failure and kidney failure are three severe organ failures (OF) that have high mortalities and are most prevalent in intensive care units. The objective of this work is to offer insights on OF clustering from the aspects of graph neural network and diagnosis history.MethodsThis paper proposes a neural network-based pipeline to cluster three types of organ failure patients by incorporating embedding pre-train using an ontology graph of International Classification of Diseases (ICD) codes. We employ an autoencoder-based deep clustering architecture jointly trained with a K-means loss, and a non-linear dimension reduction is performed to obtain patient clusters on the MIMIC-III dataset.ResultsThe clustering pipeline shows superior performance on a public-domain image dataset. For MIMIC-III, the model gives two distinct clusters that are related to the severity of the diseases. The learnt ICD embeddings present strong power in identifying the OF type in supervised learning.ConclusionOur proposed pipeline gives stable clusters, however, they do not correspond to the type of OF which indicates these OF share significant hidden characteristics in diagnosis. These clusters can be used to signal possible complications and severity of illness.SignificanceWe are the first to apply an unsupervised approach to offer insights from a biomedical engineering perspective on these three types of organ failure, and publish the pre-trained embeddings for future transfer learning.
dATP Elevation Induces Myocardial Metabolic Remodeling to Support Improved Cardiac Function
Authors: Mhatre Ketaki N , Murray Jason D , Flint Galina , McMillen Timothy S. , Weber Gerhard , Shakeri Majid , Tu An-Yue , Steczina Sonette , Weiss Robert , Marcinek David J. , Murry Charles E , Raftery Daniel , Tian Rong , Moussavi-Harami Farid , Regnier Michael 
Published: November 2022

AbstractHallmark features of systolic heart failure are reduced contractility and impaired metabolic flexibility of the myocardium. Cardiomyocytes (CMs) with elevated deoxy ATP (dATP) via overexpression of ribonucleotide reductase (RNR) enzyme robustly improve contractility. However, the effect of dATP elevation on cardiac metabolism is unknown. Here, we developed proteolysis-resistant versions of RNR and demonstrate that elevation of dATP/ATP to ~1% in CMs in a transgenic mouse (TgRRB) resulted in robust improvement of cardiac function. Pharmacological approaches showed that CMs with elevated dATP have greater basal respiratory rates by shifting myosin states to more active forms, independent of its isoform, in relaxed CMs. Targeted metabolomic profiling revealed a significant reprogramming towards oxidative phosphorylation in TgRRB-CMs. Higher cristae density and activity in the mitochondria of TgRRB-CMs improved respiratory capacity. Our results revealed a critical property of dATP to modulate myosin states to enhance contractility and induce metabolic flexibility to support improved function in CMs.HighlightsUbiquitylation-resistant variant RRB in a transgenic mice model (TgRRB) elevates dATP level up to 1% (of the total ATP pool) in the heart and improves function.TgRRB-CMs show greater basal oxygen consumption due to changes in myosin state by dATP.TgRRB-CMs respond to elevated function with a metabolic shift, such that there are higher pools of oxidative metabolites, with elevated OXPHOS, FAO, and energy reserve.Long-term mitochondrial remodeling may occur to accommodate for the higher energy demands of the high functioning TgRRB-CMs.Graphical abstract
Functional characterization ofBotrytis cinereaABC transporter geneBcatrBin response to phytoalexins produced in plants belonging to families Solanaceae, Brassicaceae and Fabaceae
Authors: Bulasag Abriel Salaria , Camagna Maurizio , Kuroyanagi Teruhiko , Ashida Akira , Ito Kento , Tanaka Aiko , Sato Ikuo , Chiba Sotaro , Ojika Makoto , Takemoto Daigo 
Published: November 2022

ABSTRACTBotrytis cinerea, a generalist fungal pathogen of economically important crop species, has been shown to exhibit reduced sensitivity to fungicides and plant toxins. Specifically, previous reports indicateB. cinerea’s efficacy in tolerating a wide array of phytoalexins, toxic plant metabolites that play key role in plant immune defense strategies. Previously, we have shown that a distinct set of genes was induced inB. cinereawhen treated with phytoalexins derived from different plant species such as rishitin (tomato and potato), capsidiol (tobacco and bell pepper) or resveratrol (grape and blueberry). In this study, we focused on the functional analyses ofB. cinereagenes induced by rishitin treatment.B. cinereacan metabolize rishitin to at least 4 oxidized forms. Heterologous expression of rishitin-inducedB. cinereagenes in the plant symbiotic fungus,Epichloë festucae, revealed that oxidoreductase (Bcin08g04910) and cytochrome P450 (Bcin16g01490) genes are involved in the oxidation of rishitin. BcatrB is an exporter of structurally unrelated anti-microbial compounds such as resveratrol, camalexin and fungicide fenpicionil. Expression ofBcatrBis upregulated by rishitin, but not by structurally resembling capsidiol.BcatrBknock out transformants (ΔbcatrB) showed enhanced sensitivity to rishitin, but not to capsidiol. Likewise,ΔbcatrBshowed reduced virulence on tomato fruits (which produce rishitin), but showed full virulence onNicotiana benthamiana(which mainly produces capsidiol), suggesting thatB. cinereadistinguishes phytoalexins and activates expression of appropriate transporter genes during the infection. Activation ofBcatrBpromoter was detected using P_BcatrB:GFPtransformant during theB. cinereainfection in plant tissues. Surveying of 26 plant species across 13 families revealed that theBcatrBpromoter is mainly activated during the infection of plants belonging to the Solanaceae, Fabaceae and Brassicaceae families. TheBcatrBpromoter is activated by the treatment with Fabaceae phytoalexins medicarpin and glyceollin, andΔbcatrBshowed reduced virulence on red clover, which produces medicarpin. These results suggest thatBcatrBplays a critical role in the strategy employed byB. cinereato bypass the plant innate immune responses in a wide variety of important crops belonging to the Solanaceae, Brassicaceae and Fabaceae families.
A F420-dependent single domain chemogenetic tool for protein de-dimerization
Authors: Antoney James , Kainrath Stephanie , Ahmed F. Hafna , Kang Suk Woo , Mackie Emily R. R. , Soares da Costa Tatiana P. , Jackson Colin J. , Janovjak Harald 
Published: November 2022

ABSTRACTProtein-protein interactions (PPIs) mediate many fundamental cellular processes and their control through optically or chemically responsive protein domains has a profound impact on basic research and some clinical applications. Most available chemogenetic methods induce the association, i.e., dimerization or oligomerization, of target proteins, and the few available dissociation approaches either break large oligomeric protein clusters or heteromeric complexes. Here, we have exploited the controlled dissociation of a dimeric oxidoreductase from mycobacteria (MSMEG_2027) by its native cofactor, F420, which is not present in mammals, as a bioorthogonal monomerization switch. We found that in the absence of F420, MSMEG_2027 forms a unique domain-swapped dimer that occludes the cofactor binding site. Substantial remodelling of the intertwined N-terminal helix upon F420binding results in the dissolution of the dimer. We then show that MSMEG_2027 can be expressed as fusion proteins in human cells and apply it as a tool to induce and release MAPK/ERK signalling downstream of a chimeric fibroblast growth factor receptor 1 (FGFR1) tyrosine kinase. This F420-dependent chemogenetic de-dimerization tool is stoichiometric, based on a single domain and presents a novel mechanism to investigate protein complexesin situ.
Methylated Cycloalkanes Fuel a Novel Genera in thePorticoccaceaeFamily and Inform Substrate Affinity for a Unique Copper Membrane Monooxygenase
Authors: Arrington Eleanor C. , Tarn Jonathan , Kittner Hailie , Kivenson Veronika , Liu Rachel M. , Valentine David L. 
Published: November 2022

AbstractCycloalkanes are an abundant and toxic class of compounds in subsurface petroleum reservoirs and their fate is quantitatively important to ecosystems impacted by natural oil seeps and spills. In this study, we focus on the microbial metabolism of methylcyclohexane (MCH) and methylcyclopentane (MCP) in the deep Gulf of Mexico. MCH and MCP are often the most abundant cycloalkanes observed in petroleum and a substantial portion of these compounds will dissolve into the water column when introduced at the seafloor via a spill or natural seep. Once dissolved into the water column, the environmental fate of MCH and MCP is presumably controlled by microbial consumption, but little is known about this environmental process. We conducted incubations using fresh Gulf of Mexico (GOM) seawater amended with MCH and MCP at four stations along a transect with a gradient in the influence of natural oil seepage. We observe microbial blooms via optical oxygen sensors that occur at all stations with bloom occurrence among replicate incubations impacted by the proximity of natural seepage. Within all incubations with active respiration of MCH and MCP, we find thatB045, a novel genus of bacteria belonging to thePorticoccaceaefamily dominates the microbial community. Using seven high-quality metagenome-assembled genomes recovered from microbial blooms on MCH and MCP, we reconstruct the biodegradation pathways and central carbon metabolism ofB045, identifying a novel clade of the particulate hydrocarbon monooxygenase (pmo) that may play a key role in MCH and MCP metabolism. Through comparative analysis of 176 genomes, we parse the taxonomy of thePorticoccaceaefamily and find evidence suggesting the acquisition ofpmoand other genes related to the degradation of cyclic and branched hydrophobic compounds were likely key events in the ecology and evolution of this group of organisms.
Using unlabeled information of embryo siblings from the same cohort cycle to enhance in vitro fertilization implantation prediction
Authors: Tzukerman Noam , Rotem Oded , Shapiro Maya Tsarfati , Maor Ron , Meseguer Marcos , Gilboa Daniella , Seidman Daniel S. , Zaritsky Assaf 
Published: November 2022

AbstractHigh content time-lapse embryo imaging assessed by machine learning is revolutionizing the field of in vitro fertilization (IVF). However, the vast majority of IVF embryos are not transferred to the uterus, and these masses of embryos with unknown implantation outcomes are ignored in current efforts that aim to predict implantation. Here, we explore whether, and to what extent the information encoded within “sibling” embryos from the same IVF cohort contribute to the performance of machine learning-based implantation prediction. First, we show that the implantation outcome is correlated with attributes derived from the cohort siblings. Second, we demonstrate that this unlabeled data boosts implantation prediction performance. Third, we characterize the cohort properties driving embryo prediction, especially those that rescued erroneous predictions. Our results suggest that predictive models for embryo implantation can benefit from the overlooked, widely available unlabeled data of sibling embryos by reducing inherent noise of the individual transferred embryo.Significance statementWe use in vitro fertilization (IVF) as a model to study the effect of genotypic and environmental variation on phenotype and demonstrate a potential translational application. This is achieved by associating the implantation potential of transferred embryos and the visual information encoded within their non-transferred “sibling” embryos from the same IVF cohort, and establishing that these cohort features contribute to consistent improvement in machine learning implantation prediction regardless of the embryo-focused model. Our results suggest a general concept where the uncertainty in the implantation potential for the transferred embryo can be reduced by information encapsulated in the correlated cohort embryos. Since the siblings’ data are routinely collected, incorporating cohort features in AI-driven embryo implantation prediction can have direct translational implications.
Rac1, Rac3 GTPases and TPC2 are required for axonal outgrowth and migration of cortical interneurons
Authors: Kounoupa Zouzana , Tivodar Simona , Theodorakis Kostas , Kyriakis Dimitrios , Denaxa Myrto , Karagogeos Domna 
Published: November 2022

ABSTRACTRho GTPases, among them Rac1 and Rac3, are major transducers of extracellular signals and are involved in multiple cellular processes. In cortical interneurons, the neurons that control excitation/inhibition balance of cortical circuits, Rac1 and Rac3 are essential for their development. Ablation of both, leads to a severe reduction in the numbers of mature interneurons found in the murine cortex, which is partially due to abnormal cell cycle progression of interneuron precursors and defective formation of their growth cones. Here we present new evidence that upon Rac1 and Rac3 ablation, centrosome, Golgi complex and lysosome positioning are significantly perturbed, thus affecting both interneuron migration and axon growth. Moreover, for the first time we provide evidence of altered expression and localization of the two-pore channel 2 (TPC2) voltage-gated ion channel that mediates Ca2+release. Pharmacological inhibition of TPC2 negatively affected axonal growth and migration of interneurons. Our data taken together suggest that TPC2 contributes to the severe phenotype in axon growth initiation, extension and interneuron migration in the absence of Rac1 and Rac3.SUMMARY STATEMENTRac1/3 severely affect cortical interneuron migration by affecting centrosome, Golgi and lysosome positioning. TPC2 likely contributes to the phenotype by decreasing axonogenesis and somatic migration.
DNA methylation regulates sex-biased gene expression in the house sparrow
Authors: Lundregan Sarah L. , Mäkinen Hannu , Viitaniemi Heidi , Rønning Bernt , Jensen Henrik , Husby Arild 
Published: November 2022

AbstractSexual dimorphism is often mediated by tissue-specific, differential gene expression, but the mechanisms that regulate these gene expression patterns are not well understood. Here, we investigate DNA methylation as a potential regulator of sex-biased gene expression in the house sparrow (Passer domesticus). First, we examine whether sex-bias in gene expression or DNA methylation is present in this species, and whether any sex differences are tissue-general or tissue-specific. Second, we assess the correlation between gene expression and DNA methylation at different genomic features in several tissues. Samples clustered by tissue type when looking at both gene expression and DNA methylation, and in gonads samples clustered according to sex. We demonstrate sex-bias in DNA methylation and gene expression on the Z-chromosome as well as on autosomes, but find that most of the sex-biased genes are tissue-specific and that the majority of sex-bias occurs in gonads, although some tissue-general sex differences were observed. This underscores the importance of choosing a tissue relevant to the studied phenotype in DNA methylation or gene expression studies. We find strong negative correlation between DNA methylation and gene expression at the transcription start site (TSS), and that the TSS of highly expressed genes is hypomethylated in comparison to the TSS of genes with low expression. Furthermore, we show that sex-biased DNA methylation can account for 14% of the sex differences in gene expression in gonads. Together these results indicate that DNA methylation differences between the sexes can provide a mechanistic explanation for sex-biased gene expression that likely contributes to trait sexual dimorphism in nature.
Long-range Hill-Robertson effect in adapting populations with recombination and standing variation
Authors: Rouzine Igor M. 
Published: November 2022

AbstractIn sexual populations, closely-situated genes have linked evolutionary fates, while genes spaced far in genome are commonly thought to evolve independently due to recombination. In the case where evolution depends essentially on supply of new mutations, this assumption has been confirmed by mathematical modeling. Here I examine it in the case of pre-existing genetic variation, where mutation is not important. A haploid population withNgenomes,Lloci, a fixed selection coefficient, and a small initial frequency of beneficial allelesf0is simulated by a Monte-Carlo algorithm. The results demonstrate the existence of extremely strong linkage effects, including clonal interference and genetic background effects, that depend neither on the distance between loci nor on the average number of recombination crossovers. When the number of loci,L, is larger than 4log2(Nf0), beneficial alleles become extinct at most loci. The substitution rate varies broadly between loci, with the fastest rate exceeding the one-locus model prediction. All observables and the transition to the independent-locus limit are controlled by single composite parameter log2(Nf0)/L. The potential link between these findings and the emergence of new Variants of Concern of SARS CoV-2 is discussed.
Long-term recoveries of forest ecosystem components after shallow landslides were asynchronized among slope positions
Authors: Hotta Wataru , Morimoto Junko , Yanai Seiji , Uchida Yoshitaka , Nakamura Futoshi 
Published: November 2022

AbstractLandslides are a common disturbance in mountainous areas of the world. Transporting and accumulating landslide debris, i.e., disturbance legacies, such as coarse woody debris (CWD), vegetation patches, and surface soils, generate a heterogeneous environment along slopes (zones), which are suggested to affect forest recovery. However, the long-term changes in forest ecosystems after landslides remain unknown, particularly zone-dependent change patterns. We aimed to reveal the differences in the changes in live trees, understory vegetation, CWD, and soils among zones by surveying forests with landslide ages (years since the landslide) ranging from 3 to 74 years and reference stands. The increase in live tree aboveground biomass occurred at a faster rate at the lower part of the slopes where the disturbance legacies were rich and surface soils were stabilized due to the smaller slope angle. Chronological patterns of understory vegetation amounts were determined by the differences in disturbance legacy richness and the timing of subsequent canopy closure. The amounts and decay-class diversity of CWD were determined by the differences in legacy richness and mortality through stand development. These zone-dependent chronological changes influenced litter production and determined the recovery rates of surface soil carbon stocks and nitrogen contents. The increase in the dominance rates of forest herbaceous species was faster in the lower part of the slopes due to the faster surface soil development and canopy closure. Our results illustrate that long-term forest ecosystem succession and recovery after landslides occurs more rapidly at the lower parts than at the upper parts of slopes.HighlightsRich landslide legacies and low slope angles promoted vegetation and soil recoveryLegacy richness and timing of canopy closure determined changes in the understoryLandslide mortality and stand development mortality determined changes in dead wood
Time to first cigarette and its impact on lung tumorigenesis
Authors: Zhang Tongwu , Sang Jian , Caporaso Neil , Gu Fangyi , Hutchinson Amy , Consonni Dario , Pesatori Angela C. , Homer Robert , Chanock Stephen , Landi Maria Teresa 
Published: November 2022

AbstractTime to first cigarette (TTFC) in the morning has been identified as the best indicator of nicotine dependence and is associated with lung cancer risk beyond other measures of tobacco smoking. Using deep whole genome sequencing of 218 lung cancers from smokers, we show that TTFC is the strongest marker of tobacco smoking mutagenicity, with impact on lung tumor mutational burden, mutational signatures, intratumor heterogeneity,KRASmutations and overall survival. These results pave the way for using TTFC as an easily measurable marker of lung tumorigenesis, with plausible therapeutic and prognostic implications.
Cell-subtype specific effects of genetic variation in the aging and Alzheimer cortex
Authors: Fujita Masashi , Gao Zongmei , Zeng Lu , McCabe Cristin , White Charles C. , Ng Bernard , Green Gilad Sahar , Rozenblatt-Rosen Orit , Phillips Devan , Amir-Zilberstein Liat , Lee Hyo , Pearse Richard V. , Khan Atlas , Vardarajan Badri N. , Kiryluk Krzysztof , Ye Chun Jimmie , Klein Hans-Ulrich , Wang Gao , Regev Aviv , Habib Naomi , Schneider Julie A. , Wang Yanling , Young-Pearse Tracy , Mostafavi Sara , Bennett David A. , Menon Vilas , De Jager Philip L. 
Published: November 2022

AbstractThe relationship between genetic variation and gene expression in individual brain cell types and subtypes has remained elusive. Here, we generated single-nucleus RNA sequencing data from the dorsolateral prefrontal cortex of 424 individuals of advanced age; analyzing 1.5 million nuclear transcriptomes, we assessed the effect of genetic variants on RNA expression incis(cis-eQTL) for 7 cell types and 81 cell subtypes. This effort identified 10,004 eGenes at the cell type level and 8,138 eGenes at the cell subtype level. Many eGenes are only detected within cell subtypes. A new variant influencesAPOEexpression only in microglia and is associated with greater cerebral amyloid angiopathy but not Alzheimer pathology, accounting for the effect ofAPOEε4, providing mechanistic insights into both pathologies. While eQTLs are readily detected, only aTMEM106Bvariant robustly affects the proportion of cell subtypes. Integration of these results with GWAS highlighted the targeted cell type and likely causal gene within susceptibility loci for Alzheimer’s, Parkinson’s, schizophrenia, and educational attainment.