bluuebunny/crossref_metadata_2025_split huggingface dataset:
Longitudinal Deep Multi-Omics Profiling in aCLN3Δex7/8Minipig Model Reveals Novel Biomarker Signatures for Batten Disease
Authors: Rechtzigel Mitchell J , Lee Brittany , Neville Christine , Huang Ting , Campos Alex Rosa , Motamedchaboki Khatereh , Hornburg Daniel , Johnson Tyler B , Swier Vicki J , Weimer Jill M , Brudvig Jon J 
Published: September 2023

AbstractDevelopment of therapies for CLN3 Batten disease, a rare pediatric lysosomal storage disorder, has been hindered by the lack of etiological insights and translatable biomarkers to clinics. Here, we used a deep multi-omics approach to discover new biomarkers using longitudinal serum samples from a porcine model of CLN3 disease. Comprehensive metabolomics was combined with a nanoparticle-based LC-MS-based proteomic profiling coupled with TMTpro 18-plex to generate quantitative data on 769 metabolites and 2,634 proteins, collectively the most exhaustive multi-omics profile conducted on serum from a porcine model, which was previously impossible due a to lack of efficient deep serum proteome profiling technologies compatible with model organisms. The presymptomatic disease state was characterized by elevations in glycerophosphodiester species and lysosomal proteases, while later timepoints were enriched with species involved in immune cell activation and sphingolipid metabolism. Cathepsin S, Cathepsin B, glycerophosphoinositol, and glycerophosphoethanolamine captured a large portion of the genotype-correlated variation between healthy and diseased animals, suggesting that an index score based on these analytes could have great utility in the clinic.
Dietary Restriction Fails to Extend Lifespan ofDrosophilaModel of Werner Syndrome
Authors: Sember Eileen , Chennakesavula Ranga , Beard Breanna , Opoola Mubaraq , Hwangbo Dae-Sung 
Published: September 2023

AbstractWerner syndrome (WS) is a rare genetic disease in humans, caused by mutations in theWRNgene that encodes a protein containing helicase and exonuclease domains. WS is characterized by symptoms of accelerated aging in multiple tissues and organs, involving increased risk of cancer, heart failure, and metabolic dysfunction. These conditions ultimately lead to the premature mortality of patients with WS. In this study, using the null mutant flies (WRNexoΔ) for the gene WRNexo (CG7670), homologous to the exonuclease domain of WRN in humans, we examined how diets affect the lifespan, stress resistance, and sleep/wake patterns of aDrosophilamodel of WS. We observed that dietary restriction (DR), one of the most robust non-genetic interventions to extend lifespan in animal models, failed to extend the lifespan ofWRNexoΔmutant flies and even had a detrimental effect in females. Interestingly, the mean lifespan ofWRNexoΔmutant flies was not reduced on a protein-rich diet compared to that of wild-type flies. Compared to wild type control flies, the mutant flies also exhibited altered responses to DR in their resistance to starvation and oxidative stress, as well as changes in sleep/wake patterns. These findings show that the WRN protein is necessary for mediating the effects of DR and suggest that the exonuclease domain of WRN plays an important role in metabolism in addition to its primary role in DNA repair and genome stability. Our results also raise the possibility that diet-mediated interventions could ameliorate the symptoms of WS.
Exploiting Charge State Distribution to Probe Intramolecular Interactions in Gas-Phase Phosphopeptides and Enhance Proteomics Analyses
Authors: Gorshkov Vladimir , Kjeldsen Frank 
Published: September 2023

AbstractCharging of analytes is a prerequisite for performing mass spectrometry analysis. In proteomics, electrospray ionization stands as the dominant technique for this process. Although the observation of differences in the peptide charge state distribution (CSD) is well-known among experimentalists, its analytical value remains underexplored. To investigate the utility of this dimension, we analyzed several public datasets, comprising over 250,000 peptide CSD profiles from the human proteome. We found that the dimension of the CSD demonstrates high reproducibility across multiple laboratories, mass analyzers, and extensive time intervals. The general observation was that the CSD enabled effective partitioning of the peptide property space, resulting in enhanced discrimination between sequence or constitutional peptide isomers. Next, by evaluating the CSD values of phosphorylated peptides, we were able to differentiate between phosphopeptides that indicate the formation of intramolecular structures in the gas phase and those that do not. The reproducibility of the CSD values (mean cosine similarity above 0.97 for most of the experiments), qualified CSD data suitable to train a deep learning model capable of accurately predicting CSD values (mean cosine similarity – 0.98). When we applied the CSD dimension to MS1- and MS2-based proteomics experiments, we consistently observed around a 5% increase in protein and peptide identification rate. Even though the CSD dimension is not as effective a discriminator as the widely-used retention time dimension, it still holds potential for application in direct infusion proteomics.
Engram cell connectivity as a mechanism for information encoding and memory function
Authors: Ortega-de San Luis Clara , Pezzoli Maurizio , Urrieta Esteban , Ryan Tomás J. 
Published: September 2023

SUMMARYInformation derived from experiences is incorporated into the brain as changes to ensembles of cells, termed engram cells, that allow memory storage and recall. The mechanism by which those changes hold specific information is unclear. Here we test the hypothesis that the specific synaptic wiring between engram cells is the substrate of information storage. First, we monitor how learning modifies the connectivity pattern between engram cells at a monosynaptic connection involving the hippocampal vCA1 region and the amygdala. Then, we assess the functional significance of these connectivity changes by artificially activating or inhibiting its presynaptic and postsynaptic components respectively. Finally, we identify a synaptic plasticity mechanism mediated by PSD-95, which impacts the connectivity pattern among engram cells and contributes to the long-term stability of the memory. These findings impact our theory of learning and memory by helping us explain the translation of specific information into engram cells and how these connections shape brain function.
Anti-S-layer monoclonal antibodies impactC. difficilephysiology
Authors: Hunault Lise , Auria Emile , England Patrick , Deschamps Julien , Briandet Romain , Kremer Vanessa , Iannascoli Bruno , Vidal-Maison Léo , Guo Chunguang , Macdonald Lynn , Péchiné Séverine , Denève-Larrazet Cécile , Dupuy Bruno , Gorochov Guy , Bruhns Pierre , Sterlin Delphine 
Published: September 2023

AbstractClostridioides difficile(C. difficile), a gram-positive anaerobic and spore-forming bacterium, is the leading cause of nosocomial antibiotic-associated diarrhea in adults and is characterized by high levels of recurrence and mortality. Surface-layer Protein A (SlpA), the most expressed protein on bacterial surface, plays a crucial role in the early stages of infection although its role inC. difficilephysiology is yet to be fully understood. Anti-S-layer antibodies have been identified in the sera of convalescent patients and correlate with improved outcome ofC. difficileinfection (CDI). However, the precise mechanisms of how anti-S-layer antibodies can confer protection to the host remain unknown. In this study, we report the first monoclonal antibodies (mAbs) targeting S-layer of the reference strain 630. Characterization of these mAbs unravels important roles for S-layer protein in growth, toxin secretion, and biofilm formation with, surprisingly, opposite effects of different anti-SlpA mAbs on these functions. One anti-SlpA mAb impairedC. difficilegrowth and restored sensitivity to lysozyme-induced lysis. These findings suggest that anti-S-layer antibody responses may include protective and detrimental effects for the host and provide important insights for designing adequate S-layer-targeting therapeutics.
The Role of Vitamin D inEmiliania huxleyi: A Microalgal Perspective on UV Exposure
Authors: Eliason Or , Malitsky Sergey , Panizel Irina , Feldmesser Ester , Porat Ziv , Sperfeld Martin , Segev Einat 
Published: September 2023

AbstractAn essential interaction between sunlight and eukaryotes involves the production of vitamin D through exposure to ultraviolet (UV) radiation. While extensively studied in vertebrates, the role of vitamin D in non-animal eukaryotes like microalgae remains unclear. To investigate the potential involvement of vitamin D in the response of microalgae to UV, we focus onEmiliania huxleyi, a microalga found in shallow ocean depths that are exposed to UV radiation. Our results show thatE. huxleyialgae produce vitamin D2and D3in response to UV irradiation. We further demonstrate thatE. huxleyialgae respond to external administration of vitamin D at the transcriptional level, regulating the expression of protective mechanisms that are also regulated in response to UV. Our data reveal that addition of vitamin D enhances the algal photosynthetic performance while reducing harmful reactive oxygen species buildup. This study contributes to understanding the function of vitamin D inE. huxleyiand sheds light on its role in non-animal eukaryotes, as well as its potential importance in marine ecosystems.
Generation and characterisation of anArabidopsis thaliana f3h/fls1/anstriple mutant that accumulates eriodictyol derivatives
Authors: Schilbert Hanna Marie , Busche Mareike , Sáez Vania , Angeli Andrea , Weisshaar Bernd , Martens Stefan , Stracke Ralf 
Published: September 2023

AbstractBackgroundFlavonoids are plant specialised metabolites, which derive from phenylalanine and acetate metabolism. They possess a variety of beneficial characteristics for plants and humans. Several modification steps in the synthesis of tricyclic flavonoids cause for the amazing diversity of flavonoids in plants. The 2-oxoglutarate-dependent dioxygenases (2-ODDs) flavanone 3-hydroxylase (F3H, synonym FHT), flavonol synthase (FLS) and anthocyanidin synthase (ANS, synonym leucoanthocyanidin dioxigenase (LDOX)), catalyse oxidative modifications to the central C ring. They are highly similar and have been shown to catalyse, at least in part, each other’s reactions. FLS and ANS have been identified as bifunctional enzymes in many species, includingArabidopsis thaliana, stressing the capability of plants to bypass missing or mutated reaction steps on the way to flavonoid production. However, little is known about such bypass reactions and the flavonoid composition of plants lacking all three central flavonoid 2-ODDs.ResultsTo address this issue, we generated af3h/fls1/ansmutant, as well as the corresponding double mutants and investigated the flavonoid composition of this mutant collection. Thef3h/fls1/ansmutant was further characterised at the genomic level by analysis of a nanopore DNA sequencing generated genome sequence assembly and at the transcriptomic level by RNA-Seq analysis. The mutant collection established, including the novel double mutantsf3h/fls1andf3h/ans, was used to validate and analyse the multifunctionalities of F3H, FLS1, and ANSin planta. Metabolite analyses revealed the accumulation of eriodictyol and additional glycosylated derivatives in mutants carrying thef3hmutant allele, resulting from the conversion of naringenin to eriodictyol by flavonoid 3’-hydroxylase (F3’H) activity.ConclusionsWe describe thein plantamultifunctionality of the three central flavonoid 2-ODDs fromA. thalianaand identify a bypass in thef3h/fls1/anstriple mutant that leads to the formation of eriodictyol derivatives. As (homo-)eriodictyols are known as bitter taste maskers, the annotated eriodictyol (derivatives) and in particular the observations made on theirin plantaproduction, could provide valuable insights for creating of novel food supplements.
Human hippocampus and dorsomedial prefrontal cortex infer and update latent causes during social interaction
Authors: Mahmoodi Ali , Luo Shuyi , Harbison Caroline , Piray Payam , Rushworth Matthew 
Published: September 2023

AbstractWhen an important event occurs, the observer should identify which features of the environment might have caused it. This is the latent cause inference problem, and it must be solved if observers are to understand their environments. The problem is acute in social settings where individuals may not make equal contributions to the outcomes they achieve together. Here, we designed a novel task in which participants inferred which of two characters was the more likely to have been responsible for outcomes achieved by working together. Using computational modelling, univariate and multivariate analysis of human fMRI, and continuous theta burst stimulation we identified two brain regions that solved the task. Notably, as each outcome occurred, it was possible to decode inference of its cause (the responsible character) from activity in hippocampus. Activity in dorsomedial prefrontal cortex updated estimates of association between cause -- the responsible character – and the outcome.
Metabotropic signaling within somatostatin interneurons controls transient thalamocortical inputs during development
Authors: Dwivedi Deepanjali , Dumontier Dimitri , Sherer Mia , Lin Sherry , Mirow Andrea MC , Qiu Yanjie , Xu Qing , Liebman Samuel A , Joseph Djeckby , Datta Sandeep R , Fishell Gord , Pouchelon Gabrielle 
Published: September 2023

AbstractDuring brain development, neural circuits undergo major activity-dependent restructuring. Circuit wiring mainly occurs through synaptic strengthening following the Hebbian “fire together, wire together” precept. However, select connections, essential for circuit development, are transient. They are effectively connected early in development, but strongly diminish during maturation. The mechanisms by which transient connectivity recedes are unknown. To investigate this process, we characterize transient thalamocortical inputs, which depress onto somatostatin inhibitory interneurons during development, by employing optogenetics, chemogenetics, transcriptomics and CRISPR-based strategies. We demonstrate that in contrast to typical activity-dependent mechanisms, transient thalamocortical connectivity onto somatostatin interneurons is non-canonical and involves metabotropic signaling. Specifically, metabotropic-mediated transcription, of guidance molecules in particular, supports the elimination of this connectivity. Remarkably, we found that this developmental process impacts the development of normal exploratory behaviors of adult mice.
The apoptotic splicing regulators RBM5 and RBM10 are subunits of the U2 snRNP engaged with intron branch sites on chromatin
Authors: Damianov Andrey , Lin Chia-Ho , Huang Jeffrey , Zhou Lin , Jami-Alahmadi Yasaman , Wohlschlegel James , Black Douglas L. 
Published: September 2023

SUMMARYUnderstanding the mechanisms of pre-mRNA splicing and spliceosome assembly is limited by technical challenges to examining spliceosomes in vivo. Here we report the isolation of RNP complexes derived from precatalytic A or B-like spliceosomes solubilized from the chromatin pellet of lysed nuclei. We found that these complexes contain U2 snRNP proteins and a portion of the U2 snRNA, bound with intronic branch sites prior to the first catalytic step of splicing. Sequencing these pre-mRNA fragments allowed the transcriptome-wide mapping of branch sites with high sensitivity. In addition to known U2 snRNP proteins, these complexes contained the proteins RBM5 and RBM10. RBM5 and RBM10 are alternative splicing regulators that control exons affecting apoptosis and cell proliferation in cancer, but were not previously shown to associate with the U2 snRNP or to play roles in branch site selection. We delineate a common segment of RBM5 and RBM10, separate from their known functional domains, that is required for their interaction with the U2 snRNP. We identify a large set of splicing events regulated by RBM5 and RBM10 and find that they predominantly act as splicing silencers. Disruption of their U2 interaction renders the proteins inactive for repression of many alternative exons. We further find that these proteins assemble on branch sites of nearly all exons across the transcriptome, including those whose splicing is not altered by them. We propose a model where RBM5 and RBM10 act as components of the U2 snRNP complex. From within this complex, they sense structural features of branchpoint recognition to either allow progression to functional spliceosome or rejection of the complex to inhibit splicing.
Inverse and ProportionaltransModulation of Gene Expression in Human Aneuploidies
Authors: Zhang Shuai , Wang Ruixue , Zhang Ludan , Birchler James A. , Sun Lin 
Published: September 2023

AbstractGenomic imbalance in aneuploidy is often detrimental to organisms. To gain insight into the molecular basis of aneuploidies in humans, we analyzed transcriptome data from several autosomal and sex chromosome aneuploidies. The results showed that in human aneuploid cells, genes located on unvaried chromosomes are inversely or proportionallytrans-modulated, while a subset of genes on the varied chromosomes are compensated. Less genome-wide modulation is found for sex chromosome aneuploidy compared with autosomal aneuploidy due to X inactivation and the retention of dosage sensitive regulators on both sex chromosomes to limit the effective dosage change. We also found that lncRNA and mRNA can have different responses to aneuploidy. Furthermore, we analyzed the relationship between dosage-sensitive transcription factors and their targets, which illustrated the modulations and indicates genomic imbalance is related to stoichiometric changes of components of gene regulatory complexes.
Dominant CIZ1 fragments drive epigenetic instability and are expressed in early stage cancers
Authors: Turvey Gabrielle L. , de Alba Ernesto López , Stewart Emma , Byrom Lewis , Cook Heather , Sofi Sajad , Alalti Ahmad , Ainscough Justin F-X , Mason Andrew , Antson Alfred A , Coverley Dawn 
Published: September 2023

AbstractCIZ1 is a nuclear matrix protein that is part of the large RNA-dependent supramolecular assembly complexes (SMACs) that form at the inactive X chromosome (Xi) in female cells, and smaller assemblies throughout the nucleus in males and females. It plays a role in maintenance of epigenetic state and gene expression in differentiated cells, via stabilisation of histone post-translational modifications H2AK119ub1 and H3K27me3, added by polycomb repressive complexes (PRC) 1 and 2.Here, we show that expression of the N-terminal replication domain (RD) and C-terminal anchor domain (AD) of human CIZ1 transcript is uncoupled, with consistently elevated AD in early stage breast cancers, and sporadically elevated AD in other common solid tumours. At the protein level CIZ1-Xi SMACs are corrupted in female breast cancers cells, and this is accompanied by elevated AD-encoding transcripts.We modelled the effect of AD fragments in primary murine embryonic fibroblasts and observed dominant-negative interference with CIZ1 SMACs during their assembly in early G1 phase. Mutagenesis identified the matrin 3 homology domain as essential for self-interaction to form stable homodimersin vitro, and as a determinant of its dominant-negative effect in cells, implicating the dimerization interface in CIZ1 SMAC integrity.SMAC disruption was coincident with depletion of PRC1-dependent H2AK119ub1 from Xi chromatin, in a manner abrogated by the PR-deubiquitinase inhibitor PR619, suggesting that CIZ1 SMACs normally stabilise H2AK119ub1 by shielding Xi chromatin from attack by deubiquitinases. Moreover, SMAC disruption was accompanied by changes in gene expression within days.Together, the data suggest that inappropriate expression of CIZ1 AD fragments could drive epigenetic instability in early stage breast cancers by destabilizing the CIZ1 SMACs that normally protect repressed chromatin.Abstract Figure
Corporate sustainability performance and firm performance: the state-of-the-art and future research agenda
Authors: Kumari Garima , Joshi Yatish 
Published: September 2023

PurposeThe past years have seen more studies exploring corporate sustainability performance (CSP) and firm performance nexus, but there has been a lack of analysis using bibliometric studies. This study aims to provide a structure for the CSP-firm performance relationship to gain valuable insights for further research.Design/methodology/approachBibliometric analysis was carried on 462 articles from the Scopus database spanning 1987–2022 using VOSviewer and R software Bibliometrix.FindingsThe study overviews the most notable articles, authors, journals, countries and institutions. Four main clusters are identified to determine research themes using bibliographic coupling (documents). Additionally, co-occurrence analysis (keywords) reveals three themes indicating current and future research trends.Originality/valueThe study presents an overview of the evolution of research on CSP-firm performance nexus. This work consolidates bibliometric analysis and systematic literature review on CSP and firm performance, covering all significant work on the topic and presenting the field's knowledge map and future research directions.
Impact of digital capability on firm resilience: the moderating role of coopetition behavior
Authors: Chen Congjun , Pan Jieyi , Liu Shasha , Feng Taiwen 
Published: September 2023

PurposeIn the digital economy, digital capability has become an important dynamic capability of enterprises and plays an essential role in enhancing firm resilience. This study aims to investigate the relationships among digital capability, knowledge search, coopetition behavior and firm resilience based on knowledge-based view and resource-based view.Design/methodology/approachThis study uses the hierarchical regression and bootstrapping methods to test the theoretical framework and research hypotheses. The survey data were collected from 241 Chinese enterprises.FindingsDigital capability has significantly positive effects on knowledge search and firm resilience. Knowledge search positively affects firm resilience and partially mediates the relationship between digital capability and firm resilience. Coopetition behavior weakens the relationship between digital capability and knowledge search, and the mediating effect of knowledge search in the relationship between digital capability and firm resilience. The moderating effect of coopetition behavior on the relationship between digital capability and firm resilience is insignificant.Originality/valueThis study clarifies the effect of digital capability on firm resilience and uncovers the “black box” from digital capability to firm resilience. In addition, this research enriches the literature on digital capability and firm resilience and expands the application of knowledge-based view and resource-based view in the digital context.