bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic insights intoLactobacillaceae: Analyzing the “Alleleome” of core pangenomes for enhanced understanding of strain diversity and revealing Phylogroup-specific unique variants
Authors: Harke Archana S. , Josephs-Spauling Jonathan , Mohite Omkar S. , Chauhan Siddharth M. , Ardalani Omid , Palsson Bernhard , Phaneuf Patrick V. 
Published: September 2023

AbstractTheLactobacillaceaefamily’s significance in food and health, combined with available strain-specific genomes, enables genome assessment through pangenome analysis. The ‘Alleleome’ of the core pangenomes ofthe Lactobacillaceaefamily, which identifies natural sequence variations, was reconstructed from the amino acid and nucleotide sequences of the core genes across 2,447 strains of 26 species. It comprised 3.71 million amino acid variants in 29,448 core genes across the family. The alleleome analysis of theLactobacillaceaefamily revealed key findings: 1) In the core pangenome, amino acid substitutions prevailed over rare insertions and deletions, 2) Purifying negative selection primarily influenced core gene variations in the family, with diversifying selection noted inL. helveticus.L. plantarum’s core alleleome was investigated due to its industrial importance. InL. plantarum, the defining characteristics of its core alleleome included: 1) It is highly conserved; 2) Among 235 isolation sources, the primary categories displaying variant prevalence were fermented food, feces, and unidentified sources; 3) It is predominantly characterized by ‘conservative’ and ‘moderately conservative’ mutations; and 4) Phylogroup-specific core variant gene analysis identified unique variants (DltX, FabZ1, Pts23B, CspP) in phylogroups ‘I’ and ‘B’ which could be used as identifier or validation markers of strain or phylogroup.
Dynamic mRNA stability changes buffer transcriptional activation during neuronal differentiation and are regulated by RNA binding proteins
Authors: Zhou Yuan , Rashad Sherif , Tominaga Teiji , Niizuma Kuniyasu 
Published: September 2023

AbstractThe steady state levels of mRNA are outcomes of a finely tuned interplay between RNA transcription and decay. Therefore, the modulation of RNA stability is generally assumed to influence RNA abundance in a positive direction. However, the correlation between mRNA transcription, translation and stability remains elusive. Here, we employed a newly developed simplified mRNA stability profiling technique to explore the role of mRNA stability in SH-SY5Y neuronal differentiation model. Transcriptome-wide mRNA stability analysis revealed neural-specific RNA stability kinetics, including stabilization of transcripts encoding regulators of neuronal morphogenesis and function and destabilization of mitochondrial electron transport and redox homeostasis. When we further examined the relationship between transcription, translation and mRNA stability, a bidirectional regulation of RNA stability was revealed, wherein mRNA stability could either exert the buffering effect on gene products or change in a same direction as transcription. Motif analysis unveiled SAMD4A as a major regulator of the dynamic changes in mRNA stability observed during differentiation. Knockdown of SAMD4A impaired neuronal differentiation and influenced the response to oxidative stress. Mechanistically, SAMD4A was found to alter the stability of several mRNAs to which it binds. Meanwhile, a dimorphic pattern of the correlation between gene expression and SAMD4A-regulated mRNA stability was observed, suggesting dynamic regulation mRNA stability during the neuronal differentiation guided by SAMD4A. The novel insights into the interplay between mRNA stability and cellular behaviors provide a foundation for understanding neurodevelopmental processes and neurodegenerative disorders and highlights dynamic mRNA stability as an important layer of gene expression regulation.
Unravelling the complexity of silk sericins:P150/sericin 6is a new silk gene inBombyx mori
Authors: Wu Bulah Chia-hsiang , Zabelina Valeriya , Zurovcova Martina , Žurovec Michal 
Published: September 2023

ABSTRACTSericins are a small family of highly divergent proteins that serve as adhesives and coatings for silk fibers and are produced in the middle part of the silk gland. So far, five genes encoding sericin proteins have been found inBombyx mori. Sericins 1 and 3 are responsible for silk adhesion in the cocoon, while sericins 2, 4, and 5 are present in non-cocoon spun silk of younger larvae (including the early last instar). We found a new gene, which we namedP150/sericin 6, which appears to be an ortholog of the sericin-like protein previously found inGalleria mellonella. TheB. morisequence of theP150/sericin 6ORF was previously incorrectly predicted and assigned to two smaller, uncharacterized genes. We present a newP150/sericin 6gene model and show that it encodes a large protein of 467 kDa. It is characterized by repeats with a high proportion of threonine residues and a short conserved region with a cysteine knot motif (CXCXCX) at the C-terminus. Expression analysis has shown thatB. mori P150/ser6has low transcriptional level in contrast to itsG. mellonellahomolog. We also discuss the synteny of homologous genes on corresponding chromosomes between moth species and possible phylogenetic relationships betweenP150/ser6and cysteine knot mucins. Our results improve our understanding of the evolutionary relationships between adhesion proteins in different lepidopteran species.
TheHelicobacter pyloriMethylome is Acid-Responsive due to Regulation by the Two-Component System ArsRS and the Type I DNA Methyltransferase HsdM1 (HP0463)
Authors: Zimmerman Elise H. , Ramsey Erin L. , Hunter Katherine E. , Villadelgado Sarah M. , Phillips Celeste M. , Shipman Ryan T. , Forsyth Mark H. 
Published: September 2023

AbstractIn addition to its role in genome protection, DNA methylation can regulate gene expression. In this study, we characterized the impact of acidity, phase variation, and the ArsRS TCS on the expression of the Type I m6A DNA methyltransferase HsdM1 (HP0463) ofHelicobacter pylori26695 and their subsequent effects on the methylome. Transcription ofhsdM1 increases at least 4-fold in the absence of the sensory histidine kinase ArsS, the major acid-sensing protein ofH. pylori.hsdM1 exists in the phase-variable operonhsdR1-hsdM1. Phase-lockinghsdR1 (HP0464), the restriction endonuclease gene, has significant impacts on the transcription ofhsdM1. To determine the impacts of methyltransferase transcription patterns on the methylome, we conducted methylome sequencing on samples cultured at pH 7 or pH 5. We found differentially methylated motifs between these growth conditions, and that deletions ofarsSand/orhsdM1 interfere with the epigenetic acid response. Deletion ofarsSleads to altered activity of HsdM1 and multiple other methyltransferases under both pH conditions indicating that the ArsRS TCS, in addition to direct effects on regulon transcription during acid acclimation, may also indirectly impact gene expression via regulation of the methylome. We determined the target motif of HsdM1 (HP0463) to be the complementary bipartite sequence pair 5’-(HH)TCAm6AVN6TGY-3’ and 3’-AGTN6GAm6ACA-5’. The Type II m5C DNA methyltransferase M.HpyAVIII (HP1121) is regulated by ArsS and HsdM1. This complex regulation of DNA methyltransferases, and thus differential methylation patterns, may have implications for the decades-long persistent infection byH. pylori.ImportanceThis study expands the possibilities for complex, epigenomic regulation inHelicobacter pylori. We demonstrate that theH. pylorimethylome is plastic and acid-sensitive via the two-component system ArsRS and the DNA methyltransferase HsdM1. The control of a methyltransferase by ArsRS may allow for a layered response to changing acidity. Likely, an early response whereby ArsR∼P affects regulon expression, including the methyltransferasehsdM1. Then, a somewhat later effect as the altered methylome, due to altered HsdM1 expression, subsequently alters the expression of other genes involved in acclimation. The intermediate methylation of certain motifs supports the hypothesis that methyltransferases play a regulatory role. Untangling this additional web of regulation could play a key role in understandingH. pyloricolonization and persistence.
Lys716 in the transmembrane domain of yeast mitofusin Fzo1 modulates anchoring and fusion
Authors: Versini Raphaëlle , Baaden Marc , Cavellini Laetitia , Cohen Mickaël M. , Taly Antoine , Fuchs Patrick F.J. 
Published: September 2023

AbstractOuter mitochondrial membrane (OMM) fusion is an important process for the cell and organism survival, as its dysfunction is linked to neurodegenerative diseases and cancer. The OMM fusion is mediated by members of the dynamin-related protein (DRP) family, named mitofusins. The exact mechanism by which the mitofusins contribute to these diseases, as well as the exact molecular fusion mechanism mediated by mitofusin, remains elusive.We have performed extensive multiscale molecular dynamics simulations using both coarse-grained and all-atom approaches to predict the dimerization of two transmembrane domain (TM) helices of the yeast mitofusin Fzo1. We identify specific residues, such as Lys716, that can modulate dimer stability. Comparison with a previous computational model reveals remarkable differences in helix crossing angles and interfacial contacts. Overall, however, the TM1-TM2 interface appears to be stable in the Martini and CHARMM force fields. Replica-exchange simulations further tune a detailed atomistic model, as confirmed by a remarkable agreement with an independent prediction of the Fzo1-Ugo1 complex by AlphaFold2. Functional implications, including a possible role of Lys716 that could affect membrane interactions during fusion, are suggested and consistent with experiments monitoring mitochondrial respiration of selected Fzo1 mutants.
Rewiring of the phosphoproteome executes two meiotic divisions
Authors: Koch Lori B. , Spanos Christos , Kelly Van , Ly Tony , Marston Adele L. 
Published: September 2023

AbstractThe cell cycle is ordered by a controlled network of kinases and phosphatases. To generate gametes via meiosis, two distinct and sequential chromosome segregation events occur without an intervening S phase. How canonical cell cycle controls are modified for meiosis is not well understood. Here, using highly synchronous budding yeast populations, we reveal how the global proteome and phosphoproteome changes during the meiotic divisions. While protein abundance changes are limited to key cell cycle regulators, dynamic phosphorylation changes are pervasive. Our data indicate that two waves of cyclin-dependent kinase and Polo (Cdc5Polo) kinase activity drive successive meiotic divisions. These two distinct waves of phosphorylation are ensured by the meiosis-specific Spo13Meikinprotein, which rewires the phosphoproteome. Spo13Meikinbinds to Cdc5Poloto promote phosphorylation of a subset of substrates in meiosis I containing a newly identified motif, which we define as the Spo13Meikin-Cdc5Poloconsensus phosphorylation motif. Overall, our findings reveal that a master regulator of meiosis redirects the activity of a kinase to change the phosphorylation landscape and elicit a developmental cascade.
Characterization and optimization of variability in a human colonic epithelium culture model
Authors: Pike Colleen M. , Zwarycz Bailey , McQueen Bryan E. , Castillo Mariana , Barron Catherine , Morowitz Jeremy M. , Levi James A. , Phadke Dhiral , Balik-Meisner Michele , Mav Deepak , Shah Ruchir , Glasspoole Danielle L. Cunningham , Laetham Ron , Thelin William , Bunger Maureen K. , Boazak Elizabeth M. 
Published: September 2023

SummaryAnimal models have historically been poor preclinical predictors of gastrointestinal (GI) directed therapeutic efficacy and drug-induced GI toxicity. Human stem and primary cell-derived culture systems are a major focus of efforts to create biologically relevant models that enhance preclinical predictive value of intestinal efficacy and toxicity. The inherent variability in stem-cell-based complex cultures makes development of useful models a challenge; the stochastic nature of stem-cell differentiation interferes with the ability to build and validate robust, reproducible assays that query drug responses and pharmacokinetics. In this study, we aimed to characterize and reduce potential sources of variability in a complex stem cell-derived intestinal epithelium model, termed RepliGut®Planar, across cells from multiple human donors, cell lots, and passage numbers. Assessment criteria included barrier formation and integrity, gene expression, and cytokine responses. Gene expression and culture metric analyses revealed that controlling for stem/progenitor-cell passage number reduces variability and maximizes physiological relevance of the model. After optimizing passage number, donor-specific differences in cytokine responses were observed in a case study, suggesting biologic variability is observable in cell cultures derived from multiple human sources. Our findings highlight key considerations for designing assays that can be applied to additional primary-cell derived systems, as well as establish utility of the RepliGut®Planar platform for robust development of human-predictive drug-response assays.
Dynamic vocal learning in adult marmoset monkeys
Authors: Phaniraj Nikhil , Wierucka Kaja , Burkart Judith M. 
Published: September 2023

AbstractWhile vocal learning is vital to language acquisition in children, adults continue to adjust their speech while adapting to different social environments in the form of social vocal accommodation (SVA). Even though adult and infant vocal learning seemingly differ in their properties, whether the mechanisms underlying them differ remains unknown. The complex structure of language creates a challenge in quantifying vocal changes during SVA. Consequently, animals with simpler vocal communication systems are powerful tools for understanding the mechanisms underlying SVA. Here, we tracked acoustic changes in the vocalizations of adult common marmoset pairs, a highly vocal primate species known to show SVA, for up to 85 days after pairing with a new partner. We identified four properties of SVA in marmosets: (1) bidirectional learning, (2) exponential decrease in vocal distance with time, (3) sensitivity to initial vocal distance, and (4) dyadic acoustic feature synchrony. We developed a mathematical model that shows all four properties. The model suggests that marmosets continuously update the memory of their partners’ vocalizations and modify their own vocalizations to match them, a dynamic form of vocal learning. The model provides crucial insights into the mechanisms underlying SVA in adult animals and how they might differ from infant vocal learning.
Do not let the beginning trap you! On inhibition, associative creative chains, and Hopfield neural networks
Authors: Mtenga Ronald , Bode Mathias , Khalil Radwa 
Published: September 2023

AbstractCreative thinking stems from the cognitive process that fosters new ideas and problem-solving solutions. Creative cognition in emerging artificial intelligence systems and neural models may reduce complexity in understanding creative cognition. Hopfield Neural Networks (HNN) is a simple neural model known for its biological plausibility to store and retrieve neuron patterns. The primary objective is to demonstrate that ideas, symbolized as patterns of ones and zeros representing clusters of neurons that synchronize their firing, can be stored within HNN and establish connections through correlation. The network can converge towards these ideas by manually adjusting specific state parameters, effectively controlling the overall network activity. When the second closest stored pattern deviated significantly from the input pattern, the network’s ability to converge decreased, enabling it to connect the input and patterns. Thus, we suggest employing HNN for the first time to create a model that emulates creative thinking processes, including making meaningful links between seemingly unrelated ideas.We implemented certain modifications to the original HNN, including introducing pattern weight control, which provides a robust representation for content addressable memory and illustrates conceptual links in stored data, a step towards the larger framework of creativity. We have made progress in identifying two mechanisms that could assist in managing the dynamics of the network and the formation of associative links. These mechanisms are related to the activation threshold of the neurons and the inhibitory stimulus on the stored patterns.
Automatic monitoring of whole-body neural activity in behavingHydra
Authors: Hanson Alison , Reme Raphael , Telerman Noah , Yamamoto Wataru , Olivo-Marin Jean-Christophe , Lagache Thibault , Yuste Rafael 
Published: September 2023

AbstractThe ability to record every spike from every neuron in a behaving animal is one of the holy grails of neuroscience. Here, we report coming one step closer towards this goal with the development of an end-to-end pipeline that automatically tracks and extracts calcium signals from individual neurons in the cnidarianHydra vulgaris. We imaged dually labeled (nuclear tdTomato and cytoplasmic GCaMP7s) transgenicHydraand developed an open-source Python platform (TraSE-IN) for the Tracking and Spike Estimation of Individual Neurons in the animal during behavior. The TraSE-IN platform comprises a series of modules that segments and tracks each nucleus over time and extracts the corresponding calcium activity in the GCaMP channel. Another series of signal processing modules allows robust prediction of individual spikes from each neuron’s calcium signal. This complete pipeline will facilitate the automatic generation and analysis of large-scale datasets of single-cell resolution neural activity inHydra, and potentially other model organisms, paving the way towards deciphering the neural code of an entire animal.
Sortilin inhibition treats multiple neurodegenerative lysosomal storage disorders
Authors: Leppert Hannah G. , Anderson Joelle T. , Timm Kaylie J. , Davoli Cristina , Pratt Melissa A. , Booth Clarissa D. , White Katherine A. , Rechtzigel Mitchell J. , Meyerink Brandon L. , Johnson Tyler B. , Brudvig Jon J. , Weimer Jill M. 
Published: September 2023

AbstractLysosomal storage disorders (LSDs) are a genetically and clinically diverse group of diseases characterized by lysosomal dysfunction. Batten disease is a family of severe LSDs primarily impacting the central nervous system. Here we show that AF38469, a small molecule inhibitor of sortilin, improves lysosomal and glial pathology across multiple LSD models. Live-cell imaging and comparative transcriptomics demonstrates that the transcription factor EB (TFEB), an upstream regulator of lysosomal biogenesis, is activated upon treatment with AF38469. Utilizing CLN2 and CLN3 Batten disease mouse models, we performed a short-term efficacy study and show that treatment with AF38469 prevents the accumulation of lysosomal storage material and the development of neuroinflammation, key disease associated pathologies. Tremor phenotypes, an early behavioral phenotype in the CLN2 disease model, were also completely rescued. These findings reveal sortilin inhibition as a novel and highly efficacious therapeutic modality for the treatment of multiple forms of Batten disease.
Rebound activation of 5-HT neurons following SSRI discontinuation
Authors: Collins Helen M. , Gullino L. Sophie , Ozdemir Dersu , Lazarenco Caroline , Sudarikova Yulia , Daly Elizabeth , Cuéllar Fuencisla Pilar , Pinacho Raquel , Bannerman David M. , Sharp Trevor 
Published: September 2023

AbstractCessation of therapy with a selective serotonin (5-HT) reuptake inhibitor (SSRI) is often associated with an early onset, disabling discontinuation syndrome the mechanism of which is surprisingly little investigated. Here we determined the effect on 5-HT neurochemistry of discontinuation from the SSRI paroxetine. Paroxetine was administered repeatedly to mice (once daily, 12 days versus saline controls) and then either continued or discontinued for up to 5 days. Whereas tissue levels of 5-HT and/or its metabolite 5-HIAA tended to decrease during continuous paroxetine, levels increased above controls after discontinuation, notably in hippocampus. In microdialysis experiments continuous paroxetine elevated hippocampal extracellular 5-HT and this effect fell to saline control levels on discontinuation. However, depolarisation (high potassium)-evoked 5-HT release was reduced by continuous paroxetine but increased above controls post-discontinuation. Extracellular hippocampal 5-HIAA also decreased during continuous paroxetine and increased above controls post-discontinuation. Next, immunohistochemistry experiments found that paroxetine discontinuation increased Fos expression in midbrain 5-HT neurons, adding further evidence for a hyperexcitable 5-HT system. The latter effect was recapitulated by 5-HT1Areceptor antagonist administration although gene expression analysis could not confirm altered expression of 5-HT1Aautoreceptors following paroxetine discontinuation. Finally, in behavioural experiments paroxetine discontinuation increased anxiety-like behaviour, which partially correlated in time with the measures of increased 5-HT function. In summary, this study finds that SSRI discontinuation triggers a rebound activation of 5-HT neurons across a range of experiments. This effect is reminiscent of neural changes associated with various psychotropic drug withdrawal states, suggesting a common unifying mechanism.