bluuebunny/crossref_metadata_2025_split huggingface dataset:
Potential role of microRNAs in regulating transcriptional profile, and sculpting development and metabolism in cavefish
Authors: Biswas Tathagata , Hassan Huzaifa , Rohner Nicolas 
Published: February 2024

AbstractAstyanax mexicanus, a species with both surface-dwelling and multiple cave-dwelling populations, offers a unique opportunity to study repeated adaptation to dark and resource-scarce environments. While previous work has identified large-scale changes in gene expression between morphs even under identical laboratory conditions, the regulatory basis of these expression differences remains largely unexplored. In this study, we focus on microRNAs (miRNAs) as key regulators of gene expression to understand cavefish adaptation nuances. Our analysis identified 683 miRNAs, which not only surpasses the number documented in related species but also provides the first comprehensive catalog of miRNAs for this species. We identified a unique subset of differentially expressed miRNAs common to all studied cave-dwelling populations, potentially orchestrating the nuanced gene expression patterns required for survival in the challenging cave milieu. Gene Ontology analysis of the predicted miRNA targets revealed involvement in developmental and metabolic pathways that are pivotal for thriving in nutrient-limited environments, such as the regulation of neuromast migration. Moreover, our study provides evidence for miRNA influence on circadian rhythm and oxidative stress response, both essential adaptations for the cave-dwelling lifestyle. The comprehensive miRNA catalog generated will guide future investigations into the intricate world of miRNA-mediated evolution of complex traits.
Perceptual and cognitive effects of focal tDCS of auditory cortex in tinnitus
Authors: Leaver Amber M. 
Published: February 2024

ABSTRACTOBJECTIVESNoninvasive brain stimulation continues to grow as an effective, low-risk way of improving the symptoms of brain conditions. Transcranial direct current stimulation (tDCS) is particularly well-tolerated, with benefits including low cost and potential portability. Nevertheless, continued study of perceptual and cognitive side effects is warranted, given the complexity of functional brain organization. This paper describes the results of a brief battery of tablet-based tasks used in a recent pilot study of auditory-cortex tDCS in people with chronic tinnitus.METHODSVolunteers with chronic tinnitus (n=20) completed two hearing tasks (pure-tone thresholds, Words In Noise) and two cognitive tasks (Flanker, Dimension Change Card Sort) from the NIH Toolbox. Volunteers were randomized to active or sham 4×1 Ag/AgCl tDCS of auditory cortex, and tasks were completed immediately before and after the first tDCS session, and after the fifth/final tDCS session. Statistics included linear mixed-effects models for change in task performance over time.RESULTSBefore tDCS, performance on both auditory tasks was highly correlated with clinical audiometry, supporting the external validity of these measures (r2>0.89 for all). Although overall auditory task performance did not change after active or sham tDCS, detection of right-ear Words in Noise stimuli modestly improved after five active tDCS sessions (t(34)=-2.07, p=0.05). On cognitive tasks, reaction times were quicker after sham tDCS, reflecting expected practice effects (e.g., t(88)=3.22, p=0.002 after 5 sessions on Flanker task). However, reaction times did not improve over repeated sessions in the active group, suggesting that tDCS interfered with learning these practice effects.CONCLUSIONSRepeated sessions of auditory-cortex tDCS does not appear to adversely affect hearing or cognition, but may modestly improve hearing in noisy environments and interfere with some types of motor learning. Low-burden cognitive/perceptual test batteries could be a powerful way to identify adverse effects and new treatment targets in brain stimulation research.
Calcium-driven In Silico Inactivation of a Human Olfactory Receptor
Authors: Pirona Lorenza , Ballabio Federico , Alfonso-Prieto Mercedes , Capelli Riccardo 
Published: February 2024

AbstractConformational changes as well as molecular determinants related to the activation and inactivation of olfactory receptors are still poorly understood due to the intrinsic difficulties in the structural determination of this GPCR family. Here, we perform, for the first time, thein silicoinactivation of the human olfactory receptor OR51E2, highlighting the possible role of calcium in this receptor state transition. Using molecular dynamics simulations, we show that a divalent ion in the ion binding site, coordinated by two acidic residues at positions 2.50 and 3.39 conserved across most ORs, stabilizes the receptor in its inactive state. In contrast, protonation of the same two acidic residues is not sufficient to drive inactivation within theµs timescale of our simulations. Our findings suggest a novel molecular mechanism for OR inactivation, potentially guiding experimental validation and offering insights into the possible broader role of divalent ions in GPCR signaling.
Assessing computational predictions of antimicrobial resistance phenotypes from microbial genomes
Authors: Hu Kaixin , Meyer Fernando , Deng Zhi-Luo , Asgari Ehsaneddin , Kuo Tzu-Hao , Münch Philipp C. , McHardy Alice C. 
Published: February 2024

AbstractThe advent of rapid whole-genome sequencing has created new opportunities for computational prediction of antimicrobial resistance (AMR) phenotypes from genomic data. Both rule-based and machine learning (ML) approaches have been explored for this task, but systematic benchmarking is still needed. Here, we evaluated four state-of-the-art ML methods (Kover, PhenotypeSeeker, Seq2Geno2Pheno, and Aytan-Aktug), an ML baseline, and the rule-based ResFinder by training and testing each of them across 78 species–antibiotic datasets, using a rigorous benchmarking workflow that integrates three evaluation approaches, each paired with three distinct sample splitting methods. Our analysis revealed considerable variation in the performance across techniques and datasets. Whereas ML methods generally excelled for closely related strains, ResFinder excelled for handling divergent genomes. Overall, Kover most frequently ranked top among the ML approaches, followed by PhenotypeSeeker and Seq2Geno2Pheno. AMR phenotypes for antibiotic classes such as macrolides and sulfonamides were predicted with the highest accuracies. The quality of predictions varied substantially across species–antibiotic combinations, particularly for beta-lactams; across species, resistance phenotyping of the beta-lactams compound, aztreonam, amox-clav, cefoxitin, ceftazidime, and piperacillin/tazobactam, alongside tetracyclines demonstrated more variable performance than the other benchmarked antibiotics. By organism,C. jejuniandE. faeciumphenotypes were more robustly predicted than those ofEscherichia coli,Staphylococcus aureus,Salmonella enterica,Neisseria gonorrhoeae,Klebsiella pneumoniae,Pseudomonas aeruginosa,Acinetobacter baumannii,Streptococcus pneumoniae, and Mycobacterium tuberculosis. In addition, our study provides software recommendations for each species–antibiotic combination. It furthermore highlights the need for optimization for robust clinical applications, particularly for strains that diverge substantially from those used for training.
Revision of splicing variants in theDMDgene
Authors: Davydenko Kseniya , Filatova Alexandra , Skoblov Mikhail 
Published: February 2024

AbstractBackgroundPathogenic variants in the dystrophin (DMD) gene lead to X-linked recessive Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). Nucleotide variants that affect splicing are a known cause of hereditary diseases. However, their representation in the public genomic variation databases is limited due to the low accuracy of their interpretation, especially if they are located within exons. The analysis of splicing variants in theDMDgene is essential both for understanding the underlying molecular mechanisms of the dystrophinopathies’ pathogenesis and selecting suitable therapies for patients.ResultsUsing deepin silicomutagenesis of the entireDMDgene sequence and subsequent SpliceAI splicing predictions, we identified 7,948DMDsingle nucleotide variants that could potentially affect splicing, 863 of them were located in exons. Next, we analyzed over 1,300 disease-associatedDMDSNVs previously reported in the literature (373 exonic and 956 intronic) and intersected them with SpliceAI predictions. We predicted that ∼95% of the intronic and ∼10% of the exonic reported variants could actually affect splicing. Interestingly, the majority (75%) of patient-derived intronic variants were located in the AG-GT terminal dinucleotides of the introns, while these positions accounted for only 13% of all intronic variants predictedin silico. Of the 97 potentially spliceogenic exonic variants previously reported in patients with dystrophinopathy, we selected 38 for experimental validation. For this, we developed and tested a minigene expression system encompassing 27DMDexons. The results showed that 35 (19 missense, 9 synonymous, and 7 nonsense) of the 38DMDexonic variants tested actually disrupted splicing. We compared the observed consequences of splicing changes between variants leading to severe Duchenne and milder Becker muscular dystrophy and showed a significant difference in their distribution. This finding provides extended insights into relations between molecular consequences of splicing variants and the clinical features.ConclusionsOur comprehensive bioinformatics analysis, combined with experimental validation, improves the interpretation of splicing variants in theDMDgene. The new insights into the molecular mechanisms of pathogenicity of exonic single nucleotide variants contribute to a better understanding of the clinical features observed in patients with Duchenne and Becker muscular dystrophy.
Mechanically Tunable, Compostable, Healable and Scalable Engineered Living Materials
Authors: Manjula-Basavanna Avinash , Duraj-Thatte Anna M. , Joshi Neel S. 
Published: February 2024

AbstractNovel design strategies are essential to realize the full potential of Engineered Living Materials (ELMs), including their biodegradability, manufacturability, sustainability, and ability to tailor functional properties. Toward these goals, we presentMechanicallyEngineered Living Material withCompostability,Healability, andScalability (MECHS) – a material that integrates these features in the form of a stretchable plastic that is simultaneously flushable, compostable, and exhibits the characteristics of paper. This plastic/paper-like material is produced directly from cultured bacterial biomass (40%) producing engineered curli protein nanofibers in scalable quantities (0.5-1 g L-1). The elongation at break (1-160%) and Young’s modulus (6-450 MPa) of MECHS was tuned to more than two orders of magnitude. By genetically encoded covalent crosslinking of curli nanofibers, we increase the Young’s modulus by two times. MECHS biodegrades completely in 15-75 days, while its mechanical properties are comparable to petrochemical plastics and thus may find use as compostable materials for primary packaging.
Depth-dependent scaling of axial distances in light microscopy
Authors: Loginov S.V. , Boltje D.B. , Hensgens M.N.F. , Hoogenboom J.P. , van der Wee E.B. 
Published: February 2024

AbstractIn volume fluorescence microscopy, refractive index matching is essential to minimize aberrations. There are however, common imaging scenarios, where a refractive index mismatch (RIM) between immersion and sample medium cannot be avoided. This RIM leads to an axial deformation in the acquired image data. Over the years, different axial scaling factors have been proposed to correct for this deformation. While some reports have suggested adepth-dependentaxial deformation, so far none of the scaling theories has accounted for a depth-dependent, non-linear scaling. Here, we derive an analytical theory based on determining the leading constructive interference band in the objective lens pupil under RIM. We then use this to calculate a depth-dependent re-scaling factor as a function of the numerical aperture (NA), the refractive indicesn1andn2, and the wavelengthλ. We compare our theoretical results with wave-optics calculations and experimental results obtained using a novel measurement scheme for different values of NA and RIM. As a benchmark, we recorded multiple datasets in different RIM conditions, and corrected these using our depth-dependent axial scaling theory. Finally, we present an online web applet that visualizes the depth-dependent axial re-scaling for specific optical setups. In addition, we provide software which will help microscopists to correctly re-scale the axial dimension in their imaging data when working under RIM.
Manipulation of the Nuclear Envelope-Associated Protein SLAP During Mammalian Brain Development Affects Cortical Lamination and Exploratory Behavior
Authors: Mestres Ivan , Atabay Azra , Escolano Joan-Carles , Arndt Solveig , Schmidtke Klara , Einsiedel Maximilian , Patsonis Melina , Castro Lizbeth Airais Bolanos , Yun Maximina , Bernhardt Nadine , Taubenberger Anna , Calegari Federico 
Published: February 2024

ABSTRACTHere we report the first characterization of the effects resulting from the manipulation of Soluble-Lamin Associated Protein (SLAP) expression during mammalian brain development. We found that SLAP localizes to the nuclear envelope and when overexpressed causes changes in nuclear morphology and lengthening of mitosis. SLAP overexpression in apical progenitors of the developing mouse brain altered asymmetric cell division, neurogenic commitment and neuronal migration ultimately resulting in unbalance in the proportion of upper, relative to deeper, neuronal layers. Several of these effects were also recapitulated upon Cas9-mediated knock-down. Ultimately, SLAP overexpression during development resulted in a reduction in subcortical projections of young mice and, notably, reduced their exploratory behavior. Our study shows the potential relevance of the previously uncharacterized nuclear envelope protein SLAP in neurodevelopmental disorders.
Distributional shifts change the biodiversity–ecosystem stability relationship under climate change
Authors: Kanamori Yuki , Nishijima Shota , Misawa Ryo , Seto Takashi , Narimatsu Yoji 
Published: February 2024

AbstractDistributional shifts under climate change are increasingly recognized as a biotic change worldwide. However, the effects of distributional shifts on ecosystem variability through changes in biodiversity remain to be clariﬁed. In this study, to elucidate the impact of population-level distributional shifts under climate change on community structure and ecosystem function through ecological hierarchy, we investigated the temporal changes in alpha and beta diversity, the contribution of individual species to the observed changes in biodiversity, and the changes in the relationship between biodiversity and ecosystem variability, using over 25 years of data on about 700 species. We found that ecosystem variability was largely stabilized by beta diversity, especially in the present period (2012 to 2021), because beta diversity increased due to the invasion of species that were distributed mainly in tropic and subtropic areas. Despite the effect of beta diversity, ecosystem variability increased in the present period. This increase in ecosystem variability was caused by the spatially synchronized temporal variation in sea-bottom temperature, which resulted in synchronized temporal variation in species abundance among local communities, as well as the increased impact of alpha variability on ecosystem variability. These results indicate that the impact of alpha diversity on ecosystem variability is more changeable than the impact of beta diversity on ecosystem variability under climate change, suggesting the importance of focusing on changes in alpha diversity resulting from local colonization from other habitats and local extinction in existing habitats.
The domesticated transposon protein L1TD1 associates with its ancestor L1 ORF1p to promote LINE-1 retrotransposition
Authors: Kavaklıoğlu Gülnihal , Podhornik Alexandra , Vcelkova Terezia , Marjanovic Jelena , Beck Mirjam A. , Phan-Canh Trinh , Mair Theresia , Miccolo Claudia , Drino Aleksej , Doni Mirko , Egger Gerda , Chiocca Susanna , Modic Miha , Seiser Christian 
Published: February 2024

ABSTRACTRepression of retrotransposition is crucial for the successful fitness of a mammalian organism. The domesticated transposon protein L1TD1, derived from LINE-1 (L1) ORF1p, is an RNA-binding protein that is expressed only in some cancers and early embryogenesis. In human embryonic stem cells, it is found to be essential for maintaining pluripotency. In cancer, L1TD1 expression is highly correlative with malignancy progression and as such considered a potential prognostic factor for tumors. However, its molecular role in cancer remains largely unknown. Our findings reveal that DNA hypomethylation induces the expression of L1TD1 in HAP1 human tumor cells. L1TD1 depletion significantly modulates both the proteome and transcriptome and thereby reduces cell viability. Notably, L1TD1 associates with L1 transcripts and interacts with L1 ORF1p protein, thereby facilitating L1 retrotransposition. Our data suggest that L1TD1 collaborates with its ancestral L1 ORF1p as an RNA chaperone, ensuring the efficient retrotransposition of L1 retrotransposons, rather than directly impacting the abundance of L1TD1 targets. In this way, L1TD1 might have an important role not only during early development but also in tumorigenesis.
Global Release of Translational Repression AcrossPlasmodium’sHost-to-Vector Transmission Event
Authors: Rios Kelly T. , McGee James P. , Sebastian Aswathy , Moritz Robert L. , Feric Marina , Absalon Sabrina , Swearingen Kristian E. , Lindner Scott E. 
Published: February 2024

AbstractMalaria parasites must be able to respond quickly to changes in their environment, including during their transmission between mammalian hosts and mosquito vectors. Therefore, before transmission, female gametocytes proactively produce and translationally repress mRNAs that encode essential proteins that the zygote requires to establish a new infection. This essential regulatory control requires the orthologues of DDX6 (DOZI), LSM14a (CITH), and ALBA proteins to form a translationally repressive complex in female gametocytes that associates with many of the affected mRNAs. However, while the release of translational repression of individual mRNAs has been documented, the details of the global release of translational repression have not. Moreover, the changes in spatial arrangement and composition of the DOZI/CITH/ALBA complex that contribute to translational control are also not known.Therefore, we have conducted the first quantitative, comparative transcriptomics and DIA-MS proteomics ofPlasmodiumparasites across the host-to-vector transmission event to document the global release of translational repression. Using female gametocytes and zygotes ofP. yoelii, we found that nearly 200 transcripts are released for translation soon after fertilization, including those with essential functions for the zygote. However, we also observed that some transcripts remain repressed beyond this point. In addition, we have used TurboID-based proximity proteomics to interrogate the spatial and compositional changes in the DOZI/CITH/ALBA complex across this transmission event. Consistent with recent models of translational control, proteins that associate with either the 5’ or 3’ end of mRNAs are in close proximity to one another during translational repression in female gametocytes and then dissociate upon release of repression in zygotes. This observation is cross-validated for several protein colocalizations in female gametocytes via ultrastructure expansion microscopy and structured illumination microscopy. Moreover, DOZI exchanges its interaction from NOT1-G in female gametocytes to the canonical NOT1 in zygotes, providing a model for a trigger for the release of mRNAs from DOZI. Finally, unenriched phosphoproteomics revealed the modification of key translational control proteins in the zygote. Together, these data provide a model for the essential translational control mechanisms used by malaria parasites to promote their efficient transmission from their mammalian host to their mosquito vector.
Topology-informed regulatory element collections coordinate cell identity gene expression programs
Authors: Lv Jie , Maher Kelsey A. , Veluchamy Alaguraj , Kim Yuna , Dong Li , Ju Bensheng , Valentine Virginia , Valentine Marc , Burden Steven , Easton John , Pounds Stanley B. , Abraham Brian J 
Published: February 2024

ABSTRACTCis-regulatory elements (CREs) contact target genes to regulate their transcription, but CRE interactions are complex and predicting their function is challenging. Contemporary approaches to predict CRE targets generally assume one-to-one associations and linear genomic proximity. These methods fail to account for long-range CRE contacts caused by folding of the genome, for circumstances in which a single CRE regulates multiple genes, or, conversely, when a single gene is regulated by multiple CREs. To address these challenges and investigate three-dimensional (3D) CRE communities, we developed BOUQUET, an integrative, graph-theory-based approach that uses multiple aspects of genome topology to probe communities of CREs, their bound apparatus, and their target genes. Using this approach, we uncover communities of CREs that are undetectable by existing unbiased methods, such as those with interactions that span insulating loop boundaries, and regulatory communities that comprise clustered promoter elements. A subset of these communities, which we term “3D super-enhancer CRE communities” (3DSE CRE communities), accrues exceptional amounts of regulatory apparatus at cell identity-defining genes and evolves the super-enhancer concept. In imaging assays, we observe co-localization and co-expression of in-community genes within puncta of transcriptional co-factors, consistent with microcompartment biology. Genome-wide, pairs of genes within the same 3D CRE community are co-expressed in single cells, and pairs of CREs are co-accessible, suggesting both chromatin activity and transcription within a topologically defined community is coordinated. Our model more accurately reflects the complexity of CRE interaction networks, underscores the need for approaches that incorporate spatial organization in the study of enhancer biology, and provides a framework for the reinterpretation of SEs, their condensates, and their target genes through the lens of 3D chromatin structure.