bluuebunny/crossref_metadata_2025_split huggingface dataset:
An in-silico approach to identify bioactive phytochemicals fromHouttuynia cordataThunb. As potential inhibitors of Human Glutathione Reductase
Authors: Sangeet Satyam , Khan Arshad 
Published: August 2023

AbstractCellular infections underpin the pathogenesis of cancer and malaria. Mitigating cellular oxidative stress via glutathione reductase (GR) inhibition emerges as a promising therapeutic avenue. Exploiting the antioxidant-richHouttuynia cordataThunb., we investigated natural GR inhibitors. Among 13 docked phytochemicals, Quercetin, Quercitrin, and Sesamin exhibited exceptional GR binding affinities. Molecular Docking analysis highlighted their propensity to precisely target the GR active site. Subsequent 150 ns molecular dynamics simulations corroborated their robust interactions, unveiling dynamic stabilizing effects on the protein structure and bolstering their antioxidant potential. Furthermore, ADME-Tox profiling affirmed their favourable drug-like attributes. These findings underscoreH. cordata’sreservoir of potent antioxidants, poised to combat various maladies, including malaria and cancer. This study distinctly accentuates the distinctive outcomes and paramount significance of harnessingH. cordataphytochemicals as efficacious antioxidants, unravelling novel therapeutic avenues.
Breakups and Hookups: a Markov model for karyotype evolution
Authors: Setter Derek 
Published: August 2023

AbstractChromosome rearrangements represent a prominent form of genetic variation that plays a key role in creating genetic isolation between emergent species. Despite their significance, the mechanisms and constraints governing chromosome evolution remain poorly understood. Relatively few species have karyotypes with very high chromosome counts, and the chromosome sizes of most species tend to be narrowly distributed around the mean length. Here, we develop and analyze a Markov model for the evolution of chromosome number and relative sizes through fission and fusion events, exploring several alternative models for the dynamics of each as well as the effect of enforcing limits on chromosome length. We compare the distribution of chromosome lengths predicted by the Markov model to karyotype data for a range of Eukaryote species to identify the best-fitting fission/fusion dynamics. We find broad support for a model which (i) favours the breaking of long chromosomes, (ii) favours the fusion of pairs of small chromosomes, and (iii) does not require size limitations to provide a good fit to the data. However, there are exceptions. On the one hand, species with micro chromosomes fit best to models with more uniform rates of fission and/or fusion. On the other hand, many species have chromosome sizes that are much more narrowly distributed than our models predict, suggesting the need to explore alternative dynamics and/or limitations to chromosome lengths.
Chemogenetic silencing of NaV1.8 positive sensory neurons reverses chronic neuropathic and bone cancer pain in FLEx PSAM4-GlyR mice
Authors: Haroun Rayan , Gossage Samuel J , Luiz Ana Paula , Arcangeletti Manuel , Sikandar Shafaq , Cox James J , Zhao Jing , Wood John N 
Published: August 2023

AbstractDrive from peripheral neurons is essential in almost all pain states, but pharmacological silencing of these neurons to effect analgesia has proved problematic. Reversible gene therapy using long-lived chemogenetic approaches is an appealing option. We used the genetically-activated chloride channel PSAM4-GlyR to examine pain pathways in mice. Using recombinant AAV9-based delivery to sensory neurons, we found a reversal of acute pain behavior and diminished neuronal activity usingin vitroandin vivoGCaMP imaging upon activation of PSAM4-GlyR with varenicline. A significant reduction in inflammatory heat hyperalgesia and oxaliplatin-induced cold allodynia was also observed. Importantly, there was no impairment of motor coordination, but innocuous von Frey sensation was inhibited. We generated a transgenic mouse that expresses a CAG-driven FLExed PSAM4-GlyR downstream of theRosa26locus that requires Cre recombinase to enable the expression of PSAM4-GlyR and tdTomato. We used NaV1.8 Cre to examine the role of predominantly nociceptive NaV1.8+ neurons in cancer-induced bone pain (CIBP) and neuropathic pain caused by chronic constriction injury (CCI). Varenicline activation of PSAM4-GlyR in NaV1.8-positive neurons reversed CCI-driven mechanical, thermal, and cold sensitivity. Additionally, varenicline treatment of mice with CIBP expressing PSAM4-GlyR in NaV1.8+ sensory neurons reversed cancer pain as assessed by weight-bearing. Moreover, when these mice were subjected to acute pain assays, an elevation in withdrawal thresholds to noxious mechanical and thermal stimuli was detected, but innocuous mechanical sensations remained unaffected. These studies confirm the utility of PSAM4-GlyR chemogenetic silencing in chronic pain states for mechanistic analysis and potential future therapeutic use.Significance statementChronic pain is a massive problem. Peripheral nerve block is effective in many chronic pain conditions, demonstrating the importance of peripheral drive in chronic pain. We used chemogenetic tools based on the modified ligand-gated chloride channel PSAM4-GlyR to silence dorsal root ganglion neuronsin vitroandin vivo. This approach reduces pain-like behavior in acute and chronic pain models, including resistant pain conditions like neuropathic pain or cancer-induced bone pain. We generated a mouse line that expresses PSAM4-GlyR in a Cre-dependent manner, providing a useful research tool to address not only the role of nociceptive sensory neurons in pain states but also the function of genetically defined sets of neurons throughout the nervous system in normal and pathological conditions.
Analyzing heterogeneity in Alzheimer Disease using multimodal normative modeling on imaging-based ATN biomarkers
Authors: Kumar Sayantan , Earnest Tom , Yang Braden , Kothapalli Deydeep , Aschenbrenner Andrew J. , Hassenstab Jason , Xiong Chengie , Ances Beau , Morris John , Benzinger Tammie L. S. , Gordon Brian A. , Payne Philip , Sotiras Aristeidis ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: August 2023

Structured AbstractINTRODUCTIONPrevious studies have applied normative modeling on a single neuroimaging modality to investigate Alzheimer Disease (AD) heterogeneity. We employed a deep learning-based multimodal normative framework to analyze individual-level variation across ATN (amyloid-tau-neurodegeneration) imaging biomarkers.METHODSWe selected cross-sectional discovery (n = 665) and replication cohorts (n = 430) with available T1-weighted MRI, amyloid and tau PET. Normative modeling estimated individual-level abnormal deviations in amyloid-positive individuals compared to amyloid-negative controls. Regional abnormality patterns were mapped at different clinical group levels to assess intra-group heterogeneity. An individual-level disease severity index (DSI) was calculated using both the spatial extent and magnitude of abnormal deviations across ATN.RESULTSGreater intra-group heterogeneity in ATN abnormality patterns was observed in more severe clinical stages of AD. Higher DSI was associated with worse cognitive function and increased risk of disease progression.DISCUSSIONSubject-specific abnormality maps across ATN reveal the heterogeneous impact of AD on the brain.
An eQTL-based Approach Reveals Candidate Regulators of LINE-1 RNA Levels in Lymphoblastoid Cells
Authors: Bravo Juan I. , Mizrahi Chanelle R. , Kim Seungsoo , Zhang Lucia , Suh Yousin , Benayoun Bérénice A. 
Published: August 2023

AbstractLong interspersed element 1 (L1) are a family of autonomous, actively mobile transposons that occupy ∼17% of the human genome. A number of pleiotropic effects induced by L1 (promoting genome instability, inflammation, or cellular senescence) have been observed, and L1’s contributions to aging and aging diseases is an area of active research. However, because of the cell type-specific nature of transposon control, the catalogue of L1 regulators remains incomplete. Here, we employ an eQTL approach leveraging transcriptomic and genomic data from the GEUVADIS and 1000Genomes projects to computationally identify new candidate regulators of L1 RNA levels in lymphoblastoid cell lines. To cement the role of candidate genes in L1 regulation, we experimentally modulate the levels of top candidatesin vitro, includingIL16, STARD5, HSDB17B12,andRNF5, and assess changes in TE family expression by Gene Set Enrichment Analysis (GSEA). Remarkably, we observe subtle but widespread upregulation of TE family expression followingIL16andSTARD5overexpression. Moreover, a short-term 24-hour exposure to recombinant human IL16 was sufficient to transiently induce subtle, but widespread, upregulation ofL1subfamilies. Finally, we find that many L1 expression-associated genetic variants are co-associated with aging traits across genome-wide association study databases. Our results expand the catalogue of genes implicated in L1 RNA control and further suggest that L1-derived RNA contributes to aging processes. Given the ever-increasing availability of paired genomic and transcriptomic data, we anticipate this new approach to be a starting point for more comprehensive computational scans for transposon transcriptional regulators.
The 3’ exonuclease TOE1 selectively processes snRNAs through recognition of Sm complex assembly and 5’ cap trimethylation
Authors: Ma Tiantai , Xiong Erica S , Lardelli Rea M , Lykke-Andersen Jens 
Published: August 2023

SummaryCompeting exonucleases that promote 3’ end maturation or degradation direct quality control of small non-coding RNAs, but how these enzymes distinguish normal from aberrant RNAs is poorly understood. The Pontocerebellar Hypoplasia 7 (PCH7)-associated 3’ exonuclease TOE1 promotes maturation of canonical small nuclear RNAs (snRNAs). Here, we demonstrate that TOE1 achieves specificity towards canonical snRNAs by recognizing Sm complex assembly and cap trimethylation, two features that distinguish snRNAs undergoing correct biogenesis from other small non-coding RNAs. Indeed, disruption of Sm complex assembly via snRNA mutations or protein depletions obstructs snRNA processing by TOE1, and in vitro snRNA processing by TOE1 is stimulated by a trimethylated cap. An unstable snRNA variant that normally fails to undergo maturation becomes fully processed by TOE1 when its degenerate Sm binding motif is converted into a canonical one. Our findings uncover the molecular basis for how TOE1 distinguishes snRNAs from other small non-coding RNAs and explain how TOE1 promotes maturation specifically of canonical snRNAs undergoing proper processing.
Deciphering Salt Stress Responses inSolanum pimpinellifoliumthrough High-Throughput Phenotyping
Authors: Morton Mitchell , Fiene Gabriele , Ahmed Hanin Ibrahim , Rey Elodie , Abrouk Michael , Angel Yoseline , Johansen Kasper , Saber Noha O. , Malbeteau Yoann , Al-Mashharawi Samir , Ziliani Matteo G. , Aragon Bruno , Oakey Helena , Berger Bettina , Brien Chris , Krattinger Simon G. , Mousa Magdi A.A. , McCabe Matthew F. , Negrão Sónia , Tester Mark , Julkowska Magdalena M. 
Published: August 2023

AbstractSoil salinity is a major environmental stressor affecting agricultural productivity worldwide. Understanding plant responses to salt stress is crucial for developing resilient crop varieties. Wild relatives of cultivated crops, such as wild tomato,Solanum pimpinellifolium, can serve as a useful resource to further expand the resilience potential of the cultivated germplasm,S. lycopersicum. In this study, we employed high-throughput phenotyping in the greenhouse and field conditions to explore salt stress responses of aS. pimpinellifoliumdiversity panel. Our study revealed extensive phenotypic variations in response to salt stress, with traits such as transpiration rate, shoot mass, and ion accumulation showing significant correlations with plant performance. We found that while transpiration was a key determinant of plant performance in the greenhouse, shoot mass strongly correlated with yield under field conditions. Conversely, ion accumulation was the least influential factor under greenhouse conditions. Through a Genome Wide Association Study, we identified candidate genes not previously associated with salt stress, highlighting the power of high-throughput phenotyping in uncovering novel aspects of plant stress responses. This study contributes to our understanding of salt stress tolerance inS. pimpinellifoliumand lays the groundwork for further investigations into the genetic basis of these traits, ultimately informing breeding efforts for salinity tolerance in tomato and other crops.
Decoding reveals the neural representation of perceived and imagined musical sounds
Authors: Quiroga Martinez David R. , Rubio Gemma Fernández , Bonetti Leonardo , Achyutuni Kriti G. , Tzovara Athina , Knight Robert T. , Vuust Peter 
Published: August 2023

AbstractVividly imagining a song or a melody is a skill that many people accomplish with relatively little effort. However, we are only beginning to understand how the brain represents, holds, and manipulates these musical “thoughts”. Here, we decoded perceived and imagined melodies from magnetoencephalography (MEG) brain data (N = 71) to characterize their neural representation. We found that, during perception, auditory regions represent the sensory properties of individual sounds. In contrast, a widespread network including fronto-parietal cortex, hippocampus, basal nuclei, and sensorimotor regions hold the melody as an abstract unit during both perception and imagination. Furthermore, the mental manipulation of a melody systematically changes its neural representation, reflecting volitional control of auditory images. Our work sheds light on the nature and dynamics of auditory representations, informing future research on neural decoding of auditory imagination.
Sulfasalazine promotes myogenic differentiation via increasing of fast myosin heavy chain isoforms
Authors: Cho Seungju , Choi Seonggyu , Chang Hyunjun , Tran Nguyen Khoi , Lee Hyunji , Ryu Sunyoung , Park Mihee , Choi Sangchul , Park Jisoo , Park Jongsun 
Published: August 2023

AbstractSarcopenia is a debilitating condition characterized by the progressive and generalized degeneration of skeletal muscle mass and function. As of now, there is no approved pharmacological treatment for sarcopenia. Previously, our research revealed that Yin Yang 1 (YY1) plays a crucial role in PHD finger protein 20 (PHF20)-mediated myogenic differentiation. A significant enhancement in YY1 transcription, mediated by PHF20, was observed in C2C12myoblasts. Within skeletal muscle, YY1 is traditionally considered to inhibit myogenesis by directly repressing the synthesis of late-stage differentiation genes, such as skeletal muscle actin, muscle creatine kinase, and myosin heavy chain IIb. Through screening of a drug library using a PHF20/YY1 promoter reporter assay, sulfasalazine emerged as a promising candidate. Sulfasalazine is known for its anti-inflammatory and immunomodulatory properties and is commonly prescribed for autoimmune diseases. In this study, the treatment of C2C12myoblasts with sulfasalazine accelerated the myogenic differentiation and bolstered the gene and protein expression of fast myosin heavy chain via a metabolic shift towards glycolysis. Additionally, oral administration of sulfasalazine demonstrated improvement in physical performance in aged mice, as well as in mice models with hindlimb disuse or damage. Moreover, sulfasalazine exhibited a remarkable ability to facilitate the recovery of muscle fibers damaged by Velcro immobilization. Collectively, our findings suggest that sulfasalazine could represent a novel therapeutic avenue for the amelioration of muscle weakness, including sarcopenia.
3D-Mol: A Novel Contrastive Learning Framework for Molecular Property Prediction with 3D Information
Authors: Kuang Taojie , Ren Yiming , Ren Zhixiang 
Published: August 2023

AbstractMolecular property prediction offers an effective and efficient approach for early screening and optimization of drug candidates. Although deep learning based methods have made notable progress, most existing works still do not fully utilize 3D spatial information. This can lead to a single molecular representation representing multiple actual molecules. To address these issues, we propose a novel 3D structure-based molecular modeling method named 3D-Mol. In order to accurately represent complete spatial structure, we design a novel encoder to extract 3D features by deconstructing the molecules into three geometric graphs. In addition, we use 20M unlabeled data to pretrain our model by contrastive learning. We consider conformations with the same topological structure as positive pairs and the opposites as negative pairs, while the weight is determined by the dissimilarity between the conformations. We compare 3D-Mol with various state-of-the-art(SOTA) baselines on 7 benchmarks and demonstrate our outstanding performance in 5 benchmarks.
How is sleep-disordered breathing linked with biomarkers of Alzheimer’s disease?
Authors: Akradi Mohammad , Farzane-Daghigh Tara , Ebneabbasi Amir , Bi Hanwen , Drzezga Alexander , Mander Bryce A. , Eickhoff Simon B. , Tahmasian Masoud ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: August 2023

AbstractSleep-disordered breathing (SDB) is prevalent in Alzheimer’s disease (AD). We assessed whether and how SDB affects neuroimaging biomarkers of AD, including amyloid-beta plaque burden (Aβ), regional uptake of fluorodeoxyglucose using positron emission tomography (rFDG-PET), grey matter volume (GMV), as well as cognitive scores and cerebrospinal fluid (CSF) biomarkers.MethodsWe selected 757 subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database based on cognitive status (AD, mild cognitive impairment (MCI), cognitively unimpaired (CU)), and SDB condition (with/without SDB). To ensure the reliability of our findings and considering imbalanced sample size across groups, we used a stratified subsampling approach generating 10,000 subsamples (n=10/group). We then selected 512 subsamples with matched covariates. The effect size of the cognitive status-SDB interaction was computed for each biomarker and cognitive score. For reference, we computed 1000 null models by shuffling group labels randomly. The average value of effect sizes for each biomarker in each region was estimated through bootstrapping with 10,000 iterations for both the main and null models and compared with the null model’s distribution. Linear regression models were next implemented to identify associations between the effect size on Aβ, rFDG, and GMV with the effect size on cognitive scores and CSF biomarkers across all subsamples.ResultsThe cognitive status-SDB interaction had a medium-sized effect on Aβ, rFDG and GMV biomarkers in several brain areas. The effect sizes of the mentioned interactions on Aβ plaque burden in the right precuneus, left middle temporal gyrus, and left occipital fusiform gyrus were associated with the effect sizes of the interactions on cognitive scores. Further, the interaction effect sizes on CSF Aβ42 were related to the interaction effect sizes on Aβ in the right precuneus and posterior cingulate cortex, as well as rFDG in the left precuneus cortex and GMV in bilateral angular gyrus and right occipital fusiform gyrus. Effect sizes on CSF p-tau were also correlated with the effect sizes on Aβ in the left lateral occipital cortex and GMV in the left middle temporal gyrus.ConclusionWe observed that SDB interacts with neuroimaging and CSF biomarkers of AD. Specifically, SDB has a robust association with markers of Aβ pathology in PET and CSF relative to rFDG and GMV in the AD group. The cognitive status-SDB interaction on Aβ is associated with cognitive decline. This study further supports the hypothesis that SDB may precipitate AD pathology.
Opsin gene duplication in Lepidoptera: retrotransposition, sex linkage, and gene expression
Authors: Mulhair Peter O. , Crowley Liam , Boyes Douglas H. , Lewis Owen T. , Holland Peter W.H. 
Published: August 2023

AbstractColour vision in insects is determined by signalling cascades, central to which are opsin proteins, resulting in sensitivity to light at different wavelengths. In certain insect groups, lineage specific evolution of opsin genes, in terms of copy number, shifts in expression patterns, and functional amino acid substitutions, has resulted in changes in colour vision with subsequent behavioural and niche adaptations. Lepidoptera are a fascinating model to address whether evolutionary change in opsin content and sequence evolution are associated with changes in vision phenotype. Until recently, the lack of high quality genome data representing broad sampling across the lepidopteran phylogeny has greatly limited our ability to accurately address this question. Here, we annotate opsin genes in 219 lepidopteran genomes representing 33 families, reconstruct their evolutionary history, and analyse shifts in selective pressures and expression between genes and species. We discover 44 duplication events in opsin genes across ∼300 million years of lepidopteran evolution. While many duplication events are species or family specific, we find retention of an ancient long-wavelength sensitive (LW) opsin duplication derived by retrotransposition within the speciose superfamily Noctuoidea (in the families Nolidae, Erebidae, and Noctuidae). This conserved LW retrogene shows life stage specific expression suggesting visual sensitivities or other sensory functions specific to the early larval stage. This study provides a comprehensive order-wide view of opsin evolution across Lepidoptera, showcasing high rates of opsin duplications and changes in expression patterns.
Whole genome sequencing provides novel insights into the evolutionary history and genetic adaptations of reindeer populations in northern Eurasia
Authors: Pokharel Kisun , Weldenegodguad Melak , Dudeck Stephan , Honkatukia Mervi , Lindeberg Heli , Mazzullo Nuccio , Paasivaara Antti , Peippo Jaana , Soppela Päivi , Stammler Florian , Kantanen Juha 
Published: August 2023

AbstractSemi-domestic reindeer (Rangifer tarandus tarandus) play a vital role in the culture and livelihoods of indigenous people across the northern Eurasia. These animals are well adapted to harsh environmental conditions, such as extreme cold, limited feed availability and long migration distances. Therefore, understanding the genomics of reindeer is crucial for improving their management, conservation, and utilization. Here we have generated a new genome assembly for the Fennoscandian semi-domestic reindeer with high contiguity, making it the most complete reference genome for reindeer to date. The new genome assembly was utilized to explore genetic diversity, population structure and selective sweeps in EurasianRangifer taranduspopulations which was based on the largest population genomic dataset for reindeer, encompassing 58 individuals from diverse populations. Phylogenetic analyses revealed distinct gene clusters, with the Finnish wild forest reindeer standing out as a unique sub-species. Divergence time estimates suggested a separation of ∼52,000 years ago between Northern-EuropeanRangifer tarandus fennicusandRangifer tarandus tarandus. Our study identified three main genetic clusters: Fennoscandian, the eastern/northern Russian and Alaskan group, and the Finnish forest reindeer. Furthermore, two independent reindeer domestication events were inferred suggesting separate origins for the semi-domestic Fennoscandian and eastern/northern Russian reindeer. Notably, shared genes under selection, including retroviral genes, point towards molecular domestication processes that aided adaptation of this species to diverse environments.