bluuebunny/crossref_metadata_2025_split huggingface dataset:
Repurposing efavirenz, the HIV antiretroviral drug for Chikungunya virus infection
Authors: Nehul Sanketkumar , Rani Ruchi , Panda Prasan Kumar , Kumar Pravindra , Tomar Shailly 
Published: September 2023

AbstractChikungunya virus (CHIKV) has frequently recurred in recent decades, causing outbreaks worldwide in tropical and subtropical regions. The re-emergence of CHIKV poses a substantial risk to human health as no efficacious drugs are currently available to curb new outbreaks. Here, the anti-CHIKV activity of efavirenz was investigated byin vitrocell culture-based antiviral assay, immunofluorescence assay (IFA), and quantitative reverse transcription polymerase chain reaction (qRT-PCR). Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) used for treatment of acquired immunodeficiency syndrome (AIDS), and it has good oral bioavailability, long half-life and affordable low cost. This study demonstrated dose-dependent robust anti-CHIKV activity of efavirenz at low micromolar concentration (EC50= 1.33 µM). To determine potential broad anti-alphavirus activity of efavirenz, its inhibitory activity against Sindbis virus (SINV) was detected. Interestingly, efavirenz also inhibited the replication of SINV at a low micromolar range (EC50= 0.7 µM). Time of addition assay, direct transfection of virus replicon RNA and minus-sense specific RT-PCR elucidated that efavirenz hinders the viral replication at an early stage after the virus entry by inhibiting the viral RNA synthesis. Efavirenz showed a binding affinity with purified CHIKV capsid protein (CHIKV CP) and it is known that CHIKV CP plays a novel role in the early phase of viral protein synthesis, suggesting CP might be one of the potential protein targets in addition to viral or host proteins involved in viral genome replication. The present study underscores the repurposing of efavirenz for antiviral therapy against CHIKV to curb future viral outbreaks.HighlightsIdentification ofin vitroanti-CHIKV activity of efavirenz.Efavirenz disrupts the early phase of virus replication by interfering in the CHIKV minus-sense RNA synthesis.Efavirenz and tomatidine also inhibit SINV replication indicating potential broad spectrum anti-alphavirus activity.Efavirenz holds potential as therapeutic treatment for clinical infections of Chikungunya.
Relating Ecological Diversity to Genetic Discontinuity across Bacterial Species
Authors: Passarelli-Araujo Hemanoel , Venancio Thiago M. , Hanage William P 
Published: September 2023

AbstractBacterial genetic discontinuity, representing abrupt breaks in genomic identity among species, is crucial for grasping microbial diversity and evolution. Advances in genomic sequencing have enhanced our ability to track and characterize genetic discontinuity in bacterial populations. However, exploring systematically the degree to which bacterial diversity exists as a continuum or is sorted into discrete and readily defined species remains a challenge in microbial ecology. Here, we aimed to quantify the genetic discontinuity (δ) and investigate how this metric is related to ecology. We harnessed a dataset comprising 210,129 genomes to systematically explore genetic discontinuity patterns across several distantly related species, finding clear breakpoints which varied depending on the taxa in question. By delving into pangenome characteristics, we uncovered a significant association between pangenome saturation and genetic discontinuity. Closed pangenomes were associated with more pronounced breaks, exemplified byMycobacterium tuberculosis. Additionally, through a machine learning approach, we detected key features that impact genetic discontinuity prediction. Our study enhances the understanding of bacterial genetic patterns and their ecological implications, offering insights into species boundaries for prokaryotes.
Attention-dependent coupling with forebrain and brainstem neuromodulatory nuclei changes across the lifespan
Authors: Cicero Nicholas G. , Riley Elizabeth , Swallow Khena M. , De Rosa Eve , Anderson Adam 
Published: September 2023

AbstractAttentional states continuously reflect the predictability and uncertainty in one’s environment having important consequences for learning and memory. Beyond well known cortical contributions, rapid shifts in attention are hypothesized to also originate from deep nuclei, such as the basal forebrain (BF) and locus coeruleus (LC) neuromodulatory systems. These systems are also the first to change with aging. Here we characterized the interplay between these systems and their regulation of afferent targets – the hippocampus (HPC) and posterior cingulate cortex (PCC) – across the lifespan. To examine the role of attentional salience on task-dependent functional connectivity, we used a target-distractor go/no go task presented during functional MRI. In younger adults, BF coupling with the HPC, and LC coupling with the PCC, increased with behavioral relevance (targets vs distractors). Although the strength and presence of significant regional coupling changed in middle age, the most striking change in network connectivity was in old age, such that in older adults BF and LC coupling with their cortical afferents was largely absent and replaced by stronger interconnectivity between LC-BF nuclei. Overall rapid changes in attention related to behavioral relevance revealed distinct roles of subcortical neuromodulatory systems. The pronounced changes in functional network architecture across the lifespan suggest a decrease in these distinct roles, with deafferentation of cholinergic and noradrenergic systems associated with a shift towards mutual support during attention guided to external stimuli.Significance statementChanges in attentional control across the lifespan may originate from cortical control networks or subcortical neuromodulatory systems, which are the first sites of age-related neuropathology. In young adults, we demonstrated functional coupling of the basal forebrain with the hippocampus, and locus coeruleus with the posterior cingulate cortex varies with task relevance. This coupling changed in middle age and most strikingly in older adults. In old age, task-dependent coupling between the locus coeruleus and basal forebrain was the predominant connection remaining within the observed network. Older adults exhibit reduced subcortical-cortical connectivity, consistent with a relative neuromodulatory deafferentation, replaced by subcortical-subcortical deep nuclear connectivity. This alteration in noradrenergic and cholinergic signaling has important implications for attention and memory formation and neurocognitive aging.
Adolescent oligodendrogenesis and myelination restrict experience-dependent neuronal plasticity in adult visual cortex
Authors: Xin Wendy , Kaneko Megumi , Roth Richard H. , Zhang Albert , Nocera Sonia , Ding Jun B. , Stryker Michael P. , Chan Jonah R. 
Published: September 2023

ABSTRACTBACKGROUNDDevelopmental myelination is a protracted process in the mammalian brain. One theory for why oligodendrocytes mature so slowly posits that myelination may stabilize neuronal circuits and temper neuronal plasticity as animals age. We tested this hypothesis in the visual cortex, which has a well-defined critical period for experience-dependent neuronal plasticity.OBJECTIVES/METHODSTo prevent myelin progression, we conditionally deleted Myrf, a transcription factor necessary for oligodendrocyte maturation, from oligodendrocyte precursor cells (Myrf cKO) in adolescent mice. To induce experience-dependent plasticity, adult control and Myrf cKO mice were monocularly deprived by eyelid suture. Functional and structural neuronal plasticity in the visual cortex were assessed in vivo by intrinsic signal optical imaging and longitudinal two photon imaging of dendritic spines, respectively.RESULTSDuring adolescence, visual experience modulated the rate of oligodendrocyte maturation in visual cortex. Myrf deletion from oligodendrocyte precursors during adolescence led to inhibition of oligodendrocyte maturation and myelination that persisted into adulthood. Following monocular deprivation, visual cortex activity in response to visual stimulation of the deprived eye remained stable in adult control mice, as expected for post-critical period animals. By contrast, visual cortex responses to the deprived eye decreased significantly following monocular deprivation in adult Myrf cKO mice, reminiscent of the plasticity observed in adolescent mice. Furthermore, visual cortex neurons in adult Myrf cKO mice had fewer dendritic spines and a higher level of spine turnover. Finally, monocular deprivation induced spatially coordinated spine size decreases in adult Myrf cKO, but not control, mice.CONCLUSIONSThese results demonstrate a critical role for oligodendrocytes in shaping the maturation and stabilization of cortical circuits and support the concept of myelin acting as a brake on neuronal plasticity during development.
Anin vivoDissection, and Analysis of Socio-Affective Symptoms related to Cerebellum-Midbrain Reward Circuitry in Humans
Authors: Hoffman Linda J. , Foley Julia M. , Leong Josiah K. , Sullivan-Toole Holly , Elliott Blake L. , Olson Ingrid R. 
Published: September 2023

AbstractEmerging research in non-human animals implicates cerebellar projections to the ventral tegmental area (VTA) in appetitive behaviors, but these circuits have not been characterized in humans. Here, we mapped cerebello-VTA white-matter connectivity in humans using probabilistic tractography on diffusion imaging data from the Human Connectome Project. We uncovered the topographical organization of these connections by separately tracking from parcels of cerebellar lobule VI, crus I/II, vermis, paravermis, and cerebrocerebellum. Results revealed that connections from the cerebellum to the VTA predominantly originate in the right hemisphere, interposed nucleus, and paravermal cortex, and terminate mostly ipsilaterally. Paravermal crus I sends the most connections to the VTA compared to other lobules. We discovered a medial-to-lateral gradient of connectivity, such that the medial cerebellum has the highest connectivity with the VTA. Individual differences in microstructure were associated with measures of negative affect and social functioning. By splitting the tracts into quarters, we found that the socio-affective effects were driven by the third quarter of the tract, corresponding to the point at which the fibers leave the deep nuclei. Taken together, we produced detailed maps of cerebello-VTA structural connectivity for the first time in humans and established their relevance for trait differences in socio-affective regulation.
Characterization of binding kinetics and intracellular signaling of new psychoactive substances targeting cannabinoid receptor using transition-based reweighting method
Authors: Dutta Soumajit , Shukla Diwakar 
Published: October 2023

AbstractNew psychoactive substances (NPS) targeting cannabinoid receptor 1 pose a significant threat to society as recreational abusive drugs that have pronounced physiological side effects. These greater adverse effects compared to classical cannabinoids have been linked to the higher downstreamβ-arrestin signaling. Thus, understanding the mechanism of differential signaling will reveal important structure-activity relationship essential for identifying and potentially regulating NPS molecules. In this study, we simulate the slow (un)binding process of NPS MDMB-Fubinaca and classical cannabinoid HU-210 from CB1using multi-ensemble simulation to decipher the effects of ligand binding dynamics on downstream signaling. The transition-based reweighing method is used for the estimation of transition rates and underlying thermodynamics of (un)binding processes of ligands with nanomolar affinities. Our analyses reveal major interaction differences with transmembrane TM7 between NPS and classical cannabinoids. A variational autoencoder-based approach, neural relational inference (NRI), is applied to assess the allosteric effects on intracellular regions attributable to variations in binding pocket interactions. NRI analysis indicate a heightened level of allosteric control of NPxxY motif for NPS-bound receptors, which contributes to the higher probability of formation of a crucial triad interaction (Y7.53-Y5.58-T3.46) necessary for strongerβ-arrestin signaling. Hence, in this work, MD simulation, data-driven statistical methods, and deep learning point out the structural basis for the heightened physiological side effects associated with NPS, contributing to efforts aimed at mitigating their public health impact.
Redescription ofDendrophthoe falcata(L. f.) Ettingsh (Loranthaceae) with notes on haustorium
Authors: Bhakat Somnath 
Published: October 2023

AbstractMorphology ofDendrophthoe falcata(L. f.) Ettingsh var coccinea is described in detail from West Bengal with notes on the histology of haustorium. Structural peculiarity of the style is explained in the light of embryo sac development. Section of immature fruit shows different zones including embryo.Three types of haustoria namely woody gall, clasping union ad epicortical root is observed in different species of the host plant. Section of haustorium shows penetration peg which reach the host xylem to suck the sap. In guava plant, two types of haustoria develop – primary or true haustorium which penetrate the host stem and secondary haustorium which develop in between two roots of the parasite. Secondary haustorium is oval in shape with a few concentric rings like thickening and never develops penetration peg.
A feature ranking algorithm for clustering medical data
Authors: Shpigelman Eran , Shamir Ron 
Published: September 2023

AbstractObjectiveClustering methods are often applied to electronic medical records (EMR) for various objectives, including the discovery of previously unrecognized disease subtypes. The abundance and redundancy of information in EMR data raises the need to rank the features by their relevance to clustering.MethodsHere we propose FRIGATE, an ensemble feature ranking algorithm for clustering. FRIGATE ranks the features by solving multiple clustering problems on subgroups of features, using game-theoretic principles to rank and weigh features. In every such problem, a Shapley-like framework is utilized to rank a selected set of features. In another version of the algorithm, multiplicative weights are employed to reduce the randomness in feature set selection. The code for the algorithms is available in:https://github.com/Shamir-Lab/FRIGATE.ResultsOn simulated data and on eleven real genomics and EMR datasets, FRIGATE outperforms extant ensemble ranking algorithms, in solution quality and in speed.ConclusionFrigate can improve disease understanding by enabling better subtype discovery from EMR data.
Asynchronous Detection of Erroneous Behaviors in Human-Robot Interaction with EEG: A Comparative Analysis of Machine Learning Models
Authors: Ren Zhezheng , Xia Xuzhe , Tang Yuzhi , Zhao Bo , Wong Chun Pang , Xiao Dongsheng 
Published: October 2023

AbstractWe present a comparative analysis of two distinct machine-learning models designed to detect asynchronous errors during Human-Robot Interaction (HRI). The models under scrutiny are a customized ResNet model and an ensemble model, both trained and validated using EEG data. The ResNet model is a unique adaptation of the Residual Network, comprising a one-dimensional convolutional layer followed by batch normalization and ReLU activation. It also features a custom Residual Block structure and an adaptive average pooling layer, concluding with a fully connected linear layer for binary classification. The ensemble model, on the other hand, incorporates various machine learning models such as MLP, logistic regression, SVM, random forest, and XGBoost, unified in a pipeline with feature extraction and transformation steps. A critical component of our research is the innovative probability map, which maintains a granularity of 0.1 seconds. This map forecasts the likelihood of forthcoming one-second intervals being classified as either Error or Non-error. Our comparative analysis reveals significant variations in the performance of the two models, both of which exhibit promising results in detecting erroneous behaviors during HRI. We provide detailed validation results, including the accuracy, F1 score, and confusion matrix for each model. This study offers valuable insights into the potential of machine learning in enhancing HRI efficiency and accuracy, indicating promising directions for future research.
53BP1 mediates sensitivity to chemotherapy and is associated with poor clinical outcomes in high-grade serous ovarian cancer
Authors: Skulimowski Michael , Bourbonnais Jessica , Malaquin Nicolas , Fleury Hubert , Clément Isabelle , Communal Laudine , Rahimi Kurosh , Provencher Diane , Mes-Masson Anne-Marie , Rodier Francis 
Published: October 2023

ABSTRACTHigh-grade serous ovarian cancer (HGSOC) remains the most lethal gynecological malignancy in North American women. At a cellular level, the current first-line chemotherapies cause DNA-damage and activate the DNA damage response signalling cascade. Here we explore the role of 53BP1, a central mediator of the DNA damage response, in HGSOC chemotherapy outcomes. Tissue 53BP1 protein levels were quantified in two independent HGSOC cohorts, the COEUR validation cohort (n = 173) and CHUM cohort (n = 56). Univariate and multivariate analyses showed that high nuclear 53BP1 levels in ovarian cancer cells were strongly associated with poor disease-specific survival in both cohorts. High 53BP1 was associated with poor progression-free survival (PFS) in the COEUR cohort, and trended towards poor PFS in the CHUM cohort. These findings were validated by whole-tumourTP53BP1mRNA of the TCGA Firehose Legacy cohort (n = 591) in which highTP53BP1mRNA levels were associated with poor overall survival on multivariate analysis. In HGSOC cell lines, 53BP1 levels were positively correlated with resistance to carboplatin using colony formation assay, and depletion of 53BP1 sensitized resistant cell lines to genotoxic therapies. These results suggest that 53BP1 is associated with poor prognosis in HGSOC and may mediate this relationship by modulating cellular sensitivity to chemotherapy.Statement of translational relevanceCurrent first-line chemotherapies in ovarian cancer cause DNA damage and activate the DNA damage response, culminating in the taking of cell fate decisions. 53BP1 is a central mediator in this signalling cascade, where it is involved at multiple levels: signal amplification, recruitment of effectors, DNA repair pathway choice, and cell cycle regulation. However, its role in ovarian cancer treatment outcomes remains unknown. In this study, we found that 53BP1 correlated with poor clinical outcomes in three ovarian cancer patient cohorts and mediated carboplatin sensitivity in ovarian cancer cells. These results reveal 53BP1 and the DNA damage response as important actors in ovarian cancer treatment response. Though further studies are necessary to gain a more complete understanding of their involvement in clinical outcomes, they appear as promising candidates for potential therapeutic targeting in ovarian cancer.
A Specialized Epithelial Cell Type Regulating Mucosal Immunity and Driving Human Crohn’s Disease
Authors: Li Jia , Simmons Alan J. , Chiron Sophie , Ramirez-Solano Marisol A. , Tasneem Naila , Kaur Harsimran , Xu Yanwen , Revetta Frank , Vega Paige N. , Bao Shunxing , Cui Can , Tyree Regina N. , Raber Larry W. , Conner Anna N. , Beaulieu Dawn B. , Dalal Robin L. , Horst Sara N. , Pabla Baldeep S. , Huo Yuankai , Landman Bennett A. , Roland Joseph T. , Scoville Elizabeth A. , Schwartz David A. , Washington M. Kay , Shyr Yu , Wilson Keith T. , Coburn Lori A. , Lau Ken S. , Liu Qi 
Published: October 2023

ABSTRACTCrohn’s disease (CD) is a complex chronic inflammatory disorder that may affect any part of gastrointestinal tract with extra-intestinal manifestations and associated immune dysregulation. To characterize heterogeneity in CD, we profiled single-cell transcriptomics of 170 samples from 65 CD patients and 18 non-inflammatory bowel disease (IBD) controls in both the terminal ileum (TI) and ascending colon (AC). Analysis of 202,359 cells identified a novel epithelial cell type in both TI and AC, featuring high expression ofLCN2,NOS2, andDUOX2, and thus is named LND. LND cells, confirmed by high-resolution in-situ RNA imaging, were rarely found in non-IBD controls, but expanded significantly in active CD. Compared to other epithelial cells, genes defining LND cells were enriched in antimicrobial response and immunoregulation. Moreover, multiplexed protein imaging demonstrated that LND cell abundance was associated with immune infiltration. Cross-talk between LND and immune cells was explored by ligand-receptor interactions and further evidenced by their spatial colocalization. LND cells showed significant enrichment of expression specificity of IBD/CD susceptibility genes, revealing its role in immunopathogenesis of CD. Investigating lineage relationships of epithelial cells detected two LND cell subpopulations with different origins and developmental potential, early and late LND. The ratio of the late to early LND cells was related to anti-TNF response. These findings emphasize the pathogenic role of the specialized LND cell type in both Crohn’s ileitis and Crohn’s colitis and identify novel biomarkers associated with disease activity and treatment response.
Light-induced trapping of endogenous proteins reveals spatiotemporal roles of microtubule and kinesin-1 in dendrite patterning ofDrosophilasensory neurons
Authors: Xu Yineng , Wang Bei , Bush Inle , Saunders Harriet AJ , Wildonger Jill , Han Chun 
Published: October 2023

ABSTRACTAnimal development involves numerous molecular events, whose spatiotemporal properties largely determine the biological outcomes. Conventional methods for studying gene function lack the necessary spatiotemporal resolution for precise dissection of developmental mechanisms. Optogenetic approaches are powerful alternatives, but most existing tools rely on exogenous designer proteins that produce narrow outputs and cannot be applied to diverse or endogenous proteins. To address this limitation, we developed OptoTrap, a light-inducible protein trapping system that allows manipulation of endogenous proteins tagged with GFP or split GFP. This system turns on fast and is reversible in minutes or hours. We generated OptoTrap variants optimized for neurons and epithelial cells and demonstrate effective trapping of endogenous proteins of diverse sizes, subcellular locations, and functions. Furthermore, OptoTrap allowed us to instantly disrupt microtubules and inhibit the kinesin-1 motor in specific dendritic branches ofDrosophilasensory neurons. Using OptoTrap, we obtained direct evidence that microtubules support the growth of highly dynamic dendrites. Similarly, targeted manipulation of Kinesin heavy chain revealed differential spatiotemporal requirements of kinesin-1 in the patterning of low- and high-order dendritic branches, suggesting that different cargos are needed for the growth of these branches. OptoTrap allows for precise manipulation of endogenous proteins in a spatiotemporal manner and thus holds great promise for studying developmental mechanisms in a wide range of cell types and developmental stages.