bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single-base m6A epitranscriptomics reveals novel HIV-1 host interaction targets in primary CD4+T cells
Authors: Huang Siyu , Zhao Yutao , Phillips Stacia , Wilms Bethany , He Chuan , Wu Li 
Published: January 2025

AbstractN6-methyladenosine (m6A) is the most prevalent cellular mRNA modification and plays a critical role in regulating RNA stability, localization, and gene expression. m6A modification plays a vital role in modulating the expression of viral and cellular genes during HIV-1 infection. HIV-1 infection increases cellular RNA m6A levels in many cell types, which facilitates HIV-1 replication and infectivity in target cells. However, the function of m6A modification in regulating HIV-1 infection of primary CD4+T cells remains unclear. Here, we demonstrate that HIV-1 infection of Jurkat CD4+T cells and primary CD4+T cells promotes the interaction between the m6A writer complex subunits methyltransferase-like 3 and 14 (METTL3/METTL14). Using single-base m6A-specific RNA sequencing, we identified several differentially m6A-modified cellular mRNAs, includingperilipin 3(PLIN3), during HIV-1 infection in primary CD4+T cells. Interestingly, HIV-1 infection increasedPLIN3mRNA level by enhancing its stability, but PLIN3 protein level was decreased. Knocking down PLIN3 in primary CD4+T cells reduced HIV-1 production but enhanced virion infectivity. In contrast, in Jurkat cells,PLIN3mRNA and protein expression levels were unaffected by HIV-1 infection, and knocking out PLIN3 did not impact HIV-1 production or infectivity. These results indicate that the interplay between HIV-1 and PLIN3 is cell-type specific and only observed in primary CD4+T cells. Overall, our results highlight the importance of m6A RNA modification in HIV-1-infected primary CD4+T cells and suggest its significance as a regulatory mechanism in HIV-1 infection.Author SummaryN6-methyladenosine (m6A) is a common chemical modification on mRNA that helps control RNA stability, localization, and gene expression. m6A modification of viral and cellular RNA is important for HIV-1 infection. In this study, we found that HIV-1 infection of CD4+T cells enhanced the interaction between two proteins, METTL3 and METTL14, which are responsible for adding m6A modifications to RNA. Using m6A-specific RNA sequencing, we identified several mRNAs with altered m6A modifications during HIV-1 infection, including one calledPLIN3. Interestingly, HIV-1 infection stabilized and increasedPLIN3mRNA levels, but reduced PLIN3 protein expression in primary CD4+T cells. When we knocked down PLIN3 in primary CD4+T cells, it decreased HIV-1 production but made the HIV-1 particles more infectious. In contrast, in the Jurkat CD4+T cell line, HIV-1 infection did not affect PLIN3 expression and knockout of PLIN3 did not alter HIV-1 production or infectivity, suggesting that the effect is specific to primary CD4+T cells. Our findings show the importance of m6A RNA modification in HIV-1 infection by regulating host genes likePLIN3and suggest a unique regulatory mechanism in HIV-1 infected primary CD4+T cells.
Precise calcium-to-spike inference using biophysical generative models
Authors: Broussard Gerard Joey , Diana Giovanni , Urra Quiroz Francisco J. , Sermet B. Semihcan , Rebola Nelson , Lynch Laura A. , DiGregorio David A. , Wang Samuel S.-H. 
Published: January 2025

AbstractThe intramolecular dynamics of fluorescent indicators of neural activity can distort the accurate estimate of action potential (“spike”) times. In order to develop a more accurate spike inference algorithm we characterized the kinetic responses to calcium of three popular indicator proteins, GCaMP6f, jGCaMP7f, and jGCaMP8f, using in vitro stopped-flow and brain slice recordings. jGCaMP8f showed a use-dependent slowing of fluorescence responses that caused existing inference methods to generate numerous false positives. From these data we developed a multistate model of GCaMP and used it to create Bayesian Sequential Monte Carlo (BiophysSMC) and machine learning (BiophysML) inference methods that reduced false positives substantially. This biophysical method dramatically improved spike time accuracy, detecting individual spikes with a median uncertainty of 4 milliseconds, a performance level that reached the theoretical limit and is twice as accurate as any previous method. Our framework thus highlights advantages of physical model-based approaches over model-free algorithms.
A comprehensive analysis of the inherited lncRNA and circRNA repertoire of zebrafish
Authors: Joshi Dheeraj Chandra , Kadam Aakanksha , Sachidanandan Chetana , Pillai Beena 
Published: January 2025

AbstractInherited non-coding RNAs can be the third major component of epigenetic information transfer from one generation to the next. Here, we present a comprehensive resource of lncRNAs and circular RNAs that are inherited, compiled from meta-analysis of zebrafish transcriptomics data and comparative genomics with mouse and human. Maternal and paternal inheritance of mRNA into the zygote is accepted to be an important regulator of embryonic development as well as adult characteristics. Although inheritance of certain specific miRNAs is known, other non-coding RNA inheritance remains less explored. We performed a comprehensive analysis of the inherited lncRNAs and circRNAs in zebrafish. We discovered that nearly 20% of all known lncRNA and 7% of circRNAs are inherited. Many of these lncRNAs are conserved in mammals, and are expressed widely in adult tissues of zebrafish. The male and female gametes carry a highly similar pool of inherited lncRNAs, with only a few sperm/ oocyte specific transcripts. The majority of inherited circRNAs originate from genes important for fertilization and can potentially regulate translational processes. Contrary to general belief, the inherited lncRNAs and circRNAs do not undergo degradation en masse coincidental to zygotic genomic activation, suggesting that these RNAs may have more sustained roles in development.
Auditory tract maturation in early infancy: Links to speech production
Authors: Liu Feihong , Wang Yaoxuan , Gu Jinchen , Liu Jiameng , Cai Xinyi , Zhang Han , Feng Jun , Wang Zhaoyan , Wu Hao , Shen Dinggang 
Published: January 2025

AbstractInfants exhibit remarkable language acquisition abilities, supported by highly plastic neural substrates that dynamically interact with early speech experiences. However, the developmental mechanisms of these neural substrates and their specific role in speech acquisition remain incompletely understood. Here, we present NeoAudi Tract (NAT), a robust automated toolbox for extracting the full set of auditory tracts in infants from birth to 24 months using3T diffusion MRI data. By characterizing the microstructural changes in these tracts, we demonstrate a gradual and continuous maturation process of the auditory system. Additionally, we identify significant correlations between auditory tract maturation and bothfine-motor skillsandexpressive languaget-scores from the Mullen Scales of Early Learning tests. Our findings highlight the role of the auditory system in speech production and indicate the intertwined development of auditory and motor systems that underlies speech acquisition, particularly during perceptual reorganization.
Hypoxia-Induced Active Dynamics Promotes Early Tumorigenesis
Authors: Wang Zhengduo , Tian Li , Li Bo 
Published: January 2025

AbstractUnderstanding early tumor formation offers critical insights for cancer prevention at the earliest stages. However, mostin vivostudies focus on later stages, providing limited information on initial tumorigenesis. Hypoxia, a common physiological condition, is a primary microenvironmental factor in cancer. While molecular studies indicate significant yet sometimes conflicting roles of hypoxia in cancer progression, experimental data on hypoxia’s impact on tumor formation from a single cell, especially regarding cellular dynamics, remain scarce. To address this gap, we developed an integrated platform for live-cell imaging under hypoxic conditions, enabling, for the first time, observation of 3D tumor spheroid development from a single cell. Our results show that tumorigenesis is markedly accelerated under hypoxia. Beyond linear growth, we demonstrate that directional movement enhances fusion events, leading to larger spheroids that, in turn, stimulate further proliferation — a positive feedback loop between spheroid dynamics and growth. Actin polymerization and cell-cell adhesion are optimized to promote spheroid fusion. Additionally, hypoxia induces cells with outreaching F-actin co-localized with smaller nuclei to bridge gaps between spheroids, facilitating fusion, while the appearance of tiny nuclei suggests genetic instability. These findings provide direct insights into hypoxia’s role in early tumorigenesis, highlighting the potential of modulating dynamic, mechanical, and physiological factors for cancer prevention.
Receptor dimerization enables ligand discrimination through tunable response heterogeneity
Authors: Biran Assaf , Antebi Yaron E. 
Published: January 2025

AbstractSignaling pathways enable cells to coordinate collective behaviors by exchanging specific information. Many pathways utilize multiple ligand variants to activate the same intracellular signaling cascade, raising the question of how cells discriminate between these seemingly redundant signals. It has been shown that individual cells can discriminate between signals based on their induced level of activity, temporal dynamics or combinatorial effect. Here, we demonstrate that ligand discrimination could also emerge at the population level. Using mathematical models of ligand-receptor interactions, we examine how response heterogeneity at the population level can encode ligand identity. We introduce a local scaling metric to quantify how variation in pathway components affects the cellular response. Our results reveal that for pathways with dimeric receptors, and more significantly for heterodimeric receptors, biochemical parameters of the ligands control the resulting heterogeneity in the response of a population of cells. Furthermore, we show that the population-level heterogeneity encodes the enzymatic activity of the resulting receptor complex. This suggests a functional advantage for utilizing heterodimeric receptor complexes in pathways acting across a population of cells, such as the type I interferon pathway, which shows several of the characteristics of our model. This contrasts to juxtacrine pathways, such as Notch, that do not act at the population level and use a single component receptor. Overall, our findings highlight a novel mechanism by which receptor architecture enables cells to encode ligand-specific information through population-level heterogeneity, offering insights into immune regulation, tissue development, and synthetic biology.Significance StatementCells often communicate using distinct molecular signals (ligands) that activate the same pathway. Yet, how cells distinguish between these signals remains unclear. This study reveals that ligand discrimination can emerge at the level of entire cell populations, not just individual cells. By analyzing mathematical models, we show that certain receptor architectures, especially those involving heterodimeric receptors, allow signals to control the heterogeneity of the response level across a population. This mechanism enables cell populations to decode specific information about their environment, impacting processes like immune responses and tissue development. Our findings provide new insights into how signals coordinate collective behaviors and suggest strategies for designing synthetic systems to precisely control biological responses.
LCORLandSTC2variants increase body size and growth rate in cattle and other animals
Authors: Bai Fengting , Cai Yudong , Qiu Min , Liang Chen , Pan Linqian , Liu Yayi , Feng Yanshuai , Cao Xuesha , Yang Qimeng , Ren Gang , Jiao Shaohua , Gao Siqi , Lu Meixuan , Wang Xihong , Heller Rasmus , Lenstra Johannes A. , Jiang Yu 
Published: January 2025

ABSTRACTUsing ancestral recombination graphs, we investigated recent selection signatures in European beef cattle breeds, pinpointing sweep-driving variants in theLCORLandSTC2loci with notable effects on body size and growth rate. The ACT-to-A frameshift mutation inLCORLoccurs mainly in central-European cattle, and stimulates growth. Remarkably, similar truncating mutations were found in seven of the other most important domesticated species, but not in most populations of wild relatives. In theSTC2locus, we identified a missense C-to-G mutation located within the conserved region across vertebrates. We validated the two natural mutations in gene-edited mouse models, where both variants in homozygous carriers increase the average weight by 11%. Our findings provide insights into a seemingly recurring gene target of body size enhancing truncating mutations across domesticated species, and offer valuable targets for gene editing-based breeding in animals.
Scrutinization on Docking Against Individually Generated Target Pockets for Each Ligand
Authors: Zhan Rui , Zhang Wenyi , Huang Jing 
Published: January 2025

AbstractThe longstanding challenge of limited exploration in protein receptor conformational space continues to constrain the precision of molecular docking. Ensemble docking, which employs methods such as molecular dynamics simulations to generate multiple receptor conformations for docking, has improved accuracy but remains limited by incomplete sampling and an inability to fully account for ligand-induced fit. To address these limitations, we introduce the concept of individual docking, a novel approach that involves docking against receptor conformations generated individually for each ligand in the docking library. This approach has only very recently become feasible due to advances in protein structure prediction, in particular end-to-end protein-ligand complex prediction technologies exemplified by AlphaFold3 and NeuralPLexer. In this study, we performed individual docking on 27 targets from the DUD-E dataset, using a two-step protocol that integrates NeuralPLexer’s inference as the receptor sampling step with subsequent physics-based docking. Our results reveal that individual docking leads to approximately 24% reduction in the enrichment factors compared with standard docking, yet it recovers different sets of active ligands. Detailed analyses of pocket and ligand conformations suggest several potential incompatibilities between deep learning-based and physics-based virtual screening tools.
Paratransgenesis: The dynamics of engineeredEnterobactersymbionts and Cry1Ac-producingEnterobacterfor biocontrol ofHelicoverpainsect pests in crop production
Authors: Ojha Abhishek 
Published: January 2025

AbstractThe potential application of insect gut microorganisms in paratransgenic crop pest management techniques is being investigated. TheHelicoverpagut is known to harbor the symbiontEnterobacter. However, little is known about the dynamics ofEnterobacterin theHelicoverpagut, its interaction with the phyllosphere, and the mechanisms by which it is delivered to this Lepidopteran species. To evaluate the insecticidal activity of Cry1Ac and its capacity to colonize theHelicoverpagut and the tomato phyllosphere, the symbiontEnterobacter, which was isolated from theHelicoverpagut, was transformed with constructs 2 (cry1Ac-KmR-pUC18) and 3 (KmR-pGFP). Within 48 hours and 24 hours, respectively, theHelicoverpagut and tomato phyllosphere were effectively colonized by the GFP-producing construct 3-Enterobacter. In insect bioassays, Cry1Ac-producing constructs 2-E. coli(K12) and 2-Enterobacterwere used for diet and leaf-dip testing.Helicoverpaneonates died 86-100% when fed diets supplemented with 10 -10 cells of Cry1Ac-producing construct 2-E. coli(K12), whereas 79–100% died when fed diets supplemented with 10 -10 cells of Cry1Ac-producing construct 2-Enterobacter. Furthermore, when the Cry1Ac-producing construct 2-Enterobacter(0.10 x 109cells) was applied to the tomato phyllosphere, it caused 100% mortality of neonates within 192 hours. The successful vector modification, genetic transformation, and establishment of recombinantEnterobactercells in the guts ofHelicoverpalarvae and on tomato leaves lay the foundation for advancing a paratransgenic strategy. This engineered bacterium could potentially replace synthetic insecticides for managing lepidopteran pests in crops.
The role of STN beta oscillations on lower extremity muscle activity in Parkinsonian stepping
Authors: Simpson Thomas G. , He Shenghong , Pogosyan Alek , Plazas Fernando Rodriguez , Hart Michael G. , Shah Rahul , Hasegawa Harutomo , Wiest Christoph , Wehmeyer Laura , Yassine Sahar , Guo Xuanjun , Merla Anca , Perera Andrea , Raslan Ahmed , O’Keeffe Andrew , Welter Marie-Laure , Ashkan Keyoumars , Morgante Francesca , Andrade Pablo , Visser-Vandewalle Veerle , Pereira Erlick A. , Tan Huiling 
Published: January 2025

ABSTRACTFreezing of gait (FOG) is a devastating symptom of Parkinson’s disease (PD) often resulting in disabling falls and loss of independence. It affects half of patients, yet current therapeutic strategies are insufficient, and the underlying neural mechanisms remain poorly understood. This study investigated beta oscillation dynamics in the STN during different locomotor states, while examining the effects of levodopa. In particular, it aimed to identify pathological activity by analysing the relationship between the STN and lower limb muscles during stepping. Local field potentials (LFP) in the STN and muscle activity (EMG) of the gastrocnemius and peroneus longus were recorded in 14 PD patients during standing and stepping, ON and OFF levodopa. Levodopa reduced stepping variability, implying improved stepping abilities. Distinct STN beta patterns were observed between stepping and standing, with lower high-beta and higher low-beta during stepping compared to standing, suggesting a distinct role of these frequency bands in motor control during postural and movement states. Levodopa reduced low-beta but increased high-beta activity, highlighting a potential physiological function of high-beta in the STN during standing and stepping. In addition, step-phase specific effects of levodopa included reduced broad-beta band activity in the STN and lower limb muscles during the late-stance and pushing-off phase of the contralateral leg when ON medication. Further analyses suggest that pathological STN activity amplifies muscle activation around movement initiation, potentially reducing the ability of the patient to move freely. These findings offer insight for developing phase-specific stimulation strategies targeting STN beta oscillations during gait.
VGluT3 BNST neurons transmit GABA and restrict feeding without affecting rewarding or aversive processing
Authors: Ly Annie , Karnosky Rachel , Prévost Emily D. , Hotchkiss Hayden , Pelletier Julianne , Spencer Robert L. , Ford Christopher P. , Root David H. 
Published: January 2025

ABSTRACTThe bed nucleus of the stria terminalis (BNST) is involved in feeding, reward, aversion, and anxiety-like behavior. We identify BNST neurons defined by the expression of vesicular glutamate transporter 3, VGluT3. VGluT3 neurons were localized to anteromedial BNST, were molecularly distinct from accumbal VGluT3 neurons, and co-express vesicular GABA transporter (VGaT). Cell-type specific presynaptic processes were identified in arcuate nucleus (ARC) and the paraventricular nucleus of the hypothalamus (PVN), regions critical for feeding and homeostatic regulation. Whole-cell patch-clamp electrophysiology revealed that, while these neurons co-express VGluT3 and VGaT, they functionally transmit GABA to both ARC and PVN, with rare glutamate co-transmission to ARC. Neuronal recordings of VGluT3 BNST neurons showed greater calcium-dependent signaling in response to sucrose consumption while sated compared with fasted. When fasted, optogenetic stimulation of BNST VGluT3 neurons decreased sucrose consumption using several stimulation conditions but not when stimulation occurred prior to sucrose access, suggesting that BNST VGluT3 activation concurrent with consumption in the fasted state reduces feeding. BNST VGluT3 activation during anxiety-like paradigms (novelty-suppressed feeding, open field, and elevated zero maze) and real-time place conditioning resulted in no changes in anxiety-like or reward/aversion behavior. We interpret these data such that VGluT3 BNST neurons represent a unique cellular population within the BNST that provides inhibitory input to hypothalamic regions to decrease feeding without affecting anxiety-like or reward/aversion behavior.
The mechanosensory DEG/ENaC channel DEGT-1 is a proprioceptor ofC. elegansforegut movement
Authors: Bayer Emily A. , Mango Susan E. , Hobert Oliver , Schier Alexander F. 
Published: January 2025

AbstractThe gastrointestinal tract is subjected to extensive mechanosensory stimulation during food ingestion. However, the identities of mechanosensory receptors in the enteric nervous system are largely unknown. The pharynx ofC. elegansis a structurally and functionally homologous model of the vertebrate foregut, but is comprised of only 20 neurons that are embedded within the muscles and epithelial cells of the organ. Here we report that the DEG/ENaC family ion channel DEGT-1 is a proprioceptor of pharynx movement. DEGT-1 protein is expressed in 4 pharyngeal neurons (MI, M3, I4, and M5) and localized to their neuronal soma in direct contact with the collagenous pharyngeal basement membrane.degt-1mutants display abnormally rapid feeding in the presence of food, causing global changes in lipid accumulation.degt-1mutants also pump rapidly when pumping is induced by the presence of serotonin alone, suggesting thatdegt-1is required for proprioception of pharyngeal pumping itself, rather than sensing ingested food. DEGT-1 is required in only two pharyngeal neurons (I4 and M5) to control pumping rate. Taken together, these results suggest that DEGT-1 modulates pharyngeal pumping rate by relaying proprioceptive feedback generated by the shear force of the pharynx against its own basement membrane. Thus, mechanosensors in enteric nervous systems modulate organ function not only by detecting forces from ingested contents, but also the movements of the organ itself.
Differences in apple fruit shape are independent of fruit size
Authors: DeViller Kylie , Chitwood Daniel H. , Myles Sean , Li Mao , Migicovsky Zoë 
Published: January 2025

AbstractPremiseFruit quality is crucial in breeding new apple accessions. Before tasting, consumers assess freshness and flavour based on the physical appearance of fruit. Understanding how fruit quality traits such as shape and size vary across diverse apples provides a foundation for future breeding efforts.MethodsWe analyzed images of 5724 apples representing 743 different trees and 534 unique accessions from Canada’s Apple Biodiversity Collection to quantify variation in fruit shape and size. To achieve this, we used a pseudo-landmarking approach paired with traditional linear measurements including length, width, area, solidity, and aspect ratio. We also incorporated previously collected fruit weight measurements from the same trees.ResultsUsing a comprehensive measure of shape, we determined that the primary source of variation in apple fruit shape was the width to length (aspect) ratio of the fruit. This variation was not significantly correlated with differences in fruit size from its area and harvest weight.ConclusionsOur findings indicate that two critical aspects of morphological variation in apple—fruit shape and size—are independent, suggesting it is possible to select for a diverse range of fruit shapes while maintaining a consistent and marketable size.