bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD8+T cells mediate vaccination-induced lymphatic containment of latentMycobacterium tuberculosisinfection following immunosuppression, while B cells are dispensable
Authors: Miranda-Hernandez Socorro , Kumar Manoharan , Henderson Alec , Graham Erin , Tan Xiao , Taylor Jim , Meehan Michael , Ceja Zuriel , del Pozo-Ramos Lidia , Pan Yi , Tsui Ellen , Donovan Meg L , Rentería Miguel E , Flores-Valdez Mario Alberto , Blumenthal Antje , Nguyen Quan , Subbian Selvakumar , Field Matt A , Kupz Andreas 
Published: January 2025

AbstractIt is estimated that two billion people are latently infected withMycobacterium tuberculosis(Mtb), the causative agent of tuberculosis (TB). LatentMtbinfection (LTBI) can occur in multiple organs, including the lymphatics. The risk of LTBI reactivation increases in immunocompromised conditions, such as coinfection with human immunodeficiency virus (HIV), and during treatment of autoimmune diseases and organ transplantation. The immunological correlates of protection against TB, including against reactivation of LTBI, remain largely elusive. Here, we used a mouse model of latent lymphaticMtbinfection to dissect the immunological mechanisms underlying LTBI containment versus reactivation. We show that immunosuppression-mediated reactivation of lymphatic LTBI and the subsequent spread to non-lymphatic organs can be prevented by vaccination with multiple recombinant BCG (rBCG) strains despite the deficiency of CD4+T cells. Using spatial transcriptomics, multi-parameter imaging, network analysis and bioinformatic integration of histopathological images, we reveal that immunosuppression is associated with a distinct repositioning of non-CD4 immune cells at the edge of TB lesions within the infection-draining cervical lymph nodes. While B cells increased in numbers, they are dispensable for the containment of LTBI. LymphaticMtbinfection in different immune cell-deficient mouse strains, antibody-mediated cell depletion and adoptive transfer experiments into highly susceptible mice unequivocally show that vaccination-mediated prevention of LTBI reactivation is critically dependent on CD8+T cells. These findings have profound implications for our understanding of immunity to TB and the management of LTBI.Graphical Abstract
A Robust Proteomics-Based Method for Identifying Preferred Protein Targets of Synthetic Glycosaminoglycan Mimetics
Authors: Afosah Daniel K. , Ongolu Ravikumar , Fayyad Rawan M. , Hawkridge Adam , Desai Umesh R. 
Published: January 2025

ABSTRACTA robust technology is critically needed for identifying preferred protein targets of glycosaminoglycans (GAGs), and synthetic mimetics thereof, in biological milieu. We present a robust 10-step strategy for identification and validation of preferred protein targets of highly sulfated, synthetic, small, GAG-like molecules using diazirine-based photoaffinity labeling– proteomics approach. Our work reveals that optimally designed, homogeneous probes based on minimalistic photoactivation and affinity pulldown groups coupled with rigorous proteomics, biochemical and orthogonal validation steps offer excellent potential to identify preferred targets of GAG mimetics from the potentially numerous possible targets that cloud GAG interaction studies. Application of this 10-step strategy for a promising highly sulfated, small GAG mimetic led to identification of only a handful of preferred targets in human plasma. This new robust strategy will greatly aid drug discovery and development efforts involving GAG sequences, or sulfated small mimetics thereof, as leads.
Evaluating genotyping strategies for a small managed population with simulation
Authors: Martin Audrey AA , Schoenebeck Jeffrey , Clements Dylan N. , Lewis Tom , Wiener Pamela , Gorjanc Gregor 
Published: January 2025

AbstractBackgroundCollecting genomic information is crucial to advance breeding for complex traits such as health, welfare, and behaviour in domesticated populations. For that purpose, different data collection scenarios can be envisioned based on the number of individuals, the number of markers, and the genotyping technology. This study developed a simulation framework, based on a service dog population, aiming to identify an optimal and cost-effective genotyping strategy that would support the implementation of genomic selection, investigation of the genetic architecture of traits of interest, and track loci of interest.MethodsWe simulated a population based on the existing pedigree, using the gene drop method in AlphaSimR. The existing pedigree was extended with additional progeny generations to evaluate the outcomes of different genotyping strategies in the future. We generated genotype data based on existing high-coverage whole-genome sequences (WGS) for the current breeding dogs and evaluated different scenarios for genotyping the progeny. The genotyping options considered SNP arrays of various densities and WGS callsets produced from different sequencing depths. We then phased and imputed the genotype data to high-coverage WGS using AlphaPeel.ResultsAll scenarios were compared based on individual imputation accuracy against the simulated true whole-genome genotype. Averaged over five generations of simulated progeny, low-pass sequencing (0.5 to 2X depth) achieved accuracies of 0.998 to 0.999. The accuracy of SNP array genotyping (25K to 710K markers) was lower, with means of 0.911 to 0.938.ConclusionsOur simulation was tailored to identify the most cost-effective and efficient strategy for downstream use in genomic selection and genetic research into traits and loci of interest. Low-pass sequencing outperformed SNP array genotyping in imputation accuracy of whole-genome genotypes as expected. Additionally, low-pass sequencing technology was the most affordable genotyping approach currently available for dogs. Thus, it appears to be the optimal choice for balancing the goals of regimented breeding programmes such as those that produce service dogs. This simulation framework could also be adapted to address other objectives for breeding organisations working with small populations.
Multiple lesion inductions intensify central sensitization driven by neuroinflammation in a mouse model of endometriosis
Authors: Harvey Madeleine E. , Shi Mingxin , Oh Yeongseok , Mitchell Debra A. , Slayden Ov D. , MacLean James A. , Hayashi Kanako 
Published: January 2025

AbstractIntroductionEndometriosis is an inflammatory disease associated with chronic pelvic pain (CPP). Growing evidence indicates that endometriotic lesions are not the sole source of pain. Instead, central nervous system (CNS) dysfunction created by prolonged peripheral and central sensitization plays a role in developing endometriosis-associated CPP. This study investigated how CPP is established using a multiple lesion induction mouse model of endometriosis, as repeated retrograde menstruation is considered underlying endometriosis pathogenesis.MethodsWe generated endometriosis-like lesions by injecting endometrial tissue fragments into the peritoneal cavity in mice. The mice received a single (1x) or multiple inductions (6x) to simulate recurrent retrograde menstruation. Lesion development, hyperalgesia by behavioral testing, signs of peripheral sensitization, chronic inflammation, and neuroinflammation were examined with lesions, peritoneal fluids, dorsal root ganglia (DRG), spinal codes, and brain.ResultsMultiple lesion inductions increased lesion numbers and elevated abdominal and hind paw hypersensitivity compared to single induction mice. Elevated persistent glial cell activation across several brain regions and/or spinal cords was found in the multiple induction mice.Specifically, IBA1+ microglial soma size was increased in the hippocampus and thalamus. IBA1+ cells were abundant in the cortex, hippocampus, thalamus, and hypothalamus of the multiple induction mice. GFAP+ astrocytes were mainly elevated in the hippocampus. Elevated TRPV1, SP, and CGRP expressions in the DRG were persistent in the multiple induction mice. Furthermore, multiple inductions induced the severe disappearance of TIM4hiMHCIIloresidential macrophages and the influx of increased proinflammatory TIM4loMHCIIhimacrophages in the peritoneal cavity. The single and multiple inductions elevated secreted TNFα, IL-1β, and IL-6 levels in the peritoneal cavity at 2 weeks. Elevated cytokine levels returned to the pre-induction levels in the single induction mice at 6 weeks; however, they remained elevated in the multiple induction mice.ConclusionsOur results indicate that the repeatedly occurring lesion inductions (=mimic retrograde menstruation) can be a peripheral stimulus that induces nociceptive pain and creates composite chronic inflammatory stimuli to cause neuroinflammation and sensitize the CNS. The circuits of neuroplasticity and stimulation of peripheral organs via a feedback loop of neuroinflammation may mediate widespread endometriosis-associated CPP.
Assessing the Evolutionary Trajectory of Arbuscular Mycorrhizal Conserved Genes in Seagrasses and Aquatic Close Relatives
Authors: Ettinger Cassandra L. , Arroyo Jennifer , Stajich Jason E. 
Published: January 2025

SummaryArbuscular mycorrhizal fungi (AMF) form beneficial associations with plants, and are thought to have been critical to the adaptation of the ancestor of terrestrial plants during the transition onto land. However, the ability of AMF to associate with aquatic plants is unclear. To address this, we used 65 publicly available genomes and transcriptomes (25 freshwater, 23 terrestrial and 17 marine plants) to interrogate the genomic potential to form AMF associations in aquatic plant lineages in the order Alismatales. We explored the presence or absence of homologs of 45 genes, with a a special focus on six critical genes including three that co-evolved with AMF associations (RAD1, STR1, STR2) and three necessary for intracellular symbiosis (SymRK, CCaMK/DMI3, CYCLOPS/IDP3). Our results indicate a pattern likely consistent with independent gene losses (or extreme divergence) of symbiosis genes across aquatic lineages suggesting a possible inability to form AMF associations. However, some of these conserved genes (i.e.,CCaMK/DMI3) are purported to function in other types of fungal symbioses, such as ectomycorrhizal symbiosis, and were observed here in a subset of aquatic lineages, including seagrasses. Overall, our findings highlight the complex evolutionary trajectories of symbiosis-related genes in aquatic plants, suggesting that while AMF associations may have been lost in certain lineages, others have genes that may allow them to form alternative fungal symbioses which may still play an underappreciated role in their ecology.
Unsupervised multi-animal tracking for quantitative ethology
Authors: Li Yixin , Li Xinyang , Zhang Qi , Zhang Yuanlong , Fan Jiaqi , Lu Zhi , Li Ziwei , Wu Jiamin , Dai Qionghai 
Published: January 2025

AbstractQuantitative ethology necessitates accurate tracking of animal locomotion, especially for population-level analyses involving multiple individuals. However, current methods rely on laborious annotations for supervised training and have restricted performance in challenging conditions. Here we present an unsupervised deep-learning method for multi-animal tracking (UDMT) that achieves state-of-the-art performance without requiring human annotations. By synergizing a bidirectional closed-loop tracking strategy, a spatiotemporal transformer network, and three sophisticatedly designed modules for localization refining, bidirectional ID correction, and automatic parameter tuning, UDMT can track multiple animals accurately in various challenging conditions, such as crowding, occlusion, rapid motion, low contrast, and cross-species experiments. We demonstrate the versatility of UDMT on five different kinds of model animals, including mice, rats,Drosophila,C. elegans, andBetta splendens. Combined with a head-mounted miniaturized microscope, we illustrate the power of UDMT for neuroethological interrogations to decipher the correlations between animal locomotion and neural activity. UDMT will facilitate advancements in ethology by providing a high-performance, annotation-free, and accessible tool for multi-animal tracking.
CANDI: self-supervised, confidence-aware denoising imputation of genomic data
Authors: Foroozandeh Mehdi , Diab Abdul Rahman , Libbrecht Maxwell 
Published: January 2025

AbstractLarge-scale epigenomic datasets such as histone modifications and DNA accessibility have greatly advanced our understanding of genomic function. However, these measurements often suffer from noise, batch effects and irreproducibility. Epigenome imputation has emerged as a promising solution to these challenges. These methods integrate patterns across experiments, cell types, and genomic loci to predict the results of experiments, yielding predictions that often surpass observed data in quality. Thus, researchers increasingly leverage imputation for denoising data prior to downstream analysis.However, existing methods for imputation-based denoising have significant limitations. Here, we propose CANDI (Confidence-Aware Neural Denoising Imputer), a method for epigenome imputation that (1) predicts raw counts and handles experiment-specific covariates such as sequencing depth, (2) can (optionally) incorporate information from a low-quality existing experiment when predicting a target without retraining, and (3) outputs a calibrated measure of uncertainty. This approach is enabled using a Transformer model with self-supervised learning (SSL) training.
Elucidation of the biosynthetic pathway of reserpine
Authors: Cao Jiaqing , Zhong Jingxiao , Li Feng , Jiang Yindi 
Published: January 2025

AbstractReserpine is a landmark natural product that has profoundly influenced our understanding of neurotransmitter biology and cardiovascular medicine. Its complex structure, featuring a unique C3 β-configuration and five consecutive chiral centers, has inspired generations of synthetic chemists to develop innovative strategies for its construction. However, the biosynthetic logic underlying nature’s assembly of this intricate molecule has remained elusive. Here, we decipher the biosynthetic pathway of reserpine inRauvolfia verticillata, revealing that α-configured strictosidine serves as the biosynthetic precursor. The crucial C3 β-configuration is established through a two-step enzymatic epimerization, orchestrated by a flavin-dependent oxidase and a NADPH-dependent reductase. The consecutive chiral centers are constructed through coordinated action of distinct enzyme families. Through the identification of eight biosynthetic enzymes, including those catalyzing late-stage methoxylation, we successfully reconstituted the biosynthesis of rauvomitorine G, a key intermediate in reserpine formation. This work unveils nature’s elegant approach to stereoselective synthesis of complex alkaloids and provides valuable biocatalytic tools for molecular functionalization.
Striatal Gradient in Value-Decay Explains Regional Differences in Dopamine Patterns and Reinforcement Learning Computations
Authors: Kato Ayaka , Morita Kenji 
Published: January 2025

AbstractDopamine has been suggested to encode reward-prediction-error (RPE) in reinforcement learning (RL) theory, but also shown to exhibit heterogeneous patterns depending on regions and conditions: some exhibiting ramping response to predictable reward while others only responding to reward-predicting cue, and some lacking response to unpredictable reward. It remains elusive how these heterogeneities relate to various RL algorithms suggested to be employed by animals/humans, such as RL under predictive state representation, hierarchical RL, and distributional RL. Here we show that these relations could be coherently explained if the decay of learned values (value-decay), implemented by the decay of dopamine-dependent plastic changes in the synaptic strengths, is considered. First, we show that value-decay causes ramping RPE under traditional non-predictive representations but not under the predictive successor representation (SR). This explained the observed gradual fading of dopamine ramping over repeated reward navigation by gradual formation of SR. Next, we constructed a hierarchical RL model that coupled two systems with and without value-decay. The model explained the observed distinct patterns of neuronal activities in parallel striatal-dopamine circuits and their suggested distinct functions in flexible learning versus stable habit. Lastly, we examined two distinct algorithms of distributional RL with and without value-decay. These algorithms explained how the reported distinct dopamine patterns in different striatal regions are linked to the suggested different strengths of distributional coding in these regions. These results suggest that within-striatum differences, or more specifically, medial-lateral gradient in value/synaptic-decay tunes regionally different RL computations through generating distinct patterns of DA/RPE.
Combinations of approved oral nucleoside analogues confer potent suppression of alphavirusesin vitroandin vivo
Authors: Verwimp Sam , Wagoner Jessica , Arenas Elijah Gabriela , De Coninck Lander , Abdelnabi Rana , Hyde Jennifer L. , Schiffer Joshua T. , White Judith M. , Matthijnssens Jelle , Neyts Johan , Polyak Stephen J. , Delang Leen 
Published: January 2025

AbstractAlphaviruses such as chikungunya virus (CHIKV) pose a significant threat to global health, yet specific antiviral therapies remain unavailable. In this study, we evaluated combinations of three approved oral directly acting antiviral (DAA) drugs (sofosbuvir (SOF), molnupiravir (MPV) and favipiravir (FAV)) against CHIKV, Semliki Forest virus (SFV), Sindbis virus (SINV), and Venezuelan Equine Encephalitis virus (VEEV)in vitroandin vivo. In human skin fibroblasts, synergistic antiviral effects were observed for the drug combinations MPV + SOF and FAV + SOF against CHIKV, and for FAV + SOF against SFV. In human liver Huh7 cells, the combinations of FAV + MPV conferred additive to synergistic activity against VEEV and SINV strains, while SOF synergized with FAV against SINV strains. In a mouse model of CHIKV arthritis, MPV improved CHIKV-induced foot swelling and reduced systemic infectious virus titers. Combination treatment with suboptimal doses of MPV and SOF significantly reduced foot swelling and decreased infectious virus titers in serum as compared to single doses of each drug. Sequencing of CHIKV RNA from mouse joint tissue revealed that MPV caused dose-dependent increases in mutations in the CHIKV genome. Upon combination therapy of MPV with SOF, the number of mutations was significantly lower compared to single treatment with several higher doses of MPV. In summary, combining approved oral nucleoside analogs confers potent suppression of multiple alphavirusesin vitroandin vivowith enhanced control of viral genetic evolution in the face of antiviral drug pressure. These drug combinations may ultimately lead to the development of potent combinations of pan-family alphavirus inhibitors.
Metastatic cell plasticity is maintained by SOX9 function during mitosis in breast cancer
Authors: Beyes Sven , Michelatti Daniela , Negri Maria Luce , Morelli Leonardo , Frigoli Enrico , Fagnocchi Luca , Zippo Alessio 
Published: January 2025

ABSTRACTDisseminated tumor cells (DTCs) contribute to metastasis formation by adapting to the hostile environmental conditions encountered at the seeded secondary organs. This phenotypic plasticity is supported by the epigenetic reprogramming of cis-regulatory elements (CREs), representing a hallmark of metastatic cells. DTCs can enter a reversible state of cancer dormancy, resulting from their ability to enter quiescence after mitosis and escape immune surveillance. In this respect, mitosis may represent a window of opportunity to increase DTCs’ fitness by priming CREs, ensuring the reactivation of a dormancy-related transcriptional program while preserving the epigenetic information. By profiling the chromatin changes occurring during the early steps of mitosis, we found that DTCs experience fluctuations in chromatin accessibility at CREs, which are bookmarked by pro-metastatic TFs. Among these, the pro-dormancy TF SOX9 remained associated with mitotic chromatin, facilitating transcriptional reactivation upon exiting mitosis. By dissecting the consequences of degrading SOX9 before mitosis, we found that its priming of dormancy-related CREs, combined with the recruitment of the Mediator kinase module, is instrumental for metastatic cells to enter quiescence and escape NK-mediated immune surveillance. These findings indicate that cancer dormancy is primed during mitosis by pro-metastatic TFs.
Shared and distinct representational dynamics of phonemes and prosody in ventral and dorsal speech streams
Authors: Baek Seung-Cheol , Kim Seung-Goo , Maess Burkhard , Grigutsch Maren , Sammler Daniela 
Published: January 2025

AbstractPhonemes and prosodic contours are fundamental building blocks of speech used to convey complementary meanings. Perceiving these elements is thought to involve a neural abstraction from acoustic to categorical representations, occurring serially in time and segregated in space. Using magnetoencephalography and behavioural psychophysics combined with time-resolved representational similarity and multivariate transfer entropy analyses, we show that the abstraction of phonemic and prosodic information does not fully align with this serial hierarchical processing. Instead, we found partially overlapping acoustic and categorical representations in space and time, for both elements. Notably, building on similarly organised acoustic representations along the ventral stream, categorical representations of prosody extended to right premotor cortex along the dorsal stream, whereas those of phonemes focally involved posterior temporal regions. These results highlight shared principles of joint and distributed processing, yet partially distinct mechanisms for the abstraction of phonemes and prosody, key to access the multilayered meaning of speech.
Cross cell-type systems genetics reveals the influence of eQTL at multiple points in the developmental trajectory of mouse neural progenitor cells
Authors: Aydin Selcan , Skelly Daniel A. , Dewey Hannah , Mahoney J. Matthew , Choi Ted , Reinholdt Laura G. , Baker Christopher L. , Munger Steven C. 
Published: January 2025

AbstractGenetic variation leads to phenotypic variability in pluripotent stem cells that presents challenges for regenerative medicine. Although recent studies have investigated the impact of genetic variation on pluripotency maintenance and differentiation capacity, less is known about how genetic variants affecting the pluripotent state influence gene regulation in later stages of development. Here, we characterized expression of more than 12,000 genes in 127 donor-matched Diversity Outbred (DO) mouse embryonic stem cell (mESC) and neural progenitor cell (mNPC) lines. Quantitative trait locus (QTL) mapping identified 2,947 expression QTL (eQTL) unique to DO mNPCs and 1,113 eQTL observed in both mNPCs and mESCs with highly concordant allele effects. We mapped three eQTL hotspots on Chromosomes (Chrs) 1, 10, and 11 that were unique to mNPCs. Target genes of the Chr 1 hotspot were overrepresented for those involved in mRNA processing, DNA repair, chromatin organization, protein degradation, and cell cycle. Mediation analysis of the Chr 1 hotspot identifiedRnf152as the best candidate mediator expressed in mNPCs, while cross-cell type mediation using mESC gene expression along with partial correlation analysis strongly implicated genetic variant(s) affectingPignexpression in the mESC state as regulating the mNPC Chr 1 eQTL hotspot. Together these findings highlight that many local eQTL confer similar effects on gene expression in multiple cell states; distant eQTL in DO mNPCs are numerous and largely unique to that cell state, with many co-localizing to mNPC-specific hotspots; and mediation analysis across cell types suggests that expression ofPignearly in development (mESCs) shapes the transcriptome of the more specialized mNPC state.