bluuebunny/crossref_metadata_2025_split huggingface dataset:
Glutamine availability regulates cDC subsets in tissue
Authors: Lobel Graham P. , Han Nanumi , Arocho William A. Molina , Silber Michal , Shoush Jason , Noji Michael C. , Jerrick To Tsun Ki , Zhai Li , Lesner Nicholas P. , Simon M. Celeste , Haldar Malay 
Published: September 2024

AbstractProliferating tumor cells take up glutamine for anabolic processes engendering glutamine deficiency in the tumor microenvironment. How this might impact immune cells is not well understood. Using multiple mouse models of soft tissue sarcomas, glutamine antagonists, as well as genetic and pharmacological inhibition of glutamine utilization, we found that the number and frequency of conventional dendritic cells (cDC) is dependent on microenvironmental glutamine levels. cDCs comprise two distinct subsets – cDC1 and cDC2, with the former subset playing a critical role in antigen cross-presentation and tumor immunity. While both subsets show dependence on Glutamine, cDC1s are particularly sensitive. Notably, glutamine antagonism did not reduce the frequency of DC precursors but decreased proliferation and survival of cDC1s. Further studies suggest a role of the nutrient sensing mTOR signaling pathway in this process. Taken together, these findings uncover glutamine dependence of cDC1s that is coopted by tumors to escape immune responses.One Sentence SummaryType 1 conventional dendritic cells require glutamine to maintain their number in non-lymphoid tissue.SignificanceImmune evasion is a key hallmark of cancer; however, the underlying pathways are diverse, tumor-specific and not fully elucidated. Many tumor cells avidly import glutamine to support their anabolic needs, creating a glutamine-deficient tumor microenvironment (TME). Herein, using mouse models of soft tissue sarcomas, we show that glutamine depletion in TME leads to reduced type 1 conventional dendritic cells – a cell type that is critical for adaptive immune responses. This work is a paradigm for how tumor cell metabolism can regulate anti-tumor immune responses and will be foundational to future efforts targeting glutamine metabolism for cancer immunotherapy.
Listening to music modulates visual perception of paintings during binocular rivalry
Authors: Jiang Xintong , Cheng Yuhui , Jiang Yi , Du Yi 
Published: September 2024

AbstractMusic, as a hierarchically organized art form, profoundly influences perception and mood through its rich information and intense emotion. While previous research has demonstrated that music can shape visual perception, its influences on visual awareness in aesthetic scenes remain largely unclear. In a series of five experiments involving 138 participants, we used the binocular rivalry paradigm to investigate how sad or lively Chinese folk music influences the perception of traditional Chinese paintings with varying aesthetic emotion (bleak vs. vivid). Paintings were presented in upright or inverted orientations or replaced by patches. Results revealed that sad music significantly increased both the average dominance duration and the predominance score of bleak paintings. Conversely, lively music with a faster tempo accelerated the switch rate of both paintings and patches. These effects were interdependent, exclusively for meaningful (upright) paintings, and correlated with individual sensitivity to musical reward. Our findings support the hierarchical predictive coding model of binocular rivalry, demonstrating that musical aesthetic emotion exerts top-down modulation, while musical tempo provides bottom-up entrainment, jointly shaping visual awareness of paintings.
High-dimensional Ageome Representations of Biological Aging across Functional Modules
Authors: Ying Kejun , Tyshkovskiy Alexander , Chen Qingwen , Latorre-Crespo Eric , Zhang Bohan , Liu Hanna , Matei-Dediu Benyamin , Poganik Jesse R. , Moqri Mahdi , Kirschne Kristina , Lasky-Su Jessica , Gladyshev Vadim N. 
Published: September 2024

AbstractThe aging process involves numerous molecular changes that lead to functional decline and increased disease and mortality risk. While epigenetic aging clocks have shown accuracy in predicting biological age, they typically provide single estimates for the samples and lack mechanistic insights. In this study, we challenge the paradigm that aging can be sufficiently described with a single biological age estimate. We describe Ageome, a computational framework for measuring the epigenetic age of thousands of molecular pathways simultaneously in mice and humans. Ageome is based on the premise that an organism’s overall biological age can be approximated by the collective ages of its functional modules, which may age at different rates and have different biological ages. We show that, unlike conventional clocks, Ageome provides a high-dimensional representation of biological aging across cellular functions, enabling comprehensive assessment of aging dynamics within an individual, in a population, and across species. Application of Ageome to longevity intervention models revealed distinct patterns of pathway-specific age deceleration. Notably, cell reprogramming, while rejuvenating cells, also accelerated aging of some functional modules. When applied to human cohorts, Ageome demonstrated heterogeneity in predictive power for mortality risk, and some modules showed better performance in predicting the onset of age-related diseases, especially cancer, compared to existing clocks. Together, the Ageome framework offers a comprehensive and interpretable approach for assessing aging, providing insights into mechanisms and targets for intervention.
A human homolog of SIR2 antiphage proteins mediates immunity via the TLR pathway
Authors: Bonhomme Delphine , Vaysset Hugo , Ednacot Eirene Marie Q. , Rodrigues Vasco , Cury Jean , Trejo Veronica Hernandez , Benaroch Philippe , Morehouse Benjamin R. , Bernheim Aude , Poirier Enzo Z. 
Published: September 2024

AbstractThe full extent of immune system conservation between prokaryotes and eukaryotes is unknown. However, recent research supports that a subset of bacterial antiphage proteins is conserved in eukaryotes and likely gave rise to key actors of mammalian immunity. Here, we show that the SIR2 protein domain, present in bacterial antiphage systems, plays a role in eukaryotic innate immunity. Through phylogenetic analysis, we identify SIRanc, a human protein with a SIRim domain (subtype of SIR2). We demonstrate that SIRanc plays a pivotal role in the animal toll-like receptor (TLR) pathway of innate immunity by mediating the transcriptional upregulation of proinflammatory genes downstream of TLR stimulation. This depends on the enzymatic activity of SIRanc, which degrades NAD+, a central cellular metabolite. Finally, we show that proteins with a SIRim domain are diverse and widespread, detected in 19% of eukaryotic genomes, with SIRanc representing one of the five sirim lineages. This work opens avenues of research on the potential role of eukaryotic SIRim proteins in immunity, as well as on the involvement of SIRanc in human pathology.
A neural network model for the evolution of reconstructive social learning
Authors: Chisausky Jacob , Daras Inès Marguerite , Weissing Franz J. , Kozielska Magdalena 
Published: September 2024

AbstractLearning from others is an important adaptation. However, the evolution of social learning and its role in the spread of socially transmitted information are not well understood. Few models of social learning account for the fact that socially transmitted information must be reconstructed by the learner, based on the learner’s previous knowledge and cognition. To represent the reconstructive nature of social learning, we present a modelling framework that incorporates the evolution of a neural network and a simple yet biologically realistic learning mechanism. The framework encompasses various forms of individual and social learning and allows the investigation of their interplay. Individual-based simulations reveal that an effective neural network structure rapidly evolves, leading to adaptive inborn behaviour in static environments, pure individual learning in highly variable environments, and a combination of individual and social learning in environments of intermediate stability. However, the evolutionary outcome depends strongly on the type of social learning (social guidance versus social instruction) and the order of individual and social learning. Moreover, the evolutionary dynamics of social learning can be surprisingly complex, with replicate simulations converging to alternative outcomes. We discuss the relevance of our modelling framework for cultural evolution and suggest future avenues of research.
Nucleus accumbens astrocytes bidirectionally modulate social behavior
Authors: VanRyzin Jonathan W , Reissner Kathryn J 
Published: September 2024

ABSTRACTSocial behaviors are critical for survival and fitness of a species, and maladaptive social behaviors are frequently associated with neurodevelopmental and psychiatric disorders. As such, the neural circuits and cellular mechanisms driving social behaviors inform critical processes contributing to both health and disease. In particular, the nucleus accumbens (NAc) is a key hub for the integration of both social and non-social information required for successful social interactions and reward motivated behaviors. While astrocytes within the NAc have a recognized role in modulating neural activity, their influence over social behavior is yet undefined. To address this question, we manipulated NAc astrocyte signaling and determined effects on social interactions. NAc core astrocytes bidirectionally influenced social behavior in rats; agonism of astrocyte-specific hM3D(Gq) DREADD receptors increased social interaction time in the social interaction test and increased social preference in the 3-chamber test. Conversely, decreasing intracellular calcium signaling in astrocytes with viral expression of hPMCA reduced both social interaction and social preference in these tests. These results suggest that NAc astrocytes actively participate in the regulation of social behavior and highlight a putative role for astrocytes in disorders characterized by social dysfunction.
T-cell receptors identified by a personalized antigen-agnostic screening approach target shared neoantigen KRAS Q61H
Authors: Lennerz Volker , Doppler Christoph , Fatho Martina , Dröge Anja , Schaper Sigrid , Gennermann Kristin , Genzel Nadine , Plassmann Stephanie , Weismann David , Lukowski Samuel W. , Bents Dominik , Beushausen Christina , Kriese Karen , Herbst Hermann , Seitz Volkhard , Hammer Rudolf , Adam Paul J. , Eggeling Stephan , Wölfel Catherine , Wölfel Thomas , Hennig Steffen 
Published: September 2024

AbstractAdoptive cell therapy (ACT) with TCR-engineered T-cells represents a promising alternative to TIL- or CAR-T therapies for patients with advanced solid cancers. Currently, selection of therapeutic TCRs critically depends on knowing the target antigens, a condition excluding most patients from treatment. Direct antigen-agnostic identification of tumor-specific T-cell clonotypes and TCR-T manufacturing using their TCRs can advance ACT for patients with aggressive solid cancers. We present a method to identify tumor-specific clonotypes from surgical specimens by comparing TCRβ-chain repertoires of TILs and adjacent tissue-resident lymphocytes. In seven NSCLC-patients, tumor-specific clonotypes were selected based on TIL-abundance and high tumor-to-nontumor frequency ratios. In two of the patients, we demonstrate that predicted tumor-specific clonotypes reacted against autologous tumors. In a third patient, we engineered TCR T-cells with four candidate tumor-specific TCRs that showed reactivity against the patient’s tumor and HLA-matched NSCLC cell lines. The TCR-T cells were then used to screen for candidate neoantigens and aberrantly expressed antigens. Three TCRs recognized recurrent driver-mutation KRAS Q61H-peptide ILDTAGHEEY presented by HLA-A*01:01. The TCRs were also dominant in a tumor relapse, one was found in cell free DNA. The finding of homologous TCRs in independent KRAS Q61H-positive cancers suggests a therapeutic opportunity for HLA-matched patients with KRAS Q61H-expressing tumors.
Increased neuronal expression of the early endosomal adaptor APPL1 leads to endosomal and synaptic dysfunction with cholinergic neurodegeneration
Authors: Jiang Ying , Sachdeva Kuldeep , Goulbourne Chris N. , Berg Martin J. , Peddy James , Stavrides Philip H. , Pensalfini Anna , Pawlik Monika , Whyte Lauren , Balapal Basavaraj S. , Shivakumar Subbanna , Bleiwas Cynthia , Smiley John F. , Mathews Paul M. , Nixon Ralph A. 
Published: September 2024

AbstractDysfunction of the endolysosomal system within neurons is a prominent feature of Alzheimer’s disease (AD) pathology. Multiple AD-risk factors are known to cause hyper-activity of the early-endosome small GTPase rab5, resulting in neuronal endosomal pathway disruption. APPL1, an important rab5 effector protein, is an interface between endosomal and neuronal function through a rab5-activating interaction with the BACE1-generated C-terminal fragment (βCTF or C99) of the amyloid precursor protein (APP), a pathogenic APP fragment generated within endolysosomal compartments. To better understand the role of APPL1 in the AD endosomal phenotype, we generated a transgenic mouse model over-expressing human APPL1 within neurons (Thy1-APPL1 mice). Consistent with the important endosomal regulatory role of APPL1, Thy1-APPL1 mice have enlarged neuronal early endosomes and increased synaptic endocytosis due to increased rab5 activation. We additionally demonstrate pathological consequences of APPL1 overexpression, including functional changes in hippocampal long-term potentiation (LTP) and long-term depression (LTD), as well as degeneration of the large projection cholinergic neurons of the basal forebrain and impairment of hippocampal-dependent memory. Our findings show that increased neuronal APPL1 levels lead to a cascade of pathological effects within neurons, including early endosomal alterations, synaptic dysfunction, and neurodegeneration. Multiple risk factors and molecular regulators, including APPL1 activity, are known to contribute to the endosomal dysregulation seen in the early stages of AD, and these findings further highlight the shared pathobiology and consequences to a neuron of early endosomal pathway disruption.Significance StatementDysfunction in the endolysosomal system within neurons is a key feature of Alzheimer’s disease (AD). Multiple AD risk factors lead to hyperactivity of the early-endosome GTPase rab5, disrupting neuronal pathways including the cholinergic circuits involved early in memory decline. APPL1, a crucial rab5 effector, connects endosomal and neuronal functions through its interaction with a specific amyloid precursor protein (APP) fragment generated within endosomes. To understand APPL1’s role, a transgenic mouse model over-expressing human APPL1 in neurons (Thy1-APPL1 mice) was developed. These mice show enlarged early endosomes and increased synaptic endocytosis due to rab5 activation, resulting in impaired hippocampal long-term potentiation and depression, the degeneration of basal forebrain cholinergic neurons, and memory deficits, highlighting a pathological cascade mediated through APPL1 at the early endosome.
Comprehensive Mutational Landscape Analysis of Monkeypox Virus Proteome
Authors: Ozaktas Tugba , Dizkirici Ayten , Carbone Alessandra , Tekpinar Mustafa 
Published: September 2024

AbstractWe present a comprehensive computational analysis of the single point mutational landscapes of the Monkeypox virus (MPXV) proteome. We reconstructed full single-point mutational landscapes of 171 MPXV proteins using two advanced mutational effect predictors, ESCOTT and iGEMME, selected for their superior performance on viral proteins, assessed by benchmarking against the experimental data in the ProteinGym (v1.0.0) dataset. A recent MPXV strain sequenced in July 2024 was used as the reference genome. Multiple sequence alignments and protein structures were generated using Colabfold v1.5.5, and the predicted structures were evaluated with pLDDT metric, secondary structure predictions, and comparisons with available experimental data, ensuring high confidence in the structural models. To prioritize the most mutation-sensitive proteins within the large MPXV proteome as prime candidates for drug or vaccine development, we introduced a novel, interpretable metric: Average Gene Mutation Sensitivity (AGMS). Among the top 20 identified proteins, several were membrane-associated proteins, expected to be important for viral interactions with the hosts. This analysis provides a valuable resource for assessing the impact of new MPXV variants and guiding therapeutic strategies. This pioneering study underscores the significance of understanding MPXV evolution in the context of the ongoing global health crisis and offers a robust computational framework to support this effort.
A unified rodent atlas reveals the cellular complexity and evolutionary divergence of the dorsal vagal complex
Authors: Hes Cecilia , Tomlinson Abigail J. , Michielsen Lieke , Murdoch Hunter J. , Soltani Fatemeh , Kokoeva Maia , Sabatini Paul V. 
Published: September 2024

AbstractThe dorsal vagal complex (DVC) is a region in the brainstem comprised of an intricate network of specialized cells responsible for sensing and propagating many appetite-related cues. Understanding the dynamics controlling appetite requires deeply exploring the cell types and transitory states harbored in this brain site. We generated a multi-species DVC cell atlas using single nuclei RNAseq (sn-RNAseq), by curating and harmonizing mouse and rat data, which includes >180,000 cells and 123 cell identities at 5 granularities of cellular resolution. We report unique DVC features such asKcnj3expression in Ca+-permeable astrocytes as well as new cell populations like neurons co-expressingThandCck, and a leptin receptor-expressing neuron population in the rat area postrema which is marked by expression of the progenitor marker,Pdgfra. In summary, our findings demonstrate a high degree of complexity within the DVC and provide a valuable tool for the study of this metabolic center.
Decoding Parametric Grip-Force Anticipation from fMRI-Data
Authors: Caccialupi Guido , Schmidt Timo Torsten , Nierhaus Till , Wesolek Sara , Esmeyer Marlon , Blankenburg Felix 
Published: September 2024

ABSTRACTPrevious functional magnetic resonance imaging (fMRI) studies have shown that activity in premotor and parietal brain-regions covaries with the intensity of upcoming grip-force. However, it remains unclear how information about the intended grip-force intensity is initially represented and subsequently transformed into a motor code before motor-execution. In this fMRI study, we used multivoxel pattern analysis (MVPA) to decode where and when information about grip-force intensities is parametrically coded in the brain. Human participants performed a delayed grip-force task in which one of four cued levels of grip-force intensity had to be maintained in working memory (WM) during a 9-second delay-period preceding motor execution. Using time-resolved MVPA, with a searchlight approach and support vector regression (SVR), we tested which brain regions exhibit multivariate WM codes of anticipated grip-force intensities. During an early delay-period, we observed above-chance decoding in the ventromedial prefrontal cortex (vmPFC). During a late delay-period, we found a network of action-specific brain regions, including the bilateral intraparietal sulcus (IPS), left dorsal premotor cortex (l-PMd) and supplementary motor areas (SMA). Additionally, cross-regression decoding was employed to test for temporal generalization of activation patterns between early and late delay-periods with those during cue presentation and motor execution. Cross-regression decoding indicated temporal generalization to the cue-period in the vmPFC, and to motor-execution in the l-IPS and l-PMd. Together, these findings suggest that the WM representation of grip-force intensities undergoes a transformation where the vmPFC encodes information about the intended grip-force, which is subsequently converted into a motor code in the l-IPS and l-PMd before execution.
EFFECTS OF SPINAL TRANSECTION AND LOCOMOTOR SPEED ON MUSCLE SYNERGIES OF THE CAT HINDLIMB
Authors: Klishko Alexander N. , Harnie Jonathan , Hanson Claire E. , Rahmati S. Mohammadali , Rybak Ilya A. , Frigon Alain , Prilutsky Boris I. 
Published: September 2024

AbstractIt was suggested that during locomotion, the nervous system controls movement by activating groups of muscles, or muscle synergies. Analysis of muscle synergies can reveal the organization of spinal locomotor networks and how it depends on the state of the nervous system, such as before and after spinal cord injury, and on different locomotor conditions, including a change in speed. The goal of this study was to investigate the effects of spinal transection and locomotor speed on hindlimb muscle synergies and their time-dependent activity patterns in adult cats. EMG activities of 15 hindlimb muscles were recorded in 9 adult cats of either sex during tied-belt treadmill locomotion at speeds of 0.4, 0.7, and 1.0 m/s before and after recovery from a low thoracic spinal transection. We determined EMG burst groups using cluster analysis of EMG burst onset and offset times and muscle synergies using non-negative matrix factorization. We found five major EMG burst groups and five muscle synergies in each of six experimental conditions (2 states x 3 speeds). In each case, the synergies accounted for at least 90% of muscle EMG variance. Both spinal transection and locomotion speed modified subgroups of EMG burst groups and the composition and activation patterns of selected synergies. However, these changes did not modify the general organization of muscle synergies. Based on the obtained results, we propose an organization for a pattern formation network of a two-level central pattern generator that can be tested in neuromechanical simulations of spinal circuits controlling cat locomotion.