Biology subjects

Chen, C.

Publications and source records attributed to Chen, C..

At least 217 records · Page 12Linked to original sources

bioRxiv2025

Transient centrosome loss in cultured prostate epithelial cells induces chromosomal instability to produce an oncogenic genotype that correlates with poor clinical outcomes

Chromosomal instability (CIN) is a hallmark of prostate cancer that strongly correlates with metastatic burden and appears prominently in both primary cancer and metastatic disease. Low Gleason score primary prostate tumors display pervasive centrosome loss, a known mechanistic driver of CIN, that disrupts normal spindle assembly and increases mitotic errors. Previously, we found that transient depletion of centrosomes in immortalized, non-tumorigenic prostate epithelial cells (PrEC) induced a burst of CIN, generating cell lines capable of forming xenograft tumors. Here, we use a multi-omics approach to identify the oncogenic alterations caused by transient centrosome loss. By integrating genomic and transcriptomic data of the prostate lines, we identified a consensus set of focal copy-number variations (CNVs) induced by centrosome loss in cultured cells that are also detectable within a subset of samples from a prostate cancer patient cohort. Using this CNV signature, we were able to derive a unique transcriptomic signature from prostate cancer patient samples that showed strong predictive value for adverse clinical outcomes. In summary, our experimental system uses centrosome loss to promote a punctuated burst of genomic crisis that is characteristic of genome evolution during prostate cancer progression. Consequently, this prostate cancer model produced recurrent structural variations that are detectable in patient samples and associate with worse outcomes. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/653266v1_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@ac4c9org.highwire.dtl.DTLVardef@fd9961org.highwire.dtl.DTLVardef@160e20corg.highwire.dtl.DTLVardef@198bf0e_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

A Foraging-Theory Based Model Captures The Full Spectrum of Human Behavioral Diversity in a Classic RL Task

Decision-making tasks involving multiple, simultaneously presented options are mainstays of cognitive neuroscience and psychology and are increasingly important to the emerging field of computational psychiatry. Modeling approaches to these tasks overwhelmingly assume that participants make choices based on explicitly comparing the values of the presented options. Contrary to this long-held assumption, we found instead that humans employ a compare-to-threshold decision process, similar to theories of foraging, when making sequential decisions about concurrently available options. We confirmed this result in a large (1000 participant) dataset with multiple converging lines of evidence comparing both model fits and model generative performance. Value-comparison models were restricted to a reduced area of the potential space of single-trial outcome-dependent behavior, demonstrating an intrinsic limitation in the ability to reproduce strategy diversity. Furthermore, we found that using even the best-fit value-comparison model led to a substantial, systematic bias and a compression of individual differences in reconstructed behavior compared to the foraging-based model, leading to weaker predictions of behavioral health measures. Our results imply that studies using value-comparison models to link behavior with neural activity or psychiatric symptoms may be less sensitive to individual differences than a simple alternative based on ethological foraging.

neuroscience↗

bioRxiv2025

Integrated Classification of Cortical Cells and Quantitative Projectomic Mapping Unveil Organizational Principles of Brain-Wide Connectomes at Single Cell Level

Molecularly defined cortical cell types have recently been linked to whole neuronal morphology (WNM), particularly those characterized by whole-brain-wide projections, such as intratelencephalic (IT), extratelencephalic (ET), and corticothalamic (CT) neurons. In contrast, classical morphological classifications (e.g., tufted TPC, small tufted SPC, and stellate SSC) are based primarily on local dendrosomatic and axonal structures, especially apical dendrites. This study bridges these perspectives by establishing a new neuronal taxonomy, analyzing the connectomes of defined cortical cell types, and comparing them with those obtained from bulk anterograde injections. Neurons were sparsely labeled via tamoxifen-inducible Cre lines with GFP reporters, and 1,419 WNM cells were comprehensively reconstructed with Vaa3D-TeraVR from [~]15 areas across six functional regions of molecularly labeled brains imaged with 2p-fMOST. These cells were newly classified by integrating current molecular-WNM and classical morphological perspectives, with sample size augmented by 1,455 publicly available WNM cells reconstructed from the Mouse-Light project and CEBSIT. This effort defined ten combined molecular-WNM-classical morphological cell types: L5ET_TPC, L6CT_NPC, L6b_HPC, and seven IT types--L2/3IT_TPC, L4IT_SSC, L4IT_UPC, L4IT_TPC, L5IT_SPC, L6IT_IPC, and L6IT_car3PC. Clustering, quantitative analyses and random Forest classifier objectively validated these types and revealed their distinct connectomes, along with convergent, topographic, and hierarchical organizations across their projection brain regions. At the single-cell level, multiple organizational principles governing cortico-cortical (C-C) and cortico-subcortical (C-subC) connectomes emerged with unprecedented detail, offering a precise GPS-like tool for in vivo recordings and robust datasets for neuronal network modeling. Comparisons with bulk anterograde injection data underscored the limitations of traditional methods in identifying projection targets. Overall, our approach provides significant insights into cortical circuitry and elucidates the complex interplay between neuronal molecular identity, whole morphology, and classical morphological classification.

neuroscience↗

bioRxiv2025

The China Brain Multi-omics Atlas Project (CBMAP)

The China Brain Multi-omics Atlas Project (CBMAP) aims to generate a comprehensive molecular reference map of over 1,000 human brains (Phase I), spanning a broad age range and multiple regions in China, to address the underrepresentation of East Asian populations in brain research. By integrating genome, epigenome, transcriptome, proteome (including multiple post-translational modifications), and metabolome data, CBMAP is set to provide a rich and invaluable resource for investigating the molecular underpinnings of aging-related brain phenotypes and neuropsychiatric disorders. Leveraging high-throughput omics data and advanced technologies, such as spatial transcriptomics, proteomics, and single-nucleus 3D chromatin structure analysis, this atlas will serve as a crucial resource for the brain science community, illuminating disease mechanisms and enhancing the utility of data from genome-wide association studies (GWAS). CBMAP is also poised to accelerate drug discovery and precision medicine for brain disorders.

neuroscience↗

bioRxiv2025

Multi-cohort, multi-sequence harmonisation for cerebrovascular brain age

IntroductionHigher brain-predicted age gaps (BAG), based on anatomical brain scans, have been associated with cognitive decline among elderly participants. Adding a cerebrovascular component, in the form of arterial spin labelling (ASL) perfusion MRI, can improve the BAG predictions and potentially increase sensitivity to cardiovascular health, a contributor to brain ageing and cognitive decline. ASL acquisition differences are likely to influence brain age estimations, and data harmonisation becomes indispensable for multi-cohort brain age studies including ASL. In this multi-cohort, multi-sequence study, we investigate harmonisation methods to improve the generalisability of cerebrovascular brain age. MethodsA multi-study dataset of 2608 participants was used, comprising structural T1-weighted (T1w), FLAIR, and ASL 3T MRI data. The single scanner training dataset consisted of 806 healthy participants, age 50{+/-}17, 18-95 years. The testing datasets comprised four cohorts (n=1802, age 67{+/-}8, 37-90 years). Image features included grey and white matter (GM/WM) volumes (T1w), WM hyperintensity volumes and counts (FLAIR), and ASL cerebral blood flow (CBF) and its spatial coefficient of variation (sCoV). Feature harmonisation was performed using NeuroComBat, CovBat, NeuroHarmonize, OPNested ComBat, AutoComBat, and RELIEF. ASL-only and T1w+FLAIR+ASL brain age models were trained using ExtraTrees. Model performance was assessed through the mean absolute error (MAE) and mean BAG. ResultsASL feature differences between cohorts decreased after harmonisation for all methods (p<0.05), mostly for RELIEF. Negative associations between age and GM CBF (b=-0.37, R2=0.13, unharmonised) increased after harmonisation for all methods (b<-0.42, R2>0.12) but weakened for RELIEF (b=-0.28, R2=0.14). In the ASL-only model, MAE improved for all harmonisation methods from 11.1{+/-}7.5 years to less than 8.8{+/-}6.2 years (p<0.001), while BAGs changed from 0.6{+/-}13.4 years to less than -1.03{+/-}7.92 years (p<0.001). For T1w+FLAIR+ASL, MAE (5.9{+/-}4.6 years, unharmonised) increased for all harmonisation methods non-significantly to above 6.0{+/-}4.9 years (p>0.42) and significantly for RELIEF (6.4{+/-}5.2 years, p=0.02), while BAGs non-significantly differed from -1.6{+/-}7.3 years to between -1.3{+/-}4.7 and -2.0{+/-}8.0 years (p>0.82). In general, the ASL-specific parameter harmonisation method AutoComBat performed nominally best. DiscussionHarmonisation of ASL features improves feature consistency between studies and also improves brain age estimations when only ASL features are used. ASL-specific parameter harmonisation methods perform nominally better than basic mean and scale adjustment or latent-factor approaches, suggesting that ASL acquisition parameters should be considered when harmonising ASL data. Although multi-modal brain age estimations were improved less by ASL-only harmonisation, possibly due to weaker associations between age and ASL features compared to T1w features feature importance, studies investigating pathological ASL-feature distributions might still benefit from harmonisation. These findings advocate for ASL-parameter specific harmonisation to explore associations between cardiovascular risk factors, brain ageing, and cognitive decline using multi-cohort ASL and cerebrovascular brain age studies.

neuroscience↗

bioRxiv2025

The C. elegans gustatory receptor homolog LITE-1 is a chemoreceptor required for diacetyl avoidance

The nematode C. elegans does not have eyes but can respond to aversive UV and blue light stimulation and even distinguish colours. The gustatory receptor homolog LITE-1 was identified in forward genetic screens for worms that failed to respond to blue light stimulation. When LITE-1 is expressed in body-wall muscles, it causes contraction in response to blue light suggesting that LITE-1 is both necessary and sufficient for blue light response. Here we show that in addition to light avoidance, LITE-1 is also required for worms avoidance of high concentrations of diacetyl, an odorant that is attractive at low concentrations. Like blue light, diacetyl causes muscle contraction in transgenic worms engineered to express LITE-1 in body-wall muscles. These data are consistent with a direct chemoreceptor function for LITE-1 which would make it a multimodal sensor of aversive stimuli.

neuroscience↗

bioRxiv2025

Interprotomer Crosstalk in Mosaic Viral Glycoprotein Trimers Provides Insight into Polyvalent Immunogen Co-assembly

SARS-CoV-2 variants have demonstrated the ability to evade immune responses, leading to waves of infection throughout the pandemic. In response, bivalent mRNA vaccines, encoding the original Wuhan-Hu-1 and emerging variants, were developed to display both spike antigens. To date, it has not been determined whether co-transfection and co-translation of different SARS-CoV-2 variants results in co-assembly of mosaic heterotrimer antigens and how this may affect trimer stability, dynamics, and antigenicity. Understanding whether such mosaic heterotrimers can form and their implications for antigen structure can provide important information to guide future polyvalent vaccine design where multiple variants of an antigen are co-formulated. To investigate this, we purified mosaic spike assemblies of both genetically close (Omicron BA.2 and XBB) and distant (Omicron BA.2 and Wuhan-Hu-1 G614) strains. We found that the stability and integrity of mosaic spike trimers were maintained without misfolding or aggregation. Glycosylation profiles likewise were preserved relative to the homotrimer counterparts. Hydrogen/deuterium-exchange mass spectrometry and biolayer-interferometry were used to investigate the mosaic spike dynamics and any impact on epitope presentation and receptor binding. The Omicron-XBB heterotrimer, sharing a common fusion subunit sequence, retained protomer-specific dynamics similar to the corresponding homotrimers in antigenically important regions. The Omicron-G614 heterotrimer, co-assembling from protomers of divergent fusion subunit sequences, likewise showed overall similar dynamics and conformations in the receptor-binding subunit compared to the homotrimers. However, the incorporation of the Wuhan-Hu-1 G614 protomer led to a stabilizing effect on the relatively unstable Omicron fusion subunit in the heterotrimer. These findings reveal structural dynamic crosstalk in mosaic trimers, suggesting a potential for enhanced immunogen display and important considerations to be aware of in the use of polyvalent nucleic acid vaccines. Author summaryHere we investigated the possibility of immunogen co-assembly from bivalent nucleic acid vaccines with a focus on probing potential impacts on antigen stability and epitope display. We purified mosaic heterotrimers composed of Omicron BA.2 and Wuhan-Hu-1 G614 protomers as well as those composed of Omicron BA.2 and XBB protomers. Both mosaic heterotrimers maintained their structural integrity, morphology, and N-glycosylation profiles. Using hydrogen/deuterium-exchange mass spectrometry, we demonstrated that both types of heterotrimers preserved strain-specific dynamics in critical antigenic regions, comparable to their homotrimer counterparts. Crosstalk between fusion subunits of Omicron BA.2 and Wuhan-Hu-1 G614 revealed a stabilizing effect of the G614 protomer on the inherently less stable fusion subunit in Omicron. Our findings provide insight into the structural dynamic profiles of co-expressed immunogen display, highlighting important considerations for polyvalent formulations that are being pursued to provide broad protection against highly variable pathogens.

microbiology↗

bioRxiv2025

Cell-type-specific transposable element demethylation and TAD remodeling in the aging mouse brain

Aging is a major risk factor for neurodegenerative diseases, yet underlying epigenetic mechanisms remain unclear. Here, we generated a comprehensive single-nucleus cell atlas of brain aging across multiple brain regions, comprising 132,551 single-cell methylomes and 72,666 joint chromatin conformation-methylome nuclei. Integration with companion transcriptomic and chromatin accessibility data yielded a cross-modality taxonomy of 36 major cell types. We observed that age-related methylation changes were more pronounced in non-neuronal cells. Transposable element methylation alone distinguished age groups, showing cell-type-specific genome-wide demethylation. Chromatin conformation analysis demonstrated age-related increases in TAD boundary strength with enhanced accessibility at CTCF binding sites. Spatial transcriptomics across 895,296 cells revealed regional heterogeneity during aging within identical cell types. Finally, we developed novel deep-learning models that accurately predict age-related gene expression changes using multi-modal epigenetic features, providing mechanistic insights into gene regulation. This dataset advances our understanding of brain aging and offers potential translational applications. HighlightsO_LISingle-cell multi-omic profiling maps the epigenetic and spatial transcriptomic landscape of brain aging across multiple regions. C_LIO_LICell-type-specific genome-wide demethylation of retrotransposable elements correlates with increased chromatin accessibility and expression. C_LIO_LIElevated TAD boundary strength emerges as a unique marker of brain aging associated with CTCF gaining accessibility. C_LIO_LIA novel deep-learning model reveals the significance of epigenetic features on age-related transcriptomic changes across genes. C_LI

genomics↗

bioRxiv2025

Directed Chemical Evolution via Navigating Molecular Encoding Space

Deep-learning techniques have significantly advanced small-molecule drug discovery. However, a critical gap remains between representation learning and small molecule generations, limiting their effectiveness in developing new drugs. We introduce Ouroboros, a unified framework that integrates molecular representation learning with generative modeling, enabling efficient chemical space exploration using pre-trained molecular encodings. By reframing molecular generation as a process of encoding space compression and decompression, Ouroboros resolves the challenges associated with iterative molecular optimization and facilitates directed chemical evolution within the encoding space. Comprehensive experimental tests demonstrate that Ouroboros significantly outperforms conventional approaches across multiple drug discovery tasks, including ligand-based virtual screening, chemical property prediction, and multi-target inhibitor design and optimization. Unlike task-specific models in traditional approaches, Ouroboros leverages a unified framework to achieve superior performance across diverse applications. Ouroboros offers a novel and highly scalable protocol for rapid chemical space exploration, fostering a potential paradigm shift in AI-driven drug discovery.

bioinformatics↗

bioRxiv2025

Pangenome analyses of tea plant reveal structural variations driven gene expression alterations and agronomic trait diversification

Tea plants, one of the worlds most economically significant beverage crops, exhibit extensive genetic diversity and a rich array of secondary metabolites. While structural variations (SVs) are key drivers of phenotypic innovation, their regulatory roles in transcriptional networks and agronomic trait diversification remain underexplored in this perennial crop. We constructed a pangenome from 21 representative tea accessions and their wild relatives. Comparative analysis revealed that wild relatives harbor a greater abundance of gibberellin-related genes, whereas cultivated accessions exhibit an expansion of defense-related genes. We identified 522,428 non-redundant SVs, primarily insertions/deletions (73.56%), which were enriched in promoter regions. These SVs influenced the expression of genes governing flavor compounds, including those involved in flavonoid, amino acid, and terpenoid biosynthesis. Population SV analysis of 275 tea accessions uncovered three haplotypes in the ANS3 gene promoter region, with Hap1, containing a 192 bp insertion, predominantly found in wild relatives but largely lost in modern cultivars. This insertion enhanced CtANS3 expression, increasing anthocyanin accumulation. Additionally, a 159 bp insertion in the CtLRR1 promoter reduced resistance to Colletotrichum gloeosporioides in wild relatives. Our findings underscore SVs as pivotal regulators of genomic diversity, flavor differentiation, and adaptive evolution in tea plant domestication.

genomics↗

bioRxiv2025

FOSL2 Directly Regulates FSHR and CYP11A1 Transcription: An Essential Transcription Factor for Gonadotropin-Dependent Folliculogenesis

The meticulous orchestration of gonadotropin-dependent folliculogenesis constitutes the cornerstone of female reproductive cyclicity and fertility, with FSH/FSHR signaling recognized as the master regulator. Achieving the necessary amplification of this signaling is essential for successful GTH-dependent folliculogenesis, yet the mechanisms remain inadequately defined. Our study utilizes single-cell and spatial transcriptomics to identify FOSL2 as an FSH-inducible transcription factor, exhibiting precise spatiotemporal co-expression with FSHR. FOSL2 knockdown in vitro resulted in notable reductions in granulosa cell proliferation, induced apoptosis, and disrupted gonadotropin-dependent folliculogenesis. In vivo studies using conditional FOSL2 deletion in mouse granulosa cells corroborated these results, demonstrating a complete halt in GTH-dependent folliculogenesis and resultant infertility. Mechanistic exploration unveiled that FSH/FSHR initiates FOSL2 expression via the cAMP/PKA/CREB cascade, while FOSL2 in turn enhances FSHR transcription through direct promoter binding, thereby establishing a self-amplifying loop. This loop represents a molecular switch, modeled to the all-or-nothing dynamics of GTH-dependent folliculogenesis. The evolutionary conservation of this mechanism was confirmed through cross-species analyses in sheep, where FOSL2 deficiency similarly attenuated FSH/FSHR signaling and inhibited follicular growth. Our findings advance the understanding of folliculogenesis by revealing a novel FOSL2-centered amplification loop for FSH/FSHR signaling, highlighting the indispensable role of FOSL2 in reproductive biology.

cell biology↗

bioRxiv2025

Brainstem circuit for sickness-induced sleep

Increased sleep induced by immune activation plays a crucial role in facilitating recovery from illness. However, the neural mechanisms underlying sickness-induced sleep remain poorly understood. Here, we identify a brainstem circuit originating in the nucleus of the solitary tract (NST) that mediates sickness-induced sleep. Using activity-dependent genetic labeling, we tagged NST neurons activated by lipopolysaccharide (LPS) injection and showed that their chemogenetic activation strongly promotes non-rapid eye movement (NREM) sleep. These NST neurons project extensively to the parabrachial nucleus (PB), where LPS-activated neurons also promote NREM sleep. Fiber photometry imaging of several wake-promoting neuromodulators using their biosensors showed that evoked norepinephrine (NE) release from locus coeruleus (LC) neurons is markedly reduced by either LPS injection or direct activation of NST or PB sickness neurons. These results suggest that sickness-induced sleep is mediated in part by a brainstem circuit that regulates neuromodulator signaling.

neuroscience↗

bioRxiv2025

The Genetic Basis of Chloride Exclusion in Grapevines

Mediterranean regions are among the most important areas for global grape production, characterized by dry climates and frequent challenges associated with soil salinity. In these environments, chloride toxicity is a major factor limiting vine growth and fruit quality. Despite the critical role of chloride exclusion in salinity tolerance, the genetic mechanisms underlying this trait remain poorly understood. In this study, we leveraged one of the largest Vitis germplasm collections, comprising 335 accessions from 18 wild and cultivated Vitis species, to characterize natural variation in chloride exclusion. This diverse panel, which includes accessions from the southwestern United States and Mexico, captures a broad range of evolutionary adaptations to abiotic stress, providing an unprecedented opportunity to investigate the genetic basis of salinity tolerance. Using genome-wide association (GWA) and quantitative trait loci (QTL) mapping, we identified a major QTL on chromosome 8 containing candidate genes encoding cation/H exchangers (CHX), which are involved in ion transport and homeostasis. To validate these findings, we analyzed a mapping population derived from V. acerifolia longii 9018 and the commercial rootstock GRN3, confirming the chromosome 8 locus as a major determinant of chloride exclusion. Structural variant analysis revealed key non-synonymous substitutions within CHX genes, suggesting potential functional roles in salinity tolerance. Additionally, we discovered a novel QTL on chromosome 19 enriched with G-type lectin S-receptor-like serine/threonine-protein kinases, known regulators of stress signaling. By integrating extensive phenotypic and genomic data across a diverse Vitis collection, this study provides novel insights into the genetic architecture of chloride exclusion and identifies valuable candidate genes for breeding salt-tolerant rootstocks.

genetics↗

bioRxiv2025

Muscle Activation of Upper Body in Different-Angle Suspension Push-Ups: An Analysis of Angle-Specific Muscle Engagement

The aim of this study was to understand the effect on upper body muscle activation of bodily angle during push-ups performed with TRX suspension training. Nineteen men (age: 21.1 {+/-} 1.2 years; height: 174.1 {+/-} 4.9 cm; weight: 70.7 {+/-} 7.2 kg) with resistance training experience participated in this study. The participants were required to perform five push-ups on a stable surface and with TRX at five angles (+30{degrees}, +15{degrees}, 0{degrees}, -15{degrees}, and -30{degrees}, where 0{degrees} indicates that the shoulder joints were at the same height as the ankle joints when the arms were extended). The recovery period between the sets at each angle was 3-5 minutes. Stable-surface and TRX push-ups were separated by at least 48 hours. During push-ups, electromyography (EMG) data from the pectoralis major (PM), anterior deltoids (AD), triceps brachii (TRI), upper trapezius (UT), and serratus anterior (SA) were recorded. Muscle activation was indicated by the percentage of maximum voluntary isometric contraction (%MVIC). The %MVIC of each muscle group was then categorized. Repeated-measured two-way analysis of variance was used to determine differences in the muscle group activation between the push-up surface types and five angles. Statistical significance was set at p < .05. The activation of the PM, AD, and TRI during TRX push-ups was categorized as medium to extremely high. Compared with that for stable-surface push-ups, the activation of the PM during TRX push-ups was significantly higher (p < .05). Furthermore, +30{degrees}, +15{degrees}, and 0{degrees} push-ups produced greater PM activation than push-ups at lower angles (p < .05). Both TRX and stable-surface push-ups resulted in greater anterior deltoids, TRI, UT, and SA activation during -30{degrees} push-ups. This study indicates the appropriate push-up practices for different muscle groups, as determined by quantifying the muscle activation.

physiology↗

bioRxiv2025

cxcl18b-defined transitional state-specific nitric oxide drives injury-induced Müller glia cell-cycle re-entry in the zebrafish retina

In lower vertebrates, retinal Muller glia (MG) exhibit a life-long capacity of cell-cycle re-entry to regenerate neurons following the retinal injury. However, the mechanism driving such injury-induced MG cell-cycle re-entry remains incompletely understood. Combining single-cell transcriptomic analysis and in-vivo clonal analysis, we identified previously undescribed cxcl18b-defined MG transitional states as essential routes towards MG proliferation following green/red cone (G/R cone) ablation. Inflammation blockage abolished the triggering of these transitional states, which expressed the gene modules shared by cells of the ciliary marginal zone (CMZ), where life-long adult neurogenesis takes place. Functional studies of the redox properties of these transitional states further demonstrated the regulatory role of nitric oxide (NO) produced by Nos2b in injury-induced MG proliferation. Finally, we developed a viral-based strategy to specifically disrupt nos2b in cxcl18b-defined MG transitional states and revealed the effect of transitional state-specific NO signaling. Our findings elucidate the precision redox mechanism underlying injury-induced MG cell-cycle re-entry, providing insights into species-specific mechanisms for vertebrate retina regeneration.

neuroscience↗

bioRxiv2025

Mapping Anhedonia-Related Damage Network: Insights for TMS Treatment

BackgroundMany studies have explored anhedonia-related functional connectivity (FC), but the findings remain inconsistent. There is a gap in identifying a consistent anhedonia-related damage network and applying it to TMS treatment. MethodsWe systematically reviewed studies on anhedonia-related functional connectivity and identified anhedonia-related brain damage locations. Using a novel functional connectivity network mapping approach applied to a large normative connectome dataset, we mapped these damage locations to anhedonia-related damage networks. Subsequently, transcriptomic analysis was conducted to uncover underlying molecular mechanisms. Additionally, we investigated the application of the anhedonia-related damage network in transcranial magnetic stimulation (TMS) treatment, focusing on changes in FC within this network following TMS treatment and its association with anhedonia improvement, as well as predicting TMS treatment efficacy based on baseline FC within the anhedonia-related damage network. ResultsA total of eight experiments from seven studies using the nucleus accumbens (NAc) as the seed were eligible for functional connectivity network mapping analysis. This study identified an anhedonia-related damage network, primarily characterized by disrupted functional connectivity between the NAc and the default mode network. Transcriptomic analysis revealed gene enrichment associated with synaptic signaling, neuronal development, ion transport, and actin cytoskeleton regulation. TMS treatment increased NAc functional connectivity within the anhedonia-related damage network in the response group, with these changes correlating with improvements in anhedonia. Furthermore, baseline NAc FC within this network demonstrated predictive potential for TMS treatment efficacy. ConclusionThe anhedonia-related damage network was identified, emphasizing its underlying mechanisms and predictive value for TMS in treating anhedonia.

neuroscience↗

bioRxiv2025

Brucella proline racemase protein A targets Tpl2 to promote IL-10 secretion for establishment of chronic infection

IL-10, an anti-inflammatory cytokine, plays a crucial role in limiting immune responses to pathogens, preventing host damage. However, the mechanisms underlying Brucella-mediated IL- 10 production remain incompletely understood. In this study, we demonstrate that the proline racemase protein A (PrpA) of Brucella melitensis M5-90 induces macrophages to secrete IL-10 by activating the Tpl2-ERK signaling pathway, thereby promoting chronic infection. Moreover, Tpl2 deletion impairs macrophage bactericidal ability, accompanied by reduced TNF- and IL-1{beta} but unaffected IL-10 levels. Additionally, Trp309, Glu103, and Glu129 of PrpA participate in interaction with Tpl2, but these residues do not influence PrpA-mediated IL-10 production in macrophages. PrpA deletion enhances IFN-{gamma} levels, specific anti-Brucella IgG, and CD4+ and CD8+ T cell numbers in mice. Furthermore, the Brucella melitensis M5-90 prpA mutant provides higher protection than the parental strain against virulent Brucella melitensis M28 infection in mice. Our findings suggest that Brucella PrpA promotes IL-10 secretion by macrophages through Tpl2 activation for bacterial survival and persistent infection, making the Brucella melitensis M5-90 prpA mutant a promising vaccine for enhanced protection. Author SummaryIL-10, an anti-inflammatory cytokine, is exploited by Brucella for survival. We identified Brucella PrpA as a potent IL-10 inducer, activating the Tpl2-ERK signaling pathway. Tpl2 deletion increased Brucella survival in macrophages, accompanied by reduced TNF- and IL-1{beta} but unaffected IL-10 secretion. Residues (Trp309, Glu103, and Glu129) of PrpA were crucial for interaction with Tpl2, yet did not impact PrpA-mediated IL-10 production. The B. melitensis M5-90 prpA mutant induced higher anti-Brucella IgG, IFN-{gamma}, and CD4+ and CD8+ T cell numbers in mice, providing better protection than B. melitensis M5-90. These findings unveil PrpAs role in IL-10 production and highlight the potential of the B. melitensis M5-90 prpA mutant as a promising vaccine for further evaluation.

microbiology↗

bioRxiv2025

Elucidation and de novo Reconstitution of Glyceollins Biosynthesis

Glyceollins are phytoalexins produced by soybeans in response to stressors such as pathogen invasion, injury, and environmental challenges. In addition to their antibacterial and antifungal activities, these compounds have attracted significant attention for their potential anticancer, anti-inflammatory, and antioxidant properties. However, their limited accessibility--due to the challenges and high costs associated with organic synthesis or purification from treated soybean seedlings--has hindered further physiological and biochemical studies. Moreover, the incomplete understanding of glyceollin biosynthesis, particularly the final cyclization steps, remains a major barrier to elucidating the physiological functions of glyceollins and achieving sustainable production through synthetic biology. In this study, we identified previously uncharacterized genes encoding two reductases for 7,2,4-trihydroxyisoflavanol (THI) biosynthesis and five P450 enzymes responsible for the final oxidative cyclization in glyceollin I, II, and III biosynthesis, thereby completing the entire glyceollin biosynthetic pathway. By reconstructing the pathway de novo through synthetic biology, we achieved the successful production of glyceollins from simple carbon sources in bakers yeast. This work advances the understanding of glyceollin biosynthesis in soybean, facilitates sustainable production in microbial hosts and offers new opportunities for their application in agriculture and biology.

biochemistry↗