Biology subjects

Lai, Z.

Publications and source records attributed to Lai, Z..

At least 19 recordsLinked to original sources

bioRxiv2026

Oxidized TRX1 and DPP8/9 stabilize the MIA40-AIFM1 complex during intrinsic apoptosis

Mammalian cells execute diverse death programs with distinct immunological consequences. Mitochondrial outer membrane permeabilization (MOMP) drives typically immunologically silent intrinsic apoptosis by releasing cytochrome c and other proapoptotic proteins into the cytosol. Here, we show that MOMP also engages two established repressors of the pyroptosis-inducing NLRP1 inflammasome, oxidized thioredoxin-1 (oxTRX1) and catalytically active DPP8/9, in a coordinated redox and proteostasis program. Immediately after MOMP, oxTRX1 forms a disulfide with MIA40 Cys4 at the MIA40-AIFM1 interface. Subsequently, DPP8/9 cleave AK2, targeting this competing AIFM1 ligand for degradation. Biochemical reconstitution and cryo-EM reveal that oxTRX1 promotes AIFM1 dimerization and preferentially stabilizes MIA40-AIFM1 over AK2-AIFM1. Thus, redox-dependent complex assembly and selective proteolysis converge to favor MIA40-bound AIFM1 after MOMP. These findings suggest how post-MOMP remodeling could reinforce NLRP1 restraint during apoptosis and how disruption of this program could trigger pyroptosis.

cell biology↗

bioRxiv2026

A Refined Developmental Transcriptomic Landscape Reveals Four Coordinated Programs in Chlamydia trachomatis

The developmental cycle of Chlamydia trachomatis requires coordinated transitions between infectious elementary bodies (EBs) and replicative reticulate bodies (RBs), yet the temporal organization of the underlying transcriptional programs remains incompletely resolved. We performed high-coverage RNA sequencing from 0 to 32 h post-infection (hpi), with closely spaced early sampling, and used unsupervised clustering of temporal expression profiles to identify four coordinated programs: immediate-early host adaptation and developmental program, RB formation and maintenance, RB proliferation and secondary differentiation, and EB formation and invasion. The immediate-early program peaked at 1 hpi and contained a strong representation of inclusion-membrane and intracellular-trafficking genes, together with the developmental regulator gene euo. The RB formation and maintenance program peaked at approximately 3 hpi and sustained expression throughout much of the cycle, encompassing genes that support transcription, translation, and core metabolism. The RB proliferation and secondary differentiation program combined DNA replication and cell-division genes with alternative sigma factors, partner-switching components, and type III secretion apparatus genes, consistent with developmental preparation during proliferation. The EB formation and invasion program contained genes associated with structural maturation, host-cell interaction, and infectious competence. These findings distinguish transient host-adaptation expression from sustained early biosynthetic expression, separate RB establishment from population expansion, and differentiate regulatory preparation for the RB-to-EB transition from later EB maturation. Together, the four programs define partially overlapping transcriptional priorities that provide a framework for investigating how gene expression coordinates chlamydial growth, differentiation, and preparation for the next infection cycle.

microbiology↗

bioRxiv2026

Decoding by Dynamics: Reframing Neural Decoding as Stable Control Inference with Behavior Priors

Continuous neural decoding is fragile under nonstationary neural recordings because unconstrained sequence regressors can turn small mapping errors into temporally inconsistent and physically implausible motion. We propose Neural State-Space Dynamic Movement Primitives (Neural SS-DMP), which shifts the inductive bias from the neural encoder to the decoded output space: instead of directly predicting kinematics, the model infers low-dimensional movement-primitive controls and realizes them through a differentiable second-order dynamical generator. This reframes decoding as structured control inference, shrinking the set of admissible trajectories while retaining expressivity through learned forcing inputs. Because a universal motor prior cannot capture subject-specific movement dynamics, we form a personalized generator by blending the base DMP dynamics with behavior-derived subject dynamics estimated solely from training kinematics. Across ECoG and multi-session spiking benchmarks, Neural SS-DMP improves strong offline baselines in accuracy, consistently improves trajectory smoothness, and shows slower degradation on chronologically held-out sessions under an offline window-causal protocol.

bioengineering↗

bioRxiv2026

GalaxyVS: Exploring 100-Billion Compounds in Seconds

We present GalaxyVS, a hardware-software co-designed virtual screening framework built to explore the 100-billion commercially accessible chemical space in seconds, deployed at the National Supercomputing Center in Tianjin. Built upon the dense vector retrieval paradigm of DrugCLIP, GalaxyVS bypasses the structural dependencies and computational overhead of classical docking to enable rapid screening against experimentally determined as well as geometrically feasible pockets on AlphaFold-predicted structures. To scale this paradigm to the 100-billion level, the system must overcome the significant computational burden of offline representation encoding, critical memory and I/O bottlenecks during online retrieval, and the risks of diversity collapse and precision loss within final screening results. Utilizing the heterogeneous supercomputing infrastructure, GalaxyVS accelerates the offline encoding through deep operator adaptations and resolves online retrieval bottlenecks via disk-native vector indexing coupled with in-memory staging to ensure both broad accessibility and high throughput. Concurrently, a two-stage refinement protocol effectively mitigates diversity collapse and ensures high-fidelity affinity ranking. Consequently, GalaxyVS achieves a daily scoring throughput of 1.5 x 1016 target-ligand pairs, representing a six-orders-of-magnitude leap over previous supercomputing records. Driven by this throughput, we screened nearly 100,000 protein structures across six species against the 100-billion compound library in just 16 hours. The resulting comprehensive cross-species interaction landscape, GalaxyDB, will be openly released at https://galaxyvs.drugclip.com.

bioinformatics↗

bioRxiv2026

Bronchus associated lymphoid tissue induced by an attenuated Mycobacterium tuberculosis vaccine prevents tuberculosis from heterologous TB challenge

Tuberculosis (TB) remains a leading cause of death from infectious disease worldwide, underscoring the urgent need for vaccines with greater and more consistent efficacy than Bacille Calmette-Guerin (BCG). We previously showed that mucosal vaccination with an isogenic Mycobacterium tuberculosis (Mtb) mutant lacking the stress-response transcription factor SigH ({Delta}sigH) prevents pulmonary TB in two macaque species. In the absence of SigH, Mtb is unable to effectively counter host oxidative stress. Vaccinated macaques were notably protected from disease, exhibiting an absence of granulomatous pathology together with the formation of lymphoid follicles and robust antigen-specific CD4+ and CD8+ T cell responses, identifying{Delta} sigH as a promising live-attenuated TB vaccine candidate. The{Delta} sigH mutant used in prior studies was generated in the Mtb CDC1551 background, a commonly used laboratory strain for challenge studies. Here, we evaluated whether{Delta} sigH-mediated protection extends to heterologous challenge with the more virulent Mtb Erdman strain. Mucosal{Delta} sigH vaccination conferred significant protection against heterologous challenge, markedly reducing pulmonary bacterial burden and TB-associated pathology. Longitudinal high-resolution PET/CT imaging demonstrated that aerosol{Delta} sigH vaccination induced robust inducible bronchus-associated lymphoid tissue (iBALT) responses in the lung. Unlike granulomas, these iBALT structures resolved over time while remaining associated with protection against subsequent Mtb challenge. Protection of highly susceptible rhesus macaques against virulent heterologous Mtb challenge following aerosol{Delta} sigH vaccination supports the further preclinical development of{Delta} sigH-based live-attenuated TB vaccines and highlights iBALT induction as a potential correlate and mechanistic driver of protective immunity against TB.

immunology↗

bioRxiv2026

Midkine Dependency Defines a Therapeutically Actionable Vulnerability in Medulloblastoma

Medulloblastoma (MB), the most common malignant pediatric brain tumor, remains associated with high recurrence rates and substantial treatment-related morbidity despite aggressive multimodal therapy. Here, we identify midkine (MDK), a secreted growth factor/cytokine, as a previously unrecognized central regulator of MB growth and survival. Tissue microarray analysis revealed elevated MDK protein expression in MB specimens, and single-cell RNA sequencing datasets showed tumor cell-specific MDK expression. Genetic depletion or antibody-mediated neutralization of MDK suppressed proliferation and survival and induced apoptosis across multiple MB cell lines, whereas recombinant MDK supplementation exerted the opposite effect. Mechanistically, phosphokinase profiling and immunoblot analyses showed that MDK signals through multiple receptors, including nucleolin (NCL), LRP1, and syndecan-2 (SDC2), to sustain oncogenic ERK1/2 and Akt-mTOR-S6 signaling. Transcriptomic profiling following MDK silencing or depletion revealed marked suppression of ribosome biogenesis, global protein translation, and MYC-driven programs, coupled with activation of inflammatory and apoptotic responses. Consistently, mechanistic studies utilizing RPS6 staining, ribosomal RNA quantification, puromycin SUnSET, and OPP incorporation assays confirmed that loss of MDK impairs ribosome biogenesis and protein synthesis. Notably, MDK suppression also triggered robust activation of the IFN-cGAS-STING pathway, linking translational stress to innate immune signaling. In orthotopic xenograft models, CRISPR-mediated MDK knockout significantly reduced tumor growth and prolonged survival. Together, these findings establish MDK as a key integrator of oncogenic signaling, translational control, and innate immunity in MB, highlighting MDK as a compelling therapeutic target.

cancer biology↗

bioRxiv2026

Diverse Mechanisms of SMARCB1 Inactivation and Genome Maintenance Defects in Ultra-Rare Malignant Rhabdoid Tumors

Malignant rhabdoid tumors (MRTs) are extremely rare and highly aggressive pediatric cancers classically defined by biallelic loss of the SMARCB1 gene, with rare involvement of SMARCA4. However, the molecular mechanisms leading to this loss are not yet fully understood. MRTs occur predominantly in infants, with the highest incidence in children under one year of age. Clinically, they are characterized by early metastatic dissemination and dismal outcomes, with 5-year event-free survival rates below 20%. There are currently no curative therapies for these patients. Here, we performed integrated genomic, transcriptomic, and epigenomic profiling of 16 patient-derived MRT models including intracranial, renal, and soft tissue origins. While SMARCB1 deficiency was ubiquitous, we observed substantial heterogeneity in the mechanisms driving its inactivation. Only two tumors harbored detectable coding single-nucleotide variants in SMARCB1; the predominant mechanisms involved large-scale deletions and broad loss-of-heterozygosity (LOH) on chromosome 22, with extensive LOH in tumors lacking point mutations or focal deletions, consistent with allelic loss as a frequent "second hit." In contrast, SMARCA4 remained intact across all models, reinforcing the mutual exclusivity of SMARCB1 and SMARCA4 alterations. Structural analyses revealed extensive variation, including more than 400 events per tumor on average and candidate gene fusions such as AHI1:MYB, whereas alterations in TP53 and BRCA1/2 genes were infrequent. Transcriptomic and epigenomic profiling showed heterogeneity driven by tissue of origin, disease progression, and therapeutic response, with subtype-specific programs and epigenetic modulation of DNA repair and immune-related genes (SLFN11, MGMT, LIF) linked to treatment sensitivity. Collectively, our findings refine the molecular definition of MRTs, showing that while SMARCB1 loss remains the foundational driver, tumor behavior is further shaped by structural variation, impaired DNA repair pathways, and dynamic epigenetic landscapes. These integrated changes contribute to tumor heterogeneity, progression, and differential therapeutic vulnerabilities. Beyond advancing mechanistic understanding and identifying candidate biomarkers for patient stratification, our multi-omics dataset represents a valuable resource for the research community, supporting future studies and efforts to improve clinical management of this highly aggressive pediatric malignancy.

cancer biology↗

bioRxiv2025

Hybridization Reveals Cell Type-Specific Regulatory Variation Driving Brain Transcriptomic Divergence

Gene expression is a molecular trait that can cumulatively contribute to more complex phenotypes. Interspecies hybrids have long been used to study the genetics basis of molecular, morphological and behavioral traits, to dissect interactions between cis- and trans-regulators with parental traits, and to uncover incompatible genetic interactions that drive extreme phenotypes in hybrid progeny. However, it remains unclear how organ functions at molecular level are affected by hybridization. We hypothesize that hybridization incited molecular level changes are cell type specific. To test this, we produced interspecies hybrid progeny from two distantly related fish species, Xiphophorus maculatus and couchianus. They are differing in mating, foraging behavior and likely neural circuits for cognition. We first performed allelic expression and bulk brain transcriptome profiling to identify expression quantitative trait loci (eQTLs) and quantitative transcript traits (QTTs) in order to quantify the scale and identify of loci contributing to gene expression variations in hybrids. It showed that QTT are predominantly influenced by additive eQTLs. Subsequently, we compared QTTs, which exemplify species-specific regulatory effects on gene expression, to cell type markers derived from single-nucleus RNA sequencing (snRNAseq). We identified 14 cell type-specific QTTs with known roles in brain functions. Overall, this study shows that transcriptomic phenotypes under species-specific regulators are associated to specific cell types in hybrids, and indicates the overall organ-level functional change could be driven by particular cell types.

genetics↗

bioRxiv2025

The Secreted Metabolite Isopentenyladenine from Faecalibacterium prausnitzii Mitigates Gut Inflammation

Colonic microbiome dysbiosis is correlated with inflammatory bowel disease (IBD), and depletion of the commensal bacterium Faecalibacterium prausnitzii (F. prausnitzii) is routinely observed in the metagenomic analyses of IBD patient microbiome samples. F. prausnitzii is likely beneficial to hosts, as oral administration of F. prausnitzii strain A2-165 has anti-inflammatory properties in murine models of colitis. Previous studies attribute the anti-inflammatory effects of F. prausnitzii A2-165 to production of the short-chain fatty acid butyrate, as well as a 15 kDa protein known as microbial anti-inflammatory molecule (MAM). Here, we verified that oral dosing of strain A2-165 protects against DSS-induced murine colitis and further show the aqueous-soluble secreted fraction of overnight cultures from a collection of F. prausnitzii strain inhibit inflammatory signatures, including the activation of the hosts NF-{kappa}B pathway, production of IL-8, and differentiation of naive T cells into the TH17 lineage. We find that MAM is secreted in extracellular vesicles; however, MAM-containing vesicles do not have anti-inflammatory properties in our collection of assays and suggests that MAM is likely not a direct contributor. Untargeted and targeted mass spectrometry metabolomics analyses on the soluble anti-inflammatory secretome yielded several unique F. prausnitzii metabolites, including isopentenyladenine. We demonstrated isopentenyladenine independently modulates host cellular signaling and immune responses and suggests this newly identified metabolite with human immunomodulatory properties may be useful towards the discovery of IBD-focused therapeutics.

microbiology↗

bioRxiv2025

Hugin-AstA circuitry is a novel central energy sensor that directly regulates sweet sensation in Drosophila and mouse

Taste sensation plays a crucial role in shaping feeding behavior and is intricately influenced by internal states like hunger or satiety. Despite the identification of numerous neural substrates regulating feeding behavior, the central neural substrate that linked energy-sensing and taste sensation remained elusive. Here, we identified a novel neural circuitry that could directly sense internal energy state and modulate sweet sensation in the Drosophila brain. Specifically, a subset of neuropeptidergic neurons expressing hugin directly detected elevated levels of circulating glucose via glucose transporter Glut1 and ATP-sensitive potassium channel. Upon activation, these neurons released hugin peptide and activated downstream Allatostatin A (AstA)+ neurons via its cognate receptor PK2-R1. Subsequently, the activation of AstA+ neurons then directly inhibited sweet sensation via AstA peptide and its cognate receptor AstA-R1 expressed in sweet-sensing Gr5a+ neurons. We also showed that neuromedin U (NMU), the mammalian homolog of fly hugin, served as an energy sensor to suppress sweet sensation. Therefore, these data identify hugin+ neuron as a glucose-responsive central energy-sensing module that modulates sweet sensation across species.

neuroscience↗

bioRxiv2025

Modeling Masticatory Myalgia to Headache-like Referred Pain Triggers Local Gene Plasticity at Referred Pain Sites

Patients with myofascial pain in the head and neck area report widespread and referred pain, including headache. Existing preclinical models fail to replicate this clinical phenotype; therefore, we aimed to develop animal models mimicking referred pain phenomenon and investigate whether referred pain leads to gene plasticity at the referred sites. We modeled masticatory myalgia by stimulation of either the masseter (MM) or temporal muscle (TM) in mice. MM and TM were stimulated with a single high-dose injection of Collagenase-type II (Col), repetitive low-dose Col injections, repetitive gentle MM stimulation, or single or repetitive forceful mouth opening. Referred pain was assessed by measuring mechanical hypersensitivity in the periorbital area (representing headache-like behavior) and another masticatory muscle. Stimulation of the MM, whether through single or repetitive Col injections or mouth opening, produced inconsistent, short-lasting (1-2 days) headache-like behavior in both males and females. In contrast, stimulation of the TM, using different paradigms, triggered mechanical hypersensitivity in both the MM and the periorbital area. Referred headache-like behavior lasted longer in females compared to males, while referred myalgia in the MM was pronouncer in males. The referred pain in the MM and periorbital areas triggered by TM stimulation was associated with significant gene plasticity in the MM and dura mater. Transcriptional changes in the MM following Col injection into the TM resembled those observed after direct MM injections. Presented data imply that referred pain modeled by TM stimulation could be accounted by nociceptive signaling from multiple local sites involved in this referred pain network.

neuroscience↗

bioRxiv2025

Accessory subunits of PRC2 mimic H3K27me3 to restrict the spread of Polycomb domains

The Polycomb repressive complex 2 (PRC2) is essential for normal development by maintaining developmental gene repression. PRC2 deposits the repressive chromatin mark H3 lysine 27 tri-methyl (H3K27me3) through a read-write loop that involves direct interactions between PRC2 and H3K27me3. According to current models, the PRC2-H3K27me3 read-write loop is initiated by the PRC2 subunits JARID2 and PALI1 that mimic H3K27me3. However, it is unknown what restricts the PRC2-H3K27me3 read-write loop from spreading H3K27me3 indefinitely. To answer this question, we generated mutant mice where PRC2 subunits cannot mimic H3K27me3. Unexpectedly, the mutations led to delayed Hox genes activation and a homeotic transformation characteristic of a Polycomb gain-of-function in vivo and the spread of H3K27me3 beyond Polycomb domains in stem cells. Collectively, we show that H3K27me3 mimicry evolved to compete against the PRC2-H3K27me3 read-write loop in a process that restrains PRC2 and restricts the spread of Polycomb domains. HighlightsO_LIH3K27me3 mimicry antagonises Polycomb function in vivo. C_LIO_LIJARID2 and PALI1 synergise to allosterically regulate PRC2 during development. C_LIO_LIH3K27me3 mimicry by JARID2 and PALI1 antagonises PRC2 in stem cells. C_LIO_LIJARID2 and PALI1 mimic H3K27me3 to restrict the spread of Polycomb domains. C_LI

molecular biology↗

bioRxiv2024

An artificial intelligence-based model for prediction of Clonal Hematopoiesis mutants in cell-free DNA samples

Circulating tumor DNA is a critical biomarker in cancer diagnostics, but its accurate interpretation requires careful consideration of clonal hematopoiesis (CH), which can contribute to variants in cell-free DNA and potentially obscure true tumor-derived signals. Accurate detection of somatic variants of CH origin in plasma samples remains challenging in the absence of matched white blood cells sequencing. Here we present an open-source machine learning framework (MetaCHIP) which classifies variants in cfDNA from plasma-only samples as CH or tumor origin, surpassing state-of-the-art classification rates.

bioinformatics↗

bioRxiv2024

Modular cloning of multigene vectors for the baculovirus system and yeast

Recombinant macromolecular complexes are often produced by the baculovirus system, using multigene expression vectors. Yet, the construction of baculovirus-compatible multigene expression vectors is complicated and time-consuming. Furthermore, while the baculovirus and yeast are popular protein expression systems, no single method for multigene vector construction is compatible with both. Here we present the modular cloning (MoClo) Baculo toolkit for constructing multigene expression vectors for the baculovirus system and, through compatibility with the MoClo Yeast toolkit, also for yeast. Vector construction by MoClo Baculo utilises Golden Gate assembly, which does not require PCR, primers or the sequencing of intermediate products. As a proof of principle, MoClo Baculo was used to construct baculovirus and yeast multigene vectors expressing the four- and five-subunit human Polycomb Repressive Complex 2. We show that MoClo Baculo simplifies and expedites the construction of multigene expression vectors for the baculovirus system and provides compatibility with yeast as an alternative expression system.

biochemistry↗

bioRxiv2024

Dysbiosis-associated gut bacterium Ruminococcus gnavus varies at the strain level in ability to utilize key mucin component sialic acid

Ruminococcus gnavus is a prevalent human gut commensal bacterium with known roles in intestinal mucus degradation, including by catabolism of the terminal mucin sugar sialic acid. While R. gnavus is not considered a pathogen, overabundance of this species is correlated with Inflammatory Bowel Disease (IBD), and its sialic acid metabolism may play a role in the dysbiotic state. Interestingly, liberation of mucin-bound sialic acid by R. gnavus yields the distinct product of 2,7-anhydro-N-acetylneuraminic acid (2,7-anhydro-Neu5Ac), in contrast to other known mucin-degrading bacteria, which generate Neu5Ac. This prompted us to look for 2,7-anhydro-Neu5Ac metabolism proteins in the genomes of 77 R. gnavus clinical isolates. We found that 2,7-anhydro-Neu5Ac metabolism is sporadically distributed in this species with respect to phylogeny and strain origin. We measured sialic acid-dependent growth of 12 sequenced isolates, finding that the presence of 2,7-anhydro-Neu5Ac catabolism proteins was predictive of growth on this substrate. Our analysis also uncovered "partial" 2,7-anhydro-Neu5Ac catabolism pathways in two R. gnavus strains, which we determined constitute the canonical Neu5Ac catabolism pathway, previously unreported in this species. These results reveal a notable diversity of sialic acid catabolism across the R. gnavus species, an essential consideration for further investigations into the importance of this metabolism in mucin degradation and in roles of R. gnavus in IBD and other gut dysbioses.

microbiology↗

bioRxiv2024

Segregation between an ornamental and a disease driver gene provides insights into pigment cell regulation

Genetic interactions are adaptive within a species. Hybridization can disrupt such species-specific genetic interactions and creates novel interactions that alter the hybrid progeny overall fitness. Hybrid incompatibility, which refers to degenerative genetic interactions that decrease the overall hybrid survival, is one of the results from combining two diverged genomes in hybrids. The discovery of spontaneous lethal tumorigenesis and underlying genetic interactions in select hybrids between diverged Xiphophorus species showed that lethal pathological process can result from degenerative genetic interactions. Such genetic interactions leading to lethal phenotype are thought to shield gene flow between diverged species. However, hybrids between certain Xiphophorus species do not develop such tumors. Here we report the identification of a locus residing in the genome of one Xiphophorus species that represses an oncogene from a different species. Our finding provides insights into normal and pathological pigment cell development, regulation and molecular mechanism in hybrid incompatibility. SignificanceThe Dobzhansky-Muller model states epistatic interactions occurred between genes in diverged species underlies hybrid incompatibility. There are a few vertebrate interspecies hybrid cases that support the Dobzhansky-Muller model. This study reports a fish hybrid system where incompatible genetic interactions are involved in neuronal regulation of pigment cell biology, and also identified a novel point of regulation for pigment cells.

genetics↗

bioRxiv2024

Targeting of SUMOylation leads to cBAF complex stabilization and disruption of the SS18::SSX transcriptome in Synovial Sarcoma

Synovial Sarcoma (SS) is driven by the SS18::SSX fusion oncoprotein. and is ultimately refractory to therapeutic approaches. SS18::SSX alters ATP-dependent chromatin remodeling BAF (mammalian SWI/SNF) complexes, leading to the degradation of canonical (cBAF) complex and amplified presence of an SS18::SSX-containing non-canonical BAF (ncBAF or GBAF) that drives an SS-specific transcription program and tumorigenesis. We demonstrate that SS18::SSX activates the SUMOylation program and SSs are sensitive to the small molecule SAE1/2 inhibitor, TAK-981. Mechanistically, TAK-981 de-SUMOylates the cBAF subunit SMARCE1, stabilizing and restoring cBAF on chromatin, shifting away from SS18::SSX-ncBAF-driven transcription, associated with DNA damage and cell death and resulting in tumor inhibition across both human and mouse SS tumor models. TAK-981 synergized with cytotoxic chemotherapy through increased DNA damage, leading to tumor regression. Targeting the SUMOylation pathway in SS restores cBAF complexes and blocks the SS18::SSX-ncBAF transcriptome, identifying a therapeutic vulnerability in SS, positioning the in-clinic TAK-981 to treat SS.

cancer biology↗

bioRxiv2024

Degenerative and regenerative peripheral processes are associated with persistent painful chemotherapy-induced neuropathies in males and females

This study aimed to investigate the time course of gene expression changes during the progression of persistent painful neuropathy caused by paclitaxel (PTX) in male and female mouse hind paws and dorsal root ganglia (DRG). Bulk RNA-seq was used to investigate the gene expression changes in the paw and DRG collected at 1, 16, and 31 days post-PTX. At these time points, differentially expressed DEGs were predominantly related to reduction or increase in epithelial, skin, bone, and muscle development and to angiogenesis, myelination, axonogenesis, and neurogenesis. These processes were accompanied by regulation of DEGs related to cytoskeleton, extracellular matrix organization and cellular energy production. This gene plasticity during persistent painful neuropathy progression likely represents biological processes linked to tissue regeneration and degeneration. Unlike regeneration/degeneration, gene plasticity related to immune processes was minimal at 1-31 days post-PTX. It was also noted that despite similarities in biological processes and pain chronicity in males and females, specific DEGs showed dramatic sex-dependency. The main conclusions of this study are that gene expression plasticity in paws and DRG during PTX neuropathy progression relates to tissue regeneration and degeneration, minimally affects the immune system processes, and is heavily sex-dependent at the individual gene level.

neuroscience↗