Biology subjects

Zhang, F.

Publications and source records attributed to Zhang, F..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

GWAS and multi-omics uncover the SLC6A3 locus for canine stranger-directed social anxiety and implicate NRIP3 in dopaminergic network regulation

The social anxiety disorder (SAD) is one of the most common mental health disorders, often developing in adolescence. It can severely impair educational achievement, career progression, and social functioning. Certain individuals within the Chinese Kunming dog (CKD) population display spontaneous, SAD-like behaviors towards strangers, offering a valuable model for genetic investigation. Using whole-genome sequencing data, we conducted a genome-wide association study on this SAD-like behavior in 100 CKDs, identifying several genes previously linked to human psychiatric disorders. Notably, SLC6A3 reached genome-wide significance, whereas CADPS2 exceeded only the suggestive threshold and is therefore considered a network-supported candidate locus. By integrating weighted gene co-expression network analysis with public RNA-seq data from the VTA of 38 mice (after quality control), we further showed that Slc6a3 and Cadps2 are part of a co-expression network module associated with the dopamine system. These findings suggest that this specific module may play a functional role in the stranger-directed anxiety-related behaviours in CKDs. Furthermore, we identified Nrip3 as a key candidate transcriptional coregulator in this specific module. Subsequent virus-mediated overexpression and behavioural experiments showed that Nrip3 regulates gene expression within this network and induces a spectrum of behavioural alterations in mice, including social avoidance, anhedonia, and increased locomotor activity. Collectively, this study highlights the involvement of dopamine system genes in canine social anxiety and suggests Nrip3 as an upstream regulator of Slc6a3 associated with anxiety. The identification of conserved anxiety-related signatures between humans and dogs further supports the dog as a valuable translational model for psychiatric research.

genetics↗

bioRxiv2026

Quantitative Modeling of TLR Signaling Reveals Missing Negative Feedback Guiding Identification of TANK-IKKε Checkpoint

Toll-like receptor (TLR) signaling must be activated rapidly and then terminated to support host defense without sustained inflammation. We developed a rule-based model of mouse macrophage TLR4 signaling at the molecular-interaction level using measured protein copy numbers, RNA-seq-based abundance estimates, literature- and structure-informed reaction rates, and 979 dynamic experimental constraints. The trained model reproduced much of the TLR4-induced NF-{kappa}B and MAP kinase response but consistently failed to capture deactivation of MyD88, TRAF6-associated species, and IKK/{beta}. The recurrent model failure conveyed important biological information, localizing missing regulation to the proximal MyD88-IRAK-TRAF6 module and guiding experimental evaluation of IKK{varepsilon} and its scaffold TANK. Loss of IKK{varepsilon} enhanced transcriptional, cytokine, MAP kinase, and NF-{kappa}B responses to MyD88-specific TLR ligands. TANK deficiency produced a similar cellular phenotype and abolished stimulus-induced IKK{varepsilon} phosphorylation. Deficiency of either protein increased IRAK1 and TRAF6 ubiquitination without increasing MyD88 ubiquitination, placing the inhibitory checkpoint at or immediately downstream of the IRAK1-TRAF6 ubiquitin-signaling node. Overlapping but non-identical in vivo phenotypes further supported a shared regulatory axis with additional protein-specific functions. Our study presents a model-experiment discovery cycle where quantitative pathway discordance identifies missing biology and reveals a TANK-dependent IKK{varepsilon} checkpoint that restrains MyD88-driven inflammation.

systems biology↗

bioRxiv2026

Microbial Immunomodulatory Function is Altered in Inflammatory Bowel Disease Independent of Microbial Composition

Inflammatory bowel diseases (IBD) are chronic and relapsing immune-mediated conditions in which the NF-{kappa}B and STAT3 signalling pathways play central roles in pathogenesis. While gut microbiome dysbiosis is well described in IBD, its functional consequences, particularly microbial immunomodulatory function (MIF) remain poorly defined. Here, we integrated functional assays with metagenomic profiling to characterise microbiome-driven immune modulation in IBD. Faecal water from non-IBD controls and IBD patients was assessed using NF-{kappa}B and STAT3 reporter systems, alongside high-throughput screening of 2,820 bacterial isolates (94 per subject). Despite minimal differences in overall microbial composition, faecal water from patients with ulcerative colitis (UC) and Crohns disease (CD) significantly increased NF-{kappa}B activity under both basal and TNF-stimulated conditions. Non-IBD controls harboured a higher proportion of suppressive bacterial isolates (21.52%) compared to UC (5.64%) and CD (2.45%), whereas activating isolates were enriched in IBD (UC: 34.47%; CD: 39.36% vs. non-IBD: 5.35%). Similar trends were observed for IL-23-mediated STAT3 activation. Integration of metagenomic and pathway-level analyses identified 24 KEGG pathways associated with inflammatory signalling and faecal lipocalin-2, as well as amino acid, carbohydrate, lipid, cofactor, and nucleotide metabolism. These findings demonstrate that the IBD microbiome is functionally reprogrammed toward pro-inflammatory activity, independent of compositional changes. Defining patient-specific MIF profiles may provide a framework for precision microbiome-based therapeutic strategies in IBD.

microbiology↗

bioRxiv2026

Integrative single-nucleus multi-omics profiling identifies candidate regulators and signaling axes in Alzheimer's disease lipid-processing microglia

Lipid-processing microglia are among the microglial states most strongly associated with Alzheimers disease (AD) pathology, yet whether this association reproduces across independent cohorts, what transcriptional programs define the state, and which upstream signals and small molecules can modulate it remain unsolved. We address these questions through a cross-cohort analysis of one such substate (MG4) by integrating differential expression, transcription factor activity inference, gene set enrichment, and cell-cell communication across five independent single-nucleus RNA sequencing cohorts (ntotal = 140 donors), with paired single-nucleus ATAC sequencing in one multi-omic cohort for epigenomic corroboration. A held-out cohort (n = 150 donors) supported donor-level regression of MG4 proportion on ligand expression, and two spatial transcriptomics datasets (ntotal = 30 donors) related ligand expression to MG4 identity in neighboring spots. MG4 was reproducibly enriched in AD across all five cohorts (pooled log2 fold change = 0.90, p = 3.0 x 10-4). Expression-based inference and motif accessibility jointly nominated MITF and BACH1 as regulators of a program led by V-ATPase-driven lysosomal acidification and cholesterol efflux, a lysosomal-biogenesis signature distinct from the catabolic DAM and lipid-storage LDAM programs, with AD-specific upregulation of energy metabolism. FGF1 and TGFB2 were the most supported candidate upstream ligands, each significant in donor-level regression with further spatial evidence. Computational drug repurposing nominated ten blood-brain barrier-penetrant compounds as perturbational probes. Together, these results advance a described disease-associated microglial state into a reproducible, mechanistically framed regulatory model, providing candidate regulators, upstream ligands, and pharmacological probes for functional validation.

bioinformatics↗

bioRxiv2026

AgroGem: A Rapid and Scalable Transient Transformation System for Functional Genetics in Multiple Plant Species

Plant genetic transformation technologies are essential for functional genomics and genome engineering in plants. While transient expression systems offer a rapid alternative to stable transformation, existing platforms are often constrained by low efficiency, technical complexity, and limited scalability. Here, we developed AgroGem, an efficient Agrobacterium-mediated transient transformation system utilizing a geminiviral replicon-based T-DNA vector for Arabidopsis and Brassicaceae species. AgroGem significantly outperformed existing transient approaches, including AGROBEST and protoplast-based assays, in CRISPR-mediated editing efficiency. Moreover, AgroGem recapitulated the mutation spectra and chromatin accessibility-dependent editing patterns observed in stable transformation across both Cas9 and Cas12a systems, indicating that it captures genome editing outcomes in native chromatin contexts. Leveraging this capability, we performed high-resolution profiling of CRISPR-induced mutation outcomes across a panel of DNA repair mutants and identified distinct repair signatures, including unexpected roles for KU80 and XRCC4 in regulating non-homologous end joining (NHEJ). AgroGem also supported bimolecular fluorescence complementation assays for protein-protein interaction studies in Arabidopsis and was readily adapted to plate-based formats for high-throughput applications. Together, these results establish AgroGem as a robust, scalable, and versatile platform for genome editing, DNA repair analysis, and functional genetics in plants.

plant biology↗

bioRxiv2026

Unearthing a fungal giant: Dianjunaceae fam. nov., a novel Paleocene lineage of Xylariales harbouring Dianjunus rex gen. et sp. nov.

During mycological surveys in Yunnan Province, China, specimens of a fungus producing massive, upright stromata up to 50 cm high and individually 2.2 Kg in weight were sampled. Through an integrative taxonomic approach combining detailed morphology, multilocus phylogeny (ITS, LSU, RPB2, TUB2), and phylogenomic analyses, this fungus is proposed as the new species Dianjunus rex gen. et sp. nov., the type of the new family Dianjunaceae (Xylariales). Phylogenetic analyses robustly place Dianjunaceae as a distinct sister clade to Graphostromataceae. Divergence time estimation dates the origin of this family to the early Paleocene ([~]65 Mya), coinciding with the post-K-Pg extinction period, when an estimated 75% of all plant and animal species went extinct, and a significant ecological reorganization of life on earth happened. The stromata of D. rex represent the largest fructifications documented within the Ascomycota, significantly expanding the known morphological range of the Xylariales. The study provides a comprehensive description, including a nodulisporium-like anamorph with periconiella-like branching patterns, and discusses the taxons phylogenetic placement, and distinctive morphology. This discovery highlights the unexplored fungal diversity in East Asian forests.

microbiology↗

bioRxiv2026

Annual life-history strategy hitchhikes low-light adaptation in a clonal seagrass

While life-history strategies are typically fixed within species, evolutionary transitions between perenniality and annuality can occur. In clonal seagrasses, annual and perennial plants often coexist in the same population, providing a unique model for studying the genetic basis of this transition. Two seagrass Zostera marina populations in South Korea display a striking dichotomy: shallow-water sub-populations follow a typical perennial strategy, whereas their deep-water counterparts are annual. Here we show that this shift from perenniality to annuality, potentially caused by the SAPK7 gene, is genetically coupled with the CAO gene, which is under strong positive selection for low-light adaptation. The up-regulation of the SAPK7 gene triggers early flowering in seedlings, before the formation of any lateral shoots via asexual reproduction. In this special case where the genet contains only one ramet, the post-reproductive death of the ramet is equivalent to the death of the whole genet, which explains the annual phenotype. Our findings reveal a mechanistic example where annuality overcomes perenniality by hitchhiking on a positively selected gene. Given that the ancestral state of plants is perennial, this coupling of annuality with beneficial alleles may represent one of the pathways for the repeated evolution of annual life histories across flowering plants.

evolutionary biology↗

bioRxiv2026

A Glutamine antagonist-modulated tumor microenvironment unleashes enzalutamides immunotherapeutic effects

Androgen receptor (AR) antagonists, such as enzalutamide, suppress prostate cancer (PCa) cells to achieve temporary therapeutic effects. In addition to tumor cell-autonomous suppressive function, AR antagonists can also potentially exert anti-tumor effects via mitigating cytotoxic T cells exhaustion. However, strategies for effectively harnessing enzalutamides immunotherapeutic effects remain elusive. In studying a recently described glutamine antagonist prodrug (DRP-104) in PCa models, we found that despite the initial response, tumors ultimately became resistant. Intriguingly, compared to the untreated (DRP-104 treatment-naive) tumors, the resistant tumors became highly susceptible to enzalutamide in vivo. Additionally, treating tumors with DRP-104 and enzalutamide simultaneously also yielded superior therapeutic efficacy. We demonstrated that DRP-104 therapy promoted the infiltration of CD8+ T cells as well as regulatory T cells (Treg) in responsive tumors, and the tumor-infiltrating Treg were mostly depleted upon enzalutamide treatments. Mechanistically, we showed that Treg differentiation from mouse CD4+ T cells was attenuated by enzalutamide. We further demonstrated that Treg induction was accompanied by the interaction between AR and aryl hydrocarbon receptor (AhR), the nuclear receptor indispensable for Treg differentiation, in the nuclei of CD4+ T cells, and this interaction was diminished by enzalutamide. In further support of AR signaling in Treg biogenesis, analysis of available gene expression datasets found that AR expression was elevated in Treg when compared to CD4+ T cells in human peripheral blood mononuclear cells (PBMCs). In addition, it was positively correlated with Treg module scores in several human cancer types. Finally, using an anti-GPC3 (Glypican 3) vaccination model, we demonstrated that CD4+ T cells subjected to Treg induction in the presence of enzalutamide were less effective in protecting GPC3-expressing tumor cells from CD8+ T cells cytotoxic killing. Collectively, these results suggest that AR promotes Treg s differentiation and/or immunosuppressive functions, and nominate enzalutamide as a Treg-mitigating agent for potentiating immunotherapies. Our results also demonstrate that an otherwise unintended, Treg-promoting property of DRP-104 can be leveraged to unleash the immune-regulatory function of enzalutamide for the treatment of PCa.

cancer biology↗

bioRxiv2026

Reverse genetics in humanized mice reveals CARD8-mediated pyroptosis causing pancytopenia in human DPP9 deficiency

Loss of function mutation in the human DPP9 gene causes Hatipoglu syndrome leading to severe inflammasomopathy. A key feature of the disease is pancytopenia and patients require bone marrow transplantation, but the mechanism of cell loss is unclear since Dpp9 mutant mice have normal hematopoiesis, suggesting that a distinct mechanism of disease occurs in humans. Here, we present a model of human DPP9 deficiency leveraging reverse genetics in the MISTRG6 humanized mice. We found that CRISPR editing of human CD34+ hematopoietic stem and progenitor cells (HSPCs) led to very efficient and persistent gene deletion in vivo. Human DPP9 deletion recapitulated cytopenia in peripheral blood and in the bone marrow, and cell loss was cell intrinsic. However, DPP9 deletion led to little transcriptional changes suggesting post-transcriptional regulation in human HSPCs. Mechanistically, DPP9 deficiency led to the activation of the CARD8 inflammasome resulting in HSPC pyroptosis, whereas NLRP1 was dispensable for cell death. Thus, our results reveal a unique human mechanism of disease and offer therapeutic insight for this inflammasomopathy.

immunology↗

bioRxiv2026

Neuroendocrine arylhydrocarbon receptor regulates gut microbiome of C. elegans via redox tone

The gut microbiome profoundly influences host health, with disrupted microbial communities implicated in inflammatory, metabolic, and neurological diseases. The aryl hydrocarbon receptor (AHR) shapes intestinal immunity and microbial composition, yet the mechanisms by which AHR mediates selective microbiome assembly remain poorly understood. Whether distant organ systems such as the nervous system actively participate in microbial community regulation is unexplored. Here we show that Caenorhabditis elegans neuronal AHR-1 orchestrates selective gut microbiome assembly through a neuroendocrine cascade that calibrates intestinal redox tone. Using a defined natural microbiome community, we demonstrate that ahr-1 loss triggers specific microbiome changes, as Enterobacterales and Pseudomonadales bloom up to 24-fold while Sphingobacteriales decline. Adult-specific AHR-1 depletion recapitulates this dysbiosis, separating the role of AHR-1 in neurodevelopment from its regulation of the microbiome. Neuronal AHR-1 regulates expression of the neuropeptide FLP-8 in oxygen-sensing URX neurons, which in turn signals to the intestine to modulate intestinal redox tone. Elevated intestinal redox tone in ahr-1 mutants favors growth of oxidative stress-tolerant Enterobacterales and Pseudomonadales, which also exhibit functional and genomic enrichment for stress resistance and AHR ligand biosynthesis pathways. This establishes a precise feedback circuit whereby AHR-1 senses bacterial metabolic output to regulate colonization by ligand-producing taxa. AHR-1 signaling regulates redox tone through downstream regulation of glutathione S-transferase GST-4 and alpha-arrestin ARRD-11. Intestinal gst-4 knockdowns had the greatest impact on restoring redox tone and microbiome compositional control in the gut. These findings reveal an evolutionarily ancient molecular circuit where AHR serves as a precision metabolic sensor that coordinates whole organismal physiology to maintain host-microbiome homeostasis.

genetics↗

bioRxiv2026

A hybrid framework integrating structural machine learning and 3D liver-on-chip assay for drug-induced liver injury prediction

Drug-induced liver injury (DILI) remains a major cause of clinical attrition and postmarketing withdrawal, but structure only DILI predictors are difficult to compare because public benchmarks are vulnerable to compound overlap, scaffold similarity and shared label provenance. We present OakuloidTM, an open DILI prediction framework that pairs a leakage audited structure based model with an optional iBAC 3D primary human hepatocyte IC50/Cmax confirmation signal. The structural model integrates gradient boosted descriptor backbones, fingerprint random forests and LivTox proxy-DILI features through a logistic meta learner. Its evaluation is designed as part of the contribution: internal DILIrank, strict external TDC, scaffold disjoint TDC and independent Geci provenance checks are reported with released per compound predictions. Oakuloid reaches AUROC 0.811 on the strict external TDC benchmark and remains competitive under scaffold and fully clean TDC filtering. A channel attribution ablation shows that the external benchmark lead is driven by descriptor based gradient boosted trees rather than by DILIPredictor derived proxy features, reducing a potential circularity concern. The wet lab IC50/Cmax signal is largely orthogonal to structure and supports a confirmation mode that shifts the internal operating point toward higher specificity without claiming a universal AUROC gain. Oakuloid is released with code, model artifacts, calibration analysis, a 122 compound wet lab benchmark and a model card under the Apache License 2.0, supporting reproducible DILI screening and benchmark auditing.

biochemistry↗

bioRxiv2026

Intra-Complex Differential Transcription Strategies for Scaffold versus Effector Proteins

Scaffold-organized multi-protein complexes are major drivers of cellular regulatory pathways, but how the expression of their constituent genes is coordinated to support efficient assembly and cell-to-cell homeostasis remains poorly understood. Using snapTotal-seq data, this study addresses this issue at the transcription level through comparative analyses of stochastic transcription bursting - a major driver of expression level and primary source of its intrinsic cell-to-cell noise. We compared scaffold proteins and their effector partners in major regulatory multi-protein complexes: TNRC6A/B/C (in the miRISC complex) and CNOT1/2 (in the CCR4-NOT complex) in mRNA regulation; and AXIN1, APC, KSR2, AKAPs, DLG1, PATJ, HOMER1/2, and SQSTM1 in signal transduction. Our analyses reveal a shared strategy: compared to genes for active effector partner proteins and the general transcriptome, genes for structural scaffold proteins consistently utilize more frequent and smaller-sized bursting to achieve the fine tuning of a homeostatic expression level. This finding establishes a fundamental link between a proteins physical role within a regulatory complex and the transcriptional bursting kinetics of its gene.

Systems Biology↗

bioRxiv2026

Connectional neuroanatomy of U-fibers in the rhesus monkey brain

The superficial white matter (SWM), the region of white matter immediately beneath the gray matter-white matter (GM-WM) border, contains short cortico-cortical association fibers that interconnect neighboring cortical regions. The SWM is estimated to comprise the majority of axons in the cerebral white matter and is thus thought to play a major role in cortical information processing. Despite this prominence, and growing attention in the diffusion MRI (dMRI) field, the connectional organization of the SWM remains poorly defined. A major component of the SWM is U-shaped fiber bundles, classically depicted in brain dissections as bundles beneath sulci that interconnect adjacent gyri. The prevailing view, from both brain dissection and dMRI, considers U-fibers to be ubiquitous elements of the SWM that form symmetric connections between corresponding portions of adjacent gyri beneath all sulci, and they are routinely reconstructed in tractography as a layer of short association connections. However, their actual prevalence and organization in the primate brain have never been systematically evaluated with experimental tract tracing. To address this gap, we analyzed 28 archival macaque tract-tracing cases in which anterograde tracers were injected on gyri adjacent to major cortical sulci (intraparietal, central, principal, superior temporal), all of which have clear anatomical correspondences to sulci in the human cerebral cortex. Several organizational principles emerged. First, although short association fibers were present in every case, U-fibers - operationally defined as labeled fibers that left the injection site, passed beneath a sulcus, and terminated on the adjacent gyrus - were only observed in a minority of cases. Second, U-fiber incidence was sulcus-dependent: U-fibers were consistently present beneath the principal and central sulci, but uncommon beneath the intraparietal and superior temporal sulci. Third, when present, U-fibers did not follow a uniform trajectory - some took a course symmetric and orthogonal to the sulcus, whereas others followed oblique trajectories to more distant regions. In addition to U-fibers, we identified shorter association fiber bundles that terminated on the sulcal bank proximal to the injection, or on the opposing bank after they crossed the fundus of the sulcus, evidence that the SWM contains multiple classes of short association fiber bundles rather than a single canonical U-fiber system. We further identified a consistent 200-300 {micro}m band of white matter beneath cortical layer 6 that contained exclusively short association fibers on approach to their cortical terminations and was selectively avoided by deeper long cortico-cortical pathways. This band was present across all examined sulci, suggesting that it is a conserved feature of the cortical white matter. Notably, U-fibers were found both within this band and in the white matter below. We also identified deeper fiber bundles that adopted a U-shaped course beneath a sulcus but did not interconnect adjacent gyri. Thus, a U-shaped trajectory alone does not define a U-fiber. Together, these findings constitute the first systematic connectional study of cortical U-fibers in major sulci of the non-human primate brain and indicate that the white matter beneath the cortex is a highly complex system in which short association fiber bundle organization reflects the selective connectivity of the cortical areas separated by a sulcus, rather than a uniform U-fiber architecture imposed by the geometry of the overlying sulcus. These results have potential consequences for dMRI and anatomical studies of white matter and provide an anatomically grounded basis to better define SWM organization in anatomy and tractography.

neuroscience↗

bioRxiv2026

CryoDiff: An uncertainty-aware diffusion model for Cryo-EM map enhancement

Cryogenic electron microscopy (cryo-EM) enables high-resolution structural determination of large macromolecular complexes. However, the interpretability of cryo-EM maps is often hindered by substantial background noise and signal attenuation, which obscure structural details. Although existing post-processing methods can partially mitigate these artifacts, they typically suffer from over-smoothing and lack reliable confidence estimation. Here, we present CryoDiff, an uncertainty-aware diffusion model for cryo-EM map enhancement. CryoDiff employs a multi-step diffusion process to progressively denoise and restore high-resolution structural features. Importantly, CryoDiff incorporates a voxel-wise confidence metric derived from Monte Carlo sampling. It unifies map enhancement and voxel-level uncertainty estimation within a diffusion-based generative framework, representing the first approach to achieve such joint modeling for cryo-EM map enhancement. In comprehensive experiments, CryoDiff markedly out-performs existing methods in both map-model correlation and map interpretability, improving the average FSC0.5 metric by 0.356 [A] over state-of-the-art approaches. When applied to de novo model building with ModelAngelo, CryoDiff further increases model completeness by 5.5%, exceeding the gains achieved by competing method.

bioinformatics↗

bioRxiv2026

SRC Knockdown Impairs Proliferation, Migration, and Invasion While Promoting Apoptosis in HTR8/SVneo Trophoblast Cells via Activation of the PI3K/Akt/Bcl-2 Signaling Pathway

SRC knockdown inhibits trophoblast cell proliferation, migration, and invasion while inducing apoptosis via activation of the PI3K/Akt/Bcl-2 signaling pathway. Trophoblast dysfunction is central to pregnancy disorders such as preeclampsia and miscarriage, yet the role of SRC, a non-receptor tyrosine kinase, in these cells remains poorly understood. This study aimed to elucidate the functional impact of SRC on trophoblast behavior and its underlying mechanism. Using siRNA-mediated knockdown in HTR8/SVneo cells, we confirmed efficient reduction of SRC mRNA and protein expression via RT-qPCR and Western blot. Functional assays demonstrated that SRC silencing significantly suppressed cell proliferation (CCK-8), migration (wound healing), and invasion (Transwell), while promoting apoptosis, evidenced by increased Annexin V-FITC/PI staining and upregulated Caspase-3 and Caspase-9 protein levels. Mechanistically, Western blot analysis revealed that SRC knockdown upregulated PI3K, Akt1, and Bcl-2 protein expression without altering IRS1 levels, indicating activation of the PI3K/Akt/Bcl-2 pro-survival pathway. This paradoxical activation appears to be a compensatory feedback insufficient to overcome SRC loss-induced dysfunction. Our findings identify SRC as a critical positive regulator of trophoblast proliferation, motility, and survival, acting through a non-canonical, IRS1-independent negative regulation of PI3K/Akt signaling. This study provides novel insights into trophoblast biology and suggests SRC as a potential therapeutic target for pregnancy complications; future in vivo studies are warranted to validate these mechanisms.

molecular biology↗

bioRxiv2026

miR-6818-5p Drives Ovarian Granulosa Cell Dysfunction in PCOS via Targeting HSD17B2 and Modulating PI3K/Caspase-9 Axis

Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovaries, with granulosa cell dysfunction being a key pathological feature. This study aimed to investigate the role of microRNA-6818-5p in PCOS pathogenesis. Quantitative PCR revealed a significant upregulation of circulating miR-6818-5p in PCOS patients compared to healthy controls. In vitro, functional assays in the human granulosa cell line KGN demonstrated that miR-6818-5p overexpression markedly inhibited cell proliferation (assessed by CCK-8 assay) and promoted apoptosis (measured by Annexin V/PI flow cytometry). Mechanistically, dual-luciferase reporter assay and Western blotting identified HSD17B2 as a direct target of miR-6818-5p, with miR-6818-5p mimics significantly suppressing HSD17B2 protein expression. In conclusion, our findings reveal that elevated miR-6818-5p in PCOS may contribute to follicular development dysfunction by targeting HSD17B2 to disrupt granulosa cell proliferation and apoptosis balance, offering novel insights into PCOS pathology and highlighting miR-6818-5p as a potential diagnostic biomarker and therapeutic target.

molecular biology↗

bioRxiv2026

In vitro-reconstituted Drosophila Arc capsids deliver gene editors to dystrophic muscle

The intracellular delivery of therapeutic macromolecules remains a major challenge in biomedicine. Here we reconstitute the Drosophila melanogaster Arc1 (dArc1) retroelement-derived capsid entirely from purified recombinant protein components and in vitro transcribed RNA, creating a fully defined, cell-free assembled protein nanoparticle system. Through affinity engineering of the dArc1 RNA-binding domain, we enable efficient encapsulation of mRNA payloads and Cas9 ribonucleoproteins. Unexpectedly, we discover that dArc1 capsids bind mammalian cells through a direct interaction with the surface receptor SORCS2. Leveraging this interaction, we show that intramuscular injection of dArc1 capsids carrying Cas9 gene editors achieves up to 18% exon skipping and restores dystrophin expression in muscle fibers of mdx mice, a model of Duchenne muscular dystrophy. Enhanced delivery efficiency in regenerating and dystrophic muscle correlates with upregulated SORCS2 expression, supporting our finding that SORCS2 facilitates cellular uptake of dArc1 capsids. This work demonstrates the potential of in vitro-assembled protein nanoparticles for delivery of molecular cargoes.

molecular biology↗

bioRxiv2026

Toward CT-based Tractography: Presurgical White Matter Tract Mapping in Intracerebral Hemorrhage

Presurgical mapping of key white matter (WM) fiber tracts is crucial for intracerebral hemorrhage (ICH) surgery, but it currently relies on tractography from diffusion MRI (dMRI), which has limited applicability in urgent or resource-constrained settings due to long scan times and limited MRI availability. To bridge this gap, we developed a deep learning approach designed to reconstruct critical fiber tracts directly from routinely acquired CT scans, focusing on the corticospinal tract (CST) due to its high clinical relevance. By training a novel network on a curated dataset of 150 paired CT-dMRI scans (101 ICH patients and 49 healthy subjects), we enabled the direct mapping of the CST from CT images alone, bypassing the traditional requirement for dMRI. Our results demonstrate that the CT-derived tracts achieve high anatomical plausibility, with neurosurgeon expert assessments yielding a Likert score of 3.64. Furthermore, the clinical relevance of these reconstructions was validated by a significant correlation between CT-derived tract integrity and patient motor scores (r = 0.726, p = 3.731x 10-7). These findings suggest that in complex clinical scenarios, particularly where dMRI signal quality is compromised by lesion-induced distortion, this CT-based mapping may serve as a useful anatomical reference. Overall, by enabling CT-based WM mapping, our method potentially offers a practical route to gain the key advantages of tractography in resource-limited or time-critical settings

neuroscience↗