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Shen, Z.

Publications and source records attributed to Shen, Z..

At least 19 recordsLinked to original sources

A spatial topology atlas of type I myofibers in porcine skeletal muscle reveals local slow-oxidative niches associated with meat quality traits

Skeletal muscle metabolism and meat quality are usually interpreted through myofiber type composition, fiber size, and histochemical state. Whether the spatial topology of myofibers constitutes an independent phenotype layer remains poorly quantified. Here, using succinate dehydrogenase (SDH)-stained cross-sectional images from multiple pig breeds and more than 40 skeletal muscle sites, we established a multiscale spatial phenotyping framework for type I myofibers. To enable scalable instance-level quantification, we developed an improved Mask R-CNN segmentation workflow, trained with SAM-assisted and manually corrected annotations, and optimized for dense, small, irregular, and variably stained muscle fibers. This framework captures single-fiber morphology and staining, local contact, connected-cluster architecture, diffusion-ring neighborhoods, and global tissue configuration. Type I myofiber abundance was separable from spatial organization capacity: some muscles formed stronger-than-expected local connectivity and clustering despite modest type I fiber abundance. Spatial transcriptomic integration further showed that slow-oxidative genes and functional modules were non-randomly organized and formed local high-expression domains in type I fiber-enriched, high-contact neighborhoods. Across muscle sites and breeds, skeletal muscles displayed distinguishable type I fiber spatial topology identities, which were remodeled by breed background in a muscle-specific manner. In samples with matched meat-quality measurements, spatial topology features improved the explanation of pH, meat color, conductivity, and intramuscular fat. These results suggest that skeletal muscle should be modeled as a spatially organized tissue system rather than a simple mixture of fiber types.

bioinformatics↗

Therapeutic AIBP expression contributes to synaptic preservation and vision restoration against glaucomatous neuroinflammation

Lowering intraocular pressure (IOP) is the only approved treatment for glaucoma, yet retinal ganglion cell (RGC) degeneration and vision loss often progress despite reducing IOP. Apolipoprotein A-I binding protein (AIBP) stabilizes ATP-binding cassette subfamily A member 1 (ABCA1) and promotes cholesterol efflux, thus controlling cholesterol-rich lipid rafts and restraining lipid raft-dependent Toll-like receptor 4 (TLR4) inflammatory signaling. Here we show that AAV2-mediated expression of human AIBP (hAIBP) preserves inner retinal synaptic integrity and visual function in experimental glaucoma without altering IOP. In DBA/2J mice, a single intravitreal injection of AAV2-hAIBP at 5 months protected RGCs and preserved pattern electroretinogram and pattern visual evoked potential responses at 10 months, even though IOP was indistinguishable from empty-vector controls. AAV2-hAIBP preserved CaMKII and synapsin phosphorylation, restored synaptophysin and PSD95 in the inner plexiform layer, and reduced the expression of TLR4, complement C1q, IBA1, IL-1b, and IL-6 induction in Muller glia and microglia. Comparable protection was observed in microbead-induced ocular hypertension in C57BL/6 mice, both when the AAV2-hAIBP was delivered before microbead injection and when it was delivered after IOP elevation was established. Elevated IOP reduced endogenous retinal AIBP and ABCA1 expression, and AAV2-hAIBP restored both. Protection required the TLR4-binding domain, as an AIBP mutant lacking this domain failed to preserve RGCs. Conversely, AIBP knockout retinas exhibited increased CaMKII phosphorylation and reduced synaptophysin in the absence of elevated IOP. These findings identify synaptic preservation through the AIBP-TLR4 axis as an IOP-independent therapeutic mechanism and support AAV2-hAIBP as a candidate gene therapy for glaucoma.

neuroscience↗

Benchmarking longitudinal local centiles for radiographic knee osteoarthritis prognosis

Cartilage thickness on MRI is a structural biomarker of osteoarthritis (OA), yet anatomical variation and aging can mask early disease, including changes occurring 12-36 months before incident OA. We propose longitudinal local centile maps that use normative growth charts as prior information and integrate a knee's earlier scans to identify cartilage that is thinner or thicker than expected. We built the reference charts from 5,045 scans of 957 persistently radiographically normal knees in the Osteoarthritis Initiative. Under participant-separated nested cross-validation, longitudinal centile profiles achieved higher 12- and 24-month AUCs for predicting incident radiographic OA than regional PCA, radiomics, cross-sectional centile features, and raw-map deep features across most classifiers. These conventional descriptors added little when combined with centile profiles, and cross-sectional centiles added little beyond longitudinal centiles. Deep centile features achieved the best AUCs (0.954 [95% CI 0.931-0.974] at 12 months and 0.969 [0.949-0.985] at 24 months; balanced accuracy 0.917 and 0.931) and outperformed raw-map deep features in all 12 classifiers after correction for multiple comparisons. No representation consistently improved 36-month prediction. Longitudinal centiles transform cartilage thickness maps into reference-based deviation maps: deep longitudinal centile features provide the highest predictive accuracy, while regional longitudinal centile profiles provide interpretable prognosis with the second-highest accuracy.

bioengineering↗

A mycovirus identified from an outbreak fungal species complex reveals a parallel antiviral system

Mycoviruses are prevalent across major fungal lineages, yet none have been reported in the Cryptococcus gattii species complex (CGSC), the causative agent of the largest known fungal outbreak in immunocompetent hosts. Consequently, the occurrence of mycoviruses and the host determinants governing their infection in this important pathogenic clade remain unexplored. Through screening of 386 Cryptococcus isolates, we identified a mycovirus, designated CgTV1, in an environmental isolate of the Cryptococcus gattii species complex (CGSC). CgTV1 is a double-stranded RNA (dsRNA) mycovirus of the genus Totivirus, with a genome encoding a capsid protein and an RNA-dependent RNA polymerase. We showed that CgTV1 establishes a cryptic infection, because neither viral presence nor its clearance significantly alters host transcriptomic profiles, suggesting the existence of mechanisms that maintain virus-host homeostasis. Population genomic analyses reveal that an intact RNAi pathway constitutes a critical genetic barrier, and CgTV1 persistence strictly requires loss of function mutations in both AGO1 and AGO2. By pan-transcriptomics across 43 CGSC strains, we further uncovered an RNase III gene, CAI1, which exhibits high expression in the mycovirus positive isolate. Biochemical analysis indicates that Cai1 directly recognizes and degrades CgTV1 dsRNA, thereby constraining excessive mycoviral proliferation. We further demonstrate that Dicer and Cai1 act in parallel to maintain virus-host homeostasis: their combined ablation results in higher viral loads and more pronounced changes in host gene expression than ablation of either factor alone. Collectively, our findings provide the evidence of the occurrence of a mycovirus in the CGSC and reveal parallel mechanisms that enable cryptic mycoviral infections.

genetics↗

CynoBrain: A unified high-resolution framework for cross-modal data integration for macaque brain mapping

The cynomolgus macaque is a widely used primate model in neuroscience, yet existing brain atlas resources remain limited in resolution and lack a standardized framework for integrating structural, molecular, and connectivity data within a common reference space. Here we present CynoBrain, a high-resolution multi-modal brain atlas constructed from population-averaged MRI data at 9.4 Tesla, yielding a 75 micron isotropic template with significant improvement in resolution. A co-registered whole-brain autofluorescence template resolves cytoarchitectural boundaries not visible in MRI template. Three major parcellation schemes, D99 143-area, M132 105-area, and SARM are incorporated in CynoBrain space. Spatial transcriptomic based laminar definition, reconstructed from 2D sections into volumetric common space, provides a six-layer cortical segmentation spanning the whole cortex. As a demonstration of the integrative capability of this framework, 2D retrograde tracing data is reconstructed and mapped to the Cynobrain space, enabling volumetric compilation of 2D macaque brain mapping data across subjects. An online interactive platform was constructed to allow full access to Cynobrain, establishing it as a scalable, open platform for cross-modal data integration for primate neuroscience. Overall, CynoBrain is a unified framework for cross-modal data integration for macaque brain mapping with high-resolution, multiple atlases and transcriptomic based laminar definition.

neuroscience↗

Comprehensive analysis of mulberry genetic diversity based on 1-DNJ content and SNP markers

Mulberry trees have high economic and ecological value, and a robust molecular marker system plus germplasm genetic diversity analysis is critical for innovative utilization of high-quality medicinal and economic mulberry germplasm. Here, 51 mulberry samples were used to develop SNP primers via genome resequencing, with the SNP-PCR system optimized by single-factor and orthogonal assays. The phenotypic diversity and SNP molecular marker genetic diversity of 1-deoxynojirimycin (1-DNJ) in mulberry leaves were analyzed respectively, and the genetic correlation between molecular markers and phenotypic traits was evaluated by Mantel test. Tested germplasm showed marked 1-DNJ variation (0.4805-2.5300 mg/g, CV=0.4241), reflecting rich genetic diversity. The optimal SNP-PCR system included Buffer (containing Mg{superscript 2}+) 2.2 L, 2.5 mM dNTP 0.4 L, forward and reverse primers (10 mol{middle dot}L-1) totaling 2.75 L, Taq DNA polymerase (5 U{middle dot}L-1) 0.3 L, DNA (50 ng{middle dot}L-1) 1.1 L, and ddH2O 13.65 L. 23 highly polymorphic ones amplified 91 loci (81 polymorphic, 89.10% polymorphism rate). Genetic diversity analysis showed that the average genetic distance was 0.3010, and the average expected heterozygosity (H) and Shannon information index (I) reached 0.4667 and 0.3104 respectively, indicating that the genetic differentiation among the tested mulberry germplasms was significant and the population had a moderate to upper level of genetic diversity. UPGMA clustering divided 51 germplasms into 6 major groups at a genetic similarity coefficient of about 0.7, while phenotypic clustering based on 1-DNJ content divided them into 2 major categories and 4 subcategories, with high 1-DNJ germplasm clustered independently. Mantel correlation analysis showed that 6 SNP sites were significantly weakly correlated with 1-DNJ content (r < 0.3, p < 0.05), and can be used as candidate molecular markers for subsequent genetic analysis of 1-DNJ content.This study established a stable mulberry SNP-PCR system, Analyze the molecular genetic characteristics of mulberry germplasm and DNJ phenotypic variation rules respectively, and provide basic data for cluster comparison. and provided a scientific basis for marker database improvement, germplasm identification and molecular-assisted breeding.

genetics↗

Transforming clinical apheresis waste into a renewable source of patient-derived CD34+ hematopoietic stem cell biobank for beta-hemoglobinopathy research and therapeutic discovery

Background aimsThe development of next-generation therapies for sickle cell disease (SCD) and beta thalassemia (beta thal), including fetal globin-inducing small molecules and gene therapy approaches, depends on patient-derived CD34+ hematopoietic stem and progenitor cells (HSPCs) for discovery and preclinical validation, but commercial vendors stock only healthy donor material and disease-specific banks hold limited inventories. Recent US Food and Drug Administration and National Institutes of Health guidance favoring human cell-based methods over animal testing underscores the value of authentic patient cells. Methods: Over 14 months we recovered, purified, and biobanked CD34+ HSPCs from clinical apheresis product waste and mobilized peripheral blood (PB) otherwise discarded after clinical procedures, using immunomagnetic selection adapted for hemoglobinopathy specimens; a microfluidic technology was evaluated separately. We quantified yield and purity for bead-selected material and cell number and viability for the microfluidic pilot; engraftment was tested in NBSGW mice. Results: Immunomagnetic selection recovered a median of 4.71 x 106 CD34+ cells from just 1 to 2 mL of apheresis product waste, comparable to the 6.0 x 106 cells from a 10 to 40 fold larger volume of PB waste, with similar purity across sources and diagnoses. Because apheresis product waste is far more concentrated, it reaches equivalent yields without the density-gradient steps required for PB waste, approximately halving processing time. Recovered cells engrafted NBSGW mice, confirming preserved repopulating capacity. The microfluidic pilot (two patients, 11 specimens) recovered 2.17 x 106 CD34+ cells per specimen at greater than 90% viability and purity. Conclusions: A center with existing apheresis infrastructure can reproducibly recover, bank, and distribute research-grade patient CD34+ HSPCs, addressing a recognized gap in the hemoglobinopathy pipeline. HighlightsO_LIClinical apheresis waste is used to generate a single-center biobank of high-quality, research-grade CD34+ HSPCs from patients with sickle cell disease and beta-thalassemia. C_LIO_LIConcentrated apheresis waste matches large-volume PB waste in CD34+ yield and purity. C_LIO_LIMicrofluidic enrichment recovers CD34+ cells at >90% viability and purity across 2 patients. C_LIO_LIRecovered CD34+ HSPCs engraft mice and form erythroid cells, preserving function. C_LI

pharmacology and toxicology↗

Multivalent Tau-Fyn interactions cooperatively arrest postsynaptic density condensate dynamics

Tau-Fyn signaling at postsynaptic sites is implicated in synaptic dysfunction and neuronal hyperexcitability in Alzheimers disease and related tauopathies, yet the molecular mechanisms by which Tau-Fyn interactions influence postsynaptic signaling assemblies remain poorly understood. Here, we reconstitute biomolecular condensates and membrane-associated assemblies that mimic the postsynaptic density (PSD) to investigate how Tau and Fyn regulate PSD organization and dynamics. We show that Tau and Fyn co-partition into PSD condensates and N-methyl D-aspartate receptor subtype 2B (NR2B)-associated PSD clusters, with both proteins preferentially enriching in the condensed phase relative to core PSD scaffold proteins. Enrichment of Fyn within PSD condensates is recapitulated by an SH3-SH2 fragment lacking the kinase domain, indicating that the kinase domain is dispensable for condensate partitioning. Fluorescence recovery after photobleaching reveals that Tau markedly reduces Fyn mobility and, together with Fyn, cooperatively drives a pronounced dynamic arrest of PSD condensate components, including the central scaffold protein PSD-95. Disruption of a major Tau-Fyn interaction hotspot by P216A/P219A mutations in Tau nearly completely restores the mobility of both Fyn and PSD-95, demonstrating that cooperative Tau-Fyn interactions are required for dynamic arrest. NMR spectroscopy identifies a multivalent interaction network between the Tau proline-rich region and the Fyn SH3 domain involving multiple binding motifs, with residues P216 and P219 acting as major interaction determinants. A 1.4 [A] crystal structure of the Fyn SH3 domain bound to a Tau peptide reveals a ternary 2:1 Fyn:Tau assembly, providing structural support for multivalent Tau- Fyn engagement. Together, our findings establish a condensate-based mechanism by which multivalent Tau-Fyn interactions cooperatively regulate PSD condensate dynamics and provide a molecular framework linking Tau-Fyn signaling to synaptic dysfunction in tauopathies.

biochemistry↗

Microbial induction of MHC-II expression in colon cancer cells overcomes immunotherapy resistance and limits metastasis

Colorectal cancer remains a major cause of cancer mortality, and most microsatellite stable tumors derive little benefit from immune checkpoint blockade. Here, we identify a microbiome-dependent mechanism that converts immune-refractory colorectal cancer into a more immunologically responsive state. Using orthotopic mouse models spanning distinct genetic and immunologic contexts, we show that a Helicobacter-containing microbiome suppresses primary tumor growth and limits metastasis. This protective state is associated with increased intratumoral lymphocyte infiltration and stronger effector programs. Mechanistically, microbial exposure induces MHC class II expression in colon cancer cells to promote anti-tumor immunity. Tumor-intrinsic loss of CIITA abrogates microbial protection, whereas enforced CIITA expression is sufficient to increase intratumoral T cell accumulation, restrict progression and metastasis, and sensitize microsatellite-stable tumors to PD-1 and CTLA-4 blockade. In human microsatellite-stable patient-derived organoids, increased cancer-cell MHC-II enhanced interactions with autologous immune cells and increased tumor cell apoptosis. Together, these findings define a microbiome-cancer cell antigen presentation axis that restrains metastasis and overcomes immunotherapy resistance in colorectal cancer.

immunology↗

Viral infection drives cell-intrinsic re-localization of the C. elegans immune-repressive STAT transcription factor STA-1

Detection of viral infection leads to both cell-intrinsic and cell-extrinsic responses. In mammals, cell-intrinsic detection of viral infection leads to cell-extrinsic activation of STAT (Signal Transduction and Activators of Transcription) proteins, a family of transcription factors that promote anti-viral defense. In the nematode C. elegans, STA-1/STAT is a negative regulator of anti-viral defense, but it is not known if it acts cell-intrinsically or cell-extrinsically and whether it has functional domains conserved with mammalian STATs. Here we show that C. elegans STA-1 protein disappears from nuclei of cells infected with the natural viral pathogen, Orsay virus, but remains nuclear in uninfected cells, indicating a cell-intrinsic site of action. During viral infection, STA-1 forms cytoplasmic puncta that interact with the RNA viral sensor DRH-1, suggesting that DRH-1 helps restrain this immune-repressive factor. STA-1 overexpression causes increased susceptibility to viral infection, in a manner dependent on conserved residues important for DNA binding, nuclear localization and phosphorylation. Structural predictions indicate that STA-1 is most similar to STAT5 proteins in mammals, which have known immune-repressive roles. Our transcriptomic analysis demonstrates that C. elegans STA-1 regulates a general anti-pathogen program, including genes upregulated later during viral infection. Altogether, our findings provide insight into conserved and distinct features of STA-1 in C. elegans, indicating an ancient role for cell-intrinsic, immune-repressive STATs. Author SummaryAll living organisms must detect viral infections and mount a defense to survive. One major antiviral defense pathway in mammals is the interferon response, which involves sensing viral infection in one cell, and delivering an interferon message to neighboring cells. These neighboring cells then turn on anti-viral defense gene expression using proteins called STAT transcription factors. We study anti-viral defense in the roundworm C. elegans, and in this study show that viral infected cells themselves use a STAT protein called STA-1, with perhaps a lesser role for STA-1 in neighboring cells, in contrast to mammals. We also extend on previous findings that STA-1 turns off anti-viral gene expression, and we analyze regions in the protein to demonstrate that STA-1 is bona fide transcription factor with an immune-repressive role. Structural prediction analysis of STA-1 indicates it is most similar to STAT5 in mammals, suggesting an ancient role for this protein as an immune-repressive factor acting directly in virally infected cells.

immunology↗

Myeloid Suclg2 deficiency attenuates aortic dissection by reshaping succinate-associated macrophage remodelling

BackgroundSuccinate has emerged as an immunometabolic mediator of cardiovascular diseases. However, the enzymatic mechanisms linking macrophage succinate metabolism to aortic dissection remain incompletely understood. This study investigated whether Suclg2, which encodes the GDP-forming {beta}-subunit of succinyl-CoA ligase, regulates succinate-associated macrophage remodelling and aortic dissection progression. MethodsSuclg2 expression was examined in BAPN-induced AD and human acute type A aortic dissection tissues by Western Blot and immunofluorescence. Myeloid- and smooth muscle cell-specific Suclg2 conditional knockout mice were subjected to BAPN treatment to evaluate survival, aortic outcomes, histological injury and aortic morphology. Aortic RNA-seq was used to discover transcriptional changes. Bone marrow-derived macrophages were analysed under basal, M1-like and M2-like conditions to assess macrophage-intrinsic transcriptional responses. Plasma succinate levels and untargeted metabolomic profiles were further examined. ResultsSuclg2 was increased in murine and human dissected aortas and partially localized to CD68 cells. Myeloid Suclg2 deletion markedly reduced BAPN-induced aortic rupture and dissection, whereas smooth muscle cell Suclg2 deletion did not confer comparable protection. Aortic transcriptomic analysis showed that myeloid Suclg2 deficiency attenuated inflammatory adhesion and matrix-destructive programmes. In macrophages, Suclg2 deletion did not induce a simple M1/M2 polarization shift; instead, it remodelled lipid-handling, phagolysosomal, adhesive and matrix-remodelling pathways across stimulation states. Metabolic profiling showed reduced circulating succinate and broader changes in central carbon, lipid-associated, nucleotide and redox-related metabolites after myeloid Suclg2 deletion. ConclusionsMyeloid Suclg2 is a succinate-associated immunometabolic regulator of aortic dissection. Its deficiency protects against aortic dissection by reshaping macrophage inflammatory-remodelling programmes and the systemic metabolic environment.

Cell Biology↗

Buffered sweat microfluidics with AI-enabled translation for clinically actionable blood urea estimation and renal risk stratification

Kidney-function assessment relies on blood urea as a clinically informative metabolic marker; however, its dependence on venipuncture and centralised laboratory testing limits high-frequency monitoring and delays timely clinical intervention. Here, we report an integrated platform combining a wearable buffered microfluidic patch with a physiology-informed, data-driven calibration framework for real-time, non-invasive estimation of blood urea from microlitre-scale sweat volumes (4.79 L). By precisely regulating the release kinetics of internal buffer salts, the device stabilises the local reaction microenvironment, mitigating variability in sweat pH and flow to ensure reproducible measurement. The resulting signals are processed through an artificial intelligence (AI)-enabled analysis pipeline that integrates sweat urea with patient-specific physiological information to generate clinically interpretable outputs. In multicentre studies, sweat urea shows a strong association with blood urea across diverse cohorts, but with nonlinear and time-lagged relationships that limit direct use. The AI-enabled calibration model compensates for these effects, enabling high-fidelity estimation of blood urea (r = 0.945 versus gold-standard measurements) at clinically relevant concordance levels. The platform further identifies kidney injury with 89.1% accuracy and stratifies disease severity with 83.2% accuracy. Notably, these results demonstrate that the integration of physicochemical stabilisation and AI-enabled data-driven translation establishes sweat as a clinically actionable surrogate for renal monitoring, supporting population-level estimation and highlighting the potential for personalised longitudinal assessment, and enabling a scalable, non-invasive strategy for high-frequency kidney disease management.

biophysics↗

Investigation of In Vivo Silk Scaffold Degradation by Decoupling Tissue Ingrowth Using a GPR-Driven Digital Twin Framework

Pelvic organ prolapse (POP) reconstruction is increasingly performed utilizing knitted silk meshes (KSM), yet tracking in vivo degradation kinetics remains challenging due to complex host tissue integration. This study developed an AI-driven semi-empirical framework utilizing Gaussian Process Regression (GPR) to bridge the kinetic mismatch between in vitro and in vivo environments. KSM scaffolds underwent 32 weeks of accelerated in vitro enzymatic degradation, with morphology (SEM), molecular conformation (FTIR), and mass loss being coupled with mechanical decay to train the GPR model. In vitro results revealed a multi-stage physical disintegration via a topochemical erosion pathway that preserved crystalline {beta}-sheet structures despite macro-scale mass and mechanical loss. When validated in a rat abdominal wall defect model, traditional tracking metrics encountered severe bottlenecks. Heterogeneous dye labeling caused premature fluorescence quenching by Week 16, while extensive tissue ingrowth masked gravimetric and SEM signatures. Intriguingly, a bi-phasic in vivo mechanical trajectory was identified, where initial degradation-led failure was followed by a secondary mechanical recovery driven by biomechanical synergy with neo-muscular tissue. Importantly, despite premature quenching, this work presents the first optical imaging approach to visually mapping the complete chronological breakdown of the scaffolds peripheral boundary layer in vivo, proving that outer functionalized layers eroded prior to internal silk cores. Furthermore, our GPR framework elegantly resolved the perennial technical barrier of tissue-mesh overlapping. By mathematically decoupling intrinsic polymer degradation from confounding tissue ingrowth, the model successfully achieved a first-of-its-kind prediction of the bare scaffolds long-term structural fate in a non-adhered state, providing a robust digital twin methodology for lifetime predictions of degradable biomaterials.

bioengineering↗

A Sandwich-Structured Silk Fibroin Mesh with ROS-Responsive and Immunoregulatory Functions for Pelvic Floor Repair

Current biodegradable meshes for pelvic floor repair are constrained by a limited ability to actively modulate the hostile immune microenvironment following implantation. To address these challenges, we developed a functionalized degradable silk fibroin mesh (SFM) integrated with a reactive oxygen species (ROS)-responsive nanocomposite hydrogel. The resulting composite mesh, SFM@Gel-NP, features a "hydrogel-mesh-hydrogel" sandwich structure, wherein the hydrogel layers are loaded with self-assembled nanoparticles (NP-H-CRFP) for the co-delivery of the STING inhibitor H-151 and the ROS-scavenging agent catechin. This design provides immediate mechanical reinforcement while enabling microenvironment-triggered drug release. In vitro, NP-H-CRFP demonstrated efficient cellular uptake, significant ROS clearance, and effective attenuation of macrophage inflammation and apoptosis. In vivo, SFM@Gel-NP remodeled the local immune milieu by inhibiting the ROS/cGAS-STING/NF-{kappa}B axis, thereby promoting a shift from pro-inflammatory M1 toward pro-regenerative M2 macrophage polarization. This immunomodulatory effect, coupled with enhanced and well-organized collagen deposition--particularly of early type III collagen--resulted in improved tissue integration and repair. This work presents a novel strategy that combines structural reinforcement with active immune regulation, offering a promising next-generation solution for durable and functional pelvic floor reconstruction.

bioengineering↗

Coordinated phase separation and phase transition underlie synaptic ribbon condensate formation and plasticity

Mesoscale molecular apparatuses with diverse functions are widespread in cells. How mesoscale cellular apparatuses are formed and regulated is poorly understood. The synaptic ribbon in sensory neurons, which can dynamically adjust its size and shape in response to light or sound, is a mesoscale molecular assembly. In this study, we demonstrate that RIBEYE, the backbone protein of synaptic ribbons, via combined ordered and disordered interactions, forms micron-sized dynamic molecular assemblies. Integrated cryo-electron microscopy and tomography studies revealed that the N-terminal SAM domain and the C-terminal B domain of RIBEYE form distinct nanoscale filaments and further assemble into ribbon-like architectures via phase transition. Unexpectedly, the N-terminal intrinsically disordered region of RIBEYE softens the solid mesoscale ribbon structures via phase separation. The mesoscale size and shape of the RIBEYE condensate are bidirectionally tuned by physiological modulators such as Piccolino and CtBP1, linking synaptic ribbon structural plasticity to functional adaptability. Thus, our study demonstrates that combined phase transition and phase separation of nanoscale protein oligomers can build mesoscale functional cellular apparatuses.

biochemistry↗

Emergence of rigidity percolation and critical behavior in tunable protein condensates

Multivalent proteins are known to form complex networks within biomolecular condensates, yet the mechanisms governing the emergence and evolution of these networks remain poorly understood. Here, we utilize a synthetic protein chimera system with tunable interactions to investigate the transition from liquid-like droplets to networked condensates. By employing single-amino-acid substitutions, we generated a series of mutants with varying protein-binding strengths. As the interaction strength increases, the condensates undergo a sharp rigidity percolation transition, characterized by a more than 200-fold increase in both elastic modulus and viscosity. Near this transition, we identify a critical scaling relation in the condensate elasticity, providing robust evidence for a percolation-driven assembly mechanism. Furthermore, we demonstrate that this network architecture is fundamentally linked to biological functions. The introduction of disease-associated mutations disrupts the network, significantly softening the condensates and rendering them fluid-like. Our findings reveal that network percolation and criticality in protein condensates can be sensitively regulated by single-amino-acid substitutions, underscoring their essential role in maintaining structural integrity and supporting physiological function.

biophysics↗

Platelets Outperform Leukocytes in Transcriptomic Liquid Biopsy Profiling of Myeloproliferative Neoplasms

Myeloproliferative neoplasms (MPNs) are characterized by progressive myelofibrosis that drives morbidity and mortality. Liquid biopsy approaches to noninvasively monitor fibrotic progression remain limited. We performed comparative transcriptomic profiling of CD45-depleted platelet-enriched and CD45+ leukocyte-enriched fractions from matched peripheral blood samples of 76 individuals (27 primary myelofibrosis, 17 polycythemia vera, 14 essential thrombocythemia, 18 healthy controls). Platelet RNA sequencing was performed in 2018-2020 on Illumina HiSeq 4000, while WBC RNA sequencing was conducted in 2023 on Illumina NovaSeq 6000 from cryopreserved CD45+ enriched fractions of specimens obtained at the identical time and from the same blood sample as the platelet RNA. Despite comparable library preparation protocols and higher sequencing depth in WBC samples, platelet transcriptomes exhibited 5.1-fold more differential expression in myelofibrosis (3,453 versus 681 genes, adjusted p<0.05, |log2FC|>1). Platelet signatures were enriched for proteostasis pathways including endoplasmic reticulum stress and unfolded protein response, reflecting megakaryocyte dysfunction in the fibrotic bone marrow niche. WBC signatures predominantly featured immune activation and proliferative pathways, indicating systemic inflammatory responses. Multinomial LASSO classification demonstrated superior performance of platelet-based models for myelofibrosis diagnosis (AUROC 0.85) compared to WBC-based (AUROC 0.77) or clinical models (AUROC 0.59). Combined platelet+WBC models did not improve performance (AUROC 0.80), indicating complementary but non-additive information. These findings establish platelet transcriptomic profiling as a superior noninvasive biomarker platform for monitoring myelofibrosis in MPNs, capturing megakaryocyte-driven fibrogenesis with greater sensitivity than peripheral leukocyte-based approaches. HighlightsUsing matched WBC and platelet RNA-seq from MPN patients, we identify myelofibrosis-associated transcriptomic signatures specifically enriched in platelets. Multinomial LASSO modeling highlights platelet-derived gene expression as a dominant and predictive biomarker of myelofibrosis, outperforming clinical parameters and WBC signatures. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=75 SRC="FIGDIR/small/714941v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@10a388borg.highwire.dtl.DTLVardef@66079org.highwire.dtl.DTLVardef@a7c29eorg.highwire.dtl.DTLVardef@1da1a96_HPS_FORMAT_FIGEXP M_FIG C_FIG

pathology↗