Biology subjects

Shen, Y.

Publications and source records attributed to Shen, Y..

At least 19 recordsLinked to original sources

bioRxiv2026

In Utero MRI of Radial Glial Fibers Highlights Their Role in Modulating Fetal Cortical Folding

The process of cortical folding is fundamental to early human brain development. While the differential growth of the cortical layers is a known driver, the biomechanical contribution of key cellular microstructures remains unclear, and there is a lack of direct in vivo markers of cortical microstructures for time-resolved observations. Using a multimodal approach combining in utero and ex vivo fetal brain MRI, histology, and computational mechanical simulation, we investigated whether developmental reorganization of cortical radial microstructures, particularly the radial glial cell (RGC)-associated scaffold, is linked to cortical folding and may modulate its mechanical progression. We characterized this radial organization noninvasively using diffusion MRI-based radial fiber density (FDrad). ex vivo fetal brain MRI and histology supported that regional variations in FDrad were strongly associated with vimentin-labelled radial architecture. Our in utero MRI data revealed closely coordinated developmental changes in cortical FDrad and curvature, with their regional timings and spatial patterns significantly coupled across the cortex. Longitudinal in utero MRI data further supported the synchronized within-individual co-development of FDrad and curvature. Furthermore, biomechanical simulations showed that reducing radial reinforcement modulated differential-growth-driven buckling, producing earlier folding and a greater cortical curvature under otherwise matched model conditions. Collectively, this study introduces FDrad as a noninvasive in utero MRI measure sensitive to radial glial fibers. By integrating spatial, temporal, histological, and computational evidence, our findings suggested a model in which developmental disassembly of the radial scaffold may modulate the mechanical response of the fetal cortex to differential growth, thereby contributing to cortical folding.

neuroscience↗

bioRxiv2026

TiSAM: fusing spatial and histopathology foundation models for whole-slide image segmentation

Semantic segmentation of whole-slide images (WSIs) quantifies tissue composition and architecture, but existing models require extensive annotation and lose accuracy as the number of tissue classes increases or on heterogeneous, cross-scanner datasets. Here, we present the Tissue Segment Anything Model (TiSAM), which fuses SAM3 spatial features with UNI2-h pathology features within a multi-scale decoder. Because public benchmarks contain few tissue classes, we release MegaMouse, comprising 36,833 annotations of 52 tissue classes from 12 mouse organs, and an 11-class human pancreas dataset. TiSAM achieved the highest overall performance across four public datasets compared to existing convolutional neural network and vision transformer models, maintained high accuracy on MegaMouse, and maintained high accuracy in the human pancreas dataset when trained on as few as 5 annotated WSIs where previous integrations of SAM with pathology foundation models did not. TiSAM segmentations were also more consistent across eight slide scanners compared to other models. These results establish TiSAM as a general and highly adaptable framework for tissue segmentation, enabling studies containing many tissue classes, limited annotations, or images from multiple scanners.

bioinformatics↗

bioRxiv2026

Pan-cancer remodeling of reactive oxygen species homeostasis: distinct roles of the ROS-generation and antioxidant arms in immune context and outcome

Reactive oxygen species (ROS) are double-edged in cancer: tumor cells sustain high ROS generation while up-regulating antioxidant defense, so that the net balance between the two arms, rather than absolute ROS abundance, is the biologically meaningful quantity. Whether that balance defines a conserved tumor state across cancer types has been unclear. Here an experimentally measured ROS phenotype, obtained from a three-channel gold-nanocluster array, was generalized to public transcriptomes through a 107-gene ROS program scored in a large cell-line panel and in pan-cancer tumor and adjacent-normal tissue. The optical readout was reproducible and fully discriminative between cell lines, establishing the fingerprint as a quantitative starting point. In tumors, the generation and antioxidant arms were coordinately up-regulated relative to normal tissue, yet the two arms dissociated in their biology. The composite balance score tracked reduced immune infiltration consistently across cohorts, but arm-level decomposition showed that it was carried by low generation-arm activity in immune-cold tumors and followed arithmetically from how the balance score is defined; the association does not implicate antioxidant defense in immune infiltration. The clinical association pointed the other way: adverse outcome was attributable to the antioxidant arm, whereas generation was null. In cohort-held-out validation, tumors were separated from adjacent normal tissue, with redox programs outperforming generic phenotypic programs, indicating that the same program transfers across tumor types. Tumor remodeling of ROS homeostasis is therefore widespread, but its two arms carry distinct meanings: the balance score, driven by its generation term, reports immune context, whereas the antioxidant arm reports clinical risk.

cancer biology↗

bioRxiv2026

VPS34 regulation in pulmonary arterial vascular smooth muscle cells in pulmonary hypertension

Pulmonary arterial hypertension (PAH) is characterized by the hyperproliferative phenotype of pulmonary arterial smooth muscle cells (PAVSMCs) and extensive extracellular matrix (ECM) remodeling. Vacuolar protein sorting 34 (VPS34), a Class III Phosphatidylinositol-3 Kinase (PI3K), regulates cell proliferation, but its specific function in pulmonary vascular remodeling remains poorly understood. We aim to determine the role of VPS34 activation and regulation in PAVSMC proliferation, matrix deposition, and the progression of PAH. First, we found a marked decrease in the inhibitory phosphorylation of VPS34 at Ser164 (P-S164-VPS34), indicative of constitutive VPS34 activation, in remodeled pulmonary arteries (PAs) from human PAH patients and male mice exposed to Sugen/Hypoxia (SuHx). In human PAH PAVSMCs, siRNA-mediated knockdown of VPS34 or pharmacological inhibition via the selective inhibitor SAR405 significantly blunted cell proliferation and reduced the production of fibronectin, a major component of the remodeled ECM. Mechanistically, we found that Akt activation in PAH PAVSMCs promotes VPS34 activation; Protein Phosphatase 1 Catalytic Subunit Alpha is a potential effector in VPS34 activation; and active VPS34 led to the activation of the mTOR/S6 signaling pathway with tuberous sclerosis complex 2 downregulation. Finally, in vivo treatment with SAR405 attenuated right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary vascular remodeling in SuHx mice, while concurrently decreasing vascular fibronectin deposition. Our study demonstrates that VPS34 activation, driven by an Akt-mediated loss of the inhibitory P-S164, is crucial in PAVSMC proliferation and fibrotic vascular remodeling in PAH. Targeting the VPS34 axis represents a promising anti-remodeling therapeutic strategy for the treatment of PAH. Keywords: Pulmonary arterial hypertension, vacuolar protein sorting 34, pulmonary vascular remodeling, pulmonary arterial vascular smooth muscle

cell biology↗

bioRxiv2026

Hypomagnetic field inhibits seed germination via ROS signaling and reprogramming transcriptome in Arabidopsis thaliana

The geomagnetic field (GMF) is a ubiquitous yet poorly understood environmental factor that affects plant growth and development. It has been suggested that the blue-light photoreceptor cryptochrome (CRY) functions as a critical magnetic-field sensor in birds and insects through the radical-pair mechanism (RPM). However, whether CRY acts as a bona fide transducer of GMF signals and what are the downstream cascades remain largely elusive in plants. To address these key issues, we generated hypomagnetic field (HMF) via Helmholtz coils and passive magnetic shielding to investigate the GMF deprivation effects in Arabidopsis thaliana. HMF significantly delays the germination speed without altering the final germination rate, suggesting that HMF specifically modulates germination kinetics rather than seed viability. Time-resolved transcriptomic profiling revealed a coordinated transcriptional shift characterized by downregulation of growth-promoting genes and concurrent upregulation of defense-related genes under HMF. This biphasic transcriptional reprogramming coincides with a significant increase of reactive oxygen species (ROS), linking redox perturbation to the germination delay. Consistently, supplementation with ROS-scavenging antioxidants (e.g., reduced glutathione and ascorbic acid) rescues both germination speed and the misregulated expression of a subset of HMF-responsive genes, suggesting the central role of ROS in mediating HMF bioeffects. Genetic analysis using cry1 cry2 double mutants further indicated that HMF-induced germination delay operates through both CRY-dependent and -independent signaling pathways, suggesting the involvement of additional magnetosensitive modules beyond the canonical CRY-based RPM. These findings suggest that the GMF acts as a positive environmental cue that fine tunes the growth-defense trade-off through a redox-dependent signaling.

plant biology↗

bioRxiv2026

A conformational switch governs the dual role of liquid-liquid phase separation in amyloid fibrillization

Biomolecular condensates provide dynamic environments that store and organize proteins, yet the fundamental principles determining whether condensation promotes or suppresses irreversible protein aggregation remain unclear. Here, we show that the receptor-interacting protein kinase 3 (RIPK3) RHIM domain follows distinct self-assembly pathways into condensates or amyloid fibrils depending on its conformational state. We find that predominantly folded proteins undergo liquid-liquid phase separation (LLPS), forming reversible condensates that kinetically suppress fibril formation. Partial unfolding instead promotes direct fibrillization that bypasses LLPS, whereas induced condensate formation via increasing ionic strength or addition of molecular crowder delays amyloid formation. In contrast, when the protein is predominantly unfolded, LLPS accelerates fibrillization through condensate-interface-mediated nucleation. These findings establish protein conformation as a determinant of whether condensates suppress or promote amyloid assembly, revealing a dual role for phase separation in regulating functional amyloid formation and providing a framework that connects condensate dynamics with cellular functions.

biophysics↗

bioRxiv2026

Interrogation of noncoding schizophrenia risk variants using CRISPR-based functional genomics

Schizophrenia (SCZ) is a highly heritable complex disorder influenced by coding and noncoding genetic variation. Its genetic causes, particularly those involving noncoding variation, are largely unknown. High-throughput CRISPR screens enable dissection of disease-associated loci and identification of noncoding regulatory elements and variants that modulate gene expression. We screened SCZ GWAS loci linked to genes that are also associated in whole-exome sequencing studies to identify regulatory elements and variants impacting expression of disease-relevant genes. We used CRISPRi paired with HCR-FlowFISH to epigenetically silence 333 putative regulatory elements and measure the downstream effects on gene expression of causal SCZ genes, FAM120A, SV2A, and STAG1, in iPSCs and iPSC-derived neurons (iNeurons). We identified 78 regulatory elements that significantly alter expression of a SCZ gene, including noncoding enhancers/silencers as well as promoters of genes and lncRNAs. Pooled prime editing screens interrogated noncoding variant influence on gene expression for SCZ-associated variants and uncharacterized common variants from diverse population studies. We find that a common variant in the promoter of SV2A, rs112851681:A>G (MAF = 3.56%, 1000 Genomes) enhances transcriptional activity in iPSCs and iNeurons. These findings show distinct noncoding mechanisms that map within GWAS signals, and provide a path forward for interrogating noncoding regulatory elements and variants in disease loci.

genomics↗

bioRxiv2026

Ourotide: decoding the hierarchical peptide recognition for generative design

The historical dichotomy between small-molecule pocket and extended protein interfaces misrepresents the physical reality of peptide recognition.1,2 Here we show that peptide binding is not a simple structural intermediate but a distinctly multimodal landscape comprising small-molecule-like pockets, protein-like interfaces, and a previously unrecognized third mode. This third regime is governed by a hierarchical subpocket architecture where a flattened surface achieves near-complete peptide engagement through spatially partitioned hydrophobic components. To maintain stability, an incompletely enclosed dominant anchor cooperates with highly hydrated auxiliary subpockets and an asymmetric receptor coupling mechanism that concentrates energy in an adjacent continuous water network. Because this unique binding mode suffers from extreme data scarcity, standard deep learning models fail to capture its physics.3,4 To resolve this, we mapped these specific geometric signatures to mine structurally faithful training distributions from global protein interactomes. Based on these data, we trained Ourotide, a deep learning framework coupling conditional geometric flow matching with interface-aware affinity learning. Evaluated across peptides up to 65 residues, Ourotide outperforms generalist models in backbone accuracy, interface recovery, and affinity prediction. This approach suggests that overcoming data scarcity in the physical sciences requires physics-guided data augmentation rather than naive statistical scaling.

bioinformatics↗

bioRxiv2026

Diffusion MR Microscopy of the Human Hippocampus at 50 μm Resolution at 14.1 T for 3D Virtual Histology

Bridging the gap between macroscopic neuroimaging and microscopic histology remains a challenge in neuroscience. Here, we present a technical feasibility study of diffusion MR microscopy (dMRM) in the ex vivo human hippocampus using a 14.1 T ultrahigh-field MRI system. Mid-hippocampal blocks from control and Alzheimers disease (AD) patients were acquired at 50 x 50 x 100 {micro}m3, representing, to our knowledge, the highest resolution reported for human brain diffusion MRI. At a spatial scale approaching cellular dimensions, dMRM maps and tractography showed close correspondence with immunohistological markers of axons and dendrites. The acquired data delineated six hippocampal laminae, distinguished the inner and outer molecular layers, and preserved short, lamina-specific trajectories that became attenuated or blurred at 100 {micro}m resolution. Tractography further depicted the major components of the hippocampal tri-synaptic circuit--the perforant path, mossy fibers, and Schaffer collaterals in 3D. In the AD specimen, dMRM revealed reduced laminar contrast, local discontinuities, and altered radial and tangential fibers that were paralleled by pathological staining. With the 3D nondestructive characterization of human brain microstructure and circuitry, ex vivo dMRM showed its potential toward the goal of 3D virtual histology.

neuroscience↗

bioRxiv2026

TRPV1-cardiac afferent ablation after completed myocardial infarction prevents arrhythmogenic remodeling

Background Therapies to prevent ventricular arrhythmias after completed myocardial infarction (MI) remain limited. Although TRPV1 afferent ablation at acute MI improves cardiac remodeling, the effect of delayed subacute targeting remains unknown. Objective We investigated whether ablating cardiac TRPV1 afferents during the subacute post-MI window mitigates structural, electrophysiological, and neuro-cardiac axis remodeling to suppress ventricular arrhythmias. Methods Yorkshire pigs underwent sham surgery or anterior MI creation. Two weeks post-MI, animals were randomized to percutaneous epicardial resiniferatoxin (RTX, for cardiac-selective TRPV1 afferent depletion) or vehicle administration. Four weeks later, terminal studies assessed the effects of RTX on cardiac structure and function, ventricular arrhythmogenesis, and neuro-cardiac axis remodeling using in vivo electrophysiologic mapping, real-time neurotransmitter sensing, immunohistochemistry, and transcriptomic profiling. Results Cardiac TRPV1 afferent depletion was confirmed by blunted responses to TRPV1 agonists. RTX-treated animals exhibited improved left ventricular function, reduced end-diastolic diameter, and suppressed ventricular tachycardia/fibrillation (VT/VF) inducibility. Endocardial electroanatomic mapping revealed improved VT/VF electrophysiologic correlates in RTX-treated animals, including fewer deceleration zones and late potentials. Epicardial multielectrode mapping demonstrated reduced electrophysiologic heterogeneity in the scar border zone. Real-time release of adrenergic neurotransmitters (noradrenaline and neuropeptide Y) was normalized during sympathoexcitation in RTX-treated animals. Histologically, RTX treatment attenuated scar border zone myocardial fibrosis and sympathetic nerve sprouting, while suppressing T cell infiltration in cardiac sensory ganglia. Bulk RNA-sequencing of stellate ganglia revealed downregulation of adrenergic genes. Conclusion Cardiac TRPV1 afferent ablation post-completed MI alters disease trajectory by mitigating structural, functional, and neuro-cardiac axis remodeling. Targeting cardiac TRPV1 afferents represents a promising subacute post-MI therapeutic strategy.

physiology↗

bioRxiv2026

In-cell structural analysis reveals a distinctive chloroplast ribosome in Chlamydomonas reinhardtii

Chloroplast ribosomes synthesize plastid-encoded components of photosynthetic machinery, yet their structure and organization remain poorly understood. We combined cryo-focused ion beam milling, cryo-electron tomography and subtomogram averaging to determine native chloroplast ribosomes in Chlamydomonas reinhardtii. The 4.4-4.9 [A] structure revealed a large arch-like extension on the small subunit (SSU). Comparisons with bacterial and plant chloroplast ribosomes, supported by proteomics, AlphaFold3 predictions and a recent atomic model, indicate that the arch is formed by insertions and extensions in SSU proteins. Classification resolved active, thylakoid-associated ribosomes with density adjacent to the nascent peptide exit and an arch-moved state enriched among thylakoid-associated particles, with coordinated displacement of the arch and beak. Phylogenetic analysis revealed an evolutionary mosaic: the uS3c insertion is broadly distributed across Chlorophyceae, whereas the uS2c insertion, uS5c and PSRP7 are concentrated in Chlamydomonadales, with PSRP7 also in Sphaeropleales. Nuclear-encoded components were recruited stepwise onto a plastid-encoded scaffold, with all four under comparable purifying selection. These findings link a lineage-specific SSU extension to ribosome dynamics, thylakoid association and evolution, highlighting the value of in-cell structural analysis.

plant biology↗

bioRxiv2026

A patient-centric therapeutic paradigm uncouples prostate cancer suppression from systemic metabolic collapse

The clinical benefits of cancer therapies are often compromised by the tolerable adverse effects that impair systemic organismal health and may evolve into latent life threats. Here, we identified profound abiraterone-induced but androgen-independent metabolic perturbations in prostate cancer patients and developed Lifehug-9892 to balance tumor therapy with systemic metabolic homeostasis. By integrating population cohorts with high-resolution metabolomics, we demonstrate that abiraterone induces profound systemic lipidomic dysregulation, characterized by the massive, pathological accumulation of desmosterol. Abiraterone inhibits but stabilizes DHCR24, leading to a metabolic trap in patients showing elevated levels of both desmosterol and cholesterol. Desmosterol accumulation is highly lipotoxic, potently triggering endothelial cell senescence and necrosis, macrophage foam cell formation, murine atherosclerosis, and hepatic senescence. To mechanistically uncouple and therapeutically rescue this systemic metabolic collapse, Lifehug-9892 was rationally designed to selectively retain on-target CYP17A1 inhibition while completely sparing DHCR24 function. Lifehug-9892 maintains potent tumor-suppressive activity while fully preserving the desmosterol-cholesterol metabolic axis and preventing systemic cardiovascular and hepatic damage. Our study uncovers a critical mechanistic link between drug-induced metabolic dysregulation and organismal health in cancer patients, providing a biochemical framework for developing patient-centric targeted therapies that preserve host homeostasis.

cancer biology↗

bioRxiv2026

Local mechanical heterogeneity drives epidermal cell delamination

Delamination within stratified epithelia like the skin epidermis describes the detachment and upward motion of cells originating from the basal layer. Despite its fundamental importance for tissue development, homeostatic regeneration and repair, the mechanisms that drive delamination remain a longstanding open question. Upward motion follows cell shape changes, which are inherently driven by physical forces, but their role is elusive. Here, we investigate delamination in stratifying keratinocytes by combining imaging, force measurements and theoretical modeling. We identify a local change in force balance between differentiating cells and their environment as the key step initiating delamination. Within a homogeneous cell layer with apically polarized contractility, differentiation leads to actomyosin remodeling, redistributing cellular force exertion to the basal side. Such mechanical heterogeneity then results in differentiating cells experiencing and inward basal and outward apical forces that manifest in the formation of a +1 force defect and promote shape changes culminating in upward motion. Simultaneously, delaminating cells actively pull on their underlying neighbors, generating convergent tissue flows which close the basal layer below. Together, we propose a general physical description of delamination initiation, which may act across various multilayered epithelia.

biophysics↗

bioRxiv2026

Curvature-guided chiral collective organization of myoblast tissues

Surface curvature is a fundamental geometric cue in tissue morphogenesis, yet its role in guiding collective cell organization has remained elusive. Here, we show that curvature acts as a geometric control parameter that shapes supracellular alignment and chirality while modulating myogenic differentiation in myoblast tissues. Cells cultured on curved substrates self-organize into robust helical assemblies whose handedness is set, and can be reversed, by the sign of curvature: convex fibers produce right-handed helices, whereas concave channels invert the chirality. We identify a previously hidden clockwise bias in single-cell motion associated with the helical actin cytoskeleton. A minimal continuum theory coupling an effective chiral drive to curvature quantitatively captures the emergence and reversal of tissue-scale chiral alignment. On substrates with spatially varying curvature, local curvature gradients organize patterned multicellular architectures while preserving a global handedness. Curvature is also associated with myogenic state, with higher curvature linked to reduced or delayed differentiation. Together, these findings reveal how complex geometries shape the alignment, symmetry, and cellular state of living tissues.

biophysics↗

bioRxiv2026

Local fluidization of an active cytoplasmic gel partitions large cells

Early animal embryos undergo rapid cleavages that partition cytoplasmic volumes orders of magnitude larger than those of somatic cells1. Each division must reposition nuclei and centrosomes and distribute organelles within minutes, over distances up to hundreds of micrometers2. Cleavage furrows are positioned by microtubule asters3,4, but the mechanical mechanism for long-range transport of cytoplasmic components before cytokinesis was unknown. Here, we show that cytoplasm behaves as a locally switchable active material. Fluidization at the midplane allows bulk actomyosin to convert a local mechanical asymmetry into directed global flows of all components as a composite material. Using an actin-intact cycling Xenopus egg extract together with Xenopus and medaka embryos, we find that F-actin mechanically couples microtubule asters, organelles, nuclei and centrosomes into a gel-like composite that propagates forces over hundreds of micrometers. After mitosis, Aurora B kinase patterns a locally fluidized midplane, from which myosin-II contractility drives coherent cytoplasmic flows. A fluid dynamics model accounts for the observed flow geometry and rates. Our results reveal how local control of the material state of cytoplasm converts mitotic symmetry breaking into long-range intracellular transport and identify bulk actomyosin as the active stress generator that partitions embryonic cytoplasm as a composite gel.

cell biology↗

bioRxiv2026

scSAID: A Comprehensive Cross-Species Single-Cell Skin Atlas Reveals Species-Specific Responses to Psoriasis

Single-cell RNA sequencing has rapidly expanded the scale of skin transcriptomic data, yet these datasets remain fragmented across studies spanning different species, diseases and experimental manipulations. An up-to-date, comprehensive, and queryable single-cell cross-species repository for skin is still lacking. Here, we present scSAID (skin-scsaid.com), a single-cell database with an interactive web portal offering a broad suite of in-depth analyses for human and mouse skin. It integrates more than 1.2 million high-quality cells collected from 252 samples, establishing a unified reference for cell-type annotation, cross-species comparison and pathological studies. Using psoriasis as a case study, we demonstrate how scSAID can be used to evaluate how faithfully mouse models reproduce human pathology. Systematic comparison with the imiquimod-induced mouse model revealed numerous species-specific molecular signatures of psoriasis, including human-specific NFKB1 activation and STAT1 involvement, indicating that the current mouse model captures only limited aspects of the disease. We further introduce psoSpotter, a disease-biomarker-selection algorithm that, coupled with in silico perturbation using scSAID data, uncovers PPIA as a novel psoriasis drug target, illustrating the potential of scSAID for identifying therapeutic approaches. Overall, scSAID delivers a large-scale, cross-species skin single-cell resource and analysis platform, opening new opportunities for the discovery of disease-relevant targets in skin diseases.

bioinformatics↗

bioRxiv2026

The secreted elastase SjCE2b drives host skin penetration by Schistosoma japonicum

Cercarial elastase is the most abundant protease secreted by Schistosoma mansoni and plays a critical role in cercarial invasion. Although Schistosoma japonicum encodes only a single elastase, SjCE2b, its secretion by cercariae and its specific function in skin penetration have remained elusive. Here, we report the first proteomic analysis of S. japonicum cercarial excretory-secretory products (ESPs) induced by linoleic acid or mouse skin, confirming the presence of SjCE2b in both ESPs preparations. Recombinant SjCE2b expressed in Pichia pastoris was characterized as a trypsin-like serine protease whose activity is entirely abolished by the elastase inhibitor MeoSuc-AAPF-CMK. Furthermore, SjCE2b expression was detected exclusively in cercarial extracts and localized specifically to the cercarial acetabular glands and ducts. Subsequent proteomic analysis indicates that SjCE2b can degrade numerous human epidermal proteins, including ten isoforms of type I and type II keratins. In vitro digestion assays further demonstrated that SjCE2b can digest key structural components of the dermis, including elastin, collogen, and fibronectin. Additionally, the cleavage of complement component C3 and immunoglobulins (IgA and IgG) suggests that SjCE2b may facilitate immune evasion by newly transformed schistosomula. Critically, the incubation of cercariae with anti-rSjCE2b antibody reduced the worm burden by 80.85%, confirming the essential role of SjCE2b in the skin penetration of S. japonicum cercariae and highlighting it as a compelling candidate for vaccine or therapeutic development. Author SummarySchistosomiasis constitutes a major global health burden caused by parasitic flatworms of the genus Schistosoma. Proteolytic and histolytic enzymes secreted by cercarial pre- and post-acetabular glands facilitate disruption of the host skin barrier and protect the parasite from localized dermal inflammatory response. Although cercarial elastase is a well-characterized invasion enzyme in Schistosoma mansoni, its role in Schistosoma japonicum remains poorly defined; consequently, S. japonicum cercariae have been hypothesized to rely on distinct repertoire of proteolytic enzymes during skin penetration. In the present study, we showed that SjCE2b was localized to the cercarial acetabular glands and ducts, and was secreted upon stimulation with linoleic acid or mouse skin. Functionally, SjCE2b can disrupt host skin integrity by degrading epidermal and dermal components, and may promote immune evasion through cleavage of complement component and immunoglobins. Furthermore, the antibody-mediated neutralization of secreted SjCE2b significantly impaired parasite penetration by greater than 80%. Together, these findings establish SjCE2b as a critical enzyme required for S. japonicum cercariae invasion and highlight its potential as a promising target for novel therapeutic interventions.

microbiology↗

bioRxiv2026

A new genome-scale model enables prediction of cancer metabolic dependencies

Cancer cells rewire metabolism to support proliferation. Intriguingly, divergent metabolic choices are made to attain this common goal. Identifying the unique metabolic requirements for a specific cell has profound implications for cancer biology and precision medicine. Genome-scale metabolic models (GEMs) have emerged as powerful tools to systematically characterize, understand, and predict metabolism of cells and tissues. Despite being comprehensive, the current GEMs remain limited in their predictive power. Here, we present a new GEM of human cells, in silico Human Metabolic Essentiality (iHME), that significantly improves the prediction of metabolic dependencies at a reduced computational cost. Wse rationally downsized, curated, and corrected previous models to remove unsupported metabolic redundancies, which led to a slim model containing 4,377 reactions, 3,241 metabolites, and 1,825 genes. When used to reconstruct metabolic networks of 1,103 cancer cell lines, iHME recalled on average 84.6% of experimental essential genes, which is two-fold increase over previous models. Cholesterol biosynthesis was revealed to be the most reliably predicted pathway with alternative dependencies. Finally, we applied the model to reconstruct individualized networks and predict essential gene profiles for 8,384 patient tumor samples. Glucose transporter SLC2A1 (GLUT1) was identified as a context-specific dependency for head and neck cancers and ovarian cancer. Likewise, CDP-diacylglycerol synthase CDS2 was identified for skin cancer. Overall, iHME is a new genome-scale model for prediction of metabolic dependency at higher accuracy and computational efficiency.

systems biology↗