Biology subjects

Lee, J.

Publications and source records attributed to Lee, J..

At least 253 records · Page 14Linked to original sources

bioRxiv2025

Faster R-CNN Model for Predicting Endometrial Cancer Recurrence: A Five-Subclass Approach with Texture Analysis and Validation

PurposeThis study investigates the prediction of endometrial cancer (EC) recurrence using MRI-based texture analysis and deep learning. EC recurrence remains a major clinical challenge, and accurate prognostic tools are needed. The study aims to identify significant imaging biomarkers for recurrence risk and evaluate the performance of a Faster R-CNN deep learning model in classifying recurrence-free survival (RFS) and recurrence (REC) groups. Materials and MethodsA total of 112 patients with histopathologically confirmed EC who underwent pre-treatment MRI between 2009 and 2018 were included. MRI texture analysis was performed using histogram and gray-level co-occurrence matrix (GLCM) methods, analyzing perimeter, integrated density, entropy, and homogeneity. A Faster R-CNN deep learning model was trained and tested on five image subclasses, using 20,000 iterations to optimize performance. REC and RFS were classified based on clinical outcomes, and probability scores were calculated to define the REC score. Feature importance was assessed using a Random Forest model. ResultsSignificant clinical predictors of recurrence included high-grade tumors, FIGO stage III-IV, and cervical invasion. Texture analysis revealed notable differences in perimeter, integrated density, contrast, entropy, and homogeneity between REC and RFS groups. Faster R-CNN achieved an average precision of 0.86 and an AUC of 0.61. Feature importance analysis identified area as the most significant factor, while REC_score was independent of texture-based parameters. ConclusionMRI texture analysis combined with deep learning provides valuable predictive insights for EC recurrence. The study highlights the potential of integrating machine learning with imaging biomarkers for personalized risk assessment, offering a promising approach for improving EC patient management..

cancer biology↗

bioRxiv2025

Gluconeogenesis in Aqueous Microdroplets: Non-Enzymatic Generation of Glucose

Glucose is a central metabolite of living organisms, serving as the primary energy substrate produced predominantly by photosynthetic organisms. Under conditions of limited external glucose supply, organisms activate gluconeogenesis, an endogenous biosynthetic pathway that sustains essential glucose levels. Yet the mechanism of glucose generation, before the advent of photosynthesis and complex enzymatic systems, remains elusive. Recently, microdroplet chemistry has emerged as a novel approach for catalyst-free organic synthesis. Here, we report the non-enzymatic formation of glucose from a simpler organic precursor, pyruvate, in aqueous microdroplets without the aid of organic or inorganic catalysts. Our results show that glucose is generated via a reaction pathway analogous to canonical gluconeogenesis, proceeding through key intermediates including oxaloacetate, glycerate, and glyceraldehyde. Furthermore, thermodynamic analysis indicates that the free energy change associated with glucose formation is overcome in aqueous microdroplets at room temperature, without the need for external energy input or enzymatic catalysis. These findings indicate that aqueous microdroplets can non-enzymatically convert C3 compound, pyruvate, into the C6 sugar glucose, offering a plausible abiotic route for anabolic carbon transformations during abiogenesis.

evolutionary biology↗

bioRxiv2025

Nucleotide-dependent conformational changes direct peptide export by the transporter associated with antigen processing

The transporter associated with antigen processing (TAP) is essential for adaptive immunity, delivering peptide antigens from the cytoplasm into the endoplasmic reticulum (ER) for loading onto MHC-I molecules. Previous studies have revealed the mechanism by which TAP selectively binds peptides while allowing for sequence diversity, but how the bound peptides are transported and released into the ER is not yet fully understood. Here, we report cryo-electron microscopy structures of human TAP in multiple functional states along the transport cycle. In the inward-facing conformation, ATP binding strengthens intradomain assembly. The transition to the outward-facing conformation is highly temperature-dependent and leads to a complete reconfiguration of the peptide-binding site, facilitating peptide release. ATP hydrolysis opens the consensus site, and the subsequent separation of the NBDs resets the transport cycle. These findings establish a comprehensive structural framework for understanding the mechanisms of peptide transport, vanadate trapping, and trans-inhibition.

biophysics↗

bioRxiv2025

The Role of Paraventricular Nucleus of Thalamus in Sleep Disturbance Induced by Withdrawal from Repeated Ethanol Exposure

Sleep disturbance is known to be comorbid with withdrawal from repeated ethanol exposure and could be a negative reinforcement for the majority of people with alcohol use disorder (AUD). The paraventricular nucleus of the thalamus (PVT) has been highlighted for its function in integrating arousal states and associated modulation in sleep homeostasis. However, there is limited understanding of the involvement of PVT neurons in regulating sleep patterns, especially during withdrawal from chronic ethanol exposure. In this study, we investigated the potential function of the PVT in sleep disturbance during ethanol withdrawal using electrophysiology, in vivo calcium imaging, biochemical, and chemogenetic approaches. At 24 hours post-withdrawal from chronic intermittent ethanol exposure (CIE) for four weeks, there is an increase in wake time and a decrease in non-rapid eye movement (NREM) sleep. The calcium transient levels in the PVT neurons are positively correlated with the transition from sleep to wakefulness. CIE elevates the PVT neuronal activity in a subregion-specific manner, resulting in a significant rise in cFos levels in the anterior PVT (aPVT). Temporal suppression of aPVT excitatory neurons via chemogenetics ameliorates the disturbance in sleep patterns generated by CIE. The aPVT has a notable distinction in the expression of the m-type potassium channel subunit, KCNQ2, with a higher expression level compared to the posterior PVT (pPVT). While the expression of KCNQ2 in the aPVT is reduced in CIE mice, the restoration of KCNQ2 expression using viral gene transfer within the aPVT alleviates the sleep disturbances produced by CIE. This data indicates a significant role of the PVT in sleep disturbance during ethanol withdrawal, which may partially be due to the downregulation of M-channels, hence underscoring M-channels in the PVT as a potential therapeutic target for sleep disturbance in alcohol use disorder.

neuroscience↗

bioRxiv2025

Differential Expression and Microsystem Physiology Reveal Predominant and Drug Reversible CFTR-Related Defects in Idiopathic Pancreatitis

Pancreatitis is a potentially fatal and difficult to control exocrine-tissue defect with no FDA approved therapies. Variants of a chloride/bicarbonate transporter cystic fibrosis transmembrane conductance regulator (CFTR) pose multi-fold increased risk of pancreatitis accounting for up to 40% of the patients with idiopathic pancreatitis. However, the relationship between the duct-restricted CFTR-function and total exocrine tissue defect during pancreatitis remains less known and animal models do not translate well to human disease. To overcome this challenge, we developed a robust and highly durable iPSC-derived model system of pancreatic ductal tissues from an idiopathic pancreatitis patient with a common pancreatitis-associated CFTR variant. In the patient line termed PANx, we found deficient CFTR function and a distinct gene expression signature for ductal tissue pancreatitis marked by aberrant mucin production, inflammatory cytokines and cystic neoplasms. By applying clinically used CFTR-modulator drug ivacaftor, we observed a remarkable restoration of deficient CFTR-mediated fluid secretion as well as upto 40% reversal of the differential gene signature for PANx including the reduction in mucinous neoplasms and immunogenic cytokines such as IL-11, CCL20 and CXCL8. We further employed a microsystem device to model hyperamylasemia, a diagnostic feature of acute pancreatitis attack, due to a ductal reaction causing acinar injury. The key mucinous signature was validated in primary pancreatitis ductal tissues with a CFTR variant. Overall, we unraveled new layers of CFTR-related pathology in pancreatitis to help us better understand the early course of this debilitating condition. The test methods and model systems discovered in this study will significantly expedite the discovery of diagnostic and therapeutic tools for treating idiopathic pancreatitis. For the first time, we provided molecular and physiologic evidence supporting the benefit of CFTR modulator drug ivacaftor in human CFTR-related pancreatitis.

pathology↗

bioRxiv2025

Mechanical compression induces neuronal apoptosis, reduces synaptic activity, and promotes glial neuroinflammation in mice and humans

Mass effect, characterized by the compression and deformation of neural tissue from space-occupying lesions, can lead to debilitating neurological symptoms and poses a significant clinical challenge. In the primary brain tumor glioblastoma (GBM), we have shown previously that compressive solid stress originating from the growing tumor reduces cerebral blood flow, leads to neuronal loss, increased functional impairment, and poor clinical outcomes. However, the direct effects of compression on neurons and the underlying biophysical mechanisms are poorly understood. Here, using multi-scale compression systems and physiologically relevant in vitro and in vivo models, we find that mechanical compression induces neuronal apoptosis and synapse loss, leading to disrupted neural network activity. This is accompanied by increased HIF-1 signaling and upregulation of downstream stress-adaptive genes in neurons. We further show that compression triggers AP-1-driven gene expression in glial cells, promoting a neuroinflammatory response. Together, these findings reveal that solid stress directly contributes to neuronal dysfunction and inflammation caused by GBM by activating distinct pathways that can be targeted in future studies for neuroprotection. SIGNIFICANCE STATEMENTGlioblastoma (GBM), the deadliest primary brain tumor in adults, exerts physical forces on surrounding brain tissue as it grows, leading to neuronal damage. However, the molecular mechanisms underlying this process are not well understood. In the present study, by applying multiple model systems, we show that mechanical compression triggers neuronal apoptosis, disrupts synaptic communication between neurons, and reduces neural network activity. We also find that compression activates inflammatory pathways in both neurons and glia, further contributing to neuronal damage. These findings reveal how compression exerted by space-occupying lesions may contribute to patients cognitive and motor impairments and suggest new directions for treatment. This work lays the groundwork for therapies that protect neurons from mechanical injury, with relevance not only to GBM but also other neurological diseases that present with mass effect.

neuroscience↗

bioRxiv2025

Hepatocyte-specific CLSTN3B ablation impairs lipid droplet maturation and alleviates diet-induced steatohepatitis in mice

Excessive lipid accumulation in hepatocytes, a hallmark of metabolic dysfunction-associated steatotic liver disease (MASLD), can lead to progressive liver damage. Understanding the molecular mechanisms governing lipid storage in hepatocytes is essential for identifying therapeutic targets to halt MASLD progression. Here, we show a pivotal role for the protein calsyntenin 3{beta} (CLSTN3B) in promoting lipid droplet (LD) maturation and lipid storage in hepatocytes. Previously characterized as an endoplasmic reticulum (ER)-LD contact protein that facilitates LD maturation in adipocytes, we now show that CLSTN3B expression is strongly induced in mouse hepatocytes by peroxisome proliferator-activated receptor gamma (PPAR{gamma}) in response to dietary caloric excess. Hepatocyte-specific deletion of CLSTN3B in mice significantly increases energy expenditure, reduces metabolic efficiency, and protects against diet-induced hepatic steatosis and fibrosis. Mechanistically, CLSTN3B deficiency causes reduced LD phospholipid coverage and increased lipase recruitment. This results in enhanced fatty acid oxidation driven by a futile cycle of lipolysis and re-esterification. Notably, human clinical data reveal a positive correlation between hepatic CLSTN3B expression and MASLD severity and progression, emphasizing its relevance to human disease. Together, our findings establish CLSTN3B as a key regulator of hepatocyte lipid storage and metabolic efficiency and highlight its potential as a therapeutic target in MASLD.

physiology↗

bioRxiv2025

THE LASSA VIRUS FUSION DOMAIN HAS STRUCTURAL PLASTICITY AND EXPLOITS BIS(MONOACYLGLYCERO)PHOSPHATE FOR FUSION

Infection with Lassa virus (LASV), an arenavirus endemic to West Africa, results in a viral hemorrhagic fever with high mortality rates and public health implications. The glycoprotein complex (GPC) is central to LASVs infectivity as it mediates viral entry via membrane fusion. The fusion domain (FD, G260 - N295) facilitates the initiation of membrane fusion and, thus, the merging of the viral and host cell membranes in a pH-dependent fashion at the lysosomal membrane. The FD consists of two distinct regions: an N-terminal fusion peptide (FP, G260 - T274) and an internal fusion loop (FL, C279 - N295) that are connected by a short linker region (P275 - Y278). Nonetheless, the precise structural and functional characteristics of the LASV FD remain unknown. Here, we demonstrate that the LASV FD associates with the host cell membrane via its FL, specifically residues R282 - L290, whereas the FP is more solvent-exposed, especially for residues D268 - T274. We found that a multitude of conformational states are adopted by the entire LASV FD before membrane association, while only the FP, and not the FL, continues to sample numerous states after membrane association. Moreover, we provide evidence that the LASV FD prefers to interact with anionic lipids, namely bis(monoacylglycero)phosphate (BMP). In conclusion, our findings indicate that the LASV FD preferentially initiates fusion in the presence of BMP, at which point the FL adopts a helical conformation to associate with the membrane, whereas the FP remains exposed to the environment.

biochemistry↗

bioRxiv2025

Ventral Hippocampus and NAc Core, but not Shell activity is required for well-learned instrumental memory destabilization

While there is increasing evidence that instrumental memories undergo destabilization and reconsolidation, little is known about the underlying neural mechanisms of these processes. Here, we focussed on instrumental memory destabilization, and the functional involvement therein of the nucleus accumbens core and shell regions, as well as the ventral hippocampus. In male rats, and using a previously established destabilization reminder procedure, we infused the GABA receptor agonists baclofen/muscimol at the time of memory reminder. We found infusions into the core but not shell impaired well-learned instrumental memory destabilization, protecting against MK-801-induced reconsolidation impairment. Moreover, infusion of baclofen/muscimol into the ventral hippocampus resulted in the same protective effect. These results suggest that the NAc core, but not the shell or vHPC, is involved in the destabilization of well-learned instrumental memory, potentially through a vHPC-NAc core projection.

animal behavior and cognition↗

bioRxiv2025

An autonomous AI agent for universal behavior analysis

Behavior analysis across species represents a fundamental challenge in neuroscience, psychology, and ethology, typically requiring extensive expert knowledge and labor-intensive processes that limit research scalability and accessibility. We introduce BehaveAgent, an autonomous multimodal AI agent designed to automate behavior analysis from video input without retraining or manual intervention. Unlike conventional methods that require manual behavior annotation, video segmentation, task-specific model training, BehaveAgent leverages the reasoning capabilities of multimodal large language models (LLM) to generalize across novel behavioral domains without need for additional training. It integrates LLMs, vision-language models (VLMs), and large-scale visual grounding modules, orchestrated through a multimodal context memory and goal-directed attention mechanism, to enable robust zero-shot visual reasoning across species and experimental paradigms, including plants, insects, rodents, primates, and humans. Upon receiving a video input, BehaveAgent autonomously identifies the correct analysis strategy and performs end-to-end behavior analysis and interpretation without human supervision. Leveraging vision-language representations, it performs general-purpose tracking, pose estimation and segmentation. We demonstrate BehaveAgents universal applicability to autonomously (1) identify the behavioral paradigm and develop an action plan specialized for the identified paradigm, (2) identify relevant subjects and objects, (3) track those features, (4) identify behavioral sequences with explicit reasoning, (5) generate and execute code for targeted analysis and (6) generate comprehensive research reports that integrate behavioral findings with relevant scientific literature. Through interpretable agentic reasoning, BehaveAgent makes its internal decision-making process transparent, clarifying why particular features are tracked or behaviors inferred. By reducing the time and expertise required for behavior analysis, BehaveAgent introduces a scalable, generalizable, and explainable paradigm for advancing biological and behavioral research.

neuroscience↗

bioRxiv2025

Chemical inhibition of asexual development leads to increased ultimate tensile strength in mycelial material.

This study investigates the chemical inhibition of asexual development in Aspergillus nidulans to enhance the mechanical properties of mycelial materials. We hypothesized that suppressing conidiation using the ornithine decarboxylase inhibitor -difluoromethylornithine (DFMO) would increase material strength by inhibiting asexual development, promoting denser hyphal packing. Mycelial materials were grown in DFMO concentrations (0, 0.05, 0.5, and 5 mM), and conidiation and ultimate tensile strength (UTS) were measured. Results showed a dose-dependent reduction in conidiation, with significant decreases at all DFMO levels (P [≤] 0.05). While lower DFMO concentrations (0.05 and 0.5 mM) did not significantly alter UTS, 5 mM DFMO treatment doubled the materials tensile strength compared to controls (P [≤] 0.05). Scanning electron microscopy confirmed reduced developmental structures in DFMO-treated samples, supporting the hypothesis. The non-linear relationship between conidiation suppression and strength improvement suggests additional mechanisms, such as hyphal morphology or cell wall changes, may contribute. These findings demonstrate that chemical modulation of fungal development can rationally tune mycelial material properties, offering a systematic approach for biomaterial engineering.

bioengineering↗

bioRxiv2025

Coronary Artery Disease Risk Variant rs6903956 Links to Endothelial Dysfunction via PHACTR1 Regulation

Ischemic heart disease, particularly coronary artery disease (CAD), remain leading causes of mortality worldwide. The single nucleotide polymorphism rs6903956 on chromosome 6p24.1 has been identified as a susceptibility locus for CAD in East Asian populations through genome-wide association studies. However, its functional role has not been fully elucidated. This study investigates the mechanistic basis of rs6903956 and its contribution to CAD pathogenesis, focusing on endothelial cell dysfunction. We first conducted cohort studies, revealing an association between the rs6903956 A risk allele and blood pressure phenotypes, along with impaired endothelial responsiveness indicated by reduced flow-mediated dilation. Single-base editing of induced pluripotent stem cell-derived endothelial cells obtained from patients with CAD and expression quantitative trait loci analysis highlighted a cisacting impact of the A allele on PHACTR1 and EDN1 expression, suggesting allelespecific regulatory effects. Using in silico modeling by AlphaFold 3 platform, the A allele exhibited enhanced binding affinity for HOXA4 and MEIS1 transcription factors, forming a stable ternary complex that promoted transcriptional activation of PHACTR1. Functional assays demonstrated the enhancer role of rs6903956 A in PHACTR1 promoter activity, supporting its locus-specific regulatory function in endothelial cells. Under pathological flow conditions, endothelial cells harboring the A allele display elevated ICAM-1 expression and increased monocyte adhesion compared to the G allele, indicating allele-specific endothelial inflammatory activation. These findings propose a model in which rs6903956 influences PHACTR1 expression via HOX-MEIS cooperative binding, thereby modulating endothelial function and contributing to CAD susceptibility. This study provides mechanistic insights into the role of rs6903956 in endothelial dysfunction and CAD, informing potential therapeutic targets arising from genetic determinants in cardiovascular pathogenesis.

molecular biology↗

bioRxiv2025

TITANiAN: Robust Prediction of T-cell Epitope Immunogenicity using Adversarial Domain Adaptation Network

T-cell immunogenicity, the ability of peptide fragments to elicit T-cell responses, is a critical determinant of the safety and efficacy of protein therapeutics and vaccines. While deep learning shows promise for in silico prediction, the scarcity of comprehensive immunogenicity data is a major challenge. We present T-SCAPE, a novel multi-domain deep learning framework that leverages adversarial domain adaptation to integrate diverse immunologically relevant data sources, including MHC presentation, peptide-MHC binding affinity, TCR-pMHC interaction, source organism information, and T-cell activation. Validated through rigorous leakage-controlled benchmarks, T-SCAPE demonstrates exceptional performance in predicting T-cell activation for specific peptide-MHC pairs. Remarkably, it also accurately predicts the ADA-inducing potential of therapeutic antibodies without requiring MHC inputs. This success is attributed to T-SCAPEs biologically grounded and data-driven multi-domain pretraining. Its consistent and robust performance highlights its potential to advance the development of safer and more effective vaccines and protein therapeutics.

bioinformatics↗

bioRxiv2025

Mechanoimmunological Control of Metastatic Site Selection

Cancer cells alter their mechanical properties in response to the rigidity of their environment. Here, we explored the implications of this environmental mechanosensing for anti-tumor immunosurveillance using single cell biophysical profiling and metastasis models. Cancer cells stiffened in more rigid environments, a biophysical change that sensitized them to cytotoxic lymphocytes. In immunodeficient mice, this behavior manifested in the outgrowth of stiffer metastatic cells in the rigid bone than in the soft lung, while in immunocompetent hosts, it led to preferential elimination of stiffer cancer cells and suppression of bone metastasis. Environmentally-induced cell stiffening and immune sensitization both required Osteopontin, a secreted glycoprotein that is upregulated during bone colonization. Analysis of patient metastases spanning mechanically distinct tissues revealed associations between environmental rigidity, immune infiltration, and cancer cell stiffness consistent with mechanically driven immunosurveillance. These results demonstrate how environmental mechanosensing modulates anti-tumor immunity and suggest a mechanoimmunological basis for metastatic site selection.

cancer biology↗

bioRxiv2025

Phylogeny-driven design of broadly protective sarbecovirus receptor-binding domain nanoparticle vaccines

Vaccines against emerging SARS-CoV-2 variants and sarbecoviruses with pandemic potential must elicit a robust humoral immune response in a population imprinted with the SARS-CoV-2 spike (S) protein. Here, we designed protein nanoparticle (NP) vaccines co-displaying the SARS-CoV-2 BA.5, SARS-CoV-1, and BtKY72 receptor-binding domains (RBDs) with or without the Wuhan-Hu-1 (Wu) RBD. We show that these vaccines elicit cross-reactive and broadly neutralizing plasma antibody responses against SARS-CoV-2 variants and sarbecoviruses in naive and pre-immune animals. Immunization with multivalent RBD-NPs overcomes immune imprinting and elicits neutralizing antibodies and memory B cells specific for the BA.5, SARS-CoV-1, and BtKY72 RBDs in mRNA-1273-vaccinated non-human primates. Multivalent RBD-NPs outperform a monovalent Wu RBD-NP vaccine by providing superior protection in mice and non-human primates challenged with the vaccine-mismatched SARS-CoV-2 XBB.1.5 or the pre-emergent RsSHC014. These data support the use of multivalent RBD-NP vaccines for SARS-CoV-2 variants and sarbecoviruses in naive and pre-immune populations.

immunology↗

bioRxiv2025

Harmonized Protocol for Subfield Segmentation in the Hippocampal Body on High-Resolution in vivo MRI from the Hippocampal Subfields Group (HSG)

Hippocampal subfields differentially develop and age, and they vary in vulnerability to neurodegenerative diseases. Innovation in high-resolution imaging has accelerated clinical research on human hippocampal subfields, but substantial differences in segmentation protocols impede comparisons of results across laboratories. The Hippocampal Subfields Group (HSG) is an international organization seeking to address this issue by developing a histologically-valid, reliable, and freely available segmentation protocol for high-resolution T2-weighted 3 tesla MRI (http://www.hippocampalsubfields.com). Here, we report the first portion of the protocol focused on subfields in the hippocampal body; protocols for the head and tail are in development. The body protocol includes definitions of the internal boundaries between subiculum, Cornu Ammonis (CA) 1-3 subfields, and dentate gyrus, in addition to the external boundaries of the hippocampus apart from surrounding white matter and cerebrospinal fluid. The segmentation protocol is based on a novel histological reference data set labeled by multiple expert neuroanatomists. With broad participation of the research community, we voted on the segmentation protocol via online survey, which included detailed protocol information, feasibility testing, demonstration videos, example segmentations, and labeled histology. All boundary definitions were rated as having high clarity and reached consensus agreement by Delphi procedure. The harmonized body protocol yielded high inter- and intra-rater reliability. In the present paper we report the procedures to develop and test the protocol, as well as the detailed procedures for manual segmentation using the harmonized protocol. The harmonized protocol will significantly facilitate cross-study comparisons and provide increased insight into the structure and function of hippocampal subfields across the lifespan and in neurodegenerative diseases.

neuroscience↗

bioRxiv2025

Plastic-elastomer heterostructure for robust flexible brain-computer interfaces

Electronics for neural signal recording must be robust across multiple and deep brain regions while preserving tissue-level flexibility to ensure stable tracking over months or years. However, existing electronics cannot simultaneously achieve robustness and tissue-level flexibility, limiting their potential for customizable and scalable neuroscience research and clinical applications. Here, we introduce FlexiSoft, an electronic platform based on a plastic-elastomer heterostructure that uniquely integrates mechanical robustness and tissue-level flexibility. Compared to conventional flexible electronics of similar thickness, the FlexiSoft platform demonstrates an order-of- magnitude improvement in both mechanical robustness (critical energy release rate) and flexibility (flexural rigidity). Leveraging these mechanical advantages, we developed FlexiSoft probe for robust implantation, demonstrated by its ability to withstand repeated insertion and removal, as well as to reach centimeter-scale depths comparable to those in the human brain. The platform enables long-term recording from the same neurons across the hippocampus (HPC) and primary motor cortex (M1) during a months-long motor learning task, thereby revealing long-term dynamic changes in neuronal firing patterns. Additionally, FlexiSofts unique robustness and flexibility enable curved implantation routes, opening new directions of customizable implantation pathways. In summary, we present FlexiSoft as a novel, robust, and tissue-level flexible heterostructure electronics platform that advances flexible brain-computer interfaces (BCIs) with strong translational potential for neuroscience and clinical applications.

bioengineering↗

bioRxiv2025

Inflammasome Activation in Cutaneous Squamous Cell Carcinoma

Epithelia maintain their barrier function by exploiting the proliferative and plastic properties of stem cells to promote continual tissue regeneration. Consequently, however, these features make epithelia prone to tumorigenesis. Skin is the largest epithelial barrier and the source of cutaneous cancers, the deadliest of which are cutaneous squamous cell carcinomas (cSCCs). Despite the pervasiveness of these cancers, however, the molecular mechanisms employed by stem cells and their microenvironment to promote skin tumor development remain poorly defined. Our previous work revealed that genotoxic damage to normal skin activates inflammasome signaling crosstalk between epidermal epithelia and fibroblasts to promote epithelial stem cell hyperproliferation and fate misspecification. We hypothesized that these phenomena would also be featured during skin cancer development. Using mouse and human skin disease specimens, we determined that in vivo stem cell misspecification is a generalizable feature across diverse pathophysiological skin conditions, including cutaneous cancers, but is not present in normal high proliferative contexts. Strikingly, in vivo inflammasome activation was observed in both the epithelial and dermal compartments of cSCC tumors but was not evident in other skin pathologies. Probing further into the mechanism, we revealed that inflammasome pathway activation in cSCC is epithelial autonomous but non-cell autonomous. Furthermore, fibroblasts juxtaposed to the cSCC epithelial tumor interface exhibited population expansion as well as IL-1 signaling activation, which was absent in overlying epithelia. Based on these findings, we propose a model whereby epithelial-to-fibroblast inflammasome crosstalk initiates a fibroblast feed-forward IL-1 signaling loop that augments the tumor-promoting cSCC milieu.

cell biology↗