Biology subjects

Son, M.

Publications and source records attributed to Son, M..

11 recordsLinked to original sources

bioRxiv2026

Hypomineralized Enamel Alters Trigeminal Sensory Afferent Architecture, Transcriptome, and Dental Injury Responses

At barrier tissues such as the skin and gut, sensory neurons interface with environmental stimuli and coordinate with neighboring epithelial and immune cells to detect tissue perturbations. In teeth, however, the sensory dentin-pulp complex is insulated from the oral environment by highly mineralized enamel. Although dentin-pulp responses to severe injury have been studied in models with direct pulp exposure, it remains unclear whether enamel barrier dysfunction alone alters pulpal and neuronal homeostasis. Using a kallikrein-related peptidase 4 knockout (KLK4 KO) mouse model of enamel hypomineralization, we demonstrated that defective enamel induced structural, molecular, and transcriptional responses in the dental pulp and in the trigeminal system innervating teeth, despite the absence of direct pulp exposure to the oral cavity. Hypomineralized molars exhibited increased reactionary dentin formation accompanied by retraction of sensory afferents from the dentin-pulp junction. Consistent with these structural findings, trigeminal ganglia of KLK4 KO mice displayed upregulation of genes associated with cytoskeletal remodeling and stimulus response pathways. Despite increased bacterial burden and biofilm accumulation on the enamel surface, enamel hypomineralization did not induce substantial innate immune responses in the pulp. In addition, following severe dental pulp injury, teeth with hypomineralized enamel exhibited reduced sensory afferent loss and tissue damage. Together, these findings reveal that enamel integrity functions as a critical regulator of dentin-pulp homeostasis and that barrier dysfunction alone can precondition tissue responses to subsequent injury.

neuroscience↗

bioRxiv2026

Lactational transfer of synthetic oxytocin and sex-specific suppression of neurodevelopmental risk gene networks in the rat prefrontal cortex

Autism spectrum disorder and related neurodevelopmental disorders (NDDs) affect males at two-to-four times the rate of females, yet the environmental contributors to this sex-differentiated vulnerability remain poorly understood. Here, using a clinically translatable postpartum rat model, we show that synthetic oxytocin (OT) administered for postpartum hemorrhage (PPH) prophylaxis ( PPH-OT), a universally administered obstetric medication, undergoes lactational transfer, confirmed by stable isotope-labeled OT and LC-MS/MS, without altering maternal behavior or neonatal cortical OT receptor expression. In offspring, PPH-OT altered ultrasonic vocalizations during dyadic interaction and caused a male-specific reduction in social approach, without affecting other behavioral domains. Sex-stratified RNA-sequencing of the medial prefrontal cortex (mPFC) revealed pronounced transcriptional dimorphism: males showed 1,732 differentially expressed genes versus 693 in females, and a sex-by-treatment interaction contrast identified 1,229 formally sex-differentiated genes. Male mPFC downregulated genes were significantly enriched for high-confidence NDD risk genes across three independent databases -- SFARI score-1 (highest confidence autism genes; OR = 4.56, p = 0.015), DBD autism (OR = 10.34, p = 7.3x10-{superscript 1}{superscript 2}), and SysNDD autosomal dominant (OR = 9.78, p = 8.4x10-) -- including core regulators of cortical circuit assembly (Grin2a, Grin2b, Reln, Tbr1, Mef2c, and Tcf4), an enrichment pattern largely restricted to males. Hypothalamic transcriptional changes were pronounced but showed no enrichment for NDD risk genes, establishing mPFC specificity. These findings identify PPH-OT as a candidate environmental modifier of male neurodevelopmental vulnerability and provide a pressing rationale for prospective investigation of neurodevelopmental outcomes in PPH-OT-exposed children.

neuroscience↗

bioRxiv2026

Display functions of dinosaur proto-wings before powered flight

Pennaceous feathers are fundamental to avian flight, yet their early function in non-volant dinosaurs remains unknown. Early-diverging pennaraptorans had simple pennaceous feathers on proto-wings and tails, which were unsuitable for flight but may have enhanced visual signals. However, the visual display hypothesis has not been empirically tested. To address this, we used computer animations of early pennaraptoran displays to measure responses in a well-established animal model of a visually sensitive neural pathway. We show that pennaceous proto-wings and tails enhance the efficiency of motion-based displays across a range of anatomically plausible movements. Integrating these results with comparative and paleontological evidence, we suggest that early pennaceous feathers functioned in diverse signaling contexts and were subsequently exapted for aerodynamic use.

evolutionary biology↗

bioRxiv2026

Rapid and reusable high-throughput microfluidics through modular assembly

High-throughput microfluidics has transformed biomedical research by enabling precise and parallel sample handling, but most devices are single-use due to channel occlusion and contamination from experiments. Alongside low fabrication yield and reduced experimental success associated with dense microfeatures, this creates a major bottleneck for scalable high-throughput applications. We present a rapid, reusable, and modular high-throughput microfluidic platform with integrated microvalves for automation. The platform employs a multilayer architecture consisting of a custom casing, PDMS layers with dense microfeatures for fluid handling and culture, and a glass substrate. Permanent bonding is applied only between control and fluid layers, while reversible bonding is used at all other interfaces, including the substrate. Because substrate is the primary cell-contact surface and can be readily detached, the remaining layers can be disassembled, thoroughly cleaned, and reused with minimal processing on a new substrate. This approach improves repeatability and experimental success while reducing preparation time from days to [~]2 hours. The disassemblable design also supports incorporation of application-specific layers between fluid layer and substrate, enhancing platform versatility for 3D culture. We validated performance through pressure/flow characterization and on-chip cell/organoid culture. Overall, our platform accelerates rapid high-throughput data generation across diverse biological applications.

bioengineering↗

bioRxiv2026

APIPred Web 1.0: A Web Platform to Predict Potential Aptamer Sequences for Protein targets

Aptamers are short single-stranded nucleic acids that bind protein targets with high specificity and are increasingly used in diagnostics and therapeutics, yet experimental discovery remains slow and variable in success. This creates a demand for computational systems that not only score candidate binders but also generate experimentally usable libraries under biologically meaningful constraints. Here, we present APIPred Web 1.0, a unified web platform that integrates constraint-aware aptamer library generation, machine learning- based aptamer- protein interaction prediction, and DNA secondary-structure analysis within a user-facing workflow. Users submit a target protein aminoacid sequence and define an aptamer template in a PREFIX - [VARIABLE] - SUFFIX format with real-time validation of key biological constraints (GC content and homopolymer limits). On the backend, sequences are converted into model- compatible features via optimized k-mer encodings (aptamer) and pseudo amino acid composition (PAAC) descriptors (protein), followed by inference with a trained XGBoost predictor. APIPred Web 1.0 improves the computational efficiency by applying precomputed protein features, vectorized batch processing (hundreds of sequences per batch), optimized XGBoost DMatrix inference, and a bounded heap that retains only the top 25 candidates during generation. The platform then computes minimum free energy (MFE) structures using ViennaRNA with parallel folding and returns ranked list of the top candidates with log-transformed interaction scores, complete sequences (variable region highlighted), dot-bracket structures, MFE values, and interactive 2D visualizations via persistent result links. In a demonstration study targeting CD64 protein, the platform produced 25 putative binders from a custom 40- nucleotide library and enabled selection of structurally diverse candidates for experimental testing. Flow cytometry showed specific binding to CD64-expressing THP-1 cells with minimal signal in Ramos control cells. Collectively, APIPred Web 1.0 offers a reproducible, structure-informed, and computationally efficient pipeline for rapid generation of aptamer candidates against target proteins for downstream experimental validation. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=50 SRC="FIGDIR/small/697194v1_ufig1.gif" ALT="Figure 1"> View larger version (14K): org.highwire.dtl.DTLVardef@1c1ca4dorg.highwire.dtl.DTLVardef@1c8b23dorg.highwire.dtl.DTLVardef@12dfe2dorg.highwire.dtl.DTLVardef@8a7c8f_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2024

Spatial proteomics of Onchocerca volvulus with pleomorphic neoplasms shows local and systemic dysregulation of protein expression

Onchocerca volvulus is the agent of onchocerciasis (river blindness) and targeted by WHO for elimination though mass drug administration with ivermectin. A small percentage of adult worms develop pleomorphic neoplasms (PN) that are positively associated with the frequency of ivermectin treatment. Worms with PN have a lower life expectancy and a better understanding about the proteins expressed in PN, and how PN affect protein expression in different tissues could help to elucidate the mechanisms of macrofilaricidal activity of ivermectin. Within a clinical trial of drug combinations that included ivermectin, we detected 24 (5.6%) O. volvulus females with PN by histology of paraffin embedded nodules. To assess the protein inventory of the neoplasms and to identify proteins that may be associated with tumor development, we used laser capture microdissection and highly sensitive mass spectrometry analysis. Neoplasm tissue from three female worms was analyzed, and compared to normal tissues from the body wall, uterus and intestine from the same worms, and to tissues from three females without PN. The healthy females showed all intact embryogenesis. In PN worms, 151 proteins were detected in the body wall, 215 proteins in the intestine, 47 proteins in the uterus and 1,577 proteins in the neoplasms. Only the uterus of one PN female with some stretched intrauterine microfilariae had an elevated number of proteins (601) detectable, while in the uteri of the healthy females 1,710 proteins were detected. Even in tissues that were not directly affected by PN (intestine, body wall), fewer proteins were detected compared to the corresponding tissue of the healthy controls. Immunolocalization of the calcium binding protein OvDig-1 (OVOC8391) confirmed the detection in PN by mass spectrometry. In conclusion we identified proteins that are potentially linked to the development of PN, and systemic dysregulation of protein expression may contribute to worm mortality. Author summaryOnchocerca volvulus, the causative agent of onchocerciasis (river blindness), is targeted for elimination by WHO. The primary strategy involves mass administration of ivermectin. A small proportion of adult female worms develop pleomorphic neoplasms (PN). Here, we used laser capture microdissection and highly sensitive mass spectrometry analysis to determine the protein inventory of PN to identify proteins that may be associated with tumor development. Neoplasm tissue from female worms was analyzed, and compared to normal tissue from the body wall, uterus and intestine from the same worms, and to tissues from females without PN. When compared, PN and healthy control (HC) worms display a different set of proteins, the PN tissue being the one with the highest number of proteins (1,390). From these, 594 were not present in any HC worm tissue. Despite the large number of proteins identified in PN tissue, their low abundance suggests also in PN dysregulation of protein expression. Immunolocalization of a calcium binding protein detected in PN confirmed the mass spectrometry results. In conclusion, we have developed a system to analyze the proteome of O. volvulus from nodule sections and identified proteins that are potentially linked to the development of PN and may contribute to worm mortality.

molecular biology↗

bioRxiv2022

NF-κB memory coordinates transcriptional responses to dynamic inflammatory stimuli

Many scenarios in cellular communication requires cells to interpret multiple dynamic signals. It is unclear how exposure to immune stimuli alters transcriptional responses to subsequent stimulus under inflammatory conditions. Using high-throughput microfluidic live cell analysis, we systematically profiled the NF-{kappa}B response to different signal sequences in single cells. We found that NF-{kappa}B dynamics stores the history of signals received by cells: depending on the dose and type of prior pathogenic and cytokine signal, the NF-{kappa}B response to subsequent stimuli varied widely, from no response to full activation. Using information theory, we revealed that these stimulus-dependent changes in the NF-{kappa}B response encode and reflect information about the identity and dose of the prior stimulus. Small-molecule inhibition, computational modeling, and gene expression profiling show that this encoding is driven by stimulus-dependent engagement of negative feedback modules. These results provide a model for how signal transduction networks process sequences of inflammatory stimuli to coordinate cellular responses in complex dynamic environments.

systems biology↗

bioRxiv2021

Spatiotemporal NF-κB dynamics encodes the position, amplitude and duration of local immune inputs

Infected cells communicate through secreted signaling molecules like cytokines, which inform nearby cells about the type, severity and location of pathogens. How differences in cytokine secretion affect inflammatory signaling over space and time, and how responding cells decode information from propagating cytokine signals are not understood. By computationally and experimentally studying NF-{kappa}B dynamics in co-cultures of signal sending cells (macrophages) and receiving cells (fibroblasts), we found that cytokine signals are transmitted by wave-like propagation of NF-{kappa}B activity and create well-defined cellular activation zones in a responding cell population. Remarkably, NF-{kappa}B dynamics in responding cells can simultaneously encode information about cytokine dose, duration, and distance to the cytokine source. Spatially-resolved transcriptional analysis revealed that responding cells transmit local cytokine information to distance specific pro-inflammatory gene expression patterns, creating "gene expression zones" in the population. Despite single-cell variability, the size and duration of the signaling zone is tightly controlled by the macrophage cytokine secretion profile. Our results highlight how macrophages tune their cytokine secretion dynamics to control signal transmission distance, and how NF-{kappa}B interprets these signals to coordinate inflammatory response in space and time.

systems biology↗

bioRxiv2021

High-dose drug heat map based on organoid array chip for drug selection with high safety and efficacy

An organoid array chip was developed by adopting a micropillar and microwell structure to test safety and efficacy of drugs using high dose drug heat map. In the chip, we encapsulated patient-derived cells in alginate and grow them to maturity for more than 7 days to form cancer organoids. When screening drug compounds in a high-density organoid array due to lack of number of patient-derived cells, changing media without damage of organoids is a very tedious and difficult process. Organoids grown in conventional well plates needed too many cells and were also easily damaged due to multiple pipetting during maintenance culture or during experimental procedures. To solve those problem, we applied a micropillar and microwell structure to the organoid array. We used patient-derived cells from patients with Glioblastoma multiforme (GBM), the most common and lethal form of central nervous system cancer, to validate the array chip performance. After forming more than 100{micro}m-diameter organoids in 12 x 36 pillar array chip (25mm x 75mm), we tested 70 drug compounds (6 replicates) with high high-dose to find out high safety and efficacy drug candidates. Comparing the drug response of organoids derived from normal cells and cancer cells, we identified four compounds (Dacomitinib, Cediranib, Ly2835219, BGJ398) as drug candidates without toxicity to GBM cells.

cancer biology↗

bioRxiv2019

Input dose differentiation by NF-κB

Cells receive a wide range of dynamic signaling inputs during immune regulation, but how gene regulatory networks measure and interpret such dynamic inputs is not understood. Here, we used microfluidic live-cell analysis and mathematical modeling to study how NF-{kappa}B pathway in single-cells responds to time-varying immune inputs such as increasing, decreasing or fluctuating cytokine signals. Surprisingly, we found that NF-{kappa}B acts as a differentiator, responding strictly to the absolute difference in cytokine concentration, and not to the concentration itself. Our analyses revealed that negative feedbacks by the regulatory proteins A20 and I{kappa}B enable dose differentiation by providing short-term memory of prior cytokine level and continuously resetting kinase cycling and receptor levels. Investigation of NF-{kappa}B target gene expression showed that cells create unique transcriptional responses under different dynamic cytokine profiles. Our results demonstrate how cells use simple network motifs and transcription factor dynamics to efficiently extract information from complex signaling environments.

systems biology↗

bioRxiv2018

Threshold regulation and stochasticity from the MecA/ClpCP proteolytic system in Streptococcus mutans competence

Many bacterial species use the MecA/ClpCP proteolytic system to block entry into genetic competence. In Streptococcus mutans, MecA/ClpCP degrades ComX (also called SigX), an alternative sigma factor for the comY operon and other late competence genes. Although the mechanism of MecA/ClpCP has been studied in multiple Streptococcus species, its role within noisy competence pathways is poorly understood. S. mutans competence can be triggered by two different peptides, CSP and XIP, but it is not known whether MecA/ClpCP acts similarly for both stimuli, how it affects competence heterogeneity, and how its regulation is overcome. We have studied the effect of MecA/ClpCP on the activation of comY in individual S. mutans cells. Our data show that MecA/ClpCP is active under both XIP and CSP stimulation, that it provides threshold control of comY, and that it adds noise in comY expression. Our data agree quantitatively with a model in which MecA/ClpCP prevents adventitious entry into competence by sequestering or intercepting low levels of ComX. Competence is permitted when ComX levels exceed a threshold, but cell-to-cell heterogeneity in MecA levels creates variability in that threshold. Therefore MecA/ClpCP provides a stochastic switch, located downstream of the already noisy comX, that enhances phenotypic diversity.

microbiology↗