Biology subjects

Lai, S.

Publications and source records attributed to Lai, S..

At least 19 recordsLinked to original sources

bioRxiv2026

Modular PEGylation Confers Reduced Immune-Cell Uptake and Enhanced Pharmacokinetic Performance to Encapsulin Protein Nanocages

Encapsulins are self-assembling prokaryotic protein nanocages with growing potential as systemic drug delivery systems, but their pharmacokinetic behaviour remains poorly characterised, and rapid immune recognition and clearance may limit delivery to target tissues. Here, we show that modular PEGylation of a SpyCatcher-decorated encapsulin Alkaliphilus metalliredigens (Am-S) markedly reduces macrophage uptake and extends systemic circulation. Site-directed surface PEGylation using SpyTagged PEG achieved 82% conjugation efficiency, corresponding to an estimated average of 49 PEG chains per 60 subunit Am-S nanocage, without compromising nanocage assembly, morphology, or colloidal stability. PEGylated Am-S also retained solubility and protein integrity following freeze-thaw cycling and six months of storage. When interacted with RAW 264.7 macrophages in vitro, PEGylation substantially reduced nanocage association and internalisation relative to non-PEGylated nanocages. Following intravenous administration in BALB/c mice, PEGylated nanocages exhibited markedly prolonged circulation, with >50% of the injected dose remaining after 1 h compared with 2.6% for non-PEGylated Am-S, and a circulatory half-life of 1 h 43 min. To our knowledge, this represents the first pharmacokinetic characterisation of an encapsulin nanocage. Together, these findings demonstrate that controlled PEGylation can substantially reduce macrophage interactions and prolong encapsulin circulation in vivo.

bioengineering↗

bioRxiv2026

Integrative Multi-Omics Analysis of Gut Microbiota Dysbiosis and Host-Microbiome Interaction Mechanisms in Hypertension

ObjectiveTo characterize gut microbiota dysbiosis in hypertension and investigate its multilevel interactions with the host immune system. MethodsIntegrated multi-cohort microbiome data were used to evaluate microbial diversity, differential abundance, and co-occurrence network features between individuals with hypertension and healthy controls. The scBPS framework was applied to analyze microbiome-cell associations, enabling the resolution of relationships between key microbial taxa and functional states of immune cells at single-cell resolution. ResultsSeveral potentially protective genera reduced in hypertension and occupied central topological positions in the co-occurrence networks. Single-cell analyses further demonstrated that multiple key genera were closely associated with the functional states of monocytes and T cells (p<0.05). Specifically, Bacteroides and Bifidobacterium were associated with the proliferation and repair of classical monocytes; Butyricimonas showed a negative association with antigen processing and presentation pathways in monocytes; and Oscillospira promoted the transition of dnT cells toward an immunoregulatory state, suggesting its potential role in immune homeostasis. ConclusionsIntegrated multi-omics analyses reveal that hypertension-associated gut microbes may contribute to disease development through immune regulation, providing insights into microbiome-immune interaction mechanisms and potential targets for precision interventions.

microbiology↗

bioRxiv2026

Staurosporine drives non-canonical melanocyte maturation by coupling β-catenin signaling to actin-dependent dendrite remodeling

Skin pigmentation relies on the coordinated regulation of melanin production and dendritic morphology to ensure effective pigment distribution. While staurosporine is widely used as a proapoptotic agent in malignant cells, its effects on normal human melanocytes have not been fully characterized. Here, we investigated the impact of staurosporine on melanocyte biology and identify it as a potent inducer of non-canonical melanocyte maturation at sub-cytotoxic concentrations. In primary human neonatal melanocytes, staurosporine treatment enhances melanogenesis and promotes pronounced dendritic remodeling, leading to functional maturation distinct from its apoptotic effects in melanoma cells. Phenotypic analyses demonstrate increased pigment production and expanded dendritic networks that support efficient pigmentation. Molecular characterization indicates that these effects are associated with coordinated activation of {beta}-catenin signaling and actin-dependent cytoskeletal remodeling. The physiological relevance of these findings was further examined in vivo. Topical application of staurosporine to normal guinea pig skin increased baseline pigmentation without detectable inflammation. In addition, staurosporine accelerated repigmentation in a rhododendrol-induced leukoderma model by restoring functionally mature melanocyte populations and enhancing nuclear localization of {beta}-catenin. Together, these results identify staurosporine as a non-canonical modulator of melanocyte maturation and highlight the coordinated regulation of pigment production and dendritic remodeling as a key process supporting pigmentation in acquired hypopigmentary conditions. SummaryO_LIStaurosporine promotes non-canonical maturation of human melanocytes at sub-cytotoxic concentrations. C_LIO_LITreatment enhances both melanogenesis and dendritic remodeling, supporting functional pigmentation. C_LIO_LIStaurosporine increases baseline skin pigmentation in vivo without inducing inflammation. C_LIO_LIRepigmentation is accelerated in a rhododendrol-induced leukoderma model through restoration of mature melanocyte populations. C_LIO_LIThese findings highlight coordinated regulation of pigment production and dendritic morphology as a potential strategy to promote pigmentation in acquired hypopigmentary conditions. C_LI SignificanceLoss of melanocyte dendricity and functional maturation is a shared feature of multiple acquired hypopigmentary disorders, including vitiligo and chemical-induced leukoderma. This study demonstrates that staurosporine promotes dendritic remodeling and pigmentation in normal human melanocytes and enhances repigmentation in vivo. By identifying a melanocyte-intrinsic, ultraviolet-independent maturation program, our findings provide a biological framework for strategies aimed at restoring functional melanocytes in depigmented skin.

cell biology↗

bioRxiv2026

A red-emitting, genetically encoded indicator for two-photon voltage recording in vivo

Genetically encoded voltage indicators (GEVIs) enable minimally invasive, cell-type-specific optical measurements of neuronal membrane potential with millisecond temporal resolution. Red-shifted GEVIs are especially advantageous because they permit spectral multiplexing with complementary sensors and enable all-optical circuit interrogation in combination with blue-light-activated opsins. Despite these advantages, existing red GEVIs remain poorly suited for in vivo use due to limited performance under two-photon (2P) excitation, the predominant modality for deep-tissue imaging. Here, we introduce VADER1, a red GEVI that overcomes this limitation and enables reliable spike detection in vivo under 2P illumination. Under 2P excitation, VADER1 supports extended voltage imaging with both random-access and resonant-scanning microscopy, enables recordings from neurons as deep as cortical layer 5, and allows dual-color imaging with calcium indicators. By filling a critical spectral gap, VADER1 enables integrated optical measurements of fast electrical activity alongside other neural signals and establishes a foundation for two-photon all-optical electrophysiology.

neuroscience↗

bioRxiv2026

A Novel Hydrogen Polysulfide Donor Alleviates Neuropathic Pain by Enhancing A-Type Potassium Currents via LIMK1-Cofilin Mediated Interaction between Filamin A and Kv4.2

Hydrogen persulfide (H2S2) is an important endogenous signaling molecule, holding significant therapeutic potential across diverse disease models due to its potent antioxidant and redox-regulating properties. Herein, we report the synthesis, characterization, and in vivo evaluation of an esterase responsive H2S2 donor, HPD1. It reduced mechanical and cold allodynia at 14 mg/kg (i.p.) in chronic constriction injury and paclitaxel-induced neuropathic pain models. Moreover, HPD1 exhibited negligible systemic toxicity and behavioral side effects even at 28 mg/kg. Electrophysiological tests showed that HPD1 suppressed PTX-induced hyperexcitability in dorsal root ganglion (DRG) neurons by specifically potentiating A-type potassium currents (IA). Mechanistically, we demonstrate that HPD1 activates LIMK1, which inactivates cofilin and stabilizes F-actin, thereby promoting the interaction between the actin-binding protein Filamin A and Kv4.2. Furthermore, both the HPD1-induced increase in Filamin A-Kv4.2 co-localization and the subsequent restoration of IA density in DRG neurons, as well as the analgesic effect of HPD1 were dampened by pharmacological inhibition of LIMK1 with BMS-5. This work has developed a new generation of H2S2 donors, demonstrated the analgesic efficacy of HPD1, and uncovered the novel LIMK1-cofilin-Filamin A-Kv4.2 dependent mechanism that restores IA, thus providing a reliable therapeutic strategy for neuropathic pain based on H2S2 donors.

pharmacology and toxicology↗

bioRxiv2026

Designer indicators for two-photon recording of subthreshold voltage dynamics

Subthreshold voltage dynamics are critical for neuronal information integration, yet they remain understudied in vivo due to the limitations of current tools. While genetically encoded voltage indicators (GEVIs) offer a promising alternative, their application for deep-tissue recording using two-photon (2P) microscopy--a preferred method for deep-tissue recording--has been hindered by insufficient sensitivity for detecting millivolt-scale subthreshold signals. Here, we refined our multiparametric two-photon high-throughput screening platform to develop two novel GEVIs, JEDI3sub and JEDI3hyp, tailored explicitly for subthreshold voltage detection. Through fast 2P optical recording in awake, behaving mice, we demonstrated the superior sensitivity of JEDI3 indicators compared to JEDI-2P. We also showed that JEDI3sub can track population-level subthreshold optical tuning, while JEDI3hyp reliably captured subthreshold dynamics associated with sharp-wave ripple oscillations in hippocampal PV interneurons. Finally, JEDI3hyp facilitated extended imaging of brain-state-dependent, millivolt-scale subthreshold voltage changes across deep-layer somas, fine dendritic structures, and diverse cell types. By addressing the critical gap in 2P optical recording of subthreshold voltage dynamics, JEDI3 indicators open new avenues for studying neural information processing and its alterations in health and disease.

neuroscience↗

bioRxiv2026

A versatile, positive-going voltage indicator that enables accessible two-photon recordings in vivo

Genetically encoded voltage indicators (GEVIs) enable cell-type-specific optical readout of membrane potential, but two-photon (2P) spike detection has been hampered by low signal-to-noise and ultrafast off-kinetics, restricting use to specialized microscopes. We introduce FORCE1s, a green, positive-going GEVI engineered to make robust 2P voltage imaging broadly accessible. FORCE1s brightens from a dark baseline during depolarization, reports spikes with [~]100% {Delta}F/F in awake mice, and displays repolarization kinetics that are tuned for reliable spike detection at sub-kilohertz frame rates. As a result, FORCE1s supports spike-resolved multi-cell recordings on standard resonant-scanning microscopes, and further scales to larger fields of view and neuron counts on advanced modalities. FORCE1s also enables multiplexed voltage-neurotransmitter imaging and extended recordings in freely moving mice using a compact, affordable MEMS-based 2P miniscope. Together, these advances establish FORCE1s as a community-ready tool that democratizes deep-tissue voltage imaging across platforms and experimental contexts.

neuroscience↗

bioRxiv2026

Pharmacological recruitment of a VTA glutamatergic arousal circuit by the natural product BN3 drives broad-spectrum emergence from general anesthesia

Pharmacological control of emergence from general anesthesia remains strikingly limited. Clinically available antagonists are largely drug-class specific, leaving recovery dependent on anesthetic clearance rather than to an actively programmable switch in brain state. Through phenotypic screening of a structurally diverse natural-product library, we identified BN3 (L-(-)-camphor) as a broad-spectrum emergence agent. BN3 robustly shortened recovery from propofol anesthesia across species--from mice and rats to rabbits, dogs, and rhesus monkeys--and remained effective after continuous infusion. In rodents, BN3 also accelerated emergence from mechanistically distinct anesthetics, including etomidate, remimazolam, sodium {gamma} - hydroxybutyrate, midazolam, ketamine, sodium pentobarbital, and isoflurane. EEG recordings revealed a rapid cortical shift from slow-wave dominance to a wake-like high-frequency spectrum. Mechanistically, BN3 preferentially recruited ventral tegmental area (VTA) glutamatergic neurons: chemogenetic silencing abolished the BN3-evoked EEG spectral shift and strongly attenuated behavioral acceleration of emergence, whereas optogenetic activation of these neurons was sufficient to promote recovery. BN3 increased glutamate release in the nucleus accumbens and medial prefrontal cortex, and projection-specific inhibition of VTA[->]NAc or VTA[->]mPFC outputs blunted BN3-induced emergence. These findings define a VTA-centered glutamatergic arousal circuit that can be pharmacologically recruited as a common gateway for anesthetic-independent emergence.

neuroscience↗

bioRxiv2026

Comorbid HIV and Cocaine Use Exacerbate Accelerated Brain Aging

BackgroundHIV and cocaine use (CU) each relate to cognitive deficits and brain abnormalities, yet their combined impact on brain aging remains unclear. This study examined how comorbid HIV and CU relate to brain aging and cognitive impairment. MethodsWe trained a morphometry-based brain-age model using harmonized Human Connectome Project-Aging data (HCP-A; n=725) with Gaussian Process Regression. The model was applied to an independent cohort with varying HIV/CU burden (HIV-/CU-, n=34; one disorder [HIV+/CU- or HIV-/CU+], n=72; HIV+/CU+, n=80). Brain age gap (BAG; predicted minus chronological age) was examined in relation to comorbidity burden and neurocognitive impairment (NCI; NIH Toolbox), adjusting for age, sex, education, depression, and image-quality indices. Analyses on SHapley Additive exPlanation (SHAP) values characterized network-wise feature-level contributions to brain age estimates. ResultsA dose-dependent effect of comorbidity burden on BAG was observed, with the HIV+/CU+ group showing the highest BAG. Greater BAG was associated with increased likelihood of NCI, and BAG partially mediated the relationship between comorbidity burden and NCI, with a stronger mediation effect in the two-disorder group than in the one-disorder group. Structural contributors to elevated BAG in the HIV/CU cohort included cortical thickness in the visual, ventral attention, and frontoparietal networks, and sulcal depth in the sensorimotor network. ConclusionComorbid HIV/CU is linked to accelerated structural brain aging. BAG may reflect brain-level alterations underlying the association between comorbid HIV/CU and cognitive impairment, and may help identify network-specific targets for intervention.

neuroscience↗

bioRxiv2025

The FERM Guild: A Differentially Correlated Microbial Module Drives Hypertension via Metabolic Flux Perturbations

BackgroundHypertension is a major risk factor for cardiovascular diseases, with changes in gut microbiota composition and function being closely associated with its onset and progression. However, the high inter-individual variability in gut microbiota complicates the identification of pathogenic mechanisms using traditional methods. In contrast, the smaller variability in gut microbial metabolites offers a more reliable and consistent basis for cross-individual comparisons. ResultsParsimonious Flux Balance Analysis (pFBA), integrated with Double Machine Learning (DoubleML), identified 17 metabolites significantly associated with hypertension (p < 0.05, RobustnessV alue > 0.1). These included meso-2,6-diaminoheptanedioate, p-hydroxyphenylacetic acid, cellobiose, dextran 40 (1,6--D-glucan), L-glutamic acid, kestopentaose, among others. Differential microbial correlation network analysis identified a key microbial sub-network, the FERM guild, consisting of 19 species, with prominent genera including Faecalibacterium,Enterobacter,Roseburia, and Methanobrevibacter. Using GSEA, the dysregulation of this guild was found to be strongly associated with a set of 17 hypertension-related metabolites(p = 0.017). Further analysis revealed that the contribution of FERM genus to key metabolites is significantly associated with blood pressure (p < 0.05), even without significant differences in their abundance; additionally, an imbalance exists between FERM genus and other species. ConclusionsOur findings reveal that hypertension is associated with a disruption of gut microbial diversity, structure, and metabolic function. Seventeen key metabolites related to blood pressure regulation were identified, exhibiting pro- or anti-hypertensive potential and linked to functional microbial modules. These results highlight the gut microbiota and its metabolites as promising targets for therapeutic intervention in hypertension.

bioinformatics↗

bioRxiv2025

Circadian clock regulates epidermal endocrine system in homeostatic skin pigmentation

The circadian clock regulates various physiological processes in the skin, including local hormone synthesis and pigment production. However, the interplay between circadian regulation and epidermal endocrine signaling remains poorly understood. In this study, we investigated the functional roles of two core circadian transcriptional regulators, Basic helix-loop-helix ARNT-like protein 1 (BMAL1) and CLOCK circadian regulator (CLOCK), in human epidermal homeostasis. Primary normal human epidermal melanocytes were cultured and analyzed using quantitative real-time PCR, Western blotting, and immunofluorescence. Both BMAL1 and CLOCK were abundantly expressed in melanocytes. siRNA-mediated knockdown of either gene led to a significant reduction in melanin synthesis and altered the expression of hormone-related factors, notably decreasing the expression of vitamin D receptor (VDR) and its associated pathways. These molecular alterations were closely correlated with changes in melanogenic activity. Consistently, immunohistochemical analysis of vitiligo patient skin revealed reduced expression of the vitamin D-related enzyme CYP27A1 in melanocytes. Collectively, our findings demonstrate that circadian clock disruption impairs pigment production partly through modulation of vitamin D signaling, uncovering a previously unrecognized link between the cutaneous circadian system and endocrine regulation of melanogenesis.

pathology↗

bioRxiv2025

The fate of melanocytes and the disorganization of basement membrane in a guinea pig model of Rhododendrol-induced chemical vitiligo

BackgroundRhododendrol (RD) is a phenolic compound that was first developed as a skin-lightening agent that occasionally induces skin depigmentation. Although it has been shown that RD induces melanocyte death in vitro, it is still not fully understood why melanocytes are gone by RD in vivo. ObjectiveThis research aimed to investigate how melanocytes are eliminated in the animal model by RD. MethodsOn the backs of black guinea pigs (JY-4) with epidermal melanocytes in the basal layer, 30% RD was administered topically three times per day, five days per week. Skin tissues were collected sequentially and histologically analyzed. ResultsOn day 21, L* values in the RD-applied skin were significantly higher than in the vehicle-applied skin. From day 1 to day 7, the number of TRP1-positive melanocytes and melanin in the basal layer decreased, but no TUNEL-positive melanocytes were identified. On the other hand, an accumulation of melanin was newly found in the dermis. Immunohistochemical staining identified several melanocytes in the upper dermis or spinous layer, away from the basement membrane. An investigation of the epidermal-dermal interface showed a structural anomaly in a portion of the basement membrane with elevated MMP2 expression and increased dermal fibroblasts. The application of the MMP2 inhibitor Ilomastat abolished the basement membrane abnormality by RD. ConclusionThese findings suggest that RD-induced alterations in basement membrane structure may contribute to melanocyte detachment and loss, which is the cause of skin depigmentation not only in RD-induced vitiligo but also in vitiligo.

pathology↗

bioRxiv2025

Atlas of Lysosomal Aging Reveals a Molecular Clock of Storage Disorder-Associated Metabolites

Lysosomal dysfunction is a well-recognized feature of aging, yet its systematic molecular investigation remains limited. Here, we employ a suite of tools for rapid lysosomal isolation to construct a multi-tissue atlas of the metabolite changes that murine lysosomes undergo during aging. Aged lysosomes in brain, heart, muscle and adipose accumulate glycerophosphodiesters and cystine, metabolites that are causally linked to juvenile lysosomal storage disorders like Batten disease. Levels of these metabolites increase linearly with age, preceding organismal decline. Caloric restriction, a lifespan-extending intervention, mitigates these changes in the heart but not the brain. Our findings link lysosomal storage disorders to aging-related dysfunction, uncover a metabolic lysosomal "aging clock," and open avenues for the mechanistic investigation of how lysosomal functions deteriorate during aging and in age-associated diseases. One-Sentence SummaryAging in mice is tracked by a lysosomal "clock", where glycerophosphodiesters and cystine - metabolites causally linked to juvenile lysosomal storage disorders - gradually accumulate in lysosomes of the brain, heart, skeletal muscle and adipose tissue.

cell biology↗

bioRxiv2025

HerbComb: an integrated database for the discovery of novel combinational therapies from herbal medicines

Drug combinations have gained increasing interest due to their potential for optimal efficacy and the ability to overcome drug resistance. Herbal medicine is a complex system with multiple ingredients and has illustrated apparent therapeutic effects through thousands of years of clinical experience, offering a rich resource for combinational therapies. However, the underlying mechanism of their synergistic therapeutic effects for disease treatment remains obscure for most herbal medicines. To fill this gap, we developed an integrated database named HerbComb (https://herbcomb.com/) to discover combinatorial therapies in herbal medicine, featuring three unique functions: drug prepositioning, customized combinatorial analysis, and biological and pharmacological features. Additionally, transcriptional gene signatures and ADMET properties were also interrogated as interactive functionalities to facilitate combinational analysis. Using Tongxinluo for Stroke as a case study, we identified and validated Oleanolic acid and Ferulic acid as synergistic ingredients. In summary, HerbComb is a versatile data exploration platform designed to characterize synergistic interactions among herbal medicines, enhancing the understanding of synergistic mechanisms and facilitating the discovery of effective drug combinations.

pharmacology and toxicology↗

bioRxiv2025

Phosphorylation-inducing molecules for regulating dynamic cellular processes

Dynamic cellular processes often employ protein phosphorylation for rapid information transfer within and between cells. Phosphorylation-inducing chimeric small molecules (PHICS) have been developed for targeted protein phosphorylation by on-demand inducing a kinase-protein pairing. However, widespread application of PHICS has been limited as previously reported PHICS that recruited AMP-activated protein kinase (AMPK) required serum starvation and target protein overexpression, recruited only a few of the potential AMPK complexes, and exhibited poor dose- and temporal control. Herein, we report an AMPK PHICS platform that operates under physiological conditions (i.e., no serum starvation or target overexpression), recruits multiple AMPK complexes, and can induce target protein phosphorylation with dose and temporal control. We demonstrated the utility of this platform for controlling phosphorylations that underlie two dynamic cellular processes, namely oncogenic signaling and phase separation. An AMPK PHICS directed against Brutons Tyrosine Kinase (BTK), which is a driver of several B cell malignancies, was effective at inducing the death of drug-resistant cancer cells. Here, PHICS induced inhibitory phosphorylations on BTK and attenuated its oncogenic pathway. Phosphorylation of Liprin-3 induces phase separation in neurons and is critical for neurotransmitter release. Using AMPK PHICS that phosphorylated Liprin-3, we induced Liprin-3 phase separation with dose and temporal control. We envision this PHICS platform to find utility in inducing and controlling protein phosphorylations for basic research and biomedicine. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=102 SRC="FIGDIR/small/652895v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@16bbb20org.highwire.dtl.DTLVardef@1ca5267org.highwire.dtl.DTLVardef@1e805d5org.highwire.dtl.DTLVardef@1d6ec22_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2025

Altered laminin signaling destinates melanocyte reprogramming in vitiligo

Vitiligo is an acquired depigmenting skin disorder characterized by progressive melanocyte loss, but the cellular mechanisms driving this process remain unclear. Here, we identify melanocyte dedifferentiation as a central and reversible pathogenic mechanism in vitiligo. In healthy human skin, melanocytes reside within a basement membrane niche defined by dystroglycan-laminin-211 adhesion. In contrast, vitiligo lesions exhibit aberrant extracellular matrix remodeling, leading to an adhesion switch to integrin 3{beta}1-laminin-332 interactions. This shift promotes melanocyte dedifferentiation via Rho-F-actin-dependent activation of Hippo and MAPK pathways, resulting in c-Jun-mediated transcriptional changes. Dedifferentiated melanocytes lose their pigment-producing identity and acquire neural crest-like features with multilineage potential. Importantly, this process is reversible. Pharmacological inhibition of involved pathways restores melanocyte differentiation and induces repigmentation in both vitiligo mouse models and ex vivo patient skin. Notably, JAK inhibitors also promote redifferentiation independently of immune modulation. These findings uncover melanocyte dedifferentiation as a fundamental driver of vitiligo and a tractable therapeutic target, offering new opportunities for therapeutic intervention.

cell biology↗

bioRxiv2025

Restoration of excitation/inhibition balance enhances neuronal signal-to-noise ratio and rescues social deficits in autism-associated Scn2a-deficiency

Social behavior is critical for survival and adaptation, which is profoundly disrupted in autism spectrum disorders (ASD). Social withdrawal due to information overload was often described in ASD, and it was suspected that increased basal noise, i.e., excessive background neuronal activities in the brain could be a disease mechanism. However, experimental test of this hypothesis is limited. Loss-of-function mutations (deficiency) in SCN2A, which encodes the voltage-gated sodium channel NaV1.2, have been revealed as a leading monogenic cause of profound ASD. Here, we revealed that Scn2a deficiency results in robust and multifaceted social impairments in mice. Scn2a-deficient neurons displayed an increased excitation-inhibition (E/I) ratio, contributing to elevated basal neuronal noise and diminished signal-to-noise ratio (SNR) during social interactions. Notably, the restoration of Scn2a expression in adulthood is able to rescue both SNR and social deficits. By balancing the E/I ratio and reducing basal neuronal firing, an FDA-approved GABAA receptor-positive allosteric modulator improves sociability in Scn2a-deficient mice and normalizes neuronal activities in translationally relevant human brain organoids carrying autism-associated SCN2A nonsense mutation. Collectively, our findings revealed a critical role of the NaV1.2 channel in the regulation of social behaviors, and identified molecular, cellular, and circuitry mechanisms underlying SCN2A-associated disorders. HIGHLIGHTSO_LINaV1.2 deficiency leads to pronounced social deficits in mice. C_LIO_LINaV1.2 deficiency results in an overall enhanced E/I ratio, elevated basal neuronal activity, and impaired signal-to-noise ratio. C_LIO_LIBoth the enhanced E/I ratio and impaired sociability are reversible through the restoration of NaV1.2 expression in adulthood. C_LIO_LITargeted restoration of NaV1.2 in striatum-projecting neurons rescues social impairments. C_LIO_LIGABA transmission is reduced in both mouse and human organoid models of SCN2A deficiency, and acute systemic administration of GABAA receptor-positive allosteric modulators restores sociability. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=193 HEIGHT=200 SRC="FIGDIR/small/641498v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@154a323org.highwire.dtl.DTLVardef@1a27fbaorg.highwire.dtl.DTLVardef@16fa3beorg.highwire.dtl.DTLVardef@6712c2_HPS_FORMAT_FIGEXP M_FIG C_FIG Graphical abstract: Severe Scn2a deficiency leads to a predominate decrease in GABA transmission with an overall enhanced E/I ratio, elevated basal neuronal activity, impaired SNR, and social deficits in adult NaV1.2-deficient mice.

neuroscience↗

bioRxiv2024

Profiling amino acid substitution on proteomic scale unveils novel protein regulation in cancer diseases

Amino acid (AA) substitutions play a critical role in regulating cellular activities, including complex signaling and cell cycle processes. Recent research on AA substitutions has primarily relied on genomic and transcriptomic data. The identification at the proteomic scale remains underexplored, despite evidence suggesting that DNA and RNA biosynthesis are not the sole sources of these substitutions. This gap persists due to challenges in analyzing large-scale proteomic data. In this study, we address this limitation by analyzing multiple independent datasets across five cancer types using PIPI-C, a novel mass spectrometry data analysis tool. And we propose AA substitutomics, a pipeline for characterizing AA substitutions arising after protein translation and dissecting the regulatory functions of key proteins with AA substitutions. Among our identified AA substitutions, 87% are novel findings and not recorded in genomic/transcriptomic databases, which indicates that the post-translational AA substitutions are prevalent. Our findings reveal biologically significant AA substitutions linked to cancer, such as F43S and E91D in hemoglobin subunit beta, P584T in filamin A, and A175N in fructose-bisphosphate aldolase B. Furthermore, our pipeline enables direct investigation of drug resistance and immune escape. By capturing functional protein-level alterations beyond genomic and transcriptomic profiling, it establishes a robust framework to advance cancer research.

cancer biology↗