Biology subjects

Sun, S.

Publications and source records attributed to Sun, S..

At least 199 records · Page 11Linked to original sources

bioRxiv2023

Co-existence of blaKPC-2 and blaVIM-2 in highly carbapenem-resistant Pseudomonas aeruginosa isolated in the ICU of a public hospital

In this study, highly carbapenem-resistant Pseudomonas aeruginosa (h-CRPA) 18102011 [the minimum inhibitory concentration (MIC) value of carbapenem antimicrobial imipenem (IP) for h-CRPA is 4,096 g/mL] was isolated from the bile of an intensive care unit (ICU) burn patient in China, and genomic sequencing revealed a complete genome. The genomes molecular characteristics were analyzed to assess the genetic environment of blaKPC-2 and blaVIM-2. Average nucleotide identity (ANI) comparisons were used for precise species-level identification, while serotyping, multi-locus sequence typing, and the identification of acquired resistance genes, and virulence genes were also carried out. The h-CRPA 18102011 strain carrying blaKPC-2 and blaVIM-2 was identified as strain ST2374 and the O4 serotype. Virulence genes (plcH, exoST) and resistance genes (aph(3)-IIb, aac(6)-Ib-cr, ant(2)-Ia, blaOXA-396, blaPAO, blaKPC-2, blaVIM-2, blaPER-1, sul1, catB7, qnrVC6, fosA) were both identified in the genome. In addition, the IncpRBL16 type mega-plasmid pP2011-1 carrying blaVIM-2 and the IncP6 type plasmid pP2011-2 carrying blaKPC-2 were identified in the strain. The genetic environment of blaVIM-2 and blaKPC-2 was specifically evaluated to assess their origins. blaVIM-2 was located in the region of In2075 (a novel type 1 integron) that was inserted into plasmid pP2011-1, this plasmid contained 3 novel recombination sites, as well as the typical recombination site 2 (umuC) observed for IncpRBL16 type plasmids. However, the core module Tn3-ISKpn27-blaKPC-{Delta}ISKpn6 was identified as the blaKPC-2 platform in plasmid pP2011-2. Conjugation experiments revealed that the plasmids pP2011-1 and pP2011-2 of the h-CRPA 18102011 strain could be transferred into Escherichia coli with a conjugation transfer efficiency of 10-6. The E. coli transconjugant carried blaKPC-2 and blaVIM-2 from the donor and the MIC value of IP to the E. coli transconjugant was 4,096 g/mL, which was the same as observed for the donor. Overall, this study revealed the molecular characteristics of a VIM-2 and KPC-2-co-producing strain that was typed as O4 and ST2374. The continuous monitoring of bacteria, such as the strain investigated here, that co-harbor different types of carbapenemase genes is critical for preventing the spread of these genes.

genomics↗

bioRxiv2023

Generation of CRISPR-edited birch Plants without DNA integration using Agrobacterium-mediated Transformation Technology

CRISPR/Cas9 system has emerged as a powerful tool in genome editing; however, generation of CRISPR-edited DNA-free plants is still challenging. In this study, Betula platyphylla (birch) was used to build a method to generate CRISPR-edited plant without foreign DNA integration using Agrobacterium-mediated transformation (CPDAT method). This technique utilizes transient genetic transformation to introduce T-DNA coding gRNA and Cas9 into birch cells, and T-DNA will express to synthesize gRNA and Cas9 protein, which will form a complex to cleave the target DNA site. The genome may be mutated due to DNA repair, and these mutations will be preserved and accumulated not dependent on whether T-DNA is integrated into the genome or not. After transient transformation, birch plants were cut into explants to induce adventitious buds without antibiotic selection pressure. Each adventitious bud can be considered as an independent potentially CRISPR-edited line for mutation detection. CRISPR-edited birch plants without foreign DNA integration are further selected by screening CRISPR-edited lines without T-DNA integration. Among 65 randomly chosen independent lines, the mutation rate was 80.00% including 40.00% of lines with both alleles mutated. In addition, 5 lines out of 65 studied lines (7.69%) were CRISPR-edited birch plants without DNA integration. In conclusion, this innovative method presents a novel strategy for generating CRISPR-edited birch plants, thereby significantly enhancing the efficiency of generating common CRISPR-edited plants. These findings offer considerable potential to develop plant genome editing techniques further.

genetics↗

bioRxiv2023

Potential intrahospital dissemination of Pseudomonas aeruginosa carrying the blaIMP-1 gene within a Tn7-like transposon

We aimed to determine the molecular characteristics of carbapenem-resistant Pseudomonas aeruginosa 18081308 and 18083286 isolated from the urine and sputum of two Chinese patients respectively, and analyzed the formation mechanism of the genetic environment in which it carries blaIMP-1. Bacterial genome sequencing was carried out on strains 18081308 and 18083286 to obtain their whole genome sequence. Average nucleotide identity (ANI) was used for their precise species identification. Serotyping and multilocus sequence typing were performed. Furthermore, the acquired resistance genes, and virulence factors of these strains were identified. The carbapenem-resistant P. aeruginosa strains isolated in the present study were of sequence type ST865 and serotype O6. They all carried the same virulence factors (PLC, ExoSTY) and resistance genes (aacC2, tmrB, and blaIMP-1). Tn6411, a Tn7-like transposon carrying blaIMP-1, was found in both strains. Detailed genetic dissection was applied to this transposon to display the genetic environment of blaIMP-1. The aacC2-tmrB region remnant-Tn6411 backbone was the original structure of this type of transposon. A Tn402-like type 1 integron (intl1-aac(6)-II-blaIMP-1) was inserted into it and formed a stable structure, which was localized in the chromosome by TnsD for transmission within P. aeruginosa; the original structure of Tn7-like transposon was localized on the plasmid by TnsE for horizontal transmission between bacterial species. The intrahospital dissemination of P. aeruginosa ST865 isolated in this study was episodic. The blaIMP-1-carrying Tn7-like transposon might enhance their ability to survive under drug selection pressure and aggravate the difficulty in treating infections.

genomics↗

bioRxiv2023

FMNL2 regulates actin for ER and mitochondria distribution in oocyte meiosis

During mammalian oocyte meiosis, spindle migration and asymmetric cytokinesis are unique steps for the successful polar body extrusion. The asymmetry defects of oocytes will lead to the failure of fertilization and embryo implantation. In present study we reported that an actin nucleating factor formin-like 2 (FMNL2) played critical roles in the regulation of spindle migration and organelle distribution. Our results showed that FMNL2 mainly localized at the oocyte cortex and periphery of spindle. Depletion of FMNL2 led to the failure of polar body extrusion and large polar bodies in oocytes. Live-cell imaging revealed that the spindle failed to migrate to the oocyte cortex, which caused polar body formation defects, and this might be due to the decreased polymerization of cytoplasmic actin by FMNL2 depletion. Furthermore, mass spectrometry analysis indicated that FMNL2 was associated with mitochondria and endoplasmic reticulum-related proteins, and FMNL2 depletion disrupted the function and distribution of mitochondria and endoplasmic reticulum, showing with decreased mitochondrial membrane potential and the occurrence of endoplasmic reticulum stress. Microinjecting Fmnl2-EGFP mRNA into FMNL2-depleted oocytes significantly rescued these defects. Thus, our results indicate that FMNL2 is essential for the actin assembly, which further involves into meiotic spindle migration and ER/mitochondria functions in mouse oocytes.

developmental biology↗

bioRxiv2023

Spatial transcriptomics of peach and nectarine elucidates the mechanism underlying fruit trichome development

Peach (Prunus persica) is an economically significant fruit-bearing tree. The trichomes of peach fruits are essential for their growth and development by playing a protective role against abiotic stresses, such as intense ultraviolet (UV) light, high temperature, cold-induced stress, and biotic stresses, such as pests and disease infestation. However, the mechanism underlying trichome development in peach fruits is unknown. Therefore, spatial transcriptome sequencing technology was used to compare the transcriptomic information seven days after flowering (DAF) of peach and nectarine fruits at an ultra-high resolution. The results revealed significant variations in how fruits at the early development stage responded to stress exposure. Comparatively, nectarine response to stress was significantly magnified than peach. Notably, a novel trichome-related marker gene, Prupe.7G196500, was identified in peach, which showed a robust function in response to jasmonic acid and wounding. Further, the Prupe.7G196500pro::GUS construct was found to specifically expressed in the trichomes of the true leaves of 10-day-old Arabidopsis thaliana (Arabidopsis) seedlings and induced by drought treatment. Finally, gain-of-function analysis showed that Prupe.7G196500 promoted trichomes development. In conclusion, this study identified the cell types and novel marker genes associated with peach fruit. The role of Prupe.7G196500 in positively regulating trichome development was also characterized, thereby laying the foundation for analyzing the mechanism involved in trichome development in peach fruits.

developmental biology↗

bioRxiv2023

A telomere-to-telomere genome assembly of Zhonghuang 13, a widely-grown soybean variety from the original center of Glycine max

Soybean (Glycine max) stands as a globally significant agricultural crop, and the comprehensive assembly of its genome is of paramount importance for unraveling its biological characteristics and evolutionary history. Nevertheless, previous soybean genome assemblies have harbored gaps and incompleteness, which have constrained in-depth investigations into soybean. Here, we present the first Telomere-to-Telomere (T2T) assembly of the Chinese soybean cultivar "Zhonghuang 13" (ZH13) genome, termed ZH13-T2T, utilizing PacBio Hifi and ONT ultralong reads. We employed a multi-assembler approach, integrating Hifiasm, NextDenovo, and Canu, to minimize biases and enhance assembly accuracy. The assembly spans 1,015,024,879 bp, effectively resolving all 393 gaps that previously plagued the reference genome. Our annotation efforts identified 50,564 high-confidence protein-coding genes, 707 of which are novel. ZH13-T2T revealed longer chromosomes, 421 not-aligned regions (NARs), 112 structure variations (SVs), and a substantial expansion of repetitive element compared to earlier assemblies. Specifically, we identified 25.67 Mb of tandem repeats, an enrichment of 5S and 48S rDNAs, and characterized their genotypic diversity. In summary, we deliver the first complete Chinese soybean cultivar T2T genome. The comprehensive annotation, along with precise centromere and telomere characterization, as well as insights into structural variations, further enhance our understanding of soybean genetics and evolution.

plant biology↗

bioRxiv2023

Using a function-first "scout fragment"-based approach to develop allosteric covalent inhibitors of conformationally dynamic helicase mechanoenzymes

Helicases, classified into six superfamilies, are mechanoenzymes that utilize energy derived from ATP hydrolysis to remodel DNA and RNA substrates. These enzymes have key roles in diverse cellular processes, such as genome replication and maintenance, ribosome assembly and translation. Helicases with essential functions only in certain cancer cells have been identified and helicases expressed by certain viruses are required for their pathogenicity. As a result, helicases are important targets for chemical probes and therapeutics. However, it has been very challenging to develop selective chemical inhibitors for helicases, enzymes with highly dynamic conformations. We envisioned that electrophilic scout fragments, which have been used for chemical proteomic based profiling, could be leveraged to develop covalent inhibitors of helicases. We adopted a function-first approach, combining enzymatic assays with enantiomeric probe pairs and mass spectrometry, to develop a covalent inhibitor that selectively targets an allosteric site in SARS-CoV-2 nsp13, a superfamily-1 helicase. Further, we demonstrate that scout fragments inhibit the activity of two human superfamily-2 helicases, BLM and WRN, involved in genome maintenance. Together, our findings suggest a covalent inhibitor discovery approach to target helicases and potentially other conformationally dynamic mechanoenzymes.

biochemistry↗

bioRxiv2023

Differential effects of aneuploidy on growth and differentiation in human intestinal stem cells

Aneuploidy, a near ubiquitous genetic feature of tumors, is a context-dependent driver of cancer evolution; however, the mechanistic basis of this role remains unclear. Here, by inducing heterogeneous aneuploidy in non-transformed human colon organoids (colonoids), we investigate how the effects of aneuploidy on cell growth and differentiation may promote malignant transformation. Single-cell RNA sequencing reveals that the gene expression signature across over 100 unique aneuploid karyotypes is enriched with p53 responsive genes. The primary driver of p53 activation is karyotype complexity. Complex aneuploid cells with multiple unbalanced chromosomes activate p53 and undergo G1 cell-cycle arrest, independent of DNA damage and without evidence of senescence. By contrast, simple aneuploid cells with 1-3 chromosomes gained or lost continue to proliferate, demonstrated by single cell tracking in colonoids. Notably, simple aneuploid cells exhibit impaired differentiation when niche factors are withdrawn. These findings suggest that while complex aneuploid cells are eliminated from the normal epithelium due to p53 activation, simple aneuploid cells can escape this checkpoint and may contribute to niche factor-independent growth of cancer-initiating cells.

cell biology↗

bioRxiv2023

GENOMES UNCOUPLED1: an RNA-binding protein required for early PSII biogenesis

Genomes Uncoupled1 (GUN1), a nuclear-encoded chloroplast pentatricopeptide repeat (PPR) protein, serves as a master integrator of diverse retrograde signals, mediating chloroplast-to-nucleus retrograde signaling. Although PPR proteins primarily function in organelle RNA metabolism, a target RNA of GUN1 remained unknown. This study reveals that GUN1 recognizes psbD transcripts derived from a blue light-responsive promoter (BLRP), transcripts referred to as psbD BLRP. Overexpression of GUN1 significantly reduces the levels of psbD BLRP, whereas the loss of GUN1 leads to the accumulation of the putative target RNA. The in vitro RNA and in vivo genetic studies further demonstrate the critical role of the C-terminal small MutS-related (SMR) domain in stimulating psbD BLRP processing and PsbD (D2, a PSII core protein) synthesis. The GUN1-dependent psbD BLRP processing promotes PSII biogenesis during the early seedling development and de-etiolation phase. This finding underscores the role of GUN1 as an RNA-binding protein, highlighting the essential function of the SMR domain in processing the target RNA. SignificanceBiogenic retrograde signaling is essential in regulating chloroplast biogenesis, and it entails a nuclear-encoded chloroplast protein, Genomes Uncoupled1 (GUN1). Since its initial discovery in 1993, the gun1 mutant has been widely used to reveal the precise function of GUN1 in plastids as well as its downstream signaling components. Although GUN1 contains pentatricopeptide repeat motifs, it has been considered a non-canonical PPR protein because no one could demonstrate GUN1-RNA interaction in planta. However, through our computational analysis of PPR codes and subsequent biochemical studies, we were able to unravel its putative target RNA, namely psbD BLRP. Therefore, our finding may lead to a reevaluation of GUN1 research in the context of RNA metabolism and a revision of our current understanding of GUN1.

plant biology↗

bioRxiv2023

Powerful and accurate detection of temporal gene expression patterns from multi-sample multi-stage single-cell transcriptomics data

We present a non-parametric statistical method called TDEseq that takes full advantage of smoothing splines basis functions to account for the dependence of multiple time points, and uses hierarchical structure linear additive mixed models to model the correlated cells within an individual. As a result, TDEseq demonstrates powerful performance in identifying four potential temporal expression patterns within a specific cell type. Extensive simulation studies and the analysis of four published scRNA-seq datasets show that TDEseq can produce well-calibrated p-values and up to 20% power gain over the existing methods for detecting temporal gene expression patterns.

genomics↗

bioRxiv2023

Evolutionary prediction for new echolocators

It was suggested over 60 years ago that echolocation is widespread in animals. Although echolocation has been found to evolve independently in several mammalian lineages, this hypothesis remains largely untested due to the difficulty of determining the presence of echolocation. To address this issue, we combined molecular convergence analyses from 190 high-quality mammalian genomes with machine learning to predict potential new mammalian echolocators. Our model predicted three promising lineages of echolocating mammals. Behavioral experiments confirmed that the gracile shrew mole (Uropsilus gracilis), the highest- ranking species among predicted echolocators, as well as almost all shrew moles (Uropsilinae), are capable of echolocation through the use of ultrasonic pulses. In contrast to most bats that use laryngeal echolocation, the characteristics of calls, the morphology of the stylohyal bone, and the results of tongue ligation experiments all suggest that shrew moles produce ultrasonic clicks with their tongues for echolocation. Finally, we estimated at least 20% of all living mammalian orders with echolocation ability, thus empirically supporting Griffins hypothesis that echolocation is widespread among animals. Our findings not only provide evidence that three novel lineages of echolocating mammals, but also demonstrate that phylogenetically replicated phenotypes can be predicted through genetic convergence. One sentence summaryShrew moles are capable of echolocation.

evolutionary biology↗

bioRxiv2023

Sodium chloride in the tumor microenvironment enhances T-cell metabolic fitness and cytotoxicity

Adoptive T-cell therapy has become a powerful weapon for cancer treatment. The efficacy of antitumor immunity is associated with the metabolic state of cytotoxic T cells, which is highly sensitive to the tumor microenvironment. It is therefore of considerable interest to bypass immunosuppressive signals in the tumor microenvironment and to identify factors that augment cytotoxic effector functions and ultimately tumor killing. Whether ionic signals serve as aberrant immune signals and influence the adaptive human antitumor immune response is still largely unexplored. We therefore investigated the effect of sodium on the phenotype, function and metabolic regulation of human CD8+ T cells using transcriptomic, metabolomic, high-dimensional flow cytometric and functional assays. We demonstrate a significant enrichment of sodium in solid tumors from patients with breast cancer, which leaves a transcriptomic imprint on intratumoral immune cells. Sodium chloride (NaCl) enhanced the activation state and effector functions of human CD8+ memory T cells. These functional alterations were associated with enhanced metabolic fitness, particularly increases in glycolysis, oxidative phosphorylation and overall nutrient uptake. These NaCl-induced effects translated into increased tumor cell killing in vitro and in a tumor mouse model in vivo. We therefore propose NaCl as a positive regulator of acute antitumor immunity that could be harnessed for ex vivo conditioning of adoptively transferred T cells, such as CAR T-cells.

immunology↗

bioRxiv2023

Accurate Prediction of Antibody Function and Structure Using Bio-Inspired Antibody Language Model

In recent decades, antibodies have emerged as indispensable therapeutics for combating diseases, particularly viral infections. However, their development has been hindered by limited structural information and labor-intensive engineering processes. Fortunately, significant advancements in deep learning methods have facilitated the precise prediction of protein structure and function by leveraging co-evolution information from homologous proteins. Despite these advances, predicting the conformation of antibodies remains challenging due to their unique evolution and the high flexibility of their antigen-binding regions. Here, to address this challenge, we present the Bio-inspired Anti-body Language Model (BALM). This model is trained on a vast dataset comprising 336 million 40% non-redundant unlabeled antibody sequences, capturing both unique and conserved properties specific to antibodies. Notably, BALM showcases exceptional performance across four antigen-binding prediction tasks. Moreover, we introduce BALMFold, an end-to-end method derived from BALM, capable of swiftly predicting full atomic antibody structures from individual sequences. Remarkably, BALMFold outperforms those well-established methods like AlphaFold2, IgFold, ESMFold, and OmegaFold in the antibody benchmark, demonstrating significant potential to advance innovative engineering and streamline therapeutic antibody development by reducing the need for unnecessary trials.

bioinformatics↗

bioRxiv2023

Nitrate-driven anaerobic oxidation of ethane and butane by bacteria

The short-chain gaseous alkanes (ethane, propane and butane; SCGAs) are important components of natural gas, yet our understanding of their fate in environmental systems is poorly understood. Microbially mediated anaerobic oxidation of SCGAs coupled to nitrate reduction has been demonstrated for propane, but is yet to be shown for ethane or butane - despite being energetically feasible. Here we report two independent bacterial enrichments performing anaerobic ethane and butane oxidation, respectively, coupled to nitrate reduction to dinitrogen gas and ammonium. Isotopic 13C-and 15N-labelling experiments, mass and electron balance tests, and metabolite and meta-omics analyses collectively reveal that the recently described propane-oxidising Candidatus Alkanivorans nitratireducens was also responsible for nitrate-dependent anaerobic oxidation of the SCGAs in both these enrichments. The complete genome of this species encodes alkylsuccinate synthase genes for the activation of ethane/butane via fumarate addition. Further substrate range tests confirm Ca. A. nitratireducens is metabolically versatile, being able to degrade ethane, propane and butane under anaerobic conditions. Moreover, our study proves nitrate as an additional electron sink for ethane and butane in anaerobic environments, and for the first time demonstrates the use of the fumarate addition pathway in anaerobic ethane oxidation. These findings significantly contribute to our understanding of microbial metabolism of SCGAs in anaerobic environments.

microbiology↗

bioRxiv2023

Duhuo Jisheng Decoction Regulates Intracellular Zinc Homeostasis by Enhancing Autophagy via PTEN/Akt/mTOR to Improve Knee Cartilage Degeneration

BackgroundArticular cartilage degeneration as well as cartilage matrix degradation is one of the key pathological changes in the early stage of knee osteoarthritis (KOA). However, currently, there are limited early prevention and treatment options available. Duhuo Jisheng Decoction (DHJSD) is a formula from Bei Ji Qian jin Yao Fang compiled by Sun Simiao in the Tang Dynasty of China. As a complementary therapy, it is widely used to treat early-stage KOA in China, but its mechanism has not been fully elucidated. ObjectiveThis study is aiming at investigating the potential role and mechanism of DHJSD in protecting cartilage from degradation. MethodsThe mechanism of DHJSD in alleviating OA was explored by gene silencing technology combined with a series of functional experiments in primary rat chondrocytes. Next, 25 wistar rats were used to validate the results obtained in vitro. The PTEN, Akt, mTOR, MMP13, Zn, collagen II, autophagy and apoptosis were determined. ResultsDHJSD reduced the phosphorylation of Akt and mTOR and the expression of zinc, MMP13, Bax and Bcl2. DHJSD increased the level of autophagy and the expression of autophagy proteins LC3 and Beclin1. After silencing PTEN gene, the phosphorylation levels of Akt and mTOR and the effects of Bax, Bcl2, LC3 and Beclin1 were weakened by DHJSD. DHJSD increased the formation of autophagosomes in chondrocytes. Histopathological staining revealed that DHJSD had a protective effect on cartilage. ConclusionDHJSD inhibits Akt/mTOR signaling pathway by targeting PTEN to promote autophagy in chondrocytes, which may be closely to repress the formation of MMP-13 by regulating the level of zinc in chondrocytes.

pharmacology and toxicology↗

bioRxiv2023

Herpes zoster mRNA vaccine induces superior vaccine immunity over licensed vaccine in mice and rhesus macaques

Herpes zoster remains an important global health issue and mainly occurs in aged and immunocompromised individuals with an early exposure history to Varicella Zoster Virus (VZV). Although the licensed vaccine Shingrix has a remarkably high efficacy, undesired reactogenicity and increasing global demand causing vaccine shortage urged the development of improved or novel VZV vaccines. In this study, we developed a novel VZV mRNA vaccine candidate (named as ZOSAL) containing sequence-optimized mRNAs encoding full-length glycoprotein E encapsulated in an ionizable lipid nanoparticle. In mice and rhesus macaques, ZOSAL demonstrated superior immunogenicity and safety in multiple aspects over Shingrix, especially in the induction of strong T cell immunity. Transcriptomic analysis revealed that both ZOSAL and Shingrix could robustly activate innate immune compartments, especially Type-I IFN signaling and antigen processing/presentation. Multivariate correlation analysis further identified several early factors of innate compartments that can predict the magnitude of T cell responses, which further increased our understanding of the mode of action of two different VZV vaccine modalities. Collectively, our data demonstrated the superiority of VZV mRNA vaccine over licensed subunit vaccine. The mRNA platform therefore holds prospects for further investigations in next-generation VZV vaccine development.

immunology↗

bioRxiv2023

Interferon response and epigenetic modulation by SMARCA4 mutations drive ovarian tumor immunogenicity

Cell-intrinsic mechanisms of immunogenicity in ovarian cancer (OC) are not well understood. The presence of damaging mutations in the SWI/SNF chromatin remodeling complex, such as the SMARCA4 (BRG1) catalytic subunit, has been associated with improved response to ICB, however the mechanism by which this occurs is unclear. The aim of this current study was to examine the alterations in tumor cell-intrinsic and extrinsic immune signaling caused by SMARCA4 loss. Using OC models with loss-of-function mutations in SMARCA4, we found that SMARCA4 loss resulted in increased cancer cell-intrinsic immunogenicity, characterized by upregulation of long-terminal RNA repeats such as endogenous retroviruses, increased expression of interferon-stimulated genes, and upregulation of antigen presentation machinery. Notably, this response was dependent on IRF3 signaling, but was independent of the type I interferon receptor. Mice inoculated with cancer cells bearing SMARCA4 loss demonstrated increased activation of cytotoxic T cells and NK cells in the tumor microenvironment as well as increased infiltration with activated dendritic cells. These results were recapitulated when animals bearing SMARCA4-proficient tumors were treated with a BRG1 inhibitor, suggesting that modulation of chromatin remodeling through targeting SMARCA4 may serve as a strategy to reverse immune evasion in OC.

cancer biology↗

bioRxiv2023

NaV1.6 inhibition drives the efficacy of voltage-gated sodium channel inhibitors to prevent electrically induced seizures in both wild type and Scn8aN1768D/+ gain-of-function mice

Inhibitors of voltage-gated sodium channels (NaVs) are important anti-epileptic drugs, but the contribution of specific channel isoforms is unknown since available inhibitors are nonselective. We created a series of compounds with diverse selectivity profiles enabling block of NaV1.6 alone or together with NaV1.2. Mice with a heterozygous gain-of-function mutation (N1768D/+) in Scn8a (encoding NaV1.6) responded with a tonic-clonic seizure to a mild 6 Hz stimulus that was innocuous to wild-type mice. Pharmacologic inhibition of NaV1.6 in Scn8aN1768D/+ mice prevented seizures. Inhibitors were also effective in a direct current maximal electroshock seizure assay in wild-type mice. NaV1.6 inhibition correlated with efficacy in both models, even without inhibition of other CNS NaV isoforms. Our data suggest NaV1.6 inhibition is a driver of efficacy for NaV inhibitor anti-seizure medicines. Selective NaV1.6 inhibitors may provide targeted therapies for human Scn8a developmental and epileptic encephalopathies and better tolerated treatments for idiopathic epilepsies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/551823v2_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@39c09borg.highwire.dtl.DTLVardef@19413b8org.highwire.dtl.DTLVardef@9aa226org.highwire.dtl.DTLVardef@b9207_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗