Comparison of the Impacts of Different Middle Ear Mucosal Conditions on Type I Tympanoplasty Outcomes.

BACKGROUND: This study aimed to explore the impacts of different middle-ear mucosal conditions on the outcomes of type I tympanoplasty. METHODS: A retrospective analysis of 164 patients with chronic otitis media was carried out. The patients were divided into 4 groups according to their mucosal condition. Preoperative hearing levels and air-bone gap (ABG) before and after surgery were compared via the Kruskal‒Wallis H test. The chi-squared test and Fisher's exact test were used to assess the postoperative complications and impact factors of functional success. RESULTS: Preoperatively, neither the air conduction nor bone conduction values differed significantly among groups with different mucosal conditions. All of the ABG closed dramatically after type I tympanoplasty (P < .05) regardless of the mucosal conditions. The functional success rates were lower when the intratympanic mucosa was moderately or severely edematous compared with mildly edematous or normal (P < .05). The disease course, perforation site, and perforation size, as well as the status of the opposite ear, were not related to the auditory functional outcome. The differences in postoperative reotorrhea and reperforation among the 4 groups were not statistically significant. CONCLUSION: Preoperative hearing levels were not affected by middle-ear mucosal conditions. The functional success rate was influenced by mucosal conditions, but hearing levels were significantly enhanced after surgical intervention regardless of the mucosal status. Postoperative complications were not related to the mucosal conditions. Thus, type I tympanoplasty is adoptable for mucosal abnormalities when pharmacotherapy cannot result in a healthy tympanum.

Identification of chrysanthemum variety via hyperspectral imaging and wavelength selection based on multitask particle swarm optimization.

Chrysanthemum, a widely favored flower tea, contains numerous phytochemicals for health benefits. Due to the different geographical origins and processing technics, its variety has a direct influence on the phytochemical content and pharmacological effect. Accordingly, an accurate identification for chrysanthemum varieties is significant for quality detection and market supervision. In this study, the hyperspectral imaging (HSI) combined with chemometrics methods was exploited to identify the chrysanthemum varieties. First, to alleviate the problem of easily trapping into local optimum in traditional spectral variable selection methods, the multi-tasking particle swarm optimization (MTPSO) was developed to select the key wavelengths by dividing hundreds of variables into low-dimensional subtasks. Second, to enrich the feature information, the spatial texture and color features contained in hyperspectral images were extracted and applied to chrysanthemum identification for the first time. Finally, an ensemble learning model, extreme gradient boosting (XGBoost), was constructed to conduct the chrysanthemum variety classification due to its strong generalization ability. Experimental results showed that the proposed MTPSO achieved the identification accuracy of 96.89%, and increased by 1.11-5.91% than classical spectral feature selection methods. Furthermore, after the involvement of spatial image information, the classification accuracy using spatial-spectral features was improved further, and reached 98.39%. Overall, this study highlights that the feature fusion of key wavelengths and spatial information is more effective for chrysanthemum variety identification, and can also provide technical reference for other HSI-related applications.

Displacement of occluder after left atrial appendage closure: A case report.

Key Clinical Message: Atrial fibrillation is closely associated with thrombotic events. In non-valvular atrial fibrillation, 90% of thrombi are formed by the left atrial appendage. Left atrial appendage occlusion (LAAC) can effectively prevent the detachment of left atrial appendage thrombus during atrial fibrillation, thereby reducing the risk of long-term disability or death caused by thromboembolic events. However, the identification and management of complications in LAAC are also very important. Abstract: The efficacy and safety of left atrial appendage occlusion (LAAC) in preventing non-valvular atrial fibrillation stroke have been confirmed by multiple randomized controlled and registered studies, and have been recommended by several guidelines for stroke prevention in patients with atrial fibrillation at high-risk of stroke. We reported an 80-year-old male patient with persistent atrial fibrillation. The patient underwent left atrial appendage closure surgery due to high risk of embolism and bleeding. On the second day after surgery, echocardiography showed displacement of the left atrial appendage occluder. Immediately perform removal of left atrial appendage occlude and left atrial appendage occlusion on the same day, and the patient was discharged on the fifth day after surgery without any special circumstances. This case demonstrates the feasibility and important clinical significance of using interventional surgery to remove the left atrial appendage occluder after displacement in clinical practice.

Aplp1 interacts with Lag3 to facilitate transmission of pathologic α-synuclein.

Pathologic α-synuclein (α-syn) spreads from cell-to-cell, in part, through binding to the lymphocyte-activation gene 3 (Lag3). Here we report that amyloid ß precursor-like protein 1 (Aplp1) interacts with Lag3 that facilitates the binding, internalization, transmission, and toxicity of pathologic α-syn. Deletion of both Aplp1 and Lag3 eliminates the loss of dopaminergic neurons and the accompanying behavioral deficits induced by α-syn preformed fibrils (PFF). Anti-Lag3 prevents the internalization of α-syn PFF by disrupting the interaction of Aplp1 and Lag3, and blocks the neurodegeneration induced by α-syn PFF in vivo. The identification of Aplp1 and the interplay with Lag3 for α-syn PFF induced pathology deepens our insight about molecular mechanisms of cell-to-cell transmission of pathologic α-syn and provides additional targets for therapeutic strategies aimed at preventing neurodegeneration in Parkinson's disease and related α-synucleinopathies.

Lymphocyte-Activation Gene 3 Facilitates Pathological Tau Neuron-to-Neuron Transmission.

The spread of prion-like protein aggregates is a common driver of pathogenesis in various neurodegenerative diseases, including Alzheimer's disease (AD) and related Tauopathies. Tau pathologies exhibit a clear progressive spreading pattern that correlates with disease severity. Clinical observation combined with complementary experimental studies has shown that Tau preformed fibrils (PFF) are prion-like seeds that propagate pathology by entering cells and templating misfolding and aggregation of endogenous Tau. While several cell surface receptors of Tau are known, they are not specific to the fibrillar form of Tau. Moreover, the underlying cellular mechanisms of Tau PFF spreading remain poorly understood. Here, it is shown that the lymphocyte-activation gene 3 (Lag3) is a cell surface receptor that binds to PFF but not the monomer of Tau. Deletion of Lag3 or inhibition of Lag3 in primary cortical neurons significantly reduces the internalization of Tau PFF and subsequent Tau propagation and neuron-to-neuron transmission. Propagation of Tau pathology and behavioral deficits induced by injection of Tau PFF in the hippocampus and overlying cortex are attenuated in mice lacking Lag3 selectively in neurons. These results identify neuronal Lag3 as a receptor of pathologic Tau in the brain，and for AD and related Tauopathies, a therapeutic target.

Integrated multi-omics analyses identify anti-viral host factors and pathways controlling SARS-CoV-2 infection.

Host anti-viral factors are essential for controlling SARS-CoV-2 infection but remain largely unknown due to the biases of previous large-scale studies toward pro-viral host factors. To fill in this knowledge gap, we perform a genome-wide CRISPR dropout screen and integrate analyses of the multi-omics data of the CRISPR screen, genome-wide association studies, single-cell RNA-Seq, and host-virus proteins or protein/RNA interactome. This study uncovers many host factors that are currently underappreciated, including the components of V-ATPases, ESCRT, and N-glycosylation pathways that modulate viral entry and/or replication. The cohesin complex is also identified as an anti-viral pathway, suggesting an important role of three-dimensional chromatin organization in mediating host-viral interaction. Furthermore, we discover another anti-viral regulator KLF5, a transcriptional factor involved in sphingolipid metabolism, which is up-regulated, and harbors genetic variations linked to COVID-19 patients with severe symptoms. Anti-viral effects of three identified candidates (DAZAP2/VTA1/KLF5) are confirmed individually. Molecular characterization of DAZAP2/VTA1/KLF5-knockout cells highlights the involvement of genes related to the coagulation system in determining the severity of COVID-19. Together, our results provide further resources for understanding the host anti-viral network during SARS-CoV-2 infection and may help develop new countermeasure strategies.

Generation and characterization of a humanized ACE2 mouse model to study long-term impacts of SARS-CoV-2 infection.

Although the COVID-19 pandemic has officially ended, the persistent challenge of long-COVID or post-acute COVID sequelae (PASC) continues to impact societies globally, highlighting the urgent need for ongoing research into its mechanisms and therapeutic approaches. Our team has recently developed a novel humanized ACE2 mouse model (hACE2ki) designed explicitly for long-COVID/PASC research. This model exhibits human ACE2 expression in tissue and cell-specific patterns akin to mouse Ace2. When we exposed young adult hACE2ki mice (6 weeks old) to various SARS-CoV-2 lineages, including WA, Delta, and Omicron, at a dose of 5 × 105 PFU/mouse via nasal instillation, the mice demonstrated distinctive phenotypes characterized by differences in viral load in the lung, trachea, and nasal turbinate, weight loss, and changes in pro-inflammatory cytokines and immune cell profiles in bronchoalveolar lavage fluid. Notably, no mortality was observed in this age group. Further, to assess the model's relevance for long-COVID studies, we investigated tau protein pathologies, which are linked to Alzheimer's disease, in the brains of these mice post SARS-CoV-2 infection. Our findings revealed the accumulation and longitudinal propagation of tau, confirming the potential of our hACE2ki mouse model for preclinical studies of long-COVID.

Extracellular Vesicles: The Invisible Heroes and Villains of COVID-19 Central Neuropathology.

Acknowledging the neurological symptoms of COVID-19 and the long-lasting neurological damage even after the epidemic ends are common, necessitating ongoing vigilance. Initial investigations suggest that extracellular vesicles (EVs), which assist in the evasion of the host's immune response and achieve immune evasion in SARS-CoV-2 systemic spreading, contribute to the virus's attack on the central nervous system (CNS). The pro-inflammatory, pro-coagulant, and immunomodulatory properties of EVs contents may directly drive neuroinflammation and cerebral thrombosis in COVID-19. Additionally, EVs have attracted attention as potential candidates for targeted therapy in COVID-19 due to their innate homing properties, low immunogenicity, and ability to cross the blood-brain barrier (BBB) freely. Mesenchymal stromal/stem cell (MSCs) secreted EVs are widely applied and evaluated in patients with COVID-19 for their therapeutic effect, considering the limited antiviral treatment. This review summarizes the involvement of EVs in COVID-19 neuropathology as carriers of SARS-CoV-2 or other pathogenic contents, as predictors of COVID-19 neuropathology by transporting brain-derived substances, and as therapeutic agents by delivering biotherapeutic substances or drugs. Understanding the diverse roles of EVs in the neuropathological aspects of COVID-19 provides a comprehensive framework for developing, treating, and preventing central neuropathology and the severe consequences associated with the disease.

Interspecies chimerism with human embryonic stem cells generates functional human dopamine neurons at low efficiency.

Interspecies chimeras offer great potential for regenerative medicine and the creation of human disease models. Whether human pluripotent stem cell-derived neurons in an interspecies chimera can differentiate into functional neurons and integrate into host neural circuity is not known. Here, we show, using Engrailed 1 (En1) as a development niche, that human naive-like embryonic stem cells (ESCs) can incorporate into embryonic and adult mouse brains. Human-derived neurons including tyrosine hydroxylase (TH)+ neurons integrate into the mouse brain at low efficiency. These TH+ neurons have electrophysiologic properties consistent with their human origin. In addition, these human-derived neurons in the mouse brain accumulate pathologic phosphorylated α-synuclein in response to α-synuclein preformed fibrils. Optimization of human/mouse chimeras could be used to study human neuronal differentiation and human brain disorders.

Cell Therapy for Parkinson's Disease.

Parkinson's Disease (PD) is a neurodegenerative disease characterized by the progressive loss of dopaminergic neurons of the substantia nigra pars compacta with a reduction in dopamine concentration in the striatum. It is a substantial loss of dopaminergic neurons that is responsible for the classic triad of PD symptoms, i.e., resting tremor, muscular rigidity, and bradykinesia. Several current therapies for PD may only offer symptomatic relief and do not address the underlying neurodegeneration of PD. The recent developments in cellular reprogramming have enabled the development of previously unachievable cell therapies and patient-specific modeling of PD through Induced Pluripotent Stem Cells (iPSCs). iPSCs possess the inherent capacity for pluripotency, allowing for their directed differentiation into diverse cell lineages, such as dopaminergic neurons, thus offering a promising avenue for addressing the issue of neurodegeneration within the context of PD. This narrative review provides a comprehensive overview of the effects of dopamine on PD patients, illustrates the versatility of iPSCs and their regenerative abilities, and examines the benefits of using iPSC treatment for PD as opposed to current therapeutic measures. In means of providing a treatment approach that reinforces the long-term survival of the transplanted neurons, the review covers three supplementary avenues to reinforce the potential of iPSCs.

Vanadium Carbide Nanosheets with Broad-Spectrum Antioxidant Activity for Pulmonary Fibrosis Therapy.

Idiopathic pulmonary fibrosis is a chronic and highly lethal lung disease that largely results from oxidative stress; however, effective antioxidant therapy by targeting oxidative stress pathogenesis is still lacking. The big challenge is to develop an ideal antioxidant material with superior antifibrotic effects. Herein, we report that V4C3 nanosheets (NSs) can serve as a potential antioxidant for treatment of pulmonary fibrosis by scavenging reactive oxygen and nitrogen species. Interestingly, subtle autoxidation can adjust the valence composition of V4C3 NSs and significantly improve their antioxidant behavior. Valence engineering triggers multiple antioxidant mechanisms including electron transfer, H atom transfer, and enzyme-like catalysis, thus endowing V4C3 NSs with broad-spectrum, high-efficiency, and persistent antioxidant capacity. Benefiting from antioxidant properties and good biocompatibility, V4C3 NSs can significantly prevent myofibroblast proliferation and extracellular matrix abnormality, thus alleviating the progression of bleomycin-induced pulmonary fibrosis in vivo by scavenging ROS, anti-inflammation, and rebuilding antioxidant defenses. This study not only provides an important strategy for designing excellent antioxidant nanomaterials, but also proposes a proof-of-concept demonstration for the treatment of pulmonary fibrosis and other oxidative stress-related diseases.

The Identification of Fritillaria Species Using Hyperspectral Imaging with Enhanced One-Dimensional Convolutional Neural Networks via Attention Mechanism.

Combining deep learning and hyperspectral imaging (HSI) has proven to be an effective approach in the quality control of medicinal and edible plants. Nonetheless, hyperspectral data contains redundant information and highly correlated characteristic bands, which can adversely impact sample identification. To address this issue, we proposed an enhanced one-dimensional convolutional neural network (1DCNN) with an attention mechanism. Given an intermediate feature map, two attention modules are constructed along two separate dimensions, channel and spectral, and then combined to enhance relevant features and to suppress irrelevant ones. Validated by Fritillaria datasets, the results demonstrate that an attention-enhanced 1DCNN model outperforms several machine learning algorithms and shows consistent improvements over a vanilla 1DCNN. Notably under VNIR and SWIR lenses, the model obtained 98.97% and 99.35% for binary classification between Fritillariae Cirrhosae Bulbus (FCB) and other non-FCB species, respectively. Additionally, it still achieved an extraordinary accuracy of 97.64% and 98.39% for eight-category classification among Fritillaria species. This study demonstrated the application of HSI with artificial intelligence can serve as a reliable, efficient, and non-destructive quality control method for authenticating Fritillaria species. Moreover, our findings also illustrated the great potential of the attention mechanism in enhancing the performance of the vanilla 1DCNN method, providing reference for other HSI-related quality controls of plants with medicinal and edible uses.

Non-destructive prediction of isoflavone and starch by hyperspectral imaging and deep learning in Puerariae Thomsonii Radix.

Accurate assessment of isoflavone and starch content in Puerariae Thomsonii Radix (PTR) is crucial for ensuring its quality. However, conventional measurement methods often suffer from time-consuming and labor-intensive procedures. In this study, we propose an innovative and efficient approach that harnesses hyperspectral imaging (HSI) technology and deep learning (DL) to predict the content of isoflavones (puerarin, puerarin apioside, daidzin, daidzein) and starch in PTR. Specifically, we develop a one-dimensional convolutional neural network (1DCNN) model and compare its predictive performance with traditional methods, including partial least squares regression (PLSR), support vector regression (SVR), and CatBoost. To optimize the prediction process, we employ various spectral preprocessing techniques and wavelength selection algorithms. Experimental results unequivocally demonstrate the superior performance of the DL model, achieving exceptional performance with mean coefficient of determination (R2) values surpassing 0.9 for all components. This research underscores the potential of integrating HSI technology with DL methods, thereby establishing the feasibility of HSI as an efficient and non-destructive tool for predicting the content of isoflavones and starch in PTR. Moreover, this methodology holds great promise for enhancing efficiency in quality control within the food industry.

PARIS undergoes liquid-liquid phase separation and poly(ADP-ribose)-mediated solidification.

ZNF746 was identified as parkin-interacting substrate (PARIS). Investigating its pathophysiological properties, we find that PARIS undergoes liquid-liquid phase separation (LLPS) and amorphous solid formation. The N-terminal low complexity domain 1 (LCD1) of PARIS is required for LLPS, whereas the C-terminal prion-like domain (PrLD) drives the transition from liquid to solid phase. In addition, we observe that poly(ADP-ribose) (PAR) strongly binds to the C-terminus of PARIS near the PrLD, accelerating its LLPS and solidification. N-Methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced PAR formation leads to PARIS oligomerization in human iPSC-derived dopaminergic neurons that is prevented by the PARP inhibitor, ABT-888. Furthermore, SDS-resistant PARIS species are observed in the substantia nigra (SN) of aged mice overexpressing wild-type PARIS, but not with a PAR binding-deficient PARIS mutant. PARIS solidification is also found in the SN of mice injected with preformed fibrils of α-synuclein (α-syn PFF) and adult mice with a conditional knockout (KO) of parkin, but not if α-syn PFF is injected into mice deficient for PARP1. Herein, we demonstrate that PARIS undergoes LLPS and PAR-mediated solidification in models of Parkinson's disease.

Identification of Turtle-Shell Growth Year Using Hyperspectral Imaging Combined with an Enhanced Spatial-Spectral Attention 3DCNN and a Transformer.

Turtle shell (Chinemys reecesii) is a prized traditional Chinese dietary therapy, and the growth year of turtle shell has a significant impact on its quality attributes. In this study, a hyperspectral imaging (HSI) technique combined with a proposed deep learning (DL) network algorithm was investigated for the objective determination of the growth year of turtle shells. The acquisition of hyperspectral images was carried out in the near-infrared range (948.72-2512.97 nm) from samples spanning five different growth years. To fully exploit the spatial and spectral information while reducing redundancy in hyperspectral data simultaneously, three modules were developed. First, the spectral-spatial attention (SSA) module was developed to better protect the spectral correlation among spectral bands and capture fine-grained spatial information of hyperspectral images. Second, the 3D convolutional neural network (CNN), more suitable for the extracted 3D feature map, was employed to facilitate the joint spatial-spectral feature representation. Thirdly, to overcome the constraints of convolution kernels as well as better capture long-range correlation between spectral bands, the transformer encoder (TE) module was further designed. These modules were harmoniously orchestrated, driven by the need to effectively leverage both spatial and spectral information within hyperspectral data. They collectively enhance the model's capacity to extract joint spatial and spectral features to discern growth years accurately. Experimental studies demonstrated that the proposed model (named SSA-3DTE) achieved superior classification accuracy, with 98.94% on average for five-category classification, outperforming traditional machine learning methods using only spectral information and representative deep learning methods. Also, ablation experiments confirmed the effectiveness of each module to improve performance. The encouraging results of this study revealed the potentiality of HSI combined with the DL algorithm as an efficient and non-destructive method for the quality control of turtle shells.

Extracellular RNAs-TLR3 signaling contributes to cognitive impairment after chronic neuropathic pain in mice.

Chronic pain is often associated with cognitive decline, which could influence the quality of the patient's life. Recent studies have suggested that Toll-like receptor 3 (TLR3) is crucial for memory and learning. Nonetheless, the contribution of TLR3 to the pathogenesis of cognitive decline after chronic pain remains unclear. The level of TLR3 in hippocampal neurons increased in the chronic constriction injury (CCI) group than in the sham group in this study. Importantly, compared to the wild-type (WT) mice, TLR3 knockout (KO) mice and TLR3-specific neuronal knockdown mice both displayed improved cognitive function, reduced levels of inflammatory cytokines and neuronal apoptosis and attenuated injury to hippocampal neuroplasticity. Notably, extracellular RNAs (exRNAs), specifically double-stranded RNAs (dsRNAs), were increased in the sciatic nerve, serum, and hippocampus after CCI. The co-localization of dsRNA with TLR3 was also increased in hippocampal neurons. And the administration of poly (I:C), a dsRNA analog, elevated the levels of dsRNAs and TLR3 in the hippocampus, exacerbating hippocampus-dependent memory. In additon, the dsRNA/TLR3 inhibitor improved cognitive function after CCI. Together, our findings suggested that exRNAs, particularly dsRNAs, that were present in the condition of chronic neuropathic pain, activated TLR3, initiated downstream inflammatory and apoptotic signaling, caused damage to synaptic plasticity, and contributed to the etiology of cognitive impairment after chronic neuropathic pain.

Pathological Tau transmission initiated by binding lymphocyte-activation gene 3.

The spread of prion-like protein aggregates is believed to be a common driver of pathogenesis in many neurodegenerative diseases. Accumulated tangles of filamentous Tau protein are considered pathogenic lesions of Alzheimer's disease (AD) and related Tauopathies, including progressive supranuclear palsy, and corticobasal degeneration. Tau pathologies in these illnesses exhibits a clear progressive and hierarchical spreading pattern that correlates with disease severity1,2. Clinical observation combined with complementary experimental studies3,4 have shown that Tau preformed fibrils (PFF) are prion-like seeds that propagate pathology by entering cells and templating misfolding and aggregation of endogenous Tau. While several receptors of Tau are known, they are not specific to the fibrillar form of Tau. Moreover, the underlying cellular mechanisms of Tau PFF spreading remains poorly understood. Here, we show that the lymphocyte-activation gene 3 (Lag3) is a cell surface receptor that binds to PFF, but not monomer, of Tau. Deletion of Lag3 or inhibition of Lag3 in primary cortical neurons significantly reduces the internalization of Tau PFF and subsequent Tau propagation and neuron-to-neuron transmission. Propagation of Tau pathology and behavioral deficits induced by injection of Tau PFF in the hippocampus and overlying cortex are attenuated in mice lacking Lag3 selectively in neurons. Our results identify neuronal Lag3 as a receptor of pathologic Tau in the brain, and for AD and related Tauopathies a therapeutic target.

Cartilage transposition and anchoring: A surgical technique for the reconstruction of congenital tragal malformation in children.

BACKGROUND: Because of the various types and complexity of congenital tragal malformation, tragal reconstruction is one of the most challenging objects in otoplasty. This study aimed to introduce a surgical technique of cartilage transposition and anchoring that was used to construct a cartilage framework for natural tragus reconstruction. METHODS: A retrospective study was performed for 49 patients who underwent cartilage transposition and anchoring from January 2020 to August 2022. Gender, age, malformation, complication, operation record, preoperative and postoperative photograph, score of esthetic outcomes (4 = excellent, 3 = good, 2 = fair, 1 = poor), and Vancouver Scar Assessment score were reviewed. RESULTS: Twenty-six boys and 23 girls with an average age of 35.79 ± 32.97 months underwent revision. The follow-up time was 13.87 ± 6.57 months. No complications were noted. The average score of esthetic outcomes and the Vancouver Scar Assessment score were 3.94 and 0.08 in the postoperative period, respectively. The overall effect was satisfactory. CONCLUSIONS: Postoperative results showed that cartilage transposition and anchoring were effective techniques for the reconstruction of congenital tragal malformation. The use of cartilage and fascia tissue around the tragus to fill up the depression and reconstruct the tragus were the emphases. The remolded tragus showed less scars and had the similar appearance like the natural tragus of the patient.

ROS-mediated SRMS activation confers platinum resistance in ovarian cancer.

Ovarian cancer is the leading cause of death among gynecological malignancies. Checkpoint blockade immunotherapy has so far only shown modest efficacy in ovarian cancer and platinum-based chemotherapy remains the front-line treatment. Development of platinum resistance is one of the most important factors contributing to ovarian cancer recurrence and mortality. Through kinome-wide synthetic lethal RNAi screening combined with unbiased datamining of cell line platinum response in CCLE and GDSC databases, here we report that Src-Related Kinase Lacking C-Terminal Regulatory Tyrosine And N-Terminal Myristylation Sites (SRMS), a non-receptor tyrosine kinase, is a novel negative regulator of MKK4-JNK signaling under platinum treatment and plays an important role in dictating platinum efficacy in ovarian cancer. Suppressing SRMS specifically sensitizes p53-deficient ovarian cancer cells to platinum in vitro and in vivo. Mechanistically, SRMS serves as a "sensor" for platinum-induced ROS. Platinum treatment-induced ROS activates SRMS, which inhibits MKK4 kinase activity by directly phosphorylating MKK4 at Y269 and Y307, and consequently attenuates MKK4-JNK activation. Suppressing SRMS leads to enhanced MKK4-JNK-mediated apoptosis by inhibiting MCL1 transcription, thereby boosting platinum efficacy. Importantly, through a "drug repurposing" strategy, we uncovered that PLX4720, a small molecular selective inhibitor of B-RafV600E, is a novel SRMS inhibitor that can potently boost platinum efficacy in ovarian cancer in vitro and in vivo. Therefore, targeting SRMS with PLX4720 holds the promise to improve the efficacy of platinum-based chemotherapy and overcome chemoresistance in ovarian cancer.