Outcome and predictive factors for perforation in orthodontic rubber band-assisted endoscopic submucosal dissection of fibrotic colorectal lesions.

Endoscopic submucosal dissection (ESD) of fibrotic colorectal lesions is difficult and has a high complication rate. There are only a few reports on the utility of orthodontic rubber band (ORB) traction in reducing the difficulty of this procedure. This study aimed to investigate the risk factors for perforation when applying ORB traction during ESD of fibrotic colorectal lesions. We continuously collected the clinical data of 119 patients with fibrotic colorectal lesions who underwent ESD with ORB and clip traction between January 2019 and January 2024. Possible risk factors for perforation were analyzed. The median ORB-ESD operative time was 40 (IQR 28-62) min, and the en bloc and R0 resection rates were 94.1% and 84.0%, respectively. Perforation occurred in 16 of 119 patients (13.4%). The lesion size, lesion at the right half of the colon or across an intestinal plica, the degree of fibrosis, operation time, and the surgeon's experience were associated with perforation during ORB-ESD (P < 0.05). Multivariate logistic regression analysis showed that lesions in the right colon (OR 9.027; 95% CI 1.807-45.098; P = 0.007) and those across an intestinal plica (OR 7.771; 95% CI 1.298-46.536; P = 0.025) were independent risk factors for perforation during ORB-ESD. ORB-ESD is an effective and feasible approach to treat fibrotic colorectal lesions. Adequate preoperative evaluation is required for lesions in the right colon and across intestinal plicas to mitigate the risk of perforation.

Spatiotemporal change characteristics of NDVI and response to climate factors in the Jixi Wetland, Eastern China.

Exploring the spatiotemporal variation characteristics of vegetation in the confluent area of water systems in western Jinan and its response mechanism to climatic factors is of great significance for the scientific evaluation of the benefits of the water system connectivity project and eco-environmental protection and can provide a reference for ecotourism development in the Jixi wetland park. Based on the Landsat series of images and meteorological data, this study used ENVI to interpret the normalized difference vegetation index (NDVI) of the confluent area from 2010 to 2021, and the spatiotemporal change characteristics and trends of NDVI were quantitatively analyzed. The response of the growing-season NDVI (GSN) to climate factors and its time-lag effect were explored. The results showed that the overall change in the interannual NDVI in the confluent area from 2010 to 2021 was stable. The GSN in the confluent area was significantly positively correlated with precipitation, average temperature, and relative humidity in 37.64%, 25.52%, and 20.87% of the area respectively, and significantly negatively correlated with sunshine hours in 15.32% of the area. There was a time-lag effect on the response of the GSN to climate factors; the response to precipitation and sunshine hours lagged by 1 month, and the response to average temperature and relative humidity was longer.

Hexadecapole Deformation of

The hexadecapole deformation (ß_{4}) of the ^{238}U nucleus has not been determined because its effect is overwhelmed by those from the nucleus' large quadrupole deformation (ß_{2}) in nuclear electric transition measurements. In this Letter, we identify the nonlinear response of the hexadecapole anisotropy to ellipticity in relativistic U+U collisions that is solely sensitive to ß_{4} and insensitive to ß_{2}. We demonstrate this by state-of-the-art hydrodynamic calculations and discuss the prospects of discovering the ß_{4} of ^{238}U in heavy-ion data at the Relativistic Heavy Ion Collider.

Hierarchical pore structure with a confined resonant mode for improving the solar energy utilizing efficiency of ultra-thin perovskite solar cells.

The perovskite solar cell (PSC) has the benefits of flexibility, inexpensiveness, and high efficiency, and has important prospective applications. However, serious optical losing and low solar energy-utilizing efficiency remain a challenge for the ultra-thin PSCs because of the interface reflection of traditional planar structure. In this study, a hierarchical pore structure with a confined resonant mode is introduced and optimized by electromagnetic theory to improve the solar energy absorbing and utilizing efficiency of ultra-thin PSCs. The large pores in the top layer that support a whispering gallery mode can focus and guide the incident light into the solar cell. The small pores in the bottom layer enable backward scattering of the unabsorbed light and can improve the effective absorption of active layer. The finite-difference time-domain method is employed to optimize the geometric parameters of hierarchical pore structure to improve the light absorption of PSCs. The proposed resonant hierarchical pore structure can greatly improve sunlight absorption of ultra-thin PSCs, and the effective light absorption and photocurrent of PSCs with a hierarchical pore structure is 20.7% higher than that of PSCs with traditional planar structure. This work can offer a beneficial guideline for improving solar energy utilizing efficiency of various thin-film solar cells.

Characterizing the impact of reservoir storage and discharge on nitrogen dynamics in an upstream wetland using a δ15N and δ18O dual-isotope approach.

The identification of nitrate sources in reservoir water is important for watershed-scale surface pollution management. Significant fluctuations in river water levels arising from reservoir storage and discharge influence nitrate sources and transport processes. The Sanmenxia Reservoir, in the middle reaches of the Yellow River in China, undergoes significant water level changes (290-316 m), altering the composition of the nitrogen sources. This study employed a δ15N and δ18O dual-isotope method and MixSIAR modeling to quantify the contributions of nitrate sources. This reveals the impact of reservoir water impoundment and discharge on nitrogen dynamics in the upstream region of the wetland and the model sensitivity for each nitrate source. The results showed that the average concentrations of nitrate­nitrogen (NO- 3-N) were elevated during the impoundment period compared to the discharge period. Nitrogen sources exhibited varying proportions in surface water, groundwater, and soil water during both the impoundment and discharge periods. The predominant sources include manure and sewage (MS), with a maximum proportion of 57.4 % in surface water. Soil nitrogen (SN) accounted for 25.8 % of groundwater nitrogen and 32.1 % of soil water nitrogen during the impoundment period, whereas, during the discharge period, soil nitrogen made up 41.4 % of surface water nitrogen, manure and sewage contributed 44.8 % of groundwater nitrogen, and manure and sewage dominated with 56.7 % of soil water nitrogen. Sensitivity analysis of the MixSIAR model revealed that the isotopic composition of the manure and sewage primary source most significantly influenced the apportionment results of the riverine nitrate source. Reservoir discharge facilitates the dissimilatory nitrate reduction to ammonium (DNRA). The migration of NO- 3 from surface water to soil water and groundwater occurred from the impoundment period to the discharge period.

Dietary Supplementation with Bupleuri Radix Reduces Oxidative Stress Occurring during Growth by Regulating Rumen Microbes and Metabolites.

Oxidative stress (OS) in ruminants is closely associated with disease; thus, improving antioxidant capacity is an important strategy for maintaining host health. Bupleuri Radix (BR) could significantly improve host health and stress levels. However, the clear antioxidant mechanism of the function of BR remains unknown. In the current study, LC-MS metabolomics combined with 16S rRNA gene sequencing was employed to explore the effects of BR on rumen microbiota and metabolites in Shanbei Fine-Wool Sheep (SFWS), and Spearman correlation analyses of rumen microbiota, metabolites, and OS were performed to investigate the mechanism of antioxidant function of BR. Our results indicated that as SFWS grows, levels of OS and antioxidant capacity increase dramatically, but providing BR to SFWS enhances antioxidant capacity while decreasing OS. Rumen microbiota and OS are strongly correlated, with total antioxidant capacity (T-AOC) showing a significant negative correlation with Succiniclasticum and a positive correlation with Ruminococcus. Importantly, the Chao1 index was significantly negatively correlated with malondialdehyde (MDA) and positively correlated with superoxide dismutase (SOD) and T-AOC. Two biomarkers connected to the antioxidant effects of BR, 5,6-DHET and LPA (a-25:0/0:0), were screened according to the results of metabolomics and Spearman analysis of rumen contents, and a significant relationship between the concentration of rumen metabolites and OS was found. Five metabolic pathways, including glycerolipid, glutathione, nucleotide, D-amino acid, and inositol phosphate metabolism, may have a role in OS. The integrated results indicate that rumen microbiota and metabolites are strongly related to OS and that BR is responsible for reducing OS and improving antioxidant capacity in post-weaned SFWS. These findings provide new strategies to reduce OS occurring during SFWS growth.

A radiomics strategy based on CT intra-tumoral and peritumoral regions for preoperative prediction of neoadjuvant chemoradiotherapy for esophageal cancer.

OBJECTIVE: Develop a method for selecting esophageal cancer patients achieving pathological complete response with pre-neoadjuvant therapy chest-enhanced CT scans. METHODS: Two hundred and one patients from center 1 were enrolled, split into training and testing sets (7:3 ratio), with an external validation set of 30 patients from center 2. Radiomics features from intra-tumoral and peritumoral images were extracted and dimensionally reduced using Student's t-test and least absolute shrinkage and selection operator. Four machine learning classifiers were employed to build models, with the best-performing models selected based on accuracy and stability. ROC curves were utilized to determine the top prediction model, and its generalizability was evaluated on the external validation set. RESULTS: Among 16 models, the integrated-XGBoost and integrated-random forest models performed the best, with average ROC AUCs of 0.906 and 0.918, respectively, and RSDs of 6.26 and 6.89 in the training set. In the testing set, AUCs were 0.845 and 0.871, showing no significant difference in ROC curves. External validation set AUCs for integrated-XGBoost and integrated-random forest models were 0.650 and 0.749. CONCLUSION: Incorporating peritumoral radiomics features into the analysis enhances predictive performance for esophageal cancer patients undergoing neoadjuvant chemoradiotherapy, paving the way for improved treatment outcomes.

Malignant cell receptor-ligand subtypes guide the prediction of prognosis and personalized immunotherapy of liver cancer.

OBJECTIVE: Liver cancer is a prevalent disease with a dismal prognosis. The aim of the research is to identify subgroups based on malignant cell receptor ligand gene from single-cell RNA, which might lead to customized immunotherapy for patients with liver cancer. METHODS: Based on scRNA-seq data, we identified the receptor-ligand genes associated with prognosis and classify patients into molecular subtypes by univariate Cox regression and consensus clustering. LASSO regression was performed to construct a prognostic model, which was validated in TCGA and ICGC datasets. Immune infiltration and prediction of immunotherapy response were analyzed using ssGSEA, ESTIMATE, TIDE, and TRS score calculation. Finally, qPCR and Western blot validation of key genes and protein levels in cell lines. RESULTS: A risk model using 16-gene expression levels predicted liver cancer patients' prognosis. The RiskScore associated significantly with tumor clinical characteristics and immunity, integrated with clinicopathological features for survival prediction. Differential expression of SRXN1 was verified in hepatocellular carcinoma and normal liver cells. CONCLUSION: Our study utilizes single-cell analysis to investigate the communication between malignant cells and other cell types, identifying molecular subtypes based on malignant cell receptor ligand genes, offering new insights for the development of personalized immunotherapy and prognostic prediction models.

Incidence of second malignancies in patients with thymic carcinoma and thymic neuroendocrine tumor.

OBJECTIVES: Thymic carcinoma and thymic neuroendocrine tumor (NET) are rare and are more likely to develop second malignancies. The purpose of this study was to explore the incidence and lifetime risk of second malignancies in thymic carcinoma and thymic NET. METHODS: The standardized incidence ratio (SIR) and the age-adjusted cancer incidence of the thymic carcinoma and thymic NET patients with second malignancies were retrospectively calculated by using the Surveillance, Epidemiology, and End Results (SEER) database. Prognosis results were also determined by Kaplan-Meier analysis and Cox regression. RESULTS: 1130 patients with thymic carcinoma (73 patients had second malignancies) and 263 patients with thymic NET (19 patients had second malignancies) from 2000 to 2018 are included. Patients with thymic carcinoma (SIR: 1.36, 95% CI 1.08-1.69) and with thymic NET (SIR: 1.73, 95% CI 1.13-2.54) demonstrate an increased overall risk of developing second malignancies in various organ systems. The age-adjusted cancer incidence of second malignancies in patients with thymic carcinoma is 3058.48 per 100,000 persons (4178.46 per 100,000 persons in patients with thymic NET). Age at diagnosis is a significant risk factor for the development of second malignancies. CONCLUSION: The incidence of second malignancies in patients with thymic carcinoma and thymic NET is significantly higher than the patients in the normal population. The occurrence of second malignancies is not related to the use of different treatments. It is important to extend the follow-up period and add other screening methods.

Diagnosis of Esophageal Squamous Cell Carcinoma by High-Performance Serum Metabolic Fingerprints: A Retrospective Study.

Esophageal squamous cell carcinoma (ESCC) is a highly prevalent and aggressive malignancy, and timely diagnosis of ESCC contributes to an increased cancer survival rate. However, current detection methods for ESCC mainly rely on endoscopic examination, limited by a relatively low participation rate. Herein, ferric-particle-enhanced laser desorption/ionization mass spectrometry (FPELDI MS) is utilized to record the serum metabolic fingerprints (SMFs) from a retrospective cohort (523 non-ESCC participants and 462 ESCC patients) to build diagnostic models toward ESCC. The PFELDI MS achieved high speed (≈30 s per sample), desirable reproducibility (coefficients of variation < 15%), and high throughput (985 samples with ≈124 200 data points for each spectrum). Desirable diagnostic performance with area-under-the-curves (AUCs) of 0.925-0.966 is obtained through machine learning of SMFs. Further, a metabolic biomarker panel is constructed, exhibiting superior diagnostic sensitivity (72.2-79.4%, p < 0.05) as compared with clinical protein biomarker tests (4.3-22.9%). Notably, the biomarker panel afforded an AUC of 0.844 (95% confidence interval [CI]: 0.806-0.880) toward early ESCC diagnosis. This work highlighted the potential of metabolic analysis for accurate screening and early detection of ESCC and offered insights into the metabolic characterization of diseases including but not limited to ESCC.

PTEN-mediated FOXO signaling affects autophagy, migration and invasion of rheumatoid arthritis fibroblast-like synoviocytes.

Rheumatoid arthritis (RA) is a chronic, progressive, systemic autoimmune disease. Among them, abnormal proliferation, migration and vascularization of fibroblast-like synoviocytes (FLS) are the main pathological basis of persistent synovitis and bone destruction in RA. In the current study, we attempted to find effective molecular mechanisms for the treatment of RA by investigating RA-FLS. Firstly, the study was conducted to identify the potential target gene PTEN and its related signaling pathway through bioinformatics analysis. Subsequently, the target gene PTEN overexpression was regulated by cell transfection. The expression of FOXO signaling factors and autophagy-related proteins were detected by western blotting assay. Cell proliferation was measured by CCK-8 and EdU assays. Inflammation level was detected by ELISA. Cell migration and invasion were detected using wound healing assay and transwell chamber assay, respectively. Cell apoptosis was detected using flow cytometry. The results showed that overexpression of PTEN activated FOXO1 signaling in RA-FLS, and regulated autophagy, proliferation, invasion, migration, and the levels of pro-inflammatory factors in the disease. In conclusion, PTEN might provide an effective therapeutic strategy for rheumatoid arthritis by mediating the FOXO1 signaling pathway.

Heat shock protein HSPA13 promotes hepatocellular carcinoma progression by stabilizing TANK.

HSPA13, an important member of the heat shock protein family, plays an essential role in the oncogenesis of many organs, but the mechanism and function in hepatocellular carcinoma (HCC) is still unclear. In the present study, we found that HSPA13 was highly expressed in HCC and predicted poor clinical prognosis. Upregulation of HSPA13 was significantly associated with vascular invasion in HCC patients. Functionally, knockdown experiments demonstrated that HSPA13 promoted HCC proliferation, migration, and invasion. Mechanistic investigation showed that HSPA13 could interact with TANK to inhibit its ubiquitination and degradation. In addition, the expression of HSPA13 and TANK were positively correlated in HCC tissues. To conclude, the present study uncovers the oncogenic function of HSPA13 in the progression of HCC by regulating the stability of TANK. These findings suggest that HSPA13 and TANK may serve as promising targets for the diagnosis and treatment of HCC.

Unexpected fibrous mediastinitis in a patient with myasthenia gravis - a case report.

BACKGROUND: Fibrous mediastinitis (FM) is a rare mediastinal lesion characterized by proliferation of fibrous tissue within the mediastinum. Previous reports have shown that this lesion can be caused by histoplasmosis and tuberculosis. In extremely rare cases, FM can also be caused by autoimmune diseases such as antineutrophil cytoplasmic antibody-associated vasculitis and large-vessel arteritis. CASE PRESENTATION: In our case, we report unexpected fibrous mediastinitis found after robotic thymectomy in a patient with myasthenia gravis (MG). The preoperative imaging indicated no obvious lesion in the mediastinum and the patient denied histories of both histoplasmosis and tuberculosis. After the operation, both proliferation of fibrous tissue and ectopic germinal centres (GCs) could be found in the thymus. CONCLUSION: This rare case might enrich our knowledge of the relationship between FM and autoimmune diseases.

The predictive value of a computed tomography-based radiomics model for the surgical separability of thymic epithelial tumors from the superior vena cava and the left innominate vein.

Background: The aim of this study was to develop a radiomics machine learning model based on computed tomography (CT) that can predict whether thymic epithelial tumors (TETs) can be separated from veins during surgery and to compare the accuracy of the radiomics model to that of radiologists. Methods: Patients who underwent thymectomy at our hospital from 2009 to 2017 were included in the screening process. After the selection of patients according to the inclusion and exclusion criteria, the cohort was randomly divided into training and testing groups, and CT images of these patients were collected. Subsequently, two-dimensional (2D) and three-dimensional (3D) regions of interest were labelled using ITK-SNAP 3.8.0 software, and Radiomics features were extracted using Python software (Python Software Foundation) and selected through the least absolute shrinkage and selection operator (LASSO) regression model. To construct the classifier, a support vector machine (SVM) was employed, and a nomogram was created using logistic regression to predict vascular inseparable TETs based on the radiomics score (radscore) and image features. To assess the accuracy of these models, area under receiver operating characteristic (ROC) curves of these models were calculated, and differences among the models were identified using the Delong test. Results: In this retrospective study, 204 patients with TETs were included, among whom 21 were diagnosed with surgical vascularly inseparable TETs. The area under ROC curve (AUC) of the 2D model, 3D model, 2D + 3D model, and radiologist diagnoses were 0.94, 0.92, 0.95, and 0.87 in the training cohort and 0.95, 0.92, 0.98, and 0.78 in testing cohort, respectively. The Delong test revealed a significant improvement in the performance of the radiomics models compared to radiologists' diagnoses. The logistic regression selected 3 image features, namely maximum diameter of the tumor, degree of abutment of vessel circumference >50%, and absence of the mediastinal fat layer or space between the tumor and surrounding structures. These features, along with the radscore, were included to develop a nomogram. The AUCs of this nomogram were 0.99 in both the training set and testing set, and the Delong test did not find a significant difference between ROC plots of the nomogram and radiomics models. Conclusions: The proposed radiomics model could accurately predict surgical vascularly inseparable TETs preoperatively and was shown to have a higher predictive value than the radiologists.

"Warm in Winter and Cool in Summer": Scalable Biochameleon Inspired Temperature-Adaptive Coating with Easy Preparation and Construction.

The highly reflective solar radiation of passive daytime radiative cooling (PDRC) increases heating energy consumption in the cold winter. Inspired by the temperature-adaptive skin color of chameleon, we efficiently combine temperature-adaptive solar absorption and PDRC technology to achieve "warm in winter and cool in summer". The temperature-adaptive radiative cooling coating (TARCC) with color variability is designed and fabricated, achieving 41% visible light regulation capability. Comprehensive seasonal outdoor tests confirm the reliability of the TARCC: in summer, the TARCC exhibits high solar reflectance (∼93%) and atmospheric transmission window emittance (∼94%), resulting in a 6.5 K subambient temperature. In the winter, the TARCC's dark color strongly absorbs solar radiation, resulting in a 4.3 K temperature rise. Compared with PDRC coatings, the TARCC can save up to 20% of annual energy in midlatitude regions and increase suitable human hours by 55%. With its low cost, easy preparation, and simple construction, the TARCC shows promise for achieving sustainable and comfortable indoor environments.

CCDC176 stabilizes microtubule doublets 1 and 9 to ensure proper sperm movement.

The molecular mechanism underlying asymmetric axonemal complexes in sperm flagella is still largely unknown. Here, we showed that the knockout of the coiled-coil domain-containing 176 (CCDC176) in mice led to male infertility due to decreased sperm motility. Ccdc176 knockout specifically destabilized microtubule doublets (MTDs) 1 and 9 during sperm maturation in the corpus epididymis. Single-sperm immunofluorescence showed that most CCDC176 was distributed along the axoneme, and further super-resolution imaging revealed that CCDC176 is asymmetrically localized in the sperm axoneme. CCDC176 could cooperate with microtubule and radial spoke proteins to stabilize MTDs 1 and 9, and its knockout results in the destabilization of some proteins in sperm flagella. Furthermore, as predicted by the sperm multibody dynamics (MBD) model, we found that MTDs 1 and 9 jutted out from the sperm flagellum annulus region in Ccdc176-/- spermatozoa, and these flagellar defects alter sperm flagellar beat patterns and swimming paths, potentially owing to the reduction and disequilibration of bending torque on the central pair. These results demonstrate that CCDC176 specifically stabilizes MTDs 1 and 9 in the sperm flagellum to ensure proper sperm movement for fertilization.

Monolithic MXene Aerogels Encapsulated Phase Change Composites with Superior Photothermal Conversion and Storage Capability.

The inherently intermittent feature of solar energy requires reliable energy conversion and storage systems for utilizing the most abundant solar energy. Phase change materials are potential solutions to store a large amount of heat produced by solar light. However, few of the phase change materials have the ability to efficiently convert solar energy into heat; additionally, phase change materials need to be encapsulated in porous substrates for enhancing their leaking resistance and photo-to-thermal performance. In this work, monolithic MXene aerogels, fabricated by Al3+ cross-linking and freeze-drying, were used as the encapsulation and photothermal materials. The composites phase change materials of MXene/polyethylene glycol can be made with a large polyethylene glycol loading above 90 wt% with the maximum of 97 wt%, owing to the large porosity of MXene aerogels. The low content of MXene has a limited impact on the phase transition temperature and enthalpy of polyethylene glycol, with an enthalpy retention rate ranging from 89.2 to 96.5% for 90-97 wt% polyethylene glycol loadings. MXene aerogels greatly improve the leaking resistance of polyethylene glycol above its melting point of 60 °C, even at 100 °C. The composites phase change materials also show outstanding cycling stability for 500 cycles of heat storage and release, retaining 97.7% of the heat storage capability. The optimized composite phase change material has a solar energy utilization of 93.5%, being superior to most of the reported results. Our strategy produces promising composite phase change materials for solar energy utilization using the MXene aerogels as the encapsulation and photothermal materials.

Gallbladder cancer: current and future treatment options.

Surgery remains the preferred treatment option for early-stage gallbladder cancer (GBC). According to the anatomical position of the primary tumor, accurate preoperative stage and strict control of surgical indications, appropriate surgical strategies are selected to achieve the optimal surgical effect. However, most patients have already been at the locally advanced stage or the tumor has metastasized at the initial diagnosis. The postoperative recurrence rate and 5-year survival rate remain unsatisfactory even after radical resection for gallbladder cancer. Hence, there is an urgent need for more treatment options, such as neoadjuvant therapy, postoperative adjuvant therapy and first-line and second-line treatments of local progression and metastasis, in the whole-course treatment management of gallbladder cancer patients. In recent years, the application of molecular targeted drugs and immunotherapy has brought greater hope and broader prospects for the treatment of gallbladder cancer, but their effects in improving the prognosis of patients still lack sufficient evidence-based medicine evidence, so many problems should be addressed by further research. Based on the latest progress in gallbladder cancer research, this review systematically analyzes the treatment trends of gallbladder cancer.

BRSK2 in pancreatic ß cells promotes hyperinsulinemia-coupled insulin resistance and its genetic variants are associated with human type 2 diabetes.

Brain-specific serine/threonine-protein kinase 2 (BRSK2) plays critical roles in insulin secretion and ß-cell biology. However, whether BRSK2 is associated with human type 2 diabetes mellitus (T2DM) has not been determined. Here, we report that BRSK2 genetic variants are closely related to worsening glucose metabolism due to hyperinsulinemia and insulin resistance in the Chinese population. BRSK2 protein levels are significantly elevated in ß cells from T2DM patients and high-fat diet (HFD)-fed mice due to enhanced protein stability. Mice with inducible ß-cell-specific Brsk2 knockout (ßKO) exhibit normal metabolism with a high potential for insulin secretion under chow-diet conditions. Moreover, ßKO mice are protected from HFD-induced hyperinsulinemia, obesity, insulin resistance, and glucose intolerance. Conversely, gain-of-function BRSK2 in mature ß cells reversibly triggers hyperglycemia due to ß-cell hypersecretion-coupled insulin resistance. Mechanistically, BRSK2 senses lipid signals and induces basal insulin secretion in a kinase-dependent manner. The enhanced basal insulin secretion drives insulin resistance and ß-cell exhaustion and thus the onset of T2DM in mice fed an HFD or with gain-of-function BRSK2 in ß cells. These findings reveal that BRSK2 links hyperinsulinemia to systematic insulin resistance via interplay between ß cells and insulin-sensitive tissues in the populations carrying human genetic variants or under nutrient-overload conditions.