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RIPK1/RIPK3-MLKL signaling molecules are fundamental in initiating necroptotic cell death, but their roles in the development of colon cancer are unclear. This study reports that RIPK3 interacted with SPOP, a component of the E3 ligase within the Cul3 complex. This interaction leads to K48-linked ubiquitination and subsequent proteasomal degradation of RIPK3. Two distinct degron motifs, PETST and SPTST, were identified within the linker domain of RIPK3 for SPOP. RIPK3 phosphorylations at Thr403 by PIM2 and at Thr412/Ser413 by ERK2 are essential to facilitate its interaction with SPOP. Computational docking studies and immunoprecipitation analyses showed that these PIM2 and ERK2 phosphorylations bolster the stability of the RIPK3-SPOP interaction. In particular, mutations of RIPK3 at the degron motifs extended the half-life of RIPK3 by preventing its phosphorylation and subsequent ubiquitination. The deletion of SPOP, which led to increased stability of the RIPK3 protein, intensified LPS/sMAC/zVAD-induced necroptotic cell death in colon cancer cells. These findings underscore the critical role of the SPOP-mediated RIPK3 stability regulation pathway in controlling necroptotic cell death.

Cyclic guanosine-adenosine monophosphate synthase (cGAS) is a key cytosolic DNA sensor that plays a pivotal role in the innate immune response. Although a decade of research on the cGAS has advanced our understanding of inflammasome formation, cytokine production, and signaling pathways, the role of cGAS in the nucleus remains unclear. In this study, we found that the nuclear localization of endogenous and stably expressed cGAS differed from transiently expressed cGAS, which mainly localized in the cytosol. In the nucleus, cGAS is tightly bound to chromatin DNA. The chromatin DNA binding of cGAS was dependent on RSK2. Our molecular mechanism study indicated that the N-lobe of RSK2 harboring 1-323 interacted with the NTase domain of cGAS harboring residues 213-330. This interaction increased RSK2-induced cGAS phosphorylation at Ser120 and Thr130, resulting in the tightly binding of cGAS to chromatin. Importantly, epidermal growth factor (EGF)-induced cell transformation and anchorage-independent colony growth showed an increase in growth factors, such as EGF or bFGF, in cGAS stable expression compared to mock expression. Notably, the cGAS-S120A/T130A mutant abolished the increasing effect of cell transformation of JB6 Cl41 cells and colony growth of SK-MEL-2 malignant melanoma cells. The results suggested that cGASs chromatin DNA binding, which is indispensable to RSK2-dependent phosphorylation of cGAS at Ser120/Thr130, provides the first clue to how cGAS may participate in chromatin remodeling in the nucleus.

PURPOSE: Vaccination with dendritic cell (DC)/multiple myeloma (MM) fusions has been shown to induce the expansion of circulating multiple myeloma-reactive lymphocytes and consolidation of clinical response following autologous hematopoietic cell transplant (auto-HCT). PATIENTS AND METHODS: In this randomized phase II trial (NCT02728102), we assessed the effect of DC/MM fusion vaccination, GM-CSF, and lenalidomide maintenance as compared with control arms of GM-CSF and lenalidomide or lenalidomide maintenance alone on clinical response rates and induction of multiple myeloma-specific immunity at 1-year posttransplant. RESULTS: The study enrolled 203 patients, with 140 randomized posttransplantation. Vaccine production was successful in 63 of 68 patients. At 1 year, rates of CR were 52.9% (vaccine) and 50% (control; P = 0.37, 80% CI 44.5%, 61.3%, and 41.6%, 58.4%, respectively), and rates of VGPR or better were 85.3% (vaccine) and 77.8% (control; P = 0.2). Conversion to CR at 1 year was 34.8% (vaccine) and 27.3% (control; P = 0.4). Vaccination induced a statistically significant expansion of multiple myeloma-reactive T cells at 1 year compared with before vaccination (P = 0.024) and in contrast to the nonvaccine arm (P = 0.026). Single-cell transcriptomics revealed clonotypic expansion of activated CD8 cells and shared dominant clonotypes between patients at 1-year posttransplant. CONCLUSIONS: DC/MM fusion vaccination with lenalidomide did not result in a statistically significant increase in CR rates at 1 year posttransplant but was associated with a significant increase in circulating multiple myeloma-reactive lymphocytes indicative of tumor-specific immunity. Site-specific production of a personalized cell therapy with centralized product characterization was effectively accomplished in the context of a multicenter cooperative group study. See related commentary by Qazilbash and Kwak, p. 4703.

Objective To explore the relationship between screen-based sedentary time and dyslipidemia among college students, and to provide a basis for the prevention and control of dyslipidemia in adolescents.Methods Newly enrolled college students from a university in Hubei province in September 2021 were selected for the study, and a questionnaire survey and physical examination were conducted from September to October of the same year. The average daily screen sitting time of the respondents in the past year was collected through questionnaires. The height, weight, blood pressure and other indexes were obtained through physical examination, and the biochemical indexes of blood lipids (triglyceride, total cholesterol, low-density lipoprotein, high-density lipoprotein) and blood glucose were detected. Binary Logistic regression, restricted cubic spline and subgroup analysis were used to analyze the association between sedentary time and dyslipidemia.Results A total of 3,383 college students were included, with an average screen-based sedentary time of (4.44±2.29) h/d. There were 598 cases of dyslipidemia among college students, and the overall prevalence of dyslipidemia was 17.68%. The prevalence of elevated cholesterol, elevated triglycerides, elevated low-density lipoprotein, and decreased high-density lipoprotein were 4.76%, 3.72%, 4.29%, and 7.06%, respectively. The mean screen-based sedentary time in the dyslipidemia population was (4.60±2.21) h/d, which was longer than the mean screen-based sedentary time in the normolipidemic population (4.41±2.30) h/d, but the difference was not statistically significant (P=0.062). Binary Logistic regression analysis showed that dyslipidemia in college students was positively correlated with screen-based sedentary time after correcting for relevant factors such as gender, age, BMI, and history of hypertension, with screen-based sedentary time

BackgroundDue to the prominent particularity of medical work， nurses are prone to developing depression， which not only poses a considerable threat to the physical and mental health of nurses， but also affects the quality of nursing to some extent. Occupational stress is a known contributor to depression in nurses， whereas relatively little research has been done to investigate the underlying mediation path.ObjectiveTo explore the mediation effect of perceived organizational support and psychological capital on the relationship between occupational stress and depression among nurses， and to provide theoretical references for the prevention and treatment of occupational stress-induced depression in nurses.MethodsFrom March to August 2019， a stratified random sampling method was utilized to select a sample size of 720 nurses in each department of a grade A tertiary hospital in Shandong Province. All subjects were assessed using Effort-Reward Imbalance Questionnaire （ERI）， Perceived Organization Support Questionnaire （POS）， Psychological Capital Questionnaire （PCQ） and Center for Epidemiologic Studies Depression Scale （CES-D）. Pearson correlation was adopted to examine the correlation among above scales， and multilevel mediation analyses were conducted with model 6 in Process macro （version 3.3） for SPSS 26.0 using Bootstrap re-sampling method.ResultsA total of 658 nurses （91.39%） completed the effective questionnaire survey. ERI score was positively correlated with CES-D score （r=0.499， P

Currently, most of the monitoring research on the head sheave of mine hoists focuses on monitoring the vibration, temperature, and deflection of the head sheave, while there is relatively little research on monitoring the structural performance of the head sheave. In order to solve the above problems, a structural performance monitoring method of mine hoist head sheave based on digital twins is proposed. Based on the actual conditions during the operation of the mine hoist head sheave, a digital twin monitoring system for the mine hoist head sheave is designed. The system consists of an object entity layer, a twin model layer, a twin data layer, an application layer, and connections between each layer. The predicted data in the twin data layer is the real-time head sheave structural performance data predicted by the head sheave structural performance prediction model during the operation of the mine hoist head sheave, including stress and strain data. The structural performance prediction model of the mine hoist head sheave is constructed using a combined surrogate model. A single surrogate model of radial basis function (RBF) is trained using processed finite element data. The weight of the single surrogate model in the combined surrogate model is obtained based on generalized mean square error, thus obtaining the head sheave structural performance prediction model. Taking the five rope friction lifting system of the vertical shaft as the experimental object, based on the Unity3D platform, a digital twin monitoring system for the mine hoist head sheave is established through the construction of virtual space, data transmission, and application modules. The experimental results show that during the operation of the head sheave, the average determination coefficient of the measured strain and predicted strain at the four test points is 0.973 98, indicating a high correlation between the predicted strain and the measured strain. This verifies that the designed prediction model can meet the needs of monitoring the structural performance of the head sheave.