Pyruvate kinase M2 sustains cardiac mitochondrial quality surveillance in septic cardiomyopathy by regulating prohibitin 2 abundance via S91 phosphorylation.

The endogenous mitochondrial quality control (MQC) system serves to protect mitochondria against cellular stressors. Although mitochondrial dysfunction contributes to cardiac damage during many pathological conditions, the regulatory signals influencing MQC disruption during septic cardiomyopathy (SC) remain unclear. This study aimed to investigate the involvement of pyruvate kinase M2 (PKM2) and prohibitin 2 (PHB2) interaction followed by MQC impairment in the pathogenesis of SC. We utilized LPS-induced SC models in PKM2 transgenic (PKM2TG) mice, PHB2S91D-knockin mice, and PKM2-overexpressing HL-1 cardiomyocytes. After LPS-induced SC, cardiac PKM2 expression was significantly downregulated in wild-type mice, whereas PKM2 overexpression in vivo sustained heart function, suppressed myocardial inflammation, and attenuated cardiomyocyte death. PKM2 overexpression relieved sepsis-related mitochondrial damage via MQC normalization, evidenced by balanced mitochondrial fission/fusion, activated mitophagy, restored mitochondrial biogenesis, and inhibited mitochondrial unfolded protein response. Docking simulations, co-IP, and domain deletion mutant protein transfection experiments showed that PKM2 phosphorylates PHB2 at Ser91, preventing LPS-mediated PHB2 degradation. Additionally, the A domain of PKM2 and the PHB domain of PHB2 are required for PKM2-PHB2 binding and PHB2 phosphorylation. After LPS exposure, expression of a phosphorylation-defective PHB2S91A mutant negated the protective effects of PKM2 overexpression. Moreover, knockin mice expressing a phosphorylation-mimetic PHB2S91D mutant showed improved heart function, reduced inflammation, and preserved mitochondrial function following sepsis induction. Abundant PKM2 expression is a prerequisite to sustain PKM2-PHB2 interaction which is a key element for preservation of PHB2 phosphorylation and MQC, presenting novel interventive targets for the treatment of septic cardiomyopathy.

Unveiling the immunogenomic landscape of cholangiocarcinoma: Identifying new prognostic markers and therapeutic targets based on CCL5 expression.

BACKGROUND: Cholangiocarcinoma (CCA) stands as an aggressive malignancy of the biliary tract. The interplay between the tumor and immune system plays a pivotal role in disease progression and treatment outcomes. Hence, the present study aimed to extensively explore the immunogenomic landscape of CCA, with the objective of unveiling unique molecular and immunological signatures that could guide personalized therapeutic approaches. METHODS: The study collected data from The Cancer Genome Atlas databases, performed gene set variation analysis for the chemokine ligand 5 (CCL5) high/low expression group, conducted principal component analysis, gene set enrichment analysis enrichment and mutation pattern analysis, generated a heatmap, and performed cox regression analysis. RESULTS: The two discrete subpopulations were found to exhibit contrasting mutational and immunogenomic characteristics, emphasizing the heterogeneity of CCA. These subsets also showed pronounced discrepancies in the infiltration of immune cells, indicating diverse interactions with the tumor immune microenvironment. Furthermore, the dissimilarities in mutational patterns were observed within the two CCA subgroups, with PBRM1 and BAP1 emerging as the most frequently mutated genes. In addition, a prognostic framework was formulated and validated utilizing the expression profiles of COX16 and RSAD2 genes, effectively segregating patients into high-risk and low-risk cohorts. Furthermore, the connections between immune-related parameters and these risk groups were identified, underscoring the potential significance of the immune microenvironment in patient prognosis. In vitro experiments have shown that COX16 promotes the proliferation and metastasis of CCA cells, whereas RSAD2 inhibits it. CONCLUSIONS: The present study provides an intricate depiction of the immunogenomic landscape of CCA based on CCL5 expression, thereby paving the way for novel immunotherapy strategies and prognostic assessment.

Upregulated TGF-ß1 contributes to hyperglycaemia in type 2 diabetes by potentiating glucagon signalling.

AIMS/HYPOTHESIS: Glucagon-stimulated hepatic gluconeogenesis contributes to endogenous glucose production during fasting. Recent studies suggest that TGF-ß is able to promote hepatic gluconeogenesis in mice. However, the physiological relevance of serum TGF-ß levels to human glucose metabolism and the mechanism by which TGF-ß enhances gluconeogenesis remain largely unknown. As enhanced gluconeogenesis is a signature feature of type 2 diabetes, elucidating the molecular mechanisms underlying TGF-ß-promoted hepatic gluconeogenesis would allow us to better understand the process of normal glucose production and the pathophysiology of this process in type 2 diabetes. This study aimed to investigate the contribution of upregulated TGF-ß1 in human type 2 diabetes and the molecular mechanism underlying the action of TGF-ß1 in glucose metabolism. METHODS: Serum levels of TGF-ß1 were measured by ELISA in 74 control participants with normal glucose tolerance and 75 participants with type 2 diabetes. Human liver tissue was collected from participants without obesity and with or without type 2 diabetes for the measurement of TGF-ß1 and glucagon signalling. To investigate the role of Smad3, a key signalling molecule downstream of the TGF-ß1 receptor, in mediating the effect of TGF-ß1 on glucagon signalling, we generated Smad3 knockout mice. Glucose levels in Smad3 knockout mice were measured during prolonged fasting and a glucagon tolerance test. Mouse primary hepatocytes were isolated from Smad3 knockout and wild-type (WT) mice to investigate the underlying molecular mechanisms. Smad3 phosphorylation was detected by western blotting, levels of cAMP were detected by ELISA and levels of protein kinase A (PKA)/cAMP response element-binding protein (CREB) phosphorylation were detected by western blotting. The dissociation of PKA subunits was measured by immunoprecipitation. RESULTS: We observed higher levels of serum TGF-ß1 in participants without obesity and with type 2 diabetes than in healthy control participants, which was positively correlated with HbA1c and fasting blood glucose levels. In addition, hyperactivation of the CREB and Smad3 signalling pathways was observed in the liver of participants with type 2 diabetes. Treating WT mouse primary hepatocytes with TGF-ß1 greatly potentiated glucagon-stimulated PKA/CREB phosphorylation and hepatic gluconeogenesis. Mechanistically, TGF-ß1 treatment induced the binding of Smad3 to the regulatory subunit of PKA (PKA-R), which prevented the association of PKA-R with the catalytic subunit of PKA (PKA-C) and led to the potentiation of glucagon-stimulated PKA signalling and gluconeogenesis. CONCLUSIONS/INTERPRETATION: The hepatic TGF-ß1/Smad3 pathway sensitises the effect of glucagon/PKA signalling on gluconeogenesis and synergistically promotes hepatic glucose production. Reducing serum levels of TGF-ß1 and/or preventing hyperactivation of TGF-ß1 signalling could be a novel approach for alleviating hyperglycaemia in type 2 diabetes.

FUNDC1 modulates mitochondrial defects and pancreatic ß-cell dysfunction under lipotoxicity.

Insulin resistance and many metabolic disorders are causally linked to mitochondrial dysfunction or defective mitochondrial quality control. Mitophagy is a highly selective mechanism that recognizes and removes damaged mitochondria to maintain mitochondrial homeostasis. Here, we addressed the potential role of FUNDC1, a mediator of mitophagy, in pancreatic ß-cell dysfunction under lipotoxicity. In pancreatic MIN6 cells, FUNDC1 deficiency aggravated palmitate-induced mitochondrial dysfunction, which led to cell death and insulin insensitivity. Interestingly, FUNDC1 overexpression prevented these cellular harms brought on by palmitate. In mice models, pancreatic-specific FUNDC1 overexpression alleviated high-fat diet (HFD)-induced insulin resistance and obesity. Mechanistically, pancreatic-specific overexpression of FUNDC1 ameliorated mitochondrial defects and endoplasmic reticulum (ER) stress upon HFD. Our research indicates that FUNDC1 plays an essential role in apoptosis and dysfunction of pancreatic ß-cells via modulating lipotoxicity-induced mitochondrial defects.

The critical role of B4GALT4 in promoting microtubule spindle assembly in HCC through the regulation of PLK1 and RHAMM expression.

Beta 1,4-galactosyltransferase (B4GALT)-family glycosyltransferases are involved in multiple biological processes promoting cancer progression, regulating the dynamic network of cancer cell proliferation and apoptosis, and are associated with metastasis. However, their roles in the dysregulation of expressions and functions in hepatocellular carcinoma (HCC) remain unclear. Herein, bioinformatic approaches have been applied to investigate their expression profiles, and to obtain correlations between gene expressions and clinicopathological parameters as well as downstream target genes in HCC. Multiple databases were used to screen the expressions of B4GALT family members in tumor tissues, and to evaluate their prognostic value among HCC patients in different aspects. Results indicated an overall upregulation of B4GALTs' transcription levels in tumor tissues and a strong correlation with poor prognosis. Through Gene Ontology analysis, gene set enrichment analysis, and verification of single-cell RNA sequencing data, we established a connection between the B4GALT family and microtubule spindle assembly, which particularly highlighted the role of B4GALT4 in this phenomenon. B4GALT4 knockdown downregulated the production of lumican, and repressed the expressions of polo-like kinase 1 and RHAMM by regulating the transforming growth factor-beta pathway, thus suggesting that B4GALT4 is a critical promotor for HCC. We believe that these studies will provide valuable insight into the role of B4GALT family members in HCC and lead to the development of new strategies to improve the outcomes for patients with HCC.

Asymmetric dimethylarginine level as biomarkers of cardiovascular or all-cause mortality in patients with chronic kidney disease: a meta-analysis.

BACKGROUND: Studies have yielded conflicting findings on the association of asymmetric dimethylarginine (ADMA) level with cardiovascular or all-cause mortality in patients with chronic kidney disease (CKD). This meta-analysis sought to evaluate the association of blood ADMA level with cardiovascular or all-cause mortality in CKD patients. MATERIALS AND METHODS: PubMed and Embase databases were comprehensively searched until September 9, 2020 for studies investigating the association of ADMA level with cardiovascular or all-cause mortality in CKD patients. RESULTS: Data were collected from nine prospective studies involving 6553 patients. The pooled adjusted risk ratio (RR) of all-cause mortality was 2.06 (95% confidence interval [CI] 1.43-2.96) for the highest versus the lowest ADMA level. Each 0.20 µmol/L ADMA increase was associated with 21% (95% CI 1.09-1.35) higher risk of all-cause mortality but not cardiovascular mortality (RR 1.07; 95% CI 0. 99-1.16). Subgroup analysis showed that each 0.20 µmol/L ADMA increase was significantly associated with all-cause mortality in end-stage renal disease (ESRD) patients (RR 1.22; 95% CI 1.05-1.41) but not in patients with stage 3 to 4 CKD (RR 1.16; 95% CI 0.86-1.56). CONCLUSIONS: Elevated ADMA level is independently associated with higher risk of all-cause mortality in ESRD patients.

Sr2Pb(BeB5O10)(BO3): An Excellent Ultraviolet Nonlinear-Optical Beryllium Borate by the Pb-Modified Construction of a Conjugated System and Lone-Pair Effect.

The design of material by chemical and/or crystalline modification of a classic structure model benefits not only the optimized physical properties but also the controllability and efficiency. Herein, a new nonlinear-optical (NLO) beryllium borate crystal, Sr2Pb(BeB5O10)(BO3) (SPBBO), is successfully designed and synthesized by chemical and crystalline modification of the perovskite-like K3B6O10Cl NLO crystal. SPBBO displays a 3D BeB5O103- open-framework structure composed of interconnecting BeB5O13 groups with filled cationic Sr/Pb and anionic BO3 groups, which exhibits the striking enhancement of the second-harmonic-generation (SHG) response (8 × KDP) and birefringence (0.10) compared to the parent model. Replacement of K by Sr and Pb with a lone pair and replacement of Cl by conjugated BO3 result in the synergistic conjugation of Pb with host BeB5O103- and filled BO3 groups, contributing to the striking enhancement of the SHG and birefringence. Single-crystal measurements show that SPBBO has a short UV absorption edge of 280 nm with a wide energy band gap of 4.35 eV and an outstanding laser-induced resistant behavior with a remarkably high laser-induced damage threshold of 2100 MW cm-2. The excellent properties indicate that the SPBBO crystal is a very promising UV NLO functional material.

Alternative splicing variant of the scaffold protein APPL1 suppresses hepatic adiponectin signaling and function.

Adiponectin is an adipocyte-derived hormone with antidiabetic activities that include increasing the sensitivity of cells to insulin. Adaptor protein containing pleckstrin homology domain, phosphotyrosine-binding domain, and leucine zipper motif (APPL1) stimulates adiponectin signaling and promotes adiponectin's insulin-sensitizing effects by binding to two adiponectin receptors, AdipoR1 and AdipoR2, and the insulin receptor. In this study, we report an alternative splicing variant of APPL1 (APPL1sv) that is highly expressed in mouse liver, pancreas, and spleen tissues. The expression levels of APPL1sv in liver tissues were enhanced in a mouse model of obesity and diabetic dyslipidemia (i.e. db/db mice) and reduced in calorie-restricted mice compared with ad libitum-fed mice. APPL1sv overexpression or suppression inhibited or enhanced, respectively, adiponectin-stimulated phosphorylation of AMP protein kinase (AMPK) in mouse hepatocytes. We also found that APPL1sv binds to AdipoR1 and AdipoR2 under basal conditions and that adiponectin treatment reduces this binding. Overexpression of APPL1sv blocked adiponectin-induced interactions of APPL1 with the adiponectin receptors. Moreover, adenovirus-mediated and short hairpin RNA-based suppression of APPL1sv greatly reduced high fat diet-induced insulin resistance and hepatic glucose production in mice. Our study identifies a key suppressor of hepatic adiponectin signaling and insulin sensitivity, a finding that may shed light on identifying effective therapeutic targets for treating insulin resistance and type 2 diabetes.

Prognostic significance of C-reactive protein to albumin ratio in colorectal cancer patients: a meta-analysis.

PURPOSE: Inconsistent results on the prognostic significance of C-reactive protein to albumin ratio (CAR) in colorectal cancer patients have been reported. This meta-analysis sought to assess the prognostic value of pretreatment CAR for survival outcomes in colorectal cancer patients. METHODS: We conducted a systematic literature search of PubMed and Embase databases until February 16, 2019. Observational studies investigating the prognostic role of pretreatment CAR for survival outcome in patients with colorectal cancer were included. Outcome measures included overall survival (OS), disease-free survival (DFS), or progression-free survival (PFS). Pooled hazard ratio (HR) with 95% confidence interval (CI) was utilized to summarize the prognostic significance of CAR for patient survival. RESULTS: Nine retrospective studies involving 2492 colorectal cancer patients were identified. A fixed-effect model meta-analysis showed that high pretreatment CAR was an independent predictor of poor OS (HR 2.25; 95% CI 1.84-2.76) and DFS (HR 2.49; 95% CI 1.43-4.33). On the other hand, no significant association was observed between high CAR and PFS (HR 1.71; 95% CI 0.44-6.60). The predictive values of OS with high pretreatment CAR caused no significant changes in different sample sizes, countries, cut-off values of CAR, treatment methods, and study quality of subgroups. CONCLUSION: This meta-analysis suggests that CAR may be a powerful prognostic indicator for colorectal cancer prognosis. High pretreatment CAR is associated with poor OS and DFS in patients with colorectal cancer.

Sensing self-referenced fiber optic long-range surface plasmon resonance sensor based on electronic coupling between surface plasmon polaritons.

A type of hollow gold nanoparticle (HGNP)-modified fiber optic long-range surface plasmon resonance (LRSPR) sensor with sensing self-reference is proposed and demonstrated. HGNPs have a stronger plasmonic field compared to solid GNPs because of the coupling between the inner and outer walls of HGNPs. The intense near-field electronic coupling between long-range surface plasmon polaritons associated with the LRSPR gold layer and localized surface plasmon polaritons of HGNPs leads to localized electromagnetic-field enhancement and LRSPR response signal amplification. Therefore, the HGNP-modified LRSPR sensor possesses a more excellent sensing property compared with the unmodified LRSPR sensor. The long-range resonance dip in the transmission spectrum is shown to shift in response to ambient refractivity change, and the characteristic absorption peak is fixed, allowing to regard it as a reference to improve detection accuracy of the sensors. The mode-field distribution of the sensors is simulated by using the finite element method, and the simulation results show that the electric-field intensity on the HGNP surface is significantly enhanced compared with that of the gold layer surface of the unmodified LRSPR sensor. 1874.79 nm/RIU improvement in sensitivity, 1.42 times improvement in figure of merit (FOM), and approximately 50% reduction in limit of detection (LOD) are achieved for the refractivity measurement of a low-concentration biological solution with the employment of HGNPs in LRSPR sensing experiments. The HGNP-modified LRSPR sensor proposed in this paper has high detection accuracy and FOM and low LOD, and can realize remote real-time online monitoring. Therefore, it has important research value and broad application prospects in the field of biochemical detection.

Selection and Evaluation of Indexes Commonly Used to Determine Contamination with T-2 Toxin in Pacific White Shrimp Litopenaeus vannamei by the Grey Relational Method.

The objectives of the present study were to evaluate the effects of different concentrations of the mycotoxin T-2 toxin in feed on muscle performance in the Pacific white shrimp Litopenaeus vannamei, evaluate indexes of physiological variables that indicate T-2 toxin contamination in the shrimp using the grey relational method, and determine the dose-response relationships between T-2 toxin and the indexes. Of the 6 physical, 7 biochemical, and 17 nutritional indexes examined, the values of the grey relational coefficients were highest for the hepatopancreas: body weight ratio (HBR), alanine aminotransferase (ALT) activity, and serine (SER) content (0.83, 0.68, and 0.82, respectively). Therefore, the HBR, ALT activity, and SER content were selected as appropriate indexes for contamination of Pacific white shrimp muscle with T-2 toxin. Based on their dose-response relationship curves, mean effective doses of 1.45, 1.69, and 1.33 mg of T-2 toxin/kg of feed were obtained for the HBR, ALT activity, and SER content, respectively. These results offer technical reference points for the evaluation and control of T-2 toxin in shrimp feed. Received April 28, 2016; accepted April 9, 2017.

Nuclear orphan receptor TLX affects gene expression, proliferation and cell apoptosis in beta cells.

Nuclear orphan receptor TLX is an essential regulator of the growth of neural stem cells. However, its exact function in pancreatic islet cells is still unknown. In the present study, gene expression profiling analysis revealed that overexpression of TLX in beta cell line MIN6 causes suppression of 176 genes and upregulation of 49 genes, including a cadre of cell cycle, cell proliferation and cell death control genes, such as Btg2, Ddit3 and Gadd45a. We next examined the effects of TLX overexpression on proliferation, apoptosis and insulin secretion in MIN6 cells. Proliferation analysis using EdU assay showed that overexpression of TLX increased percentage of EdU-positive cells. Cell cycle and apoptosis analysis revealed that overexpression of TLX in MIN6 cells resulted in higher percentage of cells exiting G1 into S-phase, and a 58.8% decrease of cell apoptosis induced by 0.5 mM palmitate. Moreover, TLX overexpression did not cause impairment of insulin secretion. Together, we conclude that TLX is among factors capable of controlling beta cell proliferation and survival, which may serve as a target for the development of novel therapies for diabetes.

Selective depression mechanism of polyaspartic acid and calcium oxide on arsenopyrite after copper ions activation and its effect on flotation separation performance.

The arsenopyrite activated by copper ions have similar flotation properties to chalcopyrite. Polyaspartic acid (PASP) and calcium oxide (CaO) using as combination depressants for the selective separation of copper-activated arsenopyrite and chalcopyrite were carried out by micro-flotation experiments, contact angle measurements, surface adsorption capacity tests, zeta potential measurements, X-ray photoelectron spectroscopy (XPS) analyses, inductively coupled plasma-optical emission spectrometer (ICP-OES) tests and time-of-flight secondary ion mass spectrometry (ToF-SIMS) analyses, and its depression mechanism was investigated. The results of flotation experiments showed that the recovery of arsenopyrite after addition of the depressants reached only 7.80 %, while the recovery of chalcopyrite reached 94.02 %. The results of contact angles, adsorption capacity tests and zeta potential measurements showed that the PASP-CaO can selectively enhance the hydrophilicity of arsenopyrite surface, but has little effect on the chalcopyrite. XPS analyses and ICP-OES tests further verified that the depressants first eliminated the activation of copper ions and then selectively adsorbed on the surface of arsenopyrite. ToF-SIMS analyses showed that the PASP-CaO would achieve selective depression of arsenopyrite in the form of PASP, PASP-Ca complexes and Ca(OH)+, respectively. Finally, the mechanism diagram of PASP-CaO selectively depressing arsenopyrite was derived. These results will provide an excellent theoretical reference for the flotation separation of copper arsenic sulfide ore.

Predictive value of angiopoietin-like protein 8 in metabolic dysfunction-associated fatty liver disease and its progression: A case-control study.

BACKGROUND: The prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) is rapidly increasing, currently affecting approximately 25% of the global population. Liver fibrosis represents a crucial stage in the development of MAFLD, with advanced liver fibrosis elevating the risks of cirrhosis and hepatocellular carcinoma. Simple serum markers are less effective in diagnosing liver fibrosis compared to more complex markers. However, imaging techniques like transient elastography face limitations in clinical application due to equipment and technical constraints. Consequently, it is imperative to identify a straightforward yet effective method for assessing MAFLD-associated liver fibrosis. AIM: To investigate the predictive value of angiopoietin-like protein 8 (ANGPTL8) in MAFLD and its progression. METHODS: We analyzed 160 patients who underwent abdominal ultrasonography in the Endocrinology Department, Xiaogan Central Hospital affiliated to Wuhan University of Science and Technology, during September 2021-July 2022. Using abdominal ultrasonography and MAFLD diagnostic criteria, among the 160 patients, 80 patients (50%) were diagnosed with MAFLD. The MAFLD group was divided into the liver fibrosis group (n = 23) and non-liver fibrosis group (n = 57) by using a cut-off fibrosis-4 index ≥ 1.45. Logistical regression was used to analyze the risk of MAFLD and the risk factors for its progression. Receiver operating characteristic curves were used to evaluate the predictive value of serum ANGPTL8 in MAFLD and its progression. RESULTS: Compared with non-MAFLD patients, MAFLD patients had higher serum ANGPTL8 and triglyceride-glucose (TyG) index (both P < 0.05). Serum ANGPTL8 (r = 0.576, P < 0.001) and TyG index (r = 0.473, P < 0.001) were positively correlated with MAFLD. Serum ANGPTL8 was a risk factor for MAFLD [odds ratio (OR): 1.123, 95% confidence interval (CI): 1.066-1.184, P < 0.001). Serum ANGPTL8 and ANGPTL8 + TyG index predicted MAFLD [area under the curve (AUC): 0.832 and 0.886, respectively; both P < 0.05]. Compared with MAFLD patients without fibrosis, those with fibrosis had higher serum ANGPTL8 and TyG index (both P < 0.05), and both parameters were positively correlated with MAFLD-associated fibrosis. Elevated serum ANGPTL8 (OR: 1.093, 95%CI: 1.044-1.144, P < 0.001) and TyG index (OR: 2.383, 95%CI: 1.199-4.736, P < 0.013) were risk factors for MAFLD-associated fibrosis. Serum ANGPTL8 and ANGPTL8 + TyG index predicted MAFLD-associated fibrosis (AUC: 0.812 and 0.835, respectively; both P < 0.05). CONCLUSION: The serum levels of ANGPTL8 are elevated and positively correlated with MAFLD. They can serve as predictors for the risk of MAFLD and liver fibrosis, with the ANGPTL8 + TyG index potentially exhibiting even higher predictive value.

Survival analysis and prognostic model establishment of secondary osteosarcoma: a SEER-based study.

Background: Surgical excision is considered one of the most effective treatments for secondary osteosarcoma (SO). It remains unclear whether the survival of patients with secondary osteosarcoma (SO) could be associated with their surgical willingness. Materials and methods: The statistics of the patients diagnosed with SO between 1975 and 2008 were gathered from the surveillance epidemiology and end results (SEER) database. The patients were divided into three subgroups according to their surgical compliance. The authors used the multivariable Logistic regression analysis and cox regression method to reveal the influence of surgical compliance on prognosis and the risk factors of surgical compliance. Additionally, the authors formulated a nomogram model to predict the overall survival (OS) of patients. The concordance index (C-index) was used to evaluate the accuracy and practicability of the above prediction model. Results: Sixty-three (9.2%) of the 688 patients with SO who were recommended for surgical treatment refused to undergo surgery. Lower surgical compliance can be ascribed to an earlier time of diagnosis and refusal of chemotherapy. The lower overall survival (OS) {[hazard ratio (HR)] 1.733, [CI] 1.205-2.494, P value [P]=0.003} of not surgical compliant patients was verified by the multivariate cox regression method, compared with surgical compliant patients. In addition, the discernibility of the nomogram model was proven to be relatively high (C-index=0.748), by which we can calibrate 3-year- and 5-year OS prediction plots to obtain good concordance to the actual situation. Conclusions: Surgical compliance was proved to be an independent prognostic factor in the survival of patients with SO.

scRNA-seq of colorectal cancer shows regional immune atlas with the function of CD20+ B cells.

Colorectal cancer (CRC) from different regions exhibits different histological, genetic characteristics, and molecular subtypes, even in response to conventional chemotherapies and immunotherapies. To characterize the immune landscape in different regions of CRC and search for potential therapeutic targets, we analyzed 39,484 single-cell transcription data from 19 samples of CRC and paired normal tissues from four regions to identify the immune characteristics of CRC among anatomic locations, especially in B cells. We discovered that immune cell infiltration in tumors significantly varied among different regions of CRC. B cells from right- and left-sided CRC had different development trajectories, but both had extensive interactions with myeloid cells and T cells. Survival analysis suggested that CD20+ B cells correlated with good prognosis in CRC patients, especially on the right side. Furthermore, the depletion of CD20+ B cells demonstrated that anti-CD20 promoted tumor growth progression and reversed the tumor-killing activity of anti-PD-1 treatment in vivo and in vitro. Our results highlight the characterization of the immune landscape of CRC in different regions. CD20+ B-cell infiltration has been associated with CRC patient prognosis and may promote the tumor-killing role of PD-1 antibodies.

The influence of China's protected areas policy on households' risk perception, forest investment, and revenue.

Protected areas are an essential policy tool for biodiversity conservation in China as elsewhere, yet the impact of protected area policies on the livelihood of local households in China remains unknown. We contend that the protected area policy achieves the two goals of ecological conservation and livelihood improvement simultaneously. In this study, we empirically investigated the influence of the protected area policy on local households' risk perception, forest investment, and forest revenue. We analyzed a sample consisting of households located inside or adjacent to two protected areas, namely, Wuyishan National Park and Longqishan Nature Reserve, both in Fujian Province. A total of 211 valid questionnaires were collected in 2021, and the data were analyzed using structural equation modeling. The results indicate that the establishment of protected areas has a positive impact on forest revenues, mediated by risk perception and forest investment, while the average levels of perceived damage increased and perceived security decreased due to the protected area policy. Our study has implications for policymakers seeking to improve biodiversity and household livelihood around protected areas.

The impact of non-driving related tasks on the development of driver sleepiness and takeover performances in prolonged automated driving.

INTRODUCTION: Vehicle automation is thought to improve road safety since numerous accidents are caused by human error. However, the lack of active involvement and monotonous driving environments due to automation may contribute to drivers' passive fatigue and sleepiness. Previous research indicated that non-driving related tasks (NDRTs) were beneficial in maintaining drivers' arousal levels but detrimental to takeover performance. METHOD: A 3·2 mixed design (between subjects: driving condition; within subjects: takeover orders) simulator experiment was conducted to explore the development of driver sleepiness in prolonged automated driving context and the effect of NDRTs on driver sleepiness development, and to further evaluate the impact of driver sleepiness and NDRTs on takeover performance. Sixty-three participants were randomly assigned to three driving conditions, each lasting 60 min: automated driving while performing driving environment monitoring task; visual NDRTs task; and visual NDRTs with scheduled driving environment monitoring task. Two hazardous events occurring at about the 5th and 55th min needed to be handled during the respective driving. RESULTS: Drivers performing monitoring tasks had a faster development of driver sleepiness than drivers in the other two conditions in terms of both subjective and objective indicators. Takeover performance of drivers performing monitoring task were undermined due to driver sleepiness in terms of braking and steering reaction times, the time between saccade latency and braking or steering reaction times, and so forth. Additionally, NDRTs impaired the drivers' takeover ability in terms of saccade latency, max braking pedal input, max steering velocity, minimum time to collision, and so forth. This study shows that NDRTs with scheduled road environment monitoring task improve takeover performance during prolonged automated driving by helping to maintain driver alertness. PRACTICAL APPLICATIONS: Findings from this work provide some technical assistance in the development of driver sleepiness monitoring systems for conditionally automated vehicles.

Serine/threonine kinase 3 promotes oxidative stress and mitochondrial damage in septic cardiomyopathy through inducing Kelch-like ECH-associated protein 1 phosphorylation and nuclear factor erythroid 2-related factor 2 degradation.

Serine/threonine kinases (STK3) is a core component of the Hippo pathway and modulates oxidative stress and inflammatory responses in cardiovascular diseases. However, its potential role in septic cardiomyopathy remains undefined. STK3-mediated phosphorylation of Kelch-like ECH-associated protein 1 (KEAP1) was shown to suppress antioxidant gene transcription controlled by nuclear factor erythroid 2-related factor 2 (Nrf2) in macrophages. To explore whether STK3 induces KEAP1-mediated suppression of Nrf2 in septic cardiomyopathy, wild-type and global STK3 knockout (STK3 -/- ) mice were treated with LPS. LPS treatment upregulated cardiac STK3 expression. STK3 deletion attenuated myocardial inflammation and cardiomyocyte death, and improved myocardial structure and function. In LPS-challenged HL-1 cardiomyocytes, shRNA-mediated STK3 knockdown normalized mitochondrial membrane potential and ATP production, attenuated apoptosis, and rescued antioxidant gene expression by preventing Nrf2 downregulation. Co-IP, docking analysis, western blotting, and immunofluorescence assays further showed that STK3 binds and phosphorylates KEAP1, promoting Nrf2 downregulation. Accordingly, transfection of phosphodefective KEAP1 mutant protein in cardiomyocyte restored Nrf2 expression and mitochondrial performance upon LPS, while expression of a phosphomimetic KEAP1 mutant abolished the mitochondria-protective and pro-survival effects of STK3 deletion. These findings suggest that STK3 upregulation contributes to septic cardiomyopathy by phosphorylating KEAP1 to promote Nrf2 degradation and suppression of the antioxidant response.

TMBIM6 prevents VDAC1 multimerization and improves mitochondrial quality control to reduce sepsis-related myocardial injury.

BACKGROUND: The regulatory mechanisms involved in mitochondrial quality control (MQC) dysfunction during septic cardiomyopathy (SCM) remain incompletely characterized. Transmembrane BAX inhibitor motif containing 6 (TMBIM6) is an endoplasmic reticulum protein with Ca2+ leak activity that modulates cellular responses to various cellular stressors. METHODS: In this study, we evaluated the role of TMBIM6 in SCM using cardiomyocyte-specific TMBIM6 knockout (TMBIM6CKO) and TMBIM6 transgenic (TMBIM6TG) mice. RESULTS: Myocardial TMBIM6 transcription and expression were significantly downregulated in wild-type mice upon LPS exposure, along with characteristic alterations in myocardial systolic/diastolic function, cardiac inflammation, and cardiomyocyte death. Notably, these alterations were further exacerbated in LPS-treated TMBIM6CKO mice, and largely absent in TMBIM6TG mice. In LPS-treated primary cardiomyocytes, TMBIM6 deficiency further impaired mitochondrial respiration and ATP production, while defective MQC was suggested by enhanced mitochondrial fission, impaired mitophagy, and disrupted mitochondrial biogenesis. Structural protein analysis, Co-IP, mutant TMBIM6 plasmid transfection, and molecular docking assays subsequently indicated that TMBIM6 exerts cardioprotection against LPS-induced sepsis by interacting with and preventing the oligomerization of voltage-dependent anion channel-1 (VDAC1), the major route of mitochondrial Ca2+ uptake. CONCLUSION: We conclude that the TMBIM6-VDAC1 interaction prevents VDAC1 oligomerization and thus sustains mitochondrial Ca2+ homeostasis as well as MQC, contributing to improved myocardial function in SCM.