Search

Human caspase-4 and its mouse homolog caspase-11 are receptors for cytoplasmic lipopolysaccharide. Activation of the caspase-4/11-dependent NLRP3 inflammasome is required for innate defense and endotoxic shock, but how caspase-4/11 is modulated remains unclear. Here, we show that mice lacking the oxidative stress sensor glutathione peroxidase 8 (GPx8) are more susceptible to colitis and endotoxic shock, and exhibit reduced richness and diversity of the gut microbiome. C57BL/6 mice that underwent adoptive cell transfer of GPx8-deficient macrophages displayed a similar phenotype of enhanced colitis, indicating a critical role of GPx8 in macrophages. GPx8 binds covalently to caspase-4/11 via disulfide bonding between cysteine 79 of GPx8 and cysteine 118 of caspase-4 and thus restrains caspase-4/11 activation, while GPx8 deficiency leads to caspase-4/11-induced inflammation during colitis and septic shock. Inhibition of caspase-4/11 activation with small molecules reduces the severity of colitis in GPx8-deficient mice. Notably, colonic tissues from patients with ulcerative colitis display low levels of Gpx8 and high caspase-4 expression. In conclusion, these results suggest that GPx8 protects against colitis by negatively regulating caspase-4/11 activity.

Amyotrophic lateral sclerosis (ALS), the most common motor neuron disease, usually occurs in middle-aged people. However, the molecular basis of age-related cumulative stress in ALS pathogenesis remains elusive. Here, we found that mice deficient in NPGPx (GPx7), an oxidative stress sensor, develop ALS-like phenotypes, including paralysis, muscle denervation, and motor neurons loss. Unlike normal spinal motor neurons that exhibit elevated O-GlcNAcylation against age-dependent oxidative stress, NPGPx-deficient spinal motor neurons fail to boost O-GlcNAcylation and exacerbate ROS accumulation, leading to cell death. Mechanistically, stress-activated NPGPx inhibits O-GlcNAcase (OGA) through disulfide bonding to fine-tune global O-GlcNAcylation. Pharmacological inhibition of OGA rescues spinal motor neuron loss in aged NPGPx-deficient mice. Furthermore, expression of NPGPx in ALS patients is significantly lower than in unaffected adults. These results suggest that NPGPx modulates O-GlcNAcylation by inhibiting OGA to cope with age-dependent oxidative stress and protect motor neurons from degeneration, providing a potential therapeutic axis for ALS.

Wavelength Division Multiplexing (WDM) devices, as one of the core components of 5G fronthaul network, have developed rapidly in recent years. The fronthaul network has proposed new requirements for WDM devices, components and products. However, the technical requirements and test method standards of WDM devices for 5G fronthaul network are not clear. Through in-depth analysis of the problems encountered in the test of WDM devices, we propose a test method of 5G fronthaul WDM devices, and build the corresponding test system, which is compared with the manual test method. The results show that the proposed test method has 10 times more efficient than manual test method with good consistency.

KRAS mutations are the earliest events found in approximately 90% of pancreatic ductal adenocarcinomas (PDACs). However, little is known as to why KRAS mutations preferentially occur in PDACs and what processes/factors generate these mutations. While abnormal carbohydrate metabolism is associated with a high risk of pancreatic cancer, it remains elusive whether a direct relationship between KRAS mutations and sugar metabolism exists. Here, we show that under high-glucose conditions, cellular O-GlcNAcylation is significantly elevated in pancreatic cells that exhibit lower phosphofructokinase (PFK) activity than other cell types. This post-translational modification specifically compromises the ribonucleotide reductase (RNR) activity, leading to deficiency in dNTP pools, genomic DNA alterations with KRAS mutations, and cellular transformation. These results establish a mechanistic link between a perturbed sugar metabolism and genomic instability that induces de novo oncogenic KRAS mutations preferentially in pancreatic cells.

BackgroundThrombospondin-2 (TSP-2) has been reported as an early diagnostic marker for pancreatic ductal adenocarcinoma (PDAC) in Caucasian populations. This study was designed to validateTSP-2 as a diagnostic marker in a large Taiwan cohort and to investigate the association of TSP-2 with the clinical outcomes of PDAC patients.MethodsThe serum TSP-2 levels in 263 PDAC patients and 230 high-risk individuals (HRIs) were measured via an enzyme-linked immunosorbent assay. The sensitivity, specificity, and accuracy of TSP-2 as a diagnostic marker to discriminating PDAC patients from HRIs and correlations between TSP-2 levels and prognosis of PDAC patients were analyzed.ResultsSerum TSP-2 levels were significantly higher in patients with PDAC (44.90 ± 40.70 ng/ml) than in the HRIs (17.52 ± 6.23 ng/ml). At a level of ≥ 29.8 ng/ml, TSP-2 exhibited 100% specificity, 55.9% sensitivity, 100% positive predictive value (PPV), and 66.5% negative predictive value (NPV) for discriminating PDAC patients from HRIs. The Cox regression analysis showed that higher serum TSP-2 levels were significantly associated with poor outcomes in PDAC patients (hazard ratio = 1.54, 95% confidence interval = 1.143-2.086, P = 0.005). Combining the carbohydrate antigen 19-9 (CA19-9) (cutoff value of 62.0 U/ml) and TSP-2 (cutoff value of 29.8 ng/ml) levels yielded 98.7% specificity, 90.5% sensitivity, 98.8% PPV, and 90.1% NPV for discriminating patients with PDAC from HRIs.ConclusionsTSP-2 is a highly specific diagnostic marker and an independent prognostic marker in patients with PDAC. A combined biomarker panel, including TSP-2 and CA19-9, may facilitate future PDAC screening.

Health monitoring based on human activity recognition (HAR) is an important means to discover health abnormalities.However,in daily activity recognition,it is difficult to obtain training samples containing all possible activity categories in advance.When new categories appear in the prediction stage,the traditional support vector machine (SVM) will incorrectly classify them as known category.A robust classifier should be able to distinguish the newly added categories so that they can be processed differently from the known categories.This paper proposes a human activity recognition method based on class increment SVM,and the idea of hypersphere is introduced,which can not only identify known activity categories with high accuracy,but also detect new categories.The multiple hyperspheres obtained through training divide the entire feature space,so that the classifier has the ability to detect newly added activity categories.The experimental results show that compared with the traditional multi-class SVM method,our method can realize the detection of new categories without significantly reducing the classification effect of known categories,thereby improving the classifier's ability to recognize human activity in an open environment.