The Sw-5b NLR nucleotide-binding domain plays a role in oligomerization, and its self-association is important for activation of cell death signaling.

Plant and animal intracellular nucleotide-binding and leucine-rich repeat (NLR) receptors play important roles in sensing pathogens and activating defense signaling. However, the molecular mechanisms underlying the activation of host defense signaling by NLR proteins remain largely unknown. Many studies have determined that the coil-coil (CC) or Toll and interleukin-1 receptor/resistance protein (TIR) domain of NLR proteins and their dimerization/oligomerization are critical for activating downstream defense signaling. In this study, we demonstrated that, in tomato, the nucleotide-binding (NB) domain Sw-5b NLR alone can activate downstream defense signaling, leading to elicitor-independent cell death. Sw-5b NB domains can self-associate, and this self-association is crucial for activating cell death signaling. The self-association was strongly compromised after the introduction of a K568R mutation into the P-loop of the NB domain. Consequently, the NBK568R mutant induced cell death very weakly. The NBCΔ20 mutant lacking the C-terminal 20 amino acids can self-associate but cannot activate cell death signaling. The NBCΔ20 mutant also interfered with wild-type NB domain self-association, leading to compromised cell death induction. By contrast, the NBK568R mutant did not interfere with wild-type NB domain self-association and its ability to induce cell death. Structural modeling of Sw-5b suggests that NB domains associate with one another and likely participate in oligomerization. As Sw-5b-triggered cell death is dependent on helper NLR proteins, we propose that the Sw-5b NB domain acts as a nucleation point for the assembly of an oligomeric resistosome, probably by recruiting downstream helper partners, to trigger defense signaling.

The Triglyceride Glucose Index Is a Risk Factor for Enlarged Perivascular Space.

The triglyceride glucose (TyG) index is considered a simple surrogate marker for insulin resistance and has been associated with cerebrovascular diseases. However, limited information is available regarding its association with the subclinical cerebral small vessel disease (CSVD). Here, we investigated the association of TyG index with the burden and distribution of enlarged perivascular space (EPVS) in the non-diabetic population. The data of 531 non-diabetic patients from 2017 to 2020 were assessed. Participants were grouped according to the burden of EPVS. TyG index was calculated using the log scale of fasting triglycerides (mg/dl) × fasting glucose (mg/dl)/2. The association of TyG index with EPVS burden and distribution was evaluated. In the multivariable logistic regression analysis, the TyG index was associated with moderate to severe EPVS [odds ratio (OR): 2.077; 95% CI = 1.268-3.403]. The TyG index was significantly associated with an increased risk of moderate to severe EPVS in subgroups of age <65 years, male, diastolic blood pressure (DBP) <90 mmHg, low-density lipoprotein cholesterol (LDL-C) ≥2.85 mmol/L, serum homocysteine <10 µmol/L, and estimated glomerular filtration rate (eGFR) <90 ml/min/1.73 m2, as well as those without smoking. Further analysis of EPVS distribution, the TyG index was found to be associated with moderate to severe EPVS in the centrum semiovale (CSO), not in the basal ganglia (BG). Conclusively, the TyG index was independently and positively associated with moderate to severe CSO EPVS. TyG index may serve as an independent risk factor for CSVD in clinical practice.

Knockdown of lncRNA Gm11974 protect against cerebral ischemic reperfusion through miR-766-3p/NR3C2 axis.

Aims: In previous studies, numerous differential lncRNAs in cerebral ischemic reperfusion injury were identified using RNA-Seq analysis. However, little is known about whether and how lncRNAs involved in cerebral I/R injury. In this study, we investigated the function and explored the possible mechanism of lncRNA Gm11974 in cerebral I/R injury. Methods: Oxygen glucose deprivation model in N2a cells were utilized to mimic the cerebral I/R injury in vitro. Trypan blue staining, Tunel, JC-1 and cell viability were measured to evaluate the function of lncRNA Gm11974. Dual-luciferase reporter assay was used to explore the potential mechanism of lncRNA Gm11974. Results: Gm11974 was mainly located in cytoplasm. Knockdown of lncRNA Gm11974 alleviated the apoptosis induced by OGD and cell death rates were significantly reduced. We further provided the possible mechanism that Gm11974/miR-766-3p/NR3C2 axis plays important role in cerebral I/R injury. Conclusions: We evaluated the function and mechanism of lncRNA Gm11974 in ischemic brain injury. LncRNA Gm11974 may serve as a potential target for new therapeutic intervention.