A GWAS-supported variant interacting with diabetes predicts risk of atherothrombotic stroke in Han Chinese population.

BACKGROUND: A recent genome-wide association study has identified that rs4376531 variant conferred risk of atherothrombotic stroke (AS) in a Japanese population. This study was to explore the association in Han Chinese population. METHODS: A total of 1036 cases and 643 healthy controls were enrolled. We genotyped rs4376531 variant with SNPscan. Multivariate logistic regression analysis was used to determine the association of genetic variation with risk of AS. Interaction analysis was examined by SNPStats web tool. RESULTS: After adjusting for gender, age, body mass index (BMI), hypertension, diabetes and smoking, compared with CC genotype, we observed that GC and GG/GC genotypes were associated with a significantly decreased risk of AS (OR = 0.76, 95% CI = 0.58-0.99 and OR = 0.76, 95% CI = 0.58-0.98, respectively). The decreased risk was more obvious among subgroups with high BMI (OR = 0.63, 95% CI = 0.45-0.88), no hypertension (OR = 0.66, 95% CI = 0.46-0.94), diabetes (OR = 0.33, 95% CI = 0.17-0.64), and smoking (OR = 0.65, 95% CI = 0.44-0.95) in the dominant model (GG/GC vs CC). Interaction analysis also revealed that compared with non-diabetic patients with CC genotype, diabetic patients with CC genotype had a 4.48-fold (OR = 4.48; 95% CI = 2.98-6.72) increased risk of AS. CONCLUSION: Our data suggested that GC and GG/GC of rs4376531 contributed to a decreased risk of AS while CC genotype, interacting with diabetes, increased the stroke risk in Han Chinese population.

Peptidylation for the determination of low-molecular-weight compounds by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.

Determination of low-molecular-weight compounds by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) has been a great challenge in the analytical research field. Here we developed a universal peptide-based derivatization (peptidylation) strategy for the sensitive analysis of low-molecular-weight compounds by MALDI-TOF-MS. Upon peptidylation, the molecular weights of target analytes increase, thus avoiding serious matrix ion interference in the low-molecular-weight region in MALDI-TOF-MS. Since peptides typically exhibit good signal response during MALDI-TOF-MS analysis, peptidylation endows high detection sensitivities of low-molecular-weight analytes. As a proof-of-concept, we analyzed low-molecular-weight compounds of aldehydes and thiols by the developed peptidylation strategy. Our results showed that aldehydes and thiols can be readily determined upon peptidylation, thus realizing the sensitive and efficient determination of low-molecular-weight compounds by MALDI-TOF-MS. Moreover, target analytes also can be unambiguously detected in biological samples using the peptidylation strategy. The established peptidylation strategy is a universal strategy and can be extended to the sensitive analysis of various low-molecular-weight compounds by MALDI-TOF-MS, which may be potentially used in areas such as metabolomics.

Unveiling the link between glymphatic function and cortical microstructures in post-traumatic stress disorder.

PURPOSE: The discovery of the glymphatic system, crucial for cerebrospinal and interstitial fluid exchange, has enhanced our grasp of brain protein balance and its potential role in neurodegenerative disease prevention and therapy. Detecting early neurodegenerative shifts via noninvasive biomarkers could be key in identifying at-risk individuals for Alzheimer's disease (AD). Our research explores a diffusion tensor imaging (DTI) method that measures cortical mean diffusivity (cMD), potentially a more sensitive indicator of neurodegeneration than traditional macrostructural methods. MATERIALS AND METHODS: We analyzed 67 post-traumatic stress disorder (PTSD)-diagnosed veterans from the Alzheimer's Disease Neuroimaging Initiative database. Participants underwent structural MRI, DTI, Aß PET imaging, and cognitive testing. We focused on the DTI-ALPS technique to assess glymphatic function and its relation to cMD, cortical Aß accumulation, and thickness, accounting for age and APOE ε4 allele variations. RESULTS: The cohort, all male with an average age of 68.1 (SD 3.4), showed a strong inverse correlation between DTI-ALPS and cMD in AD-affected regions, especially in the entorhinal, parahippocampal, and fusiform areas. Higher DTI-ALPS readings were consistently linked with greater cortical thickness, independent of Aß deposits and genetic risk factors. Age and cMD emerged as inversely proportional predictors of DTI-ALPS, indicating a complex interaction with age. CONCLUSION: The study confirms a meaningful association between glymphatic efficiency and cMD in AD-sensitive zones, accentuating cortical microstructural alterations in PTSD. It positions DTI-ALPS as a viable biomarker for assessing glymphatic function in PTSD, implicating changes in DTI-ALPS as indicative of glymphatic impairment.

Crizotinib and its enantiomer suppress ferroptosis by decreasing PE-O-PUFA content.

Ferroptosis is a specific form of cell death characterized by excessive accumulation of cellular lipid peroxides. Ferroptosis is closely associated with various diseases, inhibition of which may help alleviate multi-organ injury caused by ischemia-reperfusion and enhance the anti-tumor effect by promoting the immunity of T cells. However, clinical approved drugs targeting ferroptosis process remain rare. In this study, we unexpectedly found that (R)-crizotinib, the first-generation ALK inhibitor, has potent inhibitory activity against ferroptosis across various cell lines. Moreover, its chiral molecule (S)-crizotinib, which was considered to share no common targets with (R)-crizotinib, also suppresses ferroptosis with an efficacy similar to that of (R)-crizotinib. We further demonstrated that both crizotinib enantiomers inhibit ferroptosis independently of their known targets, but through a common mechanism involving the targeting of AGPAT3-mediated synthesis of ether-linked polyunsaturated fatty acids (PE-O-PUFA), which are known to promote lipid-ROS generation and ferroptosis. In line with their activity in cell lines, (R)-crizotinib and (S)-crizotinib effectively mitigate renal ischemia-reperfusion injury in mice. Furthermore, the two compounds also inhibit lipid-ROS accumulation in CD8+ T cells in draining lymph nodes of B16-F10 subcutaneous xenograft mice, thereby promoting anti-tumor effects. Collectively, our study firstly reports a common activity shared by (R)-crizotinib and (S)-crizotinib in ferroptosis regulation. As a clinically approved drug, (R)-crizotinib has well-established pharmacokinetics and safety, which makes it a promising candidate for repurposing. Given the current lack of FDA-approved ferroptosis inhibitors, our findings suggest therapeutically repurposing (R)-crizotinib as well as its enantiomer (S)-crizotinib for treating ferroptosis-related diseases.

MRGAT: Multi-Relational Graph Attention Network for knowledge graph completion.

One of the most effective ways to solve the problem of knowledge graph completion is embedding-based models. Graph neural networks (GNNs) are popular and promising embedding models which can exploit and use the structural information of neighbors in knowledge graphs. The current GNN-based knowledge graph completion methods assume that all neighbors of a node have equal importance. This assumption which cannot assign different weights to neighbors is pointed out in our study to be unreasonable. In addition, since the knowledge graph is a kind of heterogeneous graph with multiple relations, multiple complex interactions between nodes and neighbors can bring challenges to the effective message passing of GNNs. We then design a multi-relational graph attention network (MRGAT) which can adapt to different cases of heterogeneous multi-relational connections and then calculate the importance of different neighboring nodes through a self-attention layer. The incorporation of self-attention mechanism into the network with different node weights optimizes the network structure, and therefore, significantly results in a promotion of performance. We experimentally validate the rationality of our models on multiple benchmark knowledge graphs, where MRGAT achieves the best performance on various evaluation metrics including MRR score, Hits@ score compared with other state-of-the-art baseline models.

A Class of Disulfide Compounds Suppresses Ferroptosis by Stabilizing GPX4.

Ferroptosis is a nonapoptotic form of cell death characterized by iron-dependent lipid peroxidation and has been implicated in multiple pathological conditions. Glutathione peroxidase 4 (GPX4) plays an essential role in inhibiting ferroptosis by eliminating lipid peroxide using glutathione (GSH) as a reductant. In this study, we found Ellman's reagent DTNB and a series of disulfide compounds, including disulfiram (DSF), an FDA-approved drug, which protect cells from erastin-induced ferroptosis. Mechanistically, DTNB or DSF is conjugated to multiple cysteine residues in GPX4 and disrupts GPX4 interaction with HSC70, an adaptor protein for chaperone mediated autophagy, thus preventing GPX4 degradation induced by erastin. In addition, DSF ameliorates concanavalin A induced acute liver injury by suppressing ferroptosis in a mouse model. Our work reveals a novel regulatory mechanism for GPX4 protein stability control. We also discover disulfide compounds as a new class of ferroptosis inhibitors and suggest therapeutic repurposing of DSF in treating ferroptosis-related diseases.