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Advances in single-cell RNA sequencing (scRNA-seq) have led to successes in discovering novel cell types and understanding cellular heterogeneity among complex cell populations through cluster analysis. However, cluster analysis is not able to reveal continuous spectrum of states and underlying gene expression programs (GEPs) shared across cell types. We introduce scAAnet, an autoencoder for single-cell non-linear archetypal analysis, to identify GEPs and infer the relative activity of each GEP across cells. We use a count distribution-based loss term to account for the sparsity and overdispersion of the raw count data and add an archetypal constraint to the loss function of scAAnet. We first show that scAAnet outperforms existing methods for archetypal analysis across different metrics through simulations. We then demonstrate the ability of scAAnet to extract biologically meaningful GEPs using publicly available scRNA-seq datasets including a pancreatic islet dataset, a lung idiopathic pulmonary fibrosis dataset and a prefrontal cortex dataset.

Background Strokes significantly impair quality of life and incur high economic and societal burdens. The triglyceride and glucose (TyG) index is a biochemical marker of insulin resistance (IR) and may have important value in the prediction of strokes, especially ischemic stroke (IS). Our study aims to investigate the relationship between TyG index and IS and ascertain whether TyG index is independently associated with IS adverse outcomes. Methods The Cochrane, Embase, Medline, Web of Science, PubMed, and other relevant English databases and related websites were systematically searched for articles on ‘‘TyG index’’ and \"stroke\" published from inception to April 4, 2022. We reviewed the available literature on the TyG index and its relation to predicting IS occurrence in the general population and adverse clinical outcomes. We calculated odds ratios (OR) of TyG index and its predictability of IS occurrence and adverse outcomes. Statistical analyses were performed using the Meta Package in STATA, version 12.0. Results A total of 18 studies and 592,635 patients were included in our analysis. The pooled effect values of all stroke types showed that higher TyG index was associated with increased the risk of IS in the general population (OR 1.37; 95% CI 1.22–1.54) in a total sample of 554,334 cases with a high level of heterogeneity (P = 0.000, I 2  = 74.10%). In addition, compared to IS patients with a lower TyG index, IS patients with a higher TyG index was associated with higher risk of stroke recurrence (OR: 1.50; 95% CI 1.19–1.89) and increased risk of mortality (OR 1.40 95% CI 1.14–1.71). No correlation was found in the effect value combinations of poor functional outcomes (OR 1.12; 95% CI 0.88–1.43) and neurological worsening (OR: 1.76; 95% CI 0.79–3.95) in a total sample of 38,301 cases with a high level of heterogeneity (P = 0.000; I 2  = 77.20%). Conclusions TyG index has potential value in optimizing risk stratification for IS in the general population. Furthermore, there is a significant association between high TyG index and many adverse outcomes of stroke, especially stroke recurrence and high mortality. Future studies should focus on multi-center and multi-regional designs in order to further explore the relationship between IS and TyG index.

Flash floods are becoming increasingly frequent and severe under extreme climate, posing serious threats to mountainous communities. This study investigates a severe flash flood event occurred from July 13 to 14, 2019, in Jiubao Town, Jiangxi, China. Weather radar was used to track storm trajectories, and a Random Forest model was constructed to quantify hourly rainfall at a 6-minute temporal resolution. Discharge and water level were simulated using the Modular Distributed Hydrological Model (MDHM) at different sections neighbouring villages selected through field survey, and the village-specific flood response time were derived considering the water level rising rate. The results indicate that the storm propagated from southwest to northeast, displaying a ‘train effect’ of sequential convective cells. Among storm features, maximum reflectivity (MAX-REF) and storm top height (TOP) were the most influential, contributing 33.2% and 23.5% of the total importance, respectively, highlighting the critical role of storm intensity and vertical structure in modulating rainfall responses. Disaster-level water stages occurred during 6:40-7:50 on July 14 from upstream to downstream, with earlier flooding in the downstream Huangdu Village due to terrain-induced flow congestion. This integrated analysis of the storm-rainfall-flood disaster chain under data-limited conditions enhances the understanding of mountain torrent mechanisms and provides a scientific basis for regional disaster prevention and mitigation.

Objectives Older people are more likely to have digital exclusion, which is associated with poor health. This study investigated the relationship between digital exclusion and cognitive impairment in older adults from 23 countries across five longitudinal surveys. Design and measurements Digital exclusion is defined as self-reported non-use of the Internet. We assessed cognitive impairment on three dimensions: orientation, memory, and executive function. We used generalized estimation equations fitting binary logistic regression with exchangeable correlations to study the relationship between digital exclusion and cognitive impairment, and apply the minimum sufficiently adjusted set of causally directed acyclic graphs as the adjusted variable. Setting and participants We pooled a nationally representative sample of older adults from five longitudinal studies, including the China Health and Retirement Longitudinal study (CHARLS), the English Longitudinal Study of Ageing (ELSA), the Health and Retirement Study (HRS), the Mexican Health and Ageing Study (MHAS) and the Survey of Health, Ageing and Retirement in European (SHARE). Results We included 62,413 participants from five longitudinal studies. Digital exclusion varied by country, ranging from 21.69% (SHARE) in Denmark to 97.15% (CHARLS) in China. In the original model, digital exclusion was significantly associated with cognitive impairment in all five studies. In the adjusted model, these associations remained statistically significant: CHARLS (Odds ratio [OR] = 2.81, 95% confidence interval [CI] 1.84–4.28, ELSA (1.92 [1.70–2.18]), HRS(2.48[2.28–2.71), MHAS (1.92 [1.74–2.12]), and SHARE (2.60 [2.34–2.88]). Conclusion Our research shows that a significant proportion of older people suffer from digital exclusion, especially in China. Digital exclusion was positively correlated with cognitive impairment. These findings suggest that digital inclusion could be an important strategy to improve cognitive function and reduce the risk of cognitive impairment in older adults.

Background Preserving the integrity of the blood-brain barrier (BBB) is beneficial to avoid further brain damage after acute ischemic stroke (AIS). Astrocytes, an important component of the BBB, promote BBB breakdown in subjects with AIS by secreting inflammatory factors. The glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 (Ex-4) protects the BBB and reduces brain inflammation from cerebral ischemia, and GLP-1R is expressed on astrocytes. However, the effect of Ex-4 on astrocytes in subjects with AIS remains unclear. Methods In the present study, we investigated the effect of Ex-4 on astrocytes cultured under oxygen-glucose deprivation (OGD) plus reoxygenation conditions and determined whether the effect influences bEnd.3 cells. We used various methods, including permeability assays, western blotting, immunofluorescence staining, and gelatin zymography, in vitro and in vivo. Results Ex-4 reduced OGD-induced astrocyte-derived vascular endothelial growth factor (VEGF-A), matrix metalloproteinase-9 (MMP-9), chemokine monocyte chemoattractant protein-1 (MCP-1), and chemokine C-X-C motif ligand 1 (CXCL-1). The reduction in astrocyte-derived VEGF-A and MMP-9 was related to the increased expression of tight junction proteins (TJPs) in bEnd.3 cells. Ex-4 improved neurologic deficit scores, reduced the infarct area, and ameliorated BBB breakdown as well as decreased astrocyte-derived VEGF-A, MMP-9, CXCL-1, and MCP-1 levels in ischemic brain tissues from rats subjected to middle cerebral artery occlusion. Ex-4 reduced the activation of the JAK2/STAT3 signaling pathway in astrocytes following OGD. Conclusion Based on these findings, ischemia-induced inflammation and BBB breakdown can be improved by Ex-4 through an astrocyte-dependent manner.

Epigenetics is a biological process that modifies and regulates gene expression, affects neuronal function, and contributes to pain. However, the mechanism by which epigenetics facilitates and maintains chronic pain is poorly understood. We aimed to determine whether N 6 -methyladenosine (m6A) specifically modified by methyltransferase-like 14 (METTL14) alters neuronal activity and governs pain by sensitizing the GluN2A subunit of the N -methyl-d-aspartate receptor (NMDAR) in the dorsal root ganglion (DRG) neurons in a model of chemotherapy-induced neuropathic pain (CINP). Using dot blotting, immunofluorescence, gain/loss-of-function, and behavioral assays, we found that m6A levels were upregulated in L4–L6 DRG neurons in CINP in a DBP/METTL14-dependent manner, which was also confirmed in human DRGs. Blocking METTL14 reduced m6A methylation and attenuated pain hypersensitivity. Mechanistically, METTL14-mediated m6A modification facilitated the synaptic plasticity of DRG neurons by enhancing the GluN2A subunit of NMDAR, and inhibiting METTL14 blocked this effect. In contrast, overexpression of METTL14 upregulated m6A modifications, enhanced presynaptic NMDAR activity in DRG neurons, and facilitated pain sensation. Our findings reveal a previously unrecognized mechanism of METTL14-mediated m6A modification in DRG neurons to maintain neuropathic pain. Targeting these molecules may provide a new strategy for pain treatment.

An absolutely conflicting value for the incorporation of the Lode parameter into a fracture criterion was reported in the literature when predicting the ballistic resistance of metallic plates failing through shear plugging. In this study, a combined experimental–numerical investigation was conducted to understand the dynamic shear fracture behavior under compression–shear stress states. Flat-hat-shaped specimens of 30CrMnSiNi2A high-strength steel were loaded using a Split Hopkinson Pressure Bar apparatus, combining the ultra-high-speed photography technique, digital image correlation method, and microstructure observation. Parallel finite element simulations were performed using both a modified Johnson–Cook (MJC) fracture criterion or an extended Xue–Wierzbicki (EXW) fracture criterion with Lode dependence to reveal the value of the Lode parameter incorporation. It was found that deformed shear bands with a width of approximately 0.14 mm form at a critical impact velocity. The EXW criterion correctly predicts the critical fracture velocity and estimates the fracture initiation instants within an error of 5.3%, whereas the MJC fracture criterion overestimates the velocity by 14.3%. Detailed analysis shows that the EXW criterion predicts a combined failure mechanism involving ductile fracture and material instability, while the MJC fracture criterion attributes the failure exclusively to material instability. The improved accuracy achieved by employing the Lode-dependent EXW fracture criterion may be attributed to the compression–shear stress state and the accurate prediction of the failure mechanism of the dynamic shear fracture.

The study is aimed at investigating the immunoenhancement activity of polysaccharides from Platycodon grandiflorum polysaccharides (PGPSs) in vitro. In this study, some research on lymphocyte proliferation, cell cycle, and the levels of CD4+ and CD8+ T cells were performed. Four different concentrations of PGPSs (PGPStc, PGPS60c, PGPS80c, and PGPStp) were harvested and added to peripheral blood T lymphocytes. We observed significant increases in T lymphocyte proliferation at PGPStc groups individually or synergistically with phytohemagglutinin (PHA) at most concentrations, and their lymphocyte proliferation rates were the highest. The active sites of PGPStc and PGPS60c were subsequently chosen. Then, we utilized flow cytometry to determine lymphocyte cell cycle distribution and levels of CD4+ and CD8+ T cells. At most time points, PGPStc could facilitate lymphocyte cell cycle progression from the G0/G1 phase to the S and G2/M phases and, simultaneously, increase the levels of CD4+ and CD8+ T cells. These results indicate that PGPStc enhances the immune functions, suggesting that PGPStc could be a potential immunopotentiator for further in vivo and clinical trial experiments.

Background Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a severe autoimmune neuropsychiatric disease. Brain access of anti-NMDAR autoantibody through the blood–brain barrier (BBB) is essential for pathogenesis. Most previous animal models limit the investigation of etiologies of BBB damage in patients. Methods In this study, we established a novel humanized mouse model of anti-NMDAR encephalitis by intraperitoneal injection of patients’ peripheral blood mononuclear cells (PBMCs) into BALB/c Rag2 −/− Il2rg −/− Sirpα NOD Flk2 −/− mice. Results We found that engraftment of patients’ PBMCs not only produced potent anti-GluN1 autoantibodies, but also disrupted BBB integrity to allow brain access of autoantibodies, resulting in a hyperactive locomotor phenotype, anxiety- and depressive-like behaviors, cognitive deficits, as well as functional changes in corresponding brain regions. Transcriptome analysis suggested an exaggerated immune response and impaired neurotransmission in the mouse model and highlighted Il-1β as a hub gene implicated in pathological changes. We further demonstrated that Il-1β was produced by endothelial cells and disrupted BBB by repressing tight junction proteins. Treatment with Anakinra, an Il-1 receptor antagonist, ameliorated BBB damage and neuropsychiatric behaviors. Conclusions Our study provided a novel and clinically more relevant humanized mouse model of anti-NMDAR encephalitis and revealed an intrinsic pathogenic property of the patient’s lymphocytes.

We have developed a very simple method, termed absorbance summation (AS), for comparing protein concentrations between samples in ELISA assays without a standard. This method sums the observed absorbance values from all dilutions to obtain one data point for each sample to be used for comparison. AS is less computationally intensive than fitting sigmoidal curves, and it avoids the difficulty of parameter estimation for samples with absorbance values lying primarily at the lower tail of the curve. Our simulation studies showed that it performs much better than the sigmoidal curve fitting method and the conventional endpoint titer method. The power of this simple method is as high as the formal curve fitting followed by the estimation of area under the curve (AUC).