The incidence of exertional heat stroke (EHS) escalates during periods of elevated temperatures, potentially leading to persistent cognitive impairment postrecovery. Currently, effective prophylactic ...or therapeutic measures against EHS are nonexistent.
The selection of days 14 and 23 postinduction for detailed examination was guided by TEM of neuronal cells and HE staining of intestinal villi and the hippocampal regions. Fecal specimens from the ileum and cecum at these designated times were analyzed for changes in gut microbiota and metabolic products. Bioinformatic analyses facilitated the identification of pivotal microbial species and metabolites. The influence of supplementing these identified microorganisms on behavioral outcomes and the expression of functional proteins within the hippocampus was subsequently assessed.
TEM analyses of neurons, coupled with HE staining of intestinal villi and the hippocampal region, indicated substantial recovery in intestinal morphology and neuronal injury on Day 14, indicating this time point for subsequent microbial and metabolomic analyses. Notably, a reduction in the Lactobacillaceae family, particularly Lactobacillus murinus, was observed. Functional annotation of 16S rDNA sequences suggested diminished lipid metabolism and glycan biosynthesis and metabolism in EHS models. Mice receiving this intervention (EHS + probiotics group) exhibited markedly reduced cognitive impairment and increased expression of BDNF/TrKB pathway molecules in the hippocampus during behavioral assessment on Day 28.
Probiotic supplementation, specifically with Lactobacillus spp., appears to mitigate EHS-induced cognitive impairment, potentially through the modulation of the BDNF/TrKB signaling pathway within the hippocampus, illustrating the therapeutic potential of targeting the gut-brain axis.
We present a Graphics Processing Units (GPU) implementation of time gating based reverse time migration (TG-RTM) which uses the pseudospectral time-domain (PSTD) algorithm to solve the acoustic wave ...equation. TG-RTM adopts the prior information of surrounding media to strengthen the correlation between the wavefields, thus has advantages in locating the targets over traditional reverse time migration (RTM) methods. The PSTD algorithm adopts fast Fourier transform (FFT) to obtain the spatial derivatives and a perfectly matched layer as an absorbing boundary condition to eliminate the wraparound effect introduced by the FFT periodicity assumption. Under the Nyquist sampling theorem, the spatial sampling density of the PSTD algorithm requires only two points per minimum wavelength. Thus, the PSTD algorithm can solve the time dependent partial differential equations efficiently and save mass computer memory. Compared with traditional RTM based on the finite difference time domain (FDTD) algorithm, the proposed RTM based on the PSTD algorithm can be implemented on a memory-limited GPU and can solve much larger models. To secure a better performance and generality of FFT in GPU, we present a scheme which combines 1D FFT with matrix transpositions instead of using 3D FFT directly. The matrix transpositions use shared memory to improve memory access efficiency. We also apply an efficient FFT scheme which replaces even-sized R2C FFT with a half-sized C2C FFT. For a small amount and balanced memory swapping from computer to GPU, we save the boundaries in lieu of checkpointing scheme when we propagate the source wavefield forward and backward. The proposed RTM has an acceleration ratio of about 80 times by a Tesla K20X GPU card on a desktop computer. The simulation results of 2D and 3D models demonstrate that the proposed RTM is fast and inexpensive.
•GPU acceleration of RTM is fulfilled and gains 80 fold speedup by a Tesla K20X.•Instead of 3D FFT, we combine 1D FFT with matrix transpositions.•Instead of FDTD, PSTD is used for forward modeling.•Time gating is incorporated into RTM to improve the imaging quality.
Exertional heatstroke (EHS) mainly occurs in healthy young people with rapid onset and high mortality. EHS immune disorders can cause systemic inflammatory responses and multiple organ failure; ...however, the underlying mechanisms remain unclear. As high mobility group box 1 (HMGB1) is a prototypical alarmin that activates inflammatory and immune responses, this study aimed to investigate the effect and mechanism of HMGB1 in the pathogenesis of EHS.BACKGROUND AND OBJECTIVEExertional heatstroke (EHS) mainly occurs in healthy young people with rapid onset and high mortality. EHS immune disorders can cause systemic inflammatory responses and multiple organ failure; however, the underlying mechanisms remain unclear. As high mobility group box 1 (HMGB1) is a prototypical alarmin that activates inflammatory and immune responses, this study aimed to investigate the effect and mechanism of HMGB1 in the pathogenesis of EHS.Peripheral blood mononuclear cell (PBMC) transcriptome sequencing of healthy volunteers, classical heatstroke patients, and EHS patients was performed. A mouse model of EHS was established and murine tissue damage was evaluated by H&E staining. HMGB1 localization and release were visualized using immunofluorescence staining. Human umbilical vein endothelial cells (HUVECs) and THP-1 cells were co-cultured to study the effects of HMGB1 on macrophages. A neutralizing anti-HMGB1 antibody was used to evaluate the efficacy of EHS treatment in mice.METHODSPeripheral blood mononuclear cell (PBMC) transcriptome sequencing of healthy volunteers, classical heatstroke patients, and EHS patients was performed. A mouse model of EHS was established and murine tissue damage was evaluated by H&E staining. HMGB1 localization and release were visualized using immunofluorescence staining. Human umbilical vein endothelial cells (HUVECs) and THP-1 cells were co-cultured to study the effects of HMGB1 on macrophages. A neutralizing anti-HMGB1 antibody was used to evaluate the efficacy of EHS treatment in mice.Plasma and serum HMGB1 levels were significantly increased in EHS patients or mice. EHS-induced endothelial cell pyroptosis promoted HMGB1 release in mice. HMGB1 derived from endothelial cell pyroptosis enhanced macrophage pyroptosis, resulting in immune disorders under EHS conditions. Administration of anti-HMGB1 markedly alleviated tissue injury and systemic inflammatory responses after EHS.RESULTSPlasma and serum HMGB1 levels were significantly increased in EHS patients or mice. EHS-induced endothelial cell pyroptosis promoted HMGB1 release in mice. HMGB1 derived from endothelial cell pyroptosis enhanced macrophage pyroptosis, resulting in immune disorders under EHS conditions. Administration of anti-HMGB1 markedly alleviated tissue injury and systemic inflammatory responses after EHS.The release of HMGB1 from pyroptotic endothelial cells after EHS promotes pyroptosis of macrophages and systemic inflammatory response, and HMGB1-neutralizing antibody therapy has good application prospects for EHS.CONCLUSIONSThe release of HMGB1 from pyroptotic endothelial cells after EHS promotes pyroptosis of macrophages and systemic inflammatory response, and HMGB1-neutralizing antibody therapy has good application prospects for EHS.
The predictive value of biomarkers such as neuron specific enolase (NSE), S100B, neurofilament (NFL), interleukin-6 (IL-6), coagulation factor R, and D-Dimer (DD) after acute Stanford A type aortic ...dissection (AAAD) with neurological complications has recently gained much attention from the research community. However, results from these studies are conflicting. This meta-analysis is conducted to assess the relationship between the biomarkers and the risk of neurological complications after AAAD.
Two reviewers performed a systematic literature search across eight databases (CNKI, Wan Fang, VIP, CBM, PubMed, Web of Science, Cochrane Library, and EMBASE). The studies regarding biomarkers in AAAD patients published up to February 2022 were included. These studies were subjected to rigorous scrutiny and data extraction to determine the weighted mean difference (WMD) and the 95% confidence interval (CI), which were analyzed using the RevMan 5.4 and Stata software 14.0.
A total of 12 studies including 360 cases with neurological complications and 766 controls were incorporated into our meta-analysis. WMD analysis showed that there was a higher NSE levels in AAAD patients with postoperative neurological complications compared with controls (WMD = 0.640, 95% CI: 0.205 ~ 1.075, P = 0.004 < 0.005), and the level of S100B was related to the 6 h and 24 h postoperative neurological complications (6 h: WMD = 0.64, 95% CI: 0.27 ~ 1.02, P = 0.0007 < 0.001; 24 h: WMD = 0.281, 95% CI: 0.211 ~ 0.351, P < 0.001). Moreover, S100B levels at 6 hours after operation were significantly higher than that at 24 hours (WMD = 0.260, 95% CI: 0.166 ~ 0.354, P < 0.001).
NSE and S100B are both candidate biomarkers to predict postoperative neurological complications in patients with AAAD. Other markers are also valuable when used in conjunction with clinical judgement. The findings accentuate the necessity of further research to establish standardized values for these biomarkers in predicting neurological complications.
Abstract
Obesity is associated with chronic low-grade inflammation, contributing to an increasing prevalence of chronic metabolic diseases, such as insulin resistance, non-alcoholic fatty liver ...disease (NALFD), and steatohepatitis. Macrophages are the predominant immune cells in adipose tissues. Adipose tissue macrophages (ATMs) would switch to pro-inflammatory M1 state during obesity, causing local and systemic inflammation. However, the regulatory mechanism of ATMs has not yet been well described within this process. Using a high-fat diet (HFD)–induced mouse obesity model, we found that the costimulatory molecule CD226 was highly expressed on ATMs and knockout (KO) of CD226 alleviated obesity caused by HFD. Loss of CD226 reduced the accumulation of ATMs and hindered macrophage M1 polarization, with lower serum proinflammatory cytokine levels. Furthermore, deficiency of CD226 on ATMs decreased the phosphorylation levels of VAV1, AKT, and FOXO1 and thereby upregulated PPAR-γ. Further administration of PPAR-γ inhibitor restored M1 phenotype in CD226KO ATMs. In summary, loss of CD226 alleviates the HFD-induced obesity and systemic inflammation through inhibition of the accumulation and M1 polarization of ATMs in which PPAR-γ-dependent signaling pathway is involved, suggesting that CD226 may be identified as a potential molecular target for the clinical treatment of obesity.
Pyroptosis is a kind of cell necrosis mediated by inflammasomes. The caspase 1-induced cleavage of gasdermin D (GSDMD) is a canonical pathway to cause membrane pores and eventually cell pyroptosis. ...Poly-
-lysine (PLL) is widely used to enhance cell adhesion during experiments. Human THP-1 cells are a typical cell line used to study pyroptosis due to their monocytic and macrophage-like characteristics. However, it was found that THP-1 cells seeded on the PLL-coated slides died. To figure out the reason, we observed the morphology of THP-1 cells on PLL-coated slides, which showed obvious pore forming on the cell membranes and cell swelling. The indicated pyroptosis-related protein expression was evaluated and it showed that the conventional caspase-1 pathway of pyroptosis was activated through the NLRP3 inflammasome in THP-1 monocytes on the PLL-coated slides. Hence, PLL-guided cell adhesion induces cell pyroptosis in THP-1 monocytes, which calls for THP-1 dominant studies of pyroptosis to avoid the use of PLL-coated slides or PLL-related drugs.
Liver transplantation (LT) is the best choice for patients with end-stage liver diseases. In order to better understand pathophysiological alterations in LT, we aimed to identify potential hub genes ...and inhibitory compounds involved in the LT process. Four pairs of peripheral blood mononuclear cell (PBMC) samples of the LT recipients before and after surgery were collected and taken for transcriptome sequencing. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed for the screened differentially expressed genes (DEGs) between pre- and post-operation groups. Common DEGs were obtained from GO and KEGG enriched pathways, followed by protein-protein interaction (PPI) network construction, hub gene identification, module analysis, and structure-based virtual screening process (SBVS). Compared to the pre-operation stage, 4745 genes were down-regulated and 798 up-regulated after LT. GO analysis showed that the DEGs were enriched in ribosome-related translation regulation, and KEGG analysis indicated that infection and immune-related pathways and diseases were largely enriched. A large number of down-regulated DEGs were not only associated with ribosome-related pathways but also with the alterations of epigenetic modifications, in particular ubiquitination. Moreover, through the PPI network of 29 common genes from GO and KEGG-enriched pathways, 7 hub genes were identified, including PTEN, MYC, EIF2S1, EIF4EBP1, HSP90AB1, TP53, and HSPA8, which were mainly involved in the PI3K-AKT signaling pathway. SBVS of the seed molecule PTEN (PDB code: 1D5R) predicted top hits compounds that may serve as potential inhibitors of PTEN, of which the compound ZINC4235331 had the lowest binding affinity of -10 kcal/mol. The significance of screened hub genes and potential inhibitors involved in the process of LT provides novel therapeutic strategies for improving the outcomes of LT recipients during surgery.
•The number of downregulated DEGs is nearly 6 times that of upregulated DEGs after LT.•DEGs are enriched in ribosome-related translation regulation.•DEGs are also enriched in infection and immune-related pathways.•PTEN-led seven hub genes and potential inhibitors are identified during LT.
Survivors of sepsis may encounter cognitive impairment following their recovery from critical condition. At present, there is no standardized treatment for addressing sepsis-associated ...encephalopathy.
GG (LGG) is a prevalent bacterium found in the gut microbiota and is an active component of probiotic supplements. LGG has demonstrated to be associated with cognitive improvement. This study explored whether LGG administration prior to and following induced sepsis could ameliorate cognitive deficits, and explored potential mechanisms.
Female C57BL/6 mice were randomly divided into three groups: sham surgery, cecal ligation and puncture (CLP), and CLP+LGG. Cognitive behavior was assessed longitudinally at 7-9d, 14-16d, and 21-23d after surgery using an open field test and novel object recognition test. The impact of LGG treatment on pathological changes, the expression level of brain-derived neurotrophic factor (BDNF), and the phosphorylation level of the TrkB receptor (p-TrkB) in the hippocampus of mice at two weeks post-CLP (16d) were evaluated using histological, immunofluorescence, immunohistochemistry, and western blot analyses.
The CLP surgery induced and sustained cognitive impairment in mice with sepsis for a minimum of three weeks following the surgery. Compared to mice subjected to CLP alone, the administration of LGG improved the survival of mice with sepsis and notably enhanced their cognitive functioning. Moreover, LGG supplementation significantly alleviated the decrease in hippocampal BDNF expression and p-TrkB phosphorylation levels caused by sepsis, preserving neuronal survival and mitigating the pathological changes within the hippocampus of mice with sepsis. LGG supplementation mitigates sepsis-related cognitive impairment in mice and preserves BDNF expression and p-TrkB levels in the hippocampus.
Aims To investigate the indicators affecting the early outcome of patients with sepsis and to explore its prognostic efficacy for sepsis. Methods We collected clinical data from 201 patients with ...sepsis admitted to the emergency department of Xijing Hospital between June 2019 and June 2022. The patients were categorized into groups (survival or fatality) based on their 28-day prognosis. The clinical characteristics, biochemical indexes, organ function-related indicators, and disease scores of the patients were analyzed for both groups. Risk factor analysis was conducted for the indicators with significant differences. Results Among the indicators with significant differences between the deceased and survival groups, D-dimer (D-DI), Sequential Organ Failure Assessment (SOFA) score, platelet (PLT), international normalized ratio (INR), and D-DI/PLT were identified as independent risk factors affecting the prognosis of sepsis patients. Receiver operating characteristic (ROC) curves showed that D-DI/PLT (area under the curve (AUC) = 93.9), D-DI (AUC = 89.6), PLT (AUC = 81.3), and SOFA (AUC = 78.4) had good judgment efficacy. Further, Kaplan Meier (K-M) survival analysis indicated that the 28-day survival rates of sepsis patients were significantly decreased when they had high levels of D-DI/PLT, D-DI, and SOFA as well as low PLTs. The hazard ratio (HR) of D-DI/PLT between the two groups was the largest (HR = 16.19). Conclusions D-DI/PLT may be an independent risk factor for poor prognosis in sepsis as well as a clinical predictor of patient prognosis.
The early targeted and effective diagnosis and treatment of severe trauma are crucial for patients' outcomes. Blood leukocytes act as significant effectors during the initial inflammation and ...activation of innate immunity in trauma. This study aims to identify hub genes related to patients' prognosis in blood leukocytes at the early stages of trauma.
The expression profiles of Gene Expression Omnibus (GEO) Series (GSE) 36809 and GSE11375 were downloaded from the GEO database. R software, GraphPad Prism 9.3.1 software, STRING database, and Cytoscape software were used to process the data and identify hub genes in blood leukocytes of early trauma.
Gene Ontology (GO) analysis showed that the differentially expressed genes (DEGs) of blood leukocytes at the early stages of trauma (0–4 h, 4–8 h, and 8–12 h) were mainly involved in neutrophil activation and neutrophil degranulation, neutrophil activation involved in immune response, neutrophil mediated immunity, lymphocyte differentiation, and cell killing. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that the DEGs were mainly involved in Osteoclast differentiation and Hematopoietic cell lineage. Sixty-six down-regulated DEGs and 148 up-regulated DEGs were identified and 37 hub genes were confirmed by Molecular Complex Detection (MCODE) of Cytoscape. Among the hub genes, Lipocalin 2 (LCN2), Lactotransferrin (LTF), Olfactomedin 4 (OLFM4), Resistin (RETN), and Transcobalamin 1 (TCN1) were related to prognosis and connected with iron transport closely. LCN2 and LTF were involved in iron transport and had a moderate predictive value for the poor prognosis of trauma patients, and the AUC of LCN2 and LTF was 0.7777 and 0.7843, respectively.
As iron transport-related hub genes in blood leukocytes, LCN2 and LTF can be used for prognostic prediction of early trauma.
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