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Sepsis survivors present long-term cognitive deficits. The present study was to investigate the effect of early administration of high-dose vitamin C on cognitive function in septic rats and explore its possible cerebral protective mechanism. Rat sepsis models were established by cecal ligation and puncture (CLP). Ten days after surgery, the Morris water maze test was performed to evaluate the behavior and cognitive function. Histopathologic changes in the hippocampus were evaluated by nissl staining. The inflammatory cytokines, activities of antioxidant enzymes (superoxide dismutase or SOD) and oxidative products (malondialdehyde or MDA) in the serum and hippocampus were tested 24 h after surgery. The activity of matrix metalloproteinase-9 (MMP-9) and expressions of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1(HO-1) in the hippocampus were measured 24 h after surgery. Compared with the sham group in the Morris water maze test, the escape latency of sepsis rats was significantly (P = 0.001) prolonged in the navigation test, whereas the frequency to cross the platform and the time spent in the target quadrant were significantly (P = 0.003) reduced. High-dose vitamin C significantly decreased the escape latency (P = 0.01), but increased the time spent in the target quadrant (P = 0.04) and the frequency to cross the platform (P = 0.19). In the CLP+ saline group, the pyramidal neurons were reduced and distributed sparsely and disorderly, the levels of inflammatory cytokines of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-10 in the serum and hippocampus were significantly increased (P = 0.000), the blood brain barrier (BBB) permeability in the hippocampus was significantly (P = 0.000) increased, the activities of SOD in the serum and hippocampus were significantly (P = 0.000 and P = 0.03, respectively) diminished while the levels of MDA in the serum and hippocampus were significantly (P = 0.007) increased. High-dose vitamin C mitigated hippocampus histopathologic changes, reduced systemic inflammation and neuroinflammation, attenuated BBB disruption, inhibited oxidative stress in brain tissue, and up-regulated the expression of nuclear and total Nrf2 and HO-1. High-dose vitamin C significantly (P < 0.05) decreased the levels of tumor necrosis factor- (TNF)-α, interleukin-6 (IL-6), MDA in the serum and hippocampus, and the activity of MMP-9 in the hippocampus, but significantly (P < 0.05) increased the levels of SOD, the anti-inflammatory cytokine (IL-10) in the serum and hippocampus, and nuclear and total Nrf2, and HO-1 in the hippocampus. In conclusion, high-dose vitamin C can improve cognition impairment in septic rats, and the possible protective mechanism may be related to inhibition of inflammatory factors, alleviation of oxidative stress, and activation of the Nrf2/HO-1 pathway.

IntroductionMild cognitive impairment (MCI) and dementia impose a significant burden on individuals and their caregivers. Dyadic psychosocial education, which treats care recipients and their caregivers as a pair of active participants, has the potential to improve health outcomes for people with cognitive impairment and their caregivers. However, the results of recent studies on this subject are contradictory. We aim to evaluate the effectiveness of dyadic psychosocial education for people with MCI or dementia and their informal caregivers.Methods and analysisSix databases will be searched. We will include all randomised controlled trials that compare dyadic psychosocial education to usual care. The risk of bias will be assessed using the Cochrane Risk-of-Bias Assessment Tool (V.2). Meta-analyses, subgroup analyses and sensitivity analyses will be performed using Stata V.15.1. A narrative synthesis will be conducted if quantitative analysis is not feasible.Ethics and disseminationThis study and subsequent systematic review will not collect individual-level data and, therefore, do not require ethics committee approval. Peer-reviewed publications will disseminate the study results.PROSPERO registration numberCRD42024497554.

Background The longissimus dorsi muscle and backfat are important components of pork and complement each other in physiological function, significantly influencing key traits such as growth performance, carcass traits, and meat quality. While the transcriptomic atlas across different tissues in pigs has been widely studied, the underlying epigenetic regulatory mechanisms remain to be explored. In this study, we collected muscle and adipose tissues from hybrid offspring of lean-type (Western commercial pigs) and fat-type (Chinese indigenous pigs) pigs ( n  = 6) and performed integrated transcriptomic (RNA-seq) and DNA methylome (GM-seq) analysis to explore how DNA methylation coordinates tissue-specific differential gene expression. This has practical implications for optimizing breeding strategies and selecting superior breeds. Results Transcriptome sequencing identified 2,908 differentially expressed genes, which are primarily involved in collagen fibril organization, skeletal muscle contraction, and muscle organ development. Whole-genome DNA methylation sequencing identified 2,787 differentially methylated genes in the promoter region. Through integrative analysis, we found 571 genes that were shared, 390 of which showed a significant negative correlation between gene expression and promoter DNA methylation. These genes are mainly involved in cholesterol metabolism, PPAR signaling pathway, cytoskeleton in muscle cell, and calcium ion signaling pathways. Notably, we discovered that the differential expression of genes such as APOE , FABP4 , TNNI2 , and TNNT3 between tissues is negatively regulated by promoter DNA methylation. In other words, low methylation of these gene promoters in one tissue was associated with high expression, while high methylation of the promoter in the opposite tissue suppressed expression. Conclusions These results suggest that DNA methylation plays an extensive and subtle regulatory role in tissue-specific gene expression, thereby facilitating different tissues to execute their specific physiological functions. This study further enriches our understanding of the integrative mechanisms between epigenetic regulation and transcriptomics in pigs and provides important theoretical foundations for precision molecular breeding.

The design and development of novel titanium alloys for structural and biomedical applications require reliable thermodynamic and kinetic databases. In this study, diffusion behaviors of six Ti–X (X = Cr, Hf, Mo, Nb, V, Zr) binary systems were systematically investigated at temperatures from 800 to 1200 °C using a set of five Ti–TiAl–Cr–Hf–Mo–Nb–V–Zr diffusion multiples. Concentration profiles of the six Ti–X binary systems were collected from binary regions of the diffusion multiples using electron probe microanalysis (EPMA). Both interdiffusion and impurity (dilute) diffusion coefficients in the Ti-rich bcc phase of these systems were extracted from the concentration profiles using the forward-simulation method. Twenty impurity diffusion coefficients of all the six elements in bcc Ti as well as Ti in bcc Zr at different temperatures obtained from this study are in excellent agreement with the literature data. The interdiffusion coefficients obtained from this study are also in good agreement with previous literature results. The large amount of new experimental data obtained from this study will be essential for establishing the mobility databases for the design and development of advanced titanium alloys.

Background The dynamic interaction between cancer cells and tumour-associated macrophages (TAMs) in the hypoxic tumour microenvironment (TME) is an active barrier to the effector arm of the antitumour immune response. Cancer-secreted exosomes are emerging mediators of this cancer-stromal cross-talk in the TME; however, the mechanisms underlying this interaction remain unclear. Methods Exosomes were isolated with ExoQuick exosome precipitation solution. The polarizing effect of TAMs was evaluated by flow cytometry, western blot analysis, immunofluorescence staining and in vitro phagocytosis assays. Clinical cervical cancer specimens and an in vivo xenograft model were also employed. Results Our previous study showed that hypoxia increased the expression of ZEB1 in cervical squamous cell carcinoma (CSCC) cells, which resulted in increased infiltration of TAMs. Here, we found that hypoxia-induced ZEB1 expression is closely correlated with CD47-SIRPα axis activity in CSCC, which enables cancer cells to evade phagocytosis by macrophages and promotes tumour progression. ZEB1 was found to directly activate the transcription of the CD47 gene in hypoxic CSCC cells. We further showed that endogenous ZEB1 was characteristically enriched in hypoxic CSCC cell-derived exosomes and transferred into macrophages via these exosomes to promote SIRPα + TAM polarization. Intriguingly, exosomal ZEB1 retained transcriptional activity and reprogrammed SIRPα + TAMs via activation of the STAT3 signalling pathway in vitro and in vivo. STAT3 inhibition reduced the polarizing effect induced by exosomal ZEB1. Knockdown of ZEB1 increased the phagocytosis of CSCC cells by macrophages via decreasing CD47 and SIRPα expression. Conclusions Our results suggest that hypoxia-induced ZEB1 promotes immune evasion in CSCC by strengthening the CD47-SIRPα axis. ZEB1-targeted therapy in combination with CD47-SIRPα checkpoint immunotherapy may improve the outcomes of CSCC patients in part by disinhibiting innate immunity.

Abstract Yarrowia lipolytica is categorized as a generally recognized as safe (GRAS) organism and is a heavily documented, unconventional yeast that has been widely incorporated into multiple industrial fields to produce valuable biochemicals. This study describes the construction of a CRISPR-Cas9 system for genome editing in Y. lipolytica using a single plasmid (pCAS1yl or pCAS2yl) to transport Cas9 and relevant guide RNA expression cassettes, with or without donor DNA, to target genes. Two Cas9 target genes, TRP1 and PEX10, were repaired by non-homologous end-joining (NHEJ) or homologous recombination, with maximal efficiencies in Y. lipolytica of 85.6 % for the wild-type strain and 94.1 % for the ku70/ku80 double-deficient strain, within 4 days. Simultaneous double and triple multigene editing was achieved with pCAS1yl by NHEJ, with efficiencies of 36.7 or 19.3 %, respectively, and the pCASyl system was successfully expanded to different Y. lipolytica breeding strains. This timesaving method will enable and improve synthetic biology, metabolic engineering and functional genomic studies of Y. lipolytica.

The pressure drop characteristics of subcooled water were experimentally investigated in a circular cooling channel with and without a twisted tape (TT) under high heat fluxes, which was designed for the water-cooling structure of the divertor target in a tokamak device. The working medium was deionized water, and the main parameters were mass flux G = 3000–8000 kg·m−2·s−1, inlet pressure of the test section p = 3, 4.2, 5 MPa, equivalent one-side heating flux qe = 5~10 MW·m−2. The off-center circular channel is electrically heated to simulate the unilateral radiation heating on the divertor target by high-temperature plasma. The pressure drop experiment of vertical upward circular cooling channels under high and unilateral heat flux is carried out. The influences of the TT and system parameters such as qe, G, and p on the pressure drop of the test section (Δp) were discussed in detail. In the single-phase (SP) flow region, Δp is mainly affected by the TT, G, and qe. The pressure drop with a TT is significantly higher than that without a TT, a higher G and a lower qe lead to a greater Δp. In the subcooled boiling (SB) flow region, Δp is correlated with the TT, qe, G, and p: the influence of the TT and G decreases, while the influence of p increases. The higher the qe, the higher the G, and the lower the p, the larger the Δp. The results show that almost all of the SP pressure drop correlations for heated circular channels overestimate the experimental pressure drop coefficient ratio for a given viscosity ratio. According to the test results, a new correlation of SP pressure drop under high and unilateral heat fluxes has been proposed, the average error (AE) and root mean square error (RMSE) of which are 0.26% and 3.17%, respectively.

•Thinner temporalis muscle thickness is a novel radiographic biomarker of sarcopenia in patients with brain tumors.•Temporalis muscle thickness was an independent prognostic factor for overall survival in both primary and secondary brain tumors.•The association between thinner temporalis muscle thickness and progression-free survival was significant in patients with primary brain tumors. Sarcopenia has been identified as a prognostic factor among certain types of cancer. However, it is unclear whether there is prognostic value of temporalis muscle thickness (TMT), a potential surrogate for sarcopenia, in adults patients with brain tumors. Therefore, we searched the Medline, Embase, and PubMed to systematically review and meta-analyze the relationship between TMT and overall survival, progression-free survival, and complications in patients with brain tumors and the hazard ratio (HR) or odds ratios (OR), and 95% confidence interval (CI) were evaluated. The quality in prognostic studies (QUIPS) instrument was employed to evaluate study quality. Nineteen studies involving 4570 patients with brain tumors were included for qualitative and quantitative analysis. Meta-analysis revealed thinner TMT was associated with poor overall survival (HR, 1.72; 95% CI, 1.45–2.04; P < 0.01) in patients with brain tumors. Sub-analyses showed that the association existed for both primary brain tumors (HR, 2.02; 95% CI, 1.55-2.63) and brain metastases (HR, 1.39; 95% CI, 1.30-1.49). Moreover, thinner TMT also was the independent predictor of progression-free survival in patients with primary brain tumors (HR, 2.88; 95% CI, 1.85–4.46; P < 0.01). Therefore, to improve clinical decision making it is important to integrate TMT assessment into routine clinical settings in patients with brain tumors.

Parent-of-origin effects refer to the phenomenon whereby the gene expression and corresponding phenotype are influenced by paternal or maternal origin, and uncovering the underlying regulatory mechanisms remains a challenging task. To address this, we designed three sets of trio families by crossing divergent pig breeds to generate sufficient heterozygous loci and collected back fat and longissimus dorsi for multi-omics sequencing. Parental phases of sequencing reads are efficiently determined by leveraging long-read sequencing technology. We generate a phased multi-omics resource in hybrid pigs, identifying 10,516 phase-specific gene expressions, 104,708 methylated regions, 132,602 histone modifications, 25,667 CTCF binding sites, and, based on in situ Hi-C, 7884 topologically associated domain boundaries and 8573 chromatin loops. Our results reveal that, although nearly 83% of gene expression differences between parental phases are regulated by DNA methylation, a subset is still influenced by other epigenetic modifications. This study not only highlights complex imprinting regulation models of H19 - IGF2 and SGCE - PEG10 but also provides insight into the inheritance of advantageous traits in hybrid offspring. In modern agricultural breeding, parent-of-origin effects play a key role in the inheritance of genetic advantages in hybrid offspring and the formation of complex traits. Here, the authors crossed divergent pig breeds and integrate genomic, epigenomic, and chromatin architecture data to trace allele-specific expression and regulatory modifications across parental phasing.

To study the pressure drop characteristics of hypervapotron, which was designed as a water-cooling structure in the divertor dome of the fusion reactor, the pressure drop tests of subcooled water were carried out in a vertically upward hypervapotron. To simulate the one-side radiant heating condition in the engineering application, the non-uniform heat fluxes were obtained by using the off-center electrically heating method. The system parameters were as follows: mass flux G = 2000–5000 kg·m−2·s−1, inlet pressure p = 2–4 MPa, and equivalent one-side radiating heat flux qe = 0–5 MW·m−2. The effects of the parameters on the pressure drop were discussed in detail. It was observed that in the single-phase (SP) region, the pressure drop was little influenced by the inlet fluid temperature (Tb,in). However, in the subcooled boiling region, the pressure drop increased rapidly with the increasing Tb,in. A higher G leads to a high pressure drop. In the SP region, the influence of p on the pressure drop is not obvious, and the pressure drop decreased with the increasing qe. The test data are used to evaluate the typical pressure drop correlation, and the results show that none of these correlations can predict the pressure drop well under the test conditions. Therefore, a new pressure drop correlation is proposed for subcooled water in a hypervapotron under high and non-uniform heat fluxes. The new correlation has a high prediction accuracy for the test data, and the mean relative error (MRE) and root mean square error (RMSE) are 0.72% and 4.33%, respectively. The test results have a reference value for the design of the water-cooling structure of the diverter.