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Abstract Oral squamous cell carcinoma (OSCC) is the sixth most common malignancy worldwide. Abnormal epigenetic modifications, including DNA methylation, are hallmarks of cancer and implicated in the development of various tumors. DNA methylation is catalyzed by the DNA methyltransferase and ten-eleven translocation dioxygenase families, with DNMT3A and TET2 being the most widely studied members, respectively. The correlation of methylation β values and clinical features was conducted in patients with OSCC in The Cancer Genome Atlas database. DNA methylation and protein expression levels of DNMT3A and TET2 in tissues were analyzed with methylation-specific polymerase chain reaction (MSP) and western blotting. To evaluate the effects of DNMT3A and TET2 on the biological characteristics of OSCC, cell proliferation was assessed with 5-ethynyl-2'-deoxyuridine, and cell migration capacity was quantified with wound healing and transwell assays. A survival analysis was performed with the Kaplan–Meier approach. The correlation between different methylation β values and clinical features was revealed. MSP revealed varying methylation degrees of DNMT3A and TET2 in OSCC tissues. Furthermore, western blotting showed that the protein expression levels were significantly different in cancer and surrounding healthy tissue samples. In vitro experiments demonstrated that DNMT3A knockdown and TET2 overexpression could inhibit the proliferation and migration of OSCC. Survival analysis revealed that patients with high DNMT3A methylation levels showed higher survival rates.

Abstract Multiferroic materials offer a promising avenue for manipulating digital information by leveraging the cross-coupling between ferroelectric and ferromagnetic orders. Despite the ferroelectricity has been uncovered by ion displacement or interlayer-sliding, one-unit-cell of multiferroic materials design and wafer-scale synthesis have yet to be realized. Here we develope an interface modulated strategy to grow 1-inch one-unit-cell of non-layered chromium sulfide with unidirectional orientation on industry-compatible c-plane sapphire. The interfacial interaction between chromium sulfide and substrate induces the intralayer-sliding of self-intercalated chromium atoms and breaks the space reversal symmetry. As a result, robust room-temperature ferroelectricity (retaining more than one month) emerges in one-unit-cell of chromium sulfide with ultrahigh remanent polarization. Besides, long-range ferromagnetic order is discovered with the Curie temperature approaching 200 K, almost two times higher than that of bulk counterpart. In parallel, the magnetoelectric coupling is certified and which makes 1-inch one-unit-cell of chromium sulfide the largest and thinnest multiferroics.

To enhance the chemical mechanical polishing (CMP) efficiency of flexible display substrates, a polishing slurry based on ferric chloride and oxalic acid was proposed for polishing 304 stainless steel substrates. An orthogonal optimization test was designed to determine the significance order of the influence of abrasive size, abrasive content, oxalic acid content and ferric chloride content on the material removal rate (MRR) and surface roughness (surface arithmetical mean height of area, Sa). The aim was to investigate the effects of ferric chloride and oxalic acid on MRR. An optimized polishing slurry capable of achieving an MRR of over 560 nm/min and a Sa as low as 8 nm after 30 min was obtain. Compared with the conventional polishing slurry, whose MRR is 226.56 nm/min, the novel slurry has doubled its polishing efficiency or more.

The difunctionalization of diazo compounds, traditionally with one nucleophile and one electrophile, is a powerful strategy. Here, the authors develop a path of electrochemical oxidative difunctionalization of diazo compounds with two different nucleophiles.

Internal discharges in composite insulators often cause abnormal heating, interface failure and erosion of the core rod. However, the mechanism and the exact process of the degradation of HTV shed and FRP core rod caused by internal discharges are still unclear. In this work, abnormal heating insulator samples are taken from an AC 500 kV extra-high voltage (EHV) transmission line. Macro- and micro-scopic morphological observation, hardness tests, industrial CT tests and chemical property tests are applied on the samples. The cause of heating and the deterioration mechanism of each part of insulators is further explored. Cavities and air holes are found in the HTV skirts in this batch of insulators, which are generated during manufacturing. These cavities lead to the distortion of electrical field and become the origin of the discharges. Decomposition of polydimethylsiloxane leads to the hardening and chalking of the HTV shed. It is also found that the adhesive in the rod-housing interface fails during operation. Epoxy resin in core rod decomposes in a multi-factor aging environment, leading to the decay-like aging of the core rod surface. As the aging progress develops inward, the insulator will eventually lose its mechanical properties. It is inferred that the internal discharge is the main reason of heating and deterioration of composite insulators. Moreover, long-term discharge will lead to the decay-like aging of core rods.

Abstract Background Immune cells and stromal cells in the tumor microenvironment play a vital role in the progression of colorectal cancer (CRC). The study aimed to screen valuable prognostic biomarkers in CRC based on stromal and immune scores. Method The ESTIMATE algorithm was used to calculate the immune and stromal scores of CRC samples in TCGA. Then samples were divided into high and low score groups based on the median value of the scores. Differentially expressed genes (DEGs) associated with immune and stromal scores were screened. WGCNA and univariate COX regression analysis were performed to further identify key prognostic genes. Analysis of scRNA-seq for CRC was used for verifying the main source of the key genes. The prognostic value of they was validated based on The Gene Expression Profiling Interactive Analysis and GSE17536 dataset. TIMER and CIBERSORT algorithms were applied to analyze the correlations among key genes and tumor-infiltrating immune cells. Several pairs of colon cancer tissue were used to be proven. Result 1314 upregulated and 4 downregulated genes were identified, which were significantly enriched in immune-related biological processes and pathways. Among these DEGs, SPOCK1 and POSTN were identified as key prognostic genes and mainly expressed in cancer-associated fibroblasts for CRC. High expression of SPCOK1 and POSTN was associated with advanced clinical stage, T stage, N stage, and poor prognosis of CRC. The results from CIBERSORT and TIMER revealed that SPOCK1 and POSTN were associated with tumor-infiltrating immune cells, especially macrophages and neutrophils. Meanwhile, in several pairs of human colorectal tissue samples, SPOK1 and POSTN were found to be significantly overexpressed in colorectal tissue compared with para-cancer tissue, and macrophage surface markers CD68 (co-expressed by M1 and M2 macrophages) and CD206 (M2-specific macrophage expression) were also overexpressed in cancer tissue. Besides, SPOCK1 and POSTN expression were positively correlated with the expression of immune checkpoints. Conclusion Collectively, our results indicate that SPOCK1 and POSTN associated with CAF may be novel prognostic biomarkers in CRC and correlate with immune infiltrates.

Abstract Salmonella enterica serovar Enteritidis (S. Enteritidis) can colonize in the intestinal tract of chickens and transmit to humans. In order to decrypt the mechanism of avian resistance to S. Enteritidis, we utilized two China local chicken breeds to generate the reciprocal crosses (the Cross and the Reverse‐cross). The two lines of hybrids were orally inoculated with S. Enteritidis at 2‐day old and sampled at 3 days post‐inoculation. Along the analysis direction of multi‐omics, differential metabolites, functional pathways and correlated microbes, we found that 12 species of microbes thrived upon S. Enteritidis challenge and probably contributed to the intestinal stability in the Cross by enhancing the production of phenylpropanoids. Our findings can help to understand the symbiotic and resistant mechanisms derived from the intestinal microbiota.

Abstract Signal‐amplified imaging of microRNAs (miRNAs) is a promising strategy at the single‐cell level because liquid biopsy fails to reflect real‐time dynamic miRNA levels. However, the internalization pathways for available conventional vectors predominantly involve endo‐lysosomes, showing nonideal cytoplasmic delivery efficiency. In this study, size‐controlled 9‐tile nanoarrays are designed and constructed by integrating catalytic hairpin assembly (CHA) with DNA tile self‐assembly technology to achieve caveolae‐mediated endocytosis for the amplified imaging of miRNAs in a complex intracellular environment. Compared with classical CHA, the 9‐tile nanoarrays possess high sensitivity and specificity for miRNAs, achieve excellent internalization efficiency by caveolar endocytosis, bypassing lysosomal traps, and exhibit more powerful signal‐amplified imaging of intracellular miRNAs. Because of their excellent safety, physiological stability, and highly efficient cytoplasmic delivery, the 9‐tile nanoarrays can realize real‐time amplified monitoring of miRNAs in various tumor and identical cells of different periods, and imaging effects are consistent with the actual expression levels of miRNAs, ultimately demonstrating their feasibility and capacity. This strategy provides a high‐potential delivery pathway for cell imaging and targeted delivery, simultaneously offering a meaningful reference for the application of DNA tile self‐assembly technology in relevant fundamental research and medical diagnostics.

IntroductionExpressed emotion refers to relatives' attitudes and emotional behaviors toward mentally ill family members. It is a robust predictor of patients' illness outcomes and caregivers' wellbeing in a wide range of mental disorders. However, expressed emotion has not been fully explored in the Chinese context. One reason is the lack of reliable and cost-effective measurements. A reliable, valid, and user-friendly instrument is needed to support the research and clinical practice based on expressed emotion in China. This study aimed to translate, adapt, and examine the psychometric properties (factorial structure, measurement invariance, internal consistency reliability, and concurrent validity) of a Chinese version of the Family Questionnaire.MethodsA total of 248 caregivers participated in the study. A translation and back-translation procedure was applied to translate the Family Questionnaire into Chinese. We compared two models to examine the factor structure of the questionnaire by performing confirmatory factor analysis. We also conducted measurement invariance analysis to test whether the factor structure of the tool is invariant across male and female groups. Reliability was evaluated with Cronbach's α. The concurrent validity was examined by testing the predictivity of the expressed emotion on relevant outcomes with path analysis. We used the STROBE checklist to report.ResultsThe item-total correlation coefficients of the scale ranged from 0.375 to 0.752. The confirmatory factor analysis indicated that the Chinese version of the Family Questionnaire displays the original two-factor structure (emotional overinvolvement and criticism; X2 = 335.50, df = 169, X2/df = 1.985, RMSEA = 0.063, SRMR = 0.058, CFI = 0.913, and TLI = 0.902). In addition, the two-factor structure was invariant across the male and female groups. The two subscales showed excellent internal consistency, with Cronbach's alpha of 0.92 for both emotional overinvolvement and criticism. The concurrent validity of the Chinese version was supported by the good predictivity of the two subscales to care burden, family function, and quality of life. All path coefficients were significant, and the absolute values of path coefficients ranged from 0.23 to 0.72.ConclusionThe Chinese version of the Family Questionnaire is a valid and reliable measurement of expressed emotion in the Chinese context.

The emerging outbreak of bacterial diseases poses a major threat to the aquaculture industry, and the abuse of antibiotics leads to the emergence of drug-resistant pathogens; hence, the development of antibacterial agents from natural resources to control and manage fish bacterial diseases has become a promising strategy. In this study, seven potential Streptomyces spp. with antimicrobial activity against fish pathogenic bacteria were isolated from the soils of different regions in China. Streptomyces termitum N-15, which showed the strongest and most stable antibacterial activity, was selected for the fish disease control experiment. Then, we investigated the effect of a basal diet and N-15 supplementation (108 ​CFU/mg diet) on growth performance, blood immune parameters (ACP and AKP), and the expression of immune genes. The results demonstrated that the ACP and AKP activities of serum were significantly increased in the N-15-supplemented group. Moreover, N-15 upregulated the expression level of Toll-like receptor 4 (TLR-4) in the kidney, liver, spleen and head kidney. The challenge test showed that supplementation with N-15 could significantly improve the survival rates of grass carp infected with A. veronii. Chalcomycin A was purified from Streptomyces termitum N-15 and found to have antimicrobial activity against fish pathogenic bacteria for the first time. Furthermore, the complete genome of S. termitum N-15 was found to consist of an 8,887,222 bp circular chromosome with 72.89% GC content and a plasmid genome, including 7744 protein-coding sequences (CDSs). The genome of S. termitum N-15 contained gene clusters for the synthesis of multiple secondary metabolites, including melingomycin, sulforaphane, oromycin, chlortetracycline, isomycin, and primycin, by antiSMASH online software. Gene cluster 1.5 revealed a chalcomycin A biosynthesis gene cluster (chmGⅠ, chmGⅡ, chmGⅢ, chmGⅣ, chmGⅤ). In summary, S. termitum N-15 and its secondary metabolites are expected to be developed into inoculants for promoting fish health in aquacultural systems.

Abstract Background Studies have shown that DAB2IP inhibits cancer progression, while HSP90AA1 promotes cancer progression. However, the specific regulatory mechanism of DAB2IP and HSP90AA1 in colorectal cancer (CRC) is not clear. Our aim is to investigate the role and mechanism of DAB2IP and HSP90AA1 in the development of CRC. Methods We used bioinformation to analyze the interaction between DAB2IP and HSP90AA1 and predict their downstream pathways. Then, a series of in vitro and in vivo experiments were conducted to reveal the role of DAB2IP and HSP90AA1 in the invasion and metastasis of colorectal cancer, and flow cytometry was used to explore their effects on apoptosis. Results Loss of DAB2IP was associated with poor prognosis of CRC. In contrast, elevated expression of HSP90AA1 was associated with the malignant behavior of CRC. The present study demonstrated a negative correlation between DAB2IP and HSP90AA1. Using bioinformatic analysis, we scanned SRP9 which was highly expressed in CRC, as a co-related gene of DAB2IP and HSP90AA1. Mechanistically, DAB2IP promoted apoptosis through HSP90AA1/SRP9/ASK1/JNK signaling axis in CRC. Conclusions These findings provide evidence that DAB2IP-based therapy may enhance the anticancer effect of HSP90AA1 inhibitors, and combined targeting of DAB2IP and HSP90AA1 may be a powerful treatment strategy to combat CRC.

With the popularization of autonomous vehicle (AV) technology, mixed traffic flows that consist of AVs and human-driven vehicles (HDVs) will appear in the real world. Although many studies of the features of mixed traffic flow have been carefully evaluated, few studies have focused on the effect of aggressive driving performance on mixed traffic flow. This study aims to develop an approach to evaluate the effects of aggressive driving on the stability and capacity performance under the conditions of AV and HDV mixed traffic flow. First, since a car-following model can describe the relationship between vehicles, we calibrate a car-following model for aggressive driving and nonaggressive driving behaviors based on real traffic data and previous research results. Then, in a mixed traffic flow environment, a basic linear stability formula and capacity calculation expression are developed that consider the effects of vehicle order on the capacity. Finally, because the proportion of aggressive driving and aggressive driving parameters may change, nine combinations of three aggressive driving proportions and three driving parameter cases are used for the sensitivity analysis. The results indicate that the effect of aggressive driving on mixed traffic flow is complex. When the proportion of aggressive driving is less than 35%, the increase in the proportion of aggressive driving increases the traffic capacity and reduces the unstable part. However, when the proportion of aggressive driving is greater than 35%, the increase in the proportion of aggressive driving increases the unstable part. When the penetration rate of AVs exceeds 0.490, mixed traffic flow remains stable at all aggressive driving proportions. In addition, the capacity of a mixed traffic flow may be improved as the penetration rate of AVs increases. To a certain extent, these conclusions provide a theoretical basis for formulating different management modes of AVs and HDVs.

This study investigates the impact of various sources of social support on the mental health of unaccompanied children under residential education in China. Unaccompanied children refer to those whose parents are still alive but unable to raise them due to various reasons. The study utilized self-reported questionnaires administered at two time waves, with the first wave (T1) evaluating family support, teacher support, and peer support, and the second wave (T2) evaluating depression, subjective well-being, and resilience. A total of 202 participants completed both surveys. To examine the predictive effect of different sources of social support on the mental health of these children, the study used the structural equation model with depression and subjective well-being as indicators. The results show that neither family support nor teacher support (T1) had a significant effect on the mental health (T2) of the children. However, peer support (T1) had a significant positive predictive effect on mental health (T2), indicating the unique role of peer support in promoting the mental health of unaccompanied children. The study also explored the mediating role of resilience between social support and well-being, revealing that though the direct effect of teacher support (T1) on mental health (T2) was not significant, the indirect mediating effect of resilience on the relationship between teacher support and mental health was significant. Both the direct and indirect effect of family support (T1) on mental health (T2) were not significant. These findings highlight the importance of creating a positive peer environment for unaccompanied children to promote their mental health. This study has important practical implications for the development of effective intervention programs aimed at improving the mental health of this population.

High-temperature vulcanized silicone rubber (HTV-SR) employed for composite insulators is continuously subjected to a complex environment of alternating heat, corona discharge, humidity, etc. These stresses (especially alternating heat) complicate the aging mechanism of HTV-SR, which lacks systematic investigation. In this paper, a multi-factor aging platform considering temperature cycling, moisture, and corona discharge is established. Specifically, four temperature-cycling settings are employed, each of which lasts for 15 cycles. The surface morphology, hydrophobicity, and chemical, mechanical, and electrical properties of aged samples are methodically characterized. Experimental results show that the aging degree is correlated to the range of temperature cycling, which is attributed to diverse crosslink-degradation degrees with different temperature differences. Under a large temperature difference (70 °C), HTV-SR possesses a high crosslinking degree and a low degradation degree, making the material hard but easy to crack with alternating thermal stress. Then, severe defects and water condensation emerge on the HTV-SR surface, which promote the diffusion of corona products and water molecules into the material. The subsequent rise in crosslinking density caused by in-depth oxidation further exacerbates the aging of the material. Consequently, it brings about poor hydrophobicity, high interfacial polarization, and shallow trap energy levels in HTV-SR. This work provides a detailed analysis of the aging mechanism of HTV-SR in a simulated on-site environment.

By combining the experiments of reciprocal crosses of chicken infected with Salmonella enterica serovar Enteritidis (S. Enteritidis), we focused on the common response of cecal microbiota to an inflammatory state in respect of transcriptome and microbiome. The inoculation of S. Enteritidis improved the microbial diversity and promoted the microbiota evolution in our infection model. Correlation analysis between bacteria and inflammation-related genes showed that some intestinal microorganisms were “inflammophile” and thrived in an inflamed environment. The global function of cecal microbiome was to maintain the homeostasis likely by the up-regulation of microbial metabolism pathway in bacitracin, putrescine, and flavonoids production, although the bacitracin may affect the symbiotic bacteria Enterococcus. The action of S. Enteritidis had close relationships with multiple inflammation-related genes, including the genes PTAFR, LY96, and ACOD1 which proteins are related to the binding and tolerance of LPS, and the genes IL-18, IL-18R1 and IL-18RAP which products can form a functional complex and transmit IL-18 pro-inflammatory signal. Additionally, the infection of S. Enteritidis aroused the transcription of EXFABP, which protein has a potential to sequestrate the siderophore and might cause the decline of Escherichia-Shigella and Enterococcus. S. Enteritidis can escape from the sequestrating through the salmochelin, another kind of siderophore which cannot be recognized by EXFABP. Probably by this way, S. Enteritidis competed with the symbiotic bacteria and edged out the niches. Our research can help to understand the interplay between host, pathogen, and symbiotic bacteria.

BackgroundIncreasing attention has been paid to the role of caregivers’ burden in affecting quality of life (QoL) of schizophrenic patients. However, less is known about potential mediation mechanisms underlying this relationship. The current study aimed to explore the sequential mediating effect of expressed emotion and perceived expressed emotion on the relationship between care burden and QoL among people with schizophrenia.Methods135 Chinese families (one patient and one caregiver) participated in this study. Caregivers reported their care burden and expressed emotion, patients reported their perceived expressed emotion and QoL.ResultsThe results of the correlation analysis showed that care burden was negatively related to patients’ QoL, including physical, psychological, and social relationships domains, with patients’ sex, age, educational level, employment status, and medication-taking as covariates. The sequential mediating effects of criticism and perceived criticism between care burden and QoL were not significant. However, the sequential mediating effects of emotional over-involvement and perceived emotional over-involvement (EOI) between care burden and QoL (including physical and psychological domain) were significant.ConclusionThe results indicated that reducing the burden and expressed emotion of caregivers could be helpful to improve schizophrenia patients’ QoL.

Background: In China, bereaved parents who have lost their only child are known as Shidu parents, and they tend to present high levels of prolonged grief reactions. To date, a widespread focus has been placed on positive social support, while potential negative experiences have been relatively neglected. Additionally, the role of social support from different sources (i.e. close family members [partner, siblings, grandchildren], peers, and others [relatives, friends, colleagues]) has not been examined thoroughly. Objective: The present study investigated whether social support from different sources has a differential impact on postloss adaptation (i.e. prolonged grief and growth). The loss-orientated and restoration-orientated coping strategies of the dual process model were also tested for their mediating roles. Methods: A total of 277 Chinese Shidu parents were recruited to complete a series of questionnaires including social support from different sources, prolonged grief symptoms, posttraumatic growth, and dual process coping strategies. Correlation analyses, paired sample t tests and structural equation modelling were conducted. Results: More positive support were related to less prolonged grief symptoms and more posttraumatic growth, while more negative support was only related to more prolonged grief. Positive support from close family members and others was significantly related to prolonged grief/growth, and negative support from these sources was significantly positively associated with prolonged grief. Positive or negative support from people who shared a similar experience was unrelated to prolonged grief/growth. Positive and negative support were related to prolonged grief and growth through loss-oriented coping strategies. Conclusion: Overall, the present study indicated that positive and negative support experiences from different sources functioned differently in the recovery of Chinese Shidu parents and that loss-oriented coping played a mediating role. These findings highlight the importance of differentiating social support by traits in coping with grief and the crucial mediating role of loss-oriented coping. HIGHLIGHTS More positive support correlated with less prolonged grief and more growth, while more negative support correlated with more prolonged grief. Support from family members and friends was more potent than that from peers. Social Support correlated with prolonged grief/growth through loss-oriented coping.

N6-methyladenosine (m6A) RNA modification regulates RNA metabolism, and has been implicated in immune regulation. Here, the authors show that the m6A methyltransferase, METTL3, translocates into the cytoplasm to increase viral RNA m6A modification, decreases viral ds RNA content, and thereby dampens the RIG/MDA5-induced anti-viral immunity.

Abstract Background Hepatocellular carcinoma (HCC) is one of the most prevalent and inflammation-associated cancers. The tumor microenvironment (TME) plays an essential role in HCC development and metastasis, leading to poor prognosis. The overall TME immune cells infiltration characterizations mediated by immune-related genes (IRGs) remain unclear. In this study, we aimed to investigate whether immune-related genes could be indicators for the prognosis of HCC patients and TME cell infiltration characterization as well as responses to immunotherapy. Methods We obtained differentially expressed immune-related genes (DE IRGs) between normal liver tissues and liver cancer tissues from The Cancer Genome Atlas (TCGA) database. To identify the prognostic genes and establish an immune risk signature, we performed univariable Cox regression survival analysis and the Least Absolute Shrinkage and Selector Operation (LASSO) regression based on the DE IRGs by robust rank aggregation method. Cox regression analysis was used to identify independent prognostic factors in HCC. We estimated the immune cell infiltration in TME via CIBERSORT and immunotherapy response through TIDE algorithm. Results We constructed an immune signature and validated its predictive capability. The immune signature included 7 differentially expressed IRGs: BIRC5, CACYBP, NR0B1, RAET1E, S100A8, SPINK5, and SPP1. The univariate and multivariate cox analysis showed that the 7-IRGs signature was a robust independent prognostic factor in the overall survival of HCC patients. The 7-IRG signature was associated with some clinical features, including gender, vascular invasion, histological grade, clinical stage, T stage. We also found that the 7-IRG signature could reflect the infiltration characterization of different immunocytes in the tumor microenvironment (TME) and had a good correlation with immune checkpoint molecules, revealing that the poor prognosis might be partly due to immunosuppressive TME. The Tumour Immune Dysfunction and Exclusion (TIDE) analysis data showed that the 7-IRG signature had great potential for indicating the immunotherapy response in HCC patients. The mutation analysis demonstrated a significant difference in the tumor mutation burden (TMB) between the high- and low-risk groups, partially explaining this signature's predictive value. Conclusion In a word, we constructed and validated a novel, immune-related prognostic signature for HCC patients. This signature could effectively indicate HCC patients' survival and immunotherapy response. And it might act as potential immunotherapeutic targets for HCC patients.

Ferroptosis, a type of cell death triggered by excessive accumulation of iron-dependent lipid peroxidation, possesses an excellent potential in cancer treatment. However, many colorectal cancer (CRC) cell lines are resistant to ferroptosis induced by erastin and RSL3, the classical ferroptotic inducers. Moreover, the underlying mechanism of resistance remains poorly elucidated. This study sought to discover the major factor contributing to ferroptosis resistance in CRC. The study findings will help design strategies for triggering ferroptosis for application in individualized tumor therapy. Here, we show that tetrahydrobiopterin (BH4) determines the sensitivity of CRC cells to ferroptosis induced by erastin. GTP cyclohydrolase-1 (GCH1) is the first rate-limiting enzyme of BH4. Genetic or pharmacological inhibition of GCH1 decreased BH4 and assisted erastin in cell death induction, lipid peroxidation enhancement, and ferrous iron accumulation. BH4 supplementation completely inhibited ferroptotic features resulting from GCH1 knockdown. Unexpectedly, GCH1 knockdown failed to enhance RSL3-induced cell death in CRC. Mechanistically, GCH1 knockdown drastically activated ferritinophagy during erastin treatment rather than RSL3 treatment. Administration of an autophagy inhibitor reversed erastin resistance in GCH1-knockdown cells. GCH1 inhibitor and erastin co-treatment in vivo synergistically inhibited tumor growth in CRC. Overall, our results identified GCH1/BH4 metabolism as a burgeoning ferroptosis defense mechanism in CRC. Inhibiting GCH1/BH4 metabolism promoted erastin-induced ferroptosis by activating ferritinophagy, suggesting that combining GCH1 inhibitors with erastin in the treatment of CRC is a novel therapeutic strategy.

Abstract Background The development of new treatment strategies to improve peripheral nerve repair after injury, especially those that accelerate axonal nerve regeneration, is very important. The aim of this study is to elucidate the molecular mechanisms of how bone marrow stromal cell (BMSC)-derived exosomes (EXOs) participate in peripheral nerve regeneration and whether the regenerative effect of EXOs is correlated with dose. Method BMSCs were transfected with or without an siRNA targeting Ago2 (SiAgo2). EXOs extracted from the BMSCs were administered to dorsal root ganglion (DRG) neurons in vitro. After 48 h of culture, the neurite length was measured. Moreover, EXOs at four different doses were injected into the gastrocnemius muscles of rats with sciatic nerve crush injury. The sciatic nerve functional index (SFI) and latency of thermal pain (LTP) of the hind leg sciatic nerve were measured before the operation and at 7, 14, 21, and 28 days after the operation. Then, the number and diameter of the regenerated fibers in the injured distal sciatic nerve were quantified. Seven genes associated with nerve regeneration were investigated by qRT-PCR in DRG neurons extracted from rats 7 days after the sciatic nerve crush. Results We showed that after 48 h of culture, the mean number of neurites and the length of cultured DRG neurons in the SiAgo2-BMSC-EXO and SiAgo2-BMSC groups were smaller than that in the untreated and siRNA control groups. The average number and diameter of regenerated axons, LTP, and SFI in the group with 0.9 × 1010 particles/ml EXOs were better than those in other groups, while the group that received a minimum EXO dose (0.4 × 1010 particles/ml) was not significantly different from the PBS group. The expression of PMP22, VEGFA, NGFr, and S100b in DRGs from the EXO-treated group was significantly higher than that in the PBS control group. No significant difference was observed in the expression of HGF and Akt1 among the groups. Conclusions These results showed that BMSC-derived EXOs can promote the regeneration of peripheral nerves and that the mechanism may involve miRNA-mediated regulation of regeneration-related genes, such as VEGFA. Finally, a dose-effect relationship between EXO treatment and nerve regeneration was shown.

Background: Ulcerative colitis (UC) is a chronic recurrent disease of unknown etiology. Recently, it has been reported that autophagy-related gene polymorphism is closely associated with increased risk of UC, and the therapeutic effect of some UC drugs is mediated by regulating autophagy pathways. This study aims to identify pivotal autophagy-related regulators in UC pathogenesis and provide novel molecular targets for the treatment of active UC.Methods: Gene expression profiles and clinical information of active UC patients were obtained from GEO databases. CIBERSORT was adopted to evaluate the immune cell infiltration. We used weighted gene co-expression network analysis (WGCNA) and differential expression analysis to identify the pivotal modules and genes associated with active UC. Subsequently, we conducted validation in the validation set and explored its relationship with commonly used UC therapeutics.Results: 36 healthy controls and 46 active UC patients have been obtained from the training set of GSE53306, GSE87466, and GSE134025. There were 423 differentially expressed genes (DEGs) found, which dramatically enriched in autophagy-related pathways. And more infiltration of mast cells, activated T cells, dendritic cells, and M1 macrophages were observed in the intestinal mucosa of active UC, while more infiltration of resting immune cells and M2 macrophages in healthy controls. WGCNA indicated that the turquoise and blue modules were the critical modules. CASP1, SERPINA1, and CCL2 have been identified as the hub autophagy-related genes of active UC, after combining DEGs and 232 autophagy-related genes from HADb with the genes of turquoise and blue modules, respectively. We further verified that CASP1, SERPINA1, and CCL2 were positively associated with active UC and served as an autophagy-related biomarker for active UC. Moreover, increased SERPINA1 in the involved intestinal mucosa was reduced in patients with active UC who responded to golimumab or glucocorticoid therapy. But, neither CASP1, SERPINA1, and CCL2 were changed by treatment of 5-aminosalicylic acid (5-ASA) and azathioprine.Conclusion: CASP1, SERPINA1, and CCL2 are autophagy-related hub genes of active UC. And SERPINA1 may serve as a new pharmacological autophagy regulator of UC, which provides a new target for the use of small molecules targeting autophagy in the treatment of active UC.

Summary: Activation of nucleic acid sensing Toll-like receptors (TLRs) in B cells is involved in antiviral responses by promoting B cell activation and germinal center responses. In order to take advantage of this natural pathway for vaccine development, synthetic pathogen-like antigens (PLAs) constructed of multivalent antigens with encapsulated TLR ligands can be used to activate B cell antigen receptors and TLRs in a synergistic manner. Here we report a PLA-based coronavirus disease 2019 (COVID-19) vaccine candidate designed by combining a phage-derived virus-like particle carrying bacterial RNA as TLR ligands with the receptor-binding domain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) S protein as the target antigen. This PLA-based vaccine candidate induces robust neutralizing antibodies in both mice and non-human primates (NHPs). Using a NHP infection model, we demonstrate that the viral clearance is accelerated in vaccinated animals. In addition, the PLA-based vaccine induces a T helper 1 (Th1)-oriented response and a durable memory, supporting its potential for further clinical development.

Colorectal cancer (CRC) is one of the most common malignant carcinomas worldwide with poor prognosis, imposing an increasingly heavy burden on patients. Previous experiments and epidemiological studies have shown that vitamin D and vitamin D-related genes play a vital role in CRC. Therefore, we aimed to construct a vitamin D-related gene signature to predict prognosis in CRC. The CRC data from The Cancer Genome Atlas (TCGA) was performed as the training set. A total of 173 vitamin D-related genes in the TCGA CRC dataset were screened, and 17 genes associated with CRC prognosis were identified from them. Then, a vitamin D-related gene signature consisting of those 17 genes was established by univariate and multivariate Cox analyses. Moreover, four external datasets (GSE17536, GSE103479, GSE39582, and GSE17537) were used as testing set to validate the stability of this signature. The high-risk group presented a significantly poorer overall survival than low-risk group in both of training set and testing sets. Besides, the areas under the curve (AUCs) for signature on OS in training set at 1, 3, and 5 years were 0.710, 0.708, 0.710 respectively. The AUCs of the ROC curve in GSE17536 for 1, 3, and 5 years were 0.649, 0.654, and 0.694. These results indicated the vitamin D-related gene signature model could effectively predict the survival status of CRC patients. This vitamin D-related gene signature was also correlated with TNM stage in CRC clinical parameters, and the higher risk score from this model was companied with higher clinical stage. Furthermore, the high accuracy of this prognostic signature was validated and confirmed by nomogram model. In conclusion, we have proposed a novel vitamin D-related gene model to predict the prognosis of CRC, which will help provide new therapeutic targets and act as potential prognostic biomarkers for CRC.

Hemorrhagic chronic radiation proctopathy (CRP) is a common complication after pelvic radiotherapy in patients with prostate or gynecological cancers. This systematic review was conducted to evaluate the efficacy and safety of argon plasma coagulation (APC) in treating hemorrhagic CRP. The databases of PubMed, Embase, and Cochrane Library were searched for related studies from inception to July 2017. Finally, 33 studies were identified with a total of 821 hemorrhagic CRP patients. After APC treatment, hemoglobin levels increased from 7.7–13.4 g/L to 11–14 g/L (including 15 studies). All (n=33) studies reported an effective rate in rectal bleeding, among which five studies had a rate of 100%. Short-term complications were reported in 31 studies, while long-term complications in 33 studies and no complication in 11 studies. As for the severe complications, perforation was reported by 2 out of 33 studies, and the incidences were 3.3% (1/30) and 3.7% (1/27), respectively. As for APC setting, argon gas flow rate (median 1.5 L/min) and electric power (median 50 W) had no significant influence on complications and hemostasis. In conclusion, current literature indicated that APC therapy was an effective and safe strategy for hemorrhagic CRP, and large-scale prospective studies are needed to warrant our study.

Mouse embryonic fibroblasts (MEFs) and human foreskin fibroblasts (HFFs) are used for the culture of human embryonic stem cells (hESCs). MEFs and HFFs differed in their capacity to support the proliferation and pluripotency of hESCs and could affect cardiac differentiation potential of hESCs. The aim of this study was to evaluate the effect of MEFs and HFFs feeders on dopaminergic differentiation of hESCs lines. To minimize the impact of culture condition variation, two hESCs lines were cultured on mixed feeder cells (MFCs, MEFs: HFFs =1:1) and HFFs feeder respectively, and then were differentiated into DA neurons under the identical protocol. Dopaminergic differentiation was evaluated by immunocytochemistry, quantitative fluorescent real-time PCR (qRT-PCR), transmission and scanning electron microscopy, and patch clamp. Our results demonstrated that these hESCs-derived neurons were genuine and functional DA neurons. However, compared to hESCs line on MFCs feeder, hESCs line on HFFs feeder had a higher proportion of TH positive cells and expressed higher levels of FOXA2, PITX3, NURR1 and TH genes. In addition, the values of threshold intensity and threshold membrane potential of DA neurons from hESCs line on HFFs feeder were lower than those of DA neurons from hESCs line on the MFCs feeder. In conclusion, HFFs feeder not only facilitated the differentiation of hESCs cells into dopaminergic neurons, but also induced hESCs-derived DA neurons to express higher electrophysiological excitability. Therefore, feeder cells could affect not only dopaminergic differentiation potential of different hESCs lines, but also electrophysiological properties of hESCs-derived DA neurons.

Aiming at the large carbon emissions of facility agricultural heating in severe cold regions in winter, a compound parabolic concentrator based soil heating system was presented. The system integrated with novel trough compound parabolic concentrator and was used for soil heating in facility agriculture. Following the structure of the compound parabolic concentrator, TracePro software was selected to trace the light in the compound parabolic concentrator. The variation trend of the light escape rate of the compound parabolic concentrator with the different incident angles was analyzed. Based on the calculation results, the performance of the solar collector system was investigated, and the impact of circulating air velocity on the photo-thermal performance of the solar collector system was explored. Research results indicate that when the circulating air velocity is 1.4 m/s and the average ambient temperature is about 28.9 °C, the temperature of the system outlet is up to 90.9 °C. The average instantaneous heat collection, maximum photo-thermal conversion efficiency, and unit area heat collection of the system are 740.6 W, 27.83%, and 0.8 MJ/m², respectively. This research can effectively promote the efficient integration of the solar collector system in facility agriculture. [ABSTRACT FROM AUTHOR]