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Alzheimer's Disease (AD) is a global public health priority characterized by high mortality rates in adults and an increasing prevalence in aging populations worldwide. Despite significant advancements in comprehending the pathogenesis of AD since its initial report in 1907, there remains a lack of effective curative or preventive measures for the disease. In recent years, natural compounds sourced from diverse origins have garnered considerable attention as potential therapeutic agents for AD, owing to their anti-inflammatory, antioxidant, and neuroprotective properties. This review aims to consolidate the therapeutic effects of natural compounds on AD, specifically targeting the reduction of β-amyloid (Aβ) overproduction, anti-apoptosis, autophagy, neuroinflammation, oxidative stress, endoplasmic reticulum (ER) stress, and mitochondrial dysfunction. Notably, the identified compounds exhibiting these effects predominantly originate from plants. This review provides valuable insights into the potential of natural compounds as a reservoir of novel therapeutic agents for AD, thereby stimulating further research and contributing to the development of efficacious treatments for this devastating disease.

Summary: Overdose acetaminophen (APAP) can cause acute liver injury (ALI), but the underlying mechanism remains undetermined. This study explored the role of hepatic Zinc Finger And BTB Domain Containing 22 (ZBTB22) in defense against APAP-mediated hepatotoxicity. The results showed that hepatic ZBTB22 expression was significantly reduced in patients with ALI and mice. In mouse primary hepatocytes (MPHs), ZBTB22 deletion aggravated APAP overdose-induced ALI, whereas ZBTB22 overexpression attenuated that pathological progression. The results were further verified in ZBTB22 over-express or knockout mice models. In parallel, hepatocyte-specific ZBTB22 knockout also enhanced ALI. Furthermore, ZBTB22 decreased pregnane X receptor (PXR) expression, and the PXR activator pregnane-16α-carbonitrile suppressed the protective effect of ZBTB22 in APAP-induced ZBTB22-overexpressing mice. Collectively, our findings highlight the protective effect of ZBTB22 against APAP-induced ALI and unravel PXR signaling as the potential mechanism. Strategies to increase hepatic ZBTB22 expression represent a promising therapeutic approach for APAP overdose-induced ALI.

In order to explore the effects of high temperature stress on the physiological characteristics of Paeonia ostii, the Paeonia ostii were subjected to 25 °C, 35 °C, 38 °C, and 40 °C for 7 days. Meanwhile, the physiological indicators of oxidative stress (hydrogen peroxide, H2O2; malondialdehyde, MDA; relative electrical conductivity, REC), antioxidant enzyme activity (superoxide dismutase, SOD; ascorbate peroxidase, APX; catalase, CAT; peroxidase, POD), photosynthetic pigment content (chlorophyll a, Chla; chlorophyll b, Chlb), photosynthetic characteristics (net photosynthetic rate, Pn; intercellular CO2 concentration, Ci; stomatal conductance, Gs; transpiration rate, Tr), and osmoregulatory substances content (soluble protein, SP; soluble sugar, SS) were determined. The results showed that, with the increase in temperature and stress time, the H2O2 content, MDA content, REC value, CAT activity, and APX activity increased, while Chla content, Chlb content, SS content, and SP content decreased. With the extension of stress time, the SOD activity, POD activity, and Tr value of each high temperature stress group first increased and then decreased; Ci first decreased, then increased, and then decreased; meanwhile, Pn and Gs showed an overall downward trend. PLS-DA (partial least squares discriminant analysis) was used to analyze the changes in physiological and biochemical indexes of peony leaves under 40 °C stress for different days. SOD was found to be the biggest factor affecting the changes in physiological and biochemical indexes of peony leaves treated with different days of stress.

Concentrations of heavy metals (Cu, Pb, Zn, Cd and Cr) in surface soils and sediments collected in 2008 from 37 sampling sites in the Fildes Peninsula and Ardley Island were detected by atomic absorption spectrometry. The total contents of Cu, Pb, Zn, Cd and Cr ranged, respectively, from 61.36 to 562.2 mg/kg, 0.52 to 1.95 mg/kg, 54.61 to 577.9 mg/kg, 0.04 to 3.76 mg/kg and 6.83 to 25.9 mg/kg in soils and from 58.55 to 498.3 mg/kg, 0.60 to 2.51 mg/kg, 56.22 to 345.9 mg/kg, 0.07 to 5.77 mg/kg and 7.76 to 39.5 mg/kg in sediments. The geo-accumulation index and the pollution load index were calculated to evaluate the environmental effects of heavy metal pollutants, Cu, Zn and Cd, in the study area. Soils and sediments from Ardley Island were found to be moderately polluted with the studied metals. Pearson’s correlation analysis and principal component analysis were applied to assess the distribution pattern and potential source of heavy metals. The results suggest that Cu, Zn and Cd in the study area originated from both the lithogenic sources and penguin guano, while Pb and Cr were probably derived from lithogenic sources.

Acetaminophen (APAP) intake leads to excessive NAPQI deposition, stimulating inflammatory and oxidative stress and causing fatal liver injury. However, the detailed molecular mechanism involved is unknown, and effective therapeutic approaches remain insufficient. In this study, we discovered that treatment with ginsenoside Rc can prevent the inflammatory response caused by APAP and oxidative stress in mouse primary hepatocytes (MPHs), along with the corresponding changes in related genes. Additionally, Ginsenoside Rc effectively alleviates APAP-induced cellular apoptosis and NAPQI accumulation in MPHs. In vivo, Ginsenoside Rc administration remarkably attenuates APAP-induced hepatotoxicity, repairing liver damage and improving survival. Moreover, Ginsenoside Rc treatment modulates genes involved in APAP metabolism, leading to a decrease in NAPQI and resulting in the alleviation of fatal oxidative stress and inflammatory response after APAP exposure, along with the expression of their related indicators. Furthermore, our RNA-seq and molecular docking analysis implies that FXR expression and FXR transcriptional activity are stimulated by Ginsenoside Rc treatment. Notably, due to the lack of FXR in mice and MPHs, ginsenoside Rc can no longer play its original protective role against hepatotoxicity and cell damage caused by APAP, and it is difficult to improve the corresponding survival rate and prevent hepatic apoptosis, NAPQI generation, fatal oxidative stress, and the inflammatory response induced by APAP and the expression of related genes. In summary, our results indicate that Ginsenoside Rc could act as an effective FXR activator and effectively regulate FXR-induced antioxidant stress and eliminate inflammation while also having an anti-apoptotic function.

Objectives: Farnesoid X receptor (FXR) activation is involved in ameliorating inflammatory bowel disease (IBD), such as ulcerative colitis (UC), and inflammatory regulation may be involved in its mechanism. Ginsenoside Rc (Rc) is a major component of Panax ginseng, and it plays an excellent role in the anti-inflammatory processes. Our aim is to explore the alleviative effect of Rc on dextran sulfate sodium (DSS)-induced inflammation and deficiencies in barrier function based on FXR signaling.Materials and Methods:In vitro, we treated human intestinal epithelial cell lines (LS174T) with LPS to explore the anti-inflammatory effect of Rc supplementation. In vivo, a DSS-induced IBD mice model was established, and the changes in inflammatory and barrier function in colons after Rc treatment were measured using the disease activity index (DAI), hematoxylin and eosin (H&E) staining, immunofluorescence, ELISA, and qPCR. Molecular docking analysis, luciferase reporter gene assay, and qPCR were then used to analyze the binding targets of Rc. DSS-induced FXR-knockout (FXR−/-) mice were used for further validation.Results: Rc significantly recovered the abnormal levels of inflammation indexes (TNF-α, IL-6, IL-1β, and NF-KB) induced by LPS in LS174T. DSS-induced C57BL/6 mice exhibited a significantly decreased body weight and elevated DAI, as well as a decrease in colon weight and length. Increased inflammatory markers (TNF-α, IL-6, IL-1β, ICAM1, NF-KB, F4/80, and CD11b displayed an increased expression) and damaged barrier function (Claudin-1, occludin, and ZO-1 displayed a decreased expression) were observed in DSS-induced C57BL/6 mice. Nevertheless, supplementation with Rc mitigated the increased inflammatory and damaged barrier function associated with DSS. Further evaluation revealed an activation of FXR signaling in Rc-treated LS174T, with FXR, BSEP, and SHP found to be upregulated. Furthermore, molecular docking indicated that there is a clear interaction between Rc and FXR, while Rc activated transcriptional expression of FXR in luciferase reporter gene assay. However, these reversal abilities of Rc were not observed in DSS-induced FXR−/- mice.Conclusion: Our findings suggest that Rc may ameliorate inflammation and barrier function in the intestine, which in turn leads to the attenuation of DSS-induced UC, in which Rc may potentially activate FXR signaling to protect the intestines from DSS-induced injury.

In order to investigate the causes of the differences in heat tolerance (‘Lu He Hong’ and ‘Zhi Hong’), we studied the physiological changes, photosynthetic properties and regulatory mechanism of the two peony cultivars at high temperature. The results showed that the physiological changed of different peony cultivars varied significantly under high temperature stress. With the extension of high temperature stress time, MDA content of 'Lu He Hong' increased,while 'Zhi Hong' rised first and then decreased, SOD activity of 'Lu He Hong' rised first and then decreased, that of 'Zhi Hong' kept rising, POD activity of 'Lu He Hong' kept decreasing, while 'Zhi Hong' rised. The photosynthetic instrument records the change of peony photosynthesis parameters at high temperature; the chlorophyll A (Chla) fluorescence transient is recorded using the plant efficiency analyzer (PEA), analyzed according to the JIP test (O-J-I-P fluorescence transient analysis), and several parameters were derived to explain the photosynthetic efficiency difference between different peony cultivars. The tested cultivars responded differently to the survey conditions, and the PCA analysis showed that the ‘Zhi Hong’ was more well tolerated and showed better thermal stability of the PSII. The reduced efficiency of the ‘Lu He Hong’ PSII antenna leads to higher heat dissipation values to increase the light energy absorbed by unit reaction center (ABS/RC), the energy captured by unit reaction center (TR0/RC), and the energy dissipated by unit reaction center (DI0/RC), which significantly leads to its lower total photosynthetic performance (PItotal). The light capture complex of the variety ‘Zhi Hong’ has high connectivity with its reaction center, less damage to OEC activity, and better stability of the PSII system. The results show that ‘Zhi Hong’ improves heat resistance by stabilizing the cell membrane, a strong antioxidant system, as well as a more stable photosynthetic system. The results of this study provide a theoretical basis for the screening of heat-resistant peonies suitable for cultivation in Jiangnan area and for the selection and breeding of heat-resistant cultivars.

Abstract The accumulation of soil-borne pathogens is the main driving factor of negative plant-soil feedbacks (NPSFs), which seriously restricts the sustainable development of agriculture. Using natural volatile organic compounds (VOCs) from plants or microorganisms as biofumigants is an emerging strategy to alleviate NPSFs in an environmentally-friendly way. Here, we identified α-terpineol from the VOCs of pine needles, confirmed the ability of α-terpineol fumigation in alleviating the NPSF of Panax notoginseng via significantly reducing seed decay rate, and also deciphered the underlying mechanism by which the soil microbial community is modified. α-Terpineol fumigation could suppress culturable fungi but enrich bacteria in a dose-dependent manner. Network analysis with high-throughput sequencing data revealed that α-terpineol could distinctly modify both fungal and bacterial communities. In detail, α-terpineol significantly suppressed the relative abundance of Ascomycota from 64.04 to 32.26%, but enriched the relative abundance of Proteobacteria, Acidobacteria and Actinobacteria. Subnetwork analysis further demonstrated that α-terpineol could directly or indirectly suppress fungal pathogens and enrich plant growth-promoting rhizobacteria (PGPRs). In vitro fumigation and co-culture experiments with culturable isolates validated these findings. The antagonism between beneficial bacteria and pathogens, and the synergistic growth promotion among α-terpineol-enriched bacteria might be involved in soil microbial community assembly. In summary, α-terpineol fumigation could directly or indirectly modify the soil microbial community to alleviate NPSFs, especially by suppressing fungal pathogens and enriching beneficial bacteria. This study suggests that VOCs from natural products are worth developing as biofumigants due to their multiple functions in modifying the soil microbial community.

The fault characteristic signals of rolling bearings are coupled with each other, thus increasing the difficulty in identifying the fault characteristics. In this study, a fault diagnosis method of rolling bearing based on least squares support vector machine is proposed. First, least squares support vector machine model is trained with the samples of known classes. Least squares support vector machine algorithm involves the selection of a kernel function. The complexity of samples in high-dimensional space can be adjusted through changing the parameters of kernel function, thus affecting the search for the optimal function as well as final classification results. Particle swarm optimization and 10-fold cross-validation method are adopted to optimize the parameters in the training model. Then, with the optimized parameters, the classification model is updated. Finally, with the feature vector of the test samples as the input of least squares support vector machine, the pattern recognition of the testing samples is performed to achieve the purpose of fault diagnosis. The actual bearing fault data are analyzed with the diagnosis method. This method allows the accurate classification results and fast diagnosis and can be applied in the diagnosis of compound faults of rolling bearing.

In order to assess the bioaccumulation of metals associated with gender, tissues, and their potential ecological risk, four species of fish were collected from the Yongshu Island in the Southern South China Sea. Metals and stable Pb isotopes in their tissues (muscle, gill, liver, intestine, and ovary) were determined. The concentrations of metals (mg/kg, dry weight) in these species were ND–21.60 (Cd), 1.21–4.87 (Cr), 0.42–22.4 (Cu), 1.01–51.8 (Mn), 0.30–3.28 (Ni), 6.04–1.29 × 103 (Zn), 14.89–1.40 × 103 (Fe), and 0.22–3.36 (Pb). In general, the liver and intestine absorbed more metals than the other tissues. Metals accumulation can be influenced by gender and feeding behavior and in fact, female fish and dietary exposure are more prone to accumulate metals. In addition, Pb isotopic ratios indicated that all species had significant biological fractionation, which may not make them good tracers for source identification. The metal concentrations of most samples were lower than the national standard values of the FAO (USA), which suggested that human consumption of these species may not cause health risks. However, since the surrounding areas are developing rapidly, the potential environmental risk of metals will intensify and should receive more attention.

Abstract The semi‐conductive shielding layer is an important part of the high‐voltage cable, playing a role in uniform electric field and reducing the air gap at the interface. The overall performance of the cable is affected by the semi‐conductive shielding layer with different base resin composition. The matrix resins of ethylene‐vinyl acetate (EVA), ethylene‐ethyl acrylate (EEA) and ethylene‐butyl acrylate (EBA) were used to prepare the semi‐conductive shielding materials of CB/EVA, CB/EEA and CB/EBA. The influences of different matrix resins on the chemical, electrical, thermal and mechanical properties of the shielding materials were investigated. The results show that CB has the best dispersion in EBA resin and the worst dispersion in EEA resin. The temperature inflection points of CB/EVA, CB/EEA and CB/EBA shielding materials are 90°C, 100°C and 110°C, respectively, and the CB/EBA shielding material has the lowest resistivity and the weakest positive temperature coefficient effect at room temperature. The thermal conductivity of all three matrix resins is smaller than that of the shielding material, the thermal conductivity of CB/EVA and CB/EBA shielding materials show a slow increase with temperature, and the CB/EEA shielding material is the least affected by the temperature. The mechanical properties of the three matrix resins and the three shielding materials are EBA > EVA > EEA, among them the stress of CB/EBA shielding material is 31.0 MPa and the strain is 570%. This work has important reference significance for the selection of shielding layer matrix resin and material formulation in engineering applications.

Abstract Ferroptosis is an iron-dependent form of regulated cell death driven by the lethal lipid peroxides. Previous studies have demonstrated that inducing ferroptosis holds great potential in cancer therapy, especially for patients with traditional therapy failure. However, cancer cells can acquire ferroptosis evasion during progression. To date, the therapeutic potential of inducing ferroptosis in bladder cancer (BCa) remains unclear, and whether a ferroptosis escape mechanism exists in BCa needs further investigation. This study verified that low pathological stage BCa cells were highly sensitive to RSL3-induced ferroptosis, whereas high pathological stage BCa cells exhibited obviously ferroptosis resistance. RNA-seq, RNAi-mediated loss-of-function, and CRISPR/Cas9 experiments demonstrated that ALOX5 deficiency was the crucial factor of BCa resistance to ferroptosis in vitro and in vivo. Mechanistically, we found that ALOX5 deficiency was regulated by EGR1 at the transcriptional level. Clinically, ALOX5 expression was decreased in BCa tissues, and its low expression was associated with poor survival. Collectively, this study uncovers a novel mechanism for BCa ferroptosis escape and proposes that ALOX5 may be a valuable therapeutic target and prognostic biomarker in BCa treatment.

Introduction Mounting evidence has suggested that novel teaching strategies have a positive impact on the quality and efficiency of medical education. However, the comprehensive evidence about the superiority among various strategies is not clear. To address this issue, we aim to conduct a systematic review and network meta-analysis (NMA) to evaluate the effects of six main strategies on medical education, including case-based learning, problem-based learning, team-based learning, flipped classrooms, simulation-based education and bridge-in, objective, preassessment, participatory learning, postassessment and summary.Methods and analysis A systematic search will be conducted in PubMed, Embase, Web of Science and the Cochrane Library, covering studies published from database inception to November 2023. Randomised controlled trials which evaluated the different teaching methods and meet the eligibility criteria will be included. The effectiveness of medical students’ learning, which is evaluated by theoretical test score, experimental or practical test score, will be analysed as the primary outcomes. Besides, the secondary outcomes consist of learning satisfaction of students and formative evaluation score. The study selection and data extraction will be independently performed by two authors. The risk of bias in each study will be assessed using V.2 of the Cochrane risk-of-bias tool for randomised controlled trials. To compare the effects of six teaching strategies, pairwise meta-analysis and NMA will be performed using Rev Man, STATA and R software. Statistical analyses including homogeneity tests, sensitivity analysis, consistency tests, subgroup analysis, Egger’s test and publication bias will also be completed.Ethics and dissemination No formal research ethics approval is required because this study is a meta-analysis based on published studies. The results will be disseminated to a peer-reviewed journal for publication.Protocol registration number CRD42023456050.

Interfacial ferroelectricity may emerge in moiré superlattices. Here, the authors find that the polarized charge is much larger than the capacity of the moiré miniband and the associated anomalous screening exists outside the band.

Abstract Objectives Exosomes are essential mediators of intercellular communication as they transport proteins and RNAs between cells. Owing to their tumor‐targeting capacity, immune compatibility, low toxicity, and long half‐life, mesenchymal stem cell‐derived exosomes have great potential for the development of novel antitumor strategies. In this context, the role of exosomes produced by adipose‐derived mesenchymal stem cells (ADSCs) for the treatment of bladder cancer (BC) remains unclear. Here, we investigated the use of ADSCs as a source of therapeutic exosomes, as well as their efficacy in delivering the tumor suppressor miR‐138‐5p in BC. Methods ADSCs stably expressing miR‐138‐5p were established using Lentivirus infection, and ADSC‐derived miR‐138‐5p exosomes (Exo‐miR‐138‐5p) were isolated from the cell culture medium. The effect of Exo‐miR‐138‐5p on BC cell migration, invasion, and proliferation was evaluated in vitro using wound healing, transwell invasion, and proliferation assays. The in vivo effect of Exo‐miR‐138‐5p was investigated using a subcutaneous xenograft mouse model. Results Exo‐miR‐138‐5p prevented the migration, invasion, and proliferation of BC cells in vitro. Moreover, ADSC‐derived exosomes could penetrate tumor tissues and successfully deliver miR‐138‐5p to suppress the growth of xenograft tumors in vivo. Conclusions The present results reveal that ADSC‐derived exosomes are an effective delivery vehicle for small molecule drugs in vivo, and exosome‐delivered miR‐138‐5p is a promising therapeutic agent for BC treatment.

Abstract Background Although the lack of estrogen receptor β (ERβ) is a risk factor for the development of inflammatory bowel disease (IBD) and psychiatric disorders, the underlying cellular and molecular mechanisms are not fully understood. Herein, we revealed the role of gut microbiota in the development of IBD and related anxiety-like behavior in ERβ-deficient mice. Results In response to dextran sodium sulfate (DSS) insult, the ERβ knockout mice displayed significant shift in α and β diversity in the fecal microbiota composition and demonstrated worsening of colitis and anxiety-like behaviors. In addition, DSS-induced colitis also induced hypothalamic-pituitary-adrenal (HPA) axis hyperactivity in ERβ-deficient mice, which was associated with colitis and anxiety-like behaviors. In addition, RNA sequencing data suggested that ErbB4 might be the target of ERβ that is involved in regulating the HPA axis hyperactivity caused by DSS insult. Gut microbiota remodeling by co-housing showed that both the colitis and anxiety-like behaviors were aggravated in co-housed wild-type mice compared to single-housed wild-type mice. These findings suggest that gut microbiota play a critical role in mediating colitis disease activity and anxiety-like behaviors via aberrant neural processing within the gut-brain axis. Conclusions ERβ has the potential to inhibit colitis development and anxiety-like behaviors via remodeling of the gut microbiota, which suggests that ERβ is a promising therapeutic target for the treatment of IBD and related anxiety-like behaviors. Video Abstract

Aluminum (Al) has been classified as a cumulative environmental pollutant that endangers human health. There is increasing evidence to suggest the toxic effects of Al, but the specific action on human brain development remains unclear. Al hydroxide (Al(OH)3), the most common vaccine adjuvant, is the major source of Al and poses risks to the environment and early childhood neurodevelopment. In this study, we explored the neurotoxic effect of 5 μg/ml or 25 μg/ml Al(OH)3 for six days on neurogenesis by utilizing human cerebral organoids from human embryonic stem cells (hESCs). We found that early Al(OH)3 exposure in organoids caused a reduction in the size, deficits in basal neural progenitor cell (NPC) proliferation, and premature neuron differentiation in a time and dose-dependent manner. Transcriptomes analysis revealed a markedly altered Hippo-YAP1 signaling pathway in Al(OH)3 exposed cerebral organoid, uncovering a novel mechanism for Al(OH)3-induced detrimental to neurogenesis during human cortical development. We further identified that Al(OH)3 exposure at day 90 mainly decreased the production of outer radial glia-like cells(oRGs) but promoted NPC toward astrocyte differentiation. Taken together, we established a tractable experimental model to facilitate a better understanding of the impact and mechanism of Al(OH)3 exposure on human brain development.

IntroductionBladder cancer (BLCA) is a highly malignant tumor of the urinary system, but the prognosis and survival rates have little improvement based on current therapeutic strategy. Immune checkpoint inhibitors (ICIs) therapy revolutionized the treatment of BLCA, but the clinical application of ICIs is limited by low response rate. Oxaliplatin (OXP), a second line chemotherapy drug for BLCA, may reshape the tumor immune microenvironment (TIME) via recruiting immune cells. Here, we conducted the study of oxaliplatin combined with anti-PD-1 inhibitor in BLCA mice models.MethodsThe 6-8 weeks old female C57BL/6J mice were used to establish subcutaneous model of bladder tumor. After tumors developed, mice were given tail vein injections of PBS or oxaliplatin (2.5 mg/kg) and/or anti-PD-1 antibody (10 mg/kg). Tumor tissue samples and peripheral blood mononuclear cell (PBMC) were collected to systemically evaluate the efficiency and safety of combination OXP and anti-PD-1 inhibitor. The change of immune cells populations and the corresponding phenotypic diversity in TIME and PBMC were analysed by flow cytometry.ResultsTumor growth experiments clarified that the combination therapy was more efficient than medication alone. Flow cytometry analysis of tumor samples showed significant differences between untreated and treated mice. Oxaliplatin influences the TIME by increasing immune cells infiltration, including CD3+ T cells, CD4+ T cells, CD8+ T cells, dendritic cells (DC cells) and natural killer cells (NK cells). As for infiltrating cells, oxaliplatin upregulated the expression of CD134 and downregulated TIM-3 of CD4+ T cells, downregulated the PD-L1 expression of DC cells, which contributed to improve the anti-tumor effect and the treatment response of ICIs. Additionally, the evaluation of PBMC found that there were no significant changes in immune cell subsets and phenotypes, which validated the safety of the combination therapy. These results show the therapeutic potential for the combination of OXP and anti-PD-1 inhibitor in BLCA.ConclusionOXP could increase the infiltration of immune cells in TIME to promote the anti-tumor activity of anti-PD-1 inhibitor. The present research provided an appropriate rationale of combination chemotherapy and immunotherapy therapy for BLCA.

Objectives: To analyze the correlations between the expression and effect of DNA damage repair genes and the immune status and clinical outcomes of urothelial bladder cancer (BLCA) patients. In addition, we evaluate the efficacy and value of utilizing the DNA damage repair genes signature as a prognosis model for BLCA. Methods: Two subtype groups (C1 and C2) were produced based on the varied expression of DNA damage repair genes. Significantly differentiated genes and predicted enriched gene pathways were obtained between the two subtypes. Seven key genes were obtained from the DNA damage repair-related genes and a 7-gene signature prognosis model was established based on the key genes. The efficacy and accuracy of this model in prognosis prediction was evaluated and verified in two independent databases. Also, the difference in biological functions, drug sensitivity, immune infiltration and affinity between the high-risk group and low-risk group was analyzed. Results: The DNA damage repair gene signature could significantly differentiate the BLCA into two molecular subgroups with varied genetic expression and enriched gene pathways. Seven key genes were screened out from the 232 candidate genes for prognosis prediction and a 7-gene signature prognosis model was established based on them. Two independent patient cohorts (TCGA cohort and GEO cohort) were utilized to validate the efficacy of the prognosis model, which demonstrated an effective capability to differentiate and predict the overall survival of BLCA patients. Also, the high-risk group and low-risk group derived from the 7-gene model exhibited significantly differences in drug sensitivity, immune infiltration status and biological pathways enrichment. Conclusions: Our established 7-gene signature model based on the DNA damage repair genes could serve as a novel prognosis predictive tool for BLCA. The differentiation of BLCA patients based on the 7-gene signature model may be of great value for the appropriate selection of specific chemotherapy agents and immune-checkpoint blockade therapy administration.

TP53 (or p53) is widely accepted to be a tumor suppressor. Upon various cellular stresses, p53 mediates cell cycle arrest and apoptosis to maintain genomic stability. p53 is also discovered to suppress tumor growth through regulating metabolism and ferroptosis. However, p53 is always lost or mutated in human and the loss or mutation of p53 is related to a high risk of tumors. Although the link between p53 and cancer has been well established, how the different p53 status of tumor cells help themselves evade immune response remains largely elusive. Understanding the molecular mechanisms of different status of p53 and tumor immune evasion can help optimize the currently used therapies. In this context, we discussed the how the antigen presentation and tumor antigen expression mode altered and described how the tumor cells shape a suppressive tumor immune microenvironment to facilitate its proliferation and metastasis.

Valproic acid (VPA) exposure during pregnancy leads to a higher risk of autism spectrum disorder (ASD) susceptibility in offspring. Human dorsal forebrain organoids were used to recapitulate course of cortical neurogenesis in the developing human brain. Combining morphological characterization with massive parallel RNA sequencing (RNA-seq) on organoids to analyze the pathogenic effects caused by VPA exposure and critical signaling pathway. We found that VPA exposure in organoids caused a reduction in the size and impairment in the proliferation and expansion of neural progenitor cells (NPCs) in a dose-dependent manner. VPA exposure typically decreased the production of outer radial glia-like cells (oRGs), a subtype of NPCs contributing to mammalian neocortical expansion and delayed their fate toward upper-layer neurons. Transcriptomics analysis revealed that VPA exposure influenced ASD risk gene expression in organoids, which markedly overlapped with irregulated genes in brains or organoids originating from ASD patients. We also identified that VPA-mediated Wnt/β-catenin signaling pathway activation is essential for sustaining cortical neurogenesis and oRGs output. Taken together, our study establishes the use of dorsal forebrain organoids as an effective platform for modeling VPA-induced teratogenic pathways involved in the cortical neurogenesis and oRGs output, which might contribute to ASD pathogenesis in the developing brain.

Abstract Introduction: Staphylococcus aureus (S. aureus) is considered as one of the major causative agents of serious hospital‐ and community‐acquired infections. Recent studies have reported that S. aureus infection induced neuroinflammation and was linked with some mental disorders. To evaluate the effects of S. aureus infection on abnormal behaviors, we conducted the present study. Methods: A S. aureus USA300‐infected mouse model was established using bacterial suspension injection into tail vein. A series of behavioral tests were performed after USA300 infection. The expression of cytokines was detected in serum and mPFC. The number and some morphological parameters of microglia were also evaluated by immunofluorescence staining. Results: Anxiety‐like behaviors, instead of locomotor activity impairment or depression‐like behaviors, were observed in mice infected with S. aureus USA300 compared with control. S. aureus USA300 infection caused overexpression of IL‐6, TNF‐α, and IL‐1β in serum, resulted in microglial over‐activation and excessive release of proinflammatory cytokines in the mPFC. In addition, overexpression of TLR2 accompanied by increased GLS1 and p‐STAT3 was observed in the mPFC of mice infected with S. aureus USA300. Conclusion: This study provides evidence that S. aureus USA300 infection can lead to neuroinflammation in the mPFC of mice, which may contribute to the development of anxiety.

Bladder cancer (BLCA) is one of the most common malignant tumors of the urinary system, but the current therapeutic strategy based on chemotherapy and immune checkpoint inhibitor (ICI) therapy cannot meet the treatment needs, mainly owing to the endogenous or acquired apoptotic resistance of cancer cells. Targeting necroptosis provides a novel strategy for chemotherapy and targeted drugs and improves the efficacy of ICIs because of strong immunogenicity of necroptosis. Therefore, we systemically analyzed the necroptosis landscape on therapy and prognosis in BLCA. We first divided BLCA patients from The Cancer Genome Atlas (TCGA) database into two necroptosis-related clusters (C1 and C2). Necroptosis C2 showed a significantly better prognosis than C1, and the differential genes of C2 and C1 were mainly related to the immune response according to GO and KEGG analyses. Next, we constructed a novel necroptosis-related gene (NRG) signature consisting of SIRT6, FASN, GNLY, FNDC4, SRC, ANXA1, AIM2, and IKBKB to predict the survival of TCGA-BLCA cohort, and the accuracy of the NRG score was also verified by external datasets. In addition, a nomogram combining NRG score and several clinicopathological features was established to more accurately and conveniently predict the BLCA patient’s survival. We also found that the NRG score was significantly related to the infiltration levels of CD8 T cells, NK cells, and iDC cells, the gene expression of CTLA4, PD-1, TIGIT, and LAG3 of TME, and the sensitivity to chemotherapy and targeted agents in BLCA patients. In conclusion, the NRG score has an excellent performance in evaluating the prognosis, clinicopathologic features, tumor microenvironment (TME), and therapeutic sensitivity of BLCA patients, which could be utilized as a guide for chemotherapy, ICI therapy, and combination therapy.

Immunotherapies, such as immune-checkpoint blockade and adoptive T-cell therapy, offer novel treatment options with good efficacy for patients with urothelial bladder cancer. However, heterogeneity and therapeutic resistance have limited the use of immunotherapy. Further research into immune-regulatory mechanisms in bladder cancer is urgently required. Emerging evidence demonstrates that the commensal microbiota and its interactions with host immunity play pivotal roles in a variety of physiological and pathological processes, including in cancer. The gut microbiota has been identified as a potentially effective target of treatment that can be synergized with immunotherapy. The urothelial tract is also a key site for multiple microbes, although the immune-regulatory role of the urinary microbiome in the process of carcinogenesis of bladder cancer remains to be elucidated. We performed a comprehensive analysis of the expression and biological functions of C-type lectin receptors (CLRs), which have been recognized as innate pathogen-associated receptors for fungal microbiota, in bladder cancer. In line with previous research on fungal colonization of the urothelial tract, we found that CLRs, including Dectin-1, Dectin-2, Dectin-3, and macrophage-inducible Ca2+-dependent lectin receptor (Mincle), had a significant association with immune infiltration in bladder cancer. Multiple innate and adaptive pathways are positively correlated with the upregulation of CLRs. In addition, we found a significant correlation between the expression of CLRs and a range of immune-checkpoint proteins in bladder cancer. Based on previous studies and our findings, we hypothesize that the urinary mycobiome plays a key role in the pathogenesis of bladder cancer and call for more research on CLR-mediated anti-fungal immunity against bladder cancer as a novel target for immunotherapy in urothelial bladder cancer.

Cortisol is the main HPA axis hormone secreted by the adrenal cortex, and influences metabolism, cognition, and behavior. Recently, a plethora of studies have tried to confirm the correlation between peripheral cortisol and autism spectrum disorder (ASD). However, the results were controversial. We assessed the effects of peripheral cortisol on ASD in this study. The included studies were identified according to the inclusion and exclusion criteria. The pooled Hedges’ g and its 95% confidence interval were selected to evaluate the association between peripheral cortisol and ASD. Subgroup analyses, sensitivity analyses, meta-regression, and publication bias tests were also undertaken based on the obtained information. There were a total of twelve studies with 375 ASD patients and 335 controls included in our meta-analysis. Obvious heterogeneity across studies was found in the overall analysis. Peripheral cortisol levels were significantly elevated in ASD patients compared with controls in the absence of obvious heterogeneity. A single study did not influence the overall comparison results. Meta-regression analyses revealed that age and gender of the included subjects, sample size, and publication year did not moderate effects on the present results. These findings may provide us some targeted strategies to the diagnosis and treatment of ASD.

Autism spectrum disorder (ASD) is considered a heterogeneous neurodevelopmental disorder characterized by significant social, communication, and behavioral impairments. The gut microbiota is increasingly considered a promising therapeutic target in ASD. Farnesoid X receptor (FXR) has recently been shown to modulate the gut microbiota. We hypothesized that FXR agonist GW4064 could ameliorate behavioral deficits in an animal model for autism: BTBR T+Itpr3tf/J (BTBR) mouse. As expected, administration of GW4064 rescued the sociability of BTBR mice in the three-chamber sociability test and male-female social reciprocal interaction test, while no effects were observed in C57BL/6J mice. We also found that GW4064 administration increased fecal microbial abundance and counteracted the common ASD phenotype of a high Firmicutes to Bacteroidetes ratio in BTBR mice. In addition, GW4064 administration reversed elevated Lactobacillus and decreased Allobaculum content in the fecal matter of BTBR animals. Our findings show that GW4064 administration alleviates social deficits in BTBR mice and modulates selective aspects of the composition of the gut microbiota, suggesting that GW4064 supplementation might prove a potential strategy for improving ASD symptoms.

Autism spectrum disorder (ASD) is defined as a complex heterogeneous disorder and characterized by stereotyped behavior and deficits in communication and social interactions. The emerging microbial knowledge has pointed to a potential link between gut microbiota dysbiosis and ASD. Evidence from animal and human studies showed that shifts in composition and activity of the gut microbiota may causally contribute to the etiopathogenesis of core symptoms in the ASD individuals with gastrointestinal tract disturbances and act on microbiota-gut-brain. In this review, we summarized the characterized gut bacterial composition of ASD and the involvement of gut microbiota and their metabolites in the onset and progression of ASD; the possible underlying mechanisms are also highlighted. Given this correlation, we also provide an overview of the microbial-based therapeutic interventions such as probiotics, antibiotics, fecal microbiota transplantation therapy, and dietary interventions and address their potential benefits on behavioral symptoms of ASD. The precise contribution of altering gut microbiome to treating core symptoms in the ASD needs to be further clarified. It seemed to open up promising avenues to develop microbial-based therapies in ASD.

Cancer metastasis, a typical malignant biological behavior involving the distant migration of tumor cells from the primary site to other organs, contributed majorly to cancer-related deaths of patients. Although constant efforts have been paid by researchers to elucidate the mechanisms of cancer metastasis, we are still far away from the definite answer. Recently, emerging evidence demonstrated that cancer metastasis is a continuous coevolutionary process mediated by the interactions between tumor cells and the host organ microenvironment, and epigenetic reprogramming of metastatic cancer cells may confer them with stronger metastatic capacities. The lymph node served as the first metastatic niche for many types of cancer, and the appearance of lymph node metastasis predicted poor prognosis. Importantly, multiple immune cells and stromal cells station and linger in the lymph nodes, which constitutes the complexity of the lymph node microenvironment. The active cross talk between cancer cells and immune cells could happen unceasingly within the metastatic environment of lymph nodes. Of note, diverse immune cells have been found to participate in the formation of malignant properties of tumor, including stemness and immune escape. Based on these available evidence and data, we hypothesize that the metastatic microenvironment of lymph nodes could drive cancer cells to metastasize to further organs through epigenetic mechanisms.

Abstract Background Early detection of urothelial carcinoma (UC) by noninvasive diagnostic methods with high accuracy is still underscored. This study aimed to develop a noninvasive assay incorporating both enrichment of urine exfoliated cells and immunoassays for UC detection. Methods Polystyrene dishes were exposed to oxygen plasma and modified with 3‐aminopropyltriethoxysilane to prepare amine‐functionalized nanostructured substrates (NS). Performance characterization of NS was evaluated by atomic force microscope and X‐ray photoelectron spectroscopy. Urine exfoliated cells were captured by NS and then immunostained to detect urinary tumor cells (UTCs), which was called UTC assay. The receiver operating characteristic (ROC) curve, area under ROC curve (AUC), and Youden index were used to find the cutoff value of UTC assay. ROC analysis and McNemar test were used to compare the diagnostic accuracy of UTC assay with cytology. Kappa test was used to analyze the agreement of UTC assay and cytology with pathological diagnosis. Results Nanostructured substrates had good cell binding yields of nucleated cells and tumor cells. CK20+CD45−CD11b− cells were considered as UTCs. UTC number ≥ 1 per sample could be considered as a positive result. By AUC and Kappa analysis, UTC assay showed good performance in UC detection. McNemar test demonstrated that UTC assay had a superior sensitivity even in low‐grade subgroup and a similar specificity compared to cytology in UC diagnosis. Conclusions Nanostructured substrates could be used to enrich the exfoliated cells from urine samples. UTC assay with NS has the potential to play a role in UC detection. The value of this assay still needs additional validation by large, multi‐center studies.

Immune-checkpoint blockade (ICB) demonstrated inspiring effect and great promise in anti-cancer therapy. However, many obstacles, such as drug resistance and difficulty in patient selection, limited the efficacy of ICB therapy and awaited to be overcome. By timely identification and intervention of the key immune-suppressive promotors in the tumor microenvironment (TME), we may better understand the mechanisms of cancer immune-escape and use novel strategies to enhance the therapeutic effect of ICB. Myeloid-derived suppressor cell (MDSC) is recognized as a major immune suppressor in the TME. In this review, we summarized the roles MDSC played in the cancer context, focusing on its negative biologic functions in ICB therapy, discussed the strategies targeted on MDSC to optimize the diagnosis and therapy process of ICB and improve the efficacy of ICB therapy against malignancies.

Transient Receptor Potential Canonical 6 (TRPC6) has been suggested to be involved in synapse function and contribute to hippocampal-dependent cognitive processes. Gene silencing of TRPC6 was performed by injecting adeno-associated virus (AAV) expressing TRPC6-specific shRNA (shRNA-TRPC6) into the hippocampal dentate gyrus (DG). Spatial learning, working memory and social recognition memory were impaired in the shRNA-TRPC6 treated mice compared to control mice after 4 weeks. In addition, gene ontology (GO) analysis of RNA-sequencing revealed that viral intervention of TRPC6 expression in DG resulted in the enrichment of the process of synaptic transmission and cellular compartment of synaptic structure. KEGG analysis showed PI3K-Akt signaling pathway were significantly down-regulated. Furthermore, the shRNA-TRPC6 treatment reduced dendritic spines of DG granule neurons, in terms of spine loss, the thin and mushroom types predominated. Accompanying the spine loss, the levels of PSD95, pAkt and CREB in the hippocampus were decreased in the shRNA-TRPC6 treated animals. Taken together, our results suggest that knocking down TRPC6 in the DG have a disadvantageous effect on cognitive processes.