A Current Understanding of FXR in NAFLD: The multifaceted regulatory role of FXR and novel lead discovery for drug development.

The global prevalence of nonalcoholic fatty liver disease (NAFLD) has reached 30 %, with an annual increase. The incidence of NAFLD-induced cirrhosis is rapidly rising and has become the leading indicator for liver transplantation in the US. However, there are currently no US Food and Drug Administration-approved drugs for NAFLD. Increasing evidence underscores the close association between NAFLD and bile acid metabolism disorder, highlighting the feasibility of targeting the bile acid signaling pathway for NAFLD treatment. The farnesoid X receptor (FXR) is an endogenous receptor for bile acids that exhibits favorable effects in ameliorating the metabolic imbalance of bile acids, lipid disorders, and disruption of intestinal homeostasis, all of which are key characteristics of NAFLD, making FXR a promising therapeutic target for NAFLD. The present review provides a comprehensive overview of the diverse mechanisms through which FXR improves NAFLD, with particular emphasis on its involvement in regulating bile acid homeostasis and the recent advancements in drug development targeting FXR for NAFLD treatment.

Association of barium deficiency with Type 2 diabetes mellitus incident risk was mediated by mitochondrial DNA copy number (mtDNA-CN): A follow-up study.

Accumulating evidence indicates that plasma metals levels may associate with Type 2 diabetes mellitus (T2DM) incident risk. Mitochondrial function such as mitochondrial DNA copy number (mtDNA-CN) might be linked metal exposure and physiological metabolism. Mediation analysis was conducted to determine the mediating roles of mtDNA-CN in the associations of plasma metals with diabetes risk. In the present study, we investigated associations between plasma metals levels, mtDNA-CN and T2DM incident in elderly population with 6-year follow-up (2 times) study. Ten plasma metals (i.e. manganese (Mg), aluminium (Al), calcium (Ca), ferrum (Fe), barium (Ba), arsenic (As), copper (Cu), selenium (Se), titanium (Ti) and cesium (Sr) were measured by using inductively coupled plasma mass spectrometry (ICP-MS). Mitochondrial DNA copy number was measured by real-time PCR. Multivariable linear regression and logistic regression models were carried out to estimate the relationship between plasma metal concentrations, mtDNA-CN and T2DM incident risk in the current work. Plasma Ba deficiency and mtDNA-CN decline associated with T2DM incident risk during aging process. Meanwhile plasma Ba found to be positively associated with mtDNA-CN. Mitochondrial function mtDNA-CN demonstrated mediating effects in association between plasma Ba deficiency and T2DM incident risk, and 49.8% of the association was mediated by mtDNA-CN. These findings extend the knowledge of T2DM incident risk factors and highlight the point that mtDNA-CN may be linked metals element and T2DM incident risk.

Comparative steroidogenic effects of hexafluoropropylene oxide trimer acid (HFPO-TA) and perfluorooctanoic acid (PFOA): Regulation of histone modifications.

As a widely used alternative to perfluorooctanoic acid (PFOA), hexafluoropropylene oxide trimer acid (HFPO-TA) has been detected in the environment and humans; however, little is known regarding its male reproductive toxicity. To compare the effects of HFPO-TA on steroid hormone synthesis with PFOA, we exposed Leydig cells (MLTC-1) to non-lethal doses (0.1, 1, and 10 µM) of PFOA and HFPO-TA for 48 h. It was found that the levels of steroid hormones, 17α-hydroxyprogesterone (OHP), androstenedione (ASD), and testosterone (T) were significantly increased in 1 and 10 µM of PFOA and HFPO-TA groups, with greater elevation being observed in the HFPO-TA groups than in the PFOA groups at 10 µM. We further showed that the two rate-limiting steroidogenic genes (Star and Cyp11a1) were up-regulated, while Hsd3b, Cyp17a1, and Hsd17b were down-regulated or unchanged after PFOA/HFPO-TA exposure. Moreover, PFOA exposure significantly up-regulated histone H3K4me1/3 and H3K9me1, while down-regulated H3K4me2 and H3K9me2/3 levels. By contrast, H3K4me2/3 and H3K9me2/3 were enhanced, while H3K4me1 and H3K9me1 were repressed after HFPO-TA treatment. It was further confirmed that H3K4me1/3 were increased and H3K9me2 was decreased in Star and Cyp11a1 promoters by PFOA, while HFPO-TA increased H3K4me2/3 and decreased H3K9me1 in the two gene promoters. Therefore, we propose that low levels of PFOA/HFPO-TA enhance the expression of Star and Cyp11a1 by regulating H3K4 and H3K9 methylation, thus stimulating the production of steroid hormones in MLTC-1 cells. Collectively, HFPO-TA exhibits stronger effects on steroidogenesis compared to PFOA, which may be ascribed to the distinct regulation of histone modifications. These data suggest that HFPO-TA does not appear to be a safer alternative to PFOA on the aspect of male reproductive toxicity.

Transgenerational Effects of Arsenic Exposure on Learning and Memory in Rats: Crosstalk between Arsenic Methylation, Hippocampal Metabolism, and Histone Modifications.

Arsenic (As) is widely present in the natural environment, and exposure to it can lead to learning and memory impairment. However, the underlying epigenetic mechanisms are still largely unclear. This study aimed to reveal the role of histone modifications in environmental levels of arsenic (sodium arsenite) exposure-induced learning and memory dysfunction in male rats, and the inter/transgenerational effects of paternal arsenic exposure were also investigated. It was found that arsenic exposure impaired the learning and memory ability of F0 rats and down-regulated the expression of cognition-related genes Bdnf, c-Fos, mGlur1, Nmdar1, and Gria2 in the hippocampus. We also observed that inorganic arsenite was methylated to DMA and histone modification-related metabolites were altered, contributing to the dysregulation of H3K4me1/2/3, H3K9me1/2/3, and H3K4ac in rat hippocampus after exposure. Therefore, it is suggested that arsenic methylation and hippocampal metabolism changes attenuated H3K4me1/2/3 and H3K4ac while enhancing H3K9me1/2/3, which repressed the key gene expressions, leading to cognitive impairment in rats exposed to arsenic. In addition, paternal arsenic exposure induced transgenerational effects of learning and memory disorder in F2 male rats through the regulation of H3K4me2 and H3K9me1/2/3, which inhibited c-Fos, mGlur1, and Nmdar1 expression. These results provide novel insights into the molecular mechanism of arsenic-induced neurotoxicity and highlight the risk of neurological deficits in offspring with paternal exposure to arsenic.

The size-dependence and reversibility of polystyrene nanoplastics-induced lipid accumulation in mice: Possible roles of lysosomes.

Nanoplastics (NPs) continue to accumulate in global aquatic and terrestrial systems, posing a potential threat to human health through the food chain and/or other pathways. Both in vivo and in vitro studies have confirmed that the liver is one of the main organs targeted for the accumulation of NPs in living organisms. However, whether exposure to NPs induces size-dependent disorders of liver lipid metabolism remains controversial, and the reversibility of NPs-induced hepatotoxicity is largely unknown. In this study, the effects of long-term exposure to environmentally relevant doses of polystyrene nanoplastics (PS-NPs) on lipid accumulation were investigated in terms of autophagy and lysosomal mechanisms. The findings indicated that hepatic lipid accumulation was more pronounced in mice exposed to 100 nm PS-NPs compared to 500 nm PS-NPs. This effect was effectively alleviated after 50 days of self-recovery for 100 nm and 500 nm PS-NPs exposure. Mechanistically, although PS-NPs exposure activated autophagosome formation through ERK (mitogen-activated protein kinase 1)/mTOR (mechanistic target of rapamycin kinase) signaling pathway, the inhibition of Rab7 (RAB7, member RAS oncogene family), CTSB (cathepsin B), and CTSD (cathepsin D) expression impaired lysosomal function, thereby blocking autophagic flux and contributing to hepatic lipid accumulation. After termination of PS-NPs exposure, lysosomal exocytosis was responsible for the clearance of PS-NPs accumulated in lysosomes. Furthermore, impaired lysosomal function and autophagic flux inhibition were effectively alleviated. This might be the main reason for the alleviation of PS-NPs-induced lipid accumulation after recovery. Collectively, we demonstrate for the first time that lysosomes play a dual role in the persistence and reversibility of hepatotoxicity induced by environmental relevant doses of NPs, which provide novel evidence for the prevention and intervention of liver injury associated with nanoplastics exposure.

Exposure to haloacetic acid disinfection by-products and male steroid hormones: An epidemiological and in vitro study.

Haloacetic acids (HAAs) are ubiquitous in drinking water and have been associated with impaired male reproductive health. However, epidemiological evidence exploring the associations between HAA exposure and reproductive hormones among males is scarce. In the current study, the urinary concentrations of dichloroacetic acid (DCAA) and trichloroacetic acid (TCAA), the internal exposure markers of HAAs, as well as sex hormones (testosterone [T], progesterone [P], and estradiol [E2]) were measured among 449 Chinese men. Moreover, in vitro experiments, designed to simulate the real-world scenarios of human exposure, were conducted to assess testosterone synthesis in the Leydig cell line MLTC-1 and testosterone metabolism in the hepatic cell line HepG2 in response to low-dose HAA exposure. The DCAA and TCAA urinary concentrations were found to be positively associated with urinary T, P, and E2 levels (all p < 0.001), but negatively associated with the ratio of urinary T to E2 (p < 0.05). Combined with in vitro experiments, the results suggest that environmentally-relevant doses of HAA stimulate sex hormone synthesis and steroidogenesis pathway gene expression in MLTC-1 cells. In addition, the inhibition of the key gene CYP3A4 involved in the testosterone phase Ⅰ catabolism, and induction of the gene UGT2B15 involved in testosterone phase Ⅱ glucuronide conjugation metabolism along with the ATP-binding cassette (ABC) transport genes (ABCC4 and ABCG2) in HepG2 cells could play a role in elevation of urinary hormone excretion upon low-dose exposure to HAAs. Our novel findings highlight that exposure to HAAs at environmentally-relevant concentrations is associated with increased synthesis and excretion of sex hormones in males, which potentially provides an alternative approach involving urinary hormones for the noninvasive evaluation of male reproductive health following exposure to DBPs.

Profiles and transplacental transfer of per- and polyfluoroalkyl substances in maternal and umbilical cord blood: A birth cohort study in Zhoushan, Zhejiang Province, China.

Per- and polyfluoroalkyl substances (PFAS) can pass through the placental barrier and pose health risks to fetuses. However, exposure and transplacental transfer patterns of emerging PFAS remain unclear. Here, 24 PFAS were measured in paired maternal whole blood (n = 228), umbilical cord whole blood (n = 119) and serum (n = 120). Orthogonal partial least-squares discriminant analysis (OPLS-DA) was used to differentiate PFAS between different matrices. The transplacental transfer (TPT) of PFAS was calculated using cord to maternal whole blood concentration ratios. PFOS and PFOA were still the dominant PFAS in maternal samples. The emerging PFAS had higher TPT than PFOS and PFOA. Moreover, PFAS with the same chain length but different functional groups and C-F bonds showed different TPT, such as PFOS and PFOSA (C8, median: 0.090 vs. 0.305, p < 0.05) and PFHxS and 4:2 FTS (C6, median: 0.220 vs. 1.190, p < 0.05). A significant sex difference in 4:2 FTS (median: boys 1.250, girls 1.010, p < 0.05) were found. Furthermore, we observed a significant U-shaped trend for the TPT of carboxylates with increasing carbon chain length. PFAS showed a compound-specific transfer through placental barrier and a compound-specific distribution between different matrices in this study.

Deciphering tumor-infiltrating dendritic cells in the single-cell era.

Dendritic cells (DCs) serve as a pivotal link connecting innate and adaptive immunity by processing tumor-derived antigens and activating T cells. The advent of single-cell sequencing has revolutionized the categorization of DCs, enabling a high-resolution characterization of the previously unrecognized diversity of DC populations infiltrating the intricate tumor microenvironment (TME). The application of single-cell sequencing technologies has effectively elucidated the heterogeneity of DCs present in the tumor milieu, yielding invaluable insights into their subpopulation structures and functional diversity. This review provides a comprehensive summary of the current state of knowledge regarding DC subtypes in the TME, drawing from single-cell studies conducted across various human tumors. We focused on the categorization, functions, and interactions of distinct DC subsets, emphasizing their crucial roles in orchestrating tumor-related immune responses. Additionally, we delve into the potential implications of these findings for the identification of predictive biomarkers and therapeutic targets. Enhanced insight into the intricate interplay between DCs and the TME promises to advance our comprehension of tumor immunity and, in turn, pave the way for the development of more efficacious cancer immunotherapies.

Associations between multiple metals during early pregnancy and gestational diabetes mellitus under four statistical models.

Gestational diabetes mellitus (GDM) is one of the most common complications of pregnancy. Metal exposure is an emerging factor affecting the risk of GDM. However, the effects of metal mixture on GDM and key metals within the mixture remain unclear. This study was aimed at investigating the association between metal mixture during early pregnancy and the risk of GDM using four statistical methods and further at identifying the key metals within the mixture associated with GDM. A nested case-control study including 128 GDM cases and 318 controls was conducted in Beijing, China. Urine samples were collected before 13 gestational weeks and the concentrations of 13 metals were measured. Single-metal analysis (unconditional logistic regression) and mixture analyses (Bayesian kernel machine regression (BKMR), quantile g-computation, and elastic-net regression (ENET) models) were applied to estimate the associations between exposure to multiple metals and GDM. Single-metal analysis showed that Ni was associated with lower risk of GDM, while positive associations of Sr and Sb with GDM were observed. Compared with the lowest quartile of Ni, the ORs of GDM in the highest quartiles were 0.49 (95% CI 0.24, 0.98). In mixture analyses, Ni and Mg showed negative associations with GDM, while Co and Sb were positively associated with GDM in BKMR and quantile g-computation models. No significant joint effect of metal mixture on GDM was observed. However, interestingly, Ni was identified as a key metal within the mixture associated with decreased risk of GDM by all three mixture methods. Our study emphasized that metal exposure during early pregnancy was associated with GDM, and Ni might have important association with decreased GDM risk.

Effects of PM2.5 and high-fat diet interaction on blood glucose metabolism in adolescent male Wistar rats: A serum metabolomics analysis based on ultra-high performance liquid chromatography/mass spectrometry.

Fine particulate matter (PM2.5) and high-fat diet (HFD) are known to contribute to blood glucose metabolic disorders. However, limited research has investigated the combined impact of PM2.5 and HFD on blood glucose metabolism. This study aimed to explore the joint effects of PM2.5 and HFD on blood glucose metabolism in rats using serum metabolomics and to identify involved metabolites and metabolic pathways. The 32 male Wistar rats were exposed to filtered air (FA) or PM2.5 (real-world inhaled, concentrated PM2.5, 8 times the ambient level, ranging from 131.42 to 773.44 µg/m3) and fed normal diet (ND) or HFD for 8 weeks. The rats were divided into four groups (n = 8/group): ND-FA, ND-PM2.5, HFD-FA and HFD-PM2.5 groups. Blood samples were collected to determine fasting glucose (FBG), plasma insulin and glucose tolerance test and HOMA Insulin Resistance (HOMA-IR) index was calculated. Finally, the serum metabolism of rats was analyzed by ultra-high performance liquid chromatography/mass spectrometry (UHPLC-MS). Then we constructed the partial least squares discriminant analysis (PLS-DA) model to screen the differential metabolites, and performed pathway analysis to screen the main metabolic pathways. Results showed that combined effect of PM2.5 and HFD caused changes in glucose tolerance, increased FBG levels and HOMA-IR in rats and there were interactions between PM2.5 and HFD in FBG and insulin. By metabonomic analysis, the serum differential metabolites pregnenolone and progesterone, which involved in steroid hormone biosynthesis, were two different metabolites in the ND groups. In the HFD groups, the serum differential metabolites were L-tyrosine and phosphorylcholine, which involved in glycerophospholipid metabolism, and phenylalanine, tyrosine, and tryptophan biosynthesis. When PM2.5 and HFD coexist, they may lead to more severe and complex effects on glucose metabolism by affecting lipid metabolism and amino acid metabolism. Therefore, reducing PM2.5 exposure and controlling dietary structure are important measures for preventing and reducing glucose metabolism disorders.

Percutaneous transhepatic cholangial drainage or antibiotic therapy worsens response to immunotherapy in advanced cholangiocarcinoma.

BACKGROUND: Bile duct obstruction is a common issue for patients with advanced cholangiocarcinoma (CCA). Percutaneous transhepatic cholangial drainage (PTCD) is often required to relieve the obstruction. However, PTCD may alter the intestinal microbiota, which can affect the efficacy of immunotherapy. Antibiotics (ATB) can also have significant immunomodulatory effects by perturbing the gut microbiota. Therefore, this study aimed to investigate whether PTCD or ATB therapy is associated with overall survival (OS) or progression-free survival (PFS) in patients with advanced CCA receiving first-line chemotherapy plus immune checkpoint blockade (ICB) in clinical practice. We also explored whether the gut microbiota changes after receiving PTCD. METHODS: We conducted a single-center retrospective analysis of PTCD and ATB therapy in patients with advanced CCA. PTCD was performed before ICB initiation, and ATB was administered within 1 month before and 6 weeks after ICB initiation. Our primary outcomes were PFS and OS. Moreover, we used 16s rRNA sequencing to analyze fecal and bile samples obtained from patients who underwent PTCD. RESULTS: In total, 107 patients with CCA were included. Among patients who did not undergo PTCD, ICB plus chemotherapy significantly improved OS vs. chemotherapy alone (hazard ratio [HR] 0.21, 95% confidence interval [CI] 0.09-0.45, p < 0.0001). PFS was also significantly improved in patients who received ICB plus chemotherapy compared with chemotherapy alone (HR 0.36, 95% CI 0.16-0.80, p = 0.0024). However, ICB plus chemotherapy did not improve survival compared with chemotherapy alone among patients who received PTCD. Overall changes in the fecal microbiota of patients after PTCD involved significant reductions in which Escherichia - Shigella. CONCLUSIONS: The use of ATB or PTCD in patients with CCA receiving ICB was associated with worse OS compared with chemotherapy alone, and PTCD affects the gut microbiota. Escherichia - Shigella was significantly reduced in feces of patients after PTCD.

Integrative proteomics and metabolomics analysis of non-observable acute effect level PM2.5 induced accumulative effects in AC16 cells.

Chronic exposure to very low ambient PM2.5 has been linked to cardiovascular risks in epidemiological observation, which also brought doubts on its safety threshold. In this study, we approached this question by chronic exposure of AC16 to the non-observable acute effect level (NOAEL) PM2.5 5 µg/mL and its positive reference 50 µg/mL, respectively. The doses were respectively defined on the cell viabilities >95% (p = 0.354) and >90% (p = 0.004) when treated acutely (24 h). To mimic the long-term exposure, AC16 was cultured from the 1st to 30th generations and treated with PM2.5 24 h in every three generations. The integration of proteomic and metabolomic analysis was applied, and 212 proteins and 172 metabolites were significantly altered during the experiments. The NOAEL PM2.5 induced both dose- and time-dependent disruption, which showed the dynamic cellular proteomic response and oxidation accumulation, the main metabolomics changes were ribonucleotide, amino acid, and lipid metabolism that have involved in stressed gene expression, and starving for energy metabolism and lipid oxidation. In summary, these pathways interacted with the monotonically increasing oxidative stress and led to the accumulated damage in AC16 and implied that the safe threshold of PM2.5 may be non-existent when a long-term exposure occurred.

Metabolic biomarkers linking urinary arsenic species to gestational diabetes mellitus: A cross-sectional study in Chinese pregnant women.

Environmental arsenic (As) exposure has been associated with gestational diabetes mellitus (GDM) risk. Our recent study found that GDM was positively associated with urinary As3+ level while negatively correlated to As5+. However, the mechanisms underlying the association between arsenic species and GDM remain largely unknown. In the present study, through the measurement of urinary arsenic species and metabolome analysis in 399 pregnant women, we aimed to identify the metabolic biomarkers that may link arsenic exposure to GDM based on a novel systems epidemiology strategy termed meet-in-metabolite-analysis (MIMA). The metabolomics analysis revealed that 20 and 16 urinary metabolites were relevant to arsenic exposure and GDM, respectively. Among them, 12 metabolites were identified to be both arsenic- and GDM-related, which are mainly involved in purine metabolism, one­carbon metabolism (OCM) and glycometabolism. Moreover, it was further showed that the regulation of thiosulfate (AOR: 2.52; 95 % CI: 1.33, 4.77) and phosphoroselenoic acid (AOR: 2.35; 95 % CI: 1.31, 4.22) could significantly contribute to the negative association between As5+ and GDM. Considering the biological functions of these metabolites, it is suggested that As5+ may reduce GDM risk by disturbing OCM in the pregnant women. These data will provide novel insights into the mechanism of action of environmental arsenic exposure on GDM incidence from the aspect of metabolism disorder.

Cryptococcal meningoencephalitis with Actinomyces odontolyticus sepsis: a case report and literature review.

BACKGROUND: The combined infection of actinomyces odontolyticus sepsis and cryptococcal encephalitis is rare in routine clinical practice. Thus, we presented this case report and literature review to provide clues to improve such patients' diagnoses and treatment processes. CASE PRESENTATION: The main clinical manifestations of the patient were high fever and intracranial hypertension. Then, we completed the routine cerebrospinal fluid examination, biochemical detection, cytological examination, bacterial culture, and India ink staining. Firstly, the blood culture suggested actinomyces odontolyticus infection, considering the possibility of actinomyces odontolyticus sepsis and intracranial actinomyces odontolyticus infection. Accordingly, the patient was administered penicillin for treatment. Although the fever was slightly relieved, the symptoms of intracranial hypertension did not relieve. After 7 days, the characteristics of brain magnetic resonance imaging and the results of pathogenic metagenomics sequencing and cryptococcal capsular polysaccharide antigen suggested that cryptococcal infection. Based on the above results, the patient was diagnosed with a combined infection of cryptococcal meningoencephalitis and actinomyces odontolyticus sepsis. Anti-infection therapy with 'penicillin, amphotericin, and fluconazole' was provided, improving the clinical manifestations and objective indexes. CONCLUSION: The combined infection of Actinomyces odontolyticus sepsis and cryptococcal encephalitis is first reported in this case report, and combined antibiotics with 'penicillin, amphotericin, and fluconazole' are effective.

Gene Association Analysis of Quantitative Trait Based on Functional Linear Regression Model with Local Sparse Estimator.

Functional linear regression models have been widely used in the gene association analysis of complex traits. These models retain all the genetic information in the data and take full advantage of spatial information in genetic variation data, which leads to brilliant detection power. However, the significant association signals identified by the high-power methods are not all the real causal SNPs, because it is easy to regard noise information as significant association signals, leading to a false association. In this paper, a method based on the sparse functional data association test (SFDAT) of gene region association analysis is developed based on a functional linear regression model with local sparse estimation. The evaluation indicators CSR and DL are defined to evaluate the feasibility and performance of the proposed method with other indicators. Simulation studies show that: (1) SFDAT performs well under both linkage equilibrium and linkage disequilibrium simulation; (2) SFDAT performs successfully for gene regions (including common variants, low-frequency variants, rare variants and mix variants); (3) With power and type I error rates comparable to OLS and Smooth, SFDAT has a better ability to handle the zero regions. The Oryza sativa data set is analyzed by SFDAT. It is shown that SFDAT can better perform gene association analysis and eliminate the false positive of gene localization. This study showed that SFDAT can lower the interference caused by noise while maintaining high power. SFDAT provides a new method for the association analysis between gene regions and phenotypic quantitative traits.

Atmospheric PM2.5 induce autophagy and autophagic flux blockage in HUVEC cells via ROS/TXNIP signaling: Important role of metal components.

Autophagy was involved in vascular endothelial injury caused by PM2.5, which aggravated the pathogenesis of cardiovascular diseases. However, major toxic components and underlying mechanism responsible for PM2.5-induced autophagy remain unclear. In this study, the effects of water-extracted PM2.5 (WE-PM2.5) on autophagy in human umbilical vein endothelial cells (HUVEC) were studied. Our results showed WE-PM2.5 promoted autophagosome initiation and formation, meanwhile, lysosomal function was impaired, which further caused autophagic flux blockage in HUVEC cells. Furthermore, removal of metals alleviated WE-PM2.5-induced autophagic flux blockage, while the artificial metal mixture reproduced the WE-PM2.5 response. Mechanistically, ROS regulated autophagy-related proteins evidenced by BECN1, LC3B and p62 expression reversed by NAC pretreatment in WE-PM2.5-exposed cells. WE-PM2.5 also increased TXNIP expression mediated by ROS; moreover, knockdown of TXNIP in WE-PM2.5-exposed cells decreased BECN1 and LC3B expression, but had little effects on the expression of p62, CTSB, and CTSD, indicating WE-PM2.5-induced TXNIP was involved in autophagosome initiation and formation rather than autophagic degradation. Collectively, WE-PM2.5-induced ROS not only promoted autophagosome initiation and formation, but also inhibited autophagic degradation. However, as the downstream molecule of ROS, TXNIP was only involved in autophagosome initiation and formation. Importantly, WE-PM2.5-bound metals were largely responsible for autophagic flux blockage in HUVEC cells.

A review of the application of artificial intelligence to nuclear reactors: Where we are and what's next.

As a form of clean energy, nuclear energy has unique advantages compared to other energy sources in the present era, where low-carbon policies are being widely advocated. The exponential growth of artificial intelligence (AI) technology in recent decades has resulted in new opportunities and challenges in terms of improving the safety and economics of nuclear reactors. This study briefly introduces modern AI algorithms such as machine learning, deep learning, and evolutionary computing. Furthermore, several studies on the use of AI techniques for nuclear reactor design optimization as well as operation and maintenance (O&M) are reviewed and discussed. The existing obstacles that prevent the further fusion of AI and nuclear reactor technologies so that they can be scaled to real-world problems are classified into two categories: (1) data issues: insufficient experimental data increases the possibility of data distribution drift and data imbalance; (2) black-box dilemma: methods such as deep learning have poor interpretability. Finally, this study proposes two directions for the future fusion of AI and nuclear reactor technologies: (1) better integration of domain knowledge with data-driven approaches to reduce the high demand for data and improve the model performance and robustness; (2) promoting the use of explainable artificial intelligence (XAI) technologies to enhance the transparency and reliability of the model. In addition, causal learning warrants further attention owing to its inherent ability to solve out-of-distribution generalization (OODG) problems.

Clinical significance of immune checkpoint proteins in HPV-infected cervical cancer.

OBJECTIVE: To investigate T cell immunoreceptor with Ig and ITIM domain (TIGIT), V-domain Ig suppressor of T cell activation (VISTA), and lymphocyte-activation gene-3 (LAG-3) expression in pathological tissue of human papillomavirus (HPV)-infected cervical cancer (CC) patients and their relationship with patient prognosis. METHODS: Clinical data of 175 patients with HPV-infected CC were collected retrospectively. Tumor tissue sections were stained immunohistochemically for TIGIT, VISTA, and LAG-3. The Kaplan-Meier method calculated patient survival. Univariate and multivariate Cox proportional hazards models analyzed all potential risk factors for survival. RESULTS: When combined positive score (CPS)= 1 was used as the cut-off value, the Kaplan-Meier survival curve showed that the progression-free survival (PFS) and overall survival (OS) of patients with positive expression of TIGIT and VISTA are shorter (both p < 0.05). Univariate COX regression analysis showed that the positive expression of TIGIT and VISTA are related to patient PFS and OS (both HR>1.0 and p < 0.05). Multivariate COX regression analysis showed that TIGIT-positive patients had shorter OS and VISTA-positive patients had shorter PFS (both HR>1.0 and p < 0.05). There is no significant correlation between LAG-3 expression and PFS or OS. When CPS= 10 was used as the cut-off value, Kaplan-Meier survival curve showed that TIGIT-positive patients had shorter OS (p = 0.019). Univariate COX regression analysis showed that TIGIT-positive expression was associated with the OS of patients (HR=2.209, CI: 1.118-4.365, p = 0.023). However, multivariate COX regression analysis showed that TIGIT expression was not associated significantly with OS. There was no significant correlation between VISTA and LAG-3 expression and PFS or OS. CONCLUSION: TIGIT and VISTA are associated closely with HPV-infected CC prognosis and are effective biomarkers.

Arsenic metabolism, N6AMT1 and AS3MT single nucleotide polymorphisms, and their interaction on gestational diabetes mellitus in Chinese pregnant women.

BACKGROUND: Single nucleotide polymorphisms (SNPs) in N6AMT1 and AS3MT are associated with arsenic (As) metabolism, and efficient As methylation capacity has been associated with diabetes. However, little is known about the gene-As interaction on gestational diabetes mellitus (GDM). OBJECTIVE: This study aimed to explore the individual and combined effects of N6AMT1 and AS3MT SNPs with As metabolism on GDM. METHODS: A cross-sectional study was performed among 385 Chinese pregnant women (86 GDM and 299 Non-GDM). Four SNPs in N6AMT1 (rs1997605 and rs1003671) and AS3MT (rs1046778 and rs11191453) were genotyped. Urinary inorganic arsenic (iAs), monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) were determined, and the percentages of As species (iAs%, MMA%, and DMA%) were calculated to assess the efficiency of As metabolism. RESULTS: Pregnant women with N6AMT1 rs1997605 AA genotype had lower iAs% (B: 2.11; 95% CI: 4.08, -0.13) and MMA% (B: 0.21; 95% CI: 0.39, -0.04) than pregnant women with GG genotype. The AS3MT rs1046778 and rs11191453 C alleles were negatively associated with iAs% and MMA% but positively associated with DMA%. Higher urinary MMA% was significantly associated with a lower risk of GDM (OR: 0.54; 95% CI: 0.30, 0.97). The A allele in N6AMT1 rs1997605 (OR: 0.46; 95% CI: 0.26, 0.79) was associated with a decreased risk of GDM. The additive interactions between N6AMT1 rs1997605 GG genotypes and lower iAs% (AP: 0.50; 95% CI: 0.01, 0.99) or higher DMA% (AP: 0.52; 95% CI: 0.04, 0.99) were statistically significant. Similar additive interactions were also found between N6AMT1 rs1003671 GG genotypes and lower iAs% or higher DMA%. CONCLUSIONS: Genetic variants in N6AMT1 and efficient As metabolism (indicated by lower iAs% and higher DMA%) can interact to influence GDM occurrence synergistically in Chinese pregnant women.