Observation-Based Diagnostics of Reactive Nitrogen Recycling through HONO Heterogenous Production: Divergent Implications for Ozone Production and Emission Control.

Understanding of nitrous acid (HONO) production is crucial to photochemical studies, especially in polluted environments like eastern China. In-situ measurements of gaseous and particulate compositions were conducted at a rural coastal site during the 2018 spring Ozone Photochemistry and Export from China Experiment (OPECE). This data set was applied to investigate the recycling of reactive nitrogen through daytime heterogeneous HONO production. Although HONO levels increase during agricultural burning, analysis of the observation data does not indicate more efficient HONO production by agricultural burning aerosols than other anthropogenic aerosols. Box and 1-D modeling analyses reveal the intrinsic relationships between nitrogen dioxide (NO2), particulate nitrate (pNO3), and nitric acid (HNO3), resulting in comparable agreement between observed and simulated HONO concentrations with any one of the three heterogeneous HONO production mechanisms, photosensitized NO2 conversion on aerosols, photolysis of pNO3, and conversion from HNO3. This finding underscores the uncertainties in the mechanistic understanding and quantitative parametrizations of daytime heterogeneous HONO production pathways. Furthermore, the implications for reactive nitrogen recycling, ozone (O3) production, and O3 control strategies vary greatly depending on the HONO production mechanism. On a regional scale, the conversion of HONO from pNO3 can drastically enhance O3 production, while the conversion from NO2 can reduce O3 sensitivity to NOx changes in polluted eastern China.

ZNF384 transcriptionally activated MGST1 to confer TMZ resistance of glioma cells by negatively regulating ferroptosis.

BACKGROUND: Drug resistance is one of the major reasons of the poor prognosis and recurs frequently in glioma. Ferroptosis is considered to be a new therapeutic strategy for glioma. METHODS: Microsomal glutathione S-transferase 1 (MGST1) expression in glioma samples was ensured through GAPIA database, qRT-PCR, western blotting assay and immunohistochemistry. The interaction between zinc finger protein 384 (ZNF384) and MGST1 promoter was analyzed through UCSC and JASPAR databases and further verified by ChIP and luciferase reporter assay. Cell viability and IC50 value of temozolomide (TMZ) was measured by CCK-8 assay. The production of MDA, GSH and ROS and the level of Fe2+ were determined using the corresponding kit. RESULTS: MGST1 expression was increased in clinical glioma tissues and glioma cells. MGST1 expression was increased but ferroptosis was suppressed in TMZ-resistant cells when contrasted to parent cells. MGST1 silencing downregulated IC50 value of TMZ and cell viability but facilitated ferroptosis in TMZ-resistant cells and parent glioma cells. Moreover, our data indicated that ZNF384 interacted with MGST1 promoter and facilitated MGST1 expression. ZNF384 was also increased expression in TMZ-resistant cells, and showed a positive correlation with MGST1 expression in clinical level. ZNF384 decreasing enhanced the sensitivity of resistant cells to TMZ, while the effect of ZNF384 could be reversed by overexpression of MGST1. CONCLUSION: MGST1 transcription is regulated by transcription factor ZNF384 in TMZ-resistant cells. ZNF384 confers the resistance of glioma cells to TMZ through inhibition of ferroptosis by positively regulating MGST1 expression. The current study may provide some new understand to the mechanism of TMZ resistance in glioma.

Exosomal HMGB3 released by glioma cells confers the activation of NLRP3 inflammasome and pyroptosis in tumor-associated macrophages.

BACKGROUND: Previous evidences has highlighted the pivotal role of NOD-like receptor family pyrin domain-containing 3 (NLRP3)-mediated inflammasomes and pyroptosis activation in driving tumor malignancy and shaping the tumor microenvironment. Herein, we aimed to elucidate the impact of high-mobility group box 3 (HMGB3) released in glioma-derived exosomes on macrophage infiltration in gliomas, NLRP3 inflammasome activation and polarization. METHODS: Transcripts and protein levels of HMGB3, and cytokines associated with macrophage phenotypes and pyroptosis were assessed in glioma tissues and cell lines (U251, LN229, T98G, A172) using qRT-PCR and/or Western blot analysis. Exosomes secreted from LN229 and NHA cells were isolated via differential ultracentrifugation and characterized by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and analysis of exosome-related markers. PKH67 staining was employed to examine exosomes uptake by THP-1 differentiated macrophages. Flow cytometry was utilized to assess macrophage pyroptotic rates and polarization-related markers. RESULTS: HMGB3 expression was elevated in glioma tissues, serum samples and tumor cell lines. Kaplan-Meier curves revealed a positive correlation between higher HMGB3 expression and poor overall survival and recurrence-free survival. Moreover, glioma tissues with increased HMGB3 expression exhibited significant upregulation of M2 macrophages markers (CD68, CD206, Arg1) and NLRP3 inflammasome components (NLRP3, IL-1ß, ASC), suggesting that HMGB3 was closely associated with macrophage infiltration and NLRP3 inflammasome activation. Notably, HMGB3 was found to be enriched in glioma cell- secreted exosomes and could be internalized by macrophages. Knockdown of HMGB3 in glioma cell exosomes could restrain M2 macrophage polarization, NLRP3 inflammasome activation and pyroptosis. CONCLUSION: These findings suggested that glioma cells secreted exosomal HMGB3 could facilitate macrophage M2 polarization, pyroptosis and inflammatory infiltration, indicating HMGB3 might be a poor prognosis factor for glioma.

TRPC6 Knockout Alleviates Renal Fibrosis through PI3K/AKT/GSK3B Pathway.

OBJECTIVE: Renal fibrosis is the ultimate pathway of various forms of acute and chronic kidney damage. Notably, the knockout of transient receptor potential channel 6 (TRPC6) has shown promise in alleviating renal fibrosis. However, the regulatory impact of TRPC6 on renal fibrosis remains unclear. METHODS: In vivo, TRPC6 knockout (TRPC6-/-) mice and age-matched 129 SvEv (WT) mice underwent unilateral renal ischemia-reperfusion (uIR) injury surgery on the left renal pedicle or sham operation. Kidneys and serum were collected on days 7, 14, 21, and 28 after euthanasia. In vitro, primary tubular epithelial cells (PTECs) were isolated from TRPC6-/- and WT mice, followed by treatment with transforming growth factor ß1 (TGFß1) for 72 h. The anti-fibrotic effect of TRPC6-/- and the underlying mechanisms were assessed through hematoxylin-eosin staining, Masson staining, immunostaining, qRT-PCR, and Western blotting. RESULTS: Increased TRPC6 expression was observed in uIR mice and PTECs treated with TGFß1. TRPC6-/- alleviated renal fibrosis by reducing the expression of fibrotic markers (Col-1, α-SMA, and vimentin), as well as decreasing the apoptosis and inflammation of PTECs during fibrotic progression both in vivo and in vitro. Additionally, we found that the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/glycogen synthase kinase 3 beta (GSK3ß) signaling pathway, a pivotal player in renal fibrosis, was down-regulated following TRPC6 deletion. CONCLUSION: These results suggest that the ablation of TRPC6 may mitigate renal fibrosis by inhibiting the apoptosis and inflammation of PTECs through down-regulation of the PI3K/AKT/GSK3ß pathway. Targeting TRPC6 could be a novel therapeutic strategy for preventing chronic kidney disease.

Elevated temperature magnifies the acute and chronic toxicity of clothianidin to Eisenia fetida.

Pesticide residue and thermal stress resulting from global climate change are parallel stressors for soil fauna. However, it remains ambiguous how elevated temperatures and pesticides can interact to threaten soil fauna. In the study, the acute and chronic clothianidin (CTD) toxicity to earthworms (Eisenia fetida) at different temperatures, and the effect of increasing temperature on antioxidant defense mechanisms in response to CTD were investigated. The acute toxicity of CTD was exacerbated by increased temperature in both filter paper contact tests (a decrease in the 48-h median lethal concentration (LC50) from 0.077 µg/cm2 at 20 °C to 0.009 µg/cm2 at 30 °C) and natural soil tests (a decrease in the 48-h LC50 from 0.774 mg/kg at 20 °C to 0.199 mg/kg at 30 °C). Exposure to CTD or high temperature (30 °C) triggered reactive oxygen species (ROS) overgeneration and increased antioxidant enzyme activities in earthworms; and the effect was particularly pronounced after exposure to both higher temperatures and CTD. At 20 and 25 °C, there was no significant change in the growth and reproduction of E. fetida after 56-d exposure to CTD-contaminated soil. However, the combined effect of CTD and high temperature (30 °C) significantly reduced the weight change rate, cocoon number, hatching rate, and number of juveniles on day 56. These results indicated that elevated temperature could aggravate acute and chronic CTD toxicity to earthworms. The findings emphasize that evaluating changes in pesticide toxicity under global warming is worth further investigation.

Triglyceride-glucose index and health outcomes: an umbrella review of systematic reviews with meta-analyses of observational studies.

BACKGROUND: Numerous meta-analyses have explored the association between the triglyceride-glucose (TyG) index and diverse health outcomes, yet the comprehensive assessment of the scope, validity, and quality of this evidence remains incomplete. Our aim was to systematically review and synthesise existing meta-analyses of TyG index and health outcomes and to assess the quality of the evidence. METHODS: A thorough search of PubMed, EMBASE, and Web of Science databases was conducted from their inception through to 8 April 2024. We assessed the quality of reviews using A Measurement Tool to Assess Systematic Reviews (AMSTAR) and the certainty of the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system. This study was registered with PROSPERO (CRD: 42024518587). RESULTS: Overall, a total of 95 associations from 29 meta-analyses were included, investigating associations between TyG index and 30 health outcomes. Of these, 83 (87.4%) associations were statistically significant (P < 0.05) according to the random effects model. Based on the AMSTAR tool, 16 (55.2%) meta-analyses were high quality and none was low quality. The certainty of the evidence, assessed by the GRADE framework, showed that 6 (6.3%) associations were supported by moderate-quality evidence. When compared with the lowest category of the TyG index, the risk of contrast-induced nephropathy (CIN) [relative risk (RR) = 2.25, 95%CI 1.82, 2.77], the risk of stroke in patients with diabetes mellitus (RR = 1.26, 95%CI 1.18, 1.33) or with acute coronary syndrome disease (RR = 1.56, 95%CI 1.06, 2.28), the prognosis of coronary artery disease (CAD)-non-fatal MI (RR = 2.02, 95%CI 1.32, 3.10), and the severity of CAD including coronary artery stenosis (RR = 3.49, 95%CI 1.71, 7.12) and multi-vessel CAD (RR = 2.33, 95%CI 1.59, 3.42) increased with high TyG index. CONCLUSION: We found that the TyG index was positively associated with many diseases including the risk of CIN and stroke, the prognosis of CAD, and the severity of CAD which were supported by moderate-quality evidence. TyG index might be useful to identify people at high-risk for developing these diseases.

Human papillomavirus infection and the risk of cancer at specific sites other than anogenital tract and oropharyngeal region: an umbrella review.

BACKGROUND: Despite numerous studies having evaluated the associations between human papillomavirus (HPV) infection and risk of specific cancers other than anogenital tract and oropharyngeal, the findings are inconsistent and the quality of evidence has not been systematically quantified. We aimed to summarise the existing evidence as well as to evaluate the strength and credibility of these associations. METHODS: We conducted an umbrella review of systematic reviews and meta-analyses of observational studies. PubMed, EMBASE, and Web of Science were searched from inception to March 2024. Studies with systematic reviews and meta-analyses that examined associations between HPV or HPV-associated genotypes infection and specific cancers were eligible for this review. The quality of the methodology was evaluated using A Measurement Tool to Assess systematic Reviews (AMSTAR). The credibility of the evidence was assessed using GRADE. The protocol was preregistered with PROSPERO (CRD42023439070). FINDINGS: The umbrella review identified 31 eligible studies reporting 87 associations with meta-analytic estimates, including 1191 individual studies with 336,195 participants. Of those, 29 (93.5%) studies were rated as over moderate quality by AMSTAR. Only one association indicating HPV-18 infection associated with an increased risk of breast cancer (odds ratio [OR] = 3.48, 95% confidence interval [CI] = 2.24-5.41) was graded as convincing evidence. There were five unique outcomes identified as highly suggestive evidence, including HPV infection increased the risk of oral squamous cell carcinoma (OR = 7.03, 95% CI = 3.87-12.76), oesophageal cancer (OR = 3.32, 95% CI = 2.54-4.34), oesophageal squamous cell carcinoma (OR = 2.69, 95% CI = 2.05-3.54), lung cancer (OR = 3.60, 95% CI = 2.59-5.01), and breast cancer (OR = 6.26, 95% CI = 4.35-9.00). According to GRADE, one association was classified as high, indicating that compared with the controls in normal tissues, HPV infection was associated with an increased risk of breast cancer. INTERPRETATION: The umbrella review synthesised up-to-date observational evidence on HPV infection with the risk of breast cancer, oral squamous cell carcinoma, oesophageal cancer, oesophageal squamous cell carcinoma, and lung cancer. Further larger prospective cohort studies are needed to verify the associations, providing public health recommendations for prevention of disease. FUNDING: National Key Research and Development Program of China, Natural Science Foundation of China, Outstanding Scientific Fund of Shengjing Hospital of China Medical University, and 345 Talent Project of Shengjing Hospital of China Medical University.

Per- and polyfluoroalkyl substances and human health outcomes: An umbrella review of systematic reviews with meta-analyses of observational studies.

BACKGROUND: Although evidence on the association between per- and polyfluoroalkyl substances (PFASs) and human health outcomes has grown exponentially, specific health outcomes and their potential associations with PFASs have not been conclusively evaluated. METHODS: We conducted a comprehensive search through the databases of PubMed, Embase, and Web of Science from inception to February 29, 2024, to identify systematic reviews with meta-analyses of observational studies examining the associations between the PFASs and multiple health outcomes. The quality of included studies was evaluated using the A Measurement Tool to Assess Systematic Reviews (AMSTAR) tool, and credibility of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) criteria. The protocol of this umbrella review (UR) had been registered in PROSPERO (CRD 42023480817). RESULTS: The UR identified 157 meta-analyses from 29 articles. Using the AMSTAR measurement tool, all articles were categorized as of moderate-to-high quality. Based on the GRADE assessment, significant associations between specific types of PFASs and low birth weight, tetanus vaccine response, and triglyceride levels showed high certainty of evidence. Moreover, moderate certainty of evidence with statistical significance was observed between PFASs and health outcomes including lower BMI z-score in infancy, poor sperm progressive motility, and decreased risk of preterm birth as well as preeclampsia. Fifty-two (33%) associations (e.g., PFASs and gestational hypertension, cardiovascular disease, etc) presented low certainty evidence. Additionally, eighty-five (55%) associations (e.g., PFASs with infertility, lipid metabolism, etc) presented very low certainty evidence. CONCLUSION: High certainty of evidence supported that certain PFASs were associated with the incidence of low birth weight, low efficiency of the tetanus vaccine, and low triglyceride levels.

Nitric oxide alleviates programmed cell death induced by cadmium in Solanum lycopersicum seedlings through protein S-nitrosylation.

Cadmium (Cd), as a non-essential and toxic heavy metal in plants, has deleterious effects on plant physiological and biochemical processes. Nitric oxide (NO) is one of the most important signaling molecules for plants to response diverse stresses. Here, we found that Cd-induced programmed cell death (PCD) was accompanied by NO bursts, which exacerbated cell death when NO was removed and vice versa. Proteomic analysis of S-nitrosylated proteins showed that the differential proteins in Cd-induced PCD and in NO-alleviated PCD mainly exist together in carbohydrate metabolism and amino acid metabolism, while some of the differential proteins exist alone in metabolism of cofactors and vitamins and lipid metabolism. Meanwhile, S-nitrosylation of proteins in porphyrin and chlorophyll metabolism and starch and sucrose metabolism could explain the leaf chlorosis induced by PCD. Moreover, protein transport protein SEC23, ubiquitinyl hydrolase 1 and pathogenesis-related protein 1 were identified to be S-nitrosylated in vivo, and their expressions were increased in Cd-induced PCD while decreased in NO treatment. Similar results were obtained in tomato seedlings with higher S-nitrosylation. Taken together, our results indicate that NO might be involved in the regulation of Cd-induced PCD through protein S-nitrosylation, especially proteins involved in PCD response.

ABO and Rhesus blood groups and multiple health outcomes: an umbrella review of systematic reviews with meta-analyses of observational studies.

BACKGROUND: Numerous studies have been conducted to investigate the relationship between ABO and Rhesus (Rh) blood groups and various health outcomes. However, a comprehensive evaluation of the robustness of these associations is still lacking. METHODS: We searched PubMed, Web of Science, Embase, Scopus, Cochrane, and several regional databases from their inception until Feb 16, 2024, with the aim of identifying systematic reviews with meta-analyses of observational studies exploring associations between ABO and Rh blood groups and diverse health outcomes. For each association, we calculated the summary effect sizes, corresponding 95% confidence intervals, 95% prediction interval, heterogeneity, small-study effect, and evaluation of excess significance bias. The evidence was evaluated on a grading scale that ranged from convincing (Class I) to weak (Class IV). We assessed the certainty of evidence according to the Grading of Recommendations Assessment, Development, and Evaluation criteria (GRADE). We also evaluated the methodological quality of included studies using the A Measurement Tool to Assess Systematic Reviews (AMSTAR). AMSTAR contains 11 items, which were scored as high (8-11), moderate (4-7), and low (0-3) quality. We have gotten the registration for protocol on the PROSPERO database (CRD42023409547). RESULTS: The current umbrella review included 51 systematic reviews with meta-analysis articles with 270 associations. We re-calculated each association and found only one convincing evidence (Class I) for an association between blood group B and type 2 diabetes mellitus risk compared with the non-B blood group. It had a summary odds ratio of 1.28 (95% confidence interval: 1.17, 1.40), was supported by 6870 cases with small heterogeneity (I2 = 13%) and 95% prediction intervals excluding the null value, and without hints of small-study effects (P for Egger's test > 0.10, but the largest study effect was not more conservative than the summary effect size) or excess of significance (P < 0.10, but the value of observed less than expected). And the article was demonstrated with high methodological quality using AMSTAR (score = 9). According to AMSTAR, 18, 32, and 11 studies were categorized as high, moderate, and low quality, respectively. Nine statistically significant associations reached moderate quality based on GRADE. CONCLUSIONS: Our findings suggest a potential relationship between ABO and Rh blood groups and adverse health outcomes. Particularly the association between blood group B and type 2 diabetes mellitus risk.

Hydrogen gas: A new fresh keeping agent of perishable horticultural products.

Hydrogen gas (H2), a gaseous signaling molecule, is involved in plant growth and development. This review collates emerging evidence to show that H2 regulates the postharvest senescence of horticultural products through critical biochemical processes, including the improvement of antioxidant systems, the activation of cell wall metabolism, the promotion of energy metabolism, the inhibition of ethylene biosynthesis and the regulation of bacterial communities. Additionally, the interactions between H2 and other signaling molecules are also discussed. This paper presents the current status of H2 research in terms of its biological effects and safety in postharvest products by combining the research results on the molecular mechanisms of biological effects and H2 signaling. The action mechanism of H2 for postharvest preservation is also proposed, and it reflects the complexity and diversity of the pathways involved. Furthermore, a growing body of evidence has found a large number of downstream pathways or targets for the medical effects of H2. Therefore, the scientific and practical aspects of H2 biology are proposed for the postharvest preservation of horticultural products.

A novel PD-1/PD-L1 pathway-related seven-gene signature for the development and validation of the prognosis prediction model for breast cancer.

Background: Breast cancer (BC/BRCA) is the most common carcinoma in women. The average 5-year survival rate of BC patients with stage IV disease is 26%. A considerable proportion of patients still do not receive effective therapy. It is an unmet need to identify novel biomarkers for BC patients. Herein, we evaluated whether the programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) status is associated with the clinical outcomes of BC, based on data from The Cancer Genome Atlas (TCGA). Methods: Clinical and transcriptome data of BC patients were obtained from TCGA dataset, and prognostic genes in BC patients were identified, as well as the PD-1/PD-L1 pathway mainly associating with the BC patients. Following the execution of the consensus clustering algorithm, BC patients were segregated into two clusters, and subsequent investigation of the potential mechanisms between them was carried out. A comparison of ferroptosis and N6-methyladenosine (m6A) was conducted between the two groups with the greatest difference in prognosis. Based on least absolute shrinkage and selection operator (LASSO) analysis, a signature associated with the PD-1/PD-L1 pathway was developed, and the prognosis outcome and the predictive accuracy of the signature model were further assessed. Results: Prognostic genes in BC patients were studied using TCGA data and it was found that the PD-1/PD-L1 pathway was most associated with the BC patients. Then, a low-risk (C1) group and a high-risk (C2) group of BC patients were constructed based on a PD-1/PD-L1 pathway-related signature. The functional analyses suggested that the underlying mechanisms between these groups were mainly associated with immune-related pathways. We found that ferroptosis and m6A were significantly different between the two groups. A PD-1/PD-L1 pathway-related gene signature was further developed to predict survival of BC patients, including 7 genes [mitogen-activated protein kinase kinase 6 (MAP2K6), NF-kappa-B inhibitor alpha (NFKBIA), NFKB Inhibitor Epsilon (NFKBIE), Interferon gamma (IFNG), Toll/interleukin-1 receptor domain-containing adapter protein (TIRAP), IkappaB kinase (CHUK), and Casein kinase 2 alpha 3 gene (CSNK2A3)]. The receiver operating characteristic (ROC) curves were analyzed to further assess the prognostic values of these 7 genes. The 1-, 3-, and 5-year values of the areas under the curve (AUCs) for overall survival were 0.651, 0.658, and 0.653 in this seven gene signature model, respectively. Conclusions: PD-1/PD-L1 pathway-related subtypes of BC were identified, which were closely associated with the immune microenvironment, the ferroptosis status, and m6A in BC patients. The gene signature involved in the PD-1/PD-L1 pathway might help to make a distinction and predict prognosis in BC patients.

Functional identification of specialized diterpene synthases from Chamaecyparis obtusa and C. obtusa var. formosana to illustrate the putative evolution of diterpene synthases in Cupressaceae.

Chamaecyparis obtusa and C. obtusa var. formosana of the Cupressaceae family are well known for their fragrance and excellent physical properties. To investigate the biosynthesis of unique diterpenoid compounds, diterpene synthase genes for specialized metabolite synthesis were cloned from C. obtusa and C. obtusa var. formosana. Using an Escherichia coli co-expression system, eight diterpene synthases (diTPSs) were characterized. CoCPS and CovfCPS are class II monofunctional (+)-copalyl diphosphate synthases [(+)-CPSs]. Class I monofunctional CoLS and CovfLS convert (+)-copalyl diphosphate [(+)-CPP] to levopimaradiene, CoBRS, CovfBRS1, and CovfBRS3 convert (+)-CPP to (-)-beyerene, and CovfSDS converts (+)-CPP to (-)-sandaracopimaradiene. These enzymes are all monofunctional diterpene syntheses in Cupressaceae family of gymnosperm, and differ from those in Pinaceae. The discovery of the enzyme responsible for the biosynthesis of tetracyclic diterpene (-)-beyerene was characterized for the first time. Diterpene synthases with different catalytic functions exist in closely related species within the Cupressaceae family, indicating that this group of monofunctional diterpene synthases is particularly prone to the evolution of new functions and development of species-specific specialized diterpenoid constituents.

Tebuconazole promotes spread of a multidrug-resistant plasmid into soil bacteria to form new resistant bacterial strains.

The development of antibiotic resistance threatens human and environmental health. Non-antibiotic stressors, including fungicides, may contribute to the spread of antibiotic resistance genes (ARGs). We determined the promoting effects of tebuconazole on ARG dissemination using a donor, Escherichia coli MG1655, containing a multidrug-resistant fluorescent plasmid (RP4) and a recipient (E. coli HB101). The donor was then incorporated into the soil to test whether tebuconazole could accelerate the spread of RP4 into indigenous bacteria. Tebuconazole promoted the transfer of the RP4 plasmid from the donor into the recipient via overproduction of reactive oxygen species (ROS), enhancement of cell membrane permeability and regulation of related genes. The dissemination of the RP4 plasmid from the donor to soil bacteria was significantly enhanced by tebuconazole. RP4 plasmid could be propagated into more genera of bacteria in tebuconazole-contaminated soil as the exposure time increased. These findings demonstrate that the fungicide tebuconazole promotes the spread of the RP4 plasmid into indigenous soil bacteria, revealing the potential risk of tebuconazole residues enhancing the dissemination of ARGs in soil environments.

Federated Fuzzy Clustering for Decentralized Incomplete Longitudinal Behavioral Data.

The use of medical data for machine learning, including unsupervised methods such as clustering, is often restricted by privacy regulations such as the Health Insurance Portability and Accountability Act (HIPAA). Medical data is sensitive and highly regulated and anonymization is often insufficient to protect a patient's identity. Traditional clustering algorithms are also unsuitable for longitudinal behavioral health trials, which often have missing data and observe individual behaviors over varying time periods. In this work, we develop a new decentralized federated multiple imputation-based fuzzy clustering algorithm for complex longitudinal behavioral trial data collected from multisite randomized controlled trials over different time periods. Federated learning (FL) preserves privacy by aggregating model parameters instead of data. Unlike previous FL methods, this proposed algorithm requires only two rounds of communication and handles clients with varying numbers of time points for incomplete longitudinal data. The model is evaluated on both empirical longitudinal dietary health data and simulated clusters with different numbers of clients, effect sizes, correlations, and sample sizes. The proposed algorithm converges rapidly and achieves desirable performance on multiple clustering metrics. This new method allows for targeted treatments for various patient groups while preserving their data privacy and enables the potential for broader applications in the Internet of Medical Things.

Comprehensive analyses of m1A regulator-mediated modification patterns determining prognosis in lower-grade glioma (running title: m1A in LGG).

N1-methyladenosine (m1A) modification is a crucial post-transcriptional regulatory mechanism of messenger RNA (mRNA) in living organisms. Few studies have focused on analysis of m1A regulators in lower-grade gliomas (LGG). We employed the Nonnegative Matrix Factorization (NMF) technique on The Cancer Genome Atlas (TCGA) dataset to categorize LGG patients into 2 groups. These groups exhibited substantial disparities in terms of both overall survival (OS) and levels of infiltrating immune cells. We collected the significantly differentially expressed immune-related genes between the 2 clusters, and performed LASSO regression analysis to obtain m1AScores, and established an m1A-related immune-related gene signature (m1A-RIGS). Next, we categorized all patients with LGG into high- and low-risk subgroups, predictive significance of m1AScore was confirmed by conducting univariate/multivariate Cox regression analyses. Additionally, we confirmed variations in immune-related cells and ssGSEA and among the high-/low-risk subcategories in the TCGA dataset. Finally, our study characterized the effects of MSR1 and BIRC5 on LGG cells utilizing Edu assay and flow cytometry to explore the effects of modulation of these genes on glioma. The results of this study suggested that m1A-RIGS may be an excellent prognostic indicator for patients with LGG, and could also promote development of novel immune-based treatment strategies for LGG. Additionally, BIRC5 and MSR1 may be potential therapeutic targets for LGG.

Role of artificial intelligence in digital pathology for gynecological cancers.

The diagnosis of cancer is typically based on histopathological sections or biopsies on glass slides. Artificial intelligence (AI) approaches have greatly enhanced our ability to extract quantitative information from digital histopathology images as a rapid growth in oncology data. Gynecological cancers are major diseases affecting women's health worldwide. They are characterized by high mortality and poor prognosis, underscoring the critical importance of early detection, treatment, and identification of prognostic factors. This review highlights the various clinical applications of AI in gynecological cancers using digitized histopathology slides. Particularly, deep learning models have shown promise in accurately diagnosing, classifying histopathological subtypes, and predicting treatment response and prognosis. Furthermore, the integration with transcriptomics, proteomics, and other multi-omics techniques can provide valuable insights into the molecular features of diseases. Despite the considerable potential of AI, substantial challenges remain. Further improvements in data acquisition and model optimization are required, and the exploration of broader clinical applications, such as the biomarker discovery, need to be explored.

Ozone and its precursors at an urban site in the Yangtze River Delta since clean air action plan phase II in China.

In response to regional ozone (O3) pollution, Chinese government has implemented air pollution control measures in recent years. Here, a case study was performed at an O3-polluted city, Wuhu, in Yangtze River Delta region of China to investigate O3 variation trend and the relationship to its precursors after implementation of Clean Air Action Plan Phase II, which aims to reduce O3 pollution. The results showed that peak O3 concentration was effectively reduced since Clean Air Action Plan Phase II. Due to significant NOx reduction, O3 formation tended to shift from volatile organic compound (VOC)-limited regimes to NOx-limited regimes during 2018-2022. VOC/NOx ratios measured in 2022 revealed that peak O3 concentration tended to respond positively to NOx. Apart from high-O3 period, Wuhu was still in a VOC-limited regime. The relationship of maximum daily 8-h ozone average and NO2 followed a lognormal distribution with an inflection point at 20 µg m-3 of NO2, suggesting that Wuhu should conduct joint control of VOC and NOx with a focus on VOC reduction before the inflection point. Alkenes and aromatics were suggested to be preferentially controlled due to their higher ozone formation potentials. Using random forest meteorological normalization method, meteorology had a positive effect on O3 concentration in 2018, 2019 and 2022, but a negative effect in 2020 and 2021. The meteorology could explain 44.0 ± 19.1% of the O3 variation during 2018-2022. High temperature favors O3 production and O3 pollution occurred more easily when temperature was over 25 °C, while high relative humidity inhibits O3 generation and no O3 pollution was found at relative humidity above 70%. This study unveils some new insights into the trend of urban O3 pollution in Yangtze River Delta region since Clean Air Action Plan Phase II and the findings provide important references for formulating control strategies against O3 pollution.

Mechanisms Underlying the Overlooked Chiral Fungicide-Driven Enantioselective Proliferation of Antibiotic Resistance in Earthworm Intestinal Microbiome.

From a "One Health" perspective, the global threat of antibiotic resistance genes (ARGs) is associated with modern agriculture practices including agrochemicals application. Chiral fungicides account for a considerable proportion of wildly used agrochemicals; however, whether and how their enantiomers lead to differential proliferation of antibiotic resistance in agricultural environments remain overlooked. Focused on the soil-earthworm ecosystem, we for the first time deciphered the mechanisms underlying the enantioselective proliferation of antibiotic resistance driven by the enantiomers of a typical chiral fungicide mandipropamid (i.e., R-MDP and S-MDP) utilizing a multiomic approach. Time-series metagenomic analysis revealed that R-MDP led to a significant enhancement of ARGs with potential mobility (particularly the plasmid-borne ARGs) in the earthworm intestinal microbiome. We further demonstrated that R-MDP induced a concentration-dependent facilitation of plasmid-mediated ARG transfer among microbes. In addition, transcriptomic analysis with verification identified the key aspects involved, where R-MDP enhanced cell membrane permeability, transfer ability, biofilm formation and quorum sensing, rebalanced energy production, and decreased cell mobility versus S-MDP. Overall, the findings provide novel insights into the enantioselective disruption of microbiome and resistome in earthworm gut by chiral fungicides and offer significant contributions to the comprehensive risk assessment of chiral agrochemicals in agroecosystems.

Ultra-processed food consumption and metabolic disease risk: an umbrella review of systematic reviews with meta-analyses of observational studies.

Background and aims: There is an ongoing debate on whether to advocate reducing ultra-processed food (UPF) in dietary guidelines to control metabolic disease (such as obesity and type 2 diabetes mellitus [T2DM]). We aimed to summarize the evidence from systematic reviews with meta-analyses between UPF consumption and metabolic diseases risk, assess the credibility, and verify the robustness of these associations. Methods: We systematically searched PubMed, Web of Science, Embase, and Cochrane Library databases from their inception to July 15, 2023, to identify relevant systematic reviews with meta-analyses. We used the random-effects model to evaluate the summary effect size, along with 95% confidence interval and prediction interval. We also assessed heterogeneity, evidence of small-study effects and excess significance bias, and categorized the credibility of each association based on quantitative umbrella review criteria. Additionally, we conducted subgroup and sensitivity analyses to assess the robustness of associations based on continents, study design, dietary assessment methods, definition methods of UPF, population, and units of UPF consumption. Results: Overall, 6 systematic reviews with 13 meta-analyses were included. Three (23.08%) meta-analyses were classified as highly suggestive evidence for meeting the criteria that associations were significant at p < 10-6, had more than 1,000 cases, and presented the largest study with significance at p < 0.05. Among them, the highest UPF consumption quantile was associated with an increased risk of obesity (OR = 1.55, 95% CI: 1.36-1.77) when compared with the lowest UPF consumption quantile. The highest UPF consumption quantile was associated with an increased risk of T2DM (RR = 1.40, 95% CI: 1.23-1.59) when compared with the lowest UPF consumption quantile, and a 10% increase in UPF consumption (% g/d) was associated with an increased risk of T2DM (RR = 1.12, 95% CI: 1.10-1.13). Meanwhile, the robustness of these associations was verified by a series of subgroup and sensitivity analyses. Conclusion: UPF consumption may be a risk factor for several metabolic diseases. However, well-designed studies are still needed to verify our findings in the future.