Comprehensive analysis of B3 family genes in pearl millet (Pennisetum glaucum) and the negative regulator role of PgRAV-04 in drought tolerance.

Introduction: Members of the plant-specific B3 transcription factor superfamily play crucial roles in various plant growth and developmental processes. Despite numerous valuable studies on B3 genes in other species, little is known about the B3 superfamily in pearl millet. Methods and results: Here, through comparative genomic analysis, we identified 70 B3 proteins in pearl millet and categorized them into four subfamilies based on phylogenetic affiliations: ARF, RAV, LAV, and REM. We also mapped the chromosomal locations of these proteins and analyzed their gene structures, conserved motifs, and gene duplication events, providing new insights into their potential functional interactions. Using transcriptomic sequencing and real-time quantitative PCR, we determined that most PgB3 genes exhibit upregulated expression under drought and high-temperature stresses, indicating their involvement in stress response regulation. To delve deeper into the abiotic stress roles of the B3 family, we focused on a specific gene within the RAV subfamily, PgRAV-04, cloning it and overexpressing it in tobacco. PgRAV-04 overexpression led to increased drought sensitivity in the transgenic plants due to decreased proline levels and peroxidase activity. Discussion: This study not only adds to the existing body of knowledge on the B3 family's characteristics but also advances our functional understanding of the PgB3 genes in pearl millet, reinforcing the significance of these factors in stress adaptation mechanisms.

Reclassification of Streptomyces violarus (Artamonova and Krassilnikov 1960) Pridham 1970 as a Later Heterotypic Synonym of Streptomyces violaceus (Rossi Doria 1891) Waksman 1953 using a Polyphasic Approach.

The taxonomic relationship between Streptomyces violarus and Streptomyces violaceus was reevaluated using a polyphasic taxonomic approach in this work. Phylogenetic analysis based on 16S rRNA gene sequences indicated that Streptomyces violarus JCM 4534 T was closely related to Streptomyces arenae ISP 5293 T. However, phylogenetic analysis based on five house-keeping gene (atpD, gyrB, recA, rpoB and trpB) showed that the evolutionary neighbor of Streptomyces violarus JCM 4534 T was Streptomyces violaceus CGMCC 4.1456 T, suggesting that there was a close genetic relationship between these two strains. The average nucleotide identity and digital DNA-DNA hybridization values between them were 97.0 and 72.9%, respectively, greater than the 96.7 and 70% cut-off points recommended for delineating a Streptomyces species. This result indicated that they belonged to the same genomic species which was also verified by a comprehensive comparison of phenotypic and chemotaxonomic characteristics between Streptomyces violarus JCM 4534 T and Streptomyces violaceus CGMCC 4.1456 T. According to all these data and the rule of priority in nomenclature, it is proposed the Streptomyces violarus (Artamonova and Krassilnikov 1960) Pridham 1970 is a later heterotypic synonym of Streptomyces violaceus (Rossi Doria 1891) Waksman 1953. In addition, based on dDDH, Streptomyces violaceus and Streptomyces violarus are simultaneously designated as two different subspecies, i.e., Streptomyces violaceus subsp. violaceus and Streptomyces violaceus subsp. violarus.

Supramolecular antibody-drug conjugates for combined antibody therapy and photothermal therapy targeting HER2-positive cancers.

Antibody therapy of anti-HER2 monoclonal antibody (mAb) has been an important strategy in treating HER2-positive cancers. However, the efficacy is restricted by many factors, including the level of HER2 expressed by tumor cells and antibody resistance. To overcome these and boost the efficacy, a novel nanoparticle (NP) was constructed in this study for combined antibody therapy of antibody and photothermal therapy (PTT). This novel NP was assembled from 1-pyrenecarboxylic acid (PCA) functionalized anti-HER2 mAb and indocyanine green (ICG), a photothermal transduction agents (PTA), by non-covalent interactions, which was named as Anti-HER2 mAb-pyrene-indocyanine green (H-P-I). Notably, the constructed H-P-I NP not only maintained the affinity and cytotoxicity of anti-HER2 mAb, but also exhibited high photothermal conversion efficiency mediated by ICG. Both in vitro and in vivo assessments confirmed that compared with monotherapy of antibody or ICG, H-P-I demonstrated preferable efficacy in treating HER2-positive cancers. Further biochemistry analysis and pathological analysis ensured the biosafety of H-P-I administration. Taked together, this study proposes a feasible method for constructing tumor-targeted nano PTA based on anti-HER2 mAb through supramolecular self-assembly strategy, achieving synergistic antibody photothermal anticancer treatment, which has the potential to be a promising candidate for combination therapy of HER2-positive cancers.

Interface Synergy of Exposed Oxygen Vacancy and Pd Lewis Acid Sites Enabling Superior Cooperative Photoredox Synthesis.

Photo-driven cross-coupling of o-arylenediamines and alcohols has emerged as an alternative for the synthesis of bio-active benzimidazoles. However, tackling the key problem related to efficient adsorption and activation of both coupling partners over photocatalysts towards activity enhancement remains a challenge. Here, we demonstrate an efficient interface synergy strategy by coupling exposed oxygen vacancies (VO) and Pd Lewis acid sites for benzimidazole and hydrogen (H2) coproduction over Pd-loaded TiO2 nanospheres with the highest photoredox activity compared to previous works so far. The results show that the introduction of VO optimizes the energy band structure and supplies coordinatively unsaturated sites for adsorbing and activating ethanol molecules, affording acetaldehyde active intermediates. Pd acts as a Lewis acid site, enhancing the adsorption of alkaline amine moleculesvia Lewis acid-base pair interactions and driving the condensation process. Furthermore, VO and Pd synergistically promote interfacial charge transfer and separation. This work offers new insightful guidance for the rational design of semiconductor-based photocatalysts with interface synergy at the molecular level towards the high-performance coproduction of renewable fuels and value-added feedstocks.

Prospective study of 99mTc-3PRGD2 SPECT/CT diagnosing metastatic lymph nodes in esophageal squamous cell carcinoma.

BACKGROUND: Lymph node (LN) metastasis is a significant prognostic factor for esophageal squamous cell carcinoma (ESCC), and there are no satisfactory methods for accurately predicting metastatic LNs. The present study aimed to assess the efficacy of 99mTc-3PRGD2 single-photon emission computed tomography (SPECT)/computed tomography (CT) for diagnosing metastatic LNs in ESCC. METHODS: A total of 15 enrolled patients with ESCC underwent 99mTc-3PRGD2 SPECT/CT and 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET/CT) examinations preoperatively. High-definition bone carving reconstruction technology (HD-xSPECT Bone) was applied to quantitatively assess the LN's SUVmax via SPECT/CT. The two methods were compared for diagnosing metastatic LNs with pathology as the gold standard. RESULTS: Among 15 patients, 23 metastatic lymph node stations (mLNSs) were predicted by SPECT/CT, with a mean SUVmax of 2.71 ± 1.34, of which 15 were pathologically confirmed; 32 mLNSs were predicted by PET/CT with a mean SUVmax of 4.41 ± 4.02, of which 17 were pathologically confirmed. The sensitivity, specificity, accuracy, positive predictive value and negative predictive value of SPECT/CT for diagnosing metastatic LNs were 62.50%, 91.30%, 85.34%, 65.22%, and 90.32%, respectively, and those of PET/CT were 70.83%, 83.70%, 81.03%, 53.13%, and 91.67%, respectively. There was no significant difference in sensitivity (p = 0.061) or specificity (p = 0.058) between the two methods. The AUCSPECT/CT was 0.816 and the SUVmax threshold was 2.5. CONCLUSION: 99mTc-3PRGD2 SPECT/CT might be an effective method for diagnosing metastatic LNs in ESCC, especially in combination with HD-xSPECT Bone. The diagnostic efficiency of this method was noninferior to that of 18F-FDG PET/CT. The SUVmax threshold of 2.5 showed the highest agreement with the pathology findings.

State COVID-19 Vaccine Mandates and Uptake Among Health Care Workers in the US.

Importance: Seventeen states introduced COVID-19 vaccine mandates for health care workers (HCWs) in mid-2021. Prior research on the effect of these mandates was centered on the nursing home sector, and more evidence is needed for their effect on the entire HCW population. Objective: To examine the association between state COVID-19 vaccine mandates for HCWs and vaccine uptake in this population. Design, Setting, and Participants: This repeated cross-sectional study included biweekly, individual-level data for adults aged 25 to 64 years who were working or volunteering in health care settings obtained from the Household Pulse Survey between May 26 and October 11, 2021. Analyses were conducted between November 2022 and October 2023. Exposure: Announcement of a state COVID-19 vaccine mandate for HCWs. Main Outcomes and Measures: An indicator for whether a sampled HCW ever received a COVID-19 vaccine and an indicator for whether an HCW completed or intended to complete the primary COVID-19 vaccination series. Event study analyses using staggered difference-in-differences methods compared vaccine uptake among HCWs in mandate and nonmandate states before and after each mandate announcement. The sample was further stratified by the availability of regular COVID-19 testing in place of a vaccination (ie, a test-out option) and by the ages of HCWs (25-49 or 50-64 years) to examine heterogeneous associations. Results: The study sample included 31 142 HCWs (mean [SD] age, 45.5 [10.6] years; 72.1% female) from 45 states, 16 of which introduced COVID-19 vaccine mandates for HCWs. Results indicated a mandate-associated 3.46-percentage point (pp) (95% CI, 0.29-6.63 pp; P = .03) increase in the proportion of HCWs ever vaccinated against COVID-19 and a 3.64-pp (95% CI, 0.72-6.57 pp; P = .02) increase in the proportion that completed or intended to complete the primary vaccination series 2 weeks after mandate announcement from baseline proportions of 87.98% and 86.12%, respectively. In the stratified analyses, positive associations were only detected in mandate states with no test-out option and among HCWs aged 25 to 49 years, which suggested vaccination increases of 3.32% to 7.09% compared with baseline proportions. Conclusions and Relevance: This repeated cross-sectional study found that state COVID-19 vaccine mandates for HCWs were associated with increased vaccine uptake among HCWs, especially among younger HCWs and those in states with no test-out option. These findings suggest the potential for vaccine mandates to further promote vaccinations in an already highly vaccinated HCW population, especially when no test-out option is in place.

Augmented type 2 inflammatory response in allergic rhinitis patients experiencing systemic reactions to house dust mite subcutaneous immunotherapy.

BACKGROUND: Subcutaneous immunotherapy (SCIT) can induce systemic reactions (SRs) in certain patients, but the underlying mechanisms remain to be fully elucidated. METHODS: AR patients who were undergoing standardized HDM SCIT (Alutard, ALK) between 2018 and 2022 were screened. Those who experienced two consecutive SRs were included in the study group. A control group was established, matched 1:1 by gender, age, and disease duration with the study group, who did not experience SRs during SCIT. Clinical and immunological parameters were recorded and analyzed both before SCIT and after 1 year of treatment. RESULTS: A total of 161 patients were included, with 79 (49.07%) in the study group. The study group had a higher proportion of AR combined asthma (26.8% vs. 51.8%, p < 0.001) and higher levels of sIgE to HDM and HDM components (all p < .001). Serum IL-4 and IL-13 levels in the study group were higher than those in the control group (p < .05). The study group received a lower maintenance dosage of HDM extracts injections than control group due to SRs (50000SQ vs. 100000SQ, p < .05). After 1 year of SCIT, the VAS score, the lung function parameters of asthmatic patients over 14 years old significantly improved in both groups (all p < .05). After a 7-day exposure to 20 µg/mL HDM extracts, the percentages of Th1, Th17, Tfh10, and Th17.1 in PBMCs decreased, while the Tfh13 cells significantly increased in the study group (p < .05). CONCLUSION: The type 2 inflammatory response is augmented in HDM-induced AR patients who experienced SRs during SCIT. Despite this, SCIT remains effective in these patients when administered with low-dosage allergen extracts.

An novel effective and safe model for the diagnosis of nonalcoholic fatty liver disease in China: gene excavations, clinical validations, and mechanism elucidation.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases. NAFLD leads to liver fibrosis and hepatocellular carcinoma, and it also has systemic effects associated with metabolic diseases, cardiovascular diseases, chronic kidney disease, and malignant tumors. Therefore, it is important to diagnose NAFLD early to prevent these adverse effects. METHODS: The GSE89632 dataset was downloaded from the Gene Expression Omnibus database, and then the optimal genes were screened from the data cohort using lasso and Support Vector Machine Recursive Feature Elimination (SVM-RFE). The ROC values of the optimal genes for the diagnosis of NAFLD were calculated. The relationship between optimal genes and immune cells was determined using the DECONVOLUTION algorithm CIBERSORT. Finally, the specificity and sensitivity of the diagnostic genes were verified by detecting the expression of the diagnostic genes in blood samples from 320 NAFLD patients and liver samples from 12 mice. RESULTS: Through machine learning we identified FOSB, GPAT3, RGCC and RNF43 were the key diagnostic genes for NAFLD, and they were further demonstrated by a receiver operating characteristic curve analysis. We found that the combined diagnosis of the four genes identified NAFLD samples well from normal samples (AUC = 0.997). FOSB, GPAT3, RGCC and RNF43 were strongly associated with immune cell infiltration. We also experimentally examined the expression of these genes in NAFLD patients and NAFLD mice, and the results showed that these genes are highly specific and sensitive. CONCLUSIONS: Data from both clinical and animal studies demonstrate the high sensitivity, specificity and safety of FOSB, GPAT3, RGCC and RNF43 for the diagnosis of NAFLD. The relationship between diagnostic key genes and immune cell infiltration may help to understand the development of NAFLD. The study was reviewed and approved by Ethics Committee of Tianjin Second People's Hospital in 2021 (ChiCTR1900024415).

Prenatal EDC exposure, DNA Methylation, and early childhood growth: A prospective birth cohort study.

BACKGROUND: Exposure to endocrine-disrupting chemicals (EDCs) has been found to be associated with growth and developmental abnormalities in children. However, the potential mechanisms by which exposure to EDCs during pregnancy increases the risk of obesity in children remain unclear. OBJECTIVE: We aimed to explore associations between prenatal EDC exposure and the body mass index (BMI) of children at age two, and to further explore the potential impact of DNA methylation (DNAm). METHOD: This study included 285 mother-child pairs from a birth cohort conducted in Wuhan, China. The BMI of each child was assessed at around 24 months of age. The concentrations of sixteen EDCs at the 1st, 2nd, and 3rd trimesters were measured using ultra-high performance liquid chromatography coupled to a triple quadrupole mass spectrometer. The research utilized general linear models, weighted quantile sum regression, and Bayesian Kernel Machine Regression to assess the association between prenatal EDC exposure and childhood BMI z-scores (BMIz). Cord blood DNAm was measured using the Human Methylation EPIC BeadChip array. An epigenome-wide DNAm association study related to BMIz was performed using robust linear models. Mediation analysis was then applied to explore potential mediators of DNAm. RESULTS: Urinary concentrations of seven EDCs were positively associated with BMIz in the 1st trimester, which remained significant in the WQS model. A total of 641 differential DNAm positions were associated with elevated BMIz. Twelve CpG positions (annotated to DUXA, TMEM132C, SEC13, ID4, GRM4, C2CD2, PRAC1&PRAC2, TSPAN6 and DNAH10) mediated the associations between urine BP-3/BPS/MEP/TCS and elevated BMIz (P < 0.05). CONCLUSION: Our results revealed that prenatal exposure to EDCs was associated with a higher risk of childhood obesity, with specific DNAm acting as a partial mediator.

B-mode Ultrasound Related Combined Predictive Indicators for Benign Versus Malignant Subpleural Pulmonary Lesions.

OBJECTIVE: The purpose of this study was to analyze the independent risk factors of malignant subpleural pulmonary lesions (SPLs) on B-mode ultrasound (US) images, to construct the combined predictive indicators, and to prospectively verify their predictive efficacy. METHODS: A total of 336 patients with SPLs were included in the prospective study, of whom the single-center included patients between September 2019 and December 2019 were the development cohort (DC) (n = 219); Patients who were concurrently enrolled in three centers between January and February 2020 were the validation cohort (VC) (n = 117). The clinical features and B-mode US parameters were collected. Based on the DC, a combined predictive indicators model was developed using binary logistic regression. Then the discrimination was verified externally in the VC. The reference criteria were from the comprehensive diagnosis of clinical-radiological-pathological made by two senior respiratory physicians. RESULTS: The combined predictive indicators model was finally constructed by five parameters: age, borderline, angle between the lesion border and thoracic wall, posterior echo of the lesion and invasion of the pleura. The fitting degree of the model was good (χ2 = 9.198, p = 0.326). The area under ROC curve of the model was 0.872 (DC) and 0.808 (VC), yielding a higher net benefit than individual risk factors. CONCLUSION: The combined predictive indicators are useful in the assessment of malignant SPLs and are a useful adjunct diagnostic tool, especially in primary healthcare settings in developing countries.

Study on Quality Changes of Kelp Gel Edible Granules during Storage.

The kelp gel edible granules developed utilizing the gel properties of alginate are prone to quality deterioration if improperly stored during the storage process. This study comprehensively investigated the quality changes of kelp gel edible granules stored at 4 °C and 25 °C by evaluating indicators such as total bacterial count, coliform bacteria, pH, relaxation time, color difference, appearance, texture characteristics, gel strength, and sensory scoring. The results showed that during the storage at 4 °C, the total bacterial count remained within the national standard range, the hardness and chewiness increased, the gel strength first increased and then decreased, the partial exudation of the bound water in the product occurred, and the sensory score slightly decreased, with an overall minor change in quality. During the storage at 25 °C, significant quality changes were observed, with the total bacterial count exceeding the national standard on the 20th day; additionally, the hardness, chewiness, and gel strength all initially increased and then decreased, both the bound water and the restrained water in the product exuded, the moisture stability decreased, and the sensory score significantly decreased between 16 to 20 days. The spoilage of the product was characterized by a significant water loss, reduction in volume, color change from bright green to dark yellow-brown, and a distinct smell of decaying algae. No coliform bacteria was detected in all products during the storage period. In summary, the shelf life endpoint of the product stored at 25 °C is 16 days, and the shelf life of the product stored at 4 °C is greater than 20 days. Storage at 4 °C can better maintain product quality, extend the shelf life, and effectively maintain the overall color of the product.

Enhanced degradation of polylactic acid microplastics in acidic soils: Does the application of biochar matter?

Biodegradable plastics, as an alternative to petroleum plastics, are fiercely increasing, but their incomplete degradation under natural conditions may lead to the breakdown into microplastics (MPs). Here, we explored the impacts of chicken manure-derived (MBC) and wood waste-derived biochar (WBC) on the degradation of polylactic acid microplastics (PLA-MPs) during soil incubation for one year. Both biochars induced more pronounced degradation characteristics in PLA-MPs, including enhanced surface roughness, the proportion of MPs < 100 µm by 12.89 %-25.67 %, oxygen loading and O/C ratio to 71.74 %-75.87 % and 1.70-1.76, as well as accelerated carbon loss and the cleavage of ester group and C-C bond. Also, biochar increased soil pH, depleted inorganic nitrogen and available phosphorus, and changed enzymic activity in PLA-MP-polluted soils. We proposed that both biochars accelerated the PLA-MP degradation by inducing alkaline, aminolysis/ammonolysis, oxidative, and microbial degradation. Among these, MBC induced aminolysis/ammonolysis by NH4+ via Fe2+-driven NO3-/NO2- reduction and microbial nitrogen fixation, and oxidative degradation by radicals generated through Fenton/Fenton-like reaction. WBC caused aminolysis/ammonolysis and oxidative degradation mainly through dissimilatory nitrate reduction to ammonium and surface free radicals on biochar. These findings indicate that biochar has the potential to accelerate PLA-MP degradation, and its regulatory mechanism depends on the type of biochar.

Clinical study of chemotherapy-related cognitive impairment in patients with non-Hodgkin lymphoma.

BACKGROUND: Chemotherapy for malignant tumors can cause brain changes and cognitive impairment, leading to chemotherapy-induced cognitive impairment (CICI). Current research on CICI has focused on breast cancer and Hodgkin's lymphoma. Whether patients with non-Hodgkin's lymphoma (NHL) undergoing chemotherapy have cognitive impairment has not been fully investigated. AIM: To investigate whether NHL patients undergoing chemotherapy had cognitive impairments. METHODS: The study included 100 NHL patients who were required to complete a comprehensive psychological scale including the Brief Psychiatric Examination Scale (MMSE) at two time points: before chemotherapy and within 2 wk of two chemotherapy courses. A language proficiency test (VFT), Symbol Number Pattern Test (SDMT), Clock Drawing Test (CDT), Abbreviated Daily Cognition Scale (ECog-12), Prospective and Retrospective Memory Questionnaire, and Karnofsky Performance Status were used to assess cognitive changes before and after chemotherapy. RESULTS: The VFT scores for before treatment (BT) and after treatment (AT) groups were 45.20 ± 15.62, and 42.30 ± 17.53, respectively (t -2.16, P < 0.05). The CDT scores were 8 (3.5-9.25) for BT and 7 (2.5-9) for AT groups (Z -2.1, P < 0.05). Retrospective memory scores were 13.5 (9-17) for BT and 15 (13-18) for AT (Z -3.7, P < 0.01). The prospective memory scores were 12.63 ± 3.61 for BT and 14.43 ± 4.32 for AT groups (t -4.97, P < 0.01). The ECog-12 scores were 1.71 (1.25-2.08) for BT and 1.79 (1.42-2.08) for AT groups (Z -2.84, P < 0.01). The SDMT and MMSE values did not show a significant difference between BT and AT groups. CONCLUSION: Compared to the AT group, the BT group showed impaired language, memory, and subjective cognition, but objective cognition and execution were not significantly affected.

Automatically Detecting Pancreatic Cysts in Autosomal Dominant Polycystic Kidney Disease on MRI Using Deep Learning.

BACKGROUND: Pancreatic cysts in autosomal dominant polycystic kidney disease (ADPKD) correlate with PKD2 mutations, which have a different phenotype than PKD1 mutations. However, pancreatic cysts are commonly overlooked by radiologists. Here, we automate the detection of pancreatic cysts on abdominal MRI in ADPKD. METHODS: Eight nnU-Net-based segmentation models with 2D or 3D configuration and various loss functions were trained on positive-only or positive-and-negative datasets, comprising axial and coronal T2-weighted MR images from 254 scans on 146 ADPKD patients with pancreatic cysts labeled independently by two radiologists. Model performance was evaluated on test subjects unseen in training, comprising 40 internal, 40 external, and 23 test-retest reproducibility ADPKD patients. RESULTS: Two radiologists agreed on 52% of cysts labeled on training data, and 33%/25% on internal/external test datasets. The 2D model with a loss of combined dice similarity coefficient and cross-entropy trained with the dataset with both positive and negative cases produced an optimal dice score of 0.7 ± 0.5/0.8 ± 0.4 at the voxel level on internal/external validation and was thus used as the best-performing model. In the test-retest, the optimal model showed superior reproducibility (83% agreement between scan A and B) in segmenting pancreatic cysts compared to six expert observers (77% agreement). In the internal/external validation, the optimal model showed high specificity of 94%/100% but limited sensitivity of 20%/24%. CONCLUSIONS: Labeling pancreatic cysts on T2 images of the abdomen in patients with ADPKD is challenging, deep learning can help the automated detection of pancreatic cysts, and further image quality improvement is warranted.

Associations between long-term ambient PM2.5 exposure and the incidence of cardiopulmonary diseases and diabetes, attributable years lived with disability, and policy implication.

Long-term exposure to ambient PM2.5 is known associated with cardiovascular and respiratory health effects. However, the heterogeneous concentrationresponse function (CRF) between PM2.5 exposure across different concentration range and cardiopulmonary disease and diabetes mellitus (DM) incidence, and their implications on attributable years lived with disability (YLD) and regulation policy has not been well-studied. In this retrospective longitudinal cohort study, disease-free participants (approximately 170,000 individuals, aged ≥ 30 years) from the MJ Health Database were followed up (2007-2017) regarding incidents of coronary heart disease (CHD), ischemic stroke, chronic obstructive pulmonary disease (COPD), lower respiratory tract infections (LRIs), and DM. We used a time-dependent nonlinear weight-transformation Cox regression model for the CRF with an address-matched 3-year mean PM2.5 exposure estimate. Town/district-specific PM2.5-attributable YLD were calculated by multiplying the disease incidence rate, population attributable fraction, disability weight, and sex-age group specific subpopulation for each disease separately. The estimated CRFs for cardiopulmonary diseases were heterogeneously with the hazard ratios (HRs) increased rapidly for CHD and ischemic stroke at PM2.5 concentration lower than 10 µg/m3, whereas the HRs for DM (LRIs) increased with PM2.5 higher than 15 (20) µg/m3. Women had higher HRs for ischemic stroke and DM but not CHD. Relative to the lowest observed PM2.5 concentration of 6 µg/m3 of the study population, the PM2.5 level with an extra risk of 0.1 % (comparable to the disease incidence) for CHD, ischemic stroke, DM, and LRIs were 8.59, 11.85, 22.09, and 24.23 µg/m3, respectively. The associated attributable YLD decreased by 51.4 % with LRIs reduced most (83.6 %), followed by DM (63.7 %) as a result of PM2.5 concentration reduction from 26.10 to 16.82 µg/m3 during 2011-2019 in Taiwan. The proportion of YLD due to CHD and ischemic stroke remained dominant (56.4 %-69.9 %). The cost-benefit analysis for the tradeoff between avoidable YLD and mitigation cost suggested an optimal PM2.5 exposure level at 12 µg/m3. CRFs for cardiopulmonary diseases, attributable YLD, and regulation level, may vary depending on the national/regional background and spatial distribution of PM2.5 concentrations, as well as demographic characteristics.

Inhibitor of cardiolipin biosynthesis-related enzyme MoGep4 confers broad-spectrum anti-fungal activity.

Plant pathogens cause devastating diseases, leading to serious losses to agriculture. Mechanistic understanding of pathogenesis of plant pathogens lays the foundation for the development of fungicides for disease control. Mitophagy, a specific form of autophagy, is important for fungal virulence. The role of cardiolipin, mitochondrial signature phospholipid, in mitophagy and pathogenesis is largely unknown in plant pathogenic fungi. The functions of enzymes involved in cardiolipin biosynthesis and relevant inhibitors were assessed using a set of assays, including genetic deletion, plant infection, lipidomics, chemical-protein interaction, chemical inhibition, and field trials. Our results showed that the cardiolipin biosynthesis-related gene MoGEP4 of the rice blast fungus Magnaporthe oryzae regulates growth, conidiation, cardiolipin biosynthesis, and virulence. Mechanistically, MoGep4 regulated mitophagy and Mps1-MAPK phosphorylation, which are required for virulence. Chemical alexidine dihydrochloride (AXD) inhibited the enzyme activity of MoGep4, cardiolipin biosynthesis and mitophagy. Importantly, AXD efficiently inhibited the growth of 10 plant pathogens and controlled rice blast and Fusarium head blight in the field. Our study demonstrated that MoGep4 regulates mitophagy, Mps1 phosphorylation and pathogenesis in M. oryzae. In addition, we found that the MoGep4 inhibitor, AXD, displays broad-spectrum antifungal activity and is a promising candidate for fungicide development.

Low-grade systemic inflammation links heavy metal exposures to mortality: A multi-metal inflammatory index approach.

Certain heavy metals have been correlated to an elevated risk of inflammation-related diseases and mortality. Nevertheless, the intricate relationships between metal exposure, inflammation and mortality remain unknown. We included 3741 adults with measurements of ten urinary heavy metals in the National Health and Nutritional Examination Survey (NHANES) 2005-2010, followed up to December 31, 2019. Low-grade systemic inflammation was evaluated by various markers, including C-reactive protein (CRP) and ratios derived from regular blood tests. We assessed associations between heavy metal and all-cause mortality using multivariate COX regressions. Then we assessed the mediation effect of low-grade systemic inflammation on the associations via Sobel Test. To gauge the systemic inflammatory potential of the multi-metal mixture and its correlation with all-cause mortality, a Metal Mixture Inflammatory Index (MMII) was developed using reduced rank regression (RRR) models. The association between MMII and all-cause mortality was explored via multivariate COX regressions. Cadmium, antimony and uranium displayed positive associations with mortality, with hazard ratios (HR) ranging from 1.18 to 1.46 (all P-FDR < 0.05). Mediation analyses revealed that the associations between specific heavy metals (cadmium and antimony) and mortality risk were slightly mediated by the low-grade systemic inflammation markers, with mediation proportions ranging from 3.11 % to 5.38 % (all P < 0.05). MMII, the weighted sum of 9 heavy metals, significantly predicted platelet-to-lymphocyte ratio (PLR) and CRP (ß = 0.10 and 1.16, all P < 0.05), was positively associated with mortality risk (HR 1.28, 95 % CI 1.14 to 1.43). Exposure to heavy metals might increase all-cause mortality, partly mediated by low-grade systemic inflammation. MMII, designed to assess the potential systemic inflammatory effects of exposure to multiple heavy metals, was closely related to the all-cause mortality risk. This study introduces MMII as an approach to evaluating co-exposure and its potential health effects comprehensively.

Origin recognition complex 6 overexpression promotes growth of glioma cells.

The discovery of novel oncotargets for glioma is of immense significance. We here explored the expression patterns, biological functions, and underlying mechanisms associated with ORC6 (origin recognition complex 6) in glioma. Through the bioinformatics analyses, we found a significant increase in ORC6 expression within human glioma tissues, correlating with poorer overall survival, higher tumor grade, and wild-type isocitrate dehydrogenase status. Additionally, ORC6 overexpression is detected in glioma tissues obtained from locally-treated patients and across various primary/established glioma cells. Further bioinformatics scrutiny revealed that genes co-expressed with ORC6 are enriched in multiple signaling cascades linked to cancer. In primary and immortalized (A172) glioma cells, depleting ORC6 using specific shRNA or Cas9-sgRNA knockout (KO) significantly decreased cell viability and proliferation, disrupted cell cycle progression and mobility, and triggered apoptosis. Conversely, enhancing ORC6 expression via a lentiviral construct augmented malignant behaviors in human glioma cells. ORC6 emerged as a crucial regulator for the expression of key oncogenic genes, including Cyclin A2, Cyclin B2, and DNA topoisomerase II (TOP2A), within glioma cells. Silencing or KO of ORC6 reduced the mRNA and protein levels of these genes, while overexpression of ORC6 increased their expression in primary glioma cells. Bioinformatics analyses further identified RBPJ as a potential transcription factor of ORC6. RBPJ shRNA decreased ORC6 expression in primary glioma cells, while its overexpression increased it. Additionally, significantly enhanced binding between the RBPJ protein and the proposed ORC6 promoter region was detected in glioma tissues and cells. In vivo experiments demonstrated a significant reduction in the growth of patient-derived glioma xenografts in the mouse brain subsequent to ORC6 KO. ORC6 depletion, inhibited proliferation, decreased expression of Cyclin A2/B2/TOP2A, and increased apoptosis were detected within these ORC6 KO intracranial glioma xenografts. Altogether, RBPJ-driven ORC6 overexpression promotes glioma cell growth, underscoring its significance as a promising therapeutic target.

Branch Chain Amino Acid Metabolism Promotes Brain Metastasis of NSCLC through EMT Occurrence by Regulating ALKBH5 activity.

Metabolic reprogramming is one of the essential features of tumors that may dramatically contribute to cancer metastasis. Employing liquid chromatography-tandem mass spectrometry-based metabolomics, we analyzed the metabolic profile from 12 pairwise serum samples of NSCLC brain metastasis patients before and after CyberKnife Stereotactic Radiotherapy. We evaluated the histopathological architecture of 144 surgically resected NSCLC brain metastases. Differential metabolites were screened and conducted for functional clustering and annotation. Metabolomic profiling identified a pathway that was enriched in the metabolism of branched-chain amino acids (BCAAs). Pathologically, adenocarcinoma with a solid growth pattern has a higher propensity for brain metastasis. Patients with high BCAT1 protein levels in lung adenocarcinoma tissues were associated with a poor prognosis. We found that brain NSCLC cells had elevated catabolism of BCAAs, which led to a depletion of α-KG. This depletion, in turn, reduced the expression and activity of the m6A demethylase ALKBH5. Thus, ALKBH5 inhibition participated in maintaining the m6A methylation of mesenchymal genes and promoted the occurrence of epithelial-mesenchymal transition (EMT) in NSCLC cells and the proliferation of NSCLC cells in the brain. BCAA catabolism plays an essential role in the metastasis of NSCLC cells.