EDDS application destabilizes soil organic matter in phytoremediation: Insights from quantity and molecular composition of dissolved organic matter.

The stability of soil organic matter (SOM) is crucial for metal transport and carbon cycling. S,S-ethylenediaminedisuccinic acid (EDDS) is widely used to enhance phytoremediation efficiency for heavy metals in contaminated soils, yet its specific impacts on SOM have been underexplored. This study investigates the effects of EDDS on SOM stability using a rhizobox experiment with ryegrass. Changes in soil dissolved organic matter (DOM) quantity and molecular composition were analyzed via Fourier transform ion cyclotron resonance mass spectrometry. Results showed that the use of EDDS increased the uptake of Cu, Cd and Pb by ryegrass, but simultaneously induced the destabilization and transformation of SOM. After 7 days of EDDS application, dissolved organic carbon (DOC) and nitrogen (DON) concentrations in rhizosphere soils increased significantly by 3.44 and 10.2 times, respectively. In addition, EDDS reduced lipids (56.3%) and proteins/amino sugars-like compounds (52.1%), while increasing tannins (9.11%) and condensed aromatics-like compounds (24.4%) in the rhizosphere DOM. These effects likely stem from EDDS's dual action: extracting Fe/Al from SOM-mineral aggregates, releasing SOM into the DOM pool, and promoting microbial degradation of bioavailable carbon through chain scission and dehydration. Our study firstly revealed that the application of EDDS in phytoremediation increased the mineralization of SOM and release of CO2 from soil to the atmosphere, which is important to assess the carbon budget of phytoremediation and develop climate-smart strategy in future.

Disease trajectories before dementia: evidence from a large-scale community-based prospective study.

BACKGROUND: Systemic changes in multiple diseases may influence the onset of dementia. However, the specific temporality between exposure diseases and dementia remains uncertain. AIMS: By characterising the full spectrum of temporal disease trajectories before dementia, this study aims to yield a global picture of precursor diseases to dementia and to provide detailed instructions for risk management and primary prevention of dementia. METHOD: Using the multicentre, community-based prospective UK Biobank, we constructed disease trajectories before dementia utilising the phenome-wide association analysis, paired directional test and association quantification. Stratified disease trajectories were constructed by dementia subtypes, gender, age of diagnosis and Apolipoprotein E (ApoE) status, respectively. RESULTS: Our study population comprised 434 266 participants without baseline dementia and 4638 individuals with all-cause dementia. In total, 1253 diseases were extracted as potential components of the disease trajectory before dementia. We identified three clusters of disease trajectories preceding all-cause dementia, initiated by circulatory, metabolic and respiratory diseases occurring approximately 5-15 years before dementia. Cerebral infarction or chronic renal failure following chronic ischaemic heart disease was the specific trajectory before vascular dementia. Apolipoprotein E (ApoE) ε4 non-carriers exhibited more complex trajectories compared with carriers. Lipid metabolism disorders remained in the trajectories regardless of dementia subtypes, gender, age of diagnosis and ApoE status. CONCLUSIONS: This study provides a comprehensive view of the longitudinal disease trajectories before dementia and highlights the potential targets of midlife cardiometabolic dysfunction for dementia screening and prevention.

Report on the 4th Board Meeting of the International Human Phenome Consortium.

Phenome has become a consensus as the next innovation source of biomedicine. As the global network dedicated to large-scale research efforts on human phenome and promoting the Human Phenome Project, the Board of International Human Phenome Consortium (IHPC) plays an essential role to guide the strategy and implementation of international human phenome project and to ensure coordination across the IHPC members. The 4th International Human Phenome Consortium Board Meeting was held virtually on December 13, 2022. During the meeting, the keynote speeches highlighted the latest advancements in phenomics. The construction and discoveries of the first human phenome Atlas had shown promising potential in limb development, disease prevention, and early diagnosis. Combining genome-phenome sequencing, analysis, and wellness coaching enhanced individual wellness. Phenomics trajectories from healthy to diseased states and recovery provided insight into the metabolic risk spaces associated with COVID-19. Board members from Ghana, Malaysia, India, and Russia presented their own plans and research progress. The IHPC Board deliberated on the "Framework Guidelines for Human Phenome-related Measurements" and "Proposal of the PhenoBank Initiative". The meeting also featured a presentation of the annual report of the IHPC Journal Phenomics. Laboratory coordination, interoperable databases, and standardized platforms were productively discussed, which would enable concerted research efforts of the Human Phenome Project.

Antimicrobial activity of novel symmetrical antimicrobial peptides centered on a hydrophilic motif against resistant clinical isolates: in vitro and in vivo analyses.

Antibiotic resistance poses a significant public health threat worldwide. The rise in antibiotic resistance and the sharp decline in effective antibiotics necessitate the development of innovative antibacterial agents. Based on the central symmetric structure of glycine-serine-glycine, combined with tryptophan and arginine, we designed a range of antimicrobial peptides (AMPs) that exhibited broad-spectrum antibacterial activity. Notably, AMP W5 demonstrated a rapid and effective sterilization against methicillin-resistant Staphylococcus aureus (MRSA), displaying both a minimum inhibitory concentration and a minimum bactericidal concentration of 8 µM. Mechanistic studies revealed that AMP W5 killed bacterial cells by disrupting the cytoplasmic membrane integrity, triggering leakage of cell contents. AMP W5 also exhibited excellent biocompatibility in both in vitro and in vivo safety evaluations. AMP W5 treatment significantly reduced skin bacterial load in our murine skin infection model. In conclusion, we designed a novel centrosymmetric AMP representing a promising medical alternative to conventional antibiotics for treating MRSA infections. IMPORTANCE: Increasing antibiotic resistance and the paucity of effective antibiotics necessitate innovative antibacterial agents. Methicillin-resistant Staphylococcus aureus (MRSA) is a major pathogen causing bacterial infections with high incidence and mortality rates, showing increasing resistance to clinical drugs. Antimicrobial peptides (AMPs) exhibit significant potential as alternatives to traditional antibiotics. This study designed a novel series of AMPs, characterized by a glycine-serine-glycine-centered symmetrical structure, and our results indicated that AMP W5 exhibited a rapid and effective bactericidal effect against MRSA. AMP W5 also demonstrated excellent biocompatibility and a bactericidal mechanism that disrupted membrane integrity, leading to leakage of cellular contents. The notable reduction in skin bacterial load observed in mouse models reinforced the clinical applicability of AMP W5. This study provides a promising solution for addressing the increasing threat of antibiotic-resistant bacteria and heralds new prospects for clinical applications.

Integrated stress response activation induced by usnic acid alleviates BCL-2 inhibitor ABT-199 resistance in acute myeloid leukemia.

INTRODUCTION: ABT-199 (venetoclax) is a BCL-2 suppressor with pronounced effects on acute myeloid leukemia (AML). However, its usefulness as a monotherapy or in combination with hypomethylating medicines like azacitidine is debatable due to acquired resistance. Usnic acid, a dibenzofuran extracted from lichen Usnea diffracta Vain, exhibits anticancer properties and may counteract multidrug resistance in leukemia cells. OBJECTIVE: This study investigated whether usnic acid at low-cytotoxicity level could enhance sensitivity of AML cells with acquired resistance to ABT-199 by targeting the integrated stress response pathways. METHODS: To investigate the combined effects on AML cells, we used a cell viability test, flow cytometry to quantify apoptosis, cell cycle analysis, and mitochondrial membrane potential measurement. RNA-seq and immunoblot were used to determine the potential mechanisms of ABT-199 + usnic acid combination. RESULTS: Usnic acid, at a low cytotoxicity level, successfully restored ABT-199 sensitivity in AML cell lines that had developed ABT-199 resistance and increased ABT-199's antileukemic activity in a xenograft model. Mechanistically, the combination of usnic acid and ABT-199 cooperated to boost the expression of the integrated stress response (ISR)-associated genes ATF4, CHOP, and NOXA through the heme-regulated inhibitor kinase (HRI), while also promoting the degradation of the anti-apoptotic protein MCL-1. ISRIB, a compound that blocks the ISR, was able to reverse the growth suppression and cell death, the increase in expression of genes related with the ISR, and the inhibition of MCL-1 protein caused by combination therapy. Additionally, the downregulation of MCL-1 was linked to an increase in MCL-1 phosphorylation at serine 159 and subsequent destruction by the proteasome. CONCLUSION: In summary, usnic acid improves chemosensitivity to ABT-199 by triggering the integrated stress response, leading to decreased levels of MCL-1 protein, suggesting a potential treatment for AML cases resistant to Bcl-2 inhibitors.

Survival benefit of adjuvant TACE for patients with hepatocellular carcinoma and child-pugh B7 or B8 after hepatectomy.

BACKGROUND & AIMS: The benefit of postoperative adjuvant transcatheter arterial chemoembolization (pTACE) for patients with hepatocellular carcinoma (HCC), especially those with Child-Pugh (CP) B, remains controversial. This study aimed to assess the survival benefit of pTACE for HCC patients with CP B. METHODS: Data from 297 HCC patients with CP B7 or B8 were analyzed, dividing them into groups with and without pTACE (70, 23.6% vs. 227, 76.4%). Propensity score matching (PSM) was used to control for confounding bias, and competing-risk regression was applied to address bias from non-cancer-specific death (NCSD). RESULTS: Preliminary findings suggest that pTACE did not increase the incidence of severe complications in HCC patients with CP B7 or B8. Survival analysis indicated that the group receiving pTACE had better overall survival and recurrence-free survival than the group without pTACE after PSM. Furthermore, competitive risk analysis revealed that pTACE was an independent prognostic factor associated with reduced cancer-specific death incidence (subdistribution hazard ratio [SHR] 0.644, 95%CI: 0.378-0.784, P = 0.011) and recurrence (SHR 0.635, 95% CI: 0.379-0.855, P = 0.001). Importantly, pTACE did not increase NCSD. Subgroup analysis corroborated these results. CONCLUSION: Adjuvant TACE demonstrates the potential to significantly enhance the long-term prognosis of HCC patients with CP B7 or B8 following hepatectomy, particularly those with multiple tumors, large tumor size, macrovascular or microvascular invasion, and narrow resection margin. Hence, pTACE should be considered for patients at high risk of recurrence following thorough evaluation.

Extracellular RIPK3 Acts as a Danger-Associated Molecular Pattern to Exaggerate Cardiac Ischemia/Reperfusion Injury.

BACKGROUND: Cardiac ischemia/reperfusion (I/R) injury has emerged as an important therapeutic target for ischemic heart disease. Currently, there is no effective therapy for reducing cardiac I/R injury. Damage-associated molecular patterns are endogenous molecules released after cellular damage to exaggerate tissue inflammation and injury. RIPK3 (receptor-interacting protein kinase 3), a well-established intracellular mediator of cell necroptosis and inflammation, serves as a circulating biomarker of multiple diseases. However, whether extracellular RIPK3 also exerts biological functions in cardiac I/R injury remains totally unknown. METHODS: Patients with acute myocardial infarction receiving percutaneous coronary intervention (PCI) were recruited independently in the discovery cohort (103 patients) and validation cohort (334 patients), and major adverse cardiovascular events were recorded. Plasma samples were collected before and after PCI (6 and 24 h) for RIPK3 concentration measurement. Cultured neonatal rat ventricular myocytes, macrophages and endothelial cells, and in vivo mouse models with myocardial injury induced by I/R (or hypoxia/reoxygenation) were used to investigate the role and mechanisms of extracellular RIPK3. Another cohort including patients with acute myocardial infarction receiving PCI and healthy volunteers was recruited to further explore the mechanisms of extracellular RIPK3. RESULTS: In the discovery cohort, elevated plasma RIPK3 levels after PCI are associated with poorer short- and long-term outcomes in patients with acute myocardial infarction, as confirmed in the validation cohort. In both cultured cells and in vivo mouse models, recombinant RIPK3 protein exaggerated myocardial I/R (or hypoxia/reoxygenation) injury, which was alleviated by the RIPK3 antibody. Mechanistically, RIPK3 acted as a damage-associated molecular pattern and bound with RAGE (receptor of advanced glycation end-products), subsequently activating CaMKII (Ca2+/calmodulin-dependent kinase II) to elicit the detrimental effects. The positive correlation between plasma RIPK3 concentrations and CaMKII phosphorylation in human peripheral blood mononuclear cells was confirmed. CONCLUSIONS: We identified the positive relationship between plasma RIPK3 concentrations and the risk of major adverse cardiovascular events in patients with acute myocardial infarction receiving PCI. As a damage-associated molecular pattern, extracellular RIPK3 plays a causal role in multiple pathological conditions during cardiac I/R injury through RAGE/CaMKII signaling. These findings expand our understanding of the physiological and pathological roles of RIPK3, and also provide a promising therapeutic target for myocardial I/R injury and the associated complications.

Lnc-LINC00511 promotes gastric cancer progression by regulating MiR-29c-3p/TRIP13 axis through AKT/mTOR pathway.

Thyroid hormone receptor-interacting factor 13 (TRIP13) contributes to the development of several cancers, including hepatocellular carcinoma (HCC). Although these studies have found that TRIP13 is involved in other cancers, its specific function in gastric cancer requires further investigation. Therefore, this study aimed to investigate the hypothesis that LINC00511 may act as an oncogenic factor in gastric cancer by influencing and regulating the expression level of TRIP13. This relationship has the potential to reveal the molecular mechanisms driving gastric cancer progression and further elucidate the roles of LINC00511 and TRIP13 in gastric cancer. In this study, we confirmed that LINC00511 could act as a ceRNA targeting miR-29c-3p to further regulate the expression of TRIP13. LINC00511 was also found to be able to be positively regulated by the transcription factor IRF9. In addition, TRIP13 could activate the AKT/mTOR pathway by interacting with its downstream protein ACTN2, thus promoting the proliferation of GC cells. lnc-LINC00511 could promote GC progression by regulating the miR-29c-3p/TRIP13 axis and activating the AKT/mTOR pathway.

Bioinformatics data combined with single-cell analysis reveals patterns of immunoinflammatory infiltration and cell death in melanoma.

BACKGRUOND: Melanoma is a common cancer in dermatology, but its molecular mechanisms remain poorly explained. AIM: Utilizing single-cell analytics and bioinformatics, the work sought to discover the immunological infiltration and cellular molecular mechanisms of melanoma. METHODS: Melanoma genes databases were downloaded from GeneCards, and gene expression profiles were chosen from the Gene Expression Omnibus (GSE244889). Establishing and analyzing protein-protein interaction networks for functional enrichment made use of the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) databases. The process assesses the immunological cell infiltration variations between normal and malignant samples by Immune Cell AI software program. Different cell type differences were clarified by cell quality control, filtration, removal of batch effects and cell clustering analysis using single cell analysis techniques. RESULTS: Using a variety of machine learning techniques, 20 differentially expressed hub genes were found; among these, TP53, HSP90AB1, HSPA4, RHOA, CCND1, CYCS, PPARG, NFKBIA, CAV1, ANXA5, ENO1, ITGAM, YWHAZ, RELA, SOD1, and VDAC1 were found to be significantly significant. The results of enrichment analysis demonstrated that immune response and inflammatory response were strongly associated with melanoma. Animal mitophagy, ferroptosis, the PI3K-Akt signaling pathway, and the HIF-1 signaling pathway were the primary signaling pathways implicated. Cells of immunity, T-cells, lymphocytes, B-cells, NK-cells, monocytes, and macrophages were shown to be significantly infiltrated in melanoma patients, according to analysis. Single cell analysis also demonstrated that ferroptosis is a significant mechanism of cell death that contributes to the advancement of melanoma and that macrophages are important in the disease. CONCLUSION: In summary, different immune cell infiltrations-particularly macrophages-have a significant impact on the onset and course of melanoma, and our findings may help direct future investigations into melanoma macrophages.

Efficacy and prognostic factors of stereotactic body radiotherapy combined with immunotherapy for pulmonary oligometastases: a preliminary retrospective cohort study.

Background: Stereotactic body radiotherapy (SBRT) combined immunotherapy has a synergistic effect on patients with stage IV tumors. However, the efficacy and prognostic factors analysis of SBRT combined immunotherapy for patients with pulmonary oligometastases have rarely been reported in the studies. The purpose of this study is to explore the efficacy and prognostic factors analysis of SBRT combined immunotherapy for patients with oligometastatic lung tumors. Methods: A retrospective analysis was conducted on 43 patients with advanced tumors who received SBRT combined with immunotherapy for pulmonary oligometastases from October 2018 to October 2021. Local control (LC), progression-free survival (PFS), and overall survival (OS) were assessed using the Kaplan-Meier method. Univariate and multivariate analyses of OS were performed using the Cox regression model, and the P value <0.05 was considered statistically significant. The receiver operating characteristic (ROC) curve of neutrophil-to-lymphocyte ratio (NLR) after SBRT was generated. Spearman correlation analysis was used to determine the relationship of planning target volume (PTV) with absolute lymphocyte count (ALC) before and after SBRT and with neutrophil count (NE) after SBRT. Additionally, linear regression was used to examine the relationship between ALC after SBRT and clinical factors. Results: A total of 43 patients with pulmonary oligometastases receiving SBRT combined with immunotherapy were included in the study. The change in NLR after SBRT was statistically significant (P<0.001). At 1 and 2 years, respectively, the LC rates were 90.3% and 87.5%, the OS rates were 83.46% and 60.99%, and the PFS rates were 69.92% and 54.25%, with a median PFS of 27.00 (17.84-36.13) months. Univariate and multivariate Cox regression analyses showed that a shorter interval between radiotherapy and immunization [≤21 days; hazard ratio (HR) =1.10, 95% confidence interval (CI): 0.06-0.89; P=0.02] and a low NLR after SBRT (HR =0.24, 95% CI: 1.01-1.9; P=0.03) were associated with improved OS. The ROC curve identified 4.12 as the cutoff value for predicting OS based on NLR after SBRT. NLR after SBRT ≤4.12 significantly extended OS compared to NLR after SBRT >4.12 (log-rank P=0.001). Spearman correlation analysis and linear regression analysis showed that PTV was negatively correlated with ALC after SBRT. Conclusions: Our preliminary research shows that SBRT combined with immunotherapy has a good effect, and NLR after SBRT is a poor prognostic factor for OS. Larger PTV volume is associated with decreased ALC after SBRT.

Point-based risk score for the risk stratification and prediction of hepatocellular carcinoma: a population-based random survival forest modeling study.

Background: The precise associations between common clinical biomarkers and hepatocellular carcinoma (HCC) risk remain unclear but hold valuable insights for HCC risk stratification and prediction. Methods: We examined the linear and nonlinear associations between the baseline levels of 32 circulating biomarkers and HCC risk in the England cohort of UK Biobank (UKBB) (n = 397,702). The participants were enrolled between 2006 and 2010 and followed up to 31st October 2022. The primary outcome is incident HCC cases. We then employed random survival forests (RSF) to select the top ten most informative biomarkers, considering their association with HCC, and developed a point-based risk score to predict HCC. The performance of the risk score was evaluated in three validation sets including UKBB Scotland and Wales cohort (n = 52,721), UKBB non-White-British cohort (n = 29,315), and the Taizhou Longitudinal Study in China (n = 17,269). Findings: Twenty-five biomarkers were significantly associated with HCC risk, either linearly or nonlinearly. Based on the RSF model selected biomarkers, our point-based risk score showed a concordance index of 0.866 in the England cohort and varied between 0.814 and 0.849 in the three validation sets. HCC incidence rates ranged from 0.95 to 30.82 per 100,000 from the lowest to the highest quintiles of the risk score in the England cohort. Individuals in the highest risk quintile had a 32-73 times greater risk of HCC compared to those in the lowest quintile. Moreover, over 70% of HCC cases were detected in individuals within the top risk score quintile across all cohorts. Interpretation: Our simple risk score enables the identification of high-risk individuals of HCC in the general population. However, including some biomarkers, such as insulin-like growth factor 1, not routinely measured in clinical practice may increase the model's complexity, highlighting the need for more accessible biomarkers that can maintain or improve the predictive accuracy of the risk score. Funding: This work was supported by the National Natural Science Foundation of China (grant numbers: 82204125) and the Science and Technology Support Program of Taizhou (TS202224).

Phase II control charts for monitoring the depth-ratio of ball-bearings involving three normal variables.

This paper investigates the problem of monitoring the ratio involving three variables, jointly distributed as trivariate normal. The Shewhart-type and two exponentially weighted moving average (EWMA) type schemes for monitoring depth ratio are proposed. The ratio of a normal variable to the average of two other normal variables has wide applications in natural science, production, and engineering. It is defined with slightly different terminology in various contexts, such as depth or aspect ratios. In modern bearing manufacturing, the aspect ratio of width to the average of inner and outer diameters can be an essential indicator of product quality and process stability. While there are many helpful existing charts for monitoring the three components separately or jointly when these characteristics follow a normal distribution, the ratio aspect is often ignored. The Shewhart-type schemes' exact and approximated control limits are considered and analyzed. Numerical results based on Monte-Carlo are conducted using the average run length as a metric with different values of in-control ratio and correlation between the three variables. An application based on the parts manufacturing data illustrates the implementation design of the two control charts. The real-life data analysis shows the efficacy of the proposed monitoring schemes in practice.

Use of high-resolution fluorescence in situ hybridization for fast and robust detection of SARS-CoV-2 RNAs.

Early, rapid, and accurate diagnostic tests play critical roles not only in the identification/management of individuals infected by SARS-CoV-2, but also in fast and effective public health surveillance, containment, and response. Our aim has been to develop a fast and robust fluorescence in situ hybridization (FISH) detection method for detecting SARS-CoV-2 RNAs by using an HEK 293 T cell culture model. At various times after being transfected with SARS-CoV-2 E and N plasmids, HEK 293 T cells were fixed and then hybridized with ATTO-labeled short DNA probes (about 20 nt). At 4 h, 12 h, and 24 h after transfection, SARS-CoV-2 E and N mRNAs were clearly revealed as solid granular staining inside HEK 293 T cells at all time points. Hybridization time was also reduced to 1 h for faster detection, and the test was completed within 3 h with excellent results. In addition, we have successfully detected 3 mRNAs (E mRNA, N mRNA, and ORF1a (-) RNA) simultaneously inside the buccal cells of COVID-19 patients. Our high-resolution RNA FISH might significantly increase the accuracy and efficiency of SARS-CoV-2 detection, while significantly reducing test time. The method can be conducted on smears containing cells (e.g., from nasopharyngeal, oropharyngeal, or buccal swabs) or smears without cells (e.g., from sputum, saliva, or drinking water/wastewater) for detecting various types of RNA viruses and even DNA viruses at different timepoints of infection.

Mechanism and kinetics of thermal decomposition of decabromobiphenyl: Reaction with reactive radicals and formation chemistry of polybrominated dibenzofurans.

Although the production and usage of polybrominated biphenyls (PBBs) as brominated flame retardants have already been prohibited, they still pose a threat to the environment and human health. However, the evolutionary behaviors and decomposition mechanisms of PBBs during thermal treatment of waste remain unclear. In the present work, the mechanism and kinetics of thermal decomposition of decabromobiphenyl (deca-BB), one of the most frequently-used PBB congeners, are studied in detail using quantum chemical calculations. Results indicate that the high bond dissociation energies and large energy gap of deca-BB make its self-decomposition reaction difficult to occur, while its reactions with several reactive radicals (including hydrogen, bromine, and hydroxyl radicals) in the combustion environment are universally carried out at low energy barriers. Hydrogen, bromine, and hydroxyl radicals all exhibit a high selectivity for the para-C/Br atoms of deca-BB, resulting in the generation of several debromination products or intermediates. This study also investigates the formation mechanism of polybrominated dibenzofurans (PBDFs) from deca-BB and the effect of polymeric materials on this process. We found that the oxidation of ortho-phenyl-type radical, followed by evolution into PBDFs, is a very exothermic and relatively low-barrier process. Thus, the emergence of ortho-phenyl-type radicals from the loss of ortho-Br atoms is a critical step in the formation of PBDFs. Influence of polymeric materials on the formation of PBDFs is reflected in that various alkyl radicals and diradicals produced by their decomposition can readily abstract ortho-Br atoms to generate ortho-phenyl-type radicals, thus facilitating the formation of PBDFs. The mechanistic pathways and kinetic parameters presented in this study can offer theoretical guidance for controlling contaminant emissions in the thermal treatment of deca-BB-containing waste.

The role of lipoprotein­associated phospholipase A2 in inflammatory response and macrophage infiltration in sepsis and the regulatory mechanisms.

Lipoproteinassociated phospholipase A2 (Lp-PLA2), encoded by the phospholipase A2 group VII (Pla2g7) gene, has been pertinent to inflammatory responses. This study investigates the correlation between Lp-PLA2 and inflammatory injury in septic mice and explores its regulatory mechanism. Lp-PLA2 was found to be upregulated in the serum of septic mice induced by cecal ligation and puncture and in the culture supernatant of RAW264.7 cells following lipopolysaccharide and adenosine triphosphate treatments. The contents of Lp-PLA2 were positively correlated with increased concentrations of proinflammatory cytokines in patients with sepsis. Both animal and cellular models showed increased concentrations of proinflammatory cytokines. Spi-1 proto-oncogene (Spi1), highly expressed in these models, was found to activate Pla2g7 transcription. Knockdown of Pla2g7 or Spi1 reduced the proinflammatory cytokine production, mitigated organ damage in mice, and suppressed macrophage migration in vitro. Retinoblastoma binding protein 6 (Rbbp6), poorly expressed in both models, was found to reduce Spi1 protein stability through ubiquitination modification. Rbbp6 overexpression similarly suppressed inflammatory activation of RAW264.7 cells, which was counteracted by Pla2g7 or Spi1 upregulation. In summary, this study demonstrates that the Pla2g7 loss and Spi1 upregulation participate in inflammatory responses in sepsis by elevating the Lp-PLA2 levels.

Genome-wide analysis of the CCT gene family and functional characterization of SlCCT6 in response to drought stress in tomato.

CCT transcription factors are important for photoperiod and abiotic stress regulation in Arabidopsis and rice. However, the CCT gene family has not been reported in tomato. Here, we systematically analyzed this. Thirty-one SlCCT genes were identified and divided into five groups (CMF, TIFY, PRR, S8, and COL), with members unevenly distributed across 12 chromosomes and the third chromosome exhibiting the most distribution. SlCCT was found to interact with an interacting protein (SlGI), transcription factor (MYB), and non-coding RNA (sly-miR156-5p) to jointly regulate the tomato stress response. cis-Acting element analysis of the SlCCT promoter region indicated large stress- and hormone-response elements in this family. Real-time PCR results indicated that SlPRR subfamily genes respond to various abiotic stresses and hormones. Tissue expression analysis revealed that several PRR subfamily genes are highly expressed in flowers, and subcellular localization analysis indicated an SlCCT6 nuclear location. Notably, SlCCT6 expression was significantly induced by drought, and its silencing reduced drought stress tolerance. Moreover, SlCCT6 overexpression enhanced tomato drought resistance by increasing antioxidant enzyme activity and activating stress-related genes, whereas SlCCT6 knockout decreased drought resistance. In conclusion, this provides valuable insights for future research on SlCCT functions.

Menopausal Hormone Therapy and Osteoarthritis Risk: Retrospective Population-Based Study in South Korea.

OBJECTIVES: This study aimed to investigate the risk of osteoarthritis associated with menopausal hormone therapy (MHT). METHODS: This population-based retrospective cohort study used a database of Korean health insurance claims (2007-2020). Females aged ≥ 40 who initiated menopause-related healthcare visits between 2011 and 2014 were identified. The MHT group comprised females aged ≥ 40 who initiated MHT for ≥ 6 months during this period. The non-MHT group comprised females aged ≥ 40 who attended menopause-related healthcare visits but did not receive MHT. To account for potential confounding factors, the two groups were matched at a 1:1 ratio using propensity score matching. RESULTS: A cohort of 453,040 postmenopausal females aged ≥ 40 years was identified, with 26,354 assigned to either the MHT or non-MHT group after propensity matching. The median age was 49 years, and the median follow-up was 8.2 years. The Cox proportional hazards model demonstrated an elevated risk of osteoarthritis with MHT (hazard ratio [HR], 1.154; 95% confidence interval [CI], 1.117-1.193) for knee (HR, 1.148; 95% CI, 1.102-1.195) and other arthritis (HR, 1.205; 95% CI, 1.151-1.261), although not statistically significant for hip arthritis. Tibolone (HR, 1.211; 95% CI, 1.161-1.263), estrogen-progestogen therapy (EPT) (HR, 1.092; 95% CI, 1.048-1.137), and estrogen therapy (ET) (HR, 1.235; 95% CI, 1.148-1.329) were associated with a higher risk of osteoarthritis compared to non-MHT users. CONCLUSIONS: MHT was associated with an increased risk of osteoarthritis, consistently observed across tibolone, EPT, and ET, particularly affecting joints other than the hip, with a trend toward an elevated risk of hip osteoarthritis.

Fecal microbiota transplantation as a new way for OVA-induced atopic dermatitis of juvenile mice.

Children all over the world suffer from atopic dermatitis (AD), a prevalent condition that impairs their health. Corticosteroids, which have long-term negative effects, are frequently used to treat AD. There has been a growing body of research on the gut microbiota's function in AD. Nevertheless, the function and underlying mechanisms of fecal microbiota transplantation (FMT) in AD children remain to be established. Therefore, in order to assess the preventive effects of FMT treatment on AD and investigate the mechanisms, we constructed an ovalbumin (OVA)-induced juvenile mouse AD model in this investigation. This study explored the role and mechanism of FMT treatment in AD through 16S RNA sequencing, pathological histological staining, molecular biology, and Flow cytometry. Results demonstrated that the FMT treatment improved the gut microbiota's diversity and composition, bringing it back to a level similar to that of a close donor. Following FMT treatment, OVA-specific antibodies were inhibited, immunoglobulin (Ig) E production was decreased, the quantity of mast cells and eosinophils was decreased, and specific inflammatory markers in the skin and serum were decreased. Further mechanistic studies revealed that FMT treatment induced CD103+ DCs and programmed cell death ligand 1 (PD-L1)/programmed cell death 1 (PD-1) expression in skin-draining lymph nodes and promoted Treg production to induce immune tolerance and suppress skin inflammation. Meanwhile, changes in the gut microbiota were substantially correlated with Th2 cytokines, OVA-specific antibodies, and PD-L1/PD-1. In conclusion, FMT regulates the Th1/Th2 immunological balance and the gut microbiota. It may also inhibit AD-induced allergy responses through the PD-L1/PD-1 pathway, and providing a unique idea and possibly a fresh approach to the treatment of AD.