The joint impact of PM2.5 constituents on the risk of cerebrovascular diseases hospitalization: A large community-based cohort study.

Air pollution poses significant health risks to urban areas, with limited focus on the chronic association of PM2.5 and its constituents on cerebrovascular diseases (CERs), especially regarding the joint associations. This study explores the individual and joint associations between PM2.5 constituents and CER hospitalization risks through a cohort analysis of 36,271 adults in the Pearl River Delta, South China, from 2015 to 2020. Cox proportional hazards regression and quantile-based g-computation models were used to quantify the individual and joint associations of annual mean concentrations of PM2.5 constituents with hospitalization for CERs. 1151 participants were hospitalized due to CERs during the five-year follow-up period. Joint associations analyses identified that one quartile increase in co-exposure may result in hazard ratios of 1.530 (1.441-1.623), 1.840 (1.710-1.980), and 1.609 (1.491-1.737) for CERs, total, and ischemic stroke hospitalization, respectively. The adverse effect was primarily driven by organic matter and chlorine. Men, those with a history of tobacco or alcohol use or with low residential greenness, were more susceptible to CERs hospitalization following PM2.5 constituents co-exposure. Upcoming strategies should focus on monitoring and regulating PM2.5 constituents, encouraging healthy lifestyles, and enhancing urban greenery.

How long-term PM exposure may affect all-site cancer mortality: Evidence from a large cohort in southern China.

BACKGROUND: Evidence of a potential causal link between long-term exposure to particulate matter (PM) and all-site cancer mortality from large population cohorts remained limited and suffered from residual confounding issues with traditional statistical methods. AIMS: We aimed to examine the potential causal relationship between long-term PM exposure and all-site cancer mortality in South China using causal inference methods. METHODS: We used a cohort in southern China that recruited 580,757 participants from 2009 through 2015 and tracked until 2020. Annual averages of PM1, PM2.5, and PM10 concentrations were generated with validated spatiotemporal models. We employed a causal inference approach, the Marginal Structural Cox model, based on observational data to evaluate the association between long-term exposure to PM and all-site cancer mortality. RESULTS: With an increase of 1 µg/m³ in PM1, PM2.5, and PM10, the hazard ratios (HRs) and 95% confidence interval (CI) for all-site cancer were 1.033 (95% CI: 1.025-1.041), 1.032 (95% CI: 1.027-1.038), and 1.020 (95% CI: 1.016-1.025), respectively. The HRs (95% CI) for digestive system and respiratory system cancer mortality associated with each 1 µg/m³ increase in PM1 were 1.022 (1.009-1.035) and 1.053 (1.038-1.068), respectively. In addition, inactive participants, who never smoked, or who lived in areas of low surrounding greenness were more susceptible to the effects of PM exposure, the HRs (95% CI) for all-site cancer mortality were 1.042 (1.031-1.053), 1.041 (1.032-1.050), and 1.0473 (1.025-1.070) for every 1 µg/m³ increase in PM1, respectively. The effect of PM1 tended to be more pronounced in the low-exposure group than in the general population, and multiple sensitivity analyses confirmed the robustness of the results. CONCLUSION: This study provided evidence that long-term exposure to PM may elevate the risk of all-site cancer mortality, emphasizing the potential health benefits of improving air quality for cancer prevention.

m6A RNA Methylation and Implications for Hepatic Lipid Metabolism.

This review presents a summary of recent progress in research on the N6-methyladenosine (m6A) modification and regulatory roles in hepatic lipid metabolism. As the most abundant internal modification of eukaryotic RNA, the m6A modification is a dynamic and reversible process of the m6A enzyme system, which includes writers, erasers, and readers. m6A methylation depressed lipid synthesis and facilitated lipolysis in liver. The depletion of m6A methyltransferase Mettl14/Mettl3 raised fatty acid synthase (FAS), stearoyl-CoA desaturase-1 (SCD1), acetyl-CoA carboxylase (ACC), and elongase of very long chain fatty acids 6 (ELOVL6) in rodent liver, causing increases in liver weight, triglyceride (TG) production, and content in hepatocytes. FTO catalyzed m6A demethylation and the suppression m6A reader YTHDC2 promoted hepatocellular TG generation and hepatic steatosis in C57BL/6 mice through sterol regulatory element-binding protein 1c (SREBP-1c) signaling pathway, which upregulated the lipogenic genes FAS, SCD1, ACC, recombinant acetyl coenzyme a carboxylase alpha, and cell death-inducing DNA fragmentation factor-like effector C (CIDEC). Furthermore, FTO overexpression did not only enhance mitochondrial fusion to impair mitochondrial function and lipid oxidation but also promoted lipid peroxidation, accompanied by excessive TG in hepatocytes and rodent liver. Elevated m6A modification potently suppressed hepatic lipid accumulation, while the shrinkage of m6A modification arose hepatic lipid deposition. These findings have highlighted the beneficial role of m6A RNA methylation in hepatic lipid metabolism, potentially protecting liver from lipid metabolic disorders.

Potential causal links and mediation pathway between urban greenness and lung cancer mortality: Result from a large cohort (2009 to 2020).

Urban greenness, as a vital component of the urban environment, plays a critical role in mitigating the adverse effects of rapid urbanization and supporting urban sustainability. However, the causal links between urban greenness and lung cancer mortality and its potential causal pathway remain poorly understood. Based on a prospective community-based cohort with 581,785 adult participants in southern China, we applied a doubly robust Cox proportional hazard model to estimate the causal associations between urban greenness exposure and lung cancer mortality. A general multiple mediation analysis method was utilized to further assess the potential mediating roles of various factors including particulate matter (PM1, PM2.5-1, and PM10-2.5), temperature, physical activity, and body mass index (BMI). We observed that each interquartile range (IQR: 0.06) increment in greenness exposure was inversely associated with lung cancer mortality, with a hazard ratio (HR) of 0.89 (95 % CI: 0.83, 0.96). The relationship between greenness and lung cancer mortality might be partially mediated by particulate matter, temperature, and physical activity, yielding a total indirect effect of 0.826 (95 % CI: 0.769, 0.887) for each IQR increase in greenness exposure. Notably, the protective effect of greenness against lung cancer mortality could be achieved primarily by reducing the particulate matter concentration.

Interactions between long-term ambient particle exposures and lifestyle on the prevalence of hypertension and diabetes: insight from a large community-based survey.

INTRODUCTION: Evidence on the interaction of lifestyle and long-term ambient particle (PM) exposure on the prevalence of hypertension, diabetes, particularly their combined condition is limited. We investigate the associations between PM and these outcomes and whether the associations were modified by various lifestyles. METHODS: This was a large population-based survey during 2019-2021 in Southern China. The concentrations of PM were interpolated and assigned to participants by the residential address. Hypertension and diabetes status were from questionnaires and confirmed with the community health centres. Logistic regression was applied to examine the associations, followed by a comprehensive set of stratified analyses by the lifestyles including diet, smoking, drinking, sleeping and exercise. RESULTS: A total of 82 345 residents were included in the final analyses. For each 1 µg/m3 increase in PM2.5, the adjusted OR for the prevalence of hypertension, diabetes and their combined condition were 1.05 (95% CI 1.05 to 1.06), 1.07 (95% CI 1.06 to 1.08) and 1.05 (95% CI 1.04 to 1.06), respectively. We observed that the association between PM2.5 and the combined condition was greatest in the group with 4-8 unhealthy lifestyles (OR=1.09, 95% CI 1.06 to 1.13) followed by the group with 2-3 and those with 0-1 unhealthy lifestyle (P interaction=0.026). Similar results and trends were observed in PM10 and/or in those with hypertension or diabetes. Individuals who consumed alcohol, had inadequate sleep duration or had poor quality sleep were more vulnerable. CONCLUSION: Long-term PM exposure was associated with increased prevalence of hypertension, diabetes and their combined condition, and those with unhealthy lifestyles suffered greater risks of these conditions.

Metabolomics Differences of the Donor Livers Between In Situ and Ex Situ Conditions During Ischemia-free Liver Transplantation.

BACKGROUND: Ischemia-free liver transplantation (IFLT) has been innovated to avoid graft ischemia during organ procurement, preservation, and implantation. However, the metabolism activity of the donor livers between in the in situ and ex situ normothermic machine perfusion (NMP) conditions, and between standard criteria donor and extend criteria donor remains unknown. METHODS: During IFLT, plasma samples were collected both at the portal vein and hepatic vein of the donor livers in situ during procurement and ex situ during NMP. An ultra-high performance liquid chromatography-mass spectrometry was conducted to investigate the common and distinct intraliver metabolite exchange. RESULTS: Profound cysteine and methionine metabolism, and aminoacyl-tRNA biosynthesis were found in both in situ and ex situ conditions. However, obvious D-arginine and D-ornithine metabolism, arginine and proline metabolism were only found in the in situ condition. The suppressed activities of the urea cycle pathway during ex situ condition were confirmed in an RNA expression level. In addition, compared with extend criteria donor group, standard criteria donor group had more active intraliver metabolite exchange in metabonomics level. Furthermore, we found that the relative concentration of p-cresol, allocystathionine, L-prolyl-L-proline in the ex situ group was strongly correlated with peak alanine aminotransferase and aspartate aminotransferase at postoperative days 1-7. CONCLUSIONS: In the current study, we show the common and distinct metabolism activities during IFLT. These findings might provide insights on how to modify the design of NMP device, improve the perfusate components, and redefine the criteria of graft viability.

Cysteine carboxyethylation generates neoantigens to induce HLA-restricted autoimmunity.

Autoimmune diseases such as ankylosing spondylitis (AS) can be driven by emerging neoantigens that disrupt immune tolerance. Here, we developed a workflow to profile posttranslational modifications involved in neoantigen formation. Using mass spectrometry, we identified a panel of cysteine residues differentially modified by carboxyethylation that required 3-hydroxypropionic acid to generate neoantigens in patients with AS. The lysosomal degradation of integrin αIIb [ITGA2B (CD41)] carboxyethylated at Cys96 (ITGA2B-ceC96) generated carboxyethylated peptides that were presented by HLA-DRB1*04 to stimulate CD4+ T cell responses and induce autoantibody production. Immunization of HLA-DR4 transgenic mice with the ITGA2B-ceC96 peptide promoted colitis and vertebral bone erosion. Thus, metabolite-induced cysteine carboxyethylation can give rise to pathogenic neoantigens that lead to autoreactive CD4+ T cell responses and autoantibody production in autoimmune diseases.

Computer Image Analysis Reveals C-Myc as a Potential Biomarker for Discriminating between Keratoacanthoma and Cutaneous Squamous Cell Carcinoma.

The distinction between Keratoacanthoma (KA) and Cutaneous Squamous Cell Carcinoma (cSCC) is critical yet usually challenging to discriminate clinically and histopathologically. One approach to differentiate KA from cSCC is through assessing the immunohistochemical staining patterns of the three indicators, ß-catenin, C-Myc, and CyclinD1, which are critical molecules that play important roles in the Wnt/ß-catenin signaling pathway. Ki-67, as a proliferation biomarker for human tumor cells, was also assessed as an additional potential marker for differentiating KA from cSCC. In this report, these four indicators were analyzed in 42 KA and 30 cSCC cases with the use of the computer automated image analysis system. Computer automated image analysis is a time-based and cost-effective method of determining IHC staining in KA and cSCC samples. We found that C-Myc staining was predominantly localized in the nuclei of basal cells within KA patients, whereas cSCC staining was predominantly localized in the nuclei of diffuse cells. This C-Myc staining pattern has a sensitivity of 78.6% and a specificity of 66.7% for identifying KA. Moreover, positive rates of distinct expression patterns of C-Myc and Ki-67 may also serve as a means to clinically distinguish KA from cSCC. Taken together, our results suggest that these markers, in particular C-Myc, may be useful in differentiating KA from cSCC.

Rare mutations in NLRP3 and NLRP12 associated with familial cold autoinflammatory syndrome: two Chinese pedigrees.

Familial cold autoinflammatory syndrome (FCAS) is the mildest subtype of cryopyrin-associated periodic syndrome (CAPS) and is a rare inherited systemic autoinflammatory disease (SAID). CAPS is the consequence of a rare group of genetic disorders that are mostly reported in European and American populations, but scarcely reported in Chinese populations. NLRP3, NLRP12, PLCG2, and NLRC4 are known pathogenic genes associated with FCAS, and the aim of this study was to identify pathogenic mutations in two intact pedigrees of Chinese FCAS. We performed Sanger sequencing of genomic DNA samples from 25 affected and 32 unaffected members of the two intact pedigrees and analyzed the pathogenic mutations for their conservativeness using multiple sequence alignment tools. In addition, we reviewed previously reported pathogenic genes of FCAS and their pathogenicity classification and summarized the characteristics of different genotypes and phenotypes of FCAS. This study reported two intact FCAS pedigrees with different genotypes and phenotypes, the heterozygous mutation (p.V72M) in NLRP3 in pedigree 1 and the heterozygous mutation (p.R754H) in NLRP12 in pedigree 2. There are no reports targeting p.V72M in NLRP3 in FCAS1, and there are relatively few relevant phenotypic data on the clinical manifestations identified in previous pedigrees. Multiple sequence comparisons of NLRP3 indicate that the p.V72M mutation is highly conserved during evolution. Our study has enriched the understanding of the pathogenesis of FCAS, a rare disease especially in Asian populations. KEY POINTS: •The NLRP3 (p.V72M) variant was first discovered in the Chinese pedigree of FCAS1 •NLRP12 (p.R754H) variants are not conserved in multiple sequence alignments, but they are still co-segregated and expressed in the big Chinese diseased pedigree.

Calcium/calmodulin-dependent protein kinase IV promotes imiquimod-induced psoriatic inflammation via macrophages and keratinocytes in mice.

CaMK4 has an important function in autoimmune diseases, and the contribution of CaMK4 in psoriasis remains obscure. Here, we show that CaMK4 expression is significantly increased in psoriatic lesional skin from psoriasis patients compared to healthy human skin as well as inflamed skin from an imiquimod (IMQ)-induced mouse model of psoriasis compared to healthy mouse skin. Camk4-deficient (Camk4-/-) mice treated with IMQ exhibit reduced severity of psoriasis compared to wild-type (WT) mice. There are more macrophages and fewer IL-17A+γδ TCR+ cells in the skin of IMQ-treated Camk4-/- mice compared to IMQ-treated WT mice. CaMK4 inhibits IL-10 production by macrophages, thus allowing excessive psoriatic inflammation. Deletion of Camk4 in macrophages alleviates IMQ-induced psoriatic inflammation in mice. In keratinocytes, CaMK4 inhibits apoptosis as well as promotes cell proliferation and the expression of pro-inflammatory genes such as S100A8 and CAMP. Taken together, these data indicate that CaMK4 regulates IMQ-induced psoriasis by sustaining inflammation and provides a potential target for psoriasis treatment.

Prediction of Graft Survival Post-liver Transplantation by L-GrAFT Risk Score Model, EASE Score, MEAF Scoring, and EAD.

Background: Early allograft dysfunction (EAD) is correlated with poor patient or graft survival in liver transplantation. However, the power of distinct definitions of EAD in prediction of graft survival is unclear. Methods: This retrospective, single-center study reviewed data of 677 recipients undergoing orthotopic liver transplant between July 2015 and June 2020. The following EAD definitions were compared: liver graft assessment following transplantation (L-GrAFT) risk score model, early allograft failure simplified estimation score (EASE), model for early allograft function (MEAF) scoring, and Olthoff criteria. Risk factors for L-GrAFT7 high risk group were evaluated with univariate and multivariable logistic regression analysis. Results: L-GrAFT7 had a satisfied C-statistic of 0.87 in predicting a 3-month graft survival which significantly outperformed MEAF (C-statistic = 0.78, P = 0.01) and EAD (C-statistic = 0.75, P < 0.001), respectively. L-GrAFT10, EASE was similar to L-GrAFT7, and they had no statistical significance in predicting survival. Laboratory model for end-stage liver disease score and cold ischemia time are risk factors of L-GrAFT7 high-risk group. Conclusion: L-GrAFT7 risk score is capable for better predicting the 3-month graft survival than the MEAF and EAD in a Chinese cohort, which might standardize assessment of early graft function and serve as a surrogate endpoint in clinical trial.

Transcriptome-wide quantification of double-stranded RNAs in live mouse tissues by dsRIP-Seq.

Double-stranded RNAs (dsRNAs) are abundantly present in cells, playing multiple regulatory functions. dsRNAs of viral origin activate innate immune responses. Since RNA editing and modifications affect the structure and recognition of RNAs, their alteration can result in the accumulation of aberrant endogenous dsRNAs inducing a deleterious innate immune response. Here, we present a complete protocol for the measurement of dsRNAs in a live mouse tissue using dsRNA immunoprecipitation and sequencing (dsRIP-Seq). This protocol focuses on tissue isolation, dsRNA immunoprecipitation and downstream computational analysis. For complete details on the use and execution of this protocol, please refer to Gao et al. (2020).

Clinical Outcomes of Liver Transplantation in Patients With Hepatorenal Syndrome: A Single Center Study in China.

BACKGROUND: Liver transplantation (LT) is an optimal treatment for hepatorenal syndrome (HRS) patients but renal function recovery is not universal after operation. The aim of this study is to explore the association between stages of hepatorenal syndrome-acute kidney injury (HRS-AKI) and incidence of post-operation chronic kidney disease (CKD). METHODS: Data of HRS-AKI patients who received LT were collected from the First Affiliated Hospital of Sun Yat-sen University from 2016 to 2020. A survival and incidence curve and multivariable model were established to analyze the impacts of HRS-AKI stages and variables on 90-day survival and CKD within 12 months. RESULTS: A total of 62 HRS-AKI patients were enrolled in this study. Overall, 35 (57%), 17 (27%), and 10 (16%) patients were diagnosed as stages 1, 2, and 3, respectively. The patients at stage 3 had the poorest outcomes with the lowest rate of 90-day survival and the highest incidence of CKD in 12 months. Stage 3 (SHR = 7.186, 95% CI, 1.661-32.043) and postoperative renal replacement therapy (RRT) (SHR = 3.228, 95% CI, 1.115-9.345) were found as useful indicators for poor prognosis. CONCLUSIONS: In our study, the classification of HRS-AKI stages can be used to predict the prognosis of HRS patients after LT. The peak serum creatinine level is a risky predictor in high HRS-AKI stage patients.

Differential occurrence of lysine 2-hydroxyisobutyrylation in psoriasis skin lesions.

Lysine 2-hydroxyisobutyrylation is a newly discovered posttranslational modification. Although this modification is an important type of protein acylation, its role in psoriasis remains unstudied. We compared lesional and nonlesional psoriasis skin samples from 45 psoriasis patients. The result showed that this highly conserved modification was found in large quantities in both normal and diseased dermal tissues. However, there were a number of clear and significant differences between normal and diseased skin tissue. By comparing, lysine 2-hydroxyisobutyrylation was upregulated at 94 sites in 72 proteins and downregulated at 51 sites in 44 proteins in lesional skin. In particular, the sites with the most significant downregulation of lysine 2-hydroxyisobutyrylation were found in S100A9 (ratio = 0.140, p-value = .000371), while the most upregulated site was found in tenascin (ratio = 3.082, p-value = .0307). Loci associated with psoriasis, including FUBP1, SERPINB2 and S100A9, also exhibited significant regulation. Analyses of proteome data revealed that SERPINB2 and S100A9 were differentially expressed proteins. And bioinformatics analysis suggest that the P13K-Akt signaling pathway was more enriched with lysine 2-hydroxyisobutyrylation in lesional psoriasis skin. Our study revealed that lysine 2-hydroxyisobutyrylation is broadly present in psoriasis skin, suggesting that this modification plays a role in psoriasis pathogenesis. SIGNIFICANCE: A newly discovered protein posttranslational modification, lysine 2-hydroxyisobutyrylation, has been found to occur in a wide variety of organisms and to participate in some important metabolic processes. In this study, lysine 2-hydroxyisobutyrylation in lesional psoriasis skin and nonlesional psoriasis skin was quantified and compared for the first time. We found a number of differentially modified proteins and sites in our comparisons. Interestingly, some of the identified proteins and pathways with significantly different modifications, such as S100A9 and the PI3K-Akt signaling pathway, have been previously reported to be associated with psoriasis. We hope that this research will provide new insights into psoriasis.

Inference of differentiation time for single cell transcriptomes using cell population reference data.

Single-cell RNA sequencing (scRNA-seq) is a powerful method for dissecting intercellular heterogeneity during development. Conventional trajectory analysis provides only a pseudotime of development, and often discards cell-cycle events as confounding factors. Here using matched cell population RNA-seq (cpRNA-seq) as a reference, we developed an "iCpSc" package for integrative analysis of cpRNA-seq and scRNA-seq data. By generating a computational model for reference "biological differentiation time" using cell population data and applying it to single-cell data, we unbiasedly associated cell-cycle checkpoints to the internal molecular timer of single cells. Through inferring a network flow from cpRNA-seq to scRNA-seq data, we predicted a role of M phase in controlling the speed of neural differentiation of mouse embryonic stem cells, and validated it through gene knockout (KO) experiments. By linking temporally matched cpRNA-seq and scRNA-seq data, our approach provides an effective and unbiased approach for identifying developmental trajectory and timing-related regulatory events.

A novel anatomic severity grading score for acute Type B aortic dissections and correlation to aortic reinterventions after thoracic endovascular aortic repair.

BACKGROUND: We introduce a novel preoperative anatomic severity grading system for acute type B aortic dissections and validate the system in a cohort of patients who underwent thoracic endovascular aortic repair. METHODS: We identified a cohort of patients who received thoracic endovascular aortic repair (TEVAR) for acute type B aortic dissection from 2008 to 2014. We developed an anatomic severity grading score (ASG) to measure attributes of aortic anatomy that we hypothesized may affect difficulty or durability of repair. Measurements were made using computed tomography angiography images and based on hypothesized severity, giving a potential score range of 0-38. RESULTS: We analyzed the computed tomography angiography images on a cohort of 30 patients with acute type B aortic dissection who underwent TEVAR. We created an area under the receiver operating characteristic curve (AUROC) using anatomic severity grading to predict aortic-related reinterventions. The AUROC was 0.72 (95% CI 0.39 to 1.1). Guided by the AUROC, we divided patients into two groups: a low-score group with anatomic severity grading scores <23 (n = 22), and a high-score group with scores ≥23 (n = 8). With this cutoff, anatomic severity grading exhibited 80% sensitivity and 84% specificity in predicting aortic-related reinterventions, with reinterventions in 50% of high-score patients and 4.5% of low-score patients (P = 0.011). The high score group also had significantly greater blood loss (200 vs 100 mL, P = 0.038), fluoroscopy time (36.0 vs 16.6 min; P = 0.022), and a trend for increased procedure time (164 vs 95 min; P = 0.083) than the low-risk group. Kaplan-Meier analysis revealed that the high-score group had a significantly decreased freedom from aortic-related reinterventions than the low-score group (38% vs 100% at 12-month followup; log rank P = 0.001). CONCLUSIONS: A preoperative anatomic severity grading score for acute type B aortic dissections consists of analysis of the proximal landing zone, curvature and tortuosity of the aorta, dissection anatomy, aortic branch vessel anatomy, and supraceliac aorta anatomy. Anatomic severity grading scores ≤23 are an excellent predictor of aortic-related reinterventions.

Racial Differences in Esophageal Squamous Cell Carcinoma: Incidence and Molecular Features.

The incidence and histological type of esophageal cancer are highly variable depending on geographic location and race/ethnicity. Here we want to determine if racial difference exists in the molecular features of esophageal cancer. We firstly confirmed that the incidence rate of esophagus adenocarcinoma (EA) was higher in Whites than in Asians and Blacks, while the incidence of esophageal squamous cell carcinoma (ESCC) was highest in Asians. Then we compared the genome-wide somatic mutations, methylation, and gene expression to identify differential genes by race. The mutation frequencies of some genes in the same pathway showed opposite difference between Asian and White patients, but their functional effects to the pathway may be consistent. The global patterns of methylation and expression were similar, which reflected the common characteristics of ESCC tumors from different populations. A small number of genes had significant differences between Asians and Whites. More interesting, the racial differences of COL11A1 were consistent across multiple molecular levels, with higher mutation frequency, higher methylation, and lower expression in White patients. This indicated that COL11A1 might play important roles in ESCC, especially in White population. Additional studies are needed to further explore their functions in esophageal cancer.