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OBJECTIVES: The mitochondrial function in anti-MDA5 and TIF1-γ-positive dermatomyositis (DM) is relatively unknown. This study attempted to explore mitochondrial mass within the peripheral lymphocyte subsets of anti-MDA5 and TIF1-γ-positive DM. METHODS: This cross-sectional study enrolled 109 DM patients and 32 healthy controls (HCs). The mitochondrial mass of peripheral lymphocyte subsets was analyzed via flow cytometry using median fluorescence intensity assessment. RESULTS: Compared with HCs, there was an abnormal change in peripheral lymphocyte subsets in anti-MDA5 and anti-TIF1-γ-positive DM patients. Anti-MDA5 and anti-TIF1-γ-positive DM patients also exhibited a significantly elevated mitochondrial mass in peripheral lymphocyte subsets. Furthermore, anti-MDA5 antibody levels were positively associated with the mitochondrial mass of most lymphocyte subsets in anti-MDA5-positive DM patients. Univariate logistic regression analysis indicated that the increased mitochondrial mass in some peripheral lymphocyte subsets was related to the occurrence of anti-MDA5-positive DM and presence of anti-MDA5 antibodies. Similar results were obtained in anti-TIF1-γ-positive DM patients. CONCLUSIONS: Abnormal lymphocyte subset counts and percentages as well as altered mitochondrial mass in anti-MDA5 and TIF1-γ-positive DM patients were associated with anti-MDA5 and TIF1-γ antibodies. We believe that these results may provide novel mitochondria-based insights into DM pathogenesis.

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AIMS: Proteomic profiling offers an expansive approach to biomarker discovery and mechanistic hypothesis generation for LV remodelling, a critical component of heart failure (HF). We sought to identify plasma proteins cross-sectionally associated with left ventricular (LV) size and geometry in a diverse population-based cohort without known cardiovascular disease (CVD). METHODS AND RESULTS: Among participants of the Multi-Ethnic Study of Atherosclerosis (MESA), we quantified plasma abundances of 1305 proteins using an aptamer-based platform at exam 1 (2000-2002) and exam 5 (2010-2011) and assessed LV structure by cardiac magnetic resonance (CMR) at the same time points. We used multivariable linear regression with robust variance to assess cross-sectional associations between plasma protein abundances and LV structural characteristics at exam 1, reproduced findings in later-life at exam 5, and explored relationships of associated proteins using annotated enrichment analysis. We studied 763 participants (mean age 60 ± 10 years at exam 1; 53% female; 19% Black race; 31% Hispanic ethnicity). Following adjustment for renal function and traditional CVD risk factors, plasma levels of 3 proteins were associated with LV mass index at both time points with the same directionality (FDR < 0.05): leptin (LEP), renin (REN), and cathepsin-D (CTSD); 20 with LV end-diastolic volume index: LEP, NT-proBNP, histone-lysine N-methyltransferase (EHMT2), chordin-like protein 1 (CHRDL1), tumour necrosis factor-inducible gene 6 protein (TNFAIP6), NT-3 growth factor receptor (NTRK3), c5a anaphylatoxin (C5), neurogenic locus notch homologue protein 3 (NOTCH3), ephrin-B2 (EFNB2), osteomodulin (OMD), contactin-4 (CNTN4), gelsolin (GSN), stromal cell-derived factor 1 (CXCL12), calcineurin subunit B type 1 (PPP3R1), insulin-like growth factor 1 receptor (IGF1R), bone sialoprotein 2 (IBSP), interleukin-11 (IL-11), follistatin-related protein 1 (FSTL1), periostin (POSTN), and biglycan (BGN); and 4 with LV mass-to-volume ratio: RGM domain family member B (RGMB), transforming growth factor beta receptor type 3 (TGFBR3), ephrin-A2 (EFNA2), and cell adhesion molecule 3 (CADM3). Functional annotation implicated regulation of the PI3K-Akt pathway, bone morphogenic protein signalling, and cGMP-mediated signalling. CONCLUSIONS: We report proteomic profiling of LV size and geometry, which identified novel associations and reinforced previous findings on biomarker candidates for LV remodelling and HF. If validated, these proteins may help refine risk prediction and identify novel therapeutic targets for HF.

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The development of coronary artery disease (CAD) is significantly affected by impaired endocrine and metabolic status. Under this circumstance, improved prevention and treatment of CAD may result from knowing the connection between metabolites and CAD. This study aims to delve into the causal relationship between human metabolic biomarkers and CAD by using two-sample Mendelian randomization (MR). Utilizing two-sample bidirectional MR analysis, we assessed the correlation between 1400 blood metabolites and CAD, and the metabolites data from the CLSA, encompassing 8299 participants. Metabolite analysis identified 1091 plasma metabolites and 309 ratios as instrumental variables. To evaluate the causal link between metabolites and CAD, we analyzed three datasets: ebi-a-GCST005195 (547,261 European & East Asian samples), bbj-a-159 (29,319 East Asian CAD cases & 183,134 East Asian controls), and ebi-a-GCST005194 (296,525 European & East Asian samples). To estimate causal links, we utilized the IVW method. To conduct sensitivity analysis, we used MR-Egger, Weighted Median, and MR-PRESSO. Additionally, we employed MR-Egger interception and Cochran's Q statistic to assess potential heterogeneity and pleiotropy. What's more, replication and reverse analyses were performed to verify the reliability of the results and the causal order between metabolites and disease. Furthermore, we conducted a pathway analysis to identify potential metabolic pathways. 59 blood metabolites and 27 metabolite ratios nominally associated with CAD (P < 0.05) were identified by IVW analysis method. A total of four known blood metabolites, namely beta-hydroxyisovaleroylcarnitine (OR 1.06, 95% CI 1.027-1.094, FDR 0.07), 1-palmitoyl-2-arachidonoyl (OR 1.07, 95% CI 1.029-1.110, FDR 0.09), 1-stearoyl-2- docosahexaenoyl (OR 1.07, 95% CI 1.034-1.113, FDR 0.07) and Linoleoyl-arachidonoyl-glycerol, (OR 1.07, 95% CI 1.036-1.105, FDR 0.05), and two metabolite ratios, namely spermidine to N-acetylputrescine ratio (OR 0.94, 95% CI 0.903-0.972, FDR 0.09) and benzoate to linoleoyl-arachidonoyl-glycerol ratio (OR 0.87, 95% CI 0.879-0.962, FDR 0.07), were confirmed as having a significant causal relationship with CAD, after correcting for the FDR method (p < 0. 1). A causal relationship was found to be established between beta -hydroxyisovalerylcarnitine and CAD with the validation in other two datasets. Moreover, multiple metabolic pathways were discovered to be associated with CAD. Our study supports the hypothesis that metabolites have an impact on CAD by demonstrating a causal relationship between human metabolites and CAD. This study is important for new strategies for the prevention and treatment of CAD.

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Background: Aging is characterized by a decline in the adaptability and resistance of the body. In this study, Bushen Kangshuai Granules (BKG), as a kind of Chinese herbal formula, was developed and shown to alleviate aging-related symptoms. Methods: Self-controlled study combined with RNA-seq and metabonomics were used to expound the efficacy and safety of BKG and revealed the regulation mechanism of BKG treating aging. In vitro experiments were used to confirm the analytical results. The aging cell model of AC16 cells were treated with D-galactose. The RT-qPCR was used to detect the impact of BKG on telomere length. The DCFH-DA staining was used for detecting intracellular ROS. The targeted signaling pathway was selected and verified using Western blot. Results: After 8 weeks of treatment, BKG significantly reduced SOD level (p = 0.046), TCM aging symptoms (p < 0.001) and TNF-α level (p = 0.044) in the elderly participants. High-throughput sequencing showed that BKG reversed the expression of 70 and 79 age-related genes and metabolites, respectively. Further enrichment analysis indicated that BKG downregulated the PI3K-AKT signaling pathway, extracellular matrix (ECM)-receptor interaction, and Rap1 signaling pathway, while up-regulating sphingolipid metabolism. The results of in vitro experiments show that, after D-gal treatment, the viability and telomere length of AC16 cells significantly decreased (p < 0.05), while the expression of ROS increased (p < 0.05), BKG significantly increased the telomere length of AC16 cells and reduced the level of ROS expression (p < 0.05). In addition, BKG decreased the expression of THBS1, PDGFRA, and EPS8L1(p < 0.05), consistent with the RNA-seq results. Our results also showed that BKG affects PI3K-AKT signaling pathway. Conclusion: BKG can significantly improve aging-related symptoms and increase SOD levels, which may be associated with the reversal of the expression of various aging-related genes. The PI3K-AKT signaling pathway and sphingolipid metabolism may be potential mechanisms underlying BKG anti-aging effects.

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OBJECTIVE: The current study aimed to investigate the baseline immune and inflammatory features and in-hospital outcomes of patients infected with the Omicron variant (PIWO) who presented with different disease severities during the first wave of mass Omicron infections in the Chinese population has occurred. METHOD: A cross-sectional study was conducted on 140 hospitalized PIWO between December 11, 2022, and February 16, 2023. The clinical features, antibodies against SARS-CoV-2, immune cells, and inflammatory cytokines among mildly, severely, and critically ill PIWO at baseline and during follow-up period were compared. RESULT: Patients with severe (n = 49) and critical (n = 35) disease were primarily male, needed invasive mechanical ventilation treatment, and exhibited higher mortality than those with mild disease (n = 56). During acute infection, SARS-CoV-2-specific antibody levels fluctuated with disease severity, serum antibodies increased and the incidence of severe cases decreased in critically ill PIWO over time. Antibody titers in severe or critical PIWO with no antibody responses at baseline did not increase significantly over time. Meanwhile, CD4+T cell, CD8+T cell, and natural killer cell counts were negatively correlated with disease severity, whereas interleukin (IL)-6 and IL-10 levels were positively correlated. In addition, combined diabetes, immunosuppressive therapy before infection, serum amyloid A, IL-10 and neutrophil counts were independently associated with severe and critical illness in PIWO. Among the 11 nonsurvivors, 8, 2, 1 died of respiratory failure, sudden cardiac death, and renal failure, respectively. Compared with survivors, nonsurvivors exhibited lower seropositivity of SARS-CoV-2-specific antibody, reduced CD3+T and CD4+T cell counts, and higher IL-2R, IL-6, IL-8, and IL-10 levels. Of note, lactate dehydrogenase was a significant risk factor of death in severe or critically ill PIWO. CONCLUSION: This present study assessed the dynamic changes of SARS-CoV-2-specific antibodies, immune cells and inflammatory indexes between severely and critically ill PIWO. Critical and dead PIWO featured compromised humoral immune response and excessive inflammation, which broadened the understanding of the pathophysiology of Omicron infection and provides warning markers for severe disease and poor prognosis.

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BACKGROUND: Patients with stroke frequently experience pulmonary dysfunction. AIM: To explore the effects of information-motivation-behavioral (IMB) skills model-based nursing care on pulmonary function, blood gas indices, complication rates, and quality of life (QoL) in stroke patients with pulmonary dysfunction. METHODS: We conducted a controlled study involving 120 stroke patients with pulmonary dysfunction. The control group received routine care, whereas the intervention group received IMB-model-based nursing care. Various parameters including pulmonary function, blood gas indices, complication rates, and QoL were assessed before and after the intervention. RESULTS: Baseline data of the control and intervention groups were comparable. Post-intervention, the IMB model-based care group showed significant improvements in pulmonary function indicators, forced expiratory volume in 1 sec, forced vital capacity, and peak expiratory flow compared with the control group. Blood gas indices, such as arterial oxygen pressure and arterial oxygen saturation, increased significantly, and arterial carbon dioxide partial. pressure decreased significantly in the IMB model-based care group compared with the control group. The intervention group also had a lower complication rate (6.67% vs 23.33%) and higher QoL scores across all domains than the control group. CONCLUSION: IMB model-based nursing care significantly enhanced pulmonary function, improved blood gas indices, reduced complication rates, and improved the QoL of stroke patients with pulmonary dysfunction. Further research is needed to validate these results and to assess the long-term efficacy and broader applicability of the model.

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Chronic kidney disease (CKD) impacts about 1 in 7 adults in the United States, but African Americans (AAs) carry a disproportionately higher burden of disease. Epigenetic modifications, such as DNA methylation at cytosine-phosphate-guanine (CpG) sites, have been linked to kidney function and may have clinical utility in predicting the risk of CKD. Given the dynamic relationship between the epigenome, environment, and disease, AAs may be especially sensitive to environment-driven methylation alterations. Moreover, risk models incorporating CpG methylation have been shown to predict disease across multiple racial groups. In this study, we developed a methylation risk score (MRS) for CKD in cohorts of AAs. We selected nine CpG sites that were previously reported to be associated with estimated glomerular filtration rate (eGFR) in epigenome-wide association studies to construct a MRS in the Hypertension Genetic Epidemiology Network (HyperGEN). In logistic mixed models, the MRS was significantly associated with prevalent CKD and was robust to multiple sensitivity analyses, including CKD risk factors. There was modest replication in validation cohorts. In summary, we demonstrated that an eGFR-based CpG score is an independent predictor of prevalent CKD, suggesting that MRS should be further investigated for clinical utility in evaluating CKD risk and progression.

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Purpose: This study investigated potential predictive models associated with natural killer (NK) cell mitochondrial membrane potential (MMP or ΔΨm) in predicting death among critically ill patients with COVID-19. Patients and Methods: We included 97 patients with COVID-19 of different severities attending Peking Union Medical College Hospital from December 2022 to January 2023. Patients were divided into three groups according to oxygen and mechanical ventilation use during specimen collection and were followed for survival and death at 3 months. The lymphocyte subpopulation MMP was detected via flow cytometry. We constructed a joint diagnostic model by integrating identified key indicators and generating receiver operating curves (ROCs) and evaluated its predictive performance for mortality risk in critically ill patients. Results: The NK-cell MMP median fluorescence intensity (MFI) was significantly lower in critically ill patients who died from COVID-19 (p<0.0001) and significantly and positively correlated with D-dimer content in critically ill patients (r=0.56, p=0.0023). The random forest model suggested that fibrinogen levels and NK-cell MMP MFI were the most important indicators. Integrating the above predictive models for the ROC yielded an area under the curve of 0.94. Conclusion: This study revealed the potential of combining NK-cell MMP with key clinical indicators (D-dimer and fibrinogen levels) to predict death among critically ill patients with COVID-19, which may help in early risk stratification of critically ill patients and improve patient care and clinical outcomes.

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BACKGROUND: Immune checkpoint inhibitors (ICIs) provide modest but unsatisfactory benefits for extensive-stage small cell lung cancer (ES-SCLC). Developing strategies for treating ES-SCLC is critical. METHODS: We preliminarily explored the outcomes of salvage low-dose radiotherapy (LDRT) plus ICI on refractory SCLC patients. Next, we evaluated the combinational efficacy in murine SCLC. The tumor immune microenvironment (TIME) was analyzed for mechanistic study. Subsequently, we conducted a multicenter, prospective phase II trial that administered concurrent thoracic LDRT plus chemoimmunotherapy to treatment-naive ES-SCLC patients (MATCH trial, NCT04622228). The primary endpoint was confirmed objective response rate (ORR), and the key secondary endpoints included progression-free survival (PFS) and safety. FINDINGS: Fifteen refractory SCLC patients treated with LDRT plus ICI were retrospectively reviewed. The ORR was 73.3% (95% confidence interval [CI], 44.9-92.2). We identified a specific dose of LDRT (15 Gy/5 fractions) that exhibited growth retardation and improved survival in murine SCLC when combined with ICIs. This combination recruited a special T cell population, TCF1+ PD-1+ CD8+ stem-like T cells, from tumor-draining lymph nodes into the TIME. The MATCH trial showed a confirmed ORR of 87.5% (95% CI, 75.9-94.8). The median PFS was 6.9 months (95% CI, 5.4-9.3). CONCLUSIONS: These findings verified that LDRT plus chemoimmunotherapy was safe, feasible, and effective for ES-SCLC, warranting further investigation. FUNDING: This research was funded by West China Hospital (no. ZYJC21003), the National Natural Science Foundation of China (no. 82073336), and the MATCH trial was fully funded by Roche (China) Holding Ltd. (RCHL) and Shanghai Roche Pharmaceuticals Ltd. (SRPL).

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Objectives: To explore the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) on lung adenosquamous cell carcinoma (ASC) with EGFR mutation. Methods: Efficacy of EGFR-TKIs in the treatment of advanced or recurrent lung ASC with EGFR mutations was assessed retrospectively in 44 patients. Pooled analysis of 74 patients using EGFR-TKIs, including 30 patients selected from 11 publications, was conducted. Results: In our retrospective research, patients treated with EGFR-TKI in ASC with EGFR mutations had objective response rate (ORR) of 54.5%, disease control rate (DCR) of 79.5%, median progression free survival (mPFS) of 8.8 months, and median overall survival (mOS) of 19.43 months, respectively. A pooled analysis reveals ORR, DCR, mPFS, and mOS are, respectively, 63.4%, 85.9%, 10.00 months, and 21.37 months for ASC patients. In patients with deletions in exon 19 and exon 21 L858R mutations, mPFS (11.0 versus 10.0 months, P=0.771) and mOS (23.67 versus 20.33 months, P=0.973) were similar. Erlotinib or gefitinib-treated patients had an overall survival trend that was superior to that of icotinib-treated patients. Conclusions: ASC harboring EGFR mutations can be treated with EGFR-TKI in a similar manner to Adenocarcinoma (ADC) harboring EGFR mutations. There is still a need for further investigation to identify the separate roles of ASC's two components in treating EGFR.

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INTRODUCTION: Cigarette smoking leads to altered DNA methylation at the aryl-hydrocarbon receptor repressor (AHRR) gene. However, it remains unknown whether pipe or cigar smoking is associated with AHRR methylation. We evaluated associations of non-cigarette tobacco use with AHRR methylation and determined if AHRR methylation was associated with smoking-related health outcomes. METHODS: Data were pooled across four population-based cohorts that enrolled participants from 1985 to 2002. Tobacco exposures were evaluated using smoking questionnaires. AHRR cg05575921 methylation was measured in peripheral blood leucocyte DNA. Spirometry and respiratory symptoms were evaluated at the time of methylation measurements and in subsequent visits. Vital status was monitored using the National Death Index. RESULTS: Among 8252 adults (mean age 56.7±10.3 years, 58.1% women, 40.6% black), 4857 (58.9%) participants used cigarettes and 634 (7.7%) used non-cigarette tobacco products. Exclusive use of non-cigarette tobacco products was independently associated with lower AHRR methylation (-2.44 units, 95% CI -4.42 to -0.45), though to a lesser extent than exclusive use of cigarettes (-6.01 units, 95% CI -6.01 to -4.10). Among participants who exclusively used non-cigarette tobacco products, reduced AHRR methylation was associated with increased respiratory symptom burden (OR 1.60, 95% CI 1.03 to 2.68) and higher all-cause mortality (log-rank p=0.02). CONCLUSION: Pipe and cigar smoking were independently associated with lower AHRR methylation in a multiethnic cohort of US adults. Among users of non-cigarette tobacco products, lower AHRR methylation was associated with poor respiratory health outcomes and increased mortality. AHRR methylation may identify non-cigarette tobacco users with an increased risk of adverse smoking-related health outcomes.

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We present an innovative process for directly transforming poly(ethylene terephthalate) (PET), a polymer extensively used in food and beverage packaging, into trans-isomer-enriched 1,4-cyclohexanedimethanol (CHDM), a key ingredient in advanced specialty polymers. Our approach leverages a dual-catalyst system featuring palladium on reduced graphene oxide (Pd/r-GO) and oxalate-gel-derived copper-zinc oxide (og-CuZn), utilizing hydrogenation/hydrogenolysis relay catalysis. This method efficiently transforms PET into polyethylene-1,4-cyclohexanedicarboxylate (PECHD), which is then converted into CHDM with an impressive overall yield of 95 % in a two-stage process. Our process effectively handles various post-consumer PET plastics, converting them into CHDM with yields between 78 % and 89 % across different substrates. Additionally, we demonstrate the applicability and scalability of this approach through a temperature-programmed three-stage relay process on a 10-gram scale, which results in purified CHDM with an isolated yield of 87 % and a notably higher trans/cis ratio of up to 4.09/1, far exceeding that of commercially available CHDM. This research not only provides a viable route for repurposing PET waste but also enhances the control of selectivity patterns in multistage relay catalysis.

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Here we present a hybrid catalytic pathway for efficient synthesis of 5-aminomethyl-2-furancarboxylic acid (AMFC), a bio-based nylon-6 analogue monomer, from 5-hydroxymethylfurfural (HMF). This method combines homogeneous-catalyzed selective oxidation of HMF to 5-formyl-2-furancarboxylic acid (FFCA) with heterogeneous-catalyzed reductive amination using ammonia as the nitrogen source. Through this relay strategy, we achieve significant enhancements in overall efficiency, resulting in isolation yields of up to 92% for highly selective and scalable AMFC production from HMF.

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Background: Coronary heart disease (CHD) is representative of cardiovascular disease and the leading cause of death in humans. Previous studies have shown that kidney disease is associated with CHD, and current treatment options that can improve both cardiac and renal functions still have some limitations. The traditional Chinese medicine Bu-Shen-Huo-Xue granule (BSHXG) can promote blood rheology, inhibit platelet agglutination, and improve heart and kidney functions. Methods: This is a multicenter, randomized, double-blind, placebo-controlled clinical trial. A total of 210 participants will be randomized to the intervention group and the placebo group. The Guang'anmen Hospital of China Academy of Chinese Medical Sciences is the leading center, and the Affiliated Hospital of Shandong University of Chinese Medicine and the First Affiliated Hospital of Guangzhou University of Chinese Medicine are the participating units. In addition to conventional pharmacotherapy for angina, the intervention group will receive BSHXG while the placebo group will receive BSHXG placebo. All participants will receive 2 months of treatment with 6 months of follow-up. The primary outcome is the efficacy of angina pectoris symptoms in CHD. Secondary outcomes are nitroglycerin arrest, ECG efficacy, Seattle Angina Questionnaire score, serology indicators, assessment of safety, and cardiovascular endpoint events. The transcriptome and metabolome will be used to screen biomarkers for diagnosis and efficacy evaluation. Discussion: This study aimed to evaluate the efficacy and safety of Bu-Shen-Huo-Xue granule in the treatment of coronary heart disease, and to evaluate the benefits to patients with coronary heart disease from both cardiac and renal indicators. Trial registration: This trial is approved by the Ethical Review Committee of the Guang'anmen Hospital China Academy of Chinese Medical Sciences with the number 2022-224-KY-01, and has been registered on the Chinese Clinical Trials Registry with the number ChiCTR2300070977 on 27 April 2023.

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Objective: The goal of the research is to investigate the link between serum potassium levels and death after 28 days in sepsis patients, utilizing an extensive sample of patients from the multi-center Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Current research on serum potassium levels and 28-day mortality in sepsis patients is questionable. This study adds to the growing body of evidence linking serum potassium levels to the 28-day possibility of death in patients with sepsis. Methods: We collected 349,08 patients with sepsis from the retrospective cohort MIMIC-IV database, using serum potassium level on the first day of admission to the intensive care unit as the exposure variable and mortality at 28 days as the outcome variable. And controlled for confounding characteristics including gender, age, ethnicity, and vital signs during admission. Results: Serum potassium has a U-shaped connection with 28-day mortality in patients suffering from sepsis. The turning point was 4.10 mmol/L (95 % confidence interval: 4.03 to 4.22). Serum potassium and 28-day mortality were negatively linked on the inflection point's left side (OR: 0.72; 95 % CI: 0.63 to 0.83, P < 0.0001); on the opposing side of the point of inflexion, serum potassium was enthusiastically attached to 28-day mortality. (OR: 1.13; 95 % CI: 1.06 to 1.21, P < 0.0001). Conclusion: The research conducted found that too high or too low potassium levels were linked to a 28-day risk of mortality in humans with sepsis.

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BACKGROUNDPreclinical studies suggest that cholesterol accumulation leads to insulin resistance. We previously reported that alterations in a monocyte cholesterol metabolism transcriptional network (CMTN) - suggestive of cellular cholesterol accumulation - were cross-sectionally associated with obesity and type 2 diabetes (T2D). Here, we sought to determine whether the CMTN alterations independently predict incident prediabetes/T2D risk, and correlate with cellular cholesterol accumulation.METHODSMonocyte mRNA expression of 11 CMTN genes was quantified among 934 Multi-Ethnic Study of Atherosclerosis (MESA) participants free of prediabetes/T2D; cellular cholesterol was measured in a subset of 24 monocyte samples.RESULTSDuring a median 6-year follow-up, lower expression of 3 highly correlated LXR target genes - ABCG1 and ABCA1 (cholesterol efflux) and MYLIP (cholesterol uptake suppression) - and not other CMTN genes, was significantly associated with higher risk of incident prediabetes/T2D. Lower expression of the LXR target genes correlated with higher cellular cholesterol levels (e.g., 47% of variance in cellular total cholesterol explained by ABCG1 expression). Further, adding the LXR target genes to overweight/obesity and other known predictors significantly improved prediction of incident prediabetes/T2D.CONCLUSIONThese data suggest that the aberrant LXR/ABCG1-ABCA1-MYLIP pathway (LAAMP) is a major T2D risk factor and support a potential role for aberrant LAAMP and cellular cholesterol accumulation in diabetogenesis.FUNDINGThe MESA Epigenomics and Transcriptomics Studies were funded by NIH grants 1R01HL101250, 1RF1AG054474, R01HL126477, R01DK101921, and R01HL135009. This work was supported by funding from NIDDK R01DK103531 and NHLBI R01HL119962.

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Mosaic loss of Y (mLOY) is the most common somatic chromosomal alteration detected in human blood. The presence of mLOY is associated with altered blood cell counts and increased risk of Alzheimer's disease, solid tumors, and other age-related diseases. We sought to gain a better understanding of genetic drivers and associated phenotypes of mLOY through analyses of whole genome sequencing of a large set of genetically diverse males from the Trans-Omics for Precision Medicine (TOPMed) program. This approach enabled us to identify differences in mLOY frequencies across populations defined by genetic similarity, revealing a higher frequency of mLOY in the European American (EA) ancestry group compared to those of Hispanic American (HA), African American (AA), and East Asian (EAS) ancestry. Further, we identified two genes ( CFHR1 and LRP6 ) that harbor multiple rare, putatively deleterious variants associated with mLOY susceptibility, show that subsets of human hematopoietic stem cells are enriched for activity of mLOY susceptibility variants, and that certain alleles on chromosome Y are more likely to be lost than others.

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Systemic low-grade inflammation is a feature of chronic disease. C-reactive protein (CRP) is a common biomarker of inflammation and used as an indicator of disease risk; however, the role of inflammation in disease is not completely understood. Methylation is an epigenetic modification in the DNA which plays a pivotal role in gene expression. In this study we evaluated differential DNA methylation patterns associated with blood CRP level to elucidate biological pathways and genetic regulatory mechanisms to improve the understanding of chronic inflammation. The racially and ethnically diverse participants in this study were included as 50% White, 41% Black or African American, 7% Hispanic or Latino/a, and 2% Native Hawaiian, Asian American, American Indian, or Alaska Native (total n = 13,433) individuals. We replicated 113 CpG sites from 87 unique loci, of which five were novel (CADM3, NALCN, NLRC5, ZNF792, and cg03282312), across a discovery set of 1,150 CpG sites associated with CRP level (p < 1.2E-7). The downstream pathways affected by DNA methylation included the identification of IFI16 and IRF7 CpG-gene transcript pairs which contributed to the innate immune response gene enrichment pathway along with NLRC5, NOD2, and AIM2. Gene enrichment analysis also identified the nuclear factor-kappaB transcription pathway. Using two-sample Mendelian randomization (MR) we inferred methylation at three CpG sites as causal for CRP levels using both White and Black or African American MR instrument variables. Overall, we identified novel CpG sites and gene transcripts that could be valuable in understanding the specific cellular processes and pathogenic mechanisms involved in inflammation.

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OBJECTIVES: Demyelination and immunocyte-infiltrated lesions have been found in neuro-Behçet's disease (NBD) pathology. Lacking satisfying laboratory biomarkers in NBD impedes standard clinical diagnostics. We aim to explore the ancillary indicators for NBD diagnosis unveiling its potential etiology. METHODS: 28 NBD with defined diagnosis, 29 patients with neuropsychiatric lupus erythematosus, 30 central nervous system idiopathic inflammatory demyelination diseases (CNS-IIDD), 30 CNS infections, 30 cerebrovascular diseases, and 30 noninflammatory neurological diseases (NIND) were retrospectively enrolled. Immunoglobulins (Ig) in serum and cerebral spinal fluid (CSF) were detected by immunonephelometry and myelin basic protein (MBP) by quantitative enzyme-linked immunosorbent assay. RESULTS: IgA index is almost twice enhanced in NBD than NIND with an accuracy of 0.8488 in differential diagnosis, the sensitivity and specificity of which were 75.00 % and 90.00 % when the cutoff was > 0.6814. The accuracy of CSF Ig and quotient of Ig all exceed 0.90 in discerning NBD with damaged and intact blood-brain barrier (BBB). Clustering analyses divided NBD into two different phenotypes: one with BBB damage has lower Ig synthesis, the other with extra-synthesis in parenchymal sites but with intact BBB. MBP index is significantly correlated with kappa (KAP) index and lambda (LAM) index (r = 0.358, 0.575, P < 0.001), hinting the NBD pathogenesis of CNS demyelination in triggering excessive intrathecal Ig productions and humoral responses. CONCLUSIONS: IgA index acts as a potential diagnostic indicator in differentiating NBD from NIND and CNS-IIDD. Excessive immunoglobulin production induced by CNS inflammation and demyelination might be latent immunopathogenesis of NBD.

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