Association of hospital-treated infectious diseases and infection burden with cardiovascular diseases and life expectancy.

BACKGROUND: The association of a broad spectrum of infectious diseases with cardiovascular outcomes remains unclear. OBJECTIVES: We aim to provide the cardiovascular risk profiles associated with a wide range of infectious diseases and explore the extent to which infections reduce life expectancy. METHODS: We ascertained exposure to 900+ infectious diseases before cardiovascular disease (CVD) onset in 453,102 participants from the UK Biobank study. Time-varying Cox proportional hazard models were used. Life table was used to estimate the life expectancy of individuals aged ≥50 with different levels of infection burden (defined as the number of infection episodes over time and the number of co-occurring infections). RESULTS: Infectious diseases were associated with a greater risk of CVD events (adjusted HR [aHR] 1.79 [95% confidence interval {CI} 1.74-1.83]). For type-specific analysis, bacterial infection with sepsis had the strongest risk of CVD events [aHR 4.76 (4.35-5.20)]. For site-specific analysis, heart and circulation infections posed the greatest risk of CVD events [aHR 4.95 (95% CI 3.77-6.50)], whereas noncardiac infections also showed excess risk [1.77 (1.72-1.81)]. Synergistic interactions were observed between infections and genetic risk score. A dose-response relationship was found between infection burden and CVD risks (p-trend <0.001). Infection burden >1 led to a CVD-related life loss at age 50 by 9.3 years [95% CI 8.6-10.3]) for men and 6.6 years [5.5-7.8] for women. CONCLUSIONS: The magnitude of the infection-CVD association showed specificity in sex, pathogen type, infection burden, and infection site. High genetic risk and infection synergistically increased the CVD risk.

Hospital-treated infectious diseases, infection burden and risk of Parkinson disease: An observational and Mendelian randomization study.

BACKGROUND: Experimental and cross-sectional evidence has suggested a potential role of infection in the ethology of Parkinson's disease (PD). We aim to examine the longitudinal association of infections with the incidence of PD and to explore whether the increased risk is limited to specific infection type rather than infection burden. METHODS: Based on the UK Biobank, hospital-treated infectious diseases and incident PD were ascertained through record linkage to national hospital inpatient registers. Infection burden was defined as the sum of the number of infection episodes over time and the number of co-occurring infections. The polygenic risk score (PRS) for PD was calculated. The genome-wide association studies (GWAS) used in two-sample Mendelian Randomization (MR) were obtained from observational cohort participants of mostly European ancestry. RESULTS: Hospital-treated infectious diseases were associated with an increased risk of PD (adjusted HR [aHR] 1.35 [95 % CI 1.20-1.52]). This relationship persisted when analyzing new PD cases occurring more than 10 years post-infection (aHR 1.22 [95 % CI 1.04-1.43]). The greatest PD risk was observed in neurological/eye infection (aHR 1.72 [95 % CI 1.32-2.34]), with lower respiratory tract infection (aHR 1.43 [95 % CI 1.02-1.99]) ranked the second. A dose-response association was observed between infection burden and PD risk within each PD-PRS tertile (p-trend < 0.001). Multivariable MR showed that bacterial and viral infections increase the PD risk. CONCLUSIONS: Both observational and genetic analysis suggested a causal association between infections and the risk of developing PD. A dose-response relationship between infection burden and incident PD was revealed.

Association of regular glucosamine use with incident dementia: evidence from a longitudinal cohort and Mendelian randomization study.

BACKGROUND: Emerging data suggests the neuroprotective and anti-neuroinflammatory effects of glucosamine. We aimed to examine the association between regular glucosamine use and risk of incident dementia, including dementia subtypes. METHODS: We conducted large-scale observational and two-sample Mendelian randomization (MR) analyses. Participants in UK Biobank having accessible data for dementia incidence and who did not have dementia at baseline were included in the prospective cohort. Through the Cox proportional hazard model, we examined the risks of incident all-cause dementia, Alzheimer's disease (AD), and vascular dementia among glucosamine users and non-users. To further test the causal association between glucosamine use and dementia, we conducted a 2-sample MR utilizing summary statistics from genome-wide association studies (GWAS). The GWAS data were obtained from observational cohort participants of mostly European ancestry. RESULTS: During a median follow-up of 8.9 years, there were 2458 cases of all-cause dementia, 924 cases of AD, and 491 cases of vascular dementia. In multivariable analysis, the hazard ratios (HR) of glucosamine users for all-cause dementia, AD, and vascular dementia were 0.84 (95% CI 0.75-0.93), 0.83 (95% CI 0.71-0.98), and 0.74 (95% CI 0.58-0.95), respectively. The inverse associations between glucosamine use and AD appeared to be stronger among participants aged below 60 years than those aged above 60 years (p = 0.04 for interaction). The APOE genotype did not modify this association (p > 0.05 for interaction). Single-variable MR suggested a causal relationship between glucosamine use and lower dementia risk. Multivariable MR showed that taking glucosamine continued to protect against dementia after controlling for vitamin, chondroitin supplement use and osteoarthritis (all-cause dementia HR 0.88, 95% CI 0.81-0.95; AD HR 0.78, 95% CI 0.72-0.85; vascular dementia HR 0.73, 95% CI 0.57-0.94). Single and multivariable inverse variance weighted (MV-IVW) and MR-Egger sensitivity analyses produced similar results for these estimations. CONCLUSIONS: The findings of this large-scale cohort and MR analysis provide evidence for potential causal associations between the glucosamine use and lower risk for dementia. These findings require further validation through randomized controlled trials.

Intestinal Microbiotas and Alcoholic Hepatitis: Pathogenesis and Therapeutic Value.

Alcoholic hepatitis (AH) is a rapidly progressing and severe stage of alcoholic liver disease, presenting a grim prognosis. Extensive research has elucidated several underlying mechanisms that contribute to the development of AH, including metabolic alterations, immune stimulation, and intestinal dysbiosis. These pathological changes intricately intertwine during the progression of AH. Notably, recent studies have increasingly highlighted the pivotal role of alterations in the intestinal microbiota in the pathogenesis of AH. Consequently, future investigations should place significant emphasis on exploring the dynamics of intestinal microbiota. In this comprehensive review, we consolidate the primary causes of AH while underscoring the influence of gut microbes. Furthermore, by examining AH treatment strategies, we delineate the potential therapeutic value of interventions targeting the gut microbiota. Given the existing limitations in AH treatment options, we anticipate that this review will contribute to forthcoming research endeavors aimed at advancing AH treatment modalities.

Effects of different levels of non-pharmaceutical interventions on hand, foot and mouth disease in Guangzhou, China.

BACKGROUND: Non-pharmaceutical interventions (NPIs) against coronavirus disease 2019 (COVID-19) may have suppressed the transmission of other infectious diseases. This study aimed to evaluate the impact of different degrees of NPIs during the COVID-19 pandemic on hand, foot and mouth disease (HFMD) in Guangzhou, China. METHODS: Weekly reported HFMD cases and pathogens information during 2015-2021 in Guangzhou were collected from the China National Notifiable Disease Reporting System. The observed number of HFMD cases in 2020 and 2021 was compared to the average level in the same period during 2015-2019. Then, an interrupted time-series segmented regression analysis was applied to estimate the impact of NPIs on HFMD, such as social distancing, suspension of schools, community management and mask wearing. The effects across different subgroups stratified by gender, children groups and enterovirus subtype of HFMD were also examined. RESULTS: A total of 13,224 and 36,353 HFMD cases were reported in 2020 and 2021, which decreased by 80.80% and 15.06% respectively compared with the average number of cases in the same period during 2015-2019. A significant drop in the number of HFMD cases during time when strict NPIs were applied (relative change: 69.07% [95% confidence interval (CI): 68.84%-69.30%]). The HFMD incidence rebounded to historical levels in 2021 as the lockdown eased. The slightest reduction of HFMD cases was found among children at kindergartens or childcare centres among the three children groups (children at kindergartens or childcare centres: 55.50% [95% CI: 54.96%-56.03%]; children living at home: 72.64% [95% CI: 72.38%-72.89%]; others: 74.06% [95% CI: 73.19%-74.91%]). CONCLUSIONS: The strong NPIs during the COVID-19 epidemic may have a significant beneficial effect on mitigating HFMD. However, the incidence of HFMD rebounded as the NPIs became less stringent. Authorities should consider applying these NPIs during HFMD outbreaks and strengthening personal hygiene in routine prevention.

Diabetes duration and glycaemic control as predictors of cardiovascular disease and mortality.

AIMS: To assess the associations of diabetes duration and glycaemic control (defined by plasma glycated haemoglobin [HbA1c] level) with the risks of cardiovascular disease (CVD) and all-cause mortality and to determine whether the addition of either or both to the established CVD risk factors can improve predictions. MATERIALS AND METHODS: A total of 435 679 participants from the UK Biobank without CVD at baseline were included. Cox models adjusting for classic risk factors (sociodemographic and anthropometric characteristics, lipid profiles and medication use) were used, and predictive utility was determined by the C-index and net reclassification improvement (NRI). RESULTS: Compared with participants without diabetes, participants with longer diabetes durations and poorer glycaemic control had a higher risk of fatal/nonfatal CVD. Among participants with diabetes, the fully-adjusted hazard ratios (HRs) for diabetes durations of 5 to <10 years, 10 to <15 years and ≥15 years were 1.15 (95% confidence interval [CI] 0.99, 1.34), 1.50 (95% CI 1.26, 1.79) and 2.22 (95% CI 1.90, 2.58; P-trend <0.01), respectively, compared with participants with diabetes durations <5 years. In addition, those with the longest disease duration (≥15 years) and poorer glycaemic control (HbA1c ≥64 mmol/mol [8%]) had the highest risk of fatal/nonfatal CVD (HR 3.12, 95% CI 2.52, 3.86). Among participants with diabetes, the addition of both diabetes duration and glycaemic control levels significantly improved both the C-index (change in C-index +0.0254; 95% CI 0.0111, 0.0398) and the overall NRI for fatal/nonfatal CVD (0.0992; 95% CI 0.0085, 0.1755) beyond the use of the classic risk factors. CONCLUSIONS: Both longer diabetes duration and poorer glycaemic control were associated with elevated risks of CVD and mortality. Clinicians should consider not only glycaemic control but also diabetes duration in CVD risk assessments for participants with diabetes.

Contact Settings and Risk for Transmission in 3410 Close Contacts of Patients With COVID-19 in Guangzhou, China : A Prospective Cohort Study.

BACKGROUND: Risk for transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to close contacts of infected persons has not been well estimated. OBJECTIVE: To evaluate the risk for transmission of SARS-CoV-2 to close contacts in different settings. DESIGN: Prospective cohort study. SETTING: Close contacts of persons infected with SARS-CoV-2 in Guangzhou, China. PARTICIPANTS: 3410 close contacts of 391 index cases were traced between 13 January and 6 March 2020. Data on the setting of the exposure, reverse transcriptase polymerase chain reaction testing, and clinical characteristics of index and secondary cases were collected. MEASUREMENT: Coronavirus disease 2019 (COVID-19) cases were confirmed by guidelines issued by China. Secondary attack rates in different settings were calculated. RESULTS: Among 3410 close contacts, 127 (3.7% [95% CI, 3.1% to 4.4%]) were secondarily infected. Of these 127 persons, 8 (6.3% [CI, 2.1% to 10.5%]) were asymptomatic. Of the 119 symptomatic cases, 20 (16.8%) were defined as mild, 87 (73.1%) as moderate, and 12 (10.1%) as severe or critical. Compared with the household setting (10.3%), the secondary attack rate was lower for exposures in health care settings (1.0%; odds ratio [OR], 0.09 [CI, 0.04 to 0.20]) and on public transportation (0.1%; OR, 0.01 [CI, 0.00 to 0.08]). The secondary attack rate increased with the severity of index cases, from 0.3% (CI, 0.0% to 1.0%) for asymptomatic to 3.3% (CI, 1.8% to 4.8%) for mild, 5.6% (CI, 4.4% to 6.8%) for moderate, and 6.2% (CI, 3.2% to 9.1%) for severe or critical cases. Index cases with expectoration were associated with higher risk for secondary infection (13.6% vs. 3.0% for index cases without expectoration; OR, 4.81 [CI, 3.35 to 6.93]). LIMITATION: There was potential recall bias regarding symptom onset among patients with COVID-19, and the symptoms and severity of index cases were not assessed at the time of exposure to contacts. CONCLUSION: Household contact was the main setting for transmission of SARS-CoV-2, and the risk for transmission of SARS-CoV-2 among close contacts increased with the severity of index cases. PRIMARY FUNDING SOURCE: Guangdong Province Higher Vocational Colleges and Schools Pearl River Scholar Funded Scheme.

Enhancement of neomycin production by engineering the entire biosynthetic gene cluster and feeding key precursors in Streptomyces fradiae CGMCC 4.576.

Neomycin, an aminoglycoside antibiotic, is widely used in the livestock husbandry due to its higher antimicrobial activity and availability of feed additives in animals. However, its production yield is relatively low and cannot meet the needs of developing market and clinical application. Here, the entire natural neo cluster was cloned from Streptomyces fradiae CGMCC 4.576 by φBT1 integrase-mediated site-specific recombination. Then, the rational reconstruction of the neo cluster was performed by using λ-Red-mediated PCR targeting for improving neomycin production. In order to coordinate with this attempt, the supplementation of suitable precursors was carried out. The constructed recombinant strain Sf/pKCZ03 has multi-copy of the neo cluster modified by disrupting the negative regulatory gene neoI and replacing the native promoter of the neoE-D with PkasO*. Compared to the yield (1282 mg/L) of Streptomyces fradiae CGMCC 4.576, the engineered strain Sf/pKCZ03 had a 36% enhancement of neomycin production. Quantitative real-time PCR analysis revealed the increased transcription of structural genes (neoE, neoB, neoL, aacC8) and regulatory genes (neoR, neoH) in Sf/pKCZ03. Additionally, under the supplementation of 1 g/L N-acetyl-D-glucosamine and 5 g/L L-glutamine, the yield of engineered strain Sf/pKCZ03 showed 62% and 107% improvements compared to that of the wild-type strain in the original medium, respectively. These findings demonstrated that engineering the antibiotic gene cluster in combination with precursors feeding was an effective approach for strain improvement, and would be potentially extended to other Streptomyces for large-scale production of commercialized antibiotics.

Hospital-treated infectious diseases, genetic susceptibility and risk of type 2 diabetes: A population-based longitudinal study.

BACKGROUND: The longitudinal association between infectious diseases and the risk of type 2 diabetes (T2D) remains unclear. METHODS: Based on the UK Biobank, the prospective cohort study included a total of 396,080 participants without diabetes at baseline. We determined the types and sites of infectious diseases and incident T2D using the International Classification of Diseases 10th Revision codes (ICD-10). Time-varying Cox proportional hazard model was used to assess the association. Infection burden was defined as the number of infection episodes over time and the number of co-occurring infections. Genetic risk score (GRS) for T2D consisted of 424 single nucleotide polymorphisms. RESULTS: During a median of 9.04 [IQR, 8.3-9.7] years of follow-up, hospital-treated infectious diseases were associated with a greater risk of T2D (adjusted HR [aHR] 1.54 [95 % CI 1.46-1.61]), with risk difference per 10,000 individuals equal to 154.1 [95 % CI 140.7-168.2]. The heightened risk persisted after 5 years following the index infection. Bacterial infection with sepsis had the strongest risk of T2D (aHR 2.95 [95 % CI 2.53-3.44]) among different infection types. For site-specific analysis, bloodstream infections posed the greatest risk (3.01 [95 % CI 2.60-3.48]). A dose-response association was observed between infection burden and T2D risk within each GRS tertile (p-trend <0.001). High genetic risk and infection synergistically increased the T2D risk. CONCLUSION: Infectious diseases were associated with an increased risk of subsequent T2D. The risk showed specificity according to types, sites, severity of infection and the period since infection occurred. A potential accumulative effect of infection was revealed.

Association of Diabetes Mellitus Status and Hyperglycemia With Symptomatic Knee Osteoarthritis.

OBJECTIVE: Emerging evidence indicates that hyperglycemia has an adverse impact on the knee joint which, in turn, may increase the risk of knee osteoarthritis (OA), but evidence from the real-life settings of large-scale cohort studies remains unclear. We sought to evaluate the association of glycemic control and the risk of symptomatic knee OA in a community-based cohort of older adults. METHODS: We conducted a prospective analysis of 10,730 participants without knee OA. Comprehensive blood biomarker data were obtained. Diabetes mellitus (DM) was defined mainly using a glycosylated hemoglobin (HbA1c ) level of ≥6.5%; poor glycemic control in individuals with DM was defined as an HbA1c level of ≥7%. We fit Cox regression models, stratified according to DM status. We evaluated the hazards associated with HbA1c and fasting blood glucose levels using a spline model. RESULTS: During a median follow-up of 5 years, knee OA developed in 1,089 participants (108 with DM and 971 without). Knee OA was related to DM (hazard ratio [HR] 1.29 [95% confidence interval (95% CI) 1.02-1.78]), bad glycemic regulation in DM patients (HR 1.41 [95% CI 1.05-2.09]), and long-term DM (≥5 versus <5 years; HR 1.49 [95% CI 1.02-2.17]). High levels of HbA1c (>7.7% and 61 mmoles/mole) and fasting blood glucose (>186 mg/dl) were significantly associated with higher risk of incident knee OA. CONCLUSION: DM, bad glycemic management, and long-term DM are potential risk factors of symptomatic knee OA independent of age and body mass index. Targeting blood glucose, in addition to bodyweight, may be an important avenue for prevention of knee OA.

Association Between Glucosamine Use and the Risk of Incident Heart Failure: The UK Biobank Cohort Study and Mendelian Randomization Analysis.

OBJECTIVE: To evaluate the association between regular glucosamine intake and heart failure (HF) and to explore whether the association is mediated by relevant cardiovascular disease. PATIENTS AND METHODS: We included 479,650 participants with data available for supplement use and without HF at baseline from the UK Biobank study. Using 12 single-nucleotide polymorphisms linked to HF, a weighted genetic risk score was calculated. We evaluated the association between glucosamine use and HF by Cox regression models after inverse probability of treatment weighting. A validation and mediation analysis were performed through two-sample Mendelian randomization. The study was from May 18, 2006, to February 16, 2018. RESULTS: During a median follow-up of 9.0 (IQR, 8.3-9.8) years, we documented 5501 incident cases of HF. In multivariable analysis, the HR of glucosamine users for HF was 0.87 (95% CI, 0.81 to 0.94). The inverse associations were stronger in males and participants with unfavorable lifestyle (P<.05 for interaction). Genetic risk categories did not modify this association (P>.05 for interaction). Multivariable Mendelian randomization showed that taking glucosamine was protective against HF (HR, 0.92; 95% CI, 0.87 to 0.96). The mediated proportion of coronary heart disease and stroke were 10.5% (95% CI, 7.6% to 13.4%) and 14.4% (95% CI, 10.8% to 18.0%), respectively. The two-mediator combination accounted for 22.7% (95% CI, 17.2% to 28.2%) of the effect of glucosamine use. CONCLUSION: Regular glucosamine supplementation was associated with a lower risk of HF regardless of genetic risk status, and to a lesser extent, coronary heart disease and stroke mediated this effect. The results may inform novel pathway for prevention and intervention toward HF.

Preserved Ratio Impaired Spirometry in Relationship to Cardiovascular Outcomes: A Large Prospective Cohort Study.

BACKGROUND: Preserved ratio impaired spirometry (PRISm) findings are a heterogeneous condition characterized by a normal FEV1 to FVC ratio with underlying impairment of pulmonary function. Data relating to the association of baseline and trajectories of PRISm findings with diverse cardiovascular outcomes are sparse. RESEARCH QUESTION: How do baseline and trajectories of PRISm findings impact subsequent cardiovascular events? STUDY DESIGN AND METHODS: In the UK Biobank cohort study, we included participants free of cardiovascular disease (CVD) with spirometry (FEV1 and FVC values) at baseline (2006-2010). Participants with baseline spirometry and follow-up spirometry (2014-2020) were included in the lung function trajectory analysis. Cox proportional hazards multivariate regression was performed to evaluate the outcomes of major adverse cardiovascular events (MACEs), incident myocardial infarction (MI), stroke, heart failure (HF), and CVD mortality in association with lung function. RESULTS: For baseline analysis (329,954 participants), the multivariate adjusted hazard ratios (HRs) for participants had PRISm findings (vs normal spirometry findings) were 1.26 (95% CI, 1.17-1.35) for MACE, 1.12 (95% CI, 1.01-1.25) for MI, 1.88 (95% CI, 1.72-2.05) for HF, 1.26 (95% CI, 1.13-1.40) for stroke, and 1.55 (95% CI, 1.37-1.76) for CVD mortality, respectively. A total of 22,781 participants underwent follow-up spirometry after an average of 8.9 years. Trajectory analysis showed that persistent PRISm findings (HR, 1.96; 95% CI, 1.24-3.09) and airflow obstruction (HR, 1.43; 95% CI, 1.00-2.04) was associated with a higher incidence of MACE vs consistently normal lung function. Compared with persistent PRISm findings, changing from PRISm to normal spirometry findings was associated with a lower incidence of MACE (HR, 0.42; 95% CI, 0.19-0.99). INTERPRETATION: Individuals with baseline or persistent PRISm findings were at a higher risk of diverse cardiovascular outcomes even after adjusting for a wide range of confounding factors. However, individuals who transitioned from PRISm to normal findings showed a similar cardiovascular risk as those with normal lung function.

Long-Term Visit-To-Visit Blood Pressure Variability and Risk of Diabetes Mellitus in Chinese Population: A Retrospective Population-Based Study.

Objectives: To examine the association between visit-to-visit blood pressure variability (BPV) and incident diabetes mellitus (DM) risk in a Chinese population. Methods: Data comes from China Health and Nutrition Survey (n = 15,084). BPV was estimated as the average real variability (ARV) using at least three BP measurements from the year preceding the event and was divided into quartiles. Participants were also categorized into 9 groups on the basis of combinations of systolic BPV (SBPV) and diastolic BPV (DBPV) tertiles. Cox proportional hazards regression models were used. Results: During a median follow-up of 16.8 years, 1,030 (6.8%) participants developed diabetes (incidence rate: 4.65/1,000 person-years). The HRs (95% CIs) for the highest quartile (vs. the lowest quartile) of SBPV and DBPV were 1.60 (1.30-1.97) and 1.37 (1.13-1.67), respectively. Participants with both highest SBPV and DBPV tertile had an ≈89% higher risk of DM (HR, 1.89; 95% CI, 1.47-2.42) compared with those in the both SBPV and DBPV tertile 1 group. Conclusion: Higher SBP ARV and DBP ARV were independently associated with increased risk of incident DM, which was augmented when both presented together.

The association between daytime napping and risk of type 2 diabetes is modulated by inflammation and adiposity: Evidence from 435 342 UK-Biobank participants.

BACKGROUND: Existing evidence concerning the relationship between daytime napping and type 2 diabetes (T2D) is inconsistent, and whether the effects of napping differ by body fat percentage (BFP) and C-reactive protein (CRP) is unclear. We aimed to investigate the association between daytime napping frequency and T2D risk and whether such an association was modified by BFP and CRP. METHODS: We included 435 342 participants free of diabetes from the UK Biobank. Participants were categorized as nonnappers, occasional nappers, and frequent nappers based on napping frequency, and BFP/CRP was divided into quartiles. Cox proportional hazards models were used. RESULTS: During a median follow-up of 9.2 years, 17 592 T2D cases occurred. Higher frequency of daytime napping was significantly associated with an increased risk of T2D. Compared with nonnappers, the adjusted hazard ratios (HRs) for occasional nappers and habitual nappers were 1.28 (95% confidence interval [CI]: 1.24-1.32) and 1.49 (95% CI: 1.41-1.57), respectively. There was a significant additive and multiplicative interaction (relative excess risk due to interaction [RERI] = 0.490, 95% CI 0.307-0.673; p for multiplicative interaction <.001) between napping and BFP, whereby a higher hazard of T2D associated with more frequent napping was greatest among participants in the highest BFP quartile (HR = 4.45, 95% CI: 3.92-5.06). The results for CRP were similar (RERI = 0.266, 95% CI: 0.094-0.439; p for multiplicative interaction <.001). CONCLUSIONS: Higher daytime napping frequency is associated with an increased T2D risk, and such relationships are modified by BFP and CRP. These findings underscore the importance of adiposity and inflammation control to mitigate diabetes risk.

Multi-omics Data Reveal the Effect of Sodium Butyrate on Gene Expression and Protein Modification in Streptomyces.

Streptomycetes possess numerous gene clusters and the potential to produce large amounts of natural products. Histone deacetylase (HDAC) inhibitors play an important role in the regulation of histone modifications in fungi, but little is known about the roles of HDAC in prokaryotes. Here, we described the global effects of the HDAC inhibitor, sodium butyrate (SB), on marine-derived Streptomyces olivaceus FXJ 8.021, particularly on the activation of secondary metabolites biosynthesis. antiSMASH analysis revealed 33 secondary metabolite biosynthetic gene clusters (BGCs) in strain FXJ 8.021, among which the silent lobophorin BGC was activated by SB. Transcriptomic data showed that the expression of genes involved in lobophorin biosynthesis (ge00097-ge00139) and CoA-ester formation (e.g., ge02824), as well as glycolysis/gluconeogenesis pathway (e.g., ge01661), was mainly up-regulated in the presence of SB. Intracellular CoA-ester analysis confirmed that SB triggered the biosynthesis of CoA-ester, increasing the precursor supply for lobophorin biosynthesis. Further acetylome analysis revealed that the acetylation levels on 218 acetylation sites of 190 proteins were up-regulated and those on 411 sites of 310 proteins were down-regulated. These acetylated proteins were particularly enriched in transcriptional and translational machinery components (e.g., elongation factor GE04399), and their correlations with the proteins involved in lobophorin biosynthesis were established by protein-protein interaction network analysis, suggesting that SB might function via a complex hierarchical regulation to activate expression of lobophorin BGC. These findings provide solid evidence that acetylated proteins triggered by SB could affect the expression of genes in the biosynthesis of primary and secondary metabolites in prokaryotes.

A visualization reporter system for characterizing antibiotic biosynthetic gene clusters expression with high-sensitivity.

The crisis of antibiotic resistance has become an impending global problem. Genome sequencing reveals that streptomycetes have the potential to produce many more bioactive compounds that may combat the emerging pathogens. The existing challenge is to devise sensitive reporter systems for mining valuable antibiotics. Here, we report a visualization reporter system based on Gram-negative bacterial acyl-homoserine lactone quorum-sensing (VRS-bAHL). AHL synthase gene (cviI) of Chromobacterium violaceum as reporter gene is expressed in Gram-positive Streptomyces to synthesize AHL, which is detected with CV026, an AHL deficient mutant of C. violaceum, via its violacein production upon AHL induction. Validation assays prove that VRS-bAHL can be widely used for characterizing gene expression in Streptomyces. With the guidance of VRS-bAHL, a novel oxazolomycin derivative is discovered to the best of our knowledge. The results demonstrate that VRS-bAHL is a powerful tool for advancing genetic regulation studies and discovering valuable active metabolites in microorganisms.

Waist Circumference and Body Mass Index Variability and Incident Diabetic Microvascular Complications: A Post Hoc Analysis of ACCORD Trial.

BACKGROUND: Obesity is associated with adverse health events among diabetic patients, however, the relationship between obesity fluctuation and risk of microvascular complications among this specific population is unclear. We aimed to examine the effect of waist circumference (WC) and body mass index (BMI) variability on the risk of diabetic microvascular outcome. METHODS: Annually recorded anthropometric data in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study was used to examine the association of WC and BMI variability defined as variability independent of mean, with the risk of microvascular outcomes, including neuropathy, nephropathy, and retinopathy. Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) (Trial registration: ClinicalTrials.gov., no. NCT00000620). RESULTS: There were 4,031, 5,369, and 2,601 cases of neuropathy, nephropathy, and retinopathy during a follow-up period of 22,524, 23,941, and 23,850 person-years, respectively. Higher levels of WC and BMI variability were associated with an increased risk of neuropathy. Compared with the lowest quartile, the fully-adjusted HR (95% CI) for the highest quartile of WC and BMI variability for neuropathy risk were 1.21 (1.05 to 1.40) and 1.16 (1.00 to 1.33), respectively. Also, higher quartiles of BMI variability but not WC variability were associated with increased risk of nephropathic events. The fully-adjusted HR (95% CI) for the highest quartile compared with the lowest quartile of BMI variability was 1.31 (1.18 to 1.46). However, the results for retinopathic events were all insignificant. CONCLUSION: Among participants with type 2 diabetes mellitus, WC and BMI variability were associated with a higher risk of neuropathic events, whereas BMI variability was associated with an increased risk of nephropathic events.

Lipid variability and risk of microvascular complications in Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial: A post hoc analysis.

BACKGROUND: Greater lipid variability may cause adverse health events among diabetic patients. We aimed to examine the effect of lipid variability on the risk of diabetic microvascular outcomes among type 2 diabetes mellitus patients. METHODS: We assessed the association between visit-to-visit variability (measured by variability independent of mean) in high-density lipoprotein (HDL) cholesterol, low-density lipoprotein-cholesterol (LDL), triglyceride, and remnant cholesterol (RC) measurements among participants involved in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study and the risk of incident microvascular outcomes, including nephropathy, neuropathy, and retinopathy. Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs), adjusted for potential confounders. RESULTS: There were 2400, 2470, and 2468 cases of nephropathy, neuropathy, and retinopathy during a follow-up period of 22 600, 21 542, and 26 701 person-years, respectively. Higher levels of HDL, triglyceride, and RC variability were associated with an increased risk of incident nephropathy and neuropathy. Compared with the lowest quartile, the fully adjusted HRs (95% CI) for the highest quartile of HDL, triglyceride, and RC variability for nephropathy risk were 1.57 (1.22, 2.01), 1.50 (1.18, 1.92), and 1.40 (1.09, 1.80), respectively; and for neuropathy, the corresponding risks were 1.36 (1.05, 1.75), 1.47 (1.14, 1.91), and 1.35 (1.04, 1.74), respectively. Null association was observed between LDL variability and all microvascular complications. Additionally, all associations of variability in the other lipids with retinopathy risk were null. CONCLUSION: Among individuals with type 2 diabetes mellitus, HDL, triglyceride, and RC variability were associated with increased risks of nephropathy and neuropathy but not retinopathy. TRIAL REGISTRATION: ClinicalTrials.gov., no. NCT00000620.

Favourable Lifestyle Protects Cognitive Function in Older Adults With High Genetic Risk of Obesity: A Prospective Cohort Study.

The relationship between body mass index (BMI) and cognitive impairment remains controversial, especially in older people. This study aims to confirm the association of phenotypic and genetic obesity with cognitive impairment and the benefits of adhering to a healthy lifestyle. This prospective study included 10,798 participants (aged ≥ 50 years) with normal cognitive function from the Health and Retirement Study in the United States. Participants were divided into low (lowest quintile), intermediate (quintiles 2-4), and high (highest quintile) groups according to their polygenic risk score (PRS) for BMI. The risk of cognitive impairment was estimated using Cox proportional hazard models. Higher PRS for BMI was associated with an increased risk, whereas phenotypic obesity was related to a decreased risk of cognitive impairment. Never smoking, moderate drinking, and active physical activity were considered favourable and associated with a lower risk of cognitive impairment compared with current smoking, never drinking, and inactive, respectively. A favourable lifestyle was associated with a low risk of cognitive impairment, even in subjects with low BMI and high PRS for BMI. This study suggest that regardless of obesity status, including phenotypic and genetic, adhering to a favourable lifestyle is beneficial to cognitive function.