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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.
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Doenças Cardiovasculares , Infecção Hospitalar , Masculino , Humanos , Feminino , Pessoa de Meia-Idade , Doenças Cardiovasculares/epidemiologia , Fatores de Risco , Expectativa de Vida , HospitaisRESUMO
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.
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Doenças Transmissíveis , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Doença de Parkinson , Humanos , Doença de Parkinson/genética , Doença de Parkinson/epidemiologia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Doenças Transmissíveis/genética , Doenças Transmissíveis/epidemiologia , Fatores de Risco , Reino Unido/epidemiologia , Infecções/epidemiologia , Infecções/genética , Incidência , Hospitalização , Estudos Transversais , Estudos de CoortesRESUMO
Mutations in the hyperpolarization-activated nucleotide-gated channel 4 (HCN4) are known to be associated with arrhythmias in which QT prolongation (delayed ventricular repolarization) is rare. Here, we identified a HCN4 mutation, HCN4-R666Q, in two sporadic arrhythmia patients with sinus bradycardia, QT prolongation, and short bursts of ventricular tachycardia. To determine the functional effect of the mutation, we conducted clinical, genetic, and functional analyses using whole-cell voltage-clamp, qPCR, Western blot, confocal microscopy, and co-immunoprecipitation. The mean current density of HEK293T cells transfected with HCN4-R666Q was lower in 24 to 36 h after transfection and was much lower in 36 to 48 h after transfection relative to cells transfected with wildtype HCN4. Additionally, we determined that the HCN4-R666Q mutant was more susceptible to ubiquitin-proteasome system-mediated protein degradation than wildtype HCN4. This decreased current density for HCN4-R666Q could be partly rescued by treatment with a proteasome inhibitor. Therefore, we conclude that HCN4-R666Q had an effect on HCN4 function in two aspects, including decreasing the current density of the channel as a biophysical effect and weakening its protein stability. Our findings provide new insights into the pathogenesis of the HCN4-R666Q mutation.
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Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização , Síndrome do QT Longo , Humanos , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/genética , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/metabolismo , Canais de Potássio/metabolismo , Proteólise , Nucleotídeos/metabolismo , Células HEK293 , Proteínas Musculares/metabolismo , Arritmias Cardíacas/genética , Mutação , Canais de Cátion Regulados por Nucleotídeos Cíclicos/genéticaRESUMO
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.
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Doença de Alzheimer , Demência Vascular , Humanos , Idoso , Glucosamina/uso terapêutico , Demência Vascular/epidemiologia , Demência Vascular/genética , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Estudos Prospectivos , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
INTRODUCTION: C-Reactive protein (CRP) and monocyte chemoattractant protein-1 (MCP-1) are both implicated in the peripheral proinflammatory cascade and blood-brain barrier (BBB) disruption. Since the blood CRP level increases Alzheimer's disease (AD) risk depending on the apolipoprotein E (APOE) genotype, we hypothesized that the blood MCP-1 level exerts different effects on the AD risk depending on the genotypes. METHODS: Using multiple regression analyses, data from the Framingham Heart Study (n = 2884) and Alzheimer's Disease Neuroimaging Initiative study (n = 231) were analyzed. RESULTS: An elevated blood MCP-1 level was associated with AD risk in major histocompatibility complex, Class II, DR beta 1 (HLA-DRB1) rs9271192-AC/CC (hazard ratio [HR] = 3.07, 95% confidence interval [CI] = 1.50-6.28, p = 0.002) and in APOE ε4 carriers (HR = 3.22, 95% CI = 1.59-6.53, p = 0.001). In contrast, among HLA-DRB1 rs9271192-AA and APOE ε4 noncarriers, blood MCP-1 levels were not associated with these phenotypes. DISCUSSION: Since HLA-DRB1 and APOE are expressed in the BBB, blood MCP-1 released in the peripheral inflammatory cascade may function as a mediator of the effects of HLA-DRB1 rs9271192-AC/CC and APOE ε4 genotypes on AD pathogenesis in the brain via the BBB pathways.
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Doença de Alzheimer , Apolipoproteínas E , Quimiocina CCL2 , Cadeias HLA-DRB1 , Humanos , Doença de Alzheimer/sangue , Doença de Alzheimer/genética , Apolipoproteína E4/genética , Apolipoproteínas E/genética , Quimiocina CCL2/sangue , Genótipo , Cadeias HLA-DRB1/genéticaRESUMO
Accurate water quality predictions are critical for water resource protection, and dissolved oxygen (DO) reflects overall river water quality and ecosystem health. This study proposes a hybrid model based on the fusion of signal decomposition and deep learning for predicting river water quality. Initially, complete ensemble empirical mode decomposition with adaptive noise (CEEMDAN) is employed to split the internal series of DO into numerous internal mode functions (IMFs). Subsequently, we employed multi-scale fuzzy entropy (MFE) to compute the entropy values for each IMF component. Time-varying filtered empirical mode decomposition (TVFEMD) is used to further extract features in high-frequency subsequences after linearly aggregating the high-frequency sequences. Finally, support vector machine (SVM) and long short-term memory (LSTM) neural networks are used to predict low- and high-frequency subsequences. Moreover, by comparing it with single models, models based on 'single layer decomposition-prediction-ensemble' and combination models using different methods, the feasibility of the proposed model in predicting water quality data for the Xinlian section of Fuhe River and the Chucha section of Ganjiang River was verified. As a result, the combined prediction approach developed in this work has improved generalizability and prediction accuracy, and it may be used to forecast water quality in complicated waters.
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Aprendizado Profundo , Ecossistema , Qualidade da Água , Entropia , Água Doce , OxigênioRESUMO
A wealth of single-cell imaging studies have contributed novel insights into chromatin organization and gene regulation. However, a comprehensive understanding of spatiotemporal gene regulation requires developing tools to combine multiple monitoring systems in a single study. Here, we report a versatile tag, termed TriTag, which integrates the functional capabilities of CRISPR-Tag (DNA labeling), MS2 aptamer (RNA imaging) and fluorescent protein (protein tracking). Using this tag, we correlate changes in chromatin dynamics with the progression of endogenous gene expression, by recording both transcriptional bursting and protein production. This strategy allows precise measurements of gene expression at single-allele resolution across the cell cycle or in response to stress. TriTag enables capturing an integrated picture of gene expression, thus providing a powerful tool to study transcriptional heterogeneity and regulation.
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Cromatina/genética , Redes Reguladoras de Genes/genética , Imagem Molecular , Análise de Célula Única , Alelos , Aptâmeros de Nucleotídeos/genética , Sistemas CRISPR-Cas/genética , Ciclo Celular/genética , Imunofluorescência/métodos , Regulação da Expressão Gênica/genética , Humanos , Transcrição GênicaRESUMO
BACKGROUND: Patients who have unexplained giant T-wave inversions but do not meet criteria for hypertrophic cardiomyopathy (HCM) (left ventricular (LV) wall thickness < 1.5 cm) demonstrate LV apical morphological features that differ from healthy subjects. Currently, it remains unknown how the abnormal LV apical morphology in this patient population changes over time. The purpose of this study was to investigate LV morphological and functional changes in these patients using a mid-term cardiovascular magnetic resonance (CMR) exam. METHODS: Seventy-one patients with unexplained giant T-wave inversion who did not fulfill HCM criteria were studied. The mean interval time of the follow-up CMR was 24.4 ± 8.3 months. The LV wall thickness was measured in each LV segment according to the American Heart Association 17-segmented model. The apical angle (ApA) was also measured. A receiver operating curve (ROC) was used to identify the predictive values of the CMR variables. RESULTS: Of 71 patients, 16 (22.5%) progressed to typical apical HCM, while 55 (77.5%) did not progress to HCM criteria. The mean apical wall thickness was significantly different between the two groups at both baseline and follow-up, with the apical HCM group having greater wall thickness at both time points (all p < 0.001). There was a significant difference between the two groups in the change of ApA (- 1.5 ± 2.7°/yr vs. - 0.7 ± 2.0°/yr, p < 0.001) over time. The combination of mean apical wall thickness and ApA proved to be the best predictor for fulfilling criteria for apical HCM with a threshold value of 8.1 mm and 90° (sensitivity 93.8%, specificity 85.5%). CONCLUSIONS: CMR metrics identify predictors for progression to HCM in patients with unexplained giant T-wave inversion.
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Cardiomiopatia Hipertrófica , Arritmias Cardíacas , Cardiomiopatia Hipertrófica/diagnóstico por imagem , Seguimentos , Humanos , Espectroscopia de Ressonância Magnética , Valor Preditivo dos TestesRESUMO
Background The value of native myocardial T1 mapping and extracellular volume (ECV) fraction in patients who have hypertrophic cardiomyopathy (HCM) but no late gadolinium enhancement (LGE) and no hemodynamic obstruction are currently unknown. Purpose To evaluate myocardial fibrosis in patients with nonobstructive HCM and no LGE by using native myocardial T1 mapping and ECV fraction and to study their relationships to left ventricular (LV) function and LV hypertrophy. Materials and Methods Patients with HCM who underwent cardiac MRI between 2012 and 2015 were retrospectively evaluated. Patients were included if they had no LGE at MRI, LV ejection fraction greater than or equal to 45%, and no LV outflow tract obstruction. Healthy participants had similar age and sex distribution. Native myocardial T1 and ECV were measured with MRI. Results A total of 258 patients with HCM (mean age ± standard deviation, 49 years ± 15; 74% men) and 122 healthy participants (mean age, 50 years ± 14; 76% men) were evaluated. Native myocardial T1 was longer and ECV fraction was higher in the patients with HCM relative to the healthy participants (mean native T1, 950 msec ± 48 vs 913 msec ± 46; mean ECV, 24.5% ± 2.8 vs 23.0% ± 2.7; both P < .001). Maximum T1 and ECV values correlated strongly with LV mass index for the entire patient cohort with HCM (both r = 0.86; P < .001) and for the subgroups (r = 0.86 and 0.85 for interventricular septal group and r = 0.88 and 0.86 for apical group; all P < .001). Conclusion Prolonged myocardial T1 and elevated extracellular volume in hypertrophic cardiomyopathy suggests diffuse myocardial fibrosis, even in the absence of regionally apparent late gadolinium enhancement and hemodynamic obstruction, and is associated with left ventricular hypertrophy. © RSNA, 2019 See also the editorial by Bluemke and Lima in this issue.
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Cardiomiopatia Hipertrófica/diagnóstico por imagem , Meios de Contraste , Gadolínio , Hemodinâmica , Imageamento por Ressonância Magnética/métodos , Feminino , Coração/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Estudos RetrospectivosRESUMO
UNLABELLED: Due to similar manifestations of hypertensive ventricular walls and abnormal ventricular compliance, it is difficult to differentiate cardiac amyloidosis (CA) and nonobstructive hypertrophic cardiomyopathy (NOHCM) clinically. The purpose of the study was to investigate the value of electrocardiography (ECG) in the differentiation of the two diseases. METHODS: We enrolled 46 consecutive patients with CA and 64 patients with NOHCM and compared their ECG characteristics.Compared with NOHCM patients, the ECG of CA patients showed more low voltage on limb leads (50% versus 1.6%), atrioventricular block (21.7% versus 4.7%), pseudo-infarct pattern (84.8% versus 39.1%), and longer QRS duration (104 ± 25 versus 98 ± 14 ms) (all P < 0.05). The QRS complex voltage of avR demonstrated the highest diagnostic performance (sensitivity 89%, specificity 94%, cut-off value 0.45mV) as assessed by ROC analysis. The combination of the R wave voltage of I and avR reached a sensitivity of 95% and a specificity of 87% for the diagnosis of amyloidosis.Compared with NOHCM patients, CA patients showed more ECG characteristics of low voltage on limb leads, pseudo-infarct pattern, atrioventricular block, and longer QRS duration. The combination of the R wave voltage of I, avR, and QRS was of diagnostic value in the differentiation of CA from NOHCM.
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Amiloidose , Cardiomiopatia Hipertrófica , Eletrocardiografia/métodos , Ventrículos do Coração , Adulto , Idoso , Amiloidose/diagnóstico , Amiloidose/fisiopatologia , Cardiomiopatia Hipertrófica/diagnóstico , Cardiomiopatia Hipertrófica/fisiopatologia , China , Diagnóstico Diferencial , Feminino , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Curva ROC , Estudos Retrospectivos , Sensibilidade e EspecificidadeRESUMO
OBJECTIVE: To investigate the predictive value of cardiac magnetic resonance (CMR) on outcome of patients with hypertrophic obstructive cardiomyopathy (HOCM) undergoing percutaneous transluminal septal myocardial ablation (PTSMA). METHODS: A total of 38 consecutive HOCM patients underwent CMR imaging before PTSMA in Fuwai hospital From March 2010 to September 2012 were included in this retrospective study. The efficacy was defined as >30 mmHg (1 mmHg = 0.133 kPa) reduction of echocardiography derived left ventricular outflow tract gradient (LVOTG) at 6 months post operation. The relationship between CMR imaging derived parameters and effect of PTSMA was analyzed. Receiver operating curve (ROC) was applied to assess the predicting effectiveness of related CMR parameters. RESULTS: The effective rate of PTSMA was 65.8% (25/38). The thickness of basal anterior wall (r = 0.505, P = 0.001), basal anteroseptal wall (0.500, P = 0.001) and the sum of the two segments (r = 0.656, P < 0.001) was positively correlated to the post-procedure reduction of LVOTG. The area under the ROC curve of the thickness of basal anterior wall, basal anteroseptal wall and the sum of the two segments was 0.806, 0.675 and 0.834, respectively. The sensitivity was 84.6% and specificity was 84.0% to predict the efficacy of PTSMA using the sum of left ventricular basal anterior wall and basal anteroseptal wall thickness 49.6 mm as cut-off value. CONCLUSIONS: LVOTG reduction post PTSMA positively correlates to pre-procedure left ventricular basal anterior wall, basal anteroseptal wall and the total thickness of these two segments in patients with HOCM. The total thickness of these two segments is a superior parameter for predicting efficacy of PTSMA in HOCM patients.
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Cardiomiopatia Hipertrófica/diagnóstico , Espectroscopia de Ressonância Magnética , Procedimentos Cirúrgicos Cardíacos , Cardiomiopatia Hipertrófica/terapia , Ecocardiografia , Septos Cardíacos , Ventrículos do Coração , Humanos , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Sensibilidade e EspecificidadeRESUMO
Effective identification and regulation of water quality impact factors is essential for water resource management and environmental protection. However, the complex coupling of water quality systems poses a significant challenge to this task. This study proposes coherent model for water quality prediction, classification and regulation based on interpretable machine learning. The decomposition-reconstruction module is used to transform non-stationary water quality series into stationary series while effectively reducing the feature dimensions. Spatiotemporal multi-source data is introduced by using the Maximum Information Coefficient (MIC) for feature selection. The Temporal Convolutional Network (TCN) is used to extract the temporal features of different variables, followed by the introduction of External Attention mechanism (EA) to construct the relationship between these features. Finally, the target water quality sequence is simulated using Gated Recurrent Unit (GRU). The proposed model was applied to Poyang Lake in China to predict six water quality indicators: ammonia nitrogen (NH3-N), dissolved oxygen (DO), pH, total nitrogen (TN), total phosphorus (TP), water temperature (WT). The water quality was then classified based on the prediction results using the XGBoost algorithm. The findings indicate that the proposed model's Nash-Sutcliff Efficiency (NSE) value ranges from 0.88 to 0.99, surpassing that of the benchmark model, and demonstrates strong interval prediction performance. The results highlight the superior performance of the XGBoost algorithm (with an accuracy of 0.89) in addressing water quality classification issues, particularly in cases of category imbalance. Subsequently, interpretability analysis using the SHapley Additive exPlanation (SHAP) method revealed that the model is capable of learning relationships between different variables and there exists a possibility of learning the physical laws. Ultimately, this study proposes a water quality regulation mechanism that improves TN and DO levels by stepwise changing the magnitude of water temperature, which significantly improves in the case of data limitations. In conclusion, this study presents an overall framework for integrating water quality prediction, classification and improvement for the first time, forming a complete set of water quality early warning and improvement management strategies. This framework provides new ideas and ways for lake water quality management.
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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.
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BACKGROUND: Although infections play a role in the development of lung cancer, the longitudinal association between infection and the risk of lung cancer is disputed and data relating to pathogen types and infection sites is sparse. RESEARCH QUESTION: How do infections impact subsequent lung cancer risk and whether the impact is limited to specific microbes rather than infection burden? METHODS: We ascertained 900+ infectious diseases from the UK Biobank study. Short- and long-term effect of infections was assessed using time-varying Cox proportional hazard models. The analysis was repeated, excluding patients with concurrent multi-pathogen infections or outcomes within the ten years after initial hospitalization for the index infection. Life table was used to estimate years of life lost from lung cancer. Infection burden was defined as the sum of the number of infection episodes over time and co-occurring infections. The genome-wide association studies (GWAS) used in two-sample Mendelian randomization (MR) were obtained from mostly European ancestry. RESULTS: Hospital-treated infectious disease was associated with a greater risk of lung cancer (adjusted HR [aHR] 1.79 [95% CI 1.74-1.83]). aHRs for lung cancer ranged from 1.39 to 2.82 across pathogen types. The impact of lower respiratory tract infections (LRTIs) on lung cancer was the strongest, with an aHR of 3.22 [95% CI 2.64-3.92], while the aHR for extra-LRTIs was 1.29 [1.16-1.44]). A dose-response association was observed between infection burden and lung cancer risk across different FEV1% predicted (p-trend <0.001). Multiple infections led to a significant life lost from lung cancer at the age of 50. MR analysis reaffirmed the causal association. INTERPRETATION: Both observational and genetic analyses suggested that infectious diseases could increase the risk of lung cancer. The dual perspective on the LRTIs and extra-LRTIs impacts may inform lung cancer preventive strategies.
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Artificial forest ecosystems offer various ecosystem services (ES) and help mitigate climate change effects. Trade-offs or synergies exist among ES in artificial forests. Although forest age influences ES and ecosystem processes, the long-term dynamics of trade-offs among ES in artificial forests and during vegetation restorations remain unclear, complicating vegetation and sustainable management. We studied a Robinia pseudoacacia plantation on the Loess Plateau, China, with a restoration time of 10-44 years. The entropy weight method was used to assess five ES (carbon sequestration, water conservation, soil conservation, understory plant diversity, and runoff and sediment reduction) and investigate how ES change with forest age. The root mean square deviation (RMSD) was used to quantify the trade-offs among ES, and redundancy analysis (RDA) analysis was used to identify the key factors influencing the ES and trade-offs. The results showed that (1) as forest age increased, ES scores initially increased and then decreased. The optimal range for ES values was observed during the middle-aged to mature stages of the forest. (2) Before reaching maturity, the planted forests primarily delivered services related to water conservation and runoff and sediment reduction. (3) In young forests, ES showed a synergistic relationship (RMSD = 0.06), whereas trade-offs occurred in forests at other ages. The largest trade-off was observed in middle-aged forests. (4) The ES pairs with the dominant trade-offs in planted forests differed at different forest age stages. The largest trade-off occurred between carbon sequestration and water conservation (RMSD = 0.28). RDA analysis showed that understory vegetation coverage had a positive correlation with all ES. The ES indicators that significantly (P < 0.001) affected the watercarbon trade-off were tree carbon storage, soil organic carbon storage, soil total nitrogen, and soil total phosphorus. Thus, the water and carbon relationship must be balanced, and the key factors affecting ES trade-offs in forest management must be regulated to support ES multifunctionality.
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Ecossistema , Robinia , Carbono/análise , Solo , Florestas , China , ÁguaRESUMO
CpxA is a key member of the envelope stress-responsive Cpx two-component system ubiquitous in Gram-negative bacteria. It is responsible for signal sensing and has dual activities of phosphatase and kinase. CpxA has been revealed to participate in the regulation of physiological processes such as virulence and antimicrobial resistance of bacteria. In recent years, the development of novel antimicrobials targeting CpxA has attracted much attention. Drugs developed based on inhibition of the phosphatase activity of CpxA have shown effectiveness in the treatment of urinary tract infections caused by Escherichia coli. This review introduces the structure and functional domains of CpxA and the activation of Cpx pathways by CpxA. Furthermore, it summarizes the roles of CpxA in the development of antimicrobial resistance and the regulation of bacterial virulence and reviews the latest progress in the development of new antimicrobials targeting this protein. It is expected to assist in the exploration of CpxA-targeting anti-infection strategies for severely antimicrobial-resistant bacteria whose clinical infections are of urgent need to be controlled.
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Proteínas de Bactérias , Farmacorresistência Bacteriana , Virulência , Farmacorresistência Bacteriana/genética , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Mutação , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Antibacterianos/farmacologia , Escherichia coli/genética , Escherichia coli/efeitos dos fármacos , Escherichia coli/metabolismo , Proteínas QuinasesRESUMO
OBJECTIVE: The fragility index (FI), which is the minimum number of changes in status from "event" to "non-event" resulting in a loss of statistical significance, serves as a significant supplementary indicator for clinical physicians in interpreting clinical trial results and aids in understanding the outcomes of randomized controlled trials (RCTs). In this systematic literature survey, we evaluated the FI for RCTs evaluating Chinese herbal medicine (CHM) for irritable bowel syndrome (IBS), and explored potential associations between study characteristics and the robustness of RCTs. METHODS: A comprehensive search was conducted in four databases in Chinese and four databases in English from their inception to January 1, 2023. RCTs encompassed 1:1 ratio into two parallel arms and reported at least one binary outcome that demonstrated statistical significance were included. FI was calculated by the iterative reduction of a target outcome event in the treatment group and concomitant subtraction of a non-target event from that group, until positive significance (defined as P < 0.05 by Fisher's exact test) is lost. The lower the FI (minimum 1) of a trial outcome, the more fragile the positive result of the outcome was. Linear regression models were adopted to explore influence factors of the value of FI. RESULTS: A total of 30 trials from 2 4118 potentially relevant citations were finally included. The median FI of total trials included was 1.5 (interquartile range [IQR], 1-5), and half of the trials (n = 15) had a FI equal to 1. In 12 trials (40%), the total number of participants lost to follow-up surpassed the respective FI. The study also identified that increased FI was significantly associated with no TCM syndrome differentiation for inclusion criteria of the patients, larger total sample size, low risk of bias, and larger numbers of events. CONCLUSIONS: The majority of CHM IBS RCTs with positive results were found to be fragile. Ensuring adequate sample size, scientifically rigorous study design, proper control of confounding factors, and a quality control calibration for consistency of TCM diagnostic results among clinicians should be addressed to increase the robustness of the RCTs. We recommend reporting the FI as one of the components of sensitivity analysis in future RCTs to facilitate the assessment of the fragility of trials.
Assuntos
Medicamentos de Ervas Chinesas , Síndrome do Intestino Irritável , Ensaios Clínicos Controlados Aleatórios como Assunto , Síndrome do Intestino Irritável/tratamento farmacológico , Humanos , Medicamentos de Ervas Chinesas/uso terapêuticoRESUMO
Aim: Endothelial dysfunction has been associated with both cerebrovascular pathology and Alzheimer's disease (AD). However, the connection between circulating endothelial cells and the risk of AD remains uncertain. The objective was to leverage data from the Framingham Heart Study to investigate various circulating endothelial subtypes and their potential correlations with the risk of AD. Methods: The study conducted data analyses using Cox proportional hazard regression and linear regression methods. Additionally, genome-wide association study (GWAS) was carried out to further explore the data. Results: Among the eleven distinct circulating endothelial subtypes, only circulating endothelial progenitor cells (EPCs) expressing CD34+CD133+ were found to be negatively and dose-dependently associated with reduced AD risk. This association persisted even after adjusting for age, sex, years of education, apolipoprotein E (APOE) ε4 status, and various vascular diseases. Particularly noteworthy was the significant association observed in individuals with hypertension and cerebral microbleeds. Consistently, positive associations were identified between CD34+CD133+ EPCs and specific brain regions, such as higher proportions of circulating CD34+CD133+ cells correlating with increased volumes of white matter and the hippocampus. Additionally, a GWAS study unveiled that CD34+CD133+ cells influenced AD risk specifically in individuals with homozygous genotypes for variants in two stem cell-related genes: kirre like nephrin family adhesion molecule 3 (KIRREL3, rs580382 CC and rs4144611 TT) and exocyst complex component 6B (EXOC6B, rs61619102 CC). Conclusions: The findings suggest that circulating CD34+CD133+ EPCs possess a protective effect and may offer a new therapeutic avenue for AD, especially in individuals with vascular pathology and those carrying specific genotypes of KIRREL3 and EXOC6B genes.