Background:A shift from self-reports to wearable sensors for global physical activity(PA)surveillance has been recommended.The conventional use of a generic cut-point to assess moderate-to-vigorous PA(MVPA)is problema...Background:A shift from self-reports to wearable sensors for global physical activity(PA)surveillance has been recommended.The conventional use of a generic cut-point to assess moderate-to-vigorous PA(MVPA)is problematic as these cut-points are often derived from non-representative samples under non-ecological laboratory conditions.This study aimed to develop age-and sex-(age-sex)specific cut-points for MVPA based on population-standardized values as a feasible approach to assess the adherence to PA guidelines and to investigate its associations with all-cause mortality.Methods:A total of 7601 participants(20-85+years)were drawn from the 2003-2004 and 2005-2006 National Health and Nutrition Examination Surveys(NHANES).Minutes per week of MVPA were assessed with a hip-worn accelerometer.Counts per minute(CPM)were used to define an age-sex specific target intensity,representing the intensity each person should be able to reach based on their age and sex.Age-sex specific MVPA cut-points were defined as any activity above 40%of the target intensity.These population-and free-living-based age-sex specific cut-points overcome many of the limitations of the standard generic cut-point approach.For comparison,we also calculated MVPA with a generic cut-point of 1952 CPM.Both approaches were compared for assessing adherence to PA guidelines and association of MVPA with allcause mortality(ascertained through December 2015).Results:Both approaches indicated that 37%of the sample met the 150+min/week guideline.The generic cut-point approach showed a trend to inactivity with age,which was less pronounced using the age-sex specific cut-points.Overall mortality rates were comparable using generic cutpoint(hazard ratio(HR)=0.61,95%confidence interval(95%CI):0.50-0.73)or age-sex specific cut-points(HR=0.57,95%CI:0.50-0.66)for the entire sample.The generic cut-point method revealed an age-and sex-related gap in the benefits of achieving 150+min/week of MVPA,with older adults showing an 18%greater reduction in mortality rates than younger adults,and a larger difference in women than in men.This disparity disappeared when using age-sex specific cut-points.Conclusion:Our findings underscore the value of age-sex specific cut-points for global PA surveillance.MVPA defined with age-sex specific thresholds was associated with all-cause mortality and the dose-response was similar for all ages and sexes.This aligns with the single recommendation of accumulating 150+min/week MVPA for all adults,irrespective of age and sex.This study serves as a proof of concept to develop this methodology for PA surveillance over more advanced open-source acceleration metrics and other national and international cohorts.展开更多
Atrial fibrillation(AF)and heart failure(HF)are two cardiovascular diseases with an increasing prevalence worldwide.These conditions share common pathophysiologiesand frequently co-exit.In fact,the occurrence of eithe...Atrial fibrillation(AF)and heart failure(HF)are two cardiovascular diseases with an increasing prevalence worldwide.These conditions share common pathophysiologiesand frequently co-exit.In fact,the occurrence of either condition can‘cause’the development of the other,creating a new patient group that demands different management strategies to that if they occur in isolation.Regardless of the temproral association of the two conditions,their presence is linked with adverse cardi-ovascular outcomes,increased rate of hospitalizations,and increased economic burden on healthcare systems.The use of low-cost,easily accessible and applicable biomarkers may hasten the correct diagnosis and the effective treatment of AF and HF.Both AF and HF effect multiple physiological pathways and thus a great number of biomarkers can be measured that potentially give the clinician important diagnostic and prognostic information.These will then guide patient centred therapeutic management.The current biomarkers that offer potential for guiding therapy,focus on the physiological pathways of miRNA,myocardial stretch and injury,oxidative stress,inflammation,fibrosis,coagulation and renal impairment.Each of these has different utility in current clinincal practice.展开更多
Heart failure is common in older people and its prevalence is increasing.The Heart ＇omics＇ in AGEing（HOMAGE） project aims to provide a biomarker approach that will improve the early diagnosis of heart failure.A la...Heart failure is common in older people and its prevalence is increasing.The Heart ＇omics＇ in AGEing（HOMAGE） project aims to provide a biomarker approach that will improve the early diagnosis of heart failure.A large clinical database,based on（1） prospective population studies or（2） cross-sectional,prospective studies or randomized controlled trials（RCTs） of patients at risk for or with overt cardiovascular disease will be constructed to determine most promising ＇omics＇-based biomarkers to identify the risk of developing heart failure and/or comorbidities.Population studies,patient cohorts and RCTs are eligible for inclusion in the common database,if they received ethical approval to obtain and share data and have baseline information on cardiovascular risk factors.Currently,the HOMAGE database includes 43,065 subjects,from 20 studies in eight European countries,including healthy subjects from three population studies in France,Belgium and Italy（n = 7,124）,patients with heart failure（n = 4,312） from four cohorts in the UK,Spain and Switzerland and patients at high risk for cardiovascular disease（n = 31,629） in 13 cohorts.It is anticipated that more partners will join the consortium and enlarge the pooled data.This large merged database will be a useful resource with which to identify candidate biomarkers that play a role in the mechanism underlying the onset and progression of heart failure.展开更多
Background: Increasing workload in consultant-led clinics often means patients to wait a long time for clinic appointments. To address this, there is an increasing trend in developing nurse-led clinics across many spe...Background: Increasing workload in consultant-led clinics often means patients to wait a long time for clinic appointments. To address this, there is an increasing trend in developing nurse-led clinics across many specialities in the National Health Service. This study aims to assess whether the implementation of a nurse-led clinic in thoracic aortic surgery will optimise the utilisation of health care services and improve overall patient satisfaction. Methods: 80 follow-up patients were asked to complete a questionnaire following their appointment in an aortic clinic, which was led either by a consultant (n = 40) or an aortic specialist nurse (n = 40). All patients seen by a nurse in the clinic were assessed by a consultant surgeon prior to the clinic for suitability. No new patients were seen by a nurse. Any patient with an aortic dimension of 5 cm or greater was seen by the consultant. If there were any complicated clinical features, the patient was seen in the consultant-led clinic. Patients were asked questions about their time spent with the respective health care professionals across 12 categories (punctuality, preparedness, understanding of concerns, clarity of speech, listening, respect, explaining, letting you talk, putting you at ease, emotional support, advice and advice for next follow-up). Patients rated each category using an ordinal scale from 0 - 10. Results: Patient scores were greater in nurse-led clinics compared to consultant-led clinics across a number of categories although only punctuality reached significance (mean 9.2 vs. 6.8, p 0.05). Conclusion: Patients were highly satisfied with the nurse-led clinic across all categories, with greater satisfaction for punctuality. These findings suggest that a nurse-led clinic can be implemented for the management of carefully selected thoracic aortic surgery patient without reduction in patient satisfaction.展开更多
Erectile dysfunction(ED)has been identified as one of the most frequent chronic complications of diabetes mellitus(DM).The prevalence of ED is estimated to be about 67.4%in all DM cases worldwide.The pathophysiologica...Erectile dysfunction(ED)has been identified as one of the most frequent chronic complications of diabetes mellitus(DM).The prevalence of ED is estimated to be about 67.4%in all DM cases worldwide.The pathophysiological process leading to ED involves endothelial,neurological,hormonal,and psychological factors.In DM,endothelial and neurological factors play a crucial role.Damages in the blood vessels and erectile tissue due to insulin resistance are the hallmark of ED in DM.The current treatments for ED include phosphodiesterase-5 inhibitors and penile prosthesis surgery.However,these treatments are limited in terms of just relieving the symptoms,but not resolving the cause of the problem.The use of stem cells for treating ED is currently being studied mostly in experimental animals.The stem cells used are derived from adipose tissue,bone,or human urine.Most of the studies observed an improvement in erectile quality in the experimental animals as well as an improvement in erectile tissue.However,research on stem cell therapy for ED in humans remains to be limited.Nevertheless,significant findings from studies using animal models indicate a potential use of stem cells in the treatment of ED.展开更多
Atrial fibrillation(AF) and heart failure(HF) are complex clinical entities that occur concomitantly in a significant population of patients, and their prevalence is rising in epidemic proportions. Traditionally, both...Atrial fibrillation(AF) and heart failure(HF) are complex clinical entities that occur concomitantly in a significant population of patients, and their prevalence is rising in epidemic proportions. Traditionally, both rate and rhythm control strategies have been regarded as equivalent in the management of dysrhythmia in this AF-HF cohort with escalation of treatment largely guided by symptoms. Both disorders are involved in an elaborate pathophysiological interplay with shared cardiovascular risk factors that contribute to the development and sustenance of both AF and HF. Recent studies and continued development of evidence to support catheter ablation for AF has brought into question the traditional belief in equivalence between rate and rhythm control. Indeed, recent trials, in particular the CASTLE-AF(Catheter Ablation versus Standard Conventional Therapy in Patients with Left Ventricular Dysfunction and Atrial Fibrillation) study, suggest that catheter ablation for AF improves survival and rates of hospitalisation in patients with concomitant HF and AF, threatening a paradigm shift in the management of this patient cohort. The evident mortality benefit from clinical trials suggests that catheter ablation for AF should be considered as a therapeutic intervention in all suitable patients with the AF-HF syndrome as these patients may derive the greatest benefit from restoration of sinus rhythm. Further research is needed to refine the evidence base, especially to determine which subgroup of HF patients benefit most from catheter ablation and what is the optimal timing.展开更多
Mitochondrial aldehyde dehydrogenase(ALDH2)offers proven cardiovascular benefit,although its impact on diabetes remains elusive.This study examined the effects of ALDH2 overexpression and knockout on diabetic cardiomy...Mitochondrial aldehyde dehydrogenase(ALDH2)offers proven cardiovascular benefit,although its impact on diabetes remains elusive.This study examined the effects of ALDH2 overexpression and knockout on diabetic cardiomyopathy and the mechanism involved with a focus on mitochondrial integrity.Mice challenged with streptozotocin(STZ,200 mg/kg,via intraperitoneal injection)exhibited pathological alterations,including reduced respiratory exchange ratio,dampened fractional shortening and ejection fraction,increased left ventricular end-systolic and diastolic diameters,cardiac remodeling,cardiomyocyte contractile anomalies,intracellular Ca2+defects,myocardial ultrastructural injury,oxidative stress,apoptosis,and mitochondrial damage,which were overtly attenuated or accentuated by ALDH2 overexpression or knockout,respectively.Diabetic patients also exhibited reduced plasma ALDH2 activity,cardiac remodeling,and diastolic dysfunction.In addition,STZ challenge altered expression levels of mitochondrial proteins(PGC-1αand UCP2)and Ca2+regulatory proteins(SERCA,Na+–Ca2+exchanger,and phospholamban),dampened autophagy and mitophagy(LC3B ratio,TOM20,Parkin,FUNDC1,and BNIP3),disrupted phosphorylation of Akt,GSK3β,and Foxo3a,and elevated PTEN phosphorylation,most of which were reversed or worsened by ALDH2 overexpression or knockout,respectively.Furthermore,the novel ALDH2 activator torezolid,as well as the classical ALDH2 activator Alda-1,protected against STZ-or high glucose-induced in vivo or in vitro cardiac anomalies,which was nullified by inhibition of Akt,GSK3β,Parkin,or mitochondrial coupling.Our data discerned a vital role for ALDH2 in diabetic cardiomyopathy possibly through regulation of Akt and GSK3βactivation,Parkin mitophagy,and mitochondrial function.展开更多
Congenital heart disease(CHD)is the commonest birth defect,affecting approximately 9.4/1000 live births.^(1)Atrial Septal Defect(ASD)is one of the commonest CHD clinical phenotypes,which frequently requires treatment ...Congenital heart disease(CHD)is the commonest birth defect,affecting approximately 9.4/1000 live births.^(1)Atrial Septal Defect(ASD)is one of the commonest CHD clinical phenotypes,which frequently requires treatment either in childhood or adulthood,and can lead to severe complications such as right heart failure and cardiac arrhythmia.Previous genome-wide association studies(GWAS)have identified a region of chromosome 4p16(Ch4p16)associated with the risk of ASD.展开更多
Background:In the 1990s,there were few multicenter research collaborations and pediatric cardiovascular clinical trials.The National Heart,Lung,and Blood Institute at the National Institutes of Health established the ...Background:In the 1990s,there were few multicenter research collaborations and pediatric cardiovascular clinical trials.The National Heart,Lung,and Blood Institute at the National Institutes of Health established the Pediatric Heart Network(PHN)in 2001 to stimulate multi-center collaboration and clinical studies in children and adults with congenital heart disease(CHD)and pediatric acquired heart disease.Methods:The PHN developed a flexible infrastructure for multi-center collaborative clinical research in children and adults with CHD and pediatric acquired heart disease.The objectives of the PHN are to improve health outcomes in individuals of all ages with CHD and pediatric acquired heart disease,to disseminate findings to improve treatment options and standards of care,to train and educate new investigators,and to support families during the conduct of clinical research.Results:To date,the PHN has conducted 30 studies,including 13 clinical trials,across over 60 sites and has enrolled over 10,000 participants.PHN studies have impacted clinical practice and guidelines in CHD and have supported the career development of young investigators,research nurses,and study coordinators.None of this would have been possible without the many partnerships with patient advocacy organizations,the U.S.Food and Drug Administration,a variety of industry collaborators and clinical registries.PHN studies have leveraged registry data to improve efficiency,minimize burden and reduce errors in data collection.Conclusion:The PHN’s success is due to fostering collaboration across pediatric cardiology centers,creating a clinical research infrastructure that can adapt to different types of studies,and emphasizing career development of young investigators and research coordinators.This paper will summarize the PHN’s history,partnerships,use of clinical registries,future directions,and ways to get involved.展开更多
Cardiac fibroblast(CF)differentiation into myofibroblasts is a crucial cause of cardiac fibrosis,which increases in the extracellular matrix(ECM)stiffness.The increased stiffness further promotes CF differentiation an...Cardiac fibroblast(CF)differentiation into myofibroblasts is a crucial cause of cardiac fibrosis,which increases in the extracellular matrix(ECM)stiffness.The increased stiffness further promotes CF differentiation and fibrosis.However,the molecular mechanism is still unclear.We used bioinformatics analysis to find new candidates that regulate the genes involved in stiffnessinduced CF differentiation,and found that there were binding sites for the POU-domain transcription factor,POU2F1(also known as Oct-1),in the promoters of 50 differentially expressed genes(DEGs)in CFs on the stiffer substrate.Immunofluorescent staining and Western blotting revealed that pathological stiffness upregulated POU2F1 expression and increased CF differentiation on polyacrylamide hydrogel substrates and in mouse myocardial infarction tissue.A chromatin immunoprecipitation assay showed that POU2F1 bound to the promoters of fibrosis repressors IL1R2,CD69,and TGIF2.The expression of these fibrosis repressors was inhibited on pathological substrate stiffness.Knockdown of POU2F1 upregulated these repressors and attenuated CF differentiation on pathological substrate stiffness(35 kPa).Whereas,overexpression of POU2F1 downregulated these repressors and enhanced CF differentiation.In conclusion,pathological stiffness upregulates the transcription factor POU2F1 to promote CF differentiation by inhibiting fibrosis repressors.Our work elucidated the crosstalk between CF differentiation and the ECM and provided a potential target for cardiac fibrosis treatment.展开更多
This paper outlines the nature of microplastic contamination in rivers and the risks to freshwater fishes.We discuss how input sources influence the concentration and composition of microplastics and examine factors t...This paper outlines the nature of microplastic contamination in rivers and the risks to freshwater fishes.We discuss how input sources influence the concentration and composition of microplastics and examine factors that subsequently influence their spatiotemporal dynamics in a river system.We then discuss how the distributions and assemblages of microplastics can impact the risk of interactions with fishes,and the processes associated with the internalisation of microplastic into the body and across the organs and tissues.Finally,we examine the physical and toxicological effects of microplastic exposure in fish species,with special attention directed towards impacts at environmentally relevant concentrations.This review integrates expertise in fluvial geomorphological processes and how they influence the movement and storage of microplastics in river channel environments at a range of scales.We combine this knowledge with expertise in fish ecology and biology to set out a new and integrated analysis of microplastic dynamics in rivers and how these microplastics interact with fish.The integration of knowledge from these fields allows us also to comment upon the microplastic risk to fish and other biota in river environments.展开更多
基金supported in part by the intramural research programs at the National Institute on Aging and National Cancer Institute(USA)supported by the Spanish Ministry of Science,Innovation and Universities under Beatriz Galindo's 2022 fellowship program(BG22/00075).
文摘Background:A shift from self-reports to wearable sensors for global physical activity(PA)surveillance has been recommended.The conventional use of a generic cut-point to assess moderate-to-vigorous PA(MVPA)is problematic as these cut-points are often derived from non-representative samples under non-ecological laboratory conditions.This study aimed to develop age-and sex-(age-sex)specific cut-points for MVPA based on population-standardized values as a feasible approach to assess the adherence to PA guidelines and to investigate its associations with all-cause mortality.Methods:A total of 7601 participants(20-85+years)were drawn from the 2003-2004 and 2005-2006 National Health and Nutrition Examination Surveys(NHANES).Minutes per week of MVPA were assessed with a hip-worn accelerometer.Counts per minute(CPM)were used to define an age-sex specific target intensity,representing the intensity each person should be able to reach based on their age and sex.Age-sex specific MVPA cut-points were defined as any activity above 40%of the target intensity.These population-and free-living-based age-sex specific cut-points overcome many of the limitations of the standard generic cut-point approach.For comparison,we also calculated MVPA with a generic cut-point of 1952 CPM.Both approaches were compared for assessing adherence to PA guidelines and association of MVPA with allcause mortality(ascertained through December 2015).Results:Both approaches indicated that 37%of the sample met the 150+min/week guideline.The generic cut-point approach showed a trend to inactivity with age,which was less pronounced using the age-sex specific cut-points.Overall mortality rates were comparable using generic cutpoint(hazard ratio(HR)=0.61,95%confidence interval(95%CI):0.50-0.73)or age-sex specific cut-points(HR=0.57,95%CI:0.50-0.66)for the entire sample.The generic cut-point method revealed an age-and sex-related gap in the benefits of achieving 150+min/week of MVPA,with older adults showing an 18%greater reduction in mortality rates than younger adults,and a larger difference in women than in men.This disparity disappeared when using age-sex specific cut-points.Conclusion:Our findings underscore the value of age-sex specific cut-points for global PA surveillance.MVPA defined with age-sex specific thresholds was associated with all-cause mortality and the dose-response was similar for all ages and sexes.This aligns with the single recommendation of accumulating 150+min/week MVPA for all adults,irrespective of age and sex.This study serves as a proof of concept to develop this methodology for PA surveillance over more advanced open-source acceleration metrics and other national and international cohorts.
文摘Atrial fibrillation(AF)and heart failure(HF)are two cardiovascular diseases with an increasing prevalence worldwide.These conditions share common pathophysiologiesand frequently co-exit.In fact,the occurrence of either condition can‘cause’the development of the other,creating a new patient group that demands different management strategies to that if they occur in isolation.Regardless of the temproral association of the two conditions,their presence is linked with adverse cardi-ovascular outcomes,increased rate of hospitalizations,and increased economic burden on healthcare systems.The use of low-cost,easily accessible and applicable biomarkers may hasten the correct diagnosis and the effective treatment of AF and HF.Both AF and HF effect multiple physiological pathways and thus a great number of biomarkers can be measured that potentially give the clinician important diagnostic and prognostic information.These will then guide patient centred therapeutic management.The current biomarkers that offer potential for guiding therapy,focus on the physiological pathways of miRNA,myocardial stretch and injury,oxidative stress,inflammation,fibrosis,coagulation and renal impairment.Each of these has different utility in current clinincal practice.
文摘Heart failure is common in older people and its prevalence is increasing.The Heart ＇omics＇ in AGEing（HOMAGE） project aims to provide a biomarker approach that will improve the early diagnosis of heart failure.A large clinical database,based on（1） prospective population studies or（2） cross-sectional,prospective studies or randomized controlled trials（RCTs） of patients at risk for or with overt cardiovascular disease will be constructed to determine most promising ＇omics＇-based biomarkers to identify the risk of developing heart failure and/or comorbidities.Population studies,patient cohorts and RCTs are eligible for inclusion in the common database,if they received ethical approval to obtain and share data and have baseline information on cardiovascular risk factors.Currently,the HOMAGE database includes 43,065 subjects,from 20 studies in eight European countries,including healthy subjects from three population studies in France,Belgium and Italy（n = 7,124）,patients with heart failure（n = 4,312） from four cohorts in the UK,Spain and Switzerland and patients at high risk for cardiovascular disease（n = 31,629） in 13 cohorts.It is anticipated that more partners will join the consortium and enlarge the pooled data.This large merged database will be a useful resource with which to identify candidate biomarkers that play a role in the mechanism underlying the onset and progression of heart failure.
文摘Background: Increasing workload in consultant-led clinics often means patients to wait a long time for clinic appointments. To address this, there is an increasing trend in developing nurse-led clinics across many specialities in the National Health Service. This study aims to assess whether the implementation of a nurse-led clinic in thoracic aortic surgery will optimise the utilisation of health care services and improve overall patient satisfaction. Methods: 80 follow-up patients were asked to complete a questionnaire following their appointment in an aortic clinic, which was led either by a consultant (n = 40) or an aortic specialist nurse (n = 40). All patients seen by a nurse in the clinic were assessed by a consultant surgeon prior to the clinic for suitability. No new patients were seen by a nurse. Any patient with an aortic dimension of 5 cm or greater was seen by the consultant. If there were any complicated clinical features, the patient was seen in the consultant-led clinic. Patients were asked questions about their time spent with the respective health care professionals across 12 categories (punctuality, preparedness, understanding of concerns, clarity of speech, listening, respect, explaining, letting you talk, putting you at ease, emotional support, advice and advice for next follow-up). Patients rated each category using an ordinal scale from 0 - 10. Results: Patient scores were greater in nurse-led clinics compared to consultant-led clinics across a number of categories although only punctuality reached significance (mean 9.2 vs. 6.8, p 0.05). Conclusion: Patients were highly satisfied with the nurse-led clinic across all categories, with greater satisfaction for punctuality. These findings suggest that a nurse-led clinic can be implemented for the management of carefully selected thoracic aortic surgery patient without reduction in patient satisfaction.
基金Supported by Mandate Research Grant from Universitas Airlangga,No.1408/UN3/2019.
文摘Erectile dysfunction(ED)has been identified as one of the most frequent chronic complications of diabetes mellitus(DM).The prevalence of ED is estimated to be about 67.4%in all DM cases worldwide.The pathophysiological process leading to ED involves endothelial,neurological,hormonal,and psychological factors.In DM,endothelial and neurological factors play a crucial role.Damages in the blood vessels and erectile tissue due to insulin resistance are the hallmark of ED in DM.The current treatments for ED include phosphodiesterase-5 inhibitors and penile prosthesis surgery.However,these treatments are limited in terms of just relieving the symptoms,but not resolving the cause of the problem.The use of stem cells for treating ED is currently being studied mostly in experimental animals.The stem cells used are derived from adipose tissue,bone,or human urine.Most of the studies observed an improvement in erectile quality in the experimental animals as well as an improvement in erectile tissue.However,research on stem cell therapy for ED in humans remains to be limited.Nevertheless,significant findings from studies using animal models indicate a potential use of stem cells in the treatment of ED.
文摘Atrial fibrillation(AF) and heart failure(HF) are complex clinical entities that occur concomitantly in a significant population of patients, and their prevalence is rising in epidemic proportions. Traditionally, both rate and rhythm control strategies have been regarded as equivalent in the management of dysrhythmia in this AF-HF cohort with escalation of treatment largely guided by symptoms. Both disorders are involved in an elaborate pathophysiological interplay with shared cardiovascular risk factors that contribute to the development and sustenance of both AF and HF. Recent studies and continued development of evidence to support catheter ablation for AF has brought into question the traditional belief in equivalence between rate and rhythm control. Indeed, recent trials, in particular the CASTLE-AF(Catheter Ablation versus Standard Conventional Therapy in Patients with Left Ventricular Dysfunction and Atrial Fibrillation) study, suggest that catheter ablation for AF improves survival and rates of hospitalisation in patients with concomitant HF and AF, threatening a paradigm shift in the management of this patient cohort. The evident mortality benefit from clinical trials suggests that catheter ablation for AF should be considered as a therapeutic intervention in all suitable patients with the AF-HF syndrome as these patients may derive the greatest benefit from restoration of sinus rhythm. Further research is needed to refine the evidence base, especially to determine which subgroup of HF patients benefit most from catheter ablation and what is the optimal timing.
基金supported in part by the State Key Laboratory of Dampness Syndrome of Traditional Chinese Medicine jointly established by Guangdong Province and the Ministry(SZ2022KF10)Scientific Research Initiation Project of Guangdong Provincial Hospital of Traditional Chinese Medicine(2021KT1709)+1 种基金Guangzhou School(College)Joint Sponsorship Project for Fundamental and Applied Research(202201020605)Program of Shanghai Academic/Technology Research Leader(20XD1420900).
文摘Mitochondrial aldehyde dehydrogenase(ALDH2)offers proven cardiovascular benefit,although its impact on diabetes remains elusive.This study examined the effects of ALDH2 overexpression and knockout on diabetic cardiomyopathy and the mechanism involved with a focus on mitochondrial integrity.Mice challenged with streptozotocin(STZ,200 mg/kg,via intraperitoneal injection)exhibited pathological alterations,including reduced respiratory exchange ratio,dampened fractional shortening and ejection fraction,increased left ventricular end-systolic and diastolic diameters,cardiac remodeling,cardiomyocyte contractile anomalies,intracellular Ca2+defects,myocardial ultrastructural injury,oxidative stress,apoptosis,and mitochondrial damage,which were overtly attenuated or accentuated by ALDH2 overexpression or knockout,respectively.Diabetic patients also exhibited reduced plasma ALDH2 activity,cardiac remodeling,and diastolic dysfunction.In addition,STZ challenge altered expression levels of mitochondrial proteins(PGC-1αand UCP2)and Ca2+regulatory proteins(SERCA,Na+–Ca2+exchanger,and phospholamban),dampened autophagy and mitophagy(LC3B ratio,TOM20,Parkin,FUNDC1,and BNIP3),disrupted phosphorylation of Akt,GSK3β,and Foxo3a,and elevated PTEN phosphorylation,most of which were reversed or worsened by ALDH2 overexpression or knockout,respectively.Furthermore,the novel ALDH2 activator torezolid,as well as the classical ALDH2 activator Alda-1,protected against STZ-or high glucose-induced in vivo or in vitro cardiac anomalies,which was nullified by inhibition of Akt,GSK3β,Parkin,or mitochondrial coupling.Our data discerned a vital role for ALDH2 in diabetic cardiomyopathy possibly through regulation of Akt and GSK3βactivation,Parkin mitophagy,and mitochondrial function.
基金supported by The University of Manchester-Peking University Health Science Centre Alliance,the China Scholarships Council,and British Heart Foundation Programme Grant RG/15/12/31616.
文摘Congenital heart disease(CHD)is the commonest birth defect,affecting approximately 9.4/1000 live births.^(1)Atrial Septal Defect(ASD)is one of the commonest CHD clinical phenotypes,which frequently requires treatment either in childhood or adulthood,and can lead to severe complications such as right heart failure and cardiac arrhythmia.Previous genome-wide association studies(GWAS)have identified a region of chromosome 4p16(Ch4p16)associated with the risk of ASD.
基金The Pediatric Heart Network is funded by the National Heart,Lung,and Blood Institute,including grants HL172722,HL172707,HL172717,HL172702,HL172719,HL172695,HL172701,HL172715,HL172720,HL172706.
文摘Background:In the 1990s,there were few multicenter research collaborations and pediatric cardiovascular clinical trials.The National Heart,Lung,and Blood Institute at the National Institutes of Health established the Pediatric Heart Network(PHN)in 2001 to stimulate multi-center collaboration and clinical studies in children and adults with congenital heart disease(CHD)and pediatric acquired heart disease.Methods:The PHN developed a flexible infrastructure for multi-center collaborative clinical research in children and adults with CHD and pediatric acquired heart disease.The objectives of the PHN are to improve health outcomes in individuals of all ages with CHD and pediatric acquired heart disease,to disseminate findings to improve treatment options and standards of care,to train and educate new investigators,and to support families during the conduct of clinical research.Results:To date,the PHN has conducted 30 studies,including 13 clinical trials,across over 60 sites and has enrolled over 10,000 participants.PHN studies have impacted clinical practice and guidelines in CHD and have supported the career development of young investigators,research nurses,and study coordinators.None of this would have been possible without the many partnerships with patient advocacy organizations,the U.S.Food and Drug Administration,a variety of industry collaborators and clinical registries.PHN studies have leveraged registry data to improve efficiency,minimize burden and reduce errors in data collection.Conclusion:The PHN’s success is due to fostering collaboration across pediatric cardiology centers,creating a clinical research infrastructure that can adapt to different types of studies,and emphasizing career development of young investigators and research coordinators.This paper will summarize the PHN’s history,partnerships,use of clinical registries,future directions,and ways to get involved.
基金support of a grant from the National Natural Science Foundation of China(81530009 to Y.Y.Z.)a grant from the National Natural Science Foundation of China(81822003 and 81670205 to H.X.)a grant from Natural Science Foundation of Beijing Municipality(7191013 to E.D.D.).
文摘Cardiac fibroblast(CF)differentiation into myofibroblasts is a crucial cause of cardiac fibrosis,which increases in the extracellular matrix(ECM)stiffness.The increased stiffness further promotes CF differentiation and fibrosis.However,the molecular mechanism is still unclear.We used bioinformatics analysis to find new candidates that regulate the genes involved in stiffnessinduced CF differentiation,and found that there were binding sites for the POU-domain transcription factor,POU2F1(also known as Oct-1),in the promoters of 50 differentially expressed genes(DEGs)in CFs on the stiffer substrate.Immunofluorescent staining and Western blotting revealed that pathological stiffness upregulated POU2F1 expression and increased CF differentiation on polyacrylamide hydrogel substrates and in mouse myocardial infarction tissue.A chromatin immunoprecipitation assay showed that POU2F1 bound to the promoters of fibrosis repressors IL1R2,CD69,and TGIF2.The expression of these fibrosis repressors was inhibited on pathological substrate stiffness.Knockdown of POU2F1 upregulated these repressors and attenuated CF differentiation on pathological substrate stiffness(35 kPa).Whereas,overexpression of POU2F1 downregulated these repressors and enhanced CF differentiation.In conclusion,pathological stiffness upregulates the transcription factor POU2F1 to promote CF differentiation by inhibiting fibrosis repressors.Our work elucidated the crosstalk between CF differentiation and the ECM and provided a potential target for cardiac fibrosis treatment.
基金funded by a PhD scholarship from the Ministry ofHigher Education Malaysia(Skim Latihan Akademik Bumiputera).
文摘This paper outlines the nature of microplastic contamination in rivers and the risks to freshwater fishes.We discuss how input sources influence the concentration and composition of microplastics and examine factors that subsequently influence their spatiotemporal dynamics in a river system.We then discuss how the distributions and assemblages of microplastics can impact the risk of interactions with fishes,and the processes associated with the internalisation of microplastic into the body and across the organs and tissues.Finally,we examine the physical and toxicological effects of microplastic exposure in fish species,with special attention directed towards impacts at environmentally relevant concentrations.This review integrates expertise in fluvial geomorphological processes and how they influence the movement and storage of microplastics in river channel environments at a range of scales.We combine this knowledge with expertise in fish ecology and biology to set out a new and integrated analysis of microplastic dynamics in rivers and how these microplastics interact with fish.The integration of knowledge from these fields allows us also to comment upon the microplastic risk to fish and other biota in river environments.
