We present a comprehensive analysis of AstroSat/LAXPC data of the second spin-up and second spin-down phases of the persistent X-ray pulsar 4U 1626-67.Flares followed by a broad dip are detected in the spin-up observa...We present a comprehensive analysis of AstroSat/LAXPC data of the second spin-up and second spin-down phases of the persistent X-ray pulsar 4U 1626-67.Flares followed by a broad dip are detected in the spin-up observations.The pulse profiles changed from a shoulder-like structure to a broad sinusoidal shape as the source underwent a torque reversal from spin-up to spin-down.Energy-resolved pulse profiles in lower energies showed a double-horned profile in the spin-up state and a flat top with multiple peaks in the spin-down state.Regardless of the torque state,the pulse profiles exhibit a broad single-peaked shape at higher energies.The observation in the spin-down era is characterized by the presence of a prominent QPO at 46.5±1.0 mHz frequency.The QPO rms and center frequency show a correlation with energy.Spin-up and spin-down states show a difference in the shape of the power density spectrum.After the torque reversal,a gradual flux drop and the hardening of the spectra were observed.The difference in the shape of the pulse profiles and the presence and absence of QPOs can be explained by the change in accretion flow geometry of the pulsar,from pencil-beam to fan-beam,between spin-down and spin-up states.展开更多
This paper presents a new criterion for determining the unloading points quantitatively and consistently in a multi-stage triaxial test.The radial strain gradient(RSG)is first introduced as an arc tangent function of ...This paper presents a new criterion for determining the unloading points quantitatively and consistently in a multi-stage triaxial test.The radial strain gradient(RSG)is first introduced as an arc tangent function of the rate of change of radial strain to time.RSG is observed to correlate closely with the stress state of a compressed sample,and reaches a horizontal asymptote as approaching failure.For a given rock type,RSG value at peak stress is almost the same,irrespective of the porosity and permeability.These findings lead to the development of RSG criterion:Unloading points can be precisely determined at the time when RSG reaches a pre-determined value that is a little smaller than or equal to the RSG at peak stress.The RSG criterion is validated against other criteria and the single-stage triaxial test on various types of rocks.Failure envelopes from the RSG criterion match well with those from single-stage tests.A practical procedure is recommended to use the RSG criterion:an unconfined compression or single-stage test is first conducted to determine the RSG at peak stress for one sample,the unloading point is then selected to be a value close to the RSG at peak stress,and the multi-stage test is finally performed on another sample using the pre-selected RSG unloading criterion.Generally,the RSG criterion is applicable for any type of rocks,especially brittle rocks,where other criteria are not suitable.Further,it can be practically implemented on the most available rock mechanical testing instruments.展开更多
Robust preclinical models of transgender male(TGM) gender-affirming hormone therapy(GAHT) can inform clinicians of the isolated effects of GAHT;however existing models vary significantly in approach. We aimed to asses...Robust preclinical models of transgender male(TGM) gender-affirming hormone therapy(GAHT) can inform clinicians of the isolated effects of GAHT;however existing models vary significantly in approach. We aimed to assess existing methodology and how it influences circulating sex-hormone levels in rodent models of TGM GAHT to provide recommendations of best practise. Pub Med, Embase, and Scopus databases were systematically searched for studies that investigated GAHT in rodent models and were published from inception to the 1st of August 2024. Study characteristics and methodology were extracted and compared. Post-intervention circulating sex hormone concentrations were the primary outcome used to determine whether successful gender affirming hormone therapy had been achieved. Sixteen experimental rodent studies were included. Studies were performed on mice( n = 11) and rats( n = 5). Subcutaneous(SC) pellets and SC silastic implants were featured in some studies but weekly SC injections of testosterone enanthate was the preferred method. Sesame oil was the preferred solvent for injected testosterone formulations. Weekly doses of ~ 450 μg(mice) and ~ 420–900 μg(rats) consistently induced the testosterone levels of the male counterpart. Similarly, 10 mg of unesterified testosterone in a SC silastic implant in mice or 10 mg/100 g in rats were also successful methods. Most studies administered hormones for 6–8 weeks before performing post-treatment assessments. This review demonstrates that methods largely varied across studies and successfully identifies the effective methodological approaches that improve the reproducibility and accuracy of preclinical models. Representing an integral step forward to bridging gaps in preclinical transgender healthcare research.展开更多
Adolescent type 2 diabetes mellitus(T2DM)is on the rise in India and is commonly attributed to co-existence of overweight and obesity in adolescents.In this line,a study by Maheshwari et al titled‘Prevalence of obesi...Adolescent type 2 diabetes mellitus(T2DM)is on the rise in India and is commonly attributed to co-existence of overweight and obesity in adolescents.In this line,a study by Maheshwari et al titled‘Prevalence of obesity,determinants,and its association with hyperglycaemia among community dwelling older adolescents in India’concluded that overweight,obesity,socioeconomic factors and higher education status were responsible for hyperglycemia in adolescents aged 15-19 years in India.We highlight that there is a significant prevalence of T2DM even in normal body mass index(BMI)and below normal BMI subjects,as mentioned in their study.There is a high prevalence of normal weight obesity in Indian adolescents which often gets missed due to a large population with normal BMI in the country.In this letter,we analyze the importance of measurement of central adiposity beyond routine BMI measurements.展开更多
Today, most people know that physical activity(PA) is beneficial for their health ^(1,2)and aspire to engage in regular PA.^(3,4)However, despite their awareness of the importance of PA, it is evident that the transit...Today, most people know that physical activity(PA) is beneficial for their health ^(1,2)and aspire to engage in regular PA.^(3,4)However, despite their awareness of the importance of PA, it is evident that the transition from intention to action is challenging-a situation that has important public health implications. According to the World Health Organization,^(5)1 person dies every 6 s worldwide from causes related to physical inactivity, which underscores the urgency of addressing this situation.展开更多
Background:Elucidating mechanisms underlying atrial myopathy,which predisposes individuals to atrial fibrillation(AF),will be critical for preventing/treating AF.In a serendipitous discovery,we identified atrial enlar...Background:Elucidating mechanisms underlying atrial myopathy,which predisposes individuals to atrial fibrillation(AF),will be critical for preventing/treating AF.In a serendipitous discovery,we identified atrial enlargement,fibrosis,and thrombi in mice with reduced phosphoinositide 3-kinase(PI3K)in cardiomyocytes.PI3K(p110a)is elevated in the heart with exercise and is critical for exercise-induced ventricular enlargement and protection,but the role in the atria was unknown.Physical inactivity and extreme endurance exercise can increase AF risk.Therefore,our objective was to investigate whether too little and/or too much PI3K alone induces cardiac pathology.Methods:New cardiomyocyte-specific transgenic mice with increased or decreased PI3K(p110a)activity were generated.Multi-omics was conducted in mouse atrial tissue,and lipidomics in human plasma.Results:Elevated PI3K led to an increase in heart size with preserved/enhanced function.Reduced PI3K led to atrial dysfunction,fibrosis,arrhythmia,increased susceptibility to atrial enlargement and thrombi,and dysregulation of monosialodihexosylganglioside(GM3),a lipid that regulates insulin-like growth factor-1(IGF1)-PI3K signaling.Proteomic profiling identified distinct signatures and signaling networks acrossatria with varying degrees of dysfunction,enlargement,and thrombi,including commonalities with the human AF proteome.PI3K-related lipids were dysregulated in plasma from athletes with AF.Conclusion:PI3K(p110a)is a critical regulator of atrial biology and function in mice.This work provides a proteomic resource of candidates for further validation as potential new drug targets and biomarkers for atrial myopathy.Further investigation of PI3K-related lipids as markers for identifying individuals at risk of AF is warranted.Dysregulation of PI3K may contribute to the association between increased cardiac risk with physical inactivity and extreme endurance exercise.展开更多
Background:A greater prevalence of arrhythmias has been described in endurance athletes,but it remains unclear whether this risk persists after detraining.We aimed to evaluate the prevalence of arrhythmias and their r...Background:A greater prevalence of arrhythmias has been described in endurance athletes,but it remains unclear whether this risk persists after detraining.We aimed to evaluate the prevalence of arrhythmias and their relationship with cardiac remodeling in lifelong and retired master endurance athletes compared to non-athletic controls.Methods:We performed a cross-sectional analysis of observational studies that used echocardiography and cardiac magnetic resonance to detail cardiac structure and function,and Holter monitors to identify atrial and ventricular arrhythmias in 185 endurance athletes and 81 non-athletic controls aged≥40 years.Athletes were categorized as active lifelong(n=144)or retired(n=41)based on hours per week of high-intensity endurance exercise within 5 years of enrollment and validated by percentage of predicted maximal oxygen consumption(VO_(2max)).Athletes with overt cardiomyopathies,channelopathies,pre-excitation,and/or myocardial infarction were excluded.Results:Lifelong athletes(median age=55 years(interquartile range(IQR):46-62),79%male)were significantly fitter than retired athletes(median age=66 years(IQR:58-71),95%male)and controls(median age=53 years(IQR:48-60),96%male),respectively(predicted VO_(2max):131%±18%vs.99%±14%vs.98%±15%,p<0.001).Compared to controls,athletes in our cohort had a higher prevalence of atrial fibrillation((AF):32%vs.0%,p<0.001)and non-sustained ventricular tachycardia((NSVT):9%vs.1%,p=0.007).There was no difference in prevalence of any arrhythmia between lifelong and retired athletes.Lifelong athletes had larger ventricular volumes than retired athletes,who had ventricular volumes similar to controls(left ventricular end-diastolic volume indexed to body surface area(LVEDVi):101±20 m L/m^(2)vs.86±16 mL/m^(2)vs.94±18 mL/m^(2),p<0.001;right ventricular end-diastolic volume indexed to body surface area(RVEDVi):117±23 mL/m^(2)vs.101±19 mL/m^(2)vs.100±19 mL/m^(2),p<0.001).Athletes had more scar(40%vs.18%,p=0.002)and larger left atria(median volume=45m L/m^(2)(IQR:38-52)vs.31 mL/m^(2)(IQR:25-38),p<0.001)than controls,with no difference in atrial volumes and non-ischaemic scar between the athlete groups.Conclusion:Master endurance athletes have a higher prevalence of AF and NSVT than non-athletic controls.Whereas ventricular remodeling tends to reverse with detraining,the propensity to arrhythmias persists regardless of whether they are actively exercising or retired.展开更多
Purpose:Regular exercise can reduce incidence and progression of breast cancer,but the mechanisms for such effects are not fully understood.The purpose of this study was to examine the mechanisms behind the protective...Purpose:Regular exercise can reduce incidence and progression of breast cancer,but the mechanisms for such effects are not fully understood.The purpose of this study was to examine the mechanisms behind the protective effects of exercise.Methods:We used a variety of rodent and human experimental model systems to determine whether exercise training can reduce tumor burden in breast cancer and to identify mechanism associated with any exercise training effects on tumor burden.Results:We show that voluntary wheel running slows tumor development in the mammary specific polyomavirus middle T antigen overexpression(MMTV-PyMT)mouse model of breast cancer but only when mice are not housed alone.We identify the proteoglycan decorin as a contraction-induced secretory factor that systemically increases in patients with breast cancer immediately following exercise.Moreover,high expression of decorin in tumors is associated with improved prognosis in patients,while treatment of breast cancer cells in vitro with decorin reduces cell proliferation.Notwithstanding,when we overexpressed decorin in murine muscle or injected recombinant decorin systemically into mouse models of breast cancer,elevated plasma decorin concentrations did not result in higher tumor decorin levels and tumor burden was not improved.Conclusion:Exercise training is anti-tumorigenic in a mouse model of luminal breast cancer,but the effect is abrogated by social isolation.The proteoglycan decorin is an exercise-induced secretory protein,and tumor decorin levels are positively associated with improved prognosis in patients.The hypothesis that elevated plasma decorin is a mechanism by which exercise training improves breast cancer progression in humans is not,however,supported by our pre-clinical data since elevated circulating decorin did not increase tumor decorin levels in these models.展开更多
基金financial support from ISRO(Sanction Order:No.DS_2B-13013(2)/3/2021-Sec.2)。
文摘We present a comprehensive analysis of AstroSat/LAXPC data of the second spin-up and second spin-down phases of the persistent X-ray pulsar 4U 1626-67.Flares followed by a broad dip are detected in the spin-up observations.The pulse profiles changed from a shoulder-like structure to a broad sinusoidal shape as the source underwent a torque reversal from spin-up to spin-down.Energy-resolved pulse profiles in lower energies showed a double-horned profile in the spin-up state and a flat top with multiple peaks in the spin-down state.Regardless of the torque state,the pulse profiles exhibit a broad single-peaked shape at higher energies.The observation in the spin-down era is characterized by the presence of a prominent QPO at 46.5±1.0 mHz frequency.The QPO rms and center frequency show a correlation with energy.Spin-up and spin-down states show a difference in the shape of the power density spectrum.After the torque reversal,a gradual flux drop and the hardening of the spectra were observed.The difference in the shape of the pulse profiles and the presence and absence of QPOs can be explained by the change in accretion flow geometry of the pulsar,from pencil-beam to fan-beam,between spin-down and spin-up states.
文摘This paper presents a new criterion for determining the unloading points quantitatively and consistently in a multi-stage triaxial test.The radial strain gradient(RSG)is first introduced as an arc tangent function of the rate of change of radial strain to time.RSG is observed to correlate closely with the stress state of a compressed sample,and reaches a horizontal asymptote as approaching failure.For a given rock type,RSG value at peak stress is almost the same,irrespective of the porosity and permeability.These findings lead to the development of RSG criterion:Unloading points can be precisely determined at the time when RSG reaches a pre-determined value that is a little smaller than or equal to the RSG at peak stress.The RSG criterion is validated against other criteria and the single-stage triaxial test on various types of rocks.Failure envelopes from the RSG criterion match well with those from single-stage tests.A practical procedure is recommended to use the RSG criterion:an unconfined compression or single-stage test is first conducted to determine the RSG at peak stress for one sample,the unloading point is then selected to be a value close to the RSG at peak stress,and the multi-stage test is finally performed on another sample using the pre-selected RSG unloading criterion.Generally,the RSG criterion is applicable for any type of rocks,especially brittle rocks,where other criteria are not suitable.Further,it can be practically implemented on the most available rock mechanical testing instruments.
文摘Robust preclinical models of transgender male(TGM) gender-affirming hormone therapy(GAHT) can inform clinicians of the isolated effects of GAHT;however existing models vary significantly in approach. We aimed to assess existing methodology and how it influences circulating sex-hormone levels in rodent models of TGM GAHT to provide recommendations of best practise. Pub Med, Embase, and Scopus databases were systematically searched for studies that investigated GAHT in rodent models and were published from inception to the 1st of August 2024. Study characteristics and methodology were extracted and compared. Post-intervention circulating sex hormone concentrations were the primary outcome used to determine whether successful gender affirming hormone therapy had been achieved. Sixteen experimental rodent studies were included. Studies were performed on mice( n = 11) and rats( n = 5). Subcutaneous(SC) pellets and SC silastic implants were featured in some studies but weekly SC injections of testosterone enanthate was the preferred method. Sesame oil was the preferred solvent for injected testosterone formulations. Weekly doses of ~ 450 μg(mice) and ~ 420–900 μg(rats) consistently induced the testosterone levels of the male counterpart. Similarly, 10 mg of unesterified testosterone in a SC silastic implant in mice or 10 mg/100 g in rats were also successful methods. Most studies administered hormones for 6–8 weeks before performing post-treatment assessments. This review demonstrates that methods largely varied across studies and successfully identifies the effective methodological approaches that improve the reproducibility and accuracy of preclinical models. Representing an integral step forward to bridging gaps in preclinical transgender healthcare research.
文摘Adolescent type 2 diabetes mellitus(T2DM)is on the rise in India and is commonly attributed to co-existence of overweight and obesity in adolescents.In this line,a study by Maheshwari et al titled‘Prevalence of obesity,determinants,and its association with hyperglycaemia among community dwelling older adolescents in India’concluded that overweight,obesity,socioeconomic factors and higher education status were responsible for hyperglycemia in adolescents aged 15-19 years in India.We highlight that there is a significant prevalence of T2DM even in normal body mass index(BMI)and below normal BMI subjects,as mentioned in their study.There is a high prevalence of normal weight obesity in Indian adolescents which often gets missed due to a large population with normal BMI in the country.In this letter,we analyze the importance of measurement of central adiposity beyond routine BMI measurements.
基金supported by The Shenzhen Educational Research Funding(zdzb2014)The Shenzhen Science and Technology Innovation Commission(202307313000096)+4 种基金The Social Science Foundation from the China's Ministry of Education(23YJA880093)The Post-Doctoral Fellowship(2022M711174)The National Center for Mental Health(Z014)BC is supported by the Chaires de recherche Rennes Métropole(23C 0909)SM is supported by the National Insti-tutes of Health(R01AG72445).
文摘Today, most people know that physical activity(PA) is beneficial for their health ^(1,2)and aspire to engage in regular PA.^(3,4)However, despite their awareness of the importance of PA, it is evident that the transition from intention to action is challenging-a situation that has important public health implications. According to the World Health Organization,^(5)1 person dies every 6 s worldwide from causes related to physical inactivity, which underscores the urgency of addressing this situation.
基金supported by grants from NHMRC(Grant No.1125514 and 2029334 to JRM,and 1120129 to JRM and CEH)National Heart Foundation of Australia(Vanguard-105720)+6 种基金the Victorian Government’s Operational Infrastructure Support Programsupported by a joint Baker Heart and Diabetes Institute-La Trobe University doctoral scholarshipsupported by Future Leader Fellowships from the National Heart Foundation of Australia(Grant No.102536 to EJH,102539 to KLW,and 102206 to ALG)supported by an Alice Baker and Eleanor Shaw Fellowship(The Baker Foundation,Australia)supported by a NHMRC Senior Research(Grant No.1078985)Baker Fellowship(The Baker Foundation,Australia)Cardiovascular Research Capacity Program-Research Leadership GrantsCardiovascular Research Capacity Program-Research Leadership Grants(NSW Health)。
文摘Background:Elucidating mechanisms underlying atrial myopathy,which predisposes individuals to atrial fibrillation(AF),will be critical for preventing/treating AF.In a serendipitous discovery,we identified atrial enlargement,fibrosis,and thrombi in mice with reduced phosphoinositide 3-kinase(PI3K)in cardiomyocytes.PI3K(p110a)is elevated in the heart with exercise and is critical for exercise-induced ventricular enlargement and protection,but the role in the atria was unknown.Physical inactivity and extreme endurance exercise can increase AF risk.Therefore,our objective was to investigate whether too little and/or too much PI3K alone induces cardiac pathology.Methods:New cardiomyocyte-specific transgenic mice with increased or decreased PI3K(p110a)activity were generated.Multi-omics was conducted in mouse atrial tissue,and lipidomics in human plasma.Results:Elevated PI3K led to an increase in heart size with preserved/enhanced function.Reduced PI3K led to atrial dysfunction,fibrosis,arrhythmia,increased susceptibility to atrial enlargement and thrombi,and dysregulation of monosialodihexosylganglioside(GM3),a lipid that regulates insulin-like growth factor-1(IGF1)-PI3K signaling.Proteomic profiling identified distinct signatures and signaling networks acrossatria with varying degrees of dysfunction,enlargement,and thrombi,including commonalities with the human AF proteome.PI3K-related lipids were dysregulated in plasma from athletes with AF.Conclusion:PI3K(p110a)is a critical regulator of atrial biology and function in mice.This work provides a proteomic resource of candidates for further validation as potential new drug targets and biomarkers for atrial myopathy.Further investigation of PI3K-related lipids as markers for identifying individuals at risk of AF is warranted.Dysregulation of PI3K may contribute to the association between increased cardiac risk with physical inactivity and extreme endurance exercise.
基金funded by the National Health and Medical Research Council of Australia(Grant No.APP1130353)supported by a Royal Australian College of Physicians Research Entry Scholarship(Grant No.2023RES00039)+4 种基金The National Health and Medical Research Council Postgraduate Scholarship(Grant No.2031119)a Heart Foundation PhD Scholarship(Grant No.107659)supported through an Australian Government Research Training Program Scholarshipsupported as a postdoctoral clinical researcher by the Fund for Scientific Research Flanderssupported by a National Health and Medical Research Council of Australia Investigator Grant(Grant No.APP 2027105)。
文摘Background:A greater prevalence of arrhythmias has been described in endurance athletes,but it remains unclear whether this risk persists after detraining.We aimed to evaluate the prevalence of arrhythmias and their relationship with cardiac remodeling in lifelong and retired master endurance athletes compared to non-athletic controls.Methods:We performed a cross-sectional analysis of observational studies that used echocardiography and cardiac magnetic resonance to detail cardiac structure and function,and Holter monitors to identify atrial and ventricular arrhythmias in 185 endurance athletes and 81 non-athletic controls aged≥40 years.Athletes were categorized as active lifelong(n=144)or retired(n=41)based on hours per week of high-intensity endurance exercise within 5 years of enrollment and validated by percentage of predicted maximal oxygen consumption(VO_(2max)).Athletes with overt cardiomyopathies,channelopathies,pre-excitation,and/or myocardial infarction were excluded.Results:Lifelong athletes(median age=55 years(interquartile range(IQR):46-62),79%male)were significantly fitter than retired athletes(median age=66 years(IQR:58-71),95%male)and controls(median age=53 years(IQR:48-60),96%male),respectively(predicted VO_(2max):131%±18%vs.99%±14%vs.98%±15%,p<0.001).Compared to controls,athletes in our cohort had a higher prevalence of atrial fibrillation((AF):32%vs.0%,p<0.001)and non-sustained ventricular tachycardia((NSVT):9%vs.1%,p=0.007).There was no difference in prevalence of any arrhythmia between lifelong and retired athletes.Lifelong athletes had larger ventricular volumes than retired athletes,who had ventricular volumes similar to controls(left ventricular end-diastolic volume indexed to body surface area(LVEDVi):101±20 m L/m^(2)vs.86±16 mL/m^(2)vs.94±18 mL/m^(2),p<0.001;right ventricular end-diastolic volume indexed to body surface area(RVEDVi):117±23 mL/m^(2)vs.101±19 mL/m^(2)vs.100±19 mL/m^(2),p<0.001).Athletes had more scar(40%vs.18%,p=0.002)and larger left atria(median volume=45m L/m^(2)(IQR:38-52)vs.31 mL/m^(2)(IQR:25-38),p<0.001)than controls,with no difference in atrial volumes and non-ischaemic scar between the athlete groups.Conclusion:Master endurance athletes have a higher prevalence of AF and NSVT than non-athletic controls.Whereas ventricular remodeling tends to reverse with detraining,the propensity to arrhythmias persists regardless of whether they are actively exercising or retired.
基金supported by an NHMRC Investigator Grant (APP1194141)supported by project grants from the NHMRC (APP1042465, APP1041760, and APP1156511)。
文摘Purpose:Regular exercise can reduce incidence and progression of breast cancer,but the mechanisms for such effects are not fully understood.The purpose of this study was to examine the mechanisms behind the protective effects of exercise.Methods:We used a variety of rodent and human experimental model systems to determine whether exercise training can reduce tumor burden in breast cancer and to identify mechanism associated with any exercise training effects on tumor burden.Results:We show that voluntary wheel running slows tumor development in the mammary specific polyomavirus middle T antigen overexpression(MMTV-PyMT)mouse model of breast cancer but only when mice are not housed alone.We identify the proteoglycan decorin as a contraction-induced secretory factor that systemically increases in patients with breast cancer immediately following exercise.Moreover,high expression of decorin in tumors is associated with improved prognosis in patients,while treatment of breast cancer cells in vitro with decorin reduces cell proliferation.Notwithstanding,when we overexpressed decorin in murine muscle or injected recombinant decorin systemically into mouse models of breast cancer,elevated plasma decorin concentrations did not result in higher tumor decorin levels and tumor burden was not improved.Conclusion:Exercise training is anti-tumorigenic in a mouse model of luminal breast cancer,but the effect is abrogated by social isolation.The proteoglycan decorin is an exercise-induced secretory protein,and tumor decorin levels are positively associated with improved prognosis in patients.The hypothesis that elevated plasma decorin is a mechanism by which exercise training improves breast cancer progression in humans is not,however,supported by our pre-clinical data since elevated circulating decorin did not increase tumor decorin levels in these models.
