This paper discusses ancestral hall architecture within the context of the Cantonese folk lineage in the Pearl River Delta.Using a typological research approach and chronological analysis,various factors that have inf...This paper discusses ancestral hall architecture within the context of the Cantonese folk lineage in the Pearl River Delta.Using a typological research approach and chronological analysis,various factors that have influenced the evolution of ancestral hall architecture are analyzed.The study specifically investigates the features of ancestral halls during the Ming and Qing dynasties.Three periods of ancient China are analyzed:The transition from Ming to Qing,the mid-Qing dynasty,and the late Qing dynasty.The variables of each period and how they influence the evolution of architectural typological features are identified.Based on our analysis,architectural features are related to economic and social factors,materials available,and craftsmanship of the construction workers.展开更多
This paper studies the clan temples in four periods,namely,the development period(early Ming Dynasty and before),the shaping period(mid-Ming Dynasty to early Qing Dynasty),the maturity period(mid-Qing Dynasty),and the...This paper studies the clan temples in four periods,namely,the development period(early Ming Dynasty and before),the shaping period(mid-Ming Dynasty to early Qing Dynasty),the maturity period(mid-Qing Dynasty),and the programmed period(late Qing Dynasty),analyzes and summarizes their prototypical planform features and attempts to summarize and construct a genealogy of the architectural characteristics of the plane shape of clan temples.During the Ming and Qing dynasties,Guangfu ancestral halls in general showed a journey of development from a centripetal-single-linear-multi-linear-grid pattern,forming the unique Guangsanlu classic pattern in the Guangfu area.展开更多
Purpose: To observe the refractive status, especially the tendency for evolution of high myopia, in eyes of Chinese school children from Xi’an city.Methods: The study was conducted in 11514 eyes of the 5757students a...Purpose: To observe the refractive status, especially the tendency for evolution of high myopia, in eyes of Chinese school children from Xi’an city.Methods: The study was conducted in 11514 eyes of the 5757students aged between 7~18 years in Xi’an city primary and high schools. The inclusion criterion was >-6D of the spherical equivalent refraction. The object ophthalmic examinations were done, included non-cycloplegic objective refraction, visual acuity, intraocular pressure, fundus evaluation by ophthalmologists and nurses with professional training. Specially designed questionnaires were filled in and the data were statistically analyzed with SPSS10.0.Results: Of 11514 eyes, the detection rate was 81.4%(9376eyes) for myopia and 5.3%(615 eyes) for high myopia. High myopia was found in 2.6%.(300 eyes).of right eyes, 2.7%(315 eyes) in left eyes, and 2.4%(275 eyes) were in boys and 2.9%(340 eyes) in girls. Among 12 school grades, the detection rates of high myopia increased significantly with student age, with 0.9% in the 1stgrade of primary school and12.5% in the 3rd year of senior middle school. The average refractive error of spherical equivalent refraction was(-7.43±1.29) D with 95% confidence interval(-7.54,-7.33). No significant differences were found between the right and left eyes or both genders. The distribution of myopic severity was lowest(-6D).in primary school students younger than 12 years,was higher(-8D) in junior middle school students older than13 years, and highest(-13D) in senior middle school students.Conclusion: A continuous growth was evident in the severity of high myopia throughout 12 years of primary and middle school except for the first year of primary school, with growth occurring in two transitional stages between the senior primary and junior middle school years, and between the junior and senior middle school years. The distribution of high myopia was lowest, at-6D, in primary school, increased to-8D in junior middle school, and progressed to-10D in senior middle school, indicating a high risk of development of pathologic myopia during the students’ later lifespan. The adolescent period of 13 to 18 years of age in middle school is a critical period for the development of pathological myopia over-8D.展开更多
Electromagnetic radiation environment is one of the important environmental factors. In resent 20 years, the applications of electromagnetic technology became more and more popular. However, electromagnetic environmen...Electromagnetic radiation environment is one of the important environmental factors. In resent 20 years, the applications of electromagnetic technology became more and more popular. However, electromagnetic environment makes some negative impacts on the surrounding environments and human health, and Environmental Management and Research Department pay a lot attention to it. It will make a great significance if we study of the simulation technique for urban electromagnetic environment which supported by GIS. This paper presents some key technologies of the electromagnetic environment simulation, including terrain rendering, city building modeling and volume data superposition, basically realize the visualization of volume data (electromagnetic fields) based on city building model and real time mapping of virtual scene data.展开更多
Background and aims:Type 2 diabetes mellitus remains a substantial medical problem with increasing global prevalence.Pharmacological research is becoming increasingly focused on personalized treatment strategies.Drug ...Background and aims:Type 2 diabetes mellitus remains a substantial medical problem with increasing global prevalence.Pharmacological research is becoming increasingly focused on personalized treatment strategies.Drug development based on glucokinase(GK)activation is an important strategy for lowering blood glucose.This study aimed to investigate the effect of GK activation on glucose and lipid metabolism in diet-induced obese mice.Materials and methods:Mice were fed with a high-fat diet(HFD)for 16 weeks to induce obesity,followed by a GK activator(GKA,AZD1656)or vehicle treatment by gavage for 4 weeks.The effect of GKA treatment on glucose metabolism was evaluated using glucose and insulin tolerance tests.Hepatic lipid accumulation was assessed by hematoxylin and eosin staining,Oil Red O staining,and transmission electron microscopy.The underlying mechanism of GK activation in glucose and lipid metabolism in the liver was studied using transcriptomic analysis,with a mechanistic study in mouse livers in vivo and AML12 cells in vitro.Results:GK activation by GKA treatment improved glucose tolerance in HFD-fed mice while increasing hepatic lipid accumulation.Transcriptomic analysis of liver tissues indicated the lipogenesis and protein kinase RNA-like endoplasmic reticulum kinase(PERK)-unfolded protein response(UPR)pathway activations in GKA-treated HFD-fed mice.Inhibition of the ACC activity,which is an important protein in lipogenesis,attenuated GKA treatment-induced lipid accumulation and PERK-UPR activation in vitro.Conclusions:GK activation improved glucose tolerance and insulin sensitivity while inducing hepatic lipid accumulation by increasing the lipogenic gene expression,which subsequently activated the hepatic PERK-UPR signaling pathway.展开更多
Lung cancer is the leading cause of cancer-related deaths. Traditional chemotherapy causes serious toxicity due to the wide bodily distribution of these drugs. Curcumin is a potential anticancer agent but its low wate...Lung cancer is the leading cause of cancer-related deaths. Traditional chemotherapy causes serious toxicity due to the wide bodily distribution of these drugs. Curcumin is a potential anticancer agent but its low water solubility, poor bioavailability and rapid metabolism significantly limits clinical applications. Here we developed a liposomal curcumin dry powder inhaler(LCD) for inhalation treatment of primary lung cancer. LCDs were obtained from curcumin liposomes after freeze-drying. The LCDs had a mass mean aerodynamic diameter of 5.81 μm and a fine particle fraction of 46.71%, suitable for pulmonary delivery. The uptake of curcumin liposomes by human lung cancer A549 cells was markedly greater and faster than that of free curcumin. The high cytotoxicity on A549 cells and the low cytotoxicity of curcumin liposomes on normal human bronchial BEAS-2B epithelial cells yielded a high selection index partly due to increased cell apoptosis. Curcumin powders, LCDs and gemcitabine were directly sprayed into the lungs of rats with lung cancer through the trachea. LCDs showed higher anticancer effects than the other two medications with regard to pathology and the expression of many cancer-related markers including VEGF, malondialdehyde, TNF-α, caspase-3 and BCL-2. LCDs are a promising medication for inhalation treatment of lung cancer with high therapeutic efficiency.展开更多
Type 1 diabetes mellitus(T1D)is a chronic autoimmune condition in which the immune system destroys insulin-producing pancreatic β cells.In addition to well-established pathogenic effector T cells,regulatory T cells(T...Type 1 diabetes mellitus(T1D)is a chronic autoimmune condition in which the immune system destroys insulin-producing pancreatic β cells.In addition to well-established pathogenic effector T cells,regulatory T cells(Tregs)have also been shown to be defective in T1D.Thus,an increasing number of therapeutic approaches are being developed to target Tregs.However,the role and mechanisms of TGF-β-induced Tregs(iTregs)in T1D remain poorly understood.Here,using a streptozotocin(STZ)-induced preclinical T1D mouse model,we found that iTregs could ameliorate the development of T1D and preserve β cell function.The preventive effect was associated with the inhibition of type 1 cytotoxic T(Tel)cell function and rebalancing the Treg/Tc1 cell ratio in recipients.Furthermore,we showed that the underlying mechanisms were due to the TGF-β-mediated combinatorial actions of mTOR and TCF1.In addition to the preventive role,the therapeutic effects of iTregs on the established STZ-T1D and nonobese diabetic(NOD)mouse models were tested,which revealed improved β cell function.Our findings therefore provide key new insights into the basic mechanisms involved in the therapeutic role of iTregs in T1D.展开更多
Type 2 diabetes(T2D)is highly associated with obesity.However,the factors that drive the transition from excessive weight gain to glucose metabolism disruption are still uncertain and seem to revolve around systemic i...Type 2 diabetes(T2D)is highly associated with obesity.However,the factors that drive the transition from excessive weight gain to glucose metabolism disruption are still uncertain and seem to revolve around systemic immune disorder.Mucosal-associated invariant T(MAIT)cells,which are innate-like T cells that recognize bacterial metabolites,have been reported to be altered in obese people and to lead to metabolic dysfunction during obesity.By studying the immunophenotypes of blood MAIT cells from a cross-sectional cohort of obese participants with/without T2D,we found an elevation in CD27^(-)negative(CD27−)MAIT cells producing a high level of IL-17 under T2D obese conditions,which could be positively correlated with impaired glucose metabolism in obese people.We further explored microbial translocation caused by gut barrier dysfunction in obese people as a triggering factor of MAIT cell abnormalities.Specifically,accumulation of the bacterial strain Bacteroides ovatus in the peripheral blood drove IL-17^(-)producing CD27−MAIT cell expansion and could be associated with T2D risk in obese individuals.Overall,these results suggest that an aberrant gut microbiota–immune axis in obese people may drive or exacerbate T2D.Importantly,CD27−MAIT cell subsets and Bacteroides ovatus could represent targets for novel interventional strategies.Our findings extend current knowledge regarding the clinical relevance of body mass index(BMI)-associated variation in circulating MAIT cells to reveal the role of these cells in obesity-related T2D progression and the underlying cellular mechanisms.展开更多
Solar energy,which is essential for the origin and evolution of all life forms on Earth,can be objectively recorded through attributes such as climatic ambient temperature(CAT),ultraviolet radiation(UVR),and sunlight ...Solar energy,which is essential for the origin and evolution of all life forms on Earth,can be objectively recorded through attributes such as climatic ambient temperature(CAT),ultraviolet radiation(UVR),and sunlight duration(SD).These attributes have specific geographical variations and may cause different adaptation traits.However,the adaptation profile of each attribute and the selective role of solar energy as a whole during human evolution remain elusive.Here,we performed a genome-wide adaptation study with respect to CAT,UVR,and SD using the Human Genome Diversity Project-Centre Etude Polymorphism Humain(HGDP-CEPH)panel data.We singled out CAT as the most important driving force with the highest number of adaptive loci(6 SNPs at the genome-wide 1×10^(-7)level;401 at the suggestive 1×10^(-5)level).Five of the six genomewide significant adaptation SNPs were successfully replicated in an independent Chinese population(N=1395).The corresponding 316 CAT adaptation genes were mostly involved in development and immunity.In addition,265(84%)genes were related to at least one genome-wide association study(GWAS)-mapped human trait,being significantly enriched in anthropometric loci such as those associated with body mass index(χ^(2);P<0.005),immunity,metabolic syndrome,and cancer(χ^(2);P<0.05).For these adaptive SNPs,balancing selection was evident in Euro-Asians,whereas obvious positive and/or purifying selection was observed in Africans.Taken together,our study indicates that CAT is the most important attribute of solar energy that has driven genetic adaptation in development and immunity among global human populations.It also supports the non-neutral hypothesis for the origin of disease-predisposition alleles in common diseases.展开更多
Previous studies by us and others demonstrated that activation of Wnt/β-catenin signaling plays a pathogenic role in chronic kidney diseases(CKD).Wnt co-receptor LRP5 variants are reported to associate with autosomal...Previous studies by us and others demonstrated that activation of Wnt/β-catenin signaling plays a pathogenic role in chronic kidney diseases(CKD).Wnt co-receptor LRP5 variants are reported to associate with autosomal dominant polycystic kidney disease;but their exact roles in this disease and renal fibrosis have not been explored.Here,we observed the upregulation of LRP5 in the renal tubules of both type 1 and type 2 diabetic models and of an obstructive nephropathy model.In the obstructed kidneys,Lrp5 knockout significantly ameliorated tubulointerstitial fibrosis and tubular injury without changing Wnt/β-catenin signaling.Instead,decreased levels of TGF-β1 and TGF-βreceptors(TβRs)were detected in Lrp5 knockout kidneys,followed by attenuated activation and nuclear translocation of Smad2/3 in the renal tubules,suggesting a regulatory effect of LRP5 on TGF-β/Smad signaling.In consistent with this hypothesis,LRP5 overexpression resulted in enhanced TGF-β/Smad signaling activation in renal tubule epithelial cells.Furthermore,LRP5 was co-immunoprecipitated with TβRI and TβRII,and its extracellular domain was essential for interacting with TβRs and for its pro-fibrotic activity.In addition to stabilizing TβRs,LRP5 increased the basal membrane presentation and TGF-β1-induced internalization of these receptors.Notably,TGF-β1 also induced LRP5 internalization.These findings indicate that LRP5 promotes tubulointerstitial fibrosis,at least partially,via direct modulation of TGF-β/Smad signaling,a novel,Wnt-independent function.展开更多
文摘This paper discusses ancestral hall architecture within the context of the Cantonese folk lineage in the Pearl River Delta.Using a typological research approach and chronological analysis,various factors that have influenced the evolution of ancestral hall architecture are analyzed.The study specifically investigates the features of ancestral halls during the Ming and Qing dynasties.Three periods of ancient China are analyzed:The transition from Ming to Qing,the mid-Qing dynasty,and the late Qing dynasty.The variables of each period and how they influence the evolution of architectural typological features are identified.Based on our analysis,architectural features are related to economic and social factors,materials available,and craftsmanship of the construction workers.
文摘This paper studies the clan temples in four periods,namely,the development period(early Ming Dynasty and before),the shaping period(mid-Ming Dynasty to early Qing Dynasty),the maturity period(mid-Qing Dynasty),and the programmed period(late Qing Dynasty),analyzes and summarizes their prototypical planform features and attempts to summarize and construct a genealogy of the architectural characteristics of the plane shape of clan temples.During the Ming and Qing dynasties,Guangfu ancestral halls in general showed a journey of development from a centripetal-single-linear-multi-linear-grid pattern,forming the unique Guangsanlu classic pattern in the Guangfu area.
基金Supported by Shaanxi Province Scientific&Technology Committee(No.2009K17-02)
文摘Purpose: To observe the refractive status, especially the tendency for evolution of high myopia, in eyes of Chinese school children from Xi’an city.Methods: The study was conducted in 11514 eyes of the 5757students aged between 7~18 years in Xi’an city primary and high schools. The inclusion criterion was >-6D of the spherical equivalent refraction. The object ophthalmic examinations were done, included non-cycloplegic objective refraction, visual acuity, intraocular pressure, fundus evaluation by ophthalmologists and nurses with professional training. Specially designed questionnaires were filled in and the data were statistically analyzed with SPSS10.0.Results: Of 11514 eyes, the detection rate was 81.4%(9376eyes) for myopia and 5.3%(615 eyes) for high myopia. High myopia was found in 2.6%.(300 eyes).of right eyes, 2.7%(315 eyes) in left eyes, and 2.4%(275 eyes) were in boys and 2.9%(340 eyes) in girls. Among 12 school grades, the detection rates of high myopia increased significantly with student age, with 0.9% in the 1stgrade of primary school and12.5% in the 3rd year of senior middle school. The average refractive error of spherical equivalent refraction was(-7.43±1.29) D with 95% confidence interval(-7.54,-7.33). No significant differences were found between the right and left eyes or both genders. The distribution of myopic severity was lowest(-6D).in primary school students younger than 12 years,was higher(-8D) in junior middle school students older than13 years, and highest(-13D) in senior middle school students.Conclusion: A continuous growth was evident in the severity of high myopia throughout 12 years of primary and middle school except for the first year of primary school, with growth occurring in two transitional stages between the senior primary and junior middle school years, and between the junior and senior middle school years. The distribution of high myopia was lowest, at-6D, in primary school, increased to-8D in junior middle school, and progressed to-10D in senior middle school, indicating a high risk of development of pathologic myopia during the students’ later lifespan. The adolescent period of 13 to 18 years of age in middle school is a critical period for the development of pathological myopia over-8D.
文摘Electromagnetic radiation environment is one of the important environmental factors. In resent 20 years, the applications of electromagnetic technology became more and more popular. However, electromagnetic environment makes some negative impacts on the surrounding environments and human health, and Environmental Management and Research Department pay a lot attention to it. It will make a great significance if we study of the simulation technique for urban electromagnetic environment which supported by GIS. This paper presents some key technologies of the electromagnetic environment simulation, including terrain rendering, city building modeling and volume data superposition, basically realize the visualization of volume data (electromagnetic fields) based on city building model and real time mapping of virtual scene data.
基金This research was funded by Natural Science Foundation of Guangdong Province(2018B030311012)Natural Science Foundation of China(82070811,81770826)+2 种基金Sci-Tech Research Development Program of Guangzhou City(202201020497)National Key R&D Program of China(2017YFA0105803)Key Area R&D Program of Guangdong Province(2019B020227003).
文摘Background and aims:Type 2 diabetes mellitus remains a substantial medical problem with increasing global prevalence.Pharmacological research is becoming increasingly focused on personalized treatment strategies.Drug development based on glucokinase(GK)activation is an important strategy for lowering blood glucose.This study aimed to investigate the effect of GK activation on glucose and lipid metabolism in diet-induced obese mice.Materials and methods:Mice were fed with a high-fat diet(HFD)for 16 weeks to induce obesity,followed by a GK activator(GKA,AZD1656)or vehicle treatment by gavage for 4 weeks.The effect of GKA treatment on glucose metabolism was evaluated using glucose and insulin tolerance tests.Hepatic lipid accumulation was assessed by hematoxylin and eosin staining,Oil Red O staining,and transmission electron microscopy.The underlying mechanism of GK activation in glucose and lipid metabolism in the liver was studied using transcriptomic analysis,with a mechanistic study in mouse livers in vivo and AML12 cells in vitro.Results:GK activation by GKA treatment improved glucose tolerance in HFD-fed mice while increasing hepatic lipid accumulation.Transcriptomic analysis of liver tissues indicated the lipogenesis and protein kinase RNA-like endoplasmic reticulum kinase(PERK)-unfolded protein response(UPR)pathway activations in GKA-treated HFD-fed mice.Inhibition of the ACC activity,which is an important protein in lipogenesis,attenuated GKA treatment-induced lipid accumulation and PERK-UPR activation in vitro.Conclusions:GK activation improved glucose tolerance and insulin sensitivity while inducing hepatic lipid accumulation by increasing the lipogenic gene expression,which subsequently activated the hepatic PERK-UPR signaling pathway.
文摘Lung cancer is the leading cause of cancer-related deaths. Traditional chemotherapy causes serious toxicity due to the wide bodily distribution of these drugs. Curcumin is a potential anticancer agent but its low water solubility, poor bioavailability and rapid metabolism significantly limits clinical applications. Here we developed a liposomal curcumin dry powder inhaler(LCD) for inhalation treatment of primary lung cancer. LCDs were obtained from curcumin liposomes after freeze-drying. The LCDs had a mass mean aerodynamic diameter of 5.81 μm and a fine particle fraction of 46.71%, suitable for pulmonary delivery. The uptake of curcumin liposomes by human lung cancer A549 cells was markedly greater and faster than that of free curcumin. The high cytotoxicity on A549 cells and the low cytotoxicity of curcumin liposomes on normal human bronchial BEAS-2B epithelial cells yielded a high selection index partly due to increased cell apoptosis. Curcumin powders, LCDs and gemcitabine were directly sprayed into the lungs of rats with lung cancer through the trachea. LCDs showed higher anticancer effects than the other two medications with regard to pathology and the expression of many cancer-related markers including VEGF, malondialdehyde, TNF-α, caspase-3 and BCL-2. LCDs are a promising medication for inhalation treatment of lung cancer with high therapeutic efficiency.
基金supported by the National Key R&D Program of China(2017YFAO105803)the general program of the National Natural Science Foundation of China(81770826)+2 种基金the Science and Technology Plan Projects of Guangdong Province(2019B020227003)the Key Special Projects of Medical and Health of Guangzhou City(202007040003)the 5010 Clinical Research Projects of Sun Yatsen University(2015015).
文摘Type 1 diabetes mellitus(T1D)is a chronic autoimmune condition in which the immune system destroys insulin-producing pancreatic β cells.In addition to well-established pathogenic effector T cells,regulatory T cells(Tregs)have also been shown to be defective in T1D.Thus,an increasing number of therapeutic approaches are being developed to target Tregs.However,the role and mechanisms of TGF-β-induced Tregs(iTregs)in T1D remain poorly understood.Here,using a streptozotocin(STZ)-induced preclinical T1D mouse model,we found that iTregs could ameliorate the development of T1D and preserve β cell function.The preventive effect was associated with the inhibition of type 1 cytotoxic T(Tel)cell function and rebalancing the Treg/Tc1 cell ratio in recipients.Furthermore,we showed that the underlying mechanisms were due to the TGF-β-mediated combinatorial actions of mTOR and TCF1.In addition to the preventive role,the therapeutic effects of iTregs on the established STZ-T1D and nonobese diabetic(NOD)mouse models were tested,which revealed improved β cell function.Our findings therefore provide key new insights into the basic mechanisms involved in the therapeutic role of iTregs in T1D.
基金This study was funded by the National Key R&D Program of China(2017YFA0105803)the National Natural Science Foundation of China(32000621 and 81770826)+3 种基金the Key Area R&D Program of Guangdong Province(2019B020227003)the Science and Technology Plan Project of Guangzhou City(202102010338 and 202007040003)the 5010 Clinical Research Projects of Sun Yat-sen University(2015015)the Dengfeng Plan High-level Hospital Construction Opening Project of Foshan Fourth People’s Hospital(FSSYKF-2020009).
文摘Type 2 diabetes(T2D)is highly associated with obesity.However,the factors that drive the transition from excessive weight gain to glucose metabolism disruption are still uncertain and seem to revolve around systemic immune disorder.Mucosal-associated invariant T(MAIT)cells,which are innate-like T cells that recognize bacterial metabolites,have been reported to be altered in obese people and to lead to metabolic dysfunction during obesity.By studying the immunophenotypes of blood MAIT cells from a cross-sectional cohort of obese participants with/without T2D,we found an elevation in CD27^(-)negative(CD27−)MAIT cells producing a high level of IL-17 under T2D obese conditions,which could be positively correlated with impaired glucose metabolism in obese people.We further explored microbial translocation caused by gut barrier dysfunction in obese people as a triggering factor of MAIT cell abnormalities.Specifically,accumulation of the bacterial strain Bacteroides ovatus in the peripheral blood drove IL-17^(-)producing CD27−MAIT cell expansion and could be associated with T2D risk in obese individuals.Overall,these results suggest that an aberrant gut microbiota–immune axis in obese people may drive or exacerbate T2D.Importantly,CD27−MAIT cell subsets and Bacteroides ovatus could represent targets for novel interventional strategies.Our findings extend current knowledge regarding the clinical relevance of body mass index(BMI)-associated variation in circulating MAIT cells to reveal the role of these cells in obesity-related T2D progression and the underlying cellular mechanisms.
基金supported by grants from the National Key R&D Program of China(Grant No.2018YFE0203700)the National Natural Science Foundation of China(Grant No.81402747)+2 种基金the Applied Research Project on Nonprofit Technology of Zhejiang Province(Grant No.LGF20H260009)the KC Wong Magna Fund in Ningbo University,Chinasupported by CUHK VC discretionary fund,China。
文摘Solar energy,which is essential for the origin and evolution of all life forms on Earth,can be objectively recorded through attributes such as climatic ambient temperature(CAT),ultraviolet radiation(UVR),and sunlight duration(SD).These attributes have specific geographical variations and may cause different adaptation traits.However,the adaptation profile of each attribute and the selective role of solar energy as a whole during human evolution remain elusive.Here,we performed a genome-wide adaptation study with respect to CAT,UVR,and SD using the Human Genome Diversity Project-Centre Etude Polymorphism Humain(HGDP-CEPH)panel data.We singled out CAT as the most important driving force with the highest number of adaptive loci(6 SNPs at the genome-wide 1×10^(-7)level;401 at the suggestive 1×10^(-5)level).Five of the six genomewide significant adaptation SNPs were successfully replicated in an independent Chinese population(N=1395).The corresponding 316 CAT adaptation genes were mostly involved in development and immunity.In addition,265(84%)genes were related to at least one genome-wide association study(GWAS)-mapped human trait,being significantly enriched in anthropometric loci such as those associated with body mass index(χ^(2);P<0.005),immunity,metabolic syndrome,and cancer(χ^(2);P<0.05).For these adaptive SNPs,balancing selection was evident in Euro-Asians,whereas obvious positive and/or purifying selection was observed in Africans.Taken together,our study indicates that CAT is the most important attribute of solar energy that has driven genetic adaptation in development and immunity among global human populations.It also supports the non-neutral hypothesis for the origin of disease-predisposition alleles in common diseases.
基金supported by a grant from the Oklahoma Center for the Advancement of Science and Technology(HR16-041)and NIH grants EY012231,EY018659,EY028949,EY019309,GM122744a grant from National Nature Science Foundation of China NO.81700631Science&Technology Development Fund of Tianjin Education Commission for Higher Education 2016YD05.
文摘Previous studies by us and others demonstrated that activation of Wnt/β-catenin signaling plays a pathogenic role in chronic kidney diseases(CKD).Wnt co-receptor LRP5 variants are reported to associate with autosomal dominant polycystic kidney disease;but their exact roles in this disease and renal fibrosis have not been explored.Here,we observed the upregulation of LRP5 in the renal tubules of both type 1 and type 2 diabetic models and of an obstructive nephropathy model.In the obstructed kidneys,Lrp5 knockout significantly ameliorated tubulointerstitial fibrosis and tubular injury without changing Wnt/β-catenin signaling.Instead,decreased levels of TGF-β1 and TGF-βreceptors(TβRs)were detected in Lrp5 knockout kidneys,followed by attenuated activation and nuclear translocation of Smad2/3 in the renal tubules,suggesting a regulatory effect of LRP5 on TGF-β/Smad signaling.In consistent with this hypothesis,LRP5 overexpression resulted in enhanced TGF-β/Smad signaling activation in renal tubule epithelial cells.Furthermore,LRP5 was co-immunoprecipitated with TβRI and TβRII,and its extracellular domain was essential for interacting with TβRs and for its pro-fibrotic activity.In addition to stabilizing TβRs,LRP5 increased the basal membrane presentation and TGF-β1-induced internalization of these receptors.Notably,TGF-β1 also induced LRP5 internalization.These findings indicate that LRP5 promotes tubulointerstitial fibrosis,at least partially,via direct modulation of TGF-β/Smad signaling,a novel,Wnt-independent function.
