Hyperplasia and migration of fibroblast-like synoviocytes(FLSs)are the key drivers in the pathogenesis of rheumatoid arthritis(RA)and joint destruction.Abundant Yes-associated protein(YAP),which is a powerful transcri...Hyperplasia and migration of fibroblast-like synoviocytes(FLSs)are the key drivers in the pathogenesis of rheumatoid arthritis(RA)and joint destruction.Abundant Yes-associated protein(YAP),which is a powerful transcription co-activator for proliferative genes,was observed in the nucleus of inflammatory FLSs with unknown upstream mechanisms.Using Gene Expression Omnibus database analysis,it was found that Salvador homolog-1(SAV1),the pivotal negative regulator of the Hippo-YAP pathway,was slightly downregulated in RA synovium.However,SAV1 protein expression is extremely reduced.Subsequently,it was revealed that SAV1 is phosphorylated,ubiquitinated,and degraded by interacting with an important serine-threonine kinase,G protein-coupled receptor(GPCR)kinase 2(GRK2),which was predominately upregulated by GPCR activation induced by ligands such as prostaglandin E2(PGE2)in RA.This process further contributes to the decreased phosphorylation,nuclear translocation,and transcriptional potency of YAP,and leads to aberrant FLSs proliferation.Genetic depletion of GRK2 or inhibition of GRK2 by paroxetine rescued SAV1 expression and restored YAP phosphorylation and finally inhibited RA FLSs proliferation and migration.Similarly,paroxetine treatment effectively reduced the abnormal proliferation of FLSs in a rat model of collagen-induced arthritis which was accompanied by a significant improvement in clinical manifestations.Collectively,these results elucidate the significance of GRK2 regulation of Hippo-YAP signaling in FLSs proliferation and migration and the potential application of GRK2 inhibition in the treatment of FLSs-driven joint destruction in RA.展开更多
El Salvador established diplomatic relationship with China in 2018,opening a new chapter in the history of bilateral relations.Since the establishment of the diplomatic relationship,bilateral relations have been growi...El Salvador established diplomatic relationship with China in 2018,opening a new chapter in the history of bilateral relations.Since the establishment of the diplomatic relationship,bilateral relations have been growing steadily,with frequent reciprocal visits of high-ranking officials between the two countries.The cooperation has achieved fruitful results in the realms of politics,trade,the economy and cultural humanities.展开更多
Introduction: The occupational toxic risks from agricultural activities in El Salvador affect human and environmental health. The objective of this paper is to describe the management of pesticide by farmers confirmed...Introduction: The occupational toxic risks from agricultural activities in El Salvador affect human and environmental health. The objective of this paper is to describe the management of pesticide by farmers confirmed with a chronic kidney disease of uncertain etiology (CKDu) not associated to diabetes mellitus or hypertension. Methods: The study involved 42 male patients older than 18 years old with confirmed CKDu that have participated in different stages of pesticides management. This is a cross-sectional study;it was conducted from January to June 2011, in three communities of Bajo Lempa region, El Salvador. An interview was especially designed to investigate which pesticides were used and the farmer practices at different stages of pesticide use. Statistical descriptive analysis was carried out for the several studied variables. Results: All interviewed people had a direct relationship with agricultural activities. The majority of patients had poor education, 19% were illiterate and 55% only have primary education. Most farmers with CKDu had been exposed more than 10 years to hazardous pesticides. The most used pesticide was Hedonal/2, 4 D (100%). 95% interviewed patients mixed different pesticides and 63% dumped empty pesticide containers in the fields. Interviewees did not use appropriate personal protective equipment (100%). Conclusions: There is high use of hazardous pesticides by patients and some of these are banned and some are legal in El Salvador, but prohibited by other countries. Interviewed CKDu patients had high exposure to toxic pesticides due to the misuse in almost all stages. There is inadequate legislation and a poor law enforcement to prevent the misuse of pesticides in El Salvador.展开更多
Objectives: This paper highlights and discusses major factors affecting Salvadoran farmers’ involvement in National Health System-led efforts to prevent MeN in El Salvador and includes some recommendations to enhance...Objectives: This paper highlights and discusses major factors affecting Salvadoran farmers’ involvement in National Health System-led efforts to prevent MeN in El Salvador and includes some recommendations to enhance their involvement. Methods: The study, conducted in El Salvador in June 2018, involved 10 life-long farmers residing in five MeN-affected communities in Chalatenango and Usulutan Departments who were either MeN-free or MeN-controlled, to understand through semi-structured, qualitative interviews their experience of participation in broader epidemic control efforts. Complementary interviews held with two nephrology teams and a senior representative of the grassroots-level National Health Forum operating in the same area, provided necessary contrast. Interview questions were informed by reference to the Adaptation and Development after Persecution and Trauma (ADAPT) model [1] as applicable in post-conflict environments like El Salvador to analyze contextual factors influencing community participation. Findings: Farmers are scarcely involved in wider MeN prevention efforts in El Salvador despite greater National Health System emphasis on encouraging community participation since the approval of the 2009 Health Reform [2]. This study found that widespread insecurity due to gang warfare, declining family and social networks due to high murder rates and international migration, and unresolved sense of injustice over unremitting poverty are among major factors with potential destructive effect on farmer participation. Conclusions: Health system-led MeN prevention responses need to encompass attention to persisting social vulnerabilities in economically and socially marginalized communities in order to enhance farmer participation in this effort. This paper concludes with some recommendations on how this can be done.展开更多
Objective: It is in order to estimate the prevalence and incidence of HIV, the frequency of sexual risk behaviors, and perceptions of available resources to prevent and treat HIV among crack users in the San Salvador ...Objective: It is in order to estimate the prevalence and incidence of HIV, the frequency of sexual risk behaviors, and perceptions of available resources to prevent and treat HIV among crack users in the San Salvador Metropolitan Area. Methods: We conducted a survey of 420 crack users by using respondent-driven sampling to measure demographic characteristics, the quantity and frequency of drug use, history of STIs, including HIV, and experiences with organizations which provide prevention and treatment of HIV. Each participant offered a free and voluntary HIV test and was asked permission to share the results of the test with the study. Bernoullian modeling was used to estimate the prevalence and incidence of HIV among heterosexual males in this population. Results: The estimated prevalence was 7% (95% CI: 2.3% -9.8%) among participants who agreed to take the test and share the results, and 4.9% (95% CI: 2.8% -7.8%) assuming that those who did not take the test or share results were seronegative. Participants reported a high frequency of sexual risk behaviors. In addition, participants were reported to have little knowledge of organizations to prevent or treat HIV/AIDS;58% had never taken an HIV test prior to survey administration. Conclusions: Crack users in San Salvador are at high risk for HIV acquisition. HIV prevention interventions are urgently needed, especially interventions increasing access to HIV testing and prevention.展开更多
利用酵母双杂交系统,以鼠M ST 1(M amm alian STE 20-1 ike 1)为诱饵蛋白,在鼠胚胎库中筛选到22个Salvador的片段。通过E.coli表达系统纯化了6个组氨酸(6H is)融合的M ST 1和谷胱甘肽硫转移酶(GST)融合的Salvador,并做体外蛋白质结合实...利用酵母双杂交系统,以鼠M ST 1(M amm alian STE 20-1 ike 1)为诱饵蛋白,在鼠胚胎库中筛选到22个Salvador的片段。通过E.coli表达系统纯化了6个组氨酸(6H is)融合的M ST 1和谷胱甘肽硫转移酶(GST)融合的Salvador,并做体外蛋白质结合实验,进一步证实了两蛋白质相互结合。通过体外激酶活性分析,发现M ST 1并不直接磷酸化Salvador,但是Salvador能够较强地抑制M ST 1对M BP(磷酸丁酯)的磷酸化,提示有可能Salvador通过影响M ST 1的激酶活性来参与了M ST 1介导的细胞凋亡途径。展开更多
The evolutionarily conserved Hippo signaling pathway plays an important role in organ size control by regulating cell proliferation and apoptosis.Here,we identify Lingerer(Lig)as a growth suppressor using RNAi modifyi...The evolutionarily conserved Hippo signaling pathway plays an important role in organ size control by regulating cell proliferation and apoptosis.Here,we identify Lingerer(Lig)as a growth suppressor using RNAi modifying screen in Drosophila melanogaster.Loss of lig increases organ size and upregulates bantam(ban)and the expression of the Hippo pathway target genes,while overexpression of lig results in diminished ban expression and organ size reduction.We demonstrate that Lig C-terminal exhibits dominant-negative function on growth and ban expression,and thus plays an important role in organ size control and ban regulation.In addition,we provide evidence that both Yki and Mad are essential for Lig-induced ban expression.We also show that Lig regulates the expression of the Hippo pathway target genes partially via Yorkie.Moreover,we find that Lig physically interacts with and requires Salvador to restrict cell growth.Taken together,we demonstrate that Lig functions as a critical growth suppressor to control organ size via ban and Hippo signaling.展开更多
基金supported by the National Natural Science Foundation of China(81973314,82373865,81973332,82173824)the Anhui Provincial Natural Science Foundation for Distinguished Young Scholars(1808085J28,China)+4 种基金Collaborative Innovation Project of Key Scientific Research Platform in Anhui Universities(GXXT-2020-066,China)the Research Program for Higher Education Institutions in Anhui Province(2022AH030081,China)Anhui Provincial Key R&D Programs(2022e07020042,China)Program for Upgrading Scientific Research Level of Anhui Medical University(2019xkj T008,China)Academic Funding for Top-notch Talents in University Disciplines(Majors)of Anhui Province(gxbj ZD2021047,China)。
文摘Hyperplasia and migration of fibroblast-like synoviocytes(FLSs)are the key drivers in the pathogenesis of rheumatoid arthritis(RA)and joint destruction.Abundant Yes-associated protein(YAP),which is a powerful transcription co-activator for proliferative genes,was observed in the nucleus of inflammatory FLSs with unknown upstream mechanisms.Using Gene Expression Omnibus database analysis,it was found that Salvador homolog-1(SAV1),the pivotal negative regulator of the Hippo-YAP pathway,was slightly downregulated in RA synovium.However,SAV1 protein expression is extremely reduced.Subsequently,it was revealed that SAV1 is phosphorylated,ubiquitinated,and degraded by interacting with an important serine-threonine kinase,G protein-coupled receptor(GPCR)kinase 2(GRK2),which was predominately upregulated by GPCR activation induced by ligands such as prostaglandin E2(PGE2)in RA.This process further contributes to the decreased phosphorylation,nuclear translocation,and transcriptional potency of YAP,and leads to aberrant FLSs proliferation.Genetic depletion of GRK2 or inhibition of GRK2 by paroxetine rescued SAV1 expression and restored YAP phosphorylation and finally inhibited RA FLSs proliferation and migration.Similarly,paroxetine treatment effectively reduced the abnormal proliferation of FLSs in a rat model of collagen-induced arthritis which was accompanied by a significant improvement in clinical manifestations.Collectively,these results elucidate the significance of GRK2 regulation of Hippo-YAP signaling in FLSs proliferation and migration and the potential application of GRK2 inhibition in the treatment of FLSs-driven joint destruction in RA.
文摘El Salvador established diplomatic relationship with China in 2018,opening a new chapter in the history of bilateral relations.Since the establishment of the diplomatic relationship,bilateral relations have been growing steadily,with frequent reciprocal visits of high-ranking officials between the two countries.The cooperation has achieved fruitful results in the realms of politics,trade,the economy and cultural humanities.
文摘Introduction: The occupational toxic risks from agricultural activities in El Salvador affect human and environmental health. The objective of this paper is to describe the management of pesticide by farmers confirmed with a chronic kidney disease of uncertain etiology (CKDu) not associated to diabetes mellitus or hypertension. Methods: The study involved 42 male patients older than 18 years old with confirmed CKDu that have participated in different stages of pesticides management. This is a cross-sectional study;it was conducted from January to June 2011, in three communities of Bajo Lempa region, El Salvador. An interview was especially designed to investigate which pesticides were used and the farmer practices at different stages of pesticide use. Statistical descriptive analysis was carried out for the several studied variables. Results: All interviewed people had a direct relationship with agricultural activities. The majority of patients had poor education, 19% were illiterate and 55% only have primary education. Most farmers with CKDu had been exposed more than 10 years to hazardous pesticides. The most used pesticide was Hedonal/2, 4 D (100%). 95% interviewed patients mixed different pesticides and 63% dumped empty pesticide containers in the fields. Interviewees did not use appropriate personal protective equipment (100%). Conclusions: There is high use of hazardous pesticides by patients and some of these are banned and some are legal in El Salvador, but prohibited by other countries. Interviewed CKDu patients had high exposure to toxic pesticides due to the misuse in almost all stages. There is inadequate legislation and a poor law enforcement to prevent the misuse of pesticides in El Salvador.
文摘Objectives: This paper highlights and discusses major factors affecting Salvadoran farmers’ involvement in National Health System-led efforts to prevent MeN in El Salvador and includes some recommendations to enhance their involvement. Methods: The study, conducted in El Salvador in June 2018, involved 10 life-long farmers residing in five MeN-affected communities in Chalatenango and Usulutan Departments who were either MeN-free or MeN-controlled, to understand through semi-structured, qualitative interviews their experience of participation in broader epidemic control efforts. Complementary interviews held with two nephrology teams and a senior representative of the grassroots-level National Health Forum operating in the same area, provided necessary contrast. Interview questions were informed by reference to the Adaptation and Development after Persecution and Trauma (ADAPT) model [1] as applicable in post-conflict environments like El Salvador to analyze contextual factors influencing community participation. Findings: Farmers are scarcely involved in wider MeN prevention efforts in El Salvador despite greater National Health System emphasis on encouraging community participation since the approval of the 2009 Health Reform [2]. This study found that widespread insecurity due to gang warfare, declining family and social networks due to high murder rates and international migration, and unresolved sense of injustice over unremitting poverty are among major factors with potential destructive effect on farmer participation. Conclusions: Health system-led MeN prevention responses need to encompass attention to persisting social vulnerabilities in economically and socially marginalized communities in order to enhance farmer participation in this effort. This paper concludes with some recommendations on how this can be done.
文摘Objective: It is in order to estimate the prevalence and incidence of HIV, the frequency of sexual risk behaviors, and perceptions of available resources to prevent and treat HIV among crack users in the San Salvador Metropolitan Area. Methods: We conducted a survey of 420 crack users by using respondent-driven sampling to measure demographic characteristics, the quantity and frequency of drug use, history of STIs, including HIV, and experiences with organizations which provide prevention and treatment of HIV. Each participant offered a free and voluntary HIV test and was asked permission to share the results of the test with the study. Bernoullian modeling was used to estimate the prevalence and incidence of HIV among heterosexual males in this population. Results: The estimated prevalence was 7% (95% CI: 2.3% -9.8%) among participants who agreed to take the test and share the results, and 4.9% (95% CI: 2.8% -7.8%) assuming that those who did not take the test or share results were seronegative. Participants reported a high frequency of sexual risk behaviors. In addition, participants were reported to have little knowledge of organizations to prevent or treat HIV/AIDS;58% had never taken an HIV test prior to survey administration. Conclusions: Crack users in San Salvador are at high risk for HIV acquisition. HIV prevention interventions are urgently needed, especially interventions increasing access to HIV testing and prevention.
文摘利用酵母双杂交系统,以鼠M ST 1(M amm alian STE 20-1 ike 1)为诱饵蛋白,在鼠胚胎库中筛选到22个Salvador的片段。通过E.coli表达系统纯化了6个组氨酸(6H is)融合的M ST 1和谷胱甘肽硫转移酶(GST)融合的Salvador,并做体外蛋白质结合实验,进一步证实了两蛋白质相互结合。通过体外激酶活性分析,发现M ST 1并不直接磷酸化Salvador,但是Salvador能够较强地抑制M ST 1对M BP(磷酸丁酯)的磷酸化,提示有可能Salvador通过影响M ST 1的激酶活性来参与了M ST 1介导的细胞凋亡途径。
基金This work is supported by grants from the National Basic Research Program of China(973 Program)(2010CB912101,2012CB945001,2011CB943902)the‘Strategic Priority Research Program’of the Chinese Academy of Sciences(XDA01010406)National Natural Science Foundation of China(31171394,31371462).
文摘The evolutionarily conserved Hippo signaling pathway plays an important role in organ size control by regulating cell proliferation and apoptosis.Here,we identify Lingerer(Lig)as a growth suppressor using RNAi modifying screen in Drosophila melanogaster.Loss of lig increases organ size and upregulates bantam(ban)and the expression of the Hippo pathway target genes,while overexpression of lig results in diminished ban expression and organ size reduction.We demonstrate that Lig C-terminal exhibits dominant-negative function on growth and ban expression,and thus plays an important role in organ size control and ban regulation.In addition,we provide evidence that both Yki and Mad are essential for Lig-induced ban expression.We also show that Lig regulates the expression of the Hippo pathway target genes partially via Yorkie.Moreover,we find that Lig physically interacts with and requires Salvador to restrict cell growth.Taken together,we demonstrate that Lig functions as a critical growth suppressor to control organ size via ban and Hippo signaling.
