Androgen receptor （AR） gene has been extensively studied in diverse clinical conditions. In addition to the point mutations, trinucleotide repeat （CAG and GGN） length polymorphisms have been an additional subject ...Androgen receptor （AR） gene has been extensively studied in diverse clinical conditions. In addition to the point mutations, trinucleotide repeat （CAG and GGN） length polymorphisms have been an additional subject of interest and controversy among geneticists. The polymorphic variations in triplet repeats have been associated with a number of disorders, but at the same time contradictory findings have also been reported. Further, studies on the same disorder in different populations have generated different results. Therefore, combined analysis or review of the published studies has been of much value to extract information on the significance of variations in the gene in various clinical conditions. AR genetics has been reviewed extensively but until now review articles have focused on individual clinical categories such as androgen insensitivity, male infertility, prostate cancer, and so on. We have made the first effort to review most the aspects of AR genetics. The impact of androgens in various disorders and polymorphic variations in the AR gene is the main focus of this review. Additionally, the correlations observed in various studies have been discussed in the light of in vitro evidences available for the effect of AR gene variations on the action of androgens.展开更多
Severe asthma is "asthma which requires treatment with high dose inhaled corticosteroids (ICS) plus a second controller (and/or systemic corticosteroids) to prevent it from becoming ’’uncontrolled’ or which re...Severe asthma is "asthma which requires treatment with high dose inhaled corticosteroids (ICS) plus a second controller (and/or systemic corticosteroids) to prevent it from becoming ’’uncontrolled’ or which remains ’’uncontrolled’ despite this therapy." The state of control was defined by symptoms, exacerbations and the degree of airflow obstruction. Therefore, for the diagnosis of severe asthma, it is important to have evidence for a diagnosis of asthma with an assessment of its severity, followed by a review of comorbidities, risk factors, triggers and an assessment of whether treatment is commensurate with severity, whether the prescribed treatments have been adhered to and whether inhaled therapy has been properly administered. Phenotyping of severe asthma has been introduced with the definition of a severe eosinophilic asthma phenotype characterized by recurrent exacerbations despite being on high dose ICS and sometimes oral corticosteroids, with a high blood eosinophil count and a raised level of nitric oxide in exhaled breath. This phenotype has been associated with a Type-2 (T2) inflammatory profile with expression of interleukin (IL)-4, IL-5, and IL-13. Molecular phenotyping has also revealed non-T2 inflammatory phenotypes such as Type-1 or Type-17 driven phenotypes. Antibody treatments targeted at the T2 targets such as anti-IL5, anti-IL5Rα, and anti-IL4Rα antibodies are now available for treating severe eosinophilic asthma, in addition to anti-immunoglobulin E antibody for severe allergic asthma. No targeted treatments are currently available for non-T2 inflammatory phenotypes. Long-term azithromycin and bronchial thermoplasty may be considered. The future lies with molecular phenotyping of the airway inflammatory process to refine asthma endotypes for precision medicine.展开更多
Androgen insensitivity syndrome （AIS）, an X-linked recessive genetic disorder of sex development, is caused by mutations in the androgen receptor （AR） gene, and is characterized by partial or complete inability of...Androgen insensitivity syndrome （AIS）, an X-linked recessive genetic disorder of sex development, is caused by mutations in the androgen receptor （AR） gene, and is characterized by partial or complete inability of specific tissues to respond to androgens in individuals with the 46,XY karyotype. This study aimed to investigate AR gene mutations and to characterize genotype-phenotype correlations. Ten patients from unrelated families, aged 2-31 years, were recruited in the study. Based on karyotype, altered hormone profile, and clinical manifestations, nine patients were preliminarily diagnosed with complete AIS and one with partial AIS. Genetic analysis of AR gene revealed the existence of 10 different mutations, of which five were novel （c.2112 C〉G[p.STO4R], c.2290T〉A[p.Y764N], c.2626C〉T[p.Q876X], c.933dupC[p.K313Qfs＊28], and c.1067delC[p.A356Efs＊123]）; the other five were previously reported （c.1789G〉A[p.A597T], c.2566C〉T[p.R856C], c.2668G〉A[p.V890M], c.2679C〉T[p.P893L], and c.1605C〉G[p.Y535X]）. Regarding the distribution of these mutations, 60.0% were clustered in the ligand-binding domain of AR gene. Exons 1 and 8 of AR gene each accounted for 30.0% （3/10） of all mutations. Most of the truncation mutations were in exon 1 and missense mutations were mainly located in exons 4-8. Our study expands the spectrum of AR gene mutations and confirms the usefulness of AR gene sequencing to support a diagnosis of AIS and to enable prenatal or antenatal screening.展开更多
We investigated the androgen receptor(AR) gene mutation profiles of Chinese patients exhibiting severe androgen insensitivity syndrome(AIS) phenotypes. The present study enrolled 28 patients with genetically diagnosed...We investigated the androgen receptor(AR) gene mutation profiles of Chinese patients exhibiting severe androgen insensitivity syndrome(AIS) phenotypes. The present study enrolled 28 patients with genetically diagnosed AIS, who presented with severe phenotypes(Prader grade 0–3). Patients and some family members were screened via amplification and sequencing of their AR exons 1–8, including the corresponding intronic flanking regions. Luteinizing(LH), follicle-stimulating(FSH), and testosterone(T) hormone levels were found to be slightly, but not significantly, higher in patients with complete androgen insensitivity syndrome(CAIS) than in patients with partial androgen insensitivity syndrome(PAIS)(P>0.05). We identified 24 different AR mutations, including 12 that were novel. Ten patients(cases 2, 3, 10, 28, 11, 12, 19, 20, 24, and 25) were found to carry five recurrent mutations(p.Y572 S, p.P914 S, p.S176 R, p.Y782 N, and p.R841H); of these, p.Y572 S, p.S176 R, and p.Y782 N were novel. Among the mutations identified in patients with CAIS, six(66.7%) were characterized as single-nucleotide missense mutations, and six(66.7%) were found to be located in the AR ligand-binding domain(LBD). Among the mutations identified in patients with PAIS, 15(93.8%) were found to be missense, and 11(68.8%) were found to be located in the LBD. Patients 10 and 28 were determined to harbor the same missense mutation(p.P914S), but were diagnosed with CAIS and PAIS, respectively.Sex hormone levels were slightly, but not significantly, elevated in patients with CAIS compared to those with PAIS. Missense mutations spanning AR exons 1–8 were the predominant form of identified mutations, and these were mostly located in the AR LBD. Approximately 50% of the identified mutations were novel, and have enriched the AR gene-mutation database. Patients harboring identical mutations were in some instances found to exhibit divergent phenotypes.展开更多
Mutations in the X-linked androgen receptor （AR） gene cause androgen insensitivity syndrome （AIS）, resulting in an impaired embryonic sex differentiation in 46,XY genetic men. Complete androgen insensitivity （CAI...Mutations in the X-linked androgen receptor （AR） gene cause androgen insensitivity syndrome （AIS）, resulting in an impaired embryonic sex differentiation in 46,XY genetic men. Complete androgen insensitivity （CAIS） produces a female external phenotype, whereas cases with partial androgen insensitivity （PALS） have various ambiguities of the genitalia. Mild androgen insensitivity （MAIS） is characterized by undermasculinization and gynecomastia. Here we describe a 2-month-old 46,XY female patient, with all of the characteristics of CAIS. Defects in testosterone （T） and dihydrotestosterone （DHT） synthesis were excluded. Sequencing of the AR gene showed the presence in exon 6 of a T to C transition in the second base of codon 790, nucleotide position 2369, causing a novel missense Leu790Pro mutation in the ligand-binding domain of the AR protein. The identification of a novel AR mutation in a girl with CAIS provides significant information due to the importance of missense mutations in the ligand-binding domain of the AR, which are able to induce functional abnormalities in the androgen binding capability, stabilization of active conformation, or interaction with coactivators.展开更多
Background Glucocorticoids have been widely used to treat patients with chronic obstructive pulmonary disease (COPD). Nevertheless, corticosteroid insensitivity is a major barrier to the effective treatment of COPD an...Background Glucocorticoids have been widely used to treat patients with chronic obstructive pulmonary disease (COPD). Nevertheless, corticosteroid insensitivity is a major barrier to the effective treatment of COPD and its mechanism remains unclear. This study aimed to evaluate the effect of cathelicidin LL-37 on corticosteroid insensitivity in COPD rat model, and to explore the involved mechanisms. Methods COPD model was established by exposing male Wistar rats to cigarette smoke combined with intratracheal instillation of lipopolysaccharide (LPS). Inhaled budesonide and LL-37 were consequently applied to COPD models separately or collectively to confirm the effects on inflammatory cytokines (tumor necrosis factor [TNF]-α and transforming growth factor [TGF]-β)by enzymelinked immunosorbent assay (ELISA) and lung tissue histopathological morphology. Expression of histone deacetylase-2 (HDAC2) and phosphorylation of Akt (p-AKT) in lung were also measured. Results Briefly, COPD model rats showed an increased basal release of inflammatory cytokines (lung TNF-α:45.7±6.1 vs. 20.1 ± 3.8pg/mL, P<0.01;serum TNF-α:8.9±1.2 vs. 6.7±0.5pg/mL, P = 0.01;lung TGF-β:122.4±20.8 vs. 81.9±10.8pg/mL, P<0.01;serum TGF-β:38.9±8.5 vs. 20.6±2.3 pg/mL, P<0.01) and COPD related lung tissue histopathological changes, as well as corticosteroid resistance molecular profile characterized by an increase in phosphoinositide 3-kinase (PI3K)/Akt (0.5±0.1 fold of control vs. 0.2±0.1 fold of control, P = 0.04) and a decrease in HDAC2 expression and activity (expression: 13.1 ±0.4 μmol/μg vs. 17.4± 1.1 μmol/μg, P<0.01;activity: 1.1 ±0.1 unit vs. 1.4±0.1 unit, P< 0.01), compared with control group. In addition, LL-37 enhanced the anti-inflammatory effect of budesonide in an additive manner. Treatment with combination of inhaled corticosteroids (ICS) and LL-37 led to a significant increase of HDAC2 expression and activity (expression: 15.7±0.4 μmol/μg vs. 14.1 ±0.9 μmol/μg, P<0.01;activity: 1.3±0.1 unit vs.1.0±0.1 unit,展开更多
An ultrathin angle-insensitive color filter enabling high color saturation and a wide color gamut is proposed by relying on magnesium hydride-hydrogenated amorphous silicon[MgH2-a-Si:H]lossy dielectric layer.Based on ...An ultrathin angle-insensitive color filter enabling high color saturation and a wide color gamut is proposed by relying on magnesium hydride-hydrogenated amorphous silicon[MgH2-a-Si:H]lossy dielectric layer.Based on effective medium theory,the MgH2-a-Si:H layer with an ultrathin thickness can be equivalent to a quasi-homogeneous dielectric layer wit an effective complex refractive index,which can be tuned by altering the thickness of MgH2to obtain the targeted value o the imaginary part,corresponding to the realization of high color saturation.It is verified that the proposed color filte offers highly enhanced color saturation in conjunction with a wide color gamut by introducing a few-nanometer thic MgH2layer.As the MgH2-a-Si:H layer retains the advantages of high refractive index and tiny thickness,the proposed colo filter exhibits large angular tolerance up to±60°.In addition,MgH2with an unstable property can interconvert with Mg unde a dehydrogenation/hydrogenation reaction,which empowers the proposed color filter with dynamically tunable outpu color.The proposed scheme shows great promise in color printing and ultracompact display devices with high color sat uration,wide gamut,large angular tolerance,and dynamic tunability.展开更多
文摘Androgen receptor （AR） gene has been extensively studied in diverse clinical conditions. In addition to the point mutations, trinucleotide repeat （CAG and GGN） length polymorphisms have been an additional subject of interest and controversy among geneticists. The polymorphic variations in triplet repeats have been associated with a number of disorders, but at the same time contradictory findings have also been reported. Further, studies on the same disorder in different populations have generated different results. Therefore, combined analysis or review of the published studies has been of much value to extract information on the significance of variations in the gene in various clinical conditions. AR genetics has been reviewed extensively but until now review articles have focused on individual clinical categories such as androgen insensitivity, male infertility, prostate cancer, and so on. We have made the first effort to review most the aspects of AR genetics. The impact of androgens in various disorders and polymorphic variations in the AR gene is the main focus of this review. Additionally, the correlations observed in various studies have been discussed in the light of in vitro evidences available for the effect of AR gene variations on the action of androgens.
基金SG, JY and KFC are supported by the Sanming Project of Medicine in Shenzhen "Integrated Airways Disease Research Programme"(No. SZSM201612096)PD, HA-W, PB, and KFC are supported by UK Research Innovation projects(No. MRC MR/T010371/1EPSRC: EP/T003189/1)。
文摘Severe asthma is "asthma which requires treatment with high dose inhaled corticosteroids (ICS) plus a second controller (and/or systemic corticosteroids) to prevent it from becoming ’’uncontrolled’ or which remains ’’uncontrolled’ despite this therapy." The state of control was defined by symptoms, exacerbations and the degree of airflow obstruction. Therefore, for the diagnosis of severe asthma, it is important to have evidence for a diagnosis of asthma with an assessment of its severity, followed by a review of comorbidities, risk factors, triggers and an assessment of whether treatment is commensurate with severity, whether the prescribed treatments have been adhered to and whether inhaled therapy has been properly administered. Phenotyping of severe asthma has been introduced with the definition of a severe eosinophilic asthma phenotype characterized by recurrent exacerbations despite being on high dose ICS and sometimes oral corticosteroids, with a high blood eosinophil count and a raised level of nitric oxide in exhaled breath. This phenotype has been associated with a Type-2 (T2) inflammatory profile with expression of interleukin (IL)-4, IL-5, and IL-13. Molecular phenotyping has also revealed non-T2 inflammatory phenotypes such as Type-1 or Type-17 driven phenotypes. Antibody treatments targeted at the T2 targets such as anti-IL5, anti-IL5Rα, and anti-IL4Rα antibodies are now available for treating severe eosinophilic asthma, in addition to anti-immunoglobulin E antibody for severe allergic asthma. No targeted treatments are currently available for non-T2 inflammatory phenotypes. Long-term azithromycin and bronchial thermoplasty may be considered. The future lies with molecular phenotyping of the airway inflammatory process to refine asthma endotypes for precision medicine.
基金The authors are grateful to the patients and their family members for participating in this study. This study was supported by grants from the National Natural Science Foundation of China （81771645 and 81471432 to YQT）.
文摘Androgen insensitivity syndrome （AIS）, an X-linked recessive genetic disorder of sex development, is caused by mutations in the androgen receptor （AR） gene, and is characterized by partial or complete inability of specific tissues to respond to androgens in individuals with the 46,XY karyotype. This study aimed to investigate AR gene mutations and to characterize genotype-phenotype correlations. Ten patients from unrelated families, aged 2-31 years, were recruited in the study. Based on karyotype, altered hormone profile, and clinical manifestations, nine patients were preliminarily diagnosed with complete AIS and one with partial AIS. Genetic analysis of AR gene revealed the existence of 10 different mutations, of which five were novel （c.2112 C〉G[p.STO4R], c.2290T〉A[p.Y764N], c.2626C〉T[p.Q876X], c.933dupC[p.K313Qfs＊28], and c.1067delC[p.A356Efs＊123]）; the other five were previously reported （c.1789G〉A[p.A597T], c.2566C〉T[p.R856C], c.2668G〉A[p.V890M], c.2679C〉T[p.P893L], and c.1605C〉G[p.Y535X]）. Regarding the distribution of these mutations, 60.0% were clustered in the ligand-binding domain of AR gene. Exons 1 and 8 of AR gene each accounted for 30.0% （3/10） of all mutations. Most of the truncation mutations were in exon 1 and missense mutations were mainly located in exons 4-8. Our study expands the spectrum of AR gene mutations and confirms the usefulness of AR gene sequencing to support a diagnosis of AIS and to enable prenatal or antenatal screening.
基金supported by the Public Health Project for Residents in Beijing (Z151100003915103)the National Key Research and Development Program of China (2016YFC0901505)
文摘We investigated the androgen receptor(AR) gene mutation profiles of Chinese patients exhibiting severe androgen insensitivity syndrome(AIS) phenotypes. The present study enrolled 28 patients with genetically diagnosed AIS, who presented with severe phenotypes(Prader grade 0–3). Patients and some family members were screened via amplification and sequencing of their AR exons 1–8, including the corresponding intronic flanking regions. Luteinizing(LH), follicle-stimulating(FSH), and testosterone(T) hormone levels were found to be slightly, but not significantly, higher in patients with complete androgen insensitivity syndrome(CAIS) than in patients with partial androgen insensitivity syndrome(PAIS)(P>0.05). We identified 24 different AR mutations, including 12 that were novel. Ten patients(cases 2, 3, 10, 28, 11, 12, 19, 20, 24, and 25) were found to carry five recurrent mutations(p.Y572 S, p.P914 S, p.S176 R, p.Y782 N, and p.R841H); of these, p.Y572 S, p.S176 R, and p.Y782 N were novel. Among the mutations identified in patients with CAIS, six(66.7%) were characterized as single-nucleotide missense mutations, and six(66.7%) were found to be located in the AR ligand-binding domain(LBD). Among the mutations identified in patients with PAIS, 15(93.8%) were found to be missense, and 11(68.8%) were found to be located in the LBD. Patients 10 and 28 were determined to harbor the same missense mutation(p.P914S), but were diagnosed with CAIS and PAIS, respectively.Sex hormone levels were slightly, but not significantly, elevated in patients with CAIS compared to those with PAIS. Missense mutations spanning AR exons 1–8 were the predominant form of identified mutations, and these were mostly located in the AR LBD. Approximately 50% of the identified mutations were novel, and have enriched the AR gene-mutation database. Patients harboring identical mutations were in some instances found to exhibit divergent phenotypes.
文摘Mutations in the X-linked androgen receptor （AR） gene cause androgen insensitivity syndrome （AIS）, resulting in an impaired embryonic sex differentiation in 46,XY genetic men. Complete androgen insensitivity （CAIS） produces a female external phenotype, whereas cases with partial androgen insensitivity （PALS） have various ambiguities of the genitalia. Mild androgen insensitivity （MAIS） is characterized by undermasculinization and gynecomastia. Here we describe a 2-month-old 46,XY female patient, with all of the characteristics of CAIS. Defects in testosterone （T） and dihydrotestosterone （DHT） synthesis were excluded. Sequencing of the AR gene showed the presence in exon 6 of a T to C transition in the second base of codon 790, nucleotide position 2369, causing a novel missense Leu790Pro mutation in the ligand-binding domain of the AR protein. The identification of a novel AR mutation in a girl with CAIS provides significant information due to the importance of missense mutations in the ligand-binding domain of the AR, which are able to induce functional abnormalities in the androgen binding capability, stabilization of active conformation, or interaction with coactivators.
基金National Natural Science Foundation of China (No.81300033).
文摘Background Glucocorticoids have been widely used to treat patients with chronic obstructive pulmonary disease (COPD). Nevertheless, corticosteroid insensitivity is a major barrier to the effective treatment of COPD and its mechanism remains unclear. This study aimed to evaluate the effect of cathelicidin LL-37 on corticosteroid insensitivity in COPD rat model, and to explore the involved mechanisms. Methods COPD model was established by exposing male Wistar rats to cigarette smoke combined with intratracheal instillation of lipopolysaccharide (LPS). Inhaled budesonide and LL-37 were consequently applied to COPD models separately or collectively to confirm the effects on inflammatory cytokines (tumor necrosis factor [TNF]-α and transforming growth factor [TGF]-β)by enzymelinked immunosorbent assay (ELISA) and lung tissue histopathological morphology. Expression of histone deacetylase-2 (HDAC2) and phosphorylation of Akt (p-AKT) in lung were also measured. Results Briefly, COPD model rats showed an increased basal release of inflammatory cytokines (lung TNF-α:45.7±6.1 vs. 20.1 ± 3.8pg/mL, P<0.01;serum TNF-α:8.9±1.2 vs. 6.7±0.5pg/mL, P = 0.01;lung TGF-β:122.4±20.8 vs. 81.9±10.8pg/mL, P<0.01;serum TGF-β:38.9±8.5 vs. 20.6±2.3 pg/mL, P<0.01) and COPD related lung tissue histopathological changes, as well as corticosteroid resistance molecular profile characterized by an increase in phosphoinositide 3-kinase (PI3K)/Akt (0.5±0.1 fold of control vs. 0.2±0.1 fold of control, P = 0.04) and a decrease in HDAC2 expression and activity (expression: 13.1 ±0.4 μmol/μg vs. 17.4± 1.1 μmol/μg, P<0.01;activity: 1.1 ±0.1 unit vs. 1.4±0.1 unit, P< 0.01), compared with control group. In addition, LL-37 enhanced the anti-inflammatory effect of budesonide in an additive manner. Treatment with combination of inhaled corticosteroids (ICS) and LL-37 led to a significant increase of HDAC2 expression and activity (expression: 15.7±0.4 μmol/μg vs. 14.1 ±0.9 μmol/μg, P<0.01;activity: 1.3±0.1 unit vs.1.0±0.1 unit,
基金supported by the Natural Science Foundation of Shandong Province(No.ZR2019BF013)the National Natural Science Foundation of China(Nos.62005095 and 61905091)。
文摘An ultrathin angle-insensitive color filter enabling high color saturation and a wide color gamut is proposed by relying on magnesium hydride-hydrogenated amorphous silicon[MgH2-a-Si:H]lossy dielectric layer.Based on effective medium theory,the MgH2-a-Si:H layer with an ultrathin thickness can be equivalent to a quasi-homogeneous dielectric layer wit an effective complex refractive index,which can be tuned by altering the thickness of MgH2to obtain the targeted value o the imaginary part,corresponding to the realization of high color saturation.It is verified that the proposed color filte offers highly enhanced color saturation in conjunction with a wide color gamut by introducing a few-nanometer thic MgH2layer.As the MgH2-a-Si:H layer retains the advantages of high refractive index and tiny thickness,the proposed colo filter exhibits large angular tolerance up to±60°.In addition,MgH2with an unstable property can interconvert with Mg unde a dehydrogenation/hydrogenation reaction,which empowers the proposed color filter with dynamically tunable outpu color.The proposed scheme shows great promise in color printing and ultracompact display devices with high color sat uration,wide gamut,large angular tolerance,and dynamic tunability.
