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Studies of androgen receptor gene mutations in patients phenotypically ranging from complete androgen insensitivity to men with preserved fertility
No full textThe androgen insensitivity syndrome (AIS) is the single most common cause of male pseudohermaphroditism, i. e., deficient masculinization which is not explained by disturbed testis development. In its most severe form it affects at least 1/20 000 newborn 46, XY males. This X-linked recessive disorder is caused by mutations in the androgen receptor (AR) gene, and has classically been divided into two subgroups according to severity; complete (CAIS) and partial androgen insensitivity syndrome (PAIS). In the complete form, the 46, XY individual presents as a phenotypically normal girl, except for absence of sexual hair. These patients have intraabdominal testes and, due to regression of Müllerian ducts, a short vagina, no uterus and lack oviducts. Partial forms of AIS present as varying degrees of undermasculinization, ranging from a predominantly female phenotype to boys with genital malformations, such as hypospadias or cryptorchidism. It has also been speculated, that subtle androgen receptor defects could cause impaired spermatogenesis without genital malformations. In the present work 13 missense mutations are described, identified in the AR gene of patients phenotypically ranging from complete androgen insensitivity to men with preserved fertility at the other end of the spectrum. The functional properties of 10 mutations have been characterized, using the approaches of site-directed mutagenesis, transient expression in COS-1 cells, and transactivation assays using an androgen sensitive reporter gene. Hormone binding assays in transfected COS-1 cells and genital skin fibroblasts from some patients were also performed.With a few exceptions, the degrees of impairment of mutant ARs in vitro were roughly in agreement with the severity of symptoms seen in the patients. Mutation A596T was an exception. A596T was functionally normal at high concentrations of androgens in vitro, although it was found in two newborns with PAIS. In accordance with this finding, treatment of the two boys with high doses of androgens resulted in a positive response.When this study was initiated, there was no molecular evidence for involvement of the AR in infertility. However, an elongated CAG repeat in exon I of the AR was known to be associated with dysfunctional sperm production in Kennedy's disease. Therefore, the length of the CAG-repeat of 33 infertile men was determined and compared to the CAG-repeats of 294 normal men. We found no difference in repeat lengths between the two groups. On the other hand, two missense mutations, N233K and N756S, were identified in two out of ten cases of infertility, selected due to elevated levels of LH and testosterone as well as azoo- or oligozoospermia. In both men, in vitro studies showed reduced transactivational capacity as compared to wild type AR. The patient carrying the N233K mutation displayed additional symptoms not generally seen in patients with AIS; he suffered from musculoskeletal and urogenital pain. He reported a remarkable relief upon high-dose androgen treatment. We speculate, that these symptoms result from abnormal protein- protein interactions arising as a consequence of the mutation, which is located in the transactivating domain of the AR where very few mutations previously have been found.Mutations in the AR gene have not been considered to be compatible with fertility. The Q824K mutation was found in three individuals of a family who complained of gynecomastia and showed hormonal levels indicating AIS. The mutant AR showed slight functional impairment in vitro. The patients had inherited the mutation from their grandfathers through their mothers, and one of them has fathered a daughter. The E653K mutation was found in a father of two daughters, who were affected with congenital adrenal hyperplasia due to 2 1 -hydroxylase deficiency. The daughters, who were heterozygous for the mutation, showed unusually mild signs of androgen excess, but in vitro assays of the E653K mutant failed to detect any functional abnormality.In conclusion, mutations in the AR gene have been found in patients covering the whole range of clinical phenotypes of androgen insensitivity. We confirm that the syndrome can be classified into three entities; CAIS, PAIS, and minimal androgen insensitivity (MAIS), where MAIS is defined as biochemical signs of AIS, gynecomastia and / or infertility, but without genital malformations.List of scientific papersI. Lundberg Giwercman Y, Nikoshkov A, Lindsten K, Byström B, Pousette Å, Chibalin AV, Arvidsson S, Tiulpakov A, Semitcheva TV, Peterkova V, Hagenfeldt K, Ritzén EM, Wedell A (1998). "Functional characterisation of mutations in the ligand-binding domain of the androgen receptor gene in patients with androgen insensitivity syndrome" Hum Genet 103(4): 529-531 https://pubmed.ncbi.nlm.nih.gov/99072324II. Lundberg Giwercman Y, Nikoshkov A, Lindsten K, Byström B, Pousette Å, Knudtzon J, Alm J, Wedell A (2000). "Response to Treatment in Patients with Partial Androgen Insensitivity due to Mutations in the DNA-Binding Domain of the Androgen Receptor" Horm Res 53(2): 83-88III. Giwercman YL, Xu C, Arver S, Pousette Å, Reneland R (1998). "No association between the androgen receptor gene CAG repeat and impaired sperm production in Swedish men" Clin Genet 54(5): 435-436 https://pubmed.ncbi.nlm.nih.gov/99057132IV. Lundberg Giwercman Y, Nikoshkov A, Byström B, Arver S, Pousette Å, Wedell A (2000). "A novel mutation (N233K) in the transactivating domain and the N7556S mutation in the ligand binding domain of the androgen receptor gene are associated with male infertility" (Submitted)V. Giwercman A, Kledal T, Schwartz M, Giwercman YL, Leffers H, Zazzi H, Wedell A, Skakkebaek NE (2000). "Preserved male fertility despite decreased androgen sensitivity caused by a mutation in the ligand-binding domain of the androgen receptor gene" J Clin Endocrinol Metab 85(6): 2253-2259 https://pubmed.ncbi.nlm.nih.gov/20309299VI. Lundberg Giwercman Y, Nikoshkov A, Byström B, Nordenskjöld A, Pousette Å, Wedell A (2000). "An androgen receptor variant in a family with congenital adrenal hyperplasia" (Manuscript)</p
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Influence of diluent alkyl substitution on the extraction of Am(III) and Eu(III) by a 6,6’-bis(1,2,4-triazin-3-yl)-2,2’-bipyridine ligand dissolved in alkylated cyclohexanone Diluents
No full textSeveral alkylated cyclohexanones were investigated as potential diluents for the selective extraction of Am(III) from Eu(III) from nitric acid solutions by the CyMe4-BTBP ligand. No significant extraction of either of the metal ions was observed for these diluents themselves. In the extractions from 1 M HNO3, 3-methylcyclohexanone and 4-methylcyclohexanone gave comparable results to cyclohexanone whereas in the extractions from 4 M HNO3, 2-methylcyclohexanone, 3-methylcyclohexanone and 4-methylcyclohexanone all gave superior results. For the monomethylated diluents, DAm and SFAm/Eu decreased in the order of alkyl substitution 2 > 4 ~ 3. However, alkyl substitution of cyclohexanone significantly slows down the extraction kinetics compared to cyclohexanone, and the position of alkyl substitution was found to play an important role in the solvents properties. 3-Methylcyclohexanone was identified as the most promising of the diluent
Impact of PCB and p,p'-DDE contaminants on human sperm Y : X chromosome ratio: Studies in three European populations and the inuit population in Greenland
No full textRecent studies indicate that persistent organohalogen pollutants (POPs) may contribute to sex ratio changes in offspring of exposed populations. Our aim in the present study was to investigate whether exposure to 2,2',4,4',5,5'-hexachlorobiphenyl (PCB-153) and dichlorodiphenyldichloroethene (pp'-DDE) affects sperm Y:X chromosome distribution. SUBJECTS AND METHODS: We obtained semen and blood for analysis of PCB-153 and pp'-DDE levels from 547 men from Sweden, Greenland, Poland (Warsaw), and Ukraine (Kharkiv), with regionally different levels of POP exposure. The proportion of Y- and X-chromosome-bearing sperm in the semen samples was determined by two-color fluorescence in situ hybridization analysis. RESULTS: Swedish and Greenlandic men had on average significantly higher proportions of Y sperm (in both cohorts, 51.2%) and correspondingly higher lipid-adjusted concentrations of PCB-153 (260 ng/g and 350 ng/g, respectively) compared with men from Warsaw (50.3% and 22 ng/g) and Kharkiv (50.7% and 54 ng/g). In the Swedish cohort, log-transformed PCB- 153 and log-transformed pp'-DDE variables were significantly positively associated with Y-chromosome fractions (p-values 0.04 and < 0.001, respectively). On the contrary, in the Polish cohort PCB-153 correlated negatively with the proportion of Y-bearing fraction of spermatozoa (p = 0.008). CONCLUSIONS: The present study indicates that POP exposure might be involved in changing the proportion of ejaculated Y-bearing spermatozoa in human populations. Intercountry differences, with different exposure situations and doses, may contribute to varying Y:X chromosome ratios
Androgen receptor gene CAG repeat length as a modifier of the association between persistent organohalogen pollutant exposure markers and semen characteristics.
No full textObjectives Exposure to persistent organohalogen pollutants was suggested to impair male reproductive function. A gene-environment interaction has been proposed. No genes modifying the effect of persistent organohalogen pollutants on reproductive organs have yet been identified. We aimed to investigate whether the CAG and GGN polymorphisms in the androgen receptor gene modify the effect of persistent organohalogen pollutant exposure on human sperm characteristics. Methods Semen and blood from 680 men [mean (SD) age 34 (10) years] from Greenland, Sweden, Warsaw (Poland) and Kharkiv (Ukraine) were collected. Persistent organohalogen pollutant exposure was assessed by measuring serum levels of 2,2,4,4,5,5'-hexachlorobiphenyl (CB-153) and dichlorodiphenyl dichloroethene (p,p'-DDE). Semen characteristics (volume, sperm concentration, total count proportion of progressively motile and morphology) and DNA fragmentation index (DFI) were determined. CAG and GGN repeat lengths were determined by direct sequencing of leukocyte DNA. Results A statistically significant interaction was found between the CB-153 group and CAG repeat category in relation to sperm concentration and total sperm count (P=0.03 and 0.01, respectively). For p,p'-DDE, in the European cohorts a significant interaction was found in relation to DFI (P=0.01). For CAG<20, sperm concentration and total sperm count were 35 and 42% lower, respectively, when the group with CB-153 exposure above median was compared with that below the median. DF1 was 40% higher in the high p,p'-DDE exposure group for CAG < 21. Conclusions This study indicated that the androgen receptor CAG repeat length might modify the susceptibility of an individual to the adverse effects of persistent organohalogen pollutant exposure on semen quality. Other studies regarding this matter are warranted
Doctor-family-patient relationship: The Chinese paradigm of informed consent
No full textBioethics is a subject far removed from the Chinese, even from many Chinese medical students and medical professionals. In-depth interviews with eighteen physicians, patients, and family members provided a deeper understanding of bioethical practices in contemporary China, especially with regard to the doctor-patient relationship (DPR) and informed consent. The Chinese model of doctor-family-patient relationship (DFPR), instead of DPR, is taken to reflect Chinese Confucian cultural commitments. An examination of the history of Chinese culture and the profession of medicine in China is used to disclose the deep roots of these commitments. The author predicts that the DFPR model will further develop in China but that it will maintain its Chinese character.EthicsSocial Sciences, BiomedicalPubMedCPCI-SSH(ISSHP)SSCI4
MONTE-CARLO STUDY OF 3-D Z4 GAUGE-Z2 HIGGS THEORY WITH RADIAL DEGREE OF FREEDOM
No full textPhysics, MultidisciplinarySCI(E)中国科学引文数据库(CSCD)0ARTICLE3311-3251
CHINESE PATENT-LAW AND PATENT INFORMATION-SERVICE
No full textInformation Science & Library ScienceSSCI1ARTICLE111-182
Comments on author citations for nomenclatural novelties published in volume 15 of the Flora Reipublicae Popularis Sinicae (FRPS)
No full textSpin-Crossover in Supramolecular Iron(II)-2,6-bis(1 H-Pyrazol-1-yl)pyridine Complexes: Toward Spin-State Switchable Single-Molecule Junctions
No full textSpin-crossover (SCO) active iron(II) complexes are an integral class of switchable and bistable molecular materials. Spin-state switching properties of the SCO complexes have been studied in the bulk and single-molecule levels to progress toward fabricating molecule-based switching and memory elements. Supramolecular SCO complexes featuring anchoring groups for metallic electrodes, for example, gold (Au), are ideal candidates to study spin-state switching at the single-molecule level. In this study, we report on the spin-state switching characteristics of supramolecular iron(II) complexes 1 and 2 composed of functional 4-([2,2′-bithiophen]-5-ylethynyl)-2,6-di(1H-pyrazol-1-yl)pyridine (L1) and 4-(2-(5-(5-hexylthiophen-2-yl)thiophen-2-yl)ethynyl)-2,6-di(1H-pyrazol-1-yl)pyridine (L2) ligands, respectively. Density functional theory (DFT) studies revealed stretching-induced spin-state switching in a molecular junction composed of complex 1, taken as a representative example, and gold electrodes. Single-molecule conductance traces revealed the unfavorable orientation of the complexes in the junctions to demonstrate the spin-state dependence of the conductance.QN/van der Zant La
LOWER RANGE OF STRINGOCEPHALUS
No full textThe lower range of Stringocephalus around the world is considered within the Givetian under the SDS (Subcommission on Devonian Stratigraphy) newly proposed definition of the Eifelian/Givetian boundary. However, in a measured section at Liujing (Guangxi, China), in which conodonts and silicified brachiopods occur in the same samples, Stringocephalus occurs in a shelf-edge fauna in beds that yield conodonts diagnostic of the lower part of the ensensis Zone of the uppermost Eifelian.GeologySCI(E)0ARTICLE273-773
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