Novel mutation in the ligand-binding domain of the androgen receptor gene （1790p） associated with complete androgen insensitivity syndrome

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.

Androgen insensitivity syndrome： do trinucleotide repeats in androgen receptor gene have any role？

Aim： To investigate the role of CAG and GGN repeats as genetic background affecting androgen insensitivity syndrome （AIS） phenotype. Methods： We analyzed lengths of androgen receptor （AR）-CAG and GGN repeats in 69 AIS cases, along with 136 unrelated normal male individuals. The lengths of repeats were analyzed using polymerase chain reaction （PCR） amplification followed by allelic genotyping to determine allele length. Results： Our study revealed significantly shorter mean lengths of CAG repeats in patients （mean 18.25 repeats, range 14-26 repeats） in comparison to the controls （mean 22.57 repeats, range 12-39 repeats） （two-tailed P 〈 0.0001）. GGN repeats, however, did not differ significantly between patients （mean 21.48 repeats） and controls （mean 21.21 repeats） （two- tailed P = 0.474）. Among patients＇ groups, the mean number of CAG repeats in partial androgen insensitivity cases （mean 15.83 repeats） was significantly less than in complete androgen insensitivity cases （mean 19.46 repeats） （two- tailed P 〈 0.0001）. Conclusion： The findings suggest that shorter lengths of repeats in the AR gene might act as low penetrance genetic background in varying manifestation of androgen insensitivity.

Whole exome sequencing and single nucleotide polymorphism array analyses to identify germline alterations in genes associated with testosterone metabolism in a patient with androgen insensitivity syndrome and early-onset colorectal cancer

Background: Androgen insensitivity syndrome(AIS), a disorder of sexual development in 46, XY individuals, is caused by loss-of-function mutations in the androgen receptor(AR) gene. A variety of tumors have been reported in association with AIS, but no cases with colorectal cancer(CRC) have been described.Case presentation: Here, we present a male patient with AIS who developed multiple early-onset CRCs and his pedigree. His first cousin was diagnosed with AIS and harbored the same AR gene mutation, but with no signs of CRC. The difference in clinical management for the two patients was that testosterone treatment was given to the proband for a much longer time compared with the cousin. The CRC family history was negative, and no germline mutations in well-known CRC-related genes were identified. A single nucleotide polymorphism array revealed a microduplication on chromosome 22q11.22 that encompassed a micro RNA potentially related to CRC pathogenesis. In the proband, whole exome sequencing identified a polymorphism in an oncogene and 13 rare loss-of-function variants, of which two were in CRC-related genes and four were in genes associated with other human cancers.Conclusions: By pathway analysis, all inherited germline genetic events were connected in a unique network whose alteration in the proband, together with continuous testosterone stimulation, may have played a role in CRC pathogenesis.

Complete androgen insensitivity syndrome caused by the c.2678C>T mutation in the androgen receptor gene:A case report

BACKGROUND Androgen insensitivity syndrome is an X-linked recessive genetic disease caused by mutations in the androgen receptor gene(AR).However,the underlying molecular mechanisms for the majority of AR variants remain unclear.In this study,we identified a point variant in three patients with complete androgen insensitivity syndrome(CAIS),summarized the correlation analysis,and performed a literature review.CASE SUMMARY The proband was raised as a girl.In infancy,she was first referred to hospital with a right inguinal hernia.Ultrasonography revealed the absence of a uterus and ovaries,and a testis-like structure located at the inguinal canal.Further diagnostic workup detected a 46,XY karyotype,and fluorescence in situ hybridization analysis showed the presence of the SRY gene.Histological analysis revealed the excised tissue to be testicular.Twelve years later,she was admitted to our hospital with a lack of breast development.Her pubic hair and breasts were Tanner stage I.She had normal female external genitalia.Blood hormone tests showed normal testosterone levels,low estradiol levels,and high gonadotropin levels.Her two siblings underwent similar examinations,and all three had a rare hemizygous missense mutation in AR:c.2678C>T.In vitro functional analyses revealed decreased nuclear translocation in AR-c.2678C>T mutation cells.CONCLUSION This case of CAIS was caused by an AR variant(c.2678C>T).Functional studies showed impaired nuclear translocation ability of the mutant protein.

Mutations in the androgen receptor gene of seven Chinese patients with complete androgen insensitivity syndromes

To further investigate the molecular mechanism of androgen insensitivity syndromes (AIS), exons B to H of the androgen receptor (AR) gene in seven Chinese patients with Complete AlS (CAIS) were examined by the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis and direct DNA sequencing. Four distinct point mutations (Gly743Arg, Va1866Met, Arg752Gln, T2919→deletion) were identified in 4patients, and all the mutations were localized in exons E or G encoding androgen binding domain of AR. The frame-shift mutation caused by deletion of T2919 had not been reported yet so far, therefore, It was a novel mutation. Detection of the AR gene in 2 mothers showed both of them were heterozygotes carrying the same mutationsas their daughters. our study was helpful for further delineating the diversity of genetic alterations of the AR gene in patients with AlS and better understanding the relationships between structure and function of AR.

Polarization Insensitivity in Double-Split Ring and Triple-Split Ring Terahertz Resonators

A modified double-split ring resonator and a modified triple-split ring resonator, which offer polarization-insensitive performance, are investigated, designed and fabricated. By displacing the two gaps of the conventional double- split ring resonator away from the center, the second resonant frequency for the 0° polarized wave and the resonant frequency for the 90° polarized wave become increasingly close to each other until they are finally identical. Theoretical and experimental results show that the modified double-split ring resonator and the modified triple-split ring resonator are insensitive to different polarized waves and show strong resonant frequency dips near 433 and 444OHz, respectively. The results of this work suggest new opportunities for the investigation and design of polarization-dependent terahertz devices based on split ring resonators.

Study of bone mineral density in Chinese patients with complete androgen insensitivity syndrome

Objective:To explore the characteristics of bone mineral density(BMD)and treatment inChinese patients with complete androgen insensitivity syndrome(CAIS).Methods:Fourteen cases of CAIS were studied retrospectively through analyzing and compa-ring BMD of pre-and post-gonadectomy with healthy Chinese men and women.BMD at the lum-bar spine and the femur were measured by dual energy X-ray absorptiometry(DXA).Results:There were 10 cases of CAIS having pre-gonadectomy DXA,in which 6 cases hadvery significantly reduced lumbar 2-4 BMD[(0.92±0.08)g/cm^2]comparing with both healthymen and women(P<0.01),5 cases had significantly reduced femur neck BMD[(0.89±0.12)g/cm^2]comparing with healthy men(P<0.05).There were 7 cases having 12 post-gonadectomyDXA,in which all lumbar 2-4 BMD[(0.954-0.06)g/cm^2]were reduced very significantly com-paring with both healthy men and women(P<0.01),femur neck BMD[(0.91±0.08)g/cm^2]were also reduced significantly comparing with healthy men(P<0.01)and women(P<0.05).Conclusion:There were different degrees of osteopenia in patients of CAIS,especially inlumbar vertebra.This suggests that both estrogen and androgen play important roles in the ac-quirement and maintenance of peak bone mass.

Renal Amyloidosis Following Chronic Osteomyelitis in a Patient with Congenital Insensitivity to Pain and Anhidrosis

Congenital insensitivity to pain and anhidrosis (CIPA) is a rare form of hereditary sensory and autonomic neuropathy. It is characterized by impaired perception of pain and temperature, anhidrosis and intellectual disability. Self mutilating behaviors lead to accidental injuries. The limb lesions are often infected and frequently progress to chronic osteomyelitis. In pediatrics, amyloidosis usually occurs secondary to chronic inflammatory diseases. The coexistence of amyloidosis and CIPA has not previously been reported in literature. A CIPA case complicated with nephrotic syndrome and renal amyloidosis following chronic osteomyelitis is presented here. This report emphasizes the importance of close follow-up of patients by urine analysis for the risk of developing amyloidosis particularly in the presence of chronic infections.

Quality of Life and Psychological Distress in Women with Mayer-Rokitansky-Küster-Hauser Syndrome and Individuals with Complete Androgen Insensitivity Syndrome

Purpose: This study examines quality of life and psychological distress in individuals with Mayer-Rokitansky-Küster-Hauser Syndrome (MRKHS) and Complete Androgen Insensitivity Syndrome (CAIS), two syndromes belonging to the field of “disorders of sex development”. Methods: Fifty women with MRKHS and eleven individuals with CAIS participated. The German versions of the World Health Organization Quality of Life Questionnaire (short version, WHOQOL-Bref), the Brief Symptom Inventory (BSI), and the Patient Health Questionnaire (PHQ-D) were used as standardized instruments to measure quality of life and psychopathology. Additional questions concerning demographic variables and suicidality were included. Results: In both patient samples examined, general quality of life reported was in the average range (CAIS: mean z-score = ﹣0.43, SD = 1.05;MRKHS: mean z-score = ﹣0.11, SD = 1.06). The standardized instrument assessment revealed increased psychological distress (proportion of clinical cases according to the BSI: CAIS: 54.5%;MRKHS: 55.1%). A correlation between psychological distress and time span from first suspicion to diagnosis was found in women with MRKHS (Spearman’s rho = 0.35, p = 0.018). Conclusions: The results illustrate the importance of individualised and thorough diagnostics when dealing with patients with MRKHS or CAIS. Psychological distress might be an issue for these individuals and therefore should be considered in treatment and counselling.

Reaction mechanism,insensitivity and mechanical property of PTFE-Mg-W composites with magnesium particles surface modification

This paper aims at enhancing impact insensitivity of polytetrafluoroethylene(PTFE)-Mg-W without sacrificing bulk of energy released in the reaction and optimizing mechanical properties of PTFE-Mg-W by magnesium surface treatment.The reaction energy results indicate that the reaction energy of PTFE-Mg-W(modified 1 min)in oxygen decreases slightly to 7905 J·g^(-1)compared with that of PTFE-Mg-W(unmodified)which is8533 J·g^(-1).Under impact condition(impact velocity between 16.232 and 17.726 m·s^(-1)),compared with PTFEMg-W(unmodified),the initiation time before ignition of PTFE-Mg-W(modified 1 min)delays 50μs;the absorbed energy needed for ignition of PTFE-Mg-W(modified1 min)increases by 67.9%.This increase in impact insensitivity of PTFE-Mg-W can be contributed to the formation of passivated layers of magnesium particles after modification which effectively weakens the total interface area among reactive components and partly contributes to the loss of released energy of PTFE-Mg-W after magnesium modification.The quasi-static and dynamic compression results show that PTFE-Mg-W(modified 1 min)possess the highest strength and the best ductility.

Phenotypic and molecular characteristics of androgen insensitivity syndrome patients

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.

A non-fullerene acceptor enables efficient P3HT-based organic solar cells with small voltage loss and thickness insensitivity

Poly(3-hexylthiophene)(P3HT) is a low-cost polymer donor for organic solar cells (OSCs). However, the P3HT-based OSCs usually give low power conversion efficiencies (PCEs) due to the wide bandgap and the high-lying energy levels of P3HT. To solve this problem, in this work, we design and synthesize a new A-D-A type non-fullerene acceptor, DFPCBR, which owns an electron-donating (D) core constructed by linking a 2,5-difluorobenzene ring with two cyclopentadithiophene moieties, and two electron-accepting (A) end-groups of benzo[c][1,2,5]thiadiazole connected with 3-ethyl-2-thioxothiazolidin-4-one. Because of the strong electron-donating ability and large conjugation effect of D core, DFPCBR shows appropriate energy levels and a narrow bandgap matching well with those of P3HT. Therefore, with P3HT as the donor and DFPCBR as the acceptor, the OSCs possess broad absorption range from 350 nm to 780 nm and the reduced energy loss (Eloss) of 0.79 eV (compared with ~1.40 eV for the P3HT:PC61BM device), providing a good PCE of 5.34% with a high open-circuit voltage (VOC) of 0.80 V. Besides, we observe that the photovoltaic performances of these devices are insensitive to the thickness of the active layers:even if the active layer is as thick as 320 nm,~80%of the best PCE is maintained, which is rarely reported for fullerene-free P3HT-based OSCs, suggesting that DFPCBR has the potential application in commercial OSCs in the future.

Dynamic recrystallization-induced temperature insensitivity of yield stress in single-crystal Al1.2CrFeCoNi micropillars

High-entropy alloys, a new class of metallic materials, exhibit excellent mechanical properties at high temperatures. In spite of the worldwide interest, the underlying mechanisms for temperature dependence of mechanical properties of these alloys remain poorly understood. Here, we systemically investigate the mechanical behaviors and properties of Al_(1.2)CrFeCoNi(comprising a body-centered cubic phase) and Al_(0.3)CrFeCoNi(comprising a face-centered cubic phase) single-crystal micropillars with three orientations([100], [110], and [111]) at temperatures varying from 300 to 675 K by using in situ compression of micropillars inside a scanning electron microscope. The results show that the yield stresses of Al_(1.2)CrFeCoNi micropillars are insensitive to temperature changes, and their flow stresses and work hardening rates increase slightly with increasing temperature from 300 to550 K, which differs from the typical temperature dependence of yield/flow stresses in metals and alloys. In contrast,Al_(0.3)CrFeCoNi micropillars exhibit typical thermal softening. Furthermore, it is found that the Al_(1.2)CrFeCoNi micropillars exhibit a transition from homogenous deformation to localized deformation at a critical temperature, while the Al_(0.3)CrFeCoNi micropillars always maintain a well-distributed and fine slip deformation. Detailed transmission electron microscopy analyses reveal that dynamic recrystallization(involving dislocation tangles, and formation of dislocation cell structures and sub-grains)plays a key role in the observed temperature insensitivity of the yield stress and increasing flow stress(and work hardening rate)with increasing temperature in the Al_(1.2)CrFeCoNi micropillars, and that thermally activated dislocation slip leads to thermal softening of the Al_(0.3)CrFeCoNi micropillars. The differences in deformation modes and temperature dependence of the mechanical properties between Al_(1.2)CrFeCoNi and Al_(0.3)CrFeCoNi essentially originate from the differences in dislocation activities and slip systems since the two alloys adopt different phases. Our findings provide key insights in the temperature dependence of mechanical properties and deformation behaviors of high-entropy alloys with body-centered cubic and face-centered cubic phases.

S578N mutation of the androgen receptor in an adolescent with complete androgen insensitivity syndrome

Androgen insensitivity syndrome （AIS） was first .described by the American gynecologist Morris in 1953 and was mitially described＇in 82 patients, The syndrome was designated testicular feminization syndrome , because the testes produce hormones with estrogen-like actions. Clinical AIS manifestations include the appearance of normal female external genitalia without internal female genital organs.

360° fusion for Charcot spine caused by congenital insensitivity to pain with anhidrosis

Congenital insensitivity to pain with anhidrosis （CIPA） is an autosomal recessive form of sensory neuropathymanifesting with the lack of perception of pain.^1 There have been few reports of Charcot spine in patients with CIPA,^2 and surgery for such cases was accompanied by high revision proportion.^3＇4 The purpose of this report is to describe a patient with CIPA who developed a recurrent Charcot arthropathy in her lumbar spine and was treated by revision surgery, with the aim to discuss the strategy of surgical management for such cases.

Anesthetic management of children with congenital insensitivity to pain with anhidrosis

Introduction:Congenital analgesia is a rare autosomal recessive hereditary disease.The primary damage of congenital analgesia is central structure damage of comprehensive pain perception.Case presentation:A 1-year-old Han Chinese boy was admitted to hospital because of a tongue bite.He had no response to noxious stimulation of the body surface and was diagnosed with congenital analgesia.A small dose of remifentanil was intravenously injected during anesthetic induction to reduce the stress response caused by endotracheal intubation.A certain depth of anesthesia should be guaranteed during anesthetic induction and surgery to alleviate the stress response induced by endotracheal intubation and the operation.Conclusion:Opioid analgesics are not required for general anesthesia in patient with congenital insensitivity to pain.With a heat dissipation barrier in patients with congenital insensitivity to pain with anhidrosis,body temperature,end-tidal carbon dioxide and bispectral index should be monitored.

Shock Initiation Experiments with Modeling on a DNAN Based MeltCast Insensitive Explosive

2,4-dinitroanisole(DNAN)is a good replacement for 2,4,6-trinitrotoluene(TNT)in melt-cast explosives due to its superior insensitivity.With the increasing use of DNAN-based melt-cast explosives,the prediction of reaction violence and hazard assessment of the explosives subjected to shock is of great significance.This study investigated the shock initiation characteristics for a DNAN-based melt-cast explosive,DHFA,using the one-dimensional Lagrangian apparatus.The embedded manganin gauges in the apparatus record the pressure histories at four Lagrangian positions and show that shock-todetonation transition in DHFA needs a high input shock pressure.The experimental data are analyzed to calibrate the Ignition and Growth model.The calibration is performed using an objective function based on both pressure history and the arrival time of shock.Good agreement between experimental and calculated pressure histories indicates the high accuracy of the calibrated parameters with the optimization method.

吉他演奏家马丁诺Solo小七和弦概念化演奏分析

马丁诺在15岁就开始职业演出,演奏技巧绝佳。同时,他也是位态度上非常开放的乐手,能够接受各种不同风格的元素,他的表现方式,直接开启了Sonny Sharrock等后来的前卫吉他手的道路。本论根据马丁诺在《Linear Expressions》中对和弦的替换思维方式,结合他于1970年01月01日在《Exit》中重新演绎的《Days Of Wine And Roses》《How insensitive》Solo线条部分,分析IIM7和弦之外连接。通过对马丁诺在《Linear Expressions》中提到的他对和弦进行下的小和弦替代思维方式,这种概念化的思维方式对吉他手、爵士乐手来说具有研究和学习的价值。本文主要分析了四种和弦进行下的替换思维,包括大大七和弦组,大小七和弦以及变化的属七和弦,半减七和弦。

Congenital insensitivity to pain and anhidrosis syndrome： two cases involving a brother and sister

Congenital insensitivity to pain and anhidrosis （CIPA） is a rare entity.CIPA patients are subjected to repeated injuries,which are easily neglected.There is no specific treatment for CIPA,but supervision by parents and patient training are important to avoid further damage and to maintain quality of life.We present two cases of CIPA involving a brother and sister,whose parents did not have a consanguineous marriage.

A novel arg616Cys mutation in the DNA-binding domain of complete androgen insensitivity syndrome in a Chinese family

Awide spectrum of Androgen insensitivity syndrome （AIS） occur due to mutations in the androgen receptor（AR）. The clinical presentation of AIS ranges from a typically male phenotype with decreased body hair and/ or oligospermia to a typically female phenotype with primary amenorrhea and without pubic and axillary hair;