EPAS1 prevents telomeric damage-induced senescence by enhancing transcription of TRF1,TRF2,and RAD50

Telomeres are nucleoprotein structures located at the end of each chromosome,which function in terminal protection and genomic stability.Telomeric damage is closely related to replicative senescence in vitro and physical aging in vivo.As relatively long-lived mammals based on body size,bats display unique telomeric patterns,including the upregulation of genes involved in alternative lengthening of telomeres(ALT),DNA repair,and DNA replication.At present,however,the relevant molecular mechanisms remain unclear.In this study,we performed cross-species comparison and identified EPAS1,a well-defined oxygen response gene,as a key telomeric protector in bat fibroblasts.Bat fibroblasts showed high expression of EPAS1,which enhanced the transcription of shelterin components TRF1 and TRF2,as well as DNA repair factor RAD50,conferring bat fibroblasts with resistance to senescence during long-term consecutive expansion.Based on a human single-cell transcriptome atlas,we found that EPAS1 was predominantly expressed in the human pulmonary endothelial cell subpopulation.Using in vitro-cultured human pulmonary endothelial cells,we confirmed the functional and mechanistic conservation of EPAS1 in telomeric protection between bats and humans.In addition,the EPAS1 agonist M1001 was shown to be a protective compound against bleomycin-induced pulmonary telomeric damage and senescence.In conclusion,we identified a potential mechanism for regulating telomere stability in human pulmonary diseases associated with aging,drawing insights from the longevity of bats.

Efficacy and complications of argon plasma coagulation for hemorrhagic chronic radiation proctitis

BACKGROUND Chronic radiation proctitis(CRP) is a complication which occurs in 1%-5% of patients who undergo radiotherapy for pelvic malignancies. Although a wide range of therapeutic modalities are available, there is no literature to date showing any particularly appropriate therapeutic modality for each disease stage. Argon plasma coagulation(APC) is currently recommended as the firstchoice treatment for hemorrhagic CRP, however, its indication based on longterm follow-up is still unclear. On the hypothesis that the long-term efficacy and safety of APC are not fully understood, we reviewed APC treatment for patients with hemorrhagic CRP from a single center.AIM To assess the long-term efficacy and safety of APC for hemorrhagic CRP.METHODS This is a retrospective study of consecutive patients treated with APC for hemorrhagic CRP from January 2013 to October 2017. Demographics, clinical variables, and typical endoscopic features were recorded independently. Success was defined as either cessation of bleeding or only occasional traces of bloody stools with no further treatments for at least 12 mo after the last APC treatment.We performed univariate and multivariate analyses to identify factors associated with success and risk factors for fistulas.RESULTS Forty-five patients with a median follow-up period of 24 mo(range: 12-67 mo)were enrolled. Fifteen(33.3%) patients required blood transfusion before APC.Successful treatment with APC was achieved in 31(68.9%) patients. The mean number of APC sessions was 1.3(1-3). Multivariate analysis showed that APC failure was independently associated with telangiectasias present on more than50% of the surface area [odds ratio(OR) = 6.53, 95% confidence interval(CI): 1.09-39.19, P = 0.04] and ulcerated area greater than 1 cm^2(OR = 8.15, 95%CI: 1.63-40.88, P = 0.01). Six(13.3%) patients had severe complications involving rectal fistulation. The only factor significantly associated with severe complications was ulcerated area greater than 1 cm^2(P = 0.035).CONCLUSION The long-term efficacy of APC for hemorrhagic CRP is uncertain in patients with telangiectasias present on > 50% of the surface area and ulceration > 1 cm^2.

径向超声非实时引导下经支气管镜肺活检对周围型肺癌的诊断价值和假阴性分析

目的探讨径向超声(RP-EBUS)非实时引导下经支气管镜肺活检(TBLB)对周围型肺癌的诊断价值和假阴性的原因。方法回顾性分析2013年3月-2016年12月在南方医科大学顺德医院确诊为周围型肺癌的患者256例,所有患者在常规支气管检查正常后行RP-EBUS检查,能获得超声图像的有189例,在撤出超声探头后,沿超声探头路径伸入活检钳对病灶进行活检。评价RP-EBUS非实时引导下TBLB对周围型肺癌的诊断意义并分析其假阴性原因。结果 RP-EBUS对周围型肺癌的总体发现率为73.83%(189/256),RP-EBUS非实时引导下TBLB对周围型肺癌的诊断阳性率为61.33%(157/256)。病灶直径>2 cm、不贴近胸膜、包绕RP-EBUS探头、超声图像呈实性低回声伴周边强回声带的周围型肺癌在RP-EBUS非实时引导下TBLB的诊断阳性率高(P<0.05);诊断阳性率与RP-EBUS探头是否通过病灶和钳检次数无关(P>0.05)。主要并发症为咯血、胸痛、气胸,均无需特殊处理可缓解。结论 RP-EBUS非实时引导下TBLB对诊断周围型肺癌具有较高临床应用价值,其诊断阳性率与病灶大小、病灶是否贴近胸膜、超声图像特征、病灶是否包绕RP-EBUS探头有关,提高操作者的技术水平可降低假阴性率。

2型糖尿病视网膜动脉硬化与心脑血管系统疾病的关系

目的:探讨2型糖尿病视网膜动脉硬化情况及其与心脑血管系统疾病的关系。方法:选取2016-01/2017-01我院收治的2型糖尿病患者85例为研究对象,对患者进行眼底检查,确定其眼底动脉硬化分级情况,并对患者血糖水平进行检测,测定其糖化血红蛋白、空腹血糖和餐后2h血糖水平。患者均随访至少1. 5a,统计随访期间患者心脑血管系统疾病的发生率。比较不同眼底动脉硬化分级患者的血糖水平和心脑血管系统疾病发生率,并分析眼底动脉硬化分级与血糖水平和心脑血管系统疾病的关系。结果:患者85例中,眼底动脉硬化分级为Ⅰ级、Ⅱ级和Ⅲ级患者比例分别为15%(13/85)、52%(44/85)和33%(28/85),随访期间心脑血管系统疾病发生率为27%(23/85)。随着眼底动脉硬化分级的升高,其糖化血红蛋白、空腹血糖、餐后2h血糖水平和心脑血管系统疾病发生率亦升高,差异有统计学意义(P<0. 05)。Spearman相关分析结果显示,2型糖尿病患者眼底动脉硬化分级与其糖化血红蛋白、空腹血糖、餐后2h血糖水平和心脑血管系统疾病发生率均呈正相关(rs=0. 875、0. 792、0. 835、0. 878,P<0. 05)。结论:2型糖尿病眼底动脉硬化严重,且与其血糖水平和心脑血管系统疾病密切相关。

Minor secoiridoid aglycones from the low-polarity part of the traditional Chinese herb: Swertia mileensis

Eleven new secoiridoid aglycones involving unusual C9-skeleton:swerimilegenins A-F(1-6);bis-C9-skeleton:swerimilegenin G(7);and C_(10)-skeleton:swerimilegenins H−K(8−11),as well as six known ones,were isolated from the low-polarity part of the traditional Chinese herb medicine Swertia mileensis.Their structures were determined by extensive spectroscopic data and X-ray diffraction.Biogenetically,swerimilegenin A(1)belonged to 10-nor-secoiridoid,and swerimilegenins B-F(2-6)were 1-nor-secoiridoids.Erythrocentaurin(12)and gentiogenal(15)showed moderate anti-HBV activity on HepG 2.2.15 cell line in vitro.

The role of ezrin-associated protein network in human sperm capacitation

Membrane modifications in sperm cells represent a key step in sperm capacitation; however, the molecular basis of these modifications is not fully understood. Ezrin is the best-studied member of the ezrin/radixin/merlin family. As a cross-linker between the cortical cytoskeleton and plasma membrane proteins, ezrin contributes to remodeling of the membrane surface structure. Furthermore, activated ezrin and the Rho dissociation inhibitor, RhoGDI, promote the formation of cortical cytoskeleton-polymerized actin through Rho activation. Thus, ezrin, actin, RhoGDI, Rho and plasma membrane proteins form a complicated network in vivo, which contributes to the assembly of the structure of the membrane surface. Previously, we showed that ezrin and RhoGDI1 are expressed in human testes. Thus, we sought to determine whether the ezrin-RhoGDIl-actin-membrane protein network has a role in human sperm capacitation. Our results by Western blot indicate that ezrin is activated by phosphorylation of the threonine567 residue during capacitation. Co-immunoprecipitation studies revealed that, during sperm capacitation, the interaction between ezrin and RhoGDI1 increases, and phosphostaining of two dimensional electrophoresis gels showed that RhoGDI 1 is phosphorylated, suggesting that RhoGDI 1 dissociates from RhoA and leads to actin polymerization on the sperm head. We speculate that activated ezrin interacts with polymerized actin and the glycosylated membrane protein cd44 after capacitation. Blocking sperm capacitation using ezrin- or actin-specific monoclonal antibodies decreases their acrosome reaction （AR） rate, but has no effect on the AR alone. Taken together, our results show that a network consisting of ezrin, RhoGDI1, RhoA, F-actin and membrane proteins functions to influence the modifications that occur on the membrane of the sperm head during human sperm capacitation.

Chemical Constituents from Mentha haplocalyx Briq.(Mentha canadensis L.)and Theirα‑Glucosidase Inhibitory Activities

Mentha haplocalyx(Mentha canadensis)is widely used as a medicinal plant in traditional Chinese medicine,and the extracts of its aerial parts are found to signifcantly inhibit the activity ofα-glucosidase with an IC_(50) value of 21.0μg/mL.Bioactivity-guided isolation of the extracts aforded two new compounds(1 and 2),together with 23 known ones(3-25).Their structures were established by extensive spectroscopic analyses(1D and 2D NMR,MS,IR and UV).Compounds 1-17 and 21-25 were evaluated for theirα-glucosidase inhibitory activities.Compound 11 was the most active ones with an IC_(50) values of 83.4μM.These results verify theα-glucosidase inhibitory activity of M.haplocalyx(M.canadensis)and specify its active compounds for the frst time.

Diverting colostomy is an effective and reversible option for severe hemorrhagic radiation proctopathy

A total of 738 continual CRP patients were screened.After exclusion,14 patients in the colostomy group and 25 in the conservative group were included in the final analysis.Preoperative Hb was only 63 g/L±17.8 g/L in the colostomy group compared to 88.2 g/L±19.3 g/L(P<0.001)in the conservative group.All 14 patients in the former group achieved complete remission of bleeding,and the colostomy was successfully reversed in 13 of 14(93%),excepting one very old patient.The median duration of stoma was 16(range:9-53)mo.The Hb level increased gradually from 75 g/L at 3 mo,99 g/L at 6 mo,and 107 g/L at 9 mo to 111 g/L at 1 year and 117 g/L at 2 years after the stoma,but no bleeding cessation or significant increase in Hb levels was observed in the conservative group.Endoscopic telangiectasia and bleeding were greatly improved.Endoultrasound showed decreased vascularity,and magnetic resonance imaging revealed an increasing presarcal space and thickened rectal wall.Anorectal functions and quality of life were significantly improved after stoma reversal,when compared to those before stoma creation.CONCLUSION Diverting colostomy is a very effective method in the remission of refractory hemorrhagic CRP.Stoma can be reversed,and anorectal functions can be recovered after reversal.

Ultrasound guiding the rapid diagnosis and treatment of perioperative pneumothorax:A case report

BACKGROUND Pneumothorax is one of the most common causes of acute dyspnea.In patients under general anesthesia,the symptoms may not be obvious,which may delay diagnosis and treatment.Computed tomography is the gold standard for the diagnosis of pneumothorax,but is not suitable for rapid diagnosis of this complication.In contrast,lung ultrasonography can provide rapid diagnosis and treatment of pneumothorax.CASE SUMMARY The patient was a 53-year-old man admitted for rupture of the spleen caused by an accidental fall and emergency splenectomy was planned.Anesthesia was induced,and tracheal intubation was performed successfully with a video laryngoscope.About 2 min after tracheal intubation,the airway peak pressure increased to 50 cm H2O and the oxygen saturation dropped to 70%.According to the BLUE protocol,a recommended area of the chest was scanned by ultrasound.The pleural slide sign disappeared and obvious parallel line sign could be seen in the left lung.The boundary of pneumothorax(lung points)were rapidly confirmed by ultrasound.To avoid lung injury,a closed thoracic drainage tube was placed in the involved area.On day 9 after surgery,the patient was discharged from the hospital without any complications.CONCLUSION Perioperative pneumothorax is rare but dangerous.It can be rapidly diagnosed and treated with ultrasound guidance.

UFLC‑PDA‑MS/MS Profling of Seven Uncaria Species Integrated with Melatonin/5‑Hydroxytryptamine Receptors Agonistic Assay

Uncariae Ramulus Cum Uncis(Gou-Teng),the dried hook-bearing stems of several Uncaria plants(Rubiaceae),is a wellknown herbal medicine in China.The clinical application of Gou-Teng is bewildered for the morphological and chemical similarity between diferent species.In order to discern their chemical and biological diference,an ultra-fast liquid chromatography equipped with ion trap time-of-fight mass spectrometry(UFLC-IT/TOF-MS)combining with melatonin(MT1 and MT2)and 5-hydroxytryptamine(5-HT1A and 5-HT2C)receptors agonistic assay in vitro was conducted on seven Uncaria species.As a result,57 compounds including 35 indole alkaloids,ten favonoids,fve triterpenoids,fve chlorogenic analogues,and two other compounds were characterized based on their MS/MS patterns and UV absorptions.Specifcally,cadambine-type and corynanthein-type alkaloids were exclusively present in U.rhynchophylla and U.scandens,whereas corynoxine-type alkaloids were commonly detected in all the seven Uncaria plants.Three Uncaria species,U.rhynchophylla,U.macrophylla,and U.yunnanensis showed obviously agnostic activity on four neurotransmitter receptors(MT1,MT2,5-HT1A,and 5-HT_(2C)).This frst-time UFLCMS-IT-TOF analyses integrated with biological assay on seven Uncaria plants will provide scientifc viewpoints for the clinical application of Gou-Teng.

Artemlavanins A and B from Artemisia lavandulaefolia and Their Cytotoxicity Against Hepatic Stellate Cell Line LX2

Two new sesquiterpenoids,artemlavanins A(1)and B(3),together with fifteen known compounds(2 and 4−17)were iso-lated from the EtOH extract of Artemisia lavandulaefolia.The structures of new compounds were elucidated by extensive spectroscopic analyses(HRESIMS,1D and 2D NMR)and ECD calculations.Compound 1 was a sesquiterpenoid lactone possessing a rearranged eudesmane skeleton;compounds 2-5,6-8,9 and 10-12 belonged to the eudesmane,guaiane,oppositane and farnesane sesquiterpenoids,respectively;compounds 13-17 were the phenyl derivatives with a 4-hydroxy-acetophenone moiety.Twelve compounds(1-3,5-7,10-12,14,15 and 17)displayed cytotoxicity against hepatic stellate cell line LX2(HSC-LX2)with IC50 values ranging from 35.1 to 370.3μM.Compounds 2,7,10-12 and 17 exhibited the stronger cytotoxicity than silybin(IC50,169.6μM)with IC50 values of 82.1,35.1,95.0,83.8,81.6 and 90.1μM.Compound 7 as the most active one showed significant inhibition on the deposition of human collagen type I(Col I),human hyaluronic acid(HA)and human laminin(HL)with IC50 values of 10.7,24.5 and 13.3μM.

Sinomenine promotes differentiation of induced pluripotent stem cells into immature dendritic cells with high induction of immune tolerance

BACKGROUND Immature dendritic cells(imDCs)play an important role in the induction of donor-specific transplant immunotolerance.However,these cells have limitations,such as rapid maturation and a short lifespan in vivo.In previous studies,induced pluripotent stem cells(iPSCs)differentiated into imDCs,and sinomenine(SN)was used to inhibit the maturation of imDCs.AIM To study the capacity of SN to maintain iPSC-derived imDCs(SN-iPSCs-imDCs)in an immature state and the mechanism by which SN-iPSCs-imDCs induce immunotolerance.METHODS In this study,mouse iPSCs were induced to differentiate into imDCs in culture medium without or with SN(iPSCs-imDCs and SN-iPSCs-imDCs).The imDCrelated surface markers,endocytotic capacity of fluorescein isothiocyanate Dextran and apoptosis were analyzed by flow cytometry.The effects of iPSCs-imDCs and SNiPSCs-imDCs on T-cell stimulatory function,and regulatory T(Treg)cell proliferative function in vitro were analyzed by mixed lymphocyte reaction.Cytokine expression was detected by ELISA.The apoptosis-related proteins of iPSCs-DCs and SN-iPSCs-DCs were analyzed by western blotting.The induced immunotolerance of SN-iPSCs-DCs was evaluated by treating recipient Balb/c skin graft mice.Statistical evaluation of graft survival was performed using Kaplan–Meier curves.RESULTS Both iPSCs-imDCs and SN-iPSCs-imDCs were successfully obtained,and their biological characteristics and ability to induce immunotolerance were compared.SN-iPSCs-imDCs exhibited higher CD11c levels and lower CD80 and CD86 levels compared with iPSCs-imDCs.Reduced major histocompatibility complex II expression,worse T-cell stimulatory function,higher Treg cell proliferative function and stronger endocytotic capacity were observed with SN-iPSCs-imDCs(P<0.05).The levels of interleukin(IL)-2,IL-12,interferon-γin SN-iPSCs-imDCs were lower than those in iPSCs-imDCs,whereas IL-10 and transforming growth factor-βlevels were higher(P<0.05).The apoptosis rate of these cells was significantly higher(P<0.05),and the expression levels of cleaved caspase3,Bax and cleaved poly(ADP-ribose)polymerase were higher after treatment with lipopolysaccharides,but Bcl-2 was reduced.In Balb/c mice recipients immunized with iPSCsimDCs or SN-iPSCs-imDCs 7 d before skin grafting,the SN-iPSCs-imDCs group showed lower ability to inhibit donor-specific CD4+T-cell proliferation(P<0.05)and a higher capacity to induce CD4+CD25+FoxP3+Treg cell proliferation in the spleen(P<0.05).The survival span of C57bl/6 skin grafts was significantly prolonged in immunized Balb/c recipients with a donor-specific pattern.CONCLUSION This study demonstrated that SN-iPSCs-imDCs have potential applications in vitro and in vivo for induction of immunotolerance following organ transplantation.

Panaxadiol and Panaxatriol Derivatives as Anti-Hepatitis B Virus Inhibitors

28 Derivatives of panaxadiol(PD)and panaxatriol were synthesized and evaluated for their anti-HBV activity on HepG 2.2.15 cells,of which 17 derivatives inhibited HBV DNA replication.Compounds 4,9,10,14,and 15 showed moderate activity against HBV DNA replication with IC50 values ranged from 7.27 to 28.21 lM compared with PD.In particular,3-O-20-thenoyl panaxadiol(4)inhibited not only HBV DNA replication(IC50=16.5 lM,SI[115.7)but also HBsAg(IC50=30.8 lM,SI[62.0)and HBeAg(IC50=18.2 lM,SI[105.14)secretions.Their structure–activity relationships were discussed for guiding future research toward the discovery of new anti-HBV agents.

Correlation of acid reflux and esophageal motility in patients with gastroesophageal reflux disease

Objective:To explore the relationship between acid reflux and esophageal motility in patients with gastroesophageal reflux disease.Methods:From January 2018 to December 2019,80 patients with typical gastroesophageal reflux symptoms such as reflux and heartburn were randomly selected from the Department of Gastroenterology,First Affiliated Hospital of guangxi university of chinese medicine.The patients were divided into pathological group,sensitive group and physiological group based on the percentage of acid exposure time and reflux-symptom correlation.The GerdQ score,quality of life score,esophageal acid test and esophageal manometry related parameters of the three groups of patients were compared.Results:Compared with the sensitive group and the physiological group,the GerdQ score,DeMeester score,orthostatic acid reflux time,orthostatic acid reflux time,longest acid reflux time and acid reflux times in the pathological group were significantly higher.Sf-36 score,lower esophageal sphincter pressure and effective rate of deglutition were all significantly reduced,with statistically significant differences(P<0.05).Compared with the physiological group,the GerdQ score of the sensitive group was higher.The sf-36 score was low,and the differences were statistically significant(P<0.05).The acid indexes in the sensitive group were higher than those in the physiological group,but the differences were not statistically significant(P>0.05).Compared with the physiological group,the distal contraction integral and the amplitude of the lower esophageal sphincter 3cm above the pathological group and the sensitive group decreased significantly(P<0.05).There were no statistically significant differences in the length of the lower esophageal sphincter,the length of the lower esophageal sphincter in the abdominal segment,the amplitude of the upper esophageal sphincter at 7cm and 11cm and the peristaltic wave velocity of the esophageal body in the three groups(P>0.05).Conclusion:the decrease of lower esophageal sphincter pressure is the key factor leading to pathological acid reflux,and acid reflux is closely related to distal contraction integral and peristaltic amplitude of 3cm on lower esophageal sphincter in patients with gastroesophageal reflux disease.

Elevated levels of fructosamine are independently associated with SARS-CoV-2 reinfection:A 12-mo follow-up study

BACKGROUND The association between blood levels of fructosamine(FMN)and recurrent coronavirus disease 2019(COVID-19)is currently unclear.AIM To investigate a prospective relationship between blood levels of FMN and severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)reinfection.METHODS A total of 146 Chinese hospitalized patients infected with SARS-CoV-2 were consecutively collectively recruited and followed from January 2020 to May 2021.Diagnosis of COVID-19 and SARS-CoV-2 reinfection was based on the diagnostic criteria and treatment protocol in China.The levels of FMN were determined in blood and divided into tertiles based on their distribution in the cohort of COVID-19 patients.Multivariate-adjusted hazard ratios(HRs)with 95%confidence intervals(CIs)were estimated for SARS-CoV-2 reinfection across the tertiles of FMN levels.A Cox regression model was used to generate the HR for SARS-CoV-2 reinfection in the participants in the top tertile of FMN levels compared with those at the bottom.Disease-free survival was used as the time variable,and relapse was used as the state variable,adjusted for age,gender,influencing factors such as diabetes mellitus,hypertension,and corticosteroid therapy,and clinical indexes such as acute liver failure,acute kidney failure,white blood cell(WBC)count,C-reactive protein,prognostic nutritional index(PNI),and blood lipids.Kaplan-Meier analysis with log-rank tests was used to compare the survival rate between patients with elevated FMN levels(FMN>1.93 mmol/L,the top tertile)and those with nonelevated levels.RESULTS Clinical data for the 146 patients with confirmed COVID-19[age 49(39-55)years;49%males]were analyzed.Eleven patients had SARS-CoV-2 reinfection.The SARS-CoV-2 reinfection rate in patients with elevated FMN levels was significantly higher than that in patients with nonelevated FMN(17%vs 3%;P=0.008)at the end of the 12-mo follow-up.After adjustments for gender,age,diabetes mellitus,hypertension,corticosteroid therapy,WBC count,PNI,indexes of liver and renal function,and blood lipids,patients with nonelevated FMN levels had a lower risk of SARS-CoV-2 reinfection than those with elevated FMN levels(HR=6.249,95%CI:1.377-28.351;P=0.018).Kaplan-Meier analysis showed that the cumulative survival rate of patients infected with SARSCoV-2 was higher in patients with nonelevated FMN levels than in those with elevated FMN levels(97%vs 83%;log rank P=0.002).CONCLUSION Elevated levels of FMN are independently associated with SARS-CoV-2 reinfection,which highlights that patients with elevated FMN should be cautiously monitored after hospital discharge.

A novel mutation in PRPF31,causative of autosomal dominant retinitis pigmentosa,using the BGISEQ-500 sequencer

AIM： To study the genes responsible for retinitis pigmentosa.METHODS： A total of 15 Chinese families with retinitis pigmentosa, containing 94 sporadically afflicted cases, were recruited. The targeted sequences were captured using the Target_Eye_365_V3 chip and sequenced using the BGISEQ-500 sequencer, according to the manufacturer＇s instructions. Data were aligned to UCSC Genome Browser build hg19, using the Burroughs Wheeler Aligner MEM algorithm. Local realignment was performed with the Genome Analysis Toolkit（GATK v.3.3.0） Indel Realigner, and variants were called with the Genome Analysis Toolkit Haplotypecaller, without any use of imputation. Variants were filtered against a panel derived from 1000 Genomes Project, 1000 G_ASN, ESP6500, Ex AC and db SNP138. In all members of Family ONE and Family TWO with available DNA samples, the genetic variant was validated using Sanger sequencing.RESULTS： A novel, pathogenic variant of retinitis pigmentosa, c.357_358 del AA（p.Ser119 Serfs X5） was identified in PRPF31 in 2 of 15 autosomal-dominant retinitis pigmentosa（ADRP） families, as well as in one, sporadic case. Sanger sequencing was performed uponprobands, as well as upon other family members. This novel, pathogenic genotype co-segregated with retinitis pigmentosa phenotype in these two families. CONCLUSION： ADRP is a subtype of retinitis pigmentosa, defined by its genotype, which accounts for 20%-40% of the retinitis pigmentosa patients. Our study thus expands the spectrum of PRPF31 mutations known to occur in ADRP, and provides further demonstration of the applicability of the BGISEQ500 sequencer for genomics research.

Association of Methionine Synthase rs1805087 Polymorphism With Arsenic-Related Skin Pigmentary Changes:A Population-Based Case-Control Study

Objective:Chronic arsenic exposure causes skin lesions including skin cancers,pigmentary changes,and keratosis.Genetic polymorphism in arsenic metabolism may increase susceptibility to the development of arsenic-related skin lesions.This study was performed to determine whether arsenic metabolism-related gene variants are associated with arsenic-related pigmentary changes.Methods:This case-control study involved 189 patients with arsenic-related pigmentary changes and 103 controls.Thirty-eight polymorphisms in 10 genes determined by mass spectrometry assay served as candidate drivers of arsenic-induced pigmentary changes.Urine and plasma arsenic levels were determined by inductively coupled plasma mass spectrometry.Hair arsenic concentrations were measured by nondispersive atomic fluorescence spectrometry.Arsenic metabolites in urine were determined using high-performance liquid chromatography with inductively coupled plasma mass spectrometry.Serum folate was measured using a folate radio assay kit.Analysis of variance,nonparametric test,or the chi-square test was selected according to the data distribution.Spearman correlation analysis was used to determine the correlation between two parameters.Logistic regression was used to estimate the effect of single-nucleotide polymorphisms.Results:The arsenic concentrations in urine,plasma,and hair and the urine arsenic species were not significantly different between patients and controls.Logistic regression revealed that among the polymorphisms,the methionine synthase(MTR)rs1805087 polymorphism showed a protective effect against arsenic-related pigmentary changes.In the codominant model,the adjusted odds ratio for age,sex,and ethnicity was 0.41(95%confidence interval[CI],0.21-0.80;P=0.008)for the AG genotype and 0.11(95%CI,0.02-0.60;P=0.012)for the GG genotype.Conclusion:MTR polymorphism showed a protective effect against arsenic-related pigmentary changes in the logistic regression model.The effect of MTR rs1805087 might be independent of arsenic metabolism and one-carbon metabolism.More studies are needed to clarify the biological function of MTR rs1805087 and its relationship with the etiology of arsenic-related pigmentary changes.

Diarylheptanoid-flavanone Hybrids as Multiple-target Antidiabetic Agents from Alpinia katsumadai

The EtOAc fraction of Alpinia katsumadai seeds showed significant inhibition on glycogen phosphorylase a(GPa)with inhibitory ratios of 97.9%and 64.6%at concentrations of 200 and 100μg/mL,respectively.Bioactivity-guided isolation afforded 15 new diarylheptanoid-flavanone hybrids,katsumadainols B_(1)-B_(15)(1-15),together with eight known ones(16-23).Compounds 4-10 and 12-21 exhibited activity against GPa with IC_(50) values of 10.1-95.4μmol/L;compounds 4,5,16,and 17 displayed inhibitory effects onα-glucosidase with IC_(50) values of 7.1,12.4,7.2,and 8.3μmol/L,obviously higher than acarbose(IC_(50),209.1μmol/L);compounds 4-6,14,16-20,22,and 23 were PTP1B/TCPTP selective inhibitors with IC_(50) values of 40.7-95.8μmol/L;compounds 4,5,16,and 17 showed DPP4 inhibitory effects with inhibitory ratios of 50.0%-54.2%(200μmol/L).Diarylheptanoid-flavanone hybrids(4,5,16,and 17)with a p-hydroxybenzyl at C-6 position represent a promising class of multiple-target antidiabetic agents inhibiting GPa,α-glucosidase,PTP1B,and DPP4.

Artematrovirenolides A—D and Artematrolides S—Z,Sesquiterpenoid Dimers with Cytotoxicity against Three Hepatoma Cell Lines from Artemisia atrovirens

Inspired by the intriguing structures and remarkable activities of sesquiterpenoid dimers,12 new sesquiterpenoid dimers,artematrovirenolides A—D(1—4)and artematrolides S—Z(8—12),were isolated from the EtOAc fraction of Artemisia atrovirens through a bioactivity-guided approach.Their structures were elucidated by comprehensive spectroscopic data and absolute configuration was assigned based on single crystal X-ray diffraction data and ECD calculations.Structurally,all compounds are presumably formed via[4+2]cycloaddition involving three connecting model.Compounds 1—4 are four novel hetero-dimeric[4+2]Diels-Alder adducts dimerized from a rotundane-type unit and a guaiane-type monomer,and compounds 5—12 are eight new homo-dimeric[4+2]adducts derived from two guaianolide moieties.A putative biosynthetic pathway for compounds 1—4 was also proposed.Compounds 4,6,7,and 10 demonstrated moderate cytotoxicity against HepG2,SMMC-7721,and Huh7 cell lines with IC50 values ranging from 9.3 to 62.3μmol/L.Interestingly,compounds 5 and 11 manifested cytotoxicity with IC50 values of 13.6 and 12.8(HepG2),18.5 and 13.1(SMMC-7721),and 16.5 and 19.4μmol/L(Huh7),respectively,which were equivalent to the positive control,sorafenib.This investigation suggests that compounds 5 and 11 might be considered as potent antihepatoma candidates and deserve further structural modification and mechanism study.

基于周期性监测的牵引电机绝缘最优视情维修决策（英文）

目的:充分利用寿命信息,并考虑冲击效应对维修策略的影响,提出符合牵引电机绝缘运行特征的最优视情维修策略。方法:1.采用正常状态、潜在故障状态与功能故障状态描述牵引电机绝缘运行状况;2.应用泊松过程描述随机高电压冲击;3.以单位时间的运行成本为目标函数,以监测间隔和预防性维修寿命阈值为优化变量,建立最优视情维修决策模型。结论:该模型能显著降低牵引电机绝缘功能故障的风险,同时降低单位时间运行成本。