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The radial migration of cortical pyramidal neurons (PNs) during corticogenesis is necessary for establishing a multilayered cerebral cortex. Neuronal migration defects are considered a critical etiology of neurodevelopmental disorders, including autism spectrum disorders (ASDs), schizophrenia, epilepsy, and intellectual disability (ID). TRIO is a high-risk candidate gene for ASDs and ID. However, its role in embryonic radial migration and the etiology of ASDs and ID are not fully understood. In this study, we found that the in vivo conditional knockout or in utero knockout of Trio in excitatory precursors in the neocortex caused aberrant polarity and halted the migration of late-born PNs. Further investigation of the underlying mechanism revealed that the interaction of the Trio N-terminal SH3 domain with Myosin X mediated the adherence of migrating neurons to radial glial fibers through regulating the membrane location of neuronal cadherin (N-cadherin). Also, independent or synergistic overexpression of RAC1 and RHOA showed different phenotypic recoveries of the abnormal neuronal migration by affecting the morphological transition and/or the glial fiber-dependent locomotion. Taken together, our findings clarify a novel mechanism of Trio in regulating N-cadherin cell surface expression via the interaction of Myosin X with its N-terminal SH3 domain. These results suggest the vital roles of the guanine nucleotide exchange factor 1 (GEF1) and GEF2 domains in regulating radial migration by activating their Rho GTPase effectors in both distinct and cooperative manners, which might be associated with the abnormal phenotypes in neurodevelopmental disorders.
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Humans , Autism Spectrum Disorder/metabolism , Cell Movement/genetics , Interneurons/metabolism , Neurodevelopmental Disorders/genetics , Neurons/metabolism , Rho Guanine Nucleotide Exchange Factors/geneticsABSTRACT
OBJECTIVE: To analyze the current situation and correlation between job burnout and mental health of college counselors in Shanghai City. METHODS: With stratified cluster random sampling method, 235 counselors were selected as study subjects. Their job burnout and mental health was investigated by using Burnout Inventory Educator's Survey and Kessler Psychological Distress Scale. RESULTS: The median score of the 3 dimensions of emotional exhaustion, deindividualization and low sense of achievement of counselors was 3.4, 3.2 and 1.6, respectively. In each dimension, the ratio of moderate level job burnout was 93.2%, 94.9% and 26.8%, respectively; the ratio of high level job burnout was 6.8%, 5.1% and 73.2%, respectively. The median score of mental health was 31.0, and the grade of general, poor and very poor mental health standard was 2.6%, 35.3% and 62.1%, respectively. The scores of emotional exhaustion and deindividualization were positively correlated with the scores of mental health status(Spearman correlation coefficients were 0.54 and 0.44, all P<0.01). The score of low achievement was negatively correlated with the score of mental health status(Spearman correlation coefficient=-0.39, P<0.01). The multiple linear regression analysis showed that the scores of emotional exhaustion and deindividualization had positive predictive value on mental health after excluding gender, spouse, age, length of service, educational level, position title, household registration, authorized strength, and university level(all P<0.01). Low achievement score had a negative predictive effect on mental health(P<0.01). CONCLUSION: The job burnout in college counselors in Shanghai City is at a moderately high level and their mental health is poor. The job burnout affects their mental health. Alleviating job burnout is beneficial to improve counselors′ mental health.
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OBJECTIVE: To analyze the relationship between health promoting lifestyle and job burnout of college counselors in Shanghai. METHODS: Using stratified cluster sampling method, 294 counselors from 4 colleges were selected and investigated by Maslach Burnout Inventory Educator's Survey and Health Promoting Lifestyle Profile II. RESULTS: The median scores of emotional exhaustion, deindividualization and low sense of achievement of counselors in Shanghai were 3.3, 3.2 and 1.6 respectively. In each dimension, the ratio of moderate burnout were 93.5%, 95.2% and 26.5% respectively. The ratio of high level burnout were 6.5%, 4.8% and 73.5%. The median total score of health promoting lifestyle was 127.1, and the ratio of poor, average and good lifestyle standard was 8.5%, 50.3% and 41.2%.The total score of health promoting lifestyle was negatively correlated with the score of emotional exhaustion and deindividualization(P<0.01) and positively correlated with the score of low sense of achievement(P<0.01). The score of physical exercise, interpersonal relationship, stress management and self realization in health promoting lifestyle had positive predictive effect on the score of emotional exhaustion and deindividualization(P<0.05). The score of physical exercise and self realization had negative predictive effect on the score of low sense of achievement(P<0.01). CONCLUSION: The prevalence of job burnout in college counselors is above the intermediate level. There is a correlation between health promoting lifestyle and job burnout and cultivating a health promoting lifestyle is helpful to alleviate job burnout.
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Objective@#To understand the characteristics and dynamics of individuals with HIV-1 subtype infection among injected drug users (HIV infection IDU) in Guangzhou between 2008 and 2015.@*Methods@#HIV-1 RNAs were extracted from serum samples of the individuals that were newly diagnosed with HIV-1 infection among IDUs living in Guangzhou, between 2008 and 2015. The Pol gene segments of HIV-1 genome from these RNA samples were amplified by nested reverse transcription polymerase chain reaction (Nested-PCR) and sequenced. Subsequently, phylogenetic tree was reconstructed using both pol sequences of samples and references before the subtype of HIV-1 was determined. Distributions of HIV-1 subtypes detected in IDUs with different demographic characteristics in different years were compared.@*Results@#A total of 437 pol gene segments were successfully obtained from 517 serum samples of HIV infection IDUs. The average age of 437 HIV infected IDUs was 37.37 years with standard deviation as 8.17 years. 51.5% (225/437) of the HIV infected IDU that registered residence were not in Guangdong. The Guangxi Registered residents were accounted for 54.2% (122/225). Proportion of subtype CRF07_BC (46.5%) appeared the highest, followed by CRF01_AE (24.3%), CRF08_BC (23.3%) and other subtypes (5.9%). The annual proportions of subtype CRF07_BC (trend χ2=19.703, P=0.006) and CRF08_BC (trend χ2=25.718, P=0.001) were significantly different. The proportion of subtype CRF07_BC decreased from 56.9% to 34.2% (trend χ2=15.139, P=0.000), while the proportion of CRF08_BC increased from 11.8% to 37.0% (trend χ2=22.577, P=0.000). The proportion of CRF08_BC was significantly higher in the HIV infected IDUs with Guangxi residence (Monte Carlo simulation of exact probability P=0.000, 99%CI: 0.000-0.000).@*Conclusions@#CRF07_BC, CRF01_ AE and CRF08_BC were the predominant HIV-1 subtypes while multiple subtypes were co-circulated among the HIV infected IDUs in Guangzhou, between 2008 and 2015. Behavioral intervention set for HIV infected IDUs with Guangxi residence should be strengthened in Guangzhou.
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Objective@#To reveal the clinical and genetic features of neonatal/infantile epileptic disorders caused by KCNQ2 mutations and to provide a clue for the treatment and prognosis evaluation.@*Methods@#Twenty-two patients were collected in the Department of Pediatrics, Peking University First Hospital from April 2007 to July 2016.The phenotype-genotype analysis was conducted of the neonatal/infantile epileptic patients in whom a KCNQ2 mutation was identified by the targeted next generation sequencing.@*Results@#Twenty-two de novo KCNQ2 missense mutations from 22 patients with neonatal/infantile epileptic disorders were found.These patients had an onset of epilepsy in early infancy (median age: 2 days). The seizure type of the first onset was mainly focal seizure.Atypical absence epilepsy, a novel phenotype of KCNQ2 mutation-induced epilepsies was found.The mortality of these patients was high, as 5 patients of the 22 patients died in the follow-up period, 4 of which might result from sudden unexpected death in epilepsy.In the 22 patients, 8 patients with anti-epileptic monotherapy became seizure-free.Of the 8 patients with a monotherapy, 3 patients were treated with valproic acid and no clinical onset was observed.@*Conclusions@#This study expands the phenotype of KCNQ2-related epileptic disorders.These patients have high mortality.Valproate acid is the potentially effective monotherapy for these patients.
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Objective To understand the prevalence of drug resistance in treatment-naive injecting drug users (IDUs) infected with HIV-1 in Guangzhou.Methods HIV-1 RNA were extracted from the serum specimens of the newly confirmed HIV-1 positive IDUs living in Guangzhou,being infected through injecting drug use and receiving no antiretroviral therapy at the time of confirmation during 2008-2015.Full sequence of pol protease (PR) gene and partial sequence of reverse transcriptase (RT) gene were amplified by nested reverse transcription polymerase chain reaction (nested-PCR) and sequenced.After that,data were submitted to the HIV resistance database of Stanford University for drug resistance analysis.Results Among the 518 HIV-1 infected IDUs,H1V-1 pol gene segments were successfully obtained from the serum samples of 407 HIV-1 infected IDUs (78.57％) aged 18-64 (37.44 ± 8.14) years.Among them,males accounted for 89.68％ (365/407),those of Han ethnic group accounted for 89.93％ (366/407),the unmarried accounted for 55.28％ (225/407),and those with education level of junior high school or below accounted for 83.78％ (341/407).The distribution of subtypes was predominated by CRF07_BC (47.18％,192/407),followed by CRF01_AE (23.83％,97/407),CRF08_BC (22.85％,93/407),and other subtypes (6.14％,25/407).The overall prevalence of drug resistance was 3.44％ (14/407).The prevalence of drug resistance to protease inhibitors,nucleoside reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors were 1.47％(6/407),0.25％ (1/407) and 1.72％ (7/407) respectively.The mutation rate was 12.29％ (50/407).No major drug resistance mutation was detected in protease and nucleoside reverse transcriptase regions.Higher rate of V179E mutation in the non-nucleoside reverse transcriptase region was detected in other subtypes and subtype CRF07_BC.Mutation seemed to have occurred in all 8 cases of subtype CRF55_01B in other subtypes.The highest mutation rate of E138A was detected in subtype CRF08_BC (3.23％).Two cases were resistant to all four drugs of NNRTIs.Conclusions The prevalence of drug resistance in treatment-naive HIV-1 positive IDUs remained at a relatively low level during 2008-2015,in Guangzhou.Most infections were sensitive to existing antiviral drugs.However,drug resistance surveillance in IDUs infected with HIV should be strengthened to prevent the prevalence of multi-drug resistance and cross drug resistance.
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Objective To understand the prevalence of drug resistance in treatment-naive injecting drug users (IDUs) infected with HIV-1 in Guangzhou.Methods HIV-1 RNA were extracted from the serum specimens of the newly confirmed HIV-1 positive IDUs living in Guangzhou,being infected through injecting drug use and receiving no antiretroviral therapy at the time of confirmation during 2008-2015.Full sequence of pol protease (PR) gene and partial sequence of reverse transcriptase (RT) gene were amplified by nested reverse transcription polymerase chain reaction (nested-PCR) and sequenced.After that,data were submitted to the HIV resistance database of Stanford University for drug resistance analysis.Results Among the 518 HIV-1 infected IDUs,H1V-1 pol gene segments were successfully obtained from the serum samples of 407 HIV-1 infected IDUs (78.57％) aged 18-64 (37.44 ± 8.14) years.Among them,males accounted for 89.68％ (365/407),those of Han ethnic group accounted for 89.93％ (366/407),the unmarried accounted for 55.28％ (225/407),and those with education level of junior high school or below accounted for 83.78％ (341/407).The distribution of subtypes was predominated by CRF07_BC (47.18％,192/407),followed by CRF01_AE (23.83％,97/407),CRF08_BC (22.85％,93/407),and other subtypes (6.14％,25/407).The overall prevalence of drug resistance was 3.44％ (14/407).The prevalence of drug resistance to protease inhibitors,nucleoside reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors were 1.47％(6/407),0.25％ (1/407) and 1.72％ (7/407) respectively.The mutation rate was 12.29％ (50/407).No major drug resistance mutation was detected in protease and nucleoside reverse transcriptase regions.Higher rate of V179E mutation in the non-nucleoside reverse transcriptase region was detected in other subtypes and subtype CRF07_BC.Mutation seemed to have occurred in all 8 cases of subtype CRF55_01B in other subtypes.The highest mutation rate of E138A was detected in subtype CRF08_BC (3.23％).Two cases were resistant to all four drugs of NNRTIs.Conclusions The prevalence of drug resistance in treatment-naive HIV-1 positive IDUs remained at a relatively low level during 2008-2015,in Guangzhou.Most infections were sensitive to existing antiviral drugs.However,drug resistance surveillance in IDUs infected with HIV should be strengthened to prevent the prevalence of multi-drug resistance and cross drug resistance.
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Objective To reveal the clinical and genetic features of neonatal/infantile epileptic disorders caused by KCNQ2 mutations and to provide a clue for the treatment and prognosis evaluation. Methods Twenty－two patients were collected in the Department of Pediatrics,Peking University First Hospital from April 2007 to July 2016. The phenotype－genotype analysis was conducted of the neonatal/infantile epileptic patients in whom a KCNQ2 muta﹣tion was identified by the targeted next generation sequencing. Results Twenty－two de noνo KCNQ2 missense muta﹣tions from 22 patients with neonatal/infantile epileptic disorders were found. These patients had an onset of epilepsy in early infancy(median age:2 days). The seizure type of the first onset was mainly focal seizure. Atypical absence epi﹣lepsy,a novel phenotype of KCNQ2 mutation－induced epilepsies was found. The mortality of these patients was high,as 5 patients of the 22 patients died in the follow－up period,4 of which might result from sudden unexpected death in epi﹣lepsy. In the 22 patients,8 patients with anti－epileptic monotherapy became seizure－free. Of the 8 patients with a monotherapy,3 patients were treated with valproic acid and no clinical onset was observed. Conclusions This study expands the phenotype of KCNQ2－related epileptic disorders. These patients have high mortality. Valproate acid is the potentially effective monotherapy for these patients.
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Objective To understand the prevalence of drug resistance in treatment-naive HIV infected men who have sex with (MSM) in Guangzhou.Methods HIV-1 RNA were extracted from the serum specimens of the MSM newly confirmed to be HIV-1 positive,living in Guangzhou and receiving no anti-viral therapy from 2008 to 2015.HIV-1 pol gene segments,including full protease and part reverse transcriptase,were amplified by nested reverse transcription polymerase chain reaction (nested-PCR) and sequenced by Sanger.Subsequently,the sequence data were submitted to Stanford University HIV Drug Resistance Database for drug resistance analysis.Results Among 2 283 HIV infected MSM,HIV-1 pol gene segments were obtained from the serum samples of 1 986 HIV infected MSM aged 16-84 (30.18 ± 8.24) years.Among them,the unmarried accounted for 74.17％ (1 473/1 986),those of Han ethnic group accounted for 90.64％ (1 800/1 986),those with education level of college or above accounted for 49.65％ (986/1 986),those with education level of senior high school or secondary school accounted for 27.14％ (539/1 986),those with education level of junior high school or below accounted for 20.89％ (415/1 986).The distribution of subtypes was predominated by CRF07_BC (38.22％,759/1 986) and CRF01_AE (34.49％,685/1 986).The overall prevalence of drug resistance was 3.32％ (66/1 986).The prevalence of resistance to protease inhibitors (PIs),nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) were 1.36％(27/1 986),0.65％ (13/1 986) and 1.61％ (32/1 986),respectively.Subtype B had higher resistance to PIs,NRTIs and NNRTIs and subtype CRF55_01B had highest resistance to NNRTIs compared with other subtypes.In subtype B,the resistant rates to D4T,EFV and NVP were highest (all 4.17％,5/120),followed by those to NFV,AZT and RPV (all 3.33％,4/120).In subtype CRF55_01B,the resistant rates to EFV and NVP were highest (all 5.50％,16/291),followed by those to ETR and RPV (all 5.15％,15/291).Conclusions The prevalence of drug resistance in treatment-naive HIV infected MSM in Guangzhou remained at low level and current antiretroviral drugs are generally effective.However,subtype B and CRF55_01B have higher drug resistance.
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Objective To understand the characteristics and dynamic of HIV-1 subtype distribution in men who have sex with men (MSM) in Guangzhou between 2008 and 2015.Methods HIV-1 RNAs were extracted from serum samples of the individuals newly diagnosed with HIV-1 infection among MSM living in Guangzhou between 2008 and 2015.The pol gene segments of HIV-1 genome from these RNA samples were amplified by nested reverse transcription polymerase chain reaction (nested-PCR) and were sequenced.Subsequently,the phylogenetic tree was reconstructed using pol sequences of samples and references together and the subtype of HIV-1 was determined.The distributions of HIV-1 subtypes detected in MSM with different demographic characteristics in different years were compared.Results A total of 2 210 pol gene segments were successfully obtained from 2 473 serum samples of the MSM.The average age of 2 210 MSM was 30.19 years with standard deviation of 8.22 years,the unmarried MSM and those in Han ethnic group accounted for 73.39％ and 90.81％,respectively.The proportion of subtype CRF07_BC (38.10％) was highest,followed by CRF01_AE (34.84％),CRF55_01B (14.62％),B (6.06％),URFs (3.58％),CRF59_01B (2.17％) and other subtypes (0.63％).The annual proportions of subtype B (P=0.000,99％CI:0.000-0.000),CRF07_BC (x2=14.965,P=0.036),CRF55_01B (x2=18.161,P=0.011) and URFs (P=0.001,99％ CI:0.000-0.001) were significantly different.The proportion of subtype B showed a gradual decrease from 14.08％ to 4.33％ (P=0.000,99％ CI:0.000-0.000),while the proportion of URFs rapidly increased from 0％ to 6.40％ (P=0.000,99％CI:0.000-0.000).The rate of URFs was significantly higher in farmers and migrant workers than in other groups (P=0.017,99％ CI:0.014-0.020) and the rate of URFs was higher in individuals who had multi sexual partners (x2=5.733,P=0.017).Conclusions CRF07_BC and CRF01_AE were the predominant HIV-1 subtypes and multiple subtypes co-circulated among MSM in Guangzhou between 2008 and 2015.The recombinations of HIV-1 continue to occur in MSM.Strengthening behavioral intervention for farmers,migrant workers and individuals who have multi sexual partners has the important epidemiological significance against the emerging and circulating of the novel recombinant virus among MSM in Guangzhou.
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Objective To understand the prevalence of drug resistance in treatment-naive HIV infected men who have sex with (MSM) in Guangzhou.Methods HIV-1 RNA were extracted from the serum specimens of the MSM newly confirmed to be HIV-1 positive,living in Guangzhou and receiving no anti-viral therapy from 2008 to 2015.HIV-1 pol gene segments,including full protease and part reverse transcriptase,were amplified by nested reverse transcription polymerase chain reaction (nested-PCR) and sequenced by Sanger.Subsequently,the sequence data were submitted to Stanford University HIV Drug Resistance Database for drug resistance analysis.Results Among 2 283 HIV infected MSM,HIV-1 pol gene segments were obtained from the serum samples of 1 986 HIV infected MSM aged 16-84 (30.18 ± 8.24) years.Among them,the unmarried accounted for 74.17％ (1 473/1 986),those of Han ethnic group accounted for 90.64％ (1 800/1 986),those with education level of college or above accounted for 49.65％ (986/1 986),those with education level of senior high school or secondary school accounted for 27.14％ (539/1 986),those with education level of junior high school or below accounted for 20.89％ (415/1 986).The distribution of subtypes was predominated by CRF07_BC (38.22％,759/1 986) and CRF01_AE (34.49％,685/1 986).The overall prevalence of drug resistance was 3.32％ (66/1 986).The prevalence of resistance to protease inhibitors (PIs),nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) were 1.36％(27/1 986),0.65％ (13/1 986) and 1.61％ (32/1 986),respectively.Subtype B had higher resistance to PIs,NRTIs and NNRTIs and subtype CRF55_01B had highest resistance to NNRTIs compared with other subtypes.In subtype B,the resistant rates to D4T,EFV and NVP were highest (all 4.17％,5/120),followed by those to NFV,AZT and RPV (all 3.33％,4/120).In subtype CRF55_01B,the resistant rates to EFV and NVP were highest (all 5.50％,16/291),followed by those to ETR and RPV (all 5.15％,15/291).Conclusions The prevalence of drug resistance in treatment-naive HIV infected MSM in Guangzhou remained at low level and current antiretroviral drugs are generally effective.However,subtype B and CRF55_01B have higher drug resistance.
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Objective To understand the characteristics and dynamic of HIV-1 subtype distribution in men who have sex with men (MSM) in Guangzhou between 2008 and 2015.Methods HIV-1 RNAs were extracted from serum samples of the individuals newly diagnosed with HIV-1 infection among MSM living in Guangzhou between 2008 and 2015.The pol gene segments of HIV-1 genome from these RNA samples were amplified by nested reverse transcription polymerase chain reaction (nested-PCR) and were sequenced.Subsequently,the phylogenetic tree was reconstructed using pol sequences of samples and references together and the subtype of HIV-1 was determined.The distributions of HIV-1 subtypes detected in MSM with different demographic characteristics in different years were compared.Results A total of 2 210 pol gene segments were successfully obtained from 2 473 serum samples of the MSM.The average age of 2 210 MSM was 30.19 years with standard deviation of 8.22 years,the unmarried MSM and those in Han ethnic group accounted for 73.39％ and 90.81％,respectively.The proportion of subtype CRF07_BC (38.10％) was highest,followed by CRF01_AE (34.84％),CRF55_01B (14.62％),B (6.06％),URFs (3.58％),CRF59_01B (2.17％) and other subtypes (0.63％).The annual proportions of subtype B (P=0.000,99％CI:0.000-0.000),CRF07_BC (x2=14.965,P=0.036),CRF55_01B (x2=18.161,P=0.011) and URFs (P=0.001,99％ CI:0.000-0.001) were significantly different.The proportion of subtype B showed a gradual decrease from 14.08％ to 4.33％ (P=0.000,99％ CI:0.000-0.000),while the proportion of URFs rapidly increased from 0％ to 6.40％ (P=0.000,99％CI:0.000-0.000).The rate of URFs was significantly higher in farmers and migrant workers than in other groups (P=0.017,99％ CI:0.014-0.020) and the rate of URFs was higher in individuals who had multi sexual partners (x2=5.733,P=0.017).Conclusions CRF07_BC and CRF01_AE were the predominant HIV-1 subtypes and multiple subtypes co-circulated among MSM in Guangzhou between 2008 and 2015.The recombinations of HIV-1 continue to occur in MSM.Strengthening behavioral intervention for farmers,migrant workers and individuals who have multi sexual partners has the important epidemiological significance against the emerging and circulating of the novel recombinant virus among MSM in Guangzhou.
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Objective To study the application of Geographic Information System(GIS)electronic fence technique in Onco-melania hupensis snail monitoring. Methods The electronic fence was set around the history and existing snail environments in the electronic map,the information about snail monitoring and controlling was linked to the electronic fence,and the snail moni-toring information system was established on these bases. The monitoring information was input through the computer and smart phone. Results The electronic fence around the history and existing snail environments was set in the electronic map(Baidu map),and the snail monitoring information system and smart phone APP were established. The monitoring information was input and upload real-time,and the snail monitoring information was demonstrated in real time on Baidu map. Conclusion By using the electronic fence technology based on GIS,the unique"environment electronic archives"for each snail monitoring environ-ment can be established in the electronic map,and real-time,dynamic monitoring and visual management can be realized.
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Objective To construct the Oncomelania hupensis snail monitoring system based on the Baidu Map. Methods The environmental basic information about historical snail environment and existing snail environment,etc. was collected with the monitoring data about different kinds of O. hupensis snails,and then the O. hupensis snail monitoring system was built. Geo-graphic Information System(GIS)and the electronic fence technology and Application Program Interface(API)were applied to set up the electronic fence of the snail surveillance environments,and the electronic fence was connected to the database of the snail surveillance. Results The O. hupensis snail monitoring system based on the Baidu Map were built up,including three modules of O. hupensis Snail Monitoring Environmental Database,Dynamic Monitoring Platform and Electronic Map. The infor-mation about monitoring O. hupensis snails could be obtained through the computer and smartphone simultaneously. Conclu-sion The O. hupensis snail monitoring system,which is based on Baidu Map,is a visible platform to follow the process of snail-searching and molluscaciding.
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Objective To analyze the clinical characteristics of 3 unrelated boys with paroxysmal nonkinesigenic dyskinesia and developmental delay caused by de novo mutation in KCNMA1,and to expand the knowledge of clinical phenotype of KCNMA1 mutation.Methods Clinical data of patients were collected,including gender,age,condition of the perinatal period,personal history,and family history.And the features of genotype data were collected including features of attack,developmental milestones,physical examinations,treatments,and responses to treatment.The data including blood biochemical results,results of metabolic screening and genetic testing and the pedigree validation were collected,while the relationship between phenotype and genotype was analyzed.Results (1)Phenotypic features:3 unrelated boys were diagnosed.The ages of disease onset were 20 days,7 months and 13 months,respectively.All the patients manifested paroxysmal nonkinesigenic dyskinesia and were characterized by the episodes that occurred during wakefulness,presented with sudden onset of asymmetric limb dystonic posture,sometimes with nystagmus and strabismus,or sudden decrease of voluntary movement of limbs with hypotonia and occasional esotropia and yawning.There was no loss of awareness during attack.No precipitating factors were observed before attacks.The developmental milestones were delayed.Three children had no response to anti-epilepsy drug before diagnosis.After diagnosis,2 cases used Clonazepam and 1 case showed less attack.There was not any epileptic seizure until the last follow-up at the ages of 3 years and 6 months old,7 years old,and 5 years and 8 months old,respectively.The frequency of attacks was decreased.The episodes were recorded during video-electroencephalogram(EEG) monitoring,which showed normal ictal and interictal EEG.(2)Genotypic features:all 3 children were detected to have KCNMA1 genetic heterozygous missense mutation,while c.2650G>A (p.Glu884Lys) mutation was identified in 1 patient,and c.3158A>G(p.Asn1053Ser)mutation in the other 2 patients,but no such mutation was found in their parents.Conclusion This finding expands the phenotype of KCNMA1mutation.KCNMA1 should be considered as one of the candidate genes for screening in patients with early onset of paroxysmal nonkinesigenic dyskinesia without triggers,or early-onset of developmental delay,with or without epilepsy.
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Objective To understand the characteristic of subtype distribution among foreigners who were living with HIV-1,in Guangzhou.Methods HIV-1 RNAs were extracted from 114 serum specimens in foreigners diagnosed with HIV-1 infections between 2008 and 2010,and in 2015.Partial pol gene of HIV-1 genome from these RNA samples were amplified by nested reverse transcription polymerase chain reaction (nested-PCR) with nucleotide sequenced.Subsequently,phylogenetic tree was reconstructed using the pol sequences of samples and references.Results Among all the 114 samples,57.9％ were from males and 42.1％ from females,with an average age as 35.21 years old and the standard deviation as 9.63 years.A total of 6.8％ of the samples were from Africans.The top three subtypes were identified as CRF02_AG,subtype G and subtype C,accounted for 30.7％,14.9％ and 12.3％ respectively.Compared with samples gathered from 2008 to 2010,the proportions of subtype A1 and CRF01_AE significantly increased,while the other subtypes significantly decreased in 2015 (x 2=37.570;P=0.013,99％ CI:0.010-0.016).Proportions of CRF01_AE and subtype G among males outnumbered the females but the proportions of subtype A1,CRF02_AG and URF among females appeared the other way round (x2=15.528;P=0.029,99％CI:0.024-0.033).Proportions of CRF02_AG and subtype G among HIV-1 positive Africans were larger than those from other Southeast Asian countries or areas,However,the proportion of CRF01_AE among HIV-1 positive patients from Southeast Asian countries was higher than those patients from other areas (x2=39.399;P=0.009,99％ CI:0.006-0.011).The rates of resistance to any drug of protease inhibitors (PIs),reverse transcriptase inhibitors (RTIs),as well as to PIs,NRTIs,and NNRTIs alone,were 21.9％,12.3％,6.1％ and 7.0％,respectively.One of nine CRF01_AEs from the HIV-1 positive patients were found closely clustered in those phylogenetic tree (bootstrap=0.855) samples,collected from local patients in Guangzhou.Conclusions Our findings showed that these foreign subtypes had been spread to the natives,more from the Africans than from the other areas,in Guangzhou.These types of viruses were different from the strains identified locally,suggesting that they might have been brought in by foreigners living with HIV-1,in Guangzhou.Programs related to care,support and behavioral intervention for HIV positive foreigners living in Guangzhou,should be strengthened.
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Objective To understand the characteristic of subtype distribution among foreigners who were living with HIV-1,in Guangzhou.Methods HIV-1 RNAs were extracted from 114 serum specimens in foreigners diagnosed with HIV-1 infections between 2008 and 2010,and in 2015.Partial pol gene of HIV-1 genome from these RNA samples were amplified by nested reverse transcription polymerase chain reaction (nested-PCR) with nucleotide sequenced.Subsequently,phylogenetic tree was reconstructed using the pol sequences of samples and references.Results Among all the 114 samples,57.9％ were from males and 42.1％ from females,with an average age as 35.21 years old and the standard deviation as 9.63 years.A total of 6.8％ of the samples were from Africans.The top three subtypes were identified as CRF02_AG,subtype G and subtype C,accounted for 30.7％,14.9％ and 12.3％ respectively.Compared with samples gathered from 2008 to 2010,the proportions of subtype A1 and CRF01_AE significantly increased,while the other subtypes significantly decreased in 2015 (x 2=37.570;P=0.013,99％ CI:0.010-0.016).Proportions of CRF01_AE and subtype G among males outnumbered the females but the proportions of subtype A1,CRF02_AG and URF among females appeared the other way round (x2=15.528;P=0.029,99％CI:0.024-0.033).Proportions of CRF02_AG and subtype G among HIV-1 positive Africans were larger than those from other Southeast Asian countries or areas,However,the proportion of CRF01_AE among HIV-1 positive patients from Southeast Asian countries was higher than those patients from other areas (x2=39.399;P=0.009,99％ CI:0.006-0.011).The rates of resistance to any drug of protease inhibitors (PIs),reverse transcriptase inhibitors (RTIs),as well as to PIs,NRTIs,and NNRTIs alone,were 21.9％,12.3％,6.1％ and 7.0％,respectively.One of nine CRF01_AEs from the HIV-1 positive patients were found closely clustered in those phylogenetic tree (bootstrap=0.855) samples,collected from local patients in Guangzhou.Conclusions Our findings showed that these foreign subtypes had been spread to the natives,more from the Africans than from the other areas,in Guangzhou.These types of viruses were different from the strains identified locally,suggesting that they might have been brought in by foreigners living with HIV-1,in Guangzhou.Programs related to care,support and behavioral intervention for HIV positive foreigners living in Guangzhou,should be strengthened.
ABSTRACT
<p><b>BACKGROUND</b>Vanishing white matter disease (VWM), a human autosomal recessive inherited leukoencephalopathy, is due to mutations in eukaryotic initiation factor 2B (eIF2B). eIF2B is responsible for the initiation of protein synthesis by its guanine nucleotide exchange factor (GEF) activity. Mutations of eIF2B impair GEF activity at different degree. Previous studies implied improperly activated unfolded protein response (UPR) and endoplasmic reticulum stress (ERS) participated in the pathogenesis of VWM. Autophagy relieves endoplasmic reticulum load by eliminating the unfolded protein. It is still unknown the effects of genotypes on the pathogenesis. In this work, UPR and autophagy flux were analyzed with different mutational types.</p><p><b>METHODS</b>ERS tolerance, reflected by apoptosis and cell viability, was detected in human oligodendrocyte cell line transfected with the wild type, or different mutations of p. Arg113His, p. Arg269FNx01 or p. Ser610-Asp613del in eIF2Bε. A representative UPR-PERK component of activating transcription factor 4 (ATF4) was measured under the basal condition and ERS induction. Autophagy was analyzed the flux in the presence of lysosomal inhibitors.</p><p><b>RESULTS</b>The degree of ERS tolerance varied in different genotypes. The truncated or deletion mutant showed prominent apoptosis cell viability declination after ERS induction. The most seriously damaged GEF activity of p. Arg269FNx01 group underwent spontaneous apoptosis. The truncated or deletion mutant showed elevated ATF4 under basal as well as ERS condition. Decreased expression of LC3-I and LC3-II in the mutants reflected an impaired autophagy flux, which was more obvious in the truncated or deletion mutants after ERS induction.</p><p><b>CONCLUSIONS</b>GEF activities in different genotypes could influence the cell ERS tolerance as well as compensatory pathways of UPR and autophagy. Oligodendrocytes with truncated or deletion mutants showed less tolerable to ERS.</p>
Subject(s)
Humans , Cell Line , Endoplasmic Reticulum Stress , Genetics , Physiology , Eukaryotic Initiation Factor-2B , Genetics , Mutation , Genetics , Oligodendroglia , Metabolism , Unfolded Protein Response , Genetics , PhysiologyABSTRACT
The biological activity of ADCC by anti-CD20 monoclonal antibody was determined by BioGlo™ Luciferase Assay System using Jurkat/NFAT-luc+FcγRIIIa cell line as effector cell and WIL2-S cell line as target cell. The developed method was verified for specificity, precision and accuracy. Anti-CD20 monoclonal antibody showed a dose-response mode by the developed method, and the determination result complied with the following four-parameter equation: y = (A-D)/[1 + (X/C)(B)] + D. The optimized parameters of the method were determined including the antibodies diluted concentration (18,000 ng·mL(-1)), dilution rate (1:5), the ratio of effector cell and target cell (6:1), and induction time (6 h). The values of eight independent tests have passed a statistical test for curve regression analysis, linear or parallelism, which showed the method possessed good specificity. Four different dilute groups of recovery rates sample were determined for 3 times, and the result showed mean relative potencies of (44.39±3.93)%, (72.74±2.78)%, (128.28±7.01)% and (168.19±2.70)% respectively, with a variation coefficient of less than 10%, and the recoveries of (88.78±7.85)%, (96.99±3.70)%, (102.63±5.61)% and (112.12±1.80)% respectively. A novel reporter gene method for determination of biological activity of ADCC by anti-CD20 monoclonal antibody was successfully developed, which showed strong specificity, good reproducibility and high accuracy, and might be used routinely.
Subject(s)
Humans , Antibodies, Monoclonal, Murine-Derived , Pharmacology , Antibody-Dependent Cell Cytotoxicity , Antigens, CD20 , Allergy and Immunology , Genes, Reporter , Reproducibility of Results , RituximabABSTRACT
ObjectiveToexplorethedynamicchangesofoxidativestressandcytokinesinMongoliangerbilswith nonalcoholic fatty liver disease ( NAFLD) and their significance.Methods Forty-eight healthy male gerbils were randomly divided into normal group and model group , 24 in each group .Gerbils of the model group were fed with high fat diet while those of the normal group with normal diet .Eight gerbils in each group were killed at the end of 4 w, 8 w and 16 w, respectively .MDA content and SOD , GSH-PX and T-AOC activity in the liver tissue were detected by chemical method, and serum TNF-α, INF-γand IL-10 levels were determined using liquid suspension chip .Results With the development of NAFLD , MDA content in liver increased gradually , and the MDA contents were all significantly higher than those of the normal group ( P<0.01 ); T-AOC level slightly increased , and then decreased , the levels at 4 w and 16 w were markedly decreased compared with those of the normal group (P<0.05);SOD level was significantly increased and then markedly reduced, the level of the model group at 4 w was significantly increased (P<0.05), while that at 8 w and 16 w were significantly decreased (P<0.05, P<0.01).The level of GSH-PX was decreased gradually , the levels at 8 w and 16 w were significantly lower than those of the normal group (P<0.05).With the progression of NAFLD,serum TNF-αand IFN-γwere increased gradually , while the level of IL-10 decreased gradually , and the levels at 8 w and 16 w were significantly lower than those of the normal group ( P <0.05, P <0.01).Conclusions The oxidative stress-related indicators and inflammatory cytokines in the gerbil NAFLD models induced by high fat diet are significantly changed as simple fatty liver develops into steatohepatitis , liver fibrosis and cirrhosis , and participate in the development and progression of NAFLD .