Dichloromethane(DCM)dehalogenase stands as a crucial enzyme implicated in the degradation of methylene chloride across diverse environmental and biological contexts.However,the unbinding pathways of ligands from DCM d...Dichloromethane(DCM)dehalogenase stands as a crucial enzyme implicated in the degradation of methylene chloride across diverse environmental and biological contexts.However,the unbinding pathways of ligands from DCM dehalogenase remain unexplored.In order to gain a deeper understanding of the binding sites and dissociation pathways of dichloromethane(DCM)and glutathione(GSH)from the DCM dehalogenase,random accelerated molecular dynamics(RAMD)simulations were performed,in which DCM and GSH were forced to leave the active site.The protein structure was predicted using Alphafold2,and the conformations of GSH and DCM in the binding pocket were predicted by docking.A long equilibrium simulation was conducted to validate the structure of the complex.The results show that GSH is most commonly observed in three main pathways,one of which is more important than the other two.In addition,DCM was observed to escape along a unique pathway.The key residues and protein helices of each pathway were identified.The results can provide a theoretical foundation for the subsequent dissociation mechanism of DCM dehalogenase.展开更多
三相AC/DC整流器作为许多电力电子设备中不可或缺的电气环节得到了广泛的应用。相比于传统的二极管整流器及相控整流器,VIENNA整流器具有网侧谐波含量低、功率因数高的优点。同时,VIENNA整流器比普通桥式PWM整流器具有更少的功率开关数...三相AC/DC整流器作为许多电力电子设备中不可或缺的电气环节得到了广泛的应用。相比于传统的二极管整流器及相控整流器,VIENNA整流器具有网侧谐波含量低、功率因数高的优点。同时,VIENNA整流器比普通桥式PWM整流器具有更少的功率开关数量,进一步提高了系统功率密度。在简要介绍VIENNA整流器原理的基础上,结合3 k W系统进行了相应的工程设计,主要包括储能元件设计、滤波环节设计和控制环路设计。此外,针对电网电压畸变带来的输入电流谐波问题,采用了一种结合VIENNA整流器控制环路的指定次谐波优化方法,并针对其中LCL滤波器带来的谐振问题,从工程设计的角度进行了相应的优化。3 k W工程样机的实验结果进一步验证了设计方法以及所采用的优化方法的有效性。展开更多
BACKGROUND Under physiological conditions,sputum produced during acute exacerbation of chronic obstructive pulmonary disease(AECOPD)can move passively with the cilia in the airway;the sputum is gradually excreted from...BACKGROUND Under physiological conditions,sputum produced during acute exacerbation of chronic obstructive pulmonary disease(AECOPD)can move passively with the cilia in the airway;the sputum is gradually excreted from the depth of the airways through the stimulation of the coughing reflex on the sensory nerve on the surface of the airway.However,when the sputum is thick,the cough is weak,or the tracheal cilia are abnormal,sputum accumulation may occur and affect the exchange of oxygen and carbon dioxide in the lung.Furthermore,the presence of pathogenic microorganisms in sputum may cause or aggravate the symptoms of pulmonary infection in patients,which is the main factor leading to AECOPD.Therefore,promoting effective drainage of sputum and maintaining airway opening are key points requiring clinical attention.AIM To explore the effect of refined nursing strategies in patients with AECOPD and dysphagia.METHODS We selected 126 patients with AECOPD and difficulty of expectoration at our hospital,and divided them into a refined care group and a routine care group,with 63 cases each,using a random number table.The two groups of patients were treated with expectorant,anti-infection,oxygen inhalation,and other basic treatment measures;patients in the refined care group were given refined nursing intervention during hospitalization,and the routine care group received conventional nursing intervention.The differences in sputum expectoration,negative pressure suction rate,blood gas parameters,dyspnea score measured through the tool developed by the Medical Research Council(MRC),and quality of life were compared between the two groups.RESULTS After 7 d of intervention,the sputum expectoration effect of the refined care group was 62.30%,the effective rate was 31.15%,and the inefficiency rate was 6.56%.The sputum expectoration effect of the routine care group was 44.07%,the effective rate was 42.37%,and the inefficiency rate was 13.56%.The refined care group had better sputum expectoration than the routine care group(P<0.05).The negative pressure suction rate in the refined care group was significantly lower than that of the routine care group during the treatment(22.95%vs 44.07%,P<0.05).Before the intervention,the arterial oxygen saturation(PaO2)and arterial carbon dioxide saturation(PaCO2)values were not significantly different between the two groups(P>0.05);the PaO2 and PaCO2 values in the refined care group were comparable to those in the routine care group after 7 d of intervention(P>0.05).Before the intervention,there was no significant difference in the MRC score between the two groups(P>0.05);the MRC score of the refined care group was lower than that of the routine care group after 7 d of intervention,but the difference was not statistically significant(P>0.05).Before intervention,there was no significant difference in the symptoms,activities,disease impact,or St.George’s Respiratory questionnaire(SGRQ)total scores between the two groups(P>0.05).After 7 days of intervention,the symptoms,activities,and total score of SGRQ of the refined care group were higher than those of the routine care group,but the difference was not statistically significant(P>0.05).CONCLUSION AECOPD with thick sputum,weak coughing reflex,and abnormal tracheal cilia function will lead to sputum accumulation and affect the exchange of oxygen and carbon dioxide in the lung.Patients with AECOPD who have difficulty expectorating sputum may undergo refined nursing strategies that will promote expectoration,alleviate clinical symptoms,and improve the quality of life.展开更多
BACKGROUND Medications for inflammatory bowel disease(IBD)have changed dramatically over time.However,no study on long-term medication profiles has been conducted in the Chinese population.AIM To evaluate temporal cha...BACKGROUND Medications for inflammatory bowel disease(IBD)have changed dramatically over time.However,no study on long-term medication profiles has been conducted in the Chinese population.AIM To evaluate temporal changes in medication use and treatment patterns for Chinese patients with IBD.METHODS A multicenter retrospective cohort study was conducted among Chinese patients newly diagnosed with Crohn’s disease(CD)and ulcerative colitis(UC)between January 1999 and December 2019.Baseline characteristics and drug prescriptions were collected.Trends in medication use and therapeutic patterns were analyzed.RESULTS In total,3610 patients were analyzed.During follow-up,5-aminosalicylates(5-ASA)and corticosteroids(CS)prescriptions gradually decreased,accompanied by a notable increase in immunosuppressants(IMS)and infliximab(IFX)prescriptions in patients with CD.Prescription rates of 5-ASA and CS were stable,whereas IMS and IFX slightly increased since 2007 in patients with UC.Subgroup(n=957)analyses showed a switch from conventional medications to IFX in patients with CD,while 5-ASA and CS were still steadily prescribed in patients with UC.Logistic regression analyses revealed that surgical history,disease behavior,and disease location were associated with initial therapeutic strategies in patients with CD.However,medications before diagnosis,disease location,and diagnostic year might affect initial strategies in patients with UC.CONCLUSION Long-term treatment strategies analyses has provided unique insight into the switch from conventional drugs to IFX in Chinese patients with CD.展开更多
Laos is the only landlocked country in Southeast Asia and borders Thailand,Myanmar and Cambodia,the three countries in this region that have been hardest hit by human immunodeficiency virus(HIV).Laos has been regarded...Laos is the only landlocked country in Southeast Asia and borders Thailand,Myanmar and Cambodia,the three countries in this region that have been hardest hit by human immunodeficiency virus(HIV).Laos has been regarded as a low-HIVprevalence country for decades.To understand the status of HIV in Laos in recent years,a retrospective study was performed among 2851 patients visiting a hospital in Vientiane,the capital of Laos,from November 2011 to May 2012.Whole blood samples were obtained from the patients,and DNA was extracted.HIV status was determined by HIV gag fragment-specific PCR assay.Sixty-nine samples were detected as HIV proviral DNA positive with a positive rate of 2.4%(69/2851).Sixty-one near full-length genomic sequences were obtained from the positive samples.The results of phylogenetic analysis showed that the vast majority(91.8%)of the HIV strains belonged to CRF01AE,and the other five(8.2%)strains were identified as a new HIV circulating recombinant form CRF9701B,which had a CRF01AE backbone with an insertion of subtype B in the gag-pol region.Phylogeographic analysis revealed that HIV CRF01AE circulating in Laos were multiply introduced from Thailand.These results indicated that Laos might be suffering a considerably more serious impact of HIV than previously believed.To keep this country from undergoing the same increase in HIV prevalence observed in its neighbors,immediate intervention measures and sufficient epidemiological research are urgently needed.展开更多
This study aims to characterize the cell atlas of the epididymis derived from a 46,XY disorders of sex development(DSD)patient with a novel heterozygous mutation of the nuclear receptor subfamily 5 group A member 1(NR...This study aims to characterize the cell atlas of the epididymis derived from a 46,XY disorders of sex development(DSD)patient with a novel heterozygous mutation of the nuclear receptor subfamily 5 group A member 1(NR5A1)gene.Next-generation sequencing found a heterozygous c.124C>G mutation in NR5A1 that resulted in a p.Q42E missense mutation in the conserved DNA-binding domain of NR5A1.The patient demonstrated feminization of external genitalia and Tanner stage 1 breast development.The surgical procedure revealed a morphologically normal epididymis and vas deferens but a dysplastic testis.Microfluidic-based single-cell RNA sequencing(scRNA-seq)analysis found that the fibroblast cells were significantly increased(approximately 46.5%),whereas the number of main epididymal epithelial cells(approximately 9.2%),such as principal cells and basal cells,was dramatically decreased.Bioinformatics analysis of cell–cell communications and gene regulatory networks at the single-cell level inferred that epididymal epithelial cell loss and fibroblast occupation are associated with the epithelial-to-mesenchymal transition(EMT)process.The present study provides a cell atlas of the epididymis of a patient with 46,XY DSD and serves as an important resource for understanding the pathophysiology of DSD.展开更多
China’s AIDS epidemic started among people who inject drugs(PWID)in Ruili county-level city,a China–Myanmar border city of Yunnan Province,in 1989(Fig.1).Since then HIV has spread rapidly across the country(He and D...China’s AIDS epidemic started among people who inject drugs(PWID)in Ruili county-level city,a China–Myanmar border city of Yunnan Province,in 1989(Fig.1).Since then HIV has spread rapidly across the country(He and Detels 2005).China launched a‘‘Four Frees and One Care’’policy in 2003 to fight against HIV/AIDS.As one展开更多
Although the exact etiology of inflammatory bowel disease(IBD)remains unclear,exaggerated immune response in genetically predisposed individuals has been reported.Th1 and Th17 cells mediate IBD development.Macrophages...Although the exact etiology of inflammatory bowel disease(IBD)remains unclear,exaggerated immune response in genetically predisposed individuals has been reported.Th1 and Th17 cells mediate IBD development.Macrophages produce IL-12 and IL-23 that share p40 subunit encoded by IL12B gene as heteromer partner to drive Th1 and Th17 differentiation.The available animal and human data strongly support the pathogenic role of IL-12/IL-23 in IBD development and suggest that blocking p40 might be the potential strategy for IBD treatment.Furthermore,aberrant alteration of some cytokines expression via epigenetic mechanisms is involved in pathogenesis o f IBD.In this study,we analyzed core promoter region of IL12B gene and investigated whether IL12B expression could be regulated through targeted epigenetic modification with gene editing technology.Transcription activator-like effectors(TALEs)are widely used in the field of genome editing and can specifically target DNA sequence in the host genome.We synthesized the TALE DNA-binding domains that target the promoter of human IL12B gene and fused it with the functional catalytic domains of epigenetic enzymes.Transient expression of these engineered enzymes demonstrated that the TALE-DNMT3A targeted the selected IL12B promoter region,induced loci-specific DNA methylation,and down-regulated IL-12B expression in various human cell lines.Collectively,our data suggested that epigenetic editing of IL12B through methylating DNA on its promoter might be developed as a potential therapeutic strategy for IBD treatment.展开更多
基金National Natural Science Foundation of China(22073030)the Oriental Scholars of Shanghai Universities。
文摘Dichloromethane(DCM)dehalogenase stands as a crucial enzyme implicated in the degradation of methylene chloride across diverse environmental and biological contexts.However,the unbinding pathways of ligands from DCM dehalogenase remain unexplored.In order to gain a deeper understanding of the binding sites and dissociation pathways of dichloromethane(DCM)and glutathione(GSH)from the DCM dehalogenase,random accelerated molecular dynamics(RAMD)simulations were performed,in which DCM and GSH were forced to leave the active site.The protein structure was predicted using Alphafold2,and the conformations of GSH and DCM in the binding pocket were predicted by docking.A long equilibrium simulation was conducted to validate the structure of the complex.The results show that GSH is most commonly observed in three main pathways,one of which is more important than the other two.In addition,DCM was observed to escape along a unique pathway.The key residues and protein helices of each pathway were identified.The results can provide a theoretical foundation for the subsequent dissociation mechanism of DCM dehalogenase.
文摘三相AC/DC整流器作为许多电力电子设备中不可或缺的电气环节得到了广泛的应用。相比于传统的二极管整流器及相控整流器,VIENNA整流器具有网侧谐波含量低、功率因数高的优点。同时,VIENNA整流器比普通桥式PWM整流器具有更少的功率开关数量,进一步提高了系统功率密度。在简要介绍VIENNA整流器原理的基础上,结合3 k W系统进行了相应的工程设计,主要包括储能元件设计、滤波环节设计和控制环路设计。此外,针对电网电压畸变带来的输入电流谐波问题,采用了一种结合VIENNA整流器控制环路的指定次谐波优化方法,并针对其中LCL滤波器带来的谐振问题,从工程设计的角度进行了相应的优化。3 k W工程样机的实验结果进一步验证了设计方法以及所采用的优化方法的有效性。
文摘BACKGROUND Under physiological conditions,sputum produced during acute exacerbation of chronic obstructive pulmonary disease(AECOPD)can move passively with the cilia in the airway;the sputum is gradually excreted from the depth of the airways through the stimulation of the coughing reflex on the sensory nerve on the surface of the airway.However,when the sputum is thick,the cough is weak,or the tracheal cilia are abnormal,sputum accumulation may occur and affect the exchange of oxygen and carbon dioxide in the lung.Furthermore,the presence of pathogenic microorganisms in sputum may cause or aggravate the symptoms of pulmonary infection in patients,which is the main factor leading to AECOPD.Therefore,promoting effective drainage of sputum and maintaining airway opening are key points requiring clinical attention.AIM To explore the effect of refined nursing strategies in patients with AECOPD and dysphagia.METHODS We selected 126 patients with AECOPD and difficulty of expectoration at our hospital,and divided them into a refined care group and a routine care group,with 63 cases each,using a random number table.The two groups of patients were treated with expectorant,anti-infection,oxygen inhalation,and other basic treatment measures;patients in the refined care group were given refined nursing intervention during hospitalization,and the routine care group received conventional nursing intervention.The differences in sputum expectoration,negative pressure suction rate,blood gas parameters,dyspnea score measured through the tool developed by the Medical Research Council(MRC),and quality of life were compared between the two groups.RESULTS After 7 d of intervention,the sputum expectoration effect of the refined care group was 62.30%,the effective rate was 31.15%,and the inefficiency rate was 6.56%.The sputum expectoration effect of the routine care group was 44.07%,the effective rate was 42.37%,and the inefficiency rate was 13.56%.The refined care group had better sputum expectoration than the routine care group(P<0.05).The negative pressure suction rate in the refined care group was significantly lower than that of the routine care group during the treatment(22.95%vs 44.07%,P<0.05).Before the intervention,the arterial oxygen saturation(PaO2)and arterial carbon dioxide saturation(PaCO2)values were not significantly different between the two groups(P>0.05);the PaO2 and PaCO2 values in the refined care group were comparable to those in the routine care group after 7 d of intervention(P>0.05).Before the intervention,there was no significant difference in the MRC score between the two groups(P>0.05);the MRC score of the refined care group was lower than that of the routine care group after 7 d of intervention,but the difference was not statistically significant(P>0.05).Before intervention,there was no significant difference in the symptoms,activities,disease impact,or St.George’s Respiratory questionnaire(SGRQ)total scores between the two groups(P>0.05).After 7 days of intervention,the symptoms,activities,and total score of SGRQ of the refined care group were higher than those of the routine care group,but the difference was not statistically significant(P>0.05).CONCLUSION AECOPD with thick sputum,weak coughing reflex,and abnormal tracheal cilia function will lead to sputum accumulation and affect the exchange of oxygen and carbon dioxide in the lung.Patients with AECOPD who have difficulty expectorating sputum may undergo refined nursing strategies that will promote expectoration,alleviate clinical symptoms,and improve the quality of life.
文摘BACKGROUND Medications for inflammatory bowel disease(IBD)have changed dramatically over time.However,no study on long-term medication profiles has been conducted in the Chinese population.AIM To evaluate temporal changes in medication use and treatment patterns for Chinese patients with IBD.METHODS A multicenter retrospective cohort study was conducted among Chinese patients newly diagnosed with Crohn’s disease(CD)and ulcerative colitis(UC)between January 1999 and December 2019.Baseline characteristics and drug prescriptions were collected.Trends in medication use and therapeutic patterns were analyzed.RESULTS In total,3610 patients were analyzed.During follow-up,5-aminosalicylates(5-ASA)and corticosteroids(CS)prescriptions gradually decreased,accompanied by a notable increase in immunosuppressants(IMS)and infliximab(IFX)prescriptions in patients with CD.Prescription rates of 5-ASA and CS were stable,whereas IMS and IFX slightly increased since 2007 in patients with UC.Subgroup(n=957)analyses showed a switch from conventional medications to IFX in patients with CD,while 5-ASA and CS were still steadily prescribed in patients with UC.Logistic regression analyses revealed that surgical history,disease behavior,and disease location were associated with initial therapeutic strategies in patients with CD.However,medications before diagnosis,disease location,and diagnostic year might affect initial strategies in patients with UC.CONCLUSION Long-term treatment strategies analyses has provided unique insight into the switch from conventional drugs to IFX in Chinese patients with CD.
基金supported in part by Grants from the National Natural Science Foundation of China(U1302224,81601802,81271892,81902106)
文摘Laos is the only landlocked country in Southeast Asia and borders Thailand,Myanmar and Cambodia,the three countries in this region that have been hardest hit by human immunodeficiency virus(HIV).Laos has been regarded as a low-HIVprevalence country for decades.To understand the status of HIV in Laos in recent years,a retrospective study was performed among 2851 patients visiting a hospital in Vientiane,the capital of Laos,from November 2011 to May 2012.Whole blood samples were obtained from the patients,and DNA was extracted.HIV status was determined by HIV gag fragment-specific PCR assay.Sixty-nine samples were detected as HIV proviral DNA positive with a positive rate of 2.4%(69/2851).Sixty-one near full-length genomic sequences were obtained from the positive samples.The results of phylogenetic analysis showed that the vast majority(91.8%)of the HIV strains belonged to CRF01AE,and the other five(8.2%)strains were identified as a new HIV circulating recombinant form CRF9701B,which had a CRF01AE backbone with an insertion of subtype B in the gag-pol region.Phylogeographic analysis revealed that HIV CRF01AE circulating in Laos were multiply introduced from Thailand.These results indicated that Laos might be suffering a considerably more serious impact of HIV than previously believed.To keep this country from undergoing the same increase in HIV prevalence observed in its neighbors,immediate intervention measures and sufficient epidemiological research are urgently needed.
基金supported by grants from the National Key Research and Development Program of China (No.2018YFC1003602 to HC and No.2018YFC1003504 to HJ)the National Natural Science Foundation of China (No.81871202 to HC and No.31900484 to GCX)+2 种基金Lo Kwee Seong Start Up Fund to KLE,Shanghai Sailing Program (No.20YF1422900 to YWZ)the Natural Science Foundation of Nantong (No.JC2021081 to JWS)Startup R&D funding from Nantong University (No.135419631032 to JWS and TDYX2021021 to JWS).
文摘This study aims to characterize the cell atlas of the epididymis derived from a 46,XY disorders of sex development(DSD)patient with a novel heterozygous mutation of the nuclear receptor subfamily 5 group A member 1(NR5A1)gene.Next-generation sequencing found a heterozygous c.124C>G mutation in NR5A1 that resulted in a p.Q42E missense mutation in the conserved DNA-binding domain of NR5A1.The patient demonstrated feminization of external genitalia and Tanner stage 1 breast development.The surgical procedure revealed a morphologically normal epididymis and vas deferens but a dysplastic testis.Microfluidic-based single-cell RNA sequencing(scRNA-seq)analysis found that the fibroblast cells were significantly increased(approximately 46.5%),whereas the number of main epididymal epithelial cells(approximately 9.2%),such as principal cells and basal cells,was dramatically decreased.Bioinformatics analysis of cell–cell communications and gene regulatory networks at the single-cell level inferred that epididymal epithelial cell loss and fibroblast occupation are associated with the epithelial-to-mesenchymal transition(EMT)process.The present study provides a cell atlas of the epididymis of a patient with 46,XY DSD and serves as an important resource for understanding the pathophysiology of DSD.
基金supported by grants from the NSFC (81271892, U1302224, and 81601802)
文摘China’s AIDS epidemic started among people who inject drugs(PWID)in Ruili county-level city,a China–Myanmar border city of Yunnan Province,in 1989(Fig.1).Since then HIV has spread rapidly across the country(He and Detels 2005).China launched a‘‘Four Frees and One Care’’policy in 2003 to fight against HIV/AIDS.As one
基金The study was supported by the National Natural Science Foundation of China(No.81270468).
文摘Although the exact etiology of inflammatory bowel disease(IBD)remains unclear,exaggerated immune response in genetically predisposed individuals has been reported.Th1 and Th17 cells mediate IBD development.Macrophages produce IL-12 and IL-23 that share p40 subunit encoded by IL12B gene as heteromer partner to drive Th1 and Th17 differentiation.The available animal and human data strongly support the pathogenic role of IL-12/IL-23 in IBD development and suggest that blocking p40 might be the potential strategy for IBD treatment.Furthermore,aberrant alteration of some cytokines expression via epigenetic mechanisms is involved in pathogenesis o f IBD.In this study,we analyzed core promoter region of IL12B gene and investigated whether IL12B expression could be regulated through targeted epigenetic modification with gene editing technology.Transcription activator-like effectors(TALEs)are widely used in the field of genome editing and can specifically target DNA sequence in the host genome.We synthesized the TALE DNA-binding domains that target the promoter of human IL12B gene and fused it with the functional catalytic domains of epigenetic enzymes.Transient expression of these engineered enzymes demonstrated that the TALE-DNMT3A targeted the selected IL12B promoter region,induced loci-specific DNA methylation,and down-regulated IL-12B expression in various human cell lines.Collectively,our data suggested that epigenetic editing of IL12B through methylating DNA on its promoter might be developed as a potential therapeutic strategy for IBD treatment.
