Background:Salvage treatment for locally recurrent nasopharyngeal carcinoma(NPC) is complicated and relatively limited.Radiotherapy,combined with effective concomitant chemotherapy,may improve clinical treatment outco...Background:Salvage treatment for locally recurrent nasopharyngeal carcinoma(NPC) is complicated and relatively limited.Radiotherapy,combined with effective concomitant chemotherapy,may improve clinical treatment outcomes.We conducted a phase Ⅱ randomized controlled trial to evaluate the efficacy of intensity-modulated radiotherapy with concomitant weekly cisplatin on locally recurrent NPC.Methods:Between April 2002 and January 2008,69 patients diagnosed with non-metastatic locally recurrent NPC were randomly assigned to either concomitant chemoradiotherapy group(n = 34) or radiotherapy alone group(n = 35).All patients received intensity-modulated radiotherapy.The radiotherapy dose for both groups was 60 Gy in 27 fractions for 37 days(range 23-53 days).The concomitant chemotherapy schedule was cisplatin 30 mg/m^2 by intravenous infusion weekly during radiotherapy.Results:The median follow-up period of all patients was 35 months(range 2-112 months).Between concomitant chemoradiotherapy and radiotherapy groups,there was only significant difference in the 3-year and 5-year overall survival(OS) rates(68.7%vs.42.2%,P = 0.016 and 41.8%vs.27.5%,P = 0.049,respectively).Subgroup analysis showed that concomitant chemoradiotherapy significantly improved the 5-year OS rate especially for patients in stage rT3-4(33.0%vs.13.2%,P = 0.009),stages Ⅲ-Ⅳ(34.3%vs.13.2%,P = 0.006),recurrence interval >30 months(49.0%vs.20.6%,P = 0.017),and tumor volume >26 cm^3(37.6%vs.0%,P = 0.006).Conclusion:Compared with radiotherapy alone,concomitant chemoradiotherapy can improve OS of the patients with locally recurrent NPC,especially those with advanced T category(rT3-4) and stage(lll-IV) diseases,recurrence intervals >30 months,and tumor volume >26 cm^3.展开更多
Aging biomarkers are a combination of biological parameters to(i)assess age-related changes,(ii)track the physiological aging process,and(iii)predict the transition into a pathological status.Although a broad spectrum...Aging biomarkers are a combination of biological parameters to(i)assess age-related changes,(ii)track the physiological aging process,and(iii)predict the transition into a pathological status.Although a broad spectrum of aging biomarkers has been developed,their potential uses and limitations remain poorly characterized.An immediate goal of biomarkers is to help us answer the following three fundamental questions in aging research:How old are we?Why do we get old?And how can we age slower?This review aims to address this need.Here,we summarize our current knowledge of biomarkers developed for cellular,organ,and organismal levels of aging,comprising six pillars:physiological characteristics,medical imaging,histological features,cellular alterations,molecular changes,and secretory factors.To fulfill all these requisites,we propose that aging biomarkers should qualify for being specific,systemic,and clinically relevant.展开更多
BACKGROUND Systemic inflammation and nutrition status play an important role in cancer metastasis.The combined index of hemoglobin,albumin,lymphocyte,and platelet(HALP),consisting of haemoglobin,albumin,lymphocytes,an...BACKGROUND Systemic inflammation and nutrition status play an important role in cancer metastasis.The combined index of hemoglobin,albumin,lymphocyte,and platelet(HALP),consisting of haemoglobin,albumin,lymphocytes,and platelets,is considered as a novel marker to reflect both systemic inflammation and nutrition status.However,no studies have investigated the relationship between HALP and survival of patients with pancreatic cancer following radical resection.AIM To evaluate the prognostic value of preoperative HALP in pancreatic cancer patients.METHODS The preoperative serum levels of hemoglobin,albumin,lymphocyte counts,and platelet counts were routinely detected in 582 pancreatic adenocarcinoma patients who underwent radical resection.The relationship between postoperative survival and the preoperative level of HALP was investigated.RESULTS Low levels of HALP were significantly associated with lymph node metastasis(P=0.002),poor tumor differentiation(P=0.032),high TNM stage(P=0.008),female patients(P=0.005)and tumor location in the head of the pancreas(P<0.001).Low levels of HALP were associated with early recurrence[7.3 mo vs 16.3 mo,P<0.001 for recurrence-free survival(RFS)]and short survival[11.5 mo vs 23.6 mo,P<0.001 for overall survival(OS)]in patients with resected pancreatic adenocarcinoma.A low level of HALP was an independent risk factor for early recurrence and short survival irrespective of sex and tumor location.CONCLUSION Low levels of HALP may be a significant risk factor for RFS and OS in patients with resected pancreatic cancer.展开更多
Background Sclerostin, expressed exclusively by osteocytes, is a negative regulator of bone formation. To gain insights into the action of sclerostin in postmenopausal osteoporosis, we evaluated serum sclerostin level...Background Sclerostin, expressed exclusively by osteocytes, is a negative regulator of bone formation. To gain insights into the action of sclerostin in postmenopausal osteoporosis, we evaluated serum sclerostin levels in postmenopausal women and investigated its possible associations with bone turnover markers in patients with postmenopausal osteoporosis. Methods We detected serum sclerostin, and measured lumbar spine bone mineral density in 650 Chinese postmenopausal women. We also assessed serum levels of 13-isomerized C-terminal crosslinking of type I collagen, intact N-terminal propeptide of type I collagen, N-mid fragment of osteocalcin, 25-hydroxyvitamin D, and estradiol. Results Serum sclerostin levels were lower in postmenopausal osteoporotic women compared with non-osteoporotic postmenopausal women （（38.79＋7.43） vs. （52.86＋6.69） pmol/L, P 〈0.001）. Serum sclerostin was positively correlated with lumbar spine bone mineral density （r=0.391, P 〈0.001） and weakly negatively correlated with [3-isomerized C-terminal crosslinking of type I collagen, intact N-terminal propeptide of type I collagen, N-mid fragment of osteocalcin （t= -0.225, P 〈0.001; r= -0.091, P=0.046; r= -0.108, P=0.018; respectively） in postmenopausal osteoporosis. There was no significant association of serum sclerostin with age, body mass index, 25-hydroxyvitamin D, and estradiol （r= -0.004, P=0.926; r=0.067, P=0.143; r=0.063, P=0.165; r= -0.045, P=0.324; respectively）.Conclusion Sclerostin may be involved in the pathogenesis of postmenopausal osteoporosis and may play a role in bone turnover.展开更多
BACKGROUND Intestinal mucosal barrier injury and gastrointestinal dysfunction are important causes of sepsis.However,few studies have investigated the effects of enteral underfeeding on gastrointestinal function in se...BACKGROUND Intestinal mucosal barrier injury and gastrointestinal dysfunction are important causes of sepsis.However,few studies have investigated the effects of enteral underfeeding on gastrointestinal function in sepsis.Moreover,no consensus on goal enteral caloric intake has been reached in sepsis.AIM To investigate the effects of different goal caloric requirements of enteral nutrition on the gastrointestinal function and outcomes in the acute phase of sepsis.METHODS Patients were randomly assigned to receive 30%(defined as group A),60%(group B),or 100%(group C)of goal caloric requirements of enteral nutrition in this prospective pilot clinical trial.The acute gastrointestinal injury(AGI)grades,incidence of feeding intolerance(FI),daily caloric intake,nutritional and inflammatory markers,and biomarkers of mucosal barrier function were collected during the first 7 d of enteral feeding.The clinical severity and outcome variables were also recorded.RESULTS A total of 54 septic patients were enrolled.The days to goal calorie of group C(2.55±0.82)were significantly longer than those of group A(3.50±1.51;P=0.046)or B(4.85±1.68;P<0.001).The FI incidence of group C(16.5%)was higher than that of group A(5.0%)or B(8.7%)(P=0.009).No difference in the incidence of FI symptoms was found between groups A and B.The serum levels of barrier function biomarkers of group B were significantly lower than those of group A(P<0.05)on the 7th day of feeding.The prealbumin and IL-6 levels of group A were lower than those of group B(P<0.05)on the 7th day of feeding.No significant differences in the clinical outcome variables or 28-d mortality were found among the three groups.CONCLUSION Early moderate enteral underfeeding(60%of goal requirements)could improve the intestinal barrier function and nutritional and inflammatory status without increasing the incidence of FI symptoms in sepsis.However,further large-scale prospective clinical trials and animal studies are required to test our findings.Moreover,the effects of different prote展开更多
N^6-methyladenosine(m6A),a ubiquitous RNA modification,is installed by METTL3-METTL14 complex.The structure of the heterodimeric complex between the methyltransferase domains(MTDs)of METTL3 and METTL14 has been previo...N^6-methyladenosine(m6A),a ubiquitous RNA modification,is installed by METTL3-METTL14 complex.The structure of the heterodimeric complex between the methyltransferase domains(MTDs)of METTL3 and METTL14 has been previously determined.However,the MTDs alone possess no enzymatic activity.Here we present the solution structure for the zinc finger domain(ZFD)of METTL3,the inclusion of which fulfills the methyltransferase activity of METTL3-METTL14.We show that the ZFD specifically binds to an RNA containing 5'-GGACU-3'consensus sequence,but does not to one without.The ZFD thus serves as the target recognition domain,a structural feature previously shown for DNA methyltransferases,and cooperates with the MTDs of METTL3-METTL14 for catalysis.However,the interaction between the ZFD and the specific RNA is extremely weak,with the binding affinity at several hundred micromolar under physiological conditions.The ZFD contains two CCCH-type zinc fingers connected by an anti-parallel P-sheet.Mutational analysis and NMR titrations have mapped the functional interface to a contiguous surface.As a division of labor,the RNA-binding interface comprises basic residues from zinc finger 1 and hydrophobic residues fromβ-sheet and zinc finger 2.Further we show that the linker between the ZFD and MTD of METTL3 is flexible but partially folded,which may permit the cooperation between the two domains during catalysis.Together,the structural characterization of METTL3 ZFD paves the way to elucidate the atomic details of the entire process of RNA m6A modification.展开更多
AIM: To investigate the effects of electroacupuncture (EA) at neiguan (PC6) on gastric distention-induced transient lower esophageal sphincter relaxations (TLESRs) and discuss the mechanisms of this treatment. METHODS...AIM: To investigate the effects of electroacupuncture (EA) at neiguan (PC6) on gastric distention-induced transient lower esophageal sphincter relaxations (TLESRs) and discuss the mechanisms of this treatment. METHODS: ProtocolⅠ: Twelve healthy cats underwent gastric distention for 60 min on the first day. Electrical acupoint stimulation was applied at the neiguan or a sham point on the hip in randomized order before gastric distention, on the third day and fifth day. Those cats that underwent EA at neiguan on the fifth day were named "Neiguan Group" and the cats that underwent EA at a sham acupoint on the fifth day were named "Sham Group" (control group). During the experiment the frequency of TLESRs and lower esophageal sphincter (LES) pressure were observed by a perfused sleeve assembly. Plasma levels of gastrin (GAS) and motilin (MTL) were determined by radioimmunoassay. Nitrite/nitrate concentration in plasma and tissues were measured by Griess reagent. The nuclei in the brain stem were observed by immunohistochemistry method of c-Fos and NADPH-d dyeing. Protocol Ⅱ: Thirty six healthy cats were divided into 6 groups randomly. We gave saline (2 mL iv. control group), phaclofen (5 mg/kg iv. GABA-B antagonist), cholecystokinin octapeptide (CCK-8) (1 μg/kg per hour iv.), L-Arginine (200 mg/kg iv.), naloxone (2.5 μmol/kg iv.) and tacrine (5.6 mg/kg ip. cholinesterase inhibitor) respectively before EA at Neiguan and gastric distention. And the frequencies of TLESRs in experimental groups were compared with the control group.RESULTS: ProtocolⅠ: Not only the frequency of gastric distention-induced TLESR in 60 min but also the rate of common cavity during TLESRs were significantlydecreased by EA at neiguan compared to that of sham acupoint stimulation. C-Fos immunoreactivity and NOS reactivity in the solitarius (NTS) and dorsal motor nucleus of the vagus (DMV) were significantly decreased by EA at neiguan compared to that of the sham group. However, the positive nuclei of C-Fos and NOS in reticular formation 展开更多
AIM： To elucidate the interaction between non- parenchymal cells, extracellular matrix and oval cells during the restituting process of liver injury induced by partial hepatectomy （PH）. METHODS： We examined the lo...AIM： To elucidate the interaction between non- parenchymal cells, extracellular matrix and oval cells during the restituting process of liver injury induced by partial hepatectomy （PH）. METHODS： We examined the localization of oval cells, non-parenchymal cells, and the extracellular matrix components using immunohistochemical and double immunofluorescent analysis during the proliferation and differentiation of oval cells in N-2- acetylaminofluorene （2-AAF）/PH rat model. RESULTS： By day 2 after PH, small oval cells began to proliferate around the portal area. Most of stellate cells and laminin were present along the hepatic sinusoids in the periportal area. Kupffer cells and fibronectin markedly increased in the whole hepatic Iobule. From day 4 to 9, oval cells spread further into hepatic parenchyma, closely associated with stellate cells, fibronectin and laminin. Kupffer cells admixed with oval cells by day 6 and then decreased in the periportal zone. From day 12 to 15, most of hepatic stellate cells （HSCs）, laminin and fibronectin located around the small hepatocyte nodus, and minority of them appeared in the nodus. Kupffer cells were mainly limited in the pericentral sinusoids. After day 18, the normal liver Iobule structures began to recover.CONCLUSION： Local hepatic microenvironment may participate in the oval cell-mediated liver regeneration through the cell-cell and cell-matrix interactions.展开更多
文摘Background:Salvage treatment for locally recurrent nasopharyngeal carcinoma(NPC) is complicated and relatively limited.Radiotherapy,combined with effective concomitant chemotherapy,may improve clinical treatment outcomes.We conducted a phase Ⅱ randomized controlled trial to evaluate the efficacy of intensity-modulated radiotherapy with concomitant weekly cisplatin on locally recurrent NPC.Methods:Between April 2002 and January 2008,69 patients diagnosed with non-metastatic locally recurrent NPC were randomly assigned to either concomitant chemoradiotherapy group(n = 34) or radiotherapy alone group(n = 35).All patients received intensity-modulated radiotherapy.The radiotherapy dose for both groups was 60 Gy in 27 fractions for 37 days(range 23-53 days).The concomitant chemotherapy schedule was cisplatin 30 mg/m^2 by intravenous infusion weekly during radiotherapy.Results:The median follow-up period of all patients was 35 months(range 2-112 months).Between concomitant chemoradiotherapy and radiotherapy groups,there was only significant difference in the 3-year and 5-year overall survival(OS) rates(68.7%vs.42.2%,P = 0.016 and 41.8%vs.27.5%,P = 0.049,respectively).Subgroup analysis showed that concomitant chemoradiotherapy significantly improved the 5-year OS rate especially for patients in stage rT3-4(33.0%vs.13.2%,P = 0.009),stages Ⅲ-Ⅳ(34.3%vs.13.2%,P = 0.006),recurrence interval >30 months(49.0%vs.20.6%,P = 0.017),and tumor volume >26 cm^3(37.6%vs.0%,P = 0.006).Conclusion:Compared with radiotherapy alone,concomitant chemoradiotherapy can improve OS of the patients with locally recurrent NPC,especially those with advanced T category(rT3-4) and stage(lll-IV) diseases,recurrence intervals >30 months,and tumor volume >26 cm^3.
基金supported by the National Natural Science Foundation of China(31730036,31871380,31871382,31930055,31930058,32000500,32022034,32030033,32070730,32130046,3217050247,32150005,32200595,32222024,81730019,81730022,81830014,81921006,81925005,81970426,81971301,81971312,82030041,82061160495,82070805,82071595,82090020,82100841,82120108009,82122024,82125002,82125011,82125012,82130045,82171284,82173061,82173398,82225007,82225015,82225017,82225018,82230047,82230088,82271600,91949106,91949201,92049116,92049302,92049304,92149303,92149306,92157202,92168201,92169102,92249301,92268201)the National Key Research and Development Program of China(2018YFA0800700,2018YFC2000100,2018YFC2000102,2018YFC2002003,2019YFA0110900,2019YFA0801703,2019YFA0801903,2019YFA0802202,2019YFA0904800,2020YFA0113400,2020YFA0803401,2020YFA0804000,2020YFC2002900,2020YFC2008000,2020YFE0202200,2021YFA0804900,2021YFA1100103,2021YFA1100900,2021YFE0114200,2021ZD0202400,2022YFA0806001,2022YFA0806002,2022YFA0806600,2022YFA1103200,2022YFA1103601,2022YFA1103701,2022YFA1103800,2022YFA1103801,2022YFA1104100,2022YFA1104904,2022YFA1303000,2022YFC2009900,2022YFC2502401,2022YFC3602400,2022YFE0118000,2022ZD0213200)+9 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16030302,XDB39000000,XDB39030600)the Youth Innovation Promotion Association of Chinese Academy of Sciences(2020085,2021080)CAS Project for Young Scientists in Basic Research(YSBR-076)the Program of the Beijing Natural Science Foundation(JQ20031)Clinical Research Operating Fund of Central High level hospitals(2022-PUMCHE-001)CAMS Innovation Fund for Medical Sciences(CIFMS)(2022-I2M1-004)Talent Program of the Chinese Academy of Medical Science(2022RC310-10)Research Funds from Health@Inno HK Program launched by Innovation Technology Commission of the Hong Kong Special Administrative Region,Guangdong Basic and Applied Basic Research Foundation(2020B1515020044)Guangzhou Planned Project of Science and Technology(202002020039)the Major Technology Innovation of Hubei Province(2019ACA14
文摘Aging biomarkers are a combination of biological parameters to(i)assess age-related changes,(ii)track the physiological aging process,and(iii)predict the transition into a pathological status.Although a broad spectrum of aging biomarkers has been developed,their potential uses and limitations remain poorly characterized.An immediate goal of biomarkers is to help us answer the following three fundamental questions in aging research:How old are we?Why do we get old?And how can we age slower?This review aims to address this need.Here,we summarize our current knowledge of biomarkers developed for cellular,organ,and organismal levels of aging,comprising six pillars:physiological characteristics,medical imaging,histological features,cellular alterations,molecular changes,and secretory factors.To fulfill all these requisites,we propose that aging biomarkers should qualify for being specific,systemic,and clinically relevant.
基金Supported by the National Science Foundation for Distinguished Young Scholars of China,No.81625016the National Natural Science Foundation of Shanghai,No.19ZR1410800+2 种基金the National Natural Science Foundation of China,No.81872366,No.81871941,No.81827807,No.81802675,and No.81702341the Outstanding Academic Leader Program of the “Technological Innovation Action Plan” of the Shanghai Science and Technology Commission,No.18XD1401200the Young Talented Specialist Training Program of Shanghai
文摘BACKGROUND Systemic inflammation and nutrition status play an important role in cancer metastasis.The combined index of hemoglobin,albumin,lymphocyte,and platelet(HALP),consisting of haemoglobin,albumin,lymphocytes,and platelets,is considered as a novel marker to reflect both systemic inflammation and nutrition status.However,no studies have investigated the relationship between HALP and survival of patients with pancreatic cancer following radical resection.AIM To evaluate the prognostic value of preoperative HALP in pancreatic cancer patients.METHODS The preoperative serum levels of hemoglobin,albumin,lymphocyte counts,and platelet counts were routinely detected in 582 pancreatic adenocarcinoma patients who underwent radical resection.The relationship between postoperative survival and the preoperative level of HALP was investigated.RESULTS Low levels of HALP were significantly associated with lymph node metastasis(P=0.002),poor tumor differentiation(P=0.032),high TNM stage(P=0.008),female patients(P=0.005)and tumor location in the head of the pancreas(P<0.001).Low levels of HALP were associated with early recurrence[7.3 mo vs 16.3 mo,P<0.001 for recurrence-free survival(RFS)]and short survival[11.5 mo vs 23.6 mo,P<0.001 for overall survival(OS)]in patients with resected pancreatic adenocarcinoma.A low level of HALP was an independent risk factor for early recurrence and short survival irrespective of sex and tumor location.CONCLUSION Low levels of HALP may be a significant risk factor for RFS and OS in patients with resected pancreatic cancer.
基金This study was supported by grants from the National Natural Science Foundation of China （No. 81072943） and Health Department of Hubei Province （No. 2012Z-Z01）.
文摘Background Sclerostin, expressed exclusively by osteocytes, is a negative regulator of bone formation. To gain insights into the action of sclerostin in postmenopausal osteoporosis, we evaluated serum sclerostin levels in postmenopausal women and investigated its possible associations with bone turnover markers in patients with postmenopausal osteoporosis. Methods We detected serum sclerostin, and measured lumbar spine bone mineral density in 650 Chinese postmenopausal women. We also assessed serum levels of 13-isomerized C-terminal crosslinking of type I collagen, intact N-terminal propeptide of type I collagen, N-mid fragment of osteocalcin, 25-hydroxyvitamin D, and estradiol. Results Serum sclerostin levels were lower in postmenopausal osteoporotic women compared with non-osteoporotic postmenopausal women （（38.79＋7.43） vs. （52.86＋6.69） pmol/L, P 〈0.001）. Serum sclerostin was positively correlated with lumbar spine bone mineral density （r=0.391, P 〈0.001） and weakly negatively correlated with [3-isomerized C-terminal crosslinking of type I collagen, intact N-terminal propeptide of type I collagen, N-mid fragment of osteocalcin （t= -0.225, P 〈0.001; r= -0.091, P=0.046; r= -0.108, P=0.018; respectively） in postmenopausal osteoporosis. There was no significant association of serum sclerostin with age, body mass index, 25-hydroxyvitamin D, and estradiol （r= -0.004, P=0.926; r=0.067, P=0.143; r=0.063, P=0.165; r= -0.045, P=0.324; respectively）.Conclusion Sclerostin may be involved in the pathogenesis of postmenopausal osteoporosis and may play a role in bone turnover.
基金Supported by National Natural Science Foundation of China,No.81701881Nanjing Medical Science and Technology Development Foundation,No.YKK17102.
文摘BACKGROUND Intestinal mucosal barrier injury and gastrointestinal dysfunction are important causes of sepsis.However,few studies have investigated the effects of enteral underfeeding on gastrointestinal function in sepsis.Moreover,no consensus on goal enteral caloric intake has been reached in sepsis.AIM To investigate the effects of different goal caloric requirements of enteral nutrition on the gastrointestinal function and outcomes in the acute phase of sepsis.METHODS Patients were randomly assigned to receive 30%(defined as group A),60%(group B),or 100%(group C)of goal caloric requirements of enteral nutrition in this prospective pilot clinical trial.The acute gastrointestinal injury(AGI)grades,incidence of feeding intolerance(FI),daily caloric intake,nutritional and inflammatory markers,and biomarkers of mucosal barrier function were collected during the first 7 d of enteral feeding.The clinical severity and outcome variables were also recorded.RESULTS A total of 54 septic patients were enrolled.The days to goal calorie of group C(2.55±0.82)were significantly longer than those of group A(3.50±1.51;P=0.046)or B(4.85±1.68;P<0.001).The FI incidence of group C(16.5%)was higher than that of group A(5.0%)or B(8.7%)(P=0.009).No difference in the incidence of FI symptoms was found between groups A and B.The serum levels of barrier function biomarkers of group B were significantly lower than those of group A(P<0.05)on the 7th day of feeding.The prealbumin and IL-6 levels of group A were lower than those of group B(P<0.05)on the 7th day of feeding.No significant differences in the clinical outcome variables or 28-d mortality were found among the three groups.CONCLUSION Early moderate enteral underfeeding(60%of goal requirements)could improve the intestinal barrier function and nutritional and inflammatory status without increasing the incidence of FI symptoms in sepsis.However,further large-scale prospective clinical trials and animal studies are required to test our findings.Moreover,the effects of different prote
文摘N^6-methyladenosine(m6A),a ubiquitous RNA modification,is installed by METTL3-METTL14 complex.The structure of the heterodimeric complex between the methyltransferase domains(MTDs)of METTL3 and METTL14 has been previously determined.However,the MTDs alone possess no enzymatic activity.Here we present the solution structure for the zinc finger domain(ZFD)of METTL3,the inclusion of which fulfills the methyltransferase activity of METTL3-METTL14.We show that the ZFD specifically binds to an RNA containing 5'-GGACU-3'consensus sequence,but does not to one without.The ZFD thus serves as the target recognition domain,a structural feature previously shown for DNA methyltransferases,and cooperates with the MTDs of METTL3-METTL14 for catalysis.However,the interaction between the ZFD and the specific RNA is extremely weak,with the binding affinity at several hundred micromolar under physiological conditions.The ZFD contains two CCCH-type zinc fingers connected by an anti-parallel P-sheet.Mutational analysis and NMR titrations have mapped the functional interface to a contiguous surface.As a division of labor,the RNA-binding interface comprises basic residues from zinc finger 1 and hydrophobic residues fromβ-sheet and zinc finger 2.Further we show that the linker between the ZFD and MTD of METTL3 is flexible but partially folded,which may permit the cooperation between the two domains during catalysis.Together,the structural characterization of METTL3 ZFD paves the way to elucidate the atomic details of the entire process of RNA m6A modification.
基金the National Natural Science Foundation of China, No. C030503039
文摘AIM: To investigate the effects of electroacupuncture (EA) at neiguan (PC6) on gastric distention-induced transient lower esophageal sphincter relaxations (TLESRs) and discuss the mechanisms of this treatment. METHODS: ProtocolⅠ: Twelve healthy cats underwent gastric distention for 60 min on the first day. Electrical acupoint stimulation was applied at the neiguan or a sham point on the hip in randomized order before gastric distention, on the third day and fifth day. Those cats that underwent EA at neiguan on the fifth day were named "Neiguan Group" and the cats that underwent EA at a sham acupoint on the fifth day were named "Sham Group" (control group). During the experiment the frequency of TLESRs and lower esophageal sphincter (LES) pressure were observed by a perfused sleeve assembly. Plasma levels of gastrin (GAS) and motilin (MTL) were determined by radioimmunoassay. Nitrite/nitrate concentration in plasma and tissues were measured by Griess reagent. The nuclei in the brain stem were observed by immunohistochemistry method of c-Fos and NADPH-d dyeing. Protocol Ⅱ: Thirty six healthy cats were divided into 6 groups randomly. We gave saline (2 mL iv. control group), phaclofen (5 mg/kg iv. GABA-B antagonist), cholecystokinin octapeptide (CCK-8) (1 μg/kg per hour iv.), L-Arginine (200 mg/kg iv.), naloxone (2.5 μmol/kg iv.) and tacrine (5.6 mg/kg ip. cholinesterase inhibitor) respectively before EA at Neiguan and gastric distention. And the frequencies of TLESRs in experimental groups were compared with the control group.RESULTS: ProtocolⅠ: Not only the frequency of gastric distention-induced TLESR in 60 min but also the rate of common cavity during TLESRs were significantlydecreased by EA at neiguan compared to that of sham acupoint stimulation. C-Fos immunoreactivity and NOS reactivity in the solitarius (NTS) and dorsal motor nucleus of the vagus (DMV) were significantly decreased by EA at neiguan compared to that of the sham group. However, the positive nuclei of C-Fos and NOS in reticular formation
基金Supported by A grant from National Natural Science Foundation of China
文摘AIM： To elucidate the interaction between non- parenchymal cells, extracellular matrix and oval cells during the restituting process of liver injury induced by partial hepatectomy （PH）. METHODS： We examined the localization of oval cells, non-parenchymal cells, and the extracellular matrix components using immunohistochemical and double immunofluorescent analysis during the proliferation and differentiation of oval cells in N-2- acetylaminofluorene （2-AAF）/PH rat model. RESULTS： By day 2 after PH, small oval cells began to proliferate around the portal area. Most of stellate cells and laminin were present along the hepatic sinusoids in the periportal area. Kupffer cells and fibronectin markedly increased in the whole hepatic Iobule. From day 4 to 9, oval cells spread further into hepatic parenchyma, closely associated with stellate cells, fibronectin and laminin. Kupffer cells admixed with oval cells by day 6 and then decreased in the periportal zone. From day 12 to 15, most of hepatic stellate cells （HSCs）, laminin and fibronectin located around the small hepatocyte nodus, and minority of them appeared in the nodus. Kupffer cells were mainly limited in the pericentral sinusoids. After day 18, the normal liver Iobule structures began to recover.CONCLUSION： Local hepatic microenvironment may participate in the oval cell-mediated liver regeneration through the cell-cell and cell-matrix interactions.
