The Open Quantum Materials Database(OQMD)is a high-throughput database currently consisting of nearly 300,000 density functional theory(DFT)total energy calculations of compounds from the Inorganic Crystal Structure D...The Open Quantum Materials Database(OQMD)is a high-throughput database currently consisting of nearly 300,000 density functional theory(DFT)total energy calculations of compounds from the Inorganic Crystal Structure Database(ICSD)and decorations of commonly occurring crystal structures.To maximise the impact of these data,the entire database is being made available,without restrictions,at www.oqmd.org/download.In this paper,we outline the structure and contents of the database,and then use it to evaluate the accuracy of the calculations therein by comparing DFT predictions with experimental measurements for the stability of all elemental ground-state structures and 1,670 experimental formation energies of compounds.This represents the largest comparison between DFT and experimental formation energies to date.The apparent mean absolute error between experimental measurements and our calculations is 0.096 eV/atom.In order to estimate how much error to attribute to the DFT calculations,we also examine deviation between different experimental measurements themselves where multiple sources are available,and find a surprisingly large mean absolute error of 0.082 eV/atom.Hence,we suggest that a significant fraction of the error between DFT and experimental formation energies may be attributed to experimental uncertainties.Finally,we evaluate the stability of compounds in the OQMD(including compounds obtained from the ICSD as well as hypothetical structures),which allows us to predict the existence of~3,200 new compounds that have not been experimentally characterised and uncover trends in material discovery,based on historical data available within the ICSD.展开更多
Crohn＇s disease and ulcerative colitis are chronic relapsing immune mediated disorders that results from an aberrant response to gut luminal antigen in genetically susceptible host. The adaptive immune response that ...Crohn＇s disease and ulcerative colitis are chronic relapsing immune mediated disorders that results from an aberrant response to gut luminal antigen in genetically susceptible host. The adaptive immune response that is then triggered was widely considered to be a T-helper-1 mediated condition in Crohn＇s disease and T-helpero2 mediated condition in ulcerative colitis. Recent studies in animal models, genome wide association, and basic science has provided important insights in in the immunopathogenesis of inflammatory bowel disease, one of which was the characterization of the interleukin-23/Th-17 axis.展开更多
Hepatitis B virus(HBV) is a member of the hepadnavirus family.Hepadnaviruses can be found in both mammals(orthohepadnaviruses) and birds(avihepadnaviruses).The genetic variability of HBV is very high.There are eight g...Hepatitis B virus(HBV) is a member of the hepadnavirus family.Hepadnaviruses can be found in both mammals(orthohepadnaviruses) and birds(avihepadnaviruses).The genetic variability of HBV is very high.There are eight genotypes of HBV and three clades of HBV isolates from apes that appear to be additional genotypes of HBV.Most genotypes are now divided into subgenotypes with distinct virological and epidemiological properties.In addition,recombination among HBV genotypes increases the variability of HBV.This review summarises current knowledge of the epidemiology of genetic variability in hepadnaviruses and,due to rapid progress in the field,updates several recent reviews on HBV genotypes and subgenotypes.展开更多
Hepadnaviridae is a family of hepatotropic DNA viruses that is divided into the genera orthohepadnavirus of mammals and avihepadnavirus of birds. All members of this family can cause acute and chronic hepatic infectio...Hepadnaviridae is a family of hepatotropic DNA viruses that is divided into the genera orthohepadnavirus of mammals and avihepadnavirus of birds. All members of this family can cause acute and chronic hepatic infection, which in the case of human hepatitis B virus （HBV） constitutes a major global health problem. Although our knowledge about the molecular biology of these highly liver-specific viruses has profoundly increased in the last two decades, the mechanisms of attachment and productive entrance into the differentiated host hepatocytes are still enigmatic. The difficulties in studying hepadnaviral entry were primarily caused by the lack of easily accessible in vitro infection systems. Thus, for more than twenty years, differentiated primary hepatocytes from the respective species were the only in vitro models for both orthohepadnaviruses （e.g. HBV） and avihepadnaviruses （e.g. duck hepatitis B virus [DHBV]）. Two important discoveries have been made recently regarding HBV： （1） primary hepatoo/tes from tree-shrews; i.e., Tupaia belangeri, can be substituted for primary human hepatocytes, and （2） a human hepatoma cell line （HepaRG） was established that gains susceptibility for HBV infection upon induction of differentiation in vitro. A number of potential HBV receptor candidates have been described in the past, but none of them have been confirmed to function as a receptor. For DHBV and probably all other avian hepadnaviruses, carboxypeptidase D （CPD） has been shown to be indispensable for infection, although the exact role of this molecule is still under debate. While still restricted to the use of primary duck hepatocytes （PDH）, investigations performed with DHBV provided important general concepts on the first steps of hepadnaviral infection. However, with emerging data obtained from the new HBV infection systems, the hope that DHBV utilizes the same mechanism as HBV only partially held true. Nevertheless, both HBV and DHBV in vitro infection systems will help to： （1） 展开更多
AIM: To evaluate cut-off values and performance of acoustic radiation force impulse imaging (ARFI) using transient elastography [FibroScan■ (FS)] as a reference. METHODS: Six hundred and six patients were enrolled in...AIM: To evaluate cut-off values and performance of acoustic radiation force impulse imaging (ARFI) using transient elastography [FibroScan■ (FS)] as a reference. METHODS: Six hundred and six patients were enrolled in this study.All patients underwent liver stiffness measurement with FS (FS-LS) and ARFI (with shear wave velocity quantification; ARFI-SWV) and the performance of ARFI in comparison to FS was determined. Sixtyeight patients underwent liver biopsy. RESULTS: Significantly higher success rates for the determination of liver stiffness were found using ARFI as compared to FS [604/606 (99.7%) vs 482/606 (79.5%); P < 0.001]. ARFI-SWV correlated significantly with FS-LS (r = 0.920, P < 0.001). ARFI-SWV increased significantly with the stage of fibrosis (1.09 ± 0.13 m/s for patients with no significant fibrosis (FS-LS < 7.6 kPa); 1.46 ± 0.27 m/s for patients with significant liver fibrosis (7.6 < FS-LS ≤ 13.0 kPa); and 2.55 ± 0.77 m/s for patients with liver cirrhosis (FS-LS > 13.0 kPa)). ARFI-SWV cut-off values were identified for no significant fibrosis (1.29 m/s; sensitivity 91.4% and specificity 92.6%) and for liver cirrhosis (1.60 m/s; sensitivity 92.3% and specificity 96.5%). The optimal cut-off value for predicting liver fibrosis (F ≥ 2) was 1.32 m/s (sensitivity 87.0% and specificity 80.0%) and for liver cirrhosis (F4) 1.62 m/s (sensitivity 100% and specificity 85.7%), for patients who underwent liver biopsy. An excellent inter-and intraobserver reproducibility was observed for ARFI-SWV determinations. CONCLUSION: An ARFI-SWV cut-off value of 1.29 m/s seems to be optimal for patients with no significant liver fibrosis and 1.60 m/s for patients with liver cirrhosis.展开更多
AIM: To report 3 of 120 patients on the German MALT lymphoma trial with H. pylori associated gastric MALT lymphoma who developed early gastric cancer 4 and 5 years, after complete lymphoma remission following cure of ...AIM: To report 3 of 120 patients on the German MALT lymphoma trial with H. pylori associated gastric MALT lymphoma who developed early gastric cancer 4 and 5 years, after complete lymphoma remission following cure of H. pylori infection. PATIENTS AND RESULTS: Three patients (two men, 74 and 70 years; one women, 77 years) with H. pylori-associated low-grade MALT lymphoma achieved complete lymphoma remission after being cured. Surveillance endoscopies were performed twice a year in accordance to the protocol. Four years after complete lymphoma remission in two patients, and after 5 years in the other, early gastric adenocarcinoma of the mucosa-type, type IIa and type IIc, respectively, was detected, which were completely removed by endoscopic mucosa resection. In one patient, the gastric cancer was diagnosed at the same location as the previous MALT lymphoma, in the other patients it was detected at different sites of the stomach distant from location of the previous MALT lymphoma. The patients were H. pylori negative during the whole follow-up time. CONCLUSION: These findings strengthen the importance of regular Long-term follow-up endoscopies in patients with complete remission of gastric MALT lymphoma after cure of H. pylori infection. Furthermore, gastric adenocarcinoma may develop despite eradication of H. pylori.展开更多
The completely assembled human genome has made it possible for modern medicine to step into an era rich in genetic information and high-throughput genomic analysis. These novel and readily available genetic resources ...The completely assembled human genome has made it possible for modern medicine to step into an era rich in genetic information and high-throughput genomic analysis. These novel and readily available genetic resources and analytical tools may be the key to unravel the molecular basis of hepatocellular carcinoma (HCC). Moreover, since an efficient treatment for this disease is lacking, further understanding of the genetic background of HCC will be crucial in order to develop new therapies aimed at selected targets. We report on the current status and recent developments in HCC genetics. Special emphasis is given to the genetics and regulation of major signalling pathways involved in HCC such as p53, Wnt- signalling, TGFβ, Ras, and Rb pathways. Furthermore, we describe the influence of chromosomal aberrations as well as of DNA methylation. Finally, we report on the rapidly developing field of genomic expression profiling in HCC, mainly by microarray analysis.展开更多
This review describes the woodchuck and the woodchuck hepatitis virus (WHV) as an animal model for pathogenesis and therapy of chronic hepatitis B virus (HBV) infection and disease in humans. The establishment of wood...This review describes the woodchuck and the woodchuck hepatitis virus (WHV) as an animal model for pathogenesis and therapy of chronic hepatitis B virus (HBV) infection and disease in humans. The establishment of woodchuck breeding colonies, and use of laboratory-reared woodchucks infected with defined WHV inocula, have enhanced our understanding of the virology and immunology of HBV infection and disease pathogenesis, including major sequelae like chronic hepatitis and hepatocellular carcinoma. The role of persistent WHV infection and of viral load on the natural history of infection and disease progression has been firmly established along the way. More recently, the model has shed new light on the role of host immune responses in these natural processes, and on how the immune system of the chronic carrier can be manipulated therapeutically to reduce or delay serious disease sequelae through induction of the recovery phenotype. The woodchuck is an outbred species and is not well defined immunologically due to a limitation of available host markers. However, the recent development of several key host response assays for woodchucks provides experimental opportunities for further mechanistic studies of outcome predictors in neonatal- and adult-acquired infections. Understanding the virological and immunological mechanisms responsible for resolution of self-limited infection, andfor the onset and maintenance of chronic infection, will greatly facilitate the development of successful strategies for the therapeutic eradication of established chronic HBV infection. Likewise, the results of drug efficacy and toxicity studies in the chronic carrier woodchucks are predictive for responses of patients chronically infected with HBV. Therefore, chronic WHV carrier woodchucks provide a well-characterized mammalian model for preclinical evaluation of the safety and efficacy of drug candidates, experimental therapeutic vaccines, and immunomodulators for the treatment and prevention of HBV disease sequelae.展开更多
The occurrence of a large number of diverse arsenic species in the environment and in biological systems makes it important to compare their relative toxicity. The toxicity of arsenic species has been examined in vari...The occurrence of a large number of diverse arsenic species in the environment and in biological systems makes it important to compare their relative toxicity. The toxicity of arsenic species has been examined in various cell lines using different assays, making comparison difficult. We report real-time cell sensing of two human cell lines to examine the cytotoxicity of fourteen arsenic species： arsenite（As~Ⅲ）, monomethylarsonous acid（MMA~Ⅲ） originating from the oxide and iodide forms, dimethylarsinous acid（DMA~Ⅲ）, dimethylarsinic glutathione（DMAG~Ⅲ）, phenylarsine oxide（PAO~Ⅲ）, arsenate（AsV）, monomethylarsonic acid（MMA~Ⅴ）, dimethylarsinic acid（DMA~Ⅴ）,monomethyltrithioarsonate（MMTTA~Ⅴ）, dimethylmonothioarsinate（DMMTA~Ⅴ）,dimethyldithioarsinate（DMDTA~Ⅴ）, 3-nitro-4-hydroxyphenylarsonic acid（Roxarsone, Rox）,and 4-aminobenzenearsenic acid（p-arsanilic acid, p-ASA）. Cellular responses were measured in real time for 72 hr in human lung（A549） and bladder（T24） cells. IC50 values for the arsenicals were determined continuously over the exposure time, giving rise to IC50 histograms and unique cell response profiles. Arsenic accumulation and speciation were analyzed using inductively coupled plasma-mass spectrometry（ICP-MS）. On the basis of the 24-hr IC50 values, the relative cytotoxicity of the tested arsenicals was in the following decreasing order： PAO~Ⅲ？ MMA~Ⅲ≥ DMA~Ⅲ≥ DMAG~Ⅲ≈ DMMTA~Ⅴ≥ As~Ⅲ？ MMTTA~Ⅴ〉 AsV〉 DMDTA~Ⅴ〉DMA~Ⅴ〉 MMA~Ⅴ≥ Rox ≥ p-ASA. Stepwise shapes of cell response profiles for DMA~Ⅲ, DMAG~Ⅲ,and DMMTA~Ⅴcoincided with the conversion of these arsenicals to the less toxic pentavalent DMA~Ⅴ. Dynamic monitoring of real-time cellular responses to fourteen arsenicals provided useful information for comparison of their relative cytotoxicity.展开更多
Autoimmune hepatitis (AIH) is a necroinflammatory liver disease of unknown etiology that occurs in children and adults of all ages. Characteristics are its autoimmune features,hyperglobulinemia (IgG),and the presence ...Autoimmune hepatitis (AIH) is a necroinflammatory liver disease of unknown etiology that occurs in children and adults of all ages. Characteristics are its autoimmune features,hyperglobulinemia (IgG),and the presence of circulating autoantibodies,as well as a response to immunosuppressant drugs. Current treatment consists of prednisone and azathioprine and in most patients this disease has become very treatable. Over the past 2 years,a couple of new insights into the genetic aspects,clinical course and treatment of AIH have been reported,which will be the focus of this review. In particular,we concentrate on genome-wide microsatellite analysis,a novel mouse model of AIH,the evaluation of a large AIH cohort for overlap syndromes,suggested novel criteria for the diagnosis of AIH,and the latest studies on treatment of AIH with budenoside and mycophenolate mofetil.展开更多
We present an Euler-Lagrange method for the simulation of wood gasification in a bubbling fluidized bed. The gas phase is modeled as a continuum using the 2D Navier-Stokes equations and the solid phase is modeled by a...We present an Euler-Lagrange method for the simulation of wood gasification in a bubbling fluidized bed. The gas phase is modeled as a continuum using the 2D Navier-Stokes equations and the solid phase is modeled by a Discrete Element Method （DEM） using a soft-sphere approach for the particle collision dynamic. Turbulence is included via a Large-Eddy approach using the Smagorinsky sub-grid model. The model takes into account detailed gas phase chemistry, zero-dimensional modeling of the pyrolysis and gasification of each individual particle, particle shrinkage, and heat and mass transfer between the gas phase and the particulate phase. We investigate the influence of wood feeding rate and compare exhaust gas compositions and temperature results obtained with the model against experimental data of a laboratory scale bubbling fiuidized bed reactor.展开更多
AIM: To evaluate the role of CDX2 homeobox protein as a predictor for cancer progression and prognosis as well as its correlation with MUC2 expression. CDX2 represents a transcription factor for various intestinal gen...AIM: To evaluate the role of CDX2 homeobox protein as a predictor for cancer progression and prognosis as well as its correlation with MUC2 expression. CDX2 represents a transcription factor for various intestinal genes (including MUC2) and thus an important regulator of intestinal differentiation, which could previously be identified in gastric carcinomas and intestinal metaplasia. METHODS: Formalin-fixed and paraffin-embedded tissues from 190 gastric carcinoma patients were stained with monodonal antibodies recognizing CDX2 and MUC2, respectively. Immunoreactivity was evaluated semiquantitatively and statistical analyses including x2 tests, uni- and multi-variate survival analyses were performed. RESULTS: CDX2 was mostly expressed in a nuclear or supranuclear pattern,whereas MUC2 showed an almost exclusive supranuclear reactivity.Both antigens were present in >80% of areas exhibiting intestinal metaplasia. An immunoreactivity in >5% of the tumor area was observed in 57% (CDX2) or in 21% (MUC2) of the carcinomas.The presence of both molecules did not correlate with WHO, Lauren and Goseki classification (with the exception of a significantly stronger MUC2 expression in mucinous tumors). CDX2 correlated with a lower pT and pN stage in the subgroups of intestinal and stage I cancers and was associated with MUC2 positivity.A prognostic impact of CDX2 or MUC2 was not observed. CONCLUSION: CDX2 and MUC2 play an important role in the differentiation of normal, inflamed, and neoplastic gastric tissues. According to our results, loss of CDX2 may represent a marker of tumor progression in early gastric cancer and carcinomas with an intestinal phenotype.展开更多
AIM: To report the long-term outcome of patients after complete ablation of non-neoplastic Barrett's esophagus (BE) with respect to BE relapse and development of intraepithelial neoplasia or esophageal adenocarcin...AIM: To report the long-term outcome of patients after complete ablation of non-neoplastic Barrett's esophagus (BE) with respect to BE relapse and development of intraepithelial neoplasia or esophageal adenocarcinoma. METHODS: In 70 patients with historically proven non neoplastic BE, complete BE ablation was achieved by argon plasma coagulation (APC) and high-dose proton pump inhibitor therapy (120 mg omeprazole daily). Sixty-six patients (94.4%) underwent further surveillance endoscopy. At each surveillance endoscopy four-quadrant biopsies were taken from the neo-squamous epithelium at 2 cm intervals depending on the pre-treatment length of BE mucosa beginning at the neo-Z-line, and from any endoscopically suspicious lesion. RESULTS: The median follow-up of 66 patients was 51 mo (range 9-85 mo) giving a total of 280.5 patient years. A mean of 6 biopsies were taken during surveillance endoscopies. In 13 patients (19.7%) tongues or islands suspicious for BE were found during endoscopy. In 8 of these patients (12.1%) non-neoplastic BE relapse was confirmed histologically giving a histological relapse rate of 3% per year. In none of the patients, intraepithelial neoplasia nor an esophageal adenocarcinoma was detected. Logistic regression analysis identified endoscopic detection of islands or tongues as the only positive predictor of BE relapse (P= 0.0004). CONCLUSION: The long-term relapse rate of non neoplastic BE following complete ablation with high-power APC is low (3% per year).展开更多
Plant secondary metabolites play vital role in plant stress response. In this study we investigated whether root colonization of tomato （Solanum lycopersicum） infected by Trichoderma harzianum leads to alterations i...Plant secondary metabolites play vital role in plant stress response. In this study we investigated whether root colonization of tomato （Solanum lycopersicum） infected by Trichoderma harzianum leads to alterations in the biosynthesis of secondary plant metabolites including phytohormones and osmolyte proline under drought stress. Exposure of tomato to drought caused a drastic decline in plant growth and physiological parameters. Tomato inoculated with T. harzianum showed increased root and shoot growth and chlorophyll pigments as compared to uninoculated controls as well as drought stressed plants. Proline and total soluble protein content was increased in plants inoculated with T. harzianum under both normal as well as drought conditions. An obvious increase in phenol and flavonoid content was observed due to T. haczianum. In addition, T. hat-zianum inoculated plants maintained higher levels of growth regulators indole acetic acid, indole butyric acid, and gibberellic acid under drought stress. Improved secondary metabolites which play an important role in plant stress tolerance by T. hat-zianum may have coordinately worked for bringing the growth regulation by protecting membranes from reactive oxygen species （ROS） and enhance plant growth through accessing more nutrients by root system.展开更多
AIM:To assess and correlate the lipid content of various organs in obese subjects and in persons with a normal body weight.METHODS:Magnetic resonance spectroscopy and a previously validated gradient echo magnetic reso...AIM:To assess and correlate the lipid content of various organs in obese subjects and in persons with a normal body weight.METHODS:Magnetic resonance spectroscopy and a previously validated gradient echo magnetic resonance imaging method with Dixon's two point technique were used in this study to quantify fat in liver,pancreas as well as kidney.RESULTS:In 36 volunteers with body mass index(BMI) ranging from 20.0 to 42.9 kg/m2,the median fat content of liver,pancreas and kidney was 2.3%(interquartile range:0.2%-7.8%),2.7%(1.0%-6.5%) and 0.7%(0.1%-1.4%),respectively.BMI and subcutaneous fat correlated significantly with liver and pancreas fat content.We show for the first time the significant correlation of liver and pancreas fat content in healthy controls(r = 0.43,P < 0.01).These observations are related to body weight as measured by BMI and the amount of subcutaneous fat.Kidney fat content is very low and correlates with none of the other fat depots.CONCLUSION:Renal lipid accumulation,unlike the coupled accumulations of fat in liver and pancreas,is not observed in obese subjects.Unlike suggestions made in previous studies,renal lipid accumulation appears not to be involved in the pathogenesis of renal disease in humans.展开更多
Gastric mucosa associated lymphoid tissue （MALT） lymphoma has recently been incorporated into the World Health Organization （WHO） lymphoma classification, termed as extranodal marginal zone B-cell lymphoma of MALT...Gastric mucosa associated lymphoid tissue （MALT） lymphoma has recently been incorporated into the World Health Organization （WHO） lymphoma classification, termed as extranodal marginal zone B-cell lymphoma of MALT-type. In about 90% of cases this lymphoma is associated with H pylori infection which has been dearly shown to play a causative role in lymphomagenesis. Although much knowledge has been gained in defining the clinical features, natural history, pathology, and molecular genetics of the disease in the last decade, the optimal treatment approach for gastric MALT lymphomas, especially locally advanced cases, is still evolving. In this review we focus on data for the therapeutic, stage dependent management of gastric MALT lymphoma. Hence, the role of eradication therapy, surgery, chemotherapy and radiotherapy is critically analyzed. Based on these data, we suggest a therapeutic algorithm that might help to better stratify patients for optimal treatment success.展开更多
Heme oxygenase (HO)-1 is the inducible isoform of the first and rate-limiting enzyme of heme degradation. HO-1 not only protects against oxidative stress and apoptosis, but has received a great deal of attention in re...Heme oxygenase (HO)-1 is the inducible isoform of the first and rate-limiting enzyme of heme degradation. HO-1 not only protects against oxidative stress and apoptosis, but has received a great deal of attention in recent years because ofits potent anti-inflammatory functions. Studies with HO-1 knockout animal models have led to major advances in the understanding of how HO-1 might regulate inflammatory immune responses, although little is known on the underlying mechanisms. Due to its beneficial effects the targeted induction of this enzyme is considered to have major therapeutic po- tential for the treatment ofinflammatory disorders. This review discusses current knowledge on the mechanisms that mediate anti-inflammatory protection by HO-1. More specifically, the article deals with the role of HO-1 in the pathophysiology of viral hepatitis, inflammatorybowel disease, and pancreatitis. The effects of specific HO-1 modulation as a potential therapeutic strategy in experimental cell culture and animal models of these gastrointestinal disorders are summarized. In conclusion, targeted regulation of HO-1 holds major promise for future clinical interventions in inflammatory diseases of the gastrointestinal tract.展开更多
基金the U.S.Department of Energy,Office of Science,Office of Basic Energy Sciences under Award Number DE-SC00010543(JWD)the Ford-Boeing-Northwestern Alliance(JES)+2 种基金support by DOE under Grant No.DE-FG02-07ER46433(BM and AT)The Dow Chemical Company(MA)and the National Science Foundation under grant DRL-1348800(CW)supported by the Office of Science of the U.S.Department of Energy under Contract No.DE-AC02-05CH11231.
文摘The Open Quantum Materials Database(OQMD)is a high-throughput database currently consisting of nearly 300,000 density functional theory(DFT)total energy calculations of compounds from the Inorganic Crystal Structure Database(ICSD)and decorations of commonly occurring crystal structures.To maximise the impact of these data,the entire database is being made available,without restrictions,at www.oqmd.org/download.In this paper,we outline the structure and contents of the database,and then use it to evaluate the accuracy of the calculations therein by comparing DFT predictions with experimental measurements for the stability of all elemental ground-state structures and 1,670 experimental formation energies of compounds.This represents the largest comparison between DFT and experimental formation energies to date.The apparent mean absolute error between experimental measurements and our calculations is 0.096 eV/atom.In order to estimate how much error to attribute to the DFT calculations,we also examine deviation between different experimental measurements themselves where multiple sources are available,and find a surprisingly large mean absolute error of 0.082 eV/atom.Hence,we suggest that a significant fraction of the error between DFT and experimental formation energies may be attributed to experimental uncertainties.Finally,we evaluate the stability of compounds in the OQMD(including compounds obtained from the ICSD as well as hypothetical structures),which allows us to predict the existence of~3,200 new compounds that have not been experimentally characterised and uncover trends in material discovery,based on historical data available within the ICSD.
文摘Crohn＇s disease and ulcerative colitis are chronic relapsing immune mediated disorders that results from an aberrant response to gut luminal antigen in genetically susceptible host. The adaptive immune response that is then triggered was widely considered to be a T-helper-1 mediated condition in Crohn＇s disease and T-helpero2 mediated condition in ulcerative colitis. Recent studies in animal models, genome wide association, and basic science has provided important insights in in the immunopathogenesis of inflammatory bowel disease, one of which was the characterization of the interleukin-23/Th-17 axis.
文摘Hepatitis B virus(HBV) is a member of the hepadnavirus family.Hepadnaviruses can be found in both mammals(orthohepadnaviruses) and birds(avihepadnaviruses).The genetic variability of HBV is very high.There are eight genotypes of HBV and three clades of HBV isolates from apes that appear to be additional genotypes of HBV.Most genotypes are now divided into subgenotypes with distinct virological and epidemiological properties.In addition,recombination among HBV genotypes increases the variability of HBV.This review summarises current knowledge of the epidemiology of genetic variability in hepadnaviruses and,due to rapid progress in the field,updates several recent reviews on HBV genotypes and subgenotypes.
基金Supported by grant SFB535/A2 from DFG, EU QLK 2000- 01476 and DFG UR72/1-3, UR72/1-4
文摘Hepadnaviridae is a family of hepatotropic DNA viruses that is divided into the genera orthohepadnavirus of mammals and avihepadnavirus of birds. All members of this family can cause acute and chronic hepatic infection, which in the case of human hepatitis B virus （HBV） constitutes a major global health problem. Although our knowledge about the molecular biology of these highly liver-specific viruses has profoundly increased in the last two decades, the mechanisms of attachment and productive entrance into the differentiated host hepatocytes are still enigmatic. The difficulties in studying hepadnaviral entry were primarily caused by the lack of easily accessible in vitro infection systems. Thus, for more than twenty years, differentiated primary hepatocytes from the respective species were the only in vitro models for both orthohepadnaviruses （e.g. HBV） and avihepadnaviruses （e.g. duck hepatitis B virus [DHBV]）. Two important discoveries have been made recently regarding HBV： （1） primary hepatoo/tes from tree-shrews; i.e., Tupaia belangeri, can be substituted for primary human hepatocytes, and （2） a human hepatoma cell line （HepaRG） was established that gains susceptibility for HBV infection upon induction of differentiation in vitro. A number of potential HBV receptor candidates have been described in the past, but none of them have been confirmed to function as a receptor. For DHBV and probably all other avian hepadnaviruses, carboxypeptidase D （CPD） has been shown to be indispensable for infection, although the exact role of this molecule is still under debate. While still restricted to the use of primary duck hepatocytes （PDH）, investigations performed with DHBV provided important general concepts on the first steps of hepadnaviral infection. However, with emerging data obtained from the new HBV infection systems, the hope that DHBV utilizes the same mechanism as HBV only partially held true. Nevertheless, both HBV and DHBV in vitro infection systems will help to： （1）
文摘AIM: To evaluate cut-off values and performance of acoustic radiation force impulse imaging (ARFI) using transient elastography [FibroScan■ (FS)] as a reference. METHODS: Six hundred and six patients were enrolled in this study.All patients underwent liver stiffness measurement with FS (FS-LS) and ARFI (with shear wave velocity quantification; ARFI-SWV) and the performance of ARFI in comparison to FS was determined. Sixtyeight patients underwent liver biopsy. RESULTS: Significantly higher success rates for the determination of liver stiffness were found using ARFI as compared to FS [604/606 (99.7%) vs 482/606 (79.5%); P < 0.001]. ARFI-SWV correlated significantly with FS-LS (r = 0.920, P < 0.001). ARFI-SWV increased significantly with the stage of fibrosis (1.09 ± 0.13 m/s for patients with no significant fibrosis (FS-LS < 7.6 kPa); 1.46 ± 0.27 m/s for patients with significant liver fibrosis (7.6 < FS-LS ≤ 13.0 kPa); and 2.55 ± 0.77 m/s for patients with liver cirrhosis (FS-LS > 13.0 kPa)). ARFI-SWV cut-off values were identified for no significant fibrosis (1.29 m/s; sensitivity 91.4% and specificity 92.6%) and for liver cirrhosis (1.60 m/s; sensitivity 92.3% and specificity 96.5%). The optimal cut-off value for predicting liver fibrosis (F ≥ 2) was 1.32 m/s (sensitivity 87.0% and specificity 80.0%) and for liver cirrhosis (F4) 1.62 m/s (sensitivity 100% and specificity 85.7%), for patients who underwent liver biopsy. An excellent inter-and intraobserver reproducibility was observed for ARFI-SWV determinations. CONCLUSION: An ARFI-SWV cut-off value of 1.29 m/s seems to be optimal for patients with no significant liver fibrosis and 1.60 m/s for patients with liver cirrhosis.
文摘AIM: To report 3 of 120 patients on the German MALT lymphoma trial with H. pylori associated gastric MALT lymphoma who developed early gastric cancer 4 and 5 years, after complete lymphoma remission following cure of H. pylori infection. PATIENTS AND RESULTS: Three patients (two men, 74 and 70 years; one women, 77 years) with H. pylori-associated low-grade MALT lymphoma achieved complete lymphoma remission after being cured. Surveillance endoscopies were performed twice a year in accordance to the protocol. Four years after complete lymphoma remission in two patients, and after 5 years in the other, early gastric adenocarcinoma of the mucosa-type, type IIa and type IIc, respectively, was detected, which were completely removed by endoscopic mucosa resection. In one patient, the gastric cancer was diagnosed at the same location as the previous MALT lymphoma, in the other patients it was detected at different sites of the stomach distant from location of the previous MALT lymphoma. The patients were H. pylori negative during the whole follow-up time. CONCLUSION: These findings strengthen the importance of regular Long-term follow-up endoscopies in patients with complete remission of gastric MALT lymphoma after cure of H. pylori infection. Furthermore, gastric adenocarcinoma may develop despite eradication of H. pylori.
文摘The completely assembled human genome has made it possible for modern medicine to step into an era rich in genetic information and high-throughput genomic analysis. These novel and readily available genetic resources and analytical tools may be the key to unravel the molecular basis of hepatocellular carcinoma (HCC). Moreover, since an efficient treatment for this disease is lacking, further understanding of the genetic background of HCC will be crucial in order to develop new therapies aimed at selected targets. We report on the current status and recent developments in HCC genetics. Special emphasis is given to the genetics and regulation of major signalling pathways involved in HCC such as p53, Wnt- signalling, TGFβ, Ras, and Rb pathways. Furthermore, we describe the influence of chromosomal aberrations as well as of DNA methylation. Finally, we report on the rapidly developing field of genomic expression profiling in HCC, mainly by microarray analysis.
基金Supported by contract N01-AI-05399 to the College of Veterinary Medicine, Cornell University from the National Institute of Allergy and Infectious Diseases. PC and SM also have been supported by contract N01-AI-95390 to the Georgetown University Medical Center, Georgetown University from the National Institute of Allergy and Infectious Diseases
文摘This review describes the woodchuck and the woodchuck hepatitis virus (WHV) as an animal model for pathogenesis and therapy of chronic hepatitis B virus (HBV) infection and disease in humans. The establishment of woodchuck breeding colonies, and use of laboratory-reared woodchucks infected with defined WHV inocula, have enhanced our understanding of the virology and immunology of HBV infection and disease pathogenesis, including major sequelae like chronic hepatitis and hepatocellular carcinoma. The role of persistent WHV infection and of viral load on the natural history of infection and disease progression has been firmly established along the way. More recently, the model has shed new light on the role of host immune responses in these natural processes, and on how the immune system of the chronic carrier can be manipulated therapeutically to reduce or delay serious disease sequelae through induction of the recovery phenotype. The woodchuck is an outbred species and is not well defined immunologically due to a limitation of available host markers. However, the recent development of several key host response assays for woodchucks provides experimental opportunities for further mechanistic studies of outcome predictors in neonatal- and adult-acquired infections. Understanding the virological and immunological mechanisms responsible for resolution of self-limited infection, andfor the onset and maintenance of chronic infection, will greatly facilitate the development of successful strategies for the therapeutic eradication of established chronic HBV infection. Likewise, the results of drug efficacy and toxicity studies in the chronic carrier woodchucks are predictive for responses of patients chronically infected with HBV. Therefore, chronic WHV carrier woodchucks provide a well-characterized mammalian model for preclinical evaluation of the safety and efficacy of drug candidates, experimental therapeutic vaccines, and immunomodulators for the treatment and prevention of HBV disease sequelae.
基金supported by Alberta Health, Alberta Innovates, the Canada Research Chairs Programthe Canadian Institutes of Health Research (CIHR)the Natural Sciences and Engineering Research Council (NSERC) of Canada
文摘The occurrence of a large number of diverse arsenic species in the environment and in biological systems makes it important to compare their relative toxicity. The toxicity of arsenic species has been examined in various cell lines using different assays, making comparison difficult. We report real-time cell sensing of two human cell lines to examine the cytotoxicity of fourteen arsenic species： arsenite（As~Ⅲ）, monomethylarsonous acid（MMA~Ⅲ） originating from the oxide and iodide forms, dimethylarsinous acid（DMA~Ⅲ）, dimethylarsinic glutathione（DMAG~Ⅲ）, phenylarsine oxide（PAO~Ⅲ）, arsenate（AsV）, monomethylarsonic acid（MMA~Ⅴ）, dimethylarsinic acid（DMA~Ⅴ）,monomethyltrithioarsonate（MMTTA~Ⅴ）, dimethylmonothioarsinate（DMMTA~Ⅴ）,dimethyldithioarsinate（DMDTA~Ⅴ）, 3-nitro-4-hydroxyphenylarsonic acid（Roxarsone, Rox）,and 4-aminobenzenearsenic acid（p-arsanilic acid, p-ASA）. Cellular responses were measured in real time for 72 hr in human lung（A549） and bladder（T24） cells. IC50 values for the arsenicals were determined continuously over the exposure time, giving rise to IC50 histograms and unique cell response profiles. Arsenic accumulation and speciation were analyzed using inductively coupled plasma-mass spectrometry（ICP-MS）. On the basis of the 24-hr IC50 values, the relative cytotoxicity of the tested arsenicals was in the following decreasing order： PAO~Ⅲ？ MMA~Ⅲ≥ DMA~Ⅲ≥ DMAG~Ⅲ≈ DMMTA~Ⅴ≥ As~Ⅲ？ MMTTA~Ⅴ〉 AsV〉 DMDTA~Ⅴ〉DMA~Ⅴ〉 MMA~Ⅴ≥ Rox ≥ p-ASA. Stepwise shapes of cell response profiles for DMA~Ⅲ, DMAG~Ⅲ,and DMMTA~Ⅴcoincided with the conversion of these arsenicals to the less toxic pentavalent DMA~Ⅴ. Dynamic monitoring of real-time cellular responses to fourteen arsenicals provided useful information for comparison of their relative cytotoxicity.
文摘Autoimmune hepatitis (AIH) is a necroinflammatory liver disease of unknown etiology that occurs in children and adults of all ages. Characteristics are its autoimmune features,hyperglobulinemia (IgG),and the presence of circulating autoantibodies,as well as a response to immunosuppressant drugs. Current treatment consists of prednisone and azathioprine and in most patients this disease has become very treatable. Over the past 2 years,a couple of new insights into the genetic aspects,clinical course and treatment of AIH have been reported,which will be the focus of this review. In particular,we concentrate on genome-wide microsatellite analysis,a novel mouse model of AIH,the evaluation of a large AIH cohort for overlap syndromes,suggested novel criteria for the diagnosis of AIH,and the latest studies on treatment of AIH with budenoside and mycophenolate mofetil.
文摘We present an Euler-Lagrange method for the simulation of wood gasification in a bubbling fluidized bed. The gas phase is modeled as a continuum using the 2D Navier-Stokes equations and the solid phase is modeled by a Discrete Element Method （DEM） using a soft-sphere approach for the particle collision dynamic. Turbulence is included via a Large-Eddy approach using the Smagorinsky sub-grid model. The model takes into account detailed gas phase chemistry, zero-dimensional modeling of the pyrolysis and gasification of each individual particle, particle shrinkage, and heat and mass transfer between the gas phase and the particulate phase. We investigate the influence of wood feeding rate and compare exhaust gas compositions and temperature results obtained with the model against experimental data of a laboratory scale bubbling fiuidized bed reactor.
文摘AIM: To evaluate the role of CDX2 homeobox protein as a predictor for cancer progression and prognosis as well as its correlation with MUC2 expression. CDX2 represents a transcription factor for various intestinal genes (including MUC2) and thus an important regulator of intestinal differentiation, which could previously be identified in gastric carcinomas and intestinal metaplasia. METHODS: Formalin-fixed and paraffin-embedded tissues from 190 gastric carcinoma patients were stained with monodonal antibodies recognizing CDX2 and MUC2, respectively. Immunoreactivity was evaluated semiquantitatively and statistical analyses including x2 tests, uni- and multi-variate survival analyses were performed. RESULTS: CDX2 was mostly expressed in a nuclear or supranuclear pattern,whereas MUC2 showed an almost exclusive supranuclear reactivity.Both antigens were present in >80% of areas exhibiting intestinal metaplasia. An immunoreactivity in >5% of the tumor area was observed in 57% (CDX2) or in 21% (MUC2) of the carcinomas.The presence of both molecules did not correlate with WHO, Lauren and Goseki classification (with the exception of a significantly stronger MUC2 expression in mucinous tumors). CDX2 correlated with a lower pT and pN stage in the subgroups of intestinal and stage I cancers and was associated with MUC2 positivity.A prognostic impact of CDX2 or MUC2 was not observed. CONCLUSION: CDX2 and MUC2 play an important role in the differentiation of normal, inflamed, and neoplastic gastric tissues. According to our results, loss of CDX2 may represent a marker of tumor progression in early gastric cancer and carcinomas with an intestinal phenotype.
文摘AIM: To report the long-term outcome of patients after complete ablation of non-neoplastic Barrett's esophagus (BE) with respect to BE relapse and development of intraepithelial neoplasia or esophageal adenocarcinoma. METHODS: In 70 patients with historically proven non neoplastic BE, complete BE ablation was achieved by argon plasma coagulation (APC) and high-dose proton pump inhibitor therapy (120 mg omeprazole daily). Sixty-six patients (94.4%) underwent further surveillance endoscopy. At each surveillance endoscopy four-quadrant biopsies were taken from the neo-squamous epithelium at 2 cm intervals depending on the pre-treatment length of BE mucosa beginning at the neo-Z-line, and from any endoscopically suspicious lesion. RESULTS: The median follow-up of 66 patients was 51 mo (range 9-85 mo) giving a total of 280.5 patient years. A mean of 6 biopsies were taken during surveillance endoscopies. In 13 patients (19.7%) tongues or islands suspicious for BE were found during endoscopy. In 8 of these patients (12.1%) non-neoplastic BE relapse was confirmed histologically giving a histological relapse rate of 3% per year. In none of the patients, intraepithelial neoplasia nor an esophageal adenocarcinoma was detected. Logistic regression analysis identified endoscopic detection of islands or tongues as the only positive predictor of BE relapse (P= 0.0004). CONCLUSION: The long-term relapse rate of non neoplastic BE following complete ablation with high-power APC is low (3% per year).
基金the Deanship of Scientific Research at King Saud University,Saudi Arabia(RGP-271)
文摘Plant secondary metabolites play vital role in plant stress response. In this study we investigated whether root colonization of tomato （Solanum lycopersicum） infected by Trichoderma harzianum leads to alterations in the biosynthesis of secondary plant metabolites including phytohormones and osmolyte proline under drought stress. Exposure of tomato to drought caused a drastic decline in plant growth and physiological parameters. Tomato inoculated with T. harzianum showed increased root and shoot growth and chlorophyll pigments as compared to uninoculated controls as well as drought stressed plants. Proline and total soluble protein content was increased in plants inoculated with T. harzianum under both normal as well as drought conditions. An obvious increase in phenol and flavonoid content was observed due to T. haczianum. In addition, T. hat-zianum inoculated plants maintained higher levels of growth regulators indole acetic acid, indole butyric acid, and gibberellic acid under drought stress. Improved secondary metabolites which play an important role in plant stress tolerance by T. hat-zianum may have coordinately worked for bringing the growth regulation by protecting membranes from reactive oxygen species （ROS） and enhance plant growth through accessing more nutrients by root system.
文摘AIM:To assess and correlate the lipid content of various organs in obese subjects and in persons with a normal body weight.METHODS:Magnetic resonance spectroscopy and a previously validated gradient echo magnetic resonance imaging method with Dixon's two point technique were used in this study to quantify fat in liver,pancreas as well as kidney.RESULTS:In 36 volunteers with body mass index(BMI) ranging from 20.0 to 42.9 kg/m2,the median fat content of liver,pancreas and kidney was 2.3%(interquartile range:0.2%-7.8%),2.7%(1.0%-6.5%) and 0.7%(0.1%-1.4%),respectively.BMI and subcutaneous fat correlated significantly with liver and pancreas fat content.We show for the first time the significant correlation of liver and pancreas fat content in healthy controls(r = 0.43,P < 0.01).These observations are related to body weight as measured by BMI and the amount of subcutaneous fat.Kidney fat content is very low and correlates with none of the other fat depots.CONCLUSION:Renal lipid accumulation,unlike the coupled accumulations of fat in liver and pancreas,is not observed in obese subjects.Unlike suggestions made in previous studies,renal lipid accumulation appears not to be involved in the pathogenesis of renal disease in humans.
文摘Gastric mucosa associated lymphoid tissue （MALT） lymphoma has recently been incorporated into the World Health Organization （WHO） lymphoma classification, termed as extranodal marginal zone B-cell lymphoma of MALT-type. In about 90% of cases this lymphoma is associated with H pylori infection which has been dearly shown to play a causative role in lymphomagenesis. Although much knowledge has been gained in defining the clinical features, natural history, pathology, and molecular genetics of the disease in the last decade, the optimal treatment approach for gastric MALT lymphomas, especially locally advanced cases, is still evolving. In this review we focus on data for the therapeutic, stage dependent management of gastric MALT lymphoma. Hence, the role of eradication therapy, surgery, chemotherapy and radiotherapy is critically analyzed. Based on these data, we suggest a therapeutic algorithm that might help to better stratify patients for optimal treatment success.
基金Supported by Grant SFB547 A8 from the Deutsche Forschun-gsgemeinschaft (to Immenschuh S)
文摘Heme oxygenase (HO)-1 is the inducible isoform of the first and rate-limiting enzyme of heme degradation. HO-1 not only protects against oxidative stress and apoptosis, but has received a great deal of attention in recent years because ofits potent anti-inflammatory functions. Studies with HO-1 knockout animal models have led to major advances in the understanding of how HO-1 might regulate inflammatory immune responses, although little is known on the underlying mechanisms. Due to its beneficial effects the targeted induction of this enzyme is considered to have major therapeutic po- tential for the treatment ofinflammatory disorders. This review discusses current knowledge on the mechanisms that mediate anti-inflammatory protection by HO-1. More specifically, the article deals with the role of HO-1 in the pathophysiology of viral hepatitis, inflammatorybowel disease, and pancreatitis. The effects of specific HO-1 modulation as a potential therapeutic strategy in experimental cell culture and animal models of these gastrointestinal disorders are summarized. In conclusion, targeted regulation of HO-1 holds major promise for future clinical interventions in inflammatory diseases of the gastrointestinal tract.
