p53 DNA结合域与抗癌多肽的拉伸分子动力学研究(英文)

研究发现,取自蓝铜蛋白azurin的一段多肽p28能够进入癌细胞,结合到肿瘤抑制因子p53的DNA结合域上,进而增加p53的抗癌能力.本工作中,通过拉伸分子动力学方法,在原子尺度上研究了p28-p53 DBD复合物的解离过程.分析结果显示复合物的解离过程遵循着一定的分离顺序.对解离力的分析以及对沿着解离路径的不可逆做功的计算,使我们能够从复合物的能量地貌中提取有用的信息,而这些信息也决定了复合物的解离过程.

Management of pain in chronic pancreatitis with emphasis on exogenous pancreatic enzymes

One of the most challenging issues arising in patients with chronic pancreatitis is the management of abdominal pain. Many competing theories exist to explain pancreatic pain including ductal hypertension from strictures and stones, increased interstitial pressure from glandular fibrosis, pancreatic neuritis, and ischemia. This clinical problem is superimposed on a background of reduced enzyme secretion and altered feedback mechanisms. Throughout history, investigators have used these theories to devise methods to combat chronic pancreatic pain including: Lifestyle measures, antioxidants, analgesics, administration of exogenous pancreatic enzymes, endo-scopic drainage procedures, and surgical drainage and resection procedures. While the value of each modality has been debated over the years, pancreatic enzyme therapy remains a viable option. Enzyme therapy restores active enzymes to the small bowel and targets the altered feedback mechanism that lead to increased pancreatic ductal and tissue pressures, ischemia, and pain. Here, we review the mechanisms and treatments for chronic pancreatic pain with a specific focus on pancreatic enzyme replacement therapy. We also discuss different approaches to overcoming a lack of clinical response update ideas for studies needed to improve the clinical use of pancreatic enzymes to ameliorate pancreatic pain.

Impact of all oral anti-hepatitis C virus therapy:A metaanalysis

AIM:To investigate the efficacy,safety,and cost of treatment of direct acting antivirals(DAAs) with and without peg interferon alfa2a(P),and/or ribavirin(R) in treating hepatitis C virus(HCV) genotype 1 patients.METHODS:MEDLINE was searched for randomized controlled trials(RCT) using DAAs for HCV treatment.Phase 1 trials and studies with investigational drugs on genotype 2 or 3,and on human immunodeficiency virus patients were excluded.Data were pooled for sustained virologic response(SVR),serious adverse effects,and drug discontinuation rate on various treatment arms in trials:P + R;1st generation DAA(telaprevir or boceprevir) + P + R;2nd generation DAA(sofosbuvir or simeprevir) + P + R;2nd generation DAA + R;two 2nd generation DAA + R;and two 2nd gen DAA.Data were analyzed separately for each arm for treatment naive and non-responders(NR) to previous treatment.The cost of treatment with each regimen for achieving one SVR was also compared.RESULTS:Twenty three RCTs(n = 9354,62% male,11% cirrhosis) were analyzed.All oral(P free) regimens with combination of 2 DAA achieved SVR above 95%.The cost of treatment to achieve an SVR with DAA based regimens was lower for NR compared to P+R regimen.However,the cost per SVR remained higher for treatment naive patients.CONCLUSION:Second generation and emerging DAAs are promising agents in HCV treatment,with a very high level of safety and efficacy.An important drawback is their high cost.However,the present meta-analysis shows that the cost per SVR for non responders(but not for naive patients) was lower compared to P + R.This finding together with the superior safety profile and better compliance makes these drugs highly attractive.It is possible that further reduction in treatment duration may make them even more cost effective.

Use and barriers to chromoendoscopy for dysplasia surveillance in inflammatory bowel disease

Traditionally,patients with inflammatory bowel disease(IBD) have been thought to be at increased risk of developing colitis-associated colorectal cancer.Although there are recent data suggesting that rates of colitisassociated cancer in IBD patients is declining,current guidelines still recommend regular dysplasia surveillance for early detection and prevention of neoplasia in patients with IBD.White-light endoscopy with random biopsies has been the traditional approach for dysplasia detection;however,newer technologies and approaches have emerged.One method,dye-based chromoendoscopy,has the potential to detect more dysplasia.However,longitudinal data to showing a benefit in morbidity or mortality from the use of chromoendoscopy are still lacking.Many societies have included recommendation on the use of chromoendoscopy with targeted biopsies as a method of surveillance for colitis-associated colorectal cancer.This narrative review seeks to outline data on dysplasia detection as well as barriers to the implementation of dye-based chromoendoscopy for the prevention and early detection of colitis-associated colorectal cancer.

Adherence to cardiovascular medications in the South Asian population:A systematic review of current evidence and future directions

AIM: To review methods of assessing adherence and strategies to improve adherence to cardiovascular disease(CVD) medications,among South Asian CVD patients. METHODS: We conducted a systematic review of English language studies that examined CVD medication adherence in South Asian populations from 1966 to April 1,2015 in SCOPUS and Pub Med. Working in duplicate,we identified 61 studies. After exclusions,26 studies were selected for full text review. Of these,17 studies were included in the final review. We abstracted data on several factors including study design,study population,method of assessing adherence and adherence rate. RESULTS: These studies were conducted in India(n = 11),Pakistan(n = 3),Bangladesh(n = 1),Nepal(n = 1) and Sri Lanka(n = 1). Adherence rates ranged from 32%-95% across studies. Of the 17 total publications included,10 focused on assessing adherence to CVD medications and 7 focused on assessing the impact of interventions on medication adherence. The validated Morisky Medication Adherence Scale(MMAS) was used as the primary method of assessing adherence in five studies. Three studies used validated questionnaires similar to the MMAS,and one study utilized Medication Event Monitoring System caps,with the remainder of the studies utilizing pill count and self-report measures. As expected,studies using non-validated self-report measures described higher rates of adherence than studies using validated scale measurements and pill count. The included intervention studies examined the use of polypill therapy,provider education and patient counseling to improve medication adherence. CONCLUSION: The overall medication adherence rates were low in the region,which suggest a growing need for future interventions to improve adherence.

Conceptual Hydrogeological Model and Groundwater Resource Estimation in a Complex Hydrothermal Area: The Case of the Viterbo Geothermal Area (Central Italy)

The conceptual hydrogeological model of the Viterbo thermal area in central Italy and the yield of the groundwater sys- tem have been examined. This area is of great geothermal interest. Through new investigations, three overlapping aquifers have been found. This study examines in detail the two shallower aquifers, characterized by different hydraulic and chemical characteristics. The first aquifer is related to the regional groundwater flow of the Cimino-Vico volcanic system and is generally characterized by cold, fresh waters used for irrigation and drinking water supply. The second aquifer, i.e. the thermal aquifer, supply thermal spas and public pools;it is present where the local hydrostratigraphic, structural and geothermal conditions permit a relatively active flow of higher salinity thermal waters (40?C - 62?C). These two aquifers interact vertically and laterally, giving rise to mixed waters circulating in the first aquifer. The first aquifer is recharged by direct infiltration and inflow from regional groundwater, as well as inflow from the second aquifer. The yield of the thermal aquifer is at least 170 L/s, discharging into thermal springs and wells, besides feeding the shallow aquifer vertically and laterally. Even if a future development of the second aquifer is potentially achievable on a global scale, the exploitation of the thermal waters is strictly dependent on the specific local hydrogeological equilibrium between the overlapping aquifers, different from place to place. The case study highlights that, in the volcanic hydrogeological environment, one of the most stringent constraints in determining the correct usage of a resource is the variable level of interaction of groundwater with different qualities.

自发性卵巢早衰女性生育脆性X染色体综合征儿

Objective: To inform clinicians about a reproductive risk associated with spontaneous premature ovarian failure and the fragile X mental retardation 1 gene (FMR1). Design: Case report. Setting: National Institutes of Health Clinical Center. Patient(s): A 35-year-old woman with confirmed spontaneous premature ovarian failure. Intervention(s): FMR1 genetic testing. Main Outcome Measure(s): Number of CGG trinucleotide repeats in the 5′untranslated region of FMR1. Result(s): Despite having ovarian failure the woman subsequently conceived and delivered a son with fragile X syndrome (>200 CGG repeats). She was then found to carry an FMR1 premutation (85 CGG repeats). Conclusion(s): This is a real-life manifestation of a theoretical risk; a woman conceived subsequent to the diagnosis of spontaneous premature ovarian failure and has a child who manifests mental retardation due to fragile X syndrome. Women with spontaneous premature ovarian failure are at increased risk of having an FMR1 premutation and should be informed of the availability of fragile X testing. Should an FMR1 premutation be uncovered, this will allow patients to make informed reproductive decisions and help clinicians to properly diagnose family members who may have menstrual irregularity, developmental delay, or neurologic symptoms.

Extremotolerant rock inhabiting black fungi from Italian monumental sites

A wide sampling for isolating highly destructive and extremotolerant black fungi was performed from Italian monuments in selected historical sites which include the "Cortile della Pigna",Vatican Museum and the St Peter colonnade(Vatican City State),the monumental cemetery of Bonaria(Cagliari),and other monuments in the city of Cagliari.Thirty out of seventy-four strains isolated were identified basing on ITS Blastn comparison.Based on multilocus phylogeny and morphological data,one new genus and species Lithophila guttulata,five new species Knufia marmoricola,K.vaticanii,K.karalitana,K.mediterranea and Exophiala bonariae,order Chaetothyriales and one new genus and species,Saxophila tyrrhenica,and two new species Vermiconia calcicola and Devriesia sardiniae,order Capnodiales,were proposed.Ecological considerations are put forward.

Inhibition of CK2 Activity by TCDD via Binding to ATP-competitive Binding Site of Catalytic Subunit： Insight from Computational Studies

Alternative mechanisms of toxic effects induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin（TCDD）, instead of the binding to aryl hydrocarbon receptor（AhR）, have been taken into consideration. It has been recently shown that TCDD reduces rapidly the activity of CK2（casein kinase II） both in vivo and in vitro. It is found that TCDD has high molecular similarities to the known inhibitors of CK2 catalytic subunit（CK2a）. This suggests that TCDD could also be an ATP-competitive inhibitor of CK2a. In this work, docking TCDD to CK2 was carried out based on the two structures of CK2a from maize and human, respectively. The binding free energies of the predicted CK2a-TCDD complexes estimated by the molecular mechanics/Poisson-Boltzmann surface area（MM/PBSA） method are from -85.1 kJ/mol to -114.3 kJ/mol for maize and are from -96.1 kJ/mol to -118.2 kJ/mol for human, which are comparable to those estimated for the known inhibitor and also ATP with CK2a. The energetic analysis also reveals that the van der Waals interaction is the dominant contribution to the binding free energy. These results are also useful for designing new drugs for a target of overexpressing CK2 in cancers.

Mountain tips as reservoirs for new rock-fungal entities: Saxomyces gen. nov. and four new species from the Alps

As part of a worldwide sampling nine black fungi were isolated from rocks collected in four distinct sites of the Alps at high altitudes.Based on a nucSSU,nucLSU and mtSSU multi-locus phylogeny,seven of them were found to cluster into a distinct and wellsupported clade in a basal position within the Class Dothideomycetes.As in other rock fungi these new groups of isolates were characterized by a meristematic growth and a scarcely differentiated morphology with highly melanized and thick-walled toruloid hyphae.Nonetheless,few peculiar characters were also observed as convoluted hyphal tips and the production of spherical propagules.The new genus and species Saxomyces alpinus and S.penninicus,are here described based on morphological and molecular data,in a yet to be defined order of the Dothideomycetes.The remaining two black fungi clustered in Cryomyces,a genus previously exclusively found in rocks from the McMurdo Dry Valleys in Antarctica.These two isolates were genetically distant from other Antarctic Cryomyces species based on ITS sequences,and they showed a peculiar morphology;they are here described as the new species C.montanus and C.funiculosus.Implications of our results on the evolution,adaptation and dispersal of rock-inhabiting fungi under extreme conditions are discussed.

Phylogeny and taxonomy of meristematic rock-inhabiting black fungi in the Dothideomycetes based on multi-locus phylogenies

The last decade has revealed an unexpected fungal diversity associated with natural rocks,often collected in environments influenced by harsh climatic conditions.Yet the phylogenetic affiliations and the taxonomy of many of these extreme fungi,mainly within Dothideomycetes,the largest class of Ascomycota,have only partially been described.In the present study we confirm that most rock inhabiting-fungi(RIF)are highly polyphyletic among Dothideomycetidae,mainly within the order Capnodiales,an order otherwise incorporating several families of major plant pathological importance.Novel taxa were identified within the two major and distinct clades of Teratosphaeriaceae,both comprising meristematic black fungi.Thirty one novel species and 13 new genera are proposed,based on ITS and partial nucLSU,RPB2 and BT2 sequences.

Notes for genera:Ascomycota

Knowledge of the relationships and thus the classification of fungi,has developed rapidly with increasingly widespread use of molecular techniques,over the past 10–15 years,and continues to accelerate.Several genera have been found to be polyphyletic,and their generic concepts have subsequently been emended.New names have thus been introduced for species which are phylogenetically distinct from the type species of particular genera.The ending of the separate naming of morphs of the same species in 2011,has also caused changes in fungal generic names.In order to facilitate access to all important changes,it was desirable to compile these in a single document.The present article provides a list of generic names of Ascomycota(approximately 6500 accepted names published to the end of 2016),including those which are lichen-forming.Notes and summaries of the changes since the last edition of‘Ainsworth&Bisby’s Dictionary of the Fungi’in 2008 are provided.The notes include the number of accepted species,classification,type species(with location of the type material),culture availability,life-styles,distribution,and selected publications that have appeared since 2008.This work is intended to provide the foundation for updating the ascomycete component of the"Without prejudice list of generic names of Fungi"published in 2013,which will be developed into a list of protected generic names.This will be subjected to the XIXth International Botanical Congress in Shenzhen in July 2017 agreeing to a modification in the rules relating to protected lists,and scrutiny by procedures determined by the Nomenclature Committee for Fungi(NCF).The previously invalidly published generic names Barriopsis,Collophora(as Collophorina),Cryomyces,Dematiopleospora,Heterospora(as Heterosporicola),Lithophila,Palmomyces(as Palmaria)and Saxomyces are validated,as are two previously invalid family names,Bartaliniaceae and Wiesneriomycetaceae.Four species of Lalaria,which were invalidly published are transferred to Taphrina and validated as new combinations.Catenomycopsis Tibell&Constant.is reduced under Chaenothecopsis Vain.,while Dichomera Cooke is reduced under Botryosphaeria Ces.&De Not.(Art.59).