1.
Combinatorial Peptide Ligand Libraries For The Analysis Of Low-Expression Proteins. Validation For Normal Urine And Definition Of A First Protein Map.
Source
Laboratory of Pathophysiology of Uremia, G. Gaslini Children Hospithal, Genoa, Italy.
Abstract
In this review, we report the evolution on experimental conditions for the analysis of normal urine based on combinatorialpeptide ligand libraries (CPLL) treatment and successive 2-DE and 2-DE/MS analysis. The main topics are: 1- definitionof the urine sample requirements, 2- optimization of the urine/ligand ratio, 3- essay conditions, 4- en bloc elution. Overall, normal urine protein composition as studied by 2-DE includes over 2600 spots. Relevant data on inter-and intra-essay reproducibility obtained by the analysis of different normal urines repeated several times are also here presented. We found a 73% reproducibility upon analysis of the same sample and 68% correspondence of protein composition among different normal urine samples. Based on the above results, we are completing the characterization with LC- MS of 249 spots. The composition of normal urine proteins after CPLLs is finally shown with the indication of those spots which are currently under identification. This map will be completed in a near future; in the meantime this would represent the basic reference sample for newly-developed studies on human diseases.
Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
- PMID:
- 22246922
- [PubMed - as supplied by publisher]
Mapping the high-throughput SEREX technology screening for novel tumor antigens.
Source
Department of Gynecology and Obstetrics, West China Second Hospital, Sichuan University, Chengdu, 610041, People's Republic of China. xia-zhao@126.com.
Abstract
Advances in novel tumor-associated antigen (TAA) screening strategy have accelerated the identification and characterization of biomarkers and potential target molecules for tumor subtyping, diagnosis and therapeutics, which may facilitate early detection and diagnosis of the diseases individually and enhance treatment approaches for cancer. Over the past decades, a plethora of non-invasive methodologies dedicated to identify novel target molecules have been primarily focusing on the discovery of human tumor antigens recognized by the autologous antibody repertoire or cytotoxic T lymphocytes, among which serological analysis of recombinant cDNA expression libraries (SEREX) technology is chronologically first established and is of outstanding sensitivity and antigen coverage. This approach involves immunoscreening cDNA libraries extracted from fresh tumor tissues with sera from cancer patients to identify gene products recognized by IgG antibody. SEREX-defined clones can be directly sequenced and their expression profiles can be readily determined, allowing for immediate structural definition of the antigenic target and subsequent identification of TAAs and their cognate autoantibodies. This review is not only devoted to outline the SEREX technology and its advantages, drawbacks and recent modifications currently available for discovering provocative tumor antigens, but also to translate these SEREX-defined peptides into valuable cancer-specific signatures that would aid in the development of diagnostics, prognostics and therapeutics for cancer patients.
- PMID:
- 22221053
- [PubMed - as supplied by publisher]
The 39th David A. Karnofsky Lecture: Bench-to-Bedside Translation of Targeted Therapies in Multiple Myeloma.
Source
Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
Abstract
Multiple myeloma (MM) is a remarkable example of rapid bench-to-bedside translation in new drug development. The proteasome inhibitor bortezomib and immunomodulatory drug lenalidomide targeted MM cells in the bone marrow (BM) microenvironment to overcome conventional drug resistance in laboratory and animal models and were rapidly translated into clinical trials demonstrating their efficacy in patients with relapsed and then newly diagnosed MM, with a doubling of the median survival as a direct result. The future is even brighter. First, immune-based therapies are being developed (eg, elotuzumab monoclonal antibody [MoAb]; CD138DM immunotoxin; MM cell-dendritic cell vaccines; CD138, CS-1, and XBP-1 peptide vaccines; anti-17 MoAb; and other treatments to overcome causes of immune dysfunction). Second, promising next-generation agents target the MM cell in its microenvironment (eg, deubiquitinating enzyme inhibitors; chymotryptic [carfilzomib, Onyx 0912, MLN 9708] and broader [NPI-0052] proteasome inhibitors; immunoproteasome inhibitors; and pomalidamide). Moreover, agents targeting bone biology (eg, zoledronic acid, anti-DKK-1 MoAb, anti-B-cell activating factor MoAb and bortezomib, Btk inhibitor) show promise not only in preserving bone integrity but also against MM. Third, rationally based combination therapies, including bortezomib with Akt, mammalian target of rapamycin, or histone deacetylase inhibitors, are active even in bortezomib-refractory MM. Finally, genomics is currently being used in the definition of MM heterogeneity, new target discovery, and development of personalized therapy. Myeloma therefore represents a paradigm for targeting the tumor in its microenvironment, which has already markedly improved patient outcome in MM and has great potential in other hematologic malignancies and solid tumors as well.
"Allorestriction" should be distinguished from "alloreactivity"
Source
Conceptual Immunology Group, The Salk Institute for Biological Studies, La Jolla, CA, USA. cohn@salk.edu.
Abstract
Whether or not allorestriction should be distinguished from alloreactivity depends on one's model of the TCR-ligand interaction. If the ligand is viewed as a determinant formed by a meld between peptide and the MHC-encoded restricting element, then the TCR, like the BCR, has a single combining site specific for the composite epitope (the Centric Model). If, however, one views the recognition of peptide and the MHC-encoded restricting element as independent, then interactions at two sites of the TCR must be integrated to signal the T cell (the Tritope Model). As TCR recognition of the MHC-encoded restricting element is, by definition, restricted (allele-specific), then under the Centric Model, all TCR signaling interactions with the composite epitope are due to allorestriction, which is peptide-specific. In contrast, under the Tritope Model, there are two classes of signaling interaction, allorestriction and alloreactivity. Alloreactivity ispeptide-unspecific and is triggered by recognition of the allo-MHC-encoded restricting element allele. Alloreactivity is incompatible with the Centric Model, under which one would predict that it does not exist. Selected data are analyzed to illustrate the importance of this distinction.
Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Basket Cell Dichotomy in Microcircuit Function.
Source
University of California, Irvine;
Abstract
A diversity of GABAergic cell types exist within each brain area, and each cell type is thought to play a unique role in the modulation of principal cell output. Basket cells, whose axon terminals surround principal cell somata and proximal dendrites, have a privileged and influential position for regulating the firing of principal cells. This review explores the dichotomy of the two basket cell classes, cholecystokinin (CCK) and parvalbumin (PV)-containing basket cells, beginning with differences at the level of the individual cell and subsequently focusing on two ways in which this intrinsic dichotomy is enhanced by extrinsic factors. Neuromodulatory influences, exemplified by the effects of the peptide CCK, dynamically enhance the differential functions of the two cell types. Specifications at the level of the postsynaptic principal cell, including input-specific differences in chloride handling and differences in long-range projection patterns of the principal cell targets also enhance the distinct network function of basket cells. In this review, new findings will be highlighted concerning the roles of neuromodulatory control and postsynaptic long-range projection pattern in thedefinition of basket cell function.
Systematic conformational investigations of peptoids and peptoid-peptidechimeras.
Source
Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Weinberg 3, D-06120 Halle (Saale), Germany.
Abstract
Peptoids are originally defined as N-substituted oligoglycine derivatives, and in a broader definition as N-substitutedpeptides (peptoid-peptide chimeras). Both types were systematically investigated by force field calculations. The Merck MMFF and YASARA2 force fields were shown to be, among others, the most suitable ones for conformational investigations of peptoids with no missing parameterizations, in contrast to AMBER or CHARMM. Ramachandran-like plots were calculated for dipeptoids and chimeras using energy calculations and grid searches by varying the dihedral angels PHI and PSI in steps of 10 degrees for s-cis- and s-trans amide bonds. Barriers as well as low energy conformations are compared to peptide Ramachandran plots, showing that peptoids have both, more barriers due to additional steric interactions as well as access to minimum conformations not accessible by peptides. Low energy conformations of dimers were used as starting conformations of higher oligomers of the peptoids for extensive molecular dynamics simulations over 10 or 20 ns with the YASARA2 force field and an explicit water solvent box to evaluate their potential to form secondary structural elements. Especially peptoids with aminoisobutyric acid-like monomer units were found to form left-handed or polyproline-like helices also known from less common natural peptides. Furthermore, new secondary structures appear feasible based on stable conformations outside the allowed areas of the Ramachandran plot for peptides, but allowed for peptoids.
- PMID:
- 22180911
- [PubMed - in process]
Definition of the viral targets of protective HIV-1-specific T cell responses.
Abstract
ABSTRACT:
BACKGROUND:
The efficacy of the CTL component of a future HIV-1 vaccine will depend on the induction of responses with the most potent antiviral activity and broad HLA class I restriction. However, current HIV vaccine designs are largely based on viral sequence alignments only, not incorporating experimental data on T cell function and specificity.
METHODS:
Here, 950 untreated HIV-1 clade B or -C infected individuals were tested for responses to sets of 410 overlapping peptides (OLP) spanning the entire HIV-1 proteome. For each OLP, a "protective ratio" (PR) was calculated as the ratio of median viral loads (VL) between OLP non-responders and responders.
RESULTS:
For both clades, there was a negative relationship between the PR and the entropy of the OLP sequence. There was also a significant additive effect of multiple responses to beneficial OLP. Responses to beneficial OLP were of significantly higher functional avidity than responses to non-beneficial OLP. They also had superior in-vitro antiviral activities and, importantly, were at least as predictive of individuals' viral loads than their HLA class I genotypes.
CONCLUSIONS:
The data thus identify immunogen sequence candidates for HIV and provide an approach for T cell immunogen design applicable to other viral infections.
Targeting of proapoptotic TLR adaptor, SARM, to mitochondria: definition of critical region and residues in the signal sequence.
Abstract
The fifth and the most well conserved member of the TLR adaptor, SARM, has been reported to be an important mediator of apoptosis. However, the exact cellular localization of SARM with respect to its role is unclear. Here we show that SARM specifically co-localizes with the mitochondria. Endogenous SARM is mainly found in the mitochondria. We demonstrated that the N terminal 27 amino acids (S27) of SARM, which is hydrophobic and polybasic, acts as a mitochondria-targeting signal sequence, associating SARM to the mitochondria. The S27 peptide has an inherent ability to bind to lipids and mitochondria. This sequence effectively translocates the soluble EGFP reporter into the mitochondria. Positioning S27 downstream of the EGFP abrogates its mitochondria-targeting ability. Transmission electron microscopy confirms the ability of S27 to import EGFP into the mitochondria. Importantly, by mutagenesis study, we delineated the specificity of the mitochondria-targeting ability to the Arginine residue at the 14th position. Arg14Ala SARM mutant also showed reduced apoptotic potential when compared to the wild type. Taken together S27, which is a bona fide signal sequence that targets SARM to the mitochondria, explains the proapoptotic activity of SARM.
On how Rac controls hematopoietic stem cell activity.
Source
Hoxworth Blood Center, University of Cincinnati Academic Health Center, and Stem Cell Program, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati Medical Center, Cincinnati, Ohio, USA. Jose.Cancelas@uc.edu
Abstract
Rac GTPases form part of the family of Rho small GTPases. Rac GTPases, like other Rho family GTPases, are key molecular switches controlling the transduction of external signals to cytoplasmic and nuclear effectors. The development of genetic and pharmacological tools has allowed a more precise definition of the specific roles of Rac GTPases in hematopoietic stem cells (HSCs). Our current knowledge has enabled dissection of their specific and redundant roles. Rac GTPases are now known to be crucial in the response of HSCs to the hematopoietic microenvironment cues. This review will briefly summarize the known HSC functions that are regulated by Rac GTPases, focusing on adhesion, migration, retention, proliferation, and survival, and how Rac relates to the physiological functions of HSC. The development of small molecule inhibitors with the ability to interfere with Rac GTPase activation offers new therapeutic strategies to manipulate the function of HSC in vivo and ex vivo.
© 2011 American Association of Blood Banks.
Modifiable risk factors for RA: prevention, better than cure?
Source
Arthritis Research UK Epidemiology Unit, School of Translational Medicine, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK, Division of Rheumatology, University Medicine Cluster, National University Health System, Singapore and The Kellgren Centre for Rheumatology, Manchester NIHR Biomedical Research Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
Abstract
Objective. To perform a meta-synthesis of the evidence for modifiable lifestyle risk factors for inflammatory polyarthritis (IP) and RA.Methods. We performed a MEDLINE literature search. Case-control and cohort studies and systematic reviews published from 1948 through February 2011 and studying modifiable risk factors for RA were retrieved. The main outcome measure was diagnosis of RA according to the standard criteria.Results. Smoking contributes up to 25% of the population burden of RA. The risk is dose related, stronger in males and especially strong for anti-citrullinatedpeptide antibody positive (ACPA(+)) RA through an interaction with the shared epitope. After smoking cessation, there is, however, a latency of up to 20 years to return to baseline risk. Other associations are less definitive; however, prospective studies suggest that dietary antioxidants and breastfeeding may be protective and that high coffee consumption may increase RA risk. An inverse association with alcohol intake (especially in smokers) and with education/social class (especially seropositive RA) and an increased risk with obesity (seronegative RA) is also noted.Conclusion. There is a need for further large-scale prospective studies with a consistent definition of RA phenotype (undifferentiated IP through to ACPA(+)/RF(+) disease). This will ultimately afford the opportunity to evaluate preventative population strategies for RA akin to the well-established programmes for cardiovascular disease and cancer, targeting common risk factors.
Modern treatment of adult short bowel syndrome patients.
Source
Department of Gastroenterology CA-2121, Rigshospitalet, Copenhagen, Denmark - Bekker@dadlnet.dk.
Abstract
By definition, intestinal failure prevails when oral compensation is no longer feasible and parenteral support is necessary to maintain nutritional equilibrium. In the past, conventional treatment has mainly focused on "making the most of what the short bowel syndrome patient still had" by optimizing remnant intestinal function through dietary interventions, antidiarrheals and antisecretory agents. However, modern treatment options are in the near horizon, and the increased understanding of the mediators for intestinal adaptation will lead to the expansion of the limited treatment armamentarium in short bowel syndrome patients with intestinal failure. The clinical meaningfulness and implications of the observed effects of growth hormone, glutamine, glucagon-like peptide 2 (GLP-2) and the dipeptidyl peptidase-4 degradation resistant analog, teduglutide, is presented in this review and balanced against treatment related adverse events and possible unfavourable effects of long-term, possibly lifelong, treatments.
Emerging biomarkers in heart failure.
Source
Department of Cardiology, Maastricht University Medical Centre, Maastricht, the Netherlands;
Abstract
BACKGROUND:
Until recently, biomarker testing in heart failure (HF) syndromes has been viewed as an elective supplement to diagnostic evaluation of patients suspected to suffer from this condition. This approach to the use of biomarker testing contrasts with other cardiovascular diagnoses such as acute myocardial infarction, for which biomarkers are integral to disease process definition, risk stratification, and in some cases treatment decision making.
CONTENT:
In this review we consider various perspectives on the evaluation of biomarkers in HF. In addition, we examine recent advances in the understanding of established biomarkers in HF (such as the natriuretic peptides), the elucidation of novel biomarkers potentially useful for the evaluation and management of patients with HF, and the growing understanding of important and relevant comorbidities in HF. We also review candidate biomarkers from a number of classes: (a) myocyte stretch, (b) myocyte necrosis, (c) systemic inflammation, (d) oxidative stress, (e) extracellular matrix turnover, (f) neurohormones, and (g) biomarkers of extracardiac processes, such as renal function.
SUMMARY:
Novel applications of established biomarkers of HF as well as elucidation and validation of emerging assays for HF syndromes have collectively led to a growing interest in the more widespread use of such testing in patients affected by the diagnosis.
Survival in childhood pulmonary arterial hypertension: insights from the registry to evaluate early and long-term pulmonary arterial hypertension disease management.
Source
31 Murray Hill Rd, Scarsdale, NY 10583. robyn.barst@gmail.com.
Abstract
BACKGROUND:
Pulmonary arterial hypertension (PAH) is a rare but important cause of morbidity and mortality in children.
METHODS AND RESULTS:
We analyzed data from 216 patients ≤18 years of age at diagnosis who were enrolled in the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL). Median age at diagnosis and enrollment was 7 and 15 years, respectively. The most frequent presenting symptom was dyspnea (idiopathic/familial PAH, 53%; PAH associated with congenital heart disease, 30%). Presyncope/syncope was more frequent in patients with idiopathic PAH/familial PAH (36%) than in those with PAH associated with congenital heart disease (4%). At diagnosis, mean pulmonary artery pressure and pulmonary vascular resistance index were 56 mm Hg and 17 Wood units · m(2), respectively. Five-year survival from diagnosis for the overall cohort was 74±6%, with no significant difference between the idiopathic PAH/familial PAH (n=122, 75±7%) and PAH associated with congenital heart disease (n=77, 71±13%) cohorts (P=0.53). Older age at diagnosis was the only variable significantly associated with decreased survival from diagnosis. Variables at enrollment that were significantly associated with decreased survival from enrollment included higher pulmonary vascular resistance index, lower-weight z scores, and familial PAH. Additional variables at enrollment, identified in a secondary analysis, that were marginally associated with increased survival from enrollment included acute vasoreactivity (adaptation of conventional pediatric definition; P=0.087) and lower brain natriuretic peptide (P=0.060). None of the 22 patients who were acute responders treated with high-dose calcium channel blockade as monotherapy or combination therapy died within 5 years of diagnosis.
CONCLUSION:
Using REVEAL, we identified key predictors of survival in childhood PAH. Refining these prognostic parameters should help clinicians improve outcomes.
CLINICAL TRIAL REGISTRATION:
URL: www.clinicaltrials.gov. Unique identifier: NCT00370214.
High-resolution picture of a venom gland transcriptome: Case study with the marine snail Conus consors.
Source
Laboratoire d'Ingénierie des Anticorps pour la Santé (LIAS), CEA/DSV/iBiTec-s/SPI, CEA Saclay, Bt. 152, 91191 Gif-sur-Yvette Cedex, France.
Abstract
Although cone snail venoms have been intensively investigated in the past few decades, little is known about the whole conopeptide and protein content in venom ducts, especially at the transcriptomic level. If most of the previous studies focusing on a limited number of sequences have contributed to a better understanding of conopeptide superfamilies, they did not give access to a complete panorama of a whole venom duct. Additionally, rare transcripts were usually not identified due to sampling effect. This work presents the data and analysis of a large number of sequences obtained from high throughput 454 sequencing technology using venom ducts of Conus consors, an Indo-Pacific living piscivorous cone snail. A total of 213,561 Expressed Sequence Tags (ESTs) with an average read length of 218 base pairs (bp) have been obtained. These reads were assembled into 65,536 contiguous DNA sequences (contigs) then into 5039 clusters. The data revealed 11 conopeptide superfamilies representing a total of 53 new isoforms (full length or nearly full-length sequences). Considerable isoform diversity and major differences in transcription level could be noted between superfamilies. A, O and M superfamilies are the most diverse. The A family isoforms account for more than 70% of the conopeptide cocktail (considering all ESTs before clustering step). In addition to traditional superfamilies and families, minor transcripts including both cysteine free and cysteine-rich peptides could be detected, some of them figuring new clades of conopeptides. Finally, several sets of transcripts corresponding to proteins commonly recruited in venom function could be identified for the first time in cone snail venom duct. This work provides one of the first large-scale EST project for a cone snail venom duct using next-generation sequencing, allowing a detailed overview of the venom duct transcripts. This leads to an expanded definition of the overall cone snail venom duct transcriptomic activity, which goes beyond the cysteine-rich conopeptides. For instance, this study enabled to detect proteins involved in common post-translational maturation and folding, and to reveal compounds classically involved in hemolysis and mechanical penetration of the venom into the prey. Further comparison with proteomic and genomic data will lead to a better understanding of conopeptides diversity and the underlying mechanisms involved in conopeptide evolution.
Copyright © 2011 Elsevier Ltd. All rights reserved.
Putting into practice domain-linear motif interaction predictions for exploration of protein networks.
Source
Group Onco-Proteins, Institut de Recherche de l'Ecole de Biotechnologie de Strasbourg, Illkirch, France.
Abstract
PDZ domains recognise short sequence motifs at the extreme C-termini of proteins. A model based on microarray data has been recently published for predicting the binding preferences of PDZ domains to five residue long C-terminal sequences. Here we investigated the potential of this predictor for discovering novel protein interactions that involve PDZ domains. When tested on real negative data assembled from published literature, the predictor displayed a high false positive rate (FPR). We predicted and experimentally validated interactions between four PDZ domains derived from the human proteins MAGI1 and SCRIB and 19 peptides derived from human and viral C-termini of proteins. Measured binding intensities did not correlate with prediction scores, and the high FPR of the predictor was confirmed. Results indicate that limitations of the predictor may arise from an incomplete model definition and improper training of the model. Taking into account these limitations, we identified several novel putative interactions between PDZ domains of MAGI1 and SCRIB and the C-termini of the proteins FZD4, ARHGAP6, NET1, TANC1, GLUT7, MARCH3, MAS, ABC1, DLL1, TMEM215 and CYSLTR2. These proteins are localised to the membrane or suggested to act close to it and are often involved in G protein signalling. Furthermore, we showed that, while extension of minimal interacting domains orpeptides toward tandem constructs or longer peptides never suppressed their ability to interact, the measured affinities and inferred specificity patterns often changed significantly. This suggests that if protein fragments interact, the full length proteins are also likely to interact, albeit possibly with altered affinities and specificities. Therefore, predictors dealing with protein fragments are promising tools for discovering protein interaction networks but their application to predict binding preferences within networks may be limited.
MALDI-ToF MS analysis of glycosyltransferase activities on gold surface arrays.
Source
Manchester Interdisciplinary Biocentre & School of Chemistry, The University of Manchester, Manchester, UK.
Abstract
Glycan-processing enzymes such as glycosyltransferases and glycosidases are responsible for the makeup of the glycome. The definition of their substrate specificities is, therefore, a central task in glycomics. In addition, these enzymes are themselves useful synthetic tools for the generation of complex carbohydrate structures as an alternative to tedious chemical synthesis. There has been great interest in using microarrays for studying these glycoenzymes because it allows the specificity of the enzyme to be probed against a panel of immobilized potential substrates, and also expands the repertoire of sugar arrays available for further carbohydrate-protein interaction studies. In particular, self-assembled monolayers (SAMs) of alkanethiols on gold surfaces have proven to be a valuable platform for such studies due to their robustness and their biocompatible, well-defined structure. Furthermore, a direct observation of the change in mass of immobilized substrates due to enzymatic processing is possible through label-free MALDI-ToF MS (matrix-assisted laser desorption/ionization time-of-flight mass spectrometry) technique. In this chapter, we describe the preparation of SAMs-coated gold surface arrays presenting carbohydrate or (glyco)peptide substrates, either pre-formed or directly synthesized on-chip, and MALDI-ToF MS analysis of glycosyltransferase activities on these immobilized substrates.
Chairman's summary: Definition of idiopathic short stature.
Source
University Children's Hospital, Universitätsklinikum Tübingen, Tübingen, Germany.
Effect of canrenone on left ventricular mechanics in patients with mild systolic heart failure and metabolic syndrome: the AREA-in-CHF study.
Source
Federico II University Hospital, Department of Clinical and Experimental Medicine, Napoli, Italy. simogi@unina.it
Abstract
BACKGROUND AND AIM:
We analyzed the effect of the mineralocorticoid receptor antagonist canrenone on LV mechanics in patients with or without metabolic syndrome (MetS) and compensated (Class II NYHA) heart failure (HF) with reduced ejection fraction (EF≤45%) on optimal therapy (including ACE-i or ARB, and β-blockers).
METHODS AND RESULTS:
From a randomized, double-blind placebo-controlled trial (AREA-in-CHF), patients with (73 on canrenone [Can] and 77 on placebo [Pla]), based on modified ATPIII definition (BMI≥30kg/m(2) instead of waist girth) or without MetS (146 by arm). In addition to traditional echocardiographic parameters, we also evaluated myocardial mechano-energetic efficiency (MME) based on a previously reported method. At baseline, Can and Pla did not differ in age, BMI, blood pressure (BP), metabolic profile, BNP, and PIIINP. Compared with MetS-Pla, and controlling for age, sex and diabetes, at the final control MetS-Can exhibited increased MME, preserved E/A ratio, and decreased atrial dimensions (0.04
CONCLUSIONS:
Treatment with canrenone given on the top of optimal therapy in patients with MetS and chronic, stabilized HF with reduced EF, protects deterioration of MME, improves diastolic dysfunction and maximizes the decrease in BNP.
Copyright © 2010 Elsevier B.V. All rights reserved.
Characterization of a venom peptide from a crassispirid gastropod.
Source
Marine Science Institute, University of the Philippines, Diliman, Quezon City.
Abstract
The crassispirids are a large branch of venomous marine gastropods whose venoms have not been investigated previously. We demonstrate that crassispirids comprise a major group of toxoglossate snails in a clade distinct from all turrids whose venoms have been analyzed. The isolation and biochemical definition of the first venom component from any crassispirid is described. Crassipeptide cce9a from Crassispira cerithina (Anton, 1838) was purified from crude venom by following biological activity elicited in young mice, lethargy and a lack of responsiveness to external stimuli. Using Edman sequencing and mass spectrometry, the purified peptide was shown to be 29 amino acid residues long, with the sequence: GSCGLPCHENRRCGWACYCDDGICKPLRV. The sequence assignment was verified through the analysis of a cDNA clone encoding the peptide. The peptide was chemically synthesized and folded; the syntheticpeptide was biologically active and coelution with the native venom peptide was demonstrated. When injected into mice of various ages, the peptide elicited a striking shift in behavioral phenotype between 14 and 16 days, from lethargy to hyperactivity.
Published by Elsevier Ltd.
Association of ET-1 gene polymorphisms with COPD phenotypes in a Caucasian population.
Source
Pulmonary Department, Division of Internal Medicine, University Hospital of Patras, Greece. pneumonas@hotmail.com
Abstract
BACKGROUND AND AIM:
The phenotypic expression of COPD consists of pulmonary emphysema and chronic bronchitis. An imprecise phenotypic definition may result in inconsistencies among genetic studies regarding COPD pathogenesis. Endothelin-1 gene polymorphisms have been linked to increased susceptibility of COPD development. The present study examined the involvement of +138 insA/delA and G198T ET-1 polymorphisms with emphysematous and bronchitic COPD phenotypes.
METHODS:
In order to narrow down the phenotypic choices to either COPD-associated pulmonary emphysema or chronic bronchitis, a DLCO < 60% predicted threshold was chosen as an indicator of severe emphysema. 116 COPD smokers and 74 non-related, non-COPD smokers were evaluated.
RESULTS:
Statistical analysis showed that the 4A allele of the +138insA/delA SNP and the 4A:T haplotype were associated predominantly with a chronic bronchitis phenotype, whereas the TT genotype of the G198T SNP was found to be protective from emphysema development.
CONCLUSIONS:
The presence of both the 4A and T allele seems to modify the final expression of COPD towards a chronic bronchitis phenotype, since the G:3A haplotype was associated with a predominantly emphysematous phenotype in our study.
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