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31.
Sophie Perrin Jonathan Cremer Olivia Faucher Jacques Reynes Pierre Dellamonica Jo?lle Micallef Caroline Solas Bruno Lacarelle Charlotte Stretti Elise Kaspi Andrée Robaglia-Schlupp Corine Nicolino-Brunet Catherine Tamalet Nicolas Lévy Isabelle Poizot-Martin Pierre Cau Patrice Roll 《PloS one》2012,7(12)
Background
The ANRS EP45 “Aging” study investigates the cellular mechanisms involved in the accelerated aging of HIV-1 infected and treated patients. The present report focuses on lamin A processing, a pathway known to be altered in systemic genetic progeroid syndromes.Methods
35 HIV-1 infected patients being treated with first line antiretroviral therapy (ART, mean duration at inclusion: 2.7±1.3 years) containing boosted protease inhibitors (PI/r) (comprising lopinavir/ritonavir in 65% of patients) were recruited together with 49 seronegative age- and sex-matched control subjects (http://clinicaltrials.gov/, ). In more than 88% of patients, the viral load was <40 copies/ml and the CD4+ cell count was >500/mm3. Prelamin A processing in peripheral blood mononuclear cells (PBMCs) from patients and controls was analysed by western blotting at inclusion. PBMCs from patients were also investigated at 12 and 24 months after enrolment in the study. PBMCs from healthy controls were also incubated with boosted lopinavir in culture medium containing various concentrations of proteins (4 to 80 g/L). NCT01038999Results
Lamin A precursor was not observed in cohort patient PBMC regardless of the PI/r used, the dose and the plasma concentration. Prelamin A was detected in PBMC incubated in culture medium containing a low protein concentration (4 g/L) but not in plasma (60–80 g/L) or in medium supplemented with BSA (40 g/L), both of which contain a high protein concentration.Conclusions
Prelamin A processing abnormalities were not observed in PBMCs from patients under the PI/r first line regimen. Therefore, PI/r do not appear to contribute to lamin A-related aging in PBMCs. In cultured PBMCs from healthy donors, prelamin A processing abnormalities were only observed when the protein concentration in the culture medium was low, thus increasing the amount of PI available to enter cells.ClinicalTrials.gov http://clinicaltrials.gov/ct2/show/ NCT01038999. NCT01038999相似文献32.
Diane Frankel Valérie Delecourt Karim Harhouri Annachiara De Sandre‐Giovannoli Nicolas Lévy Elise Kaspi Patrice Roll 《Aging cell》2018,17(4)
Hereditary and sporadic laminopathies are caused by mutations in genes encoding lamins, their partners, or the metalloprotease ZMPSTE24/FACE1. Depending on the clinical phenotype, they are classified as tissue‐specific or systemic diseases. The latter mostly manifest with several accelerated aging features, as in Hutchinson–Gilford progeria syndrome (HGPS) and other progeroid syndromes. MicroRNAs are small noncoding RNAs described as powerful regulators of gene expression, mainly by degrading target mRNAs or by inhibiting their translation. In recent years, the role of these small RNAs has become an object of study in laminopathies using in vitro or in vivo murine models as well as cells/tissues of patients. To date, few miRNAs have been reported to exert protective effects in laminopathies, including miR‐9, which prevents progerin accumulation in HGPS neurons. The recent literature has described the potential implication of several other miRNAs in the pathophysiology of laminopathies, mostly by exerting deleterious effects. This review provides an overview of the current knowledge of the functional relevance and molecular insights of miRNAs in laminopathies. Furthermore, we discuss how these discoveries could help to better understand these diseases at the molecular level and could pave the way toward identifying new potential therapeutic targets and strategies based on miRNA modulation. 相似文献
33.
Xin-Qiu Yao Rabia U. Malik Nicholas W. Griggs Lars Skj?rven John R. Traynor Sivaraj Sivaramakrishnan Barry J. Grant 《The Journal of biological chemistry》2016,291(9):4742-4753
G protein α subunits cycle between active and inactive conformations to regulate a multitude of intracellular signaling cascades. Important structural transitions occurring during this cycle have been characterized from extensive crystallographic studies. However, the link between observed conformations and the allosteric regulation of binding events at distal sites critical for signaling through G proteins remain unclear. Here we describe molecular dynamics simulations, bioinformatics analysis, and experimental mutagenesis that identifies residues involved in mediating the allosteric coupling of receptor, nucleotide, and helical domain interfaces of Gαi. Most notably, we predict and characterize novel allosteric decoupling mutants, which display enhanced helical domain opening, increased rates of nucleotide exchange, and constitutive activity in the absence of receptor activation. Collectively, our results provide a framework for explaining how binding events and mutations can alter internal dynamic couplings critical for G protein function. 相似文献
34.
Heterodimeric class I major histocompatibility complex (MHC) molecules consist of a putative 45-kDa heavy chain and a 12-kDa beta2-microglobulin (beta2m) light chain. The knowledge about MHC genes in Atlantic salmon accumulated during the last decade has allowed us to generate soluble and stable MHC class I molecules with biological activity. We report here the use of a bacterial expression system to produce the recombinant single-chain MHC molecules based on a specific allele Sasa-UBA*0301. This particular allele was selected because previous work has shown its association with the resistance to infectious salmon anaemia virus. The single-chain salmon MHC class I molecule has been designed and generated, in which the carboxyl terminus of beta2m is joined together with a flexible 15 or 20 amino acid peptide linker to the amino terminus of the heavy chain (Sasabeta2mUBA*0301). Monoclonal antibodies were successfully produced against both the MHC class I heavy chain and beta(2)m, and showed binding to the recombinant molecule. The recombinant complex Sasabeta2mUBA*0301 was expressed and isolated; the production was scaled up by adjusting to its optimal conditions. Subsequently, the recombinant proteins were purified by affinity chromatography using mAb against beta2m and alpha3. Eluates were analyzed by Western blot and refolded by the removal of denaturant. The correct folding was confirmed by measuring its binding capacity against mAb produced to recognize the native form of MHC molecules by biosensor analysis. This production of sufficient amounts of class I MHC proteins may represent a useful tool to study the peptide-binding specificity of MHC class I molecules, in order to design a peptide vaccine against viral pathogens. 相似文献
35.
There is an increased need for alginate materials with both enhanced and controllable mechanical properties in the fields of food, pharmaceutical and specialty applications. In the present work, well-characterized algal polymers and mannuronan were enzymatically modified using C-5 epimerases converting mannuronic acid residues to guluronic acid in the polymer chain. Composition and sequential structure of controls and epimerized alginates were analyzed by (1)H NMR spectroscopy. Mechanical properties of Ca-alginate gels were further examined giving Young's modulus, syneresis, rupture strength, and elasticity of the gels. Both mechanical strength and elasticity of hydrogels could be improved and manipulated by epimerization. In particular, alternating sequences were found to play an important role for the final mechanical properties of alginate gels, and interestingly, a pure polyalternating sample resulted in gels with extremely high syneresis and rupture strength. In conclusion, enzymatic modification was shown to be a valuable tool in modifying the mechanical properties of alginates in a highly specific manner. 相似文献
36.
Maya P. Singh Margaret M. Leighton Laurel R. Barbieri Deborah M. Roll Susan E. Urbance Linda Hoshan Leonard A. McDonald 《Journal of industrial microbiology & biotechnology》2010,37(4):335-340
Fungi are well known for their vast diversity of secondary metabolites that include many life-saving drugs and highly toxic mycotoxins. In general, fungal cultures producing such metabolites are immune to their toxic effects. However, some are known to produce self-toxic compounds that can pose production optimization challenges if the metabolites are needed in large amounts for chemical modification. One such culture, LV-2841, was identified as the lead for one of our exploratory projects. This culture was found to be a slow grower that produced trace amounts of a known metabolite, cercosporamide, under the standard flask fermentation conditions, and extensive medium optimization studies failed to yield higher titers. Poor growth of the culture in liquid media was attributed to the self-toxicity of cercosporamide to the producing organism, and the minimum inhibitory concentration (MIC) of cercosporamide was estimated to be in the range of 8–16 μg/ml. Fermentations carried out in media containing Diaion® HP20 resin afforded significantly higher titers of the desired compound. While several examples of resin-based fermentations of soil streptomyces have been published, this approach has rarely been used for fungal fermentations. Over a 100-fold increase in the production titer of cercosporamide, a self-toxic secondary metabolite, was achieved by supplementing the production medium with a commercially available neutral adsorbent resin. 相似文献
37.
Sarah Jamali Annick Salzmann Nader Perroud Magali Ponsole-Lenfant Jennifer Cillario Patrice Roll Nathalie Roeckel-Trevisiol Ariel Crespel Jorg Balzar Kurt Schlachter Ursula Gruber-Sedlmayr Ekaterina Pataraia Christoph Baumgartner Alexander Zimprich Fritz Zimprich Alain Malafosse Pierre Szepetowski 《PloS one》2010,5(9)
38.
Ian Mayer Justin Meager Jon Egil Skjæraasen Petra Rodewald Gisle Sverdrup Anders Fernö 《Environmental Biology of Fishes》2011,92(2):181-186
Brain and heart development is very plastic in teleost fishes, and receptive to changes in social and environmental conditions.
Domestication in salmonids has been reported to result in pronounced changes in both heart and brain morphology. In particular,
a high prevalence of heart deformities has been reported in farmed salmonids, which has been linked to increased stress responsiveness
that can impair survival of both farmed and escaped fish. Here we report for the first time that significant changes in heart
and brain morphology occur following domestication of Atlantic cod (Gadus morhua), an emerging aquaculture species. Juvenile farmed cod developed significantly larger hearts and smaller brains, by weight,
compared to their wild conspecifics. These differences occurred within the first captive generation, suggesting that they
were driven largely by the strong contrast in environmental and social conditions experienced within their respective rearing
environments. Changes in brain and heart morphology, as a consequence of domestication could affect the well-being and survival
of Atlantic cod raised under intensive aquaculture conditions. 相似文献
39.
One predicted impact of climate change is a poleward shift in the boundaries of species ranges. Existing methods for identifying such a boundary shift based on changes in the observed pattern of occupancy within a grid of cells are sensitive to changes in the overall rate of sightings and their latitudinal distribution that are unconnected to a boundary shift. A formal test for a boundary shift is described that allows for such changes. The test is applied to detect northward shifts in the northern boundary of the Essex skipper (Thymelicus lineola) butterfly and the European goldfinch (Carduelis carduelis) in Great Britain. A shift is detected in the latter case but not in the former. Results from a simulation study are presented showing that the test performs well. 相似文献
40.