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101.
Haga-Friedman A Horovitz-Fried M Cohen CJ 《Journal of immunology (Baltimore, Md. : 1950)》2012,188(11):5538-5546
TCR-gene transfer represents an effective way to redirect the specificity of T lymphocytes for therapeutic purposes. Recent successful clinical trials have underscored the potential of this approach in which efficient expression of the exogenous TCR has been directly linked to the efficacy of T cell activity. It has been also demonstrated that the TCR exhibits a lack of stability associated with the presence of positively charged residues in its transmembrane (TM) region. In this study, we designed an original approach selectively to improve exogenous TCR stability by increasing the hydrophobic nature of the TCRα TM region. Incorporation of hydrophobic residues at evolutionarily permissive positions resulted in an enhanced surface expression of the TCR chains, leading to an improved cellular avidity and anti-tumor TCR activity. Furthermore, this strategy was successfully applied to different TCRs, enabling the targeting of human tumors from different histologies. We also show that the combination of these hydrophobic mutations with another TCR-enhancing approach further improved TCR expression and function. Overall, these findings provide information regarding TCR TM composition that can be applied for the improvement of TCR-gene transfer-based treatments. 相似文献
102.
Dubots E Botté C Boudière L Yamaryo-Botté Y Jouhet J Maréchal E Block MA 《Biochimie》2012,94(1):86-93
Phosphatidic acid (PA) is a precursor metabolite for phosphoglycerolipids and also for galactoglycerolipids, which are essential lipids for formation of plant membranes. PA has in addition a main regulatory role in a number of developmental processes notably in the response of the plant to environmental stresses. We review here the different pools of PA dispatched at different locations in the plant cell and how these pools are modified in different growth conditions, particularly during plastid membrane biogenesis and when the plant is exposed to phosphate deprivation. We analyze how these modifications can affect galactolipid synthesis by tuning the activity of MGD1 enzyme allowing a coupling of phospho- and galactolipid metabolisms. Some mechanisms are considered to explain how physicochemical properties of PA allow this lipid to act as a central internal sensor in plant physiology. 相似文献
103.
Gayet L Picault N Cazalé AC Beyly A Lucas P Jacquet H Suso HP Vavasseur A Peltier G Forestier C 《FEBS letters》2006,580(30):6891-6897
ABC transporters from the multidrug resistance-associated protein (MRP) subfamily are glutathione S-conjugate pumps exhibiting a broad substrate specificity illustrated by numerous xenobiotics, such as anticancer drugs, herbicides, pesticides and heavy metals. The engineering of MRP transporters into plants might be interesting either to reduce the quantity of xenobiotics taken up by the plant in the context of “safe-food” strategies or, conversely, in the development of phytoremediation strategies in which xenobiotics are sequestered in the vacuolar compartment. In this report, we obtained Arabidopsis transgenic plants overexpressing human MRP1. In these plants, expression of MRP1 did not increase plant resistance to antimony salts (Sb(III)), a classical glutathione-conjugate substrate of MRP1. However, the transporter was fully translated in roots and shoots, and targeted to the plasma membrane. In order to investigate the functionality of MRP1 in Arabidopsis, mesophyll cell protoplasts (MCPs) were isolated from transgenic plants and transport activities were measured by using calcein or Sb(III) as substrates. Expression of MRP1 at the plasma membrane was correlated with an increase in the MCPs resistance to Sb(III) and a limitation of the metalloid content in the protoplasts due to an improvement in Sb(III) efflux. Moreover, Sb(III) transport was sensitive to classical inhibitors of the human MRP1, such as MK571 or glibenclamide. These results demonstrate that a human ABC transporter can be functionally introduced in Arabidopsis, which might be useful, with the help of stronger promoters, to reduce the accumulation of xenobiotics in plants, such as heavy metals from multi-contaminated soils. 相似文献
104.
Johnson LA Heemskerk B Powell DJ Cohen CJ Morgan RA Dudley ME Robbins PF Rosenberg SA 《Journal of immunology (Baltimore, Md. : 1950)》2006,177(9):6548-6559
Cell-based antitumor immunity is driven by CD8(+) cytotoxic T cells bearing TCR that recognize specific tumor-associated peptides bound to class I MHC molecules. Of several cellular proteins involved in T cell:target-cell interaction, the TCR determines specificity of binding; however, the relative amount of its contribution to cellular avidity remains unknown. To study the relationship between TCR affinity and cellular avidity, with the intent of identifying optimal TCR for gene therapy, we derived 24 MART-1:27-35 (MART-1) melanoma Ag-reactive tumor-infiltrating lymphocyte (TIL) clones from the tumors of five patients. These MART-1-reactive clones displayed a wide variety of cellular avidities. alpha and beta TCR genes were isolated from these clones, and TCR RNA was electroporated into the same non-MART-1-reactive allogeneic donor PBMC and TIL. TCR recipient cells gained the ability to recognize both MART-1 peptide and MART-1-expressing tumors in vitro, with avidities that closely corresponded to the original TCR clones (p = 0.018-0.0003). Clone DMF5, from a TIL infusion that mediated tumor regression clinically, showed the highest avidity against MART-1 expressing tumors in vitro, both endogenously in the TIL clone, and after RNA electroporation into donor T cells. Thus, we demonstrated that the TCR appeared to be the core determinant of MART-1 Ag-specific cellular avidity in these activated T cells and that nonreactive PBMC or TIL could be made tumor-reactive with a specific and predetermined avidity. We propose that inducing expression of this highly avid TCR in patient PBMC has the potential to induce tumor regression, as an "off-the-shelf" reagent for allogeneic melanoma patient gene therapy. 相似文献
105.
Buchheit M Gindre C 《American journal of physiology. Heart and circulatory physiology》2006,291(1):H451-H458
The objective of this study was to establish the separate associations between parasympathetic modulations of the heart [evaluated through heart rate (HR) variability (HRV) indexes and postexercise HR recovery (HRR) indexes] with cardiorespiratory fitness and training load. We have measured cardiorespiratory fitness through peak oxygen consumption (Vo2 max) and estimated weekly training load with the Baecke sport score in 55 middle-aged individuals (30.8 +/- 1.8 yr, body mass index 24.5 +/- 0.4 kg/m2). HRV indexes were analyzed at rest under controlled breathing, and HRR was estimated from HR curve fitting after maximal exercise or from measurements of the number of beats recovered at 60 s after exercise. Multiple linear regressions were used to investigate the separate relationships between vagal-related HRV indexes and Vo2 max and Baecke scores. On the basis of their Vo2 max and Baecke scores, subjects were classified as fit or unfit and as low trained (LT) or moderately trained (MT), which yielded four groups: UnfitLT, UnfitMT, FitLT, and FitMT. Vagal-related HRV indexes were positively correlated with Vo2 max (P < 0.05) but not with Baecke scores. In contrast, HRR indexes were related to Baecke scores (P < 0.05) but not with Vo2 max. FitLT and FitMT had significantly higher (P < 0.05) normalized vagal-related HRV indexes than UnfitLT and UnfitMT, but HRR did not change. Moderate training was associated with significantly lower HRR indexes both in UnfitMT and FitMT compared with UnfitLT and FitLT, but there was no difference in vagal-related HRV indexes. These results indicate that vagal-related HRV indexes are related more to cardiorespiratory fitness, whereas HRR appears to be better associated with training load. 相似文献
106.
Goarant C Reynaud Y Ansquer D de Decker S Saulnier D le Roux F 《Systematic and applied microbiology》2006,29(7):570-580
A collection of 57 isolates of Vibrio nigripulchritudo from either diseased or healthy shrimp and from shrimp farms environment was studied in order to gain a better understanding of the epidemiology of this pathogen, notably isolated from two distinct shrimp disease complexes. Molecular typing using two different techniques, arbitrarily primed PCR (AP-PCR) and multi-locus sequence typing (MLST), studied together with experimental pathology data allowed a relevant epidemiological insight into this possibly emerging pathogen. Additionally, results obtained with the two molecular typing techniques were congruent and allowed discriminating the strains associated with the "Summer Syndrome" from strains isolated from other contexts, especially the other shrimp vibriosis "Syndrome 93". These results highlight that the "Summer Syndrome" is most probably caused by an emergent clonal pathogen that therefore deserves surveillance and that AP-PCR can satisfactorily be used for that purpose. 相似文献
107.
Zhijian Zhao William H. Leister Julie A. O’Brien Wei Lemaire David L. Williams Marlene A. Jacobson Cyrille Sur Gene G. Kinney Doug J. Pettibone Philip R. Tiller Sheri Smith George D. Hartman Craig W. Lindsley Scott E. Wolkenberg 《Bioorganic & medicinal chemistry letters》2009,19(5):1488-1491
Employing an iterative analogue library approach, novel potent and selective glycine transporter 1 (GlyT1) inhibitors containing a 4-pyridin-2-ylpiperidine sulfonamide have been discovered. These inhibitors are devoid of time-dependent CYP inhibition activity and exhibit improved aqueous solubility versus the corresponding 4-phenylpiperidine analogues. 相似文献
108.
Hassen Ratni Denise Blum-Kaelin Henrietta Dehmlow Peter Hartman Philippe Jablonski Raffaello Masciadri Cyrille Maugeais Angelique Patiny-Adam Narendra Panday Matthew Wright 《Bioorganic & medicinal chemistry letters》2009,19(6):1654-1657
A series of tetrahydro-cyclopenta[b]indoles modulating the activity of the liver-X-receptor (LXR) were derived from a high throughput screening hit. The potency and selectivity for LXRβ versus LXRα was improved. One compound, administered to wild-type mice modestly increased plasma HDL-cholesterol with no change in plasma triglycerides (TG) and reduced effects on liver TG content compared to T0901317. This novel series of LXR agonists shows promise to improve therapeutic efficacy with reduced potential to increase TG. 相似文献
109.
Virginie Rimbert Hubert Vidal Cyrille Debard Yves Boirie Jean-Michel Chardigny Béatrice Morio 《FEBS letters》2009,583(17):2927-32800
The association between impairment in mitochondrial muscle fat oxidative capacity (OXFA) and occurrence of insulin resistance was examined in 14 healthy trained men (age, 24 ± 4 yr) submitted to 4 weeks of training cessation. Training stop induced a significant decrease in mRNA levels of proteins involved in muscle fat metabolism, particularly PPARα (−58%, P < 0.01) and PGC-1α (−30%, P < 0.05), a 21% reduction in OXFA (P < 0.01), and reduced fat oxidation during moderately intense exercise (P < 0.05). In contrast, there was no significant alteration in insulin sensitivity. In conclusion, decline in OXFA is a rapid metabolic event following training cessation. It is involved in the regulation of whole body fat balance but not in the deterioration of insulin sensitivity. 相似文献
110.
Claire Fortunel Cyrille Violle Catherine Roumet Bruno Buatois Marie-Laure Navas Eric Garnier 《Perspectives in Plant Ecology, Evolution and Systematics》2009,11(4):267-283
Species performance depends on ecological strategies, revealed by suites of traits, conferring different relative ecological advantages in different environments. Although current knowledge on plant strategies along successional gradients is derived from studies conducted in situ, actually quantifying these strategies requires disentangling the effects of environmental factors from intrinsic differences between species.Here we tested whether allocation strategies and seed traits differ among successional stages and nitrogen levels. To this aim, we assessed biomass and nitrogen allocations and seed traits variations for 18 species, differing in life history and belonging to three stages of a Mediterranean old-field succession. These species were grown as monocultures in an experimental garden under limiting and non-limiting nitrogen supply.Early successional species allocated allometrically more nitrogen and proportionally more biomass to reproduction, and set more seeds than later successional species. Seed mass increased with successional status and was negatively related to seed number. Early successional species thus produced more but less-provisioned seeds, suggesting better colonization abilities. These patterns were not the sole consequence of the replacement of annuals by perennials along the successional gradient, since comparable trends were also observed within each life history. Allocation patterns were generally not altered by nitrogen supply and the higher nitrogen content in vegetative organs of plants grown under high nitrogen supply was not retranslocated from leaves to seeds during seed development.We therefore conclude that differences in plant ecological strategies in species characteristics from contrasting successional stages appear to be intrinsic properties of the studied species, and independent from environmental conditions. 相似文献