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281.
Pamonsinlapatham P Hadj-Slimane R Raynaud F Bickle M Corneloup C Barthelaix A Lepelletier Y Mercier P Schapira M Samson J Mathieu AL Hugo N Moncorgé O Mikaelian I Dufour S Garbay C Colas P 《PloS one》2008,3(8):e2902
The Ras GTPase-activating protein RasGAP catalyzes the conversion of active GTP-bound Ras into inactive GDP-bound Ras. However, RasGAP also acts as a positive effector of Ras and exerts an anti-apoptotic activity that is independent of its GAP function and that involves its SH3 (Src homology) domain. We used a combinatorial peptide aptamer approach to select a collection of RasGAP SH3 specific ligands. We mapped the peptide aptamer binding sites by performing yeast two-hybrid mating assays against a panel of RasGAP SH3 mutants. We examined the biological activity of a peptide aptamer targeting a pocket delineated by residues D295/7, L313 and W317. This aptamer shows a caspase-independent cytotoxic activity on tumor cell lines. It disrupts the interaction between RasGAP and Aurora B kinase. This work identifies the above-mentioned pocket as an interesting therapeutic target to pursue and points its cognate peptide aptamer as a promising guide to discover RasGAP small-molecule drug candidates. 相似文献
282.
283.
Ammar Al-Chalabi Alexandra Dürr Nicholas W. Wood Michael H. Parkinson Agnes Camuzat Jean-Sébastien Hulot Karen E. Morrison Alan Renton Sigurd D. Sussmuth Bernhard G. Landwehrmeyer Albert Ludolph Yves Agid Alexis Brice P. Nigel Leigh Gilbert Bensimon for the NNIPPS Genetic Study Group 《PloS one》2009,4(9)
Background
Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by parkinsonism, cerebellar ataxia and autonomic dysfunction. Pathogenic mechanisms remain obscure but the neuropathological hallmark is the presence of α-synuclein-immunoreactive glial cytoplasmic inclusions. Genetic variants of the α-synuclein gene, SNCA, are thus strong candidates for genetic association with MSA. One follow-up to a genome-wide association of Parkinson''s disease has identified association of a SNP in SNCA with MSA.Methodology/Findings
We evaluated 32 SNPs in the SNCA gene in a European population of 239 cases and 617 controls recruited as part of the Neuroprotection and Natural History in Parkinson Plus Syndromes (NNIPPS) study. We used 161 independently collected samples for replication. Two SNCA SNPs showed association with MSA: rs3822086 (P = 0.0044), and rs3775444 (P = 0.012), although only the first survived correction for multiple testing. In the MSA-C subgroup the association strengthened despite more than halving the number of cases: rs3822086 P = 0.0024, OR 2.153, (95% CI 1.3–3.6); rs3775444 P = 0.0017, OR 4.386 (95% CI 1.6–11.7). A 7-SNP haplotype incorporating three SNPs either side of rs3822086 strengthened the association with MSA-C further (best haplotype, P = 8.7×10−4). The association with rs3822086 was replicated in the independent samples (P = 0.035).Conclusions/Significance
We report a genetic association between MSA and α-synuclein which has replicated in independent samples. The strongest association is with the cerebellar subtype of MSA.Trial Registration
ClinicalTrials.gov . [ NCT00211224] NCT00211224相似文献284.
Biomarker discovery in biological fluids 总被引:2,自引:0,他引:2
Gao J Garulacan LA Storm SM Opiteck GJ Dubaquie Y Hefta SA Dambach DM Dongre AR 《Methods (San Diego, Calif.)》2005,35(3):291-302
Discovery of novel protein biomarkers is essential for successful drug discovery and development. These novel protein biomarkers may aid accelerated drug efficacy, response, or toxicity decision making based on their enhanced sensitivity and/or specificity. These biomarkers, if necessary, could eventually be converted into novel diagnostic marker assays. Proteomic platforms developed over the past few years have given us the ability to rapidly identify novel protein biomarkers in various biological matrices from cell cultures (lysates, supernatants) to human clinical samples (serum, plasma, and urine). In this article, we delineate an approach to biomarker discovery. This approach is divided into three steps, (i) identification of markers, (ii) prioritization of identified markers, and (iii) preliminary validation (qualification) of prioritized markers. Using drug-induced idiosyncratic hepatotoxicity as a case study, the article elaborates methods and techniques utilized during the three steps of biomarker discovery process. The first step involves identification of markers using multi-dimensional protein identification technology. The second step involves prioritization of a subset of marker candidates based on several criteria such as availability of reagent set for assay development and literature association to disease biology. The last step of biomarker discovery involves development of preliminary assays to confirm the bio-analytical measurements from the first step, as well as qualify the marker(s) in pre-clinical models, to initiate future marker validation and development. 相似文献
285.
Changes in airway resistance induced by nasal inhalation of cold dry, dry, or moist air in normal individuals 总被引:3,自引:0,他引:3
Fontanari Pierre; Burnet Henri; Zattara-Hartmann Marie Caroline; Jammes Yves 《Journal of applied physiology》1996,81(4):1739-1743
Fontanari, Pierre, Henri Burnet, Marie CarolineZattara-Hartmann, and Yves Jammes. Changes in airway resistanceinduced by nasal inhalation of cold dry, dry, or moist air in normalindividuals. J. Appl. Physiol. 81(4):1739-1743, 1996.Nasopulmonary bronchomotor reflexes elicited bymechanical or irritant stimulation of the nose have been described inanimals and asthmatic patients. However, few studies were devoted tothe consequences of nasal breathing of cold and dry air or of only dryor only moist air on the bronchomotor control in normal individuals.The present study reported changes in interruption resistance (Rint)measured during eupneic breathing of moderately cold (4 or10°C) and dry [0.3% relative humidity (RH)] airor of room air at 23°C that is either dry (0.3% RH) or moist (97%RH). Nasal inhalation of cold (4°C) dry air or of only dryair significantly increased baseline Rint value (17 and 21%,respectively) throughout the 15-min test periods. The response to cold was significantly accentuated when the air temperature was lowered to 10°C (42%). After nasal anesthesia orinhalation of a cholinergic antagonist, cold air did not induce achange in Rint. Nasal inhalation of moist room air had no effect. No Rint changes were measured during oral breathing of the three testagents. It is concluded that the activation of cold receptors orosmoreceptors in the nasal mucosa induces protective bronchoconstrictor responses in normal individuals. 相似文献
286.
Genomic sequence of Spodoptera frugiperda Ascovirus 1a, an enveloped, double-stranded DNA insect virus that manipulates apoptosis for viral reproduction 总被引:2,自引:0,他引:2 下载免费PDF全文
Bideshi DK Demattei MV Rouleux-Bonnin F Stasiak K Tan Y Bigot S Bigot Y Federici BA 《Journal of virology》2006,80(23):11791-11805
Ascoviruses (family Ascoviridae) are double-stranded DNA viruses with circular genomes that attack lepidopterans, where they produce large, enveloped virions, 150 by 400 nm, and cause a chronic, fatal disease with a cytopathology resembling that of apoptosis. After infection, host cell DNA is degraded, the nucleus fragments, and the cell then cleaves into large virion-containing vesicles. These vesicles and virions circulate in the hemolymph, where they are acquired by parasitic wasps during oviposition and subsequently transmitted to new hosts. To develop a better understanding of ascovirus biology, we sequenced the genome of the type species Spodoptera frugiperda ascovirus 1a (SfAV-1a). The genome consisted of 156,922 bp, with a G+C ratio of 49.2%, and contained 123 putative open reading frames coding for a variety of enzymes and virion structural proteins, of which tentative functions were assigned to 44. Among the most interesting enzymes, due to their potential role in apoptosis and viral vesicle formation, were a caspase, a cathepsin B, several kinases, E3 ubiquitin ligases, and especially several enzymes involved in lipid metabolism, including a fatty acid elongase, a sphingomyelinase, a phosphate acyltransferase, and a patatin-like phospholipase. Comparison of SfAV-1a proteins with those of other viruses showed that 10% were orthologs of Chilo iridescent virus proteins, the highest correspondence with any virus, providing further evidence that ascoviruses evolved from a lepidopteran iridovirus. The SfAV-1a genome sequence will facilitate the determination of how ascoviruses manipulate apoptosis to generate the novel virion-containing vesicles characteristic of these viruses and enable study of their origin and evolution. 相似文献
287.
There's no place like home: seedling mortality contributes to the habitat specialisation of tree species across Amazonia 总被引:1,自引:0,他引:1 下载免费PDF全文
Claire Fortunel C. E. Timothy Paine Paul V. A. Fine Italo Mesones Jean‐Yves Goret Benoit Burban Jocelyn Cazal Christopher Baraloto 《Ecology letters》2016,19(10):1256-1266
Understanding the mechanisms generating species distributions remains a challenge, especially in hyperdiverse tropical forests. We evaluated the role of rainfall variation, soil gradients and herbivory on seedling mortality, and how variation in seedling performance along these gradients contributes to habitat specialisation. In a 4‐year experiment, replicated at the two extremes of the Amazon basin, we reciprocally transplanted 4638 tree seedlings of 41 habitat‐specialist species from seven phylogenetic lineages among the three most important forest habitats of lowland Amazonia. Rainfall variation, flooding and soil gradients strongly influenced seedling mortality, whereas herbivory had negligible impact. Seedling mortality varied strongly among habitats, consistent with predictions for habitat specialists in most lineages. This suggests that seedling performance is a primary determinant of the habitat associations of adult trees across Amazonia. It further suggests that tree diversity, currently mostly harboured in terra firme forests, may be strongly impacted by the predicted climate changes in Amazonia. 相似文献
288.
289.
Cell wall chitosaccharides are essential components and exposed patterns of the phytopathogenic oomycete Aphanomyces euteiches 下载免费PDF全文
Badreddine I Lafitte C Heux L Skandalis N Spanou Z Martinez Y Esquerré-Tugayé MT Bulone V Dumas B Bottin A 《Eukaryotic cell》2008,7(11):1980-1993
Chitin is an essential component of fungal cell walls, where it forms a crystalline scaffold, and chitooligosaccharides derived from it are signaling molecules recognized by the hosts of pathogenic fungi. Oomycetes are cellulosic fungus-like microorganisms which most often lack chitin in their cell walls. Here we present the first study of the cell wall of the oomycete Aphanomyces euteiches, a major parasite of legume plants. Biochemical analyses demonstrated the presence of ca. 10% N-acetyl-D-glucosamine (GlcNAc) in the cell wall. Further characterization of the GlcNAc-containing material revealed that it corresponds to noncrystalline chitosaccharides associated with glucans, rather than to chitin per se. Two putative chitin synthase (CHS) genes were identified by data mining of an A. euteiches expressed sequence tag collection and Southern blot analysis, and full-length cDNA sequences of both genes were obtained. Phylogeny analysis indicated that oomycete CHS diversification occurred before the divergence of the major oomycete lineages. Remarkably, lectin labeling showed that the Aphanomyces euteiches chitosaccharides are exposed at the cell wall surface, and study of the effect of the CHS inhibitor nikkomycin Z demonstrated that they are involved in cell wall function. These data open new perspectives for the development of antioomycete drugs and further studies of the molecular mechanisms involved in the recognition of pathogenic oomycetes by the host plants. 相似文献
290.
Granich R Kahn JG Bennett R Holmes CB Garg N Serenata C Sabin ML Makhlouf-Obermeyer C De Filippo Mack C Williams P Jones L Smyth C Kutch KA Ying-Ru L Vitoria M Souteyrand Y Crowley S Korenromp EL Williams BG 《PloS one》2012,7(2):e30216