Efficacy response in CF patients treated with ivacaftor: Post-hoc analysis

Clinical studies in patients with cystic fibrosis and G551D-CFTR showed that the group treated with ivacaftor had improved clinical outcomes. To better understand the effect of ivacaftor therapy across the distribution of individual FEV1 responses, data from Phase 3 studies (STRIVE/ENVISION) were re-examined. In this post-hoc analysis of patients (n=209) who received 48 weeks of ivacaftor or placebo, patients were assigned to tertiles according to FEV1 response. These groups were then used to evaluate response (FEV1, sweat chloride, weight, CFQ-R, and pulmonary exacerbation). The number needed to treat (NNT) was calculated for specific thresholds for each outcome. Across all tertiles, numerical improvements in FEV1, sweat chloride, CFQ-R and the frequency of pulmonary exacerbations were observed in ivacaftor-treated patients: the treatment difference versus placebo was statistically significant for all outcomes in the upper tertile and for some outcomes in the lower and middle tertiles. The NNT for a≥5% improvement in %predicted FEV1 was 1.90, for a≥5% body weight increase was 5.74, and to prevent a pulmonary exacerbation was 3.85. This analysis suggests that the majority of patients with clinical characteristics similar to STRIVE/ENVISION patients have the potential to benefit from ivacaftor therapy.

Long-term macrolide maintenance therapy in non-CF bronchiectasis: Evidence and questions

Phenotypic characterization of an international Pseudomonas aeruginosa reference panel: strains of cystic fibrosis (CF) origin show less in vivo virulence than non-CF strains

Pseudomonas aeruginosa causes chronic lung infections in people with cystic fibrosis (CF) and acute opportunistic infections in people without CF. Forty two P. aeruginosa strains from a range of clinical and environmental sources were collated into a single reference strain panel to harmonise research on this diverse opportunistic pathogen. To facilitate further harmonized and comparable research on P. aeruginosa, we characterised the panel strains for growth rates, motility, virulence in the Galleria mellonella infection model, pyocyanin and alginate production, mucoid phenotype, lipopolysaccharide (LPS) pattern, biofilm formation, urease activity, antimicrobial and phage susceptibilities. Phenotypic diversity across the P. aeruginosa panel was apparent for all phenotypes examined agreeing with the marked variability seen in this species. However, except for growth rate, the phenotypic diversity among strains from CF versus non-CF sources was comparable. CF strains were less virulent in the G. mellonella model than non-CF strains (p=0.037). Transmissible CF strains generally lacked O antigen, produced less pyocyanin, and had low virulence in G. mellonella. Further, in the three sets of sequential CF strains, virulence, O-antigen expression and pyocyanin production were higher in the earlier isolate compared to the isolate obtained later in infection. Overall, full phenotypic characterization of the defined panel of P. aeruginosa strains increases our understanding of the virulence and pathogenesis of P. aeruginosa and may provide a valuable resource for the testing of novel therapies against this problematic pathogen.

Nano-CF: a Coordination Framework for macro-programming in wireless sensor networks

Wireless Sensor Networks (WSN) are being used for a number of applications involving infrastructure monitoring, building energy monitoring and industrial sensing. The difficulty of programming individual sensor nodes and the associated overhead have encouraged researchers to design macro-programming systems which can help program the network as a whole or as a combination of subnets. Most of the current macro-programming schemes do not support multiple users seamlessly deploying diverse applications on the same shared sensor network. As WSNs are becoming more common, it is important to provide such support, since it enables higher-level optimizations such as code reuse, energy savings, and traffic reduction. In this paper, we propose a macro-programming framework called Nano-CF, which, in addition to supporting in-network programming, allows multiple applications written by different programmers to be executed simultaneously on a sensor networking infrastructure. This framework enables the use of a common sensing infrastructure for a number of applications without the users having to worrying about the applications already deployed on the network. The framework also supports timing constraints and resource reservations using the Nano-RK operating system. Nano- CF is efficient at improving WSN performance by (a) combining multiple user programs, (b) aggregating packets for data delivery, and (c) satisfying timing and energy specifications using Rate- Harmonized Scheduling. Using representative applications, we demonstrate that Nano-CF achieves 90% reduction in Source Lines-of-Code (SLoC) and 50% energy savings from aggregated data delivery.

Recueil de pièces originales, copies et gravures, formé par GAIGNIÈRES sur les duels et les combats. I Gravures allemandes représentant des duels (fol. 6), tournois et combats, signées « L. C. 1506 » [Lucas de Cranach] (fol. 8), « L. C. 1509 » (fol. 44 et suiv.) en triple exemplaire, et 71). [Cf. Bartsch, Le peintre-graveur, nos 124, 125, 126.] — Gravure de [Jacques Androuet-Ducerceau], avec légende, représentant Le chien de Montargis ou « Le combat d'un chien contre un gentilhomme qui avoit tué son maistre » (fol. 10).

Cartel, en italien, de Cagnino di Gonzaga à Cesare Fregoso. Bozolo,31 juillet 1539 (fol. 112), orig. imprimé, avec le sceau de Gonzaga. — Extraits des Mémoires de Sully (fol. 14). — Duels de Jean de Harcourt et Guillaume III de Tancarville, 1286 (fol. 20), — Raymond du Marcadil de Penne en Agenois et Étienne Donnadieu, 1330 (fol. 24), — M. de Sauvebeuf et Peyrot de Rastinhac, 1587 (fol. 26), — baron de Conros et Carbonat (fol. 29), — Louis de Loudierche, de Grizol et de Cheyladet, 1612 (fol 31, 59), — MM. de Candale et de Schomberg (fol. 36), — combat de la Barrière, 1605 (fol. 37). — Édit de Henri IV défendant les duels (fol. 39). — Accords faits par le connétable, les maréchaux de France et les lieutenants généraux des provinces entre MM. de Clermont et de S. Gery d'Avignon (fol. 50), — de Reilhac et de Drageac (fol. 53), — le duc de Nevers et M. de Montpensier, 1580 (fol. 55), — de Brezolles et de Carluz de Calvimond, 1610 (fol. 57), — de Naves et de Montaignac, 1613 (fol. 61), — le comte de Sault et M. de Brissac, 1638 (fol. 62). — Extraits du « stylus antiquus Parlamenti Parisiensis Caroli Molinoei », éd. 1558 (fol. 66, 72, 74, 156), — du « Coustumier de Normendie », éd. 1539 (fol. 76). — Duels de Jacques Le Gris et Jean de Carouges, 1387 (fol. 84) et autres duels extraits de Froissart (fol. 99 et suiv.). — Lettre orig. de Gaucher de Dinteville à Mgr le Dauphin [Henri II], Venise, 20 décembre 1538 (fol. 142). — « Les Cartelz, reponces et procès-verbaux du different d'entre le sieur de Vassé et le comte Guillaume de Furstenberg, 1540 (fol. 144).

Circadian Pattern of Wheel-Running Activity of a South American Subterranean Rodent (Ctenomys cf knightii)

Circadian rhythms are regarded as essentially ubiquitous features of animal behavior and are thought to confer important adaptive advantages. However, although circadian systems of rodents have been among the most extensively studied, most comparative biology is restricted to a few related species. In this study, the circadian organization of locomotor activity was studied in the subterranean, solitary north Argentinean rodent, Ctenomys knightii. The genus, Ctenomys, commonly known as Tuco-tucos, comprises more than 50 known species over a range that extends from 12S latitude into Patagonia, and includes at least one social species. The genus, therefore, is ideal for comparative and ecological studies of circadian rhythms. Ctenomys knightii is the first of these to be studied for its circadian behavior. All animals were wild caught but adapted quickly to laboratory conditions, with clear and precise activity-rest rhythms in a light-dark (LD) cycle and strongly nocturnal wheel running behavior. In constant dark (DD), the rhythm expression persisted with free-running periods always longer than 24h. Upon reinstatement of the LD cycle, rhythms resynchronized rapidly with large phase advances in 7/8 animals. In constant light (LL), six animals had free-running periods shorter than in DD, and 4/8 showed evidence of splitting. We conclude that under laboratory conditions, in wheel-running cages, this species shows a clear nocturnal rhythmic organization controlled by an endogenous circadian oscillator that is entrained to 24h LD cycles, predominantly by light-induced advances, and shows the same interindividual variable responses to constant light as reported in other non-subterranean species. These data are the first step toward understanding the chronobiology of the largest genus of subterranean rodents.

The P-Loop domain of yeast Clp1 mediates interactions between CF IA and CPF factors in Pre-mRNA 3′ end formation

 Cleavage factor IA (CF IA), cleavage and polyadenylation factor (CPF), constitute major protein complexes required for pre-mRNA 3' end formation in yeast. The Clp1 protein associates with Pcf11, Rna15 and Rna14 in CF IA but its functional role remained unclear. Clp1 carries an evolutionarily conserved P-loop motif that was previously shown to bind ATP. Interestingly, human and archaean Clp1 homologues, but not the yeast protein, carry 5' RNA kinase activity. We show that depletion of Clp1 in yeast promoted defective 3' end formation and RNA polymerase II termination; however, cells expressing Clp1 with mutant P-loops displayed only minor defects in gene expression. Similarly, purified and reconstituted mutant CF IA factors that interfered with ATP binding complemented CF IA depleted extracts in coupled in vitro transcription/3' end processing reactions. We found that Clp1 was required to assemble recombinant CF IA and that certain P-loop mutants failed to interact with the CF IA subunit Pcf11. In contrast, mutations in Clp1 enhanced binding to the 3' endonuclease Ysh1 that is a component of CPF. Our results support a structural role for the Clp1 P-loop motif. ATP binding by Clp1 likely contributes to CF IA formation and cross-factor interactions during the dynamic process of 3' end formation.

Ecologia alimentar e reprodutiva da piaba-do-rabo-amarelo, Astyanax cf. lacustris (Reinhardt, 1874) (Osteichthyes: Characidae) na Lagoa do Piató, Assu, Rio Grande do Norte, Brasil

The feeding habits and biological aspects of the reproductive cycle of two-spot astyanax, Astyanax cf. lacustris (Reinhardt, 1874) were investigated. Fish samples were captured on a monthly basis, using gillnets of 4 cm mesh size, from the Piató Lake, Assu, Rio Grande do Norte, during the period of September, 2006 to August, 2007. Physico-chemical parameters, such as, temperature, electrical conductivity and dissolved oxygen of the lake were registered. The monthly values of rainfall also were obtained. The 360 individuals captured, were measured, weighed, dissected, and stomach weight and the stage of gonadal maturity were registered. The stomach contents analyses were carried out based on volumetric method, points, frequency of occurrence and applying the Index of Relative Importance. The degrees of repletion of the stomachs were determined besides the Index of Repletion relating to feeding activity variations and frequency of ingestion with limnological parameters and rainfall. The food items identified were separated into distinct groups according to their origin. Sex ratio and Gonadosomatic Relation of females were verified to determine the spawning period and fecundity. The physico-chemical parameters presented the following annual mean values: temperature = 28.8ºC, electrical conductivity = 992.5 µS.cm-1; dissolved oxygen = 4.9 mg.L-1 during the study period. The annual mean of the rainfall was 63.5 mm. The results indicate that this species present an omnivorous feeding habit with a tendency towards insectivory, with an increase in feeding activity during the dry season. The aquatic oxygen to interfere very importance in the feeding activity than the others factors physico-chemicals of water and rainfall. There was a predominance of females, with a sex proportion of 1M:7F. The macroscopic characteristics of the ovaries and testicles revealed four stages of gonadal development: immature, maturing, mature and spent. A temporal variation was observed for the gonadal development of males and females. There was reproductive activity through out the year, with peaks in the months of February, April and June to correspond with the rain of precipitation of the region. The mean fecundity was 7.681 mature oocytes, varying from 4.476 to 12.036, with mean of 7.681. There was positive relation between fecundity and body mass. Condition Factor is not an efficient indicator of the reproductive period of this species. The species A. cf. lacustris is an opportunist and is well adapted to the conditions of the semi-arid Caatinga Biome