AE-C attitude determination and control prelaunch analysis and operations plan

A description of attitude control support being supplied by the Mission and Data Operations Directorate is presented. Included are descriptions of the computer programs being used to support the missions for attitude determination, prediction, and control. In addition, descriptions of the operating procedures which will be used to accomplish mission objectives are provided

Both resistance- and endurance-type exercise reduce the prevalence of hyperglycaemia in individuals with impaired glucose tolerance and in insulin-treated and non-insulin-treated type 2 diabetic patients

Aims/hypothesis The present study compares the impact of endurance- vs resistance-type exercise on subsequent 24 h blood glucose homeostasis in individuals with impaired glucose tolerance (IGT) and type 2 diabetes. Methods Fifteen individuals with IGT, 15 type 2 diabetic patients treated with exogenous insulin (INS), and 15 type 2 diabetic patients treated with oral glucose-lowering medication (OGLM) participated in a randomised crossover experiment. Participants were studied on three occasions for 3 days under strict dietary standardisation, but otherwise free-living conditions. Blood glucose homeostasis was assessed by ambulatory continuous glucose monitoring over the 24 h period following a 45 min session of resistance-type exercise (75% one repetition maximum), endurance-type exercise (50% maximum workload capacity) or no exercise at all. Results Average 24 h blood glucose concentrations were reduced from 7.4±0.2, 9.6±0.5 and 9.2±0.7 mmol/l during the control experiment to 6.9±0.2, 8.6±0.4 and 8.1±0.5 mmol/l (resistance-type exercise) and 6.8±0.2, 8.6±0.5 and 8.5±0.5 mmol/l (endurance-type exercise) over the 24 h period following a single bout of exercise in the IGT, OGLM and INS groups, respectively (p 10 mmol/l) was reduced by 35±7 and 33±11% over the 24 h period following a single session of resistanceand endurance-type exercise, respectively (p< 0.001 for both treatments). Conclusions/interpretation A single session of resistanceor endurance-type exercise substantially reduces the prevalence of hyperglycaemia during the subsequent 24 h period in individuals with IGT, and in insulin-treated and non-insulin-treated type 2 diabetic patients. Both resistance- and endurance-type exercise can be integrated in exercise intervention programmes designed to improve glycaemic control. Trial registration: Clinicaltrials.gov NCT00945165 Funding: The Netherlands Organization for Health Research and Development (ZonMw, the Netherlands). © 2011 The Author(s)

The small GTPase Rab29 is a common regulator of immune synapse assembly and ciliogenesis

Acknowledgements We wish to thank Jorge Galán, Gregory Pazour, Derek Toomre, Giuliano Callaini, Joel Rosenbaum, Alessandra Boletta and Francesco Blasi for generously providing reagents and for productive discussions, and Sonia Grassini for technical assistance. The work was carried out with the financial support of Telethon (GGP11021) and AIRC.Peer reviewedPostprin

"Resurrection of clinical efficacy" after resistance to endocrine therapy in metastatic breast cancer

BACKGROUND: In a significant proportion of metastatic breast cancer (MBC) patients whose tumour has progressed within 6 months of endocrine therapy (de novo resistance), it is generally believed that the chance of achieving clinical benefit (CB) with further endocrine therapy is minimal. METHODS: Data was retrieved from a prospectively updated database of metastatic breast cancer. Relevant data was exported to SPSS™ software for statistical analysis. RESULTS: In oestrogen receptor (ER) positive MBC patients with assessable disease, CB was achieved in 159 (71.3%) (1(st )line) patients. When these patients were put on further endocrine therapy, the CB rates were 63.2% (on 2(nd )line), 46.1% (on 3(rd )line) and 20% (on 4(th )line) with a median duration of response (DOR) in those with CB of 22, 12, 11 and 15 months respectively. The remaining 64(28.7%) patients had de novo resistance on 1(st )line endocrine therapy. Seventeen of these patients were treated with further endocrine therapy. The CB rates were 29.4% (on 2(nd )line) and 22.2% (on 3(rd )line) with a median DOR in those with CB of 22.7 months and 14 months respectively. CONCLUSION: The chance of further endocrine response continues to decrease with each line of therapy, yet CB is still seen with reasonable duration even with a 4(th )line agent. In addition, further endocrine response, with long duration, can be seen in a significant proportion of patients who have developed de novo resistance to 1(st )line endocrine therapy. The use of further endocrine therapy should not be excluded under these circumstances

The endogenous caspase-8 inhibitor c-FLIPL regulates ER morphology and crosstalk with mitochondria

Components of the death receptors-mediated pathways like caspase-8 have been identified in complexes at intracellular membranes to spatially restrict the processing of local targets. In this study, we report that the long isoform of the cellular FLICE-inhibitory protein (c-FLIPL), a well- known inhibitor of the extrinsic cell death initiator caspase-8, localizes at the endoplasmic reticulum (ER) and mitochondria-associated membranes (MAMs). ER morphology was disrupted and ER Ca2+-release as well as ER-mitochondria tethering were decreased in c-FLIP-/- mouse embryonic fibroblasts (MEFs). Mechanistically, c-FLIP ablation resulted in enhanced basal caspase-8 activation and in caspase-mediated processing of the ER-shaping protein reticulon-4 (RTN4) that was corrected by re-introduction of c-FLIPL and caspase inhibition, resulting in the recovery of a normal ER morphology and ER-mitochondria juxtaposition. Thus, the caspase-8 inhibitor c-FLIPL emerges as a component of the MAMs signaling platforms, where caspases appear to regulate ER morphology and ER-mitochondria crosstalk by impinging on ER-shaping proteins like the RTN4

Measurement of S-phase duration of adult stem cells in the flatworm Macrostomum lignano by double replication labelling and quantitative colocalization analysis

Platyhelminthes are highly attractive models for addressing fundamental aspects of stem cell biology in vivo. These organisms possess a unique stem cell system comprised of neoblasts that are the only proliferating cells during adulthood. We have investigated T-s (S-phase duration) of neoblasts during homoeostasis and regeneration in the flatworm, Macrostomum lignano. A double immunohistochemical technique was used, performing sequential pulses with the thymidine analogues CldU (chlorodeoxyuridine) and IdU (iododeoxyuridine), separated by variable chase times in the presence of colchicine. Owing to the localized nature of the fluorescent signals (cell nuclei) and variable levels of autofluorescence, standard intensity-based colocalization analyses could not be applied to accurately determine the colocalization. Therefore, an object-based colocalization approach was devised to score the relative number of double-positive cells. Using this approach, T-s (S-phase duration) in the main population of neoblasts was similar to 13 h. During early regeneration, no significant change in T-s was observed

New Algorithm to Determine True Colocalization in Combination with Image Restoration and Time-Lapse Confocal Microscopy to Map Kinases in Mitochondria

The subcellular localization and physiological functions of biomolecules are closely related and thus it is crucial to precisely determine the distribution of different molecules inside the intracellular structures. This is frequently accomplished by fluorescence microscopy with well-characterized markers and posterior evaluation of the signal colocalization. Rigorous study of colocalization requires statistical analysis of the data, albeit yet no single technique has been established as a standard method. Indeed, the few methods currently available are only accurate in images with particular characteristics. Here, we introduce a new algorithm to automatically obtain the true colocalization between images that is suitable for a wide variety of biological situations. To proceed, the algorithm contemplates the individual contribution of each pixel's fluorescence intensity in a pair of images to the overall Pearsońs correlation and Manders' overlap coefficients. The accuracy and reliability of the algorithm was validated on both simulated and real images that reflected the characteristics of a range of biological samples. We used this algorithm in combination with image restoration by deconvolution and time-lapse confocal microscopy to address the localization of MEK1 in the mitochondria of different cell lines. Appraising the previously described behavior of Akt1 corroborated the reliability of the combined use of these techniques. Together, the present work provides a novel statistical approach to accurately and reliably determine the colocalization in a variety of biological images