Ares I Aerodynamic Testing at the Boeing Polysonic Wind Tunnel

Throughout three full design analysis cycles, the Ares I project within the Constellation program has consistently relied on the Boeing Polysonic Wind Tunnel (PSWT) for aerodynamic testing of the subsonic, transonic and supersonic portions of the atmospheric flight envelope (Mach=0.5 to 4.5). Each design cycle required the development of aerodynamic databases for the 6 degree-of-freedom (DOF) forces and moments, as well as distributed line-loads databases covering the full range of Mach number, total angle-of-attack, and aerodynamic roll angle. The high fidelity data collected in this facility has been consistent with the data collected in NASA Langley s Unitary Plan Wind Tunnel (UPWT) at the overlapping condition ofMach=1.6. Much insight into the aerodynamic behavior of the launch vehicle during all phases of flight was gained through wind tunnel testing. Important knowledge pertaining to slender launch vehicle aerodynamics in particular was accumulated. In conducting these wind tunnel tests and developing experimental aerodynamic databases, some challenges were encountered and are reported as lessons learned in this paper for the benefit of future crew launch vehicle aerodynamic developments

Shut-down of type IX protein secretion alters the host immune response to Tannerella forsythia and Porphyromonas gingivalis

Tannerella forsythia and Porphyromonas gingivalis target distinct virulence factors bearing a structurally conserved C-terminal domain (CTD) to the type IX protein secretion system (T9SS). The T9SS comprises an outer membrane translocation complex which works in concert with a signal peptidase for CTD cleavage. Among prominent T9SS cargo linked to periodontal diseases are the TfsA and TfsB components of T. forsythia’s cell surface (S-) layer, the bacterium’s BspA surface antigen and a set of cysteine proteinases (gingipains) from P. gingivalis. To assess the overall role of the bacterial T9SS in the host response, human macrophages and human gingival fibroblasts were stimulated with T. forsythia and P. gingivalis wild-type bacteria and T9SS signal peptidase-deficient mutants defective in protein secretion, respectively. The immunostimulatory potential of these bacteria was compared by analyzing the mRNA expression levels of the pro-inflammatory mediators IL-6, IL-8, MCP-1 and TNF-$\alpha$ by qPCR and by measuring the production of the corresponding proteins by ELISA. Shot-gun proteomics analysis of T. forsythia and P. gingivalis outer membrane preparations confirmed that several CTD-bearing virulence factors which interact with the human immune system were depleted from the signal peptidase mutants, supportive of effective T9SS shut-down. Three and, more profoundly, 16 hours post stimulation, the T. forsythia T9SS mutant induced significantly less production of cytokines and the chemokine in human cells compared to the corresponding parent strain, while the opposite was observed for the P. gingivalis T9SS mutant. Our data indicate that T9SS shut-down translates into an altered inflammatory response in periodontal pathogens. Thus, the T9SS as a potential novel target for periodontal therapy needs further evaluation

The Effect of Fish Oil Supplementation on Resistance Training-induced Adaptations

Background: Resistance exercise training (RET) is a common and well-established method to induce hypertrophy and improvement in strength. Interestingly, fish oil supplementation (FOS) may aug-ment RET-induced adaptations. However, few studies have been conducted on young, healthy adults. Methods: A randomized, placebo-controlled design was used to determine the effect of FOS, a concentrated source of eicosapen-taenoic acid (EPA) and docosahexaenoic acid (DHA), compared to placebo (PL) on RET-induced adaptations following a 10-week RET program (3 days·week−1). Body composition was measured by dual- energy x-ray absorptiometry (LBM, fat mass [FM], percent body fat [%BF]) and strength was measured by 1-repetition maximum bar-bell back squat (1RMSQT) and bench press (1RMBP) at PRE (week 0) and POST (10 weeks). Supplement compliance was assessed via self-report and bottle collection every two weeks and via fatty acid dried blood spot collection at PRE and POST. An a priori α- level of 0.05 was used to determine statistical significance and Cohen’s d was used to quantify effect sizes (ES). Results: Twenty-one of 28 male and female participants (FOS, n = 10 [4 withdrawals]; PL, n = 11 [3 withdrawals]) completed the 10- week progressive RET program and PRE/POST measurements. After 10-weeks, blood EPA+DHA substantially increased in the FOS group (+109.7%, p\u3c .001) and did not change in the PL group (+1.3%, p = .938). Similar between-group changes in LBM (FOS: +3.4%, PL: +2.4%, p = .457), FM (FOS: −5.2%, PL: 0.0%, p = .092), and %BF (FOS: −5.9%, PL: −2.5%, p = .136) were observed, although, the between- group ES was considered large for FM (d = 0.84). Absolute and relative (kg·kg [body mass]−1) 1RMBP was significantly higher in the FOS group compared to PL (FOS: +17.7% vs. PL: +9.7%, p = .047; FOS: +17.6% vs. PL: +7.3%, p = .011; respectively), whereas absolute 1RMSQT was similar between conditions (FOS: +28.8% vs. PL: +20.5%, p = .191). Relative 1RMSQT was higher in the FOS group (FOS: +29.3% vs. PL: +17.9%, p = .045). Conclusions: When combined with RET, FOS improves absolute and relative 1RM upper-body and relative 1RM lower-body strength to a greater extent than that observed in the PL group of young, recreationally trained adults

OWA-FRPS: A Prototype Selection method based on Ordered Weighted Average Fuzzy Rough Set Theory

The Nearest Neighbor (NN) algorithm is a well-known and effective classification algorithm. Prototype Selection (PS), which provides NN with a good training set to pick its neighbors from, is an important topic as NN is highly susceptible to noisy data. Accurate state-of-the-art PS methods are generally slow, which motivates us to propose a new PS method, called OWA-FRPS. Based on the Ordered Weighted Average (OWA) fuzzy rough set model, we express the quality of instances, and use a wrapper approach to decide which instances to select. An experimental evaluation shows that OWA-FRPS is significantly more accurate than state-of-the-art PS methods without requiring a high computational cost.Spanish Government TIN2011-2848

Human Lifespan: To Live and Outlive 100 Years?

Starenje populacije je dominantno demografsko obilježje razvijenih zemalja. Stogodišnjaci su selekcionirana skupina i samo jedna od 7.000 do 10.000 osoba dosegne tu dob. Čimbenici dugovječnosti vjerojatno su brojni i uključuju gensko predodređenje (lokus na 4. kromosomu), zdrav okoliš i zdrave životne navike (prehrana s malo kalorija), redovita tjelesna i psihička aktivnost, kao i dostupnost te učinkovitost zdravstvene zaštite s primjenom geroprofi lakse. Stogodišnjaci se adaptiraju na novi život i na gubitak tjelesnih funkcija koji bivaju postupno sve izraženiji kako se dob povisuje. Granice ljudskog života produžuju se - do sada najstarija poznata osoba doživjela je 128 godina. Pojedina zemljopisna područja bilježe izrazito veći broj stogodišnjaka. Navedene su i neke dugovječne osobe s više od 100 godina u svijetu i na području Republike Hrvatske i nekih susjednih zemalja. Iako se uglavnom smatra da se granica trajanja života čovjeka ne može produžiti iznad 120 godina, za sada je ipak teško predvidjeti gdje su njezine granice.Aged population dominates in developed countries. Centenarians are a select group, and only one in 7,000 to 10,000 reach that age. Factors of longevity are numerous and include genetic predisposition (a locus on chromosome 4), environment, healthy lifestyle (hypocaloric diet, regular physical and mental exercise), accessible health services, and effi cient health protection at old age. Centenarians are well adapted to the new life and compensate for the loss of functions with age. The limits of human life are extended, so that nowadays the oldest person has reached the age of 128. Some geographic areas are characterised by higher numbers of centenarians. This article mentions a few individuals who outlived 100 years in the world, Croatia, and neighbouring countries. Although some argue that the limits of human life cannot be extended over the age of 120 years, for now we cannot predict the actual limits of human life

Increased immunogenicity of surviving tumor cells enables cooperation between liposomal doxorubicin and IL-18

<p>Abstract</p> <p>Background</p> <p>Liposomal doxorubicin (Doxil) is a cytotoxic chemotherapy drug with a favorable hematologic toxicity profile. Its active drug, doxorubicin, has interesting immunomodulatory properties. Here, the effects of Doxil on surviving tumor cell immunophenotype were investigated.</p> <p>Methods</p> <p>Using ID8 murine ovarian cancer cells, the immunomodulatory effects of Doxil were studied by measuring its impact on ovarian cancer cell expression of MHC class-I and Fas, and susceptibility to immune attack <it>in vitro</it>. To evaluate the ability of Doxil to cooperate with cancer immunotherapy, the interaction between Doxil and Interleukin 18 (IL-18), a pleiotropic immunostimulatory cytokine, was investigated <it>in vivo </it>in mice bearing ID8-Vegf tumors.</p> <p>Results</p> <p>While Doxil killed ID8 tumor cells in a dose-dependent manner, tumor cells escaping Doxil-induced apoptosis upregulated surface expression of MHC-I and Fas, and were sensitized to CTL killing and Fas-mediated death <it>in vitro</it>. We therefore tested the hypothesis that the combination of immunotherapy with Doxil provides positive interactions. Combination IL-18 and Doxil significantly suppressed tumor growth compared with either monotherapy <it>in vivo </it>and uniquely resulted in complete tumor regression and long term antitumor protection in a significant proportion of mice.</p> <p>Conclusion</p> <p>These data demonstrate that Doxil favorably changes the immunophenotype of a large fraction of the tumor that escapes direct killing thus creating an opportunity to expand tumor killing by immunotherapy, which can be capitalized through addition of IL-18 <it>in vivo</it>.</p

Phenotype-dependent apoptosis signalling in mesothelioma cells after selenite exposure

<p>Abstract</p> <p>Background</p> <p>Selenite is a promising anticancer agent which has been shown to induce apoptosis in malignant mesothelioma cells in a phenotype-dependent manner, where cells of the chemoresistant sarcomatoid phenotype are more sensitive.</p> <p>Methods</p> <p>In this paper, we investigate the apoptosis signalling mechanisms in sarcomatoid and epithelioid mesothelioma cells after selenite treatment. Apoptosis was measured with the Annexin-PI assay. The mitochondrial membrane potential, the expression of Bax, Bcl-XL, and the activation of caspase-3 were assayed with flow cytometry and a cytokeratin 18 cleavage assay. Signalling through JNK, p38, p53, and cathepsins B, D, and E was investigated with chemical inhibitors. Furthermore, the expression, nuclear translocation and DNA-binding activity of p53 was investigated using ICC, EMSA and the monitoring of p21 expression as a downstream event. Levels of thioredoxin (Trx) were measured by ELISA.</p> <p>Results</p> <p>In both cell lines, 10 μM selenite caused apoptosis and a marked loss of mitochondrial membrane potential. Bax was up-regulated only in the sarcomatoid cell line, while the epithelioid cell line down-regulated Bcl-XL and showed greater caspase-3 activation. Nuclear translocation of p53 was seen in both cell lines, but very little p21 expression was induced. Chemical inhibition of p53 did not protect the cells from apoptosis. p53 lost its DNA binding ability after selenite treatment and was enriched in an inactive form. Levels of thioredoxin decreased after selenite treatment. Chemical inhibition of MAP kinases and cathepsins showed that p38 and cathepsin B had some mediatory effect while JNK had an anti-apoptotic role.</p> <p>Conclusion</p> <p>We delineate pathways of apoptosis signalling in response to selenite, showing differences between epithelioid and sarcomatoid mesothelioma cells. These differences may partly explain why sarcomatoid cells are more sensitive to selenite.</p

The Implementation of Managed Entry Agreements in Central and Eastern Europe : Findings and Implications

Funding Information: In Bosnia and Herzegovina, both The Federation of Bosnia and Herzegovina and the Republic of Srpska, also have special funds and budgets in place for the financing of expensive medicines, which are innovative and under patent. Similar earmarked funds are available in Scotland (the New Medicines Fund funded by the Pharmaceutical Price Regulation Scheme [PPRS] rebates) [35] and England (the Cancer Drugs Fund) [36]. However, support for such earmarked funds is mixed. While they facilitate access, critics raised issues about fairness towards other disease areas and patient groups that are not eligible for special funding [3, 39]. Further, the views of a Patient and Clinician Engagement meeting in Scotland [37] and the end-of-life criteria in England [38] offer opportunities for special considerations affecting medicines for end-of-life and very rare conditions to be taken into account in the health technology assessment process. Funding Information: The authors would like to acknowledge Dr. Jan Jones from the Scottish Medicines Consortium, Scotland, for contributing to the discussion with information on Scotland, Drs. Lyudmila Bezmelnitsyna and Anastasia Isaeva for contributing to data collection in Russia and Dr. Kate?ina Podrazilov? from SZP ?R for providing information on the Czech Republic. Alessandra Ferrario was a Research Officer at the LSE Health at the time this research was conducted. She is now a postdoctoral Research Fellow at the Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, USA. Email: [email protected] No sources of funding were used for this study. The authors declare they have no conflicts of interest. However, Di?na Ar?ja, Maria Dimitrova, Jurij F?rst, Ieva Grei?i?t?-Kuprijanov, Iris Hoxha, Arianit Jakupi, Erki Laidm?e, Vanda Markovic-Pekovic, Dmitry Meshkov, Guenka Petrova, Maciej Pomorski and Patricia Vella Bonanno work directly for national health authorities or are advisers to them. Alessandra Ferrario, Tomasz Bochenek, Ileana Mardare, Dominik Tomek, Luka Voncina, Alan Haycox, Panos Kanavos,?Olga L?blov?, and Brian Godman are academics and independent researchers also working with national and regional health authorities and others to improve the quality and efficiency of prescribing, and Tarik Catic, D?vid Dank?,and Tanja Novakovic are involved with pharmaceutical, pharmacoeconomics and outcomes research groups in their countries. Olga L?blov? has also carried out remunerated consultancy activities for A&R Partners, Baxter AG and Instytut Arcana and Ileana Mardare has signed a consulting contract with Ewopharma A.G. Romania. The content of the paper and the conclusions are those of each author and may not necessarily reflect those of any organisation that employs them. Publisher Copyright: © 2017, The Author(s).Background: Managed entry agreements (MEAs) are a set of instruments to facilitate access to new medicines. This study surveyed the implementation of MEAs in Central and Eastern Europe (CEE) where limited comparative information is currently available. Method: We conducted a survey on the implementation of MEAs in CEE between January and March 2017. Results: Sixteen countries participated in this study. Across five countries with available data on the number of different MEA instruments implemented, the most common MEAs implemented were confidential discounts (n = 495, 73%), followed by paybacks (n = 92, 14%), price-volume agreements (n = 37, 5%), free doses (n = 25, 4%), bundle and other agreements (n = 19, 3%), and payment by result (n = 10, >1%). Across seven countries with data on MEAs by therapeutic group, the highest number of brand names associated with one or more MEA instruments belonged to the Anatomical Therapeutic Chemical (ATC)-L group, antineoplastic and immunomodulating agents (n = 201, 31%). The second most frequent therapeutic group for MEA implementation was ATC-A, alimentary tract and metabolism (n = 87, 13%), followed by medicines for neurological conditions (n = 83, 13%). Conclusions: Experience in implementing MEAs varied substantially across the region and there is considerable scope for greater transparency, sharing experiences and mutual learning. European citizens, authorities and industry should ask themselves whether, within publicly funded health systems, confidential discounts can still be tolerated, particularly when it is not clear which country and party they are really benefiting. Furthermore, if MEAs are to improve access, countries should establish clear objectives for their implementation and a monitoring framework to measure their performance, as well as the burden of implementation.publishersversionPeer reviewe