4 research outputs found

    Commercial access for UK/ESA student experiments on board the ISS

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    School students in the US have the ability tocommercially fly experiments on-board the International SpaceStation (ISS) via programmes like the Nanoracks sponsoredStudent Spaceflight Experiment Program (SSEP). Programs likeSSEP do allow international schools to participate but similarprogrammes do not currently exist within the European SpaceAgency (ESA). ESA does, however, support commercial access tospace via companies like Airbus and Kayser Italia. A key principleof SSEP is that students propose to fly experiments that will workwithin existing spaceflight hardware. This is similar to the idea ofusing standardized CubeSat platforms in education and ESA’slong-standing use of standardized Experiment Containers (ECs).These ECs form the starting point for Airbus and Kayser Italia’scommercial access programmes. In 2018 we were selected by theUK Space Agency to develop and fly a UK national payload to theISS. This payload will conduct scientific experiments proposed byourselves, international partners, and schools in the UK. Allexperiments will take place inside ECs that are refurbished, andflight qualified in the UK. If we can successfully conduct studentexperiments during this mission, we will have demonstrated thepossibility of conducting UK student experiments in space via aUK company. This should pave the way for UK-based commercialaccess to the ISS that could be used by schools much like the USbased SSEP.</div

    Novel essential amino acid supplements following resistance exercise induce aminoacidemia and enhance anabolic signaling irrespective of age: A proof-of-concept trial

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    We investigated the e ects of ingesting a leucine-enriched essential amino acid (EAA) gel alone or combined with resistance exercise (RE) versus RE alone (control) on plasma aminoacidemia and intramyocellular anabolic signaling in healthy younger (28 4 years) and older (71 3 years) adults. Blood samples were obtained throughout the three trials, while muscle biopsies were collected in the postabsorptive state and 2 h following RE, following the consumption of two 50 mL EAA gels (40% leucine, 15 g total EAA), and following RE with EAA (combination (COM)). Protein content and the phosphorylation status of key anabolic signaling proteins were determined via immunoblotting. Irrespective of age, during EAA and COM peak leucinemia (younger: 454 32 M and 537 111 M; older: 417 99 M and 553 136 M) occurred ~60–120 min post-ingestion (younger: 66 6 min and 120 60 min; older: 90 13 min and 78 12 min). In the pooled sample, the area under the curve for plasma leucine and the sum of branched-chain amino acids was significantly greater in EAA and COM compared with RE. For intramyocellular signaling, significant main e ects were found for condition (mTOR (Ser2481), rpS6 (Ser235/236)) and age (S6K1 (Thr421/Ser424), 4E-BP1 (Thr37/46)) in age group analyses. The phosphorylation of rpS6 was of similar magnitude (~8-fold) in pooled and age group data 2 h following COM. Our findings suggest that a gel-based, leucine-enriched EAA supplement is associated with aminoacidemia and a muscle anabolic signaling response, thus representing an e ective means of stimulating muscle protein anabolism in younger and older adults following EAA and COM

    Fragment-Based Discovery of a Potent, Orally Bioavailable Inhibitor That Modulates the Phosphorylation and Catalytic Activity of ERK1/2

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    Aberrant activation of the MAPK pathway drives cell proliferation in multiple cancers. Inhibitors of BRAF and MEK kinases are approved for the treatment of BRAF mutant melanoma, but resistance frequently emerges, often mediated by increased signaling through ERK1/2. Here, we describe the fragment-based generation of ERK1/2 inhibitors that block catalytic phosphorylation of downstream substrates such as RSK but also modulate phosphorylation of ERK1/2 by MEK without directly inhibiting MEK. X-ray crystallographic and biophysical fragment screening followed by structure-guided optimization and growth from the hinge into a pocket proximal to the C-α helix afforded highly potent ERK1/2 inhibitors with excellent kinome selectivity. In BRAF mutant cells, the lead compound suppresses pRSK and pERK levels and inhibits proliferation at low nanomolar concentrations. The lead exhibits tumor regression upon oral dosing in BRAF mutant xenograft models, providing a promising basis for further optimization toward clinical pERK1/2 modulating ERK1/2 inhibitors

    Fragment-Based Discovery of a Potent, Orally Bioavailable Inhibitor That Modulates the Phosphorylation and Catalytic Activity of ERK1/2

    No full text
    Aberrant activation of the MAPK pathway drives cell proliferation in multiple cancers. Inhibitors of BRAF and MEK kinases are approved for the treatment of BRAF mutant melanoma, but resistance frequently emerges, often mediated by increased signaling through ERK1/2. Here, we describe the fragment-based generation of ERK1/2 inhibitors that block catalytic phosphorylation of downstream substrates such as RSK but also modulate phosphorylation of ERK1/2 by MEK without directly inhibiting MEK. X-ray crystallographic and biophysical fragment screening followed by structure-guided optimization and growth from the hinge into a pocket proximal to the C-α helix afforded highly potent ERK1/2 inhibitors with excellent kinome selectivity. In BRAF mutant cells, the lead compound suppresses pRSK and pERK levels and inhibits proliferation at low nanomolar concentrations. The lead exhibits tumor regression upon oral dosing in BRAF mutant xenograft models, providing a promising basis for further optimization toward clinical pERK1/2 modulating ERK1/2 inhibitors
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