Directed evolution of an enantioselective Bacillus subtilis lipase

Chiral compounds are of steadily increasing importance to the chemical industry, in particular for the production of pharmaceuticals. Where do these compounds come from? Apart from natural resources, two synthetic strategies are available: asymmetric chemical catalysis using transition metal catalysts and biocatalysis using enzymes. In the latter case, screening programs have identified a number of enzymes. However, their enantioselectivity is often not high enough for a desired reaction. This problem can be solved by applying directed evolution to create enantioselective enzymes as shown here for a lipase from Bacillus subtilis. The reaction studied was the asymmetric hydrolysis of meso-1,4-diacetoxy-2-cyclopentene with the formation of chiral alcohols which were detected by electrospray ionization mass spectrometry. Iterative cycles of random mutagenesis and screening allowed the identification of several variants with improved enantioselectivities. In parallel, we have started to use X-ray structural data to simulate the Bacillus subtilis lipase A-catalyzed substrate hydrolysis by using quantum mechanical and molecular mechanical calculations. This combined approach should finally enable us to devise more efficient strategies for the directed evolution of enantioselective enzymes

Mars- plus Europa-INPPS Flagship Missions with High Power Electric Thrusters and Heavy Science Payload

2020/2021 orbit calculations (DLR Bremen + MAI Moscow): 3 Orbits for one non-human MARS/EUROPA-INPPS flagship 1. Orbit Earth (11 Oct 2026) => Mars (28 Jan 2028); 2. Orbit Mars (22 Sept 2028) => Earth (29 Jul 2029); 3. Orbit Earth (12 Oct 2031) => Jupiter / Europa (6 Dec 2035) 22 ETs (for the INPPS flagship CET): example - gridded CET plate with combined ET

Non-Human + Human Deep Space Exploration: By The NEP INPPS Flagship

INPPS Flagship Structure & Subsystems, Ground Based Tests, Pure NEP, International Electric Thrusters, Humans Internationally To Mar

Humans to Mars: by MARS- plus EUROPA-INPPS Flagship Mission

The first non-human INPPS (International Nuclear Power and Propulsion System) flagship flight with orbits Earth-Mars-Earth-Jupiter/Europa (after 2025) is the most maximal space qualification test of INPPS flagship to carry out the second INPPS flagship flight to Mars with humans (in the 2030th). This high power space transportation tug is realistic because of A) the successful finalization of the European-Russian DEMOCRITOS and MEGAHIT projects with their three concepts of space, ground and nuclear demonstrators for INPPS realization (reached in 2017), B) the successful ground based test of the Russian nuclear reactor with 1MWel plus important heat dissipation solution via droplet radiators (confirmed in 2018), C) the space qualification of the Russian reactor by 2025 and D) the perfect celestial constellation for a Earth-Mars/Phobos-Earth-Jupiter/Europa trajectory between 2026 and 2035. Therefore the talk sketches the preparation status of INPPS flagship with its subsystems. Critical performance will be studied by parallel realizations of the ground and nuclear demonstrators of DEMOCRITOS (until 2025). The space qualification of INPPS with all subsystems including the nuclear reactor in the middle of the 2020th plus the INPPS tests for about one to two years - first in high Earth orbit robotic assembly phase of INPPS and later extended in nearby Earth space environment flight - means a complete concepts driven approval for all applied INPPS space subsystem technologies. It is also important to consider wider aspects for the overall mission implementation phase. Component like the nuclear reactor as the power source for the propulsion system will have to agree with the 1992 UN principles relevant to the use of nuclear power sources (NPS) in outer space. Therefore this talk will look into the legal and policy issues of nuclear space systems related to the international realization of mission design, requirements of associated safety regulations (including AI applications in the subsystems) and new aspects for INPPS flagship commercialization and new media communication on board

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline