Identification of a novel type of polyunsaturated fatty acid synthase involved in arachidonic acid biosynthesis

AbstractArachidonic acid (ARA) is a polyunsaturated fatty acid (PUFA) and an essential component of membrane lipids. However, the PUFA synthase required for ARA biosynthesis has not been identified in any organism. To identify the PUFA synthase producing ARA, we determined the draft genome sequence of the marine bacterium Aureispira marina, which produces a high level of ARA, and found a gene cluster encoding a putative PUFA synthase for ARA production. Expression of the gene cluster in Escherichia coli induced production of ARA, demonstrating that the gene cluster encodes a PUFA synthase required for ARA biosynthesis

アラキドン酸を生産する多価不飽和脂肪酸合成酵素に関する研究

学位の種別: 課程博士審査委員会委員 : (主査)東京大学教授 和田 元, 東京大学教授 池内 昌彦, 東京大学教授 増田 建, 東京大学教授 佐藤 直樹, 東京大学教授 渡邊 雄一郎University of Tokyo(東京大学

Current Status of the Development of a Transportable and Compact VLBI System by NICT and GSI

MARBLE (Multiple Antenna Radio-interferometer for Baseline Length Evaluation) is under development by NICT and GSI. The main part of MARBLE is a transportable VLBI system with a compact antenna. The aim of this system is to provide precise baseline length over about 10 km for calibrating baselines. The calibration baselines are used to check and validate surveying instruments such as GPS receiver and EDM (Electro-optical Distance Meter). It is necessary to examine the calibration baselines regularly to keep the quality of the validation. The VLBI technique can examine and evaluate the calibration baselines. On the other hand, the following roles are expected of a compact VLBI antenna in the VLBI2010 project. In order to achieve the challenging measurement precision of VLBI2010, it is well known that it is necessary to deal with the problem of thermal and gravitational deformation of the antenna. One promising approach may be connected-element interferometry between a compact antenna and a VLBI2010 antenna. By measuring repeatedly the baseline between the small stable antenna and the VLBI2010 antenna, the deformation of the primary antenna can be measured and the thermal and gravitational models of the primary antenna will be able to be constructed. We made two prototypes of a transportable and compact VLBI system from 2007 to 2009. We performed VLBI experiments using theses prototypes and got a baseline length between the two prototypes. The formal error of the measured baseline length was 2.7 mm. We expect that the baseline length error will be reduced by using a high-speed A/D sampler

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Enhanced production of polyunsaturated fatty acids by enzyme engineering of tandem acyl carrier proteins

In some microorganisms, polyunsaturated fatty acids (PUFAs) are biosynthesized by PUFA synthases characterized by tandem acyl carrier proteins (ACPs) in subunit A. These ACPs were previously shown to be important for PUFA productivity. In this study, we examined their function in more detail. PUFA productivities increased depending on the number of ACPs without profile changes in each subunit A of eukaryotic and prokaryotic PUFA synthases. We also constructed derivative enzymes from subunit A with 5 x ACPs. Enzymes possessing one inactive ACP at any position produced similar to 30% PUFAs compared with the parental enzyme but unexpectedly had similar to 250% productivity compared with subunit A with 4 x ACPs. Enzymes constructed by replacing the 3rd ACP with an inactive ACP from another subunit A or ACP-unrelated sequences produced similar to 100% and similar to 3% PUFAs compared with the parental 3rd ACP-inactive enzyme, respectively. These results suggest that both the structure and number of ACP domains are important for PUFA productivity