78 research outputs found

    Structure and function of eukaryotic fatty acid synthases

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    In all organisms, fatty acid synthesis is achieved in variations of a common cyclic reaction pathway by stepwise, iterative elongation of precursors with two-carbon extender units. In bacteria, all individual reaction steps are carried out by monofunctional dissociated enzymes, whereas in eukaryotes the fatty acid synthases (FASs) have evolved into large multifunctional enzymes that integrate the whole process of fatty acid synthesis. During the last few years, important advances in understanding the structural and functional organization of eukaryotic FASs have been made through a combination of biochemical, electron microscopic and X-ray crystallographic approaches. They have revealed the strikingly different architectures of the two distinct types of eukaryotic FASs, the fungal and the animal enzyme system. Fungal FAS is a 2·6 MDa α6β6 heterododecamer with a barrel shape enclosing two large chambers, each containing three sets of active sites separated by a central wheel-like structure. It represents a highly specialized micro-compartment strictly optimized for the production of saturated fatty acids. In contrast, the animal FAS is a 540 kDa X-shaped homodimer with two lateral reaction clefts characterized by a modular domain architecture and large extent of conformational flexibility that appears to contribute to catalytic efficienc

    Structure of the quaternary complex between SRP, SR, and translocon bound to the translating ribosome

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    During co-translational protein targeting, the signal recognition particle (SRP) binds to the translating ribosome displaying the signal sequence to deliver it to the SRP receptor (SR) on the membrane, where the signal peptide is transferred to the translocon. Using electron cryo-microscopy, we have determined the structure of a quaternary complex of the translating Escherichia coli ribosome, the SRP–SR in the ‘activated’ state and the translocon. Our structure, supported by biochemical experiments, reveals that the SRP RNA adopts a kinked and untwisted conformation to allow repositioning of the ‘activated’ SRP–SR complex on the ribosome. In addition, we observe the translocon positioned through interactions with the SR in the vicinity of the ribosome exit tunnel where the signal sequence is extending beyond its hydrophobic binding groove of the SRP M domain towards the translocon. Our study provides new insights into the mechanism of signal sequence transfer from the SRP to the translocon

    Drug-coated balloons for small coronary artery disease in patients with chronic kidney disease: a pre-specified analysis of the BASKET-SMALL 2 trial

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    Background Data on the safety and efcacy of drug-coated balloon (DCB) compared to drug-eluting stent (DES) in patients with chronic kidney disease (CKD) are scarce, particularly at long term. This pre-specifed analysis aimed to investigate the 3-year efcacy and safety of DCB versus DES for small coronary artery disease (<3 mm) according to renal function at baseline. Methods BASKET-SMALL-2 was a large multi-center, randomized, controlled trial that tested the efcacy and safety of DCBs (n=382) against DESs (n=376) in small vessel disease. CKD was defned as eGFR<60 ml/min/1.73m2 . The primary endpoint was the composite of cardiac death, non-fatal myocardial infarction, and target vessel revascularization (MACE) during 3 years. Results A total of 174/758 (23%) patients had CKD, out of which 91 were randomized to DCB and 83 to DES implantation. The primary efcacy outcome during 3 years was similar in both, DCB and DES patients (HR 0.98; 95%-CI 0.67–1.44; p=0.937) and patients with and without CKD (HR 1.18; 95%-CI 0.76–1.83; p=0.462), respectively. Rates of cardiac death and all-cause death were signifcantly higher among patients with CKD but not afected by treatment with DCB or DES. Major bleeding events were lower in the DCB when compared to the DES group (12 vs. 3, HR 0.26; 95%-CI 0.07–0.92; p=0.037) and not infuenced by presence of CKD. Conclusions The long-term efcacy and safety of DCB was similar in patients with and without CKD. The use of DCB was associated with signifcantly fewer major bleeding events (NCT 01574534)

    Impact of Insulin-Treated Compared to Non-Insulin-Treated Diabetes Mellitus on Outcome of Percutaneous Coronary Intervention with Drug-Coated Balloons versus Drug-Eluting Stents in De Novo Coronary Artery Disease: The Randomized BASKET-SMALL 2 Trial

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    Background: We evaluated the outcome of PCI of de novo stenosis with drug-coated balloons (DCB) versus drug-eluting stents (DES) in patients with insulin-treated diabetes mellitus (ITDM) versus non-insulin-treated diabetes mellitus (NITDM). Methods: Patients were randomized in the BASKET-SMALL 2 trial to DCB or DES and followed over 3 years for MACE (cardiac death, non-fatal myocardial infarction [MI], and target vessel revascularization [TVR]). Outcome in the diabetic subgroup (n = 252) was analyzed with respect to ITDM or NITDM. Results: In NITDM patients (n = 157), rates of MACE (16.7% vs. 21.9%, hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.29–1.58, p = 0.37), death, non-fatal MI, and TVR (8.4% vs. 14.5%, HR 0.30, 95% CI 0.09–1.03, p = 0.057) were similar between DCB and DES. In ITDM patients (n = 95), rates of MACE (DCB 23.4% vs. DES 22.7%, HR 1.12, 95% CI 0.46–2.74, p = 0.81), death, non-fatal MI, and TVR (10.1% vs. 15.7%, HR 0.64, 95% CI 0.18–2.27, p = 0.49) were similar between DCB and DES. TVR was significantly lower with DCB versus DES in all diabetic patients (HR 0.41, 95% CI 0.18–0.95, p = 0.038). Conclusions: DCB compared to DES for treatment of de novo coronary lesions in diabetic patients was associated with similar rates of MACE and numerically lower need for TVR both for ITDM and NITDM patients

    Haematopoietic cell transplantation in Switzerland, changes and results over 20 years: a report from the Swiss Blood Stem Cell Transplantation Working Group for Blood and Marrow Transplantation registry 1997-2016.

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    In 1997, the Swiss Blood Stem Cell Transplantation Group (SBST) initiated a mandatory national registry for all haematopoietic stem cell transplants (HCTs) in Switzerland. As of 2016, after 20 years, information was available for 7899 patients who had received an HCT (2781 allogeneic [35%] and 5118 autologous [65%]). As some patients had more than one transplant the total number of transplants was 3067 allogeneic and 6448 autologous. We compared patient characteristics and outcome of the first decade (1997-2006) and second decade (2007-2016) of the registry. There were numerous changes over time. For allogeneic HCT, transplant rates, and therefore use of HCT technology, increased from 14 to 21.8 HCTs per 1 million inhabitants per year from the first to the second decade. Likewise autologous HCTs increased from 24.8 to 37.2 annually corrected for population growth. Allogeneic transplant recipients were older (38.4 vs 48.3 years) and more frequently had unrelated donors in the second decade. Similarly, age increased for recipients of autologous HCT (50.8 vs 56.4 years). Analysis of outcome showed that the probabilities of overall and progression-free survival were stable over time, in spite of the treatment of older and higher risk patients. In multivariate analysis, nonrelapse mortality decreased in recipients of allogeneic HCT (relative risk 0.68, 95% confidence interval 0.52-0.87) over the two decades. Improvement in adjusted nonrelapse mortality compensated for the fact that higher risk patients were treated in more recent years, resulting in similar overall survival. Five-year survival probabilities were 56% (53-59%) in the first and 54% (51-57%) in the second decade for allogeneic HCT, and 59% (57-61%) in the first and 61% (59-63%) in the second decade for autologous HCT. Detailed analyses of changes over time are presented. This study included all HCTs performed in Switzerland during the period of observation and the data are useful for quality assurance programmes, healthcare cost estimation and healthcare planning. Between 50 and 60% of patients were long-term survivors after both types of HCT, indicating growing populations of surviving patients requiring long-term care and observation

    Drug-coated balloons for small coronary artery disease (BASKET-SMALL 2): an open-label randomised non-inferiority trial

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    Drug-coated balloons (DCB) are a novel therapeutic strategy for small native coronary artery disease. However, their safety and efficacy is poorly defined in comparison with drug-eluting stents (DES).; BASKET-SMALL 2 was a multicentre, open-label, randomised non-inferiority trial. 758 patients with de-novo lesions (&lt;3 mm in diameter) in coronary vessels and an indication for percutaneous coronary intervention were randomly allocated (1:1) to receive angioplasty with DCB versus implantation of a second-generation DES after successful predilatation via an interactive internet-based response system. Dual antiplatelet therapy was given according to current guidelines. The primary objective was to show non-inferiority of DCB versus DES regarding major adverse cardiac events (MACE; ie, cardiac death, non-fatal myocardial infarction, and target-vessel revascularisation) after 12 months. The non-inferiority margin was an absolute difference of 4% in MACE. This trial is registered with ClinicalTrials.gov, number NCT01574534.; Between April 10, 2012, and February 1, 2017, 382 patients were randomly assigned to the DCB group and 376 to DES group. Non-inferiority of DCB versus DES was shown because the 95% CI of the absolute difference in MACE in the per-protocol population was below the predefined margin (-3·83 to 3·93%, p=0·0217). After 12 months, the proportions of MACE were similar in both groups of the full-analysis population (MACE was 7·5% for the DCB group vs 7·3% for the DES group; hazard ratio [HR] 0·97 [95% CI 0·58-1·64], p=0·9180). There were five (1·3%) cardiac-related deaths in the DES group and 12 (3·1%) in the DCB group (full analysis population). Probable or definite stent thrombosis (three [0·8%] in the DCB group vs four [1·1%] in the DES group; HR 0·73 [0·16-3·26]) and major bleeding (four [1·1%] in the DCB group vs nine [2·4%] in the DES group; HR 0·45 [0·14-1·46]) were the most common adverse events.; In small native coronary artery disease, DCB was non-inferior to DES regarding MACE up to 12 months, with similar event rates for both treatment groups.; Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Basel Cardiovascular Research Foundation, and B Braun Medical AG

    How do high glycemic load diets influence coronary heart disease?

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    LowEx Solar Building System: Integration of PV/T Collectors into Low Exergy Building Systems

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    The integration of an unglazed solar photovoltaic/thermal (PV/T) collector to a ground source coupled heat pump system has the potential to increase the heat pump performance to a minimal SPF of 6 by providing higher average source temperature. Furthermore the integration of a PV/T collector increases the system stability and introduces new degrees of freedom in the design of renewable and zero emission energy supply for buildings. This study shows the design of a low exergy (LowEx) solar building system and its potential for the total solar energy building supply in moderate climates as in the EU and northern China. The collector array is dimensioned according to the building heat load. The area can be maximized to provide the entire yearly heat demand, without the problem of excess collector heat in summer, by employing solar ground regeneration. The low-temperature thermal collector supplies the heat needed by the heat pump to provide hot water and heating of the building, while the PV production exceeds the annual electricity demand of the heat pump and auxiliary pumps. Different hydronic circuit layouts and controls have been evaluated by simulation according to reference buildings of SHC IEA task 44 with regard to the criteria of simplicity and reliability in order to realize LowEx solar buildings. An implementation of a system that maximizes the thermal system input considering minimal internal exergetic losses is presented. A PV/T collector has been realized as prototype, installed and tested in LowEx building systems.ISSN:1876-610
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