Structural and mechanistic insights into the biosynthesis of CDP-archaeol in membranes

The divergence of archaea, bacteria and eukaryotes was a fundamental step in evolution. One marker of this event is a major difference in membrane lipid chemistry between these kingdoms. Whereas the membranes of bacteria and eukaryotes primarily consist of straight fatty acids ester-bonded to glycerol-3-phosphate, archaeal phospholipids consist of isoprenoid chains ether-bonded to glycerol-1-phosphate. Notably, the mechanisms underlying the biosynthesis of these lipids remain elusive. Here, we report the structure of the CDP-archaeol synthase (CarS) of Aeropyrum pernix (ApCarS) in the CTP- and Mg(2+)-bound state at a resolution of 2.4 Å. The enzyme comprises a transmembrane domain with five helices and cytoplasmic loops that together form a large charged cavity providing a binding site for CTP. Identification of the binding location of CTP and Mg(2+) enabled modeling of the specific lipophilic substrate-binding site, which was supported by site-directed mutagenesis, substrate-binding affinity analyses, and enzyme assays. We propose that archaeol binds within two hydrophobic membrane-embedded grooves formed by the flexible transmembrane helix 5 (TM5), together with TM1 and TM4. Collectively, structural comparisons and analyses, combined with functional studies, not only elucidated the mechanism governing the biosynthesis of phospholipids with ether-bonded isoprenoid chains by CTP transferase, but also provided insights into the evolution of this enzyme superfamily from archaea to bacteria and eukaryotes.Cell Research advance online publication 29 September 2017; doi:10.1038/cr.2017.122

Ca 2+-CaM Dependent Inactivation of RyR2 Underlies Ca 2+ Alternans in Intact Heart

Rationale: Ca2+ alternans plays an essential role in cardiac alternans that can lead to ventricular fibrillation, but the mechanism underlying Ca2+ alternans remains undefined. Increasing evidence suggests that Ca2+ alternans results from alternations in the inactivation of cardiac RyR2 (ryanodine receptor 2). However, what inactivates RyR2 and how RyR2 inactivation leads to Ca2+ alternans are unknown. Objective: To determine the role of CaM (calmodulin) on Ca2+ alternans in intact working mouse hearts. Methods and results: We used an in vivo local gene delivery approach to alter CaM function by directly injecting adenoviruses expressing CaM-wild type, a loss-of-function CaM mutation, CaM (1-4), and a gain-of-function mutation, CaM-M37Q, into the anterior wall of the left ventricle of RyR2 wild type or mutant mouse hearts. We monitored Ca2+ transients in ventricular myocytes near the adenovirus-injection sites in Langendorff-perfused intact working hearts using confocal Ca2+ imaging. We found that CaM-wild type and CaM-M37Q promoted Ca2+ alternans and prolonged Ca2+ transient recovery in intact RyR2 wild type and mutant hearts, whereas CaM (1-4) exerted opposite effects. Altered CaM function also affected the recovery from inactivation of the L-type Ca2+ current but had no significant impact on sarcoplasmic reticulum Ca2+ content. Furthermore, we developed a novel numerical myocyte model of Ca2+ alternans that incorporates Ca2+-CaM-dependent regulation of RyR2 and the L-type Ca2+ channel. Remarkably, the new model recapitulates the impact on Ca2+ alternans of altered CaM and RyR2 functions under 9 different experimental conditions. Our simulations reveal that diastolic cytosolic Ca2+ elevation as a result of rapid pacing triggers Ca2+-CaM dependent inactivation of RyR2. The resultant RyR2 inactivation diminishes sarcoplasmic reticulum Ca2+ release, which, in turn, reduces diastolic cytosolic Ca2+, leading to alternations in diastolic cytosolic Ca2+, RyR2 inactivation, and sarcoplasmic reticulum Ca2+ release (ie, Ca2+ alternans). Conclusions: Our results demonstrate that inactivation of RyR2 by Ca2+-CaM is a major determinant of Ca2+ alternans, making Ca2+-CaM dependent regulation of RyR2 an important therapeutic target for cardiac alternans.This work was supported by research grants from the Heart and Stroke Foundation of Canada (G-19-0026444), the Heart and Stroke Foundation Chair in Cardiovascular Research (END611955), the Canadian Institutes of Health Research to S.R.W. Chen (PJT-155940), the Spanish Ministry of Science Innovation and Universities SAF2017-88019-C3-1R, 2R, and 3R (to L. Hove-Madsen, R. Benitez, and B. Echebarria), Marato-TV3 20152030 (to L. Hove-Madsen) and 20151110 (to B. Echebarria), and Generalitat de Catalunya SGR2017-1769 (to L. Hove-Madsen).Peer reviewe

Investigation and control of three-dimensional separation/stall in compressors

Pas de résuméAs one of the key components in the modern propulsion system, compressor plays an important role on the performance of the aero-engine. Flow near the endwall in the compressor is complex and corner separation which generates at the corner region by the blade suction surface and the endwall is an inherent flow structure in the blade passage. As a reduction of the compressor performance can be caused by the corner separation especially at off-design and multi-stage conditions. Understanding the mechanism and also control of the corner separation is an effective approach to enhance the compressor stability. Mechanism and control methods of the corner separation in the cascade passage have been investigated in this thesis, following contents are included: l. Simulation by the RANS methods on a highly-loaded PVD cascade has been conducted. The numerical method used is verified by the comparison with the experiment. The topology analysis, overall performance and the flow characteristics of the corner separation are analyzed. The effects of some aerodynamic parameters such as the solidity, aspect ratio and blade fillet on the corner separation have also been studied. 2. The control effects of one active control method by the boundary layer suction and two passive control methods by the slot at the root of the blade and the hub clearance on the corner separation in PVD cascade are studied and compared systematically. The slot configuration on the blade combined under the influence of the aerodynamic parameters have also been conducted in order to know the cascade performance by the aerodynamic parameters under the introduction of the control method. 3. Optimization of the slot configuration at 4° incidence angle is conducted on the NACA65 cascade of LMFA in Lyon. The optimized slotted cascade is verified by the experiment at three incidence angle. 4. DDES method based on the SST k - ω model is used to simulate the optimized NACA65 slotted cascade. The turbulent characteristics in the corner separation and slot jet flow are analyzed, such as the turbulent anisotropy and the velocity spectra. 5. The study of the slot configuration on the corner separation is carried out on a realistic fan stator with high loading and high Mach number. The feasibility and effectiveness of this passive control method in the practical engineering are verified

Neo-Confucians on the differentiation between living people and ghosts = Song dai li xue jia ren gui zhi bian

This dissertation studies the discussions on ghosts by the Neo-Confucians of the Song Dynasty, in particular Zhu Xi and Chen Chun. According to these thinkers, Gui (the ghost) refers to the deceased and represents the fading away of Qi (materials), and it is also part of the ancestor worship. Based on the typically Neo-Confucian interpretation of Li (principles) and Qi (materials), this dissertation demonstrates how Zhu and Chen explicated the idea of “Li persist on even though Qi fade away” by an articulation of their understanding of the ghost. The thesis consists of five chapters. The introduction summarizes previous works concerning Neo-Confucians’ discussion on Gui. It also briefly explains why the idea of Li and Qi is significant to the distinction between living people and ghosts as seen by Neo-Confucian thinkers. The definition of “Neo-Confucians” is briefly explained at the beginning of the introduction. Chapter one presents how Neo-Confucians apply the Qi theory to Gui, and their idea of an appropriate worship as intimately related to Qi, yet with its rationality lying with Li of human relations. Chapter two analyzes the Neo-Confucian idea of li gui (haunting ghosts) which is differentiated from the ghost in the ancestry worship system. For Neo-Confucians, li gui fail to understand the appropriate relation between Qi and Li and try to reject the fading away of Qi after death. In Chapter three, it is examined that Zhu Xi and Chen Chun’s opinion that living people play a role in the ghosts’ haunting because of their lack of knowledge of either Qi or Li, and suggest that they become the human form of “haunting ghosts” because of such a failure in understanding. In conclusion, the thesis suggests that the right way to live out the true potentiality of human beings is to accept the limitation of Qi but try to grasp the eternal Li through the observation of the movements of Qi.published_or_final_versionChineseMasterMaster of Philosoph

Corner Separation Control by Boundary Layer Suction Applied to a Highly Loaded Axial Compressor Cascade

Control of corner separation has attracted much interest due to its improvement of performance and energy utilization in turbomachinery. Numerical studies have been performed under both design and off-design flow conditions to investigate the effects of boundary layer suction (BLS) on corner separation in a highly loaded compressor cascade. Two new BLS slot configurations are proposed and a total of five suction slot configurations were studied and compared. Averaged static pressure rise, exit loss coefficient, passage blockage and flow turning angle have been given and compared systematically over a range of operation incidence angles. Distributions of significant loss removal, blade loading, exit deviation and total pressure loss at 3 degree and 7 degree incidence have also been studied. Under the same suction mass flows of 0.7% of the inlet mass flows, the pitchwise suction slot on the endwall shows a better optimal performance over the whole operation incidence among single suction slots. By using of the new proposed compound slot configuration with one spanwise slot on the blade suction side and one pitchwise slot on the endwall, the maximum reduction of total pressure loss at 7 degree incidence can be 39.4%

Effects of Additional Dietary Fiber Supplements on Pregnant Women with Gestational Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Studies

The efficacy of different types and doses of dietary fiber supplementation in the treatment of gestational diabetes (GDM) remains controversial. The purpose of this study is to investigate the effect of dietary fiber on blood glucose control in pregnant women with gestational diabetes mellitus, and further observe the effect on their blood lipids and pregnancy outcomes. We searched on Web of Science, PubMed, Embase, Scopus, and Cochrane, and included several articles on additional fortification with dietary fiber for gestational diabetes interventions. This meta-analysis included 8 trials. We found that additional dietary fiber supplements significantly reduced fasting glucose (Hedges’g = −0.3; 95% CI [−0.49, −0.1]), two-hour postprandial glucose (Hedges’g = −0.69; 95% CI [−0.88, −0.51]), glycated hemoglobin (Hedges’g = −0.5; 95% CI [−0.68, −0.31]), TC (Hedges’g = −0.44; 95% CI [−0.69, −0.19]), TG (Hedges’g = −0.3; 95% CI [−0.4, −0.2]) and LDL-C (Hedges’g = −0.48; 95% CI [−0.63, −0.33]). It also significantly reduced preterm delivery (Hedges’g = 0.4, 95% CI [0.19~0.84]), cesarean delivery (Hedges’g = 0.6; 95% CI [0.37~0.97]), fetal distress (Hedges’g = 0.51; 95% CI [0.22~1.19]), and neonatal weight (Hedges’g = −0.17; 95% CI [−0.27~−0.07]). In a subgroup analysis comparing dietary fiber type and dose, insoluble dietary fiber was more effective than soluble dietary fiber in reducing fasting glucose (Hedges’g = −0.44; 95% CI [−0.52, −0.35]). ≥12 g fiber per day may be more effective in improving glycemic lipid and pregnancy outcomes than <12 g/day, but the difference was not statistically significant. In conclusion, our meta-analysis showed that dietary fiber supplementation significantly improved glycolipid metabolism and pregnancy outcomes in gestational diabetes. Dietary fiber may be considered adjunctive therapy for gestational diabetes, and an additional supplement with insoluble dietary fiber is more recommended for those with poor fasting glucose. However, more high-quality studies are needed on the further effect of fiber type and the dose-effect relationship

Control of Corner Separation by Optimized Slot Configuration in a Linear Compressor Cascade

International audienc

A Test Case Generation Technique for VMM Fuzzing

Part 2: Asian Conference on Availability, Reliability and Security (AsiaARES)International audienceIn this paper, we first give a short introduction to the security situation of virtualization technology, and then analyze the implementation challenges of the CPU virtualization component of a hybrid system virtual machine with support of running a guest machine of the IA-32 instruction set. Based on a formal definition of the CPU’s execution state, we propose a fuzzing test case generation technique for both the operands and operators of instructions, which can be applied to fuzz testing the virtual machine monitor (VMM) of a hybrid system virtual machine