Systems Analyses Reveal Physiological Roles and Genetic Regulators of Liver Lipid Species.

peer reviewedThe genetics of individual lipid species and their relevance in disease is largely unresolved. We profiled a subset of storage, signaling, membrane, and mitochondrial liver lipids across 385 mice from 47 strains of the BXD mouse population fed chow or high-fat diet and integrated these data with complementary multi-omics datasets. We identified several lipid species and lipid clusters with specific phenotypic and molecular signatures and, in particular, cardiolipin species with signatures of healthy and fatty liver. Genetic analyses revealed quantitative trait loci for 68% of the lipids (lQTL). By multi-layered omics analyses, we show the reliability of lQTLs to uncover candidate genes that can regulate the levels of lipid species. Additionally, we identified lQTLs that mapped to genes associated with abnormal lipid metabolism in human GWASs. This work provides a foundation and resource for understanding the genetic regulation and physiological significance of lipid species

Genetic Regulation of Plasma Lipid Species and Their Association with Metabolic Phenotypes.

The genetic regulation and physiological impact of most lipid species are unexplored. Here, we profiled 129 plasma lipid species across 49 strains of the BXD mouse genetic reference population fed either chow or a high-fat diet. By integrating these data with genomics and phenomics datasets, we elucidated genes by environment (diet) interactions that regulate systemic metabolism. We found quantitative trait loci (QTLs) for approximately 94% of the lipids measured. Several QTLs harbored genes associated with blood lipid levels and abnormal lipid metabolism in human genome-wide association studies. Lipid species from different classes provided signatures of metabolic health, including seven plasma triglyceride species that associated with either healthy or fatty liver. This observation was further validated in an independent mouse model of non-alcoholic fatty liver disease (NAFLD) and in plasma from NAFLD patients. This work provides a resource to identify plausible genes regulating the measured lipid species and their association with metabolic traits

Radiological findings of complications after lung transplantation.

Complications following lung transplantation may impede allograft function and threaten patient survival. The five main complications after lung transplantation are primary graft dysfunction, post-surgical complications, alloimmune responses, infections, and malignancy. Primary graft dysfunction, a transient ischemic/reperfusion injury, appears as a pulmonary edema in almost every patient during the first three days post-surgery. Post-surgical dysfunction could be depicted on computed tomography (CT), such as bronchial anastomosis dehiscence, bronchial stenosis and bronchomalacia, pulmonary artery stenosis, and size mismatch. Alloimmune responses represent acute rejection or chronic lung allograft dysfunction (CLAD). CLAD has three different forms (bronchiolitis obliterans syndrome, restrictive allograft syndrome, acute fibrinoid organizing pneumonia) that could be differentiated on CT. Infections are different depending on their time of occurrence. The first post-operative month is mostly associated with bacterial and fungal pathogens. From the second to sixth months, viral pneumonias and fungal and parasitic opportunistic infections are more frequent. Different patterns according to the type of infection exist on CT. Malignancy should be depicted and corresponded principally to post-transplantation lymphoproliferative disease (PTLD). In this review, we describe specific CT signs of these five main lung transplantation complications and their time of occurrence to improve diagnosis, follow-up, medical management, and to correlate these findings with pathology results. KEY POINTS: • The five main complications are primary graft dysfunction, surgical, alloimmune, infectious, and malignancy complications. • CT identifies anomalies in the setting of unspecific symptoms of lung transplantation complications. • Knowledge of the specific CT signs can allow a prompt diagnosis. • CT signs maximize the yield of bronchoscopy, transbronchial biopsy, and bronchoalveolar lavage. • Radiopathological correlation helps to understand CT signs after lung transplantation complications

X-ray Structures of the Signal Recognition Particle Receptor Reveal Targeting Cycle Intermediates

The signal recognition particle (SRP) and its conjugate receptor (SR) mediate cotranslational targeting of a subclass of proteins destined for secretion to the endoplasmic reticulum membrane in eukaryotes or to the plasma membrane in prokaryotes. Conserved active site residues in the GTPase domains of both SRP and SR mediate discrete conformational changes during formation and dissociation of the SRP·SR complex. Here, we describe structures of the prokaryotic SR, FtsY, as an apo protein and in two different complexes with a non-hydrolysable GTP analog (GMPPNP). These structures reveal intermediate conformations of FtsY containing GMPPNP and explain how the conserved active site residues position the nucleotide into a non-catalytic conformation. The basis for the lower specificity of binding of nucleotide in FtsY prior to heterodimerization with the SRP conjugate Ffh is also shown. We propose that these structural changes represent discrete conformational states assumed by FtsY during targeting complex formation and dissociation

Structures of the Signal Recognition Particle Receptor from the Archaeon Pyrococcus furiosus: Implications for the Targeting Step at the Membrane

In all organisms, a ribonucleoprotein called the signal recognition particle (SRP) and its receptor (SR) target nascent proteins from the ribosome to the translocon for secretion or membrane insertion. We present the first X-ray structures of an archeal FtsY, the receptor from the hyper-thermophile Pyrococcus furiosus (Pfu), in its free and GDP•magnesium-bound forms. The highly charged N-terminal domain of Pfu-FtsY is distinguished by a long N-terminal helix. The basic charges on the surface of this helix are likely to regulate interactions at the membrane. A peripheral GDP bound near a regulatory motif could indicate a site of interaction between the receptor and ribosomal or SRP RNAs. Small angle X-ray scattering and analytical ultracentrifugation indicate that the crystal structure of Pfu-FtsY correlates well with the average conformation in solution. Based on previous structures of two sub-complexes, we propose a model of the core of archeal and eukaryotic SRP•SR targeting complexes

Scintigraphy With Indium-labeled Leukocytes in Acute-pancreatitis

The authors assessed the clinical and prognostic value of abdominal (ASCl) and pulmonary (PSCl) scintiscans with Indium-111-labelled leukocytes in the early phase of acute pancreatitis. A grading scale was constructed for both ASCl (scored 0 to 3) and PSCl (scored 0 to 2) according to the intensity of isotope fixation versus adjacent structures. Results were compared in accordance to the presence or absence of a Ranson's score greater-than-or-equal-to 3, the presence or absence of respiratory failure and of late pancreatic complications. ASCl showed an important lack of specificity making its use uninteresting. PSCl revealed a very significant correlation with evaluation by Ranson's score and appears to have a high sensitivity and specificity to evaluate the patients who will develop ARDS or risk of ARDS. This demonstrates the pathophysiological role of leukocytes in the early phase of severe acute pancreatitis. The test might also be a reliable test for the assessment of therapeutic efficiency in acute pancreatitis

Scintigraphy with Indium-labelled leukocytes in acute pancreatitis.

The authors assessed the clinical and prognostic value of abdominal (ASCI) and pulmonary (PSCI) scintiscans with 111Indium-labelled leukocytes in the early phase of acute pancreatitis. A grading scale was constructed for both ASCI (scored 0 to 3) and PSCI (scored 0 to 2) according to the intensity of isotope fixation versus adjacent structures. Results were compared in accordance to the presence or absence of a Ranson's score greater than or equal to 3, the presence or absence of respiratory failure and of late pancreatic complications. ASCI showed an important lack of specificity making its use uninteresting. PSCI revealed a very significant correlation with evaluation by Ranson's score and appears to have a high sensitivity and specificity to evaluate the patients who will develop ARDS or risk of ARDS. This demonstrates the pathophysiological role of leukocytes in the early phase of severe acute pancreatitis. The test might also be a reliable test for the assessment of therapeutic efficiency in acute pancreatitis

Novel cross-coupling reactions between organotellurides and Grignard reagents employing a MnCl2/CuI catalytic system

We present a general protocol for the cross-coupling reaction of Grignard reagents and organic tellurides. Aryl Grignard reagents react stereospecifically with vinyl tellurides in the presence of a catalytic amount of manganese (II) chloride and copper (I) iodide to produce good yields of the corresponding cross-coupling products. (C) 2012 Published by Elsevier Ltd.FAPESPFAPESPCNPqCNPqCAPESCAPE

Numerical analysis of port diameter effect on hybrid rocket fuel regression rate with axial injection

Numerical simulations of the flowfield in a hybrid rocket motor are carried out with a Reynolds averaged Navier-Stokes solver including detailed gas surface interaction modeling based on surface mass and energy balances. Results are compared with several test data obtained from two dedicated test campaigns conducted with static firings of a laboratory-scaled hybrid rocket in which gaseous oxygen is fed into axisymmetric hydroxyl-terminated polybutadiene cylindrical grains through an axial conical subsonic nozzle. A first numerical rebuilding of all of the firing tests has been performed to validate the model, highlighting its prediction capabilities and modeling limits. Despite the several geometrical simplifications, which allowed relatively modest grid sizes to be used and efficient parametrical analysis to be performed, the presented CFD approach is fairly able to capture the main features of the motor internal ballistics both in terms of average chamber pressure and regression rate trends with oxidizer mass flux and port diameter. Computed flowfields showed the establishment of a significant recirculation region at the motor head end, which promotes propellant mixing, and raises the fuel regression rate. Numerical simulations, supported by the experimental results, demonstrated the main role played by the characteristics of this particular injection configuration in determining the fuel regression rate spatial distribution and trend, and clarified the mechanism for which the port diameter has a direct influence on the fuel regression