Recent advances in expanding the coverage of the lipidome

The lipidome comprises a large array of molecules with diverse physicochemical properties. Lipids are structural components of cells, act as a source of energy, and function as signaling mediators. Alterations in lipid metabolism are involved in the onset and progression of a variety of diseases, including metabolic syndrome and cancer. Because of this, interest in lipidomics, the comprehensive characterization of the lipidome by mass spectrometry, has intensified in recent years. However, obtaining a truly complete overview of all lipids in a sample has remained very challenging due to their enormous structural diversity. Here, we provide an overview of the collection of analytical approaches used to study various lipid classes, emphasizing innovations in sample preparation and liquid chromatography–mass spectrometry (LC–MS). Additionally, we provide practical suggestions for increasing the coverage of the lipidome

Distributed and Robust Support Vector Machine

In this paper, we consider the distributed version of Support Vector Machine (SVM) under the coordinator model, where all input data (i.e., points in R^d space) of SVM are arbitrarily distributed among k nodes in some network with a coordinator which can communicate with all nodes. We investigate two variants of this problem, with and without outliers. For distributed SVM without outliers, we prove a lower bound on the communication complexity and give a distributed (1-epsilon)-approximation algorithm to reach this lower bound, where epsilon is a user specified small constant. For distributed SVM with outliers, we present a (1-epsilon)-approximation algorithm to explicitly remove the influence of outliers. Our algorithm is based on a deterministic distributed top t selection algorithm with communication complexity of O(k log (t)) in the coordinator model. Experimental results on benchmark datasets confirm the theoretical guarantees of our algorithms

SAR Studies on the Inhibitors for the Treatment of Inflammatory Diseases

School of Molecular Sciences(Chemistry)Inflammation is defensive host response that occurs from infection and injury and the inflammatory process is the pivotal physiological response of our body and essential part of the human physiology. Due to the mechanistic relationship between chronic diseases and inflammation, a better understanding for the molecular mechanism of chronic inflammation could attenuate cellular inflammation pathways. Under inflammatory pathways, the impetus of proinflammatory mediators usually caused by the increased expression of transcriptional factors which is also a potential targets in the development of novel and effective anti-inflammatory therapeutics. Among others, we are interested in the Nuclear Factor Kappa-B (NF-??B) which is reported as a major mediator that regulates inflammatory gene expression and also decrease the prevalence of inflammation responses. To suppress the inflammatory activity, inhibitors that could selectively target this protein are needed. We therefore, chose the natural product cerulenin which has been studied widely because of its antifungal and antibacterial properties, for designing inhibitors. In light of the interesting inhibitory properties displayed by cerulenin for fatty acid synthase (FASN), we were keen to explore the possible binding mode of this natural product with a view to design various derivatives that would be amicable to synthetic manipulation in order to enable SAR studies. Potent analogues of cerulenin, with various chain lengths and substitutions, are synthesized and evaluated for their ability to inhibit NF-??B enhanceosome. Taken together, by identifying target protein with constructed inhibitors derived from cerulenin might give revolutionary effect on discovering new therapeutic agents.ope

Immune-mediated mechanisms of atherosclerosis and implications for the clinic.

A large body of evidence supports the inflammatory hypothesis of atherosclerosis, and both innate and adaptive immune responses play important roles in all disease stages. Areas covered: Here, we review our understanding of the role of the immune response in atherosclerosis, focusing on the pathways currently amenable to therapeutic modulation. We also discuss the advantages or undesirable effects that may be foreseen from targeting the immune response in patients at high cardiovascular risk, suggesting new avenues for research. Expert commentary: There is an extraordinary opportunity to directly test the inflammatory hypothesis of atherosclerosis in the clinic using currently available therapeutics. However, a more balanced interpretation of the experimental and translational data is needed, which may help address and identify in more detail the appropriate settings where an immune pathway can be targeted with minimal risk.This is the author accepted manuscript. The final version is available from Taylor & Francis at http://dx.doi.org/10.1080/1744666X.2016.1195686

Update on LIPID MAPS classification, nomenclature, and shorthand notation for MS-derived lipid structures

A comprehensive and standardized system to report lipid structures analyzed by mass spectrometry is essentialfor the communication and storage of lipidomics data. Herein, an update on both the LIPID MAPSclassification system and shorthand notation of lipid structures is presented for lipid categories Fatty Acyls(FA), Glycerolipids (GL), Glycerophospholipids (GP), Sphingolipids (SP), and Sterols (ST). With its majorchanges, i.e. annotation of ring double bond equivalents and number of oxygens, the updated shorthandnotation facilitates reporting of newly delineated oxygenated lipid species as well. For standardized reportingin lipidomics, the hierarchical architecture of shorthand notation reflects the diverse structural resolutionpowers provided by mass spectrometric assays. Moreover, shorthand notation is expanded beyond mammalianphyla to lipids from plant and yeast phyla. Finally, annotation of atoms is included for the use of stableisotope-labelled compounds in metabolic labelling experiments or as internal standards

Lipid peroxidation modifies the assembly of biological membranes "The Lipid Whisker Model"

The aim of this opinion article is to point out the basic principles that modify the assembly of biological membranes during lipid peroxidation. With this objective in mind, I describe: the structural and functional properties of membranes, the transport and diffusion of oxygen regulated by cholesterol and fatty acids; the "Lipid Whisker Model" and finally analyzed the changes induced by lipid peroxidation in membrane structure and dynamics, both at the lipid and protein level. Several reviews have appeared in recent years related to the kinetics and biology of lipid peroxidation products (Catala, 2010; Yin et al., 2011; Pinchuk and Lichtenberg, 2014; Vigor et al., 2014; Davies and Guo, 2014). The analysis of lipid peroxidation products has been particularly important in the advancement of research in this field because of the complexity of product mixtures. I also discuss the effect of other membrane modifications, triggered by lipid peroxidation products and reducing sugars. Contrary to what is expected by the LWM, Garrec et al. (2014) have recently investigated the validity of the "floating peroxyl radical" hypothesis by means of molecular modeling and predicted that the peroxyl radical does not "float" at the surface of the membrane.Facultad de Ciencias ExactasInstituto de Investigaciones Fisicoquímicas Teóricas y Aplicada

Development of mass spectrometry protocols for analysis of oxidised lipidome in inflammatory disease models:Using semi-targeted mass spectrometry based approach & optimized chromatographic separation

Phospholipid oxidation generates a wide variety of products with potentially novel biological activities that may be associated with disease pathogenesis. To understand their role in disease requires precise information about their abundance in biological samples. Liquid chromatography-mass spectrometry (LCMS) is a sensitive technique that can provide detailed information about the oxidative lipidome, but challenges still remain.The work in this thesis developed improved methods for detection of OxPLs by improvement of chromatographic separation through the comparison and optimisation of several HPLC columns such as C8, C18 and C30 reverse phase, polystyrene-divinylbenzene based monolithic, and mixed-mode hydrophilic interaction (HILIC) columns & solvent systems, with use of semi-targeted mass spectrometry approaches. The results suggests that the monolithic column was the most robust method for separating short chain oxPLs from long chain oxidised and native PLs. In addition, several approaches for method validation were explored such as testing of reproducibility and repeatability of the methods, together with the reanalysis of samples on a high resolution QToF mass spectrometer with automated quantitative data analysis using the Progenesis QI software to validate the identification. The combination of the developed methods allowed the identification of several oxPLs in biological samples. These were: i) ascites fluid of lean and obese rat model of acute pancreatitis; ii) isolated components of red blood cells (RBCs) infected with the malarial parasite Plasmodium falciparum; and iii) plasma samples of healthy and diabetic patients. In addition, an evaluation of post-acquisition data handling to minimise inherent biological variation was performed. Quantitative differences in oxPLs were observed in isolated malarial components as well as other studied disease models.Overall, several protocols were developed that provide improved performance for the identification of OxPL in biological samples that can be used as a reference method by research laboratories interested in oxidative lipidomics work