Lipidomics at the Interface of Structure and Function in Systems Biology

Cells, tissues, and biological fluids contain a diverse repertoire of many tens of thousands of structurally distinct lipids that play multiple roles in cellular signaling, bioenergetics, and membrane structure and function. In an era where lipid-related disease states predominate, lipidomics has assumed a prominent role in systems biology through its unique ability to directly identify functional alterations in multiple lipid metabolic and signaling networks. The development of shotgun lipidomics has led to the facile accrual of high density information on alterations in the lipidome mediating physiologic cellular adaptation during health and pathologic alterations during disease. Through both targeted and nontargeted investigations, lipidomics has already revealed the chemical mechanisms underlying many lipid-related disease states

The foundations and development of lipidomics

For over a century, the importance of lipid metabolism in biology was recognized but difficult to mechanistically understand due to the lack of sensitive and robust technologies for identification and quantification of lipid molecular species. The enabling technological breakthroughs emerged in the 1980s with the development of soft ionization methods (Electrospray Ionization and Matrix Assisted Laser Desorption/Ionization) that could identify and quantify intact individual lipid molecular species. These soft ionization technologies laid the foundations for what was to be later named the field of lipidomics. Further innovative advances in multistage fragmentation, dramatic improvements in resolution and mass accuracy, and multiplexed sample analysis fueled the early growth of lipidomics through the early 1990s. The field exponentially grew through the use of a variety of strategic approaches, which included direct infusion, chromatographic separation, and charge-switch derivatization, which facilitated access to the low abundance species of the lipidome. In this Thematic Review, we provide a broad perspective of the foundations, enabling advances, and predicted future directions of growth of the lipidomics field

Shotgun lipidomics identifies a paired rule for the presence of isomeric ether phospholipid molecular species

BACKGROUND: Ether phospholipids are abundant membrane constituents present in electrically active tissues (e.g., heart and the brain) that play important roles in cellular function. Alterations of ether phospholipid molecular species contents are associated with a number of genetic disorders and human diseases. METHODOLOGY/PRINCIPAL FINDINGS: Herein, the power of shotgun lipidomics, in combination with high mass accuracy/high resolution mass spectrometry, was explored to identify a paired rule for the presence of isomeric ether phospholipid molecular species in cellular lipidomes. The rule predicts that if an ether phospholipid A′-B is present in a lipidome, its isomeric counterpart B′-A is also present (where the ′ represents an ether linkage). The biochemical basis of this rule results from the fact that the enzymes which participate in either the sequential oxidation of aliphatic alcohols to fatty acids, or the reduction of long chain fatty acids to aliphatic alcohols (metabolic precursors of ether lipid synthesis), are not entirely selective with respect to acyl chain length or degree of unsaturation. Moreover, the enzymatic selectivity for the incorporation of different aliphatic chains into the obligatory precursor of ether lipids (i.e., 1-O-alkyl-glycero-3-phosphate) is also limited. CONCLUSIONS/SIGNIFICANCE: This intrinsic amplification of the number of lipid molecular species present in biological membranes predicted by this rule and demonstrated in this study greatly expands the number of ether lipid molecular species present in cellular lipidomes. Application of this rule to mass spectrometric analyses provides predictive clues to the presence of specific molecular species and greatly expands the number of identifiable and quantifiable ether lipid species present in biological samples. Through appropriate alterations in the database, use of the paired rule increases the number of identifiable metabolites in metabolic networks, thereby facilitating identification of biomarkers presaging disease states

Critical Behaviour of a Fermionic Random Matrix Model at Large-N

We study the large-$N$ limit of adjoint fermion one-matrix models. We find one-cut solutions of the loop equations for the correlators of these models and show that they exhibit third order phase transitions associated with $m$-th order multi-critical points with string susceptibility exponents $\gamma_{\rm str}=-1/m$. We also find critical points which can be interpreted as points of first order phase transitions, and we discuss the implications of this critical behaviour for the topological expansion of these matrix models.Comment: 14 pages LaTeX; UBC/S-94/

Pain Experiences and Their Relation to Opioid Misuse Risk and Emotion Dysregulation

Pain is a complex, multidimensional experience but often is measured as a unidimensional experience. This study aimed to separately assess the sensory and affective components of pain and identify their relations to important pain-related outcomes, particularly in terms of opioid misuse risk and emotion dysregulation among patients with chronic pain receiving treatment in Appalachia. Two hundred and twelve patients presenting to a multidisciplinary pain center completed the Difficulties in Emotion Regulation Scale (DERS-18), Screener and Opioid Assessment for Patients with Pain—Revised (SOAPP-R), and short-form McGill Pain Questionnaire (SF-MPQ). The sensory experience of pain was unrelated to emotion dysregulation (r = 0.06, p = 0.57) and weakly related to opioid misuse risk (r = 0.182, p \u3c 0.05). In contrast, the affective experience of pain was moderately related to emotion dysregulation (r = 0.217, p \u3c 0.05) and strongly related to opioid misuse risk (r = 0.37, p \u3c 0.01). In addition, emotion dysregulation predicted variance in opioid misuse risk above and beyond the affective and sensory experiences of pain ((b = 0.693, p \u3c 0.001). The results suggest patients with a strong affective experience versus sensory experience of pain and challenges with emotion regulation may require a more comprehensive intervention to address these underlying components in order to reduce their risk of misusing opioid medications

Long-term potentiation requires activation of calcium-independent phospholipase A2

AbstractThe predominant phospholipase activity present in rat hippocampus is a calcium-independent phospholipase A2 (302.9 ± 19.8 pmol/mg·min for calcium-independent phospholipase A2 activity vs. 14.6 ± 1.0 pmol/mg·min for calcium-dependent phospholipase A2 activity). This calcium-independent phospholipase A2 is exquisitely sensitive to inhibition by the mechanism-based inhibitor, (E)-6-(bromomethylene)-tetrahydro-3-(1-naphthalenyl)-2H-pyran -2-one (BEL). Moreover, treatment of hippocampal slices with BEL prior to tetanic stimulation prevents the induction of LTP (40.8 ± 5.6% increase in excitatory postsynaptic potential (EPSP) slope for control slices (n = 6) vs. 5.8 ± 8.5% increase in EPSP slope for BEL-treated slices (n = 8)). Importantly, LTP can be induced following mechanism-based inhibition of phospholipase A2 by providing the end product of the phospholipase A2 reaction, arachidonic acid, during the application of tetanic stimulation. Furthermore, the induction of LTP after treatment with BEL is dependent on the stereoelectronic configuration of the fatty acid provided since eicosa-5,8,11-trienoic acid, but not eicosa-8,11,14-trienoic acid, rescues LTP after BEL treatment (37.6 ± 16.1% increase in EPSP slope for eicosa-5,8,11-trienoic acid vs. −3.7 ± 5.2% increase in EPSP slope for eicosa-8,11,14-trienoic acid). Collectively, these results provide the first demonstration of the essential role of calcium-independent phospholipase A2 in synaptic plasticity