Numerical investigation of nanostructured silica PCFs for sensing applications.

Photonic crystal fibers (PCFs) developed using nanostructured composite materials provide special optical properties. PCF light propagation and modal characteristics can be tailored by modifying their structural and material parameters. Structuring and infusion of liquid crystal materials enhances the capabilities of all silica PCFs, facilitating their operation in different spectral regimes. The wavelength tunability feature of nanostructured PCFs can be utilized for many advanced sensing applications. This paper discusses a new approach to modify the optical properties of PCFs by periodic nanostructuring and composite material (liquid crystal-silica) infiltration. PCF characteristics like confinement wavelength, confinement loss, mode field diameter (MFD) and bandwidth are investigated by varying the structural parameters and material infiltrations. Theoretical study revealed that composite material infusion resulted in a spectral band shift accompanied by an improvement in PCF bandwidth. Moreover, nanostructured PCFs also achieved reduced confinement losses and improved MFD which is very important in long-distance remote sensing applications

High-Affinity Inhibitors of Human NAD+-Dependent 15-Hydroxyprostaglandin Dehydrogenase: Mechanisms of Inhibition and Structure-Activity Relationships

BACKGROUND: 15-Hydroxyprostaglandin dehydrogenase (15-PGDH, EC 1.1.1.141) is the key enzyme for the inactivation of prostaglandins, regulating processes such as inflammation or proliferation. The anabolic pathways of prostaglandins, especially with respect to regulation of the cyclooxygenase (COX) enzymes have been studied in detail; however, little is known about downstream events including functional interaction of prostaglandin-processing and -metabolizing enzymes. High-affinity probes for 15-PGDH will, therefore, represent important tools for further studies. PRINCIPAL FINDINGS: To identify novel high-affinity inhibitors of 15-PGDH we performed a quantitative high-throughput screen (qHTS) by testing >160 thousand compounds in a concentration-response format and identified compounds that act as noncompetitive inhibitors as well as a competitive inhibitor, with nanomolar affinity. Both types of inhibitors caused strong thermal stabilization of the enzyme, with cofactor dependencies correlating with their mechanism of action. We solved the structure of human 15-PGDH and explored the binding modes of the inhibitors to the enzyme in silico. We found binding modes that are consistent with the observed mechanisms of action. CONCLUSIONS: Low cross-reactivity in screens of over 320 targets, including three other human dehydrogenases/reductases, suggest selectivity of the present inhibitors for 15-PGDH. The high potencies and different mechanisms of action of these chemotypes make them a useful set of complementary chemical probes for functional studies of prostaglandin-signaling pathways. ENHANCED VERSION: This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available in Text S2

PGH1, the Precursor for the Anti-Inflammatory Prostaglandins of the 1-series, Is a Potent Activator of the Pro-Inflammatory Receptor CRTH2/DP2

Prostaglandin H1 (PGH1) is the cyclo-oxygenase metabolite of dihomo-γ-linolenic acid (DGLA) and the precursor for the 1-series of prostaglandins which are often viewed as “anti-inflammatory”. Herein we present evidence that PGH1 is a potent activator of the pro-inflammatory PGD2 receptor CRTH2, an attractive therapeutic target to treat allergic diseases such as asthma and atopic dermatitis. Non-invasive, real time dynamic mass redistribution analysis of living human CRTH2 transfectants and Ca2+ flux studies reveal that PGH1 activates CRTH2 as PGH2, PGD2 or PGD1 do. The PGH1 precursor DGLA and the other PGH1 metabolites did not display such effect. PGH1 specifically internalizes CRTH2 in stable CRTH2 transfectants as assessed by antibody feeding assays. Physiological relevance of CRTH2 ligation by PGH1 is demonstrated in several primary human hematopoietic lineages, which endogenously express CRTH2: PGH1 mediates migration of and Ca2+ flux in Th2 lymphocytes, shape change of eosinophils, and their adhesion to human pulmonary microvascular endothelial cells under physiological flow conditions. All these effects are abrogated in the presence of the CRTH2 specific antagonist TM30089. Together, our results identify PGH1 as an important lipid intermediate and novel CRTH2 agonist which may trigger CRTH2 activation in vivo in the absence of functional prostaglandin D synthase

Loren Parsons' contribution to addiction neurobiology

Loren (Larry) H. Parsons passed away at the age of 51. In spite of his premature departure, Larry much contributed to the drug abuse field. Since his graduate studies for the Ph.D. in Chemistry in J.B. Justice lab, microdialysis is the tread that links Larry's research topics, namely, the role of dopamine (DA), serotonin (5-HT), gamma-aminobutyric acid (GABA), glutamate and endocannabinoids (eCBs) in drug reinforcement and dependence. Larry was the first to show that abstinence from chronic cocaine reduces extracellular DA in the NAc, consistent with the so called 'dopamine depletion hypothesis' of cocaine addiction. Another Larry's major contributions are the studies on 5-HT and 5-HT receptors' role in cocaine stimulant actions, which resulted in the identification of 5-HT1B receptors as a critical substrate of cocaine reinforcement. By applying mass spectrometry to eCBs analysis in brain dialysates, Larry's lab showed that ethanol, heroin, nicotine and cocaine differentially affect anandamide and 2-arachidonoylglicerol overflow in the NAc shell, a critical site of drugs of abuse DA stimulant actions. Larry also applied microdialysis to study GABA and glutamate's role in ethanol dependence and heroin reinforcement, providing in vivo evidence for a sensitization of corticotropin-releasing factor-dependent release of GABA in the central amygdala in withdrawal from chronic ethanol and for a reduction of GABA transmission in the ventral pallidum in heroin but not cocaine intravenous self-administration. Larry showed the wide possibilities of microdialysis as a general purpose methodology for monitoring neurotransmitters and neuromodulators in the brain extracellular compartment. From this viewpoint, he stands as the best advocate for microdialysis

Spinal glial TLR4-mediated nociception and production of prostaglandin E2 and TNF

Background and purposeToll-like receptor 4 (TLR4) expressed on spinal microglia and astrocytes has been suggested to play an important role in the regulation of pain signalling. The purpose of the present work was to examine the links between TLR4, glial activation and spinal release of prostaglandin E(2) (PGE(2)) and tumour necrosis factor (TNF), and the role these factors play in TLR4-induced tactile allodynia.Experimental approachToll-like receptor 4 was activated by intrathecal (i.t.) injection of lipopolysaccharide (LPS) and KDO(2)-Lipid A (KDO(2)) to rats. Tactile allodynia was assessed using von Frey filaments and cerebrospinal fluid collected through spinal dialysis and lumbar puncture. PGE(2) and TNF levels were measured by mass spectometry and elisa. Minocycline and pentoxifylline (glia inhibitors), etanercept (TNF-blocker) and ketorolac (COX-inhibitor) were given i.t. prior to injection of the TLR4-agonists, in order to determine if these agents alter TLR4-mediated nociception and the spinal release of PGE(2) and TNF.Key resultsSpinal administration of LPS and KDO(2) produced a dose-dependent tactile allodynia, which was attenuated by pentoxifylline, minocycline and etanercept but not ketorolac. Both TLR4 agonists induced the spinal release of PGE(2) and TNF. Intrathecal pentoxifylline blunted PGE(2) and TNF release, while i.t. minocycline only prevented the spinal release of TNF. The release of PGE(2) induced by LPS and KDO(2) was attenuated by i.t. administration of ketorolac.Conclusions and implicationsActivation of TLR4 induces tactile allodynia, which is probably mediated by TNF released by activated spinal glia