Activation of myeloid cell-specific adhesion class G protein-coupled receptor EMR2 via ligation-induced translocation and interaction of receptor subunits in lipid raft microdomains.

The adhesion class G protein-coupled receptors (adhesion-GPCRs) play important roles in diverse biological processes ranging from immunoregulation to tissue polarity, angiogenesis, and brain development. These receptors are uniquely modified by self-catalytic cleavage at a highly conserved GPCR proteolysis site (GPS) dissecting the receptor into an extracellular subunit (α) and a seven-pass transmembrane subunit (β) with cellular adhesion and signaling functions, respectively. Using the myeloid cell-restricted EMR2 receptor as a paradigm, we exam the mechanistic relevance of the subunit interaction and demonstrate a critical role for GPS autoproteolysis in mediating receptor signaling and cell activation.

Topiramate for the treatment of methamphetamine addiction: a multi-center placebo-controlled trial.

Aims:   Topiramate has shown efficacy at facilitating abstinence from alcohol and cocaine abuse. This double-blind, placebo-controlled out-patient trial tested topiramate for treating methamphetamine addiction.

Design:   Participants (n = 140) were randomized to receive topiramate or placebo (13 weeks) in escalating doses from 25 mg/day [DOSAGE ERROR CORRECTED] to the target maintenance of 200 mg/day in weeks 6-12 (tapered in week 13).

Metabolomics-lipidomics of eicosanoids and docosanoids generated by phagocytes.

Lipid mediators derived from essential fatty acids, such as arachidonic acid, play important roles in physiologic and pathophysiologic processes. Prostaglandins, thromboxane, and leukotrienes are well-known eicosanoids that play critical roles in hemodynamics and inflammation. New families of mediators were recently uncovered that constitute a new genus stimulating resolution of acute inflammation, and are organ-protective.

Modafinil for the treatment of methamphetamine dependence.

Aim: Modafinil was tested for efficacy in decreasing use in methamphetamine-dependent participants, compared to placebo.

Methods: This was a randomized, double-blind, placebo-controlled study, with 12 weeks of treatment and a 4-week follow-up. Eight outpatient substance abuse treatment clinics participated in the study.

Photoabsorption of Ag(n)(N∼6-6000) nanoclusters formed in helium droplets: transition from compact to multicenter aggregation.

Ag(N) clusters with up to thousands of atoms were grown in large He droplets and studied by optical spectroscopy. For N≲10(3) the spectra are dominated by a surface plasmon resonance near 3.8 eV and a broad feature in the UV, consistent with absorption by individual metallic particles.

Disease-associated GPR56 mutations cause bilateral frontoparietal polymicrogyria via multiple mechanisms.

Loss-of-function mutations in the gene encoding G protein-coupled receptor 56 (GPR56) lead to bilateral frontoparietal polymicrogyria (BFPP), an autosomal recessive disorder affecting brain development. The GPR56 receptor is a member of the adhesion-GPCR family characterized by the chimeric composition of a long ectodomain (ECD), a GPCR proteolysis site (GPS), and a seven-pass transmembrane (7TM) moiety. Interestingly, all identified BFPP-associated missense mutations are located within the extracellular region of GPR56 including the ECD, GPS, and the extracellular loops of 7TM.

Novel anti-inflammatory--pro-resolving mediators and their receptors.

Resolution of inflammation, an actively coordinated program, is essential to maintain host health. It involves effective removal of inflammatory stimuli and the spatio-temporal control of leukocyte trafficking as well as chemical mediator generation. During the active resolution process, new classes of small, local acting endogenous autacoids, namely the lipoxins, D and E series resolvins, (neuro)protectins, and maresins have been identified.

Identification of IgG(1) variants with increased affinity to FcγRIIIa and unaltered affinity to FcγRI and FcRn: comparison of soluble receptor-based and cell-based binding assays.

Clinical response to the anti-CD20 antibody rituximab has been demonstrated to correlate with the polymorphism in the FcγRIIIa receptor where patients homozygous for the higher affinity V158 allotype showed a better response rate. This finding suggests that engineering of anti-CD20 for increased FcγRIIIa affinity could result in improved clinical outcome. To identify variants with increased affinity to FcγRIIIa, we developed quantitative assays using soluble receptors as well as engineered cell lines expressing FcγRI or FcγRIIIa on the cell surface.

MicroRNAs in resolution of acute inflammation: identification of novel resolvin D1-miRNA circuits.

Mechanisms controlling resolution of acute inflammation are of wide interest. Here, we investigated microRNAs (miRNAs) in self-limited acute inflammatory exudates and their regulation by resolvin D1 (RvD1). Using real-time PCR analysis, we found in resolving exudates that miR-21, miR-146b, miR-208a, miR-203, miR-142, miR-302d, and miR-219 were selectively regulated (P<0.

Development of a two-part strategy to identify a therapeutic human bispecific antibody that inhibits IgE receptor signaling.

The development of bispecific antibodies as therapeutic agents for human diseases has great clinical potential, but broad application has been hindered by the difficulty of identifying bispecific antibody formats that exhibit favorable pharmacokinetic properties and ease of large-scale manufacturing. Previously, the development of an antibody technology utilizing heavy chain knobs-into-holes mutations and a single common light chain enabled the small-scale generation of human full-length bispecific antibodies. Here we have extended the technology by developing a two-part bispecific antibody discovery strategy that facilitates proof-of-concept studies and clinical candidate antibody generation.

Nanomaterial-based surface-assisted laser desorption/ionization mass spectrometry of peptides and proteins.

We have investigated six nanomaterials for their applicability as surfaces for the analyses of peptides and proteins using surface-assisted laser desorption/ionization mass spectrometry (SALDI-MS). Gold nanoparticles (NPs) were useful nanomaterials for small analytes (e.g.

Resolvin D1 binds human phagocytes with evidence for proresolving receptors.

Endogenous mechanisms that act in the resolution of acute inflammation are essential for host defense and the return to homeostasis. Resolvin D1 (RvD1), biosynthesized during resolution, displays potent and stereoselective anti-inflammatory actions, such as limiting neutrophil infiltration and proresolving actions. Here, we demonstrate that RvD1 actions on human polymorphonuclear leukocytes (PMNs) are pertussis toxin sensitive, decrease actin polymerization, and block LTB(4)-regulated adhesion molecules (beta2 integrins).

Detection of aminothiols through surface-assisted laser desorption/ionization mass spectrometry using mixed gold nanoparticles.

We have employed mixtures of two differently sized (average diameters: 3.5 and 14 nm) gold nanoparticles (Au NPs) as selective probes and matrices for the determination of aminothiols using surface-assisted laser desorption/ionization mass spectrometry (SALDI-MS). When using 38 and 150 pM solutions of the 3.

Modafinil for the treatment of cocaine dependence.

Aim: Modafinil was tested for efficacy in facilitating abstinence in cocaine-dependent patients, compared to placebo.

Methods: This was a double-blind placebo-controlled study, with 12 weeks of treatment and a 4-week follow-up. Six outpatient substance abuse treatment clinics participated in the study.

Multi-center trial of baclofen for abstinence initiation in severe cocaine-dependent individuals.

Cocaine dependence is a major public health problem for which there is no FDA-approved pharmacological treatment. Baclofen is a GABA(B) receptor agonist that in preclinical and early pilot clinical trials has shown promise for the treatment of cocaine dependence. The purpose of this multi-site, double-blind study, was to compare the safety and efficacy of baclofen (60 mg/day) vs placebo in an 8-week treatment of individuals with severe cocaine dependence.

Anti-angiogenesis effect of the novel anti-inflammatory and pro-resolving lipid mediators.

Purpose: Resolvins and lipoxins are lipid mediators generated from essential polyunsaturated fatty acids that are the first dual anti-inflammatory and pro-resolving signals identified in the resolution phase of inflammation. Here the authors investigated the potential of aspirin-triggered lipoxin (LX) A4 analog (ATLa), resolving (Rv) D1, and RvE1, in regulating angiogenesis in a murine model.

Methods: ATLa and RvE1 receptor expression was tested in different corneal cell populations by RT-PCR.

Expression of nitric oxide synthase during germ cell apoptosis in testis of cynomolgus monkey after testosterone and heat treatment.

This study investigates the possible involvement of nitric oxide synthase (NOS) in activating germ cell death in monkeys after mild testicular hyperthermia and/or hormonal deprivation. Groups of 8 adult male monkeys received 1 of the following treatments for 12 weeks: 1) 2 empty Silastic implants, 2) 2 testosterone (T) implants, 3) daily exposure of testes to heat (43 degrees C for 30 minutes) for 2 consecutive days, or 4) 2 T implants plus testicular heat exposure. Testicular biopsies were performed before and on days 3, 8, 28, and 84 of the treatment.

Evaluation of surgical performance using V-POSSUM risk-adjusted mortality rates.

Vascular-Physiological and Operative Severity Score for the enUmeration of Mortality and Morbidity (V-POSSUM) is a risk-adjusted scoring system for predicting 30-day mortality in patients undergoing vascular surgery. It can assess surgical performance by comparing predicted deaths with observed deaths. The aim of this analysis was to assess trends in surgical performance over time using risk-adjusted 30-day mortality as the primary outcome.

Resolvin E1, an EPA-derived mediator in whole blood, selectively counterregulates leukocytes and platelets.

Resolvin E1 (RvE1) is an omega-3 eicosapentaenoic acid (EPA)-derived lipid mediator generated during resolution of inflammation and in human vasculature via leukocyte-endothelial cell interactions. RvE1 possesses anti-inflammatory and proresolving actions. Here, we report that RvE1 in human whole blood rapidly regulates leukocyte expression of adhesion molecules.

Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators.

Active resolution of acute inflammation is a previously unrecognized interface between innate and adaptive immunity. Once thought to be a passive process, the resolution of inflammation is now shown to involve active biochemical programmes that enable inflamed tissues to return to homeostasis. This Review presents new cellular and molecular mechanisms for the resolution of inflammation, revealing key roles for eicosanoids, such as lipoxins, and recently discovered families of endogenous chemical mediators, termed resolvins and protectins.

Anesthetics impact the resolution of inflammation.

Background: Local and volatile anesthetics are widely used for surgery. It is not known whether anesthetics impinge on the orchestrated events in spontaneous resolution of acute inflammation. Here we investigated whether a commonly used local anesthetic (lidocaine) and a widely used inhaled anesthetic (isoflurane) impact the active process of resolution of inflammation.

The SRPHK1 outcome measure for cocaine-dependence trials combines self-report, urine benzoylecgonine levels, and the concordance between the two to determine a cocaine-use status for each study day.

Background: There is currently no FDA-approved medication for cocaine dependence and no standard primary outcome measure for reduction of cocaine use in cocaine-dependence trials. The ability to detect a significant medication effect will depend, in part, on the primary outcome measure utilized. The goal of the present paper is to compare self-report or either of two urine toxicology measures used alone to a relatively new measure -- the SRPHK1 -- which combines self-report, quantitative urine benzoylecgonine levels, and an estimate of the concordance between the two to determine the cocaine-use status of each study day.

Endogenous pro-resolving and anti-inflammatory lipid mediators: a new pharmacologic genus.

Complete resolution of an acute inflammatory response and its return to homeostasis are essential for healthy tissues. Here, we overview ongoing efforts to characterize cellular and molecular mechanisms that govern the resolution of self-limited inflammation. Systematic temporal analyses of evolving inflammatory exudates using mediator lipidomics-informatics, proteomics, and cellular trafficking with murine resolving exudates demonstrate novel endogenous pathways of local-acting mediators that share both anti-inflammatory and pro-resolving properties.

Learning geographical information from hypothetical maps.

People show biases or distortions in their geographical judgments, such as mistakenly judging Rome to be south of Chicago (the Chicago-Rome illusion). These errors may derive from either perceptual heuristics or categorical organization. However, previous work on geographic knowledge has generally examined people's judgments of real-world locations for which learning history is unknown.

Bupropion for the treatment of methamphetamine dependence.

Bupropion was tested for efficacy in increasing weeks of abstinence in methamphetamine-dependent patients, compared to placebo. This was a double-blind placebo-controlled study, with 12 weeks of treatment and a 30-day follow-up. Five outpatient substance abuse treatment clinics located west of the Mississippi participated in the study.