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Ma X.,Genentech | Lin W.Y.,Genentech | Chen Y.,Genentech | Stawicki S.,Genentech | And 6 more authors.
Structure | Year: 2012

Lacking any discernible sequence similarity, interleukin-34 (IL-34) and colony stimulating factor 1 (CSF-1) signal through a common receptor CSF-1R on cells of mononuclear phagocyte lineage. Here, the crystal structure of dimeric IL-34 reveals a helical cytokine fold homologous to CSF-1, and we further show that the complex architecture of IL-34 bound to the N-terminal immunoglobulin domains of CSF-1R is similar to the CSF-1/CSF-1R assembly. However, unique conformational adaptations in the receptor domain geometry and intermolecular interface explain the cross-reactivity of CSF-1R for two such distantly related ligands. The docking adaptations of the IL-34 and CSF-1 quaternary complexes, when compared to the stem cell factor assembly, draw a common evolutionary theme for transmembrane signaling. In addition, the structure of IL-34 engaged by a Fab fragment reveals the mechanism of a neutralizing antibody that can help deconvolute IL-34 from CSF-1 biology, with implications for therapeutic intervention in diseases with myeloid pathogenic mechanisms. © 2012 Elsevier Ltd.

Asherson P.,King's College London | Bushe C.,Eli Lilly and Company | Saylor K.,Neuroscience Inc. | Tanaka Y.,Eli Lilly and Company | And 2 more authors.
Journal of Psychopharmacology | Year: 2014

Persistence of attention deficit hyperactivity disorder (ADHD) into adulthood can be disabling or lead to substantial impairment. Several clinical trials of atomoxetine (ATX) in adults with ADHD have been reported following the National Institute for Health and Clinical Excellence (NICE) guidelines issued in 2008. We performed an integrated analysis of all Eli Lilly-sponsored, randomized, double-blind, placebo-controlled studies of ATX in adults with ADHD completed as of May 2012. Individual patient data were pooled from six short-term (10-16 week) studies (1961 patients) and three longer-term (six-month) studies (1413 patients). In the short-term analysis, ATX patients achieved a significantly greater mean reduction in ADHD symptoms than placebo patients (-12.2 vs -8.1; Conners' Adult ADHD Rating Scale-Investigator-Rated: Screening Version (CAARS-Inv: SV); p<0.001). In the longer-term analysis, respective improvements after six months were -13.2 vs -9.7 (p<0.001). Response rates at study endpoints for ATX vs placebo, based on CAARS-Inv: SV improvement ≥30% and Clinical Global Impressions of ADHD-Severity (CGI-ADHD-S) ≥3 were 34.8% vs 22.3% in the short-term and 43.4% vs 28.0% after six months, and CAARS-Inv: SV improvements ≥40% were 41.3% vs 25.3% in the short-term and 44.0% vs 31.4% after six months (all p<0.001). Overall, ATX had a clinically significant effect in adults with ADHD, with reductions in core symptoms and clinically meaningful responder rates. © The Author(s) 2014.

Vojdani A.,Immunosciences Laboratory Inc. | Lambert J.,Immunosciences Laboratory Inc. | Kellermann G.,NeuroScience Inc.
Evidence-based Complementary and Alternative Medicine | Year: 2011

Abundant research has mapped the inflammatory pathways leading to autoimmunity and neuroinflammatory disorders. The latest T helper to be identified, Th17, through its proinflammatory cytokine IL-17, plays a pathogenic role in many inflammatory conditions. Today, healthcare providers have a wealth of anti-inflammatory agents from which to choose. On one hand, pharmaceutical companies market brand-name drugs direct to the public and physicians. Medical botanical knowledge, on the other hand, has been passed down from generation to generation. The demands for natural healing therapies have brought corresponding clinical and laboratory research studies to elucidate the medicinal properties of alternative practices. With a variety of options, it can be difficult to pinpoint the proper anti-inflammatory agent for each case presented. In this review, the authors highlight a vast array of anti-inflammatory medicaments ranging from drugs to vitamins and from botanicals to innate molecules. This compilation may serve as a guide for complimentary and alternative healthcare providers who need to target neuroinflammation driven by Th17 and its inflammatory cytokine IL-17. By understanding the mechanisms of anti-inflammatory agents, CAM practitioners can tailor therapeutic interventions to fit the needs of the patient, thereby providing faster relief from inflammatory complaints. Copyright © 2011 Aristo Vojdani et al.

Nichkova M.,Pharmasan Labs Inc. | Wynveen P.M.,Pharmasan Labs Inc. | Marc D.T.,NeuroScience Inc. | Huisman H.,Pharmasan Labs Inc. | Kellermann G.H.,NeuroScience Inc.
Journal of Neurochemistry | Year: 2013

Dopamine is a catecholamine that serves as a neurotransmitter in the central and peripheral nervous system. Non-invasive, reliable, and high-throughput techniques for its quantification are needed to assess dysfunctions of the dopaminergic system and monitor therapies. We developed and validated a competitive ELISA for direct determination of dopamine in urine samples. The method provides high specificity, good accuracy, and precision (average inter-assay variation < 12%). The analysis is not affected by general urinary components and structurally related drugs and metabolites. The correlation between ELISA and LC-MS/MS analyses was very good (r = 0.986, n = 28). The reference range was 64-261 μg/g Cr (n = 64). Week-to-week biological variations of second morning urinary dopamine under free-living conditions were 23.9% for within- and 35.5% for between-subject variation (n = 10). The assay is applied in monitoring Parkinson's disease patients under different treatments. Urinary dopamine levels significantly increase in a dose-dependent manner for Parkinson's disease patients under l-DOPA treatment. The present ELISA provides a cost-effective alternative to chromatographic methods to monitor patients receiving dopamine restoring treatment to ensure appropriate dosing and clinical efficacy. The method can be used in pathological research for the assessment of possible peripheral biological markers for disorders related to the dopaminergic system. Our competitive ELISA for direct dopamine quantification in urine samples is a viable cost-effective alternative to chromatographic analysis. The method is robust, sensitive, and very specific and it does not require sample pre-treatment. It can be used in monitoring dopamine-modulating therapies. Urinary dopamine levels significantly increase in a dose-dependent manner for Parkinson's disease patients under l-DOPA treatment. © 2013 International Society for Neurochemistry.

Nichkova M.I.,Pharmasan Labs Inc. | Huisman H.,Pharmasan Labs Inc. | Wynveen P.M.,Pharmasan Labs Inc. | Marc D.T.,NeuroScience Inc. | And 2 more authors.
Analytical and Bioanalytical Chemistry | Year: 2012

Depression is a common disorder with physical and psychological manifestations often associated with low serotonin. Since noninvasive diagnostic tools for depression are sparse, we evaluated the clinical utility of a novel ELISA for the measurement of serotonin in urine from depressed subjects and from subjects under antidepressant therapy. We developed a competitive ELISA for direct measurement of serotonin in derivatized urine samples. Assay performance was evaluated and applied to clinical samples. The analytical range of the assay was from 6.7 to 425 μg serotonin/g creatinine (Cr). The limit of quantification was 4.7 μg/g Cr. The average recovery for spiked urine samples was 104.4%. Average intra-assay variation was 4.4%, and inter-assay variation was <20%. The serotonin analysis was very specific. No significant interferences were observed for 44 structurally and nonstructurally related urinary substances. Very good correlation was observed between urinary serotonin levels measured by ELISA and liquid chromatography tandem mass spectrometry (LC-MS/MS; ELISA∈=∈1.16∈×∈LC-MS/MS∈-∈53.8; r∈=∈0.965; mean % bias∈=∈11%; n∈=∈18). Serotonin was stable in acidified urine for 30 days at room temperature and at -20°C. The established reference range for serotonin was 54-366 μg/g Cr (n∈=∈64). Serotonin levels detected in depressed patients (87.53∈±∈4.89 μg/g Cr; n∈=∈60) were significantly lower (p∈<∈0.001) than in nondepressed subjects (153.38∈±∈7.99 μg/g Cr). Urinary excretion of serotonin in depressed individuals significantly increased after antidepressant treatment by 5-hydroxy-tryptophane and/or selective serotonin re-uptake inhibitor (p∈<∈0.01). The present ELISA provides a convenient and robust method for monitoring urinary serotonin. It is suitable to monitor serotonin imbalances and may be particularly helpful in evaluating antidepressant therapies. © 2011 Springer-Verlag.

Huisman H.,Pharmasan Laboratories Inc. | Wynveen P.,Pharmasan Laboratories Inc. | Nichkova M.,Pharmasan Laboratories Inc. | Kellermann G.,Pharmasan Laboratories Inc. | Kellermann G.,NeuroScience Inc.
Analytical Chemistry | Year: 2010

The inhibitory neurotransmitters GABA, glycine and agmatine and neuromodulators β-phenylethylamine (β-PEA) and taurine are important biogenic amines of the sympathetic and parasympathetic nervous systems in the body. Abnormalities in the metabolism of these biomarkers have been implicated in a vast number of neurological diseases. Novel competitive immunoassays, using one unique whole urine derivatization procedure applicable for all five biomarkers, have been developed. The determination of these biomarkers was highly reproducible: the coefficient of variance of inter- and intra-assay variation is between 3.9% and 9.8% for all assays. The assays show a good linearity in urine samples within the range of 100-400 mg Cr/dL and specificity when urine samples are spiked with biogenic amines. The recoveries are between 76 and 154%. The correlation between HPLC and ELISA for glycine and taurine (n = 10) showed regression coefficients of 0.97 and 0.98, respectively. An in vivo study on the urinary clearance of β-PEA, agmatine and taurine after oral intake by healthy individuals demonstrated the specificity and clinical significance of these new immunoassays. The immunoassays are useful for clinical and basic research where a fast and accurate assay for the screening of biogenic amines in urine is required, without preclearance of the sample. © 2010 American Chemical Society.

Kheirandish-Gozal L.,University of Chicago | McManus C.J.T.,NeuroScience Inc. | Kellermann G.H.,NeuroScience Inc. | Samiei A.,University of Chicago | Gozal D.,University of Chicago
Chest | Year: 2013

Background: Pediatric obstructive sleep apnea (OSA) is associated with cognitive dysfunction, suggesting altered neurotransmitter function. We explored overnight changes in neurotransmitters in the urine of children with and without OSA. Methods: Urine samples were collected from children with OSA and from control subjects before and after sleep studies. A neurocognitive battery assessing general cognitive ability (GCA) was administered to a subset of children with OSA. Samples were subjected to multiple enzyme-linked immunosorbent assays for 12 neurotransmitters, and adjusted for creatinine concentrations. Results: The study comprised 50 children with OSA and 20 control subjects. Of the children with OSA, 20 had normal GCA score (mean ± SD) (101.2 ± 14.5) and 16 had a reduced GCA score (87.3 ± 13.9; P<.001). Overnight increases in epinephrine, norepinephrine, and γ-aminobutyric acid (GABA) levels emerged in children with OSA; taurine levels decreased. Using combinatorial approaches and cutoff values for overnight changes of these four neurotransmitters enabled prediction of OSA (area under the curve [AUC]: 0.923; P<.0001). Furthermore, GABA and taurine alterations, as well as overnight reductions in phenylethylamine, were more prominent in children with OSA and low GCA than in children with OSA and normal GCA (P<.001), and they reliably discriminated GCA status (AUC: 0.977; P<.0001). Conclusions: Pediatric OSA is associated with overnight increases in urinary concentrations of catecholamines indicative of heightened sympathetic outflow. Increases in GABA levels and decreases in taurine levels could underlie mechanisms of neuronal excitotoxicity and dysfunction. Combinatorial approaches using defined cutoffs in overnight changes in concentrations of selected neurotransmitters in urine may not only predict OSA but also the presence of cognitive deficits. Larger cohort studies appear warranted to confirm these findings. © 2013 American College of Chest Physicians.

Troutman T.D.,University of Texas Southwestern Medical Center | Bazan J.F.,NeuroScience Inc. | Pasare C.,University of Texas Southwestern Medical Center
Cell Cycle | Year: 2012

TLRs are a family of pattern recognition receptors that recognize conserved molecular structures/products from a wide variety of microbes.1,2Following recognition of ligands, TLRs recruit signaling adapters to initiate a pro-inflammatory signaling cascade culminating in the activation of several transcription factor families. Additionally, TLR signals lead to activation of PI3K, affecting many aspects of the cellular response, including cell survival, proliferation and regulation of the pro-inflammatory response.3-10 The recent discovery of BCAP as a TLR signaling adaptor, crucial for linking TLRs to PI3K activation, allows new questions of the importance of PI3K activation downstream of TLRs. Here, we summarize the current understanding of signaling pathways activated by TLRs and provide our perspective on TLR mediated activation of PI3K and its impact on regulating cellular processes. © 2012 Landes Bioscience.

Nookala R.K.,University of Cambridge | Langemeyer L.,University of Oxford | Pacitto A.,University of Cambridge | Ochoa-Montano B.,University of Cambridge | And 6 more authors.
Open Biology | Year: 2012

Mutations in the renal tumour suppressor protein, folliculin, lead to proliferative skin lesions, lung complications and renal cell carcinoma. Folliculin has been reported to interact with AMP-activated kinase, a key component of the mammalian target of rapamycin pathway. Most cancer-causing mutations lead to a carboxy-terminal truncation of folliculin, pointing to a functional importance of this domain in tumour suppression. We present here the crystal structure of folliculin carboxy-terminal domain and demonstrate that it is distantly related to differentially expressed in normal cells and neoplasia (DENN) domain proteins, a family of Rab guanine nucleotide exchange factors (GEFs). Using biochemical analysis, we show that folliculin has GEF activity, indicating that folliculin is probably a distantly related member of this class of Rab GEFs. © 2012 The Authors.

This document provides methods and materials related to managing weight, supporting appetite control, and controlling cravings associated with smoking reduction or cessation regimens and/or nicotine reduction or cessation regimens. For example, compositions comprising an agent to support acetylcholine and an agent to support one or more biogenic amines, and methods for using such compositions for craving and appetite control are provided. Methods and materials to reduce cravings associated with the reduction or cessation of the use of chemical substances (e.g., drugs of abuse, including opioids, cocaine, methamphetamine, cannabis, alcohol), and to reduce cravings associated with addictive and/or compulsive behaviors (e.g., gambling, sex, and repetitive behaviors) are also provided.

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