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News Article | December 20, 2016
Site: www.eurekalert.org

Scientists at Washington University School of Medicine in St. Louis have detailed the structure of a molecule that has been implicated in Alzheimer's disease. Knowing the shape of the molecule -- and how that shape may be disrupted by certain genetic mutations -- can help in understanding how Alzheimer's and other neurodegenerative diseases develop and how to prevent and treat them. The study is published Dec. 20 in the journal eLife. The idea that the molecule TREM2 is involved in cognitive decline -- the hallmark of neurodegenerative diseases, including Alzheimer's -- has gained considerable support in recent years. Past studies have demonstrated that certain mutations that alter the structure of TREM2 are associated with an increased risk of developing late-onset Alzheimer's, frontal temporal dementia, Parkinson's disease and sporadic amyotrophic lateral sclerosis (ALS). Other TREM2 mutations are linked to Nasu-Hakola disease, a rare inherited condition that causes progressive dementia and death in most patients by age 50. "We don't know exactly what dysfunctional TREM2 does to contribute to neurodegeneration, but we know inflammation is the common thread in all these conditions," said senior author Thomas J. Brett, PhD, an assistant professor of medicine. "Our study looked at these mutations in TREM2 and asked what they do to the structure of the protein itself, and how that might impact its function. If we can understand that, we can begin to look for ways to correct it." The analysis of TREM2 structure, completed by first author, Daniel L. Kober, a doctoral student in Brett's lab, revealed that the mutations associated with Alzheimer's alter the surface of the protein, while those linked to Nasu-Hakola influence the "guts" of the protein. The difference in location could explain the severity of Nasu-Hakula, in which signs of dementia begin in young adulthood. The internal mutations totally disrupt the structure of TREM2, resulting in fewer TREM2 molecules. The surface mutations, in contrast, leave TREM2 intact but likely make it harder for the molecule to connect to proteins or send signals as normal TREM2 molecules would. TREM2 lies on the surface of immune cells called microglia, which are thought to be important "housekeeping" cells. Via a process called phagocytosis, such cells are responsible for engulfing and cleaning up cellular waste, including the amyloid beta that is known to accumulate in Alzheimer's disease. If the microglia lack TREM2, or the TREM2 that is present doesn't function properly, the cellular housekeepers can't perform their cleanup tasks. "Exactly what TREM2 does is still an open question," Brett said. "We know mice without TREM2 have defects in microglia, which are important in maintaining healthy brain biology. Now that we have these structures, we can study how TREM2 works, or doesn't work, in these neurodegenerative diseases." TREM2 also has been implicated in other inflammatory conditions, including chronic obstructive pulmonary disease and stroke, making the structure of TREM2 important for understanding chronic and degenerative diseases throughout the body, he added. This work was supported by the National Institutes of Health (NIH), grant numbers R01-HL119813, R01-AG044546, R01-AG051485, R01-HL120153, R01-HL121791, K01-AG046374, T32-GM007067, K08-HL121168, and P50-AG005681-30.1; the Burroughs-Wellcome Fund; the Alzheimer's Association, grant number AARG-16-441560; and the American Heart Association, grant number PRE22110004. Results were derived from work performed at Argonne National Laboratory (ANL) Structural Biology Center. ANL is operated by U. Chicago Argonne, LLC, for the U.S. DOE, Office of Biological and Environmental Research, supported by grant number DE-AC02-06CH11357. Kober DL, Alexander-Brett JM, Karch CM, Cruchaga C, Colonna M, Holtzman MJ, Brett TJ. Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms. eLife. Dec. 20, 2016. Washington University School of Medicine's 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.


Kamtekar K.T.,DL Inc | Monkman A.P.,Durham University | Bryce M.R.,Durham University
Advanced Materials | Year: 2010

White organic light-emitting devices (WOLEDs) offer new design opportunities in practical solid-state lighting and could play a significant role in reducing global energy consumption. Obtaining white light from organic LEDs is a considerable challenge. Alongside the development of new materials with improved color stability and balanced charge transport properties, major issues involve the fabrication of large-area devices and the development of low-cost manufacturing technology. © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Romach M.K.,DL Inc | Schoedel K.A.,INC Research | Sellers E.M.,DL Inc | Sellers E.M.,University of Toronto
Drug and Alcohol Dependence | Year: 2013

An expert panel convened in 2005 by the College on Problems of Drug Dependence (CPDD) to consider strategies to reduce the risk of prescription medication abuse concluded that drug formulation plays a significant role in determining risk of abuse. Efforts on the part of the pharmaceutical industry to develop drugs that deter abuse have focused primarily on opioid formulations resistant to common forms of tampering, most notably crushing or dissolving the tablet to accelerate release. Several opioid formulations developed to be tamper resistant have been approved, but the US Food and Drug Administration has not approved explicit label claims of abuse deterrence and has stated that any such claim will require substantial postmarketing data. Drug development efforts in this area raise questions about the relative impact of abuse-deterrent formulations, not only on individuals who might abuse a medication, but also on patients who are compliant with therapy. This review discusses progress since the 2005 CPDD meeting with an emphasis on opioids. Articles cited in the review were identified via a PubMed search covering the period between January 1, 2000, and October 5, 2011. Scientific work presented by the authors and their colleagues at meetings held through May 2012 also was included. Published literature suggests that development of abuse-deterrent products will require broad public health support and continued encouragement from regulatory authorities so that such products will become the expected standard of care for certain drug classes. © 2013 Elsevier Ireland Ltd.


Romach M.K.,University of Toronto | Romach M.K.,DL Inc | Schoedel K.A.,INC Research | Sellers E.M.,University of Toronto | Sellers E.M.,DL Inc
Neuropharmacology | Year: 2014

Psychoactive drugs that increase alertness, attention and concentration and energy, while also elevating mood, heart rate and blood pressure are referred to as stimulants. Despite some overlapping similarities, stimulants cannot be easily categorized by their chemical structure, mechanism of action, receptor binding profile, effects on monoamine uptake, behavioral pharmacology (e.g., effects on locomotion, temperature, and blood pressure), therapeutic indication or efficacy. Because of their abuse liability, a pre-market assessment of abuse potential is required for drugs that show stimulant properties; this review article focuses on the clinical aspects of this evaluation. This includes clinical trial adverse events, evidence of diversion or tampering, overdoses and the results of a human abuse potential study. While there are different types of human experimental studies that can be employed to evaluate stimulant abuse potential (e.g., drug discrimination, self-administration), only the human abuse potential study and clinical trial adverse event data are required for drug approval. The principal advances that have improved human abuse potential studies include using study enrichment strategies (pharmacologic qualification), larger sample sizes, better selection of endpoints and measurement strategies and more carefully considered interpretation of data. Because of the methodological advances, comparisons of newer studies with historical data is problematic and may contribute to a biased regulatory framework for the evaluation of newer stimulant-like drugs, such as A2 antagonists. This article is part of the Special Issue entitled 'CNS Stimulants'. © 2014 Elsevier Ltd. All rights reserved.


Sellers E.M.,DL Inc | Perrino P.J.,Purdue Pharma | Colucci S.V.,Purdue Pharma | Harris S.C.,Purdue Pharma
Journal of Psychopharmacology | Year: 2013

Reformulated OxyContin® (oxycodone HCl controlled-release or ORF) was developed as a tamper and abuse-deterrent product, to reduce the risk of product abuse, misuse and their consequences. This noninterventional single-session study asked participants who were medically-healthy recreational opioid users, aged 18 years and older, to consider how they would use commonly available supplies to tamper with placebo ORF and placebo original OxyContin (OC) tablets, and how they would assess the attractiveness of tampering and abusing ORF tablets, as compared with other opioid formulations. Participants provided information on past opioid use, and they assessed the properties of five nonhypothetical oxycodone products and two hypothetical oxycodone products. Participants provided feedback on tampering preferences, preferred tamper methods for each product, overall tampering potential and product preferences. We had 30 participants (27 males and 3 females; mean age 35 years, range 18-51) complete both the interview and tampering sessions. Participants judged OC as the most attractive, valuable, desirable and most likely to be tampered with, from among all opioid products studied. By contrast, they rated ORF as the least attractive, least valuable, least desirable, and least likely to be tampered with among all the nonhypothetical opioid products studied. These results suggested that recreational drug abusers view ORF tablets as tamper-deterrent products. © The Author(s) 2013.


Trademark
DL Inc | Date: 2013-03-20

Vacuum packing machines and replacement parts for vacuum packing machines; replacement vacuum seal bags for said vacuum packing machines.


Trademark
DL Inc | Date: 2013-06-12

Irrigation equipment namely, irrigation drippers.


Trademark
DL Inc | Date: 2014-08-20

Gardening and hydroponic tools and equipment, namely, agricultural irrigation units; Air conditioning units for greenhouse purposes; Air purifiers; Aquarium filters; Aquarium heaters; Cultivation lamps and parts thereof, namely, high pressure sodium (HPS), metal halide, plasma, and light emitting diode (LED); Drip irrigation systems comprised of pipes, tubes, hoses, valves, filters, timers, and regulators; Electric fans for greenhouse purposes; Electric lighting fixtures for indoor plant growing purposes; Filters, heaters and pumps, all of the foregoing sold as component parts of hydroponic systems, namely, hydroponics grow box in the nature of a closed environment equipped with lights, exhaust system, and hydroponics growing container; Irrigation spray nozzles; Lamp reflectors for indoor plant growing purposes; Pressure regulators for gas tanks, namely, pressure regulators for gas tanks containing carbon dioxide, for indoor plant growing purposes.


Trademark
DL Inc | Date: 2016-03-08

Trimmers and mulchers for plants.


Trademark
DL Inc | Date: 2015-04-02

Trimmers and mulchers for plants.

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