Role of central cannabinoid receptor GPR18 in cardiovascular regulation

The primary goal of this study was to characterize the role of GPR18 in the rostral ventrolateral medulla (RVLM) in blood pressure (BP) regulation and elucidate the mechanisms involved in central GPR18 mediated hypotensive response. The central hypothesis of this study was "central GPR18 signaling exerts a tonic sympathoinhibitory effect". The data provide the first evidence for expression of GPR18 in the RVLM, the cardiovascular regulatory nuclei of the brainstem and its co-localization in tyrosine hydroxylase (TH)-expressing neurons as well as in RVLM neurons expressing cannabinoid� receptors (CB�R). Also intra-RVLM activation of GPR18 receptors with abnormal cannabidiol (Abn CBD) produced a dose-dependent reduction in BP in conscious male Sprague Dawley rats whereas blockade of those receptors with 1, 3-dimethoxy-5-methyl-2-[(1R, 6R)-3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl] benzene (O-1918) increased BP and abrogated the Abn CBD-evoked reduction in BP. Additional studies tested the hypothesis that the negligible hypotensive effect caused by the endogenous GPR18 ligand n-arachidonoyl glycine (NAGly) could be due to concurrent activation of CB�R in the RVLM. Our findings supported this hypothesis because NAGly-evoked hypotension was doubled following RVLM CB�R blockade (SR141716). Ex-vivo studies revealed that intra-RVLM GPR18 activation (Abn CBD; 0.4 [mu]g) enhanced RVLM Akt, ERK1/2 and nNOS phosphorylation and increased adiponectin (ADN) levels, during the hypotensive response. In contrast, prior GPR18 receptor blockade (O-1918) produced the opposite effects, and abrogated Abn CBD-evoked responses in conscious Sprague Dawley rats. Inhibition of RVLM PI3K/Akt (wortmannin), ERK1/2 (PD98059) or nNOS (N[omega]-propyl-L-arginine, NPLA) or activation of adenylyl cyclase (forskolin) virtually abolished the intra-RVLM Abn CBD-evoked hypotension. Further, wortmannin, PD98059, NPLA or forskolin abrogated the GPR18-mediated increases in RVLM Akt, ERK1/2, nNOS phosphorylation and ADN levels, along with increased ROS generation. Our in-vitro studies show that GPR18 is co-expressed with CB1R in nPC12 cells. Our in-vitro studies are in line with our in-vivo findings in normotensive rats indicating that GPR18 signals through the PI3K/Akt-ERK1/2-nNOS/ADN pathway. Additionally, our confocal imaging findings show that GPR18 is associated with lipid rafts (LRs). Furthermore, activation of GPR18 (Abn CBD/ NAGly) displaces it from the LRs and this response was abrogated by prior GPR18 blockade (O-1918). Furthermore, cholesterol depletion by methyl-[beta]-cyclodextrin (M[beta]CD) enhanced GPR18 signaling and uncovered O-1918 blockade in nPC12 cells. Collectively, these studies provide insight into identifying the potential signaling pathway(s) triggered by central GPR18 activation in conscious animals and the potential role of lipid rafts in modulating GPR18 signaling in-vitroPh.D

Food allergen extracts to diagnose food-induced allergic diseases

OBJECTIVE: To review the manufacturing procedures of food allergen extracts and applicable regulatory requirements from government agencies, potential approaches to standardization, and clinical application of these products. The effects of thermal processing on allergenicity of common food allergens are also considered. DATA SOURCES: A broad literature review was conducted on the natural history of food allergy, the manufacture of allergen extracts, and the allergenicity of heated food. Regulations, guidance documents, and pharmacopoeias related to food allergen extracts from the United States and Europe were also reviewed. STUDY SELECTIONS: Authoritative and peer-reviewed research articles relevant to the topic were chosen for review. Selected regulations and guidance documents are current and relevant to food allergen extracts. RESULTS: Preparation of a food allergen extract may require careful selection and identification of source materials, grinding, defatting, extraction, clarification, sterilization, and product testing. Although extractions for all products licensed in the United States are performed using raw source materials, many foods are not consumed in their raw form. Heating foods may change their allergenicity, and doing so before extraction may change their allergenicity and the composition of the final product. CONCLUSION: The manufacture of food allergen extracts requires many considerations to achieve the maximal quality of the final product. Allergen extracts for a select number of foods may be inconsistent between manufacturers or unreliable in a clinical setting, indicating a potential area for future improvement

Cannabinoids Modulate Neuronal Activity and Cancer by CB1 and CB2 Receptor-Independent Mechanisms

Cannabinoids include the active constituents of Cannabis or are molecules that mimic the structure and/or function of these Cannabis-derived molecules. Cannabinoids produce many of their cellular and organ system effects by interacting with the well-characterized CB1 and CB2 receptors. However, it has become clear that not all effects of cannabinoid drugs are attributable to their interaction with CB1 and CB2 receptors. Evidence now demonstrates that cannabinoid agents produce effects by modulating activity of the entire array of cellular macromolecules targeted by other drug classes, including: other receptor types; ion channels; transporters; enzymes, and protein- and non-protein cellular structures. This review summarizes evidence for these interactions in the CNS and in cancer, and is organized according to the cellular targets involved. The CNS represents a well-studied area and cancer is emerging in terms of understanding mechanisms by which cannabinoids modulate their activity. Considering the CNS and cancer together allow identification of non-cannabinoid receptor targets that are shared and divergent in both systems. This comparative approach allows the identified targets to be compared and contrasted, suggesting potential new areas of investigation. It also provides insight into the diverse sources of efficacy employed by this interesting class of drugs. Obtaining a comprehensive understanding of the diverse mechanisms of cannabinoid action may lead to the design and development of therapeutic agents with greater efficacy and specificity for their cellular targets

Smart Glasses Prototype: A Wearable Technology for Cyclists

A project team of 9 people as part of R&D group has been assembled to develop the prototype of smart glasses for cyclists. The team is tasked to start from defining the product based on customer requirements and market conditions, designing the hardware and software aspects of the smart glasses, and performing various tests to ensure the quality and reliability of the smart glasses prototype. The development of the smart glasses is the responsibility of the R&D group, the team project consists of people with unique skills from various groups in R&D organization. The success criteria adopted for this prototype: ● Capable of communicating to the smartphone using Android, iOS, and Windows phone Operating Systems ● Capable of displaying the information associated with cycling, such as: heart rate, calories burned, distance traveled, speed, and all other data specified in the prototype specifications ● Pass the field testing during beta-release phase to limited users ● Pass the extreme or corner-case testing in the lab, such as humidity, temperature cycling, water resistance, and all other tests specified in the qualification plan Upon the conclusion of this project, a well-designed and reliable prototype will be delivered to other groups such as manufacturing and production, as well as sales and marketing, for further developments to enter the market and high-volume manufacturing

Trip Kit Organizer (Development Log)

The economic success of a company depends on the ability to identify the needs of the customers and analyzing the market[1]. In this process report we are going to highlight some of the techniques and concepts adapted from [1] for developing our product. The Trip Kit is a product that is designed to be secured into a car seat, and secure various items that people tend to carry in their cars. There will be some fixed compartments for bottle/cup holders and some customizable dividers similar to drawer dividers. This prevents loose items in your car rolling about, driver needing access to items while driving, and securing food and drink items. The paper covers all the characteristics required for a successful product development and the roadmap for the product development process

Role of central cannabinoid receptor GPR18 in cardiovascular regulation

The primary goal of this study was to characterize the role of GPR18 in the rostral ventrolateral medulla (RVLM) in blood pressure (BP) regulation and elucidate the mechanisms involved in central GPR18 mediated hypotensive response. The central hypothesis of this study was "central GPR18 signaling exerts a tonic sympathoinhibitory effect". The data provide the first evidence for expression of GPR18 in the RVLM, the cardiovascular regulatory nuclei of the brainstem and its co-localization in tyrosine hydroxylase (TH)-expressing neurons as well as in RVLM neurons expressing cannabinoid1 receptors (CB1R). Also intra-RVLM activation of GPR18 receptors with abnormal cannabidiol (Abn CBD) produced a dose-dependent reduction in BP in conscious male Sprague Dawley rats whereas blockade of those receptors with 1, 3-dimethoxy-5-methyl-2-[(1R, 6R)-3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl] benzene (O-1918) increased BP and abrogated the Abn CBD-evoked reduction in BP. Additional studies tested the hypothesis that the negligible hypotensive effect caused by the endogenous GPR18 ligand n-arachidonoyl glycine (NAGly) could be due to concurrent activation of CB1R in the RVLM. Our findings supported this hypothesis because NAGly-evoked hypotension was doubled following RVLM CB1R blockade (SR141716). Ex-vivo studies revealed that intra-RVLM GPR18 activation (Abn CBD\; 0.4 [mu]g) enhanced RVLM Akt, ERK1/2 and nNOS phosphorylation and increased adiponectin (ADN) levels, during the hypotensive response. In contrast, prior GPR18 receptor blockade (O-1918) produced the opposite effects, and abrogated Abn CBD-evoked responses in conscious Sprague Dawley rats. Inhibition of RVLM PI3K/Akt (wortmannin), ERK1/2 (PD98059) or nNOS (N[omega]-propyl-L-arginine, NPLA) or activation of adenylyl cyclase (forskolin) virtually abolished the intra-RVLM Abn CBD-evoked hypotension. Further, wortmannin, PD98059, NPLA or forskolin abrogated the GPR18-mediated increases in RVLM Akt, ERK1/2, nNOS phosphorylation and ADN levels, along with increased ROS generation. Our in-vitro studies show that GPR18 is co-expressed with CB1R in nPC12 cells. Our in-vitro studies are in line with our in-vivo findings in normotensive rats indicating that GPR18 signals through the PI3K/Akt-ERK1/2-nNOS/ADN pathway. Additionally, our confocal imaging findings show that GPR18 is associated with lipid rafts (LRs). Furthermore, activation of GPR18 (Abn CBD/ NAGly) displaces it from the LRs and this response was abrogated by prior GPR18 blockade (O-1918). Furthermore, cholesterol depletion by methyl-[beta]-cyclodextrin (M[beta]CD) enhanced GPR18 signaling and uncovered O-1918 blockade in nPC12 cells. Collectively, these studies provide insight into identifying the potential signaling pathway(s) triggered by central GPR18 activation in conscious animals and the potential role of lipid rafts in modulating GPR18 signaling in-vitr

Rescheduling Staff Shifts in X-Ray Department: PCC Airfolds

Employee schedule is an important concern for every business manager. A well-managed schedule keeps the organization moving and resolves many complex situations. In our paper, we’re going to look into the best staff scheduling practices and come up with an optimal solution for rescheduling staff in an X-ray Department at PCC Airfoils - Deer Creek Facility in Portland, Oregon, based on the production plan. PCC X-Ray department is looking for a good staff shift schedule to find out how many outside contractors the department needs to use to meet the production requirements accordingly. So, based on that information we can decide regarding hiring more people, bringing in-house contractors, or sending parts for outside contractors. Through this paper we attempt the following: 1) To minimize the cost based on the production plan. 2) Create a resource allocation model to identify how to allocate the time to process the part