Mapping of multiple neurotransmitter receptor subtypes and distinct protein complexes to the connectome.

Neurons express various combinations of neurotransmitter receptor (NR) subunits and receive inputs from multiple neuron types expressing different neurotransmitters. Localizing NR subunits to specific synaptic inputs has been challenging. Here, we use epitope-tagged endogenous NR subunits, expansion light-sheet microscopy, and electron microscopy (EM) connectomics to molecularly characterize synapses in Drosophila. We show that in directionally selective motion-sensitive neurons, different multiple NRs elaborated a highly stereotyped molecular topography with NR localized to specific domains receiving cell-type-specific inputs. Developmental studies suggested that NRs or complexes of them with other membrane proteins determine patterns of synaptic inputs. In support of this model, we identify a transmembrane protein selectively associated with a subset of spatially restricted synapses and demonstrate its requirement for synapse formation through genetic analysis. We propose that mechanisms that regulate the precise spatial distribution of NRs provide a molecular cartography specifying the patterns of synaptic connections onto dendrites.

Mapping of multiple neurotransmitter receptor subtypes and distinct protein complexes to the connectome.

Neurons express different combinations of neurotransmitter receptor (NR) subunits and receive inputs from multiple neuron types expressing different neurotransmitters. Localizing NR subunits to specific synaptic inputs has been challenging. Here we use epitope tagged endogenous NR subunits, expansion light-sheet microscopy, and EM connectomics to molecularly characterize synapses in Drosophila. We show that in directionally selective motion sensitive neurons, different multiple NRs elaborated a highly stereotyped molecular topography with NR localized to specific domains receiving cell-type specific inputs. Developmental studies suggested that NRs or complexes of them with other membrane proteins determines patterns of synaptic inputs. In support of this model, we identify a transmembrane protein associated selectively with a subset of spatially restricted synapses and demonstrate through genetic analysis its requirement for synapse formation. We propose that mechanisms which regulate the precise spatial distribution of NRs provide a molecular cartography specifying the patterns of synaptic connections onto dendrites.

Acute pharmacodynamic responses to exenatide: Drug-induced increases in insulin secretion and glucose effectiveness.

AIM: Glucagon-like peptide-1 receptor agonists provide multiple benefits to patients with type 2 diabetes, including improved glycaemic control, weight loss and decreased risk of major adverse cardiovascular events. Because drug responses vary among individuals, we initiated investigations to identify genetic variants associated with the magnitude of drug responses. METHODS: Exenatide (5 µg, subcutaneously) or saline (0.2 ml, subcutaneously) was administered to 62 healthy volunteers. Frequently sampled intravenous glucose tolerance tests were conducted to assess the impact of exenatide on insulin secretion and insulin action. This pilot study was a crossover design in which participants received exenatide and saline in random order. RESULTS: Exenatide increased first phase insulin secretion 1.9-fold (p = 1.9 × 10-9 ) and accelerated the rate of glucose disappearance 2.4-fold (p = 2 × 10-10 ). Minimal model analysis showed that exenatide increased glucose effectiveness (Sg ) by 32% (p = .0008) but did not significantly affect insulin sensitivity (Si ). The exenatide-induced increase in insulin secretion made the largest contribution to interindividual variation in exenatide-induced acceleration of glucose disappearance while interindividual variation in the drug effect on Sg contributed to a lesser extent (ß = 0.58 or 0.27, respectively). CONCLUSIONS: This pilot study provides validation for the value of a frequently sampled intravenous glucose tolerance test (including minimal model analysis) to provide primary data for our ongoing pharmacogenomic study of pharmacodynamic effects of semaglutide (NCT05071898). Three endpoints provide quantitative assessments of the effects of glucagon-like peptide-1 receptor agonists on glucose metabolism: first phase insulin secretion, glucose disappearance rates and glucose effectiveness.

Acute pharmacodynamic responses to exenatide: Drug-induced increases in insulin secretion and glucose effectiveness.

Background: GLP1R agonists provide multiple benefits to patients with type 2 diabetes - including improved glycemic control, weight loss, and decreased risk of major adverse cardiovascular events. Because drug responses vary among individuals, we initiated investigations to identify genetic variants associated with the magnitude of drug responses. Methods: Exenatide (5 µg, sc) or saline (0.2 mL, sc) was administered to 62 healthy volunteers. Frequently sampled intravenous glucose tolerance tests were conducted to assess the impact of exenatide on insulin secretion and insulin action. This pilot study was designed as a crossover study in which participants received exenatide and saline in random order. Results: Exenatide increased first phase insulin secretion 1.9-fold (p=1.9×10 -9 ) and accelerated the rate of glucose disappearance 2.4-fold (p=2×10 -10 ). Minimal model analysis demonstrated that exenatide increased glucose effectiveness (S g ) by 32% (p=0.0008) but did not significantly affect insulin sensitivity (S i ). The exenatide-induced increase in insulin secretion made the largest contribution to inter-individual variation in exenatide-induced acceleration of glucose disappearance while inter-individual variation in the drug effect on S g contributed to a lesser extent (ß=0.58 or 0.27, respectively). Conclusions: This pilot study provides validation for the value of an FSIGT (including minimal model analysis) to provide primary data for our ongoing pharmacogenomic study of pharmacodynamic effects of semaglutide ( NCT05071898 ). Three endpoints provide quantitative assessments of GLP1R agonists' effects on glucose metabolism: first phase insulin secretion, glucose disappearance rates, and glucose effectiveness. Registration: NCT02462421 (clinicaltrials.gov). Funding: American Diabetes Association (1-16-ICTS-112); National Institute of Diabetes and Digestive and Kidney Disease (R01DK130238, T32DK098107, P30DK072488).

Exploring the therapeutic potential of Neem (Azadirachta Indica) for the treatment of prostate cancer: a literature review.

Background and Objective: Multiple studies have demonstrated the medical potency of plant extracts and specific phytochemicals as therapeutics for prostate cancer (PCa) patients. Of note, the Neem plant known for its role as an antibiotic and anti-inflammatory is underexplored with an untapped potential for further development. This review focuses on extracts and phytochemicals derived from the Neem tree (Latin name; Azadirachta indica), commonly used throughout Southeast Asia for the prevention and treatment of a wide array of diseases including cancer. To date, there are more than 130 biologically active compounds that have been isolated from the Neem tree including azadirachtin, nimbolinin, nimbin, nimbidin, nimbidol, which have demonstrated a wide range of biological activities including anti-microbial, anti-fertility, anti-inflammatory, anti-arthritic, hepatoprotective, anti-diabetic, anti-ulcer, and anti-cancer effects. Very few scientific reports focus on the benefits of Neem in PCa, even though this herb has been used to prevent the disease and its progression for years in complementary and alternative medicine. Methods: We used the search engines like PubMed, InCommon and Google using the key words: "Neem", "Cancer", "Prostate Cancer" and related words to find the information and data within the time frame from 1980-2022 for our article study. Key Content and Findings: Here, we provide an overview of Neem extracts and phytochemical derivatives with a focus on their known potential and ability to inhibit specific cellular signaling pathways and processes which drive PCa incidence and progression. Conclusions: The information presented here indicate that Neem and its derivatives have a therapeutic potential for the treatment of PCa when used as a single agent or in combination with conventional chemotherapeutics.

Expertise in emotion: A scoping review and unifying framework for individual differences in the mental representation of emotional experience.

Expertise refers to outstanding skill or ability in a particular domain. In the domain of emotion, expertise refers to the observation that some people are better at a range of competencies related to understanding and experiencing emotions, and these competencies may help them lead healthier lives. These individual differences are represented by multiple constructs including emotional awareness, emotional clarity, emotional complexity, emotional granularity, and emotional intelligence. These constructs derive from different theoretical perspectives, highlight different competencies, and are operationalized and measured in different ways. The full set of relationships between these constructs has not yet been considered, hindering scientific progress and the translation of findings to aid mental and physical well-being. In this article, we use a scoping review procedure to integrate these constructs within a shared conceptual space. Scoping reviews provide a principled means of synthesizing large and diverse literature in a transparent fashion, enabling the identification of similarities as well as gaps and inconsistencies across constructs. Using domain-general accounts of expertise as a guide, we build a unifying framework for expertise in emotion and apply this to constructs that describe how people understand and experience their own emotions. Our approach offers opportunities to identify potential mechanisms of expertise in emotion, encouraging future research on those mechanisms and on educational or clinical interventions. (PsycInfo Database Record (c) 2022 APA, all rights reserved).