Discovery of MK-1462: GLP-1 and Glucagon Receptor Dual Agonist for the Treatment of Obesity and Diabetes.

Peptide-based analogues of the gut-derived incretin hormone, glucagon-like peptide 1 (GLP1), stimulate insulin secretion in a glucose-dependent manner. Currently marketed GLP1 receptor (GLP1R) agonists are safe and effective in the management of Type 2 diabetes but often offer only modest weight loss. This has prompted the search for safe and effective alternatives to enhance the weight loss component of these treatments.

Comparative Analysis of Multiplex Platforms for Detecting Vitreous Biomarkers in Diabetic Retinopathy.

Purpose: To evaluate the feasibility of using the Proximity Extension Assay (PEA) platform to detect biomarkers in vitreous and to compare the findings with results obtained with an electrochemiluminescent (ECL) sandwich immunoassay.

Methods: Vitreous samples from patients with proliferative diabetic retinopathy (PDR) and non-diabetic controls were tested using two different proteomics platforms. Forty-one assays were completed with the ECL platform and 459 with the PEA platform.

Conspecific chemical cues facilitate mate trailing by invasive Argentine black and white tegus.

Squamate reptiles (snakes and lizards) rely on chemical cues from conspecifics to search the environment for potential mates. How such cues are used by invasive species to facilitate reproduction, especially seasonally, is a key question that can inform management practices. The Argentine black and white tegu (Salvator merianae) is an invasive reptile species in south Florida threatening native fauna in biodiverse regions such as Everglades National Park.

Mid-infrared resonant cavity light emitting diodes operating at 4.5 µm.

We report on a mid-infrared resonant cavity light emitting diode (RCLED) operating at the wavelength of 4.5 µm with a narrow spectral linewidth at room temperature. Compared to a reference LED without a resonant cavity, our RCLED exhibits (85x) higher peak intensity, (13x) higher integrated output power, (16x) narrower spectral linewidth and (7x) superior temperature stability.

Impact of Extracellular Fatty Acids and Oxygen Tension on Lipid Synthesis and Assembly in Pancreatic Cancer Cells.

Lipid oxidation and biosynthesis are crucial for cell survival, especially for rapidly proliferating cancer cells in a heterogeneous metabolic environment. The storage of high-energy lipid reservoirs competitively advantages the cancer cell over non-neoplastic tissue. Disrupting lipid biosynthetic processes, through modulation of fatty acid (FA) esterification or lipogenesis (DNL), is of interest in drug discovery.

Effect of the cap layer growth temperature on the Sb distribution in InAs/InSb/InAs sub-monolayer heterostructures for mid-infrared devices.

Sub-monolayer (SML) deposition of InSb within InAs matrix by migration enhanced epitaxy tends to form type II SML nanostructures offering efficient light emission within the mid-infrared (MIR) range between 3 and 5 μm. In this work, we report on the Sb distribution in InSb/InAs SML nanostructures with InAs cap layers grown at temperatures lower than that associated with the under-grown InSb active layer. Analysis by transmission electron microscopy (TEM) in 002 dark field conditions shows that the reduction in the growth temperature of the InAs cap layer increases the amount of Sb deposited in the layers, in good agreement with the x-ray diffraction results.

Polypharmacy through Phage Display: Selection of Glucagon and GLP-1 Receptor Co-agonists from a Phage-Displayed Peptide Library.

A promising emerging area for the treatment of obesity and diabetes is combinatorial hormone therapy, where single-molecule peptides are rationally designed to integrate the complementary actions of multiple endogenous metabolically-related hormones. We describe here a proof-of-concept study on developing unimolecular polypharmacy agents through the use of selection methods based on phage-displayed peptide libraries (PDL). Co-agonists of the glucagon (GCG) and GLP-1 receptors were identified from a PDL sequentially selected on GCGR- and GLP1R-overexpressing cells.

Room-Temperature Mid-Infrared Emission from Faceted InAsSb Multi Quantum Wells Embedded in InAs Nanowires.

There is considerable interest in the development of InAsSb-based nanowires for infrared photonics due to their high tunability across the infrared spectral range, high mobility, and integration with silicon electronics. However, optical emission is currently limited to low temperatures due to strong nonradiative Auger and surface recombination. Here, we present a new structure based on conical type II InAsSb/InAs multiquantum wells within InAs nanowires which exhibit bright mid-infrared photoluminescence up to room temperature.

Glucagon like receptor 1/ glucagon dual agonist acutely enhanced hepatic lipid clearance and suppressed de novo lipogenesis in mice.

Lipid lowering properties of glucagon have been reported. Blocking glucagon signaling leads to rise in plasma LDL levels. Here, we demonstrate the lipid lowering effects of acute dosing with Glp1r/Gcgr dual agonist (DualAG).

GPR40 partial agonist MK-2305 lower fasting glucose in the Goto Kakizaki rat via suppression of endogenous glucose production.

GPR40 (FFA1) is a fatty acid receptor whose activation results in potent glucose lowering and insulinotropic effects in vivo. Several reports illustrate that GPR40 agonists exert glucose lowering in diabetic humans. To assess the mechanisms by which GPR40 partial agonists improve glucose homeostasis, we evaluated the effects of MK-2305, a potent and selective partial GPR40 agonist, in diabetic Goto Kakizaki rats.

Personal support networks, social capital, and risk of relapse among individuals treated for substance use issues.

Background: The success of treatment for substance use issues varies with personal and social factors, including the composition and structure of the individual's personal support network. This paper describes the personal support networks and social capital of a sample of Italian adults after long-term residential therapeutic treatment for substance use issues, and analyses network correlates of post-treatment substance use (relapse).

Methods: Using a social network analysis approach, data were obtained from structured interviews (90-120 min long) with 80 former clients of a large non-governmental therapeutic treatment agency in Italy providing voluntary residential treatments and rehabilitation services for substance use issues.

The black widow spider bite: differential diagnosis, clinical manifestations, and treatment options.

Unrecognized and untreated black widow spider bites cause significant pain, impairment, and rarely death. The widow venom, a powerful neurotoxin known as a-latrotoxin, causes muscle pain, diaphoresis, tachycardia, flushing, and hypertension. Treatment is usually symptomatic with a combination of opioid analgesics and muscle relaxants.

The British Society for Haematology: 'What have the Romans ever done for us?'.

'….Alright, but apart from the sanitation, medicine, education, wine, public order, irrigation, the roads, fresh water and public health………………what have the Romans ever done for us?' From Monty Python's Life of Brian An organizational review of the British Society for Haematology (BSH) was started in November 2013 and completed in June 2014. Many members of the Society participated in the surveys and have given their views, including those on the Shape of Training Greenaway report.

Ofatumumab in poor-prognosis chronic lymphocytic leukemia: a phase IV, non-interventional, observational study from the European Research Initiative on Chronic Lymphocytic Leukemia.

We report the largest retrospective, phase IV non-interventional, observational study of ofatumumab therapy in heavily pre-treated patients with poor-prognosis chronic lymphocytic leukemia. Total number of patients was 103; median age was 65 years (range 39-85). Median number of prior lines of therapy was 4 (range 1-13), including, in most cases, rituximab-, fludarabine- and alemtuzumab-based regimens; 13 patients had been allografted.

Seven transmembrane G protein-coupled receptor repertoire of gastric ghrelin cells.

The molecular mechanisms regulating secretion of the orexigenic-glucoregulatory hormone ghrelin remain unclear. Based on qPCR analysis of FACS-purified gastric ghrelin cells, highly expressed and enriched 7TM receptors were comprehensively identified and functionally characterized using in vitro, ex vivo and in vivo methods. Five Gαs-coupled receptors efficiently stimulated ghrelin secretion: as expected the β1-adrenergic, the GIP and the secretin receptors but surprisingly also the composite receptor for the sensory neuropeptide CGRP and the melanocortin 4 receptor.

A PEGylated analog of the gut hormone oxyntomodulin with long-lasting antihyperglycemic, insulinotropic and anorexigenic activity.

Peptide agonists of the glucagon-like peptide 1 (GLP-1) receptor (GLP1R) are rapidly gaining favor as antidiabetic agents, since in addition to increasing glucose-dependent insulin secretion, they also cause weight loss. Oxyntomodulin (OXM), a natural peptide with sequence homology to both glucagon and GLP-1, has glucose-lowering activity in rodents and anorectic activity in rodents and humans, but its clinical utility is limited by a short circulatory half-life due to rapid renal clearance and degradation by dipeptidyl peptidase IV (DPP-IV). Here, we describe the development of a novel DPP-IV-resistant, long-acting GLP1R agonist, based on derivatization of a suitably chosen OXM analog with high molecular weight polyethylene glycol (PEG) ('PEGylation').

Optimization of co-agonism at GLP-1 and glucagon receptors to safely maximize weight reduction in DIO-rodents.

The ratio of GLP-1/glucagon receptor (GLP1R/GCGR) co-agonism that achieves maximal weight loss without evidence of hyperglycemia was determined in diet-induced obese (DIO) mice chronically treated with GLP1R/GCGR co-agonist peptides differing in their relative receptor agonism. Using glucagon-based peptides, a spectrum of receptor selectivity was achieved by a combination of selective incorporation of GLP-1 sequences, C-terminal modification, backbone lactam stapling to stabilize helical structure, and unnatural amino acid substitutions at the N-terminal dipeptide. In addition to α-amino-isobutyric acid (Aib) substitution at position two, we show that α,α'-dimethyl imidazole acetic acid (Dmia) can serve as a potent replacement for the highly conserved histidine at position one.

The glucagon receptor is involved in mediating the body weight-lowering effects of oxyntomodulin.

Oxyntomodulin (OXM) is a peptide secreted postprandially from the L-cells of the gut that has a weak affinity for both the glucagon-like peptide-1 receptor (GLP1R) and the glucagon receptor (GCGR). Peripheral administration of OXM in humans and rodents causes weight loss reducing food intake and increasing energy expenditure. It has been suggested that OXM modulates energy intake solely through GLP1R agonism.

DPP-IV-resistant, long-acting oxyntomodulin derivatives.

Obesity is one of the major risk factors for type 2 diabetes, and the development of agents, that can simultaneously achieve glucose control and weight loss, is being actively pursued. Therapies based on peptide mimetics of the gut hormone glucagon-like peptide 1 (GLP-1) are rapidly gaining favor, due to their ability to increase insulin secretion in a strictly glucose-dependent manner, with little or no risk of hypoglycemia, and to their additional benefit of causing a modest, but durable weight loss. Oxyntomodulin (OXM), a 37-amino acid peptide hormone of the glucagon (GCG) family with dual agonistic activity on both the GLP-1 (GLP1R) and the GCG (GCGR) receptors, has been shown to reduce food intake and body weight in humans, with a lower incidence of treatment-associated nausea than GLP-1 mimetics.

The structure of FADD and its mode of interaction with procaspase-8.

The structure of FADD has been solved in solution, revealing that the death effector domain (DED) and death domain (DD) are aligned with one another in an orthogonal, tail-to-tail fashion. Mutagenesis of FADD and functional reconstitution with its binding partners define the interaction with the intracellular domain of CD95 and the prodomain of procaspase-8 and reveal a self-association surface necessary to form a productive complex with an activated "death receptor." The identification of a procaspase-specific binding surface on the FADD DED suggests a preferential interaction with one, but not both, of the DEDs of procaspase-8 in a perpendicular arrangement.