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Preclinical evaluation and first-in-human phase 1 trial of AZD0186, a novel, oral small molecule glucagon-like peptide-1 receptor agonist
No full textSmall molecule glucagon-like peptide-1 receptor agonist AZD0186 was developed to provide accessible and convenient treatment for a broad patient population with type 2 diabetes mellitus and/or obesity. We describe the preclinical and first-in-human single ascending dose data (NCT05694741) for this novel small molecule glucagon-like peptide-1 receptor agonist. AZD0186 was profiled in cell lines overexpressing human or cynomolgus glucagon-like peptide-1 receptor (GLP-1R) and in human-derived EndoC-βH5 cells. Glucose-stimulated insulin secretion (GSIS) was assessed following an intravenous glucose tolerance test in obese nonhuman primates and humanized GLP-1R (hGLP-1R) mice. Effects of oral repeated dosing on body weight and food intake were assessed in hGLP-1R mice. AZD0186 was evaluated at 4 oral single ascending dose levels (5, 15, 50, and 150 mg) in healthy participants. Results showed that AZD0186 is potent on the hGLP-1R and showed a concentration-dependent potentiation of GSIS in EndoC-βH5 cells (EC 50 = 0.6 nM). Insulin secretion was enhanced in obese nonhuman primates at all 3 dose levels evaluated following an intravenous glucose tolerance test. In hGLP-1R mice, body weight was reduced 9.9% ± 2.3% (mean ± SD) following 5 days of oral dosing (25 mg/kg per day twice a day). In the healthy participants, AZD0186 was well tolerated, with nausea reported at 150 mg, in keeping with GLP-1RA class effects. Across the dose range, AZD0186 area under the concentration-time curve increased in an approximately dose-proportional manner. Median terminal half-life ranged from 1.95 to 7.58 hours. Findings demonstrate that AZD0186 is a potent agonist of the GLP-1R, and the first-in-human study indicates a favorable safety and tolerability profile. SIGNIFICANCE STATEMENT: AZD0186 is a novel small molecule glucagon-like peptide-1 receptor agonist that allows for oral dosing. We describe the preclinical and first-in-human single ascending dose data for AZD0186. The findings demonstrate that AZD0186 is a potent agonist of the human glucagon-like peptide-1 receptor, improves glucose control and reduces body weight in a human glucagon-like peptide-1 receptor mouse model, and has a favorable safety and tolerability profile in healthy human participants
Enhanced Search for Neutral Current Radiative Single-Photon Production in MicroBooNE
Get PDFWe report results from an updated search for neutral current (NC) resonant (1232) baryon production and subsequent radiative decay (NC ). We consider events with and without final state protons; events with a proton can be compared with the kinematics of a baryon decay, while events without a visible proton represent a more generic phase space. In order to maximize sensitivity to each topology, we simultaneously make use of two different reconstruction paradigms, Pandora and Wire-Cell, which have complementary strengths, and select mostly orthogonal sets of events. Considering an overall scaling of the NC rate as an explanation of the MiniBooNE anomaly, our data exclude this hypothesis at 94.4% CL. When we decouple the expected correlations between NC events with and without final state protons, and allow independent scaling of both types of events, our data exclude explanations in which excess events have associated protons, and do not exclude explanations in which excess events have no associated protons
Catastrophe risk models as quantitative tools for climate change loss and damage : A demonstration for flood in Malawi, Vietnam, and the Philippines
Get PDFClimate change loss and damage is a critical part of the international climate policy framework, addressing the residual climate impacts that cannot be avoided through mitigation or adaptation, which disproportionately affect vulnerable communities with limited capacity to recover. Major gaps remain in quantifying loss and damage, including developing equitable, operational mechanisms for financing and redress. Here, our contribution is to show how catastrophe models, as commonly used to explore loss and damages in the insurance and reinsurance industries, can be used to calculate loss and damages in a climate policy sense, addressing this urgent quantification gap in international climate policy. We explore the impact of climate change on inland flood risk in three Global South regions (Chikwawa in Malawi, Hanoi in Vietnam, and Cagayan in the Philippines) and three exposure types (residential buildings, agricultural crops, and population) to demonstrate the ability and potential flexibility of catastrophe models to quantify impacts for both economic and non-economic loss and damage. We show that standard catastrophe model metrics can be used to quantify climate policy loss and damage and discuss how they can be used to guide and evaluate adaptation and disaster risk resilience measures. We also show how new metrics can be developed to better suit catastrophe models to this application, including through novel use of a relative wealth metric to explore a social vulnerability dimension. We also discuss and summarise the challenges that remain to be overcome, including sourcing high-quality exposure and vulnerability data and confronting the deeply uncertain climate change information at the scales of interest for climate policy loss and damage. For the latter, we propose a “storylines” framework to tractably sample the uncertainty space. Progress in this area will need meaningful collaboration between stakeholders, developers, local experts, and vulnerable communities, to increase the quality of the data and ensure that the economic and non-economic losses are appropriately, legitimately, and justly chosen and quantified. Our key message is that users and developers of catastrophe models within (re)insurance can leverage their tools and expertise to make much needed and meaningful contributions to the broad issues of climate change loss(es) and damage(s) (e.g., climate finance), but only through extensive collaboration outside of the industry
Public health across a cycle of investment and disinvestment: how English local authorities allocated the public health grant across prescribed and non-prescribed programmes (2013–2019)
No full textECOBRIDGE An expert system for spatial downscaling of land use/land cover change scenario outputs
No full textPresent day mapping captures fine land cover/land use (LC/LU) details, but future/alterative LC/LU scenarios are typically constructed at coarser spatial resolution, hindering comparisons. ECOBRIDGE (Ecology and Biodiversity Integrated Downscale Generation) is an open, knowledge-based ArcGIS Pro workflow, to produce high-resolution LC/LU maps from coarser sources. ECOBRIDGE draws on specialist knowledge to parse a low-resolution baseline and scenario, a higher-resolution baseline and information defining LC/LU change, to generate high-resolution spatial data for the scenario. These outputs are produced in the form of two datasets: as a raw pixel map and as an intelligent mapping layout which considers the structure of the landscape. The datasets created by ECOBRIDGE can contribute to more detailed analysis, bridging the gap between low-resolution datasets and more precise high-resolution information
Investigating visual attention differences and relationships with accuracy during word learning in autistic and neurotypical children.
Get PDFSuccessful word learning requires children to pay attention to corresponding auditory and visual input during naming events. However, differences in autistic children’s visual attention that restrict their intake of information may impact encoding of novel word-referent associations in memory. This study investigated differences in autistic and neurotypical children’s visual attention to stimuli, and whether these differences predicted referent selection and retention accuracy. Fifteen autistic (Mage = 91.87 months) and sixteen neurotypical (Mage = 52.31 months) children matched on receptive vocabulary (Mage autistic children = 53.27 months; Mage neurotypical children = 60.31) used a touch-screen computer to fast map novel words associated with animals (high-interest stimuli) and objects (neutral-interest stimuli). Retention was assessed after 5 minutes and 24 hours. Children’s frequency and duration of looking towards targets was recorded directly via multiple cameras. Neurotypical children spent longer looking at targets during referent selection than autistic children. Autistic children looked at targets significantly more frequently than neurotypical children across word learning stages, and more frequently at targets in the animal condition at 5-minute retention. In-trial visual attention predicted response accuracy across word learning stages for both groups. Visual attention at referent selection also predicted 5-minute and 24-hour retention accuracy for both groups. Visual input during initial encoding influences children’s likelihood of successfully forming long-term word-referent representations, indicating strong relationships between attention and learning accuracy. Moreover, population differences in visual attention may not have a detrimental impact on autistic children’s word learning under experimental conditions when expectations are based on receptive vocabulary
Shared neural signatures in Functional Neurological Disorder and Chronic Pain : a multimodal narrative review
No full textBackground: Functional neurological disorder (FND) frequently co-exists with chronic pain (CP), notably nociceptive and nociplastic (primary) pain disorders. The considerable overlap implies shared underlying mechanisms because of their similar clinical and epidemiological profiles. Although standard neuroimaging and electrophysiological tests typically show normal results in both FND and primary pain disorders, recent advancements in neuroimaging techniques have begun identifying neural biomarkers common to both conditions, though these findings remain preliminary and require further exploration. Method: We performed a detailed literature review of studies investigating neural activity in FND and chronic pain using electroencephalogram, magneto-encephalography, functional MRI, positron emission tomography and single photon emission computed tomography. Given the diverse nature of the reviewed studies, the synthesis is presented narratively. Results: Despite methodological differences, convergent data suggest disrupted neural networks across both FND and CP. Common findings include (1) hyperactivation of sensorimotor networks, (2) altered activity within the default mode network—a critical region for self-referential thought—and (3) dysfunction in emotional processing regions, notably the anterior cingulate cortex and insula. Thalamocortical dysrhythmia was identified as a potential unifying concept, characterised by abnormal theta and beta oscillations that enhance pain perception in CP and trigger functional symptoms in FND. Both conditions also exhibit reduced alpha oscillations, likely amplifying sensory sensitivity and emotional responsiveness. Conclusion: This review highlights shared neural abnormalities (Triple Network model) and introduces thalamocortical dysrhythmia as a novel explanatory framework linking FND and CP. Future research should target populations with coexisting disorders, potentially paving the way for innovative treatments, including hypnosis and neuromodulation/neurofeedback
A portable smartphone-based electrochemical sensing platform for rapid and sensitive detection of creatinine in blood serum †
No full textMuscle metabolism produces creatinine, a waste product whose levels in the blood and urine are crucial markers of kidney health. Herein, a smartphone-based electrochemical detection strategy was developed to quantify creatinine in human blood serum. Since creatinine was electrochemically inactive, a standard copper solution was added as an electro-activator to produce an electrochemically active creatinine–copper complex. At a pH of 7.4, the creatinine–copper composite was oxidized in a phosphate buffer solution (PBS). Electrochemical oxidation of the free Cu+ ion in PBS is tested by the surface modification of Ti2C2Tx@poly(l-Arg) nanocomposite. The analytical performance of the developed electrochemical sensor was evaluated by differential pulse voltammetry. The developed electrochemical sensor was evaluated using a combination of techniques: electrochemical methods like cyclic voltammetry and electrochemical impedance spectroscopy, morphological analysis with scanning electron microscopy, and structural analysis with attenuated total reflectance Fourier transform infrared spectroscopy and X-ray diffraction. Notably, the developed sensor demonstrated an impressively low detection limit of 0.05 μM and a linear range of 1–200 μM. Moreover, the sensor remarkably exhibited a stable creatinine detection response with an acceptable reproducibility for two two-week periods and demonstrated a robust immunity against interfering molecules. This is the first report on the synthesis of Ti2C2Tx@poly(l-Arg) nanocomposites and their application in the electrochemical detection of creatinine. This smartphone-based creatinine sensor offers a promising, rapid, and reliable technique for creatinine detection, with potential applications in clinical diagnostics and biomedical research, due to its high sensitivity, selectivity, and portability
On-chip adiabatic demagnetisation refrigeration
Get PDFThis thesis describes the thermal modelling and simulation of on-chip adiabatic demagnetisation refrigeration. On-chip cooling is a novel refrigeration technique which has been developed to solve the apparent poor thermalisation of electrons in microkelvin nanoelectronics. Micrometre- and nanometre-scale electronics are fundamental to the development of quantum technologies and hot electrons often degrade the performance of these devices. Microkelvin electron temperatures, will allow for the investigation of new physical phenomena and exotic electronic states of matter. Prior to this work, microkelvin electron temperatures have been produced by a combination of on-chip and off-chip refrigeration. The combination of cooling elements obfuscates the importance and necessity of off-chip cooling components. Without a complete description of on-chip cooling thermal dynamics, this combination of techniques also complicated the optimisation of on-chip refrigeration. This thesis presents a first-principles thermal model and simulation of on-chip demagnetisation refrigeration. This work finds that the thermal dynamics of a coulomb blockade thermometer with on-chip cooling are well-captured by this model. Using the simulation, this work explores the limits, constraints and optimisation of on-chip cooling. The results of this exploration outline a path towards microkelvin electrons in a 10 mK refrigerator with on-chip demagnetisation cooling