Advances in therapeutic peptides targeting G protein-coupled receptors.

Dysregulation of peptide-activated pathways causes a range of diseases, fostering the discovery and clinical development of peptide drugs. Many endogenous peptides activate G protein-coupled receptors (GPCRs) - nearly 50 GPCR peptide drugs have been approved to date, most of them for metabolic disease or oncology, and more than 10 potentially first-in-class peptide therapeutics are in the pipeline. The majority of existing peptide therapeutics are agonists, which reflects the currently dominant strategy of modifying the endogenous peptide sequence of ligands for peptide-binding GPCRs. Increasingly, novel strategies are being employed to develop both agonists and antagonists, to both introduce chemical novelty and improve drug-like properties. Pharmacodynamic improvements are evolving to allow biasing ligands to activate specific downstream signalling pathways, in order to optimize efficacy and reduce side effects. In pharmacokinetics, modifications that increase plasma half-life have been revolutionary. Here, we discuss the current status of the peptide drugs targeting GPCRs, with a focus on evolving strategies to improve pharmacokinetic and pharmacodynamic properties.Wellcome Trust [WT107715/Z/15/Z], Cambridge Biomedical Research Centre Biomedical Resources Gran

Virtual learning environments and digital tools for implementing formative assessment of transversal skills in STEM

This publication is the fourth report in a series of reports part of the Assessment of Transversal Skills in Science, Technology, Engineering and Mathematics (ATS STEM) project. The report is written within the framework of the project ATS STEM (http://www.atsstem.eu/). Assessment of Transversal Skills in STEM is an innovative policy experimentation project being conducted across 8 EU countries and involving a partner network of 12 educational institutions

LGBT+ Youth Perspectives on Sexual Orientation and Gender Identity Questions in the Growing Up in Ireland Survey: A Qualitative Study

The increasing importance of identifying lesbian, gay, bisexual and transgender (LGBT+) populations is a key driver in changes to demographic data collection in representative surveys of youth. While such population-based data are rare, Growing Up in Ireland (GUI), an Irish, government-funded, longitudinal survey, includes sexual orientation and gender identity (SOGI) measurements. This qualitative study responds to a query from the GUI study team and aims to identify how best to collect SOGI data in future waves of GUI. A university Human Research Ethics Committee granted approval for online consultations with LGBT+ youth (n = 6) with experiential expertise in policy making. The research is underpinned by rights-based public patient involvement (PPI) with recorded discussions, which were transcribed and imported into NVivo 12, generating the theme “recognition in research, policy and society”. This co-created article, with the LGBT+ young PPI Panel members, commends the inclusion of SOGI data in GUI and recommends changes in question placement and phrasing. Aligning with best practice, the PPI members provide a template for wording on consecutive sex and gender questions, expanded sexual orientation identity categories and maintaining the existing well-phrased transgender question from GUI. This offers potential to improve the quality of the SOGI data collected and the experience of those completing the questionnaire. These findings extend beyond GUI, with relevance for surveys with youth populations. This paper underscores the potential and benefits of participatory approaches to research with youth and views their role beyond simply as sources of data

Microscopic gel – liquid interfaces supported by hollow microneedle array for voltammetric drug detection

This report describes a method for integration of a gel–liquid interface in hollow microneedles compatible with minimally invasive, electrochemical detection of drugs in vivo. The electrochemical sensor was characterised using cyclic voltammetry with tetraethyl ammonium. The experimental work demonstrated the detection of propranolol as a representative drug in physiological buffer with the microneedle system. A calibration curve for propranolol was built from measurements with differential pulse stripping voltammetry, indicating a sensitivity of 43nAμM−1, a limit of detection of 50nM and a linear range between 50 and 200nM

Assessor cognition and inter-rater reliability in nursing objective structured clinical examinations

The consistency of judgements made by examiners of performance assessments is an important issue when high stakes are associated with the outcomes of such assessments for examinees. In order to minimize variance between assessors, it is imperative that designers and users of assessments understand and account for variations that may arise when different assessors observe the same performance. Objective Structured Clinical Examinations (OSCEs) are high-fidelity performance assessments common in the health sciences, which require that students are judged by a range of different assessors. Despite the current prominence of OSCEs within undergraduate nursing programs, two problematic issues are highlighted in the research literature: relatively little is known about the specific cognitive processes that assessors employ when reaching judgements about the students they observe; and inter-rater reliability can be low. This mixed-methods study sought to address both issues using a combination of semi-structured interviews and a think-aloud protocol, in which assessors (n=12) shared their thought processes with the researcher as they reviewed four videos of students completing two OSCEs: blood pressure measurement and naso-gastric tube insertion. Participants also completed the associated marking guides for each OSCE, the data from which were used to determine the percent agreement between assessors (inter-rater reliability) of the viewed student performances. The results of the study indicated idiosyncrasy in the cognitive processes that assessors employed while judging the recorded performances. The data suggested that although each assessor watched the same four videos, they had different methods of determining how well or badly the students performed. Perhaps unsurprisingly, the completed marking guides revealed substantial variance in the scores the assessors awarded, with the harshest assessor awarding 29/52 checklist items across the videos compared to 45/52 for the most lenient assessor. Notably, there were discrepancies at the pass/fail decision for three out of the four performances

Simplified Method to Derive the Kalman Filter Covariance Matrices to Predict Wind Speeds from a NWP Model

AbstractThis paper espouses a simplified approach to predict wind speed 1 hour ahead for a wind turbine located on the Cork Institute of Technology (CIT) college campus by utilising a Kalman Filter to predict the bias between a campus based turbine and the output from a Numerical Weather Prediction (NWP) model for Cork Airport.Furthermore, this paper investigates the optimum number of samples required (n) in a fixed sampling interval process to derive the covariance matrix of the system equation Qt and the covariance matrix of the observation equation Rt . The main contents of this paper include wind speed analysis, state space analysis and Kalman Filtering application to Numerical Weather Prediction (NWP) data for wind speed prediction

Mercury binding by ferrocenoyl peptides with sulfur-containing side chains: Electrochemical, spectroscopic and structural studies

Ferrocenoyl peptides incorporating amino acids derived from either l-methionine, l-cysteine or dl-homocysteine have been synthesised and investigated as agents for heavy metal binding and detection. Heavy metal–peptide interactions have been characterised using cyclic voltammetry to follow changes in the potential of the Fe(II)/Fe(III) redox couple, revealing that these systems interact with mercury(II) ions more strongly than with other thiophilic heavy metals such as cadmium(II), silver(I) and lead(II). Proton NMR experiments have demonstrated 1:1 peptide:mercury binding and enabled quantitative characterisation of this binding interaction. Crystal structures for two of these ferrocenoyl peptide derivatives have been elucidated, revealing that these compounds adopt a P-1,3′ open solid state conformation in the absence of mercury; this arrangement precludes intramolecular hydrogen bonding between chains, while extensive intermolecular hydrogen bonding is evident. The particular affinity of these systems for mercury(II) opens the possibility of incorporating them in new, biologically inspired sensors for detecting this toxic pollutant

Synthesis, electrochemistry and metal binding properties of monosubstituted ferrocenoyl peptides with thioether-containing sidechains

Ferrocenoyl peptides incorporating thioether functionality respond more strongly to mercury(II) than to other heavy metal ions in solution. Compounds reported previously in this context are all 1,1′-disubstituted, and all include two or more sulfur-containing amino acids. To test whether two thioether groups are required for effective mercury binding by these systems, we have prepared a series of singly-substituted ferrocenoyl peptides from ferrocenecarboxylic acid and l-methionine, S-methyl-l-cysteine or S-trityl-l-cysteine, and tested them as electrochemical probes for mercury(II). Nine ferrocenoyl peptides have been synthesised using a Boc-protecting group strategy and HBTU-mediated peptide coupling. The electrochemical properties of these compounds have been determined using cyclic voltammetry, and all show fully reversible one electron oxidation steps. Forward sweep half wave peaks (E), reverse sweep half wave peaks (E), peak separations (ΔE) and half wave potentials (E) are reported. Changes in the potential of the iron(II)/iron(III) redox couple of the ferrocene core have been used to quantify heavy metal-peptide interactions, revealing that these monotopic systems also respond more strongly to mercury(II) than to zinc(II), cadmium(II), silver(I) and lead(II). NMR experiments to characterise the peptide-mercury interaction implicate the thioether sulfur as the site of mercury binding and indicate 1:1 stoichiometry. The crystal structure of ferrocenoyl-S-methyl-l-cysteine methyl ester is also reported. The greater responsiveness of these systems to mercury(II) makes them interesting leads for the development of biologically inspired sensors for this toxic heavy metal

McMurry reactions of (g5-acetylcyclopentadienyl) cobalt-(g4-tetraphenylcyclobutadiene) with benzophenone: ketone couplings and a pinacol/pinacolone rearrangement

The reaction of (g4-C4Ph4) Co[g5-C5H4–C(@O)Me], 5, with benzophenone under McMurry conditions (TiCl4/Zn/THF) gives the hetero-coupled product (g4-C4Ph4)Co[g5-C5H4–C(Me)@CPh2], 7, together with the dicobalt species: trans-(g4-C4Ph4)Co[(g5-C5H4– C(Me)@C(Me)-g5-C5H4] Co(g4-C4Ph4), 9, and the pinacolone Me[(g4-C4Ph4)Co(g5-C5H4)]2C–C(@O)Me, 10. The latter is apparently formed from the pinacol by migration of an (g4-C4Ph4)Co[(g5-C5H4)] group. Preferential migration of the cobalt sandwich moiety rather than a methyl group is rationalized in terms of a favored transition state involving a metal-stabilized cation. The products 7, 9 and 10, and also the ketone (g4-C4Ph4)Co[g5-C5H4–C(@O)Et], 6, were all characterized by X-ray crystallography