Phosphoproteomics-directed manipulation reveals SEC22B as a hepatocellular signaling node governing metabolic actions of glucagon.

The peptide hormone glucagon is a fundamental metabolic regulator that is also being considered as a pharmacotherapeutic option for obesity and type 2 diabetes. Despite this, we know very little regarding how glucagon exerts its pleiotropic metabolic actions. Given that the liver is a chief site of action, we performed in situ time-resolved liver phosphoproteomics to reveal glucagon signaling nodes.

Chemoproteomics validates selective targeting of M1 alanyl aminopeptidase as an antimalarial strategy.

New antimalarial drug candidates that act via novel mechanisms are urgently needed to combat malaria drug resistance. Here, we describe the multi-omic chemical validation of M1 alanyl metalloaminopeptidase as an attractive drug target using the selective inhibitor, MIPS2673. MIPS2673 demonstrated potent inhibition of recombinant (A-M1) and (A-M1) M1 metalloaminopeptidases, with selectivity over other and human aminopeptidases, and displayed excellent in vitro antimalarial activity with no significant host cytotoxicity.

Chemoproteomics validates selective targeting of Plasmodium M1 alanyl aminopeptidase as an antimalarial strategy.

New antimalarial drug candidates that act via novel mechanisms are urgently needed to combat malaria drug resistance. Here, we describe the multi-omic chemical validation of M1 alanyl metalloaminopeptidase as an attractive drug target using the selective inhibitor, MIPS2673. MIPS2673 demonstrated potent inhibition of recombinant ( A-M1) and ( A-M1) M1 metalloaminopeptidases, with selectivity over other and human aminopeptidases, and displayed excellent antimalarial activity with no significant host cytotoxicity.

On-target, dual aminopeptidase inhibition provides cross-species antimalarial activity.

To combat the global burden of malaria, development of new drugs to replace or complement current therapies is urgently required. Here, we show that the compound is a selective, nanomolar inhibitor of both and aminopeptidases M1 and M17, leading to inhibition of end-stage hemoglobin digestion in asexual parasites. can kill sexual-stage , is active against murine malaria, and does not show any shift in activity against a panel of parasites resistant to other antimalarials.

Experimental evidence that browsing for activewear lowers explicit body image attitudes and implicit self-esteem in women.

Online apparel shopping is popular amongst women and offers salient visual information for making body image and self-worth judgements. Apparel segments which emphasize the value of women's bodies are particularly effective for eliciting low body image and self-worth. Across two studies, we investigated the association between self-reported and experimental online activewear exposure on women's self-worth, body image, appearance attitudes, mood and gaze behavior.

Current and emerging target identification methods for novel antimalarials.

New antimalarial compounds with novel mechanisms of action are urgently needed to combat the recent rise in antimalarial drug resistance. Phenotypic high-throughput screens have proven to be a successful method for identifying new compounds, however, do not provide mechanistic information about the molecular target(s) responsible for antimalarial action. Current and emerging target identification methods such as in vitro resistance generation, metabolomics screening, chemoproteomic approaches and biophysical assays measuring protein stability across the whole proteome have successfully identified novel drug targets.

Discovery and development of 2-aminobenzimidazoles as potent antimalarials.

The emergence of Plasmodium falciparum resistance to frontline antimalarials, including artemisinin combination therapies, highlights the need for new molecules that act via novel mechanisms of action. Herein, we report the design, synthesis and antimalarial activity of a series of 2-aminobenzimidazoles, featuring a phenol moiety that is crucial to the pharmacophore. Two potent molecules exhibited IC values against P.

Multi-omic Characterization of the Mode of Action of a Potent New Antimalarial Compound, JPC-3210, Against .

The increasing incidence of antimalarial drug resistance to the first-line artemisinin combination therapies underpins an urgent need for new antimalarial drugs, ideally with a novel mode of action. The recently developed 2-aminomethylphenol, JPC-3210, (MMV 892646) is an erythrocytic schizonticide with potent antimalarial activity against multidrug-resistant lines, low cytotoxicity, potent efficacy against murine malaria, and favorable preclinical pharmacokinetics including a lengthy plasma elimination half-life. To investigate the impact of JPC-3210 on biochemical pathways within infected red blood cells, we have applied a "multi-omics" workflow based on high resolution orbitrap mass spectrometry combined with biochemical approaches.

Concussion in field hockey: a retrospective analysis into the incidence rates, mechanisms, symptoms and recovery of concussive injuries sustained by elite field hockey players.

Objectives: To identify the incidence and mechanisms of concussion in elite Field Hockey in different age groups and also the postconcussion symptoms and recovery times.

Methods: Data was collected retrospectively, for both training and matches, over a 12-month period from national level Field Hockey players across under-16, under-18, under-21, Development and Senior players. Mechanism of injury (including player role and field position), postconcussive symptoms and recovery times were recorded following a semistructured interview with each player.

In vivo ultrasonic detection of polyurea crosslinked silica aerogel implants.

Background: Polyurea crosslinked silica aerogels are highly porous, lightweight, and mechanically strong materials with great potential for in vivo applications. Recent in vivo and in vitro studies have demonstrated the biocompatibility of this type of aerogel. The highly porous nature of aerogels allows for exceptional thermal, electric, and acoustic insulating capabilities that can be taken advantage of for non-invasive external imaging techniques.

Cyclic pneumatic soft-tissue compression enhances recovery following fracture of the distal radius: a randomised controlled trial.

Questions: Does the addition of cyclic pneumatic soft-tissue compression during the 6-week immobilisation period following fracture of the distal radius result in a faster recovery of muscle strength and joint range of motion? Does it result in a larger recovery of muscle strength and joint range of motion immediately after the immobilisation period (at 6 weeks) or four weeks after the immobilisation period (at 10 weeks)?

Design: Randomised controlled trial with concealed allocation and assessor blinding.

Participants: 21 patients with fracture of the distal radius.

Intervention: The experimental group received cyclic pneumatic soft-tissue compression during the 6-week immobilisation period whereas the control group received usual care.

Methysergide-induced valvular heart disease: a report of 2 cases.

Methysergide is a serotonin antagonist and is used as a long-term prophylactic treatment for migraine. Although many patients experience adequate control of migraine episodes, methysergide has been reported to cause retroperitoneal and pleuropulmonary fibrosis. Cardiovascular side effects mainly in the form of valvular fibrosis have been less recognized.

Cyclic pneumatic soft-tissue compression accelerates the union of distal radial osteotomies in an ovine model.

The aim of this randomised, controlled in vivo study in an ovine model was to investigate the effect of cyclic pneumatic pressure on fracture healing. We performed a transverse osteotomy of the right radius in 37 sheep. They were randomised to a control group or a treatment group where they received cyclic loading of the osteotomy by the application of a pressure cuff around the muscles of the proximal forelimb.

Effect of cyclic pneumatic soft tissue compression on simulated distal radius fractures.

We investigated the effect of pneumatic pressure applied to the proximal musculature of the sheep foreleg on load at the site of a transverse osteotomy of the distal radius. The distal radii of 10 fresh sheep foreleg specimens were osteotomized and a pressure sensor was inserted between the two bone fragments. An inflatable cuff, connected to a second pressure sensor, was positioned around the proximal forelimb musculature and the leg then was immobilized in a plaster cast.

Linking assessment to learning: a new route to quality assurance in medical practice.

Background: If continuing professional development is to work and be sensible, an understanding of clinical practice is needed, based on the daily experiences of doctors within the multiple factors that determine the nature and quality of practice. Moreover, there must be a way to link performance and assessment to ensure that ongoing learning and continuing competence are, in reality, connected. Current understanding of learning no longer holds that a doctor enters practice thoroughly trained with a lifetime's storehouse of knowledge.

The use of portfolios for assessment of the competence and performance of doctors in practice.

Background: The use of portfolios can potentially provide flexibility in the summative assessment of doctors in practice. An assessment system should reflect and reinforce the active and planned professional development goals of individual doctors. This paper discusses some of the issues involved in developing such a system.

Educational supervision for PRHOs: getting it right?

The New Doctor highlights aspects of educational supervision for preregistration house officers that may serve as a lesson for improving the educational experience of all doctors in training. On the basis of research carried out in mid-Trent, this article highlights some of the issues relating to the training of educational supervisors and how these need to be put into context if further advances in education and training are to take place.

Perceptions of flexible training in medicine.

Most flexible trainees believe that their full-time colleagues perceive flexible training as flawed in some way. However, most consultants and full-time trainees actually view flexible trainees and their posts in a positive light.

Portfolios in continuing medical education--effective and efficient?

Introduction: A cross over comparison between 'traditional' continuing medical education (CME) activities and portfolio-based learning in general practice is described.

Method: Thirty-two volunteer general practitioners (GPs) were divided into two cohorts; each cohort spent six months following a 'traditional' route to postgraduate educational accreditation (PGEA) and six months following a portfolio-based learning route supported by three CME tutors.

Outcome Measures: These were the submission of a completed portfolio with evidence of the completion of learning cycles and participants reflections on the educational process.

Supporting Pre-registration House Officers: the needs of educational supervisors of the first phase of postgraduate medical education.

The GMC's publications The New Doctor (GMC 1997) outlines an approach for the education of Pre-registration House Officers using designated educational supervisors. In order to establish appropriate means of training consultants to undertake this role, the Centre for Postgraduate and Continuing Medical Education at the Queens Medical Centre, Nottingham undertook a needs analysis. This consisted of a series of individual interviews with directors of postgraduate education in the mid-Trent region, four focus groups with consultants, and two dissemination workshops.

Portfolio-based learning: continuing medical education for general practitioners--a mid-point evaluation.

In October 1994 a project was initiated by the General Practice Continuing Medical Education Tutors in the Department of General Practice at Sheffield University. The project sought to evaluate the efficiency (effort expended) and effectiveness (distance travelled) of a model of continuing professional development for general practitioners through individual portfolio-based learning in co-mentoring groups. Learning demonstrated through the portfolio was accredited for the postgraduate education allowance of participants.