Visualizing the molecular recognition trajectory of an intrinsically disordered protein using multinuclear relaxation dispersion NMR

Despite playing important roles throughout biology, molecular recognition mechanisms in intrinsically disordered proteins remain poorly understood. We present a combination of (1)H(N), (13)C', and (15)N relaxation dispersion NMR, measured at multiple titration points, to map the interaction between the disordered domain of Sendai virus nucleoprotein (NT) and the C-terminal domain of the phosphoprotein (PX). Interaction with PX funnels the free-state equilibrium of NT by stabilizing one of the previously identified helical substates present in the prerecognition ensemble in a nonspecific and dynamic encounter complex on the surface of PX. This helix then locates into the binding site at a rate coincident with intrinsic breathing motions of the helical groove on the surface of PX. The binding kinetics of complex formation are thus regulated by the intrinsic free-state conformational dynamics of both proteins. This approach, providing high-resolution structural and kinetic information about a complex folding and binding interaction trajectory, can be applied to a number of experimental systems to provide a general framework for understanding conformational disorder in biomolecular function

Obesity prevalence from a European perspective: a systematic review

<p>Abstract</p> <p>Background</p> <p>Obesity has been recognised as an important contributing factor in the development of various diseases, but comparative data on this condition are limited. We therefore aimed to identify and discuss current epidemiological data on the prevalence of obesity in European countries.</p> <p>Methods</p> <p>We identified relevant published studies by means of a MEDLINE search (1990–2008) supplemented by information obtained from regulatory agencies. We only included surveys that used direct measures of weight and height and were representative of each country's overall population.</p> <p>Results</p> <p>In Europe, the prevalence of obesity (body mass index ≥ 30 kg/m²) in men ranged from 4.0% to 28.3% and in women from 6.2% to 36.5%. We observed considerable geographic variation, with prevalence rates in Central, Eastern, and Southern Europe being higher than those in Western and Northern Europe.</p> <p>Conclusion</p> <p>In Europe, obesity has reached epidemic proportions. The data presented in our review emphasise the need for effective therapeutic and preventive strategies.</p

Targeting the disordered C terminus of PTP1B with an allosteric inhibitor

PTP1B, a validated therapeutic target for diabetes and obesity, has a critical positive role in HER2 signaling in breast tumorigenesis. Efforts to develop therapeutic inhibitors of PTP1B have been frustrated by the chemical properties of the active site. We define a new mechanism of allosteric inhibition that targets the C-terminal, noncatalytic segment of PTP1B. We present what is to our knowledge the first ensemble structure of PTP1B containing this intrinsically disordered segment, within which we identified a binding site for the small-molecule inhibitor MSI-1436. We demonstrate binding to a second site close to the catalytic domain, with cooperative effects between the two sites locking PTP1B in an inactive state. MSI-1436 antagonized HER2 signaling, inhibited tumorigenesis in xenografts and abrogated metastasis in the NDL2 mouse model of breast cancer, validating inhibition of PTP1B as a therapeutic strategy in breast cancer. This new approach to inhibition of PTP1B emphasizes the potential of disordered segments of proteins as specific binding sites for therapeutic small molecules

What influences on their professional development do general practice trainees report from their hospital placements?: A qualitative study

BACKGROUND: The clinical learning environment is important in GP specialty training and impacts professional development. Uniquely for GP trainees, about half of their training periods occur in a hospital environment, which is not their final workplace. There is still little understanding of how hospital-based training influences GP's professional development. OBJECTIVES: To seek the views of GP trainees on how their hospital experience contributes to their professional development as a GP. METHODS: This international and qualitative study seeks the views of GP trainees from Belgium, Ireland, Lithuania, and Slovenia. Semi-structured interviews were performed in the original languages. A joint thematic analysis in the English language resulted in key categories and themes. RESULTS: From the four themes identified, GP trainees were found to experience additional challenges on top of the service provision/education tensions, which are common to all hospital trainees. Despite these, the hospital rotation component of GP training is valued by trainees. A strong finding of our study is the need to ensure that learning from the hospital placements is placed firmly in the context of general practice, e.g. GP placements prior or parallel with the hospital placements, educational activities resourced by GPs during their hospital experience, encouraging hospital teachers to have greater awareness of the educational needs of GPs, including an awareness of their training curriculum. CONCLUSION: This novel study highlights how hospital placements for GP trainees could be enhanced. Further study could be broadened to recently qualified GPs, which may uncover new areas of interest

Evaluation of a textile-based near infrared spectroscopy system in calf muscle oxygenation measurements

We recently introduced a novel textile-based NIRS sensor (TexNIRS). Here, we evaluate TexNIRS in ten subjects (16 legs, age 28.5 ± 2.32 years, adipose tissue thickness (ATT) 4.17 ± 1.71 mm). Three venous occlusions at 50 mmHg were performed on their calf muscle. After 3 min of occlusion, oxy/deoxy hemoglobin concentration ([O₂Hb], [HHb]) changes were 3.71 ± 1.89/1.79 ± 1.08 μM; venous oxygen saturation (SvO₂) was 75 ± 9.7 %, oxygen consumption (VO₂) was 0.02 ± 0.01 mL/100 g/min, hemoglobin flow (HF) was 0.93 ± 0.48 μmol/100 mL/min, and blood flow (BF) was 2.01 ± 1.04 mL/100 mL/min. Our results are in good agreement with the literature, but the TexNIRS enables a much higher level of comfort