Rubredoxin Variant Folds without Iron

Pyroccocus furiosus rubredoxin (PFRD), like most studied hyperthermophilic proteins, does not undergo reversible folding. The irreversibility of folding is thought to involve PFRD’s iron-binding site. Here we report a PFRD variant (PFRD-XC4) whose iron binding site was redesigned to eliminate iron binding using a computational design algorithm. PFRD-XC4 folds without iron and exhibits reversible folding with a melting temperature of 82 °C, a thermodynamic stability of 3.2 kcal mol^(-1) at 1 °C, and NMR chemical shifts similar to that of the wild-type protein. This variant should provide a tractable model system for studying the thermodynamic origins of protein hyperthermostability

Analytic models for mechanotransduction: gating a mechanosensitive channel

Analytic estimates for the forces and free energy generated by bilayer deformation reveal a compelling and intuitive model for MscL channel gating analogous to the nucleation of a second phase. We argue that the competition between hydrophobic mismatch and tension results in a surprisingly rich story which can provide both a quantitative comparison to measurements of opening tension for MscL when reconstituted in bilayers of different thickness and qualitative insights into the function of the MscL channel and other transmembrane proteins

The relationship between extracurricular activities assessed during selection and during medical school and performance

Several medical schools include candidates’ extracurricular activities in their selection procedure, with promising results regarding their predictive value for achievement during the clinical years of medical school. This study aims to reveal whether the better achievement in clinical training of students selected on the basis of their extracurricular activities could be explained by persistent participation in extracurricular activities during medical school (msECAs). Lottery-admitted and selected student admission groups were compared on their participation in three types of msECAs: (1) research master, (2) important board positions or (3) additional degree programme. Logistic regression was used to measure the effect of admission group on participation in any msECA, adjusted for pre-university GPA. Two-way ANCOVA was used to examine the inter-relationships between admission group, participation in msECAs and clerkship grade, with pre-university GPA as covariate. Significantly more selected students compared to lottery-admitted students participated in any msECA. Participation in msECAs was associated with a higher pre-university GPA for lottery-admitted students only, whereas participation in msECAs was associated with higher clerkship grades for selected students only. These results suggest that persistent participation in extracurricular activities of selected students favours better clinical achievement, supporting the inclusion of ECAs in the selection procedure. More insight in the rationale behind participation in extracurricular activities during medical school may explain differences found between lottery-admitted and selected students

Cosmologies of Selection:Lessons from the faculty biscuit tin

We conducted an ethnography of the faculty biscuit tin as we were interested in the lived experience of the biscuits contained within it. We used a constructivist epistemology, a social constructionist interpretive framework and a phenomenological methodology that included analysis from the perspectives of deixis and cosmology. The biscuits perceived that they were important to a selecting force and that the characteristics of one particular group had a specific value to the selector. Some enduring benefits may derive from the selection of this group, although its attractions were less immediately obvious than those of others. What is immediately attractive may not be the most fit for purpose; lessons for the selection of medical students may arise from this exploration of the selection experiences of biscuits in a faculty biscuit tin

A future research agenda for selection into healthcare

Historically, selection into healthcare education and practitioner roles has relied heavily on prior academic attainment; however, there is now evidence demonstrating the value of selecting for ‘non-academic’ attributes such as integrity and empathy. Given that selection into healthcare roles is ‘high-stakes’ in nature, it is essential that selection processes are designed and developed in line with research evidence. This commentary outlines four key challenges to consider in the development of a future research agenda for selection into healthcare

Germline-encoded neutralization of a Staphylococcus aureus virulence factor by the human antibody repertoire.

Staphylococcus aureus is both an important pathogen and a human commensal. To explore this ambivalent relationship between host and microbe, we analysed the memory humoral response against IsdB, a protein involved in iron acquisition, in four healthy donors. Here we show that in all donors a heavily biased use of two immunoglobulin heavy chain germlines generated high affinity (pM) antibodies that neutralize the two IsdB NEAT domains, IGHV4-39 for NEAT1 and IGHV1-69 for NEAT2. In contrast to the typical antibody/antigen interactions, the binding is primarily driven by the germline-encoded hydrophobic CDRH-2 motifs of IGHV1-69 and IGHV4-39, with a binding mechanism nearly identical for each antibody derived from different donors. Our results suggest that IGHV1-69 and IGHV4-39, while part of the adaptive immune system, may have evolved under selection pressure to encode a binding motif innately capable of recognizing and neutralizing a structurally conserved protein domain involved in pathogen iron acquisition

The role of MscL amphipathic N terminus indicates a blueprint for bilayer-mediated gating of mechanosensitive channels

The bacterial mechanosensitive channel MscL gates in response to membrane tension as a result of mechanical force transmitted directly to the channel from the lipid bilayer. MscL represents an excellent model system to study the basic biophysical principles of mechanosensory transduction. However, understanding of the essential structural components that transduce bilayer tension into channel gating remains incomplete. Here using multiple experimental and computational approaches, we demonstrate that the amphipathic N-terminal helix of MscL acts as a crucial structural element during tension-induced gating, both stabilizing the closed state and coupling the channel to the membrane. We propose that this may also represent a common principle in the gating cycle of unrelated mechanosensitive ion channels, allowing the coupling of channel conformation to membrane dynamics

Developing a Tool for Selection for Medical School : A search for academic and non-academic parameters to predict future medical school performance

Worldwide places in medical school are scarce and medical education and training are expensive for providers and learners. Therefore, medical schools aim to offer the places available only to those applicants with the highest probability of successful medical training and subsequent career. To reach this goal, medical schools have developed several selection procedures, including interviews, admission tests and other measures of personal competencies. Uniquely in the Netherlands, selection was organised nationally based on a lottery that is weighted for academic attainment. However, both the lottery and the unproven selection procedures have been described as unfair to medical school applicants, as neither includes any truly objective criteria for predicting future performance. The Dutch situation in which access to medical school was granted by lottery and the possibility to select up to 50% of the students by a selection procedure provided a unique opportunity to form a control group of randomly admitted students to compare with those selected. We developed an evidence-based selection procedure addressing non-academic (i.e. motivation) as well as academic skills. The former evaluated motivation through the determination of the candidate’s active involvement in extracurricular activities, the latter by tests concerning the study skills of candidates in a medical school context. The main outcome was that the relative risk for dropping out of medical school was significantly lower in selected students than in controls admitted by lottery. Those selected obtained a higher mean grade than the lottery admitted students on their clerkships. Thereby selected students participated more often in extracurricular activities, which was also associated with higher clerkship grades