Structural basis of complement membrane attack complex formation

In response to complement activation, the membrane attack complex (MAC) assembles from fluid-phase proteins to form pores in lipid bilayers. MAC directly lyses pathogens by a ‘multi-hit’ mechanism; however, sublytic MAC pores on host cells activate signalling pathways. Previous studies have described the structures of individual MAC components and subcomplexes; however, the molecular details of its assembly and mechanism of action remain unresolved. Here we report the electron cryo-microscopy structure of human MAC at subnanometre resolution. Structural analyses define the stoichiometry of the complete pore and identify a network of interaction interfaces that determine its assembly mechanism. MAC adopts a ‘split-washer’ configuration, in contrast to the predicted closed ring observed for perforin and cholesterol-dependent cytolysins. Assembly precursors partially penetrate the lipid bilayer, resulting in an irregular β-barrel pore. Our results demonstrate how differences in symmetric and asymmetric components of the MAC underpin a molecular basis for pore formation and suggest a mechanism of action that extends beyond membrane penetration

How Accurately Can We Measure the Reconnection Rate E M for the MMS Diffusion Region Event of 11 July 2017?

We investigate the accuracy with which the reconnection electric field E M can be determined from in situ plasma data. We study the magnetotail electron diffusion region observed by National Aeronautics and Space Administration's Magnetospheric Multiscale (MMS) on 11 July 2017 at 22:34 UT and focus on the very large errors in E M that result from errors in an L M N boundary normal coordinate system. We determine several L M N coordinates for this MMS event using several different methods. We use these M axes to estimate E M. We find some consensus that the reconnection rate was roughly E M = 3.2 ± 0.6 mV/m, which corresponds to a normalized reconnection rate of 0.18 ± 0.035. Minimum variance analysis of the electron velocity (MVA-v e), MVA of E, minimization of Faraday residue, and an adjusted version of the maximum directional derivative of the magnetic field (MDD-B) technique all produce reasonably similar coordinate axes. We use virtual MMS data from a particle-in-cell simulation of this event to estimate the errors in the coordinate axes and reconnection rate associated with MVA-v e and MDD-B. The L and M directions are most reliably determined by MVA-v e when the spacecraft observes a clear electron jet reversal. When the magnetic field data have errors as small as 0.5% of the background field strength, the M direction obtained by MDD-B technique may be off by as much as 35°. The normal direction is most accurately obtained by MDD-B. Overall, we find that these techniques were able to identify E M from the virtual data within error bars ≥20%

A three-protein biomarker panel assessed in diagnostic tissue predicts death from prostate cancer for men with localized disease

Only a minority of prostate cancers lead to death. Because no tissue biomarkers of aggressiveness other than Gleason score are available at diagnosis, many nonlethal cancers are treated aggressively. We evaluated whether a panel of biomarkers, associated with a range of disease outcomes in previous studies, could predict death from prostate cancer for men with localized disease. Using a case-only design, subjects were identified from three Australian epidemiological studies. Men who had died of their disease, cases (N = 83), were matched to referents (N = 232), those who had not died of prostate cancer, using incidence density sampling. Diagnostic tissue was retrieved to assess expression of AZGP1, MUC1, NKX3.1, p53, and PTEN by semiquantitative immunohistochemistry (IHC). Poisson regression was used to estimate mortality rate ratios (MRRs) adjusted for age, Gleason score, and stage and to estimate survival probabilities. Expression of MUC1 and p53 was associated with increased mortality (MRR 2.51, 95% CI 1.14-5.54, P = 0.02 and 3.08, 95% CI 1.41-6.95, P = 0.005, respectively), whereas AZGP1 expression was associated with decreased mortality (MRR 0.44, 95% CI 0.20-0.96, P = 0.04). Analyzing all markers under a combined model indicated that the three markers were independent predictors of prostate cancer death and survival. For men with localized disease at diagnosis, assessment of AZGP1, MUC1, and p53 expression in diagnostic tissue by IHC could potentially improve estimates of risk of dying from prostate cancer based only on Gleason score and clinical stage

Appreciative inquiry in medical education*

The practice of medicine, and also medical education, typically adopts a problem-solving approach to identify "what is going wrong" with a situation. However, an alternative is Appreciative Inquiry (AI), which adopts a positive and strengths-based approach to identify "what is going well" with a situation. The AI approach can be used for the development and enhancement of the potential of both individuals and organizations. An essential aspect of the AI approach is the generative process, in which a new situation is envisioned and both individual and collective strengths are mobilized to make changes to achieve the valued future situation. The AI approach has been widely used in the world of business and general education, but is has an exciting potential for medical education, including curriculum development, faculty development, supporting learners through academic advising and mentoring, but also for enhancing the teaching and learning of both individuals and groups. This AMEE Guide describes the core principles of AI and their practical application in medical education

Electron-Scale Quadrants of the Hall Magnetic Field Observed by the Magnetospheric Multiscale spacecraft during Asymmetric Reconnection

An in situ measurement at the magnetopause shows that the quadrupole pattern of the Hall magnetic field, which is commonly observed in a symmetric reconnection, is still evident in an asymmetric component reconnection, but the two quadrants adjacent to the magnetosphere are strongly compressed into the electron scale and the widths of the remaining two quadrants are still ion scale. The bipolar Hall electric field pattern generally created in a symmetric reconnection is replaced by a unipolar electric field within the electron-scale quadrants. Furthermore, it is concluded that the spacecraft directly passed through the inner electron diffusion region based on the violation of the electron frozen-in condition, the energy dissipation, and the slippage between the electron flow and the magnetic field. Within the inner electron diffusion region, magnetic energy was released and accumulated simultaneously, and it was accumulated in the perpendicular directions while dissipated in the parallel direction. The localized thinning of the current sheet accounts for the energy accumulation in a reconnection