Stress concentrations around voids in three dimensions : The roots of failure

Funding This work forms part of a NERC New Investigator award for DH (NE/I001743/1), which is gratefully acknowledged. Acknowledgments The authors would like to acknowledge the reviewers, Elizabeth Ritz and Phillip Resor. Their reviews were very constructive, both helping to improve the manuscripts consistency and highlighting a number of errors in the initial submission. The authors would also like to thank Lydia Jagger's keen eye and patience, she helped greatly in removing a number of grammatical errors from the initial draft.Peer reviewedPublisher PD

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

Pore geometry as a control on rock strength

This study was funded via RJW's University of Leicester start-up fund, as part of AAB's PhD project. We thank Don Swanson and Mike Poland at HVO, Hawai'i, for their help and advice during fieldwork planning and sample collection in the Koa'e fault system, and the National Park Service for granting a research permit to collect rock samples. Sergio Vinciguerra is thanked for access to the Rock Mechanics and Physics lab at the British Geological Survey and Audrey Ougier-Simonin is thanked for her help preparing samples and advice during testing. We thank Mike Heap (EOST Strasbourg) and an anonymous reviewer for their detailed and careful comments that greatly improved the manuscript.Peer reviewedPostprin

Analysis of Different Types of Regret in Continuous Noisy Optimization

The performance measure of an algorithm is a crucial part of its analysis. The performance can be determined by the study on the convergence rate of the algorithm in question. It is necessary to study some (hopefully convergent) sequence that will measure how "good" is the approximated optimum compared to the real optimum. The concept of Regret is widely used in the bandit literature for assessing the performance of an algorithm. The same concept is also used in the framework of optimization algorithms, sometimes under other names or without a specific name. And the numerical evaluation of convergence rate of noisy algorithms often involves approximations of regrets. We discuss here two types of approximations of Simple Regret used in practice for the evaluation of algorithms for noisy optimization. We use specific algorithms of different nature and the noisy sphere function to show the following results. The approximation of Simple Regret, termed here Approximate Simple Regret, used in some optimization testbeds, fails to estimate the Simple Regret convergence rate. We also discuss a recent new approximation of Simple Regret, that we term Robust Simple Regret, and show its advantages and disadvantages.Comment: Genetic and Evolutionary Computation Conference 2016, Jul 2016, Denver, United States. 201

On the Prior Sensitivity of Thompson Sampling

The empirically successful Thompson Sampling algorithm for stochastic bandits has drawn much interest in understanding its theoretical properties. One important benefit of the algorithm is that it allows domain knowledge to be conveniently encoded as a prior distribution to balance exploration and exploitation more effectively. While it is generally believed that the algorithm's regret is low (high) when the prior is good (bad), little is known about the exact dependence. In this paper, we fully characterize the algorithm's worst-case dependence of regret on the choice of prior, focusing on a special yet representative case. These results also provide insights into the general sensitivity of the algorithm to the choice of priors. In particular, with $p$ being the prior probability mass of the true reward-generating model, we prove $O(\sqrt{T/p})$ and $O(\sqrt{(1-p)T})$ regret upper bounds for the bad- and good-prior cases, respectively, as well as \emph{matching} lower bounds. Our proofs rely on the discovery of a fundamental property of Thompson Sampling and make heavy use of martingale theory, both of which appear novel in the literature, to the best of our knowledge.Comment: Appears in the 27th International Conference on Algorithmic Learning Theory (ALT), 201

Parallel Gaussian Process Optimization with Upper Confidence Bound and Pure Exploration

In this paper, we consider the challenge of maximizing an unknown function f for which evaluations are noisy and are acquired with high cost. An iterative procedure uses the previous measures to actively select the next estimation of f which is predicted to be the most useful. We focus on the case where the function can be evaluated in parallel with batches of fixed size and analyze the benefit compared to the purely sequential procedure in terms of cumulative regret. We introduce the Gaussian Process Upper Confidence Bound and Pure Exploration algorithm (GP-UCB-PE) which combines the UCB strategy and Pure Exploration in the same batch of evaluations along the parallel iterations. We prove theoretical upper bounds on the regret with batches of size K for this procedure which show the improvement of the order of sqrt{K} for fixed iteration cost over purely sequential versions. Moreover, the multiplicative constants involved have the property of being dimension-free. We also confirm empirically the efficiency of GP-UCB-PE on real and synthetic problems compared to state-of-the-art competitors

Therapeutic impact of 2-[fluorine-18]fluoro-2-deoxy-D-glucose positron emission tomography in the pre- and postoperative staging of patients with clinically intermediate or high-risk breast cancer

Background: Positron emission tomography with 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG-PET) is an accurate imaging modality for the staging of breast cancer. The aim of this study was to determine the potential therapeutic impact of pre- and postoperative FDG-PET in patients with clinically intermediate or high-risk breast cancer. Patients and methods: One hundred and fourteen patients with newly diagnosed breast cancer were examined before (73) or after (41) surgery. Patient data were translated into three scoring sheets corresponding to information available before positron emission tomography (PET), after PET and after further diagnostic tests. Three medical oncologists independently reviewed the retrospectively acquired patient data and prospectively made decisions on the theoretically planed treatment for each time point, according to the recommendations of St Gallen Consensus Guidelines 2005. Results: FDG-PET changed the planed treatment in 32% of 114 patients. In 20% of cases, therapeutic intention (curative versus palliative) was modified. Radiation treatment planning was changed in 27%, surgical planning in 9%, chemotherapy in 11% and intended therapy with bisphosphonates in 13% of all patients. Conclusion: Based on current treatment guidelines, FDG-PET, as a staging procedure in patients with newly diagnosed clinically intermediate or high-risk breast cancer examined pre- and postoperatively, may have a substantial therapeutic impact on treatment plannin

AlphaFold2-multimer guided high-accuracy prediction of typical and atypical ATG8-binding motifs

Macroautophagy/autophagy is an intracellular degradation process central to cellular homeostasis and defense against pathogens in eukaryotic cells. Regulation of autophagy relies on hierarchical binding of autophagy cargo receptors and adaptors to ATG8/LC3 protein family members. Interactions with ATG8/LC3 are typically facilitated by a conserved, short linear sequence, referred to as the ATG8/LC3 interacting motif/region (AIM/LIR), present in autophagy adaptors and receptors as well as pathogen virulence factors targeting host autophagy machinery. Since the canonical AIM/LIR sequence can be found in many proteins, identifying functional AIM/LIR motifs has proven challenging. Here, we show that protein modelling using Alphafold-Multimer (AF2-multimer) identifies both canonical and atypical AIM/LIR motifs with a high level of accuracy. AF2-multimer can be modified to detect additional functional AIM/LIR motifs by using protein sequences with mutations in primary AIM/LIR residues. By combining protein modelling data from AF2-multimer with phylogenetic analysis of protein sequences and protein-protein interaction assays, we demonstrate that AF2-multimer predicts the physiologically relevant AIM motif in the ATG8-interacting protein 2 (ATI-2) as well as the previously uncharacterized noncanonical AIM motif in ATG3 from potato (Solanum tuberosum). AF2-multimer also identified the AIM/LIR motifs in pathogen-encoded virulence factors that target ATG8 members in their plant and human hosts, revealing that cross-kingdom ATG8-LIR/AIM associations can also be predicted by AF2-multimer. We conclude that the AF2-guided discovery of autophagy adaptors/receptors will substantially accelerate our understanding of the molecular basis of autophagy in all biological kingdoms

Structural basis for tuning activity and membrane specificity of bacterial cytolysins

Cholesterol-dependent cytolysins (CDCs) are pore-forming proteins that serve as major virulence factors for pathogenic bacteria. They target eukaryotic cells using different mechanisms, but all require the presence of cholesterol to pierce lipid bilayers. How CDCs use cholesterol to selectively lyse cells is essential for understanding virulence strategies of several pathogenic bacteria, and for repurposing CDCs to kill new cellular targets. Here we address that question by trapping an early state of pore formation for the CDC intermedilysin, bound to the human immune receptor CD59 in a nanodisc model membrane. Our cryo electron microscopy map reveals structural transitions required for oligomerization, which include the lateral movement of a key amphipathic helix. We demonstrate that the charge of this helix is crucial for tuning lytic activity of CDCs. Furthermore, we discover modifications that overcome the requirement of cholesterol for membrane rupture, which may facilitate engineering the target-cell specificity of pore-forming proteins

Igneous sills record far-field and near-field stress interactions during volcano construction: Isle of Mull, Scotland

Sill emplacement is typically associated with horizontally mechanically layered host rocks in a near-hydrostatic far-field stress state, where contrasting mechanical properties across the layers promote transitions from dykes, or inclined sheets, to sills. We used detailed field observations from the Loch Scridain Sill Complex (Isle of Mull, UK), and mechanical models to show that layering is not always the dominant control on sill emplacement. The studied sills have consistently shallow dips (1°–25°) and cut vertically bedded and foliated metamorphic basement rocks, and horizontally bedded cover sedimentary rocks and lavas. Horizontal and shallowly-dipping fractures in the host rock were intruded with vertical opening in all cases, whilst steeply-dipping discontinuities within the sequence (i.e. vertical fractures and foliation in the basement, and vertical polygonal joints in the lavas) were not intruded during sill emplacement. Mechanical models of slip tendency, dilation tendency, and fracture susceptibility for local and overall sill geometry data, support a radial horizontal compression during sill emplacement. Our models show that dykes and sills across Mull were emplaced during NW–SE horizontal shortening, related to a far-field tectonic stress state. The dykes generally accommodated phases of NE–SW horizontal tectonic extension, whereas the sills record the superposition of the far-field stress with a near-field stress state, imposed by emplacement of the Mull Central Volcano. We show that through detailed geometric characterisation coupled with mechanical modelling, sills may be used as an indication of fluctuations in the paleostress state