Hydrophobic gating of mechanosensitive channel of large conductance evidenced by single-subunit resolution

Mechanosensitive (MS) ion channels are membrane proteins that detect and respond to membrane tension in all branches of life. In bacteria, MS channels prevent cells from lysing upon sudden hypoosmotic shock by opening and releasing solutes and water. Despite the importance of MS channels and ongoing efforts to explain their functioning, the molecular mechanism of MS channel gating remains elusive and controversial. Here we report a method that allows single-subunit resolution for manipulating and monitoring “mechanosensitive channel of large conductance” from Escherichia coli. We gradually changed the hydrophobicity of the pore constriction in this homopentameric protein by modifying a critical pore residue one subunit at a time. Our experimental results suggest that both channel opening and closing are initiated by the transmembrane 1 helix of a single subunit and that the participation of each of the five identical subunits in the structural transitions between the closed and open states is asymmetrical. Such a minimal change in the pore environment seems ideal for a fast and energy-efficient response to changes in the membrane tension.

Locked and loading megathrust linked to active subduction beneath the Indo-Burman Ranges

The Indo-Burman mountain rangesmarkthe boundary between the Indian and Eurasian plates, north of the Sumatra–Andaman subduction zone. Whether subduction still occurs along this subaerial section of the plate boundary, with 46mm/yr of highly oblique motion, is contentious. About 21mm/yr of shear motion is taken up along the Sagaing Fault, on the eastern margin of the deformation zone. It has been suggested that the remainder of the relative motion is taken up largely or entirely by horizontal strike-slip faulting and that subduction has stopped. Here we present GPS measurements of plate motions in Bangladesh, combined with measurements from Myanmar and northeast India, taking advantage of a more than 300 km subaerial accretionary prism spanning the Indo-Burman Ranges to the Ganges–Brahmaputra Delta. They reveal 13–17mm/yr of plate convergence on an active, shallowly dipping and locked megathrust fault. Most of the strike-slip motion occurs on a few steep faults, consistent with patterns of strain partitioning in subduction zones. Our results strongly suggest that subduction in this region is active, despite the highly oblique plate motion and thick sediments. We suggest that the presence of a locked megathrust plate boundary represents an underappreciated hazard in one of the most densely populated regions of the world

Insights into the function of ion channels by computational electrophysiology simulations

Ion channels are of universal importance for all cell types and play key roles in cellular physiology and pathology. Increased insight into their functional mechanisms is crucial to enable drug design on this important class of membrane proteins, and to enhance our understanding of some of the fundamental features of cells. This review presents the concepts behind the recently developed simulation protocol Computational Electrophysiology (CompEL), which facilitates the atomistic simulation of ion channels in action. In addition, the review provides guidelines for its application in conjunction with the molecular dynamics software package GROMACS. We first lay out the rationale for designing CompEL as a method that models the driving force for ion permeation through channels the way it is established in cells, i.e., by electrochemical ion gradients across the membrane. This is followed by an outline of its implementation and a description of key settings and parameters helpful to users wishing to set up and conduct such simulations. In recent years, key mechanistic and biophysical insights have been obtained by employing the CompEL protocol to address a wide range of questions on ion channels and permeation. We summarize these recent findings on membrane proteins, which span a spectrum from highly ion-selective, narrow channels to wide diffusion pores. Finally we discuss the future potential of CompEL in light of its limitations and strengths. This article is part of a Special Issue entitled: Membrane Proteins edited by J.C. Gumbart and Sergei Noskov

Exploring new physics frontiers through numerical relativity

The demand to obtain answers to highly complex problems within strong-field gravity has been met with significant progress in the numerical solution of Einstein's equations - along with some spectacular results - in various setups. We review techniques for solving Einstein's equations in generic spacetimes, focusing on fully nonlinear evolutions but also on how to benchmark those results with perturbative approaches. The results address problems in high-energy physics, holography, mathematical physics, fundamental physics, astrophysics and cosmology

Collaborating for Innovation: the socialised management of knowledge

Although the importance of diverse knowledge is widely recognised for open innovation, there may be a gap in our understanding of the social processes that shape how collaborators engage in knowledge exchange. This social gap may be significant because of the powerful, but largely unexplained, role attributed to trust as a social artefact. Moreover, we see trust as a process and that different types of trust are involved in the collaborative process. Thus, this paper uses a qualitative methodology to capture the experiences of innovation collaborators. As explanation of the dynamic interplays of knowledge and trust, we offer a description of phases in the process. Our analysis finds that the relationship moves from transactional to social. The early phases are characterised by technical knowledge, but the later and mature phases are identified with knowledge of the person and by personal trust. The success of innovation is a result of relationships with augmented trust. We found that a fabric of trust is woven from the weft of professional knowledge and the warp of personal knowledge to support innovation. We propose that this developing of relationships might be conceived as becoming more open in the sense of sharing with one another. If so, we seem to have described and offered a social dimension of open innovation

Failures in collaborative design with suppliers: Literature review and future research avenues

The focus of the firms on their core competencies associated with the increasing complexity of products due to an integration of various technologies has led to an extension of their New Product Development (NPD) activity across organisational boundaries. In this respect, it is now acknowledged that Early Supplier Involvement (ESI) in product development confers a competitive advantage. Nevertheless appraising the benefits of such collaboration on the product development performance is not easy. Our method is based on the “glitch ” concept that enables to appraise ESI benefits from the opposite direction i.e. by identifying what happens when the collaboration with suppliers is absent. Our previous work presented at IPSERA 2011 dealt with an in-depth case study analysis of an unsuccessful collaborative development with a supplier. In this previous paper, we identified ten “glitches ” that prevented from reaping the benefits of supplier involvement. The aim of this paper is to carry out a literature review about failures in collaborative development of new product between a customer and a supplier. By comparing those literature review results with case study results, we aim at proposing a classification of the failures currently encountered in collaborative development with suppliers in order to tackle them

Estimation of the pore size of the large-conductance mechanosensitive ion channel of Escherichia coli.

The open channel diameter of Escherichia coli recombinant large-conductance mechanosensitive ion channels (MscL) was estimated using the model of Hille (Hille, B. 1968. Pharmacological modifications of the sodium channels of frog nerve. J. Gen. Physiol. 51:199-219) that relates the pore size to conductance. Based on the MscL conductance of 3.8 nS, and assumed pore lengths, a channel diameter of 34 to 46 A was calculated. To estimate the pore size experimentally, the effect of large organic ions on the conductance of MscL was examined. Poly-L-lysines (PLLs) with a diameter of 37 A or larger significantly reduced channel conductance, whereas spermine (approximately 15 A), PLL19 (approximately 25 A) and 1,1'-bis-(3-(1'-methyl-(4,4'-bipyridinium)-1-yl)-propyl)-4,4'-b ipyridinium (approximately 30 A) had no effect. The smaller organic ions putrescine, cadaverine, spermine, and succinate all permeated the channel. We conclude that the open pore diameter of the MscL is approximately 40 A, indicating that the MscL has one of the largest channel pores yet described. This channel diameter is consistent with the proposed homohexameric model of the MscL