The essential process of protein secretion is achieved by the ubiquitous Sec machinery. In prokaryotes, the drive for translocation comes from ATP hydrolysis by the cytosolic motor-protein SecA, in concert with the proton motive force (PMF). However, the mechanism through which ATP hydrolysis by SecA is coupled to directional movement through SecYEG is unclear. Here, we combine all-atom molecular dynamics (MD) simulations with single molecule FRET and biochemical assays. We show that ATP binding by SecA causes opening of the SecY-channel at long range, while substrates at the SecY-channel entrance feed back to regulate nucleotide exchange by SecA. This two-way communication suggests a new, unifying 'Brownian ratchet' mechanism, whereby ATP binding and hydrolysis bias the direction of polypeptide diffusion. The model represents a solution to the problem of transporting inherently variable substrates such as polypeptides, and may underlie mechanisms of other motors that translocate proteins and nucleic acids.DOI: http://dx.doi.org/10.7554/eLife.15598.001
Protein translocation across cell membranes is a ubiquitous process required for protein secretion and membrane protein insertion. In bacteria, this is mostly mediated by the conserved SecYEG complex, driven through rounds of ATP hydrolysis by the cytoplasmic SecA, and the trans-membrane proton motive force. We have used single molecule techniques to explore SecY pore dynamics on multiple timescales in order to dissect the complex reaction pathway. The results show that SecA, both the signal sequence and mature components of the pre-protein, and ATP hydrolysis each have important and specific roles in channel unlocking, opening and priming for transport. After channel opening, translocation proceeds in two phases: a slow phase independent of substrate length, and a length-dependent transport phase with an intrinsic translocation rate of ~40 amino acids per second for the proOmpA substrate. Broad translocation rate distributions reflect the stochastic nature of polypeptide transport.
The Stages of Change model has become a prominent feature within health promotion and most of the literature associated with the model portrays it as being 'effective'. Based on an extensive review of the literature, this paper suggests that contrary to this view, there exist a relative paucity of sufficiently strong supportive evidence. The paper describes the features of the existing evidence base, and highlights problems in relation to various aspects of design and execution. Two wider issues relating to the core nature of the model and the evidence associated with it are identified as important and discussed. Two main conclusions are drawn. First, better quality quantitative outcome studies are needed. These should be complemented with significant qualitative case studies with a focus on practitioner and organizational utilization of the model. Second, the disproportionate popularity of the model may be skewing the practical and conceptual nature of health promotion. Stages of Change activities are seen to equate to 'health promotion' at the expense of other activities and approaches.
Neonatal herpes simplex virus (HSV) infection usually is the consequence of intrapartum infection, with disease onset between 5 and 15 days of life. More recently, intrauterine HSV infection has been identified. Intrauterine infection is apparent within the first 24-48 hr of life and is associated with skin vesicles/scarring, chorioretinitis, and/or hydraencephaly. The recognition that babies with these findings can have disease caused by HSV should prompt enhanced physician awareness in the evaluation of newborns with suspected intrauterine infection. The frequency of intrauterine infection appears to be about 5% of all babies with neonatal HSV infection.
AB S T R A C T The transtheoretical or 'stages of change' model has greatly influenced health promotion practice in the USA, Australia and the UK since the late 1980s. Application of the model has shaped service planning, provision and implementation. 'Stages of change' also has impacted on training agendas at local, regional and national levels. Associated areas of motivational interviewing and brief intervention have led health promotion initiatives in areas such as smoking cessation and alcohol-reduction policies. A number of critiques have recently challenged the 'stages of change' model and health promotion orthodoxy. This review examines these critiques, with a focus on the 'scienti c' status of 'stages of change'. The review also examines a data-based approach to stages of change, model adequacy, the social and ideological context of change theories in health promotion contexts, levels of explanation and prediction in the 'stages of change' framework. Some reasons are offered for the apparent popularity of the model amongst health promotion workers.Recommendations are made about alternative conceptual frameworks.
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