Competitive binding of MatP and topoisomerase IV to the MukB hinge domain.

Structural Maintenance of Chromosomes (SMC) complexes have ubiquitous roles in compacting DNA linearly, thereby promoting chromosome organization-segregation. Interaction between the Escherichia coli SMC complex, MukBEF, and matS-bound MatP in the chromosome replication termination region, ter, results in depletion of MukBEF from ter, a process essential for efficient daughter chromosome individualization and for preferential association of MukBEF with the replication origin region. Chromosome-associated MukBEF complexes also interact with topoisomerase IV (ParC2E2), so that their chromosome distribution mirrors that of MukBEF. We demonstrate that MatP and ParC have an overlapping binding interface on the MukB hinge, leading to their mutually exclusive binding, which occurs with the same dimer to dimer stoichiometry. Furthermore, we show that matS DNA competes with the MukB hinge for MatP binding. Cells expressing MukBEF complexes that are mutated at the ParC/MatP binding interface are impaired in ParC binding and have a mild defect in MukBEF function. These data highlight competitive binding as a means of globally regulating MukBEF-topoisomerase IV activity in space and time

Endoscopists attitudes on the publication of "quality" data for endoscopic procedures: a cross-sectional survey

<p>Abstract</p> <p>Background</p> <p>Whilst the public now have access to mortality & morbidity data for cardiothoracic surgeons, such "quality" data for endoscopy are not generally available. We studied endoscopists' attitudes to and the practicality of this data being published.</p> <p>Methods</p> <p>We sent a questionnaire to all consultant gastrointestinal (GI) surgeons, physicians and medical GI specialist registrars in the Northern region who currently perform GI endoscopic procedures (n = 132). We recorded endoscopist demographics, experience and current data collection practice. We also assessed the acceptability and utility of nine items describing endoscopic "quality" (e.g. mortality, complication & completion rates).</p> <p>Results</p> <p>103 (78%) doctors responded of whom 79 were consultants (77%). 61 (59%) respondents were physicians. 77 (75%) collect any "quality" data. The most frequently collected item was colonoscopic completion rate. Data were most commonly collected for appraisal, audit or clinical governance. The majority of doctors (54%) kept these data only available to themselves, and just one allowed the public to access this. The most acceptable data item was annual number of endoscopies and the least was crude upper GI bleeding mortality. Surgeons rated information less acceptable and less useful than physicians. Acceptability and utility scores were not related to gender, length of experience or current activity levels. Only two respondents thought all items totally unacceptable and useless.</p> <p>Conclusion</p> <p>The majority of endoscopists currently collect "quality" data for their practice although these are not widely available. The endoscopists in this study consider the publication of their outcome data to be "fairly unacceptable/not very useful" to "neutral" (score 2–3). If these data were made available to patients, consideration must be given to both its value and its acceptability.</p

MODEM: a comprehensive approach to modelling outcome and costs impacts of interventions for dementia. Protocol paper

Background The MODEM project (A comprehensive approach to MODelling outcome and costs impacts of interventions for DEMentia) explores how changes in arrangements for the future treatment and care of people living with dementia, and support for family and other unpaid carers, could result in better outcomes and more efficient use of resources. Methods MODEM starts with a systematic mapping of the literature on effective and (potentially) cost-effective interventions in dementia care. Those findings, as well as data from a cohort, will then be used to model the quality of life and cost impacts of making these evidence-based interventions more widely available in England over the period from now to 2040. Modelling will use a suite of models, combining microsimulation and macrosimulation methods, modelling the costs and outcomes of care, both for an individual over the life-course from the point of dementia diagnosis, and for individuals and England as a whole in a particular year. Project outputs will include an online Dementia Evidence Toolkit, making evidence summaries and a literature database available free to anyone, papers in academic journals and other written outputs, and a MODEM Legacy Model, which will enable local commissioners of services to apply the model to their own populations. Discussion Modelling the effects of evidence-based cost-effective interventions and making this information widely available has the potential to improve the health and quality of life both of people with dementia and their carers, while ensuring that resources are used efficiently

Histone Acetylation-Mediated Regulation of the Hippo Pathway

The Hippo pathway is a signaling cascade recently found to play a key role in tumorigenesis therefore understanding the mechanisms that regulate it should open new opportunities for cancer treatment. Available data indicate that this pathway is controlled by signals from cell-cell junctions however the potential role of nuclear regulation has not yet been described. Here we set out to verify this possibility and define putative mechanism(s) by which it might occur. By using a luciferase reporter of the Hippo pathway, we measured the effects of different nuclear targeting drugs and found that chromatin-modifying agents, and to a lesser extent certain DNA damaging drugs, strongly induced activity of the reporter. This effect was not mediated by upstream core components (i.e. Mst, Lats) of the Hippo pathway, but through enhanced levels of the Hippo transducer TAZ. Investigation of the underlying mechanism led to the finding that cancer cell exposure to histone deacetylase inhibitors induced secretion of growth factors and cytokines, which in turn activate Akt and inhibit the GSK3 beta associated protein degradation complex in drug-affected as well as in their neighboring cells. Consequently, expression of EMT genes, cell migration and resistance to therapy were induced. These processes were suppressed by using pyrvinium, a recently described small molecule activator of the GSK 3 beta associated degradation complex. Overall, these findings shed light on a previously unrecognized phenomenon by which certain anti-cancer agents may paradoxically promote tumor progression by facilitating stabilization of the Hippo transducer TAZ and inducing cancer cell migration and resistance to therapy. Pharmacological targeting of the GSK3 beta associated degradation complex may thus represent a unique approach to treat cancer. © 2013 Basu et al

Insulin resistance in type 1 diabetes: what is ‘double diabetes’ and what are the risks?

In this review, we explore the concept of ‘double diabetes’, a combination of type 1 diabetes with features of insulin resistance and type 2 diabetes. After considering whether double diabetes is a useful concept, we discuss potential mechanisms of increased insulin resistance in type 1 diabetes before examining the extent to which double diabetes might increase the risk of cardiovascular disease (CVD). We then go on to consider the proposal that weight gain from intensive insulin regimens may be associated with increased CV risk factors in some patients with type 1 diabetes, and explore the complex relationships between weight gain, insulin resistance, glycaemic control and CV outcome. Important comparisons and contrasts between type 1 diabetes and type 2 diabetes are highlighted in terms of hepatic fat, fat partitioning and lipid profile, and how these may differ between type 1 diabetic patients with and without double diabetes. In so doing, we hope this work will stimulate much-needed research in this area and an improvement in clinical practice

Toward a Unified Genetic Map of Higher Plants, Transcending the Monocot-Dicot Divergence

Closely related (confamilial) genera often retain large chromosomal tracts in which gene order is colinear, punctuated by structural mutations such as inversions and translocations 1. To explore the possibility that conservation of gene order might extrapolate to more distantly related taxa, we first estimated an average structural mutation rate. Nine pairs of taxa, for which there exist both comparative genetic maps and plausible estimates of divergence time, showed an average of0.14 (±0.06) structural mutations per chromosome per million years of divergence (Myr; Table 1). This value is offered as a first approximation, acknowledging that refined comparative data and/or divergence estimates may impel revision

Is it feasible to deliver a complex intervention to improve the outcome of falls in people with dementia? A protocol for the DIFRID feasibility study

Background: People with dementia (PWD) experience ten times as many incident falls as people without dementia. Little is known about how best to deliver services to people with dementia following a fall. We used an integrated, mixed-methods approach to develop a new intervention which combines theory generated via a realist synthesis and data on current provision and pathways, gathered through a prospective observational study as well as qualitative interviews, focus groups, and ethnographic observation. This intervention is to be tested in a feasibility study in the UK National Health Service. Methods: People living with dementia in one of three geographical areas will be eligible for the study if they experience a fall requiring healthcare attention and have an informal carer. Potential participants will be identified by community services (primary care, paramedics, telecare), secondary care (ED; facilitated discharge services; rehabilitation outreach teams) and research case registers. Participants will receive a complex multidisciplinary intervention focused on their goals and interests for up to 12 weeks. The intervention will be delivered by occupational therapists, physiotherapists and rehabilitation support workers. Feasibility outcomes will include recruitment and retention, suitability and acceptability of outcome measures and acceptability, feasibility and fidelity of intervention components. PWD outcome measures will include number of falls, Montreal Cognitive Assessment (MOCA), European Quality of Life Instrument (EQ-5D-5L), Quality of Life–Alzheimer’s Disease Scale (QOL-AD), Modified Falls Efficacy Scale (MFES) and Goal Attainment Scaling (GAS). PWD outcome measures completed by an informal carer will include Disability Assessment for Dementia (DAD), EQ-5D-5L Proxy, QoL-AD Proxy and a Health Utilisation Questionnaire (HUQ), The carer outcome measure will be the Zarit Burden Interview (ZBI). An embedded process evaluation will explore barriers and facilitators to recruitment and intervention delivery. Discussion: The study results will inform whether and how a larger multicentre RCT should be undertaken. A full RCT would have the potential to show how outcomes can be improved for people with dementia who have fallen. Ethics and dissemination: The National Research Ethics Service Committee Newcastle and North Tyneside 2 approved the feasibility study. Trial registration: International Standard Randomised Controlled Trial Registry Registration number: ISRCTN41760734 Date of registration: 16/11/201

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente