The nuclear envelope can control gene expression and cell cycle progression via miRNA regulation

This article is available open access through the publisher’s website. Copyright @ 2010 Landes Bioscience.The nuclear envelope can regulate gene expression through its interaction with chromatin and by the sequestration of specific transcription factors. In this study, we show that such regulation can be achieved via microRNA regulation. We identify a set of miRNAs that are dysregulated in the absence of a fully functional nuclear lamina. We then focus on miRNA-31 and experimentally confirm its targets. The target set identified is significantly enriched in genes involved in controlling progress through the cell cycle such as Cdkn2a. Normalizing miRNA-31 levels, either using a specific inhibitor or by restoration of the nuclear lamina, also normalizes cell cycle distribution and cell proliferation rates. We show that the 3’UTR of p16Ink4a/p19Arf has a functional miRNA-31 binding site which contributes to the observed regulation of cell cycle progression. Our findings are the first demonstration that the nuclear envelope can control gene expression by regulating specific miRNA levels, and that miRNA-31 is involved in the regulation of cell proliferation and progress through the cell cycle at least in part by regulating the levels of p16Ink4a/p19Arf.The EPA Trust and the MRC

Selective flow-induced vesicle rupture to sort by membrane mechanical properties

International audienceVesicle and cell rupture caused by large viscous stresses in ultrasonication is central to biomedical and bioprocessing applications. The flow-induced opening of lipid membranes can be exploited to deliver drugs into cells, or to recover products from cells, provided that it can be obtained in a controlled fashion. Here we demonstrate that differences in lipid membrane and vesicle properties can enable selective flow-induced vesicle break-up. We obtained vesicle populations with different membrane properties by using different lipids (SOPC, DOPC, or POPC) and lipid:cholesterol mixtures (SOPC:chol and DOPC:chol). We subjected vesicles to large deformations in the acoustic microstreaming flow generated by ultrasound-driven microbubbles. By simultaneously deforming vesicles with different properties in the same flow, we determined the conditions in which rupture is selective with respect to the membrane stretching elasticity. We also investigated the effect of vesicle radius and excess area on the threshold for rupture, and identified conditions for robust selectivity based solely on the mechanical properties of the membrane. Our work should enable new sorting mechanisms based on the difference in membrane composition and mechanical properties between different vesicles, capsules, or cells

Evaluation of air-displacement plethysmography in children aged 5-7 years using a three-component model of body composition

The aim of the present study was to evaluate air-displacement plethysmography (ADP) in children aged 5-7 years. Body-composition measurements were obtained by ADP, H-2 dilution and anthropometry in twenty-eight children. Calculation of body volume by ADP was undertaken using adult and children's equations for predicting lung volume and surface area. Fat-free mass (FFM) was calculated using a three-component model. Measured FFM hydration was then compared with values from the reference child. Differences between measured and reference hydration were back-extrapolated, to calculate the error in ADP that would account for any disagreement. Propagation of error was used to distinguish the contributions of methodological precision and biological variability to total hydration variability. The use of children's equations influenced the results for lung volume but not surface area. The mean difference between measured and reference hydration was 0.6 (SD 1.7) % (P<0.10), equivalent to an error in body volume of 0.04 (So 0.20) litres (P<0.30), and in percentage fat of 0.4 (SD 1.9) (P<0.28). The limits of agreement in individuals could be attributed to methodological precision and biological variability in hydration. It is concluded that accuracy of ADP was high for the whole group, with a mean bias of <0.5% fat using the three-component model, and after taking into account biological variability in hydration, the limits of agreement were around 2 % fat in individuals. Paediatric rather than adult equations for lung volume estimation should be used

Achieving high coverage of larval-stage mosquito surveillance: challenges for a community-based mosquito control programme in urban Dar es Salaam, Tanzania

Background: Preventing malaria by controlling mosquitoes in their larval stages requires regular sensitive monitoring of vector populations and intervention coverage. The study assessed the effectiveness of operational, community-based larval habitat surveillance systems within the Urban Malaria Control Programme (UMCP) in urban Dar es Salaam, Tanzania. Methods: Cross-sectional surveys were carried out to assess the ability of community-owned resource persons (CORPs) to detect mosquito breeding sites and larvae in areas with and without larviciding. Potential environmental and programmatic determinants of habitat detection coverage and detection sensitivity of mosquito larvae were recorded during guided walks with 64 different CORPs to assess the accuracy of data each had collected the previous day. Results: CORPs reported the presence of 66.2% of all aquatic habitats (1,963/2,965), but only detected Anopheles larvae in 12.6% (29/230) of habitats that contained them. Detection sensitivity was particularly low for late-stage Anopheles (2.7%, 3/111), the most direct programmatic indicator of malaria vector productivity. Whether a CORP found a wet habitat or not was associated with his/her unfamiliarity with the area (Odds Ratio (OR) [95% confidence interval (CI)] = 0.16 [0.130, 0.203], P < 0.001), the habitat type (P < 0.001) or a fence around the compound (OR [95% CI] = 0.50 [0.386, 0.646], P < 0.001). The majority of mosquito larvae (Anophelines 57.8% (133/230) and Culicines 55.9% (461/825) were not reported because their habitats were not found. The only factor affecting detection of Anopheline larvae in habitats that were reported by CORPs was larviciding, which reduced sensitivity (OR [95% CI] = 0.37 [0.142, 0.965], P = 0.042). Conclusions: Accessibility of habitats in urban settings presents a major challenge because the majority of compounds are fenced for security reasons. Furthermore, CORPs under-reported larvae especially where larvicides were applied. This UMCP system for larval surveillance in cities must be urgently revised to improve access to enclosed compounds and the sensitivity with which habitats are searched for larvae

Allele-sharing models: LOD scores and accurate linkage tests.

RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.Starting with a test statistic for linkage analysis based on allele sharing, we propose an associated one-parameter model. Under general missing-data patterns, this model allows exact calculation of likelihood ratios and LOD scores and has been implemented by a simple modification of existing software. Most important, accurate linkage tests can be performed. Using an example, we show that some previously suggested approaches to handling less than perfectly informative data can be unacceptably conservative. Situations in which this model may not perform well are discussed, and an alternative model that requires additional computations is suggested

Solutions of the Generic Non-Compact Weyl Equation

In this paper, solutions of the generic non-compact Weyl equation are obtained. In particular, by identifying a suitable similarity transformation and introducing a non-trivial change of variables we are able to implement azimuthal dependence on the solutions of the diagonal non-compact Weyl equation. We also discuss some open questions related to the construction of infinite BPS monopole configurations.Comment: 12 pages, Latex. Few extra comments and a reference adde

The consequences of replicating in the wrong orientation: Bacterial chromosome duplication without an active replication origin

Chromosome replication is regulated in all organisms at the assembly stage of the replication machinery at specific origins. In Escherichia coli the DnaA initiator protein regulates the assembly of replication forks at oriC. This regulation can be undermined by defects in nucleic acid meta¬bolism. In cells lacking RNase HI replication initiates indepen¬dently of DnaA and oriC, presumably at persisting R-loops. A similar mechanism was assumed for origin-independent synthesis in cells lacking RecG. However, recently we suggested that this synthesis initiates at intermediates resulting from replication fork fusions. Here we present data suggesting that in cells lacking RecG or RNase HI origin-independent synthesis arises by different mechanisms, indicative of these two proteins having different roles in vivo. Our data support the idea that RNase HI processes R-loops, while RecG is required to process replication fork fusion intermediates. However, regardless of how origin-independent synthesis is initiated, a fraction of forks will proceed in an orientation opposite to normal. We show that the resulting head-on encounters with transcription threaten cell viability, especially if taking place in highly-transcribed areas. Thus, despite their different functions, RecG and RNase HI are both important factors for maintaining replication control and orientation. Their absence causes severe replication problems, highlighting the advantages of the normal chromosome arrangement, which exploits a single origin to control the number of forks and their orientation relative to transcription, and a defined termination area to contain fork fusions. Any changes to this arrangement endanger cell cycle control, chromosome dynamics and, ultimately, cell viability.This work was supported by the Royal Society (RG110414 to C.J.R.) and The Biotechnology and Biological Sciences Research Council (BB/K015729/1 to C.J.R.)

Animal cognition: the benefits of remembering

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this record.How cognitive abilities evolve through natural selection is poorly understood. Two new studies show that a good spatial memory helps birds that hide their food to survive and produce more offspring

Plasma REST: a novel candidate biomarker of Alzheimer's disease is modified by psychological intervention in an at-risk population.

The repressor element 1-silencing transcription (REST) factor is a key regulator of the aging brain's stress response. It is reduced in conditions of stress and Alzheimer's disease (AD), which suggests that increasing REST may be neuroprotective. REST can be measured peripherally in blood plasma. Our study aimed to (1) examine plasma REST levels in relation to clinical and biological markers of neurodegeneration and (2) alter plasma REST levels through a stress-reduction intervention-mindfulness training. In study 1, REST levels were compared across the following four well-characterized groups: healthy elderly (n=65), mild cognitive impairment who remained stable (stable MCI, n=36), MCI who later converted to dementia (converter MCI, n=29) and AD (n=65) from the AddNeuroMed cohort. REST levels declined with increasing severity of risk and impairment (healthy elderly&gt;stable MCI&gt;converter MCI&gt;AD, F=6.35, P&lt;0.001). REST levels were also positively associated with magnetic resonance imaging-based hippocampal and entorhinal atrophy and other putative blood-based biomarkers of AD (Ps&lt;0.05). In study 2, REST was measured in 81 older adults with psychiatric risk factors for AD before and after a mindfulness-based stress reduction intervention or an education-based placebo intervention. Mindfulness-based training caused an increase in REST compared with the placebo intervention (F=8.57, P=0.006), and increased REST was associated with a reduction in psychiatric symptoms associated with stress and AD risk (Ps&lt;0.02). Our data confirm plasma REST associations with clinical severity and neurodegeneration, and originally, that REST is modifiable by a psychological intervention with clinical benefit