Time delays in quasi-periodic pulsations observed during the X2.2 solar flare on 2011 February 15

We report observations of quasi-periodic pulsations (QPPs) during the X2.2 flare of 2011 February 15, observed simultaneously in several wavebands. We focus on fluctuations on time scale 1-30 s and find different time lags between different wavebands. During the impulsive phase, the Reuven Ramaty High Energy Solar Spectroscopic Imager (RHESSI) channels in the range 25-100 keV lead all the other channels. They are followed by the Nobeyama RadioPolarimeters at 9 and 17 GHz and the Extreme Ultra-Violet (EUV) channels of the Euv SpectroPhotometer (ESP) onboard the Solar Dynamic Observatory (SDO). The Zirconium and Aluminum filter channels of the Large Yield Radiometer (LYRA) onboard the Project for On-Board Autonomy (PROBA2) satellite and the SXR channel of ESP follow. The largest lags occur in observations from the Geostationary Operational Environmental Satellite (GOES), where the channel at 1-8 {\AA} leads the 0.5-4 {\AA} channel by several seconds. The time lags between the first and last channels is up to 9 s. We identified at least two distinct time intervals during the flare impulsive phase, during which the QPPs were associated with two different sources in the Nobeyama RadioHeliograph at 17 GHz. The radio as well as the hard X-ray channels showed different lags during these two intervals. To our knowledge, this is the first time that time lags are reported between EUV and SXR fluctuations on these time scales. We discuss possible emission mechanisms and interpretations, including flare electron trapping

Designing information for families caring for people with dementia

A health communication project, to develop information to support families caring for people with dementia, is described. Close collaboration of designers with carers – ‘experts by experience’ – and clinicians and other professionals – ‘experts by training’ – was used. Carer consultation led to a printed (rather than digital) handbook. An iterative process of carer and clinician consultation and design shaped the material form of the handbook. Carers’ needs for different kinds of information were met by a modular approach, and tailored module design. Evaluation following distribution of the handbook suggested it improved carers’ understanding of dementia significantly compared to the information from diverse sources supplied previously. It did not, however, influence people’s confidence in their ability to care, which appeared to be supported better through carer education courses. The specific contribution of information design and its potential for delivering return on investment are discussed

SWI/SNF regulates a transcriptional programme that induces senescence to prevent liver cancer

Oncogene-induced senescence (OIS) is a potent tumour suppressor mechanism. To identify senescence regulators relevant to cancer, we screened an shRNA library targeting genes deleted in hepatocellular carcinoma (HCC). Here, we describe how knockdown of the SWI/SNF component ARID1B prevents OIS and cooperates with RAS to induce liver tumours. ARID1B controls p16INK4a and p21CIP1a transcription but also regulates DNA damage, oxidative stress and p53 induction, suggesting that SWI/SNF uses additional mechanisms to regulate senescence. To systematically identify SWI/SNF targets regulating senescence, we carried out a focused shRNA screen. We discovered several new senescence regulators including ENTPD7, an enzyme that hydrolyses nucleotides. ENTPD7 affects oxidative stress, DNA damage and senescence. Importantly, expression of ENTPD7 or inhibition of nucleotide synthesis in ARID1B-depleted cells results in re-establishment of senescence. Our results identify novel mechanisms by which epigenetic regulators can affect tumor progression and suggest that pro-senescence therapies could be employed against SWI/SNF-mutated cancers

Use of a targeted, combinatorial next-generation sequencing approach for the study of bicuspid aortic valve

BACKGROUND: Bicuspid aortic valve (BAV) is the most common type of congenital heart disease with a population prevalence of 1-2%. While BAV is known to be highly heritable, mutations in single genes (such as GATA5 and NOTCH1) have been reported in few human BAV cases. Traditional gene sequencing methods are time and labor intensive, while next-generation high throughput sequencing remains costly for large patient cohorts and requires extensive bioinformatics processing. Here we describe an approach to targeted multi-gene sequencing with combinatorial pooling of samples from BAV patients. METHODS: We studied a previously described cohort of 78 unrelated subjects with echocardiogram-identified BAV. Subjects were identified as having isolated BAV or BAV associated with coarctation of aorta (BAV-CoA). BAV cusp fusion morphology was defined as right-left cusp fusion, right non-coronary cusp fusion, or left non-coronary cusp fusion. Samples were combined into 19 pools using a uniquely overlapping combinatorial design; a given mutation could be attributed to a single individual on the basis of which pools contained the mutation. A custom gene capture of 97 candidate genes was sequenced on the Illumina HiSeq 2000. Multistep bioinformatics processing was performed for base calling, variant identification, and in-silico analysis of putative disease-causing variants. RESULTS: Targeted capture identified 42 rare, non-synonymous, exonic variants involving 35 of the 97 candidate genes. Among these variants, in-silico analysis classified 33 of these variants as putative disease-causing changes. Sanger sequencing confirmed thirty-one of these variants, found among 16 individuals. There were no significant differences in variant burden among BAV fusion phenotypes or isolated BAV versus BAV-CoA. Pathway analysis suggests a role for the WNT signaling pathway in human BAV. CONCLUSION: We successfully developed a pooling and targeted capture strategy that enabled rapid and cost effective next generation sequencing of target genes in a large patient cohort. This approach identified a large number of putative disease-causing variants in a cohort of patients with BAV, including variants in 26 genes not previously associated with human BAV. The data suggest that BAV heritability is complex and polygenic. Our pooling approach saved over $39,350 compared to an unpooled, targeted capture sequencing strategy

The SWAP EUV Imaging Telescope Part I: Instrument Overview and Pre-Flight Testing

The Sun Watcher with Active Pixels and Image Processing (SWAP) is an EUV solar telescope on board ESA's Project for Onboard Autonomy 2 (PROBA2) mission launched on 2 November 2009. SWAP has a spectral bandpass centered on 17.4 nm and provides images of the low solar corona over a 54x54 arcmin field-of-view with 3.2 arcsec pixels and an imaging cadence of about two minutes. SWAP is designed to monitor all space-weather-relevant events and features in the low solar corona. Given the limited resources of the PROBA2 microsatellite, the SWAP telescope is designed with various innovative technologies, including an off-axis optical design and a CMOS-APS detector. This article provides reference documentation for users of the SWAP image data.Comment: 26 pages, 9 figures, 1 movi

Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas

Although cancer arises from a combination of mutations in oncogenes and tumour suppressor genes, the extent to which tumour suppressor gene loss is required for maintaining established tumours is poorly understood. p53 is an important tumour suppressor that acts to restrict proliferation in response to DNA damage or deregulation of mitogenic oncogenes, by leading to the induction of various cell cycle checkpoints, apoptosis or cellular senescence(1,2). Consequently, p53 mutations increase cell proliferation and survival, and in some settings promote genomic instability and resistance to certain chemotherapies(3). To determine the consequences of reactivating the p53 pathway in tumours, we used RNA interference (RNAi) to conditionally regulate endogenous p53 expression in a mosaic mouse model of liver carcinoma(4,5). We show that even brief reactivation of endogenous p53 in p53-deficient tumours can produce complete tumour regressions. The primary response to p53 was not apoptosis, but instead involved the induction of a cellular senescence program that was associated with differentiation and the upregulation of inflammatory cytokines. This program, although producing only cell cycle arrest in vitro, also triggered an innate immune response that targeted the tumour cells in vivo, thereby contributing to tumour clearance. Our study indicates that p53 loss can be required for the maintenance of aggressive carcinomas, and illustrates how the cellular senescence program can act together with the innate immune system to potently limit tumour growth

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

The Impact of Boreal Forest Fire on Climate Warming

We report measurements and analysis of a boreal forest fire, integrating the effects of greenhouse gases, aerosols, black carbon deposition on snow and sea ice, and postfire changes in surface albedo. The net effect of all agents was to increase radiative forcing during the first year (34 ± 31 Watts per square meter of burned area), but to decrease radiative forcing when averaged over an 80-year fire cycle (–2.3 ± 2.2 Watts per square meter) because multidecadal increases in surface albedo had a larger impact than fire-emitted greenhouse gases. This result implies that future increases in boreal fire may not accelerate climate warming

A cluster of cooperating tumor-suppressor gene candidates in chromosomal deletions

The large chromosomal deletions frequently observed in cancer genomes are often thought to arise as a "two-hit" mechanismin the process of tumor-suppressor gene (TSG) inactivation. Using a murine model system of hepatocellular carcinoma (HCC) and in vivo RNAi, we test an alternative hypothesis, that such deletions can arise from selective pressure to attenuate the activity of multiple genes. By targeting the mouse orthologs of genes frequently deleted on human 8p22 and adjacent regions, which are lost in approximately half of several other major epithelial cancers, we provide evidence suggesting that multiple genes on chromosome 8p can cooperatively inhibit tumorigenesis in mice, and that their cosuppression can synergistically promote tumor growth. In addition, in human HCC patients, the combined down-regulation of functionally validated 8p TSGs is associated with poor survival, in contrast to the down-regulation of any individual gene. Our data imply that large cancer-associated deletions can produce phenotypes distinct from those arising through loss of a single TSG, and as such should be considered and studied as distinct mutational events