The impulsive phase of magnetar giant flares: assessing linear tearing as the trigger mechanism

Giant $\gamma$-ray flares comprise the most extreme radiation events observed from magnetars. Developing on (sub)millisecond timescales and generating vast amounts of energy within a fraction of a second, the initial phase of these extraordinary bursts present a significant challenge for candidate trigger mechanisms. Here we assess and critically analyse the linear growth of the relativistic tearing instability in a globally twisted magnetosphere as the trigger mechanism for giant $\gamma$-ray flares. Our main constraints are given by the observed emission timescales, the energy output of the giant flare spike, and inferred dipolar magnetic field strengths. We find that the minimum growth time of the linear mode is comparable to the $e$-folding rise time, i.e. $\sim10^{-1}$ ms. With this result we constrain basic geometric parameters of the current sheet. We also discuss the validity of the presumption that the $e$-folding emission timescale may be equated with the growth time of an MHD instability.Comment: 15 pages, 4 figures, MNRAS in pres

Magnetar giant flare high-energy emission

High energy ($> 250$ keV) emission has been detected persisting for several tens of seconds after the initial spike of magnetar giant flares. It has been conjectured that this emission might arise via inverse Compton scattering in a highly extended corona generated by super-Eddington outflows high up in the magnetosphere. In this paper we undertake a detailed examination of this model. We investigate the properties of the required scatterers, and whether the mechanism is consistent with the degree of pulsed emission observed in the tail of the giant flare. We conclude that the mechanism is consistent with current data, although the origin of the scattering population remains an open question. We propose an alternative picture in which the emission is closer to that star and is dominated by synchrotron radiation. The $RHESSI$ observations of the December 2004 flare modestly favor this latter picture. We assess the prospects for the Fermi Gamma-Ray Space Telescope to detect and characterize a similar high energy component in a future giant flare. Such a detection should help to resolve some of the outstanding issues.Comment: 20 pages, 14 figure

Rotational phase dependence of magnetar bursts

The trigger for the short bursts observed in $\gamma$-rays from many magnetar sources remains unknown. One particular open question in this context is the localization of burst emission to a singular active region or a larger area across the neutron star. While several observational studies have attempted to investigate this question by looking at the phase dependence of burst properties, results have been mixed. At the same time, it is not obvious a priori that bursts from a localized active region would actually give rise to a detectable phase-dependence, taking into account issues such as geometry, relativistic effects, and intrinsic burst properties such brightness and duration. In this paper, we build a simple theoretical model to investigate the circumstances under which the latter effects could affect detectability of a dependence of burst emission on rotational phase. We find that even for strongly phase-dependent emission, inferred burst properties may not show a rotational phase dependence depending on the geometry of the system and the observer. Furthermore, the observed properties of bursts with durations short as 10-20% of the spin period can vary strongly depending on the rotational phase at which the burst was emitted. We also show that detectability of a rotational phase dependence depends strongly on the minimum number of bursts observed, and find that existing burst samples may simply be too small to rule out a phase dependence.Comment: 15 pages, 17 figure

Dissecting magnetar variability with Bayesian hierarchical models

Neutron stars are a prime laboratory for testing physical processes under conditions of strong gravity, high density, and extreme magnetic fields. Among the zoo of neutron star phenomena, magnetars stand out for their bursting behaviour, ranging from extremely bright, rare giant flares to numerous, less energetic recurrent bursts. The exact trigger and emission mechanisms for these bursts are not known; favoured models involve either a crust fracture and subsequent energy release into the magnetosphere, or explosive reconnection of magnetic field lines. In the absence of a predictive model, understanding the physical processes responsible for magnetar burst variability is difficult. Here, we develop an empirical model that decomposes magnetar bursts into a superposition of small spike-like features with a simple functional form, where the number of model components is itself part of the inference problem. The cascades of spikes that we model might be formed by avalanches of reconnection, or crust rupture aftershocks. Using Markov Chain Monte Carlo (MCMC) sampling augmented with reversible jumps between models with different numbers of parameters, we characterise the posterior distributions of the model parameters and the number of components per burst. We relate these model parameters to physical quantities in the system, and show for the first time that the variability within a burst does not conform to predictions from ideas of self-organised criticality. We also examine how well the properties of the spikes fit the predictions of simplified cascade models for the different trigger mechanisms.Comment: accepted for publication in The Astrophysical Journal; code available at https://bitbucket.org/dhuppenkothen/magnetron, data products at http://figshare.com/articles/SGR_J1550_5418_magnetron_data/129242

Nitraat, nitriet en N-nitrosaminen in voedingsmiddelen

Dit verslag geeft een inventarisatie van de problematiek betreffende nitraat, nitriet en N-nitrosamines. Aan de hand van gegevens over groenten, vleesprodukten en rnelkprodukten wordt waar mogelijk de Nederlandse situatie geschetst. De moeilijkheden bij de analyse van N-nitrosamines worden kort aangegeven

MEK inhibition leads to BRCA2 downregulation and sensitization to DNA damaging agents in pancreas and ovarian cancer models

Targeting the DNA damage response (DDR) in tumors with defective DNA repair is a clinically successful strategy. The RAS/RAF/MEK/ERK signalling pathway is frequently deregulated in human cancers. In this study, we explored the effects of MEK inhibition on the homologous recombination pathway and explored the potential for combination therapy of MEK inhibitors with DDR inhibitors and a hypoxia-activated prodrug. We studied effects of combining pimasertib, a selective allosteric inhibitor of MEK1/2, with olaparib, a small molecule inhibitor of poly (adenosine diphosphate [ADP]-ribose) polymerases (PARP), and with the hypoxia-activated prodrug evofosfamide in ovarian and pancreatic cancer cell lines. Apoptosis was assessed by Caspase 3/7 assay and protein expression was detected by immunoblotting. DNA damage response was monitored with γH2AX and RAD51 immunofluorescence staining. In vivo antitumor activity of pimasertib with evofosfamide were assessed in pancreatic cancer xenografts. We found that BRCA2 protein expression was downregulated following pimasertib treatment under hypoxic conditions. This translated into reduced homologous recombination repair demonstrated by levels of RAD51 foci. MEK inhibition was sufficient to induce formation of γH2AX foci, suggesting that inhibition of this pathway would impair DNA repair. When combined with olaparib or evofosfamide, pimasertib treatment enhanced DNA damage and increased apoptosis. The combination of pimasertib with evofosfamide demonstrated increased anti-tumor activity in BRCA wild-type Mia-PaCa-2 xenograft model, but not in the BRCA mutated BxPC3 model. Our data suggest that targeted MEK inhibition leads to impaired homologous recombination DNA damage repair and increased PARP inhibition sensitivity in BRCA- 2 proficient cancers

Clonogenic growth of human breast cancer cells co-cultured in direct contact with serum-activated fibroblasts

INTRODUCTION: Accumulating evidence suggests that fibroblasts play a pivotal role in promoting the growth of breast cancer cells. The objective of the present study was to characterize and validate an in vitro model of the interaction between small numbers of human breast cancer cells and human fibroblasts. METHODS: We measured the clonogenic growth of small numbers of human breast cancer cells co-cultured in direct contact with serum-activated, normal human fibroblasts. Using DNA microarrays, we also characterized the gene expression profile of the serum-activated fibroblasts. In order to validate the in vivo relevance of our experiments, we then analyzed clinical samples of metastatic breast cancer for the presence of myofibroblasts expressing α-smooth muscle actin. RESULTS: Clonogenic growth of human breast cancer cells obtained directly from in situ and invasive tumors was dramatically and consistently enhanced when the tumor cells were co-cultured in direct contact with serum-activated fibroblasts. This effect was abolished when the cells were co-cultured in transwells separated by permeable inserts. The fibroblasts in our experimental model exhibited a gene expression signature characteristic of 'serum response' (i.e. myofibroblasts). Immunostaining of human samples of metastatic breast cancer tissue confirmed that myofibroblasts are in direct contact with breast cancer cells. CONCLUSION: Serum-activated fibroblasts promote the clonogenic growth of human breast cancer cells in vitro through a mechanism that involves direct physical contact between the cells. This model shares many important molecular and phenotypic similarities with the fibroblasts that are naturally found in breast cancers

Human breast cancer stem cell markers CD44 and CD24: enriching for cells with functional properties in mice or in man?

Identification of breast cancer stem cells as the cells within breast tumors that have the ability to give rise to cells that make up the bulk of the tumor mass has shifted the focus of cancer research. However, there is still much debate concerning the unique nature of the markers that distinguish cancer stem cells in the breast. As such, understanding whether CD44+/CD24- breast cancer cells are merely more successful in overcoming an engraftment incompatibility that exists when injecting human cells into the mouse adipose tissue or are indeed bona fide cancer stem cells is of great importance

Dynamic Regulation of Tgf-B Signaling by Tif1γ: A Computational Approach

TIF1γ (Transcriptional Intermediary Factor 1 γ) has been implicated in Smad-dependent signaling by Transforming Growth Factor beta (TGF-β). Paradoxically, TIF1γ functions both as a transcriptional repressor or as an alternative transcription factor that promotes TGF-β signaling. Using ordinary differential-equation models, we have investigated the effect of TIF1γ on the dynamics of TGF-β signaling. An integrative model that includes the formation of transient TIF1γ-Smad2-Smad4 ternary complexes is the only one that can account for TGF-β signaling compatible with the different observations reported for TIF1γ. In addition, our model predicts that varying TIF1γ/Smad4 ratios play a critical role in the modulation of the transcriptional signal induced by TGF-β, especially for short stimulation times that mediate higher threshold responses. Chromatin immunoprecipitation analyses and quantification of the expression of TGF-β target genes as a function TIF1γ/Smad4 ratios fully validate this hypothesis. Our integrative model, which successfully unifies the seemingly opposite roles of TIF1γ, also reveals how changing TIF1γ/Smad4 ratios affect the cellular response to stimulation by TGF-β, accounting for a highly graded determination of cell fate

Generation of Breast Cancer Stem Cells through Epithelial-Mesenchymal Transition

Recently, two novel concepts have emerged in cancer biology: the role of so-called “cancer stem cells” in tumor initiation, and the involvement of an epithelial-mesenchymal transition (EMT) in the metastatic dissemination of epithelial cancer cells. Using a mammary tumor progression model, we show that cells possessing both stem and tumorigenic characteristics of “cancer stem cells” can be derived from human mammary epithelial cells following the activation of the Ras-MAPK pathway. The acquisition of these stem and tumorigenic characters is driven by EMT induction