Potential magnetic field calculator for solar physics applications using staggered grids

A program has been designed for accurately generating a potential magnetic field on a staggered grid by extrapolating the magnetic field normal to the photospheric surface. The code first calculates a magnetic potential using the Green's function method and then uses a finite differencing scheme to calculate the magnetic field from the potential. A new finite differencing formula was derived which accounts for grid staggering, it is shown that this formula gives a numerical approximation that is closest to the real potential field. It is also shown that extending the region over which normal photospheric field is specified can improve the accuracy of the potential field produced. The program is a FORTRAN 90 code that can be used to generate potential magnetic field inputs for Lare3d and other MHD solvers that use a staggered grid for magnetic field components. The program can be parallelised to run quickly over multiple computing cores. The code and supporting description are provided in the appendices and can also be found at https://github.com/calboo/Potential_Field_Calculator.Comment: Revision of some typos spotted whilst writing thesi

The Effects of Oscillations and Collisions of Emerging Bipolar Regions on the Triggering of Solar Flares

The ability to predict the occurrence of solar flares in advance is important to humankind due to the potential damage they can cause to Earth's environment and infrastructure. It has been shown in Kusano et al. (2012) that a small-scale bipolar region (BR), with its flux reversed relative to the potential component of the overlying field, appearing near the polarity inversion line (PIL) is sufficient to effectively trigger a solar flare. In this study we perform further 3D magnetohydrodynamic simulations to study the effect that the motion of these small-scale BRs has on the effectiveness of flare triggering. The effect of two small-scale BRs colliding is also simulated. The results indicate that the strength of the triggered flare is dependent on how much of the overlying field is disrupted by the BR. Simulations of linear oscillations of the BR showed that oscillations along the PIL increase the flare strength whilst oscillations across the PIL detract from the flare strength. The flare strength is affected more by larger amplitude oscillations but is relatively insensitive to the frequency of oscillations. In the most extreme case the peak kinetic energy of the flare increased more than threefold compared to a non-oscillating BR. Simulations of torsional oscillations of the BR showed a very small effect on the flare strength. Finally, simulations of colliding BRs showed the generation of much stronger flares as the flares triggered by each individual BR coalesce. These results show that significantly stronger flares can result from motion of the BR along the PIL of a sheared field or from the presence of multiple BRs in the same region.Comment: 10 pages, 10 figures, 1 table, Corrections made to Fig.3 captio

International Sport Coaching Journal Digest

Digest contains a listing of pertinent, recent coaching and coach education articles and updates from other sources

The evaluation criteria used by venture capitalists:evidence from a UK fund

GRAHAM BOOCOCK AND MARGARET WOODS are Lecturers in Banking and Finance, and Financial Management, respectively, at Loughborough University Business School, England. The paper examines how venture fund managers select their investee companies, by exploring the evaluation criteria and the decision-making process adopted at one United Kingdom regional venture fund (henceforth referred to as the Fund). The analysis confirms that relatively consistent evaluation criteria are applied across the industry and corroborates previous models which suggest that the venture capitalist's decision-making consists of several stages. With the benefit of access to the Fund's internal records, however, this paper adds to the current literature by differentiating the evaluation criteria used at each successive stage of the decision-making process. The paper presents a model of the Fund's activities which demonstrates that the relative importance attached to the evaluation criteria changes as applications are systematically processed. Proposals have to satsfy different criteria at each stage of the decision-making process before they receive funding. In the vast majority of cases, applications are rejected by the fund managers. In addition, the length of time taken by the fund managers in appraising propositions can lead to withdrawal of applications at an advanced stage

Proteomic profiling reveals the transglutaminase-2 externalization pathway in kidneys after unilateral ureteric obstruction

Increased export of transglutaminase-2 (TG2) by tubular epithelial cells (TECs) into the surrounding interstitium modifies the extracellular homeostatic balance, leading to fibrotic membrane expansion. Although silencing of extracellular TG2 ameliorates progressive kidney scarring in animal models of CKD, the pathway through which TG2 is secreted from TECs and contributes to disease progression has not been elucidated. In this study, we developed a global proteomic approach to identify binding partners of TG2 responsible for TG2 externalization in kidneys subjected to unilateral ureteric obstruction (UUO) using TG2 knockout kidneys as negative controls. We report a robust and unbiased analysis of the membrane interactome of TG2 in fibrotic kidneys relative to the entire proteome after UUO, detected by SWATH mass spectrometry. The data have been deposited to the ProteomeXchange with identifier PXD008173. Clusters of exosomal proteins in the TG2 interactome supported the hypothesis that TG2 is secreted by extracellular membrane vesicles during fibrosis progression. In established TEC lines, we found TG2 in vesicles of both endosomal (exosomes) and plasma membrane origin (microvesicles/ectosomes), and TGF-β1 stimulated TG2 secretion. Knockout of syndecan-4 (SDC4) greatly impaired TG2 exosomal secretion. TG2 coprecipitated with SDC4 from exosome lysate but not ectosome lysate. Ex vivo, EGFP-tagged TG2 accumulated in globular elements (blebs) protruding/retracting from the plasma membrane of primary cortical TECs, and SDC4 knockout impaired bleb formation, affecting TG2 release. Through this combined in vivo and in vitro approach, we have dissected the pathway through which TG2 is secreted from TECs in CKD

β2-adrenergic signalling promotes cell migration by upregulating expression of the metastasis-associated molecule LYPD3

Metastasis is associated with poor prognosis in breast cancer. Although some studies suggest beta-blockers increase survival by delaying metastasis, others have been discordant. This study provides both insights into the anomalous findings and identifies potential biomarkers that may be treatment targets. Cell line models of basal-type and oestrogen receptor-positive breast cancer were profiled for basal levels of adrenoceptor gene/protein expression, and β2-adrenoceptor mediated cell behaviour including migration, invasion, adhesion, and survival in response to adrenoceptor agonist/antagonist treatment. Protein profiling and histology identified biomarkers and drug targets. Baseline levels of adrenoceptor gene expression are higher in basal-type rather than oestrogen receptor-positive cancer cells. Norepinephrine (NE) treatment increased invasive capacity in all cell lines but did not increase proliferation/survival. Protein profiling revealed the upregulation of the pro-metastatic gene Ly6/PLAUR Domain-Containing Protein 3 (LYPD3) in norepinephrine-treated MDA-MB-468 cells. Histology confirmed selective LYPD3 expression in primary and metastatic breast tumour samples. These findings demonstrate that basal-type cancer cells show a more aggressive adrenoceptor-β2-activated phenotype in the resting and stimulated state, which is attenuated by adrenoceptor-β2 inhibition. This study also highlights the first association between ADRβ2 signalling and LYPD3; its knockdown significantly reduced the basal and norepinephrine-induced activity of MCF-7 cells in vitro. The regulation of ADRβ2 signalling by LYPD3 and its metastasis promoting activities, reveal LYPD3 as a promising therapeutic target in the treatment of breast and other cancers

Neurite outgrowth inhibitory levels of organophosphates induce tissue transglutaminase activity in differentiating N2a cells: evidence for covalent adduct formation

Organophosphate compounds (OPs) induce both acute and delayed neurotoxic effects, the latter of which is believed to involve their interaction with proteins other than acetylcholinesterase. However, few OP-binding proteins have been identified that may have a direct role in OP-induced delayed neurotoxicity. Given their ability to disrupt Ca2+ homeostasis, a key aim of the current work was to investigate the effects of sub-lethal neurite outgrowth inhibitory levels of OPs on the Ca2+-dependent enzyme tissue transglutaminase (TG2). At 1–10 µM, the OPs phenyl saligenin phosphate (PSP) and chlorpyrifos oxon (CPO) had no effect cell viability but induced concentration-dependent decreases in neurite outgrowth in differentiating N2a neuroblastoma cells. The activity of TG2 increased in cell lysates of differentiating cells exposed for 24 h to PSP and chlorpyrifos oxon CPO (10 µM), as determined by biotin-cadaverine incorporation assays. Exposure to both OPs (3 and/or 10 µM) also enhanced in situ incorporation of the membrane permeable substrate biotin-X-cadaverine, as indicated by Western blot analysis of treated cell lysates probed with ExtrAvidin peroxidase and fluorescence microscopy of cell monolayers incubated with FITC-streptavidin. Both OPs (10 µM) stimulated the activity of human and mouse recombinant TG2 and covalent labelling of TG2 with dansylamine-labelled PSP was demonstrated by fluorescence imaging following SDS-PAGE. A number of TG2 substrates were tentatively identified by mass spectrometry, including cytoskeletal proteins, chaperones and proteins involved protein synthesis and gene regulation. We propose that the elevated TG2 activity observed is due to the formation of a novel covalent adduct between TG2 and OPs

A new inhibitor of glucose-6-phospate dehydrogenase blocks pentose phosphate pathway and suppresses malignant proliferation and metastasis in vivo

Pentose Phosphate Pathway (PPP) is a major glucose metabolism pathway which has a fundamental role in cancer growth and metastasis. Even though PPP blockade has been pointed out as a very promising strategy against cancer, effective anti-PPP agents are not still available in the clinical setting. Here, we demonstrate that the natural molecule polydatin inhibits glucose-6-phosphate dehydrogenase (G6PD), the key enzyme of PPP. Polydatin blocks G6PD causing accumulation of reactive oxygen species and strong increase of endoplasmic reticulum stress. These effects are followed by cell cycle block in S phase, an about 50% of apoptosis, and 60% inhibition of invasion in vitro. Accordingly, in an orthotopic metastatic model of tongue cancer, 100 mg/kg polydatin induced an about 30% tumor size reduction with an about 80% inhibition of lymph node metastases and 50% reduction of lymph node size (p< 0.005). Polydatin is not toxic in animals up to a dose of 200 mg/kg and a phase II clinical trial shows that a is also well tolerated in humans (40 mg twice a day for 90 days). Thus, polydatin may be used as a reliable tool to limit human cancer growth and metastatic spread

The vitamin D binding protein axis modifies disease severity in Lymphangioleiomyomatosis

Background: Lymphangioleiomyomatosis (LAM) is a rare disease of women. Decline in lung function is variable making appropriate targeting of therapy difficult. We used unbiased serum proteomics to identify markers associated with outcome in LAM. Methods: 101 women with LAM and 22 healthy controls were recruited from the National Centre for LAM (Nottingham, UK). 152 DNA and serum samples with linked lung function and outcome data were obtained from patients in the NHLBI LAM Registry (USA). Proteomic analysis was performed on a discovery cohort of 50 LAM and 20 control sera using a SCIEX SWATH mass spectrometric workflow. Protein levels were quantitated by ELISA and SNPs in GC encoding Vitamin D Binding Protein (VTDB) genotyped. Results: Proteomic analysis showed VTDB was 2.6 fold lower in LAM than controls. Serum VTDB was lower in progressive compared with stable LAM (p=0.001) and correlated with diffusing capacity (p=0.01). Median time to death or lung transplant was reduced by 46 months in those with CC genotypes at rs4588 and 38 months in those with non-A containing haplotypes at rs7041/4588 (p=0.014 and 0.008 respectively). Conclusions: The VTDB axis is associated with disease severity and outcome, and GC genotype could help predict transplant free survival in LAM

Cytoplasmic PML promotes TGF-β-associated epithelial–mesenchymal transition and invasion in prostate cancer

Epithelial–mesenchymal transition (EMT) is a key event that is involved in the invasion and dissemination of cancer cells. Although typically considered as having tumour-suppressive properties, transforming growth factor (TGF)-β signalling is altered during cancer and has been associated with the invasion of cancer cells and metastasis. In this study, we report a previously unknown role for the cytoplasmic promyelocytic leukaemia (cPML) tumour suppressor in TGF-β signalling-induced regulation of prostate cancer-associated EMT and invasion. We demonstrate that cPML promotes a mesenchymal phenotype and increases the invasiveness of prostate cancer cells. This event is associated with activation of TGF-β canonical signalling pathway through the induction of Sma and Mad related family 2 and 3 (SMAD2 and SMAD3) phosphorylation. Furthermore, the cytoplasmic localization of promyelocytic leukaemia (PML) is mediated by its nuclear export in a chromosomal maintenance 1 (CRM1)-dependent manner. This was clinically tested in prostate cancer tissue and shown that cytoplasmic PML and CRM1 co-expression correlates with reduced disease-specific survival. In summary, we provide evidence of dysfunctional TGF-β signalling occurring at an early stage in prostate cancer. We show that this disease pathway is mediated by cPML and CRM1 and results in a more aggressive cancer cell phenotype. We propose that the targeting of this pathway could be therapeutically exploited for clinical benefit