Spectral and Timing Properties of IGR J17091-3624 in the Rising Hard State During its 2016 Outburst

We present a spectral and timing study of the NuSTAR and Swift observations of the black hole candidate IGR J17091-3624 in the hard state during its outburst in 2016. Disk reflection is detected in each of the NuSTAR spectra taken in three epochs. Fitting with relativistic reflection models reveals that the accretion disk is truncated during all epochs with $R_{\rm in}>10~r_{\rm g}$, with the data favoring a low disk inclination of $\sim 30^{\circ}-40^{\circ}$. The steepening of the continuum spectra between epochs is accompanied by a decrease in the high energy cut-off: the electron temperature $kT_{\rm e}$ drops from $\sim 64$ keV to $\sim 26$ keV, changing systematically with the source flux. We detect type-C QPOs in the power spectra with frequency varying between 0.131 Hz and 0.327 Hz. In addition, a secondary peak is found in the power spectra centered at about 2.3 times the QPO frequency during all three epochs. The nature of this secondary frequency is uncertain, however a non-harmonic origin is favored. We investigate the evolution of the timing and spectral properties during the rising phase of the outburst and discuss their physical implications.Comment: 11 pages, 9 figures, accepted by Ap

Regulation of Ack1 localization and activity by the amino-terminal SAM domain

<p>Abstract</p> <p>Background</p> <p>The mechanisms that regulate the activity of the nonreceptor tyrosine kinase Ack1 (activated Cdc42-associated kinase) are poorly understood. The amino-terminal region of Ack1 is predicted to contain a sterile alpha motif (SAM) domain. SAM domains share a common fold and mediate protein-protein interactions in a wide variety of proteins. Here, we addressed the importance of the Ack1 SAM domain in kinase activity.</p> <p>Results</p> <p>We used immunofluorescence and Western blotting to show that Ack1 deletion mutants lacking the N-terminus displayed significantly reduced autophosphorylation in cells. A minimal construct comprising the N-terminus and kinase domain (NKD) was autophosphorylated, while the kinase domain alone (KD) was not. When expressed in mammalian cells, NKD localized to the plasma membrane, while KD showed a more diffuse cytosolic localization. Co-immunoprecipitation experiments showed a stronger interaction between full length Ack1 and NKD than between full length Ack1 and KD, indicating that the N-terminus was important for Ack1 dimerization. Increasing the local concentration of purified Ack1 kinase domain at the surface of lipid vesicles stimulated autophosphorylation and catalytic activity, consistent with a requirement for dimerization and trans-phosphorylation for activity.</p> <p>Conclusions</p> <p>Collectively, the data suggest that the N-terminus of Ack1 promotes membrane localization and dimerization to allow for autophosphorylation.</p

Protective actions of des-acylated ghrelin on brain injury and blood-brain barrier disruption after stroke in mice

The major ghrelin forms, acylated ghrelin and des-acylated ghrelin, are novel gastrointestinal hormones. Moreover, emerging evidence indicates that these peptides may have other functions including neuro- and vaso-protection. Here, we investigated whether post-stroke treatment with acylated ghrelin or des-acylated ghrelin could improve functional and histological endpoints of stroke outcome in mice after transient middle cerebral artery occlusion (tMCAo). We found that des-acylated ghrelin (1 mg/kg) improved neurological and functional performance, reduced infarct and swelling, and decreased apoptosis. In addition, it reduced blood-brain barrier (BBB) disruption in vivo and attenuated the hyper-permeability of mouse cerebral microvascular endothelial cells after oxygen glucose deprivation and reoxygenation (OGD + RO). By contrast, acylated ghrelin (1 mg/kg or 5 mg/kg) had no significant effect on these endpoints of stroke outcome. Next we found that des-acylated ghrelin's vasoprotective actions were associated with increased expression of tight junction proteins (occludin and claudin-5), and decreased cell death. Moreover, it attenuated superoxide production, Nox activity and expression of 3-nitrotyrosine. Collectively, these results demonstrate that post-stroke treatment with des-acylated ghrelin, but not acylated ghrelin, protects against ischaemia/reperfusion-induced brain injury and swelling, and BBB disruption, by reducing oxidative and/or nitrosative damage

A Case of Metastatic Atypical Neuroendocrine Tumor with ALK Translocation and Diffuse Brain Metastases.

A challenge in precision medicine requires identification of actionable driver mutations. Critical to such effort is the deployment of sensitive and well-validated assays for mutation detection. Although identification of such alterations within the tumor tissue remains the gold standard, many advanced non-small cell lung cancer cases have only limited tissue samples, derived from small biopsies or fine-needle aspirates, available for testing. More recently, noninvasive methods using either circulating tumor cells or tumor DNA (ctDNA) have become an alternative method for identifying molecular biomarkers and screening patients eligible for targeted therapies. In this article, we present a case of a 52-year-old never-smoking male who presented with widely metastatic atypical neuroendocrine tumor to the bones and the brain. Molecular genotyping using DNA harvested from a bone metastasis was unsuccessful due to limited material. Subsequent ctDNA analysis revealed an ALK translocation. The clinical significance of the mutation in this particular cancer type and therapeutic strategies are discussed.Key pointsTo our knowledge, this index case represents the first reported ALK translocation identified in an atypical carcinoid tumor.Liquid biopsy such as circulating tumor DNA is a feasible alternative platform for identifying sensitizing genomic alterations.Second-generation ALK inhibitors represent a new paradigm for treating ALK-positive patients with brain metastases

The biochemistry and regulation of S100A10: a multifunctional plasminogen receptor involved in oncogenesis

The plasminogen receptors mediate the production and localization to the cell surface of the broad spectrum proteinase, plasmin. S100A10 is a key regulator of cellular plasmin production and may account for as much as 50% of cellular plasmin generation. In parallel to plasminogen, the plasminogen-binding site on S100A10 is highly conserved from mammals to fish. S100A10 is constitutively expressed in many cells and is also induced by many diverse factors and physiological stimuli including dexamethasone, epidermal growth factor, transforming growth factor-alpha, interferon-gamma, nerve growth factor, keratinocyte growth factor, retinoic acid, and thrombin. Therefore, S100A10 is utilized by cells to regulate plasmin proteolytic activity in response to a wide diversity of physiological stimuli. The expression of the oncogenes, PML-RAR alpha and KRas, also stimulates the levels of S100A10, suggesting a role for S100A10 in pathophysiological processes such as in the oncogenic-mediated increases in plasmin production. The S100A10-null mouse model system has established the critical role that S100A10 plays as a regulator of fibrinolysis and oncogenesis. S100A10 plays two major roles in oncogenesis, first as a regulator of cancer cell invasion and metastasis and secondly as a regulator of the recruitment of tumor-associated cells, such as macrophages, to the tumor site.Canadian Cancer Society Research Institute; Canadian Institutes of Health Research; Foundation for Science and Technology of Portuga

The SMC SNR 1E0102.2-7219 as a Calibration Standard for X-ray Astronomy in the 0.3-2.5 keV Bandpass

The flight calibration of the spectral response of CCD instruments below 1.5 keV is difficult in general because of the lack of strong lines in the on-board calibration sources typically available. We have been using 1E 0102.2-7219, the brightest supernova remnant in the Small Magellanic Cloud, to evaluate the response models of the ACIS CCDs on the Chandra X-ray Observatory (CXO), the EPIC CCDs on the XMM-Newton Observatory, the XIS CCDs on the Suzaku Observatory, and the XRT CCD on the Swift Observatory. E0102 has strong lines of O, Ne, and Mg below 1.5 keV and little or no Fe emission to complicate the spectrum. The spectrum of E0102 has been well characterized using high-resolution grating instruments, namely the XMM-Newton RGS and the CXO HETG, through which a consistent spectral model has been developed that can then be used to fit the lower-resolution CCD spectra. We have also used the measured intensities of the lines to investigate the consistency of the effective area models for the various instruments around the bright O (~570 eV and 654 eV) and Ne (~910 eV and 1022 eV) lines. We find that the measured fluxes of the O VII triplet, the O VIII Ly-alpha line, the Ne IX triplet, and the Ne X Ly-alpha line generally agree to within +/-10 % for all instruments, with 28 of our 32 fitted normalizations within +/-10% of the RGS-determined value. The maximum discrepancies, computed as the percentage difference between the lowest and highest normalization for any instrument pair, are 23% for the O VII triplet, 24% for the O VIII Ly-alpha line, 13% for the Ne IX triplet, and 19% for the Ne X Ly-alpha line. If only the CXO and XMM are compared, the maximum discrepancies are 22% for the O VII triplet, 16% for the O VIII Ly-alpha line, 4% for the Ne IX triplet, and 12% for the Ne X Ly-alpha line.Comment: 16 pages, 11 figures, to be published in Proceedings of the SPIE 7011: Space Telescopes and Instrumentation II: Ultraviolet to Gamma Ray 200

Acceptance and commitment therapy for symptom interference in metastatic breast cancer patients: a pilot randomized trial

PURPOSE: Breast cancer is the leading cause of cancer mortality in women worldwide. With medical advances, metastatic breast cancer (MBC) patients often live for years with many symptoms that interfere with activities. However, there is a paucity of efficacious interventions to address symptom-related suffering and functional interference. Thus, this study examined the feasibility and preliminary efficacy of telephone-based acceptance and commitment therapy (ACT) for symptom interference with functioning in MBC patients. METHODS: Symptomatic MBC patients (N = 47) were randomly assigned to six telephone sessions of ACT or six telephone sessions of education/support. Patients completed measures of symptom interference and measures assessing the severity of pain, fatigue, sleep disturbance, depressive symptoms, and anxiety. RESULTS: The eligibility screening rate (64%) and high retention (83% at 8 weeks post-baseline) demonstrated feasibility. When examining within-group change, ACT participants showed decreases in symptom interference (i.e., fatigue interference and sleep-related impairment; Cohen's d range = - 0.23 to - 0.31) at 8 and 12 weeks post-baseline, whereas education/support participants showed minimal change in these outcomes (d range = - 0.03 to 0.07). Additionally, at 12 weeks post-baseline, ACT participants showed moderate decreases in fatigue and sleep disturbance (both ds = - 0.43), whereas education/support participants showed small decreases in these outcomes (ds = - 0.24 and - 0.18 for fatigue and sleep disturbance, respectively). Both the ACT and education/support groups showed reductions in depressive symptoms (ds = - 0.27 and - 0.28) at 12 weeks post-baseline. Group differences in all outcomes were not statistically significant. CONCLUSIONS: ACT shows feasibility and promise in improving fatigue and sleep-related outcomes in MBC patients and warrants further investigation

The definition of dietary fiber – discussions at the Ninth Vahouny Fiber Symposium: building scientific agreement

A definition for dietary fiber was adopted in June 2009 by the Codex Alimentarius Commission based on the recommendation for endorsement of the Codex Committee on Nutrition and Foods for Special Dietary Uses (CCNFSDU) in November 2008. The definition listed three categories of carbohydrate polymers that are not hydrolyzed by the endogenous enzymes in the small intestine of humans. However, the definition left the inclusion of carbohydrates with degrees of polymerization (DP) in the range of 3 and 9 to the discretion of national authorities and left the ‘physiological effect(s) of benefit to health’ as undefined. The ILSI Europe and ILSI North America's committees on dietary carbohydrates organized a forum at the Ninth Vahouny Fiber Symposium in 2010 to discuss these implementation issues with the objective of building scientific consensus on how to resolve them. The results of this session are encouraging and indicated that the scientific community agrees on maintaining a worldwide consensus regarding the inclusion of non-digestible carbohydrates with ≥DP3 as dietary fiber and on a core, non-exhaustive list of beneficial physiological effects that dietary fibers have. These results are consistent with previous worldwide agreements

An emerging field of research: challenges in pediatric decision making

There is growing interest in pediatric decision science, spurred by policies advocating for children's involvement in medical decision making. Challenges specific to pediatric decision research include the dynamic nature of child participation in decisions due to the growth and development of children, the family context of all pediatric decisions, and the measurement of preferences and outcomes that may inform decision making in the pediatric setting. The objectives of this article are to describe each of these challenges, to provide decision researchers with insight into pediatric decision making, and to establish a blueprint for future research that will contribute to high-quality pediatric medical decision making. Much work has been done to address gaps in pediatric decision science, but substantial work remains. Understanding and addressing the challenges that exist in pediatric decision making may foster medical decision-making science across the age spectrum

Availability, aff ordability, and consumption of fruits and vegetables in 18 countries across income levels: fi ndings from the Prospective Urban Rural Epidemiology (PURE) study

Background Several international guidelines recommend the consumption of two servings of fruits and three servings of vegetables per day, but their intake is thought to be low worldwide. We aimed to determine the extent to which such low intake is related to availability and aff ordability. Methods We assessed fruit and vegetable consumption using data from country-specifi c, validated semi-quantitative food frequency questionnaires in the Prospective Urban Rural Epidemiology (PURE) study, which enrolled participants from communities in 18 countries between Jan 1, 2003, and Dec 31, 2013. We documented household income data from participants in these communities; we also recorded the diversity and non-sale prices of fruits and vegetables from grocery stores and market places between Jan 1, 2009, and Dec 31, 2013. We determined the cost of fruits and vegetables relative to income per household member. Linear random eff ects models, adjusting for the clustering of households within communities, were used to assess mean fruit and vegetable intake by their relative cost. Findings Of 143 305 participants who reported plausible energy intake in the food frequency questionnaire, mean fruit and vegetable intake was 3·76 servings (95% CI 3·66–3·86) per day. Mean daily consumption was 2·14 servings (1·93–2·36) in low-income countries (LICs), 3·17 servings (2·99–3·35) in lower-middle-income countries (LMICs), 4·31 servings (4·09–4·53) in upper-middle-income countries (UMICs), and 5·42 servings (5·13–5·71) in highincome countries (HICs). In 130 402 participants who had household income data available, the cost of two servings of fruits and three servings of vegetables per day per individual accounted for 51·97% (95% CI 46·06–57·88) of household income in LICs, 18·10% (14·53–21·68) in LMICs, 15·87% (11·51–20·23) in UMICs, and 1·85% (–3·90 to 7·59) in HICs (ptrend=0·0001). In all regions, a higher percentage of income to meet the guidelines was required in rural areas than in urban areas (p<0·0001 for each pairwise comparison). Fruit and vegetable consumption among individuals decreased as the relative cost increased (ptrend=0·00040). Interpretation The consumption of fruit and vegetables is low worldwide, particularly in LICs, and this is associated with low aff ordability. Policies worldwide should enhance the availability and aff ordability of fruits and vegetables