Variability of Blue Supergiants in the LMC with TESS

The blue supergiant problem, namely the overabundance of blue supergiants (BSGs) inconsistent with classical stellar evolution theory, remains an open question in stellar astrophysics. Several theoretical explanations have been proposed, which may be tested by their predictions for the characteristic time variability. In this work, we analyze the light curves of a sample of 20 BSGs obtained from the Transiting Exoplanet Survey Satellite (TESS) mission. We report a characteristic signal in the low-frequency ($f\lesssim2\,\mathrm{d}^{-1}$) range for all our targets. The power spectra has a peak frequency at $\sim0.2\,\mathrm{d}^{-1}$, and we are able to fit it by a modified Lorentzian profile. The signal itself shows strong stochasticity across different TESS sectors, suggesting its driving mechanism happens on short ($\lesssim\mathrm{months}$) timescales. Our signals resemble those obtained for a limited sample of hotter OB stars and yellow supergiants, suggesting their possible common origins. We discuss three possible physical explanations: stellar winds launched by rotation, convection motions that reach the stellar surface, and waves from the deep stellar interior. The peak frequency of the signal favors processes related to convection caused by the iron opacity peak, and the shape of the spectra might be explained by the propagation of high-order, damped gravity waves. We discuss the uncertainties and limitations of all these scenarios.Comment: submitted to ApJ, comments welcom

Deconvolution of Interplanetary Transport of Solar Energetic Particles

We address the problem of deconvolving the effects of interplanetary transport on observed intensity and anisotropy profiles of solar energetic particles with the goal of determining the time profile and spectrum of particle injection near the Sun as well as the interplanetary scattering mean free path. Semi-automated techniques have been developed to quantitatively determine the best fit injection profile, assuming (1) a general piecewise linear profile or (2) a Reid profile of the form [C/(t-t_0)]exp[-A/(t-t_0)-(t-t_0)/B]. The two assumptions for the form of the injection profile yielded similar results when we tested the techniques using ISEE 3 proton data from the solar flare events of July 20, 1981 (gradual flare), and January 2, 1982 (impulsive flare). For the former event, the duration of injection was much shorter for protons of higher energy (75-147 MeV), which may be interpreted as indicating that the coronal mass ejection-driven shock lost the ability to accelerate protons to $\sim$100 MeV after traveling beyond a certain distance from the Sun.Comment: 14 pages + 5 figures, LaTeX style files included, to appear in J. Geophys. Re

Feasibility of metabolic imaging of hyperpolarized 13C-pyruvate in human breast cancer

Introduction Imaging of the breast with hyperpolarized 13C yields new challenges compared to imaging the prostate [1]. E.g. large anteroposterior B0 gradients [2] require correction and the anatomy and patient positioning need a new, highly optimized RF coil array for achieving sufficient SNR/spatial resolution. As a first step, we have investigated single-breast imaging in the coronal plane. Methods A BRCA gene carrier with a 38-mm diameter grade 3 triple-negative invasive ductal carcinoma was studied on a 3T MRI (GE Healthcare) using a prototype 8-channel 13C breast coil (Rapid Biomedical), containing 2 transmit/receive coils and 6 receive-only covering both breasts in a prone position. 1H imaging was performed with the body coil. Following injection of 40ml of 250mM 13C-pyruvate, polarized to c. 25%, a 1-minute time series of spirals with IDEAL encoding (3) was collected (flip angle 10°, TR=260ms, 8-step cycle, time resolution 2.08s, 3 x 3-cm thick slices, 3mm gap, 40-pt spiral, 24cm coronal FOV, real pixel size 12 x 12 x 30mm). IDEAL reconstruction of images was optimized separately for each slice to enable independent frequency offsets to be applied. Kinetic modelling was performed in MATLAB, with automated tumour segmentation. Results Tumour pixels were identified by the segmentation algorithm only in the tumour-containing slice 2, and the average estimated flux from pyruvate to lactate kPL within this ROI was 0.022 s-1 (Fig. 1). The frequency shift of pyruvate relative to slice 2 was +6 Hz in slice 3 and -34 Hz in slice 1, confirming a sharp gradient in B0 approaching the nipple, which was corrected by optimizing slices separately (Fig 2). Images of lactate and pyruvate summed over the time course (Fig 3) showed strong signal of both metabolites over the tumour in slice 2, lower pyruvate in the slice toward the chest wall, and no consistent signal in slice 1. Conclusion This first-in-Europe study in breast cancer established the feasibility of obtaining metabolite images with high temporal and moderate spatial resolution in humans in vivo following administration of hyperpolarized 13C-pyruvate. Coronal image orientation allowed application of significant corrections for a known limitation, the anteroposterior B0 gradient, as well as a small FOV to improve spatial resolution. Kinetic rate constants within the tumour were found to be consistent with previous reports in human prostate cancer (1). References 1) Nelson SJ et al. Sci Transl Med 5, 198ra108 (2013). 2) Maril N, et al. Magn. Reson. Med. 2005; 54:1139-1145. 3) Wiesinger F, et al. Magn Reson Med 2012; 68:8-16

Multifunctional T-cell Analyses to Study Response and Progression in Adoptive Cell Transfer Immunotherapy

Adoptive cell transfer (ACT) of genetically engineered T cells expressing cancer-specific T-cell receptors (TCR) is a promising cancer treatment. Here, we investigate the in vivo functional activity and dynamics of the transferred cells by analyzing samples from 3 representative patients with melanoma enrolled in a clinical trial of ACT with TCR transgenic T cells targeted against the melanosomal antigen MART-1. The analyses included evaluating 19 secreted proteins from individual cells from phenotypically defined T-cell subpopulations, as well as the enumeration of T cells with TCR antigen specificity for 36 melanoma antigens. These analyses revealed the coordinated functional dynamics of the adoptively transferred, as well as endogenous, T cells, and the importance of highly functional T cells in dominating the antitumor immune response. This study highlights the need to develop approaches to maintaining antitumor T-cell functionality with the aim of increasing the long-term efficacy of TCR-engineered ACT immunotherapy. Significance: A longitudinal functional study of adoptively transferred TCR–engineered lymphocytes yielded revealing snapshots for understanding the changes of antitumor responses over time in ACT immunotherapy of patients with advanced melanoma

Appropriate disclosure of a diagnosis of dementia : identifying the key behaviours of 'best practice'

Background: Despite growing evidence that many people with dementia want to know their diagnosis, there is wide variation in attitudes of professionals towards disclosure. The disclosure of the diagnosis of dementia is increasingly recognised as being a process rather than a one-off behaviour. However, the different behaviours that contribute to this process have not been comprehensively defined. No intervention studies to improve diagnostic disclosure in dementia have been reported to date. As part of a larger study to develop an intervention to promote appropriate disclosure, we sought to identify important disclosure behaviours and explore whether supplementing a literature review with other methods would result in the identification of new behaviours. Methods: To identify a comprehensive list of behaviours in disclosure we conducted a literature review, interviewed people with dementia and informal carers, and used a consensus process involving health and social care professionals. Content analysis of the full list of behaviours was carried out. Results: Interviews were conducted with four people with dementia and six informal carers. Eight health and social care professionals took part in the consensus panel. From the interviews, consensus panel and literature review 220 behaviours were elicited, with 109 behaviours over-lapping. The interviews and consensus panel elicited 27 behaviours supplementary to the review. Those from the interviews appeared to be self-evident but highlighted deficiencies in current practice and from the panel focused largely on balancing the needs of people with dementia and family members. Behaviours were grouped into eight categories: preparing for disclosure; integrating family members; exploring the patient's perspective; disclosing the diagnosis; responding to patient reactions; focusing on quality of life and well-being; planning for the future; and communicating effectively. Conclusion: This exercise has highlighted the complexity of the process of disclosing a diagnosis of dementia in an appropriate manner. It confirms that many of the behaviours identified in the literature (often based on professional opinion rather than empirical evidence) also resonate with people with dementia and informal carers. The presence of contradictory behaviours emphasises the need to tailor the process of disclosure to individual patients and carers. Our combined methods may be relevant to other efforts to identify and define complex clinical practices for further study.This project is funded by UK Medical Research Council, Grant reference number G0300999

Mutation Size Optimizes Speciation in an Evolutionary Model

The role of mutation rate in optimizing key features of evolutionary dynamics has recently been investigated in various computational models. Here, we address the related question of how maximum mutation size affects the formation of species in a simple computational evolutionary model. We find that the number of species is maximized for intermediate values of a mutation size parameter μ; the result is observed for evolving organisms on a randomly changing landscape as well as in a version of the model where negative feedback exists between the local population size and the fitness provided by the landscape. The same result is observed for various distributions of mutation values within the limits set by μ. When organisms with various values of μ compete against each other, those with intermediate μ values are found to survive. The surviving values of μ from these competition simulations, however, do not necessarily coincide with the values that maximize the number of species. These results suggest that various complex factors are involved in determining optimal mutation parameters for any population, and may also suggest approaches for building a computational bridge between the (micro) dynamics of mutations at the level of individual organisms and (macro) evolutionary dynamics at the species level

Control of intestinal stem cell function and proliferation by mitochondrial pyruvate metabolism.

Most differentiated cells convert glucose to pyruvate in the cytosol through glycolysis, followed by pyruvate oxidation in the mitochondria. These processes are linked by the mitochondrial pyruvate carrier (MPC), which is required for efficient mitochondrial pyruvate uptake. In contrast, proliferative cells, including many cancer and stem cells, perform glycolysis robustly but limit fractional mitochondrial pyruvate oxidation. We sought to understand the role this transition from glycolysis to pyruvate oxidation plays in stem cell maintenance and differentiation. Loss of the MPC in Lgr5-EGFP-positive stem cells, or treatment of intestinal organoids with an MPC inhibitor, increases proliferation and expands the stem cell compartment. Similarly, genetic deletion of the MPC in Drosophila intestinal stem cells also increases proliferation, whereas MPC overexpression suppresses stem cell proliferation. These data demonstrate that limiting mitochondrial pyruvate metabolism is necessary and sufficient to maintain the proliferation of intestinal stem cells

Hashimoto thyroiditis with an unusual presentation of cardiac tamponade in Noonan syndrome

Noonan syndrome is an autosomal dominant, multisystem disorder. Autoimmune thyroiditis with hypothyroidism is an infrequent feature in patients with Noonan syndrome. A 16-year-old boy was admitted because of chest discomfort and dyspnea; an echocardiogram revealed pericardial effusion. Additional investigations led to a diagnosis of severe hypothyroidism due to Hashimoto thyroiditis. The patient was treated with L-thyroxine at 0.15 mg daily. However, during admission, he developed symptoms of cardiac tamponade. Closed pericardiostomy was performed, after which the patient's chest discomfort improved, and his vital signs stabilized. Herein, we report a case of an adolescent with Noonan syndrome, who was diagnosed with Hashimoto thyroiditis with an unusual presentation of cardiac tamponade

Alignathon: A competitive assessment of whole-genome alignment methods

© 2014 Earl et al. Multiple sequence alignments (MSAs) are a prerequisite for a wide variety of evolutionary analyses. Published assessments and benchmark data sets for protein and, to a lesser extent, global nucleotide MSAs are available, but less effort has been made to establish benchmarks in the more general problem of whole-genome alignment (WGA). Using the same model as the successful Assemblathon competitions, we organized a competitive evaluation in which teams submitted their alignments and then assessments were performed collectively after all the submissions were received. Three data sets were used: Two were simulated and based on primate and mammalian phylogenies, and one was comprised of 20 real fly genomes. In total, 35 submissions were assessed, submitted by 10 teams using 12 different alignment pipelines. We found agreement between independent simulation-based and statistical assessments, indicating that there are substantial accuracy differences between contemporary alignment tools. We saw considerable differences in the alignment quality of differently annotated regions and found that few tools aligned the duplications analyzed. We found that many tools worked well at shorter evolutionary distances, but fewer performed competitively at longer distances. We provide all data sets, submissions, and assessment programs for further study and provide, as a resource for future benchmarking, a convenient repository of code and data for reproducing the simulation assessments