Apsidal Motion of the Massive, Benchmark Eclipsing Binary V578 Mon

V578 Mon is a system of two early B-type stars in the Rosette Nebula star-forming region (NGC 2244), and is one of only nine eclipsing binaries with component masses greater than 10 M\odot whose physical parameters have been determined with an accuracy of better than 3%. It is therefore a benchmark system for evolutionary and stellar structure models of newly formed massive stars. Combining our multi-band light curves spanning 40 yr with previous light curve data from the literature, we fit a model light curve that for the first time includes the effects of apsidal motion of the system. We measure an apsidal period of 33.48+0.10-0.06 yr. As a consequence of incorporating the apsidal motion into the modeling of the system's orbital parameters, we determine an updated eccentricity of e = 0.07755+0.00022-0.00027, which differs significantly from the value previously reported in the literature. Evidently, the inclusion of apsidal motion in the light curve modeling significantly affects the eccentricity determination. Incorporating these key parameters into a comprehensive model of the system's physical parameters-including internal structure constraints- will bring V578 Mon to the next level of benchmark precision and utility.Comment: 17 pages, 7 figures, to appear in the Astronomical Journa

Common activation of canonical Wnt signaling in pancreatic adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDA) is an extremely aggressive malignancy, which carries a dismal prognosis. Activating mutations of the Kras gene are common to the vast majority of human PDA. In addition, recent studies have demonstrated that embryonic signaling pathway such as Hedgehog and Notch are inappropriately upregulated in this disease. The role of another embryonic signaling pathway, namely the canonical Wnt cascade, is still controversial. Here, we use gene array analysis as a platform to demonstrate general activation of the canonical arm of the Wnt pathway in human PDA. Furthermore, we provide evidence for Wnt activation in mouse models of pancreatic cancer. Our results also indicate that Wnt signaling might be activated downstream of Hedgehog signaling, which is an early event in PDA evolution. Wnt inhibition blocked proliferation and induced apoptosis of cultured adenocarcinoma cells, thereby providing evidence to support the development of novel therapeutical strategies for Wnt inhibition in pancreatic adenocarcinoma

Feeding synthetic zeolite to transition dairy cows alters neutrophil gene expression.

Synthetic zeolites are used to control the availability of dietary minerals (e.g., Ca, Mg, and P) in dairy cows. Due to calcium demand increasing with lactation onset, most cows become hypocalcemic immediately postpartum, which likely contributes to poorer immune function because calcium is important for immune cell signaling. To overcome postpartum hypocalcemia, we fed transition cows synthetic zeolite A (sodium aluminosilicate) precalving and hypothesized that it would alter calcium and thus neutrophil function during the transition period. Multiparous Holstein-Friesian cows in late gestation were randomly allocated to an untreated control group (n = 10) or a treatment group in which each cow received 500 g of zeolite A daily (n = 10) for 14 d prior to the expected calving date (actual duration = 17 ± 3 d prepartum). The cows grazed pasture, and each was supplemented with 2 kg/d of maize silage (dry matter basis), with or without zeolite, until calving. Blood samples for neutrophil isolation and analysis of plasma indicators of mineral status, energy status, liver function, and inflammation were collected pretreatment (covariate; d -19); on d -14 and -7 precalving; on the day of calving (d 0); and on d 1, 4, 7, and 28 postcalving. Neutrophils were isolated and gene expression was analyzed using microfluidic gene expression arrays. Neutrophil respiratory burst was assessed using stimulation with phorbol 12-myristate 13-acetate and flow cytometry. Plasma calcium and phosphorus revealed a treatment by time interaction; cows offered zeolite had greater plasma calcium concentrations at d 0, 1, and 4 postcalving and plasma phosphorus concentrations were lower in zeolite-treated cows during the precalving period until d 1 postcalving compared with control animals. Zeolite treatment downregulated neutrophil gene expression of CXCR4 and S100A8 and tended to lower gene expression for other immune mediators (CXCR1, IFNG, S100A12, and S100A9) compared with the control. Zeolite treatment did not affect neutrophil respiratory burst or expression of the other genes investigated. Plasma concentrations of cytokine IL-6 were reduced with zeolite treatment, which was most evident immediately postcalving (d 0, 1, and 7). Overall, feeding zeolite precalving had few effects on neutrophil gene expression and function; however, the lower gene expression of neutrophil inflammatory mediators may be due to altered availability of dietary minerals prepartum and indicates that zeolite A may control inflammation during the transition period

Three-way symbolic tree-maps and ultrametrics

Three-way dissimilarities are a generalization of (two-way) dissimilarities which can be used to indicate the lack of homogeneity or resemblance between any three objects. Such maps have applications in cluster analysis and have been used in areas such as psychology and phylogenetics, where three-way data tables can arise. Special examples of such dissimilarities are three-way tree-metrics and ultrametrics, which arise from leaf-labelled trees with edges labelled by positive real numbers. Here we consider three-way maps which arise from leaf-labelled trees where instead the interior vertices are labelled by an arbitrary set of values. For unrooted trees, we call such maps three-way symbolic tree-maps; for rooted trees, we call them three-way symbolic ultrametrics since they can be considered as a generalization of the (two-way) symbolic ultrametrics of Bocker and Dress. We show that, as with two- and three-way tree-metrics and ultrametrics, three-way symbolic tree-maps and ultrametrics can be characterized via certain k-point conditions. In the unrooted case, our characterization is mathematically equivalent to one presented by Gurvich for a certain class of edge-labelled hypergraphs. We also show that it can be decided whether or not an arbitrary three-way symbolic map is a tree-map or a symbolic ultrametric using a triplet-based approach that relies on the so-called BUILD algorithm for deciding when a set of 3-leaved trees or triplets can be displayed by a single tree. We envisage that our results will be useful in developing new approaches and algorithms for understanding 3-way data, especially within the area of phylogenetics

Therapeutic limitations in tumor-specific CD8+ memory T cell engraftment

BACKGROUND: Adoptive immunotherapy with cytotoxic T lymphocytes (CTL) represents an alternative approach to treating solid tumors. Ideally, this would confer long-term protection against tumor. We previously demonstrated that in vitro-generated tumor-specific CTL from the ovalbumin (OVA)-specific OT-I T cell receptor transgenic mouse persisted long after adoptive transfer as memory T cells. When recipient mice were challenged with the OVA-expressing E.G7 thymoma, tumor growth was delayed and sometimes prevented. The reasons for therapeutic failures were not clear. METHODS: OT-I CTL were adoptively transferred to C57BL/6 mice 21 – 28 days prior to tumor challenge. At this time, the donor cells had the phenotypical and functional characteristics of memory CD8+ T cells. Recipients which developed tumor despite adoptive immunotherapy were analyzed to evaluate the reason(s) for therapeutic failure. RESULTS: Dose-response studies demonstrated that the degree of tumor protection was directly proportional to the number of OT-I CTL adoptively transferred. At a low dose of OT-I CTL, therapeutic failure was attributed to insufficient numbers of OT-I T cells that persisted in vivo, rather than mechanisms that actively suppressed or anergized the OT-I T cells. In recipients of high numbers of OT-I CTL, the E.G7 tumor that developed was shown to be resistant to fresh OT-I CTL when examined ex vivo. Furthermore, these same tumor cells no longer secreted a detectable level of OVA. In this case, resistance to immunotherapy was secondary to selection of clones of E.G7 that expressed a lower level of tumor antigen. CONCLUSIONS: Memory engraftment with tumor-specific CTL provides long-term protection against tumor. However, there are several limitations to this immunotherapeutic strategy, especially when targeting a single antigen. This study illustrates the importance of administering large numbers of effectors to engraft sufficiently efficacious immunologic memory. It also demonstrates the importance of targeting several antigens when developing vaccine strategies for cancer

No Language-Specific Activation during Linguistic Processing of Observed Actions

It has been suggested that cortical neural systems for language evolved from motor cortical systems, in particular from those fronto-parietal systems responding also to action observation. While previous studies have shown shared cortical systems for action--or action observation--and language, they did not address the question of whether linguistic processing of visual stimuli occurs only within a subset of fronto-parietal areas responding to action observation. If this is true, the hypothesis that language evolved from fronto-parietal systems matching action execution and action observation would be strongly reinforced.We used functional magnetic resonance imaging (fMRI) while subjects watched video stimuli of hand-object-interactions and control photo stimuli of the objects and performed linguistic (conceptual and phonological), and perceptual tasks. Since stimuli were identical for linguistic and perceptual tasks, differential activations had to be related to task demands. The results revealed that the linguistic tasks activated left inferior frontal areas that were subsets of a large bilateral fronto-parietal network activated during action perception. Not a single cortical area demonstrated exclusive--or even simply higher--activation for the linguistic tasks compared to the action perception task.These results show that linguistic tasks do not only share common neural representations but essentially activate a subset of the action observation network if identical stimuli are used. Our findings strongly support the evolutionary hypothesis that fronto-parietal systems matching action execution and observation were co-opted for language, a process known as exaptation

Therapeutic Rescue of Misfolded Mutants: Validation of Primary High Throughput Screens for Identification of Pharmacoperone Drugs

Functional rescue of misfolded mutant receptors by small non-peptide molecules has been demonstrated. These small, target-specific molecules (pharmacological chaperones or "pharmacoperones") serve as molecular templates, promote correct folding and allow otherwise misfolded mutants to pass the scrutiny of the cellular quality control system (QCS) and be expressed at the plasma membrane (PM) where they function similarly to wild type (WT) proteins. In the case of the gonadotropin releasing hormone receptor (GnRHR), drugs that rescue one mutant typically rescue many mutants, even if the mutations are located at distant sites (extracellular loops, intracellular loops, transmembrane helices). This increases the value of these drugs. These drugs are typically identified, post hoc, from "hits" in screens designed to detect antagonists or agonists. The therapeutic utility of pharmacoperones has been limited due to the absence of screens that enable identification of pharmacoperones per se.We describe a generalizable primary screening approach for pharmacoperone drugs based on measurement of gain of activity in stable HeLa cells stably expressing the mutants of two different model G-protein coupled receptors (GPCRs) (hGnRHR[E(90)K] or hV2R[L(83)Q]). These cells turn off expression of the receptor mutant gene of interest in the presence of tetracycline and its analogs, which provides a convenient means to identify false positives.The methods described and characterized here provide the basis of novel primary screens for pharmacoperones that detect drugs that rescue GPCR mutants of specific receptors. This approach will identify structures that would have been missed in screens that were designed to select only agonists or antagonists. Non-antagonistic pharmacoperones have a therapeutic advantage since they will not compete for endogenous agonists and may not have to be washed out once rescue has occurred and before activation by endogenous or exogenous agonists

Bcl-2 protein family: Implications in vascular apoptosis and atherosclerosis

Apoptosis has been recognized as a central component in the pathogenesis of atherosclerosis, in addition to the other human pathologies such as cancer and diabetes. The pathophysiology of atherosclerosis is complex, involving both apoptosis and proliferation at different phases of its progression. Oxidative modification of lipids and inflammation differentially regulate the apoptotic and proliferative responses of vascular cells during progression of the atherosclerotic lesion. Bcl-2 proteins act as the major regulators of extrinsic and intrinsic apoptosis signalling pathways and more recently it has become evident that they mediate the apoptotic response of vascular cells in response to oxidation and inflammation either in a provocative or an inhibitory mode of action. Here we address Bcl-2 proteins as major therapeutic targets for the treatment of atherosclerosis and underscore the need for the novel preventive and therapeutic interventions against atherosclerosis, which should be designed in the light of molecular mechanisms regulating apoptosis of vascular cells in atherosclerotic lesions

‘With us, we, like, physically can’t’: transport, mobility and the leisure experiences of teenage wheelchair users

This paper reflects upon the experiences of 69 British teenage wheelchair users in their attempts to access leisure environments. Heiser’s (Heiser, B. 1995. “The Nature and Causes of Transport Disability in Britain, and How to Remove It.” In Removing Disability Barriers, edited by G. Zarb, 49–64. London: Policy Studies Institute) notion of transport disability is developed, and the concepts of transport anxiety and mobility dependency are explored. The challenges that young people in general experience when attempting to access public and private forms of transport (namely, buses, trains, taxis and private cars) are discussed, and the additional ‘layers’ of disadvantage experienced by teenage wheelchair users explored. The ramifications of barriers to transport for young wheelchair users in particular are shown