Testosterone enables growth and hypertrophy in fusion impaired myoblasts that display myotube atrophy: deciphering the role of androgen and IGF-I receptors

We have previously highlighted the ability of testosterone to improve differentiation and myotube hypertrophy in fusion impaired myoblasts that display reduced myotube hypertrophy at 72hrs (after transfer to low serum media) via multiple population doublings (PD) vs. their parental controls (CON); an observation which is abrogated via PI3K/Akt inhibition (Deane et al. 2013). However, whether the most predominant molecular mechanism responsible for T induced hypertrophy occurs directly via androgen receptor or indirectly via IGF-IR/PI3K/Akt pathway is currently debated. PD and CON C2C12 muscle cells were exposed to low serum conditions in the presence or absence of T (100 nM) ± inhibitors of AR (flutamide/F, 40 μm) and IGF-IR (Picropodophyllin/PPP, 150 nM) for 72 hrs and 7 days (early/late muscle differentiation respectively). T increased AR and Akt abundance, myogenin expression, and myotube hypertrophy, but not ERK1/2 activity in both CON and PD cell types. Akt activity was not increased significantly in either cell type with T. Testosterone was unable to promote early differentiation in the presence of IGF-IR inhibitor (PPP) yet still able to promote appropriate later increases in myotube hypertrophy and AR abundance despite IGF-IR inhibition. The addition of the AR inhibitor powerfully attenuated all T induced increases in differentiation and myotube hypertrophy with corresponding reductions in AR abundance, phosphorylated Akt, ERK1/2 and gene expression of IGF-I, myoD and myogenin with increases in myostatin mRNA both cell types. Interestingly, despite basally reduced differentiation and myotube hypertrophy, PD cells showed larger increased in AR abundance vs. CON cells, a response abrogated in the presence of AR but not IGF-IR inhibitors. Furthermore, T induced increases in Akt abundance were sustained despite the presence of IGF-IR inhibition in PD cells only. However, flutamide alone reduced IGF-IR mRNA in both cell types across time points, with an observed reduction in activity of ERK and Akt, perhaps suggesting that IGF-IR was transcriptionally regulated by AR. However, where testosterone increased AR protein content there was no increases observed in IGF-IR gene expression. Overall, this suggested that sufficient AR was important to enable normal gene expression of IGF-IR and downstream signalling, yet elevated levels of AR due to testosterone had no further effect on IGF-IR, despite testosterone increasing Akt abundance in the presence of IGF-IR inhibitor. In conclusion, testosterones ability to improve differentiation and myotube hypertrophy occurred predominately via increases in AR and Akt abundance in both CON and PD cells, with fusion impaired cells (PD) showing an increased responsiveness to T induced AR levels. Finally, T induced increases in myotube hypertrophy (but not early differentiation) occurred independently of upstream IGF-IR input, however it appears that normal AR function in basal conditions is required for adequate IGF-IR gene expression and downstream Akt abundance

A remark on an overdetermined problem in Riemannian Geometry

Let $(M,g)$ be a Riemannian manifold with a distinguished point $O$ and assume that the geodesic distance $d$ from $O$ is an isoparametric function. Let $\Omega\subset M$ be a bounded domain, with $O \in \Omega$, and consider the problem $\Delta_p u = -1$ in $\Omega$ with $u=0$ on $\partial \Omega$, where $\Delta_p$ is the $p$-Laplacian of $g$. We prove that if the normal derivative $\partial_{\nu}u$ of $u$ along the boundary of $\Omega$ is a function of $d$ satisfying suitable conditions, then $\Omega$ must be a geodesic ball. In particular, our result applies to open balls of $\mathbb{R}^n$ equipped with a rotationally symmetric metric of the form $g=dt^2+\rho^2(t)\,g_S$, where $g_S$ is the standard metric of the sphere.Comment: 8 pages. This paper has been written for possible publication in a special volume dedicated to the conference "Geometric Properties for Parabolic and Elliptic PDE's. 4th Italian-Japanese Workshop", organized in Palinuro in May 201

Proopiomelanocortin peptide immunocytochemistry in rhesus monkey brain

The immunocytochemical distribution of Proopiomelanocortin (POMC) peptides ([beta]-endorphin, ACTH, [alpha]-MSH, 16K fragment) was studied in the brain of the rhesus monkey (Macaca mulatta). Some animals were administered colchicine intracerebroventricularly prior to sacrifice to enhance the visualization of perikaryal immunoreactivity. Immunoreactive perikarya are localized to hypothalamic infundibular nucleus, giving rise to several distinct projections. Rostral projections extend through midline diencephalic and preoptic areas, and enter the telencephalon. Along this course, immunoreactive fibers are seen in midline hypothalamic and preoptic nuclei, nucleus of the diagonal band, olfactory tubercle, nucleus accumbens, bed nucleus of stria terminalis, septum, and other limbic structures in telencephalon. Caudal to the anterior commissure, some fibers ascend dorsally to enter the midline thalamus, which they innervate. Lateral projections of the infundibular perikarya course through the medial-basal hypothalamus, dorsal to the optic tracts, and enter the amygdala region where they innervate more medially situated amygdaloid nuclei. Caudal projections of the POMC neurons also extend through midline diencephalon, some coursing along a periventricular path to innervate midline hypothalamic and thalamic nuclei. This projection extends into the mesencephalic substantia grisea centralis and may also contribute to the innervation of more dorsally situated nuclei in the pons and medulla, such as the parabrachial nuclei and nucleus tractus solitarius. Other caudal projections originating in the hypothalamus course through the ventral tegmentum of mesencephalon and pons and may contribute to the innervation of midline raphe and other ventrally situated nuclei in the pons and medulla. The distribution of immunoreactive perikarya and fibers in the brain of rhesus monkey is strikingly similar to that found in the rat brain. However, subtle differences appear to exist in the innervation patterns of particular brain regions.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/24629/1/0000040.pd

'Word from the street' : when non-electoral representative claims meet electoral representation in the United Kingdom

Taking the specific case of street protests in the UK – the ‘word from the street’– this article examines recent (re)conceptualizations of political representation, most particularly Saward’s notion of ‘representative claim’. The specific example of nonelectoral claims articulated by protestors and demonstrators in the UK is used to illustrate: the processes of making, constituting, evaluating and accepting claims for and by constituencies and audiences; and the continuing distinctiveness of claims based upon electoral representation. Two basic questions structure the analysis: first, why would the political representative claims of elected representatives trump the nonelectoral claims of mass demonstrators and, second, in what ways does the ‘perceived legitimacy’ of the former differ from the latter

Radiopaque drug-eluting embolisation beads as fiducial markers for stereotactic liver radiotherapy

OBJECTIVE: To determine the feasibility of using radiopaque (RO) beads as direct tumour surrogates for image-guided radiotherapy (IGRT) in patients with liver tumours after transarterial chemoembolisation (TACE). METHODS: A novel vandetanib-eluting RO bead was delivered via TACE as part of a first-in-human clinical trial in patients with either hepatocellular carcinoma or liver metastases from colorectal cancer. Following TACE, patients underwent simulated radiotherapy imaging with 4-dimensional computed tomography (4D-CT) and cone-beam CT (CBCT) imaging. RO beads were contoured using automated thresholding, and feasibility of matching between the simulated radiotherapy planning dataset (AVE-IP image from 4D data) and CBCT scans assessed. Additional kV, MV, helical CT and CBCT images of RO beads were obtained using an in-house phantom. Stability of RO bead position was assessed by comparing 4D-CT imaging to CT scans taken 6-20 days following TACE. RESULTS: Eight patients were treated and 4D-CT and CBCT images acquired. RO beads were visible on 4D-CT and CBCT images in all cases and matching successfully performed. Differences in centre of mass of RO beads between CBCT and simulated radiotherapy planning scans (AVE-IP dataset) were: 2.0 mm mediolaterally, 1.7 mm anteroposteriorally, 3.5 mm craniocaudally. RO beads in the phantom were visible on all imaging modalities assessed. RO bead position remained stable up to 29 days post-TACE. CONCLUSION: RO beads are visible on IGRT imaging modalities, showing minimal artefact. They can be used for on-set matching with CBCT and remain stable over time. ADVANCES IN KNOWLEDGE: The role of RO beads as fiducial markers for stereotactic liver radiotherapy is feasible and warrants further exploration as a combination therapy approach

Polynomial-sized Semidefinite Representations of Derivative Relaxations of Spectrahedral Cones

We give explicit polynomial-sized (in $n$ and $k$) semidefinite representations of the hyperbolicity cones associated with the elementary symmetric polynomials of degree $k$ in $n$ variables. These convex cones form a family of non-polyhedral outer approximations of the non-negative orthant that preserve low-dimensional faces while successively discarding high-dimensional faces. More generally we construct explicit semidefinite representations (polynomial-sized in $k,m$, and $n$) of the hyperbolicity cones associated with $k$th directional derivatives of polynomials of the form $p(x) = \det(\sum_{i=1}^{n}A_i x_i)$ where the $A_i$ are $m\times m$ symmetric matrices. These convex cones form an analogous family of outer approximations to any spectrahedral cone. Our representations allow us to use semidefinite programming to solve the linear cone programs associated with these convex cones as well as their (less well understood) dual cones.Comment: 20 pages, 1 figure. Minor changes, expanded proof of Lemma

Seafloor character and sedimentary processes in eastern Long Island Sound and western Block Island Sound

Author Posting. © The Author(s), 2006. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Geo-Marine Letters 26 (2006): 59-68, doi: 10.1007/s00367-006-0016-4.Multibeam bathymetric data and seismic-reflection profiles collected in eastern Long Island and western Block Island Sounds reveal previously unrecognized glacial features and modern bedforms. Glacial features include an ice-sculptured bedrock surface, a newly identified recessional moraine, exposed glaciolacustrine sediments, and remnants of stagnant-ice-contact deposits. Modern bedforms include fields of transverse sand waves, barchanoid waves, giant scour depressions, and pockmarks. Bedform asymmetry and scour around obstructions indicate that net sediment transport is westward across the northern par of the study area near Fishers Island and eastward across the southern par near Great Gull Island.This work was supported by the Coastal and Marine Geology Program of the U.S. Geological Survey, the Connecticut Department of Environmental Protection, and the Atlantic Hydrographic Branch of the National Oceanic and Atmospheric Administration

Border Terriers under primary veterinary care in England: demography and disorders

The Border Terrier is a working terrier type that is generally considered to be a relatively healthy and hardy breed. This study aimed to characterise the demography and common disorders of Border Terriers receiving veterinary care in England using de-identified electronic patient record data within the VetCompass™ Programme

Use of NON-PARAMETRIC Item Response Theory to develop a shortened version of the Positive and Negative Syndrome Scale (PANSS)

<p>Abstract</p> <p>Background</p> <p>Nonparametric item response theory (IRT) was used to examine (a) the performance of the 30 Positive and Negative Syndrome Scale (PANSS) items and their options ((levels of severity), (b) the effectiveness of various subscales to discriminate among differences in symptom severity, and (c) the development of an abbreviated PANSS (Mini-PANSS) based on IRT and a method to link scores to the original PANSS.</p> <p>Methods</p> <p>Baseline PANSS scores from 7,187 patients with Schizophrenia or Schizoaffective disorder who were enrolled between 1995 and 2005 in psychopharmacology trials were obtained. Option characteristic curves (OCCs) and Item Characteristic Curves (ICCs) were constructed to examine the probability of rating each of seven options within each of 30 PANSS items as a function of subscale severity, and summed-score linking was applied to items selected for the Mini-PANSS.</p> <p>Results</p> <p>The majority of items forming the Positive and Negative subscales (i.e. 19 items) performed very well and discriminate better along symptom severity compared to the General Psychopathology subscale. Six of the seven Positive Symptom items, six of the seven Negative Symptom items, and seven out of the 16 General Psychopathology items were retained for inclusion in the Mini-PANSS. Summed score linking and linear interpolation was able to produce a translation table for comparing total subscale scores of the Mini-PANSS to total subscale scores on the original PANSS. Results show scores on the subscales of the Mini-PANSS can be linked to scores on the original PANSS subscales, with very little bias.</p> <p>Conclusions</p> <p>The study demonstrated the utility of non-parametric IRT in examining the item properties of the PANSS and to allow selection of items for an abbreviated PANSS scale. The comparisons between the 30-item PANSS and the Mini-PANSS revealed that the shorter version is comparable to the 30-item PANSS, but when applying IRT, the Mini-PANSS is also a good indicator of illness severity.</p