Transcriptional profiling of mesenchymal stem cells, undergoing chondrogenesis, and mesenchymal tumours.

Mesenchymal stem cells (MSC) represent an adult stem cell population isolated from the bone marrow with the ability to differentiate down various mesenchymal lineages including cartilage. The development of cartilage is a complex multiphase process regulated by the interplay of factors such as cell density and oxygen availability as well as many signalling pathways including TGFp, MAPK, FGF and Wnt. Using microarrays, the temporal transcriptional changes occurring in the in vitro MSC chondrogenesis model were analysed. The results obtained support the validity of the MSC model system for the study of chondrogenesis, as genes known to play a role in the process such as collagens 2, 9 and 11, aggrecan and the transcription factor Sox9, are expressed in the chronological pattern expected. Genes were also identified that had been previously noted to be expressed in limb development but whose role in chondrogenesis remains unknown, as well as a group of novel factors not previously associated with chondrogenesis. Hes1 and Hey1, the targets of Notch signalling were both found to be upregulated early, and their role in chondrogenesis was investigated by inhibiting Notch signalling. Abolishing the expression of Hes1 and Hey1 had a deleterious effect on the accumulation of the chondrogenic matrix, indicating that these transcription factors are implicated in chondrogenesis. Microarray analysis was also used to compare the expression profiles of a broad range of mesenchymal tumours, resulting in the identification of factors specific to each. The brachyury gene was found to be specifically expressed on chordomas, a tumour derived from notochordal remnants often misdiagnosed for a chondrosarcoma. Immunohistochemistry was performed using a polyclonal antibody to this molecule and was found to distinguish chordomas from over 300 other lesions, including a wide variety of chondroid neoplasms. Brachyury is therefore a specific marker for chordomas, and can be exploited for diagnostic purposes

A molecular map of mesenchymal tumors

Background Bone and soft tissue tumors represent a diverse group of neoplasms thought to derive from cells of the mesenchyme or neural crest. Histological diagnosis is challenging due to the poor or heterogenous differentiation of many tumors, resulting in uncertainty over prognosis and appropriate therapy. Results We have undertaken a broad and comprehensive study of the gene expression profile of 96 tumors with representatives of all mesenchymal tissues, including several problem diagnostic groups. Using machine learning methods adapted to this problem we identify molecular fingerprints for most tumors, which are pathognomonic (decisive) and biologically revealing. Conclusion We demonstrate the utility of gene expression profiles and machine learning for a complex clinical problem, and identify putative origins for certain mesenchymal tumor

Towards Growing Robots: A Piecewise Morphology-Controller Co-adaptation Strategy for Legged Locomotion

Control of robots has largely been based on the assumption of a fixed morphology. Accordingly, robot designs have been stationary in time, except for the case of modular robots. Any drastic change in morphology, hence, requires a remodelling of the controller. This work takes inspiration from developmental robotics to present a piecewise morphology-controller growth/adaptation strategy that facilitates fast and reliable control adaptation to growing robots. We demonstrate our methodology on a simple 3 degree of freedom walking robot with adjustable foot lengths and with varying inertial conditions. Our results show not only the effectiveness and reliability of the piecewise morphology controller co-adaptation (PMCCA) strategy, but also highlight the need for morphological adaptation as a robot design strategy

Frontal fibrosing alopecia in men: an association with leave-on facial cosmetics and sunscreens

SCOPUS: le.jinfo:eu-repo/semantics/publishe

Single and Combined Effects of Acute and Chronic Non-Thermal Stressors on Rat Interscapular Brown Adipose Tissue Metabolic Activity

The aim of this study was to examine whether the thermogenic potential of rat interscapular brown adipose tissue (IBAT) changes in response to acute and/or chronic exposure to non-thermal stressors (immobilization and isolation), by measuring the uncoupling protein 1 (UCP-1) content, MAO-A, SOD and CAT activities, as well as the number of IBAT sympathetic noradrenaline-containing nerve fibers. Both acute immobilization (2 h) and chronic isolation (21 days), as well as their combined effects, significantly increased the IBAT UCP-1 content in comparison to non-stressed animals. When applied individually, stressors increased the number of sympathetic fibers in comparison to controls, whereas in combination they decreased it. The activity of IBAT monoamine oxidase-A (MAO-A) decreased under the influence of each stressor independent of its type or duration. SOD activity coincided with MAO-A decrement, whereas CAT activity had an opposite pattern of changes. We conclude that acute and chronic exposure to non-thermal stressors, immobilization and isolation, respectively, affect the metabolic potential of rat IBAT, judging by the increase in UCP-1 content and sympathetic outflow. However, when acute immobilization was applied as a novel stressor to previously chronically isolated animals, an increase in the UCP-1 content was accompanied by a lower IBAT sympathetic outflow, suggesting that IBAT metabolic function under various stress condition is not solely dependent on SNS activity

Pharmacological evaluation of 3-carbomethoxy fentanyl in mice

In many animal species, as well as in humans, high doses of fentanyl (F) produce marked neurotoxic effects, such as muscular rigidity and respiratory depression. The antinociception (hot-plate test), impairment of motor coordination (rotarod test) and acute toxicity of intraperitoneal newly synthesized analogs, (±)cis-3-carbomethoxy- fentanyl (C) and (±)trans-3-carbomethoxyfentanyl (T) were evaluated in mice. The compounds tested induced antinociception, impairment of performance on the rotarod, and lethality in a dosedependent manner. The relative order of antinociceptive potency was similar to motor impairment potency, as well as lethality: F gt C gt T. Naloxone hydrochloride (1 mg/kg; sc) abolished all the effects observed, suggesting that they are mediated via opioid receptors, most probably of μ type. There were no significant differences between the therapeutic indices of F, C and T. It is concluded, the introduction of 3-carbomethoxy group in the piperidine ring of the fentanyl skeleton reduced the potency, but did not affect tolerability and safety of the compound. © 2011 by the authors

Some Experiments on the influence of Problem Hardness in Morphological Development based Learning of Neural Controllers

Natural beings undergo a morphological development process of their bodies while they are learning and adapting to the environments they face from infancy to adulthood. In fact, this is the period where the most important learning pro-cesses, those that will support learning as adults, will take place. However, in artificial systems, this interaction between morphological development and learning, and its possible advantages, have seldom been considered. In this line, this paper seeks to provide some insights into how morphological development can be harnessed in order to facilitate learning in em-bodied systems facing tasks or domains that are hard to learn. In particular, here we will concentrate on whether morphological development can really provide any advantage when learning complex tasks and whether its relevance towards learning in-creases as tasks become harder. To this end, we present the results of some initial experiments on the application of morpho-logical development to learning to walk in three cases, that of a quadruped, a hexapod and that of an octopod. These results seem to confirm that as task learning difficulty increases the application of morphological development to learning becomes more advantageous.Comment: 10 pages, 4 figure

Nocturnin Expression Is Induced by Fasting in the White Adipose Tissue of Restricted Fed Mice

The relationship between circadian clocks and metabolism is intimate and complex and a number of recent studies have begun to reveal previously unknown effects of food and its temporal availability on the clock and the rhythmic transcriptome of peripheral tissues. Nocturnin, a circadian deadenylase, is expressed rhythmically in a wide variety of tissues, but we report here that Nocturnin expression is arrhythmic in epididymal white adipose tissue (eWAT) of mice housed in 12∶12 LD with ad libitum access to food. However, Nocturnin expression becomes rhythmic in eWAT of mice placed on restricted feeding. We show here that Nocturnin's rhythmic expression pattern is not dependent upon feeding, nor is it acutely induced by feeding in the liver or eWAT of ad libitum fed mice. However, Nocturnin is acutely induced by the absence of the expected meal in eWAT of restricted fed mice. A rise in cAMP levels also induces Nocturnin expression, suggesting that Nocturnin's induction in eWAT by fasting is likely mediated through the same pathways that activate lipolysis. Therefore, this suggests that Nocturnin plays a role in linking nutrient sensing by the circadian clock to lipid mobilization in the adipocytes

Natural history of Charcot-Marie-Tooth disease type 2A: a large international multicentre study

Mitofusin-2 (MFN2) is one of two ubiquitously expressed homologous proteins in eukaryote cells, playing a critical role in mitochondrial fusion. Mutations in MFN2 (most commonly autosomal dominant) cause Charcot-Marie-Tooth disease type 2A (CMT2A), the commonest axonal form of CMT, with significant allelic heterogeneity. Previous, moderately-sized, cross sectional genotype-phenotype studies of CMT2A have described the phenotypic spectrum of the disease, but longitudinal natural history studies are lacking. In this large multicentre prospective cohort study of 196 patients with dominant and autosomal recessive CMT2A, we present an in-depth genotype-phenotype study of the baseline characteristics of patients with CMT2A and longitudinal data (1-2 years) to describe the natural history. A childhood onset of autosomal dominant CMT2A is the most predictive marker of significant disease severity and is independent of the disease duration. When compared to adult onset autosomal dominant CMT2A, it is associated with significantly higher rates of use of ankle-foot orthoses, full-time use of wheelchair, dexterity difficulties and also has significantly higher CMT Examination Score (CMTESv2) and CMT Neuropathy Score (CMTNSv2) at initial assessment. Analysis of longitudinal data using the CMTESv2 and its Rasch-weighted counterpart, CMTESv2-R, show that over 1 year, the CMTESv2 increases significantly in autosomal dominant CMT2A (mean change 0.84 ± 2.42; two-tailed paired t-test P = 0.039). Furthermore, over 2 years both the CMTESv2 (mean change 0.97 ± 1.77; two-tailed paired t-test P = 0.003) and the CMTESv2-R (mean change 1.21 ± 2.52; two-tailed paired t-test P = 0.009) increase significantly with respective standardized response means of 0.55 and 0.48. In the paediatric CMT2A population (autosomal dominant and autosomal recessive CMT2A grouped together), the CMT Pediatric Scale increases significantly both over 1 year (mean change 2.24 ± 3.09; two-tailed paired t-test P = 0.009) and over 2 years (mean change 4.00 ± 3.79; two-tailed paired t-test P = 0.031) with respective standardized response means of 0.72 and 1.06. This cross-sectional and longitudinal study of the largest CMT2A cohort reported to date provides guidance for variant interpretation, informs prognosis and also provides natural history data that will guide clinical trial design