GSK3β Regulates Differentiation and Growth Arrest in Glioblastoma

Cancers are driven by a population of cells with the stem cell properties of self-renewal and unlimited growth. As a subpopulation within the tumor mass, these cells are believed to constitute a tumor cell reservoir. Pathways controlling the renewal of normal stem cells are deregulated in cancer. The polycomb group gene Bmi1, which is required for neural stem cell self-renewal and also controls anti-oxidant defense in neurons, is upregulated in several cancers, including medulloblastoma. We have found that Bmi1 is consistently and highly expressed in GBM. Downregulation of Bmi1 by shRNAs induced a differentiation phenotype and reduced expression of the stem cell markers Sox2 and Nestin. Interestingly, expression of glycogen synthase kinase 3 beta (GSK3β), which was found to be consistently expressed in primary GBM, also declined. This suggests a functional link between Bmi1 and GSK3β. Interference with GSK3β activity by siRNA, the specific inhibitor SB216763, or lithium chloride (LiCl) induced tumor cell differentiation. In addition, tumor cell apoptosis was enhanced, the formation of neurospheres was impaired, and clonogenicity reduced in a dose-dependent manner. GBM cell lines consist mainly of CD133-negative (CD133-) cells. Interestingly, ex vivo cells from primary tumor biopsies allowed the identification of a CD133- subpopulation of cells that express stem cell markers and are depleted by inactivation of GSK3β. Drugs that inhibit GSK3, including the psychiatric drug LiCl, may deplete the GBM stem cell reservoir independently of CD133 status

Russian Artistic Gymnastics as a Sports Tourism Product: Some Observations and a Research Agenda

Tourism and its importance to the Russian Federation are very much in the headlines at present. Considering the huge investment made in facilities for the Winter Olympics, the building of new sports facilities for such mega events as the Football World Cup, and the status of St Petersburg as a candidate city for the 2028 Olympics, it is clear that Russia has long term plans to attract visitors to their sporting events. The purpose of this paper is to develop a research agenda to explore the potential of artistic gymnastics, a sport in which the Russian Federation has excelled for many years, as an agent of tourism development. The paper will take a case study approach, considering the nature of fandom and identifying features of artistic gymnastics as cultural heritage and sports tourism product. The national and international environment within which it is set are examined, prior to the development of a research agenda. A detailed review of literature on the historic, current and emerging trends in Russian artistic gymnastics; the place of artistic gymnastics in tourism development and sports tourism in Russia will be carried out. The paper’s findings will include considerations of: • The nature of gymnastics fandom, both in Russia and internationally • The nature of sports tourism development in the Russian Federation • The nature of gymnastics as a sport and its competition cycle • Artistic gymnastics as cultural heritage, and its potential as an autonomous means of promoting Russian national identity • The relationship between Russia’s sometimes fading gymnastics competition results, and its potential to leverage the sport for tourism interest • The potential for tourism product development linked to artistic gymnastics in the Russian Federation. The paper contributes to the literature on the nature of sports tourism as it relates to artistic gymnastics in the Russian Federation in particular

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD

Essential versus accessory aspects of cell death: recommendations of the NCCD 2015

Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as ‘accidental cell death’ (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. ‘Regulated cell death’ (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death

Prevalence of dyslipidaemia and associated risk factors in a rural population in south-western Uganda : a community based survey

BACKGROUND: The burden of dyslipidaemia is rising in many low income countries. However, there are few data on the prevalence of, or risk factors for, dyslipidaemia in Africa. METHODS: In 2011, we used the WHO Stepwise approach to collect cardiovascular risk data within a general population cohort in rural south-western Uganda. Dyslipidaemia was defined by high total cholesterol (TC) ≥ 5.2 mmol/L or low high density lipoprotein cholesterol (HDL-C) 6% (men aOR=3.00, 95%CI=1.37-6.59; women aOR=2.74, 95%CI=1.77-4.27). The odds of high TC was also higher among married men, and women with higher education or high BMI. CONCLUSION: Low HDL-C prevalence in this relatively young rural population is high whereas high TC prevalence is low. The consequences of dyslipidaemia in African populations remain unclear and prospective follow-up is required

Gold nanoparticle-polymer nanocomposites synthesized by room temperature atmospheric pressure plasma and their potential for fuel cell electrocatalytic application

Conductive polymers have been increasingly used as fuel cell catalyst support due to their electrical conductivity, large surface areas and stability. The incorporation of metal nanoparticles into a polymer matrix can effectively increase the specific surface area of these materials and hence improve the catalytic efficiency. In this work, a nanoparticle loaded conductive polymer nanocomposite was obtained by a one-step synthesis approach based on room temperature direct current plasmaliquid interaction. Gold nanoparticles were directly synthesized from HAuCl4 precursor in poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT: PSS). The resulting AuNPs/PEDOT: PSS nanocomposites were subsequently characterized under a practical alkaline direct ethanol fuel cell operation condition for its potential application as an electrocatalyst. Results show that AuNPs sizes within the PEDOT: PSS matrix are dependent on the plasma treatment time and precursor concentration, which in turn affect the nanocomposites electrical conductivity and their catalytic performance. Under certain synthesis conditions, unique nanoscale AuNPs/PEDOT: PSS core-shell structures could also be produced, indicating the interaction at the AuNPs/polymer interface. The enhanced catalytic activity shown by AuNPs/PEDOT: PSS has been attributed to the effective electron transfer and reactive species diffusion through the porous polymer network, as well as the synergistic interfacial interaction at the metal/polymer and metal/metal interfaces.Funding Agencies|UK EPSRC [EP/K022237/1, EP/M024938/1, EP/P00394X/1, EP/I013229/1]; National Natural Science Foundation of China [51203135]; InvestNI [PoC-325]; Department of Employment Learning; EU-COST Action [TD1208]</p

Rheumatoid Arthritis is an Autoimmune Disease Triggered by Proteus Urinary Tract Infection

Rheumatoid arthritis (RA) is a chronic and disabling polyarthritic disease, which affects mainly women in middle and old age

Ageing exacerbates damage of systemic and salivary neutrophils from patients presenting Candida-related denture stomatitis

<p>Abstract</p> <p>Background</p> <p>Ageing leads to a decline in the function of the immune system, increasing the body's susceptibility to infections through the impairment of T-cells, macrophages, neutrophils and dendritic cells Denture stomatitis is a primary oral disease affecting elderly denture wearers. The major etiologic factor involved in this pathology is the infection by <it>Candida albicans</it>, an opportunistic pathogen that causes local and disseminated diseases in immunosuppressed humans. Neutrophils play a critical role in the immune response against <it>C. albicans </it>and are continually present in the salivary fluid and in the blood. The aim of this study was to determine ageing-related changes in salivary and blood neutrophils and their potential implications in <it>Candida</it>-related denture stomatitis.</p> <p>Results</p> <p>Our results showed a lower number of neutrophils in the saliva from patients presenting <it>Candida</it>-related denture stomatitis in comparison to their matched controls. Furthermore, fewer neutrophils were isolated from the saliva of aged control individuals in comparison to matched younger subjects. CXCR1, CD62L and CD11b expression were significantly greater on systemic neutrophils from younger control individuals. Elderly individuals showed more apoptotic salivary neutrophils and lower GM-CSF levels than younger ones, regardless of the occurrence of <it>Candida </it>infection. On the other hand, CXCL-8 concentrations were higher in the saliva from elderly individuals. Besides, TNF-α was detected at elevated levels in the saliva from infected elderly subjects. Salivary neutrophils from elderly and young patients presented impaired phagocytic activity against <it>C. albicans</it>. However, just systemic neutrophils from elderly showed decreased phagocytosis when compared to the younger ones, regardless of the occurrence of infection. In addition, neutrophils from aged individuals and young patients presented low fungicidal activity.</p> <p>Conclusion</p> <p>The data suggests that the <it>Candida </it>related-denture stomatitis is associated to neutrophils function deficiency, and ageing drastically appears to alter important characteristics of such cells, facilitating the establishment of this infection.</p