2,577 research outputs found
Phenotyping clonal populations of glioma stem cell reveals a high degree of plasticity in response to changes of microenvironment
The phenotype of glioma-initiating cells (GIC) is modulated by cell-intrinsic and cell-extrinsic factors. Phenotypic heterogeneity and plasticity of GIC is an important limitation to therapeutic approaches targeting cancer stem cells. Plasticity also presents a challenge to the identification, isolation, and propagation of purified cancer stem cells. Here we use a barcode labelling approach of GIC to generate clonal populations over a number of passages, in combination with phenotyping using the established stem cell markers CD133, CD15, CD44, and A2B5. Using two cell lines derived from isocitrate dehydrogenase (IDH)-wildtype glioblastoma, we identify a remarkable heterogeneity of the phenotypes between the cell lines. During passaging, clonal expansion manifests as the emergence of a limited number of barcoded clones and a decrease in the overall number of clones. Dual-labelled GIC are capable of forming traceable clonal populations which emerge after as few as two passages from mixed cultures and through analyses of similarity of relative proportions of 16 surface markers we were able to pinpoint the fate of such populations. By generating tumour organoids we observed a remarkable persistence of dominant clones but also a significant plasticity of stemness marker expression. Our study presents an experimental approach to simultaneously barcode and phenotype glioma-initiating cells to assess their functional properties, for example to screen newly established GIC for tumour-specific therapeutic vulnerabilities
Relational grounding facilitates development of scientifically useful multiscale models
We review grounding issues that influence the scientific usefulness of any biomedical multiscale model (MSM). Groundings are the collection of units, dimensions, and/or objects to which a variable or model constituent refers. To date, models that primarily use continuous mathematics rely heavily on absolute grounding, whereas those that primarily use discrete software paradigms (e.g., object-oriented, agent-based, actor) typically employ relational grounding. We review grounding issues and identify strategies to address them. We maintain that grounding issues should be addressed at the start of any MSM project and should be reevaluated throughout the model development process. We make the following points. Grounding decisions influence model flexibility, adaptability, and thus reusability. Grounding choices should be influenced by measures, uncertainty, system information, and the nature of available validation data. Absolute grounding complicates the process of combining models to form larger models unless all are grounded absolutely. Relational grounding facilitates referent knowledge embodiment within computational mechanisms but requires separate model-to-referent mappings. Absolute grounding can simplify integration by forcing common units and, hence, a common integration target, but context change may require model reengineering. Relational grounding enables synthesis of large, composite (multi-module) models that can be robust to context changes. Because biological components have varying degrees of autonomy, corresponding components in MSMs need to do the same. Relational grounding facilitates achieving such autonomy. Biomimetic analogues designed to facilitate translational research and development must have long lifecycles. Exploring mechanisms of normal-to-disease transition requires model components that are grounded relationally. Multi-paradigm modeling requires both hyperspatial and relational grounding
Pre-cooling for endurance exercise performance in the heat: a systematic review.
PMCID: PMC3568721The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1741-7015/10/166.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Endurance exercise capacity diminishes under hot environmental conditions. Time to exhaustion can be increased by lowering body temperature prior to exercise (pre-cooling). This systematic literature review synthesizes the current findings of the effects of pre-cooling on endurance exercise performance, providing guidance for clinical practice and further research
Effectiveness, cost-effectiveness and cost-benefit of a single annual professional intervention for the prevention of childhood dental caries in a remote rural Indigenous community
Background
The aim of the study is to reduce the high prevalence of tooth decay in children in a remote, rural Indigenous community in Australia, by application of a single annual dental preventive intervention. The study seeks to (1) assess the effectiveness of an annual oral health preventive intervention in slowing the incidence of dental caries in children in this community, (2) identify the mediating role of known risk factors for dental caries and (3) assess the cost-effectiveness and cost-benefit of the intervention.
Methods/design
The intervention is novel in that most dental preventive interventions require regular re-application, which is not possible in resource constrained communities. While tooth decay is preventable, self-care and healthy habits are lacking in these communities, placing more emphasis on health services to deliver an effective dental preventive intervention. Importantly, the study will assess cost-benefit and cost-effectiveness for broader implementation across similar communities in Australia and internationally.
Discussion
There is an urgent need to reduce the burden of dental decay in these communities, by implementing effective, cost-effective, feasible and sustainable dental prevention programs. Expected outcomes of this study include improved oral and general health of children within the community; an understanding of the costs associated with the intervention provided, and its comparison with the costs of allowing new lesions to develop, with associated treatment costs. Findings should be generalisable to similar communities around the world.
The research is registered with the Australian New Zealand Clinical Trials Registry (ANZCTR), registration number ACTRN12615000693527; date of registration: 3rd July 2015
Microglia promote glioblastoma via mTOR-mediated immunosuppression of the tumour microenvironment
Tumour-associated microglia/macrophages (TAM) are the most
numerous non-neoplastic populations in the tumour microenvironment in glioblastoma multiforme (GBM), the most common malignant brain tumour in adulthood. The mTOR pathway, an important
regulator of cell survival/proliferation, is upregulated in GBM, but
little is known about the potential role of this pathway in TAM. Here,
we show that GBM-initiating cells induce mTOR signalling in the
microglia but not bone marrow-derived macrophages in both in vitro
and in vivo GBM mouse models. mTOR-dependent regulation of STAT3
and NF-jB activity promotes an immunosuppressive microglial
phenotype. This hinders effector T-cell infiltration, proliferation and
immune reactivity, thereby contributing to tumour immune evasion
and promoting tumour growth in mouse models. The translational
value of our results is demonstrated in whole transcriptome datasets
of human GBM and in a novel in vitro model, whereby expandedpotential stem cells (EPSC)-derived microglia-like cells are conditioned by syngeneic patient-derived GBM-initiating cells. These
results raise the possibility that microglia could be the primary target
of mTOR inhibition, rather than the intrinsic tumour cells in GB
Evanescent light-matter Interactions in Atomic Cladding Wave Guides
Alkali vapors, and in particular rubidium, are being used extensively in
several important fields of research such as slow and stored light non-linear
optics3 and quantum computation. Additionally, the technology of alkali vapors
plays a major role in realizing myriad industrial applications including for
example atomic clocks magentometers8 and optical frequency stabilization.
Lately, there is a growing effort towards miniaturizing traditional
centimeter-size alkali vapor cells. Owing to the significant reduction in
device dimensions, light matter interactions are greatly enhanced, enabling new
functionalities due to the low power threshold needed for non-linear
interactions. Here, taking advantage of the mature Complimentary
Metal-Oxide-Semiconductor (CMOS) compatible platform of silicon photonics, we
construct an efficient and flexible platform for tailored light vapor
interactions on a chip. Specifically, we demonstrate light matter interactions
in an atomic cladding wave guide (ACWG), consisting of CMOS compatible silicon
nitride nano wave-guide core with a Rubidium (Rb) vapor cladding. We observe
the highly efficient interaction of the electromagnetic guided mode with the
thermal Rb cladding. The nature of such interactions is explained by a model
which predicts the transmission spectrum of the system taking into account
Doppler and transit time broadening. We show, that due to the high confinement
of the optical mode (with a mode area of 0.3{\lambda}2), the Rb absorption
saturates at powers in the nW regime.Comment: 10 Pages 4 Figures. 1 Supplementar
Food-web structure in relation to environmental gradients and predator-prey ratios in tank-bromeliad ecosystems
Little is known of how linkage patterns between species change along environmental gradients. The small, spatially discrete food webs inhabiting tank-bromeliads provide an excellent opportunity to analyse patterns of community diversity and food-web topology (connectance, linkage density, nestedness) in relation to key environmental variables (habitat size, detrital resource, incident radiation) and predators: prey ratios. We sampled 365 bromeliads in a wide range of understorey environments in French Guiana and used gut contents of invertebrates to draw the corresponding 365 connectance webs. At the bromeliad scale, habitat size (water volume) determined the number of species that constitute food-web nodes, the proportion of predators, and food-web topology. The number of species as well as the proportion of predators within bromeliads declined from open to forested habitats, where the volume of water collected by bromeliads was generally lower because of rainfall interception by the canopy. A core group of microorganisms and generalist detritivores remained relatively constant across environments. This suggests that (i) a highly-connected core ensures food-web stability and key ecosystem functions across environments, and (ii) larger deviations in food-web structures can be expected following disturbance if detritivores share traits that determine responses to environmental changes. While linkage density and nestedness were lower in bromeliads in the forest than in open areas, experiments are needed to confirm a trend for lower food-web stability in the understorey of primary forests
Reduction in Phencyclidine Induced Sensorimotor Gating Deficits in the Rat Following Increased System Xc â Activity in the Medial Prefrontal Cortex
Rationale: Aspects of schizophrenia, including deficits in sensorimotor gating, have been linked to glutamate dysfunction and/or oxidative stress in the prefrontal cortex. System xc â, a cystineâglutamate antiporter, is a poorly understood mechanism that contributes to both cellular antioxidant capacity and glutamate homeostasis.
Objectives: Our goal was to determine whether increased system xc â activity within the prefrontal cortex would normalize a rodent measure of sensorimotor gating.
Methods: In situ hybridization was used to map messenger RNA (mRNA) expression of xCT, the active subunit of system xc â, in the prefrontal cortex. Prepulse inhibition was used to measure sensorimotor gating; deficits in prepulse inhibition were produced using phencyclidine (0.3â3 mg/kg, sc). N-Acetylcysteine (10â100 ÎŒM) and the system xc â inhibitor (S)-4-carboxyphenylglycine (CPG, 0.5 ÎŒM) were used to increase and decrease system xc â activity, respectively. The uptake of 14C-cystine into tissue punches obtained from the prefrontal cortex was used to assay system xc â activity.
Results: The expression of xCT mRNA in the prefrontal cortex was most prominent in a lateral band spanning primarily the prelimbic cortex. Although phencyclidine did not alter the uptake of 14C-cystine in prefrontal cortical tissue punches, intraprefrontal cortical infusion of N-acetylcysteine (10â100 ÎŒM) significantly reduced phencyclidine- (1.5 mg/kg, sc) induced deficits in prepulse inhibition. N-Acetylcysteine was without effect when coinfused with CPG (0.5 ÎŒM), indicating an involvement of system xc â.
Conclusions: These results indicate that phencyclidine disrupts sensorimotor gating through system xc â independent mechanisms, but that increasing cystineâglutamate exchange in the prefrontal cortex is sufficient to reduce behavioral deficits produced by phencyclidine
Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report.
We identified a PSEN1 (presenilin 1) mutation carrier from the world's largest autosomal dominant Alzheimer's disease kindred, who did not develop mild cognitive impairment until her seventies, three decades after the expected age of clinical onset. The individual had two copies of the APOE3 Christchurch (R136S) mutation, unusually high brain amyloid levels and limited tau and neurodegenerative measurements. Our findings have implications for the role of APOE in the pathogenesis, treatment and prevention of Alzheimer's disease
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