Young children's understanding of disabilities: the influence of development, context and cognition

Throughout Europe, educational support for children with disabilities has moved towards a model of inclusive education. Such policy changes mean that for all children there will be an increased likelihood of working with and encountering children with differing disabilities and difficulties. Previous research had indicated that children had poorly differentiated views of developmental differences. The present study investigated children?s representations of different disabilities. Seventy-nine 8-9 and 10-11 year old Greek children from an urban school and a rural school completed an attitudes toward school inclusion rating scale and a semi-structured interview. Responses to the attitude scale provided generally positive views of educational inclusion. However, children were less positive about activities that might directly reflect upon themselves. Children?s responses in the interviews indicated that they were developing rich representations of differences and diversities. Children had the greatest understanding of sensory and physical disabilities, followed by learning disabilities. There was limited knowledge of dyslexia and hyperactivity and no child was familiar with the term autism. Both groups of children identified a range of developmental difficulties, with older children being more aware of specific learning disabilities, their origin and impact. Results are discussed in terms of children?s developing knowledge systems and the implications for educational practices

Structural and functional analysis of coral Hypoxia Inducible Factor

<div><p>Tissues of symbiotic Cnidarians are exposed to wide, rapid and daily variations of oxygen concentration. Indeed, during daytime, intracellular O₂ concentration increases due to symbiont photosynthesis, while during night, respiration of both host cells and symbionts leads to intra-tissue hypoxia. The Hypoxia Inducible Factor 1 (HIF-1) is a heterodimeric transcription factor used for maintenance of oxygen homeostasis and adaptation to hypoxia. Here, we carried out a mechanistic study of the response to variations of O₂ concentrations of the coral model <i>Stylophora pistillata</i>. <i>In silico</i> analysis showed that homologs of HIF-1 α (SpiHIF-1α) and HIF-1β (SpiHIF-1β) exist in coral. A specific SpiHIF-1 DNA binding on mammalian Hypoxia Response Element (HRE) sequences was shown in extracts from coral exposed to dark conditions. Then, we cloned the coral HIF-1α and β genes and determined their expression and transcriptional activity. Although HIF-1α has an incomplete Oxygen-dependent Degradation Domain (ODD) relative to its human homolog, its protein level is increased under hypoxia when tested in mammalian cells. Moreover, co-transfection of SpiHIF-1α and β in mammalian cells stimulated an artificial promoter containing HRE only in hypoxic conditions. This study shows the strong conservation of molecular mechanisms involved in adaptation to O₂ concentration between Cnidarians and Mammals whose ancestors diverged about 1,200–1,500 million years ago.</p></div

SpiHIF promotes human HRE transcriptional activation.

<p>HEK293 were transfected either with luciferase reporter plasmid together with empty, <i>spiHIF</i>α, <i>spiHIFβ</i>, or a combination of both <i>spiHIF</i> expression vectors. In all cases, a control Renilla expression vector was co-transfected to normalize for transfection efficiency. 24h after transfection, cells were maintained under normoxic or hypoxic conditions in an anaerobic workstation for 24h. Cells were lyzed and firefly and renilla luciferase activity were measured. A ratio of firefly/renilla luciferase activity is shown. Results are representative of three independent experiments performed in triplicate. Values are means ± SD (n = 3). * P< 0.05.</p

Electrophoretic-Mobility Shift Assay using biotin-labeled W18 probes.

<p>Nuclear extracts from <i>Stylophora pistillata</i> sampled at light (lane 1) or dark (lane 2 to 7) were incubated with labeled synthetic HRE (W18) then subjected on 5% TBE acrylamide gel. Competition reactions with W18 as competitive probe (lane 3 and 6) or M18 as non-competitive (lane 4 and 7) were performed by adding 200-fold excess unlabeled oligonucleotides. Super shift experiment (lane 5 to 7) was performed mixing anti-SpiHIFα with nuclear extract prior incubation with labelled W18. The complex formed by SpiHIFα and probe (and anti-SpiHIFα when added) is indicated by arrows.</p

Sp<i>i</i>HIFα has a functional ODD domain.

<p>HEK293 cells were transfected with 0.1μg of <i>spiHIF</i> α or <i>spiHIFβ</i> plasmids. 24h post-transfection, cells were maintained in normoxic (21%) or hypoxic (<1%) conditions during 6h. Whole cell extracts migrated within a 7.5% SDS PAGE gel, were analyzed by immuno blot with different antibodies: anti-Histidine tag for SpiHIFα, anti-Myc for SpiHIFβ, and anti-actin as a loading control.</p

Resistance to sunitinib in renal clear cell carcinoma results from sequestration in lysosomes and inhibition of the autophagic flux

<p>Metastatic renal cell carcinomas (mRCC) are highly vascularized tumors that are a paradigm for the treatment with antiangiogenesis drugs targeting the vascular endothelial growth factor (VEGF) pathway. The available drugs increase the time to progression but are not curative and the patients eventually relapse. In this study we have focused our attention on the molecular mechanisms leading to resistance to sunitinib, the first line treatment of mRCC. Because of the anarchic vascularization of tumors the core of mRCC tumors receives only suboptimal concentrations of the drug. To mimic this in vivo situation, which is encountered in a neoadjuvant setting, we exposed sunitinib-sensitive mRCC cells to concentrations of sunitinib below the concentration of the drug that gives 50% inhibition of cell proliferation (IC50). At these concentrations, sunitinib accumulated in lysosomes, which downregulated the activity of the lysosomal protease CTSB (cathepsin B) and led to incomplete autophagic flux. Amino acid deprivation initiates autophagy enhanced sunitinib resistance through the amplification of autolysosome formation. Sunitinib stimulated the expression of ABCB1 (ATP-binding cassette, sub-family B [MDR/TAP], member 1), which participates in the accumulation of the drug in autolysosomes and favor its cellular efflux. Inhibition of this transporter by elacridar or the permeabilization of lysosome membranes with Leu-Leu-O-methyl (LLOM) resensitized mRCC cells that were resistant to concentrations of sunitinib superior to the IC50. Proteasome inhibitors also induced the death of resistant cells suggesting that the ubiquitin-proteasome system compensates inhibition of autophagy to maintain a cellular homeostasis. Based on our results we propose a new therapeutic approach combining sunitinib with molecules that prevent lysosomal accumulation or inhibit the proteasome.</p