Project 17233 : intellectual disability (Compulsory Care) legislation : a thesis presented in partial fulfilment of the requirements for the degree of Master in Philosophy in Sociology at Massey University

This study presents an exploration of the history of people who have an intellectual disability and the proposed Compulsory Care legislation that is currently before Parliament. The hypothesis posed is that the legislation is the result of a moral panic. An analysis of the components of a moral panic were identified and examined. The history of the 'eugenics' era is outlined. This era involved the systematic marginalisation of intellectually disabled people on the basis that they posed a 'serious' threat to Western society. This period of history spanning the years 1880 to 1930 is examined for evidence of a moral panic. The 1950's to the present day are briefly reviewed for evidence of a continuation of eugenic thinking. The process and progress of the Compulsory Care legislation is documented and analysed. The findings show there is some evidence to support the hypothesis but that it is insufficient to confirm the view that the legislation resulted from a moral panic

Fluidity in the perception of auditory speech: Cross-modal recalibration of voice gender and vowel identity by a talking face

Article first published online: January 13, 2020Humans quickly adapt to variations in the speech signal. Adaptation may surface as recalibration, a learning effect driven by error-minimisation between a visual face and an ambiguous auditory speech signal, or as selective adaptation, a contrastive aftereffect driven by the acoustic clarity of the sound. Here, we examined whether these aftereffects occur for vowel identity and voice gender. Participants were exposed to male, female, or androgynous tokens of speakers pronouncing /e/, /ø/, (embedded in words with a consonant-vowel-consonant structure), or an ambiguous vowel halfway between /e/ and /ø/ dubbed onto the video of a male or female speaker pronouncing /e/ or /ø/. For both voice gender and vowel identity, we found assimilative aftereffects after exposure to auditory ambiguous adapter sounds, and contrastive aftereffects after exposure to auditory clear adapter sounds. This demonstrates that similar principles for adaptation in these dimensions are at play.The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported by Gravitation Grant 024.001.006 of the Language in Interaction Consortium from Netherlands Organization for Scientific Research. The third author was supported by The Netherlands Organization for Scientific Research (NWO: VENI Grant 275-89-027)

The antiproliferative activity of kinase inhibitors in chronic myeloid leukemia cells is mediated by FOXO transcription factors

Chronic myeloid leukemia (CML) is initiated and maintained by the tyrosine kinase BCR-ABL which activates a number of signal transduction pathways, including PI3K/AKT signaling and consequently inactivates FOXO transcription factors. ABL-specific tyrosine kinase inhibitors (TKIs) induce minimal apoptosis in CML progenitor cells, yet exert potent antiproliferative effects, through as yet poorly understood mechanisms. Here, we demonstrate that in CD34+ CML cells, FOXO1 and 3a are inactivated and relocalized to the cytoplasm by BCR-ABL activity. TKIs caused a decrease in phosphorylation of FOXOs, leading to their relocalization from cytoplasm (inactive) to nucleus (active), where they modulated the expression of key FOXO target genes, such as Cyclin D1, ATM, CDKN1C, and BCL6 and induced G1 arrest. Activation of FOXO1 and 3a and a decreased expression of their target gene Cyclin D1 were also observed after 6 days of in vivo treatment with dasatinib in a CML transgenic mouse model. The over-expression of FOXO3a in CML cells combined with TKIs to reduce proliferation, with similar results seen for inhibitors of PI3K/AKT/mTOR signaling. While stable expression of an active FOXO3a mutant induced a similar level of quiescence to TKIs alone, shRNA-mediated knockdown of FOXO3a drove CML cells into cell cycle and potentiated TKI-induced apoptosis. These data demonstrate that TKI-induced G1 arrest in CML cells is mediated through inhibition of the PI3K/AKT pathway and reactivation of FOXOs. This enhanced understanding of TKI activity and induced progenitor cell quiescence suggests that new therapeutic strategies for CML should focus on manipulation of this signaling network

Potential Role of Protein Kinase B in Insulin-induced Glucose Transport, Glycogen Synthesis, and Protein Synthesis

Various biological responses stimulated by insulin have been thought to be regulated by phosphatidylinosi-tol 3-kinase, including glucose transport, glycogen syn-thesis, and protein synthesis. However, the molecular link between phosphatidylinositol 3-kinase and these biological responses has been poorly understood. Re-cently, it has been shown that protein kinase B (PKB/c-Akt/ Rac) lies immediately downstream from phosphati-dylinositol 3-kinase. Here, we show that expression of a constitutively active form of PKB induced glucose up-take, glycogen synthesis, and protein synthesis in L6 myotubes downstream of phosphatidylinositol 3-kinase and independent of Ras and mitogen-activated protein kinase activation. Introduction of constitutively active PKB induced glucose uptake and protein synthesis but not glycogen synthesis in 3T3L-1 adipocytes, which lack expression of glycogen synthase kinase 3 different from L6 myotubes. Furthermore, we show that deactivation of glycogen synthase kinase 3 and activation of rapamy-cin- sensitive serine/threonine kinase by PKB in L6 myo-tubes might be involved in the enhancement of glycogen synthesis and protein synthesis, respectively. These re-sults suggest that PKB acts as a key enzyme linking phosphatidylinositol 3-kinase activation to multiple bi-ological functions of insulin through regulation of downstream kinases in skeletal muscle, a major target tissue of insulin

Роль совершенствования бухгалтерского учета в управлении производственными запасами

Целью проведения исследования является обоснование направлений повышения эффективности использования материальных производственных запасов на предприятии в условиях рыночной экономики

Mdm2 Induces Mono-Ubiquitination of FOXO4

Background: The Forkhead box O (FOXO) class of transcription factors are involved in the regulation of several cellular responses including cell cycle progression and apoptosis. Furthermore, in model organisms FOXOs act as tumor suppressors and affect aging. Previously, we noted that FOXOs and p53 are remarkably similar within their spectrum of regulatory proteins [1]. For example, the de-ubiquitinating enzyme USP7 removes ubiquitin from both FOXO and p53. However, Skp2 has been identified as E3 ligase for FOXO1, whereas Mdm2 is the prime E3 ligase for p53. Principal Findings/Methodology: Here we provide evidence that Mdm2 acts as an E3 ligase for FOXO as well. In vitro incubation of Mdm2 and FOXO results in ATP-dependent (multi)mono-ubiquitination of FOXO similar to p53. Furthermore, in vivo co-expression of Mdm2 and FOXO induces FOXO mono-ubiquitination and consistent with this result, siRNAmediated depletion of Mdm2 inhibits mono-ubiquitination of FOXO induced by hydrogen peroxide. Regulation of FOXO ubiquitination by Mdm2 is likely to be direct since Mdm2 and FOXO co-immunoprecipitate. In addition, Mdm2-mediated ubiquitination regulates FOXO transcriptional activity. Conclusions/Significance: These data identify Mdm2 as a novel E3 ligase for FOXOs and extend the analogous mode o

Phosphoinositide-dependent kinase 1 controls migration and malignant transformation but not cell growth and proliferation in PTEN-null lymphocytes

In normal T cell progenitors, phosphoinositide-dependent kinase l (PDK1)–mediated phosphorylation and activation of protein kinase B (PKB) is essential for the phosphorylation and inactivation of Foxo family transcription factors, and also controls T cell growth and proliferation. The current study has characterized the role of PDK1 in the pathology caused by deletion of the tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN). PDK1 is shown to be essential for lymphomagenesis caused by deletion of PTEN in T cell progenitors. However, PTEN deletion bypasses the normal PDK1-controlled signaling pathways that determine thymocyte growth and proliferation. PDK1 does have important functions in PTEN-null thymocytes, notably to control the PKB–Foxo signaling axis and to direct the repertoire of adhesion and chemokine receptors expressed by PTEN-null T cells. The results thus provide two novel insights concerning pathological signaling caused by PTEN loss in lymphocytes. First, PTEN deletion bypasses the normal PDK1-controlled metabolic checkpoints that determine cell growth and proliferation. Second, PDK1 determines the cohort of chemokine and adhesion receptors expressed by PTEN-null cells, thereby controlling their migratory capacity

Возможность прогнозирования клеточного типа увеальных меланом без использования инвазивных методов диагностики

Резюме. С помощью дискриминантного анализа установлена возможность определения клеточного типа меланомы увеального тракта в процессе проведения комбинированного (фотокоагуляция + брахитерапия) лечения. Разработана высокозначимая (l = 0,08; р = 0,002) дискриминантная модель, включающая ряд клинических (степень пигментации, пол, скорость роста меланомы) и иммунологических (количество Т- и В-лимфоцитов, процент Т-хелперов и др.) показателей. Особое место в модели занимают признаки, в наибольшей степени отражающие биологические особенности увеальных меланом различного клеточного состава, а именно — скорость изменения размера опухоли в процессе лечения и изменение показателей клеточного иммунитета. Ключевые слова: увеальная меланома, клеточный тип, клинико-морфологические, иммунологические показатели, дискриминантный анализ.Summary. Application of the discriminant analysis shows that it is possible to define the cell type of melanoma of uveal tract of the eye in the process of combined (photocoagulation + brachytherapy) treatment. A highly reliable (l= 0,08; р = 0,002) discriminant model was elaborated, involving a number of both clinical (pigmentation level, gender, melanoma growth rate) and immunological (number of T and B lymphocytes, T helper rate, etc.) indicators. In this model, especially important are those traits that most pronouncedly reflect the biological peculiarities of uveal melanomas of various cellular compositions, namely — the pace of tumor size growth in the process of treatment and changes in cell immunity indicators. Key Words: uveal melanoma, cell type, clinical and morphological, immunological indicators, discriminant analysis