19200 research outputs found
Sort by
Inhibition of PI3K Class IA Kinases Using GDC-0941 Overcomes Cytoprotection of Multiple Myeloma Cells in the Osteoclastic Bone Marrow Microenvironment Enhancing the Efficacy of Current Clinical Therapeutics
No full textOsteoclasts contribute to bone marrow (BM)-mediated drug resistance in multiple myeloma (MM) by providing cytoprotective cues. Additionally, 80% of patients develop osteolytic lesions, which is a major cause of morbidity in MM. Although targeting osteoclast function is critical to improve MM therapies, pre-clinical studies rarely consider overcoming osteoclast-mediated cytoprotection within the selection criteria of drug candidates. We have performed a drug screening and iden-tified PI3K as a key regulator of a signalling node associated with resistance to dexamethasone lenalidomide, pomalidomide, and bortezomib mediated by osteoclasts and BM fibroblastic stro-mal cells, which was blocked by the pan-PI3K Class IA inhibitor GDC-0941. Additionally, GDC-0941 repressed the maturation of osteoclasts derived from MM patients and disrupted the organisation of the F-actin cytoskeleton in sealing zones required for bone degradation, corre-lating with decreased bone resorption by osteoclasts. In vivo, GDC-0941 improved the efficacy of dexamethasone against MM in the syngeneic GFP-5T33/C57-Rawji mouse model. Taken together, our results indicate that GDC-0941 in combination with currently used therapeutic agents could effectively kill MM cells in the presence of the cytoprotective BM microenvironment while in-hibiting bone resorption by osteoclasts. These data support investigating GDC-0941 in combina-tion with currently used therapeutic drugs for MM patients with active bone disease
Philosophical Reflections on Child Poverty and Education
Get PDFThe harmful effects of Covid 19 on children living in poverty have refocused attention on the complex nature of child poverty and the vexed question of its relationship to education. The paper examines a tension at the heart of much discussion of child poverty and education. On the one hand, education is often regarded as essential for children’s flourishing and a means by which children can “escape” poverty; yet on the other hand, education systems, institutions, and practices, often reflect and entrench the disadvantages associated with poverty. Narratives concerning education as an escape from poverty tend not to deal in any depth with the injustices associated with poverty, stressing instead the transformative potential of education. By contrast, largely sociological analyses of the ways in which schooling reproduces inequalities tend to stop short of developing a normative account of how education can contribute to transforming the structural injustices related to poverty and its effects on children’s lives. In working to move beyond this analytic impasse, the paper shows how the cluster of concepts, which Robeyns (2018) locates as central to the capability approach, give insights which help to address these two different lacunae. The notion of conversion factors highlights the significance of taking account of existing relationships in education, while the distinction between capabilities and functionings helps guide practices regarding the education of children living in poverty. Drawing on literature on the heightened inequalities associated with poor children’s experience of lack of schooling during the COVID pandemic, the paper sketches some of the ways in which sociological analysis and normative evaluation can be linked in taking forward an “ethically engaged political philosophy” (Wolff, 2018) to discuss child poverty and education in real schools
The Authenticity Scale as an Outcome Measure for Psychotherapy: A Psychometric Evaluation
Get PDFWe aimed to evaluate how the Authenticity Scale, a measure of authenticity based on humanistic psychology, functioned as an outcome measure for psychological therapies. Ninety participating clients completed the Authenticity Scale at set intervals throughout their therapy. We considered the measure?s reliability, construct validity, acceptability, and sensitivity to therapeutic intervention. The Authenticity Scale and each of its subscales (Authentic Living, Accepting External Influences, and Self-Alienation) were found to have excellent internal reliability and very high completion rates. The full scale was also found to be sensitive to psychotherapeutic intervention, along with two of its three subscales. However, subscale intercorrelations revealed issues with the factor structure of the measure, with one subscale not correlating with the other two, drawing into question whether the Authenticity Scale should be seen to operationalize a single, multi-faceted construct as intended. Our study provides preliminary evidence that the Authenticity Scale can be used as an outcome measure in clinical practice, though caution and further psychometric testing are strongly recommended.© 2023, Sage. This is an author produced version of a paper published in Journal of Humanistic Psychology uploaded in accordance with the publisher’s self- archiving policy. The final published version (version of record) is available online at the link. Some minor differences between this version and the final published version may remain. We suggest you refer to the final published version should you wish to cite from it
Good, Quarrelsome, Bad: Animal Agency and Human-Elephant Interactions in the Western Ghats, India
No full textEditorial: The pancreatic islet - a multifaceted hub of inter-cellular communication:The pancreatic islet - a multifaceted hub of inter-cellular communication
No full textLand use drives detritivore size structure and decomposition through shifts in resource quality and quantity
No full textLand use change and nutrient pollution are two pervasive stressors that can modify carbon cycling, as they influence the inputs and the transformation of detritus. Understanding their impact on stream food webs and on diversity is particularly pressing, as streams are largely fuelled by detrital material received from the adjacent riparian environment. Here we assess how a switch from native deciduous forest to Eucalyptus plantations and nutrient enrichment alter the size distribution of stream detritivore communities and decomposition rates of detritus. As expected, more detritus resulted in higher size-independent, or overall, abundance (i.e. higher intercept of size spectra). This change in overall abundance was mainly driven by a change of the relative contribution of large taxa (Amphipoda and Trichoptera), which changed from an average relative abundance of 55.5 to 77.2 % between the sites compared for resource quantity differences in our study. In contrast, detritus quality modified the relative abundance of large vs small individuals (i.e. size spectra slopes), with shallow slopes of size spectra (proportionately more large individuals) associated with sites with nutrient-richer waters and steeper slopes (proportionately fewer large individuals) associated with sites draining Eucalyptus plantations. Decomposition rates of alder leaves due to macroinvertebrates increased from 0.0003 to 0.0142 when relative contribution of large organisms increased (modelled slopes of size spectra: -1.00 and - 0.33, respectively), highlighting the importance of large sized individuals for ecosystem functioning. Our study reveals that land use change and nutrient pollution can greatly impair the transfer of energy through the detrital or 'brown' food web by means of intra- and inter-specific responses to quality and quantity of the detritus. These responses enable linking land use change and nutrient pollution to ecosystem productivity and carbon cycling. [Abstract copyright: Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.
Dose imbalance of DYRK1A kinase causes systemic progeroid status in Down syndrome by increasing the un-repaired DNA damage and reducing LaminB1 levels
No full textPeople with Down syndrome (DS) show clinical signs of accelerated ageing. Causative mechanisms remain unknown and hypotheses range from the (essentially untreatable) amplified-chromosomal-instability explanation, to potential actions of individual supernumerary chromosome-21 genes. The latter explanation could open a route to therapeutic amelioration if the specific over-acting genes could be identified and their action toned-down. Biological age was estimated through patterns of sugar molecules attached to plasma immunoglobulin-G (IgG-glycans, an established "biological-ageing-clock") in n = 246 individuals with DS from three European populations, clinically characterised for the presence of co-morbidities, and compared to n = 256 age-, sex- and demography-matched healthy controls. Isogenic human induced pluripotent stem cell (hiPSCs) models of full and partial trisomy-21 with CRISPR-Cas9 gene editing and two kinase inhibitors were studied prior and after differentiation to cerebral organoids. Biological age in adults with DS is (on average) 18.4-19.1 years older than in chronological-age-matched controls independent of co-morbidities, and this shift remains constant throughout lifespan. Changes are detectable from early childhood, and do not require a supernumerary chromosome, but are seen in segmental duplication of only 31 genes, along with increased DNA damage and decreased levels of LaminB1 in nucleated blood cells. We demonstrate that these cell-autonomous phenotypes can be gene-dose-modelled and pharmacologically corrected in hiPSCs and derived cerebral organoids. Using isogenic hiPSC models we show that chromosome-21 gene DYRK1A overdose is sufficient and necessary to cause excess unrepaired DNA damage. Explanation of hitherto observed accelerated ageing in DS as a developmental progeroid syndrome driven by DYRK1A overdose provides a target for early pharmacological preventative intervention strategies. Main funding came from the "Research Cooperability" Program of the Croatian Science Foundation funded by the European Union from the European Social Fund under the Operational Programme Efficient Human Resources 2014-2020, Project PZS-2019-02-4277, and the Wellcome Trust Grants 098330/Z/12/Z and 217199/Z/19/Z (UK). All other funding is described in details in the "Acknowledgements". [Abstract copyright: Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.
Which Translation?:Identifying the True Source of Patten Wilson’s Shahnameh Illustrations
No full textRecent scholarship has stressed the influence of translation on late nineteenth-century literary and artistic developments (indeed, ‘Decadence and Translation’ was the theme of a Volupté special issue in 2020). Focusing on the British context, Annmarie Drury describes how English poetry at this time was ‘profoundly pervious, susceptible to historical-cultural currents arising from the territorial expansion and imperialist tensions that Britain experienced at the time’. Translators, in her phrase, ‘ministered to this susceptibility’, mediating foreign genres and prosodic forms that by their assimilation into anglophone literary culture both ‘tested’ and ‘transformed’ English poetry. Given the importance of translators at this time, and the potential ramifications of their decisions and methods in translation, an obvious question to ask when trying to gauge the reception of a single work of foreign literature by one individual British writer or artist is, ‘which translation were they using?’ Take the poetry of Sappho: until relatively recently, most translators of her ‘Ode to Aphrodite’ gendered the speaker’s beloved as male. But as early as 1835, the philologist Theodor Bergk proposed the opposite – a distinction of perhaps major significance for a contemporary reader into whose hands his translation happened to fall. Similarly, any scholar investigating a fin-de-siècle dramatist who was influenced by Ibsen is likely to consider which of the various English translations then available he or she consulted, and if both, then which was preferred. The subtle differences between Gosse’s and Archer’s versions are even the subject of a comic misunderstanding in J. M. Barrie’s 1891 farce, Ibsen’s Ghost, when it emerges that two characters in dialogue have been speaking their lines from variant play texts. If translational variants were conspicuous enough to be a subject for popular humour in the 1890s, then for us in the present they must be an object of serious enquiry