The Role of the Cell Adhesion Molecules N-cadherin, MCAM, and Beta 3 Integrin in Human Melanoma

Melanoma, which accounts for only 4% of all skin cancers, but 75% of skin cancer-related deaths, continues to rise at an alarming rate worldwide. When a melanoma is detected and resected at an early stage, the cure rate for patients is favorable. However, the response rate of patients with metastatic melanoma to chemotherapy is less than 15%, and biological therapies have limited efficacy. Therefore, identification of genes that can serve as therapeutic targets for advanced-stage melanoma is crucial. The cell adhesion molecules N-cadherin, MCAM, and Beta3 integrin have been postulated to represent melanoma progression markers; yet, little is known regarding whether they may constitute valuable therapeutic targets for the disease. Furthermore, no studies conducted to date have examined the expression and function of these three molecules in concert in melanoma. The results of our whole-genome and tissue microarray profiling illustrate N-cadherin, MCAM, and Beta3 integrin expression in the distinct stages of melanoma progression. We demonstrate that N-cadherin and Beta3 integrin are melanoma progression markers, but MCAM is not. Furthermore, greater than 95% of metastatic melanomas analyzed in our study express at least one of the three adhesion molecules, and 50% express all three. Our next objective was to determine whether inhibition of N-cadherin, MCAM, or Beta3 integrin impairs melanoma cell proliferation, migration, and/or invasion. We hypothesized that due to redundancy in the functions of N-cadherin, MCAM, and Beta3 integrin, simultaneous inhibition of all three molecules may elicit the most effective therapeutic response. We demonstrate that inhibiting expression of N-cadherin, MCAM, or Beta3 integrin decreases melanoma cell proliferation. However, inhibiting their expression in parallel does not augment the anti-proliferative effect. In contrast, downregulation of N-cadherin, MCAM, and Beta3 integrin in parallel inhibits melanoma cell migration and invasion to a significantly greater extent than targeting each gene alone. Our results indicate that of the three adhesion molecules, MCAM and Beta3 integrin play the most pronounced role in migration and invasion, and therefore, in combination, may represent the most promising therapeutic targets. The data presented in this dissertation provide the foundation for future clinical studies that target adhesion molecules in advanced-stage melanoma patients

Conceptualising transformative undergraduate experiences: a phenomenographic exploration of students' personal projects

Existing ways of understanding the transformative potential of students’ undergraduate experiences either focus solely on the formal educational elements of these experiences or present an overly static picture of students’ intentions in engaging in higher education. In this article we argue that the notion of ‘personal project’ offers a more flexible way of understanding what students are trying to gain from being at university. Based on a phenomenographic analysis of interviews with 31 students over the three years of their degrees, we examine how sociology students’ accounts of their personal projects develop over the three years of their degree programmes and how these relate to their accounts of their integration into their institutions and the development of their intellectual engagement with their discipline. We argue that students’ accounts of their personal projects are relatively stable over the course of their degrees but do not appear to shape the development of their intellectual engagement with their degree programme. What appears to be more significant is whether or not students understand their time at university as an educational experience. Based on this, we argue that the transformative elements of an undergraduate education lie in students developing their personal projects and intellectual engagement through the educational context that is offered at university

Reference to the index of miscellaneous notes on Tasmanian history by William Graham Robertson.

Collection contains letters from Frederick Watson of Historical Records of Australia in answer to various queries about early settlers. Also answers to queries on early land grants etc., some in answer to Robertson's correspondence in the Critic under the pseudonym "Antil", and miscellaneous historical notes

Causes and consequences of purifying selection on SARS-CoV-2

Owing to a lag between a deleterious mutation’s appearance and its selective removal, gold-standard methods for mutation rate estimation assume no meaningful loss of mutations between parents and offspring. Indeed, from analysis of closely related lineages, in SARS-CoV-2, the Ka/Ks ratio was previously estimated as 1.008, suggesting no within-host selection. By contrast, we find a higher number of observed SNPs at 4-fold degenerate sites than elsewhere and, allowing for the virus’s complex mutational and compositional biases, estimate that the mutation rate is at least 49–67% higher than would be estimated based on the rate of appearance of variants in sampled genomes. Given the high Ka/Ks one might assume that the majority of such intrahost selection is the purging of nonsense mutations. However, we estimate that selection against nonsense mutations accounts for only ∼10% of all the “missing” mutations. Instead, classical protein-level selective filters (against chemically disparate amino acids and those predicted to disrupt protein functionality) account for many missing mutations. It is less obvious why for an intracellular parasite, amino acid cost parameters, notably amino acid decay rate, is also significant. Perhaps most surprisingly, we also find evidence for real-time selection against synonymous mutations that move codon usage away from that of humans. We conclude that there is common intrahost selection on SARS-CoV-2 that acts on nonsense, missense, and possibly synonymous mutations. This has implications for methods of mutation rate estimation, for determining times to common ancestry and the potential for intrahost evolution including vaccine escape

Wavelet and R/S analysis of the X-ray flickering of cataclysmic variables

Recently, wavelets and R/S analysis have been used as statistical tools to characterize the optical flickering of cataclysmic variables. Here we present the first comprehensive study of the statistical properties of X-ray flickering of cataclysmic variables in order to link them with physical parameters. We analyzed a sample of 97 X-ray light curves of 75 objects of all classes observed with the XMM-Newton space telescope. By using the wavelets analysis, each light curve has been characterized by two parameters, alpha and Sigma, that describe the energy distribution of flickering on different timescales and the strength at a given timescale, respectively. We also used the R/S analysis to determine the Hurst exponent of each light curve and define their degree of stochastic memory in time. The X-ray flickering is typically composed of long time scale events (1.5 < alpha < 3), with very similar strengths in all the subtypes of cataclysmic variables (-3 < Sigma < -1.5). The X-ray data are distributed in a much smaller area of the alpha-Sigma parameter space with respect to those obtained with optical light curves. The tendency of the optical flickering in magnetic systems to show higher Sigma values than the non-magnetic systems is not encountered in the X-rays. The Hurst exponents estimated for all light curves of the sample are larger than those found in the visible, with a peak at 0.82. In particular, we do not obtain values lower than 0.5. The X-ray flickering presents a persistent memory in time, which seems to be stronger in objects containing magnetic white dwarf primaries. The similarity of the X-ray flickering in objects of different classes together with the predominance of a persistent stochastic behavior can be explained it terms of magnetically-driven accretion processes acting in a considerable fraction of the analyzed objects.Comment: 10 pages, 3 figures, 2 tables. Language revision. Accepted for publication in A&

Recent and Current Educational Research with and in Developing Countries by Researchers from Britain

SUMMARY A survey of British work on education in developing countries lists projects under a number of headings — from ‘qualifications and job selection’, to ‘small countries’, and ‘in service training’. The article ends with a plea for more interdisciplinary work, as well as more cross?national collaboration. RESUMEN Investigación educacional británica reciente con y en los países en desarrollo Este estudio del trabajo británico sobre educación en los países en desarrollo, proporciona una lista de proyectos bajo títulos que van desde ‘calificaciones y selección de trabajo’ a ‘países pequeños’ y ‘en capacitación de servicio’. El artículo termina solicitando mayor trabajo interdisciplinario y mayor colaboración bilateral. SOMMAIRE La récente recherche actuelle sur l'éducation par des chercheurs de Grande?Bretagne avec et dans les pays en voie de développement Un rapport du travail britannique sur l'éducation dans les pays en voie de développement énumère les projets sous différentes rubriques — de ‘qualifications et sélection d'emploi’, à ‘petits pays’, et ‘formation sur le tas’. L'article se termine par des arguments pour un travail plus interdisciplinaire, ainsi qu'une plus grande collaboration transnationale

A critical re-evaluation of the Thorne-Zytkow object candidate HV 2112

It has been argued in the literature that the star HV 2112 in the Small Magellanic Cloud (SMC) is the first known example of a Thorne–Żytkow object (TŻO), a red supergiant with a degenerate neutron core. This claim is based on the star having a high luminosity (log (L/L⊙) ≳ 5), an extremely cool effective temperature, and a surface enriched in in lithium, calcium, and various irp-process elements. In this paper we re-examine this evidence, and present new measurements of the stellar properties. By compiling archival photometry from blue to mid-infrared for HV 2112 and integrating under its spectral energy distribution, we find a bolometric luminosity in the range of log (L/L⊙) = 4.70–4.91, lower than that found in previous work and comparable to bright asymptotic giant branch (AGB) stars. We compare a VLT+XSHOOTER spectrum of HV 2112 to other late-type, luminous SMC stars, finding no evidence for enhancements in Rb, Ca, or K, though there does seem to be an enrichment in Li. We therefore conclude that a much more likely explanation for HV 2112 is that it is an intermediate mass (∼5 M⊙) AGB star. However, from our sample of comparison stars we identify a new TŻO candidate, HV 11417, which seems to be enriched in Rb but for which we cannot determine a Li abundance

Detail-oriented cognitive style and social communicative deficits, within and beyond the autism spectrum: independent traits that grow into developmental interdependence

At the heart of debates over underlying causes of autism is the "Kanner hypothesis" that autistic deficits in social reciprocity, and a cognitive/perceptual 'style' favouring detail-oriented cognition, co-vary in autistic individuals. A separate line of work indicates these two domains are normally distributed throughout the population, with autism representing an extremity. This realisation brings the Kanner debate into the realm of normative co-variation, providing more ways to test the hypothesis, and insights into typical development; for instance, in the context of normative functioning, the Kanner hypothesis implies social costs to spatial/numerical prowess

Challenges to science and society in the sustainable management and use of water: investigating the role of social learning

Water catchments are characterised by connectedness, complexity, uncertainty, conflict, multiple stakeholders and thus, multiple perspectives. Catchments are thus unknowable in objective terms although this understanding does not currently form the dominant paradigm for environmental management and policy development. In situations of this type it is no longer possible to rely only on scientific knowledge for management and policy prescriptions. 'Social learning', which is built on different paradigmatic and epistemological assumptions, offers managers and policy makers alternative and complementary possibilities. Social learning is central to non-coercion. It is gaining recognition as a potential governance or coordination mechanism in complex natural resource situations such as the fulfilment of the European Water Framework Directive, but its underlying assumptions and successful conduct need to be much better understood. SLIM (social learning for the integrated management and sustainable use of water at catchment scale), a European Union, Fifth Framework project assembled a multidisciplinary group of researchers to research social learning in catchments of different type, scale, and socio-economic situation. Social tools and methods were developed from this research which also employed a novel approach to project management. In this introductory paper the rationale for the project, the project design intentions and realisations, and the case for researching social learning in contexts such as water catchments are described. Some challenges presented by a social learning approach for science (as a form of practice) and society in the sustainable management and use of water are raised