A polymorphism in the HLA-DPB1 gene is associated with susceptibility to multiple sclerosis

We conducted an association study across the human leukocyte antigen (HLA) complex to identify loci associated with multiple sclerosis (MS). Comparing 1927 SNPs in 1618 MS cases and 3413 controls of European ancestry, we identified seven SNPs that were independently associated with MS conditional on the others (each ). All associations were significant in an independent replication cohort of 2212 cases and 2251 controls () and were highly significant in the combined dataset (). The associated SNPs included proxies for HLA-DRB1*15:01 and HLA-DRB1*03:01, and SNPs in moderate linkage disequilibrium (LD) with HLA-A*02:01, HLA-DRB1*04:01 and HLA-DRB1*13:03. We also found a strong association with rs9277535 in the class II gene HLA-DPB1 (discovery set , replication set , combined ). HLA-DPB1 is located centromeric of the more commonly typed class II genes HLA-DRB1, -DQA1 and -DQB1. It is separated from these genes by a recombination hotspot, and the association is not affected by conditioning on genotypes at DRB1, DQA1 and DQB1. Hence rs9277535 represents an independent MS-susceptibility locus of genome-wide significance. It is correlated with the HLA-DPB1*03:01 allele, which has been implicated previously in MS in smaller studies. Further genotyping in large datasets is required to confirm and resolve this association.

Genome-wide association study identifies new multiple sclerosis susceptibility loci on chromosomes 12 and 20

To identify multiple sclerosis (MS) susceptibility loci, we conducted a genome-wide association study (GWAS) in 1,618 cases and used shared data for 3,413 controls. We performed replication in an independent set of 2,256 cases and 2,310 controls, for a total of 3,874 cases and 5,723 controls. We identified risk-associated SNPs on chromosome 12q13-14 (rs703842, P = 5.4 x 10(-11); rs10876994, P = 2.7 x 10(-10); rs12368653, P = 1.0 x 10(-7)) and upstream of CD40 on chromosome 20q13 (rs6074022, P = 1.3 x 10(-7); rs1569723, P = 2.9 x 10(-7)). Both loci are also associated with other autoimmune diseases. We also replicated several known MS associations (HLA-DR15, P = 7.0 x 10(-184); CD58, P = 9.6 x 10(-8); EVI5-RPL5, P = 2.5 x 10(-6); IL2RA, P = 7.4 x 10(-6); CLEC16A, P = 1.1 x 10(-4); IL7R, P = 1.3 x 10(-3); TYK2, P = 3.5 x 10(-3)) and observed a statistical interaction between SNPs in EVI5-RPL5 and HLA-DR15 (P = 0.001).

A transcription factor map as revealed by a genome-wide gene expression analysis of whole-blood mRNA transcriptome in multiple sclerosis

Background Several lines of evidence suggests that transcription factors are involved in the pathogenesis of Multiple Sclerosis (MS) but a complete mapping the whole network has been elusive. One of the reasons is that there are several clinical subtypes of MS and transcription factors which may be involved in one subtype may not be in others. We investigated the possibility that this network could be mapped using microarray technologies and modern bioinformatics methods on a dataset from whole blood in 99 untreated MS patients (36 Relapse Remitting MS, 43 Primary Progressive MS, and 20 Secondary Progressive MS) and 45 age-matched healthy controls, Methodology/Principal Findings We have used two different analytical methodologies: a differential expression analysis and a differential co-expression analysis, which have converged on a significant number of regulatory motifs that seem to be statistically overrepresented in genes which are either differentially expressed (or differentially co-expressed) in cases and controls (e.g. V$KROX_Q6, p-value < 3.31E-6; V$CREBP1_Q2, p-value < 9.93E-6, V$YY1_02, p-value < 1.65E-5). Conclusions/significance: Our analysis uncovered a network of transcription factors that potentially dysregulate several genes in MS or one or more of its disease subtypes. Analysing the published literature we have found that these transcription factors are involved in the early T-lymphocyte specification and commitment as well as in oligodendrocytes dedifferentiation and development. The most significant transcription factors motifs were for the Early Growth response EGR/KROX family, ATF2, YY1 (Yin and Yang 1), E2F-1/DP-1 and E2F-4/DP-2 heterodimers, SOX5, and CREB and ATF families.

Voltammetric monitoring of gold nanoparticle formation facilitated by glycyl-L-tyrosine : relation to electronic spectra and transmission electron microscopy images

Voltammetric techniques have been introduced to monitor the formation of gold nanoparticles produced via the reaction of the amino acid glycyl-L-tyrosine with Au(III) (bromoaurate) in 0.05 M KOH conditions. The alkaline conditions facilitate amino acid binding to Au(III), inhibit the rate of reduction to Au(0), and provide an excellent supporting electrolyte for voltammetric studies. Data obtained revealed that a range of time-dependent gold solution species are involved in gold nanoparticle formation and that the order in which reagents are mixed is critical to the outcome. Concomitantly with voltammetric measurements, the properties of gold nanoparticles formed are probed by examination of electronic spectra in order to understand how the solution environment present during nanoparticle growth affects the final distribution of the nanoparticles. Images obtained by the ex situ transmission electron microscopy (TEM) technique enable the physical properties of the nanoparticles isolated in the solid state to be assessed. Use of this combination of in situ and ex situ techniques provides a versatile framework for elucidating the details of nanoparticle formation.

Getting there, being there, staying and belonging: a case study of two indigenous Australian children’s transition to school

Indigenous Australians are among the most unhealthy populations in the world and yet they reside in a country where the non-Indigenous population enjoys high standards of well-being. Education has been identified as the key mechanism for closing this equity gap. At school commencement many Indigenous children are already at risk of disengagement. This four-year longitudinal study of two Indigenous boys from a socially marginalised community examined key factors affecting transitional trajectories into school. While child characteristics affected level of achievement the critical factors in sustaining positive educational engagement were social support, school practices, inclusion of family and positive expectation.

Bonding and bridging : transition to school and social capital formation among a community of Indigenous Australian children

This study reports on an intervention program designed to facilitate transition to school of a whole community of Indigenous Australian children who had previously not been attending. The children were from families displaced from their traditional lands and experienced on-going social marginalisation and transience. A social capital framework was employed to track change in the children’s social inclusion and family-school engagement for two years, from school entry. Sociometric measurement and interview techniques were applied to assess the children’s social connectedness and peer relationship quality. Using these data, analyses examined whether bonding within the group supported or inhibited formation of new social relationships. Although transience disrupted attendance, there was a group trend towards increased social inclusion with some evidence that group bonds supported bridging to new social relationships. Change in family-school engagement was tracked using multi-informant interviews. Limited engagement between school and families presented an on-going challenge to sustained educational engagement.

Financial Reserves : A Necessary Condition for Not-for-Profit Sustainability?

Should not-for-profit (NFP) organisations hold reserves to hedge uncertainty and protect mission delivery? This chapter outlines the nature and contxt of NFP reserves. many would accept that actors within NFP organisations have a broad accountability to ensure sustinability where an appropriate mission exists, and that sustinability is assisted or ensured through the purposeful accumulation of reserves. This chapter examins current relevant literature on reserves, reviews various approaches to reserves accumulation across jurisdictions and reports what is known about practice. We highlight the tension faced by NFP organisations, balancing mission spending against the need to hedge uncertainty. We investigate the role of reserves, and how an appropriate level is determined to ensure a NFP board's accountability for organisational sustinability. This issue is particularly significant in the period following the global financial crisis, and while practitioner interest is evident, there has been little academic attention paid to the topic of NFP reserves, and 'very few [articles] have even forcused on related topics' (Calabrese, 2011, p. 282).

Defining the InstaBooth: Facilitating debate and content creation from situated users

Through ubiquitous computing and location-based social media, information is spreading outside the traditional domains of home and work into the urban environment. Digital technologies have changed the way people relate to the urban form supporting discussion on multiple levels, allowing more citizens to be heard in new ways (Fredericks et al. 2013; Houghton et al. 2014; Caldwell et al. 2013). Face-to-face and digitally mediated discussions, facilitated by tangible and hybrid interaction, such as multi-touch screens and media façades, are initiated through a telephone booth inspired portable structure: The InstaBooth. The InstaBooth prototype employs a multidisciplinary approach to engage local communities in a situated debate on the future of their urban environment. With it, we capture citizens’ past stories and opinions on the use and design of public places. The way public consultations are currently done often engages only a section of the population involved in a proposed development; the more vocal citizens are not necessarily the more representative of the communities (Jenkins 2006). Alternative ways to engage urban dwellers in the debate about the built environment are explored at the moment, including the use of social media or online tools (Foth 2009). This project fosters innovation by providing pathways for communities to participate in the decision making process that informs the urban form. The InstaBooth promotes dialogue and mediation between a bottom-up and a top-down approach to urban design, with the aim of promoting community connectedness with the urban environment. The InstaBooth provides an engagement and discussion platform that leverages a number of locally developed display and interaction technologies in order to facilitate a dialogue of ideas and commentary. The InstaBooth combines multiple interaction techniques into a hybrid (digital and analogue) media space. Through the InstaBooth, urban design and architectural proposals are displayed encouraging commentary from visitors. Inside the InstaBooth, visitors can activate a multi-touch screen in order to browse media, write a note, or draw a picture to provide feedback. The purpose of the InstaBooth is to engage with a broader section of society, including those who are often marginalised. The specific design of the internal and external interfaces, the mutual relationship between these interfaces with regards to information display and interaction, and the question how visitors can engage with the system, are part of the research agenda of the project.

Multi-site study of additive genetic effects on fractional anisotropy of cerebral white matter: Comparing meta and megaanalytical approaches for data pooling

Combining datasets across independent studies can boost statistical power by increasing the numbers of observations and can achieve more accurate estimates of effect sizes. This is especially important for genetic studies where a large number of observations are required to obtain sufficient power to detect and replicate genetic effects. There is a need to develop and evaluate methods for joint-analytical analyses of rich datasets collected in imaging genetics studies. The ENIGMA-DTI consortium is developing and evaluating approaches for obtaining pooled estimates of heritability through meta-and mega-genetic analytical approaches, to estimate the general additive genetic contributions to the intersubject variance in fractional anisotropy (FA) measured from diffusion tensor imaging (DTI). We used the ENIGMA-DTI data harmonization protocol for uniform processing of DTI data from multiple sites. We evaluated this protocol in five family-based cohorts providing data from a total of 2248 children and adults (ages: 9-85) collected with various imaging protocols. We used the imaging genetics analysis tool, SOLAR-Eclipse, to combine twin and family data from Dutch, Australian and Mexican-American cohorts into one large "mega-family". We showed that heritability estimates may vary from one cohort to another. We used two meta-analytical (the sample-size and standard-error weighted) approaches and a mega-genetic analysis to calculate heritability estimates across-population. We performed leave-one-out analysis of the joint estimates of heritability, removing a different cohort each time to understand the estimate variability. Overall, meta- and mega-genetic analyses of heritability produced robust estimates of heritability.

The ENIGMA Consortium: Large-scale collaborative analyses of neuroimaging and genetic data

The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA's first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.

El Aprendizaje Informado

Welcome to Informed Learning. If you have opened this book, it is probably because you are interested in how people learn. It may also be because you are interested in how learners interact with their information environment and would like to help them do so in ways that help them learn better. What should we teach and how, so that our students will use information successfully, creatively and responsibly in their journey as lifelong learners? Informed learning provides a unique perspective on helping students become successful learners in our rapidly evolving information environments. It presents a new framework for informed learning, that will enable teachers, librarians, researchers and teacher-researchers to work together as they continue to respond to the need to help students use information to learn. Do you want to help your students engage with the information practices of their discipline or chosen profession? Are you looking for ideas to invigorate and refresh your curriculum? Are you looking for ways to help your students write better essays or search the internet more successfully? Are you looking for strategies to enhance your research supervision? Are you trying to discover how information literacy and information literacy education can contribute to academic curriculum? Informed Learning can help you. Informed learning is using information, creatively and reflectively, in order to learn. It is learning that draws on the different ways in which we use information in academic, professional and community life; and it is learning that draws on emerging understanding of our varied experiences of using information to learn. Indeed, we cannot learn without using information. It is problemetising the interdependence between information use and learning that is the foundation of this book. Most of the time we take for granted that aspect of learning which we call information use. What might happen to the learning experience if we attend to it? Informed Learning examines research into the experience of using information to learn in academic, workplace and community contexts, that can be used to inform learning and learning design at many levels. It draws on contemporary higher education teaching and learning theory to suggest ways forward for a learning agenda that values the need for engaging with the wider world of information. In doing so, it offers a new and unified framework for implementing curriculum that recognises the importance of successful, creative and reflective information use as a strategy for learning as well as a learning outcome; and proposes a research agenda that will continue to inform learning. Informed Learning reconceptualises information literacy as being about engaging in information practices in order to learn; engaging with the different ways of using information to learn. Based on the author’s work in developing the seven faces of information literacy, it proposes the need for teaching and learning to 1) bring about new ways of experiencing and using information, and 2) engage students with those information practices relevant to their discipline or profession. This book is written for a diverse audience of educators from many disciplines, curriculum designers, researchers, and administrators. While this book both establishes a new approach to learning design and an associated research agenda, it is also intended to be practical. I have sought to ground the ideas in practice through: • using Steve and Jane as academics from different disciplines on a journey; experiencing the implementation of informed learning; • using examples from the literature and personal experience; • using reflective questions towards the end of each chapter. In this book you will find many examples of how people experience information use as they go about learning in different contexts. The research reported here shows that as people go about learning they interact with information in different ways. They may be learning about a content area in a formal context, they may be engaged in informal learning as they go about their everyday work, or they may be learning through doing original research. The emphasis on experience and ways of seeing comes from the work of researchers into student learning such as Ference Marton, Paul Ramsden, Shirley Booth, Michael Prosser, Keith Trigwell and others who have shown that, if we are to help students learn, we must first be aware of how they experience those aspects of the world about which they are learning. Different ways of reading this book The first three chapters of this book establish the broad theoretical framework for informed learning; and the remaining chapters consider the out workings of this in a range of contexts. If you want to browse the general directions of this book, read the narratives at the start of each chapter. If you want to see how the book might influence your practice, read the narratives and the reflective questions at the end of each chapter. If you want to help your students become informed learners in their discipline or profession, focus on chapters one, two, three and five. If you are looking for help with students engaged in information practices such as internet searching or essay writing, focus on chapters one, three and four. If you are interested in informed learning in the community or workplace, focus on chapters one, two, three and six. If you want to help your research students become informed learners, focus on chapters one, two, three, seven and eight. If you are working with colleagues to promote information literacy education and are looking for ideas, read chapter nine. If you are interested in researching informed learning read chapter ten

The MS risk allele of CD40 is associated with reduced cell-membrane bound expression in antigen presenting cells: Implications for gene function

Human genetic and animal studies have implicated the costimulatory molecule CD40 in the development of multiple sclerosis (MS). We investigated the cell specific gene and protein expression variation controlled by the CD40 genetic variant(s) associated with MS, i.e. the T-allele at rs1883832. Previously we had shown that the risk allele is expressed at a lower level in whole blood, especially in people with MS. Here, we have defined the immune cell subsets responsible for genotype and disease effects on CD40 expression at the mRNA and protein level. In cell subsets in which CD40 is most highly expressed, B lymphocytes and dendritic cells, the MS-associated risk variant is associated with reduced CD40 cell-surface protein expression. In monocytes and dendritic cells, the risk allele additionally reduces the ratio of expression of full-length versus truncated CD40 mRNA, the latter encoding secreted CD40. We additionally show that MS patients, regardless of genotype, express significantly lower levels of CD40 cell-surface protein compared to unaffected controls in B lymphocytes. Thus, both genotype-dependent and independent down-regulation of cell-surface CD40 is a feature of MS. Lower expression of a co-stimulator of T cell activation, CD40, is therefore associated with increased MS risk despite the same CD40 variant being associated with reduced risk of other inflammatory autoimmune diseases. Our results highlight the complexity and likely individuality of autoimmune pathogenesis, and could be consistent with antiviral and/or immunoregulatory functions of CD40 playing an important role in protection from MS. © 2015 Field et al.

Polymorphisms in the receptor tyrosine kinase MERTK gene are associated with Multiple Sclerosis susceptibility

Multiple sclerosis (MS) is a debilitating, chronic demyelinating disease of the central nervous system affecting over 2 million people worldwide. The TAM family of receptor tyrosine kinases (TYRO3, AXL and MERTK) have been implicated as important players during demyelination in both animal models of MS and in the human disease. We therefore conducted an association study to identify single nucleotide polymorphisms (SNPs) within genes encoding the TAM receptors and their ligands associated with MS. Analysis of genotype data from a genome-wide association study which consisted of 1618 MS cases and 3413 healthy controls conducted by the Australia and New Zealand Multiple Sclerosis Genetics Consortium (ANZgene) revealed several SNPs within the MERTK gene (Chromosome 2q14.1, Accession Number NG_011607.1) that showed suggestive association with MS. We therefore interrogated 28 SNPs in MERTK in an independent replication cohort of 1140 MS cases and 1140 healthy controls. We found 12 SNPs that replicated, with 7 SNPs showing p-values of less than 10-5 when the discovery and replication cohorts were combined. All 12 replicated SNPs were in strong linkage disequilibrium with each other. In combination, these data suggest the MERTK gene is a novel risk gene for MS susceptibility. © 2011 Ma et al.

A "Candidate-Interactome" Aggregate Analysis of Genome-Wide Association Data in Multiple Sclerosis

Though difficult, the study of gene-environment interactions in multifactorial diseases is crucial for interpreting the relevance of non-heritable factors and prevents from overlooking genetic associations with small but measurable effects. We propose a "candidate interactome" (i.e. a group of genes whose products are known to physically interact with environmental factors that may be relevant for disease pathogenesis) analysis of genome-wide association data in multiple sclerosis. We looked for statistical enrichment of associations among interactomes that, at the current state of knowledge, may be representative of gene-environment interactions of potential, uncertain or unlikely relevance for multiple sclerosis pathogenesis: Epstein-Barr virus, human immunodeficiency virus, hepatitis B virus, hepatitis C virus, cytomegalovirus, HHV8-Kaposi sarcoma, H1N1-influenza, JC virus, human innate immunity interactome for type I interferon, autoimmune regulator, vitamin D receptor, aryl hydrocarbon receptor and a panel of proteins targeted by 70 innate immune-modulating viral open reading frames from 30 viral species. Interactomes were either obtained from the literature or were manually curated. The P values of all single nucleotide polymorphism mapping to a given interactome were obtained from the last genome-wide association study of the International Multiple Sclerosis Genetics Consortium & the Wellcome Trust Case Control Consortium, 2. The interaction between genotype and Epstein Barr virus emerges as relevant for multiple sclerosis etiology. However, in line with recent data on the coexistence of common and unique strategies used by viruses to perturb the human molecular system, also other viruses have a similar potential, though probably less relevant in epidemiological terms. © 2013 Mechelli et al.