Novel Approach to Identify Optimal Metabotypes of Elongase and Desaturase Activities in Prevention of Acute Coronary Syndrome

Both metabolomic and genomic approaches are valuable for risk analysis, however typical approaches evaluating differences in means do not model the changes well. Gene polymorphisms that alter function would appear as distinct populations, or metabotypes, from the predominant one, in which case risk is revealed as changed mixing proportions between control and case samples. Here we validate a model accounting for mixed populations using biomarkers of fatty acid metabolism derived from a case/control study of acute coronary syndrome subjects in which both metabolomic and genomic approaches have been used previously. We first used simulated data to show improved power and sensitivity in the approach compared to classic approaches. We then used the metabolic biomarkers to test for evidence of distinct metabotypes and different proportions among cases and controls. In simulation, our model outperformed all other approaches including Mann-Whitney, t-tests, and χ2. Using real data, we found distinct metabotypes of six of the seven activities tested, and different mixing proportions in five of the six activity biomarkers: D9D, ELOVL6, ELOVL5, FADS1, and Sprecher pathway chain shortening (SCS). High activity metabotypes of non-essential fatty acids and SCS decreased odds for acute coronary syndrome (ACS), however high activity metabotypes of 20-carbon fatty acid synthesis increased odds. Our study validates an approach that accounts for both metabolomic and genomic theory by demonstrating improved sensitivity and specificity, better performance in real world data, and more straightforward interpretability

Gain-of-Sensitivity Mutations in a Trim5-Resistant Primary Isolate of Pathogenic SIV Identify Two Independent Conserved Determinants of Trim5α Specificity

Retroviral capsid recognition by Trim5 blocks productive infection. Rhesus macaques harbor three functionally distinct Trim5 alleles: Trim5αQ, Trim5αTFP and Trim5CypA. Despite the high degree of amino acid identity between Trim5αQ and Trim5αTFP alleles, the Q/TFP polymorphism results in the differential restriction of some primate lentiviruses, suggesting these alleles differ in how they engage these capsids. Simian immunodeficiency virus of rhesus macaques (SIVmac) evolved to resist all three alleles. Thus, SIVmac provides a unique opportunity to study a virus in the context of the Trim5 repertoire that drove its evolution in vivo. We exploited the evolved rhesus Trim5α resistance of this capsid to identify gain-of-sensitivity mutations that distinguish targets between the Trim5αQ and Trim5αTFP alleles. While both alleles recognize the capsid surface, Trim5αQ and Trim5αTFP alleles differed in their ability to restrict a panel of capsid chimeras and single amino acid substitutions. When mapped onto the structure of the SIVmac239 capsid N-terminal domain, single amino acid substitutions affecting both alleles mapped to the β-hairpin. Given that none of the substitutions affected Trim5αQ alone, and the fact that the β-hairpin is conserved among retroviral capsids, we propose that the β-hairpin is a molecular pattern widely exploited by Trim5α proteins. Mutations specifically affecting rhesus Trim5αTFP (without affecting Trim5αQ) surround a site of conservation unique to primate lentiviruses, overlapping the CPSF6 binding site. We believe targeting this site is an evolutionary innovation driven specifically by the emergence of primate lentiviruses in Africa during the last 12 million years. This modularity in targeting may be a general feature of Trim5 evolution, permitting different regions of the PRYSPRY domain to evolve independent interactions with capsid

Virtual worlds for learning: Done and dusted?

When Second Life first came to the attention of the mainstream media in 2007, educators recognised the potential of virtual worlds for teaching and learning. They seemed to be the ideal environments to facilitate authentic learning, alleviate the tyranny of distance for students not on campus, and provide an inexpensive and safe environment to teach skills that were too dangerous or expensive to teach in the real world. In spite of all this fanfare, virtual worlds have failed to gain significant traction in higher education. This paper outlines a preliminary investigation into the reasons why virtual worlds have not been adopted for learning and teaching. The reflections of the six authors on this topic were subjected to a thematic analysis with themes arranged under four broad topics. This information informed the development of a survey to be distributed more widely to further explore this phenomenon

Spatial correlations in attribute communities

Community detection is an important tool for exploring and classifying the properties of large complex networks and should be of great help for spatial networks. Indeed, in addition to their location, nodes in spatial networks can have attributes such as the language for individuals, or any other socio-economical feature that we would like to identify in communities. We discuss in this paper a crucial aspect which was not considered in previous studies which is the possible existence of correlations between space and attributes. Introducing a simple toy model in which both space and node attributes are considered, we discuss the effect of space-attribute correlations on the results of various community detection methods proposed for spatial networks in this paper and in previous studies. When space is irrelevant, our model is equivalent to the stochastic block model which has been shown to display a detectability-non detectability transition. In the regime where space dominates the link formation process, most methods can fail to recover the communities, an effect which is particularly marked when space-attributes correlations are strong. In this latter case, community detection methods which remove the spatial component of the network can miss a large part of the community structure and can lead to incorrect results.Comment: 10 pages and 7 figure

Characterizing the community structure of complex networks

Community structure is one of the key properties of complex networks and plays a crucial role in their topology and function. While an impressive amount of work has been done on the issue of community detection, very little attention has been so far devoted to the investigation of communities in real networks. We present a systematic empirical analysis of the statistical properties of communities in large information, communication, technological, biological, and social networks. We find that the mesoscopic organization of networks of the same category is remarkably similar. This is reflected in several characteristics of community structure, which can be used as ``fingerprints'' of specific network categories. While community size distributions are always broad, certain categories of networks consist mainly of tree-like communities, while others have denser modules. Average path lengths within communities initially grow logarithmically with community size, but the growth saturates or slows down for communities larger than a characteristic size. This behaviour is related to the presence of hubs within communities, whose roles differ across categories. Also the community embeddedness of nodes, measured in terms of the fraction of links within their communities, has a characteristic distribution for each category. Our findings are verified by the use of two fundamentally different community detection methods.Comment: 15 pages, 20 figures, 4 table

Employing culturally responsive pedagogy to foster literacy learning in schools

 In recent years it has become increasingly obvious that, to enable students in schools from an increasingly diverse range of cultural backgrounds to acquire literacy to a standard that will support them to achieve academically, it is important to adopt pedagogy that is responsive to, and respectful of, them as culturally situated. What largely has been omitted from the literature, however, is discussion of a relevant model of learning to underpin this approach. For this reason this paper adopts a socio-cultural lens (Vygotsky, 1978) through which to view such pedagogy and refers to a number of seminal texts to justify of its relevance. Use of this lens is seen as having a particular rationale. It forces a focus on the agency of the teacher as a mediator of learning who needs to acknowledge the learner’s cultural situatedness (Kozulin, 2003) if school literacy learning for all students is to be as successful as it might be. It also focuses attention on the predominant value systems and social practices that characterize the school settings in which students’ literacy learning is acquired. The paper discusses implications for policy and practice at whole-school, classroom and individual student levels of culturally-responsive pedagogy that is based on a socio-cultural model of learning. In doing so it draws on illustrations from the work of a number of researchers, including that of the author

The CMS Integration Grid Testbed

The CMS Integration Grid Testbed (IGT) comprises USCMS Tier-1 and Tier-2 hardware at the following sites: the California Institute of Technology, Fermi National Accelerator Laboratory, the University of California at San Diego, and the University of Florida at Gainesville. The IGT runs jobs using the Globus Toolkit with a DAGMan and Condor-G front end. The virtual organization (VO) is managed using VO management scripts from the European Data Grid (EDG). Gridwide monitoring is accomplished using local tools such as Ganglia interfaced into the Globus Metadata Directory Service (MDS) and the agent based Mona Lisa. Domain specific software is packaged and installed using the Distrib ution After Release (DAR) tool of CMS, while middleware under the auspices of the Virtual Data Toolkit (VDT) is distributed using Pacman. During a continuo us two month span in Fall of 2002, over 1 million official CMS GEANT based Monte Carlo events were generated and returned to CERN for analysis while being demonstrated at SC2002. In this paper, we describe the process that led to one of the world's first continuously available, functioning grids.Comment: CHEP 2003 MOCT01

CANDELS Observations Of The Structural Properties Of Cluster Galaxies At Z=1.62

We discuss the structural and morphological properties of galaxies in a z = 1.62 proto-cluster using near-IR imaging data from Hubble Space Telescope Wide Field Camera 3 data of the Cosmic Assembly Near-IR Deep Extragalactic Legacy Survey (CANDELS). The cluster galaxies exhibit a clear color-morphology relation: galaxies with colors of quiescent stellar populations generally have morphologies consistent with spheroids, and galaxies with colors consistent with ongoing star formation have disk-like and irregular morphologies. The size distribution of the quiescent cluster galaxies shows a deficit of compact (less than or similar to 1 kpc), massive galaxies compared to CANDELS field galaxies at z = 1.6. As a result, the cluster quiescent galaxies have larger average effective sizes compared to field galaxies at fixed mass at greater than 90% significance. Combined with data from the literature, the size evolution of quiescent cluster galaxies is relatively slow from z similar or equal to 1.6 to the present, growing as (1 + z)(-0.6 +/- 0.1). If this result is generalizable, then it implies that physical processes associated with the denser cluster region seem to have caused accelerated size growth in quiescent galaxies prior to z = 1.6 and slower subsequent growth at z < 1.6 compared to galaxies in the lower density field. The quiescent cluster galaxies at z = 1.6 have higher ellipticities compared to lower redshift samples at fixed mass, and their surface-brightness profiles suggest that they contain extended stellar disks. We argue that the cluster galaxies require dissipationless (i.e., gas-poor or "dry") mergers to reorganize the disk material and to match the relations for ellipticity, stellar mass, size, and color of early-type galaxies in z < 1 clusters.NASA NAS5-26555HST GO-12060NASA through from the Space Telescope Science Institute GO-12060European Research CouncilRoyal SocietyTexas AM UniversityGeorge P. and Cynthia Woods Institute for Fundamental Physics and AstronomyAstronom

Barriers in phase I cancer clinical trials referrals and enrollment: five-year experience at the Princess Margaret Hospital

BACKGROUND: There is a paucity of literature on the referral outcome of patients seen in phase I trial clinics in academic oncology centres. This study aims to provide information on the accrual rate and to identify obstacles in the recruitment process. METHODS: A retrospective chart review was performed for all new patients referred and seen in the phase I clinic at the Princess Margaret Hospital between January 2000 and June 2005. Data on their demographics, medical history, and details of trial participation or non-entry were recorded. RESULTS: A total of 667 new phase I referrals were seen during the stated period. Of these patients, 197 (29.5%) patients were enrolled into a phase I trial, and 64.5% of them started trial within 1 month of the initial visit. About a quarter (165 of 667) of the patients referred were deemed ineligible at their first visit, with the most frequent reasons for ineligibility being poor performance status, unacceptable bloodwork, too many prior treatments and rapid disease progression. The remaining 305 patients (45.7%) were potentially eligible at their initial visit, but never entered a phase I trial. The main reasons for their non-entry were patient refusal, other treatment recommended first, and lack of available trials or trial spots. CONCLUSION: This study provides information on the clinical realities underlying a referral to a phase I clinic and eventual trial enrollment. Better selection of patients, appropriate education of referring physicians, and opening phase I trials with fewer restrictions on some criteria such as prior therapy may enhance their recruitment rates