Fine mapping and functional analysis of the multiple sclerosis risk gene CD6

CD6 has recently been identified and validated as risk gene for multiple sclerosis (MS), based on the association of a single nucleotide polymorphism (SNP), rs17824933, located in intron 1. CD6 is a cell surface scavenger receptor involved in T-cell activation and proliferation, as well as in thymocyte differentiation. In this study, we performed a haptag SNP screen of the CD6 gene locus using a total of thirteen tagging SNPs, of which three were non-synonymous SNPs, and replicated the recently reported GWAS SNP rs650258 in a Spanish-Basque collection of 814 controls and 823 cases. Validation of the six most strongly associated SNPs was performed in an independent collection of 2265 MS patients and 2600 healthy controls. We identified association of haplotypes composed of two non-synonymous SNPs [rs11230563 (R225W) and rs2074225 (A257V)] in the 2nd SRCR domain with susceptibility to MS (Pmax(T) permutation=161024). The effect of these haplotypes on CD6 surface expression and cytokine secretion was also tested. The analysis showed significantly different CD6 expression patterns in the distinct cell subsets, i.e. – CD4+ naı¨ve cells, P = 0.0001; CD8+ naı¨ve cells, P,0.0001; CD4+ and CD8+ central memory cells, P = 0.01 and 0.05, respectively; and natural killer T (NKT) cells, P = 0.02; with the protective haplotype (RA) showing higher expression of CD6. However, no significant changes were observed in natural killer (NK) cells, effector memory and terminally differentiated effector memory T cells. Our findings reveal that this new MS-associated CD6 risk haplotype significantly modifies expression of CD6 on CD4+ and CD8+ T cells.

BAMS: A Tool for Supervised Burned Area Mapping Using Landsat Data

A new supervised burned area mapping software named BAMS (Burned Area Mapping Software) is presented in this paper. The tool was built from standard ArcGIS (TM) libraries. It computes several of the spectral indexes most commonly used in burned area detection and implements a two-phase supervised strategy to map areas burned between two Landsat multitemporal images. The only input required from the user is the visual delimitation of a few burned areas, from which burned perimeters are extracted. After the discrimination of burned patches, the user can visually assess the results, and iteratively select additional sampling burned areas to improve the extent of the burned patches. The final result of the BAMS program is a polygon vector layer containing three categories: (a) burned perimeters, (b) unburned areas, and (c) non-observed areas. The latter refer to clouds or sensor observation errors. Outputs of the BAMS code meet the requirements of file formats and structure of standard validation protocols. This paper presents the tool's structure and technical basis. The program has been tested in six areas located in the United States, for various ecosystems and land covers, and then compared against the National Monitoring Trends in Burn Severity (MTBS) Burned Area Boundaries Dataset.

Epitope mapping of antibodies to alpha-synuclein in LRRK2 mutation carriers, idiopathic Parkinson disease patients, and healthy controls

Alpha-synuclein (Snca) plays a major role in Parkinson disease (PD). Circulating anti-Snca antibodies has been described in PD patients and healthy controls, but they have been poorly characterized. This study was designed to assess the prevalence of anti-Snca reactivity in human subjects carrying the LRRK2 mutation, idiopathic PD (iPD) patients, and healthy controls and to map the epitopes of the anti-Snca antibodies. Antibodies to Snca were detected by ELISA and immunoblotting using purified recombinant Snca in plasma from individuals carrying LRRK2 mutations (104), iPD patients (59), and healthy controls (83). Epitopes of antibodies were mapped using recombinant protein constructs comprising different regions of Snca. Clear positive anti-Snca reactivity showed no correlation with age, sex, years of evolution, or the disability scores for PD patients and anti-Snca reactivity was not prevalent in human patients with other neurological or autoimmune diseases. Thirteen of the positive individuals were carriers of LRRK2 mutations either non-manifesting (8 out 49 screened) or manifesting (5 positive out 55), three positive (out of 59) were iPD patients, and five positive (out of 83) were healthy controls. Epitope mapping showed that antibodies against the N-terminal (a.a. 1-60) or C-terminal (a.a. 109-140) regions of Snca predominate in LRRK2 mutation carriers and iPD patients, being N122 a critical amino acid for recognition by the anti-C-terminal directed antibodies. Anti-Snca circulating antibodies seem to cluster within families carrying the LRRK2 mutation indicating possible genetic or common environmental factors in the generation of anti-Snca antibodies. These results suggest that case-controls' studies are insufficient and further studies in family cohorts of patients and healthy controls should be undertaken, to progress in the understanding of the possible relationship of anti-Snca antibodies and PD patholog

On Best Proximity Point Theorems and Fixed Point Theorems for p-Cyclic Hybrid Self-Mappings in Banach Spaces

This paper relies on the study of fixed points and best proximity points of a class of so-called generalized point-dependent (K-Lambda)hybrid p-cyclic self-mappings relative to a Bregman distance Df, associated with a Gâteaux differentiable proper strictly convex function f in a smooth Banach space, where the real functions Lambda and K quantify the point-to-point hybrid and nonexpansive (or contractive) characteristics of the Bregman distance for points associated with the iterations through the cyclic self-mapping.Weak convergence results to weak cluster points are obtained for certain average sequences constructed with the iterates of the cyclic hybrid self-mappings.

Some Results on Fixed and Best Proximity Points of Multivalued

This paper is devoted to investigate the fixed points and best proximity points of multivalued cyclic self-mappings on a set of subsets of complete metric spaces endowed with a partial order under a generalized contractive condition involving a Hausdorff distance. The existence and uniqueness of fixed points of both the cyclic self-mapping and its associate composite self-mappings on each of the subsets are investigated, if the subsets in the cyclic disposal are nonempty, bounded and of nonempty convex intersection. The obtained results are extended to the existence of unique best proximity points in uniformly convex Banach spaces.

An Open and Social Spaced Repetition System for Language Learning

In the last decades big improvements have been done in the field of computer aided learning, based on improvements done in computer science and computer systems. Although the field has been always a bit lagged, without using the latest solutions, it has constantly gone forward taking profit of the innovations as they show up. As long as the train of the computer science does not stop (and it won’t at least in the near future) the systems that take profit of those improvements will not either, because we humans will always need to study; Sometimes for pleasure and some other many times out of need. Not all the attempts in the field of computer aided learning have been in the same direction. Most of them address one or some few of the problems that show while studying and don’t take into account solutions proposed for some other problems. The reasons for this can be varied. Sometimes the solutions simply are not compatible. Some other times, because the project is an investigation it’s interesting to isolate the problem. And, in commercial products, licenses and patents often prevent the new projects to use previous work. The world moved forward and this is an attempt to use some of the options offered by technology, mixing some old ideas with new ones.

Thrombotic Antiphospholipid Syndrome Shows Strong Haplotypic Association with SH2B3-ATXN2 Locus

Background : Thrombotic antiphospholipid syndrome is defined as a complex form of thrombophilia that is developed by a fraction of antiphospholipid antibody (aPLA) carriers. Little is known about the genetic risk factors involved in thrombosis development among aPLA carriers. Methods: To identify new loci conferring susceptibility to thrombotic antiphospholipid syndrome, a two-stage genotyping strategy was performed. In stage one, 19,000 CNV loci were genotyped in 14 thrombotic aPLA+ patients and 14 healthy controls by array-CGH. In stage two, significant CNV loci were fine-mapped in a larger cohort (85 thrombotic aPLA+, 100 non-thrombotic aPLA+ and 569 healthy controls). Results : Array-CGH and fine-mapping analysis led to the identification of 12q24.12 locus as a new susceptibility locus for thrombotic APS. Within this region, a TAC risk haplotype comprising one SNP in SH2B3 gene (rs3184504) and two SNPs in ATXN2 gene (rs10774625 and rs653178) exhibited the strongest association with thrombotic antiphospholipid syndrome (p-value = 5,9 × 10−4 OR 95% CI 1.84 (1.32–2.55)). Conclusion : The presence of a TAC risk haplotype in ATXN2-SH2B3 locus may contribute to increased thrombotic risk in aPLA carriers.

Open Personalization: Involving Third Parties in Improving the User Experience of Websites

Traditional software development captures the user needs during the requirement analysis. The Web makes this endeavour even harder due to the difficulty to determine who these users are. In an attempt to tackle the heterogeneity of the user base, Web Personalization techniques are proposed to guide the users’ experience. In addition, Open Innovation allows organisations to look beyond their internal resources to develop new products or improve existing processes. This thesis sits in between by introducing Open Personalization as a means to incorporate actors other than webmasters in the personalization of web applications. The aim is to provide the technological basis that builds up a trusty environment for webmasters and companion actors to collaborate, i.e. "an architecture of participation". Such architecture very much depends on these actors’ profile. This work tackles three profiles (i.e. software partners, hobby programmers and end users), and proposes three "architectures of participation" tuned for each profile. Each architecture rests on different technologies: a .NET annotation library based on Inversion of Control for software partners, a Modding Interface in JavaScript for hobby programmers, and finally, a domain specific language for end-users. Proof-of-concept implementations are available for the three cases while a quantitative evaluation is conducted for the domain specific language.

Enhanced Operation of Electricity Distribution Grids Through Smart Metering PLC Network Monitoring, Analysis and Grid Conditioning

Low Voltage (LV) electricity distribution grid operations can be improved through a combination of new smart metering systems' capabilities based on real time Power Line Communications (PLC) and LV grid topology mapping. This paper presents two novel contributions. The first one is a new methodology developed for smart metering PLC network monitoring and analysis. It can be used to obtain relevant information from the grid, thus adding value to existing smart metering deployments and facilitating utility operational activities. A second contribution describes grid conditioning used to obtain LV feeder and phase identification of all connected smart electric meters. Real time availability of such information may help utilities with grid planning, fault location and a more accurate point of supply management.

The basque ecological debt: global socioecological impacts of a small open economy

4 p.

Towards a Comprehensive Approach to Quantifying and Mapping Ecosystem Services Flows

25 p.

Properties of convergence of a class of iterative processes generated by sequences of self-mappings with applications to switched dynamic systems

This article investigates the convergence properties of iterative processes involving sequences of self-mappings of metric or Banach spaces. Such sequences are built from a set of primary self-mappings which are either expansive or non-expansive self-mappings and some of the non-expansive ones can be contractive including the case of strict contractions. The sequences are built subject to switching laws which select each active self-mapping on a certain activation interval in such a way that essential properties of boundedness and convergence of distances and iterated sequences are guaranteed. Applications to the important problem of stability of dynamic switched systems are also given.

Physiological modules for generating discrete and rhythmic movements: action identification by a dynamic recurrent neural network

In this study we employed a dynamic recurrent neural network (DRNN) in a novel fashion to reveal characteristics of control modules underlying the generation of muscle activations when drawing figures with the outstretched arm. We asked healthy human subjects to perform four different figure-eight movements in each of two workspaces (frontal plane and sagittal plane). We then trained a DRNN to predict the movement of the wrist from information in the EMG signals from seven different muscles. We trained different instances of the same network on a single movement direction, on all four movement directions in a single movement plane, or on all eight possible movement patterns and looked at the ability of the DRNN to generalize and predict movements for trials that were not included in the training set. Within a single movement plane, a DRNN trained on one movement direction was not able to predict movements of the hand for trials in the other three directions, but a DRNN trained simultaneously on all four movement directions could generalize across movement directions within the same plane. Similarly, the DRNN was able to reproduce the kinematics of the hand for both movement planes, but only if it was trained on examples performed in each one. As we will discuss, these results indicate that there are important dynamical constraints on the mapping of EMG to hand movement that depend on both the time sequence of the movement and on the anatomical constraints of the musculoskeletal system. In a second step, we injected EMG signals constructed from different synergies derived by the PCA in order to identify the mechanical significance of each of these components. From these results, one can surmise that discrete-rhythmic movements may be constructed from three different fundamental modules, one regulating the co-activation of all muscles over the time span of the movement and two others elliciting patterns of reciprocal activation operating in orthogonal directions.

Results on proximal and generalized weak proximal contractions including the case of iteration-dependent range sets

This paper presents some further results on proximal and asymptotic proximal contractions and on a class of generalized weak proximal contractions in metric spaces. The generalizations are stated for non-self-mappings of the forms for and , or , subject to and , such that converges uniformly to T, and the distances are iteration-dependent, where , , and are non-empty subsets of X, for , where is a metric space, provided that the set-theoretic limit of the sequences of closed sets and exist as and that the countable infinite unions of the closed sets are closed. The convergence of the sequences in the domain and the image sets of the non-self-mapping, as well as the existence and uniqueness of the best proximity points, are also investigated if the metric space is complete. Two application examples are also given, being concerned, respectively, with the solutions through pseudo-inverses of both compatible and incompatible linear algebraic systems and with the parametrical

Density-potential mapping in the standard and quantum electrodynamical time-dependent density functional theory

131 p.