A whole genome screen for association with multiple sclerosis in portuguese patients

Multiple sclerosis (MS) is common in Europe affecting up to 1:500 people. In an effort to identify genes influencing susceptibility to the disease, we have performed a population-based whole genome screen for association. In this study, 6000 microsatellite markers were typed in separately pooled DNA samples from MS patients (n = 188) and matched controls (n = 188). Interpretable data was obtained from 4661 of these markers. Refining analysis of the most promising markers identified 10 showing potential evidence for association.SERONO (Portugal).Fundação para a Ciência e a Tecnologia (FCT) - grant FRH/BD/9111/2002.British Council/ICCTI.Wellcome Trust, Multiple Sclerosis Societies of the United States and Great Britain, Multiple Sclerosis International Federation - GAMES project - grant 057097

(No) Time for Change : When and Why Entrepreneurs Act During Underperforming Fundraising Attempts

Entrepreneurs need to mobilize funds, but they do so under considerable uncertainty about resource holders’ preferences, leading often to fundraising attempts that perform below entrepreneurs’ aspirations. Past research has offered contrasting theorizing and evidence for why entrepreneurs then make changes to their product offering during such attempts as well as for why entrepreneurs refrain from taking such action. This paper develops and tests behavioral theory to reconcile this tension, explicating when and why entrepreneurs change their product offering during underperforming fundraising attempts. Specifically, we argue that entrepreneurs draw on three sources of information that are inherent to fundraising attempts and that inform the extent of their actions to change their product offering: the degree to which they perform below their own fundraising aspirations, the degree to which they fall below peer fundraising performance, and the time that remains until the deadline for the fundraising attempt. Longitudinal data on 576 fundraising campaigns (6,758 observations) published on the crowdfunding platform Kickstarter support our theory. By developing novel behavioral theory on when and why entrepreneurs take action during resource mobilization, we offer contributions to research on entrepreneurial resource mobilization, the crowdfunding literature, and the Behavioral Theory of the Firm.© 2023 The Author(s). This work is licensed under a Creative Commons Attribution-NonCommercialNoDerivatives 4.0 International License. You are free to download this work and share with others, but cannot change in any way or use commercially without permission, and you must attribute this work as Organization Science. https://doi.org/10.1287/orsc.2020.13803, used under a Creative Commons Attribution License: https://creativecommons.org/licenses/by-nc-nd/4.0/.fi=vertaisarvioitu|en=peerReviewed

Understanding Interorganizational Learning Based on Social Spaces and Learning Episodes

Different organizational settings have been gaining ground in the world economy, resulting in a proliferation of different forms of strategic alliances that translate into a growth in the number of organizations that have started to deal with interorganizational relationships with different actors. These circumstances reinforce Crossan, Lane, White and Djurfeldt (1995) and Crossan, Mauer and White (2011) in exploring what authors refer to as the fourth, interorganizational, level of learning. These authors, amongst others, suggest that the process of interorganizational learning (IOL) warrants investigation, as its scope of analysis needs widening and deepening. Therefore, this theoretical essay is an attempt to understand IOL as a dynamic process found in interorganizational cooperative relationships that can take place in different structured and unstructured social spaces and that can generate learning episodes. According to this view, IOL is understood as part of an organizational learning continuum and is analyzed within the framework of practical rationality in an approach that is less cognitive and more social-behavioral

Variants of ST8SIA1 Are Associated with Risk of Developing Multiple Sclerosis

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system of unknown etiology with both genetic and environmental factors playing a role in susceptibility. To date, the HLA DR15/DQ6 haplotype within the major histocompatibility complex on chromosome 6p, is the strongest genetic risk factor associated with MS susceptibility. Additional alleles of IL7 and IL2 have been identified as risk factors for MS with small effect. Here we present two independent studies supporting an allelic association of MS with polymorphisms in the ST8SIA1 gene, located on chromosome 12p12 and encoding ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 1. The initial association was made in a single three-generation family where a single-nucleotide polymorphism (SNP) rs4762896, was segregating together with HLA DR15/DQ6 in MS patients. A study of 274 family trios ( affected child and both unaffected parents) from Australia validated the association of ST8SIA1 in individuals with MS, showing transmission disequilibrium of the paternal alleles for three additional SNPs, namely rs704219, rs2041906, and rs1558793, with p = 0.001, p = 0.01 and p = 0.01 respectively. These findings implicate ST8SIA1 as a possible novel susceptibility gene for MS

HLA-class I markers and multiple sclerosis susceptibility in the Italian population

Previous studies reported an association with multiple sclerosis (MS) of distinct HLA-class I markers, namely HLA-A*02, HLA-Cw*05 and MOG-142L. In this work, we tested the association with MS of A*02 and Cw*05 in 1273 Italian MS patients and 1075 matched controls, which were previously analyzed for MOG-142, and explored the relationship among these three markers in modulating MS risk. HLA-A*02 conferred a statistically robust MS protection (odds ratio, OR=0.61; 95% confidence intervals, CI=0.51–0.72, P<10−9), which was independent of DRB1*15 and of any other DRB1* allele and remained similar after accounting for the other two analyzed class I markers. Conversely, the protective effect we previously observed for MOG-142L was secondary to its linkage disequilibrium with A*02. Cw*05 was not associated considering the whole sample, but its presence significantly enhanced the protection in the HLA-A*02-positive group, independently of DRB1: the OR conferred by A*02 in Cw*05-positive individuals (0.22, 95% CI=0.13–0.38) was significantly lower than in Cw*05-negative individuals (0.69, 95% CI=0.58–0.83) with a significant (P=4.94 × 10−5) multiplicative interaction between the two markers. In the absence of A*02, Cw*05 behaved as a risk factor, particularly in combination with DRB1*03 (OR=3.89, P=0.0006), indicating that Cw*05 might be a marker of protective or risk haplotypes, respectively

The regularized visible fold revisited

The planar visible fold is a simple singularity in piecewise smooth systems. In this paper, we consider singularly perturbed systems that limit to this piecewise smooth bifurcation as the singular perturbation parameter $\epsilon\rightarrow 0$. Alternatively, these singularly perturbed systems can be thought of as regularizations of their piecewise counterparts. The main contribution of the paper is to demonstrate the use of consecutive blowup transformations in this setting, allowing us to obtain detailed information about a transition map near the fold under very general assumptions. We apply this information to prove, for the first time, the existence of a locally unique saddle-node bifurcation in the case where a limit cycle, in the singular limit $\epsilon\rightarrow 0$, grazes the discontinuity set. We apply this result to a mass-spring system on a moving belt described by a Stribeck-type friction law

Development and Validation of a New Method to Measure Walking Speed in Free-Living Environments Using the Actibelt® Platform

Walking speed is a fundamental indicator for human well-being. In a clinical setting, walking speed is typically measured by means of walking tests using different protocols. However, walking speed obtained in this way is unlikely to be representative of the conditions in a free-living environment. Recently, mobile accelerometry has opened up the possibility to extract walking speed from long-time observations in free-living individuals, but the validity of these measurements needs to be determined. In this investigation, we have developed algorithms for walking speed prediction based on 3D accelerometry data (actibelt®) and created a framework using a standardized data set with gold standard annotations to facilitate the validation and comparison of these algorithms. For this purpose 17 healthy subjects operated a newly developed mobile gold standard while walking/running on an indoor track. Subsequently, the validity of 12 candidate algorithms for walking speed prediction ranging from well-known simple approaches like combining step length with frequency to more sophisticated algorithms such as linear and non-linear models was assessed using statistical measures. As a result, a novel algorithm employing support vector regression was found to perform best with a concordance correlation coefficient of 0.93 (95%CI 0.92–0.94) and a coverage probability CP1 of 0.46 (95%CI 0.12–0.70) for a deviation of 0.1 m/s (CP2 0.78, CP3 0.94) when compared to the mobile gold standard while walking indoors. A smaller outdoor experiment confirmed those results with even better coverage probability. We conclude that walking speed thus obtained has the potential to help establish walking speed in free-living environments as a patient-oriented outcome measure

MYO9B polymorphisms in multiple sclerosis

"Single-nucleotide polymorphisms (SNPs) in the 30 region of myosin IXB (MYO9B) gene have recently been reported to associate with different inflammatory or autoimmune diseases. We monitored for the association of MYO9B variants to multiple sclerosis (MS) in four Northern European populations. First, 18 SNPs including 6 SNPs with previous evidence for association to immune disorders, were tested in 730 Finnish MS families, but no linkage or family-based association was observed. To ensure the power to detect variants with a modest effect size, we further analyzed 10 variants in 899 Finnish cases and 1325 controls, and in a total of 1521 cases and 1476 controls from Denmark, Norway and Sweden, but found no association. Our results thereby do not support a major function of the tested MYO9B variants in MS. European Journal of Human Genetics (2009) 17, 840-843; doi: 10.1038/ejhg.2008.251; published online 14 January 2009""Single-nucleotide polymorphisms (SNPs) in the 30 region of myosin IXB (MYO9B) gene have recently been reported to associate with different inflammatory or autoimmune diseases. We monitored for the association of MYO9B variants to multiple sclerosis (MS) in four Northern European populations. First, 18 SNPs including 6 SNPs with previous evidence for association to immune disorders, were tested in 730 Finnish MS families, but no linkage or family-based association was observed. To ensure the power to detect variants with a modest effect size, we further analyzed 10 variants in 899 Finnish cases and 1325 controls, and in a total of 1521 cases and 1476 controls from Denmark, Norway and Sweden, but found no association. Our results thereby do not support a major function of the tested MYO9B variants in MS. European Journal of Human Genetics (2009) 17, 840-843; doi: 10.1038/ejhg.2008.251; published online 14 January 2009""Single-nucleotide polymorphisms (SNPs) in the 30 region of myosin IXB (MYO9B) gene have recently been reported to associate with different inflammatory or autoimmune diseases. We monitored for the association of MYO9B variants to multiple sclerosis (MS) in four Northern European populations. First, 18 SNPs including 6 SNPs with previous evidence for association to immune disorders, were tested in 730 Finnish MS families, but no linkage or family-based association was observed. To ensure the power to detect variants with a modest effect size, we further analyzed 10 variants in 899 Finnish cases and 1325 controls, and in a total of 1521 cases and 1476 controls from Denmark, Norway and Sweden, but found no association. Our results thereby do not support a major function of the tested MYO9B variants in MS. European Journal of Human Genetics (2009) 17, 840-843; doi: 10.1038/ejhg.2008.251; published online 14 January 2009"Peer reviewe

Investigation of the Role of Mitochondrial DNA in Multiple Sclerosis Susceptibility

Several lines of evidence suggest that mitochondrial genetic factors may influence susceptibility to multiple sclerosis. To explore this hypothesis further, we re-sequenced the mitochondrial genome (mtDNA) from 159 patients with multiple sclerosis and completed a haplogroup analysis including a further 835 patients and 1,506 controls. A trend towards over-representation of super-haplogroup U was the only evidence for association with mtDNA that we identified in these samples. In a parallel analysis of nuclear encoded mitochondrial genes, we also found a trend towards association with the complex I gene, NDUFS2. These results add to the evidence suggesting that variation in mtDNA and nuclear encoded mitochondrial genes may contribute to disease susceptibility in multiple sclerosis