Role of the repeat expansion size in predicting age of onset and severity in RFC1 disease

RFC1 disease, caused by biallelic repeat expansion in RFC1, is clinically heterogeneous in terms of age of onset, disease progression and phenotype. We investigated the role of the repeat size in influencing clinical variables in RFC1 disease. We also assessed the presence and role of meiotic and somatic instability of the repeat. In this study, we identified 553 patients carrying biallelic RFC1 expansions and measured the repeat expansion size in 392 cases. Pearson’s coefficient was calculated to assess the correlation between the repeat size and age at disease onset. A Cox model with robust cluster standard errors was adopted to describe the effect of repeat size on age at disease onset, on age at onset of each individual symptoms, and on disease progression. A quasi-Poisson regression model was used to analyse the relationship between phenotype and repeat size. We performed multivariate linear regression to assess the association of the repeat size with the degree of cerebellar atrophy. Meiotic stability was assessed by Southern blotting on first-degree relatives of 27 probands. Finally, somatic instability was investigated by optical genome mapping on cerebellar and frontal cortex and unaffected peripheral tissue from four post-mortem cases. A larger repeat size of both smaller and larger allele was associated with an earlier age at neurological onset [smaller allele hazard ratio (HR) = 2.06, P < 0.001; larger allele HR = 1.53, P < 0.001] and with a higher hazard of developing disabling symptoms, such as dysarthria or dysphagia (smaller allele HR = 3.40, P < 0.001; larger allele HR = 1.71, P = 0.002) or loss of independent walking (smaller allele HR = 2.78, P < 0.001; larger allele HR = 1.60; P < 0.001) earlier in disease course. Patients with more complex phenotypes carried larger expansions [smaller allele: complex neuropathy rate ratio (RR) = 1.30, P = 0.003; cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) RR = 1.34, P < 0.001; larger allele: complex neuropathy RR = 1.33, P = 0.008; CANVAS RR = 1.31, P = 0.009]. Furthermore, larger repeat expansions in the smaller allele were associated with more pronounced cerebellar vermis atrophy (lobules I–V β = −1.06, P < 0.001; lobules VI–VII β = −0.34, P = 0.005). The repeat did not show significant instability during vertical transmission and across different tissues and brain regions. RFC1 repeat size, particularly of the smaller allele, is one of the determinants of variability in RFC1 disease and represents a key prognostic factor to predict disease onset, phenotype and severity. Assessing the repeat size is warranted as part of the diagnostic test for RFC1 expansion

How are we creative together?: comparing sociocognitive and sociocultural answers

The present article aims to distinguish between a sociocognitive and a sociocultural approach to forms of “collective” creativity. While the first is well-illustrated by studies of group or team creativity, the second has generally supported investigations of collaborative creativity, most of them performed in the last few decades. The comparison between these two fields takes different levels into account, from the epistemological position adopted to issues concerning the theories and methods used. Special attention is given to reviewing models of creativity. However, although the literature on group creativity contains several cognitive models, there is a scarcity of such constructions for collaborative creativity. This is why a secondary aim of this material is to introduce a sociocultural theoretical framework and discuss its implications for developing situated models of creativity. In the end, the similarities and differences between the two paradigms are examined with reference to both theory and research and arguments are given for why it would be beneficial for sociocognitivists and socioculturalists to engage in a more consistent dialogue

The ‘Relay Ideation’ Technique: Moving from Problem Understanding to Problem Solving in the Design Process

Part 2: Interactive PostersInternational audienceWhen describing the design process in product innovation, many authors identify phases that can be described as ‘problem analysis’ and ‘generating ideas’. Several techniques are available to support design teams in each of these phases, but it remains a challenge to move from understanding a problem to coming up with ideas for concepts that might solve the problem. In addition, some of these techniques have counterproductive social side effects, which in fact may impede creativity in a design team. In this paper we describe a new technique for product idea generation called the ‘relay ideation’ technique. This technique was developed to help design teams move from understanding a problem to thinking creatively and concretely about the problem in order to generate concepts for innovative products or services. The technique is illustrated with a case study about IT applications for hearing-impaired children

Na+/H+ exchanger blockade inhibits enterocyte inflammatory response and protects against colitis

Na+/H+exchangers (NHEs) are integral transmembrane proteins found in all mammalian cells. There is substantial evidence indicating that NHEs regulate inflammatory processes. Because intestinal epithelial cells express a variety of NHEs, we tested the possibility that NHEs are also involved in regulation of the epithelial cell inflammatory response. In addition, since the epithelial inflammatory response is an important contributor to mucosal inflammation in inflammatory bowel disease (IBD), we examined the role of NHEs in the modulation of disease activity in a mouse model of IBD. In human gut epithelial cells, NHE inhibition using a variety of agents, including amiloride, 5-( N-methyl- N-isobutyl)amiloride, 5-( N-ethyl- N-isopropyl)- amiloride, harmaline, clonidine, and cimetidine, suppressed interleukin-8 (IL-8) production. The inhibitory effect of NHE inhibition on IL-8 was associated with a decrease in IL-8 mRNA accumulation. NHE inhibition suppressed both activation of the p42/p44 mitogen-activated protein kinase and nuclear factor-κB. Finally, NHE inhibition ameliorated the course of IBD in dextran sulfate-treated mice. Our data demonstrate that inhibition of NHEs may be an approach worthy of pursuing for the treatment of IBD.</jats:p