Genetic determination of exocrine pancreatic function in cystic fibrosis

We showed elsewhere that the pancreatic function status of cystic fibrosis (CF) patients could be correlated to mutations in the CF transmembrane conductance regulator (CFTR) gene. Although the majority of CF mutations- including the most common, ΔF508-strongly correlated with pancreatic insufficiency (PI), approximately 10% of the mutant alleles may confer pancreatic sufficiency (PS). To extend this observation, genomic DNA of 538 CF patients with well-documented pancreatic function status were analyzed for a series of known mutations in their CFTR genes. Only 20 of the 25 mutations tested were found in this population. They accounted for 84% of the CF chromosomes, with ΔF508 being the most frequent (71%), and the other mutations accounted for less than 5% each. A total of 30 different, complete genotypes could be determined in 394 (73%) of the patients. The data showed that each genotype was associated only with PI or only with PS, but not with both. This result is thus consistent with the hypothesis that PI and PS in CF are predisposed by the genotype at the CFTR locus; the PS phenotype occurs in patients who have one or two mild CFTR mutations, such as R117H, R334W, R347P, A455E, and P574H, whereas the PI phenotype occurs in patients with two severe alleles, such as ΔF508, ΔI507, Q493X, G542X, R553X, W1282X, 621 + 1G→T, 1717-1G→A, 556delA, 3659delC, I148T, G480C, V520F, G551D, and R560T.published_or_final_versio

Genetic specification of left-right asymmetry in the diaphragm muscles and their motor innervation.

The diaphragm muscle is essential for breathing in mammals. Its asymmetric elevation during contraction correlates with morphological features suggestive of inherent left-right (L/R) asymmetry. Whether this asymmetry is due to L versus R differences in the muscle or in the phrenic nerve activity is unknown. Here, we have combined the analysis of genetically modified mouse models with transcriptomic analysis to show that both the diaphragm muscle and phrenic nerves have asymmetries, which can be established independently of each other during early embryogenesis in pathway instructed by Nodal, a morphogen that also conveys asymmetry in other organs. We further found that phrenic motoneurons receive an early L/R genetic imprint, with L versus R differences both in Slit/Robo signaling and MMP2 activity and in the contribution of both pathways to establish phrenic nerve asymmetry. Our study therefore demonstrates L-R imprinting of spinal motoneurons and describes how L/R modulation of axon guidance signaling helps to match neural circuit formation to organ asymmetry

Cohabitation : the Pan-America View

In this concluding chapter we reflect on a series of issues of both a methodological and substantive nature encountered in this research project. Firstly, we must realize that the use of individual census records not only opened vast possibilities, but also entails a number of limitations. Secondly, the very large sample sizes allowed for the disaggregation of national trends into far more detailed spatial, ethnic and educational patterns. This, in its turn, allowed us to adopt a "geo-historical" view of the rise of cohabitation for almost the entire American continent, from Alaska to Tierra del Fuego. Furthermore, statistical analyses could be performed at the individual and contextual levels simultaneously. Results show that the effects of social stratification, religion and ethnicity are continuing to be of major importance. This not only holds at the individual level, but at the contextual level as well. Nevertheless, an entirely new wave of change started rolling over the pre-existing patterns from the 1970s onward. These trends are following a firm course, irrespective of the economic ups and downs. The Americas, as opposed to many Asian societies and Africa, are now following in the European footsteps, be it with their own distinct and path-dependent characteristics associated with regionally varying historical antecedents

Influencers in Multiplayer Online Shooters Evidence of Social Contagion in Playtime and Social Play

In a wide range of social networks, people’s behavior is influenced by social contagion: we do what our network does. Networks often feature particularly influential individuals, commonly called influencers. Existing work suggests that in-game social networks in online games are similar to real life social networks in many respects. However, we do not know whether there are in-game equivalents to influencers. We therefore applied standard social network features used to identify influencers to the online multiplayer shooter Tom Clancy’s The Division. Results show that network features defined influencers had indeed an outsized impact on playtime and social play of players joining their in-game network

SURF1 deficiency causes demyelinating Charcot-Marie-Tooth disease

Objective: To investigate whether mutations in the SURF1 gene are a cause of Charcot-Marie-Tooth (CMT) disease. Methods: We describe 2 patients from a consanguineous family with demyelinating autosomal recessive CMT disease (CMT4) associated with the homozygous splice site mutation c.107-2A>G in the SURF1 gene, encoding an assembly factor of the mitochondrial respiratory chain complex IV. This observation led us to hypothesize that mutations in SURF1 might be an unrecognized cause of CMT4, and we investigated SURF1 in a total of 40 unrelated patients with CMT4 after exclusion of mutations in known CMT4 genes. The functional impact of c.107-2A>G on splicing, amount of SURF1 protein, and on complex IV activity and assembly was analyzed. Results: Another patient with CMT4 was found to harbor 2 additional SURF1 mutations. All 3 patients with SURF1-associated CMT4 presented with severe childhood-onset neuropathy, motor nerve conduction velocities G mutation produced no normally spliced transcript, leading to SURF1 absence. However, complex IV remained partially functional in muscle and fibroblasts. Conclusions: We found SURF1 mutations in 5% of families (2/41) presenting with CMT4. SURF1 should be systematically screened in patients with childhood-onset severe demyelinating neuropathy and additional features such as lactic acidosis, brain MRI abnormalities, and cerebellar ataxia developing years after polyneuropathy