Computational modelling reveals distinct patterns of cognitive and physical motivation in elite athletes

Effort can be perceived both cognitively and physically, but the computational mechanisms underlying the motivation to invest effort in each domain remain unclear. In particular, it is unknown whether intensive physical training is associated with higher motivation specific to that domain, or whether it is accompanied by corresponding changes in cognitive motivation. Here, we tested a group of elite Oxford University rowers, and compared their behaviour to matched non-athletic controls. We trained participants on two tasks involving cognitive or physical effort. They then decided between a baseline low level of effort for low reward, versus higher levels of effort for higher rewards. Separate choices were made for the cognitive and physical tasks, which allowed us to computationally model motivation in each domain independently. As expected, athletes were willing to exert greater amounts of physical effort than non-athletes. Critically, however, the nature of cognitive effort-based decisions was different between groups, with a concave pattern of effort discounting for athletes but a convex pattern for non-athletes. These data suggest that the greater physical drive in athletes is accompanied by fundamentally different patterns of cognitive effort discounting, and suggests a complex relationship between motivation in the two domains

Nonsense Mutations in AAGAB Cause Punctate Palmoplantar Keratoderma Type Buschke-Fischer-Brauer

Punctate palmoplantar keratodermas (PPKPs) are rare autosomal-dominant inherited skin diseases that are characterized by multiple hyperkeratotic plaques distributed on the palms and soles. To date, two different loci in chromosomal regions 15q22-15q24 and 8q24.13-8q24.21 have been reported. Pathogenic mutations, however, have yet to be identified. In order to elucidate the genetic cause of PPKP type Buschke-Fischer-Brauer (PPKP1), we performed exome sequencing in five affected individuals from three families, and we identified in chromosomal region 15q22.33-q23 two heterozygous nonsense mutations—c.370C>T (p.Arg124∗) and c.481C>T (p.Arg161∗)—in AAGAB in all affected individuals. Using immunoblot analysis, we showed that both mutations result in premature termination of translation and truncated protein products. Analyses of mRNA of affected individuals revealed that the disease allele is either not detectable or only detectable at low levels. To assess the consequences of the mutations in skin, we performed immunofluorescence analyses. Notably, the amount of granular staining in the keratinocytes of affected individuals was lower in the cytoplasm but higher around the nucleus than it was in the keratinocytes of control individuals. AAGAB encodes the alpha-and gamma-adaptin-binding protein p34 and might play a role in membrane traffic as a chaperone. The identification of mutations, along with the results from additional studies, defines the genetic basis of PPKP1 and provides evidence that AAGAB plays an important role in skin integrity

Genome-Wide MicroRNA Analysis Implicates miR-30b/d in the Etiology of Alopecia Areata

Alopecia areata (AA) is one of the most common forms of human hair loss. Although genetic studies have implicated autoimmune processes in AA etiology, understanding of the etiopathogenesis is incomplete. Recent research has implicated microRNAs, a class of small noncoding RNAs, in diverse autoimmune diseases. To our knowledge, no study has investigated the role of microRNAs in AA. In this study, gene-based analyses were performed for microRNAs using data of the largest genome-wide association meta-analysis of AA to date. Nominally, significant P -values were obtained for 78 of the 617 investigated microRNAs. After correction for multiple testing, three of the 78 microRNAs remained significant. Of these, miR-30b/d was the most significant microRNA for the follow-up analyses, which also showed lower expression in the hair follicle of AA patients. Target gene analyses for the three microRNAs showed 42 significantly associated target genes. These included IL2RA , TNXB , and ERBB3 , which had been identified as susceptibility loci in previous genome-wide association studies. Using luciferase assay, site-specific miR-30b regulation of the AA risk genes IL2RA, STX17, and TNXB was validated. This study implicates microRNAs in the pathogenesis of AA. This finding may facilitate the development of future treatment strategie

Sex and APOE: A memory advantage in male APOE ε4 carriers in midlife

Short-term memory in middle-aged individuals with different APOE alleles was examined using a recently developed task which is sensitive to medial temporal lobe damage. Individuals (age-range: 40-51 years) with ε3/ε3, ε3/ε4 and ε4/ε4 APOE genotypes (N=60) performed a delayed estimation task with a sensitive continuous measure of report. The paradigm allowed us to measure memory for items and their locations, as well as maintenance of identity-location feature binding in memory. There was a significant gene-dosage dependent effect of the ε4 allele on performance: memory decay or forgetting was slower in ε4 carriers, as measured by localization error and after controlling for misbinding errors. Furthermore ε4 carriers made less misbinding errors. These findings were specific to male carriers only. Thus, male ε4 carriers are at a behavioral advantage in midlife on a sensitive task of short-term memory. The results would be consistent with an antagonistic pleiotropy hypothesis and highlight the interaction of gender on the influence of APOE in cognition