Mutations causing expansions of polyalanine domains are responsible for nine hereditary diseases. Other GC-rich sequences coding for some polyalanine domains were found to be polymorphic in human. These observations prompted us to identify all sequences in the human genome coding for polyalanine stretches longer than four alanines and establish their degree of polymorphism. We identified 494 annotated human proteins containing 604 polyalanine domains. Thirty-two percent (31/98) of tested sequences coding for more than seven alanines were polymorphic. The length of the polyalanine-coding sequence and its GCG or GCC repeat content are the major predictors of polymorphism. GCG codons are over-represented in human polyalanine coding sequences. Our data suggest that GCG and GCC codons play a key role in polyalanine-coding sequence appearance and polymorphism. The grouping by shared function of polyalanine-containing proteins in Homo sapiens, Drosophila melanogaster and Caenorhabditis elegans shows that the majority are involved in transcriptional regulation. Phylogenetic analyses of HOX, GATA and EVX protein families demonstrate that polyalanine domains arose independently in different members of these families, suggesting that convergent molecular evolution may have played a role. Finally polyalanine domains in vertebrates are conserved between mammals and are rarer and shorter in Gallus gallus and Danio rerio. Together our results show that the polymorphic nature of sequences coding for polyalanine domains makes them prime candidates for mutations in hereditary diseases and suggests that they have appeared in many different protein families through convergent evolution.
This randomized clinical trial compared cognitive-behavioral therapy (CBT), applied relaxation (AR), and wait-list control (WL) in a sample of 65 adults with a primary diagnosis of generalized anxiety disorder (GAD). The CBT condition was based on the intolerance of uncertainty model of GAD, whereas the AR condition was based on general theories of anxiety. Both manualized treatments were administered over 12 weekly 1-hour sessions. Standardized clinician ratings and self-report questionnaires were used to assess GAD and related symptoms at pretest, posttest, and at 6-, 12-, and 24-month follow-ups. At posttest, CBT was clearly superior to WL, AR was marginally superior to WL, and CBT was marginally superior to AR. Over follow-up, CBT and AR were equivalent, but only CBT led to continued improvement. Thus, direct comparisons of CBT and AR indicated that the treatments were comparable; however, comparisons of each treatment with another point of reference (either waiting list or no change over follow-up) provided greater support for the efficacy of CBT than AR.
Over the past decade, a number of well-controlled studies have supported the validity of a cognitive model of generalized anxiety disorder (GAD) that has four main components: intolerance of uncertainty, positive beliefs about worry, negative problem orientation, and cognitive avoidance. Although these studies have shown that the model components are associated with high levels of worry in nonclinical samples and with a diagnosis of GAD in clinical samples, they have not addressed the question of whether the model components can predict the severity of GAD. Accordingly, the present study sought to determine if the model components are related to diagnostic severity, worry severity, and somatic symptom severity in a sample of 84 patients with a primary diagnosis of GAD. All model components were related to GAD severity, although positive beliefs about worry and cognitive avoidance were only modestly associated with the severity of the disorder. Intolerance of uncertainty and negative problem orientation had more robust relationships with the severity of GAD (and with worry severity, in particular). When participants were divided into Mild, Moderate, and Severe GAD groups, intolerance of uncertainty and negative problem orientation distinguished the Moderate and Severe GAD groups from the Mild GAD group, even when age, gender, and depressive symptoms were statistically controlled. Overall, the results lend further support to the validity of the model and suggest that intolerance of uncertainty and negative problem orientation are related to the severity of GAD, independently of sociodemographic and associated clinical factors. The theoretical and clinical implications of the findings are discussed.
In two visuospatial working memory (VSWM) span experiments, older and young participants were tested under conditions of either high or low interference, using two different displays: computerized versions of a 3 ϫ 3 matrix or the standard (randomly arrayed) Corsi block task (P. M. Corsi, 1972). Older adults' VSWM estimates were increased in the low-interference, compared with the high-interference, condition, replicating findings with verbal memory span studies. Young adults showed the opposite pattern, and together the findings suggest that typical VSWM span tasks include opposing components (interference and practice) that differentially affect young and older adults.
Two experiments examined age-related differences in sequence learning using computerized versions of the D. O. Hebb (1961) paradigm. In this learning task, the participant executes immediate serial recall of 24 supraspan sequences. Without the participants' knowledge, 1 sequence is presented several times. Repetition leads to improved recall of this repeated sequence relative to random sequences. Results showed a dissociation in age-related learning deficits depending on the nature of the to-be-remembered material. The effect of repetition is similar for younger and older adults with familiar and unfamiliar verbal material (words and pseudowords) but is significantly reduced in older adults when learning is assessed with a visuospatial version of Hebb's supraspan learning task (P. M. Corsi, 1972).
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