Motor coordination, working memory, and academic achievement in a normative adolescent sample: Testing a mediation model

The aim of the present study was to examine whether the relationship between motor coordination and academic achievement is mediated by working memory (WM) in a normative adolescent sample. Participants included 93 adolescents aged 12–16. The Movement Assessment Battery for Children-2 provided three indicators of motor coordination (Manual Dexterity, Aiming and Catching, and Balance), the WM Index of the Wechsler Intelligence Scale for Children-IV and the N-back paradigm provided two indicators of WM, and the Wechsler Individual Achievement Test-II provided three indicators of academic achievement (Word Reading, Spelling, and Numerical Operations). Structural equation modeling, controlling for verbal comprehension, attention deficit hyperactivity disorder symptoms, and socioeconomic status, suggested that the association between motor coordination and academic achievement may be best understood in terms of a mechanism whereby motor coordination (specifically, Aiming and Catching skills) has an indirect impact on academic outcomes via WM. These findings have important implications for the assessment and treatment of motor coordination and learning difficulties as well as in increasing the understanding of the possible neural mechanisms underpinning the relationship between these areas

Cognitive endpoints for therapy development for neuronopathic mucopolysaccharidoses: Results of a consensus procedure

The design and conduct of clinical studies to evaluate the effects of novel therapies on central nervous system manifestations in children with neuronopathic mucopolysaccharidoses is challenging. Owing to the rarity of these disorders, multinational studies are often needed to recruit enough patients to provide meaningful data and statistical power. This can make the consistent collection of reliable data across study sites difficult. To address these challenges, an International MPS Consensus Conference for Cognitive Endpoints was convened to discuss approaches for evaluating cognitive and adaptive function in patients with mucopolysaccharidoses. The goal was to develop a consensus on best practice for the design and conduct of clinical studies investigating novel therapies for these conditions, with particular focus on the most appropriate outcome measures for cognitive function and adaptive behavior. The outcomes from the consensus panel discussion are reported here

Training of attention functions in children with attention deficit hyperactivity disorder

Pharmacological treatment of children with ADHD has been shown to be successful; however, medication may not normalize attention functions. The present study was based on a neuropsychological model of attention and assessed the effect of an attention training program on attentional functioning of children with ADHD. Thirty-two children with ADHD and 16 healthy children participated in the study. Children with ADHD were randomly assigned to one of the two conditions, i.e., an attention training program which trained aspects of vigilance, selective attention and divided attention, or a visual perception training which trained perceptual skills, such as perception of figure and ground, form constancy and position in space. The training programs were applied in individual sessions, twice a week, for a period of four consecutive weeks. Healthy children did not receive any training. Alertness, vigilance, selective attention, divided attention, and flexibility were examined prior to and following the interventions. Children with ADHD were assessed and trained while on ADHD medications. Data analysis revealed that the attention training used in the present study led to significant improvements of various aspects of attention, including vigilance, divided attention, and flexibility, while the visual perception training had no specific effects. The findings indicate that attention training programs have the potential to facilitate attentional functioning in children with ADHD treated with ADHD drugs

Progress report no. 1

Statement of responsibility on title-page reads: Editors: I.A. Forbes, M.J. Driscoll, D.D. Lanning, I. Kaplan, N.C. Rasmussen; Contributors: S.A. Ali, S.T. Brewer, D.K. Choi, F.M. Clikeman, W.R. Corcoran, M.J. Driscoll, I.A. Forbes, C.W. Forsberg, S.L. Ho, C.S. Kang, I. Kaplan, J.L. Klucar, D.D. Lanning, T.C. Leung, E.L. McFarland P.G. Mertens, N.R. Ortiz, A. Pant, N.A. Passman, N.C. Rasmussen, M.K. Sheaffer, D.A. Shupe, G.E. Sullivan, A.T. Supple, J.W. Synan, C.P. Tzanos, W.J. Westlake"MIT-4105-3."Includes bibliographical referencesProgress report; June 30, 1970U.S. Atomic Energy Commission contracts: AT(30-1)410

Friedreich's Ataxia (GAA)n•(TTC)n Repeats Strongly Stimulate Mitotic Crossovers in Saccharomyces cerevisae

Expansions of trinucleotide GAA•TTC tracts are associated with the human disease Friedreich's ataxia, and long GAA•TTC tracts elevate genome instability in yeast. We show that tracts of (GAA)230•(TTC)230 stimulate mitotic crossovers in yeast about 10,000-fold relative to a “normal” DNA sequence; (GAA)n•(TTC)n tracts, however, do not significantly elevate meiotic recombination. Most of the mitotic crossovers are associated with a region of non-reciprocal transfer of information (gene conversion). The major class of recombination events stimulated by (GAA)n•(TTC)n tracts is a tract-associated double-strand break (DSB) that occurs in unreplicated chromosomes, likely in G1 of the cell cycle. These findings indicate that (GAA)n•(TTC)n tracts can be a potent source of loss of heterozygosity in yeast

A Fine-Structure Map of Spontaneous Mitotic Crossovers in the Yeast Saccharomyces cerevisiae

Homologous recombination is an important mechanism for the repair of DNA damage in mitotically dividing cells. Mitotic crossovers between homologues with heterozygous alleles can produce two homozygous daughter cells (loss of heterozygosity), whereas crossovers between repeated genes on non-homologous chromosomes can result in translocations. Using a genetic system that allows selection of daughter cells that contain the reciprocal products of mitotic crossing over, we mapped crossovers and gene conversion events at a resolution of about 4 kb in a 120-kb region of chromosome V of Saccharomyces cerevisiae. The gene conversion tracts associated with mitotic crossovers are much longer (averaging about 12 kb) than the conversion tracts associated with meiotic recombination and are non-randomly distributed along the chromosome. In addition, about 40% of the conversion events have patterns of marker segregation that are most simply explained as reflecting the repair of a chromosome that was broken in G1 of the cell cycle

Rif1 maintains telomeres and mediates DNA repair by encasing DNA ends

In yeast, Rif1 is part of the telosome, where it inhibits telomerase and checkpoint signaling at chromosome ends. In mammalian cells, Rif1 is not telomeric, but it suppresses DNA end resection at chromosomal breaks, promoting repair by nonhomologous end joining (NHEJ). Here, we describe crystal structures for the uncharacterized and conserved ∼125-kDa N-terminal domain of Rif1 from Saccharomyces cerevisiae (Rif1-NTD), revealing an α-helical fold shaped like a shepherd's crook. We identify a high-affinity DNA-binding site in the Rif1-NTD that fully encases DNA as a head-to-tail dimer. Engagement of the Rif1-NTD with telomeres proved essential for checkpoint control and telomere length regulation. Unexpectedly, Rif1-NTD also promoted NHEJ at DNA breaks in yeast, revealing a conserved role of Rif1 in DNA repair. We propose that tight associations between the Rif1-NTD and DNA gate access of processing factors to DNA ends, enabling Rif1 to mediate diverse telomere maintenance and DNA repair functions

Deletion of the Pichia pastoris KU70 Homologue Facilitates Platform Strain Generation for Gene Expression and Synthetic Biology

Targeted gene replacement to generate knock-outs and knock-ins is a commonly used method to study the function of unknown genes. In the methylotrophic yeast Pichia pastoris, the importance of specific gene targeting has increased since the genome sequencing projects of the most commonly used strains have been accomplished, but rapid progress in the field has been impeded by inefficient mechanisms for accurate integration. To improve gene targeting efficiency in P. pastoris, we identified and deleted the P. pastoris KU70 homologue. We observed a substantial increase in the targeting efficiency using the two commonly known and used integration loci HIS4 and ADE1, reaching over 90% targeting efficiencies with only 250-bp flanking homologous DNA. Although the ku70 deletion strain was noted to be more sensitive to UV rays than the corresponding wild-type strain, no lethality, severe growth retardation or loss of gene copy numbers could be detected during repetitive rounds of cultivation and induction of heterologous protein production. Furthermore, we demonstrated the use of the ku70 deletion strain for fast and simple screening of genes in the search of new auxotrophic markers by targeting dihydroxyacetone synthase and glycerol kinase genes. Precise knock-out strains for the well-known P. pastoris AOX1, ARG4 and HIS4 genes and a whole series of expression vectors were generated based on the wild-type platform strain, providing a broad spectrum of precise tools for both intracellular and secreted production of heterologous proteins utilizing various selection markers and integration strategies for targeted or random integration of single and multiple genes. The simplicity of targeted integration in the ku70 deletion strain will further support protein production strain generation and synthetic biology using P. pastoris strains as platform hosts