Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) represents the most common pathological subtype of FTLD. We established the international FTLD-TDP whole-genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1131 unrelated Caucasian patients, we estimated that C9orf72 repeat expansions and GRN loss-of-function mutations account for 25.5% and 13.9% of FTLD-TDP patients, respectively. Mutations in TBK1 (1.5%) and other known FTLD genes (1.4%) were rare, and the disease in 57.7% of FTLD-TDP patients was unexplained by the known FTLD genes. To unravel the contribution of common genetic factors to the FTLD-TDP etiology in these patients, we conducted a two-stage association study comprising the analysis of whole-genome sequencing data from 517 FTLD-TDP patients and 838 controls, followed by targeted genotyping of the most associated genomic loci in 119 additional FTLD-TDP patients and 1653 controls. We identified three genome-wide significant FTLD-TDP risk loci: one new locus at chromosome 7q36 within the DPP6 gene led by rs118113626 (p value = 4.82e − 08, OR = 2.12), and two known loci: UNC13A, led by rs1297319 (p value = 1.27e − 08, OR = 1.50) and HLA-DQA2 led by rs17219281 (p value = 3.22e − 08, OR = 1.98). While HLA represents a locus previously implicated in clinical FTLD and related neurodegenerative disorders, the association signal in our study is independent from previously reported associations. Through inspection of our whole-genome sequence data for genes with an excess of rare loss-of-function variants in FTLD-TDP patients (n ≥ 3) as compared to controls (n = 0), we further discovered a possible role for genes functioning within the TBK1-related immune pathway (e.g., DHX58, TRIM21, IRF7) in the genetic etiology of FTLD-TDP. Together, our study based on the largest cohort of unrelated FTLD-TDP patients assembled to date provides a comprehensive view of the genetic landscape of FTLD-TDP, nominates novel FTLD-TDP risk loci, and strongly implicates the immune pathway in FTLD-TDP pathogenesis

An upstream regulator of the 26S proteasome modulates organ size in Arabidopsis thaliana.

In both animal and plant kingdoms, body size is a fundamental but still poorly understood attribute of biological systems. Here we report that the Arabidopsis NAC transcription factor 'Regulator of Proteasomal Gene Expression' (RPX) controls leaf size by positively modulating proteasome activity. We further show that the cis-element recognized by RPX is evolutionarily conserved between higher plant species. Upon over-expression of RPX, plants exhibit reduced growth, which may be reversed by a low concentration of the pharmacological proteasome inhibitor MG132. These data suggest that the rate of protein turnover during growth is a critical parameter for determining final organ size

Correlates of gross motor competence in children and adolescents: A systematic review and meta-analysis

Background Gross motor competence confers health benefits, but levels in children and adolescents are low. While interventions can improve gross motor competence, it remains unclear which correlates should be targeted to ensure interventions are most effective, and for whom targeted and tailored interventions should be developed. Objective The aim of this systematic review was to identify the potential correlates of gross motor competence in typically developing children and adolescents (aged 3–18 years) using an ecological approach. Methods Motor competence was defined as gross motor skill competency, encompassing fundamental movement skills and motor coordination, but excluding motor fitness. Studies needed to assess a summary score of at least one aspect of motor competence (i.e., object control, locomotor, stability, or motor coordination). A structured electronic literature search was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Six electronic databases (CINAHL Complete, ERIC, MEDLINE Complete, PsycINFO, Scopus and SPORTDiscus with Full Text) were searched from 1994 to 5 August 2014. Meta-analyses were conducted to determine the relationship between potential correlates and motor competency if at least three individual studies investigated the same correlate and also reported standardized regression coefficients. Results A total of 59 studies were identified from 22 different countries, published between 1995 and 2014. Studies reflected the full range of age groups. The most examined correlates were biological and demographic factors. Age (increasing) was a correlate of children’s motor competence. Weight status (healthy), sex (male) and socioeconomic background (higher) were consistent correlates for certain aspects of motor competence only. Physical activity and sport participation constituted the majority of investigations in the behavioral attributes and skills category. Whilst we found physical activity to be a positive correlate of skill composite and motor coordination, we also found indeterminate evidence for physical activity being a correlate of object control or locomotor skill competence. Few studies investigated cognitive, emotional and psychological factors, cultural and social factors or physical environment factors as correlates of motor competence. Conclusion This systematic review is the first that has investigated correlates of gross motor competence in children and adolescents. A strength is that we categorized correlates according to the specific ways motor competence has been defined and operationalized (object control, motor coordination, etc.), which enables us to have an understanding of what correlates assist what types of motor competence. Indeed our findings do suggest that evidence for some correlates differs according to how motor competence is operationalized