p53-Dependent Transcriptional Responses to Interleukin-3 Signaling

p53 is critical in the normal response to a variety of cellular stresses including DNA damage and loss of p53 function is a common feature of many cancers. In hematological malignancies, p53 deletion is less common than in solid malignancies but is associated with poor prognosis and resistance to chemotherapy. Compared to their wild-type (WT) counterparts, hematopoietic progenitor cells lacking p53 have a greater propensity to survive cytokine loss, in part, due to the failure to transcribe Puma, a proapoptotic Bcl-2 family member. Using expression arrays, we have further characterized the differences that distinguish p53−/− cells from WT myeloid cells in the presence of Interleukin-3 (IL-3) to determine if such differences contribute to the increased clonogenicity and survival responses observed in p53−/− cells. We show that p53−/− cells have a deregulated intracellular signaling environment and display a more rapid and sustained response to IL-3. This was accompanied by an increase in active ERK1/2 and a dependence on an intact MAP kinase signaling pathway. Contrastingly, we find that p53−/− cells are independent on AKT for their survival. Thus, loss of p53 in myeloid cells results in an altered transcriptional and kinase signaling environment that favors enhanced cytokine signaling

de Sitter Galileon

We generalize the Galileon symmetry and its relativistic extension to a de Sitter background. This is made possible by studying a probe-brane in a flat five-dimensional bulk using a de Sitter slicing. The generalized Lovelock invariants induced on the probe brane enjoy the induced Poincar\'e symmetry inherited from the bulk, while living on a de Sitter geometry. The non-relativistic limit of these invariants naturally maintain a generalized Galileon symmetry around de Sitter while being free of ghost-like pathologies. We comment briefly on the cosmology of these models and the extension to the AdS symmetry as well as generic FRW backgrounds

Does Bone Resorption Stimulate Periosteal Expansion? A Cross-Sectional Analysis of b-C-telopeptides of Type I Collagen ( CTX),Genetic Markers of the RANKL Pathway, and Periosteal Circumference as Measured by

Peer reviewe

Concordance of randomised controlled trials for artificial intelligence interventions with the CONSORT-AI reporting guidelines

The Consolidated Standards of Reporting Trials extension for Artificial Intelligence interventions (CONSORT-AI) was published in September 2020. Since its publication, several randomised controlled trials (RCTs) of AI interventions have been published but their completeness and transparency of reporting is unknown. This systematic review assesses the completeness of reporting of AI RCTs following publication of CONSORT-AI and provides a comprehensive summary of RCTs published in recent years. 65 RCTs were identified, mostly conducted in China (37%) and USA (18%). Median concordance with CONSORT-AI reporting was 90% (IQR 77–94%), although only 10 RCTs explicitly reported its use. Several items were consistently under-reported, including algorithm version, accessibility of the AI intervention or code, and references to a study protocol. Only 3 of 52 included journals explicitly endorsed or mandated CONSORT-AI. Despite a generally high concordance amongst recent AI RCTs, some AI-specific considerations remain systematically poorly reported. Further encouragement of CONSORT-AI adoption by journals and funders may enable more complete adoption of the full CONSORT-AI guidelines

Adult height variants affect birth length and growth rate in children

Previous studies identified 180 single nucleotide polymorphisms (SNPs) associated with adult height, explaining ∼10% of the variance. The age at which these begin to affect growth is unclear. We modelled the effect of these SNPs on birth length and childhood growth. A total of 7768 participants in the Avon Longitudinal Study of Parents and Children had data available. Individual growth trajectories from 0 to 10 years were estimated using mixed-effects linear spline models and differences in trajectories by individual SNPs and allelic score were determined. The allelic score was associated with birth length (0.026 cm increase per ‘tall’ allele, SE = 0.003, P = 1 × 10−15, equivalent to 0.017 SD). There was little evidence of association between the allelic score and early infancy growth (0–3 months), but there was evidence of association between the allelic score and later growth. This association became stronger with each consecutive growth period, per ‘tall’ allele per month effects were 0.015 SD (3 months–1 year, SE = 0.004), 0.023 SD (1–3 years, SE = 0.003) and 0.028 SD (3–10 years, SE = 0.003). By age 10, the mean height difference between individuals with ≤170 versus ≥191 ‘tall’ alleles (the top and bottom 10%) was 4.7 cm (0.8 SD), explaining ∼5% of the variance. There was evidence of associations with specific growth periods for some SNPs (rs3791675, EFEMP1 and rs6569648, L3MBTL3) and supportive evidence for previously reported age-dependent effects of HHIP and SOCS2 SNPs. SNPs associated with adult height influence birth length and have an increasing effect on growth from late infancy through to late childhood. By age 10, they explain half the height variance (∼5%) of that explained in adults (∼10%)

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis

Allergic rhinitis is the most common clinical presentation of allergy, affecting 400 million people worldwide, with increasing incidence in westernized countries1,2. To elucidate the genetic architecture and understand the underlying disease mechanisms, we carried out a meta-analysis of allergic rhinitis in 59,762 cases and 152,358 controls of European ancestry and identified a total of 41 risk loci for allergic rhinitis, including 20 loci not previously associated with allergic rhinitis, which were confirmed in a replication phase of 60,720 cases and 618,527 controls. Functional annotation implicated genes involved in various immune pathways, and fine mapping of the HLA region suggested amino acid variants important for antigen binding. We further performed genome-wide association study (GWAS) analyses of allergic sensitization against inhalant allergens and nonallergic rhinitis, which suggested shared genetic mechanisms across rhinitis-related traits. Future studies of the identified loci and genes might identify novel targets for treatment and prevention of allergic rhinitis

Diversity Arrays Technology (DArT) for Pan-Genomic Evolutionary Studies of Non-Model Organisms

Background: High-throughput tools for pan-genomic study, especially the DNA microarray platform, have sparked a remarkable increase in data production and enabled a shift in the scale at which biological investigation is possible. The use of microarrays to examine evolutionary relationships and processes, however, is predominantly restricted to model or near-model organisms. Methodology/Principal Findings: This study explores the utility of Diversity Arrays Technology (DArT) in evolutionary studies of non-model organisms. DArT is a hybridization-based genotyping method that uses microarray technology to identify and type DNA polymorphism. Theoretically applicable to any organism (even one for which no prior genetic data are available), DArT has not yet been explored in exclusively wild sample sets, nor extensively examined in a phylogenetic framework. DArT recovered 1349 markers of largely low copy-number loci in two lineages of seed-free land plants: the diploid fern Asplenium viride and the haploid moss Garovaglia elegans. Direct sequencing of 148 of these DArT markers identified 30 putative loci including four routinely sequenced for evolutionary studies in plants. Phylogenetic analyses of DArT genotypes reveal phylogeographic and substrate specificity patterns in A. viride, a lack of phylogeographic pattern in Australian G. elegans, and additive variation in hybrid or mixed samples. Conclusions/Significance: These results enable methodological recommendations including procedures for detecting and analysing DArT markers tailored specifically to evolutionary investigations and practical factors informing the decision to use DArT, and raise evolutionary hypotheses concerning substrate specificity and biogeographic patterns. Thus DArT is a demonstrably valuable addition to the set of existing molecular approaches used to infer biological phenomena such as adaptive radiations, population dynamics, hybridization, introgression, ecological differentiation and phylogeography

Socio-economic inequalities in physical activity practice among Italian children and adolescents: a cross-sectional study

Aim: The aim of the study was to evaluate whether socio-economic inequalities in the practice of physical activity existed among children and adolescents, using different indicators of socio-economic status (SES). Subjects and methods: Data were derived from the Italian National Health Interview Survey carried out in 2004–2005, which examined a large random sample of the Italian population using both an interviewer-administered and a self-compiled questionnaire. This study was based on a sample of 15,216 individuals aged 6–17 years. The practice of physical activity was measured on the basis of questions regarding frequency and intensity of activity during leisure time over the past 12 months. Parents’ educational and occupational level, as well as family’s availability of material resource, were used as indicators of SES. Multivariable logistic regression analyses were performed to estimate the contribution of each SES indicator to the practice of physical activity, adjusting for potential confounding factors. The results of the regression models are expressed as odds ratio (OR) with 95% confidence intervals (95% CI). Results: About 64% of children and adolescents in the sample declared that they participated in moderate or vigorous physical activity at least once a week. After adjustment for gender, age, parental attitudes towards physical activity and geographical area, the practice of physical activity increased with higher parental educational and occupational level and greater availability of material resources. Children and adolescents whose parents held a middle or high educational title were 80% more likely to practice moderate or vigorous physical activity than subjects whose parents had a lower level of education (OR = 1.80, 95% CI: 1.40–2.33), while subjects with unemployed parents had an odds of practicing moderate or vigorous physical activity 0.43 times that of those children whose parents belonged to the top job occupation category (administrative/professionals). Socio-economic differences were about the same when the practice of vigorous physical activity only was considered instead of that of moderate or vigorous physical activity. Conclusion: Interventions that promote the practice of physical activity, and especially those aimed at the wider physical and social environment, are strongly needed to contrast socio-economic differences in physical activity among children and adolescents