Genome-wide association study identifies multiple loci associated with both mammographic density and breast cancer risk

Mammographic density reflects the amount of stromal and epithelial tissues in relation to adipose tissue in the breast and is a strong risk factor for breast cancer. Here we report the results from meta-analysis of genome-wide association studies (GWAS) of three mammographic density phenotypes: dense area, non-dense area and percent density in up to 7,916 women in stage 1 and an additional 10,379 women in stage 2. We identify genome-wide significant (P<5×10−8) loci for dense area (AREG, ESR1, ZNF365, LSP1/TNNT3, IGF1, TMEM184B, SGSM3/MKL1), non-dense area (8p11.23) and percent density (PRDM6, 8p11.23, TMEM184B). Four of these regions are known breast cancer susceptibility loci, and four additional regions were found to be associated with breast cancer (P<0.05) in a large meta-analysis. These results provide further evidence of a shared genetic basis between mammographic density and breast cancer and illustrate the power of studying intermediate quantitative phenotypes to identify putative disease susceptibility loci

Alternating Hemiplegia of Childhood-Related Neural and Behavioural Phenotypes in Na+,K+-ATPase α3 Missense Mutant Mice

Missense mutations in ATP1A3 encoding Na(+),K(+)-ATPase α3 have been identified as the primary cause of alternating hemiplegia of childhood (AHC), a motor disorder with onset typically before the age of 6 months. Affected children tend to be of short stature and can also have epilepsy, ataxia and learning disability. The Na(+),K(+)-ATPase has a well-known role in maintaining electrochemical gradients across cell membranes, but our understanding of how the mutations cause AHC is limited. Myshkin mutant mice carry an amino acid change (I810N) that affects the same position in Na(+),K(+)-ATPase α3 as I810S found in AHC. Using molecular modelling, we show that the Myshkin and AHC mutations display similarly severe structural impacts on Na(+),K(+)-ATPase α3, including upon the K(+) pore and predicted K(+) binding sites. Behavioural analysis of Myshkin mice revealed phenotypic abnormalities similar to symptoms of AHC, including motor dysfunction and cognitive impairment. 2-DG imaging of Myshkin mice identified compromised thalamocortical functioning that includes a deficit in frontal cortex functioning (hypofrontality), directly mirroring that reported in AHC, along with reduced thalamocortical functional connectivity. Our results thus provide validation for missense mutations in Na(+),K(+)-ATPase α3 as a cause of AHC, and highlight Myshkin mice as a starting point for the exploration of disease mechanisms and novel treatments in AHC

Características químicas do resíduo do leite de soja obtido a partir do farelo e da farinha do grão integral de soja

O objetivo do presente trabalho foi estudar os efeitos de diferentes tempos de processamento (duas, quatro e seis horas) e temperaturas (50°C, 65°C e 80°C) em dois substratos: farinha do grão integral de soja e farelo de soja. Para obtenção do resíduo, utilizou-se uma máquina de aço inoxidável com termostato para controle de temperatura e agitador constante. O delineamento estatístico utilizado na análise dos dados foi inteiramente casualizado, segundo o esquema fatorial 3 x 3 x 2 com duas repetições. Concluiu-se que os tratamentos não apresentaram diferenças marcantes na composição química e mineral do resíduo. O teor de proteína no resíduo do farelo foi 3,5% superior ao teor do farelo que lhe deu origem, o contrário ocorreu com o resíduo da farinha que foi 9,8% inferior. O teor de extrato etéreo no resíduo da farinha, aproximou-se bastante do teor da farinha do grão integral (21,41%) e no resíduo do farelo foi ligeiramente inferior

Chest wall regional volume in heart failure patients during inspiratory loaded breathing.

Were evaluated individuals divided into two groups: we studied chronic heart failure (CHF) (19 patients with CHF plus cardiomegaly) and control (12 healthy volunteers) during performance of inspiratory loaded breathing (ILB). We evaluated: spirometry, functional capacity through the six-minute walk test (6MWT), and distribution of thoracoabdominal volumes via optoelectronic plethysmography (OEP), namely volume variations of pulmonary rib cage (Vrc,p), abdominal rib cage (Vrc,a), and abdomen (Vab). In each compartment, the percentage contributions of right and left sides were also calculated. During ILB, patients with heart failure were characterized by a significant reduction of the Vrc,a volume variations compared to the control group. Correlations were found between left %Vrc,a on the left side measured during ILB and left ventricular ejection fraction (r=0.468; p=0.049), and dyspnea after the 6MWT (r=-0.878; p&lt;0.01).Then, patients with CHF and cardiomegaly are characterized by a reduced mobility in left part of the lower part of the rib cage, that contributes leading to increased perception of dyspnea during submaximal exercise

Chest wall regional volume in heart failure patients during inspiratory loaded breathing.

Were evaluated individuals divided into two groups: we studied chronic heart failure (CHF) (19 patients with CHF plus cardiomegaly) and control (12 healthy volunteers) during performance of inspiratory loaded breathing (ILB). We evaluated: spirometry, functional capacity through the six-minute walk test (6MWT), and distribution of thoracoabdominal volumes via optoelectronic plethysmography (OEP), namely volume variations of pulmonary rib cage (Vrc,p), abdominal rib cage (Vrc,a), and abdomen (Vab). In each compartment, the percentage contributions of right and left sides were also calculated. During ILB, patients with heart failure were characterized by a significant reduction of the Vrc,a volume variations compared to the control group. Correlations were found between left \%Vrc,a on the left side measured during ILB and left ventricular ejection fraction (r=0.468; p=0.049), and dyspnea after the 6MWT (r=-0.878; p<0.01).Then, patients with CHF and cardiomegaly are characterized by a reduced mobility in left part of the lower part of the rib cage, that contributes leading to increased perception of dyspnea during submaximal exercise

Immunochip analyses identify a novel risk locus for primary biliary cirrhosis at 13q14, multiple independent associations at four established risk loci and epistasis between 1p31 and 7q32 risk variants

To further characterize the genetic basis of primary biliary cirrhosis (PBC), we genotyped 2426 PBC patients and 5731 unaffected controls from three independent cohorts using a single nucleotide polymorphism (SNP) array (Immunochip) enriched for autoimmune disease risk loci. Meta-analysis of the genotype data sets identified a novel disease-associated locus near the TNFSF11 gene at 13q14, provided evidence for association at six additional immune-related loci not previously implicated in PBC and confirmed associations at 19 of 22 established risk loci. Results of conditional analyses also provided evidence for multiple independent association signals at four risk loci, with haplotype analyses suggesting independent SNP effects at the 2q32 and 16p13 loci, but complex haplotype driven effects at the 3q25 and 6p21 loci. By imputing classical HLA alleles from this data set, four class II alleles independently contributing to the association signal from this region were identified. Imputation of genotypes at the non-HLA loci also provided additional associations, but none with stronger effects than the genotyped variants. An epistatic interaction between the IL12RB2 risk locus at 1p31and the IRF5 risk locus at 7q32 was also identified and suggests a complementary effect of these loci in predisposing to disease. These data expand the repertoire of genes with potential roles in PBC pathogenesis that need to be explored by follow-up biological studies