Abrogation of Junctional Adhesion Molecule-A Expression Induces Cell Apoptosis and Reduces Breast Cancer Progression

Intercellular junctions promote homotypic cell to cell adhesion and transfer intracellular signals which control cell growth and apoptosis. Junctional adhesion molecule-A (JAM-A) is a transmembrane immunoglobulin located at tight junctions of normal epithelial cells of mammary ducts and glands. In the present paper we show that JAM-A acts as a survival factor for mammary carcinoma cells. JAM-A null mice expressing Polyoma Middle T under MMTV promoter develop significantly smaller mammary tumors than JAM-A positive mice. Angiogenesis and inflammatory or immune infiltrate were not statistically modified in absence of JAM-A but tumor cell apoptosis was significantly increased. Tumor cells isolated from JAM-A null mice or 4T1 cells incubated with JAM-A blocking antibodies showed reduced growth and increased apoptosis which paralleled altered junctional architecture and adhesive function. In a breast cancer clinical data set, tissue microarray data show that JAM-A expression correlates with poor prognosis. Gene expression analysis of mouse tumor samples showed a correlation between genes enriched in human G3 tumors and genes over expressed in JAM-A +/+ mammary tumors. Conversely, genes enriched in G1 human tumors correlate with genes overexpressed in JAM-A−/− tumors. We conclude that down regulation of JAM-A reduces tumor aggressive behavior by increasing cell susceptibility to apoptosis. JAM-A may be considered a negative prognostic factor and a potential therapeutic target

The association of HFE gene H63D polymorphism with endurance athlete status and aerobic capacity: novel findings and a meta-analysis.

PURPOSE: Iron is an important component of the oxygen-binding proteins and may be critical to optimal athletic performance. Previous studies have suggested that the G allele of C/G rare variant (rs1799945), which causes H63D amino acid replacement, in the HFE is associated with elevated iron indexes and may give some advantage in endurance-oriented sports. The aim of the present study was to investigate the association between the HFE H63D polymorphism and elite endurance athlete status in Japanese and Russian populations, aerobic capacity and to perform a meta-analysis using current findings and three previous studies. METHODS: The study involved 315 international-level endurance athletes (255 Russian and 60 Japanese) and 809 healthy controls (405 Russian and 404 Japanese). Genotyping was performed using micro-array analysis or by PCR. VO2max in 46 male Russian endurance athletes was determined using gas analysis system. RESULTS: The frequency of the iron-increasing CG/GG genotypes was significantly higher in Russian (38.0 vs 24.9%; OR 1.85, P = 0.0003) and Japanese (13.3 vs 5.0%; OR 2.95, P = 0.011) endurance athletes compared to ethnically matched controls. The meta-analysis using five cohorts (two French, Japanese, Spanish, and Russian; 586 athletes and 1416 controls) showed significant prevalence of the CG/GG genotypes in endurance athletes compared to controls (OR 1.96, 95% CI 1.58-2.45; P = 1.7 × 10-9). Furthermore, the HFE G allele was associated with high V̇O2max in male athletes [CC: 61.8 (6.1), CG/GG: 66.3 (7.8) ml/min/kg; P = 0.036]. CONCLUSIONS: We have shown that the HFE H63D polymorphism is strongly associated with elite endurance athlete status, regardless ethnicities and aerobic capacity in Russian athletes

The clinical significance of tumor infiltrating lymphoctyes in breast cancer: does subtype matter?

Tumor infiltrating lymphocytes (TILs) are commonly detected in breast tumors but their bearing on disease outcome is uncertain. The importance of TILs appears to be subtype-specific and varies depending on the histologic characteristics of the tumor. As our understanding of tumorigenesis is increasing the relevance of immunobiology will become apparent

Phenotypic covariance of longevity, immunity and stress resistance in the Caenorhabditis nematodes

Background \ud Ageing, immunity and stresstolerance are inherent characteristics of all organisms. In animals, these traits are regulated, at least in part, by forkhead transcription factors in response to upstream signals from the Insulin/Insulin– like growth factor signalling (IIS) pathway. In the nematode Caenorhabditis elegans, these phenotypes are molecularly linked such that activation of the forkhead transcription factor DAF-16 both extends lifespan and simultaneously increases immunity and stress resistance. It is known that lifespan varies significantly among the Caenorhabditis species but, although DAF-16 signalling is highly conserved, it is unclear whether this phenotypic linkage occurs in other species. Here we investigate this phenotypic covariance by comparing longevity, stress resistance and immunity in four \ud Caenorhabditis species. \ud \ud Methodology/Principal Findings \ud We show using phenotypic analysis of DAF-16 influenced phenotypes that among four closely related Caenorhabditis nematodes, the gonochoristic species (Caenorhabditis remanei and Caenorhabditis brenneri) have diverged \ud significantly with a longer lifespan, improved stress resistance and higher immunity than the hermaphroditic species (C. elegans and Caenorhabditis briggsae). Interestingly, we also observe significant differences in expression levels between the daf-16 homologues in these species using Real-Time PCR, which positively correlate with the observed phenotypes. Finally, we provide additional evidence in support of a role for DAF-16 in regulating phenotypic coupling by using a combination of wildtype isolates, constitutively active daf-16 mutants and bioinformatic analysis. \ud \ud Conclusions \ud The gonochoristic species display a significantly longer lifespan (p < 0.0001)and more robust immune and stress response (p<0.0001, thermal stress; p<0.01, heavy metal stress; p<0.0001, pathogenic stress) than the hermaphroditic species. Our data suggests that divergence in DAF-16 mediated phenotypes may underlie many of the differences observed between these four species of Caenorhabditis nematodes. These findings are further supported by the correlative higher daf-16 expression levels among the gonochoristic species and significantly higher lifespan, immunity and stress tolerance in the constitutively active daf-16 hermaphroditic mutants

Phenotypic covariance of Longevity, Immunity and Stress Resistance in the Caenorhabditis Nematodes

Background: Ageing, immunity and stresstolerance are inherent characteristics of all organisms. In animals, these traits are regulated, at least in part, by forkhead transcription factors in response to upstream signals from the Insulin/Insulin–like growth factor signalling (IIS) pathway. In the nematode Caenorhabditis elegans, these phenotypes are molecularly linked such that activation of the forkhead transcription factor DAF-16 both extends lifespan and simultaneously increases immunity and stress resistance. It is known that lifespan varies significantly among the Caenorhabditis species but, although DAF-16 signalling is highly conserved, it is unclear whether this phenotypic linkage occurs in other species. Here we investigate this phenotypic covariance by comparing longevity, stress resistance and immunity in four Caenorhabditis species. \ud \ud Methodology/Principal Findings: We show using phenotypic analysis of DAF-16 influenced phenotypes that among four closely related Caenorhabditis nematodes, the gonochoristic species (Caenorhabditis remanei and Caenorhabditis brenneri) have diverged significantly with a longer lifespan, improved stress resistance and higher immunity than the hermaphroditic species (C. elegans and Caenorhabditis briggsae). Interestingly, we also observe significant differences in expression levels between the daf-16 homologues in these species using Real-Time PCR, which positively correlate with the observed phenotypes. Finally, we provide additional evidence in support of a role for DAF-16 in regulating phenotypic coupling by using a combination of wildtype isolates, constitutively active daf-16 mutants and bioinformatic analysis. \ud \ud Conclusions: The gonochoristic species display a significantly longer lifespan (p<0.0001) and more robust immune and stress response (p<0.0001, thermal stress; p<0.01, heavy metal stress; p<0.0001, pathogenic stress) than the hermaphroditic species. Our data suggests that divergence in DAF-16 mediated phenotypes may underlie many of the differences observed between these four species of Caenorhabditis nematodes. These findings are further supported by the correlative higher daf-16 expression levels among the gonochoristic species and significantly higher lifespan, immunity and stress tolerance in the constitutively active daf-16 hermaphroditic mutants

Soil pyrogenic carbon in southern Amazonia: Interaction between soil, climate, and above-ground biomass

This is the final version. Available on open access from Frontiers Media via the DOI in this recordData availability statement: The original contributions presented in this study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author/s.The Amazon forest represents one of the world’s largest terrestrial carbon reservoirs. Here, we evaluated the role of soil texture, climate, vegetation, and distance to savanna on the distribution and stocks of soil pyrogenic carbon (PyC) in intact forests with no history of recent fire spanning the southern Amazonia forest-Cerrado Zone of Transition (ZOT). In 19 one hectare forest plots, including three Amazonian Dark Earth (ADE, terra preta) sites with high soil PyC, we measured all trees and lianas with diameter ≥ 10 cm and analyzed soil physicochemical properties, including texture and PyC stocks. We quantified PyC stocks as a proportion of total organic carbon using hydrogen pyrolysis. We used multiple linear regression and variance partitioning to determine which variables best explain soil PyC variation. For all forests combined, soil PyC stocks ranged between 0.9 and 6.8 Mg/ha to 30 cm depth (mean 2.3 ± 1.5 Mg/ha) and PyC, on average, represented 4.3% of the total soil organic carbon (SOC). The most parsimonious model (based on AICc) included soil clay content and above-ground biomass (AGB) as the main predictors, explaining 71% of soil PyC variation. After removal of the ADE plots, PyC stocks ranged between 0.9 and 3.8 Mg/ha (mean 1.9 ± 0.8 Mg/ha–1) and PyC continued to represent ∼4% of the total SOC. The most parsimonious models without ADE included AGB and sand as the best predictors, with sand and PyC having an inverse relationship, and sand explaining 65% of the soil PyC variation. Partial regression analysis did not identify any of the components (climatic, environmental, and edaphic), pure or shared, as important in explaining soil PyC variation with or without ADE plots. We observed a substantial amount of soil PyC, even excluding ADE forests; however, contrary to expectations, soil PyC stocks were not higher nearer to the fire-dependent Cerrado than more humid regions of Amazonia. Our findings that soil texture and AGB explain the distribution and amount of soil PyC in ZOT forests will help to improve model estimates of SOC change with further climatic warming.Coordination for the Improvement of Higher Education Personnel (CAPES)Natural Environment Research Council (NERC

Smc5/6 coordinates formation and resolution of joint molecules with chromosome morphology to ensure meiotic divisions

During meiosis, Structural Maintenance of Chromosome (SMC) complexes underpin two fundamental features of meiosis: homologous recombination and chromosome segregation. While meiotic functions of the cohesin and condensin complexes have been delineated, the role of the third SMC complex, Smc5/6, remains enigmatic. Here we identify specific, essential meiotic functions for the Smc5/6 complex in homologous recombination and the regulation of cohesin. We show that Smc5/6 is enriched at centromeres and cohesin-association sites where it regulates sister-chromatid cohesion and the timely removal of cohesin from chromosomal arms, respectively. Smc5/6 also localizes to recombination hotspots, where it promotes normal formation and resolution of a subset of joint-molecule intermediates. In this regard, Smc5/6 functions independently of the major crossover pathway defined by the MutLγ complex. Furthermore, we show that Smc5/6 is required for stable chromosomal localization of the XPF-family endonuclease, Mus81-Mms4Eme1. Our data suggest that the Smc5/6 complex is required for specific recombination and chromosomal processes throughout meiosis and that in its absence, attempts at cell division with unresolved joint molecules and residual cohesin lead to severe recombination-induced meiotic catastroph

Alimentary fluoride intake in preschool children

<p>Abstract</p> <p>Background</p> <p>The knowledge of background alimentary fluoride intake in preschool children is of utmost importance for introducing optimal and safe caries preventive measures for both individuals and communities. The aim of this study was to assess the daily fluoride intake analyzing duplicate samples of food and beverages. An attempt was made to calculate the daily intake of fluoride from food and swallowed toothpaste.</p> <p>Methods</p> <p>Daily alimentary fluoride intake was measured in a group of 36 children with an average age of 4.75 years and an average weight of 20.69 kg at baseline, by means of a double plate method. This was repeated after six months. Parents recorded their child's diet over 24 hours and collected duplicated portions of food and beverages received by children during this period. Pooled samples of food and beverages were weighed and solid food samples were homogenized. Fluoride was quantitatively extracted from solid food samples by a microdiffusion method using hexadecyldisiloxane and perchloric acid. The content of fluoride extracted from solid food samples, as well as fluoride in beverages, was measured potentiometrically by means of a fluoride ion selective electrode.</p> <p>Results</p> <p>Average daily fluoride intake at baseline was 0.389 (SD 0.054) mg per day. Six months later it was 0.378 (SD 0.084) mg per day which represents 0.020 (SD 0.010) and 0.018 (SD 0.008) mg of fluoride respectively calculated per kg bw/day.</p> <p>When adding the values of unwanted fluoride intake from the toothpaste shown in the literature (0.17-1.21 mg per day) the estimate of the total daily intake of fluoride amounted to 0.554-1.594 mg/day and recalculated to the child's body weight to 0.027-0.077 mg/kg bw/day.</p> <p>Conclusions</p> <p>In the children studied, observed daily fluoride intake reached the threshold for safe fluoride intake. When adding the potential fluoride intake from swallowed toothpaste, alimentary intake reached the optimum range for daily fluoride intake. These results showed that in preschool children, when trying to maximize the benefit of fluoride in caries prevention and to minimize its risk, caution should be exercised when giving advice on the fluoride containing components of child's diet or prescribing fluoride supplements.</p