ATF3-Induced Mammary Tumors Exhibit Molecular Features of Human Basal-Like Breast Cancer

Basal-like breast cancer (BLBC) is an aggressive and deadly subtype of human breast cancer that is highly metastatic, displays stem-cell like features, and has limited treatment options. Therefore, developing and characterizing preclinical mouse models with tumors that resemble BLBC is important for human therapeutic development. ATF3 is a potent oncogene that is aberrantly expressed in most human breast cancers. In the BK5.ATF3 mouse model, overexpression of ATF3 in the basal epithelial cells of the mammary gland produces tumors that are characterized by activation of the Wnt/β-catenin signaling pathway. Here, we used RNA-Seq and microRNA (miRNA) microarrays to better define the molecular features of BK5.ATF3-derived mammary tumors. These analyses showed that these tumors share many characteristics of human BLBC including reduced expression of Rb1, Esr1, and Pgr and increased expression of Erbb2, Egfr, and the genes encoding keratins 5, 6, and 17. An analysis of miRNA expression revealed reduced levels of Mir145 and Mir143, leading to the upregulation of their target genes including both the pluripotency factors Klf4 and Sox2 as well as the cancer stem-cell-related gene Kras. Finally, we show through knock-down experiments that ATF3 may directly modulate MIR145/143 expression. Taken together, our results indicate that the ATF3 mouse mammary tumor model could provide a powerful model to define the molecular mechanisms leading to BLBC, identify the factors that contribute to its aggressiveness, and, ultimately, discover specific genes and gene networks for therapeutic targeting.     

Brain activation in restrained and unrestrained eaters: An fMRI study.

Restraint theory has been used to model the process that produces binge eating. However, there is no satisfactory explanation for the tendency of restrained eaters (REs) to engage in counterregulatory eating, an ostensible analogue of binge eating. Using functional magnetic resonance imaging (fMRI), the authors investigated brain activation of normal weight REs (N = 9) and unrestrained eaters (UREs; N = 10) when fasted and fed and viewing pictures of highly and moderately palatable foods and neutral objects. When fasted and viewing highly palatable foods, UREs showed widespread bilateral activation in areas associated with hunger and motivation, whereas REs showed activation only in the cerebellum, an area previously implicated in low-level processing of appetitive stimuli. When fed and viewing high palatability foods, UREs showed activation in areas related to satiation and memory, whereas REs showed activation in areas implicated in desire, expectation of reward, and goal-defined behavior. These findings parallel those from behavioral research. The authors propose that the counterintuitive findings from preload studies and the present study are due to the fact that REs are less hungry than UREs when fasted and find palatable food more appealing than UREs when fed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Barn vs. free-range chickens: Differences in their diets determined by stable isotopes

We compared δ¹³C and δ¹⁵N ratios of barn-raised and free-range chickens to determine if differences in their diets were reflected in the stable isotope composition of their tissues. We conducted a 120-day feeding trial with Caipirinha birds fed a corn-soybean based diet, milled-corn diet and free-range diet. Additionally, we analysed the stable isotope composition of barn-raised chickens bought in grocery stores and free-range homegrown chickens. In the feeding trials, the δ¹³C and δ¹⁵N values of the barn-raised corn-soybean-fed Caipirinha chickens did not change with age, and their stable isotope composition reflected the composition of their diet. The δ¹³C and δ¹⁵N values of barn-raised corn-fed and free-range Caipirinha chickens changed with age toward a diet reflecting a predominance of C₄ carbon. The main difference between the free-range and the barn-raised chickens was the significantly higher δ¹⁵N of the former in relation to the latter, probably due to ingestion of animal protein.     

Development of Potent Inhibitors of the Mycobacterium tuberculosis Virulence Factor Zmp1 and Evaluation of Their Effect on Mycobacterial Survival inside Macrophages

The enzyme Zmp1 is a zinc‐containing peptidase that plays a critical role in the pathogenicity of Mycobacterium tuberculosis. Herein we describe the identification of a small set of Zmp1 inhibitors based on a novel 8‐hydroxyquinoline‐2‐hydroxamate scaffold. Among the synthesized compounds, N‐(benzyloxy)‐8‐hydroxyquinoline‐2‐carboxamide ( 1 c ) was found to be the most potent Zmp1 inhibitor known to date, and its binding mode was analyzed both by kinetics studies and molecular modeling, identifying critical interactions of 1 c with the zinc ion and residues in the active site. The effect of 1 c on intracellular Mycobacterium survival was assayed in J774 murine macrophages infected with M. tuberculosis H37Rv or M. bovis BCG and human monocyte‐derived macrophages infected with M. tuberculosis H37Rv. Cytotoxicity and genotoxicity were also assessed. Overall, inhibitor 1 c displays interesting in vitro antitubercular properties worthy of further investigation.     

Reptile heme protein structure: X-ray crystallographic study of the aquo-met and cyano-met derivatives of the loggerhead sea turtle (Caretta caretta) myoglobin at 2.0 A resolution

The X-ray crystal structures of the aquo-met and cyano-met derivatives of the loggerhead sea turtle (Caretta caretta) myoglobin have been determined at 2.0 A resolution (R = 0.182, and 0.178, respectively). The results here reported, representing the first reptile globin solved by X-ray crystallography, have been analyzed in parallel with data for related monomeric hemoproteins, and indicate a strong overall structural similarity between the loggerhead sea turtle and mammalian myoglobins, reflected by the 63% amino acid identity of their primary structures. The root-mean-square deviation between the entire polypeptide backbones of loggerhead sea turtle and sperm whale myoglobins, after structure superposition, is 0.83 A. Upon cyanide binding to the protein distal site, the iron-bound water molecule present in the aquo-met form is displaced by the incoming ligand. Cyanide is oriented towards the inner part of the heme distal site forming a Fe-C-N angle of 133 degrees.     

Distributed information fusion models for regional public health surveillance

Biosurveillance systems designed and deployed in the United States and abroad to allow public health authorities to monitor the health of their communities have significant design limitations despite their wide usage. One limitation is the lack of algorithmic solutions to combine local data sources for regional situation awareness. The objective of the current study is to develop and demonstrate the value of automated information fusion methods applied to the distributed neighboring public health sites. A prototype system consisting of distributed Bayesian models was designed to enable informed regional and local cognitive decision support response. The Intelligent Decision Support Network (IDSN) is composed of Bayesian Information Fusion Models (BIFMs) that target a particular syndrome or disease type. Using local data from county health departments in Northern Virginia for the time period between August 2005 and May 2007, we estimated the probability of a gastrointestinal (GI) outbreak in two ways: First, based on data from the local hospitals only; and second, based on the relative probability of outbreak by combining local hospital data and probabilities of GI events from the neighboring counties’ BIFMs. Preliminary findings showed that the network of distributed models detected events that would be undetected without multi-jurisdictional data.     

An association analysis between OXT genotype and milk yield and flow in Italian Mediterranean river buffalo

The aim of this study was to evaluate possible associations between three SNPs at the oxytocin locus (AM234538: g.28C>T; g.204A>G and g.1627G>T) and two productive traits, milk yield and milkability, in Italian Mediterranean river buffaloes. Effects of parity, calving season and month of production were also evaluated. A total of 41 980 test-day records belonging to 219 lactations of 163 buffalo cows were investigated. The allele call rate was 98·8% and the major allele frequency for all the investigated loci was 0·76. The OXT genotype was significantly associated with milk yield (P=0·029). The TT genotype showed an average daily milk yield approximately 1·7 kg higher than GT buffaloes. Such a difference represents about 23% more milk/d. A large dominance effect (-1·17±0·43 kg) was estimated, whereas the contribution of OXT genotype (r(2)(OXT)) to the total phenotypic variance in milk yield was equal to 0·06. The TT genotype showed higher values also for the milk flow, even though the estimated difference did not reach a level of statistical significance (P=0·07). Such an association, among the first reported for the oxytocin locus in ruminants, should be tested on a population scale and possible effects on milk composition traits should be evaluated in order to supply useful indications for the application of marker-assisted selection programmes in river buffaloes.     

Can the influence of childhood socioeconomic status on men’s and women’s adult body mass be explained by adult socioeconomic status or personality? Findings from a national sample.

Objectives: On the basis of a life-course risk-chain framework, the authors examined whether (a) residual associations between childhood socioeconomic status (SES) and adult obesity and body mass index (BMI) would be observed in women but not men after adjusting for adult SES, (b) adult Big Five personality traits would be associated with adult body mass in both genders, and (c) personality would explain unique variation in outcomes beyond child and adult SES. Design: National survey (Midlife Development in the United States study; N = 2,922). Main Outcome Measures: BMI and obesity. Results: (a) In both genders, association between childhood SES and adult obesity were accounted for entirely by adult SES, but its effect on adult BMI was observed only in women; (b) higher conscientiousness was associated with lower obesity prevalence and BMI in both genders, although more strongly in women, and in men, greater obesity prevalence was associated with higher agreeableness and neuroticism; and (c) personality explained unique outcome variation in both genders. Conclusions: Early social disadvantage may affect adult weight status more strongly in women owing to gender differences in the timing and nature of weight-management socialization. Personality may enhance or detract from risks incurred by childhood or adulthood SES in either gender, necessitating the consideration of dispositional differences in prevention and intervention programs. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Carotenoid and Chlorophyll-Derived Compounds in Some Wine Grapes Grown in Apulian Region

ABSTRACT: Carotenoid compounds in wine grapes (Chardonnay, Merlot, Primitivo, Negroamaro) grown in Apulian region were investigated by chromatographic and spectrometric analyses. Cis-isomers of lutein and β-carotene (9Z, 9′Z-lutein and 9Z-β-carotene) and 5,6-epoxyxanthophylls were detected: 9′Z-neoxanthin, violaxanthin, and 5,6-epoxylutein. Moreover, zeaxanthin was efficiently resolved from lutein by a selective factor > 1 (α= 1.06) and was found in high amounts (50 to 300 μg/kg) in the grape extracts analyzed in 3 y of study (2006 to 2008). At grape maturity, β-carotene had concentration approximately 2-to 4-fold higher than (all-E)-lutein in all varieties. Because carotenoids are potential precursors of aroma compounds, it was determined carotenoids change ΔC (μg/kg), from the difference of total carotenoids concentration between veraison and maturity. Chardonnay and Merlot had the highest ΔC values and principal component analysis showed that they were characterized by 5,6-epoxyxanthophylls derivatives and zeaxanthin, lutein, and β-carotene derivatives, respectively. An important effect of vintage on ΔC values in the analyzed grapes was also observed. A strong positive correlation was determined between ΔC and temperature data that seem to be responsible for the difference of ΔC in the Chardonnay and Merlot compared to the Primitivo and Negroamaro varieties.