Contribution of an alveolar cell of origin to the high-grade malignant phenotype of pregnancy-associated breast cancer.

Pregnancy-associated breast cancers (PABCs) are tumors diagnosed during pregnancy or up to 5 years following parturition, and are usually high-grade, connective tissue-rich, and estrogen receptor (ER)/progesterone receptor-negative. Little is known about the cellular origin of PABCs or the mechanisms by which PABCs are initiated. Using the RCAS retrovirus to deliver the ErbB2 oncogene into the mammary epithelium of our previously reported MMTV-tva transgenic mice, we detected high-grade, poorly differentiated, stroma-rich and ER-negative tumors during pregnancy and lactation. These high-grade and stroma-rich tumors were less frequent in involuted mice or in age-matched nulliparous mice. More importantly, by generating a WAP-tva transgenic line for expression of ErbB2 selectively in WAP(+) mammary alveolar cells, we found that tumors had similar morphological phenotypes (high grade, poorly differentiated, stroma-rich and ER-negative), irrespective of the time since pregnancy and even in the absence of pregnancy. These data suggest that PABCs arise preferentially from an alveolar cell population that expands during pregnancy and lactation. This somatic mouse model may also be useful for preclinical testing of new prophylactic and therapeutic strategies against PABC

A smoother end to the dark ages

Independent lines of evidence suggest that the first stars, which ended the cosmic dark ages, came in pairs, rather than singly. This could change the prevailing view that the early Universe had a Swiss-cheese-like appearance.Comment: Nature News and Views, April 7, 201

Tobacco smoking is associated with DNA methylation of diabetes susceptibility genes.

AIMS/HYPOTHESIS: Tobacco smoking, a risk factor for diabetes, is an established modifier of DNA methylation. We hypothesised that tobacco smoking modifies DNA methylation of genes previously identified for diabetes. METHODS: We annotated CpG sites available on the Illumina Human Methylation 450K array to diabetes genes previously identified by genome-wide association studies (GWAS), and investigated them for an association with smoking by comparing current to never smokers. The discovery study consisted of 630 individuals (Bonferroni-corrected p = 1.4 × 10(-5)), and we sought replication in an independent sample of 674 individuals. The replicated sites were tested for association with nearby genetic variants and gene expression and fasting glucose and insulin levels. RESULTS: We annotated 3,620 CpG sites to the genes identified in the GWAS on type 2 diabetes. Comparing current smokers to never smokers, we found 12 differentially methylated CpG sites, of which five replicated: cg23161492 within ANPEP (p = 1.3 × 10(-12)); cg26963277 (p = 1.2 × 10(-9)), cg01744331 (p = 8.0 × 10(-6)) and cg16556677 (p = 1.2 × 10(-5)) within KCNQ1 and cg03450842 (p = 3.1 × 10(-8)) within ZMIZ1. The effect of smoking on DNA methylation at the replicated CpG sites attenuated after smoking cessation. Increased DNA methylation at cg23161492 was associated with decreased gene expression levels of ANPEP (p = 8.9 × 10(-5)). rs231356-T, which was associated with hypomethylation of cg26963277 (KCNQ1), was associated with a higher odds of diabetes (OR 1.06, p = 1.3 × 10(-5)). Additionally, hypomethylation of cg26963277 was associated with lower fasting insulin levels (p = 0.04). CONCLUSIONS/INTERPRETATION: Tobacco smoking is associated with differential DNA methylation of the diabetes risk genes ANPEP, KCNQ1 and ZMIZ1. Our study highlights potential biological mechanisms connecting tobacco smoking to excess risk of type 2 diabetes

Cognitively-inspired Agent-based Service Composition for Mobile & Pervasive Computing

Automatic service composition in mobile and pervasive computing faces many challenges due to the complex and highly dynamic nature of the environment. Common approaches consider service composition as a decision problem whose solution is usually addressed from optimization perspectives which are not feasible in practice due to the intractability of the problem, limited computational resources of smart devices, service host's mobility, and time constraints to tailor composition plans. Thus, our main contribution is the development of a cognitively-inspired agent-based service composition model focused on bounded rationality rather than optimality, which allows the system to compensate for limited resources by selectively filtering out continuous streams of data. Our approach exhibits features such as distributedness, modularity, emergent global functionality, and robustness, which endow it with capabilities to perform decentralized service composition by orchestrating manifold service providers and conflicting goals from multiple users. The evaluation of our approach shows promising results when compared against state-of-the-art service composition models.Comment: This paper will appear on AIMS'19 (International Conference on Artificial Intelligence and Mobile Services) on June 2

Sudden Unexpected Death in Epilepsy: A PersonaliZed Prediction Tool

OBJECTIVE: To develop and validate a tool for individualised prediction of Sudden Unexpected Death in Epilepsy (SUDEP) risk, we re-analysed data from one cohort and three case-control studies undertaken 1980-2005. METHODS: We entered 1273 epilepsy cases (287 SUDEP, 986 controls) and 22 clinical predictor variables into a Bayesian logistic regression model. RESULTS: Cross-validated individualized model predictions were superior to baseline models developed from only average population risk or from generalised tonic-clonic seizure frequency (pairwise difference in leave-one-subject-out expected log posterior density = 35.9, SEM +/-12.5, and 22.9, SEM +/-11.0 respectively). The mean cross-validated (95% Credibility Interval) Area Under the Receiver Operating Curve was 0.71 (0.68 to 0.74) for our model versus 0.38 (0.33 to 0.42) and 0.63 (0.59 to 0.67) for the baseline average and generalised tonic-clonic seizure frequency models respectively. Model performance was weaker when applied to non-represented populations. Prognostic factors included generalized tonic-clonic and focal-onset seizure frequency, alcohol excess, younger age of epilepsy onset and family history of epilepsy. Anti-seizure medication adherence was associated with lower risk. CONCLUSIONS: Even when generalised to unseen data, model predictions are more accurate than population-based estimates of SUDEP. Our tool can enable risk-based stratification for biomarker discovery and interventional trials. With further validation in unrepresented populations it may be suitable for routine individualized clinical decision-making. Clinicians should consider assessment of multiple risk factors, and not only focus on the frequency of convulsions

Flavor SU(3) symmetry and QCD factorization in B→PPB \to PP and PVPV decays

Using flavor SU(3) symmetry, we perform a model-independent analysis of charmless $\bar B_{u,d} (\bar B_s) \to PP, ~PV$ decays. All the relevant topological diagrams, including the presumably subleading diagrams, such as the QCD- and EW-penguin exchange diagrams and flavor-singlet weak annihilation ones, are introduced. Indeed, the QCD-penguin exchange diagram turns out to be important in understanding the data for penguin-dominated decay modes. In this work we make efforts to bridge the (model-independent but less quantitative) topological diagram or flavor SU(3) approach and the (quantitative but somewhat model-dependent) QCD factorization (QCDF) approach in these decays, by explicitly showing how to translate each flavor SU(3) amplitude into the corresponding terms in the QCDF framework. After estimating each flavor SU(3) amplitude numerically using QCDF, we discuss various physical consequences, including SU(3) breaking effects and some useful SU(3) relations among decay amplitudes of $\bar B_s \to PV$ and $\bar B_d \to PV$.Comment: 47 pages, 3 figures, 28 table

Electronic stress tensor analysis of hydrogenated palladium clusters

We study the chemical bonds of small palladium clusters Pd_n (n=2-9) saturated by hydrogen atoms using electronic stress tensor. Our calculation includes bond orders which are recently proposed based on the stress tensor. It is shown that our bond orders can classify the different types of chemical bonds in those clusters. In particular, we discuss Pd-H bonds associated with the H atoms with high coordination numbers and the difference of H-H bonds in the different Pd clusters from viewpoint of the electronic stress tensor. The notion of "pseudo-spindle structure" is proposed as the region between two atoms where the largest eigenvalue of the electronic stress tensor is negative and corresponding eigenvectors forming a pattern which connects them.Comment: 22 pages, 13 figures, published online, Theoretical Chemistry Account