Combined Inactivation of pRB and Hippo Pathways Induces Dedifferentiation in the Drosophila Retina

Functional inactivation of the Retinoblastoma (pRB) pathway is an early and obligatory event in tumorigenesis. The importance of pRB is usually explained by its ability to promote cell cycle exit. Here, we demonstrate that, independently of cell cycle exit control, in cooperation with the Hippo tumor suppressor pathway, pRB functions to maintain the terminally differentiated state. We show that mutations in the Hippo signaling pathway, wts or hpo, trigger widespread dedifferentiation of rbf mutant cells in the Drosophila eye. Initially, rbf wts or rbf hpo double mutant cells are morphologically indistinguishable from their wild-type counterparts as they properly differentiate into photoreceptors, form axonal projections, and express late neuronal markers. However, the double mutant cells cannot maintain their neuronal identity, dedifferentiate, and thus become uncommitted eye specific cells. Surprisingly, this dedifferentiation is fully independent of cell cycle exit defects and occurs even when inappropriate proliferation is fully blocked by a de2f1 mutation. Thus, our results reveal the novel involvement of the pRB pathway during the maintenance of a differentiated state and suggest that terminally differentiated Rb mutant cells are intrinsically prone to dedifferentiation, can be converted to progenitor cells, and thus contribute to cancer advancement

PADB : Published Association Database

<p>Abstract</p> <p>Background</p> <p>Although molecular pathway information and the International HapMap Project data can help biomedical researchers to investigate the aetiology of complex diseases more effectively, such information is missing or insufficient in current genetic association databases. In addition, only a few of the environmental risk factors are included as gene-environment interactions, and the risk measures of associations are not indexed in any association databases.</p> <p>Description</p> <p>We have developed a published association database (PADB; <url>http://www.medclue.com/padb</url>) that includes both the genetic associations and the environmental risk factors available in PubMed database. Each genetic risk factor is linked to a molecular pathway database and the HapMap database through human gene symbols identified in the abstracts. And the risk measures such as odds ratios or hazard ratios are extracted automatically from the abstracts when available. Thus, users can review the association data sorted by the risk measures, and genetic associations can be grouped by human genes or molecular pathways. The search results can also be saved to tab-delimited text files for further sorting or analysis. Currently, PADB indexes more than 1,500,000 PubMed abstracts that include 3442 human genes, 461 molecular pathways and about 190,000 risk measures ranging from 0.00001 to 4878.9.</p> <p>Conclusion</p> <p>PADB is a unique online database of published associations that will serve as a novel and powerful resource for reviewing and interpreting huge association data of complex human diseases.</p

Menopausal Status Modifies Breast Cancer Risk Associated with the Myeloperoxidase (MPO) G463A Polymorphism in Caucasian Women: A Meta-Analysis

BACKGROUND: Breast cancer susceptibility may be modulated partly through polymorphisms in oxidative enzymes, one of which is myeloperoxidase (MPO). Association of the low transcription activity variant allele A in the G463A polymorphism has been investigated for its association with breast cancer risk, considering the modifying effects of menopausal status and antioxidant intake levels of cases and controls. METHODOLOGY/PRINCIPAL FINDINGS: To obtain a more precise estimate of association using the odds ratio (OR), we performed a meta-analysis of 2,975 cases and 3,427 controls from three published articles of Caucasian populations living in the United States. Heterogeneity among studies was tested and sensitivity analysis was applied. The lower transcriptional activity AA genotype of MPO in the pre-menopausal population showed significantly reduced risk (OR 0.56-0.57, p = 0.03) in contrast to their post-menopausal counterparts which showed non-significant increased risk (OR 1.14; p = 0.34-0.36). High intake of antioxidants (OR 0.67-0.86, p = 0.04-0.05) and carotenoids (OR 0.68-0.86, p = 0.03-0.05) conferred significant protection in the women. Stratified by menopausal status, this effect was observed in pre-menopausal women especially those whose antioxidant intake was high (OR 0.42-0.69, p = 0.04). In post-menopausal women, effect of low intake elicited susceptibility (OR 1.19-1.67, p = 0.07-0.17) to breast cancer. CONCLUSIONS/SIGNIFICANCE: Based on a homogeneous Caucasian population, the MPO G463A polymorphism places post-menopausal women at risk for breast cancer, where this effect is modified by diet

Rapid assembly of customized TALENs into multiple

Transcriptional activator-like effector nucleases (TALENs) have become a powerful tool for genome editing. Here we present an efficient TALEN assembly approach in which TALENs are assembled by direct Golden Gate ligation into Gateway® Entry vectors from a repeat variable di-residue (RVD) plasmid array. We constructed TALEN pairs targeted to mouse Ddx3 subfamily genes, and demonstrated that our modified TALEN assembly approach efficiently generates accurate TALEN moieties that effectively introduce mutations into target genes. We generated "user friendly" TALEN Entry vectors containing TALEN expression cassettes with fluorescent reporter genes that can be efficiently transferred via Gateway (LR) recombination into different delivery systems. We demonstrated that the TALEN Entry vectors can be easily transferred to an adenoviral delivery system to expand application to cells that are difficult to transfect. Since TALENs work in pairs, we also generated a TALEN Entry vector set that combines a TALEN pair into one PiggyBac transposon-based destination vector. The approach described here can also be modified for construction of TALE transcriptional activators, repressors or other functional domains. © 2013 Zhang et al

Epidemiological Features of Infantile Hypertrophic Pyloric Stenosis in Taiwanese Children: A Nation-Wide Analysis of Cases during 1997–2007

OBJECTIVE: To describe the epidemiological characteristics of infantile hypertrophic pyloric stenosis (IHPS) in ethnic Chinese children. MATERIALS AND METHODS: We reviewed the National Health Insurance claims database and analyzed data from children less than one year of age who had been diagnosed with IHPS (ICD-9-CM 750.5) and had undergone pyloromyotomy (ICD-9-CM 43.3). We analyzed the incidence, gender, age at diagnosis, length of hospital stay, seasonal variation and cost of IHPS from data collected between January 1997 and December 2007. RESULTS: A total of 1,077 infants met inclusion criteria, including 889 boys and 188 girls. The annual incidence of IHPS ranged from 0.30 to 0.47 per 1,000 live births with a mean incidence of 0.39 per 1,000 live births. Between 2002 and 2007, the incidence showed a declining trend (P = 0.025) with coincidentally increasing trends for both exclusive breastfeeding (P = 0.014) and breastfeeding plus bottle feeding (P = 0.004). The male-to-female rate ratio was dynamic and increased from 3.03 during the first two weeks of life to 8.94 during the 8(th) through 10th weeks of life. The overall male-to-female rate ratio was 4.30. The mean age at diagnosis was 43.1 ± 2.4 days. After analyzing the months of birth and hospital admission, no seasonal variation associated with IHPS was detected. The mean length of hospital stay was 8.28 ± 7.10 days. CONCLUSIONS: The incidence of IHPS in Taiwan, a country with a majority ethnic Chinese population, was lower than observed incidences in Caucasian populations living in Western countries. Breastfeeding campaigns and low maternal smoking rates may contribute to the lower incidence of IHPS in Taiwan. However, additional studies with longer follow-up periods are needed

Characterization of collective ground states in single-layer NbSe2

Layered transition metal dichalcogenides (TMDs) are ideal systems for exploring the effects of dimensionality on correlated electronic phases such as charge density wave (CDW) order and superconductivity. In bulk NbSe2 a CDW sets in at TCDW = 33 K and superconductivity sets in at Tc = 7.2 K. Below Tc these electronic states coexist but their microscopic formation mechanisms remain controversial. Here we present an electronic characterization study of a single 2D layer of NbSe2 by means of low temperature scanning tunneling microscopy/spectroscopy (STM/STS), angle-resolved photoemission spectroscopy (ARPES), and electrical transport measurements. We demonstrate that 3x3 CDW order in NbSe2 remains intact in 2D. Superconductivity also still remains in the 2D limit, but its onset temperature is depressed to 1.9 K. Our STS measurements at 5 K reveal a CDW gap of {\Delta} = 4 meV at the Fermi energy, which is accessible via STS due to the removal of bands crossing the Fermi level for a single layer. Our observations are consistent with the simplified (compared to bulk) electronic structure of single-layer NbSe2, thus providing new insight into CDW formation and superconductivity in this model strongly-correlated system.Comment: Nature Physics (2015), DOI:10.1038/nphys352