SCRIBBLE is required for pregnancy-induced alveologenesis in the adult mammary gland

The cell polarity protein SCRIB is a critical regulator of polarization, cell migration and tumourigenesis. Whereas SCRIB is known to regulate early stages of mouse mammary gland development, its function in the adult gland is not known. Using an inducible RNAi mouse model for downregulating SCRIB expression, we report an unexpected role for SCRIB as a positive regulator of cell proliferation during pregnancy associated mammary alveologenesis. SCRIB was required in the epithelial cell compartment of the mammary gland. Lack of SCRIB attenuated prolactin-induced activation of the JAK2/STAT5 signaling pathway. In addition, loss of SCRIB resulted in the downregulation of PRLR at cell surface and accumulation in intracellular structures that express markers of the Golgi apparatus and the recycling endosome. Unlike its role in virgin gland as a negative regulator cell proliferation, SCRIB is a positive regulator of mammary epithelial cell proliferation during pregnancy

Identification of prostate-enriched proteins by in-depth proteomic analyses of expressed prostatic secretions in urine

Urinary expressed prostatic secretion or \u201cEPS-urine\u201d is proximal tissue fluid that is collected after a digital rectal exam (DRE). EPS-urine is a rich source of prostatederived proteins that can be used for biomarker discovery for prostate cancer (PCa) and other prostatic diseases. We previously conducted a comprehensive proteome analysis of direct expressed prostatic secretions (EPS). In the current study, we defined the proteome of EPS-urine employing Multidimensional Protein Identification Technology (MudPIT) and providing a comprehensive catalogue of this body fluid for future biomarker studies. We identified 1022 unique proteins in a heterogeneous cohort of 11 EPS-urines derived from biopsy negative noncancer diagnoses with some benign prostatic diseases (BPH) and lowgrade PCa, representative of secreted prostate and immune system-derived proteins in a urine background. We further applied MudPIT-based proteomics to generate and compare the differential proteome from a subset of pooled urines (pre-DRE) and EPS-urines (post- DRE) from noncancer and PCa patients. The direct proteomic comparison of these highly controlled patient sample pools enabled us to define a list of prostate-enriched proteins detectable in EPS-urine and distinguishable from a complex urine protein background. A combinatorial analysis of both proteomics data sets and systematic integration with publicly available proteomics data of related body fluids, human tissue transcriptomic data, and immunohistochemistry images from the Human Protein Atlas database allowed us to demarcate a robust panel of 49 prostate-derived proteins in EPS-urine. Finally, we validated the expression of seven of these proteins using Western blotting, supporting the likelihood that they originate from the prostate. The definition of these prostatic proteins in EPS-urine samples provides a reference for future investigations for prostatic-disease biomarker studies

Integrated proteomic and transcriptomic profiling of mouse lung development and Nmyc target genes

Although microarray analysis has provided information regarding the dynamics of gene expression during development of the mouse lung, no extensive correlations have been made to the levels of corresponding protein products. Here, we present a global survey of protein expression during mouse lung organogenesis from embryonic day E13.5 until adulthood using gel-free two-dimensional liquid chromatography coupled to shotgun tandem mass spectrometry (MudPIT). Mathematical modeling of the proteomic profiles with parallel DNA microarray data identified large groups of gene products with statistically significant correlation or divergence in coregulation of protein and transcript levels during lung development. We also present an integrative analysis of mRNA and protein expression in Nmyc loss- and gain-of-function mutants. This revealed a set of 90 positively and negatively regulated putative target genes. These targets are evidence that Nmyc is a regulator of genes involved in mRNA processing and a repressor of the imprinted gene Igf2r in the developing lung

Global Survey of Organ and Organelle Protein Expression in Mouse: Combined Proteomic and Transcriptomic Profiling

SummaryOrgans and organelles represent core biological systems in mammals, but the diversity in protein composition remains unclear. Here, we combine subcellular fractionation with exhaustive tandem mass spectrometry-based shotgun sequencing to examine the protein content of four major organellar compartments (cytosol, membranes [microsomes], mitochondria, and nuclei) in six organs (brain, heart, kidney, liver, lung, and placenta) of the laboratory mouse, Mus musculus. Using rigorous statistical filtering and machine-learning methods, the subcellular localization of 3274 of the 4768 proteins identified was determined with high confidence, including 1503 previously uncharacterized factors, while tissue selectivity was evaluated by comparison to previously reported mRNA expression patterns. This molecular compendium, fully accessible via a searchable web-browser interface, serves as a reliable reference of the expressed tissue and organelle proteomes of a leading model mammal

Immunohistochemical study of N-epsilon-carboxymethyl lysine (CML) in human brain: relation to vascular dementia

<p>Abstract</p> <p>Background</p> <p>Advanced glycation end-products (AGEs) and their receptor (RAGE) occur in dementia of the Alzheimer's type and diabetic microvascular disease. Accumulation of AGEs relates to risk factors for vascular dementia with ageing, including hypertension and diabetes. Cognitive dysfunction in vascular dementia may relate to microvascular disease resembling that in diabetes. We tested if, among people with cerebrovascular disease, (1) those with dementia have higher levels of neuronal and vascular AGEs and (2) if cognitive dysfunction depends on neuronal and/or vascular AGE levels.</p> <p>Methods</p> <p>Brain Sections from 25 cases of the OPTIMA (Oxford Project to Investigate Memory and Ageing) cohort, with varying degrees of cerebrovascular pathology and cognitive dysfunction (but only minimal Alzheimer type pathology) were immunostained for N^<it>ε</it>-(carboxymethyl)-lysine (CML), the most abundant AGE. The level of staining in vessels and neurons in the cortex, white matter and basal ganglia was compared to neuropsychological and other clinical measures.</p> <p>Results</p> <p>The probability of cortical neurons staining positive for CML was higher in cases with worse cognition (p = 0.01) or a history of hypertension (p = 0.028). Additionally, vascular CML staining related to cognitive impairment (p = 0.02) and a history of diabetes (p = 0.007). Neuronal CML staining in the basal ganglia related to a history of hypertension (p = 0.002).</p> <p>Conclusion</p> <p>CML staining in cortical neurons and cerebral vessels is related to the severity of cognitive impairment in people with cerebrovascular disease and only minimal Alzheimer pathology. These findings support the possibility that cerebral accumulation of AGEs may contribute to dementia in people with cerebrovascular disease.</p

Restricting quark matter models by gravitational wave observation

We consider the possibilities for obtaining information about the equation of state for quark matter by using future direct observational data on gravitational waves. We study the nonradial oscillations of both fluid and spacetime modes of pure quark stars. If we observe the $f$ and the lowest $w_{\rm II}$ modes from quark stars, by using the simultaneously obtained radiation radius we can constrain the bag constant $B$ with reasonable accuracy, independently of the $s$ quark mass.Comment: To appear in Phys. Rev.

Perturbation Theory with a Variational Basis: the Generalized Gaussian Effective Potential

The perturbation theory with a variational basis is constructed and analyzed.The generalized Gaussian effective potential is introduced and evaluated up to the second order for selfinteracting scalar fields in one and two spatial dimensions. The problem of the renormalization of the mass is discussed in details. Thermal corrections are incorporated. The comparison between the finite temperature generalized Gaussian effective potential and the finite temperature effective potential is critically analyzed. The phenomenon of the restoration at high temperature of the symmetry broken at zero temperature is discussed.Comment: RevTex, 49 pages, 16 eps figure