Keratin 6a marks mammary bipotential progenitor cells that can give rise to a unique tumor model resembling human normal-like breast cancer.

Progenitor cells are considered an important cell of origin of human malignancies. However, there has not been any single gene that can define mammary bipotential progenitor cells, and as such it has not been possible to use genetic methods to introduce oncogenic alterations into these cells in vivo to study tumorigenesis from them. Keratin 6a is expressed in a subset of mammary luminal epithelial cells and body cells of terminal end buds. By generating transgenic mice using the Keratin 6a (K6a) gene promoter to express tumor virus A (tva), which encodes the receptor for avian leukosis virus subgroup A (ALV/A), we provide direct evidence that K6a(+) cells are bipotential progenitor cells, and the first demonstration of a non-basal location for some biopotential progenitor cells. These K6a(+) cells were readily induced to form mammary tumors by intraductal injection of RCAS (an ALV/A-derived vector) carrying the gene encoding the polyoma middle T antigen. Tumors in this K6a-tva line were papillary and resembled the normal breast-like subtype of human breast cancer. This is the first model of this subtype of human tumors and thus may be useful for preclinical testing of targeted therapy for patients with normal-like breast cancer. These observations also provide direct in vivo evidence for the hypothesis that the cell of origin affects mammary tumor phenotypes

The role of metabolic remodeling in macrophage polarization and its effect on skeletal muscle regeneration

Macrophages are crucial for tissue homeostasis. Based on their activation, they might display classical/M1 or alternative/M2 phenotypes. M1 macrophages produce pro-inflammatory cytokines, reactive oxygen species (ROS), and nitric oxide (NO). M2 macrophages upregulate arginase-1 and reduce NO and ROS levels; they also release anti-inflammatory cytokines, growth factors, and polyamines, thus promoting angiogenesis and tissue healing. Moreover, M1 and M2 display key metabolic differences; M1 polarization is characterized by an enhancement in glycolysis and in the pentose phosphate pathway (PPP) along with a decreased oxidative phosphorylation (OxPhos), whereas M2 are characterized by an efficient OxPhos and reduced PPP. Recent Advances: The glutamine-related metabolism has been discovered as crucial for M2 polarization. Vice versa, flux discontinuities in the Krebs cycle are considered additional M1 features; they lead to increased levels of immunoresponsive gene 1 and itaconic acid, to isocitrate dehydrogenase 1-downregulation and to succinate, citrate, and isocitrate over-expression

Deep level defect in Si-implanted GaN n +-p junction

The results of deep level transient spectroscopy (DLTS) experiments on GaN junctions, fabricated by silicon implantation, were discussed. An unusual appearance of a minority peak in the majority carrier DLTS spectra within the interfacial region of the junctions was observed. The presence of this minority peak suggested a high concentration of a deep level defect within the interfacial region.published_or_final_versio

Growth factor restriction impedes progression of wound healing following cataract surgery: identification of VEGF as a putative therapeutic target

Secondary visual loss occurs in millions of patients due to a wound-healing response, known as posterior capsule opacification (PCO), following cataract surgery. An intraocular lens (IOL) is implanted into residual lens tissue, known as the capsular bag, following cataract removal. Standard IOLs allow the anterior and posterior capsules to become physically connected. This places pressure on the IOL and improves contact with the underlying posterior capsule. New open bag IOL designs separate the anterior capsule and posterior capsules and further reduce PCO incidence. It is hypothesised that this results from reduced cytokine availability due to greater irrigation of the bag. We therefore explored the role of growth factor restriction on PCO using human lens cell and tissue culture models. We demonstrate that cytokine dilution, by increasing medium volume, significantly reduced cell coverage in both closed and open capsular bag models. This coincided with reduced cell density and myofibroblast formation. A screen of 27 cytokines identified nine candidates whose expression profile correlated with growth. In particular, VEGF was found to regulate cell survival, growth and myofibroblast formation. VEGF provides a therapeutic target to further manage PCO development and will yield best results when used in conjunction with open bag IOL designs

Wide-Scale Analysis of Human Functional Transcription Factor Binding Reveals a Strong Bias towards the Transcription Start Site

We introduce a novel method to screen the promoters of a set of genes with shared biological function, against a precompiled library of motifs, and find those motifs which are statistically over-represented in the gene set. The gene sets were obtained from the functional Gene Ontology (GO) classification; for each set and motif we optimized the sequence similarity score threshold, independently for every location window (measured with respect to the TSS), taking into account the location dependent nucleotide heterogeneity along the promoters of the target genes. We performed a high throughput analysis, searching the promoters (from 200bp downstream to 1000bp upstream the TSS), of more than 8000 human and 23,000 mouse genes, for 134 functional Gene Ontology classes and for 412 known DNA motifs. When combined with binding site and location conservation between human and mouse, the method identifies with high probability functional binding sites that regulate groups of biologically related genes. We found many location-sensitive functional binding events and showed that they clustered close to the TSS. Our method and findings were put to several experimental tests. By allowing a "flexible" threshold and combining our functional class and location specific search method with conservation between human and mouse, we are able to identify reliably functional TF binding sites. This is an essential step towards constructing regulatory networks and elucidating the design principles that govern transcriptional regulation of expression. The promoter region proximal to the TSS appears to be of central importance for regulation of transcription in human and mouse, just as it is in bacteria and yeast.Comment: 31 pages, including Supplementary Information and figure

The Galactic Center Black Hole Laboratory

The super-massive 4 million solar mass black hole Sagittarius~A* (SgrA*) shows flare emission from the millimeter to the X-ray domain. A detailed analysis of the infrared light curves allows us to address the accretion phenomenon in a statistical way. The analysis shows that the near-infrared flare amplitudes are dominated by a single state power law, with the low states in SgrA* limited by confusion through the unresolved stellar background. There are several dusty objects in the immediate vicinity of SgrA*. The source G2/DSO is one of them. Its nature is unclear. It may be comparable to similar stellar dusty sources in the region or may consist predominantly of gas and dust. In this case a particularly enhanced accretion activity onto SgrA* may be expected in the near future. Here the interpretation of recent data and ongoing observations are discussed.Comment: 30 pages - 7 figures - accepted for publication by Springer's "Fundamental Theories of Physics" series; summarizing GC contributions of 2 conferences: 'Equations of Motion in Relativistic Gravity' at the Physikzentrum Bad Honnef, Bad Honnef, Germany, (Feb. 17-23, 2013) and the COST MP0905 'The Galactic Center Black Hole Laboratory' Granada, Spain (Nov. 19 - 22, 2013

A formally verified compiler back-end

This article describes the development and formal verification (proof of semantic preservation) of a compiler back-end from Cminor (a simple imperative intermediate language) to PowerPC assembly code, using the Coq proof assistant both for programming the compiler and for proving its correctness. Such a verified compiler is useful in the context of formal methods applied to the certification of critical software: the verification of the compiler guarantees that the safety properties proved on the source code hold for the executable compiled code as well

Genome wide association mapping of grain arsenic, copper, molybdenum and zinc in rice (Oryza sativa L.) grown at four international field sites

Peer reviewedPublisher PD

Gain control network conditions in early sensory coding

Gain control is essential for the proper function of any sensory system. However, the precise mechanisms for achieving effective gain control in the brain are unknown. Based on our understanding of the existence and strength of connections in the insect olfactory system, we analyze the conditions that lead to controlled gain in a randomly connected network of excitatory and inhibitory neurons. We consider two scenarios for the variation of input into the system. In the first case, the intensity of the sensory input controls the input currents to a fixed proportion of neurons of the excitatory and inhibitory populations. In the second case, increasing intensity of the sensory stimulus will both, recruit an increasing number of neurons that receive input and change the input current that they receive. Using a mean field approximation for the network activity we derive relationships between the parameters of the network that ensure that the overall level of activity of the excitatory population remains unchanged for increasing intensity of the external stimulation. We find that, first, the main parameters that regulate network gain are the probabilities of connections from the inhibitory population to the excitatory population and of the connections within the inhibitory population. Second, we show that strict gain control is not achievable in a random network in the second case, when the input recruits an increasing number of neurons. Finally, we confirm that the gain control conditions derived from the mean field approximation are valid in simulations of firing rate models and Hodgkin-Huxley conductance based models

Roy-Steiner equations for pion-nucleon scattering

Starting from hyperbolic dispersion relations, we derive a closed system of Roy-Steiner equations for pion-nucleon scattering that respects analyticity, unitarity, and crossing symmetry. We work out analytically all kernel functions and unitarity relations required for the lowest partial waves. In order to suppress the dependence on the high-energy regime we also consider once- and twice-subtracted versions of the equations, where we identify the subtraction constants with subthreshold parameters. Assuming Mandelstam analyticity we determine the maximal range of validity of these equations. As a first step towards the solution of the full system we cast the equations for the $\pi\pi\to\bar NN$ partial waves into the form of a Muskhelishvili-Omn\`es problem with finite matching point, which we solve numerically in the single-channel approximation. We investigate in detail the role of individual contributions to our solutions and discuss some consequences for the spectral functions of the nucleon electromagnetic form factors.Comment: 106 pages, 18 figures; version published in JHE