Mapping genomic and transcriptomic alterations spatially in epithelial cells adjacent to human breast carcinoma.

Almost all genomic studies of breast cancer have focused on well-established tumours because it is technically challenging to study the earliest mutational events occurring in human breast epithelial cells. To address this we created a unique dataset of epithelial samples ductoscopically obtained from ducts leading to breast carcinomas and matched samples from ducts on the opposite side of the nipple. Here, we demonstrate that perturbations in mRNA abundance, with increasing proximity to tumour, cannot be explained by copy number aberrations. Rather, we find a possibility of field cancerization surrounding the primary tumour by constructing a classifier that evaluates where epithelial samples were obtained relative to a tumour (cross-validated micro-averaged AUC = 0.74). We implement a spectral co-clustering algorithm to define biclusters. Relating to over-represented bicluster pathways, we further validate two genes with tissue microarrays and in vitro experiments. We highlight evidence suggesting that bicluster perturbation occurs early in tumour development

The rad18 Gene of Schizosaccharomyces pombe Defines a New Subgroup of the SMC Superfamily Involved in DNA Repair

The rad18 mutant of Schizosaccharomyces pombe is very sensitive to killing by both UV and ¿ radiation. We have cloned and sequenced the rad18 gene and isolated and sequenced its homolog from Saccharomyces cerevisiae, designated RHC18. The predicted Rad18 protein has all the structural properties characteristic of the SMC family of proteins, suggesting a motor function- the first implicated in DNA repair. Gene deletion shows that both rad18 and RHC18 are essential for proliferation. Genetic and biochemical analyses suggest that the product of the rad18 gene acts in a DNA repair pathway for removal of UV-induced DNA damage that is distinct from classical nucleotide excision repair. This second repair pathway involves the products of the rhp51 gene (the homolog of the RAD51 gene of S. cerevisiae) and the rad2 gene

The 74MHz System on the Very Large Array

The Naval Research Laboratory and the National Radio Astronomy Observatory completed implementation of a low frequency capability on the VLA at 73.8 MHz in 1998. This frequency band offers unprecedented sensitivity (~25 mJy/beam) and resolution (~25 arcsec) for low-frequency observations. We review the hardware, the calibration and imaging strategies, comparing them to those at higher frequencies, including aspects of interference excision and wide-field imaging. Ionospheric phase fluctuations pose the major difficulty in calibrating the array. Over restricted fields of view or at times of extremely quiescent ionospheric ``weather'', an angle-invariant calibration strategy can be used. In this approach a single phase correction is devised for each antenna, typically via self-calibration. Over larger fields of view or at times of more normal ionospheric ``weather'' when the ionospheric isoplanatic patch size is smaller than the field of view, we adopt a field-based strategy in which the phase correction depends upon location within the field of view. This second calibration strategy was implemented by modeling the ionosphere above the array using Zernike polynomials. Images of 3C sources of moderate strength are provided as examples of routine, angle-invariant calibration and imaging. Flux density measurements indicate that the 74 MHz flux scale at the VLA is stable to a few percent, and tied to the Baars et al. value of Cygnus A at the 5 percent level. We also present an example of a wide-field image, devoid of bright objects and containing hundreds of weaker sources, constructed from the field-based calibration. We close with a summary of lessons the 74 MHz system offers as a model for new and developing low-frequency telescopes. (Abridged)Comment: 73 pages, 46 jpeg figures, to appear in ApJ

Some Effects of Stator Cone Angle and Blade-tip Leakage on 40 Percent Reaction Turbine Having Rotor-blade Caps

An investigation of the effects of stator cone angle and tip leakage on turbine performance

(OC-6-35)-(2,2′-Bipyridine-κ2 N,N′)dimeth­yl(3-sulfido­propionato-κ2 S,O)platinum(IV)

The title complex, [Pt(CH3)2(SCH2CH2CO2)(C10H8N2)], is formed by the unusual oxidative addition of the disulfide, R 2S2 (R = CH2CH2CO2H), to (2,2′-bipyridine)­dimethyl­platin­um(II) with elimination of RSH. The product contains an unusual six-membered thiol­ate–carboxyl­ate chelate ring. This slightly distorted octa­hedral complex exhibits cis angles ranging from 77.55 (11) to 97.30 (8)° due to the presence of the thiol­ate–carboxyl­ate chelate ring and the constrained bipyridine group. The crystal packing appears to be controlled by a combination of π-stacking [centroid–centroid distance = 3.611 (2) Å] and C—H⋯O inter­actions

Must . . . stay . . . strong!

This is the fourth installment in our trilogy of papers on epistemic modality.It is a recurring matra that epistemic must creates a statement that is weaker than the corresponding flat-footed assertion: It must be raining vs. It’s raining. Contrary to classic discussions of the phenomenon such as by Karttunen, Kratzer, and Veltman, we argue that instead of having a weak semantics, must presupposes the presence of an indirect inference or deduction rather than of a direct observation. This is independent of the strength of the claim being made. Epistemic must is therefore quite similar to evidential markers of indirect evidence known from languages with rich evidential systems. We work towards a formalization of the evidential component, relying on a structured model of information states (analogous to some models used in the belief dynamics literature). We explain why in many contexts, one can perceive a lack of confidence on the part of the speaker who uses must

An Impermeant Ganetespib Analog Inhibits Extracellular Hsp90-Mediated Cancer Cell Migration that Involves Lysyl Oxidase 2-like Protein

Extracellular Hsp90 (eHsp90) activates a number of client proteins outside of cancer cells required for migration and invasion. Therefore, eHsp90 may serve as a novel target for anti-metastatic drugs as its inhibition using impermeant Hsp90 inhibitors would not affect the numerous vital intracellular Hsp90 functions in normal cells. While some eHsp90 clients are known, it is important to establish other proteins that act outside the cell to validate eHsp90 as a drug target to limit cancer spread. Using mass spectrometry we identified two precursor proteins Galectin 3 binding protein (G3BP) and Lysyl oxidase 2-like protein (LOXL2) that associate with eHsp90 in MDA-MB231 breast cancer cell conditioned media and confirmed that LOXL2 binds to eHsp90 in immunoprecipitates. We introduce a novel impermeant Hsp90 inhibitor STA-12-7191 derived from ganetespib and show that it is markedly less toxic to cells and can inhibit cancer cell migration in a dose dependent manner. We used STA-12-7191 to test if LOXL2 and G3BP are potential eHsp90 clients. We showed that while LOXL2 can increase wound healing and compensate for STA-12-7191-mediated inhibition of wound closure, addition of G3BP had no affect on this assay. These findings support of role for LOXL2 in eHsp90 stimulated cancer cell migration and provide preliminary evidence for the use of STA-12-7191 to inhibit eHsp90 to limit cancer invasion