Victorian Mining Communities of Colorado: An Investigation of a Society Through its Architecture

For purposes of clarity, the study is divided into two parts. Part I includes discussions on Colorado mining history and community planning and is intended to provide a framework for the reader to relate the architectural analysis which follows. Part II is introduced with a section dealing with architectural styles to familiarize the reader with their influence on the architecture of the mining communities as well as the country as a whole. This introductory discussion is followed by the architectural analysis of building types comprising 19th century Colorado mining communities. The analysis is divided into the categories of residential, commercial, institutional, and industrial within which all such building types fall. Photographs by the author are used to provide visual illustrations. Historical pictures have purposely been avoided for the intent is to show present day remains. The study offers an insight into the life, times and architecture of a unique bygone era

A SILAC-based Approach Identifies Substrates of Caspase-dependent Cleavage upon TRAIL-induced Apoptosis

The extracellular ligand-induced extrinsic pathway of apoptosis is executed via caspase protease cascades that activate downstream effectors by means of site-directed proteolysis. Here we identify proteome changes upon the induction of apoptosis by the cytokine tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in a Jurkat T cell line. We detected caspase-dependent cleavage substrates by quantifying protein intensities before and after TRAIL induction in SDS gel slices. Apoptotic protein cleavage events are identified by a characteristic stable isotope labeling with amino acids in cell culture (SILAC) ratio pattern across gel slices that results from differential migration of the cleaved and uncleaved proteins. We applied a statistical test to define apoptotic substrates in the proteome. Our approach identified more than 650 of these cleaved proteins in response to TRAIL-induced apoptosis, including many previously unknown substrates and cleavage sites. Inhibitor treatment combined with triple SILAC demonstrated that the detected cleavage events were caspase dependent. Proteins located in the lumina of organelles such as mitochondria and endoplasmic reticulum were significantly underrepresented in the substrate population. Interestingly, caspase cleavage is generally observed in not only one but several members of stable complexes, but often with lower stoichiometry. For instance, all five proteins of the condensin I complex were cleaved upon TRAIL treatment. The apoptotic substrate proteome data can be accessed and visualized in the MaxQB database and might prove useful for basic and clinical research into TRAIL-induced apoptosis. The technology described here is extensible to a wide range of other proteolytic cleavage events

Two Multiplex Assays That Simultaneously Identify 22 Possible Mutation Sites in the KRAS, BRAF, NRAS and PIK3CA Genes

Recently a number of randomized trials have shown that patients with advanced colorectal cancer do not benefit from therapies targeting the epidermal growth factor receptor when their tumors harbor mutations in the KRAS, BRAF and PIK3CA genes. We developed two multiplex assays that simultaneously screen 22 nucleotides in the KRAS, NRAS, BRAF and PIK3CA genes for mutations. The assays were validated on 294 tumor DNA samples from patients with advanced colorectal cancer. In these samples 119 KRAS codon 12 and 13 mutations had been identified by sequence analysis, 126 tumors were wild-type for KRAS and the analysis failed in 49 of the 294 samples due to poor DNA quality. The two mutation assays detected 130 KRAS mutations, among which were 3 codon 61 mutations, and in addition 32 PIK3CA, 13 BRAF and 6 NRAS mutations. In 19 tumors a KRAS mutation was found together with a mutation in the PIK3CA gene. One tumor was mutant for both PIK3CA and BRAF. In summary, the mutations assays identified 161 tumors with a mutation, 120 were wild-type and the analysis failed in 13. The material cost of the 2 mutation assays was calculated to be 8-fold lower than the cost of sequencing required to obtain the same data. In addition, the mutation assays are less labor intensive. We conclude that the performance of the two multiplex mutation assays was superior to direct sequencing. In addition, these assays are cheaper and easier to interpret. The assays may also be of use for selection of patients with other tumor types

Functional improvement and maturation of rat and human engineered heart tissue by chronic electrical stimulation

Spontaneously beating engineered heart tissue (EHT) represents an advanced in vitro model for drug testing and disease modeling, but cardiomyocytes in EHTs are less mature and generate lower forces than in the adult heart. We devised a novel pacing system integrated in a setup for videooptical recording of EHT contractile function over time and investigated whether sustained electrical field stimulation improved EHT properties. EHTs were generated from neonatal rat heart cells (rEHT, n=96) or human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (hEHT, n=19). Pacing with biphasic pulses was initiated on day 4 of culture. REHT continuously paced for 16-18 days at 0.5Hz developed 2.2× higher forces than nonstimulated rEHT. This was reflected by higher cardiomyocyte density in the center of EHTs, increased connexin-43 abundance as investigated by two-photon microscopy and remarkably improved sarcomere ultrastructure including regular M-bands. Further signs of tissue maturation include a rightward shift (to more physiological values) of the Ca(2+)-response curve, increased force response to isoprenaline and decreased spontaneous beating activity. Human EHTs stimulated at 2Hz in the first week and 1.5Hz thereafter developed 1.5× higher forces than nonstimulated hEHT on day 14, an ameliorated muscular network of longitudinally oriented cardiomyocytes and a higher cytoplasm-to-nucleus ratio. Taken together, continuous pacing improved structural and functional properties of rEHTs and hEHTs to an unprecedented level. Electrical stimulation appears to be an important step toward the generation of fully mature EHT

A Keck/DEIMOS spectroscopic survey of faint Galactic satellites: searching for the least massive dwarf galaxies

[abridged] We present the results of a spectroscopic survey of the recently discovered faint Milky Way satellites Boo, UMaI, UMaII and Wil1. Using the DEIMOS spectrograph on Keck, we have obtained samples that contain from 15 to 85 probable members of these satellites for which we derive radial velocities precise to a few km/s down to i~21-22. About half of these stars are observed with a high enough S/N to estimate their metallicity to within \pm0.2 dex. From this dataset, we show that UMaII is the only object that does not show a clear radial velocity peak. However, the measured systemic radial velocity (v_r=115\pm5 km/s) is in good agreement with recent simulations in which this object is the progenitor of the recently discovered Orphan Stream. The three other satellites show velocity dispersions that make them highly dark-matter dominated systems. In particular the Willman 1 object is not a globular cluster given its metallicity scatter over -2.0<[Fe/H]<-1.0 and is therefore almost certainly a dwarf galaxy or dwarf galaxy remnant. We measure a radial velocity dispersion of only 4.3_{-1.3}^{+2.3} km/s around a systemic velocity of -12.3\pm2.3 km/s which implies a mass-to-light ratio of ~700 and a total mass of ~5x10^5 Msun for this satellite, making it the least massive satellite galaxy known to date. Such a low mass could mean that the 10^7 Msun limit that had until now never been crossed for Milky Way and Andromeda satellite galaxies may only be an observational limit and that fainter, less massive systems exist within the Local Group. However, more modeling and an extended search for potential extra-tidal stars are required to rule out the possibility that these systems have not been significantly heated by tidal interaction.Comment: 24 pages, 11 figures, MNRAS accepte

The optical calcium frequency standards of PTB and NIST

We describe the current status of the Ca optical frequency standards with laser-cooled neutral atoms realized in two different laboratories for the purpose of developing a possible future optical atomic clock. Frequency measurements performed at the Physikalisch-Technische Bundesanstalt (PTB) and the National Institute of Standards and Technology (NIST) make the frequency of the clock transition of 40Ca one of the best known optical frequencies (relative uncertainty 1.2e-14) and the measurements of this frequency in both laboratories agree to well within their respective uncertainties. Prospects for improvement by orders of magnitude in the relative uncertainty of the standard look feasible.Comment: 13 pages, 11 figures, to appear in Comptes Rendus Physiqu

The VO: A Powerful Tool for Global Astronomy

Since its inception in the early 2000's, the Virtual Observatory (VO), developed as a collaboration of many national and international projects, has become a major factor in the discovery and dissemination of astronomical information worldwide. The International Virtual Observatory Alliance (IVOA) has been coordinating all these efforts worldwide to ensure a common VO framework that enables transparent access to and interoperability of astronomy resources (data and software) around the world. The VO is not a magic solution to all astronomy data management challenges but it does bring useful solutions in many areas borne out by the fact that VO interfaces are broadly found in astronomy's major data centres and projects worldwide. Astronomy data centres have been building VO services on top of their existing data services to increase interoperability with other VO-compliant data resources to take advantage of the continuous and increasing development of VO applications. VO applications have made multi-instrument and multi-wavelength science, a difficult and fruitful part of astronomy, somewhat easier. More recently, several major new astronomy projects have been directly adopting VO standards to build their data management infrastructure, giving birth to ‘VO built-in' archives. Embracing the VO framework from the beginning brings the double gain of not needing to reinvent the wheel and ensuring from the start interoperability with other astronomy VO resources. Some of the IVOA standards are also starting to be used by neighbour disciplines like planetary sciences. There is still quite a lot to be done on the VO, in particular tackling the upcoming big data challenge and how to find interoperable solutions to the new data analysis paradigm of bringing and running the software close to the data. We report on the current status and also desire to encourage others to adopt VO technology and engage them in the effort of developing the VO. Thus, we wish to ensure that the VO standards fit new astronomy projects requirements and needs

The Substructure Hierarchy in Dark Matter Haloes

We present a new algorithm for identifying the substructure within simulated dark matter haloes. The method is an extension of that proposed by Tormen et al. (2004) and Giocoli et al. (2008a), which identifies a subhalo as a group of self-bound particles that prior to being accreted by the main progenitor of the host halo belonged to one and the same progenitor halo (hereafter satellite). However, this definition does not account for the fact that these satellite haloes themselves may also have substructure, which thus gives rise to sub-subhaloes, etc. Our new algorithm identifies substructures at all levels of this hierarchy, and we use it to determine the mass function of all substructure (counting sub-haloes, sub-subhaloes, etc.). On average, haloes which formed more recently tend to have a larger mass fraction in substructure and to be less concentrated than average haloes of the same mass. We provide quantitative fits to these correlations. Even though our algorithm is very different from that of Gao et al. (2004), we too find that the subhalo mass function per unit mass at redshift z = 0 is universal. This universality extends to any redshift only if one accounts for the fact that host haloes of a given mass are less concentrated at higher redshifts, and concentration and substructure abundance are anti-correlated. This universality allows a simple parametrization of the subhalo mass function integrated over all host halo masses, at any given time. We provide analytic fits to this function which should be useful in halo model analyses which equate galaxies with halo substructure when interpreting clustering in large sky surveys. Finally, we discuss systematic differences in the subhalo mass function that arise from different definitions of (host) halo mass.Comment: 18 pages, 24 figures, accepted for publication on MNRA