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

Shape matters: effects of silver nanospheres and wires on human alveolar epithelial cells

<p>Abstract</p> <p>Background</p> <p>In nanotoxicology, the exact role of particle shape, in relation to the composition, on the capacity to induce toxicity is largely unknown. We investigated the toxic and immunotoxic effects of silver wires (length: 1.5 - 25 μm; diameter 100 - 160 nm), spherical silver nanoparticles (30 nm) and silver microparticles (<45 μm) on alveolar epithelial cells (A549).</p> <p>Methods</p> <p>Wires and nanoparticles were synthesized by wet-chemistry methods and extensively characterized. Cell viability and cytotoxicity were assessed and potential immunotoxic effects were investigated. To compare the effects on an activated and a resting immune system, cells were stimulated with rhTNF-α or left untreated. Changes in intracellular free calcium levels were determined using calcium imaging. Finally, ion release from the particles was assessed by ICP-MS and the effects of released ions on cell viability and cytotoxicity were tested.</p> <p>Results</p> <p>No effects were observed for the spherical particles, whereas the silver wires significantly reduced cell viability and increased LDH release from A549 cells. Cytokine promoter induction and NF-κB activation decreased in a concentration dependent manner similar to the decrease seen in cell viability. In addition, a strong increase of intracellular calcium levels within minutes after addition of wires was observed. This toxicity was not due to free silver ions, since the samples with the highest ion release did not induce toxicity and ion release control experiments with cells treated with pre-incubated medium did not show any effects either.</p> <p>Conclusions</p> <p>These data showed that silver wires strongly affect the alveolar epithelial cells, whereas spherical silver particles had no effect. This supports the hypothesis that shape is one of the important factors that determine particle toxicity.</p

Numerical study of halo concentrations in dark-energy cosmologies

We study the concentration parameters, their mass dependence and redshift evolution, of dark-matter halos in different dark-energy cosmologies with constant and time-variable equation of state, and compare them with "standard'' Lambda-CDM and OCDM models. We find that previously proposed algorithms for predicting halo concentrations can be well adapted to dark-energy models. When centred on the analytically expected values, halo concentrations show a log-normal distribution with a uniform standard deviation of ~0.2. The dependence of averaged halo concentrations on mass and redshift permits a simple fit of the form (1+z) c=c0 (M/M0)^a, with a~-0.1 throughout. We find that the cluster concentration depends on the dark energy equation of state at the cluster formation redshift z_{coll} through the linear growth factor D_+(z_{coll}). As a simple correction accounting for dark-energy cosmologies, we propose scaling c0 from Lambda-CDM with the ratio of linear growth factors, c0 -> c0 D_+(z_{coll})/D_{+,Lambda-CDM}(z_{coll}).Comment: 11 pages, submitted to Astronomy & Astrophysic

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

Observation of Dirac surface states in the noncentrosymmetric superconductor BiPd

Funding from the MPG-UBC center and the Engineering and Physical Sciences Research Council (EP/I031014/1 and EP/L505079/1) are acknowledged. This work was supported by the DFG within projects STA315/8-1 and BE5190/1-1.Materials with strong spin-orbit coupling (SOC) have in recent years become a subject of intense research due to their potential applications in spintronics and quantum information technology. In particular, in systems which break inversion symmetry, SOC facilitates the Rashba-Dresselhaus effect, leading to a lifting of spin degeneracy in the bulk and intricate spin textures of the Bloch wave functions. Here, by combining angular resolved photoemission (ARPES) and low temperature scanning tunneling microscopy (STM) measurements with relativistic first-principles band structure calculations, we examine the role of SOC in single crystals of noncentrosymmetric BiPd. We report the detection of several Dirac surface states, one of which exhibits an extremely large spin splitting. Unlike the surface states in inversion-symmetric systems, the Dirac surface states of BiPd have completely different properties at opposite faces of the crystal and are not trivially linked by symmetry. The spin-splitting of the surface states exhibits a strong anisotropy by itself, which can be linked to the low in-plane symmetry of the surface termination.PostprintPeer reviewe

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