Measurement of T1 of the ultrashort T2* components in white matter of the brain at 3T.

Recent research demonstrates that white matter of the brain contains not only long T2 components, but a minority of ultrashort T2* components. Adiabatic inversion recovery prepared dual echo ultrashort echo time (IR-dUTE) sequences can be used to selectively image the ultrashort T2* components in white matter of the brain using a clinical whole body scanner. The T2*s of the ultrashort T2* components can be quantified using mono-exponential decay fitting of the IR-dUTE signal at a series of different TEs. However, accurate T1 measurement of the ultrashort T2* components is technically challenging. Efficient suppression of the signal from the majority of long T2 components is essential for robust T1 measurement. In this paper we describe a novel approach to this problem based on the use of IR-dUTE data acquisitions with different TR and TI combinations to selectively detect the signal recovery of the ultrashort T2* components. Exponential recovery curve fitting provides efficient T1 estimation, with minimized contamination from the majority of long T2 components. A rubber phantom and a piece of bovine cortical bone were used for validation of this approach. Six healthy volunteers were studied. An averaged T2* of 0.32 ± 0.09 ms, and a short mean T1 of 226 ± 46 ms were demonstrated for the healthy volunteers at 3T

Sintering oxide ceramics based on AI[2]O[3] and ZrO[2], activated by MgO, TiO[2] and SiO[2] additives

The positive effect of the addition of MgO and TiO[2] in an amount of no more than 1 wt. % on sintering and physico-mechanical properties of alumina ceramics is established. Addition of 5% of SiO[2] to A1[2]O[3] provides the mechanism of liquid phase sintering of ceramics, which leads to increase in its density and strength up to 480 MPa. In ceramic system A1[2]O[3] - ZrO[2] - Y[2]O[3] highest level of physical and mechanical properties of the composition had a hypereutectic composition 16.6% A1[2]O[3] - 76% Z1O[2] - 7.4% Y[2]O[3]. In this composition two mechanisms of hardening are realized simultaneously, such as transformational hardening by t-m -ZrO[2] transition and dispersion strengthening with high-modulus particles of [alpha]- A1[2]O[3]

Computational design of syntheses leading to compound libraries or isotopically labelled targets

Although computer programs for retrosynthetic planning have shown improved and in some cases quite satisfactory performance in designing routes leading to specific, individual targets, no algorithms capable of planning syntheses of entire target libraries - important in modern drug discovery - have yet been reported. This study describes how network-search routines underlying existing retrosynthetic programs can be adapted and extended to multi-target design operating on one common search graph, benefitting from the use of common intermediates and reducing the overall synthetic cost. Implementation in the Chematica platform illustrates the usefulness of such algorithms in the syntheses of either (i) all members of a user-defined library, or (ii) the most synthetically accessible members of this library. In the latter case, algorithms are also readily adapted to the identification of the most facile syntheses of isotopically labelled targets. These examples are industrially relevant in the context of hitto-lead optimization and syntheses of isotopomers of various bioactive molecules

Extensive role of the general regulatory factors, Abf1 and Rap1, in determining genome-wide chromatin structure in budding yeast

The packaging of eukaryotic DNA into chromatin has profound consequences for gene regulation, as well as for other DNA transactions such as recombination, replication and repair. Understanding how this packaging is determined is consequently a pressing problem in molecular genetics. DNA sequence, chromatin remodelers and transcription factors affect chromatin structure, but the scope of these influences on genome-wide nucleosome occupancy patterns remains uncertain. Here, we use high resolution tiling arrays to examine the contributions of two general regulatory factors, Abf1 and Rap1, to nucleosome occupancy in Saccharomyces cerevisiae. These factors have each been shown to bind to a few hundred promoters, but we find here that thousands of loci show localized regions of altered nucleosome occupancy within 1 h of loss of Abf1 or Rap1 binding, and that altered chromatin structure can occur via binding sites having a wide range of affinities. These results indicate that DNA-binding transcription factors affect chromatin structure, and probably dynamics, throughout the genome to a much greater extent than previously appreciated

8-Azatetracyclines: Synthesis and Evaluation of a Novel Class of Tetracycline Antibacterial Agents

bS Supporting Information ABSTRACT: A novel series of fully synthetic 8-azatetracyclines was prepared and evaluated for antibacterial activity. Compounds were identified that overcome both efflux (tet(K)) and ribosomal protection (tet(M)) tetracycline resistance mechanisms and are active against Gram-positive and Gram-negative organisms. Two compounds were identified that exhibit comparable efficacy to marketed tetracyclines in in vivo models of bacterial infection. The tetracycline class of antibacterial agents has seen wide-spread clinical use for over 50 years due to its broad spectrum anti-bacterial activity.1 Tetracyclines inhibit bacterial growth by prevent-ing protein biosynthesis through binding to the 30S ribosome

The 2010 Interim Report of the Long-Baseline Neutrino Experiment Collaboration Physics Working Groups

Corresponding author R.J.Wilson ([email protected]); 113 pages, 90 figuresCorresponding author R.J.Wilson ([email protected]); 113 pages, 90 figuresIn early 2010, the Long-Baseline Neutrino Experiment (LBNE) science collaboration initiated a study to investigate the physics potential of the experiment with a broad set of different beam, near- and far-detector configurations. Nine initial topics were identified as scientific areas that motivate construction of a long-baseline neutrino experiment with a very large far detector. We summarize the scientific justification for each topic and the estimated performance for a set of far detector reference configurations. We report also on a study of optimized beam parameters and the physics capability of proposed Near Detector configurations. This document was presented to the collaboration in fall 2010 and updated with minor modifications in early 2011

Advancing Research on Racial–Ethnic Health Disparities: Improving Measurement Equivalence in Studies with Diverse Samples

To conduct meaningful, epidemiologic research on racial–ethnic health disparities, racial–ethnic samples must be rendered equivalent on other social status and contextual variables via statistical controls of those extraneous factors. The racial–ethnic groups must also be equally familiar with and have similar responses to the methods and measures used to collect health data, must have equal opportunity to participate in the research, and must be equally representative of their respective populations. In the absence of such measurement equivalence, studies of racial–ethnic health disparities are confounded by a plethora of unmeasured, uncontrolled correlates of race–ethnicity. Those correlates render the samples, methods, and measures incomparable across racial–ethnic groups, and diminish the ability to attribute health differences discovered to race–ethnicity vs. to its correlates. This paper reviews the non-equivalent yet normative samples, methodologies and measures used in epidemiologic studies of racial–ethnic health disparities, and provides concrete suggestions for improving sample, method, and scalar measurement equivalence

Mitochondrial Electron Transport Is the Cellular Target of the Oncology Drug Elesclomol

Elesclomol is a first-in-class investigational drug currently undergoing clinical evaluation as a novel cancer therapeutic. The potent antitumor activity of the compound results from the elevation of reactive oxygen species (ROS) and oxidative stress to levels incompatible with cellular survival. However, the molecular target(s) and mechanism by which elesclomol generates ROS and subsequent cell death were previously undefined. The cellular cytotoxicity of elesclomol in the yeast S. cerevisiae appears to occur by a mechanism similar, if not identical, to that in cancer cells. Accordingly, here we used a powerful and validated technology only available in yeast that provides critical insights into the mechanism of action, targets and processes that are disrupted by drug treatment. Using this approach we show that elesclomol does not work through a specific cellular protein target. Instead, it targets a biologically coherent set of processes occurring in the mitochondrion. Specifically, the results indicate that elesclomol, driven by its redox chemistry, interacts with the electron transport chain (ETC) to generate high levels of ROS within the organelle and consequently cell death. Additional experiments in melanoma cells involving drug treatments or cells lacking ETC function confirm that the drug works similarly in human cancer cells. This deeper understanding of elesclomol's mode of action has important implications for the therapeutic application of the drug, including providing a rationale for biomarker-based stratification of patients likely to respond in the clinical setting