Identification and characterization of small compound inhibitors of human FATP2

Fatty acid transport proteins (FATPs) are bifunctional proteins, which transport long chain fatty acids into cells and activate very long chain fatty acids by esterification with coenzyme A. In an effort to understand the linkage between cellular fatty acid transport and the pathology associated with excessive accumulation of exogenous fatty acids, we targeted FATP-mediated fatty acid transport in a high throughput screen of more than 100,000 small diverse chemical compounds in yeast expressing human FATP2 (hsFATP2). Compounds were selected for their ability to depress the transport of the fluorescent long chain fatty acid analogue, C1-BODIPY-C12. Among 234 hits identified in the primary screen, 5 compounds, each representative of a structural class, were further characterized in the human Caco-2 and HepG2 cell lines, each of which normally expresses FATP2, and in 3T3-L1 adipocytes, which do not. These compounds were effective in inhibiting uptake with IC50s in the low micromolar range in both Caco-2 and HepG2 cells. Inhibition of transport was highly specific for fatty acids and there were no effects of these compounds on cell viability, trans-epithelial electrical resistance, glucose transport, or long chain acyl-CoA synthetase activity. The compounds were less effective when tested in 3T3-L1 adipocytes suggesting selectivity of inhibition. These results suggest fatty acid transport can be inhibited in a FATP-specific manner without causing cellular toxicity

Probing the physiology of ASH neuron in Caenorhabditis elegans using electric current stimulation

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/98694/1/ApplPhysLett_99_053702.pd

Young stars and non-stellar emission in the aligned radio galaxy 3C 256

We present ground-based images of the z=1.824 radio galaxy 3C 256 in the standard BVRIJHK filters and an interference filter centered at 8800A, a Hubble Space Telescope image in a filter dominated by Ly-alpha emission (F336W), and spectra covering rest-frame wavelengths from Ly-alpha to [O III] 5007. Together with published polarimetry observations, we use these to decompose the overall spectral energy distribution into nebular continuum emission, scattered quasar light, and stellar emission. The nebular continuum and scattered light together comprise half (one third) of the V-band (K-band) light within a 4-arcsec aperture, and are responsible for the strong alignment between the optical/near-infrared light and the radio emission. The stellar emission is dominated by a population estimated to be 100-200 Myr old (assuming a Salpeter IMF), and formed in a short burst with a peak star formation rate of 1-4x10^3 Msun/yr. The total stellar mass is estimated to be no more than 2x10^{11} Msun, which is far less than other luminous radio galaxies at similar redshifts, and suggests that 3C 256 will undergo further star formation or mergers.Comment: 35 pages including 10 figures; to appear in Nov 10 Ap

Review of public comments on proposed seismic design criteria

During the first quarter of 1988, the Nuclear Regulatory Commission (NRC) prepared a proposed Revision 2 to the NUREG-0800 Standard Review Plan (SRP) Sections 2.5.2 (Vibratory Ground Motion), 3.7.1 (Seismic Design Parameters), 3.7.2 (Seismic Systems Analysis) and 3.7.3 (Seismic Subsystem Analysis). The proposed Revision 2 to the SRP was a result of many years' work carried out by the NRC and the nuclear industry on the Unresolved Safety Issue (USI) A-40: ''Seismic Design Criteria.'' The background material related to NRC's efforts for resolving the A-40 issue is described in NUREG-1233. In June 1988, the proposed Revision 2 of the SRP was issued by NRC for public review and comments. Comments were received from Sargent and Lundy Engineers, Westinghouse Electric Corporation, Stevenson and Associates, Duke Power Company, General Electric Company and Electric Power Research Institute. In September 1988, Brookhaven National Laboratory (BNL) and its consultants (C.J. Costantino, R.P. Kennedy, J. Stevenson, M. Shinozuka and A.S. Veletsos) were requested to carry out a review of the comments received from the above six organizations. The objective of this review was to assist the NRC staff with the evaluation and resolution of the public comments. This review was initiated during October 1988 and it was completed on January 1989. As a result of this review, a set of modifications to the above mentioned sections of the SRP were recommended by BNL and its consultants. This paper summarizes the recommended modifications. 4 refs

Geodesic motions versus hydrodynamic flows in a gravitating perfect fluid: Dynamical equivalence and consequences

Stimulated by the methods applied for the observational determination of masses in the central regions of the AGNs, we examine the conditions under which, in the interior of a gravitating perfect fluid source, the geodesic motions and the general relativistic hydrodynamic flows are dynamically equivalent to each other. Dynamical equivalence rests on the functional similarity between the corresponding (covariantly expressed) differential equations of motion and is obtained by conformal transformations. In this case, the spaces of the solutions of these two kinds of motion are isomorphic. In other words, given a solution to the problem "hydrodynamic flow in a perfect fluid", one can always construct a solution formally equivalent to the problem "geodesic motion of a fluid element" and vice versa. Accordingly, we show that, the observationally determined nuclear mass of the AGNs is being overestimated with respect to the real, physical one. We evaluate the corresponding mass-excess and show that it is not always negligible with respect to the mass ofthe central dark object, while, under circumstances, can be even larger than the rest-mass of the circumnuclear gas involved.Comment: LaTeX file, 22 page

Age-Related Degradation of Nuclear Power Plant Structures and Components

This paper summarizes and highlights the results of the initial phase of a research project on the assessment of aged and degraded structures and components important to the safe operation of nuclear power plants (NPPs). A review of age-related degradation of structures and passive components at NPPs was performed. Instances of age-related degradation have been collected and reviewed. Data were collected from plant generated documents such as Licensing Event Reports, NRC generic communications, NUREGs and industry reports. Applicable cases of degradation occurrences were reviewed and then entered into a computerized database. The results obtained from the review of degradation occurrences are summarized and discussed. Various trending analyses were performed to identify which structures and components are most affected, whether degradation occurrences are worsening, and what was the most common aging mechanisms. The paper also discusses potential aging issues and degradation-susceptible structures and passive components which would have the greatest impact on plant risk

Supermassive Stars in Quasar Disks

We propose that supermassive stars may form in quasar accretion disks, and we discuss possible observational consequences. The structure and stability of very massive stars are reviewed. Because of high accretion rates, quasar disks are massive and the fringes of their optically luminous parts are prone to fragmentation. Starting from a few hundred solar masses, a dominant fragment will grow to the isolation mass, which is a significant fraction of the disk mass, more quickly than the fragment contracts onto the stellar main sequence. A gap will form in the disk and the star will migrate inward on the accretion timescale, which is comparable to the star's main sequence lifetime. By interrupting the gas supply to the inner disk, the gap may temporarily dim and redden the quasar. The final stages of stellar migration will be a strong source of low-frequency gravitational waves.Comment: 14 pages, 4 figures; accepted to ApJ; expanded discussio

Epitaxial growth in dislocation-free strained alloy films: Morphological and compositional instabilities

The mechanisms of stability or instability in the strained alloy film growth are of intense current interest to both theorists and experimentalists. We consider dislocation-free, coherent, growing alloy films which could exhibit a morphological instability without nucleation. We investigate such strained films by developing a nonequilibrium, continuum model and by performing a linear stability analysis. The couplings of film-substrate misfit strain, compositional stress, deposition rate, and growth temperature determine the stability of film morphology as well as the surface spinodal decomposition. We consider some realistic factors of epitaxial growth, in particular the composition dependence of elastic moduli and the coupling between top surface and underlying bulk of the film. The interplay of these factors leads to new stability results. In addition to the stability diagrams both above and below the coherent spinodal temperature, we also calculate the kinetic critical thickness for the onset of instability as well as its scaling behavior with respect to misfit strain and deposition rate. We apply our results to some real growth systems and discuss the implications related to some recent experimental observations.Comment: 26 pages, 13 eps figure

Experiences with community engagement and informed consent in a genetic cohort study of severe childhood diseases in Kenya

<p>Abstract</p> <p>Background</p> <p>The potential contribution of community engagement to addressing ethical challenges for international biomedical research is well described, but there is relatively little documented experience of community engagement to inform its development in practice. This paper draws on experiences around community engagement and informed consent during a genetic cohort study in Kenya to contribute to understanding the strengths and challenges of community engagement in supporting ethical research practice, focusing on issues of communication, the role of field workers in 'doing ethics' on the ground and the challenges of community consultation.</p> <p>Methods</p> <p>The findings are based on action research methods, including analysis of community engagement documentation and the observations of the authors closely involved in their development and implementation. Qualitative and quantitative content analysis has been used for documentation of staff meetings and trainings, a meeting with 24 community leaders, and 40 large public and 70 small community group meetings. Meeting minutes from a purposive sample of six community representative groups have been analysed using a thematic framework approach.</p> <p>Results</p> <p>Field workers described challenges around misunderstandings about research, perceived pressure for recruitment and challenges in explaining the study. During consultation, leaders expressed support for the study and screening for sickle cell disease. In community meetings, there was a common interpretation of research as medical care. Concerns centred on unfamiliar procedures. After explanations of study procedures to leaders and community members, few questions were asked about export of samples or the archiving of samples for future research.</p> <p>Conclusions</p> <p>Community engagement enabled researchers to take account of staff and community opinions and issues during the study and adapt messages and methods to address emerging ethical challenges. Field workers conducting informed consent faced complex issues and their understanding, attitudes and communication skills were key influences on ethical practice. Community consultation was a challenging concept to put into practice, illustrating the complexity of assessing information needs and levels of deliberation that are appropriate to a given study.</p

Nearby quasar remnants and ultra-high energy cosmic rays

As recently suggested, nearby quasar remnants are plausible sites of black-hole based compact dynamos that could be capable of accelerating ultra-high energy cosmic rays (UHECRs). In such a model, UHECRs would originate at the nuclei of nearby dead quasars, those in which the putative underlying supermassive black holes are suitably spun-up. Based on galactic optical luminosity, morphological type, and redshift, we have compiled a small sample of nearby objects selected to be highly luminous, bulge-dominated galaxies, likely quasar remnants. The sky coordinates of these galaxies were then correlated with the arrival directions of cosmic rays detected at energies $> 40$ EeV. An apparently significant correlation appears in our data. This correlation appears at closer angular scales than those expected when taking into account the deflection caused by typically assumed IGM or galactic magnetic fields over a charged particle trajectory. Possible scenarios producing this effect are discussed, as is the astrophysics of the quasar remnant candidates. We suggest that quasar remnants be also taken into account in the forthcoming detailed search for correlations using data from the Auger Observatory.Comment: 2 figures, 4 tables, 11 pages. Final version to appear in Physical Review