High-order combination effects and biological robustness

Biological systems are robust, in that they can maintain stable phenotypes under varying conditions or attacks. Biological systems are also complex, being organized into many functional modules that communicate through interlocking pathways and feedback mechanisms. In these systems, robustness and complexity are linked because both qualities arise from the same underlying mechanisms. When perturbed by multiple attacks, such complex systems become fragile in both theoretical and experimental studies, and this fragility depends on the number of agents applied. We explore how this relationship can be used to study the functional robustness of a biological system using systematic high-order combination experiments. This presents a promising approach toward many biomedical and bioengineering challenges. For example, high-order experiments could determine the point of fragility for pathogenic bacteria and might help identify optimal treatments against multi-drug resistance. Such studies would also reinforce the growing appreciation that biological systems are best manipulated not by targeting a single protein, but by modulating the set of many nodes that can selectively control a system's functional state

The FIRST-Optical-VLA Survey for Lensed Radio Lobes

We present results from a survey for gravitationally lensed radio lobes. Lensed lobes are a potentially richer source of information about galaxy mass distributions than lensed point sources, which have been the exclusive focus of other recent surveys. Our approach is to identify radio lobes in the FIRST catalog and then search optical catalogs for coincident foreground galaxies, which are candidate lensing galaxies. We then obtain higher-resolution images of these targets at both optical and radio wavelengths, and obtain optical spectra for the most promising candidates. We present maps of several radio lobes that are nearly coincident with galaxies. We have not found any new and unambiguous cases of gravitational lensing. One radio lobe in particular, FOV J0743+1553, has two hot spots that could be multiple images produced by a z=0.19 spiral galaxy, but the lensing interpretation is problematic.Comment: 38 pages, 18 figures, aastex, accepted to A

NICMOS and VLA Observations of the Gravitatonally Lensed Ultraluminous BAL Quasar APM~08279+5255: Detection of a Third Image

We present a suite of observations of the recently identified ultraluminous BAL quasar APM 08279+5255, taken both in the infra-red with the NICMOS high resolution camera on board the Hubble Space Telescope, and at 3.5cm with the Very Large Array. With an inferred luminosity of ~5x10^15 Solar luminosities, APM 08279+5255 is apparently the most luminous system known. Extant ground-based images show that APM 08279+5255 is not point-like, but is instead separated into two components, indicative of gravitational lensing. The much higher resolution images presented here also reveal two point sources, A and B, of almost equal brightness (f_B/f_A=0.782 +/- 0.010), separated by 0."378 +/- 0."001, as well as a third, previously unknown, fainter image, C, seen between the brighter images. While the nature of C is not fully determined, several lines of evidence point to it being a third gravitationally lensed image of the quasar, rather than being the lensing galaxy. Simple models which recover the relative image configuration and brightnesses are presented. While proving to be substantially amplified, APM 08279+5255 possesses an intrinsic bolometric luminosity of ~10^14 to 10^15 Solar luminosities and remains amongst the most luminous objects known.Comment: 21 pages, 5 figures (2 as GIF files); accepted for publication in the Astronomical Journa

MGC2214+3550: A New Binary Quasar

We report the discovery of a binary quasar, MGC2214+3550 A,B, whose components have similar optical spectra at a redshift z=0.88. The quasars are separated on the sky by 3.0", and have a magnitude difference of Delta(m_I)=0.5 mag. The VLA radio map at 3.6 cm shows a single 47mJy radio source with a core-jet morphology that is coincident with the brighter optical quasar A. Gravitational lensing is ruled out by the lack of radio emission from quasar B, and the lack of any visible galaxies to act as the lens. We conclude that MGC 2214+3550 A and B are physically associated. With a projected separation of 12.7h^{-1} kpc (Omega_0=1), MGC 2214+3550 A,B is one of the smallest z>0.5 binary quasars.Comment: 13 pages, 3 .ps figs, submitted to ApJ

Simulating Serial-Target Antibacterial Drug Synergies Using Flux Balance Analysis

Flux balance analysis (FBA) is an increasingly useful approach for modeling the behavior of metabolic systems. However, standard FBA modeling of genetic knockouts cannot predict drug combination synergies observed between serial metabolic targets, even though such synergies give rise to some of the most widely used antibiotic treatments. Here we extend FBA modeling to simulate responses to chemical inhibitors at varying concentrations, by diverting enzymatic flux to a waste reaction. This flux diversion yields very similar qualitative predictions to prior methods for single target activity. However, we find very different predictions for combinations, where flux diversion, which mimics the kinetics of competitive metabolic inhibitors, can explain serial target synergies between metabolic enzyme inhibitors that we confirmed in Escherichia coli cultures. FBA flux diversion opens the possibility for more accurate genome-scale predictions of drug synergies, which can be used to suggest treatments for infections and other diseases

The Central Component of Gravitational Lens Q0957+561

In 1981, a faint radio source (G') was detected near the center of the lensing galaxy of the famous "twin quasar" Q0957+561. It is still unknown whether this central radio source is a third quasar image or an active nucleus of the lensing galaxy, or a combination of both. In an attempt to resolve this ambiguity, we observed Q0957+561 at radio wavelengths of 13cm, 18cm, and 21cm, using the Very Long Baseline Array in combination with the phased Very Large Array and the Green Bank Telescope. We measured the spectrum of G' for the first time and found it to be significantly different from the spectra of the two bright quasar images. This finding suggests that the central component is primarily or entirely emission from the foreground lens galaxy, but the spectrum is also consistent with the hypothesis of a central quasar image suffering free-free absorption. In addition, we confirm the previously-reported VLBI position of G' just north of the optical center of the lens galaxy. The position slightly favors the hypothesis that G' originates in the lens, but is not conclusive. We discuss the prospects for further clarification of this issue.Comment: 18 pages, accepted for publication in A

Ring-Like Structure in the Radio Lobe of MG0248+0641

We present radio and optical observations of MG0248+0641, which contains a kiloparsec-scale ring-like structure in one of its radio lobes. The radio observations show a typical core-double morphology: a central core between two lobes, each of which has a hotspot. The western radio lobe appears as a nearly continuous ring, with linear polarization electric field vectors which are oriented in a radial direction from the ring center. We consider several different interpretations for the nature of this ring, including gravitational lensing of a normal jet by a foreground galaxy. Even though simple lensing models can describe the ring morphology reasonably well, the high linear polarization seen around the ring cannot be easily explained. The chance interposition of a galactic supernova remnant, nova, planetary nebula, or H II region, has been ruled out. The highly polarized ring of MG0248+0641 is much like the prominent ring seen in 3C219, and the multiple ones in 3C310 and Hercules A, suggesting that similar physical processes are producing shell structures in these radio galaxies. The ring in MG0248+0641 may be caused by the formation of ``bubbles'', as a result of instabilities in the energy flow down the western radio jet. It may also be possible that the required instabilities are triggered by the infall of gas, via tidal interaction of the central source with a nearby galaxy. This scenario may be indicated by our marginal detection of an optical source close to the western hotspot.Comment: 21 pages. Submitted to AJ Aug 15, 1997; Accepted Sep 30, 1997. Minor changes in conten

Chemical combinations elucidate pathway interactions and regulation relevant to Hepatitis C replication

SREBP-2, oxidosqualene cyclase (OSC) or lanosterol demethylase were identified as novel sterol pathway-associated targets that, when probed with chemical agents, can inhibit hepatitis C virus (HCV) replication.Using a combination chemical genetics approach, combinations of chemicals targeting sterol pathway enzymes downstream of and including OSC or protein geranylgeranyl transferase I (PGGT) produce robust and selective synergistic inhibition of HCV replication. Inhibition of enzymes upstream of OSC elicit proviral responses that are dominant to the effects of inhibiting all downstream targets.Inhibition of the sterol pathway without inhibition of regulatory feedback mechanisms ultimately results in an increase in HCV replication because of a compensatory upregulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) expression. Increases in HMGCR expression without inhibition of HMGCR enzymatic activity ultimately stimulate HCV replication through increasing the cellular pool of geranylgeranyl pyrophosphate (GGPP).Chemical inhibitors that ultimately prevent SREBP-2 activation, inhibit PGGT or encourage the production of polar sterols have great potential as HCV therapeutics if associated toxicities can be reduced

Radio Astronomy

Contains table of contents for Section 4 and reports on eight research projects.National Science Foundation Grant AST 88-19848National Aeronautics and Space Administration Goddard Space Flight Center Grant NAGW-2310SM Systems and Research, IncNational Aeronautics and Space Administration Goddard Space Flight Center Grant NAG 5-537National Aeronautics and Space Administration Goddard Space Flight Center Grant NAG 5-10Leaders for Manufacturing ProgramNational Aeronautics and Space Administration Goddard Space Flight Center Grant NAS 5-3079