Introduction

Recently, important strides have been made in clinical neurology and clinical neurosurgery, culminating in improved patient care. The last ten years have witnessed a new sophistication in neuroradiology, and the clear development of neuroophthalmology as a subspecialty. It is to these areas that the speakers at the 27th Stoneburner Lecture Series addressed themselves. The first part of the program emphasized cerebral vascular disease, and is presented in this issue. The second part of the program related primarily to the clinical care of patients with mechanical brain injury, brain tumors, and seizures, and will be presented in the following issue of the MCV Quarterly

Introduction

This issue represents the second part of the 27th Annual Stoneburner Lecture Series delivered at the Medical College of Virginia in February 1974. Here, we are dealing with clinical applications of recent advances in our understanding of brain mechanisms and brain disease processes

Two New Gravitationally Lensed Double Quasars from the Sloan Digital Sky Survey

We report the discoveries of the two-image gravitationally lensed quasars, SDSS J0746+4403 and SDSS J1406+6126, selected from the Sloan Digital Sky Survey (SDSS). SDSS J0746+4403, which will be included in our lens sample for statistics and cosmology, has a source redshift of z_s=2.00, an estimated lens redshift of z_l~0.3, and an image separation of 1.08". SDSS J1406+6126 has a source redshift of z_s=2.13, a spectroscopically measured lens redshift of z_l=0.27, and an image separation of 1.98". We find that the two quasar images of SDSS J1406+6126 have different intervening MgII absorption strengths, which are suggestive of large variations of absorbers on kpc scales. The positions and fluxes of both the lensed quasar systems are easily reproduced by simple mass models with reasonable parameter values. These objects bring to 18 the number of lensed quasars that have been discovered from the SDSS data.Comment: 25 pages, 6 figures, The Astronomical Journal accepte

SDSS J115517.35+634622.0: A Newly Discovered Gravitationally Lensed Quasar

We report the discovery of SDSSJ115517.35+634622.0, a previously unknown gravitationally lensed quasar. The lens system exhibits two images of a $z = 2.89$ quasar, with an image separation of 1{\farcs}832 \pm 0.007 . Near-IR imaging of the system reveals the presence of the lensing galaxy between the two quasar images. Based on absorption features seen in the Sloan Digital Sky Survey (SDSS) spectrum, we determine a lens galaxy redshift of $z = 0.1756$. The lens is rather unusual in that one of the quasar images is only 0{\farcs}22\pm0{\farcs}07 ($\sim 0.1 R_{\rm eff}$) from the center of the lens galaxy and photometric modeling indicates that this image is significantly brighter than predicted by a SIS model. This system was discovered in the course of an ongoing search for strongly lensed quasars in the dataset from the SDSS.Comment: 18 pages, 6 figures. Accepted for publication in A

Protein/Protein Interactions in the Mammalian Heme Degradation Pathway: Heme Oxygenase-2, Cytochrome P450 Reductase, and Biliverdin Reductase

Heme oxygenase (HO) catalyzes the rate-limiting step in the O2- dependent degradation of heme to biliverdin, CO, and iron with electrons delivered from NADPH via cytochrome P450 reductase (CPR). Biliverdin reductase (BVR) then catalyzes conversion of bili­verdin to bilirubin. We describe mutagenesis combined with kinetic, spectroscopic (fluorescence and NMR), surface plasmon resonance, cross-linking, gel filtration, and analytical ultracentrifugation studies aimed at evaluating interactions of HO-2 with CPR and BVR. Based on these results, we propose a model in which HO-2 and CPR form a dynamic ensemble of complex(es) that precede formation of the productive electron transfer complex. The 1H-15N TROSY NMR spectrum of HO-2 reveals specific residues, including Leu-201, near the heme face of HO-2 that are affected by the addition of CPR, im­plicating these residues at the HO/CPR interface. Alanine substitu­tions at HO-2 residues Leu-201 and Lys-169 cause a respective 3- and 22-fold increase in Km values for CPR, consistent with a role for these residues in CPR binding. Sedimentation velocity experiments confirm the transient nature of the HO-2·CPR complex (Kd = 15.1 μm). Our results also indicate that HO-2 and BVR form a very weak complex that is only captured by cross-linking. For example, under conditions where CPR affects the 1H-15N TROSY NMR spectrum of HO-2, BVR has no effect. Fluorescence quenching experiments also suggest that BVR binds HO-2 weakly, if at all, and that the previously reported high affinity of BVR for HO is artifactual, resulting from the effects of free heme (dissociated from HO) on BVR fluorescenc

Protein/Protein Interactions in the Mammalian Heme Degradation Pathway: Heme Oxygenase-2, Cytochrome P450 Reductase, and Biliverdin Reductase

Heme oxygenase (HO) catalyzes the rate-limiting step in the O2- dependent degradation of heme to biliverdin, CO, and iron with electrons delivered from NADPH via cytochrome P450 reductase (CPR). Biliverdin reductase (BVR) then catalyzes conversion of bili­verdin to bilirubin. We describe mutagenesis combined with kinetic, spectroscopic (fluorescence and NMR), surface plasmon resonance, cross-linking, gel filtration, and analytical ultracentrifugation studies aimed at evaluating interactions of HO-2 with CPR and BVR. Based on these results, we propose a model in which HO-2 and CPR form a dynamic ensemble of complex(es) that precede formation of the productive electron transfer complex. The 1H-15N TROSY NMR spectrum of HO-2 reveals specific residues, including Leu-201, near the heme face of HO-2 that are affected by the addition of CPR, im­plicating these residues at the HO/CPR interface. Alanine substitu­tions at HO-2 residues Leu-201 and Lys-169 cause a respective 3- and 22-fold increase in Km values for CPR, consistent with a role for these residues in CPR binding. Sedimentation velocity experiments confirm the transient nature of the HO-2·CPR complex (Kd = 15.1 μm). Our results also indicate that HO-2 and BVR form a very weak complex that is only captured by cross-linking. For example, under conditions where CPR affects the 1H-15N TROSY NMR spectrum of HO-2, BVR has no effect. Fluorescence quenching experiments also suggest that BVR binds HO-2 weakly, if at all, and that the previously reported high affinity of BVR for HO is artifactual, resulting from the effects of free heme (dissociated from HO) on BVR fluorescenc

Structure of the Proline Utilization A Proline Dehydrogenase Domain Inactivated by \u3ci\u3eN\u3c/i\u3e-propargylglycine Provides Insight into Conformational Changes Induced by Substrate Binding and Flavin Reduction

Proline utilization A (PutA) from Escherichia coli is a flavoprotein that has mutually exclusive roles as a transcriptional repressor of the put regulon and a membrane-associated enzyme that catalyzes the oxidation of proline to glutamate. Previous studies have shown that the binding of proline in the proline dehydrogenase (PRODH) active site and subsequent reduction of the FAD trigger global conformational changes that enhance PutA-membrane affinity. These events cause PutA to switch from its repressor to enzymatic role, but the mechanism by which this signal is propagated from the active site to the distal membrane-binding domain is largely unknown. Here, it is shown that N-propargylglycine irreversibly inactivates PutA by covalently linking the flavin N(5) atom to the ε-amino of Lys329. Furthermore, inactivation locks PutA into a conformation that may mimic the proline reduced, membrane-associated form. The 2.15 Å resolution structure of the inactivated PRODH domain suggests that the initial events involved in broadcasting the reduced flavin state to the distal membrane binding domain include major reorganization of the flavin ribityl chain, severe (35 degree) butterfly bending of the isoalloxazine ring, and disruption of an electrostatic network involving the flavin N(5), Arg431, and Asp370. The structure also provides information about conformational changes associated with substrate binding. This analysis suggests that the active site is incompletely assembled in the absence of the substrate, and the binding of proline draws together conserved residues in helix 8 and the β1-αl loop to complete the active site

New Pulsars from an Arecibo Drift Scan Search

We report the discovery of pulsars J0030+0451, J0711+0931, and J1313+0931 that were found in a search of 470 square degrees at 430 MHz using the 305m Arecibo telescope. The search has an estimated sensitivity for long period, low dispersion measure, low zenith angle, and high Galactic latitude pulsars of ~1 mJy, comparable to previous Arecibo searches. Spin and astrometric parameters for the three pulsars are presented along with polarimetry at 430 MHz. PSR J0030+0451, a nearby pulsar with a period of 4.8 ms, belongs to the less common category of isolated millisecond pulsars. We have measured significant polarization in PSR J0030+0451 over more than 50% of the period, and use these data for a detailed discussion of its magnetospheric geometry. Scintillation observations of PSR J0030+0451 provide an estimate of the plasma turbulence level along the line of sight through the local interstellar medium.Comment: 21 pages, 4 figures, Accepted for Publication in Ap

Discovery of Two Gravitationally Lensed Quasars with Image Separations of 3 Arcseconds from the Sloan Digital Sky Survey

We report the discovery of two doubly-imaged quasars, SDSS J100128.61+502756.9 and SDSS J120629.65+433217.6, at redshifts of 1.838 and 1.789 and with image separations of 2.86'' and 2.90'', respectively. The objects were selected as lens candidates from the Sloan Digital Sky Survey (SDSS). Based on the identical nature of the spectra of the two quasars in each pair and the identification of the lens galaxies, we conclude that the objects are gravitational lenses. The lenses are complicated; in both systems there are several galaxies in the fields very close to the quasars, in addition to the lens galaxies themselves. The lens modeling implies that these nearby galaxies contribute significantly to the lens potentials. On larger scales, we have detected an enhancement in the galaxy density near SDSS J100128.61+502756.9. The number of lenses with image separation of ~3'' in the SDSS already exceeds the prediction of simple theoretical models based on the standard Lambda-dominated cosmology and observed velocity function of galaxies.Comment: 24 pages, 9 figures, accepted for publication in Ap

Small-angle X-ray Scattering Studies of the Oligomeric State and Quaternary Structure of the Trifunctional Proline Utilization A (PutA) Flavoprotein from \u3ci\u3eEscherichia coli\u3c/i\u3e

Background: Trifunctional proline utilization A (PutA) proteins are multifunctional flavoproteins that catalyze two reactions and repress transcription of the put regulon. Results: PutA from Escherichia coli is a V-shaped dimer, with the DNA-binding domain mediating dimerization. Conclusion: Oligomeric state and quaternary structures are not conserved by PutAs. Significance: The first three-dimensional structural information for any trifunctional PutA is reported