Microlensing Constraints on Broad Absorption and Emission Line Flows in the Quasar H1413+117

We present new integral field spectroscopy of the gravitationally lensed broad absorption line (BAL) quasar H1413+117, covering the ultraviolet to visible rest-frame spectral range. We observe strong microlensing signatures in lensed image D, and we use this microlensing to simultaneously constrain both the broad emission and broad absorption line gas. By modeling the lens system over the range of probable lensing galaxy redshifts and using on a new argument based on the wavelength-independence of the broad line lensing magnifications, we determine that there is no significant broad line emission from smaller than ~20 light days. We also perform spectral decomposition to derive the intrinsic broad emission line (BEL) and continuum spectrum, subject to BAL absorption. We also reconstruct the intrinsic BAL absorption profile, whose features allow us to constrain outflow kinematics in the context of a disk-wind model. We find a very sharp, blueshifted onset of absorption of 1,500 km/s in both C IV and N V that may correspond to an inner edge of a disk-wind's radial outflow. The lower ionization Si IV and Al III have higher-velocity absorption onsets, consistent with a decreasing ionization parameter with radius in an accelerating outflow. There is evidence of strong absorption in the BEL component which indicates a high covering factor for absorption over two orders of magnitude in outflow radius.Comment: 29 pages, 8 figure

Novel cruzain inhibitors for the treatment of Chagas' disease.

The protozoan parasite Trypanosoma cruzi, the etiological agent of Chagas' disease, affects millions of individuals and continues to be an important global health concern. The poor efficacy and unfavorable side effects of current treatments necessitate novel therapeutics. Cruzain, the major cysteine protease of T. cruzi, is one potential novel target. Recent advances in a class of vinyl sulfone inhibitors are encouraging; however, as most potential therapeutics fail in clinical trials and both disease progression and resistance call for combination therapy with several drugs, the identification of additional classes of inhibitory molecules is essential. Using an exhaustive virtual-screening and experimental validation approach, we identify several additional small-molecule cruzain inhibitors. Further optimization of these chemical scaffolds could lead to the development of novel drugs useful in the treatment of Chagas' disease

On the Role of Dewetting Transitions in Host-Guest Binding Free Energy Calculations.

We use thermodynamic integration (TI) and explicit solvent molecular dynamics (MD) simulation to estimate the absolute free energy of host-guest binding. In the unbound state, water molecules visit all of the internally accessible volume of the host, which is fully hydrated on all sides. Upon binding of an apolar guest, the toroidal host cavity is fully dehydrated; thus, during the intermediate λ stages along the integration, the hydration of the host fluctuates between hydrated and dehydrated states. Estimating free energies by TI can be especially challenging when there is a considerable difference in hydration between the two states of interest. We investigate these aspects using the popular TIP3P and TIP4P water models. TI free energy estimates through MD largely depend on water-related interactions, and water dynamics significantly affect the convergence of binding free energy calculations. Our results indicate that wetting/dewetting transitions play a major role in slowing the convergence of free energy estimation. We employ two alternative approaches-one analytical and the other empirically based on actual MD sampling-to correct for the standard state free energy. This correction is sizable (up to 4 kcal/mol), and the two approaches provide corrections that differ by about 1 kcal/mol. For the system considered here, the TIP4P water model combined with an analytical correction for the standard state free energy provides higher overall accuracy. This observation might be transferable to other systems in which water-related contributions dominate the binding process

Stroke-Like Presentation Following Febrile Seizure in a Patient with 1q43q44 Deletion Syndrome

Hemiconvulsion–hemiplegia–epilepsy syndrome (HHE) is a rare outcome of prolonged hemiconvulsion that is followed by diffuse unilateral hemispheric edema, hemiplegia, and ultimately hemiatrophy of the affected hemisphere and epilepsy. Here, we describe the case of a 3-year-old male with a 1;3 translocation leading to a terminal 1q43q44 deletion and a terminal 3p26.1p26.3 duplication that developed HHE after a prolonged febrile seizure and discuss the pathogenesis of HHE in the context of the patient’s complex genetic background

Stroke-Like Presentation Following Febrile Seizure in a Patient with 1q43q44 Deletion Syndrome

Hemiconvulsion–hemiplegia–epilepsy syndrome (HHE) is a rare outcome of prolonged hemiconvulsion that is followed by diffuse unilateral hemispheric edema, hemiplegia, and ultimately hemiatrophy of the affected hemisphere and epilepsy. Here, we describe the case of a 3-year-old male with a 1;3 translocation leading to a terminal 1q43q44 deletion and a terminal 3p26.1p26.3 duplication that developed HHE after a prolonged febrile seizure and discuss the pathogenesis of HHE in the context of the patient’s complex genetic background

Signal peptide mutations in RANK prevent downstream activation of NF-κB

Familial expansile osteolysis and related disorders are caused by heterozygous tandem duplication mutations in the signal peptide region of the gene encoding receptor activator of NF-κB (RANK), a receptor critical for osteoclast formation and function. Previous studies have shown that overexpression of these mutant proteins causes constitutive activation of NF-κB signaling in vitro, and it has been assumed that this accounts for the focal osteolytic lesions that are seen in vivo. We show here that constitutive activation of NF-κB occurred in HEK293 cells overexpressing wild-type or mutant RANK but not in stably transfected cell lines expressing low levels of each RANK gene. Importantly, only cells expressing wild-type RANK demonstrated ligand-dependent activation of NF-κB. When overexpressed, mutant RANK did not localize to the plasma membrane but localized to extensive areas of organized smooth endoplasmic reticulum, whereas, as expected, wild-type RANK was detected at the plasma membrane and in the Golgi apparatus. This intracellular accumulation of the mutant proteins is probably the result of lack of signal peptide cleavage because, using two in vitro translation systems, we demonstrate that the mutations in RANK prevent cleavage of the signal peptide. In conclusion, signal peptide mutations lead to accumulation of RANK in the endoplasmic reticulum and prevent direct activation by RANK ligand. These results strongly suggest that the increased osteoclast formation/activity caused by these mutations cannot be explained by studying the homozygous phenotype alone but requires further detailed investigation of the heterozygous expression of the mutant RANK proteins. © 2011 American Society for Bone and Mineral Researc

St. Louis Area Earthquake Hazards Mapping Project: Seismic and Liquefaction Hazard Maps

We present probabilistic and deterministic seismic and liquefaction hazard maps for the densely populated St. Louis metropolitan area that account for the expected effects of surficial geology on earthquake ground shaking. Hazard calculations were based on a map grid of 0.005°, or about every 500 m, and are thus higher in resolution than any earlier studies. To estimate ground motions at the surface of the model (e.g., site amplification), we used a new detailed near-surface shear-wave velocity model in a 1D equivalent- linear response analysis. When compared with the 2014 U.S. Geological Survey (USGS) National Seismic Hazard Model, which uses a uniform firm-rock-site condition, the new probabilistic seismic-hazard estimates document much more variability. Hazard levels for upland sites (consisting of bedrock and weathered bedrock overlain by loess-covered till and drift deposits), show up to twice the ground-motion values for peak ground acceleration (PGA), and similar ground-motion values for 1.0 s spectral acceleration (SA). Probabilistic ground-motion levels for lowland alluvial floodplain sites (generally the 20-40-m-thick modern Mississippi and Missouri River floodplain deposits overlying bedrock) exhibit up to twice the ground-motion levels for PGA, and up to three times the ground-motion levels for 1.0 s SA. Liquefaction probability curves were developed from available standard penetration test data assuming typical lowland and upland water table levels. A simplified liquefaction hazard map was created from the 5%-in-50-year probabilistic ground-shaking model. The liquefaction hazard ranges from low (\u3c40% of area expected to liquefy) in the uplands to severe (\u3e60% of area expected to liquefy) in the lowlands. Because many transportation routes, power and gas transmission lines, and population centers exist in or on the highly susceptible lowland alluvium, these areas in the St. Louis region are at significant potential risk from seismically induced liquefaction and associated ground deformation

Strategies for Improved CALIPSO Aerosol Optical Depth Estimates

In the spring of 2010, the Cloud-Aerosol Lidar and Infrared Pathfinder Satellite Observation (CALIPSO) project will be releasing version 3 of its level 2 data products. In this paper we describe several changes to the algorithms and code that yield substantial improvements in CALIPSO's retrieval of aerosol optical depths (AOD). Among these are a retooled cloud-clearing procedure and a new approach to determining the base altitudes of aerosol layers in the planetary boundary layer (PBL). The results derived from these modifications are illustrated using case studies prepared using a late beta version of the level 2 version 3 processing code