Fusion of simian immunodeficiency virus with liposomes and erythrocyte ghost membranes: Effects of lipid composition, pH and calcium

Simian immunodeficiency virus from macaques (SIV(mac)) is closely related in its structure and biological activity to human immunodeficiency virus, and is the best animal model for the acquired immunodeficiency syndrome. We investigated the kinetics of membrane fusion between SIV(mac) and phospholipid vesicles and the effects of various parameters on this process. Purified SIV(mac) was labelled with octadecyl rhodamine B chloride, and fusion was continuously monitored as the dilution of the probe in target membranes. These studies show that SIV(mac) fusion is strongly dependent upon the liposome composition. Fusion with pure cardiolipin (CL) liposomes is significantly faster than with CL/dioleoylphosphatidylcholine (DOPC) (3 : 7), phosphatidylserine (PS) or disialoganglioside (G(D1a))/DOPC (1.5 : 8.5) vesicles. SIV(mac) does not fuse appreciably with pure DOPC liposomes. Reduction of pH from 7.5 to 4.5 greatly enhances the rate of SIV(mac) fusion with CL, CL/DOPC and PS membranes, but does not affect fusion with DOPC or G(D1a)/DOPC membranes. Calcium stimulates viral fusion with CL liposomes, but not with CL/DOPC or DOPC liposomes. SIV(mac) fuses with human erythrocyte ghost membranes only slowly at reduced pH. Our results indicate that SIV(mac) can fuse with membranes lacking the known viral receptor, CD4. Although the mechanism of SIV(mac) fusion with model and biological membranes remains to be determined, the fusion activity of SIV(mac) shares similarities with other lipid-enveloped viruses such as Sendai and influenza viruses

Formation of the oxygen torus in the inner magnetosphere: Van Allen Probes observations

We study the formation process of an oxygen torus during the 12–15 November 2012 magnetic storm, using the magnetic field and plasma wave data obtained by Van Allen Probes. We estimate the local plasma mass density (ρL) and the local electron number density (neL) from the resonant frequencies of standing Alfvén waves and the upper hybrid resonance band. The average ion mass (M) can be calculated by M ∼ ρL/neL under the assumption of quasi-neutrality of plasma. During the storm recovery phase, both Probe A and Probe B observe the oxygen torus at L = 3.0–4.0 and L = 3.7–4.5, respectively, on the morning side. The oxygen torus has M = 4.5–8 amu and extends around the plasmapause that is identified at L∼3.2–3.9. We find that during the initial phase, M is 4–7 amu throughout the plasma trough and remains at ∼1 amu in the plasmasphere, implying that ionospheric O+ ions are supplied into the inner magnetosphere already in the initial phase of the magnetic storm. Numerical calculation under a decrease of the convection electric field reveals that some of thermal O+ ions distributed throughout the plasma trough are trapped within the expanded plasmasphere, whereas some of them drift around the plasmapause on the dawnside. This creates the oxygen torus spreading near the plasmapause, which is consistent with the Van Allen Probes observations. We conclude that the oxygen torus identified in this study favors the formation scenario of supplying O+ in the inner magnetosphere during the initial phase and subsequent drift during the recovery phase

Space Shuttle Debris Impact Tool Assessment Using the Modern Design of Experiments

Complex computer codes are used to estimate thermal and structural reentry loads on the Shuttle Orbiter induced by ice and foam debris impact during ascent. Such debris can create cavities in the Shuttle Thermal Protection System. The sizes and shapes of these cavities are approximated to accommodate a code limitation that requires simple "shoebox" geometries to describe the cavities -- rectangular areas and planar walls that are at constant angles with respect to vertical. These approximations induce uncertainty in the code results. The Modern Design of Experiments (MDOE) has recently been applied to develop a series of resource-minimal computational experiments designed to generate low-order polynomial graduating functions to approximate the more complex underlying codes. These polynomial functions were then used to propagate cavity geometry errors to estimate the uncertainty they induce in the reentry load calculations performed by the underlying code. This paper describes a methodological study focused on evaluating the application of MDOE to future operational codes in a rapid and low-cost way to assess the effects of cavity geometry uncertainty

A preliminary investigation of norms and relationships for the Stern Fixation Test in the elementary school population

The Stern Fixation Test was investigated for its usefulness as a screening test for detecting visual problems associated with reading. Preliminary norms were established based on age and reading level, significant relationships between these norms and subject reading level for certain groups were found, and correlations between Stern Fixation Teat scores and the 21-point examination were found to be of low order. While the Stern Fixation Test cannot be expected to screen for all visual factors involved in reading, it can serve as a useful screening tool for many visual factors related to reading difficulties

Excitation of EMIC waves detected by the Van Allen Probes on 28 April 2013

Abstract We report the wave observations, associated plasma measurements, and linear theory testing of electromagnetic ion cyclotron (EMIC) wave events observed by the Van Allen Probes on 28 April 2013. The wave events are detected in their generation regions as three individual events in two consecutive orbits of Van Allen Probe-A, while the other spacecraft, B, does not detect any significant EMIC wave activity during this period. Three overlapping H+ populations are observed around the plasmapause when the waves are excited. The difference between the observational EMIC wave growth parameter (Eh) and the theoretical EMIC instability parameter (Sh) is significantly raised, on average, to 0.10 ± 0.01, 0.15 ± 0.02, and 0.07 ± 0.02 during the three wave events, respectively. On Van Allen Probe-B, this difference never exceeds 0. Compared to linear theory (Eh\u3eSh), the waves are only excited for elevated thresholds

Setting Financial Accounting Standards for the Twenty-first Century

This paper was prepared for the purpose of facilitating discussion at the Symposium on Financial Reporting and Standard Setting sponsored by the American Institute of Certified Public Accountants. The authors of the paper believe that the changing environment necessitates a thorough reexamination of financial accounting standard-setting processes in the United States. The following observations underlie the propositions offered in the paper: * The increasing demand for and availability of alternative information is decreasing the demand for traditional financial accounting information. * The conventional historical-cost-based accounting model is becoming increasingly inadequate for decision-support purposes

Strategy for tumor selective disruption of androgen receptor function in the spectrum of prostate cancer

Purpose: Testosterone suppression in prostate cancer (PC) is limited by serious side effects and resistance via restoration of androgen receptor (AR) functionality. ELK1 is required for ARdependent growth in various hormone-dependent and castration resistant PC models. The amino terminal domain of AR docks at two sites on ELK1 to co-activate essential growth genes. This study explores the ability of small molecules to disrupt the ELK1-AR interaction in the spectrum of PC, inhibiting AR activity in a manner that would predict functional tumor selectivity. Experimental design: Small molecule drug discovery and extensive biological characterization of a lead compound. Results: We have discovered a lead molecule (KCI807) that selectively disrupts ELK1-dependent promoter activation by wild-type and variant ARs without interfering with ELK1 activation by ERK. KCI807 has an obligatory flavone scaffold and functional hydroxyl groups on C5 and C3'. KCI807 binds to AR, blocking ELK1 binding, and selectively blocks recruitment of AR to chromatin by ELK1. KCI807 primarily affects a subset of AR target growth genes selectively suppressing AR-dependent growth of PC cell lines with a better inhibitory profile than enzalutamide. KCI807 also inhibits in vivo growth of castration/enzalutamide-resistant cell line-derived and patient-derived tumor xenografts. In the rodent model, KCI807 has a plasma half-life of 6h and maintenance of its antitumor effect is limited by self-induced metabolism at its 3'-hydroxyl. Conclusions: The results offer a mechanism-based therapeutic paradigm for disrupting the AR growth-promoting axis in the spectrum of prostate tumors while reducing global suppression of testosterone actions. KCI807 offers a good lead molecule for drug development

Genetic fixity in the human major histocompatibility complex and block size diversity in the class I region including HLA-E

BACKGROUND: The definition of human MHC class I haplotypes through association of HLA-A, HLA-Cw and HLA-B has been used to analyze ethnicity, population migrations and disease association. RESULTS: Here, we present HLA-E allele haplotype association and population linkage disequilibrium (LD) analysis within the ~1.3 Mb bounded by HLA-B/Cw and HLA-A to increase the resolution of identified class I haplotypes. Through local breakdown of LD, we inferred ancestral recombination points both upstream and downstream of HLA-E contributing to alternative block structures within previously identified haplotypes. Through single nucleotide polymorphism (SNP) analysis of the MHC region, we also confirmed the essential genetic fixity, previously inferred by MHC allele analysis, of three conserved extended haplotypes (CEHs), and we demonstrated that commercially-available SNP analysis can be used in the MHC to help define CEHs and CEH fragments. CONCLUSION: We conclude that to generate high-resolution maps for relating MHC haplotypes to disease susceptibility, both SNP and MHC allele analysis must be conducted as complementary techniques

The Heavy Photon Search test detector

The Heavy Photon Search (HPS), an experiment to search for a hidden sector photon in fixed target electroproduction, is preparing for installation at the Thomas Jefferson National Accelerator Facility (JLab) in the Fall of 2014. As the first stage of this project, the HPS Test Run apparatus was constructed and operated in 2012 to demonstrate the experiment׳s technical feasibility and to confirm that the trigger rates and occupancies are as expected. This paper describes the HPS Test Run apparatus and readout electronics and its performance. In this setting, a heavy photon can be identified as a narrow peak in the e+e− invariant mass spectrum above the trident background or as a narrow invariant mass peak with a decay vertex displaced from the production target, so charged particle tracking and vertexing are needed for its detection. In the HPS Test Run, charged particles are measured with a compact forward silicon microstrip tracker inside a dipole magnet. Electromagnetic showers are detected in a PbW04 crystal calorimeter situated behind the magnet, and are used to trigger the experiment and identify electrons and positrons. Both detectors are placed close to the beam line and split top-bottom. This arrangement provides sensitivity to low-mass heavy photons, allows clear passage of the unscattered beam, and avoids the spray of degraded electrons coming from the target. The discrimination between prompt and displaced e+e− pairs requires the first layer of silicon sensors be placed only 10 cm downstream of the target. The expected signal is small, and the trident background huge, so the experiment requires very large statistics. Accordingly, the HPS Test Run utilizes high-rate readout and data acquisition electronics and a fast trigger to exploit the essentially 100% duty cycle of the CEBAF accelerator at JLab