A Receptor-based Switch that Regulates Anthrax Toxin Pore Formation

Cellular receptors can act as molecular switches, regulating the sensitivity of microbial proteins to conformational changes that promote cellular entry. The activities of these receptor-based switches are only partially understood. In this paper, we sought to understand the mechanism that underlies the activity of the ANTXR2 anthrax toxin receptor-based switch that binds to domains 2 and 4 of the protective antigen (PA) toxin subunit. Receptor-binding restricts structural changes within the heptameric PA prepore that are required for pore conversion to an acidic endosomal compartment. The transfer cross-saturation (TCS) NMR approach was used to monitor changes in the heptameric PA-receptor contacts at different steps during prepore-to-pore conversion. These studies demonstrated that receptor contact with PA domain 2 is weakened prior to pore conversion, defining a novel intermediate in this pathway. Importantly, ANTXR2 remained bound to PA domain 4 following pore conversion, suggesting that the bound receptor might influence the structure and/or function of the newly formed pore. These studies provide new insights into the function of a receptor-based molecular switch that controls anthrax toxin entry into cells

Life Cycle Aware Computing: Reusing Silicon Technology

Despite the high costs associated with processor manufacturing, the typical chip is used for only a fraction of its expected lifetime. Reusing processors would create a food chain of electronic devices that amortizes the energy required to build chips over several computing generations

Presence of C-type natriuretic peptide in human kidney and urine

Presence of C-type natriuretic peptide in human kidney and urine. The current study was undertaken to investigate the presence of CNP immunoreactivity in both human kidney and urine. Immunohistochemical staining with an indirect immunoperoxidase method utilizing an antibody which is 100% cross-reactive to both CNP-53 and CNP-22 was performed on five human kidney specimens (three biopsies of normal cadaveric donor kidneys and two of normal autopsy specimens). CNP immunoreactivity was positive in proximal, distal and medullary collecting duct tubular cells in a cytoplasmic and granular staining pattern. CNP immunoreactivity was also determined in the urine of five healthy volunteers utilizing a sensitive and specific double-antibody radioimmunoassay with a mean concentration of 10.8 ± 1.0 pg/ml. With the utilization of high pressure liquid chromatography, this immunoreactivity proved to be consistent with both the low molecular weight form, CNP-22, as well as the high molecular weight form, CNP-53. Urinary excretion of CNP was also measured in normal subjects (N = 5) and in patients with congestive heart failure (CHF, N = 6). CHF patients excreted over three times more CNP than normals (27.2 ± 2.8 vs. 8.7 ± 0.81 pg/min, P < 0.004) despite no difference between the two groups in plasma CNP concentrations (6.97 ± 0.28 vs. 8.08 ± 1.52 pg/ml, P = NS). This study demonstrates for the first time the presence of CNP immunoreactivity in human kidney and suggests that renal tubular cells may be an additional non-vascular site of synthesis for this cardiorenal acting peptide. This study also demonstrates an increase in urinary CNP excretion in congestive heart failure

Graphics mini manual

The computer graphics capabilities available at the Center are introduced and their use is explained. More specifically, the manual identifies and describes the various graphics software and hardware components, details the interfaces between these components, and provides information concerning the use of these components at LaRC

The Orbit of the Eclipsing X-ray Pulsar EXO 1722-363

With recent and archival Rossi X-Ray Timing Explorer (RXTE) X-ray measurements of the heavily obscured X-ray pulsar EXO 1722-363 (IGR J17252-3616), we carried out a pulse timing analysis to determine the orbital solution for the first time. The binary system is characterized by a_x sin(i) = 101 +/- 3 lt-s and P_orb = 9.7403 +/- 0.0004 days (90% confidence), with the precision of the orbital period being obtained by connecting datasets separated by more than 7 years (272 orbital cycles). The orbit is consistent with circular, and e < 0.19 at the 90% confidence level. The mass function is 11.7 +/- 1.2 M_sun and confirms that this source is a High Mass X-ray Binary (HMXB) system. The orbital period, along with the previously known ~414 s pulse period, places this system in the part of the Corbet diagram populated by supergiant wind accretors. Using previous eclipse time measurements by Corbet et al. and our orbital solution, combined with the assumption that the primary underfills its Roche lobe, we find i > 61 degrees at the 99% confidence level, the radius of the primary is between 21 R_sun and 37 R_sun, and its mass is less than about 22 M_sun. The acceptable range of radius and mass shows that the primary is probably a supergiant of spectral type B0I-B5I. Photometric measurements of its likely counterpart are consistent with the spectral type and luminosity if the distance to the system is between 5.3 kpc and 8.7 kpc. Spectral analysis of the pulsar as a function of orbital phase reveals an evolution of the hydrogen column density suggestive of dense filaments of gas in the downstream wake of the pulsar, with higher levels of absorption seen at orbital phases 0.5-1.0, as well as a variable Fe K_alpha line.Comment: Submitted to ApJ, 11 pages, 11 figure

Cell-specific discrimination of desmosterol and desmosterol mimetics confers selective regulation of LXR and SREBP in macrophages.

Activation of liver X receptors (LXRs) with synthetic agonists promotes reverse cholesterol transport and protects against atherosclerosis in mouse models. Most synthetic LXR agonists also cause marked hypertriglyceridemia by inducing the expression of sterol regulatory element-binding protein (SREBP)1c and downstream genes that drive fatty acid biosynthesis. Recent studies demonstrated that desmosterol, an intermediate in the cholesterol biosynthetic pathway that suppresses SREBP processing by binding to SCAP, also binds and activates LXRs and is the most abundant LXR ligand in macrophage foam cells. Here we explore the potential of increasing endogenous desmosterol production or mimicking its activity as a means of inducing LXR activity while simultaneously suppressing SREBP1c-induced hypertriglyceridemia. Unexpectedly, while desmosterol strongly activated LXR target genes and suppressed SREBP pathways in mouse and human macrophages, it had almost no activity in mouse or human hepatocytes in vitro. We further demonstrate that sterol-based selective modulators of LXRs have biochemical and transcriptional properties predicted of desmosterol mimetics and selectively regulate LXR function in macrophages in vitro and in vivo. These studies thereby reveal cell-specific discrimination of endogenous and synthetic regulators of LXRs and SREBPs, providing a molecular basis for dissociation of LXR functions in macrophages from those in the liver that lead to hypertriglyceridemia

Determining the Cosmic Distance Scale from Interferometric Measurements of the Sunyaev-Zel'dovich Effect

We determine the distances to 18 galaxy clusters with redshifts ranging from z~0.14 to z~0.78 from a maximum likelihood joint analysis of 30 GHz interferometric Sunyaev-Zel'dovich effect (SZE) and X-ray observations. We model the intracluster medium (ICM) using a spherical isothermal beta model. We quantify the statistical and systematic uncertainties inherent to these direct distance measurements, and we determine constraints on the Hubble parameter for three different cosmologies. These distances imply a Hubble constant of 60 (+4, -4) (+13, -18) km s-1 Mpc-1 for an Omega_M = 0.3, Omega_Lambda = 0.7 cosmology, where the uncertainties correspond to statistical followed by systematic at 68% confidence. With a sample of 18 clusters, systematic uncertainties clearly dominate. The systematics are observationally approachable and will be addressed in the coming years through the current generation of X-ray satellites (Chandra & XMM-Newton) and radio observatories (OVRO, BIMA, & VLA). Analysis of high redshift clusters detected in future SZE and X-ray surveys will allow a determination of the geometry of the universe from SZE determined distances.Comment: ApJ Submitted; 40 pages, 9 figures (fig 3 B&W for size constraint), 13 tables, uses emulateapj5 styl

Digital Twin of a Network and Operating Environment Using Augmented Reality

We demonstrate the digital twin of a network, network elements, and operating environment using machine learning. We achieve network card failure localization and remote collaboration over 86 km of fiber using augmented reality

Multiple Transporters Associated with Malaria Parasite Responses to Chloroquine and Quinine

Mutations and/or overexpression of various transporters are known to confer drug resistance in a variety of organisms. In the malaria parasite Plasmodium falciparum, a homologue of P-glycoprotein, PfMDR1, has been implicated in responses to chloroquine (CO), quinine (ON) and other drugs, and a putative transporter, PfCRT, was recently demonstrated to be the key molecule in CO resistance. However, other unknown molecules are probably involved, as different parasite clones carrying the same pfcrt and pfmdr1 alleles show a wide range of quantitative responses to CO and ON. Such molecules may contribute to increasing incidences of ON treatment failure, the molecular basis of which is not understood. To identify additional genes involved in parasite CO and ON responses, we assayed the in vitro susceptibilities of 97 culture-adapted cloned isolates to CO and ON and searched for single nucleotide polymorphisms (SNPs) in DNA encoding 49 putative transporters (total 113 kb) and in 39 housekeeping genes that acted as negative controls. SNPs in 11 of the putative transporter genes, including pfcrt and pfmdr1, showed significant associations with decreased sensitivity to CQ and/or ON in P. faliparum. Significant linkage disequilibria within and between these genes were also detected, suggesting interactions among the transporter genes. This study provides specific leads for better understanding of complex drug resistances in malaria parasite