Pharmacologic restoration of αδF508 CFTR-mediated chloride current

Pharmacologic restoration of αδF508 CFTR-mediated chloride current. Cystic fibrosis (CF) is an autosomal inherited disorder caused by over 800 different mutations in the CFTR gene. The most common mutation, αδF508, causes a trafficking arrest in the endoplasmic reticulum and the CFTR protein is degraded. Restoration of CFTR trafficking in vitro restores cAMP-mediated chloride transport at the cell surface. The hypothesis of this discussion is that the short chain fatty acids, butyrate and 4-phenylbutyrate, up-regulate mature CFTR at the plasma membrane. Evidence that these compounds regulate CFTR production and maturation in part through effects on molecular chaperones in CF cells in culture is discussed. The oral drug, 4-phenylbutyrate, was tested in a Phase I clinical trial in CF subjects and further trials are underway. Other new therapeutic approaches directed at different classes of mutations in CFTR are also discussed. Chemical and pharmacologic agents that regulate endogenous gene expression at different steps in the biosynthetic processing pathway of a membrane glycoprotein will be needed to comprehensively treat a complex inherited disorder like cystic fibrosis

Using monoclonal antibodies to prevent mucosal transmission of epidemic infectious diseases.

Passive immunization with antibodies has been shown to prevent a wide variety of diseases. Recent advances in monoclonal antibody technology are enabling the development of new methods for passive immunization of mucosal surfaces. Human monoclonal antibodies, produced rapidly, inexpensively, and in large quantities, may help prevent respiratory, diarrheal, and sexually transmitted diseases on a public health scale

CFTR Is a Negative Regulator of NFκB Mediated Innate Immune Response

Dysfunctional CFTR in the airways is associated with elevated levels of NFkappaB mediated IL-8 signaling leading to neutrophil chemotaxis and chronic lung inflammation in cystic fibrosis. The mechanism(s) by which CFTR mediates inflammatory signaling is under debate.We tested the hypothesis that wt-CFTR down-regulates NFkappaB mediated IL-8 secretion. We transiently co-expressed wt-CFTR and IL-8 or NFkappaB promoters driving luciferase expression in HEK293 cells. Wt-CFTR expression in HEK293 cells suppresses both basal and IL1beta induced IL-8, and NFkappaB promoter activities as compared to the control cells transfected with empty vector (p<0.05). We also confirmed these results using CFBE41o- cells and observed that cells stably transduced with wt-CFTR secrete significantly lower amounts of IL-8 chemokine as compared to non-transfected control cells. To test the hypothesis that CFTR must be localized to cell surface lipid rafts in polarized airway epithelial cells in order to mediate the inflammatory response, we treated CFBE41o- cells that had been stably transduced with wt-CFTR with methyl-beta-cyclodextrin (CD). At baseline, CD significantly (p<0.05) induced IL-8 and NFkappaB reporter activities as compared to control cells suggesting a negative regulation of NFkappaB mediated IL-8 signaling by CFTR in cholesterol-rich lipid rafts. Untreated cells exposed to the CFTR channel blocker CFTR-172 inhibitor developed a similar increase in IL-8 and NFkappaB reporter activities suggesting that not only must CFTR be present on the cell surface but it must be functional. We verified these results in vivo by comparing survival, body weight and pro-inflammatory cytokine response to P. aeruginosa LPS in CFTR knock out (CFKO) mice as compared to wild type controls. There was a significant (p<0.05) decrease in survival and body weight, an elevation in IL-1beta in whole lung extract (p<0.01), as well as a significant increase in phosphorylated IkappaB, an inducer of NFkappaB mediated signaling in the CFKO mice.Our data suggest that CFTR is a negative regulator of NFkappaB mediated innate immune response and its localization to lipid rafts is involved in control of inflammation

GCR access to the Moon as measured by the CRaTER instrument on LRO

[1] Recent modeling efforts have yielded varying and conflicting results regarding the possibility that Earth\u27s magnetosphere is able to shield energetic particles of \u3e10 MeV at lunar distances. This population of particles consists of galactic cosmic rays as well as energetic particles that are accelerated by solar flares and coronal mass ejections. The Cosmic Ray Telescope for the Effects of Radiation (CRaTER) onboard the Lunar Reconnaissance Orbiter is in orbit about the Moon and is thus able to directly test these modeling results. Over the course of a month, CRaTER samples the upstream solar wind as well as various regions of Earth\u27s magnetotail. CRaTER data from multiple lunations demonstrate that Earth\u27s magnetosphere at lunar distances produces no measurable influence on energetic particle flux, even at the lowest energies (\u3e14 MeV protons) where any effect should be maximized. For particles with energies of 14–30 MeV, we calculate an upper limit (determined by counting statistics) on the amount of shielding caused by the magnetosphere of 1.7%. The high energy channel (\u3e500 MeV) provides an upper limit of 3.2%

Quantization of the N=2 Supersymmetric KdV Hierarchy

We continue the study of the quantization of supersymmetric integrable KdV hierarchies. We consider the N=2 KdV model based on the $sl^{(1)}(2|1)$ affine algebra but with a new algebraic construction for the L-operator, different from the standard Drinfeld-Sokolov reduction. We construct the quantum monodromy matrix satisfying a special version of the reflection equation and show that in the classical limit, this object gives the monodromy matrix of N=2 supersymmetric KdV system. We also show that at both the classical and the quantum levels, the trace of the monodromy matrix (transfer matrix) is invariant under two supersymmetry transformations and the zero mode of the associated U(1) current.Comment: LaTeX2e, 12 page

The first cosmic ray albedo proton map of the Moon

[1] Neutrons emitted from the Moon are produced by the impact of galactic cosmic rays (GCRs) within the regolith. GCRs are high-energy particles capable of smashing atomic nuclei in the lunar regolith and producing a shower of energetic protons, neutrons and other subatomic particles. Secondary particles that are ejected out of the regolith become “albedo” particles. The neutron albedo has been used to study the hydrogen content of the lunar regolith, which motivates our study of albedo protons. In principle, the albedo protons should vary as a function of the input GCR source and possibly as a result of surface composition and properties. During the LRO mission, the total detection rate of albedo protons between 60 MeV and 150 MeV has been declining since 2009 in parallel with the decline in the galactic cosmic ray flux, which validates the concept of an albedo proton source. On the other hand, the average yield of albedo protons has been increasing as the galactic cosmic ray spectrum has been hardening, consistent with a disproportionately stronger modulation of lower energy GCRs as solar activity increases. We construct the first map of the normalized albedo proton emission rate from the lunar surface to look for any albedo variation that correlates with surface features. The map is consistent with a spatially uniform albedo proton yield to within statistical uncertainties

Measurements of galactic cosmic ray shielding with the CRaTER instrument

[1] The Cosmic Ray Telescope for the Effects of Radiation (CRaTER) instrument aboard the Lunar Reconnaissance Orbiter has been measuring energetic charged particles from the galactic cosmic rays (GCRs) and solar particle events in lunar orbit since 2009. CRaTER includes three pairs of silicon detectors, separated by pieces of tissue-equivalent plastic that shield two of the three pairs from particles incident at the zenith-facing end of the telescope. Heavy-ion beams studied in previous ground-based work have been shown to be reasonable proxies for the GCRs when their energies are sufficiently high. That work, which included GCR simulations, led to predictions for the amount of dose reduction that would be observed by CRaTER. Those predictions are compared to flight data obtained by CRaTER in 2010–2011

Cross Section Measurements Using the Zero Degree Detector

The Zero Degree Detector (ZDD) is an instrument that has been used in accelerator exposures to measure the angular dependence of particles produced in heavy ion fragmentation experiments. The ZDD uses two identical layers of pixelated silicon detectors that make coincident measurements over the active area of the instrument. The angular distribution of secondary particle produced in nuclear interactions for several heavy ions: and target materials will be presented along with performance characteristic of the instrument

Producing valid statistics when legislation, culture, and medical practices differ for births at or before the threshold of survival: Report of a European workshop

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