The entry of diphtheria toxin into the mammalian cell cytoplasm: evidence for lysosomal involvement

Lysosomotropic amines, such as ammonium chloride, are known to protect cells from the cytotoxic effects of diphtheria toxin. These drugs are believed to inhibit the transport of the toxin from a receptor at the cell exterior into the cytoplasm where a fragment of the toxin arrests protein synthesis. We studied the effects of lysosomotropic agents on the cytotoxic process to better understand how the toxin enters the cytoplasm. The cytotoxic effects of diphtheria toxin were not inhibited by antitoxin when cells were preincubated at 37 degrees C with toxin and ammonium chloride, exposed to antitoxin at 4 degrees C, washed to relieve the ammonium chloride inhibition, and finally warmed to 37 degrees C. The antigenic determinants of the toxin were, therefore, either altered or sheltered. It is likely that the combination of ammonium chloride and a low temperature trapped the toxin in an intracellular vesicle from which the toxin could proceed to the cytoplasm. Because lysosomotropic amines raise the pH within acidic intracellular vesicles, such as lysosomes, they could trap the toxin within such a vesicle if an acidic environment were necessary for the toxin to penetrate into the cytoplasm. We simulated acidic conditions which the toxin might encounter by exposing cells with toxin bound to their surface to acidic medium. We then measured the effects of lysosomotropic amines on the activity of the toxin to see if the acidic environment substituted for the function normally inhibited by the drugs. The drugs no longer protected the cells. This suggests that exposing the toxin to an acidic environment, such as that found within lysosomes, is an important step in the penetration of diphtheria toxin into the cytoplasm

Lifting the Veil on Obscured Accretion: Active Galactic Nuclei Number Counts and Survey Strategies for Imaging Hard X-Ray Missions

Finding and characterizing the population of active galactic nuclei (AGNs) that produces the X-ray background (XRB) is necessary to connect the history of accretion to observations of galaxy evolution at longer wavelengths. The year 2012 will see the deployment of the first hard X-ray imaging telescope which, through deep extragalactic surveys, will be able to measure the AGN population at the energies where the XRB peaks (~20-30 keV). Here, we present predictions of AGN number counts in three hard X-ray bandpasses: 6-10 keV, 10-30 keV, and 30-60 keV. Separate predictions are presented for the number counts of Compton thick AGNs, the most heavily obscured active galaxies. The number counts are calculated for five different models of the XRB that differ in the assumed hard X-ray luminosity function, the evolution of the Compton thick AGNs, and the underlying AGN spectral model. The majority of the hard X-ray number counts will be Compton thin AGNs, but there is a greater than tenfold increase in the Compton thick number counts from the 6-10 keV to the 10-30 keV band. The Compton thick population shows enough variation that a hard X-ray number counts measurement will constrain the models. The computed number counts are used to consider various survey strategies for the NuSTAR mission, assuming a total exposure time of 6.2 Ms. We find that multiple surveys will allow a measurement of Compton thick evolution. The predictions presented here should be useful for all future imaging hard X-ray missions

An empirical study on the preferred size of the participant information sheet in research

Background: Informed consent is a requirement for all research. It is not, however, clear how much information is sufficient to make an informed decision about participation in research. Information on an online questionnaire about childhood development was provided through an unfolding electronic participant sheet in three levels of information. \ud Methods: 552 participants, who completed the web-based survey, accessed and spent time reading the participant information sheet (PIS) between July 2008 and November 2009. The information behaviour of the participants was investigated. The first level contained less information than might be found on a standard PIS, the second level corresponded to a standard PIS, and the third contained more information than on a standard PIS. The actual time spent on reading the information provided in three incremental levels and the participants' evaluation of the information were calculated. \ud Results: 77% of the participants chose to access the first level of information, whereas 12% accessed the first two levels, 6% accessed all three levels of information and 23% participated without accessing information. The most accessed levels of information were those that corresponded to the average reading times. \ud Conclusion: The brief information provided in the first level was sufficient for participants to make informed decisions, while a sizeable minority of the participants chose not to access any information at all. This study adds to the debate about how much information is required to make a decision about participation in research and the results may help inform the future development of information sheets by providing data on participants' actual needs when deciding about questionnaire surveys.\u

Chiral Properties of Pseudoscalar Mesons on a Quenched 20420^4 Lattice with Overlap Fermions

The chiral properties of the pseudoscalar mesons are studied numerically on a quenched $20^4$ lattice with the overlap fermion. We elucidate the role of the zero modes in the meson propagators, particularly that of the pseudoscalar meson. The non-perturbative renormalization constant $Z_A$ is determined from the axial Ward identity and is found to be almost independent of the quark mass for the range of quark masses we study; this implies that the $O(a^2)$ error is small. The pion decay constant, $f_{\pi}$, is calculated from which we determine the lattice spacing to be 0.148 fm. We look for quenched chiral log in the pseudoscalar decay constants and the pseudoscalar masses and we find clear evidence for its presence. The chiral log parameter $\delta$ is determined to be in the range 0.15 -- 0.4 which is consistent with that predicted from quenched chiral perturbation theory.Comment: Version accepted for publication by PRD. A few minor typographical errors have been corrected. 24 pages, 11 figure

The Blaine House: A Brief History and Guide

Few executive mansions in the United States have such rich historical associations as the Blaine House, the official residence of Maine\u27s governors. From 1862 until his death in 1893, it was home to James Gillespie Blaine and his family. Blaine bestrode the political world like a colossus in the post-Civil War Gilded Age. Dazzling, charismatic, worshiped by his friends, loathed by his enemies, ( contemporaries called him variously the \u27\u27Plumed Knight of the Republican Party and the continental liar from the State of Maine ), he dominated the Maine Republican party for a generation, served brilliantly as Speaker of the U.S. House of Representatives; United States Senator; trail-blazing Secretary of State for the two Presidents, and in 1884 came within a whisker of winning the Presidency of the United States himself.https://digitalcommons.usm.maine.edu/mhpc-docs/1004/thumbnail.jp