A New Approach to Reduce Uncertainties in Space Radiation Cancer Risk Predictions

The prediction of space radiation induced cancer risk carries large uncertainties with two of the largest uncertainties being radiation quality and dose-rate effects. In risk models the ratio of the quality factor (QF) to the dose and dose-rate reduction effectiveness factor (DDREF) parameter is used to scale organ doses for cosmic ray proton and high charge and energy (HZE) particles to a hazard rate for γ-rays derived from human epidemiology data. In previous work, particle track structure concepts were used to formulate a space radiation QF function that is dependent on particle charge number Z, and kinetic energy per atomic mass unit, E. QF uncertainties where represented by subjective probability distribution functions (PDF) for the three QF parameters that described its maximum value and shape parameters for Z and E dependences. Here I report on an analysis of a maximum QF parameter and its uncertainty using mouse tumor induction data. Because experimental data for risks at low doses of γ-rays are highly uncertain which impacts estimates of maximum values of relative biological effectiveness (RBE_max), I developed an alternate QF model, denoted QF_γAcute where QFs are defined relative to higher acute γ-ray doses (0.5 to 3 Gy). The alternate model reduces the dependence of risk projections on the DDREF, however a DDREF is still needed for risk estimates for high-energy protons and other primary or secondary sparsely ionizing space radiation components. Risk projections (upper confidence levels (CL)) for space missions show a reduction of about 40% (CL∼50%) using the QF_γAcute model compared the QFs based on RBE_max and about 25% (CL∼35%) compared to previous estimates. In addition, I discuss how a possible qualitative difference leading to increased tumor lethality for HZE particles compared to low LET radiation and background tumors remains a large uncertainty in risk estimates.     

A note on a modified membrane-Bovis agar for the enumeration of Streptococcus bovis by membrane filtration

The effect of dilution and temperature on the antibacterial properties of potassium sorbate was determined. The time taken to kill a standard inoculum of Escherichia coli was increased considerably after either dilution of the preservative or lowering of the temperature. The value for the concentration exponent, eta, was approximately 3 and that for the temperature coefficient, Q10, was 2.3.     

A novel spirocyclic tropanyl-Δ2-isoxazoline derivative enhances citalopram and paroxetine binding to serotonin transporters as well as serotonin uptake

A group of spirocyclic tropanyl-Δ²-isoxazolines was synthesized exploiting the 1,3-dipolar cycloaddition of nitrile oxides to olefins. Their interaction with the dopamine and serotonin transporters (DAT and SERT, respectively) was evaluated through binding experiments. The majority of the compounds had no inhibitory effects (IC₅₀ >> 10 μM), while some had an IC₅₀ value in the range 5–10 μM (8a–c, 10b and 11c on DAT, 12b on SERT). Unexpectedly, one of the tertiary amines under investigation, that is 3′-methoxy-8-methyl-spiro{8-azabicyclo[3.2.1]octane-3,5′(4′H)-isoxazole 7a, was able to enhance at a concentration of 10 μM both [³H]citalopram and [³H]paroxetine binding to SERT in rat brain homogenate (up to 25%, due to an increase of B_max) and [³H]serotonin uptake (up to 30%) in cortical synaptosomes. This peculiar pharmacological profile of 7a suggests it binds to an allosteric site on SERT, and positions derivative 7a as a very useful tool to investigate SERT machinery.     

Differential expression of two types of sucrose synthase-encoding genes in wheat in response to anaerobiosis, cold shock and light

The expression of two types of sucrose synthase-encoding genes, Ss1 and Ss2, in hexaploid wheat (Triticum aestivum, L.), has been investigated using type-specific probes, corresponding to the 250-270 bp C-terminal portions of the respective cDNA clones. Both types of genes are highly expressed in developing endosperm, where the expression of the Ss2 type slightly precedes in time that of the Ss1 type. Expression of Ss genes is lower in etiolated leaves and in roots than in endosperm. In the first two tissues, the Ss1 mRNA is much more abundant than the Ss2 mRNA, and the Ss1 mRNA level sharply increases in response to anaerobiosis and to cold shock (6 degrees C), while the level of Ss2 mRNA is not significantly affected. Upon illumination of etiolated leaves, the Ss1 level mRNA decreases significantly and the Ss2 mRNA level increases.     

Intestinal-epithelial LSD1 controls goblet cell maturation and effector responses required for gut immunity to bacterial and helminth infection

Infectious and inflammatory diseases in the intestine remain a serious threat for patients world-wide. Reprogramming of the intestinal epithelium towards a protective effector state is important to manage inflammation and immunity and can be therapeutically targeted. The role of epigenetic regulatory enzymes within these processes is not yet defined. Here, we use a mouse model that has an intestinal-epithelial specific deletion of the histone demethylase Lsd1 (cKO mice), which maintains the epithelium in a fixed reparative state. Challenge of cKO mice with bacteria-induced colitis or a helminth infection model both resulted in increased pathogenesis. Mechanistically, we discovered that LSD1 is important for goblet cell maturation and goblet-cell effector molecules such as RELMß. We propose that this may be in part mediated by directly controlling genes that facilitate cytoskeletal organization, which is important in goblet cell biology. This study therefore identifies intestinal-epithelial epigenetic regulation by LSD1 as a critical element in host protection from infection.