Effect of recent changes in atomic bomb survivor dosimetry on cancer mortality risk estimates

The Radiation Effects Research Foundation has recently implemented a new dosimetry system, DS02, to replace the previous system, DS86. This paper assesses the effect of the change on risk estimates for radiation-related solid cancer and leukemia mortality. The changes in dose estimates were smaller than many had anticipated, with the primary systematic change being an increase of about 10% in gamma-ray estimates for both cities. In particular, an anticipated large increase of the neutron component in Hiroshima for low-dose survivors did not materialize. However, DS02 improves on DS86 in many details, including the specifics of the radiation released by the bombs and the effects of shielding by structures and terrain. The data used here extend the last reported follow-up for solid cancers by 3 years, with a total of 10,085 deaths, and extends the follow-up for leukemia by 10 years, with a total of 296 deaths. For both solid cancer and leukemia, estimated age-time patterns and sex difference are virtually unchanged by the dosimetry revision. The estimates of solid-cancer radiation risk per sievert and the curvilinear dose response for leukemia are both decreased by about 8% by the dosimetry revision, due to the increase in the gamma-ray dose estimates. The apparent shape of the dose response is virtually unchanged by the dosimetry revision, but for solid cancers, the additional 3 years of follow-up has some effect. In particular, there is for the first time a statistically significant upward curvature for solid cancer on the restricted dose range 0-2 Sv. However, the low-dose slope of a linear-quadratic fit to that dose range should probably not be relied on for risk estimation, since that is substantially smaller than the linear slopes on ranges 0-1 Sv, 0-0.5 Sv, and 0- 0.25 Sv. Although it was anticipated that the new dosimetry system might reduce some apparent dose overestimates for Nagasaki factory workers, this did not materialize, and factory workers have significantly lower risk estimates. Whether or not one makes allowance for this, there is no statistically significant city difference in the estimated cancer risk.     

Functional BMP receptor in endocardial cells is required in atrioventricular cushion mesenchymal cell formation in chick

Transformation of atrioventricular (AV) canal endocardium into invasive mesenchyme correlates spatially and temporally with the expression of bone morphogenetic protein (BMP)-2 in the AV myocardium. We revealed the presence of mRNA of Type I BMP receptors, BMPR-1A (ALK3), BMPR-1B (ALK6) and ALK2 in chick AV endocardium at stage-14(-), the onset of epithelial to mesenchymal transformation (EMT), by RT-PCR and localized BMPR-1B mRNA in the endocardium by in situ hybridization. To circumvent the functional redundancies among the Type I BMP receptors, we applied dominant-negative (dn) BMPR-1B-viruses to chick AV explants and whole-chick embryo cultures to specifically block BMP signaling in AV endocardium during EMT. dnBMPR-1B-virus infection of AV endocardial cells abolished BMP-2-supported AV endocardial EMT. Conversely, caBMPR-1B-virus infection promoted AV endocardial EMT in the absence of AV myocardium. Moreover, dnBMPR-1B-virus treatments significantly reduced myocardially supported EMT in AV endocardial-myocardial co-culture. AV cushion mesenchymal cell markers, alpha-smooth muscle actin (SMA), and TGFbeta3 in the endocardial cells were promoted by caBMPR-1B and reduced by dnBMPR-1B infection. Microinjection of the virus into the cardiac jelly in the AV canal at stage-13 in vivo (ovo) revealed that the dnBMPR-1B-virus-infected cells remained in the endocardial epithelium, whereas caBMPR-1B-infected cells invaded deep into the cushions. These results provide evidence that BMP signaling through the AV endocardium is required for the EMT and the activation of the BMP receptor in the endocardium can promote AV EMT in the chick.     

Essential structure of orexin 1 receptor antagonist YNT-707, part III: Role of the 14-hydroxy and the 3-methoxy groups in antagonistic activity toward the orexin 1 receptor in YNT-707 derivatives lacking the 4,5-epoxy ring

Morphinan derivatives lacking the 4,5-epoxy ring were synthesized to examine the participation of the 14-OH group, the 3-OMe group, and the aromaticity of the A-ring in the activity and selectivity for the orexin 1 receptor (OX₁R). The assay results and the conformational analyses of the 14-dehydrated and 14-H derivatives suggested that the orientations of the 6-amide side chain and the 17-benzenesulfonyl group would play important roles in the activity for OX₁R. In the 6β-derivatives, removal of the 3-OMe group and the reduction of the A-ring significantly decreased the activity toward the OX₁R, but these changes did not affect the 6α-derivatives. These results indicate that the 3-OMe group and the A-ring would be essential structural moieties for the 6β-derivatives.     

The correlation between active oxygens scavenging and antioxidative effects of flavonoids

The abilities of 15 flavonoids as a scavenger of active oxygens (hydroxyl radical and superoxide anion) were studied. Hydroxyl radical (^.OH) was generated by the Fenton system, and assayed by the determination of methanesulfinic acid (MSA) formed from the reaction of dimethyl sulfoxide (DMSO) with ^.OH. (+)-Catechin, (−)-epicatechin, 7,8-dihydroxy flavone, and rutin showed the ^.OH scavenging effect 100–300 times superior to that of mannitol, a typical ^.OH scavenger. The other flavonoids showed no ^.OH scavenging effect at their concentrations up to 50 μM. Baicalein, quercetin, morin, and myricetin unexpectedly increased the ^.OH production in the Fenton system. The flavonoids tested now, except monohydroxy flavones, were more or less inhibitive to the superoxide anion (O₂) generation in the hypoxanthine-xanthine oxidase system. A great part of this inhibitory effect was likely owing to suppression of xanthine oxidase activity by the flavonoids. The flavonoids, which scavenged ^.OH or O₂⁻, were necessarily antioxidants to the peroxidation of methyl linoleate. However, there was a type of flavonoid such as morin, which have neither ^.OH nor O₂⁻ scavenging effect, but was a strong antioxidant.     

Conserved metabolic enzymes as vaccine antigens for giardiasis

Giardia lamblia is a leading protozoal cause of diarrheal disease worldwide. Infection is associated with abdominal pain, malabsorption and weight loss, and protracted post-infectious syndromes. A human vaccine is not available against G. lamblia. Prior studies with human and murine immune sera have identified several parasite antigens, including surface proteins and metabolic enzymes with intracellular functions. While surface proteins have demonstrated vaccine potential, they can exhibit significant variation between G. lamblia strains. By comparison, metabolic enzymes show greater conservation but their vaccine potential has not been established. To determine whether such proteins can serve as vaccine candidates, we focused on two enzymes, α-enolase (ENO) and ornithine carbamoyl transferase (OCT), which are involved in glycolysis and arginine metabolism, respectively. We show in a cohort of patients with confirmed giardiasis that both enzymes are immunogenic. Intranasal immunization with either enzyme antigen in mice induced strong systemic IgG1 and IgG2b responses and modest mucosal IgA responses, and a marked 100- to 1,000-fold reduction in peak trophozoite load upon oral G. lamblia challenge. ENO immunization also reduced the extent and duration of cyst excretion. Examination of 44 cytokines showed only minimal intestinal changes in immunized mice, although a modest increase of CCL22 was observed in ENO-immunized mice. Spectral flow cytometry revealed increased numbers and activation state of CD4 T cells in the small intestine and an increase in α4β7-expressing CD4 T cells in mesenteric lymph nodes of ENO-immunized mice. Consistent with a key role of CD4 T cells, immunization of CD4-deficient and Rag-2 deficient mice failed to induce protection, whereas mice lacking IgA were fully protected by immunization, indicating that immunity was CD4 T cell-dependent but IgA-independent. These results demonstrate that conserved metabolic enzymes can be effective vaccine antigens for protection against G. lamblia infection, thereby expanding the repertoire of candidate antigens beyond primary surface proteins.     

A perm-selective model membrane exhibiting oscillatory behavior

An enzymic model membrane capable of simulating such permeability characteristics of chemically excitable membranes as generation of an action potential-like overshoot, selectivity over permeants, and saturation and hysteresis of transmembrane flow is constructed by means of coupling a nonlinear, interfacial flow regulating the attachment of permeants to the surface of the oligomeric membrane with a transmembrane allosteric conversion flow recently formulated by Blumenthal. Periods of sustained oscillation, as well as the predicted values of threshold, and height of an action potential-like overshoot are calculated for different choices of external and internal parameters of the membrane.     

Is Working More Costly than Waiting in Monkeys?

We studied how value for instrumental action is discounted by predicted effort and delay. The monkeys were trained to perform instrumental trials that required a bar release when a visual target changed from red-to-green. There were two trial conditions. In delay trials, after the monkeys performed one instrumental trial correctly a reward was delivered 0–7 seconds later. In work trials, the monkeys had to perform 0, 1, or 2 additional instrumental trials to obtain a reward. The lengths of trials in delay matched the time it took to complete work trials. The length of delay or number of trials was indicated by a visual cue presented throughout the trial. Our hypothesis was that the monkeys would all show temporal discounting of reward in the delay trials, and that in the work trials the monkeys’ performance might reflect an additional cost due to working. The error rate increased linearly as remaining cost increased for all 8 monkeys. For 4 monkeys the error rate was significantly larger in work trials than in delay trials (effort sensitive monkeys). For the other 4 monkeys there was no significant difference in error rate (effort insensitive monkeys). Since the error rate has an inverse relation with value for action, these results suggest that value is discounted hyperbolically by effort as well as by delay. Error rates generally increased as the testing sessions progressed and the total reward accumulated (i.e., effect of reward devaluation). The relative impact of delay and effort on error rates was reasonably stable within subjects. Thus, within the monkey population there seems to be a significant dichotomy in the sensitivity governing whether working is more costly than waiting, possibly arising from a constitutional or genetic trait.     

Expression of cell adhesion molecule,Gicerin/CD146 during the formation of heart and in the cardiac hypertrophy

Molecular and Cellular Biochemistry - Gicerin/CD146 is a cell adhesion molecule which belongs to the immunoglobulin (Ig) superfamily. We have reported the existence of gicerin/CD146 in the nervous...