Abnormal error processing in depressive states: a translational examination in humans and rats.

Depression has been associated with poor performance following errors, but the clinical implications, response to treatment and neurobiological mechanisms of this post-error behavioral adjustment abnormality remain unclear. To fill this gap in knowledge, we tested depressed patients in a partial hospital setting before and after treatment (cognitive behavior therapy combined with medication) using a flanker task. To evaluate the translational relevance of this metric in rodents, we performed a secondary analysis on existing data from rats tested in the 5-choice serial reaction time task after treatment with corticotropin-releasing factor (CRF), a stress peptide that produces depressive-like signs in rodent models relevant to depression. In addition, to examine the effect of treatment on post-error behavior in rodents, we examined a second cohort of rodents treated with JDTic, a kappa-opioid receptor antagonist that produces antidepressant-like effects in laboratory animals. In depressed patients, baseline post-error accuracy was lower than post-correct accuracy, and, as expected, post-error accuracy improved with treatment. Moreover, baseline post-error accuracy predicted attentional control and rumination (but not depressive symptoms) after treatment. In rats, CRF significantly degraded post-error accuracy, but not post-correct accuracy, and this effect was attenuated by JDTic. Our findings demonstrate deficits in post-error accuracy in depressed patients, as well as a rodent model relevant to depression. These deficits respond to intervention in both species. Although post-error behavior predicted treatment-related changes in attentional control and rumination, a relationship to depressive symptoms remains to be demonstrated.

A reappraisal of the reported dose equivalents at the boundary of the University of California Radiation Laboratory during the early days of Bevatron operation.

The Bevatron of the Lawrence Berkeley National Laboratory operated with no permanent shielding-roof from 1954 to 1962. Neutron fluences measured at the laboratory perimeter reached a maximum in 1959, and were reported as an annual dose equivalent of 8.1 mSv (54% of the then operative radiation limit). The addition of temporary local shielding and improved operational techniques subsequently led to a steady decline in dose equivalent at the laboratory perimeter. A permanent concrete shielding-roof was constructed in 1962. In those early years of operation the reported dose equivalent, H, was derived from a measured total neutron fluence, phi, and an estimated spectrum-weighted fluence to dose equivalent conversion coefficient, (g), where H= (g) phi. The uncertainty in H was almost entirely due to the uncertainty in (g). While the measurements of phi were accurate the estimates of (g) were quite crude and depended upon measurements of average neutron energy, on assumptions about the shape of the neutron energy spectrum, and primitive values of fluence to dose equivalent conversion coefficients for monoenergetic neutrons. These early reported dose equivalents were known to be overestimated. This paper has reappraised the dose equivalents in the light of better information now available. Environmental neutron spectra have been calculated which more accurately correspond to the operational conditions of the Bevatron in the 1950s and early 1960s. than did those spectra available at that time. A new fluence to dose equivalent conversion function based on the latest data and for isotropic irradiation geometry was developed. From these two parameters better estimates of the coefficient (g) were determined and compared with the earlier values. From this reappraisal it is shown that the early reported dose equivalents were conservative by a factor of at least five.

Direct influence of the p53 tumor suppressor on mitochondrial biogenesis and function.

Mitochondrial localization of p53 has been observed in several cell systems, but an understanding of its organelle-based physiological activity remains incomplete. The purpose of the present study was to investigate the mitochondrial DNA genomic response to dominant-negative p53 mutant miniprotein (p53DD) fused to a mitochondrial import signal. Constructs were generated to express mitochondrial targeted enhanced green fluorescent protein (mEGFP) or dominant-negative mutant p53 miniprotein (m53DD) by in-frame fusion to the signal peptide sequence of murine Cox8l. Control cytosolic vectors (cEGFP, c53DD) had the signal sequence placed in antisense orientation. NIH 3T3 cells were transiently transfected with these vectors in various combinations. Mitochondrial 16S ribosomal RNA (16S rRNA) expression and fluorochrome staining with Mitotracker Red CMXRos (DeltaPsim) were decreased in cells expressing m53DD. Both alterations were specific for mitochondrial import competence (e.g., m53DD vs. c53DD) as well as the passenger protein (e.g., m53DD vs. mEGFP). The normal functional state of mitochondria was restored with PK11195, a specific ligand of the mitochondrial peripheral-type benzodiazepine receptor. Negative dominance of m53DD on 16S rRNA expression and CMXRos staining, and rescue of these parameters with PK11195, imply a direct positive effect of p53 on mitochondrial biogenesis and function.

Designing accelerator-based epithermal neutron beams for boron neutron capture therapy.

The 7Li(p,n)7Be reaction has been investigated as an accelerator-driven neutron source for proton energies between 2.1 and 2.6 MeV. Epithermal neutron beams shaped by three moderator materials, Al/AlF3, 7LiF, and D2O, have been analyzed and their usefulness for boron neutron capture therapy (BNCT) treatments evaluated. Radiation transport through the moderator assembly has been simulated with the Monte Carlo N-particle code (MCNP). Fluence and dose distributions in a head phantom were calculated using BNCT treatment planning software. Depth-dose distributions and treatment times were studied as a function of proton beam energy and moderator thickness. It was found that an accelerator-based neutron source with Al/AlF3 or 7LiF as moderator material can produce depth-dose distributions superior to those calculated for a previously published neutron beam design for the Brookhaven Medical Research Reactor, achieving up to approximately 50% higher doses near the midline of the brain. For a single beam treatment, a proton beam current of 20 mA, and a 7LiF moderator, the treatment time was estimated to be about 40 min. The tumor dose deposited at a depth of 8 cm was calculated to be about 21 Gy-Eq.

Altered expression of mitochondrial 16S ribosomal RNA in p53-deficient mouse embryos revealed by differential display.

Inactivation of the tumor suppressor p53 is associated with neural tube defects and altered teratogenicity in early embryos. To gain insight into the function of p53 during early embryogenesis, RNA profiles of wild-type p53(+/+) and p53(-/-) null mutant mouse embryos were compared at the head-fold stage (day 8 post coitum) using HPLC-based mRNA differential display. The results of this screen revealed a deficiency of mitochondrial 16S ribosomal RNA in p53(-/-) embryos. RT-PCR showed abnormalities in 16S rRNA levels relative to some representative nuclear (COIV, beta-actin) and mitochondrial (COIII) transcripts in p53(-/-) embryos, and that 16S rRNA expression increased with development of p53(+/+) embryos during neurulation. Embryos that lack p53 also displayed weakened cytochrome c oxidase staining and reduced ATP content. During neurulation, the mouse embryo switches from an anaerobic (glycolytic) to an aerobic (oxidative) metabolism. The preliminary results of the present study suggest that p53 may be involved, directly or indirectly, in this transition.