The influence of chemical inhibitors of DNA repair on the recovery of mammalian cell damages induced by ionizing radiation

Using experimental results published by other authors the irreversible component of radiation damage and recovery constant, characterized the probability of recovery of mammalian cells of various origin from radiation damages per unit time, have been calculated. It was shown that the inhibition of postirradiation recovery, displayed in the decreasing of both the rate and the volume of recovery, has occurred due to the increasing in the portion of radiation damages from which the cell is incapable to recover. At the same time the recovery constant was independent on the conditions of combined action in the most cases, being decreasing in small extent only for hydroxyurea and 3-aminobenzamide. It was concluded that the inhibition of recovery is not the main reason of chemical radiosensibilization, but is a quite expected consequence of the increase in the portion of irreversibly damaged cells.     

The recovery parameters of DNA strand breaks of Ehrlich ascites cells after the combined action of ionizing radiation and hyperthermia

A mathematical model of DNA strand breaks postirradiation repair and the methodology allowing to differentiate the mechanism of inhibition of DNA strand breaks recovery after combined actions of ionizing radiation and hyperthermia have been described in this paper. Using this model and the results published by other authors for DNA strand breaks of Ehrlich ascites cells, there have been obtained the data showing that the portion of DNA-damages that the cell incapable to recover after consecutive thermoradiation action was risen with an increase in thermal load under insignificant change of repair constant. It means the mechanism of DNA strand breaks recovery inhibition is realized in a greater extent through the formation of irreversible damages but not through the damage of repair process itself.     

Osteoblast Menin Regulates Bone Mass in Vivo

Menin, the product of the multiple endocrine neoplasia type 1 (Men1) tumor suppressor gene, mediates the cell proliferation and differentiation actions of transforming growth factor-β (TGF-β) ligand family members. In vitro, menin modulates osteoblastogenesis and osteoblast differentiation promoted and sustained by bone morphogenetic protein-2 (BMP-2) and TGF-β, respectively. To examine the in vivo function of menin in bone, we conditionally inactivated Men1 in mature osteoblasts by crossing osteocalcin (OC)-Cre mice with floxed Men1 (Men1^f/f) mice to generate mice lacking menin in differentiating osteoblasts (OC-Cre;Men1^f/f mice). These mice displayed significant reduction in bone mineral density, trabecular bone volume, and cortical bone thickness compared with control littermates. Osteoblast and osteoclast number as well as mineral apposition rate were significantly reduced, whereas osteocyte number was increased. Primary calvarial osteoblasts proliferated more quickly but had deficient mineral apposition and alkaline phosphatase activity. Although the mRNA expression of osteoblast marker and cyclin-dependent kinase inhibitor genes were all reduced, that of cyclin-dependent kinase, osteocyte marker, and pro-apoptotic genes were increased in isolated Men1 knock-out osteoblasts compared with controls. In contrast to the knock-out mice, transgenic mice overexpressing a human menin cDNA in osteoblasts driven by the 2.3-kb Col1a1 promoter, showed a gain of bone mass relative to control littermates. Osteoblast number and mineral apposition rate were significantly increased in the Col1a1-Menin-Tg mice. Therefore, osteoblast menin plays a key role in bone development, remodeling, and maintenance.     

High degree of heterogeneity in Alzheimer's disease progression patterns

There have been several reports on the varying rates of progression among Alzheimer's Disease (AD) patients; however, there has been no quantitative study of the amount of heterogeneity in AD. Obtaining a reliable quantitative measure of AD progression rates and their variances among the patients for each stage of AD is essential for evaluating results of any clinical study. The Global Deterioration Scale (GDS) and Functional Assessment Staging procedure (FAST) characterize seven stages in the course of AD from normal aging to severe dementia. Each GDS/FAST stage has a published mean duration, but the variance is unknown. We use statistical analysis to reconstruct GDS/FAST stage durations in a cohort of 648 AD patients with an average follow-up time of 4.78 years. Calculations for GDS/FAST stages 4-6 reveal that the standard deviations for stage durations are comparable with their mean values, indicating the presence of large variations in the AD progression among patients. Such amount of heterogeneity in the course of progression of AD is consistent with the existence of several sub-groups of AD patients, which differ by their patterns of decline.     

Plant-made trastuzumab (herceptin) inhibits HER2/Neu+ cell proliferation and retards tumor growth

Background

Plant biotechnology provides a valuable contribution to global health, in part because it can decrease the cost of pharmaceutical products. Breast cancer can now be successfully treated by a humanized monoclonal antibody (mAb), trastuzumab (Herceptin). A course of treatment, however, is expensive and requires repeated administrations of the mAb. Here we used an Agrobacterium-mediated transient expression system to produce trastuzumab in plant cells.

Methodology/Principal Findings

We describe the cloning and expression of gene constructs in Nicotiana benthamiana plants using intron-optimized Tobacco mosaic virus- and Potato virus X-based vectors encoding, respectively, the heavy and light chains of trastuzumab. Full-size antibodies extracted and purified from plant tissues were tested for functionality and specificity by (i) binding to HER2/neu on the surface of a human mammary gland adenocarcinoma cell line, SK-BR-3, in fluorescence-activated cell sorting assay and (ii) testing the in vitro and in vivo inhibition of HER-2-expressing cancer cell proliferation. We show that plant-made trastuzumab (PMT) bound to the Her2/neu oncoprotein of SK-BR-3 cells and efficiently inhibited SK-BR-3 cell proliferation. Furthermore, mouse intraperitoneal PMT administration retarded the growth of xenografted tumors derived from human ovarian cancer SKOV3 Her2+ cells.

Conclusions/Significance

We conclude that PMT is active in suppression of cell proliferation and tumor growth.     

Increase in the level of proline and osmotic pressure of cytoplasm in transformed tobacco bearing an antisense suppressor of the proline dehydrogenase gene

The antisense suppressor was constructed for proline dehydrogenase gene (PDH; a fragment of PDH from Arabidopsis in antisense orientation and under the control of 35S promoter of cauliflower mosaic virus, CMV). In Nicotiana tabacum SR1 tobacco transformants bearing antisense suppressor for PDH, the proline content and the cytoplasm osmotic pressure were increased. The proline content in these transformants varied, whereas cytoplasm osmotic pressure was stable, which seems to reflect complicated relationships between these characteristics of the plant cell.     

Population heterogeneity and color stimulus heterogeneity in agent-based color categorization

Investigating the interactions between universal and culturally specific influences on color categorization across individuals and cultures has proven to be a challenge for human color categorization and naming research. The present article simulates the evolution of color lexicons to evaluate the role of two realistic constraints found in the human phenomenon: (i) heterogeneous observer populations and (ii) heterogeneous color stimuli. Such constraints, idealized and implemented as agent categorization and communication games, produce interesting and unexpected consequences for stable categorization solutions evolved and shared by agent populations. We find that the presence of a small fraction of color deficient agents in a population, or the presence of a “region of increased salience” in the color stimulus space, break rotational symmetry in population categorization solutions, and confine color category boundaries to a subset of available locations. Further, these heterogeneities, each in a different, predictable, way, might lead to a change of category number and size. In addition, the concurrent presence of both types of heterogeneity gives rise to novel constrained solutions which optimize the success rate of categorization and communication games. Implications of these agent-based results for psychological theories of color categorization and the evolution of color naming systems in human societies are discussed.     

Asymmetric induction in catalyzed synthesis of organic compounds as an important stage in the evolution of life on earth

It is shown that natural chiral catalysts, which could be formed e.g., from optically active amino acids on basic natural minerals, could lead, at early stages of evolution, to the formation of rather complex optically active products from starting achiral compounds. Using biomimetic combinations of vanadium ion complexes and chiral ligands synthesized from widely occurring natural compounds, we created novel catalytic systems, permitting the transfer of optical activity in the course of catalytic chemical transformations of achiral compounds. We found that in the presence of natural clay, optically active terpenoids from the pinane series undergo multistage transformations, forming unexpected new products with preservation of optical purity.