Timing of the steps in transformation of C3H 10T 1/2 cells by X-irradiation

Transformation of cells in culture by chemical carcinogens or X rays seems to require at least two steps. The initial step is a frequent event; for example, after transient exposure to either methylcholanthrene or X rays, almost every cell of established lines of mouse embryo fibroblasts proved capable of yielding transformed, tumorigenic descendants. Although results were interpreted as indicating that 100% of the progeny of methylcholanthrene-treated cells were potentially transformed, later experiments showed that only a very small minority of the progeny of cells initiated by X rays or methylcholanthrene actually produced transformed colonies. We thus concluded that there must be a second step in transformation that is a very rare event. We assumed that this event occurred after the cultures became confluent, a time when transformed cells have a selective growth advantage. Since then, however, others have shown that transformation can occur soon after initiation and that clones of transformed cells may already be present by the time initiated cultures become confluent. It has been hypothesized that the second step behaves like a spontaneous mutation in having a constant but small probability of occurring each time an initiated cell divides. We show here that the clone size distribution of transformed cells in growing cultures initiated by X rays is, indeed, exactly what would be expected on that hypothesis.     

Sequence polymorphism of HLA DR beta 1 alleles relating to T-cell-recognized determinants

HLA class II molecules are a highly polymorphic family of dimeric cell-surface proteins primarily involved in regulating T-cell responses to extrinsic antigens. To define regions of class II molecules involved in T-cell recognition, we have now compared sequences of three HLA DR beta cDNA clones obtained from cells that all express the same serologically defined determinants but differ in terms of T-cell-recognized specificities. The comparisons indicate that very few (one to four) nucleotides differ between what are almost certainly alleles of the DR beta 1 locus. All differences were in the first domain of the molecule and all localized to a region from amino acids 71-86. Because all differences were found only in this region of the molecule, and because DR alpha-chains seem to be relatively non-polymorphic, these positions in the DR beta-chain must have a major role in influencing T-cell recognition of the DR molecule.     

Decreased levels of complex III core protein 1 and complex V beta chain in brains from patients with Alzheimer's disease and Down syndrome

Ubiquinol:cytochrome c oxidoreductase (complex III) and ATP synthase (complex V) are important enzymes in the mitochondrial electron transport chain. Defects in mitochondrial respiratory enzymes have been reported for several neurodegenerative diseases. In this study, we applied the proteomic approach to investigate protein levels of complex III core protein and complex V beta chain in brain regions of Alzheimer's disease (AD) and Down syndrome (DS) patients. Complex III core protein 1 was significantly reduced in the temporal cortex of AD patients. Complex V beta chain was significantly reduced in the frontal cortex of DS patients. We conclude that decreased mitochondrial respiratory enzymes could contribute to the impairment of energy metabolism observed in DS. These decreases could also cause the generation of reactive oxygen species and neuronal cell death (apoptosis) in DS as well as AD.     

Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal-dominant central nervous system white-matter disease with variable clinical presentations, including personality and behavioral changes, dementia, depression, parkinsonism, seizures and other phenotypes. We combined genome-wide linkage analysis with exome sequencing and identified 14 different mutations affecting the tyrosine kinase domain of the colony stimulating factor 1 receptor (encoded by CSF1R) in 14 families with HDLS. In one kindred, we confirmed the de novo occurrence of the mutation. Follow-up sequencing identified an additional CSF1R mutation in an individual diagnosed with corticobasal syndrome. In vitro, CSF-1 stimulation resulted in rapid autophosphorylation of selected tyrosine residues in the kinase domain of wild-type but not mutant CSF1R, suggesting that HDLS may result from partial loss of CSF1R function. As CSF1R is a crucial mediator of microglial proliferation and differentiation in the brain, our findings suggest an important role for microglial dysfunction in HDLS pathogenesis.     

Fast Implementation of Iterative Reconstruction with Exact Ray-Driven Projector on GPUs

Iterative methods are popular choices in image reconstruction fields due to their capability of recovering object information from incomplete acquisition data.However,the computation process involves frequent uses of forward and backward projections that are computationally expensive.Past research has proved that a forward projector that can produce high quality images is crucial to achieve a good convergence rate.In this paper a high performance iterative reconstruction framework is introduced,where two mo...     

Random components in mutagenesis

The mutability of DNA varies enormously from one base pair to another. Part of this variation is due to the specificity of the reaction between mutagens and base, but much of the variation is due to unknown causes. A genetic system developed by Miller and colleagues allows the mutation frequencies of a large number of different base pairs in the lacI gene of Escherichia coli to be compared. For example, Coulondre and Miller found that the sites most readily mutated by UV light are almost 100 times more often mutated than the least susceptible sites. A recently completed study of mutagenesis with neocarzinostatin (NCS) in the lacI gene has prompted us to re-examine some previous studies, of mutagenesis in this gene. Our analysis, reported here, suggests that the mutations induced by certain mutagens fall into two classes: mutations in one class are clearly distributed non-randomly, that is, they are very common at some sites and significantly less common at others; mutations in the second class, however, occur at low frequency and appear to be randomly distributed. Both classes of mutations seem to occur only at damaged bases.     

The origin of mutants

Nucleic acids are replicated with conspicuous fidelity. Infrequently, however, they undergo changes in sequence, and this process of change (mutation) generates the variability that allows evolution. As the result of studies of bacterial variation, it is now widely believed that mutations arise continuously and without any consideration for their utility. In this paper, we briefly review the source of this idea and then describe some experiments suggesting that cells may have mechanisms for choosing which mutations will occur.     

Life choices simulation: Model and methodology

The life choices stimulation (LCS) is a computer-managed simulation which permits participants to explore the impact of decision making in an extended time frame. It is designed primarily for individuals who wish to explore a variety of possible futures and to develop an appreciation for the complexity of relationships and career planning. A general systems approach was used to design a model of complexity within the simulation. “Situation” scenarios were developed to represent common life experiences to which the participant must respond (such as single parenting, divorce, career choice, and old age). The realism of the simulation is provided by a supporting data base which includes such data points as average income of male and female workers, types of employment and their salary levels, and time unit allowances for life-style choices. These data are kept current and are used to generate the results of various choices. This paper describes the process of simulation development, outlines the LCS, and suggests research uses.