Modeling stochastic gene expression: implications for haploinsufficiency

There is increasing recognition that stochastic processes regulate highly predictable patterns of gene expression in developing organisms, but the implications of stochastic gene expression for understanding haploinsufficiency remain largely unexplored. We have used simulations of stochastic gene expression to illustrate that gene copy number and expression deactivation rates are important variables in achieving predictable outcomes. In gene expression systems with non-zero expression deactivation rates, diploid systems had a higher probability of uninterrupted gene expression than haploid systems and were more successful at maintaining gene product above a very low threshold. Systems with relatively rapid expression deactivation rates (unstable gene expression) had more predictable responses to a gradient of inducer than systems with slow or zero expression deactivation rates (stable gene expression), and diploid systems were more predictable than haploid, with or without dosage compensation. We suggest that null mutations of a single allele in a diploid organism could decrease the probability of gene expression and present the hypothesis that some haploinsufficiency syndromes might result from an increased susceptibility to stochastic delays of gene initiation or interruptions of gene expression.     

Mercury-induced autoimmunity in Brown Norway rats: kinetics of changes in RT6+ T lymphocytes correlated with IgG isotypes of circulating autoantibodies to laminin 1

Repeated exposure to mercury causes various autoimmune effects in rats of the Brown Norway (BN) strain. Previous studies from our laboratory have shown that on day 15 of HgCl2 treatment BN rats exhibit a relative decrease in RT6.2+ T cells. At the same time, they produce high levels of autoantibodies to renal antigens and experience a membranous glomerulonephropathy. In contrast, Lewis (LEW) rats are resistant to autoimmunity caused by mercury and do not demonstrate a decrease in RT6+ cells after administration of HgCl2. In the present paper we provide novel information on the correlation between changes in RT6.2+ lymph node T cells and the production of autoantibodies to laminin 1, obtained by detailed kinetic studies of HgCl2-treated BN rats. We have confirmed a decrease in the percentage of RT6.2+ lymphocytes on day 15 of mercury treatment, despite a significant increase in the number of peripheral lymphocytes. No such changes were observed in LEW rats. We have determined that on day 15 the percentage decrease in RT6+ cells is evident in both RT6.2+CD4+ and RT6.2+CD8+ T cell subsets. Kinetic studies demonstrated that significant changes in the percentage of RT6.2+ cells are first observed by day 8 and continue through days 11 and 15. We have also observed a significant percent decrease in CD4+ T lymphocytes as well as an increase in CD4-CD8- cells. The dramatic increase in the percentage of these double negative cells at the level of peripheral lymphoid tissues does not appear to be due to higher thymic output, since there was a decrease in the percentage of TCR+Thy1+ cells, a phenotype that is associated with recent thymic emigrants. Finally, we have demonstrated that 100% of HgCl2-treated BN rats had circulating antibodies that reacted with both mouse and rat laminin 1, i.e. are autoantibodies to laminin 1. These autoantibodies were predominantly of the IgG1 and IgG2a isotype, possibly as the result of a polarized autoimmune response driven by Type 2 cytokines. A kinetic investigation showed that significant levels of IgG1 and IgG2a autoantibodies to laminin 1 were first presentin the circulation by day 11. The inverse correlation between levels of RT6.2+ T lymphocytes and autoantibodies to laminin 1 suggests that mercury may induce autoimmune responses in BN rats by its effects on these immunoregulatory cells.     

Organization of direct hippocampal efferent projections to the cerebral cortex of the rhesus monkey: projections from CA1, prosubiculum, and subiculum to the temporal lobe

This study investigates direct hippocampal efferent projections to the temporal lobe of the rhesus monkey. Tritiated amino acid injections were placed into the hippocampal formation to identify terminal fields, and complementary fluorescent retrograde tracer injections were placed into the cortex to identify the cells of origin. Tritiated amino acid injections into CA1, prosubicular, or subicular subfields produced anterograde label over parts of the parahippocampal gyrus and temporal pole. Injections of fluorescent retrograde tracers demonstrated that these projections originate from longitudinal strips of neurons that occupy part of the CA1 subfield as well as from strips of neurons in adjacent prosubicular and subicular subfields. Thus, an injection into area TH of the posterior parahippocampal gyrus labeled neurons in a longitudinal strip of proximal CA1 (i.e., near CA2) as well as a strip in the subiculum; injections into areas TF, TL, 35, or Pro labeled neurons in a longitudinal strip of distal CA1 (i.e., near the prosubiculum) as well as one in the prosubiculum; and an injection into area TFO labeled neurons in a longitudinal strip in the middle of CA1. These strips of neurons extended longitudinally throughout the entire rostrocaudal length of the hippocampus. These results demonstrate that, in the monkey, CA1 projections to cortex arise topographically from longitudinally oriented strips of neurons that occupy only a part of the transverse extent of CA1 but that cover most of the anteroposterior extent of the hippocampus. Thus, in the monkey, CA1 is not a single uniform entity and may have a unique role as a source of direct hippocampal projections to the cerebral cortex.     

The effects of functional knee braces on speed in collegiate basketball players

Knee braces are worn by many athletes following injury. The purpose of this study was to determine whether two functional knee braces (noncustom design) significantly affected straight line and successive turning trial running times in noninjured collegiate basketball players. Twenty-five coed basketball players completed 2 days of running trials. Subjects ran three full lengths of a basketball court and 10 lengths between the baseline and the foul line first without wearing a brace, then wearing either a DonJoy GoldPoint brace or an Omni OS-5 brace, and finally wearing the other brace. The results indicated no significant difference (p < .05) in straight line or successive turning running times when the two braces were compared with the nonbraced condition and when the two braces were compared with each other. The results implied that speed was not significantly affected by a functional knee brace in noninjured collegiate basketball players.