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PubMed1986

Use of dual control groups to estimate false positive rates in laboratory animal carcinogenicity studies.

Tumor incidence data from 18 recently completed carcinogenicity studies utilizing male and female mice and rats were examined to determine if the frequency of significant (p less than 0.05) pairwise differences between the two concurrent control groups employed in these experiments exceeded chance expectation. Although marked study-to-study variability was observed for some tumors, no evidence of extra-binomial within-study variability between the two concurrent control groups was found. The total number of observed significant (p less than 0.05) paired-control differences was virtually identical to what would be expected from the usual binomial model assumptions; the corresponding overall observed (44%) and expected (47-50%) false positive rates were essentially the same. While one should not overgeneralize the implications of these findings, these results should lessen concerns that elevated false positive rates resulting from extra-binomial within-study variability might be adversely affecting the interpretation of long-term laboratory animal carcinogenicity studies. On the other hand, these results reaffirm the conclusions of other investigators that (particularly for commonly occurring tumors) more stringent evidence than an isolated p less than 0.05 effect should be required before an increased tumor incidence is regarded as biologically significant; otherwise, the study may have an unacceptably high false positive rate.

Analysis of Variance↗
PubMed1989

Dual control over microvillus elongation during enterocyte development.

1. Previously determined logistic growth constants describing enterocyte microvillus development for a variety of species were analysed for possible interactions taking place between enterocyte migration rate (R) and the size of individual crypts (CD). 2. Microvillus elongation, the c-value of a logistic growth curve, was found to increase linearly with crypt depth and reciprocally with decreasing migration rate. The starting microvillus length of a basal crypt enterocyte, the a-value, also increased linearly with CD without being affected by R. 3. The mathematical equation describing the effects of CD and R on M, the maximal microvillus length, was M = 0.0016 CD + 0.073 CD/R, where M and CD are measured in micron and R in micron/hr. 4. The relationship found between R, CD and M is explained by suggesting that the crypt environment enables enterocytes to respond to an initiating signal imposed on cells as they begin to migrate onto villi. The possible nature of this putative signal is also discussed.

Animals↗
PubMed2004

Dual control of membrane targeting by PtdIns(4)P and ARF.

In mammalian cells, three types of phosphatidylinositol 4-kinase (PI4K) are associated with the Golgi complex, where their product, phosphatidylinositol 4-phosphate [PtdIns(4)P], is concentrated. The role of PtdIns(4)P in this compartment and how the PtdIns(4)P-positive membrane domain is formed and maintained despite continuous membrane flow are, however, poorly understood. Recent work has shown that PtdIns(4)P and the small GTPase ARF1 function cooperatively in the recruitment of four-phosphate adaptor proteins (FAPPs) to the trans-Golgi network (TGN) and has implicated FAPPs in formation of the membrane domain and in post-Golgi trafficking.

1-Phosphatidylinositol 4-Kinase↗
PubMed2000

Dual control of the brainstem on the spindle oscillation in humans.

In human subjects, the excitability change of the brainstem was investigated over the course of the spindle oscillation. The investigation was carried out by a sequential analysis of brainstem auditory evoked potentials (BAEPs) with reference to one sequence of spindle oscillation. The method was based on the characteristics of BAEPs, i.e. far-field evoked potential. The brainstem revealed two types of excitability change: one in the lower ventral brainstem (wave-III components), and the other in the upper dorsal brainstem (wave-V components). The excitability in the dorsal brainstem showed an oscillation with one cycle period of about 1.5 s, whereas in the ventral brainstem, the excitability showed a long-range biphasic (decaying-growing) fluctuation. Both excitability changes in the brainstem preceded the spindle oscillation, and the phase was reversed during the emerging period of spindle oscillation. The results suggest a primary triggering mechanism of the brainstem for the spindle oscillation, which is independent of preceding cortical drives (K-complexes) upon the thalamus. The difference of the excitability change between the spindle oscillation and the paroxysmal discharge (spike-and-wave complex) was also discussed.

Adult↗
PubMed2002

Health and economic effects of adding nateglinide to metformin to achieve dual control of glycosylated hemoglobin and postprandial glucose levels in a model of type 2 diabetes mellitus.

BACKGROUND: Type 2 diabetes mellitus is a common disease whose complications have great costs, both in quality of life and expense of treatment. Improving glycemic control, as measured by monitoring glycosylated hemoglobin (HbA1c) levels, can reduce the rate of such complications. OBJECTIVES: The aims of this study were to estimate the lifetime costs associated with diabetes-related complications in a theoretical population receiving metformin monotherapy and to predict the health and economic effect of improving glycemic control in this theoretical population by combining metformin with nateglinide. METHODS: A pharmacoeconomic model was developed to simulate the long-term (30 years) complication rates (microvascular and macrovascular) of a cohort of patients with type 2 diabetes mellitus. The model simulated each year of life for each patient in a theoretical cohort of 10,000 patients until diabetes-related complications were present or death occurred. The mean accumulated costs (direct medical costs for acute care and subsequent care for diabetes-related complications), mean survival time, and the frequency of each type of complication were estimated. Both effectiveness and cost data were discounted at 3%. Sensitivity analyses were conducted on key model input parameters. RESULTS: Average costs of treating complications in theoretical patients undergoing metformin monotherapy were estimated at $29,565 per patient. Savings of $2,742 were estimated per patient for all complications--particularly, nephropathy ($1,166) and macrovascular disease ($632)--when nateglinide was added. The cost-effectiveness ratio of adding nateglinide to metformin was estimated at $27,131 per undiscounted life-year gained (95% CI, $23,710-$28,577) or $43,024 (95% CI, $37,285-$45,193) per additional discounted life-year gained. In the sensitivity analyses, decreasing HbA1c level at baseline, HbA1c upward drift, and duration of disease improved survival. CONCLUSIONS: Combination therapy with nateglinide and metformin, compared with metformin alone, was predicted to reduce the frequency of complications and, thus, treatment costs in this theoretical model. The major factor in cost savings was fewer complications due to nephropathy. The increased drug treatment costs were expected to be offset by the long-term savings from reducing complication rates.

Adult↗
PubMedDate not supplied

Chromosome segregation: dual control ensures fidelity.

A mitotic checkpoint arrests cell cycle progression in response to spindle damage. It now appears that this checkpoint has two separate arms, one that prevents anaphase and a second that prevents cytokinesis and DNA re-replication.

Anaphase↗
PubMed1990

Dual controls for screening pigment movement in photoreceptors of the Limulus lateral eye: circadian efferent input and light.

The radial and longitudinal distribution of retinular screening pigment in the lateral eye of the horseshoe crab Limulus polyphemus was quantified under a variety of experimental conditions. Pigment position was characterized by the center and width of the radial distribution at four levels in the ommatidium. Under diurnal lighting, intact animals show movement of pigment granules from the periphery of the retinular cell at night towards the junction of the arhabdomeral and rhabdomeral segments of the retinular cell in the day. In constant darkness, intact animals exhibit the same circadian rhythm in pigment migration. Animals with bilaterally cut optic nerves do not receive circadian efferent input from the brain and show little pigment movement in diurnal lighting. In all of these cases, pigment was either aggregated in a band just peripheral to the rays of the rhabdom or dispersed to the periphery of the retinular cell. When dark-adapted animals are exposed to a sudden large light increment, pigment moves inward between the rays of the rhabdom. During the day, this inward response begins immediately and reverses as the ommatidial aperture begins to close. At night, the onset of the inward movement is delayed, but then occurs more rapidly than during the day. No significant longitudinal movement of photoreceptor screening pigment was detected under any of these experimental conditions. Two opposing mechanisms control the movement of screening pigment in these cells. Release of neurotransmitters from the circadian efferents causes outward movement; large increments of light cause inward movement. In the absence of sudden changes in light intensity, circadian efferent input, not cyclic lighting, appears to be the major determinant of screening pigment position. A sudden and large increment of light triggers the rapid inward movement which appears to be a protective mechanism optimized for daytime performance.

Animals↗
PubMed2002

The C-terminus and linker region of S100B exert dual control on protein-protein interactions with TRTK-12.

S100B, an EF-hand calcium-binding protein composed of two S100beta monomers, undergoes a calcium-dependent conformational change that provides a surface for target interactions. In this study, the calcium-sensitive S100B-binding epitope TRTK-12 has been used to probe the contributions of the linker and C-terminal regions of S100B to protein-protein interactions. These contributions were quantified using C-terminal mutant S100B proteins lacking the C-terminal seven (S100B85stop) or nine (S100B83stop) residues or containing alanine substitutions at Phe87 (F87A), Phe88 (F88A), or both (F8788A). Both F8788A and F88A bound TRTK-12 less tightly (K(d) = 1.85 +/- 0.02 and 0.97 +/- 0.08 microM, respectively) than the wild-type protein (K(d) = 0.27 +/- 0.03 microM, DeltaG = -37.2 kJ/mol), indicating these residues are important for TRTK-12 interaction. The truncated S100B proteins bound TRTK-12 much more weakly (K(d) = 659.7 +/- 119.3 microM, DeltaG = -17.9 kJ/mol), indicating the linker region contributed about 50% to the binding of TRTK-12, while the C-terminus contributed the remaining 50% of the binding energy. Based on mutagenesis and NMR chemical shift studies, a comparison with known S100-target protein complexes showed the S100B-TRTK-12 complex has the strongest resemblance to the S100A10-annexin II interaction.

Amino Acid Sequence↗
PubMed1979

Dual control of cell growth by somatomedins and platelet-derived growth factor.

Quiescent BALB/c 3T3 cells exposed briefly to a platelet-derived growth factor (PDGF) become "competent" to replicate their DNA but do not "progress" into S phase unless incubated with growth factors contained in platelet-poor plasma. Plasma from hypophysectomized rats is deficient in progression activity; it does not stimulate PDGF-treated competent cells to synthesize DNA, demonstrating that somatomedin C is required for progression. Various growth factors were tested for progression activity and competence activity by using BALB/c 3T3 tissue culture assays. Multiplication stimulating activity and other members of the somatomedin family of growth factors are (like somatomedin C) potent mediators of progression. Other mitogenic agents, such as fibroblast growth factor, are (like PDGF) potent inducers of competence. Growth factors with potent progression activity have little or no competence activity and vice versa. In contrast, simian virus 40 provides both competence and progression activity. Coordinate control of BALB/c 3T3 cell growth in vitro by competence factors and somatomedins may be a specific example of a common pattern of growth regulation in animal tissues.

Animals↗
PubMed1993

Dual control of heat shock response: involvement of a constitutive heat shock element-binding factor.

Heat shock factor (HSF) has been implicated as the key regulatory protein in the heat shock response. Our studies on the response of rodent cells to heat shock or sodium arsenite indicate that a high level of HSF-DNA-binding activity, by itself, is not sufficient for the induction of hsp70 mRNA synthesis; furthermore, a high level of HSF binding is also not necessary for this induction. Analysis of the binding of protein factors to the heat shock element (HSE) in extracts of stressed rodent cells indicates that the regulation of heat shock response involves the heat-inducible HSF and a constitutive HSE-binding factor. Our results also suggest that overexpression of human hsp70 may decrease the level of heat-induced HSF-HSE-binding activity in rat cells.

Animals↗
PubMed1997

A new approach for containment of microorganisms: dual control of streptavidin expression by antisense RNA and the T7 transcription system.

The use of microorganisms in the open environment would be of less concern if they were endowed with programmed self-destruction mechanisms. Here, we propose a new genetic design to increase the effectiveness of cell suicide systems. It ensures very tight control of the derepression of cell death by the combination of the bacteriophage T7 RNA polymerase-lysozyme system and an inducible synthesis of antisense RNA and the Escherichia coli LacI repressor. Functionality of this regulatory concept was tested by applying it to containment of Gram-negative bacteria, based on the conditional expression of the lethal Streptomyces avidinii streptavidin gene. Toxicity of streptavidin is derived from its exceptionally high binding affinity for an essential prosthetic group, D-biotin. The entire construct was designed to allow the soil bacterium Pseudomonas putida to survive only in the presence of aromatic hydrocarbons and their derivatives which it can degrade. Under favorable growth conditions, clones escaping killing appeared at frequencies of only 10(-7)-10(-8) per cell per generation. The general requirement for biotin through the living world should make streptavidin-based conditional lethal designs applicable to a broad range of containment strategies.

Bacterial Proteins↗
PubMed2001

Dual control of replication timing. Stochastic onset but programmed completion of mammalian chromosome duplication.

In mammalian cells, DNA replication proceeds according to a precise temporal order during the S phase, but how this program is controlled remains poorly understood. We analyzed the replication-dependent bromodeoxyuridine banding of chromosomes in Chinese hamster cells treated with the spindle poison nocodazole. In these cells, nocodazole induces a transient mitotic arrest, followed by DNA re-replication without intervening cell division. Nuclear fragmentation is often observed in tetraploid derivatives, and previous studies suggest that replication timing of chromosomes could be affected when they are segregated into different micronuclei. Here we show that the onset of replication is frequently asynchronous on individual chromosomes during the re-replication process. Moreover, fluorescence in situ hybridization analysis revealed that replication synchrony is equally altered in fragmented and non-fragmented nuclei, indicating that asynchronous onset of replication is not dependent on physical separation of the chromosomes into isolated compartments. We also show that the ordered program of replication is always preserved along individual chromosomes. Our results demonstrate that the onset of replication of individual chromosomes in the same nuclear compartment can be uncoupled from the time of S-phase entry and from the programmed replication of chromosome sub-domains, revealing that multi-level controls contribute to establish replication timing in mammalian cells.

Animals↗