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PubMed1993

Germination and Dormancy of Abscisic Acid- and Gibberellin-Deficient Mutant Tomato (Lycopersicon esculentum) Seeds (Sensitivity of Germination to Abscisic Acid, Gibberellin, and Water Potential).

Germination responses of wild-type (MM), abscisic acid (ABA)-deficient (sitw), and gibberellin (GA)-deficient (gib-1) mutant tomato (Lycopersicon esculentum Mill. cv Moneymaker) seeds to ABA, GA4+7, reduced water potential ([psi]), and their combinations were analyzed using a population-based threshold model (B.R. Ni and K.J. Bradford [1992] Plant Physiol 98: 1057-1068). Among the three genotypes, sitw seeds germinated rapidly and completely in water, MM seeds germinated more slowly and were partially dormant, and gib-1 seeds did not germinate without exogenous GA4+7. Times to germination were inversely proportional to the differences between the external osmoticum, ABA, or GA4+7 concentrations and the corresponding threshold levels that would either prevent ([psi]b, log[ABAb]) or promote (log[GAb]) germination. The sensitivity of germination to ABA, GA4+7, and [psi] varied widely among individual seeds in the population, resulting in a distribution of germination times. The rapid germination rate of sitw seeds was attributable to their low mean [psi]b (-1.17 MPa). Postharvest dormancy in MM seeds was due to a high mean [psi]b (-0.35 MPa) and a distribution of [psi]b among seeds such that some seeds were unable to germinate even on water. GA4+7 (100 [mu]M) stimulated germination of MM and gib-1 seeds by lowering the mean [psi]b to -0.75 MPa, whereas ABA inhibited germination of MM and sitw seeds by increasing the mean [psi]b. The changes in [psi]b were not due to changes in embryo osmotic potential. Rather, hormonal effects on endosperm weakening opposite the radicle tip apparently determine the threshold [psi] for germination. The analysis demonstrates that ABA- and GA-dependent changes in seed dormancy and germination rates, whether due to endogenous or exogenous growth regulators, are based primarily upon corresponding shifts in the [psi] thresholds for radicle emergence. The [psi] thresholds, in turn, determine both the rate and final extent of germination within the seed population.

Journal Article↗

PubMed2006

Residential radon and lung cancer: end of the story?

The earliest evidence of increased lung cancer risk associated with radon came largely from studies of highly exposed underground miners. In the United States, concerns about residential exposures became prominent in the early 1980s with the identification of the Watras home, which had remarkably elevated radon concentrations. By then, the problem of indoor radon was already recognized in Europe and the first epidemiological studies on indoor radon had been reported. The concern about the risk of indoor radon motivated a series of case-control studies of residential radon and lung cancer in the United States, Canada, China, and a number of European countries. In 1999, the U.S. National Research Council Committee on the Biological Effects of Ionizing Radiation (BEIR VI) weighed the scientific evidence available at that time on this issue and concluded that residential radon was an important contributor to the lung cancer burden and that risks were appropriately estimated by a linear nonthreshold model. Since individual case-control studies have not provided consistent direct evidence of excess lung cancer risk at residential exposure levels, combined analyses of residential radon studies have been undertaken in both North America and Europe. These combined analyses, including the North American pooled analysis described in this issue, represent an important complement to the findings of the miner studies and further support the linear no-threshold model for cancer risk adopted by the BEIR VI Committee and other groups.

Air Pollutants, Radioactive↗

PubMed1992

The molecular mechanism of peroxisome proliferator action: a model for species differences and mechanistic risk assessment.

An increasing number of chemicals that produce tumours in rodent bioassays belong to the non-genotoxic class of carcinogens. There are no suitable tests for these carcinogens and our understanding of their mechanism of action is poor. Importantly, assessment of their potential hazard to man is usually difficult without extensive research. Peroxisome proliferators (PP) are a diverse group of rodent non-genotoxic carcinogens that include hypolipidemic drugs, plasticizers and herbicides. We have reported previously the cloning of a member of the nuclear hormone receptor superfamily and, through the use of chimeric receptors, discovered that it could be activated by PPs. The receptor is therefore termed the PP activated receptor (PPAR). The most widely used marker of PP action is the peroxisomal beta-oxidation enzyme acyl CoA oxidase (ACO). Interestingly, it has been speculated that the hydrogen peroxide produced as a result of ACO activity could lead to DNA damage and tumorigenesis. We have now demonstrated that PPAR recognizes a specific PP response element (PPRE) located in the ACO gene promoter and that the response is dependent upon the presence of receptor and the addition of the PP Wy-14,643. These data therefore support a model in which the mechanism of PP action is mediated by PPAR in a manner similar to that of steroid hormone action. Learning more about the function of PPAR offers a unique opportunity to understand the mechanism of action of some non-genotoxic carcinogens. Furthermore, this knowledge when combined with comparison of receptor expression between rodents and man will be important in providing a framework for a new threshold model of risk assessment based upon receptor-mediated carcinogenesis.

Acyl-CoA Oxidase↗

PubMed1997

Modeling genetic and environmental influences in the etiology of conduct disorder: a study of 2,682 adult twin pairs.

The etiology of conduct disorder (CD) was examined retrospectively in a sample of 2,682 male, female, and unlike-sex adult twin pairs from the community-based Australian Twin Register. Model-fitting analyses indicated a substantial genetic influence on risk for CD, accounting for 71% of the variance (95% confidence interval [CI] = 32-79%). There was not a statistically significant effect of the shared environment in the best-fitting model of CD, but a modest effect of the shared environment on the risk for CD could not be rejected (95% CI = 0-32%). The magnitude of genetic and environmental influences for CD liability did not vary significantly for boys and girls, and the specific genetic and environmental mechanisms important for the development of CD appeared to be largely the same for both sexes. The fit of a multiple-threshold model raises the possibility that CD may not necessarily be a discrete entity but rather an extreme of the normal variation in conduct-disordered behavior found in the general population.

Adult↗

PubMed1992

Is the anaerobic threshold truly anaerobic?

This study was done to address the question as to whether there was an exercise metabolic rate below which the O2 supply to the muscles was adequate to meet the O2 requirement and above which the O2 supply was inadequate, ie, an anaerobic threshold (AT). The question was addressed using 2 approaches: (1) The arterial lactate/pyruvate ratio was measured to see if it increased at an O2 uptake (VO2) threshold or continuously as a log function over the entire range of exercise work rates. (2) Anticipating that the VO2 would be affected by reducing O2 supply only for work rates above the AT, the effect of reducing O2 delivery on VO2 for work rates over the entire range of the subject's work capacity was determined. Lactate (L) and pyruvate (P) were measured in arterial blood in 10 normal subjects. The L/P ratio was found not to increase until a threshold work rate was reached, the VO2 being that identified as the AT. Above that VO2, the L/P ratio climbed steeply. Arterial L/P ratio measurements fit a threshold model considerably better than a continuous model, supporting the concept that exercise done at low and moderate work rates can be performed without a change in cell redox state; but redox state does change rapidly in relation to the work rate increase above the AT. In the second study, the cardiorespiratory responses to various levels of exercise were studied in 10 normal subjects before and after carboxyhemoglobin (COHb) was increased to 10% and 20%. The lactic acidosis threshold and VO2 kinetics were examined. Blood lactate concentration increased only above the AT. The AT was systematically decreased by the percent of COHb increase. Importantly, VO2 was reduced and VO2 kinetics were slowed in response to exercise only for the metabolic rates above the AT. These studies demonstrate that lactate increase in response to exercise is O2 flow sensitive, and there is a threshold work rate above which this sensitivity becomes manifest.

Acidosis, Lactic↗

PubMed2006

Making omelets without breaking eggs: E2F-mediated induction of cardiomyoycte cell proliferation without stimulation of apoptosis.

The fundamental role of E2F transcription factors in the regulation of proliferation is well established. According to a widely accepted model, E2F1, E2F2, and E2F3 are classified as "activating" E2Fs since they induce proliferation of quiescent cells whereas E2F4 and E2F5 do not have the power to incite cell cycle progression but are related to differentiation processes and were therefore considered to be "repressive". In addition, it has been postulated that "activating" E2Fs induce apoptosis in a wide variety of cell types depending on their expression level. However, we demonstrated recently that this 'threshold model' does not hold true for cardiomyocytes. In a series of experiments in which we overexpressed individual E2Fs we found that directed expression of E2F2, unlike E2F1, E2F3 and E2F5, did not induce apoptosis but even suppressed expression of several pro-apoptotic genes in primary cardiomyocytes. Furthermore, we established that not only E2F1, E2F2, and E2F3 but also E2F4 was able to induce S-phase entry of primary cardiomyocytes. Our results suggest that it is possible to utilize the proliferation-inducing properties of the E2Fs in cardiomyocytes without activation of potentially harmful pro-apoptotic traits. This finding might open a new access to stimulate regeneration in postmitotic tissues such as the heart.

Animals↗

PubMed2001

Community health risk assessment after a fire with asbestos containing fallout.

BACKGROUND: A factory fire in Tranmere, Merseyside, England, deposited asbestos containing fallout in an urban area. There was considerable community anxiety for months after the incident. Therefore an assessment of the long term health risks of this acute environmental incident were requested by the local health authority. METHODS: The facts of the incident were gathered and appraised from unpublished and press reports, involved personnel, and further analysis of material collected at the time of the incident. The literature on the long term health risks of asbestos was reviewed, and combined with evidence on asbestos exposure to estimate community health risk. RESULTS: Risk was almost entirely from exposure to fire fallout of chrysotile in asbestos bitumen paper covering the factory roof. Amosite was only detected in a few samples and in trace amounts. The number of people who lived in the area of fallout was 16 000 to 48 000. From a non-threshold model with assumptions likely to overestimate risk, the lung cancer risk is estimated to be undetectably small. Risk of mesothelioma from chrysotile exposure, and risks of lung cancer and mesothelioma from amosite exposure were based on observational studies and were estimated to be even lower than that of lung cancer risk from chrysotile exposure. Academically, there are assumptions that while reasonable cannot be proven, for example, the validity of extrapolating observed risk from much higher exposures to lower exposures, estimates of individual exposure, and that there is no threshold for asbestos to cause cancer. CONCLUSIONS: The author is unaware of a similar study on long term health risks in a community exposed to asbestos in a fire. It is concluded that, using methods that do not underestimate risk, risk is undetectably small. Practical lessons from this methodology and approach to health risk assessment are discussed.

Asbestos↗

PubMed1985

Observations on sire evaluation with categorical data using heteroscedastic mixed linear models.

The ability of three mixed linear models to rank sires correctly for dichotomous and ordered tetrachotomous traits was studied using simulated half-sib progeny data. The models differed in the assumptions made regarding homogeneity of residual variance. Ranking ability was assessed by estimating the realized response to truncation selection (20% of the candidates selected) upon sire evaluations in populations consisting of 50 such sires. Results suggested that weighting for unequal residual variances, in spite of reducing apparent prediction error variance, impairs the ability of best linear unbiased prediction to identify superior sires. This is consistent with theoretical arguments stemming from threshold models.

Animals↗

PubMed2001

A numerical analysis of phonation using a two-dimensional flexible channel model of the vocal folds.

A two-dimensional flexible channel model of the vocal folds coupled with an unsteady one-dimensional flow model is presented for an analysis of the mechanism of phonation. The vocal fold is approximated by springs and dampers distributed in the main flow direction that are enveloped with an elastic cover. In order to approximate three-dimensional collision of the vocal folds using the two-dimensional model, threshold values for the glottal width are introduced. The numerical results show that the collision plays an important role in speech sound, especially for higher resonant frequency components, because it causes the source sound to include high-frequency components.

Computer Simulation↗

PubMed1997

The diagnostic validity of melancholic major depression in a population-based sample of female twins.

BACKGROUND: Although the diagnosis of melancholia is among the oldest in psychiatry, the validity of the melancholic subtype of major depression (MD) is still debated. If melancholia is a valid subtype of depression, is it quantitatively more severe than or qualitatively distinct from nonmelancholic depression? METHODS: The lifetime history of MD and melancholia, defined by DSM-IV criteria, was assessed at interview in 1902 female twins selected from a population-based register. Patterns of comorbidity and the relationship between melancholia and risk for MD in the co-twin were assessed by logistic regression and Cox proportional hazards models respectively. RESULTS: In those with a lifetime history of MD, melancholia was associated with the following: (1) increased comorbidity with anxiety disorders and nicotine dependence but not alcohol dependence or bulimia; (2) greater number of episodes, more impairment, and help seeking; (3) lower levels of neuroticism; and (4) an increased risk of MD in cotwins-greater in monozygotic than in dizygotic pairs. Within twin pairs concordant for MD, no resemblance was found for melancholia. A multiple threshold model in which melancholic MD represented a quantitatively more severe form of depressive illness fitted the data well. CONCLUSIONS: Melancholia, defined by DSM-IV criteria, is a valid subtype of MD and identifies a subset of affected individuals with distinct clinical features and a particularly high familial liability to depressive illness. However, from a familial perspective, the differences between melancholic and nonmelancholic MD are quantitative, not qualitative. ie, melancholic MD is more severe than, but is not etiologically distinct from, nonmelancholic MD.

Adult↗

PubMed1997

Quantitating tertiary binding energies of 2' OH groups on the P1 duplex of the Tetrahymena ribozyme: intrinsic binding energy in an RNA enzyme.

Binding of the Tetrahymena ribozyme's oligonucleotide substrate (S) involves P1 duplex formation with the ribozyme's internal guide sequence (IGS) to give an open complex, followed by docking of the P1 duplex into the catalytic core via tertiary interactions to give a closed complex. The overall binding energies provided by 2' OH groups on S and IGS have been measured previously. To obtain the energetic contribution of each of these 2' OH groups in the docking step, we have separately measured their contribution to the stability of a model P1 duplex using "substrate inhibition". This new approach allows measurement of duplex stabilities under conditions identical to those used for ribozyme binding measurements. The tertiary binding energies from the individual 2' OH groups include a small destabilizing contribution of 0.7 kcal/mol and stabilizing contributions of up to -2.9 kcal/mol. The energetic contributions of specific 2' OH groups are discussed in the context of considerable previous work that has characterized the tertiary interactions of the P1 duplex. A "threshold" model for the open and closed complexes is presented that provides a framework to interpret the energetic effects of functional group substitutions on the P1 duplex. The sum of the tertiary stabilization provided by the conserved G x U wobble at the cleavage site and the individual 2' OH groups on the P1 duplex is significantly greater than the observed tertiary stabilization of S (11.0 vs 2.2 kcal/mol). It is suggested that there is an energetic cost for docking the P1 duplex into the active site that is paid for by the "intrinsic binding energy" of groups on the P1 duplex. Substrates that lack sufficient tertiary binding energy to overcome this energetic barrier exhibit reduced reactivities. Thus, the ribozyme appears to use the intrinsic binding energy of groups on the P1 duplex for catalysis. This intrinsic binding energy may be used to position reactants within the active site and to induce electrostatic destabilization of the substrate, relative to its interactions in solution.

Animals↗

PubMed1996

On determinants of first-spike latency in auditory cortex.

The first-spike latency of neurones at any level of the auditory pathway decreases with stimulus amplitude. As stimuli are generally shaped with rise functions to avoid spectral splatter, a common interpretation of the latency decrease is that the amplitude of the signal reaches the neurone's firing threshold earlier during the rise time. We demonstrate here, for auditory cortex neurones and by varying the amplitude and rise time of tonal stimuli, that this threshold model is inadequate to account for the observed latency changes, particularly when adaptive processes are taken into account. The data raise the possibility that latency may be a function of other properties associated with a signal's onset, such as rate of change of peak pressure.

Acoustic Stimulation↗

PubMed2005

DNA damage responses at low radiation doses.

Increased cell killing after exposure to low acute doses of X rays (0-0.5 Gy) has been demonstrated in cells of a number of human tumor cell lines. The mechanisms underlying this effect have been assumed to be related to a threshold dose above which DNA repair efficiency or fidelity increases. We have used cells of two radioresistant human tumor cell lines, one that shows increased sensitivity to low radiation doses (T98G) and one that does not (U373), to investigate the DNA damage response at low doses in detail and to establish whether there is a discontinuous dose response or threshold in activation of any important mediators of this response. In the two cell lines studied, we found a sensitive, linear dose response in early signaling and transduction pathways between doses of 0.1 and 2 Gy with no evidence of a threshold dose. We demonstrate that ATM-dependent signaling events to downstream targets including TP53, CHK1 and CHK2 occur after doses as low as 0.2 Gy and that these events promote an effective damage response. Using chemical inhibition of specific DNA repair enzymes, we show that inhibition of DNA-PK-dependent end joining has relatively little effect at low (<1 Gy) doses in hyper-radiosensitive cells and that at these doses the influence of RAD51-mediated repair events may increase, based on high levels of RAD51/BRCA2 repair foci. These data do not support a threshold model for activation of DNA repair in hyper-radiosensitive cells but do suggest that the balance of repair enzyme activity may change at low doses.

Ataxia Telangiectasia Mutated Proteins↗

PubMed1999

Pharmacokinetic factors and concentration-time threshold in m-dinitrobenzene-induced neurotoxicity.

m-Dinitrobenzene is a multitarget toxicant. This study presents a concentration-time threshold model in m-dinitrobenzene (m-DNB)-induced neurotoxicity in F344 rats based on pharmacokinetic modeling and variable duration infusions with neuropathological end points. Pharmacokinetic parameters for m-DNB were determined after giving a single i.v. dose of 10 mg/kg m-DNB. Time dependency of the brain lesions was studied by either giving a single bolus i.v. dose of 30 mg/kg m-DNB or infusing this dose over 6, 12, or 24 h, or 2, 4, 6, 8, or 14 days. The results show that the 6-day infusion, in which the theoretical steady-state blood concentration was 2.0 microM, caused brain damage, whereas the 8- and 14-day infusions, in which the steady-state blood concentrations were 1.5 and 0.8 microM, respectively, did not induce apparent brain damage. When this dose was infused over 6 h, the peak blood concentration of m-DNB was 35 microM and the time (T(m)) for which m-DNB exceeded the 2-microM concentration threshold was 18.8 h, but no brain damage was observed. However, when the same total dosage was infused over periods of either 12 or 24 h, or 2, 4, or 6 days, the theoretical blood concentrations were from 21.9 to 2.0 microM and the T(m) was from 22. 7 to 144 h, and brain damage was produced. Hence a T(m) of 22.7 h was considered to be the time threshold for m-DNB-induced brain damage. It is concluded that a high concentration alone does not result in m-DNB-induced neurotoxicity and that in addition to a concentration threshold, there also exists a time threshold. Both apparently need to be exceeded before neurotoxicity is seen.

Aniline Compounds↗

PubMed2002

Word frequency and receiver operating characteristic curves in recognition memory: evidence for a dual-process interpretation.

Dual-process models of the word-frequency mirror effect posit that low-frequency words are recollected more often than high-frequency words, producing the hit rate differences in the word-frequency effect, whereas high-frequency words are more familiar, producing the false-alarm-rate differences. In this pair of experiments, the authors demonstrate that the analysis of receiver operating characteristic (ROC) curves provides critical information in support of this interpretation. Specifically, when participants were required to discriminate between studied nouns and their plurality reversed complements, the ROC curve was accurately described by a threshold model that is consistent with recollection-based recognition. Further, the plurality discrimination ROC curves showed characteristics consistent with the interpretation that participants recollected low-frequency items more than high-frequency items.

Association Learning↗

PubMed1993

Cellular tolerance as a dynamic state of the adaptable lymphocyte.

The regulation of immunological tolerance is considered from the perspective of contextual discrimination, rather than self-nonself discrimination. According to the adaptive lymphocyte hypothesis, the scale of immune aggression versus tolerance can be regulated at the cell population level, but individual cells also tune and update their responsiveness under the influence of recurrent signals. The generation of a sizeable conventional immune response, which is transient and aggressive, depends critically on the perturbation to the system, which is related to the rate of appearance of the immunizing agent. These characteristics are explained in quantitative terms by the "balance of growth and differentiation model". Strong perturbations are typically associated, physiologically, with acute infections. Full activation of individual lymphocytes also requires strong metabolic perturbations, where the perturbation is defined as a measure of variation in the intensity of stimulation. Cells that fail to be activated in this way may be driven into a state which formally conforms to the operational definition of anergy. This state is characterized by a variable degree of resistance to the stereotypic mode of activation for which the cell has been programmed before. While in this state, the cell interacts with its environment: these interactions promote its viability, update its activation thresholds and its excitability, and may reprogram the cell for a different mode of response when activated later. In addition, cells engaged in such interactions may mediate context-dependent immunological functions. The characteristics of the interactions involving such anergic cells are discussed in semi-quantitative terms with the help of the "tunable activation-thresholds model". Several aspects of immunological tolerance are interpreted in a unifying way based on this conceptual framework. It is suggested that progress in our ability to evaluate and manipulate the regulation of immunological tolerance would require a methodology to conjoin many pieces of data together and to look for patterns.

Adaptation, Physiological↗

PubMed1984

Sex-related differences in depression. Familial evidence.

After a description of threshold models of familial transmission based on an underlying continuous liability distribution, family data from the NIMH-CRB Collaborative Psychobiology of Depression Program-Clinical are described. No sex differences are found for bipolar illness, whereas female relatives have an increased rate of primary unipolar illness when compared to male relatives. This effect persists when relatives are classified according to recurrence, current illness, onset within the last 10 years, and treatment. Moreover, a cohort effect is present in the data and indicates a sex ratio close to one in the young cohort (less than or equal to 25). We considered the transmission of illness from parent to offspring by using survival analysis to examine the proportion of ill brothers and sisters of probands according to the affection status of parents. A maternal effect is found, with the mother having a greater influence on the liability of offspring of either sex. This is at odds with the notion that males and females have identical liabilities, but females have a lower threshold reflecting acknowledgement of more symptoms, etc. However, the mean difference in liability between the sexes may be due to systematic biological/cultural differences, with parental transmission contributing to variation about their means.

Bipolar Disorder↗

PubMed2006

Rubella immunity levels in the United States population: has the threshold of viral elimination been reached?

After the 1989-1991 rubella resurgence, rubella vaccination efforts targeted children and women of childbearing age. Utilizing National Health and Nutrition Examination Survey data collected during 1988-1994 and 1999-2004, we assessed whether US levels of rubella seropositivity are consistent with rubella elimination and whether changes are consistent with immunization efforts. Serum samples with rubella antibody levels > or =10 IU tested by rubella immunoglobulin G enzyme immunoassay were considered to be positive. In 1999-2004, the overall age-adjusted rubella seropositivity level was 91.3% (95% confidence interval [CI], 90.5%-92.1%), a significant increase from 88.1% (95% CI, 86.9%-89.1%) in 1988-1994 (P<.001). Among children, seropositivity was highest in children 6-11 years of age (96.2%), followed by adolescents 12-19 years of age (93.7%). Both groups showed significant increases in immunity levels, in comparison with those in 1988-1994 (P<.001). Among adults, seropositivity among women increased (from 88.9% to 91.5%; P=.015), and there was no change among men (from 87.8% to 88.0%; P=.84). In 1999-2004, population rubella immunity levels were at or above the modeled threshold for elimination of rubella virus transmission. Increases in immunity levels are consistent with vaccination efforts.

Adolescent↗