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PubMed2001

Radiation risk to low fluences of alpha particles may be greater than we thought.

Based principally on the cancer incidence found in survivors of the atomic bombs dropped in Hiroshima and Nagasaki, the International Commission on Radiation Protection (ICRP) and the United States National Council on Radiation Protection and Measurements (NCRP) have recommended that estimates of cancer risk for low dose exposure be extrapolated from higher doses by using a linear, no-threshold model. This recommendation is based on the dogma that the DNA of the nucleus is the main target for radiation-induced genotoxicity and, as fewer cells are directly damaged, the deleterious effects of radiation proportionally decline. In this paper, we used a precision microbeam to target an exact fraction (either 100% or < or =20%) of the cells in a confluent population and irradiated their nuclei with exactly one alpha particle each. We found that the frequencies of induced mutations and chromosomal changes in populations where some known fractions of nuclei were hit are consistent with non-hit cells contributing significantly to the response. In fact, irradiation of 10% of a confluent mammalian cell population with a single alpha particle per cell results in a mutant yield similar to that observed when all of the cells in the population are irradiated. This effect was significantly eliminated in cells pretreated with a 1 mM dose of octanol, which inhibits gap junction-mediated intercellular communication, or in cells carrying a dominant negative connexin 43 vector. The data imply that the relevant target for radiation mutagenesis is larger than an individual cell and suggest a need to reconsider the validity of the linear extrapolation in making risk estimates for low dose, high linear-energy-transfer (LET) radiation exposure.

Alpha Particles↗

PubMed1997

Alphabeta T cell receptor interactions with syngeneic and allogeneic ligands: affinity measurements and crystallization.

Cellular immunity is mediated by the interaction of an alphabeta T cell receptor (TCR) with a peptide presented within the context of a major histocompatibility complex (MHC) molecule. Alloreactive T cells have alphabeta TCRs that can recognize both self- and foreign peptide-MHC (pMHC) complexes, implying that the TCR has significant complementarity with different pMHC. To characterize the molecular basis for alloreactive TCR recognition of pMHC, we have produced a soluble, recombinant form of an alloreactive alphabeta T cell receptor in Drosophila melanogaster cells. This recombinant TCR, 2C, is expressed as a correctly paired alphabeta heterodimer, with the chains covalently connected via a disulfide bond in the C-terminal region. The native conformation of the 2C TCR was probed by surface plasmon resonance (SPR) analysis by using conformation-specific monoclonal antibodies, as well as syngeneic and allogeneic pMHC ligands. The 2C interaction with H-2Kb-dEV8, H-2Kbm3-dEV8, H-2Kb-SIYR, and H-2Ld-p2Ca spans a range of affinities from Kd = 10(-4) to 10(-6)M for the syngeneic (H-2Kb) and allogeneic (H-2Kbm3, H-2Ld) ligands. In general, the syngeneic ligands bind with weaker affinities than the allogeneic ligands, consistent with current threshold models of thymic selection and T cell activation. Crystallization of the 2C TCR required proteolytic trimming of the C-terminal residues of the alpha and beta chains. X-ray quality crystals of complexes of 2C with H-2Kb-dEV8, H-2Kbm3-dEV8 and H-2Kb-SIYR have been grown.

Amino Acid Sequence↗

PubMed2006

Rescue of a human cell line from endogenous Cdk1 depletion by Cdk1 lacking inhibitory phosphorylation sites.

Cells that transiently overexpress cyclin-dependent kinase 1 lacking inhibitory phosphorylation sites (Cdk1-AF) undergo premature and catastrophic mitosis, reflecting the key role for Cdk1 in promoting a timely transit from G(2) into mitosis. Conversely, cells depleted of Cdk1 undergo repeated S phases without intervening mitoses (endoreduplication), reflecting a role for Cdk1 in preventing premature S phases. It is not known how Cdk1 prevents entry into S phase at times in G(2) when it does not promote mitosis. Also uncertain is the extent of redundancy between inhibitory phosphorylation and other mechanisms for controlling Cdk1 activity. We describe here human cells that not only tolerate stable Cdk1-AF expression but also rely on it for survival when endogenous Cdk1 is depleted. When residual endogenous Cdk1 expression is further depleted, however, proliferation of Cdk1-AF-rescued cells is inhibited. Interestingly, this inhibition is not accompanied by endoreduplication. These results are consistent with a two-threshold model for Cdk1 kinase activity, one for suppressing endoreduplication and one for promoting mitosis. They also indicate that inhibitory phosphorylation is indispensable for only a fraction of the total cellular complement of Cdk1.

CDC2 Protein Kinase↗

PubMed2006

Response of the polyphagous whitefly Bemisia tabaci B-biotype (Hemiptera: Aleyrodidae) to crop diversification - influence of multiple sensory stimuli on activity and fecundity.

A fundamental question concerning crop diversification is which mechanisms determine pest population size in polycultures compared to monocultures. It has been proposed that polyphagous insects experience a difficulty in decision-making when selecting food and oviposition sites in the presence of different host plants. This hypothesis was tested in the extremely polyphagous whitefly Bemisia tabaci (Gennadius) B-biotype, where behaviour (movement) and fecundity of females were compared in choice and no-choice experiments in the laboratory. Two parallel tests, one on different crops, including cucumber, bean and tomato, and one on different tomato cultivars, were conducted using both a mixture of crops and of tomato cultivars, as opposed to the same crop or cultivar respectively. Bemisia tabaci showed a distinct behavioural preference for cucumber when exposed to different crops simultaneously suggesting that B. tabaci has no difficulty in choosing a host plant, i.e. in making a decision, when one of the plants offered in the choice test is a high-ranking host plant. Conversely, when only low-ranking hosts of similar, but not identical, signatures were present, female whiteflies appeared to have difficulty in making a decision, resulting in increased movement and reduced fecundity. This is consistent with both the hypothesis that polyphagous insects have a problem selecting a host plant when given multiple choices and with the hierarchy threshold model, under which egg loads are lessened between periods of searching for better host plants. The study illustrates how insect behaviour can be affected by inter-cropping not only with different crops, but also with different cultivars of the same crop, thus potentially providing a simple and efficient way of reducing whitefly population build-up.

Animals↗

PubMedDate not supplied

Contribution of cadmium in cigarettes to lung cancer: an evaluation of risk assessment methodologies.

This investigation concerned the use of quantitative risk assessment for estimating cancer mortality at low-level exposures. We empirically tested whether extrapolating by linear no-threshold models predicted implausible risks at low-level exposures. Cadmium in cigarette smoke was the low-level exposure, and extrapolation was based on potencies estimated from an occupational study and a rodent cancer bioassay. Inhaled cadmium in mainstream and sidestream smoke was estimated from published laboratory experiments. Smoking-specific lung cancer and all-cause mortality rates were estimated from large population-based studies. The mortality rates, amount of inhaled cadmium, and potency values were used to construct life tables for calculating lifetime lung cancer risk with and without a contribution from cadmium in cigarette smoke. The epidemiologic data predicted that 1 to 18 lung cancer deaths per 10,000 smokers may be attributable to inhaled cadmium in cigarette smoke, or approximately 0.2% to 1.6% of smoking-induced lung cancer deaths. Upper 95% bounds on these figures are 7 to 95 lung cancer deaths or 1.6% to 8.8% of smoking-related deaths. The rodent data predicted that 80 to 416 lung cancer deaths per 10,000 smokers (95% upper bounds: 136-707) or 13% to 47% (23-81%) of smoking-induced lung cancer mortality may be attributable to cadmium in cigarette smoke. Linear extrapolation from human data appears to provide plausible estimates of risk at low doses. Considering the large number of carcinogens present in cigarette smoke, the extrapolation from rodents appears to overestimate human risks.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Chromosomal aberrations in human lymphocytes induced in vitro by very low doses of X-rays.

This paper presents results of a collaborative experiment between six laboratories which examined the yields of unstable chromosomal aberrations in human lymphocytes induced in vitro by X-rays over the dose range 0-300 mGy. The work included data points of nominal doses of 0, 3, 5, 6, 10, 20, 30, 50 and 300 mGy. Cells from 24 donors were examined and a total of about 300,000 metaphases were scored. The work was undertaken to determine the limits of sensitivity of the system taking into account variations in scoring data due to inter-donor sample and inter-laboratory effects. Despite the existence of these effects, aberration yields significantly in excess of control values were seen at doses greater than 20 mGy and these were consistent with a linear extrapolation from higher doses. Below 20 mGy the observed dicentric yields were generally lower than background, but not significantly so. Excess acentric aberrations, on the other hand, and centric rings, were higher than the controls but the increase was usually not significant. It is concluded that the statistical uncertainties are such that below 20 mGy this technique cannot distinguish between a linear or a threshold model.

Chromosome Aberrations↗

PubMed2006

The health benefits of reduced tropospheric ozone in California.

Californians are exposed daily to concentrations of ozone (O3) that are among the highest in the United States. Recently, the state adopted a new 8-hr ambient standard of 0.070 ppm, more stringent than the current federal standard. The new standard is based on controlled human studies and on dozens of epidemiologic studies reporting associations between O3 at current ambient levels and a wide range of adverse health outcomes. Clearly, the new O3 standards will require further reductions in the precursor pollutants and additional expenditures for pollution control. Therefore, it is important to quantify the incremental health benefits of moving from current conditions to the new California standard. In this paper, a standard methodology is applied to quantify the health benefits associated with O3 concentration reductions in California. O3 concentration reductions are estimated using ambient monitoring data and a proportional rollback approach in which changes are specific to each air basin, and control strategies may impact concentrations both below and above the standard. Health impacts are based on published epidemiologic studies, including O3-related mortality and morbidity, and economic values are assigned to these outcomes based on willingness-to-pay and cost-of-illness studies. Central estimates of this research indicate that attaining the California 8-hr standard, relative to current concentrations, would result in annual reductions of 630 cases of premature mortality, 4200 respiratory hospital admissions, 660 pediatric emergency room visits for asthma, 4.7 million days of school loss, and 3.1 million minor restricted activity days, with a median estimated economic value of dollar 4.5 billion. Sensitivity analyses indicate that these findings are robust with respect to exposure assessment methods but are influenced by assumptions about the slope of the concentration-response function in threshold models and the magnitude of the O3-mortality relationship. Although uncertainties exist for several components of the methodology, these results indicate that the benefits of reducing O3 to the California standard may be substantial and that further research on the shape of the O3-mortality concentration-response function and economic value of O3-related mortality would best reduce these uncertainties.

Air Pollution↗

PubMed2004

Music interventions for people with dementia: a review of the literature.

This paper provides a qualitative review of 21 published articles of clinical empirical studies looking at the effects of a variety of music activities on the emotional and behavioural responses in people with dementia. General information is reviewed such as the setting and context of studies, research findings and explanatory variables. Methodological issues are also discussed, particularly in relation to observational methods, and theoretical frameworks such as the progressively lowered stress threshold model are evaluated. Music appears to have a range of applications in dementia care but previous reviews have highlighted methodological weaknesses of studies. Recommendations for future research include the use of continuous time sampling methodology and to record the duration of observed behaviours. This review paper also argues for the use of Kitwood's theory of personhood as a framework to inform and guide future research.

Adaptation, Psychological↗

PubMed2000

Genetic susceptibility to thrombosis and its relationship to physiological risk factors: the GAIT study. Genetic Analysis of Idiopathic Thrombophilia.

Although there are a number of well-characterized genetic defects that lead to increased risk of thrombosis, little information is available on the relative importance of genetic factors in thrombosis risk in the general population. We performed a family-based study of the genetics of thrombosis in the Spanish population to assess the heritability of thrombosis and to identify the joint actions of genes on thrombosis risk and related quantitative hemostasis phenotypes. We examined 398 individuals in 21 extended pedigrees. Twelve pedigrees were ascertained through a proband with idiopathic thrombosis, and the remaining pedigrees were randomly ascertained. The heritability of thrombosis liability and the genetic correlations between thrombosis and each of the quantitative risk factors were estimated by means of a novel variance component method that used a multivariate threshold model. More than 60% of the variation in susceptibility to common thrombosis is attributable to genetic factors. Several quantitative risk factors exhibited significant genetic correlations with thrombosis, indicating that some of the genes that influence quantitative variation in these physiological correlates also influence the risk of thrombosis. Traits that exhibited significant genetic correlations with thrombosis included levels of several coagulation factors (factors VII, VIII, IX, XI, XII, and von Willebrand), tissue plasminogen activator, homocysteine, and the activated protein C ratio. This is the first study that quantifies the genetic component of susceptibility to common thrombosis. The high heritability of thrombosis risk and the significant genetic correlations between thrombosis and related risk factors suggest that the exploitation of correlated quantitative phenotypes will aid the search for susceptibility genes.

Adolescent↗

PubMed1992

The evolution of delayed dispersal in cooperative breeders.

Why do the young of cooperative breeders--species in which more than two individuals help raise offspring at a single nest--delay dispersal and live in groups? Answering this deceptively simple question involves examining the costs and benefits of three alternative strategies: (1) dispersal and attempting to breed, (2) dispersal and floating, and (3) delayed dispersal and helping. If, all other things being equal, the fitness of individuals that delay dispersal is greater than the fitness of individuals that disperse and breed on their own, intrinsic benefits are paramount to the current maintenance of delayed dispersal. Intrinsic benefits are directly due to living with others and may include enhanced foraging efficiency and reduced susceptibility to predation. However, if individuals that disperse and attempt to breed in high-quality habitat achieve the highest fitness, extrinsic constraints on the ability of offspring to obtain such high-quality breeding opportunities force offspring to either delay dispersal or float. The relevant constraint to independent reproduction has frequently been termed habitat saturation. This concept, of itself, fails to explain the evolution of delayed dispersal. Instead, we propose the delayed-dispersal threshold model as a guide for organizing and evaluating the ecological factors potentially responsible for this phenomenon. We identify five parameters critical to the probability of delayed dispersal: relative population density, the fitness differential between early dispersal/breeding and delayed dispersal, the observed or hypothetical fitness of floaters, the distribution of territory quality, and spatiotemporal environmental variability. A key conclusion from the model is that no one factor by itself causes delayed dispersal and cooperative breeding. However, a difference in the dispersal patterns between two closely related species or populations (or between individuals in the same population in different years) may be attributable to one or a small set of factors. Much remains to be done to pinpoint the relative importance of different ecological factors in promoting delayed dispersal. This is underscored by our current inability to explain satisfactorily several patterns including the relative significance of floating, geographic biases in the incidence of cooperative breeding, sexual asymmetries in delayed dispersal, the relationship between delayed dispersal leading to helping behavior and cooperative polygamy, and the rarity of the co-occurrence of helpers and floaters within the same population. Advances in this field remain to be made along several fronts.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1998

The report of the French Academy of Science: 'Problems associated with the effects of low doses of ionising radiation'.

In 1995 the French Academy of Science published a report on 'Problems associated with low doses of ionising radiation'. This report aroused interest among French-speaking scientists and a translation in English was published a year later. The report pointed out that an important issue in radioprotection was not whether to accept or reject the linear no-threshold model but rather to test its validity. The aim of this review is to analyse the report and its recommendations, and to briefly indicate the progress which has been made and the questions which remain open. Three areas of the report are covered in this review: DNA repair, carcinogenesis and epidemiological data.

Animals↗

PubMed1994

Biological effects: asbestos-cement manufacturing.

Fourteen cohorts of asbestos-cement workers have been studied. These studies have demonstrated exposure-response relationships for lung cancer, mesothelioma and asbestosis. For lung cancer, relatively consistent results have been observed, with risk two-fold or less in 13 of the 14 cohorts. Among New Orleans workers, excess risk was restricted to those with X-ray evidence of asbestosis. Workers employed at least 21 years but without X-ray abnormalities, experienced no elevated risk, while those with small opacities (1/0 or higher) had substantially elevated risk (SMR > 400). Exposures in these two groups had been similar. These results suggest that asbestosis may be a necessary precursor for asbestos-induced lung cancer; if so, then the no-threshold model for lung cancer risk is inappropriate since there is general agreement that very low exposures will not result in radiologically detectable lung fibrosis. Further data on this potential link are needed. As in other industries, mesothelioma risk was strongly related to amphibole exposure, especially to crocidolite in asbestos-cement pipe manufacture. A cluster of cases has recently been reported in a family amosite-cement business. Among New Orleans workers, risk of asbestosis was related to cumulative exposure but there was little evidence of risk below 30 f ml-1-years. Progression of asbestosis in these workers was slow, related to past cumulative exposure and not related to lung function decline. Asbestosis risk is therefore not likely to develop in workers under current controlled exposure conditions.

Asbestos↗

PubMed2025

Genomic study for pregnancy loss in Brahman cattle.

Reproduction has major influence on productivity of beef cattle operations. Maintaining an animal in the herd for an extended period without producing a marketable product can result in significant economic losses, compromising the efficiency of the production system. Understanding genetic variation's role in pregnancy loss (PL) is crucial for improving reproductive success in cattle. Identifying genomic regions that influence embryo and fetal survival, as well as pinpointing candidate genes associated with PL, can enhance breeding strategies. The objective of this study was to estimate variance components and investigate genetic factors associated with PL in Brahman cattle. Phenotypic records consisted of 29,905 pregnancy (28,691) and abortion (1,214) records from nulliparous, primiparous, and multiparous cows. A total of 921 animals were genotyped using a medium-density SNP chip (∼52K markers). Variance components were estimated using a threshold model to assess the binary response to PL through a single-step genomic BLUP procedure. The heritability estimate for PL was low (0.11), but the presence of genetic variance suggests that selection for improved reproductive performance is feasible. Genome-wide association analyses identified 17 candidate regions containing 92 genes. Regions on BTA4, 7, 8, 9, 11, 12, 16, 18, 19, 21, 22, and 29 harbored genes associated with embryonic development and implantation, fertilization, G protein-coupled receptors, embryonic brain development, olfactory receptor activity, and calcium signaling. Orthologous genes were also identified in humans (Homo sapiens), rats (Rattus norvegicus), and mice (Mus musculus). The candidate regions reported in this study provide insights for identifying and selecting animals with improved reproductive performance, ultimately enhancing the productivity of Brahman cattle. Moreover, our findings contribute to a better understanding of the genetic and physiological mechanisms underlying pregnancy retention in beef cattle.

Animals↗

PubMed2006

Identification of two novel quantitative trait loci for pre-eclampsia susceptibility on chromosomes 5q and 13q using a variance components-based linkage approach.

Pre-eclampsia/eclampsia (PE/E) is a common and serious disorder of human pregnancy that is associated with substantial maternal and perinatal morbidity and mortality. The suspected aetiology of PE/E is complex, with susceptibility being attributable to multiple environmental factors and a large genetic component. By assuming that the underlying liability towards PE/E susceptibility is inherently quantitative, any PE/E susceptibility gene would represent a quantitative trait locus (QTL). This assumption enables a more refined and powerful variance components procedure using a threshold model for our PE/E statistical analysis. Using this more efficient linkage approach, we have now re-analysed our previously completed Australian/New Zealand genome scan data to identify two novel PE/E susceptibility QTLs on chromosomes 5q and 13q. We have obtained strong evidence of linkage on 5q with a peak logarithm-of-odds (LOD) score of 3.12 between D5S644 and D5S433 [at approximately 121 centimorgan (cM)] and strong evidence of linkage on 13q with a peak LOD score of 3.10 between D13S1265 and D13S173 (at approximately 123 cM). Objective identification and prioritization of positional candidate genes using the quantitative bioinformatics program GeneSniffer revealed highly plausible PE/E candidate genes encoding aminopeptidase enzymes and a placental peptide hormone on the 5q QTL and two type IV collagens on the 13q QTL regions, respectively.

Analysis of Variance↗

PubMed1997

Lung cancer rate vs. mean radon level in U.S. counties of various characteristics.

Plots of lung cancer rates corrected for smoking prevalence vs. average home radon levels are presented for U.S. counties with a wide variety of socioeconomic characteristics. The data are generally well described by the same negative slope linear, plus positive slope quadratic, "standard" curve. Plots are presented for geographic regions and these are also reasonably well fit by the standard curve. The findings are not consistent with predictions based on a linear no-threshold model.

Air Pollution, Indoor↗

PubMed1997

Setting standards for radiation protection: the process appraised.

Present radiation protection standards are based to a large extent on data that have been forced to conform with the linear non-threshold model. A review of the literature shows that there are examples of both data and theory that disagree with such a model. Established standard setting bodies seem not to have recognized this disagreement; indeed, as will be shown, there are many studies that they have neither cited, discussed, nor refuted. Additionally, examples of data adaptation and circular reasoning are to be found in the standard-setting process. Consequently, a new approach to the process is desirable. Numerous citations and quotations are given.

Dose-Response Relationship, Radiation↗

PubMed1998

On the discrepancy between epidemiologic studies in individuals of lung cancer and residential radon and Cohen's ecologic regression.

There is still substantial confusion in the radiation effects community about the inherent limitations of ecologic analysis. As a result, inordinate attention has been given to the discrepant results of Cohen, in which a negative estimate is observed for the regression of county mortality rates for lung cancer on estimated county radon levels. This paper demonstrates that Cohen's ecologic analysis cannot produce valid inference on the exposure-response relationship for individuals unless lung cancer risk factors (smoking, age, occupation, etc.) for individuals are statistically uncorrelated with indoor radon level within counties or unless risk effects for radon and other factors are additive. Both of these assumptions are contradicted in the literature. Thus, contrary to common assumption, when a linear no-threshold model is the true model for radon risk for individuals, higher average radon concentration for a county does not necessarily imply a higher lung cancer rate for the county. In addition, valid inference from county-level ecologic analysis and the elimination of the ecologic bias cannot be achieved with the addition of county-wide summary variables (including "stratification" variables) to the regression equation. Using hypothetical data for smoking and radon and assuming a true positive association for radon and lung cancer for individuals, the analysis demonstrates that a negative county-level ecologic regression can be induced when correlation coefficients for smoking and radon within county are in the range -0.05 to 0.05. Since adverse effects for radon at low exposures are supported by analysis of miner data (all data and data restricted only to low cumulative exposures), a meta-analysis of indoor radon studies, and molecular and cellular studies, and since ecologic regressions are burdened by severe limitations, the negative results from Cohen's analysis are most likely due to bias and should be rejected.

Air Pollutants, Radioactive↗

PubMed1981

Automatic outlining of regions on CT scans.

A computer software system for automatic outlining of borders between regions of differing CT numbers on computed tomography scans has been developed. The technique was originally intended for application in defining inhomogeneities for radiation therapy treatment planning; however, several other applications are possible. The system scans an image using a simple threshold model to locate initial outline points and then completes the outline with a border-following algorithm. Results of the automatic outlining system are given along with histograms of the enclosed regions, demonstrating several further applications of these techniques.

Data Display↗