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At least 109 records · Page 6Linked to original sources
PubMed2000

A ligand-receptor signaling threshold model of stem cell differentiation control: a biologically conserved mechanism applicable to hematopoiesis.

A major limitation to the widespread use of hematopoietic stem cells (HSC) is the relatively crude level of our knowledge of how to maintain these cells in vitro without loss of the long-term multilineage growth and differentiation properties required for their clinical utility. An experimental and theoretical framework for predicting and controlling the outcome of HSC stimulation by exogenous cytokines would thus be useful. An emerging theme from recent HSC expansion studies is that a net gain in HSC numbers requires the maintenance of critical signaling ligand(s) above a threshold level. These ligand-receptor complex thresholds can be maintained, for example, by high concentrations of soluble cytokines or by extracellular matrix- or cell-bound cytokine presentation. According to such a model, when the relevant ligand-receptor interaction falls below a critical level, the probability of a differentiation response is increased; otherwise, self-renewal is favored. Thus, in addition to the identity of a particular receptor-ligand interaction being important to the regulation of stem cell responses, the quantitative nature of this interaction, as well as the dynamics of receptor expression, internalization, and signaling, may have a significant influence on stem cell fate decisions. This review uses examples from hematopoiesis and other tissue systems to examine existing evidence for a role of receptor activation thresholds in regulating hematopoietic stem cell self-renewal versus differentiation events. (Blood. 2000;96:1215-1222)

Animals↗
PubMed1994

Comments on "Evaluating a speech-reception threshold model for hearing-impaired listeners" [J. Acoust. Soc. Am. 93, 2879-2885 (1993)].

As everyday practice as well as laboratory experiments have shown abundantly, the hearing aid falls short in eliminating the difficulties of many subjects with sensorineural hearing losses in understanding speech in noise. The attempt by Lee and Humes to demonstrate the opposite with only 11 spondees as speech-material does not alter this situation. As far as their experiment allows any conclusion, it supports the view that the speech-reception threshold of hearing-impaired listeners is characterized by a distortion factor as well as an attenuation factor.

Aged↗
PubMed1996

Segregation analysis of the testis-determining autosomal trait, Tda, that differs between the C57Bl/6J and DBA/2J mouse strains suggests a multigenic threshold model.

The testis-determining autosomal trait (Tda) of the mouse was uncovered when the Y chromosome of the poschiavinus variety of Mus musculus domesticus was introduced into the C57BL/6J laboratory strain background. Testis development is normal in the F1 generation but, in the backcross and subsequent crosses to C57BL/6J females, XY individuals with the poschiavinus Y chromosome expressed bilateral ovaries or various combinations of an ovotestis with a contralateral ovary or testis or bilateral ovotestes and few had testes bilaterally. In other strain backgrounds, such as DBA/2J, XY individuals with the poschiavinus Y chromosome always expressed normal testes bilaterally. The first breeding analysis of this difference in the interaction of strain background with the poschiavinus Y chromosome suggested that the Tda trait was due to a single gene, but attempts to map it failed. We constructed two strains of C57BL/6J and DBA/2J that are consomic for the poschiavinus Y chromosome in order to conduct a segregation analysis of the Tda trait. In the C57BL/6J.Y-POS consomic strain, liability to express incomplete testis development is normally distributed and thresholds in development specify the probability of different classes of ovary, ovotestis, and testis combinations. Testis development is complete in the DBA/2J.Y-POS consomic strain. We demonstrated previously that the Tda trait of C57BL/6J is recessive to that of DBA/2J and the segregating first backcross generation of embryos rejected the single-gene model. We have extended our analysis to a F2 generation of embryos that also rejects a single-gene model. We also report a test mating analysis of the first backcross generation. It was initiated to provide an independent assessment of the single-gene model, but the analysis of the distribution of test mating results suggests that the difference in the Tda trait between C57BL/6J and DBA/2J may be due to a small number of loci, possibly four or five, and that the phenotypic effect between loci may be additive.

Animals↗
PubMed2006

Variations of maternal care alter offspring levels of behavioural defensiveness in adulthood: evidence for a threshold model.

Natural variations of maternal care in the rat influence the development of neuronal systems that regulate defensive responses to threat. Thus, as adults, rats that received higher levels of maternal licking/grooming (LG) in infancy display dramatic reductions in burying in the shock-probe test, relative to offspring of low LG mothers. We sought to replicate that finding and determine whether maternal care similarly influences offspring responses to social threat, using the resident-intruder test. We also examined whether maternal LG influences offspring behaviour along a continuum by comparing defensive responses of offspring of mid LG mothers to those of offspring of high LG and low LG mothers. A final goal was to assess whether the reductions in adult offspring reactivity to threat that typically follow corticosterone (CORT) administration to dams across lactation are mediated through CORT-induced changes in maternal care. Adult offspring of high LG mothers spent less time burying the shock-probe, relative to offspring of mid and low LG mothers, whereas offspring of CORT-treated mothers did not differ from any group. Similarly, offspring of high LG (but not CORT-treated) mothers displayed fewer defensive responses in the resident-intruder test. Thus, only natural variations of maternal care were associated with individual differences in offspring reactivity to threat. Furthermore, because offspring of mid and low LG mothers displayed equivalent levels of defensive responding in both tests, it appears that a critical threshold of maternal LG is necessary to alter the developmental trajectory of neural systems mediating defensive behaviours.

Aggression↗
PubMed1992

Inhibition of hematopoietic tumor growth by combined treatment with deferoxamine and an IgG monoclonal antibody against the transferrin receptor: evidence for a threshold model of iron deprivation toxicity.

Recent studies have suggested that iron deprivation may represent a useful new approach in cancer therapy, and several strategies for producing such deprivation are now under investigation. Thus, for example, we recently provided evidence that combined treatment with the iron chelator deferoxamine and an IgG monoclonal antibody against the transferrin receptor (ATRA) produces synergistic inhibition of hematopoietic tumor cell growth in vitro (J. D. Kemp, K. M. Smith, L. J. Kanner, F. Gomez, J. A. Thorson, and P. W. Naumann, Blood, 76: 991-995, 1990). The current study is an attempt to analyze the mechanisms responsible for the synergistic interaction. The data show that a single IgG ATRA can produce up to 75% inhibition of iron uptake while having little effect on DNA synthesis; this suggests that tumor cells either take up or have stored amounts of iron well in excess of that required to support immediate metabolic needs. When deferoxamine and the IgG ATRA are used together, the effects on iron acquisition and receptor down-modulation are either additive or subadditive but are clearly not synergistic. Overall, the findings suggest that the IgG ATRA produces an injury to iron uptake that is just below a critical threshold and that the additional effect provided by the iron chelator is sufficient to exceed that threshold and produce a rapid depletion of iron pools that are vital for short-term DNA synthesis. IgG ATRAS thus seem to be of even greater interest as therapeutic reagents, and further study of their properties and of how they interact with deferoxamine appears to be warranted.

Animals↗
PubMed1998

Multiple threshold model for the onset of Alzheimer's disease in the NAS-NRC twin panel.

The three common alleles at the APOE locus influence the onset and lifetime risk of typical late-onset Alzheimer's disease (AD). Other loci may also alter risk of late-onset AD. One may assess the relative influence of APOE on the genetic contribution to AD by estimating the proportion of AD heritability that is explained by APOE polymorphism. To do this requires an initial estimate of the heritability of AD. Traditional methods are not appropriate for this estimation since they do not consider right-censoring (incomplete expression of the genotype owing to death) nor do they model the relation of onset age and disease liability. Here we present an analytic model that addresses both of these issues. Genetic and environmental influences on AD are examined by assuming that onset of dementia in AD is a late event in an extended degenerative process where earlier onset reflects a more rapid course of neurodegeneration. The model is fitted to the occurrence of AD among 9,786 members of the National Academy of Sciences-National Research Council Registry of aging veteran twins. When both additive genetic and common environmental effects are used in the model, they explain 37% and 35%, respectively, of the variation in AD onset. Given the limited numbers of AD cases now available, models containing only additive genetic or shared environmental effects (explaining 75% and 65% of individual differences in disease onset, respectively) cannot be rejected in favor of a model that retains both influences.

Age of Onset↗
PubMed1997

A variance component approach to dichotomous trait linkage analysis using a threshold model.

We developed and utilized a multipoint variance components method to test for linkage between a disease trait and markers on chromosome 5 in the simulated data provided in GAW10 Problem 2. We demonstrated that the discrete trait variance components method recovers unbiased estimates of quantitative trait locus (QTL) location and reasonable estimates of effect size. We also showed that dichotomization of (a continuous trait such as) Q1 diminished the power to detect linkage compared to direct analysis of Q1, and that extended pedigree analyses provided superior power to detect linkage compared to those in nuclear families.

Analysis of Variance↗
PubMed1981

A goodness-of-fit test for the polygenic threshold model: application to multiple sclerosis.

Recently it has been suggested that multiple sclerosis may be a multifactorial disorder. We found in British Columbia 364 families (sibship size greater than or equal to 2) in which at least on sibling was diagnosed as having "clinically definite" multiple sclerosis. The data were tested for goodness-of-fit to the multifactorial model using an analysis that considers various parameters including ascertainment probability heritability, and sex-dependent prevalence rates. The results suggest that multiple sclerosis does not fit the multifactorial model. As an alternative genetic model we propose that a major gene could be responsible for at least a portion of the cases of multiple sclerosis.

Alleles↗
PubMed2006

Application of the Progressively Lowered Stress Threshold Model across the continuum of care.

Over the last two decades, increasing attention has been paid to the nature of behavioral symptoms in dementia. Early notions that all behaviors were an inevitable component of cognitive impairment have all but disappeared in the face of evidence that diverse personal, social, and environmental factors regularly act as antecedents to behavioral and psychologic symptoms of dementia (BPSD). The quality of care provided to persons with dementia has been advanced through nursing care conceptual models that explain antecedents to BPSD and, in turn, offer specific interventions to promote comfort and optimal function.

Adaptation, Psychological↗
PubMed1992

Jamaican and American adult perspectives on child psychopathology: further exploration of the threshold model.

Although several factors determine whether children receive psychological intervention, cultural determinants may be particularly influential. Cultural factors may influence adults' levels of concern over child psychopathology. This possibility was explored by comparing adult attitudes in two socioculturally different societies. Jamaican and American parents, teachers, and clinicians (total N = 382) judged vignettes of two children, one with overcontrolled (e.g., fearfulness) and one with undercontrolled (e.g., fighting) problems. Regression analyses revealed that although years of education affected some adult ratings, culture had the most profound effect.

Attitude↗
PubMed1993

Allergy and depression: a neurochemical threshold model of the relation between the illnesses.

Empirical studies suggest a very high prevalence of atopic disorder in people with depression. Research indicates that individuals with allergy have cholinergic hyperresponsiveness and beta-adrenergic hyporesponsiveness in the autonomic nervous system. Evidence is reviewed that similar imbalances in central nervous system cholinergic-adrenergic activity play a casual role in depression behaviors. It is hypothesized that the allergic state or allergic reactions can accentuate cholinergic-adrenergic activity imbalances in the central nervous system of a small subgroup of people at risk for endogenous depression thereby producing depression symptomatology.

Adrenergic Agonists↗