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PubMed2001

Explaining mortality rate plateaus.

We propose a stochastic model of aging to explain deviations from exponential growth in mortality rates commonly observed in empirical studies. Mortality rate plateaus are explained as a generic consequence of considering death in terms of first passage times for processes undergoing a random walk with drift. Simulations of populations with age-dependent distributions of viabilities agree with a wide array of experimental results. The influence of cohort size is well accounted for by the stochastic nature of the model.

Aging↗

PubMed1989

Ordered appearance of antigenic variants of African trypanosomes explained in a mathematical model based on a stochastic switch process and immune-selection against putative switch intermediates.

Antigenic variation of African trypanosomes results from the periodic activation of a single new variant cell surface glycoprotein (VSG) gene out of a repertoire of about a 1000 VSG genes. In spite of the apparently random genetic basis of the process of antigenic variation, the relapsing parasitemias are characterized by an as yet unexplained order of appearance of major VSG variants. Here we mathematically test hypotheses concerning the blood-based parasitemia. In our model the antigenic switches occur at random at the DNA level. A variable proportion of the switches has a short intermediate phase in which two different VSGs simultaneously occur on the cell surface. We show that, in a theoretical population of 230 single expressor variants in an immunocompetent or in an immunodeficient host, it is not possible to explain the ordered appearance of variants by affecting the growth coefficients of single expressors or double expressors or by affecting the antigen switch probabilities. Rather, a realistic parasitemia can be obtained if the majority of switches has a double expressor switch-intermediate phase and if the double expressors have a differential susceptibility to the immune control. This study is significant in providing a theoretical basis for the ordered appearance of variants and in explaining previously unresolved discrepancies between the rate of appearance of new variants in culture and in vivo. In addition, testable predictions as to the development of the infections, switch rate of variants, fraction of double expressors, and parasite mortality coefficients are generated.

Animals↗

PubMed1996

Gly-63-->Gln substitution adjacent to His-64 in rodent carbonic anhydrase IVs largely explains their reduced activity.

Carbonic anhydrase (CA) IV is a glycosyl-phosphatidylinositol-anchored isozyme expressed on plasma membranes of capillary endothelial cells and certain epithelial cells of the nephron, the colon, and the genitourinary tract. CA IVs purified from bovine and rabbit lungs are high-activity enzymes, like human CA IV, while CA IV from mouse and rat lungs had only 10-20% as much catalytic activity. To explain the molecular basis for these differences in activity, we isolated and characterized the full-length cDNAs for bovine and rabbit CA IVs and compared their sequences to those we previously reported for human, murine, and rat CA IVs. These comparisons led us to postulate that a Gly-63-->Gln substitution adjacent to His-64 in the rodent enzymes accounts for their lower activity. To test this hypothesis, we made the Gly-63-->Gln mutants of bovine and rabbit CA IVs and the Gln-63-->Gly mutant of murine CA IV by site-directed mutagenesis, and compared the activities of mutant and wild-type CA IVs expressed in COS-7 cells. In addition, we produced recombinant cDNAs expressing secretory forms of the Gly-63 and Gln-63 forms of each of the three enzymes and compared the activities of the enzymes purified from transfected COS-7 cell secretions with the activities of CA IVs purified from lungs. These studies demonstrated that Gly-63 is important for the high activity of bovine and rabbit CA IVs, and they showed that the low activity of murine CA IV could be improved by the Gln-63-->Gly substitution. We suggest that the lower activity of the rodent CA IVs can be largely explained by the Gln-63 substitution which reduces the efficiency of proton transfer by the adjacent His-64.

Amino Acid Sequence↗

PubMed1999

Stripe formation in juvenile Pomacanthus explained by a generalized turing mechanism with chemotaxis.

Current interest in pattern formation can be traced to a seminal paper by Turing, who demonstrated that a system of reacting and diffusing chemicals, called morphogens, can interact so as to produce stable nonuniform concentration patterns in space. Recently, a Turing model has been suggested to explain the development of pigmentation patterns on species of growing angelfish such as Pomacanthus semicirculatus, which exhibit readily observed changes in the number, size, and orientation of colored stripes during development of juvenile and adult stages, but the model fails to predict key features of the observations on stripe formation. Here we develop a generalized Turing model incorporating cell growth and movement, we analyze the effects of these processes on patterning, and we demonstrate that the model can explain important features of pattern formation in a growing system such as Pomacanthus. The applicability of classical Turing models to biological pattern formation is limited by virtue of the sensitivity of patterns to model parameters, but here we show that the incorporation of growth results in robustly generated patterns without strict parameter control. In the model, chemotaxis in response to gradients in a morphogen distribution leads to aggregation of one type of pigment cell into a striped spatial pattern.

Animals↗

PubMed2001

Evidence that proteolysis of Gal4 cannot explain the transcriptional effects of proteasome ATPase mutations.

The Gal system of Saccharomyces cerevisiae is a paradigm for eukaryotic gene regulation. Expression of genes required for growth on galactose is regulated by the transcriptional activator Gal4. The activation function of Gal4 has been localized to 34 amino acids near the C terminus of the protein. The gal4D allele of GAL4 encodes a truncated protein in which only 14 amino acids of the activation domain remain. Expression of GAL genes is dramatically reduced in gal4D strains and these strains are unable to grow on galactose as the sole carbon source. Overexpression of gal4D partially relieves the defect in GAL gene expression and allows growth on galactose. A search for extragenic suppressors of gal4D identified recessive mutations in the SUG1 and SUG2 genes, which encode ATPases of the 19S regulatory complex of the proteasome. The proteasome is responsible for the ATP-dependent degradation of proteins marked for destruction by the ubiquitin system. It has been commonly assumed that effects of SUG1 and SUG2 mutations on transcription are explained by alterations in the proteolysis of gal4D protein. We have investigated this assumption. Surprisingly, we find that SUG1 and SUG2 alleles that are unable to suppress gal4D cause a larger increase in gal4D protein levels than do suppressing alleles. In addition, mutations in genes encoding subunits of the proteolytic 20S sub-complex of the proteasome increase the levels of gal4D protein but do not rescue its transcriptional activity. Therefore, an alteration in the proteolysis of gal4D by the proteasome cannot explain the effects of mutations in SUG1 and SUG2 on expression of GAL genes. These findings suggest that the 19S regulatory complex may play a more direct role in transcription.

Adenosine Triphosphatases↗

PubMed2003

The modified Q-cycle explains the apparent mismatch between the kinetics of reduction of cytochromes c1 and bH in the bc1 complex.

Crystallographic structures of the bc1 complex from different sources have provided evidence that a movement of the Rieske iron-sulfur protein (ISP) extrinsic domain is essential for catalysis. This dynamic feature has opened up the question of what limits electron transfer, and several authors have suggested that movement of the ISP head, or gating of such movement, is rate-limiting. Measurements of the kinetics of cytochromes and of the electrochromic shift of carotenoids, following flash activation through the reaction center in chromatophore membranes from Rhodobacter sphaeroides, have allowed us to demonstrate that: (i) ubiquinol oxidation at the Qo-site of the bc1 complex has the same rate in the absence or presence of antimycin bound at the Qi-site, and is the reaction limiting turnover. (ii) Activation energies for transient processes to which movement of the ISP must contribute are much lower than that of the rate-limiting step. (iii) Comparison of experimental data with a simple mathematical model demonstrates that the kinetics of reduction of cytochromes c1 and bH are fully explained by the modified Q-cycle. (iv) All rates for processes associated with movement of the ISP are more rapid by at least an order of magnitude than the rate of ubiquinol oxidation. (v) Movement of the ISP head does not introduce a significant delay in reduction of the high potential chain by quinol, and it is not necessary to invoke such a delay to explain the kinetic disparity between the kinetics of reduction of cytochromes c1 and bH.

Antifungal Agents↗

PubMed2003

A direct mass-action mechanism explains capacitative calcium entry in Jurkat and skeletal L6 muscle cells.

We examined capacitative calcium entry (CCE) in Jurkat and in L6 skeletal muscle cells. We found that extracellular Ca2+ can enter the endoplasmic reticulum (ER) of both cell types even in the presence of thapsigargin, which blocks entry into the ER from the cytosol through the CaATPase. Moreover, extracellular Ca2+ entry into the ER was evident even when intracellular flow of Ca2+ was in the direction of ER to cytosol due to the presence of caffeine. ER Ca2+ content was assessed by two separate means. First, we used the Mag-Fura fluorescent dye, which is sensitive only to the relatively high concentrations of Ca2+ found in the ER. Second, we transiently expressed an ER-targeted derivative of aequorin, which reports Ca2+ by luminescence. In both cases, the Ca2+ concentration in the ER increased in response to extracellular Ca2+ after the ER had been previously depleted despite blockade by thapsigargin. We found two differences between the Jurkat and L6 cells. L6, but not Jurkat cells, inhibited Ca2+ uptake at very high Ca2+ concentrations. Second, ryanodine receptor blockers inhibited the appearance of cytosolic Ca2+ during CCE if added before Ca2+ in both cases, but the L6 cells were much more sensitive to ryanodine. Both of these can be explained by the known difference in ryanodine receptors between these cell types. These findings imply that the origin of cytosolic Ca2+ during CCE is the ER. Furthermore, kinetic data demonstrated that Ca2+ filled the ER before the cytosol during CCE. Our results suggest a plasma membrane Ca2+ channel and an ER Ca2+ channel joined in tandem, allowing Ca2+ to flow directly from the extracellular space to the ER. This explains CCE; any decrease in ER [Ca2+] relative to extracellular [Ca2+] would provide the gradient for refilling the ER through a mass-action mechanism.

Aequorin↗

PubMed2002

Moderating factors explaining stress reactions: comparing chronic-without-acute-stress and chronic-with-acute-stress situations.

The author compared patterns of moderating factors explaining stress reactions during 2 states: chronic-without-acute-stress and chronic-with-acute-stress. She hypothesized that personal dispositions would contribute more to understanding stress reactions during a prolonged stress state than during an acute state. The participants were Israeli Jewish adolescents living in West Bank settlements during the prolonged (chronic-without-acute-stress) state of the intifada (the Palestinian uprising against Israeli occupation) and during the chronic-with-acute-stress state, immediately after the assassination of Prime Minister Rabin. The author examined 5 variables as moderating factors--trait anxiety, sense of coherence, cognitive appraisal of the political situation, family sense of coherence, and sense of community--and measured 2 stress reactions--state anxiety and psychological distress. Data were collected from 266 8th-grade students during the chronic-without-acute-stress state and 448 students at the same grade level at the chronic-with-acute-stress state. The overall magnitude of variance explanation was different at each state: The author found a relatively high explained variance of state anxiety and psychological distress in the chronic-without-acute-stress situation but not in the chronic-with-acute stress state. These data support the value of developing a model that would recognize the different types of stress situations for moderating the effects of stress.

Adolescent↗

PubMed1988

Explaining adolescent drug use: an elaboration strategy for structural equations modeling.

We report a series of analyses designed to estimate increasingly elaborated theoretical models that explain adolescent drug use. Each of the successive elaborations adds a theoretical construct to the explanatory model in order to increase our understanding of drug use by specifying in greater detail the nature of the structural relationships among the latent variables. The more detailed specification is accomplished by 1) specifying new direct effects that increase explained variance in drug use, 2) decomposing direct effects through the interpolation of hypothesized intervening variables, 3) specifying antecedents of variables that modify their direct effects, and 4) exposing suppressor effects. Where indicated, we evaluate alternative explanations of the observed relationships. We do this by controlling for common antecedent effects to reduce spuriousness or by examining different specifications of causal linkages among the explanatory constructs.

Adolescent↗

PubMed2005

Polymorphism in the coding part of the sterol 12alpha-hydroxylase gene does not explain the marked differences in the ratio of cholic acid and chenodeoxycholic acid in human bile.

OBJECTIVE: In humans, two primary bile acids are synthesized: cholic acid (CA) and chenodeoxycholic acid (CDCA), the first and rate-limiting enzyme being cholesterol 7alpha-hydroxylase (CYP7A1). CA has one more hydroxyl group at position 12alpha. This hydroxylation is carried out by the sterol 12alpha-hydroxylase (CYP8B1). Earlier, we and others have noticed a marked variation in the ratio between CA and CDCA in human bile. The aim of this study was to investigate whether this marked difference could be due to a genetic polymorphism in the gene of the CYP8B1. MATERIAL AND METHODS: Screening for genetic polymorphisms was carried out in a 2.4-kb-long area including the exon and part of the promoter region in subjects who had undergone cholecystectomy earlier, and where bile acid analysis had been performed. Among these subjects those with very high or low CA/CDCA ratios (ranging from 0.9 to 6.8) were investigated. The subjects were all female, normolipidaemic, having normal weight and a normal thyroid function. RESULTS: No polymorphisms were found in the investigated sequence. However, a statistically significant correlation was found between the activity of the CYP7A1 and the ratio between CA and CDCA. The difference in ratio could, at least in part, be explained by the difference in rate of bile acid synthesis. CONCLUSION: The difference in ratio between CA and CDCA cannot be explained by a polymorphism in the coding area of the CYP8B1.

Adult↗

PubMed1995

Does digestibility of meat protein help explain large bowel cancer risk?

An association between meat eating and large bowel cancer risk has been shown in a variety of epidemiologic studies. One reason could be that meat is less well digested than other protein foods and leads to greater amounts of protein entering the large bowel and being metabolized by colonic bacteria to potential carcinogens. To test this hypothesis, five subjects with ileostomies were fed, for five days, a basal diet to which were added test meals of cheese, a small or a large fried beef steak, and a large steak with resistant starch (RS). Ileal true nitrogen digestibility was similar for all five diets: control, 86.3%; cheese, 89.4%; low beef, 88.6%; high beef, 89.6%; and high beef + RS, 88.7%. Beef, at both low and high intake levels, was as well digested as cheese, suggesting that poor digestibility of meat does not explain the association between meat intake and large bowel cancer risk. Ileal starch output on the high beef + RS diet was 27% greater than expected on the basis of the measurement of dietary RS in vitro (p = 0.005 for linear trend), and this was confirmed by a meta analysis with eight other published studies. The relation between meat and large bowel cancer may reflect higher protein intakes in meat eaters or may be explained by other mechanisms.

Animals↗

PubMed2002

Explaining differences in the metabolic cost and efficiency of treadmill locomotion in children.

The metabolic cost of locomotion at any given speed, when expressed per kilogram of body mass, is greater for children than for older individuals. Incomplete explanations for the age-related difference motivated this study, which used a multidisciplinary method to examine metabolic, kinematic and electromyographic data from three maturational groups of children. Thirty children aged 7-8 (n = 10), 10-12 (n = 10) and 15-16 (n = 10) years completed 4 min bouts of submaximal treadmill exercise at six speeds--two walking and four running--assigned in random order. Metabolic (net VO2), kinematic (total body mechanical power, energy transfer rates, stride rate) and electromyographic (co-contraction of agonist and antagonist muscles in thigh and leg segments) data were collected. Multiple regression analysis was performed with net VO2 or efficiency as the dependent variable and mechanical power, thigh and leg co-contraction, stride rate and age as independent variables. It was possible to explain up to 77% of the age-related variance in net VO2 and 62% of the variation in efficiency using combinations of these variables. Age was the best single predictor of both VO2 and efficiency. Co-contraction, possibly used to enhance joint stability, was an important component of the observed age-related differences, although mechanical power was not. Additional variance might be explained as specific growth-related factors affecting the metabolic cost of locomotion are identified, as mechanical work models improve, and as methods are developed to measure the effects of stored elastic energy and the metabolic cost of isometric muscle actions.

Adolescent↗

PubMed1997

Explaining hierarchical and interprovincial migrations of Chinese young adults by personal factors and place attributes: a nested logit analysis.

"This paper uses a two-level nested logit model to explain the inter-stratum (city, town and rural county) and interprovincial migration behaviors of the young adults (aged 17-29) in China during a three-year period (1985-87), based on the micro data of the 1987 National Population Survey. The migration propensity of each person is represented by a departure probability and a destination choice probability. These probabilities are then expressed as functions of personal factors and place attributes. The main findings are that personal factors are of paramount importance in explaining the departure behaviors, and that both departure and destination behaviors responded to market forces in a sensible way, despite government control on territorial movements."

Asia↗

PubMed2003

Can the pathophysiology of autism be explained by the nature of the discovered urine peptides?

Opioid peptides derived from food proteins (exorphins) have been found in urine of autistic patients. Based on the work of several groups, we try to show that exorphins and serotonin uptake stimulating factors may explain many of the signs and symptoms seen in autistic disorders. The individual symptoms ought to be explainable by the properties and behavioural effects of the found peptides. The data presented form the basis of an autism model, where we suggest that exorphins and serotonin uptake modulators are key mediators for the development of autism. This may be due to a genetically based peptidase deficiency in at least two or more peptidases and, or of peptidase regulating proteins made manifest by a dietary overload of exorphin precursors such as by increased gut uptake.

Aging↗

PubMed2005

Serum amyloid A serum concentrations and genotype do not explain low incidence of amyloidosis in Hyper-IgD syndrome.

BACKGROUND: Hyper-IgD and periodic fever syndrome (HIDS) is an autosomal recessively inherited disorder characterized by recurrent episodes of fever and inflammation. Unlike other chronic inflammatory conditions, amyloidosis is very rare in HIDS. For deposition of amyloid of the AA type, high concentrations of SAA are a prerequisite, together with certain SAA1 gene polymorphisms. The SAA1.1 genotype predisposes for amyloidosis, while SAA1.5 genotype exerts a protective effect. AIM OF THE STUDY: To determine if SAA concentrations and SAA1 gene polymorphisms could explain the virtual absence of amyloidosis in HIDS patients. METHODS: We measured SAA and CRP concentrations in serum of 20 HIDS patients during an attack and during the asymptomatic phase. Genotype of SAA1 gene was determined in 60 HIDS patients. RESULTS: SAA serum concentrations during attacks were very high (median 205 mg/l; range 75-520 mg/l, normal <3.1 mg/l). During attack-free periods 45% of patients still had elevated SAA concentrations. The distribution of the genotype of SAA1 gene in HIDS was similar to healthy controls (SAA1.1 0.41 vs. 0.50 p=0.32). CONCLUSION: Patients with HIDS have high SAA during attacks and show sub-clinical inflammation when asymptomatic. The low incidence of amyloidosis cannot be explained by a predominance of non amyloidogenic SAA related genotypes.

Amyloidosis↗

PubMed2002

Is the association between short stature and myocardial infarction explained by childhood exposures--a population-based case referent study (SHEEP).

AIMS: This study was undertaken to examine the association between short stature and acute non-fatal myocardial infarction and to analyse causal mechanisms related to height with a focus on childhood risk factors. METHOD: The SHEEP (Stockholm Heart Epidemiology Program) is a population-based case-referent study. The outcome was incident first events of myocardial infarction. The study base included all Swedish citizens aged 45 to 70, who lived in Stockholm County during 1992-94. This analysis is based on 967 male cases, 412 female cases and 1696 referents. Exposure information was obtained through questionnaires, interviews, health examinations, and obstetric records. RESULTS: Adult height was inversely related to myocardial infarction. The odds ratio for men in the shortest quartile (< 173 cm) compared with the tallest was 1.78 (95% CI: 1.39, 2.28). For women the corresponding odds ratio in the shortest quartile (<159 cm) was 1.86 (95% CI: 1.28, 2.71). Height was also inversely associated with fetal growth and indicators of material resources during childhood. Within each social class of origin short stature was associated with number of siblings, lack of higher education, and absence of upward social mobility. Adjustment for childhood risk factors decreased the excess relative risk of short stature with around 25%. Adult social, behavioural, and biological risk factors could not explain the association. The findings were similar for men and women. CONCLUSION: Height is associated with many risk factors of myocardial infarction, which increase the risk of disease through many different causal pathways. Childhood exposures have no dominant role in explaining the association between short stature and myocardial infarction.

Aged↗

PubMedDate not supplied

HIV epidemics in Africa: what explains the variations in HIV prevalence?

There are large differences in the prevalence of HIV infection between different regions in sub-Saharan Africa, ranging from less than 10% in pregnant women in most of West Africa, to over 25% in pregnant women in large cities in Eastern and Southern Africa. These differences in HIV prevalence are in many instances due to differences in rate of spread of the virus. The multicenter study on factors determining the differential spread of HIV in four African cities tried to identify factors that could explain differences in spread of HIV between different regions in sub-Saharan Africa. The study was conducted in four cities, including two cities with a relatively low HIV prevalence (Cotonou in Bénin and Yaoundé in Cameroon) and two cities with a high HIV prevalence (Kisumu in Kenya and Ndola in Zambia). The difference in HIV prevalence between the four cities could not be explained by differences in sexual behavior. Any differences in sexual behavior were outweighed by differences in factors that influence HIV transmission, i.e. male circumcision and HSV-2 infection. These findings have important implications for the design of interventions.

Africa↗

PubMed2006

Geographic differences in antimalarial drug efficacy in Uganda are explained by differences in endemicity and not by known molecular markers of drug resistance.

BACKGROUND: Recent clinical trials from Uganda have shown that the risk of failure following antimalarial therapy varies geographically. We tested the hypothesis that geographic differences in the response to therapy could be explained by differences in the prevalence of known molecular markers of drug resistance. METHODS: Samples from 2084 patients treated with chloroquine (CQ) plus sulfadoxine-pyrimethamine (SP) and amodiaquine (AQ) plus SP were tested for the presence of known molecular markers of resistance. Differences in the risk of treatment failure across 6 sites were compared, and age and complexity of infection were controlled for. RESULTS: The prevalence of molecular markers of drug resistance was high at all of the sites: 61%-91% of patients were infected with parasites containing the pfcrt Thr-76 mutation and dhfr/dhps quintuple mutation. The risk of treatment failure decreased with increasing transmission intensity for both CQ plus SP (73% to 19%) and AQ plus SP (38% to 2%). Restricting the analyses to patients infected with parasites containing all 6 mutations of interest did not affect these trends. CONCLUSIONS: The risk of treatment failure was inversely proportional to transmission intensity and was not explained by differences in molecular markers of antimalarial drug resistance. Our findings strongly suggest that geographic differences in response to antimalarial therapy in Uganda are primarily mediated by acquired immunity associated with malaria transmission intensity, rather than by parasite factors.

Adolescent↗