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PubMed2002

Segregation at three loci explains familial and population risk in Hirschsprung disease.

Hirschsprung disease (HSCR), the most common hereditary cause of intestinal obstruction, shows considerable variation and complex inheritance. Coding sequence mutations in RET, GDNF, EDNRB, EDN3 and SOX10 lead to long-segment (L-HSCR) and syndromic HSCR but fail to explain the transmission of the much more common short-segment form (S-HSCR). We conducted a genome scan in families with S-HSCR and identified susceptibility loci at 3p21, 10q11 and 19q12 that seem to be necessary and sufficient to explain recurrence risk and population incidence. The gene at 10q11 is probably RET, supporting its crucial role in all forms of HSCR; however, coding sequence mutations are present in only 40% of linked families, suggesting the importance of noncoding variation. Here we show oligogenic inheritance of S-HSCR, the 3p21 and 19q12 loci as RET-dependent modifiers, and a parent-of-origin effect at RET. This study demonstrates by a complete genetic dissection why the inheritance pattern of S-HSCR is nonmendelian.

Alleles↗

PubMed2003

The crystal structure of the proprotein processing proteinase furin explains its stringent specificity.

In eukaryotes, many essential secreted proteins and peptide hormones are excised from larger precursors by members of a class of calcium-dependent endoproteinases, the prohormone-proprotein convertases (PCs). Furin, the best-characterized member of the mammalian PC family, has essential functions in embryogenesis and homeostasis but is also implicated in various pathologies such as tumor metastasis, neurodegeneration and various bacterial and viral diseases caused by such pathogens as anthrax and pathogenic Ebola virus strains. Furin cleaves protein precursors with narrow specificity following basic Arg-Xaa-Lys/Arg-Arg-like motifs. The 2.6 A crystal structure of the decanoyl-Arg-Val-Lys-Arg-chloromethylketone (dec-RVKR-cmk)-inhibited mouse furin ectodomain, the first PC structure, reveals an eight-stranded jelly-roll P domain associated with the catalytic domain. Contoured surface loops shape the active site by cleft, thus explaining furin's stringent requirement for arginine at P1 and P4, and lysine at P2 sites by highly charge-complementary pockets. The structure also explains furin's preference for basic residues at P3, P5 and P6 sites. This structure will aid in the rational design of antiviral and antibacterial drugs.

Amino Acid Sequence↗

PubMed2003

Palliative chemotherapy or best supportive care? A prospective study explaining patients' treatment preference and choice.

In palliative cancer treatment, the choice between palliative chemotherapy and best supportive care may be difficult. In the decision-making process, giving information as well as patients' values and preferences become important issues. Patients, however, may have a treatment preference before they even meet their medical oncologist. An insight into the patient's decision-making process can support clinicians having to inform their patients. Patients (n=207) with metastatic cancer, aged 18 years or older, able to speak Dutch, for whom palliative chemotherapy was a treatment option, were eligible for the study. We assessed the following before they consulted their medical oncologist: (1) socio-demographic characteristics, (2) disease-related variables, (3) quality-of-life indices, (4) attitudes and (5) preferences for treatment, information and participation in decision-making. The actual treatment decision, assessed after it had been made, was the main study outcome. Of 207 eligible patients, 140 patients (68%) participated in the study. At baseline, 68% preferred to undergo chemotherapy rather than wait watchfully. Eventually, 78% chose chemotherapy. Treatment preference (odds ratio (OR)=10.3, confidence interval (CI) 2.8-38.0) and a deferring style of decision-making (OR=4.9, CI 1.4-17.2) best predicted the actual treatment choice. Treatment preference (total explained variance=38.2%) was predicted, in turn, by patients' striving for length of life (29.5%), less striving for quality of life (6.1%) and experienced control over the cause of disease (2.6%). Patients' actual treatment choice was most strongly predicted by their preconsultation treatment preference. Since treatment preference is positively explained by striving for length of life, and negatively by striving for quality of life, it is questionable whether the purpose of palliative treatment is made clear. This, paradoxically, emphasises the need for further attention to the process of information giving and shared decision-making.

Adult↗

PubMed1998

Explaining the effect of ethnic group on weight concern: finding a role for family values.

OBJECTIVE: To examine the impact of ethnic group on aspects of weight concern and to assess the role of family values in explaining this association. SUBJECTS AND MEASURES: 20 Asian and 20 white daughters gave a questionnaire to their mother, father and sibling closest in age, concerning their profile characteristics (age, education) values and beliefs and completed a matched questionnaire containing additional measures of aspects of their weight concern. RESULTS: The results showed no differences between the white and Asian daughters in terms of either their restrained eating or body dissatisfaction. However, the results showed consistent differences between the members of the two family groups in terms of the value placed on achievement, child/parent relationships, competition, the role of women, and some differences in terms of materialism, the value of appearance and their idea of the perfect female body. The results were then analysed to assess the best predictors of the daughter's weight concern. Whereas restrained eating was related to the mother's rating of the value of physical appearance and the sibling's ratings of competitiveness and a non-traditional role for women (40% of the variance), the results showed that body dissatisfaction was related to the daughter's rating of materialism, having a father who preferred a thinner female body, the siblings ratings of a non-traditional role for women, degree of concordance within the family concerning the value of competitiveness and the educational level of the 'head of the family' (49% of variance). CONCLUSION: Whereas a dichotomous model of ethnicity may be insufficient to explain differences in aspects of weight concern, an expanded model of cultural beliefs may be a more powerful construct. Accordingly, the absence or presence of differences in weight concern according to ethnic group may simply reflect the extent to which the different groups chosen for analysis are differentiated by these predictive values.

Adolescent↗

PubMed2001

Utility of health belief model as a guide for explaining or predicting breast cancer screening behaviours.

AIM: The purpose of this study was to assess the utility of HBM as a theoretical guide for predicting breast cancer screening and therefore for guiding intervention studies. BACKGROUND: Breast cancer is the leading cause of death for middle age women (35-50) and the second leading cause of cancer deaths in all women in the United States (US). Early detection of breast cancer through screening is the only option available to women. However, less than half of all women in the US participate in screening. The health belief model (HBM), which specifies interactions of values and beliefs about health and their influence on choices, has been widely used to explain screening behaviour. METHODS: An integrative research review analysed 16 published descriptive studies employing HBM. Literature was located through a search of research based studies listed in Cumulative Index of Nursing and Allied Health (CINAHL), Medline, and cancer literature databases and studies cited in other references between 1990 and 1999. FINDINGS: Application of HBM was inconsistent. No study tested nonlinear relationships between variables as specified in the model. At best, the model explained 47% of the variance in screening behaviour when socioeconomic status was included. Otherwise predictive power was low, ranging from 15 to 27%. CONCLUSIONS: While the model provides some description of the values, beliefs and behaviours of middle-aged women primarily, HBM does not appear to have the power to consistently predict behaviours. Further research is needed to provide more thorough depiction of the social, nonhealth care meaning of breast cancer.

Adult↗

PubMed2003

A QSAR analysis to explain the analgesic properties of Aconitum alkaloids.

Aconitum roots are traditionally prescribed for the management of different types of painful affections in Asiatic countries. A quantitative structure-activity relationship (QSAR) analysis was performed to study the effect of chemical substitutes in the analgesic potency of alkaloids available in Chinese Aconitum roots. Using the CAChe program package for biomolecules, molecular modelling was performed in 12 alkaloids previously tested in a model of acetic acid-induced writhing in rats. The ED50 (micromol/kg) was used as the activity parameter. Structural parameters were compared between alkaloids with an aroyl/aroyloxy group at R14 and alkaloids with the aroyloxy group at R4. Single linear regression analyses were performed in order to find the parameters explaining activity. Alkaloids with an aroyl/aroyloxy group at R14 exhibited the highest potency (significantly less ED50). The stability parameters were different between groups, e.g. total energy was -8.0 +/- 0.4 in the potent analgesic alkaloids and -6.7 +/- 0.3 in the weak analgesic alkaloids (P = 0.001). The reactivity index of C2', C3' and C5' of the aromatic ring was also different between groups, e.g. the reactivity index of C5' was 40.8 +/- 0.6 in potent analgesic alkaloids and 48.1 +/- 0.6 in weaker analgesic alkaloids (P < 0.001). Several structural parameters explained analgesic activity of alkaloids, being the reactivity index of C5' on the aromatic group the most important factor (r = 0.89; P < 0.001).

Aconitum↗

PubMed1998

Assimilation of achromatic color cannot explain the brightness effects in the achromatic neon effect.

If the mouths of the pacmen of a Kanizsa square are colored, for example red, then an illusory red transparent square is seen. In many visual theories such 'neon color spreading' is explained by assimilation of chromatic and achromatic color. In this paper the achromatic case was investigated. In a two-alternative forced-choice task thirty observers judged the brightness of achromatic neon figures. The results suggest that assimilation of achromatic color inside and/or outside of the illusory figures cannot explain the brightness effects seen in achromatic neon color spreading. Although these displays may produce assimilation, it appears that contrast (perhaps acting nonlocally) is a stronger influence on their perceived brightness.

Color Perception↗

PubMed2001

Perceptual continuation and depth in visual phantoms can be explained by perceptual transparency.

We try to explain perceptual continuation and depth in the visual-phantom illusion in terms of perceptual transparency. Perceptual continuation of inducing gratings across the occluder in stationary phantoms could be explained with unique transparency, a notion proposed by Anderson (1997 Perception 26 419-453). This view is consistent with a number of previous reports including that of McCourt (1994 Vision Research 34 1609-1617) who criticized the stationary phantom illusion from the viewpoint of his counterphase lightness induction or grating induction, which might involve invalid transparency. Here we confirm that the photopic phantom illusion (Kitaoka et al, 1999 Perception 28 825-834) really gives in-phase lightness induction and involves bistable transparency. It is thus suggested that perceptual continuation and depth in the visual-phantom illusion depend on perceptual transparency.

Analysis of Variance↗

PubMed2002

Neuronal deactivation explains decreased cerebellar blood flow in response to focal cerebral ischemia or suppressed neocortical function.

Functional neuroimaging in humans with acute brain damage often reveals decreases in blood flow and metabolism in areas unaffected by the lesion. This phenomenon, termed diaschisis, is presumably caused by disruption of afferent excitatory input from the lesioned area to other brain regions. By characterizing its neurophysiological basis, we used cerebellar diaschisis to study the relationship between electrical activity and blood flow during decreased neuronal activity. Here we show that focal cerebral ischemia in rats causes diaschisis in the cerebellar cortex characterized by pronounced decreases in Purkinje cell spiking activity and small decreases in cerebellar blood flow. The findings were explained by decreased excitatory input to the cerebellar cortex, i.e., deactivation, as cerebellar neuronal excitability and vascular reactivity were preserved. Functional ablation of the cerebral cortex by either spreading depression or tetrodotoxin reproduced the changes in cerebellar function with complete recovery of Purkinje cell activity and cerebellar blood flow concomitant with recovery of neocortical function. Decreases of activity involving the contralateral frontal cortex produced the largest decrease in cerebellar electrical activity and blood flow. Our data suggest that deactivation explains the decreases in blood flow and metabolism in cerebellar diaschisis observed in human neuroimaging studies. Decreases in spiking activity were 3-7 times larger than the respective decreases in flow. Therefore, under pathological conditions, neuroimaging methods based on hemodynamic signals may only show small changes, although the underlying decrease in neuronal activity is much larger.

Animals↗

PubMed2002

The observed human sperm mutation frequency cannot explain the achondroplasia paternal age effect.

The lifelong spermatogonial stem cell divisions unique to male germ cell production are thought to contribute to a higher mutation frequency in males. The fact that certain de novo human genetic conditions (e.g., achondroplasia) increase in incidence with the age of the father is consistent with this idea. Although it is assumed that the paternal age effect is the result of an increasing frequency of mutant sperm as a man grows older, no direct molecular measurement of the germ-line mutation frequency has been made to confirm this hypothesis. Using sperm DNA from donors of different ages, we determined the frequency of the nucleotide substitution in the fibroblast growth factor receptor 3 (FGFR3) gene that causes achondroplasia. Surprisingly, the magnitude of the increase in mutation frequency with age appears insufficient to explain why older fathers have a greater chance of having a child with this condition. A number of alternatives may explain this discrepancy, including selection for sperm that carry the mutation or an age-dependent increase in premutagenic lesions that remain unrepaired in sperm and are inefficiently detected by the PCR assay.

Achondroplasia↗

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↗