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PubMed1994

A cellular model to explain the pathogenesis of infection by the hepatitis B virus.

The natural history of infection by the hepatitis B virus (HBV) depends on many factors, including the age and immunological status of the patient, and can range from acute transient infection to subclinical chronic hepatitis. Persistent infection often leads to the development of primary hepatocellular carcinoma. We consider a cellular model of HBV infection based on the hypothesis that the liver contains two populations of cells with contrasting responses to the virus. Our findings show that the model can be used to account for the wide variety of clinical manifestations of infection and can explain the observed age dependence of the main different outcomes of the disease.

Carcinoma, Hepatocellular↗

PubMed1995

Does lipoprotein or hepatic lipase activity explain the protective lipoprotein profile of premenopausal women?

Numerous studies have reported that women have a lipoprotein profile suggestive of a reduced risk of coronary heart disease (CHD). We have therefore tested whether the "protective" lipoprotein profile of women could be explained by differences in hepatic lipase (HL) or lipoprotein lipase (LPL) activities. In the present study, 14 non-obese healthy premenopausal women had higher plasma concentrations of high-density lipoprotein cholesterol (HDL-C), HDL2-C, HDL3-C, and HDL-apolipoprotein (apo) AI, and a higher ratio of HDL-C to low-density lipoprotein cholesterol (LDL-C) than 17 non-obese healthy men. Women also had lower plasma triglyceride (TG), HDL-TG, and apo B levels than men. Plasma postheparin LPL (PH-LPL) and HL activities showed no significant sex dimorphism, whereas abdominal and femoral adipose tissue (AT)-LPL activities were significantly higher in women (P < .005). In men, PH-LPL activity correlated significantly with plasma HDL2-C (r = .52, P < .05), LDL-C (r = -.47, P < .05), and apo B (r = -.56, P < .01) levels, as well as with the HDL-C/LDL-C ratio (r = .67, P < .005). No such relationships were found in women, with the exception of HL activity, which was negatively correlated with HDL-apo AI levels. In both genders, abdominal AT-LPL activity showed no significant association with plasma lipoprotein levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗

PubMed1992

A simplified two-pore filtration model explains the effects of hypoproteinemia on lung and soft tissue lymph flux in awake sheep.

We used a simplified two-pore filtration model to examine the effects of hypoproteinemia on lung and soft tissue lymph flux in awake sheep (n = 7). To induce hypoproteinemia, we subjected each animal to 3 days of batch plasmapheresis (6 units per day). Data were collected in near steady-state conditions, 15-18 hr following completion of the last plasmapheresis episode. At this time, plasma protein concentration had fallen by 34%, while lung and soft tissue lymph protein concentrations had fallen by 55 and 62%, respectively. Lung and soft tissue lymph flows increased 52 and 87%, respectively. The plasma-to-lymph osmotic pressure gradients for lung and soft tissue lymph were unchanged by protein depletion (soft tissue, 7.7 mm Hg; lung, 4.8 mm Hg). We applied these results to a heteropore model of the microvascular barrier that consisted of two types of pores: those which plasma proteins could not cross (sigma = 1) and those which proteins could cross without restriction (sigma = 0). We varied the proportion of small pores to large pores until the measured data fit a model in which the calculated microvascular hydrostatic pressures in normal and hypoproteinemic conditions were equal. This was based on the assumption that microvascular hydrostatic pressure did not change with plasma protein depletion. These conditions could be satisfied when the small pores accounted for 90% of total barrier porosity. According to the model, lymph flow increased in hypoproteinemia because of an increase in protein-free liquid flux through the large percentage of small pores; protein flux through the small percentage of large pores remained unchanged. The net result was an increase in lymph flow and a decrease in the lymph protein concentration. The model reproduced these changes even though the plasma-to-lymph osmotic pressure gradients were unchanged. We conclude that a simplified heteropore model can explain the effects of hypoproteinemia on lung and soft tissue lymph flux.

Animals↗

PubMed1976

Scanning and transmission electron microscopy of the spermiophores of Ornithodoros ticks: an attempt to explain their motility.

The spermiophores of two tick species, the kangaroo tick, Ornithodoros gurneyi and the cave tick, Ornithodoros tholozani have been examined by scanning and transmission electron microscopy. The anterior end (head) of the spermiophore is a hemisphere covered with a hexagonal network of small projections. The rest of the spermiophore is covered with longitudinal ridges, seen in sections as cellular processes whose membranes are attached only at their anterior ends by specialized 'feet'. In the cytoplasm of the sperm cell body and just beneath the cellular processes are find filaments, which form a continuous layer in O. tholozani and bundles in O. gurneyi. Fibrils tend to be situated beneath the larger cellular processes. In scanning micrographs helical constrictions have been observed in the posterior parts of some spermiophores. It is proposed that certain of the movements observed by light microscopy in living cultures of spermiophores may be explained by contraction of the cytoplasmic filaments seen in the electron microscope.

Animals↗

PubMed1989

A model to explain the pharmacological effects of snake venom phospholipases A2.

Snake venom phospholipase A2 enzymes induce a wide variety of pathological symptoms in animals, despite sharing a common catalytic activity and similar structural features with nontoxic mammalian pancreatic enzymes. A hypothetical model is described to explain how specific pharmacological effects, such as presynaptic neurotoxicity, cardiotoxicity, myotoxicity, anticoagulant and platelet effects are exhibited by venom PLA2 enzymes. The model is an effort to elucidate many controversial and contradictory observations which have previously been difficult to interpret. The essential feature of the model is the targeting of venom PLA2 enzymes to the specific tissue or cell due to their affinity towards specific proteins, rather than lipid domains. After the initial binding, PLA2 enzymes induce various pharmacological effects by mechanisms which are either dependent or independent of their enzymatic activity. The model and its predicted target proteins thus provide a new focus for toxin research.

Blood Coagulation↗

PubMed1986

Responses of spatial mechanisms can explain hyperacuity.

A recently developed nonlinear mathematical model for spatial pattern discrimination, which is formally analogous to line element models in color vision, was applied to a variety of hyperacuity tasks. The computed results are in reasonable agreement with data on vernier acuity as a function of line length and separation, chevron acuity, periodic vernier acuity using sinusoidal lines, three line bisection acuity, vernier acuity using cosine gratings, and spatial interference with vernier acuity. In agreement with model predictions, data are presented showing that vernier acuity improves as a power function of contrast. It is concluded that the nonlinear, contrast dependent responses of visual mechanisms tuned for size and orientation can explain a wide range of hyperacuity and other spatial pattern discrimination tasks.

Discrimination, Psychological↗

PubMed1990

Contrast discrimination cannot explain spatial frequency, orientation or temporal frequency discrimination.

Current models of spatial frequency (SF) and orientation discrimination are based on contrast discrimination data. In these "error propagation" models, the precision of all discrimination tasks is limited by "peripheral" noise in contrast-sensitive channels. Therefore, all discrimination thresholds should be proportional to the contrast Weber fraction delta c/c. To test this prediction, increment thresholds were measured for contrast, SF, orientation and temporal frequency (TF) for contrasts ranging from 2 to 50%. All measurements used the same stimuli, procedures and observers. For contrasts of 2% and higher, the contrast discrimination threshold delta c rises with approximately the 0.6 power of contrast, while SF and TF discrimination are independent of contrast. Furthermore, orientation discrimination is nearly independent of contrast at a SF of 4 cpd. No error-propagation model can explain these results. Therefore, SF and TF discrimination, and orientation discrimination at 4 cpd are limited by contrast-independent central noise.

Contrast Sensitivity↗

PubMed1995

Reversals of the colour-depth illusion explained by ocular chromatic aberration.

Although many colour-depth phenomena are predictable from the interocular difference in monocular chromatic diplopia caused by the eye's transverse chromatic aberration (TCA), several reports in the literature suggest that other factors may also be involved. To test the adequacy of the optical model under a variety of conditions, we have determined experimentally the effects of background colour on perceived monocular chromatic diplopia and perceived depth (chromostereopsis). A Macintosh colour monitor was used to present red, blue, and green test stimuli which were viewed monocularly or binocularly (haploscopically) through 1.78 mm artificial pupils. These apertures were displaced nasally and temporally from the visual axis under controlled conditions to induce a variable degree of TCA. Monocular chromatic diplopia and binocular chromostereopsis were measured for red and blue targets, and also for red and green targets, presented on either a black background or on a background which was composed of the sum of the targets' spectral composition (e.g. red and blue presented on magenta; red and green presented on yellow). In all cases, chromatic diplopia and chromostereopsis were found experimentally to reverse in sign with this change in background. Furthermore, we found that a given coloured target could be located in different depth planes within the same display when located on different background colours. These seemingly paradoxical results could nevertheless be explained by a simple model of optical TCA without the need to postulate additional factors or mechanisms.

Adult↗

PubMed1994

A theory that may explain the Hayflick limit--a means to delete one copy of a repeating sequence during each cell cycle in certain human cells such as fibroblasts.

A model that may explain the limited division potential of certain cells such as human fibroblasts in culture is presented. The central postulate of this theory is that there exists, prior to certain key exons that code for materials needed for cell division, a unique sequence of specific repeating segments of DNA. One copy of such repeating segments is deleted during each cell cycle in cells that are not protected from such deletion through methylation of their cytosine residues. According to this theory, the means through which such repeated sequences are removed, one per cycle, is through the sequential action of enzymes that act much as bacterial restriction enzymes do--namely to produce scissions in both strands of DNA in areas that correspond to the DNA base sequence recognition specificities of such enzymes. After the first scission early in a replicative cycle, that enzyme becomes inhibited, but the cleavage of the first site exposes the closest site in the repetitive element to the action of a second restriction enzyme after which that enzyme also becomes inhibited. Then repair occurs, regenerating the original first site. Through this sequential activation and inhibition of two different restriction enzymes, only one copy of the repeating sequence is deleted during each cell cycle. In effect, the repeating sequence operates as a precise counter of the numbers of cell doubling that have occurred since the cells involved differentiated during development.

Base Sequence↗

PubMed1985

Combined stack effect in houses and eskers explaining transients in radon source.

Concentrations of radon indoors and temperatures indoors and outdoors have been recorded every hour with some interruptions for one 12-week period in a dwelling situated on top of an esker outside Stockholm. The concentration of radon in the house shows variations, which can be explained as a combined stack effect in the esker and in the building. The stack effect is not only dependent on temperature differences, but also on the pressure effect that the wind creates. In this study no local wind observations have been made as this was not the main purpose on this occasion. The temperature in the esker is assumed to be at a constant level equivalent to groundwater temperature. From these data the pressure gradient has been calculated and then compared with the radon source.

Atmospheric Pressure↗

PubMed1990

Colocalized transmembrane determinants for ER degradation and subunit assembly explain the intracellular fate of TCR chains.

The intracellular fate of T cell antigen receptor (TCR) subunits (alpha beta gamma delta epsilon zeta 2) is determined by their assembly in the endoplasmic reticulum (ER). To study the structural bases for this tight correlation between assembly and intracellular fate, we sought to define the nature of determinants for both ER degradation and subunit assembly within the TCR-alpha chain. We found that a 9 amino acid transmembrane sequence of the TCR-alpha chain, containing 2 critical charged residues, was sufficient to cause ER degradation when placed in the context of the Tac antigen, used here as a reporter protein. CD3-delta assembled with chimeric proteins containing this short transmembrane sequence, and this assembly resulted in abrogation of targeting for ER degradation. Thus, the colocalization of determinants for ER degradation and sites of subunit interactions explains how the fate of some newly synthesized TCR chains can be decided on the basis of their assembly status.

Amino Acid Sequence↗

PubMed1992

Attempts to explain and reduce variability of superovulation.

The variability in response to superovulation treatment is a major disadvantage for economical use of embryo transfer and clearly limits use of embryo transfer in animal breeding. Despite considerable efforts, it has not yet been possible to reduce this variability drastically. Less than 40% of the causes for variability has been explained to date. The high proportion of unexplained variability leads to the hypothesis that variability is a special biological function that supports natural selection over the long term. Corresponding data from laboratory animal studies support this hypothesis.

Journal Article↗

PubMed1996

Explaining conversation rules to children: an intervention study to facilitate children's accurate responses.

In the past few years there has been increased concern over the role of social influences on children's reports during interviews. It is argued that the number of wrong answers can be reduced by explaining a set of social rules of conversation to children at the beginning of an interview. In the present experiment, the effects of two conversation rules were tested. Children were informed that (a) "I-don't-know" is an acceptable answer, and (b) the interviewer would not be able to help them in answering the questions. A total of 114 children, aged 4 to 10, watched a staged event and were interviewed afterwards. The two factors were systematically varied in the experiment by utilizing a 2 x 2 factorial design. The results supported the hypotheses that introduction of these rules would reduce suggestibility. Our findings have implications for interviewing child witnesses.

Analysis of Variance↗

PubMed1994

Deletion and duplication sequences induced in CHO cells by teniposide (VM-26), a topoisomerase II targeting drug, can be explained by the processing of DNA nicks produced by the drug-topoisomerase interaction.

Frameshift mutations induced by acridines in bacteriophage T4 have been shown to be due to the ability of these mutagens to cause DNA cleavage by the type II topoisomerase of T4 and the subsequent processing of the 3' ends at DNA nicks by DNA polymerase or its associated 3' exonuclease followed by ligation of the processed end to the original 5' end. An analysis of the ability of nick-processing models is presented here to test the ability of nick processing to account for the DNA sequences of duplications and deletions induced in the aprt gene of CHO cells by teniposide (VM-26) [Han et al. (1993) J. Mol. Biol., 229, 52]. Although teniposide is not an acridine, it induces topoisomerase II-mediated DNA cutting in aprt sequences in vitro and mutagenesis in vivo. Although the previous study noted a correlation between mutation sites and nearby DNA discontinuities induced by the enzyme in vitro, neither the nick-processing model responsible for T4 mutations, nor double-strand break models alone were able to account for most of the mutant sequences. Thus, no single model explained the correlation between teniposide-induced DNA cleavage and mutagenic specificity. This report describes an expanded analysis of the ways that nick-processing models might be related to mutagenesis and demonstrates that a modified nick-processing model provides a biochemical rationale for the mutant specificities. The successful nick-processing model proposes that either 3' ends at nicks are elongated by DNA polymerase and/or that 5' ends of nicks are subject to nuclease activity; 3'-nuclease activity is not implicated. The mutagenesis model for nick-processing of teniposide-induced nicks in CHO cells when compared to the mechanism of nick-processing in bacteriophage T4 at acridine-induced nicks provides a framework for considering whether the differences may be due to cell-specific modes of DNA processing and/or due to the precise characteristics of topoisomerase-DNA intermediates created by teniposide or acridine that lead to mutagenesis.

Acridines↗

PubMed1985

"Unusual SCD" explained by differences in BrdU incorporation during subsequent cell cycles.

In the course of three consecutive cell cycles, V79 cells were labeled with BrdU by different labeling protocols. Cells treated for three cycles with bromodeoxyuridine (BrdU) showed third division metaphases, with the typical appearance after fluorescent plus Giemsa (FPG) staining (i.e., 75% of the chromatids showed light staining, 25% showed dark staining). The same staining pattern is achieved by the second labeling protocol, during which the cells have replicated for two cycles in the presence of BrdU and, during the last cycle, in the absence of BrdU. Cells that have replicated only for one cell cycle in BrdU-containing medium, and the following two cycles in normal medium, depict just the opposite staining pattern (i.e., 75% dark, 25% light). These experiments explain how the variation of BrdU substitution in the DNA leads to altered FPG staining. Unexpected staining patterns ("unusual SCD") are also observed after seemingly permanent BrdU substitution. This phenomenon, which has been found in cancer cells, is due to the decrease in BrdU concentration and not to a peculiarity of the cells investigated.

Animals↗

PubMed1987

Mitotic recombination can explain the apparent polyclonal origin of some tumors.

Although most human tumors appear to be monoclonal in origin, a few express two G6PD types; on this basis they have been thought to be polyclonal in origin and exceptions to the general rule of monoclonality. In light of the recent discovery that mitotic recombination can cause a shift from genetic heterozygosity to homozygosity in tumor cells, we suggest that such a mechanism can also explain the occasional occurrence of two G6PD types in a monoclonal tumor.

Dosage Compensation, Genetic↗

PubMed1991

High catabolism of BrdU may explain unusual sister chromatid differentiation and replication banding patterns in cancer cells.

Two T-cell acute lymphoblastic leukemia (ALL) cell lines, PEER and CCRF-CEM, were studied by various chromosome banding techniques, including 5-bromodeoxyuridine (BrdU) incorporation methods. Although of very similar origin, these two cell lines behave quite differently. In particular, CEM cell line exhibited an abnormal replication banding pattern (RBP) and poor sister chromatid differentiation (SCD). Study of their thymidylate synthase and thymidine kinase activities indicated that CEM had a more active salvage pathway for thymidylate synthesis than did PEER cell line, which may suggest an efficient BrdU incorporation and its fast decrease in culture medium, resulting in the observed peculiarities. However, this was contradictory to the fact that CEM need a higher dose of BrdU than do PEER cells to induce SCD and RBP. Finally, the radioactivity from 3H-thymidine decreased in the culture medium much faster for PEER cell line than for CEM cell line, and about 50% of the remaining radioactivity was due to 3H-thymidine for CEM cell line. Thus, the abnormal SCD and RBP are explained by an active catabolism of thymidine and BrdU in CEM cell line.

Bromodeoxyuridine↗

PubMed1996

Explaining variations in inpatient length of stay in the National Health Service.

This paper seeks to explain variations in acute inpatient length of stay in the National Health Service in England. A model is proposed in which the length of stay is allowed to vary according to patient characteristics, the local supply of NHS care. the local pressure on NHS resources, other non-NHS health care supply factors, and local policy effects. Length of stay data are obtained from the 1991/1992 Hospital Episode Statistics. They are standardized for age, sex and broad specialty group, and are aggregated to the level of small areas with populations of about 10,000. Explanatory variables include socio-economic data from the 1991 Census of Population, health status data, waiting time data, measures of access to inpatient and GP services, and measures of local private health care provision. The paper finds that variability in length of stay is greatest in the over-65 age group. The most important determinants of variations in length of stay are access to NHS hospitals, access to private hospitals, waiting times for elective surgery, indicators of poverty, and indicators of the availability of informal care.

Analysis of Variance↗