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PubMed1981

A simple electrostatic model can explain the effect of pH upon the force-pCa relation of skinned frog skeletal muscle fibers.

The relative force-pCa relation of skinned frog skeletal muscle fibers is shifted along the pCa axis by changes in pH. This shift has been interpreted as arising from competition between H+ and Ca2+ for a binding site on troponin. Unfortunately, binding studies have been unable to confirm such competition. Alternatively, however, the data fit a model where H+ influences the degree of dissociation of ionizable groups on the surface of the thin filaments, thus altering the electrostatic potential surrounding the filaments. Alterations in the potential will, in turn, change the concentration of Ca2+ near the troponin binding sites in accordance with the Boltzmann relation. A simple model, based upon the Gouy-Chapman relation between surface potential and charge density, provides a quantitative explanation for the shift of the relative force-pCa curve with pH, given a reasonable estimate of the surface charge density on the thin filament. A best fit is obtained when the ionizable groups giving rise to the potential have a log proton ionization constant (pKa) of 6.1, similar to that for the imidazole group on histidine, and when the density of these groups is near that estimated from amino acid analysis of thin filament proteins and from filament geometry. In preliminary experiments, reaction of skinned frog fibers with diethylpyrocarbonate (DEP) at pH 6 shifted the force-pCa curve toward lower Ca2+. This would be expected in the model since DEP at pH 6 is reported to specifically react with histidine imidazole groups and to irreversibly decrease their pKa, which would increase the net negative charge of the filaments.

Animals↗

PubMed2000

The influence of trust and perceptions of risks and benefits on the acceptance of gene technology.

A causal model explaining acceptance of gene technology was tested. It was hypothesized that trust in institutions using gene technology or using modified products has a positive impact on perceived benefit and a negative influence on perceived risk of this technology. Furthermore, perceived benefit and perceived risk determine acceptance of biotechnology. In other words, trust has an indirect influence on the acceptance of the technology. The postulated model was tested using structural equation modeling procedures and data from a random quota sample of 1001 Swiss citizens between 18 and 74 years old. Results indicated that the proposed model fits the data very well. The same causal model explains females' and males' acceptance of gene technology. Gender differences were found for the latent variables trust, perceived benefit, and acceptance of gene technology. Females indicated more trust, perceived less benefit, and demonstrated less acceptance than did males. No significant difference was observed for perceived risk. The implications of the results are discussed.

Adolescent↗

PubMed1991

A hypothetical model to explain the 'termination' of chronic myeloid leukemia into blastic crisis.

Chronic myeloid leukemia is characterised by two discrete phases, a 'benign' phase which terminates into an 'acute' phase. Various explanations have been given to explain the cause of 'blastic' crisis in CML. But the consistency and regularity with which blast crisis occurs and the irregularity with which the factors which are ascribed to cause it (e.g. additional chromosomal abnormalities, change in bcr/abl rearrangement, etc. occur, suggests that CML-BC is not a stochastic process in the natural history of CML but is predetermined at the time of the first mutation in the stem cell. A hypothetical model is put forward proposing this. Different points supporting the model are discussed. The most important implication of this model would be to provide an insight that should lead to the development of more selective and appropriate treatment strategies for this disease.

Blast Crisis↗

PubMed1995

Predictive study of the conformation of the cytotoxic protein alpha-sarcin: a structural model to explain alpha-sarcin-membrane interaction.

Alpha-sarcin is a cytotoxic protein composed of a single polypeptide chain. This protein shows a significant degree of amino acid sequence similarity with a group of several phylogenetically related fungal ribonucleases. The leading member of such a group is ribonuclease T1. Three proteins of this group, ribonucleases T1, Ms and F1, are well known in terms of their crystal structures. These data have been used to propose a conformation for alpha-sarcin. The secondary structure of the cytotoxin would contain one alpha-helix segment as well as around six beta-strands and 14 beta-turns. The folding of these structural motifs is proposed by comparison with the three-dimensional structure of the three proteins from the ribonuclease T1 subfamily. The four longest beta-strands of alpha-sarcin would define an antiparallel beta-sheet structure resulting in a highly hydrophobic domain. The predicted folding for alpha-sarcin is discussed in terms of the ability of this protein to electrostatically and hydrophobically interact with phospholipid vesicles. The proposed conformation would explain how a highly polar protein, such as alpha-sarcin, can produce membrane destabilization resulting in protein translocation across lipid bilayers.

Amino Acid Sequence↗

PubMed1987

The limitations of control-of-supply models for explaining and preventing alcoholism and drug addiction.

The primary approach to eliminating drug abuse in America for most of the 20th century has been to prohibit the use and sale of certain drugs and to shut down drug supply lines. Yet drug abuse persists at high levels and the use of outlawed substances is a common feature of American life from high school on. The failure of drug policies has not discouraged, but seemingly fuels, renewed efforts of the same kind. Contrasting with this focus on the inherent dangers of the substance itself, the effort to control alcohol abuse has instead focused, since the end of Prohibition, on the characteristics of the individual alcoholic. In recent years, however, the public-health model of alcohol abuse and the psychophysiological formulation of alcohol dependence have emphasized that alcoholism is a consequence of the amount of alcohol available in the society and consumed by the individual drinker. In this way, alcohol and drug dependence (or addiction) formulations have coalesced: both assume that uncontrolled use results from regular or excessive consumption of these substances. This unified model of addiction based on exposure to a substance fails to account for substantial interindividual, intraindividual and cultural variability in patterns of use. The evidence is, moreover, that control-of-supply policies will never reduce substance abuse significantly and that such policies may backfire by propagating images of substances as being inherently overpowering.

Alcoholic Beverages↗

PubMed1989

A model that explains the varying frequency of aneuploid children with maternal age (J-shaped curve) as well as aneuploidy of paternal origin.

A compromised microcirculation could account for aneuploidy incidence in women of any reproductive age, the frequency varying with the probability of events leading to reduced development and/or function of the critical perifollicular capillary bed. This would explain the J-shaped curve of changing frequency of Down syndrome children with maternal age (Erickson, 1978). The seminiferous tubule of the testis, like the follicle, has no internal circulation, so small localized regions of reduced circulation could occur and result in aneuploidy. From all that we know about the deficiency of regional microcirculation in tumors (see Hall, 1978), it is reasonable to speculate that reduced pH could be responsible for some of the aneuploidy that is seen in practically all advanced tumors. As a first step in testing the model proposed here, we are beginning studies with mouse oocytes, on the assumption that ovarian conditions are responsible for the maternal age effect rather than uterine conditions (reduced rejection of trisomic fetuses). Should our model for aneuploidy induction in both germ and somatic cells prove to be correct, the molecular mechanism(s) would still have to be ascertained.

Aneuploidy↗

PubMed1998

Crossbridge head detachment rate constants determined from a model that explains the behavior of both weakly- and strongly-binding crossbridges.

Experimentally it is observed that the head regions of weakly-binding myosin crossbridges (crossbridges with ATP or ADP.Pi at the nucleotide binding site) are mobile while attached to actin, while strongly-binding crossbridge heads, such as those with PPi or AMP-PNP at the nucleotide binding site, are immobile (Pate and Cooke, Biophys. J., 1988; Fajer et al., Biophys. J., 1988). I postulate that the fundamental difference between weakly- and strongly-binding crossbridges is not their difference in affinity for actin, but the difference in mobility of the myosin heads attached to actin. Because the heads of weakly-binding crossbridges are mobile while attached to actin, the heads function independently and their behavior can be described by a simple independent-head model. With strongly-binding crossbridges, when one head detaches, it cannot re-attach in a position of lesser strain while the other is attached immobile; both heads must be detached concurrently before the crossbridge can relocate to a position of less strain and relax any tension it supports. This makes the heads appear to act cooperatively. A double-headed crossbridge model is presented which takes into account the difference between weakly- and strongly-binding crossbridges. The model is quite successful at describing the experimental data. In particular, for weakly-binding crossbridges the time constant of the response to stretch is shown to be relatively insensitive to ionic strength and for strongly-binding crossbridges, the model predicts with great accuracy the large ionic strength dependence of the rate constant for force decay. When the experimental results are interpreted according to the model, an important conclusion that emerges is that in all cases (for both weakly- and strongly-binding crossbridges) unstrained crossbridge heads in the muscle fiber detach from actin with approximately the same rate constant as myosin subfragment-1 detaches from actin in solution.

Actins↗

PubMed1998

Activation/attenuation model for RNase H. A one-metal mechanism with second-metal inhibition.

Ribonucleases H (RNases H) comprise a family of metal-dependent enzymes that catalyze the hydrolysis of the 3'-O---P bond of RNA in RNA.DNA hybrids. The mechanism by which RNases H use active-site metal(s) for catalysis is unclear. Based upon the seemingly contradictory structural observations of one divalent metal bound to Escherichia coli RNase HI and two divalent metals bound to the HIV RNase H domain, two models explaining RNase H metal dependence have been proposed: a one-metal mechanism and a two-metal mechanism. In this paper, we show that the Mn2+-dependent activity of E. coli RNase HI is not consistent with either of these mechanisms. RNase H activity in the presence of Mn2+ is complex, with activation and inhibition of the enzyme at low and high Mn2+ concentrations, respectively. Mutations at Asp-134 result in a partial loss of this inhibition, with little effect on activation. Neutralization of His-124 by mutation to Ala results in an enzyme with a significantly decreased specific activity and an absolute loss of Mn2+ inhibition. Inhibition by high Mn2+ concentrations is shown to be due to a reduction in kcat; this attenuation has a critical dependence on the presence of His-124. Based upon these results, we propose an "activation/attenuation" model explaining the metal dependence of RNase H activity where one metal is required for enzyme activation and binding of a second metal is inhibitory.

Amino Acid Substitution↗

PubMed1993

Development of a trehalose 6,6'-dimycolate model which explains cord formation by Mycobacterium tuberculosis.

Trehalose 6,6'-dimycolate (TDM) is a glycolipid of mycobacteria that displays an unusual toxicity and has been reported to be a virulence factor for Mycobacterium tuberculosis. Lack of understanding of the toxicity has impeded acceptance of TDM as a virulence factor. We previously reported that the toxicity of TDM depends on its presentation as a surface monolayer consisting of 30% trehalose and 70% exposed mycolic acid moieties. This paper further investigates the structure of the TDM monolayer. It began with the observation that beads coated with TDM, but not with closely related analogs, aggregate to form organized structures resembling the cords of virulent mycobacteria. This implied that the TDM molecules in the monolayer were arranged in an organized structure. This structure was investigated by real-time kinetic microscopy, scanning electron microscopy, and gross observations of the adhesion patterns of TDM-coated beads. In each of these models, the structures induced by TDM differed from those of analogs or other amphiphiles studied. These observations were used to construct a model of the structure of TDM monolayer which envisions linear arrays of TDM molecules arranged in a circumferential pattern on beads with discontinuities only at the two poles.

Cord Factors↗

PubMed1986

A mismatch repair-based model can explain some features of u.v. mutagenesis in yeast.

Our studies on the REV2-dependent processes of DNA repair and u.v. mutagenesis in yeast are summarized and compared with the general features of DNA damage-induced mutagenesis in yeast. On the basis of the data available, we propose that mismatch repair is an essential process in u.v. mutagenesis. We assume that a photoproduct site in double-stranded DNA can be handled as a replicative mismatch leading to misinsertion opposite the lesion.

DNA Repair↗

PubMed1989

A structural model to explain the partial catalytic activity of human prorenin.

Human prorenin, secreted from a Chinese hamster ovary cell line transfected with the cDNA for preprorenin, has been purified in mg quantities by a novel single-step procedure. The method takes advantage of reversible acid activation as a means of generating active prorenin that may be bound and eluted from an affinity column for renin. Analysis of the prorenin so purified revealed that it contained about 80% intact zymogen; the remaining 20% comprised a mixture of various prorenin derivatives truncated in the prosegment, and a small amount of renin. After exposure to 37 degrees C and pH 7.5, the refolded, partially active preparation was passed once more over the affinity column to remove renin and any truncated prorenin forms that were still active and that were, therefore, again retained by the column. Over a period of several hours, refolded and inactive prorenin not bound to the column slowly regains 5% to 10% renin activity, even when maintained under conditions that are optimal for zymogen inactivation. This activity is observed toward both model peptide substrates and natural human angiotensinogen. On the basis of these findings, we propose a model in which, under physiological conditions, a small amount of open, active prorenin is in equilibrium with a predominant, closed, and inactive form of the zymogen. Support for the model is provided by binding studies with a strong renin inhibitor that displaces the equilibrium entirely to a 1:1 zymogen:inhibitor complex. Limited cleavage of prorenin by several different proteinases has provided a number of fully active renin derivatives with varying N-terminal sequences. Results thus obtained, together with analysis of prorenin and its truncated forms bound, or not bound, to the affinity column under a variety of conditions, suggest that the propeptide region, -Arg-Ile-Phe-Leu-Lys- (positions 10P-14P), is essential for the reversible refolding of the prosegment that leads to zymogen inactivation.

Binding Sites↗

PubMed2002

[Pathophysiology of migraine: models to explain the generation of migraine headache].

Migraine attacks can be elicited by many different trigger situations such as light, food and the menstruation cycle. However, patients share a common pathophysiology, and a number of theories have been proposed as to how migraine can be generated. After a brief introduction of the trigeminal nociceptive system, 4 attempts to explain the generation of migraine attacks are described and discussed: One deals with the "cortical spreading depression (CSD) theory" which favors a cortical dysfunction. The second provides some evidence that a genetic mutation of calcium channels might be the cause. The third is based on a pathophysiological role of endogenous serotonin because serotonin agonists are effective drugs in the treatment of migraine and the last one postulates a migraine generator in the brainstem.

Chromosomes, Human, Pair 19↗

PubMed1997

The enhancer shift: a model to explain the developmental control of IgH gene expression in B-lineage cells.

The roles attributed to the E mu enhancer and the downstream 3' regions acting as locus control regions (LCRs) have allowed comparisons to be drawn between regulation of the IgH locus in early and late B-cell development and other systems governed by LCR activity. Here, the importance of the IgH 3'LCR and its putative functional role in the control of IgH gene expression is evaluated and compared with the 5'LCR regulatory region of the human beta-globin locus.

B-Lymphocytes↗

PubMedDate not supplied

Cervical intraepithelial lesions and cervical cancer among Asian Pacific Islander women in a cervical cancer screening program.

Utilizing data from a cervical cancer screening program in California, we examined the relationship between being a woman of Asian/Pacific Islander (API) origin and receiving different types of abnormal cervical diagnoses. Initial descriptive data reflected a higher than expected percentage of API subjects with a final diagnosis of in situ and invasive cervical cancer when compared with other subjects in other ethnic groups (N = 2792). Results of multivariate analysis indicated that being of API origin retained significance in a model explaining the level of severity of the cervical final diagnosis, even when controlling for other significant predictors such as having a prior pap smear, age, referral source, the presence of cervical abnormalities and the time from screening to diagnosis. We conclude that women of API origin may not be accessing health care sufficiently early to prevent increasingly severe final diagnoses. Utilizing data from a cervical cancer screening program in California, we examined the relationship between being a woman of Asian/Pacific Islander (API) origin and receiving different types of abnormal cervical diagnoses. Initial descriptive data reflected a higher than expected percentage of API subjects with a final diagnosis of in situ and invasive cervical cancer when compared with other subjects in other ethnic groups (N = 2792). Results of multivariate analysis indicated that being of API origin retained significance in a model explaining the level of severity of the cervical final diagnosis, even when controlling for other significant predictors such as having a prior pap smear, age, referral source, the presence of cervical abnormalities and the time from screening to diagnosis. We conclude that women of API origin may not be accessing health care sufficiently early to prevent increasingly severe final diagnoses.

Adult↗

PubMed1990

Toward a model to explain infant preferences by cerebral emotional asymmetry and hemisphere priming.

This paper argues that the rightward preference observed in most infants can be described as the consequence of two characteristics of the human brain: (1) hemispheric asymmetry of processes underlying emotional experience and (2) priming of cerebral function. Ample research evidence supports each of these propositions, and they have gained increasing, though not universal, acceptance. In combination, they provide a sufficient explanation for several preferences which may have human survival value. They also produce several side-effects in human behavior which can be observed, but which appear to have no survival function.

Brain↗

PubMed2002

TSC1 and TSC2 mutations in tuberous sclerosis, the associated phenotypes and a model to explain observed TSC1/ TSC2 frequency ratios.

UNLABELLED: Tuberous sclerosis (TSC) is a multisystem disease with manifestations in the central nervous system, skin, kidneys, heart, and other visceral organs. The development of TSC is associated with alterations within a gene on chromosome 9q34 ( TSC1) and a gene on chromosome 16p13 ( TSC2). Most de-novo patients show a mutation in TSC2, whereas only 50% of all familial cases can be related to TSC2 mutations. In the present study, 68 unrelated patients with confirmed clinical manifestations of TSC were tested for mutations in the TSC1 and TSC2 genes. In total, we studied 59 sporadic cases and 9 familial cases, including one large family with TSC2 linkage. Two pathogenic mutations were found in TSC1. The TSC2 gene analysis revealed 29 mutations, including 3 large deletions and 26 small mutations, 15 of them truncating. CONCLUSION: the TSC1-TSC2 mutation ratio in our group of patients differs significantly from the 1:1 ratio previously predicted on the basis of linkage studies. There is an obvious paradox between the observed frequency of TSC1 mutations in familial cases and sporadic cases. An interestingly mild phenotype, observed in one of our TSC1 mutation carriers, led to the elaboration of a model that provides a plausible explanation for this paradox. We propose the presence of a very mildly affected patient group with TSC1-related disease who are not regularly detected by clinical diagnosis.

Blotting, Southern↗

PubMed1988

Dosage-dependent modifiers of position effect variegation in Drosophila and a mass action model that explains their effect.

Twelve dominant enhancers of position effect variegation, representing four loci on the second and third chromosomes of Drosophila melanogaster, have been induced by P-element mutagenesis. Instead of simple transposon insertions, seven of these mutations are cytologically visible duplications and three are deficiencies. The duplications define two distinct regions, each coinciding with a locus that also behaves as a dominant haplo-dependent suppressor of variegation. Conversely, two of the deficiencies overlap with a region that contains a haplo-dependent enhancer of variegation while duplications of this same region act to suppress variegation. The third deficiency defines another haplo-dependent enhancer. These data indicate that loci capable of modifying variegation do so in an antipodal fashion through changes in the wild-type gene copy number and may be divided into two reciprocally acting classes. Class I modifiers enhance variegation when duplicated or suppress variegation when deficient. Class II modifiers enhance when deficient but suppress when duplicated. From our data, and those of others, we propose that in Drosophila there are about 20 to 30 dominant loci that modify variegation. Most appear to be of the class I type whereas only two class II modifiers have been identified so far. From these observations we put forth a model, based on the law of mass action, for understanding how such suppressor-enhancer loci function. We propose that each class I modifier codes for a structural protein component of heterochromatin and their effects on variegation are a consequence of their dosage dependent influence on the extent of the assembly of heterochromatin at the chromosomal site of the position effect. It is further proposed that class II modifiers may inhibit the class I products directly, bind to hypothetical termination sites that define heterochromatin boundaries or promote euchromatin formation. Consistent with our mass action model we find that combining two enhancers together produce additive and not epistatic effects. Also, since different enhancers have different relative strengths on different variegating mutants, we suggest that heterochromatic domains are constructed by a combinatorial association of proteins. The mass action model proposed here is of general significance for any assembly driven reaction and has implications for understanding a wide variety of biological phenomena.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1985

Simple model can explain self-inhibition of red cell anion exchange.

Ion translocation in red cell anion exchange is assumed to occur by means of an alternating access mechanism, in which a critical binding site for the transported ion alternates between two conformational states, each accessible from only one side of the membrane. If this alternating site is located within the transport protein at some distance from one or both surfaces of the membrane, an access channel is required to connect the alternating site to the adjacent bulk solution. This automatically leads to inhibition of transport at high concentrations of the transported ion because release of the ion from the alternating site can occur only via unoccupied channel sites.

Anions↗