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PubMed1998

A regional net charge and structural compensation model to explain how negatively charged amino acids can be accepted within a mitochondrial leader sequence.

Mitochondrial leader sequences have been found to be statistically enriched for positively charged residues, with only a few known leader sequences possessing negatively charged residues. Mutational studies that have introduced negatively charged residues into various leader sequences have shown a general, but not absolute, trend toward reduced import. The leader sequence of rat liver aldehyde dehydrogenase has been previously determined by NMR to form a helix-linker-helix structure. A negative charge introduced into this leader did not prevent import, provided that a net positive charge remained in the N-helical segment. When the net charge of the N-terminal helical segment was reduced to zero, import could be recovered by removing the linker, which resulted in a longer, more stable leader. This structural recovery of import was effective enough to compensate for a net charge of zero within the first 10 residues, even when a glutamate is the first charged side chain presented in the sequence.

Aldehyde Dehydrogenase↗
PubMed2001

A new biodemographic model to explain the trajectory of mortality.

Since Buffon's time (1749), biologists and demographers have repeatedly stated that a man in good health will live to be 90, 100 or 110 years old but not longer. For demographers, mortality measures essentially the current conditions: the quality of the ecological and social environment. For biologists, mortality measures mainly the ageing process. Can a biodemographic approach measure the current conditions (i.e. the quality of the environment) and the ageing schedule together, taking into account that human beings spend the greater part of their time improving the quality of their physical and social environment, making it more and more favourable to the realisation of their potential longevity? I propose two measures of the quality of this environment: first at the age when individuals (in average by cohort), in the course of their development, are the most robust and the most resistant to environmental hazards, indicated by the lowest mortality rate recorded; second at the age when individuals (in average by cohort) become frail because of the passage of time, with no or extremely little resistance to environmental hazards, indicated by a constant mortality rate among the oldest old. Between these two measures of the quality of the environment, mortality measures the ageing process leading young vigorous individuals into frail senile elders.

Animals↗
PubMed2001

CD4(+) T cells from lupus-prone mice are hyperresponsive to T cell receptor engagement with low and high affinity peptide antigens: a model to explain spontaneous T cell activation in lupus.

Polyclonal CD4(+) T cell activation is characteristic of spontaneous lupus. As a potential explanation for this phenotype, we hypothesized that T cells from lupus-prone mice are intrinsically hyperresponsive to stimulation with antigen, particularly to those peptide ligands having a low affinity for the T cell receptor (TCR). To test this hypothesis, we backcrossed the alpha and beta chain genes of the AND TCR specific for amino acids 88-104 of pigeon cytochrome C (PCC) to the Fas-intact MRL/Mp(+)(Fas-lpr) and to the H-2(k)-matched control backgrounds B10.BR and CBA/CaJ (MRL.AND, B10.AND, and CBA.AND, respectively), and assessed naive CD4(+) TCR transgenic T cell activation in vitro after its encounter with cognate antigen and lower affinity altered peptide ligands (APLs). MRL.AND T cells, compared with control B10.AND and CBA.AND cells, proliferated more when stimulated with agonist antigen. More strikingly, MRL.AND T cells proliferated significantly more and produced more interleukin 2 when stimulated with the APLs of PCC 88-104, having lower affinity for the transgenic TCR. These results imply that one of the forces driving polyclonal activation of alpha/beta T cells in lupus is an intrinsically heightened response to peptide antigen, particularly those with low affinity for the TCR, independent of the nature of the antigen-presenting cell and degree of costimulation.

Amino Acid Sequence↗
PubMed1995

Transcranial magnetic stimulation of the trigeminal nerve: intraoperative study on stimulation characteristics in man.

We studied responses from the masseter and nasalis muscles following magnetic stimulation (magStim) and compared these responses with those obtained by direct electrical stimulation of the trigeminal (NV) and facial (NVII) nerve near the root exit zone during microvascular decompression operations of NVII. We found that (1) magStim threshold to excite the nerve is high for NV and low for NVII; (2) excitation of all motor fibers is impossible for NV, and easy for NVII; (3) optimal coil placement is critical for NV, but not critical for NVII; and (4) between and within subjects, the excitation site is variable on NV, but stable on NVII. We estimated that the anatomical location of magStim to be either within or outside the cerebrospinal fluid for NV, and to be in the labyrinthine segment of the facial canal for NVII. Physical models explain and clinical lesion models support these differences found between NV and NVII.

Adult↗
PubMed2002

Liarozole markedly increases all trans-retinoic acid toxicity in mouse limb bud cell cultures: a model to explain the potency of the aromatic retinoid (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylenyl)-1-propenyl] benzoic acid.

The remarkable toxicity of (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylenyl)-1-propenyl] benzoic acid (TTNPB) compared to all trans-retinoic acid (tRA) is due to multiple factors, including reduced affinities for cytosolic binding proteins (CRABPs), resistance to metabolism, and prolonged nuclear receptor activation. To further investigate the role of half-life in retinoid toxicity, experiments were performed to determine whether, and to what extent, inhibition of tRA metabolism by liarozole increased its toxicity comparable to that of TTNPB in the mouse limb bud system. Liarozole is a known inhibitor of tRA 4-hydroxylation (CYP26). In the absence of liarozole, the IC50 for inhibition of chondrogenesis by tRA was 140 nM compared to 0.3 nM for TTNPB, a 467-fold difference. Following the addition of liarozole (10(-6) M) to limb bud cultures, the potency of tRA to inhibit chondrogenesis was increased approximately 14-fold (IC50 of 9.8 nM). Although liarozole markedly increased toxicity of tRA in mouse limb bud micromass cultures, tRA metabolism was inhibited only about 10%. These results indicate that a relatively minor decrease in the metabolism of tRA in the mouse limb bud system is associated with a marked enhancement of toxicity that is likely related to the prolongation of tRA half-life during a critical period of development. Thus, the prolonged half-life of TTNPB is the most significant factor contributing to the remarkable teratogenicity of this synthetic aromatic retinoid.

Animals↗
PubMed2005

Modeling of weak blast wave propagation in the lung.

Blast injuries of the lung are the most life-threatening after an explosion. The choice of physical parameters responsible for trauma is important to understand its mechanism. We developed a one-dimensional linear model of an elastic wave propagation in foam-like pulmonary parenchyma to identify the possible cause of edema due to the impact load. The model demonstrates different injury localizations for free and rigid boundary conditions. The following parameters were considered: strain, velocity, pressure in the medium and stresses in structural elements, energy dissipation, parameter of viscous criterion. Maximum underpressure is the most suitable wave parameter to be the criterion for edema formation in a rabbit lung. We supposed that observed scattering of experimental data on edema severity is induced by the physiological variety of rabbit lungs. The criterion and the model explain this scattering. The model outlines the demands for experimental data to make an unambiguous choice of physical parameters responsible for lung trauma due to impact load.

Blast Injuries↗
PubMed1997

The tendency of magainin to associate upon binding to phospholipid bilayers.

Fluorescence energy transfer (FET) from [Trp16]-magainin-2-amide (Trp-Mag) and [D-Ala15,D-Trp16]magainin-2-amide (DD-Trp-Mag) to N(alpha)-dansyl-magainin-2-amide (DNS-Mag) was used to study the association of magainin 2 analogs bound to phosphatidylglycerol vesicles. As shown by circular dichroism and fluorescence spectroscopy, the all-L-analogs exist in a helical conformation and are completely bound to the lipid membrane. The observed FET between Trp-Mag and DNS-Mag is rather small and increases with the DNS-Mag surface concentration. The experimentally determined transfer efficiency is lower than predicted for monomeric magainin analogs randomly distributed exclusively at the outer leaflet of lipid vesicles. These observations can be explained by two different models of spatial distribution for the monomeric magainin analogs. The first model takes into account translocation of magainin which might result in a uniform distribution of magainin at the inner and outer vesicle leaflets. The second model assumes that at least one shell of lipids exists between two magainin molecules, thus reducing the probability of direct contact. Both models explain the measured FET without any contribution of stable associates of magainin analogs. Furthermore, for Trp-Mag and DD-Trp-Mag, an identical energy transfer efficiency was observed, although the nonhelical double-D substituted analog should have a significantly reduced association tendency resulting in decreased FET. Our conclusion that the observed FET is not the result of magainin association is confirmed by the equivalence of the measured energy transfer efficiencies.

Anti-Infective Agents↗
PubMed1980

Structure of the body-centered cubic phase of lipid systems.

A new model is proposed for the structure of the body-centered cubic phase of lipid systems. Infinite rods of polar groups (and water) are arranged with axes parallel to the four cubic [unk]1 1 1[unk] directions. The hydrocarbon chains fill the space between the rods to form a continuous matrix. With this unified topology, the model explains satisfactorily the x-ray diffraction patterns of strontium soaps, lecithin, galactolipids, potassium soaps, and hexadecyltrimethylammonium bromide and explains the transition between cubic/H(II) phases. The paradoxical thermal effects on the lipid cubic phase, in particular the decrease of unit cell dimensions with increasing temperature, can be explained with the proposed model by mechanisms similar to those used for the monodimensional and bidimensional (mesomorphic) phases.

Journal Article↗
PubMed2000

A test of the perceived norms model to explain drinking patterns among university student athletes.

The author tested the ability of perceived drinking norms to discriminate among drinking patterns in a sample of National Collegiate Athletic Association (NCAA) Division I student athletes. He used an anonymous questionnaire to assess 297 athletes, representing 18 teams, at a public university in the Midwest. Alcohol use patterns showed considerable variation, with many athletes (37.1%) abstaining during their season of competition. A discriminant function analysis revealed that higher levels of alcohol involvement are disproportionately found among athletes who began drinking regularly at an early age. Perceived drinking norms were less important in the discrimination of student athlete drinker groups. Women and those with higher grade point averages were somewhat more likely to refrain from in-season drinking than other survey respondents.

Adult↗
PubMed2004

The role of beverage consumption, physical activity, sedentary behavior, and demographics on body mass index of adolescents.

The percentage of US adolescents who are overweight or at-risk of overweight has increased over the past 20 years. Using data from the third National Health and Nutrition Examination Survey 1988-1994, multivariate regression models of body mass index (BMI) for adolescent males and females aged 12-16 years were developed to examine the relative importance of demographics, beverage consumption, physical activity, and sedentary behavior for maintaining a healthy body weight. The models explained between 11% and 19% of the variance in BMI. Demographic characteristics accounted for roughly one-half of the explained variance in the models. Age was positively associated with BMI for males and females. Family income had a negative association with BMI for females, but no association with BMI for males. The variables for race/ethnicity and region were only occasionally statistically significant. A strong negative association was found between BMI and participation in team sports or exercise programs for both males and females. The estimate of the relationship between television viewing and BMI was positive but not statistically significant. Consumption of regular carbonated soft drinks (RCSD) and fruit drinks/ades--two beverages widely hypothesized to be positively associated with BMI--were not statistically significant in any of the models. Consumption of diet carbonated soft drinks was very low and was positively associated with BMI for females but not for males. The potential impacts of increasing participation in teams or exercise programs, reducing television viewing, and reducing RCSD consumption on BMI were examined. Increasing participation in teams or exercise programs consistently had the largest impact on reducing predicted BMI. The impact of reducing television viewing had the next largest impact. Reducing consumption of RCSD had the smallest impact. Policies that revitalize physical activity and physical education programs for all students--not just student athletes--and educational efforts that discourage sedentary behavior will be far more successful in combating overweight than an undue focus on beverage consumption.

Adolescent↗
PubMed2006

Mutational analysis of the Escherichia coli melR gene suggests a two-state concerted model to explain transcriptional activation and repression in the melibiose operon.

Transcription of the Escherichia coli melAB operon is regulated by the MelR protein, an AraC family member whose activity is modulated by the binding of melibiose. In the absence of melibiose, MelR is unable to activate the melAB promoter but autoregulates its own expression by repressing the melR promoter. Melibiose triggers MelR-dependent activation of the melAB promoter and relieves MelR-dependent repression of the melR promoter. Twenty-nine single amino acid substitutions in MelR that result in partial melibiose-independent activation of the melAB promoter have been identified. Combinations of different substitutions result in almost complete melibiose-independent activation of the melAB promoter. MelR carrying each of the single substitutions is less able to repress the melR promoter, while MelR carrying some combinations of substitutions is completely unable to repress the melR promoter. These results argue that different conformational states of MelR are responsible for activation of the melAB promoter and repression of the melR promoter. Supporting evidence for this is provided by the isolation of substitutions in MelR that block melibiose-dependent activation of the melAB promoter while not changing melibiose-independent repression of the melR promoter. Additional experiments with a bacterial two-hybrid system suggest that interactions between MelR subunits differ according to the two conformational states.

DNA Mutational Analysis↗
PubMed1985

Geoperception in primary and lateral roots of Phaseolus vulgaris (Fabaceae). III. A model to explain the differential georesponsiveness of primary and lateral roots.

Half-tipped primary and lateral roots of Phaseolus vulgaris bend toward the side of the root on which the intact half tip remains. Therefore, tips of lateral and primary roots produce growth effectors capable of inducing gravicurvature. The asymmetrical placement of a tip of a lateral root onto a detipped primary root results in the root bending toward the side of the root onto which the tip was placed. That is, the lesser graviresponsiveness of lateral roots as compared with primary roots is not due to the inability of their caps to produce growth inhibitors. The more pronounced graviresponsiveness of primary roots is positively correlated with the presence of columella tissues that are 3.8 times longer, 1.7 times wider, and 10.5 times more voluminous than the columellas of lateral roots. We propose that the lack of graviresponsiveness exhibited by lateral roots is due to the fact that they (i) produce smaller amounts of the inhibitor than primary (i.e., strongly graviresponsive) roots and (ii) are unable to redistribute the inhibitor so as to be able to create a concentration gradient sufficient to induce a pronounced gravitropic response.

Fabaceae↗
PubMed1988

Maximizing present value: A model to explain why moderate response rates obtain on variable-interval schedules.

In Phases 1 and 3, two Japanese monkeys responded on a multiple variable-ratio 80 variable-interval X schedule, where the value of X was adjusted to ensure equal between-schedule reinforcement rates. Components strictly alternated following the delivery of a food pellet, and each session ended following 50 components. Phase 2 differed from the others only in that the 50 pellets previously earned during the session were delivered together at session's end. Variable-ratio response rates did not decrease across phases, but variable-interval response rates decreased substantially during the Phase 2 procedure. This rate decrease was attributed to the food-at-session's-end manipulation removing the greater immediacy of reinforcement provided by short interresponse times relative to long interresponse times. Without this time preference for short interresponse times, the variable-interval interresponse-time reinforcement feedback function largely controlled response emission, dictating a response-rate reduction. This result was explained in terms of the economic notion of "maximizing present value."

Journal Article↗
PubMed2006

A model to explain the therapeutic effects of serotonin reuptake inhibitors: the role of 5-HT2 receptors.

In this article, it is posited that major depression involves an underfunctioning dopamine system resulting from hypersensitive inhibitory 5-HT2 receptors located on dopaminergic neurons. After a few weeks, treatment with most antidepressant drugs leads to a downregulation of the 5-HT2 receptors that allows for increased dopaminergic firing, which is proposed to be decisive for the antidepressant effect. However, serotonin reuptake inhibitors (SRIs) therapeutic mechanisms probably differ between different therapeutic outcomes. It is hypothesized, that in women, the use of female sex steroids leads to a downregulation of 5-HT2C receptors that contributes to atypical depressive symptoms and premenstrual dysphoria. Consequently, these conditions can be assumed to benefit from the acute increase of serotonergic neurotransmission following ingestion of an SRI rather than the secondary receptor changes, which would explain why there is a therapeutic lag time when SRIs are used to treat depression but not premenstrual dysphoric disorder. The clinical predictions derived from this hypothesis are that 5-HT2 antagonists would be an effective treatment in melancholic depression, have a fast onset of action, speed the onset of SRIs, and can be an effective augmentation for SRI-refractory patients. In contrast, in atypical depression and premenstrual dysphoria a 5-HT2 antagonist would counteract the therapeutic effect of an SRI, while 5-HT2 agonists have a therapeutic potential. It is suggested that therapeutic response to 5-HT2 antagonists/agonists may be used as a diagnostic tool to dissect subgroups of depression.

Brain↗