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At least 181 records · Page 10Linked to original sources
PubMed1991

A model to explain the pH-dependent specificity of cathepsin B-catalysed hydrolyses.

1. Three synthetic substrates of cathepsin B (EC 3.4.22.1) with various amino acid residues at the P2 position (Cbz-Phe-Arg-NH-Mec, Cbz-Arg-Arg-NH-Mec and Cbz-Cit-Arg-NH-Mec, where Cbz represents benzyloxycarbonyl and NH-Mec represents 4-methylcoumarin-7-ylamide) were used to investigate the pH-dependency of cathepsin B-catalysed hydrolyses and to obtain information on the nature of enzyme-substrate interactions. 2. Non-linear-regression analysis of pH-activity profiles for these substrates indicates that at least four ionizable groups on cathepsin B with pKa values of 3.3, 4.55, 5.46 and greater than 7.3 can affect the rate of substrate hydrolysis. 3. Ionization of the residue with a pKa of 5.46 has a strong effect on activity towards the substrate with an arginine in P2 (8.4-fold increase in activity) but has only a moderate effect on the rate of hydrolysis with Cbz-Cit-Arg-NH-Mec (2.3-fold increase in activity) and virtually no effect with Cbz-Phe-Arg-NH-Mec. The kinetic data are consistent with this group being an acid residue with a side chain able to interact with the side chains of an arginine or a citrulline in the P2 position of a substrate. Amino acid sequence alignment and model building with the related enzyme papain (EC 3.4.22.2) suggest that Glu-245 of cathepsin B is a likely candidate. The relative importance of electrostatic and hydrophobic interactions in the S2 subsite of cathepsin B is discussed. 4. For all three substrates, activity appears after ionization of a group with a pKa of 3.3, believed to be the active-site Cys-29 of cathepsin B. The identity of the groups with pKa values of 4.55 and greater than 7.3 remains unknown.

Cathepsin B↗
PubMed1996

A dynamic model for explaining changes in use of IADL/ADL care in the community.

Evidence exists that support services for community elders vary with need. However, few controlled longitudinal analyses have been carried out regarding descriptive profiles of elders experiencing differential change in service levels -- the focus of analysis here. Using a multivariate profile procedure (PC-Group), 1,730 elders followed over an 18-month period were first classified according to change in functional status groupings that predicted change in hours of service over this period, and each group was subsequently subdivided. Five of nine profiles identified (82% of the sample) were relatively stable functionally. In general, changes in service levels reflected change in functional status; profiles reflected differential change in service level depending upon whether functional status declined; the network provided an unusually high level of service (overextended) at baseline; or the informal network consisted exclusively of children.

Activities of Daily Living↗
PubMed1986

A proposed model to explain persistent infection of host cells with Coxiella burnetii.

L929 mouse fibroblast cells and J774 macrophage-like cells are both susceptible to persistent infection with the Q fever agent Coxiella burnetti. Previously this laboratory has shown that persistently infected cell populations multiply with unaltered generation times or cell cycle progression. It has also been reported by others and us that highly infected cells typically exhibit one large parasite-containing vacuole. We now report that lightly and heavily infected cells are capable of division and in the process segregate the parasite-containing vacuole into one of the emerging daughter cells; the companion daughter cell emerges parasite-free. This asymmetric division of infected cells, revealed via photomicrography of stained cells, accounts for the appearance of uninfected cells within persistently infected host cell populations that were previously 100% infected. Some of the persistently infected L929 populations were maintained in culture for over two years without the addition of normal cells.

Animals↗
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↗
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↗
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↗
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↗
PubMed1996

[Experimental and pathological models that explain the regulation of cellular migration and axon's orientations].

Since Cajal discovery of nerve growth cones and their role in the growth, metabolism and destination of the axon in 1890 numerous studies have corroborated with more sophisticated techniques his original findings and ideas. The use of modified Golgi staining, drawing from the camera lucida in 2 combination with electron microscopy and t retrograde biochemical markers have helped to identify the neuronal sites of synapsis. Dynamic studies of the nerve growth cones using time-lapsed video microscopic images of living neuroblast in t culture or the intact animal have demonstrated their protactil and retractile membranes and exploratory filipodia properties. Interaction between growth cone membrane receptors and different molecules along the migrating axon determine also its final destination. Finally the role that genes play on neuronal migration and in guiding the axons to reach their targets have been identified in patients with Kallmann syndrome, a migrational disorder of olfactory axons and hypothalamic gonadotropic hormone-releasing hormone with absent gene at Xp22.3 locus manifested by anosmia and hypogonadotropic hypogonadism.

Axons↗
PubMed1999

Noisy templates explain area summation.

The noisy template model is a variant of an ideal detector for a signal known except for contrast. The ideal detector cross-correlates the stimulus with a normalised template which is matched to the known signal pattern. The noisy template model simply adds noise to the matched template every time it is cross-correlated with the signal. This paper outlines the predictions of the noisy template model for area summation. The noisy template model explains Piper's Law, as does the ideal-observer, but it also explains critical area phenomena and the lack of area summation for contrast discrimination.

Computer Simulation↗
PubMed1991

Clinical and pathophysiological observations in migraine and tension-type headache explained by integration of vascular, supraspinal and myofascial inputs.

A vascular-supraspinal-myogenic (VSM) model for pain in migraine based on our previous clinical and pathophysiological observations is proposed. According to the model, perceived pain (headache) intensity is determined by the sum of nociception from cephalic arteries and pericranial myofascial tissues converging upon the same neurons and integrated with supraspinal effects (usually facilitating). Vascular input predominates over myofascial input in migraine, whereas significance of supraspinal facilitation is difficult to estimate. The importance of these 3 effects may vary between patients and in the same individual with time. The model is in accordance with recent experimental studies showing convergence of somatovisceral afferents upon n. caudalis neurons. Also, long term potentiation due to nociceptive activation and sensitization of neurons to input from wider areas and non-nociceptive stimuli are relevant to our model. In tension-type headache, nociception is primarily myofascial, but vascular input cannot be disregarded. Supraspinal facilitation probably plays a large, sometimes dominant role (the MSV model). The model explains much of the complexity of the clinical picture of these disorders as well as their tendency to overlap and to change into one another. Also, a number of pathophysiological observations such as why muscles are tender during migraine, why trigger-point injection may cure migraine attacks and why chronic tension-type headache is often associated with episodes of pulsating pain, can be explained. The model gives a rational explanation of empirically developed, internationally accepted, multimodal treatment strategies for migraine and tension-type headache. It may thus serve a useful purpose in explaining the disorder to patients. Finally, the model points to several avenues of future research in animals and man.

Animals↗