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PubMed1994

The differential activation of phosphatidylinositol-3 kinase and mitogen-activated protein kinases by PDGF-AA and IGF-I might explain the synergistic effect of the two growth factors on the proliferation of AKR-2B fibroblasts.

AKR-2B mouse fibroblasts express similar numbers of alpha- or beta-type PDGF receptors on their surface. Previous studies showed that PDGF-AA alone was unable to stimulate cell proliferation. Simultaneous addition together with insulin-like growth factor I (IGF-I), itself also inactive, led to a significant proliferation of the cells. In an effort to explain this synergism of the two growth factors we describe here the effects of the isoforms PDGF-AA or -BB and insulin-like growth factor I on three distinct signaling pathways, i.e., polyphosphoinositol turnover and [Ca2+]i increase, phosphatidylinositol-3 kinase, and mitogen-activated protein kinases. Whereas PDGF-BB effectively stimulated all three events, PDGF-AA failed to stimulate the phosphatidylinositol-3 kinase activity, but stimulated the mitogen-activated protein kinase to a maximum extent. In contrast IGF-I had no effect on mitogen-activated kinase but strongly stimulated phosphatidylinositol-3 kinase activity.

Animals↗

PubMed1996

The synergistic effect of PDGF-AA and IGF-1 on VSMC proliferation might be explained by the differential activation of their intracellular signaling pathways.

As previous studies showed, PDGF-AA exerts a poor mitogenic effect on vascular smooth muscle cells. Simultaneous addition of insulin-like growth factor 1 (IGF-1), itself also poorly mitogenic, led to a significant increase in [3H]thymidine incorporation into the cell DNA as well as a strong increase in cell number. To explain the synergistic effect of PDGF-AA and IGF-1 on VSMC proliferation, we describe the effects of the two growth factors on distinct intracellular signals: on the activation of the signal proteins mitogen-activated protein kinase (MAPK) isoforms p42 and p44 and on the protein kinase C (PKC) isoforms alpha, delta, and epsilon, and on the induction of the transcription factor c-fos. PDGF-AA strongly activated the MAPK isoforms and PKC delta as well as the induction of c-fos. In contrast, IGF-1 exerted no effect on the signals induced by PDGF-AA, but strongly activated PKC epsilon isoform. Comparing this signal pattern to the one of the mitogenically potent PDGF isoform PDGF-BB, we found that PDGF-BB activated all of the signal proteins investigated.

Animals↗

PubMed1997

Possible mechanism for resistance to Alzheimer's disease (AD) in mice suggests a new approach to generate a mouse model for sporadic AD and may explain familial resistance to AD in man.

An overproduction of beta-amyloid (A beta) is associated with Alzheimer's disease (AD) and appears to be its primary cause. A model has been recently described which accounts for the overproduction of A beta in sporadic AD, this constituting the majority of all cases of AD. The proposed mechanism suggests the antisense RNA-Mediated generation of a 5'-truncated beta-amyloid precursor protein (beta APP) mRNA encoding a 12-kDa C-terminal fragment of beta APP, the immediate precursor of A beta. In the truncated mRNA, the first AUG codon, which contiguously precedes the A beta-coding segment, becomes the site of translation initiation of a polypeptide that can be further processed to generate A beta, this subsequently being secreted. Among the predictions of the proposed model is that mice and rats do not and indeed cannot develop sporadic AD because they lack the crucial component of the proposed mechanism, namely the ability of the beta APP antisense RNA to self-prime the synthesis of a new sense strand. According to the proposed model, however, mice could be rendered susceptible to AD by mutating the beta APP gene so as to confer self-priming ability on the antisense strand. In contrast to existing mouse models which by design are fundamentally unsuitable for study of the mechanism underlying sporadic AD, the AD pathology of the proposed model would be expected to faithfully reflect the human condition. The availability of such an acutely needed, experimental model would allow investigators to study not only the manifestation of the disease but, most significantly, also the factors triggering it. The proposed mouse model may explain familial resistance to AD in man, provide extremely valuable insights into the etiology of AD, and suggest means for its prevention.

Alzheimer Disease↗

PubMed2000

Can pseudo entrainment explain the synchrony of estrous cycles among golden hamsters (Mesocricetus auratus)?

Synchrony among golden hamsters is often cited in the menstrual-cycle synchrony literature and has recently become a paradigm for explaining menstrual synchrony in humans (L. Weller, A. Weller, and S. Roizman (1999), J. Comp. Psychol. 113, 261-268). It has also stimulated further research on synchrony in Djungarian hamsters, for which no evidence of synchrony was found (G. E. Erb, H. E. Edwards, K. L. Jenkins, L. C. Mucklow, and K. E. Wynne-Edwards (1993), Physiol. Behav. 54, 955-959). The case for synchrony in the golden hamster is reexamined in this paper. It is demonstrated, with the help of computer simulation experiments, that the experimental method used by G. Handelmann, R. Ravizza, and W. J. Ray (1980, Horm. Behav. 14, 107-115) for detecting synchrony has a critical flaw. It does not distinguish synchrony that can occur by chance (pseudo entrainment) from synchrony due to a process of entrainment. It is suggested that the apparent entrainment of estrous cycles in hamsters and the role of social dominance may be due to the stress caused by moving animals to different rooms or grouping them. Thus, because we cannot reject the possibility of pseudo entrainment as an explanation for these results, it must be concluded that there is no evidence that golden hamsters synchronize their estrous cycles. Finally, an approach is briefly outlined for testing synchrony in golden hamsters.

Animals↗

PubMed1997

Electrokinetic Behavior of Fluoride Salts as Explained from Water Structure Considerations

Unlike the other silver halides, silver fluoride is positively charged in its saturated solution as determined by nonequilibrium electrophoresis measurements. In the absence of surface hydrolysis reactions, other fluoride salts (LiF, CaF2 , and MgF2 ) also are positively charged in their saturated solutions. Furthermore, the electrokinetic behavior of these fluoride salts is rather insensitive to the fluoride ion activity in neutral or acidic solutions, and reversal of the sign of the surface charge by fluoride addition is not possible. Based on FTIR transmission spectra to describe the water structure of ionic solutions, in situ FTIR/internal reflection spectroscopy (FTIR/IRS) has been used to spectroscopically characterize interfacial water at fluoride salt surfaces. The experimental spectra were examined by consideration of the O-H stretching region (3000-3800 cm-1 ) associated with the vibrational spectra of interfacial water. These results reveal a unique hydration state for fluorides and explain the anomalous electrokinetic behavior of fluoride salts such as LiF, CaF2 , and MgF2 , which show an unexpected insensitivity to the fluoride ion concentration in solution. It appears that this insensitivity is due to the formation of strong hydrogen bonding of the fluoride ions with water molecules. This hydration state prevents the accommodation of excess fluoride ions at surface lattice sites and accounts for the observed electrokinetic behavior.

Journal Article↗

PubMed1994

Location of the streptomycin ribosomal binding site explains its pleiotropic effects on protein biosynthesis.

Photoaffinity-labeling experiments using three nitroguaiacol ether streptomycin derivatives with spacers of different lengths between the antibiotic and the photoreactive moiety (8, 12 and 17 A) allow us to: (1) unambiguously locate the boundaries of the antibiotic binding site; and (2) test the topographical consistency of the photolabeling results. The streptomycin binding site is located in the interface between the ribosomal subunits, close to proteins S5 in the 30 S and to L11 in the 50 S ribosomal subunits. This location explains most of the antibiotic's pleiotropic effects on protein biosynthesis, especially those related to the tRNA selection mechanism, and it also correlates with the location of the ribosomal components involved in the different streptomycin phenotypes.

Affinity Labels↗

PubMed2000

A thermodynamic coupling mechanism can explain the GroEL-mediated acceleration of the folding of barstar.

Despite extensive structural and kinetic studies, the mechanism by which the Escherichia coli chaperonin GroEL assists protein folding has remained somewhat elusive. It appears that GroEL might play an active role in facilitating folding, in addition to its role in restricting protein aggregation by secluding folding intermediates. We have investigated the kinetic mechanism of GroEL-mediated refolding of the small protein barstar. GroEL accelerates the observed fast (millisecond) refolding rate, but it does not affect the slow refolding kinetics. A thermodynamic coupling mechanism, in which the concentration of exchange-competent states is increased by the law of mass action, can explain the enhancement of the fast refolding rates. It is not necessary to invoke a catalytic role for GroEL, whereby either the intrinsic refolding rate of a productive folding transition or the unfolding rate of a kinetically trapped off-pathway intermediate is increased by the chaperonin.

Adenosine Triphosphate↗

PubMed1996

Myocardial glycogen depletion cannot explain the cardioprotective effects of ischemic preconditioning in the rat heart.

The mechanism of ischemic preconditioning remains unknown. The role of glycogen depletion prior to prolonged ischemia was examined as a potential mechanism of ischemic preconditioning. The glycogen content of the rat heart varies in a 24-h rhythm. In a retrospective study, the relationships between the time of day the animals were sacrificed, pre-ischemic myocardial glycogen content, and post-ischemic functional recovery were assessed in non-conditioned and ischemically preconditioned hearts. The analyses were performed on previously published data (Asimakis et al.. 1992, 1993). After an equilibration perfusion, isolated rat hearts were given 40 min of global ischemia followed by 30 min of reperfusion. Preconditioned hearts received 5 min of ischemia followed by a 5-min recovery period prior to the 40-min ischemic period. Some of the hearts were freeze-clamped immediately prior to the 40-min ischemic period to determine pre-ischemic glycogen content. Pre-ischemic glycogen was higher in the morning than afternoon. The time of day correlated significantly with the pre-ischemic glycogen content of non-conditioned (r = 0.67; P < 0.005) and preconditioned (r = 0.79; P < 0.001) hearts. However, time of day did not correlate significantly with post-ischemic recovery of heart rate x developed pressure (HR x DP) on end-diastolic pressure (EDP) in either the non-conditioned or preconditioned hearts. The relationships were also assessed by subdividing the groups into either morning (a.m.) or afternoon (p.m.) hearts. The pre-ischemic glycogen content was lower in the non-conditioned-p.m. (n = 5) hearts compared to the non-conditioned-a.m. (n = 10) hearts (67.6 +/- 9.0 nu 128.1 +/- 13.3 nmol glucose/mg protein P < 0.005). However, there were no significant differences between p.m. (n = 13) and a.m. (n = 9) non-conditioned hearts with respect to post-ischemic recovery of HR x DP (20.6 +/- 4 nu 12.0 +/- 4% of baseline, respectively, P = N.S.). In contrast, preconditioned-p.m. (n = 6) and -a.m. (n = 7) had pre-ischemic glycogen contents of 49.6 +/- 6 and 76.6 +/- 5.0 nmol glucose/mg protein, respectively. These glycogen values were not significantly different from the non-conditioned-p.m. hearts (67.6 nmol/mg protein). However, post-ischemic recovery of HR x DP in the preconditioned-p.m. (n = 5) and -a.m. (n = 6) hearts were 54.6 +/- 5 and 51.4 +/- 8% of baseline, respectively (these values were significantly higher (P < 0.05) than the recovery for the non-conditioned-p.m. and -a.m. hearts). The results imply that the cardioprotection of ischemic preconditioning cannot be explained solely by myocardial glycogen depletion.

Adenosine Triphosphate↗

PubMed1994

Will neuroscience explain consciousness?

This paper is a defence of a pragmatic version of mind-brain reductionism from a neuroscientist's point of view. It is claimed that there are good reasons to believe that future neuroscience will be able to explain (in a weak and pragmatic sense) the puzzling aspects of mind and consciousness. Opposition to reductionism comes from both philosophical and empirical quarters. It is argued here that philosophical arguments, such as semantic problems with the concept of identity, are unconvincing and should be regarded with the greatest suspicion. The most influential empirical result that has been claimed to constitute a problem for reductionism is the temporal delay and mental antedating of consciousness found by Benjamin Libet. It is argued that these results, far from being a problem for reductionism, constitute evidence for a particular view of the physiological origins of consciousness. Finally, it is argued that many subjective aspects of experience can already be given satisfactory scientific explanations and that scientific progress is likely to rob the mind and subjective experience of their mystery.

Brain↗

PubMed1995

A mathematical model explaining the molecular weights and distribution of very long chain dicarboxylic acids formed during the adaptive response of Sarcina ventriculi.

A simple mathematical model is presented to explain a recent new discovery of an unusual membrane adaptive response in Sarcina ventriculi. In this response, this organism synthesizes very long chain alpha, omega-dicarboxylic acids ranging from 28 to 36 carbon atoms in length. The distribution of chain lengths of the new fatty acid species is not consistent with de novo synthesis but suggests elaboration from the existing regular-chain fatty acids by a coupling process. Here, we demonstrate, using a mathematical model, that if the molecular weights and relative abundances of regular chain fatty acids are known, the molecular weights and relative abundances of the new, very long chain dicarboxylic fatty acid species can be predicted using a model based on the random, pairwise combination of regular chain species. This combination takes place across the bilayer leaflet to form transmembrane fatty acids. It is proposed that this coupling phenomenon is regulated by the motional dynamics of the membrane.

Cell Membrane↗

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↗

PubMed2000

Selection for high gamete encounter rates explains the success of male and female mating types.

Sexual reproduction occurs in many small eukaryotes by fusion of similar gametes (isogamy). In the absence of distinguishable sperm and eggs, male and female mating types are missing. However, species with distinct males and females have so prospered that almost all familiar plants and animals have these mating types. Why has sexual reproduction involving sperm and eggs been so successful? An answer is obtained by considering physical limitations on encounter rates between gametes. A biophysical model based on well-established relationships produces fitness landscapes for the evolution of gamete size and energy allocation between motility and pheromone production. These landscapes demonstrate that selection for high gamete encounter rates favors large, pheromone-producing eggs and small, motile sperm. Thus, broadcast-spawning populations with males and females can reproduce at lower population densities and survive under conditions where populations lacking males and females go extinct. It appears that physical constraints on gamete encounter rates are sufficient to explain the first two steps in the isogamy-->anisogamy-->oogamy-->internal fertilization evolutionary sequence observed in several lineages of the eukaryotes. Unlike previous models, assumptions concerning zygote fitness or decreasing speed of swimming with increasing gamete size are not required.

Animals↗

PubMed2000

A single theory explains two empirical laws applicable to plant populations.

Two empirical laws, formulated independently, are known to be well satisfied in even-aged plant monocultures. One relates yield to plant density in different plant populations, and the other relates cumulative plant mass to cumulative plant number from the largest individual within a population. In this paper, we construct a mathematical model of plant growth under asymmetric competition between individuals in a population, where large individuals grow larger than small individuals because they pre-empt resources, especially light. The model categorizes influences on the growth of a plant into those from individuals larger than itself, and those from all individuals in the population. We derive the two laws from our model. Thus, individual growth, determined by asymmetric interaction between individuals in a population, can explain the two different laws relating to plant populations.

Models, Biological↗

PubMed2001

Structural changes in the neck linker of kinesin explain the load dependence of the motor's mechanical cycle.

The two-headed motor protein kinesin hydrolyzes ATP and moves on microtubule tracks towards the plus end. The motor develops speeds and forces of the order of hundreds of nanometers per second and piconewtons, respectively. Recently, the dependence of the velocity, the dissociation rate and the displacement variance on the load and the ATP concentration were measured in vitro for individual kinesin molecules (Coppin et al., 1997; Visscher et al., 1999) over a wide range of forces. The structural changes in the kinesin motor that drive motility were discovered by Rice et al. (1999). Here we present a phenomenological model for force generation in kinesin based on the bi-stable, nucleotide-dependent behavior of the neck linker. We demonstrate that the model explains the mechanical, kinetic and statistical (experimental) data of Coppin et al. (1997). We also discuss the relationship between the model results and experimental data of Visscher et al. (1999).

Adenosine Diphosphate↗

PubMed1998

Anticarcinogenic responses in rodent cancer bioassays are not explained by random effects.

Anticarcinogenicity in a long-term rodent bioassay is defined as a statistically significant decrease of a specific tumor type in a dosed group following chemical exposure. About 92% of chemicals tested by the National Toxicology Program prior to 1983 reveal at least one site with a significant (p < or = 0.05) tumor rate decrease in one or more tested groups, a result consistent with those of J. K. Haseman and F. M. Johnson (1996, Mutat. Res. 350, 131-141) for a database of recently tested chemicals. Detection of tumor decreases in a specific site can be explained not only by biological effects, but also as a result of random variability in the background tumor rates, decreases in body weight, or decreases in survival of treated animals. This paper evaluates the rate of false-positive anticarcinogenic findings due to random effects (variations in tumor rates and the multiple comparisons undertaken in evaluating a bioassay), while a companion paper addresses the influence of weight and survival depression. Monte-Carlo simulation was conducted to assess the contribution of random effects. This contribution was found to be important even when a statistical significance cutoff of p0 < or = 0.05 was chosen. If a more stringent statistical criterion was used (p0 < or = 0.01 or p < or = 0.005), the proportion of false positive determinations diminishes. The number of anticarcinogens in the database remains substantially higher than predicted by the stimulations. An examination of the distribution of all p values (T. Schweder and E. Spjøtvoll, 1982, Biometrika 69, 493-502) also indicates that statistically significant anticarcinogenic responses are found in the database at a higher rate than would result from purely random responses. Finally, the cross-species prediction of anticarcinogenic responses was examined in a manner similar to a study of cross-species prediction of carcinogenic responses (G. M. Gray et al., 1995, Reg. Toxicol. Pharmacol. 20, 281-301). The analyses show that anticarcinogenic effects in one rodent species predict well anticarcinogenic effect in another rodent species. It seems likely that biological factors are involved in anticarcinogenic responses observed in rodent cancer bioassays.

Animals↗

PubMed1992

Insensitivity to cyclosporine may explain the HLA-DRw6 recipient effect.

Clinical as well as experimental studies have found an interindividual variability in the immunosuppressive effect of cyclosporine (CsA). In renal transplant patients treated with CsA and prednisolone alone, biopsy-verified rejections were significantly more frequent in DRw6-positive than in DRw6-negative graft recipients. The relative risk for developing a graft rejection independently of the CsA blood levels increased in HLA-DRw6-positive transplant patients. Although no statistical significance of the CsA levels within different DR phenotypes could be assessed, HLA-DR2-positive graft recipients with biopsy-verified rejection episodes had significantly lower CsA levels than DR2-negative patients (P = 0.01). Our results would indicate a very low CsA sensitivity of HLA-DRw6-positive graft recipients and might explain previous results describing an increased incidence of rejection and decreased graft survival rates in these patients.

Antilymphocyte Serum↗

PubMed1988

Complex dose-response curves of atropine in man explained by different functions of M1- and M2-cholinoceptors.

In the present study we set out to explain the complex atropine dose-response curves in man in relation to M-cholinoceptor subtype occupancy. In healthy volunteers the effects of atropine on heart rate and salivary flow were quantified. M-cholinoceptor subtype occupancy by antagonist present in plasma samples was detected in an in vitro radioreceptor assay. Atropine effects were studied without and after propranolol (240 mg oral dose) and without and after pirenzepine (1.1 mg i.v.) to differentiate beta-adrenoceptor and M-cholinoceptor subtype mediated effects. 1. In receptor binding studies, M-cholinoceptors in bovine cerebral cortex membranes were labelled with 3H-pirenzepine (pKd = 8.05), M-cholinoceptors in rat salivary gland membranes with 3H-N-methylscopolamine (pKd = 9.02). Atropine competed for binding of these ligands with a small (2.1-fold) preferential selectivity via the cerebral in comparison to the glandular receptors (pKi = 9.18 versus 8.86). Pirenzepine showed a marked selectivity (40-fold) in this respect with pKi-values of 8.05 (M1: cerebral cortex) and 6.45 (M2: salivary glands). 2. At heart rate and at salivary flow, bivalent dose-response curves of atropine were observed with opposite effect vectors. The typical antagonist effects at M-cholinoceptors (i.e. an increase of heart rate and an inhibition of salivary flow) were observed at doses greater than 1 microgram/kg, whereas "paradoxical" cholinomimetic effects of atropine became apparent at lower doses. From a superposition of two isotherms with opposite effect vectors ED50-values were calculated, which were in the range of half-maximal M-cholinoceptor occupancy in the in vitro radioreceptor assay of plasma samples.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1992

Interchromosomal gene conversion as a possible mechanism for explaining divergence patterns of ZFY-related genes.

The divergence pattern of mammalian ZFY-related genes from human (ZFY and ZFX) and mouse (Zfy-1 and Zfx) was reexamined on the basis of nucleotide substitutions at the synonymous codon-alternating positions. It is possible to explain the unusual divergence pattern of the mammalian Y-linked ZF genes by interchromosomal gene conversion by X-linked ZF genes. Furthermore, the rates of evolution of mammalian X- and Y-linked ZF genes were shown to agree well with those expected from our model.

Animals↗