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Biomedical subjects

G Cooper

Publications and source records attributed to G Cooper.

At least 73 records · Page 4Linked to original sources
PubMed1998

Ascertainment bias cannot entirely account for human microsatellites being longer than their chimpanzee homologues.

A large majority of human microsatellite markers are longer than their homologues in chimpanzees, suggesting that more expansion mutations have occurred in the lineage leading to humans. However, such a length difference has also been explained as arising from the selection of unusually long microsatellites as genetic markers. In order to resolve this controversy and to establish the true source of the observed length differences, we have now conducted the necessary reciprocal study. We have compared the lengths of size-selected markers cloned from chimpanzees between this species and humans. We find that of 19 markers which were informative and polymorphic in both species, 13 are longer in humans. This result is incompatible with ascertainment bias being the sole explanation for the inter-specific length differences. We estimate that dinucleotide repeat microsatellites are an average of 3.2 repeat units longer in humans than in chimpanzees, implying a mutational bias in favour of microsatellite expansions and a higher average genome-wide microsatellite mutation rate in the human lineage.

Animals↗
PubMed1998

Pressure-overload hypertrophy is unabated in mice devoid of AT1A receptors.

Mechanisms controlling cardiac growth are under intense investigation. Among these, the renin-angiotensin system has received great interest. In the current study, we tested the hypothesis that the renin-angiotensin system was not an obligate factor in cardiac hypertrophy. We examined the left ventricular hypertrophic response to a pressure overload in mice devoid of the AT1A receptor, the putative major effector of the growth response of the renin-angiotensin system. Aortic banding produced similar transband gradients in wild-type and AT1A knockout mice. The left ventricular mass-to-body weight ratio increased from 3.44 +/- 0.08 to 5.62 +/- 0.25 in wild-type ascending aortic-banded mice. The response in the knockout mice was not different (from 2.97 +/- 0.13 to 5.24 +/- 0.37). We conclude that the magnitude of cardiac hypertrophy is not affected by the absence of the AT1A receptor and its signaling pathway and that this component of the renin-angiotensin system is not necessary in cardiac hypertrophy.

Angiotensin II↗
PubMed1997

Microtubule stabilization in pressure overload cardiac hypertrophy.

Increased microtubule density, for which microtubule stabilization is one potential mechanism, causes contractile dysfunction in cardiac hypertrophy. After microtubule assembly, alpha-tubulin undergoes two, likely sequential, time-dependent posttranslational changes: reversible carboxy-terminal detyrosination (Tyr-tubulin left and right arrow Glu-tubulin) and then irreversible deglutamination (Glu-tubulin --> Delta2-tubulin), such that Glu- and Delta2-tubulin are markers for long-lived, stable microtubules. Therefore, we generated antibodies for Tyr-, Glu-, and Delta2-tubulin and used them for staining of right and left ventricular cardiocytes from control cats and cats with right ventricular hypertrophy. Tyr- tubulin microtubule staining was equal in right and left ventricular cardiocytes of control cats, but Glu-tubulin and Delta2-tubulin staining were insignificant, i.e., the microtubules were labile. However, Glu- and Delta2-tubulin were conspicuous in microtubules of right ventricular cardiocytes from pressure overloaded cats, i.e., the microtubules were stable. This finding was confirmed in terms of increased microtubule drug and cold stability in the hypertrophied cells. In further studies, we found an increase in a microtubule binding protein, microtubule-associated protein 4, on both mRNA and protein levels in pressure-hypertrophied myocardium. Thus, microtubule stabilization, likely facilitated by binding of a microtubule-associated protein, may be a mechanism for the increased microtubule density characteristic of pressure overload cardiac hypertrophy.

Animals↗
PubMed1997

Premorbid determinants of left ventricular dysfunction in a novel model of gradually induced pressure overload in the adult canine.

BACKGROUND: When a pressure overload is placed on the left ventricle, some patients develop relatively modest hypertrophy whereas others develop extensive hypertrophy. Likewise, the occurrence of contractile dysfunction also is variable. The cause of this heterogeneity is not well understood. METHODS AND RESULTS: We recently developed a model of gradual proximal aortic constriction in the adult canine that mimicked the heterogeneity of the hypertrophic response seen in humans. We hypothesized that differences in outcome were related to differences present before banding. Fifteen animals were studied initially. Ten developed left ventricular dysfunction (dys group). Five dogs maintained normal function (nl group). At baseline, the nl group had a lower mean systolic wall stress (96 +/- 9 kdyne/cm2; dys group, 156 +/- 7 kdyne/cm2; P < .0002) and greater relative left ventricular mass (left ventricular weight [g]/body wt [kg], 5.1 +/- 0.36; dys group, 3.9 +/- 0.26; P < .02). On the basis of differences in mean systolic wall stress at baseline, we predicted outcome in the next 28 dogs by using a cutoff of 115 kdyne/cm2. Eighteen of 20 dogs with baseline mean systolic stress > 115 kdyne/cm2 developed dysfunction whereas 6 of 8 dogs with resting stress < or = 115 kdyne/cm2 maintained normal function. CONCLUSIONS: We conclude that this canine model mimicked the heterogeneous hypertrophic response seen in humans. In the group that eventually developed dysfunction there was less cardiac mass despite 60% higher wall stress at baseline, suggesting a different set point for regulating myocardial growth in the two groups.

Animals↗
PubMed1997

Association of tyrosine-phosphorylated c-Src with the cytoskeleton of hypertrophying myocardium.

Given the central position of the focal adhesion complex, both physically in coupling integrins to the interstitium and biochemically in providing an upstream site for anabolic signal generation, we asked whether the recruitment of non-receptor tyrosine kinases to the cytoskeleton might be a mechanism whereby cellular loading could activate growth regulatory signals responsible for cardiac hypertrophy. Analysis revealed cytoskeletal association of c-Src, FAK, and beta3-integrin, but no Fyn, in the pressure-overloaded right ventricle. This association was seen as early as 4 h after right ventricular pressure overloading, increased through 48 h, and reverted to normal in 1 week. Cytoskeletal binding of non-receptor tyrosine kinases was synchronous with tyrosine phosphorylation of several cytoskeletal proteins, including c-Src. Examination of cytoskeleton-bound c-Src revealed that a significant portion of the tyrosine phosphorylation was not at the Tyr-527 site and therefore presumably was at the Tyr-416 site. Thus, these studies strongly suggest that non-receptor tyrosine kinases, in particular c-Src, may play a critical role in hypertrophic growth regulation by their association with cytoskeletal structures, possibly via load activation of integrin-mediated signaling.

Animals↗
PubMed1997

INKBLOT: a neurological diagnostic decision support system integrating causal and anatomical knowledge.

As an initial step in the diagnostic process, human neurologists often use anatomical localization to constrain the set of diagnostic hypotheses deserving further consideration. We describe an automated system, INKBLOT-1, which uses anatomical localization in much the same way as human neurologists. Given a set of manifestations, INKBLOT-1 generates a set of hypothetical localizations relative to a coordinate system of nested cubes and then uses these localization(s) to explain the manifestations. We trace the reasoning mechanism utilized by INKBLOT-1 for a particular set of symptoms and show how INKBLOT-1 is able to generate novel hypotheses that explain the observed manifestations. In doing this, INKBLOT-1 demonstrates capabilities not demonstrated by previously described systems.

Artificial Intelligence↗
PubMed1997

Exposure to hepatitis A virus among blood donors, injecting drug users and prison entrants in Victoria.

To assess prevalence of exposure to hepatitis A virus (HAV) among injecting drug users (IDUs) and prison entrants in Victoria, and to compare this with prevalence of HAV among a reference population of blood donors, sera stored from two previous studies and from randomly selected blood donors were tested for total antibody to HAV. The first study was a longitudinal study of field-recruited IDUs from 1990 to 1992 and the second was a study of all prison entrants in 1991-92 (both studies were carried out in Victoria); blood donors were from the Australian Red Cross Blood Bank Victoria in 1995. Forty-five per cent of 2175 prison entrants and 51% of 293 IDUs were seropositive for HAV, compared with 30% of 2995 blood donors. When standardized for age against the blood donors, HAV seropositivity in IDUs was 44% and in prison entrants 60%. The strongest association of HAV seropositivity among the IDUs on multivariate analysis was a history of imprisonment. There are high rates of exposure to HAV among prison entrants, whether with a history of IDU or not, and among IDUs who have a prison history. The role of sharing contaminated injecting equipment in transmission of HAV seems to be less important than institutionalization per se. With adequate resourcing, both populations are appropriate targets for HAV vaccination, especially in a context of continuing decline of transmission of HAV in the general community.

Adolescent↗
PubMed1997

Basic determinants of myocardial hypertrophy: a review of molecular mechanisms.

The essential cardiac response to a fixed increase in hemodynamic load is an increase in cardiac mass. If the load increase is neither too severe initially nor indefinitely progressive, cardiac stress is renormalized, and compensated hypertrophy ensues. But hypertrophic compensation is often abrogated by progressively abnormal contractile performance per unit mass of myocardium, even when function at the organ level is maintained by the mass increase itself. That is, even when hypertrophy is appropriate to the load imposed, and in a manner analogous to dystrophic growth of skeletal muscle, specific phenotypic changes occurring during this growth response render compensation imperfect such that congestive heart failure ensues. This fact, and the fact that the presence of deleterious phenotypic changes in hypertrophied myocardium is critically dependent on the type of hemodynamic load imposed, mandates that cardiac hypertrophy be understood on the most basic level as a growth process if early, definitive interventions to prevent congestive heart failure following pathological hemodynamic overloads are to be realized.

Animals↗
PubMed1997

Cytoskeletal mechanics in pressure-overload cardiac hypertrophy.

We have shown that the cellular contractile dysfunction characteristic of pressure-overload cardiac hypertrophy results not from an abnormality intrinsic to the myofilament portion of the cardiocyte cytoskeleton but rather from an increased density of the microtubule component of the extramyofilament portion of the cardiocyte cytoskeleton. To determine how, in physical terms, this increased microtubule density mechanically overloads the contractile apparatus at the cellular level, we measured cytoskeletal stiffness and apparent viscosity in isolated cardiocytes via magnetic twisting cytometry, a technique by which magnetically induced force is applied directly to the cytoskeleton through integrin-coupled ferromagnetic beads coated with Arg-Gly-Asp (RGD) peptide. Measurements were made in two groups of cardiocytes from cats with right ventricular (RV) hypertrophy induced by pulmonary artery banding: (1) those from the pressure-overloaded RV and (2) those from the normally loaded same-animal control left ventricle (LV). Cytoskeletal stiffness increased almost twofold, from 8.53 +/- 0.77 dyne/cm2 in the normally loaded LV cardiocytes to 16.46 +/- 1.32 dyne/cm2 in the hypertrophied RV cardiocytes. Cytoskeletal apparent viscosity increased almost fourfold, from 20.97 +/- 1.92 poise in the normally loaded LV cardiocytes to 87.85 +/- 6.95 poise in the hypertrophied RV cardiocytes. In addition to these baseline data showing differing stiffness and, especially, apparent viscosity in the two groups of cardiocytes, microtubule depolymerization by colchicine was found to return both the stiffness and the apparent viscosity of the pressure overload-hypertrophied RV cells fully to normal. Conversely, microtubule hyperpolymerization by taxol increased the stiffness and apparent viscosity values of normally loaded LV cardiocytes to the abnormal values given above for pressure-hypertrophied RV cardiocytes. Thus, increased microtubule density constitutes primarily a viscous load on the cardiocyte contractile apparatus in pressure-overload cardiac hypertrophy.

Animals↗
PubMed1996

Butyl Acrylate/Vinyl Acetate Copolymer Latex Synthesis Using Ultrasound As an Initiator

The polymerization of oil-in-water (o/w) emulsions of monomeric species has been performed at 30&deg;C (&plusmn;5&deg;C) under ultrasonic irradiation, in the absence of any added chemical initiators. Emulsions of butyl acrylate and vinyl acetate as well as emulsified mixtures of the two monomers have been reacted in this way. In all cases, the radicals formed as a result of the ultrasonic cavitation were sufficient to cause polymerization. Stable blue-white or white dispersions of polymer latex particles were obtained. The kinetics of the copolymerization process were monitored. The data obtained here show that the polymerization rate depends strongly upon the monomer concentration dissolved in the aqueous phase and on its vapor pressure. The more volatile of the monomers examined, vinyl acetate, was seen to have a markedly lower polymerization rate at equivalent monomer concentrations when compared to the butyl acrylate. This was attributed to monomer evaporation into the cavities formed by the ultrasound, causing a dampening of the cavitation process and hence a lower radical density. Data of particle sizes and polymer molecular weights for the latex samples support this hypothesis.

Journal Article↗
PubMed1996

Nudicauline and elatine as potent norditerpenoid ligands at rat neuronal alpha-bungarotoxin binding sites: importance of the 2-(methylsuccinimido)benzoyl moiety for neuronal nicotinic acetylcholine receptor binding.

Methyllycaconitine (MLA, 1) is a novel, potent probe for mammalian and insect nicotinic acetylcholine receptors (nAChR) and displays remarkable selectivity toward neuronal [125I]-alpha-bungarotoxin (alpha BgTX) binding sites that correspond to alpha 7-type nAChR in mammalian brain. We have shown that, among a number of selected norditerpenoid alkaloids, elatine (2) and nudicauline (3) are equipotent with, or better than, MLA (1) in binding to brain [125I]-alpha BgTX binding sites, with IC50 values of 6.1, 1.7, and 7.6 nM, respectively. The 2-((S)-methylsuccinimido)benzoyl moiety of these ligands is crucial for high-affinity binding, whereas structural modifications to the norditerpenoid core of the ligand can be tolerated without loss of activity or selectivity. In addition to MLA (1), elatine (2), and nudicauline (3), we have examined lycoctonine (4), inuline (6), lappaconitine (7), N-desacetyllappaconitine (8), delsoline (10), delcorine (11), deltaline (12), condelphine (13), and karacoline (14). This study therefore extends the range of norditerpenoids, other than MLA, which can be used to probe this important class of nAChR. All 12 alkaloids were assessed for activity at [3H]nicotine binding sites which are considered to represent alpha 4 beta 2 nAChR. Furthermore, the 1H and 13C NMR spectroscopic data of MLA and elatine have been critically compared.

Aconitine↗
PubMed1996

Molecular genetic analysis of sperm competition in the damselfly Ischnura elegans (Vander Linden).

Sperm competition can be a powerful selective force in the evolution of mating systems. Several odonate species have attracted study to assess the extent and mechanism of last-male sperm precedence. Members of the genus Ischnura (Zygoptera) display a particularly interesting range of mating systems, and Ischnura elegans was selected for study. Polymorphic microsatellites were cloned, sequenced and used to determine paternity of I. elegans larvae, to reveal patterns of sperm precedence. More than 3000 larvae, collected from both wild and captively bred I. elegans females, were typed for one or two microsatellite loci and paternity was determined by comparison with parental genotypes. Microsatellite typing showed that most wild-caught females had mated with several males. Analysis of offspring from females which mated in captivity showed that multiple-matings result in a large proportion of last-male sperm precedence (mean value for immediate last male precedence is 0.79 +/- 0.2 (+/- s.d.; n = 11, range = 0.44-1)). There is appreciable variation in the extent and patterns of immediate and longer-term precedence, which could reflect differences in male sperm removal ability or selective use of sperm by females.

Animals↗