Biomedical subjects

M E Young

Publications and source records attributed to M E Young.

At least 19 recordsLinked to original sources

PubMed2002

The vesicular transport protein Cgp1p/Vps54p/Tcs3p/Luv1p is required for the integrity of the actin cytoskeleton.

The CGP1 gene was identified in a screen for mutations that were synthetic lethal in combination with a deletion of the gene (CPF1) for centromere and promoter factor 1. Cells deleted for CGP1 showed reduced viability, were temperature sensitive for growth and exhibited altered sensitivity to microtubule-destabilizing drugs. Furthermore, Deltacgp1 cells showed increased rates of loss of a circular minichromosome and defects in the positioning of the short mitotic spindle. Further phenotypic analysis of Deltacgp1 cells revealed that loss of Cgp1p function led to severe depolarization of the actin cytoskeleton. In addition, cells deleted for CGP1 were hypersensitive to the actin-disrupting compound Latrunculin-A, exhibited strongly reduced polarized localization of the unconventional myosin Myo2p, and showed defects in other actin-related processes, such as shmoo formation and cell wall integrity. Cgp1p was recently identified by several groups as Vps54p, which is a member of the VFT complex that is involved in vesicular protein transport at the level of the late Golgi, acting as a tethering factor. Our data show for the first time that Cgp1p/Vps54p links aspects of vesicular protein transport with the organization of the actin cytoskeleton.

Actins↗

PubMed2001

Metabolic gene expression in fetal and failing human heart.

BACKGROUND: Previous studies suggest that the failing heart reactivates fetal genes and reverts to a fetal pattern of energy substrate metabolism. We tested this hypothesis by examining metabolic gene expression profiles in the fetal, nonfailing, and failing human heart. METHODS AND RESULTS: Human left ventricular tissue (apex) was obtained from 9 fetal, 10 nonfailing, and 10 failing adult hearts. Using quantitative reverse transcription-polymerase chain reaction, we measured transcript levels of atrial natriuretic factor, myosin heavy chain-alpha and -beta, and 13 key regulators of energy substrate metabolism, of which 3 are considered "adult" isoforms (GLUT4, mGS, mCPT-I) and 3 are considered "fetal" isoforms (GLUT1, lGS, and lCPT-I), primarily through previous studies in rodent models. Compared with the nonfailing adult heart, steady-state mRNA levels of atrial natriuretic factor were increased in both the fetal and the failing heart. The 2 myosin heavy chain isoforms showed the highest expression level in the nonfailing heart. Transcript levels of most of the metabolic genes were higher in the nonfailing heart than the fetal heart. Adult isogenes predominated in all groups and always showed a greater induction than the fetal isogenes in the nonfailing heart compared with the fetal heart. In the failing heart, the expression of metabolic genes decreased to the same levels as in the fetal heart. CONCLUSIONS: In the human heart, metabolic genes exist as constitutive and inducible forms. The failing adult heart reverts to a fetal metabolic gene profile by downregulating adult gene transcripts rather than by upregulating fetal genes.

Acyl-CoA Dehydrogenase↗

PubMed2001

Intrinsic diurnal variations in cardiac metabolism and contractile function.

Diurnal variation of cardiac function in vivo has been attributed primarily to changes in factors such as sympathetic activity. No study has investigated previously the intrinsic properties of the heart throughout the day. We therefore investigated diurnal variations in metabolic flux and contractile function of the isolated working rat heart and how this related to circadian expression of metabolic genes. Contractile performance, carbohydrate oxidation, and oxygen consumption were greatest in the middle of the night, with little variation in fatty acid oxidation. The expression of all metabolic genes investigated (including regulators of carbohydrate utilization, fatty acid oxidation, and mitochondrial function) showed diurnal variation, with a general peak in the night. In contrast, pressure overload-induced cardiac hypertrophy completely abolished this diurnal variation of metabolic gene expression. Thus, over the course of the day, the normal heart anticipates, responds, and adapts to physiological alterations within its environment, a trait that is lost by the hypertrophied heart. We speculate that loss of plasticity of the hypertrophied heart may play a role in the subsequent development of contractile dysfunction.

Animals↗

PubMed2001

Reactivation of peroxisome proliferator-activated receptor alpha is associated with contractile dysfunction in hypertrophied rat heart.

In pressure overload-induced hypertrophy, the heart increases its reliance on glucose as a fuel while decreasing fatty acid oxidation. A key regulator of this substrate switching in the hypertrophied heart is peroxisome proliferator-activated receptor alpha (PPARalpha). We tested the hypothesis that down-regulation of PPARalpha is an essential component of cardiac hypertrophy at the levels of increased mass, gene expression, and metabolism by pharmacologically reactivating PPARalpha. Pressure overload (induced by constriction of the ascending aorta for 7 days in rats) resulted in cardiac hypertrophy, increased expression of fetal genes (atrial natriuretic factor and skeletal alpha-actin), decreased expression of PPARalpha and PPARalpha-regulated genes (medium chain acyl-CoA dehydrogenase and pyruvate dehydrogenase kinase 4), and caused substrate switching (measured ex vivo in the isolated working heart preparation). Treatment of rats with the specific PPARalpha agonist WY-14,643 (8 days) did not affect the trophic response or atrial natriuretic factor induction to pressure overload. However, PPARalpha activation blocked skeletal alpha-actin induction, reversed the down-regulation of measured PPARalpha-regulated genes in the hypertrophied heart, and prevented substrate switching. This PPARalpha reactivation concomitantly resulted in severe depression of cardiac power and efficiency in the hypertrophied heart (measured ex vivo). Thus, PPARalpha down-regulation is essential for the maintenance of contractile function of the hypertrophied heart.

Actins↗

PubMed2001

Hypoxia in vivo decreases peroxisome proliferator-activated receptor alpha-regulated gene expression in rat heart.

We tested the hypothesis that hypoxia decreases PPARalpha-regulated gene expression in heart muscle in vivo. In two rat models of systemic hypoxia (cobalt chloride treatment and iso-volemic hemodilution), transcript levels of PPARalpha and PPARalpha-regulated genes (pyruvate dehydrogenase kinase 4 (PDK4), muscle carnitine palmitoyltransferase-I (mCPT-I), and malonyl-CoA decarboxylase (MCD)) were measured using real-time quantitative RT-PCR. Data were normalized to the housekeeping gene beta-actin. Atrial natriuretic factor (ANF) and pyruvate dehydrogenase kinase 2 (PDK2), which are not regulated by PPARalpha, served as controls. CoCl(2) treatment decreased PPARalpha, PDK4, mCPT-I, and MCD mRNA levels. Iso-volemic anemia also caused a significant decrease in PPARalpha, PDK4, and MCD mRNA levels. Transcript levels of mCPT-I showed a slight, but not significant decrease (P = 0.08). Gene expression of beta-actin, ANF, and PDK2 did not change with either CoCl(2) treatment nor with anemia. Myocardial PPARalpha-regulated gene expression is decreased in two models of hypoxia in vivo. These results suggest a transcriptional mechanism for decreased fatty oxidation and increased reliance of the heart for glucose during hypoxia.

Animals↗

PubMed2001

Clock genes in the heart: characterization and attenuation with hypertrophy.

We investigated whether the heart, like other mammalian organs, possesses internal clocks, and, if so, whether pressure overload-induced hypertrophy alters the clock mechanism. Clock genes are intrinsically maintained, as shown by rhythmic changes even in single cells. Clocks are believed to confer a selective advantage by priming the cell for the expected environmental stimulus. In this way, clocks allow anticipation, thereby synchronizing responsiveness of the cell with the timing of the stimulus. We have found that in rat heart all mammalian homologues of known Drosophila clock genes (bmal1, clock, cry1, cry2, per1, per2, per3, dbp, hlf, and tef) show circadian patterns of expression and that the induction of clock output genes (the PAR [rich in proline and acidic amino acid residues] transcription factors dbp, hlf, and tef) is attenuated in the pressure-overloaded hypertrophied heart. The results expose a new dynamic regulatory system in the heart, which is partially lost with hypertrophy. Although the target genes of these PAR transcription factors are not known in the heart, the results provide evidence for a diminished ability of the hypertrophied heart to anticipate and subsequently adapt to physiological alterations during the day.

ARNTL Transcription Factors↗

PubMed2001

Calcitonin gene-related peptide is not essential for the development of pressure overload-induced hypertrophy in vivo.

The regulatory neuropeptide calcitonin-gene related peptide (CGRP) has been shown to evoke a hypertrophic response in isolated cardiomyocytes in vitro, an effect which was attributed to PKC activation. Activation of PKC has previously been implicated in the development of cardiac hypertrophy. We therefore investigated the role of CGRP in pressure overload-induced hypertrophy in vivo, which has not previously been reported. Constriction of the ascending aorta of rats resulted in an increase in the heart weight to body weight ratio, increased myocyte diameter, re-expression of the fetal genes ANF, MHCbeta and skeletal alpha-actin, and decreased expression of the adult genes GLUT4 and SERCA2a. Treatment of neonatal rat pups (1-2 days old) with capsaicin (50 mg/kg), resulted in the permanent de-afferentation of small-diameter unmyelinated CGRP-containing sensory C-fibres. Such treatment caused a 68% decrease in the CGRP-like immunoreactivity of hearts isolated from 10 week old rats (p < 0.001). Contrary to expectations, aortic constriction of capsaicin treated rats had no effect on the development of hypertrophy at the trophic, morphometric or gene expression levels. The results suggest that the development of pressure overload-induced hypertrophy in vivo does not require the regulatory neuropeptide CGRP.

Actins↗

PubMed2001

Same-different conceptualization by baboons (Papio papio): the role of entropy.

The authors trained 6 baboons (Papio papio) to make 1 of 2 report responses to 16-icon same arrays versus 16-icon different arrays. In the same arrays, the icons were all the same as one another, whereas in the different arrays the icons were all different from one another. In Experiment 1, the baboons discriminated the same arrays from the different arrays, and they transferred their discriminative responding to arrays of novel icons. In Experiments 2 and 3, the baboons exhibited strong sensitivity to the degree of display variability when they were shown mixed arrays that comprised some same and some different items. The information theoretic measure "entropy" systematically described these results and outperformed several rival metrics. Finally, in Experiments 4 and 5, the baboons' responses to displays that contained jittered and blurred icons suggested that their same-different conceptual behavior was not based on the spatial orderliness of the visual arrays.

Animals↗

PubMed2001

Uncoupling protein 3 transcription is regulated by peroxisome proliferator-activated receptor (alpha) in the adult rodent heart.

Relatively little is known concerning the regulation of uncoupling proteins (UCPs) in the heart. We investigated in the adult rodent heart 1) whether changes in workload, substrate supply, or cytokine (TNF-alpha) administration affect UCP-2 and UCP-3 expression, and 2) whether peroxisome proliferator-activated receptor alpha (PPARalpha) regulates the expression of either UCP-2 or UCP-3. Direct comparisons were made between cardiac and skeletal muscle. UCP-2, UCP-3, and PPARalpha expression were reduced when cardiac workload was either increased (pressure overload by aortic constriction) or decreased (mechanical unloading by heterotopic transplantation). Similar results were observed during cytokine administration. Reduced dietary fatty acid availability resulted in decreased expression of both cardiac UCP-2 and UCP-3. However, when fatty acid (the natural ligand for PPARalpha) supply was increased (high-fat feeding, fasting, and STZ-induced diabetes), cardiac UCP-3 but not UCP-2 expression increased. Comparable results were observed in rats treated with the specific PPARalpha agonist WY-14,643. The level of cardiac UCP-3 but not UCP-2 expression was severely reduced (20-fold) in PPARalpha-/- mice compared to wild-type mice. These results suggest that in the adult rodent heart, UCP-3 expression is regulated by PPARalpha. In contrast, cardiac UCP-2 expression is regulated in part by a fatty acid-dependent, PPARalpha-independent mechanism.

Animals↗

PubMed2001

Regulation of cardiac and skeletal muscle malonyl-CoA decarboxylase by fatty acids.

Malonyl-CoA decarboxylase (MCD) catalyzes the degradation of malonyl-CoA, an important modulator of fatty acid oxidation. We hypothesized that increased fatty acid availability would increase the expression and activity of heart and skeletal muscle MCD, thereby promoting fatty acid utilization. The results show that high-fat feeding, fasting, and streptozotocin-induced diabetes all significantly increased the plasma concentration of nonesterified fatty acids, with a concomitant increase in both rat heart and skeletal muscle MCD mRNA. Upon refeeding of fasted animals, MCD expression returned to basal levels. Fatty acids are known to activate peroxisome proliferator-activated receptor-alpha (PPARalpha). Specific PPARalpha stimulation, through Wy-14643 treatment, significantly increased the expression of MCD in heart and skeletal muscle. Troglitazone, a specific PPARgamma agonist, decreased MCD expression. The sensitivity of MCD induction by fatty acids and Wy-14643 was soleus > extensor digitorum longus > heart. High plasma fatty acids consistently increased MCD activity only in solei, whereas MCD activity in the heart actually decreased with high-fat feeding. Pressure overload-induced cardiac hypertrophy, in which PPARalpha expression is decreased (and fatty acid oxidation is decreased), resulted in decreased MCD mRNA and activity, an effect that was dependent on fatty acids. The results suggest that fatty acids induce the expression of MCD in rat heart and skeletal muscle. Additional posttranscriptional mechanisms regulating MCD activity appear to exist.

Animals↗

PubMed2001

Regulation of fatty acid oxidation and glucose metabolism in rat soleus muscle: effects of AICAR.

Previous studies have shown that 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), a cell-permeable activator of AMP-activated protein kinase, increases the rate of fatty acid oxidation in skeletal muscle of fed rats. The present study investigated the mechanism by which this occurs and, in particular, whether changes in the activity of malonyl-CoA decarboxylase (MCD) and the beta-isoform of acetyl-CoA carboxylase (ACC beta) are involved. In addition, the relationship between changes in fatty acid oxidation induced by AICAR and its effects on glucose uptake and metabolism was examined. In incubated soleus muscles isolated from fed rats, AICAR (2 mM) increased fatty acid oxidation (90%) and decreased ACC beta activity (40%) and malonyl-CoA concentration (50%); however, MCD activity was not significantly altered. In soleus muscles from overnight-fasted rats, AICAR decreased ACC beta activity (40%), as it did in fed rats; however, it had no effect on the already high rate of fatty acid oxidation or the low malonyl-CoA concentration. In keeping with its effect on fatty acid oxidation, AICAR decreased glucose oxidation by 44% in fed rats but did not decrease glucose oxidation in fasted rats. It had no effect on glucose oxidation when fatty acid oxidation was inhibited by 2-bromopalmitate. Surprisingly, AICAR did not significantly increase glucose uptake or assayable AMP-activated protein kinase activity in incubated soleus muscles from fed or fasted rats. These results indicate that, in incubated rat soleus muscle, 1) AICAR does not activate MCD or stimulate glucose uptake as it does in extensor digitorum longus and epitrochlearis muscles, 2) the ability of AICAR to increase fatty acid oxidation and diminish glucose oxidation and malonyl-CoA concentration is dependent on the nutritional status of the rat, and 3) the ability of AICAR to diminish assayable ACC activity is independent of nutritional state.

AMP-Activated Protein Kinases↗

PubMed2001

Evidence for a conceptual account of same-different discrimination learning in the pigeon.

We trained pigeons to peck two different buttons in response to 16-icon same arrays versus 16-icon different arrays. In the same arrays, the icons were all the same as one another, whereas in the different arrays, the icons were all different from one another. In Experiment 1, we upset the spatial regularities of the displays by disarranging the icons--randomly displacing each icon to reduce the degree of perceptual order. The pigeons' discriminative performance was unaffected by disarranging. In Experiment 2, spatial regularities were disturbed by varying the rotation of the icons within a display. Again, no disruption in discriminative performance was observed. These and other findings suggest that pigeons treat the 16 icons as either the same or different despite changes in the spatial organization or orientation of the icons, thus implicating a conceptual rather than a perceptual process in same-different discrimination.

Animals↗

PubMed2001

Entropy and variability discrimination.

Two experiments examined college students' discrimination of complex visual displays that involved different degrees of variability or "entropy." Displays depicted 16 black and white line drawings of various types (e.g., a brain, a clock, a hand); the participants were required to classify a display in terms of its variability (e.g., a low-variability display contains many identical items, whereas a high-variability display contains few identical items). The participants' accuracy and reaction time scores on a 2-alternative forced-choice discrimination disclosed that people can and do use entropy to classify different levels of visual display variability. Individuals differed in their use of absolute rather than relative entropy.

Adult↗

PubMed2001

Internal poverty and teen pregnancy.

The subjects for the present study were drawn from the female students who participated in the National Education Longitudinal Study (NELS) initial eighth-grade data collection. Adolescent females who later became pregnant were matched on race, birth month, and birth year with adolescent females who did not report a pregnancy. The study examined selected predictor variables from the baseline 1988 wave of data in relation to the outcome variable of pregnancy status. Results indicated a statistically significant difference in locus of control between those females who later became pregnant and those who later did not experience a pregnancy during adolescence. Those who later became pregnant were much more likely to have an external locus of control (p = .0001). Females who later became pregnant were also more likely to have a poorer sense of personal efficacy (p = .0001). Finally, females who later experienced a teen pregnancy had more traditional occupational expectations (p = .006) and lower educational expectations (p = .001) than did those who did not later report a teen pregnancy.

Adolescent↗

PubMed2001

Discriminating the relation between relations: the role of entropy in abstract conceptualization by baboons (Papio papio) and humans (Homo sapiens).

Two baboons (Papio papio) successfully learned relational matching-to-sample: They picked the choice display that involved the same relation among 16 pictures (same or different) as the sample display, although the sample display shared no pictures with the choice displays. The baboons generalized relational matching behavior to sample displays created from novel pictures. Further experiments varying the number of sample pictures and the mixture of same and different sample pictures suggested that entropy plays a key role in the baboons' conceptual behavior. Two humans (Homo sapiens) were similarly trained and tested; their behavior was both similar to and different from the baboons' behavior. The results suggest that animals other than humans and chimpanzees can discriminate the relation between relations. They further suggest that entropy detection may underlie same-different conceptualization, but that additional processes may participate in human conceptualization.

Animals↗

PubMed2000

Streptozotocin-induced changes in cardiac gene expression in the absence of severe contractile dysfunction.

UNLABELLED: Diabetes mellitus alters energy substrate metabolism and gene expression in the heart. It is not known whether the changes in gene expression are an adaptive or maladaptive process. To answer this question, we determined both the time-course and the extent of the alteration of gene expression induced by insulin-deficient diabetes. Transcript analysis with real-time quantitative polymerase chain reaction (PCR) was performed in rat hearts 1 week (acute group) or 6 months (chronic group) after administration of streptozotocin (55 mg/kg). In the acute group, insulin-dependent diabetes induced a 55-70% decrease of both glucose transporter 1 (GLUT1) and GLUT4 transcripts, a slight decrease of liver-specific carnitine palmitoyltransferase I (CPT I), and no change in muscle-specific CPT I. The uncoupling protein UCP-3 increased three-fold, with no change in UCP-2. These metabolic alterations were accompanied by an isoform switching from the normally expressed alpha myosin heavy chain (MHC) to the fetal isoform betaMHC mRNA, by a 50% decrease of cardiac alpha-actin mRNA, a 30% decrease of the sarcoplasmic Ca++-ATPase mRNA, and a 50% decrease of muscle creatine kinase (P<0.01 v controls). All genomic changes were also present in the chronic group. Genomic markers of ventricular dysfunction [tumor necrosis factor alpha (TNF-alpha), inducible nitric oxide synthase, cyclo-oxygenase-2] were not affected by chronic diabetes. In both groups, there were no changes in resting left ventricular function by echocardiography. CONCLUSION: The heart adapts to insulin-deficient diabetes by a rapid and simultaneous response of multiple genes involved in cardiac metabolism and function. This genomic adaptation resembles the adaptation of cardiac hypertrophy, remains stable over time, and does not lead to major contractile dysfunction.

Animals↗

PubMed2000

Seeing things from a different angle: the pigeon's recognition of single geons rotated in depth.

In 2 experiments involving computer-rendered versions of single shapes or "geons," the extent to which depth rotation affects the visual discrimination performance of pigeons in both go/no-go and forced-choice tasks was documented. The pigeons were able to recognize geons at most rotations in depth; however, the pigeons' recognition performance was better at the training view than at most other views. Aspects of these results are both consistent with and problematic for object-centered and viewer-centered theories of object recognition.

Animals↗

PubMed2000

Display variability and spatial organization as contributors to the pigeon's discrimination of complex visual stimuli.

Three experiments assessed the contributions of display variability and spatial organization to the pigeon's discrimination of 16-icon visual displays. After training to discriminate 4 x 4 arrays of same and different computer icons, 4 pigeons were shown testing displays that systematically manipulated the variability of the depicted icons and their spatial organization on the display screen. Display variability and spatial organization each reliably controlled the pigeon's behavior. These seemingly separate effects could be collectively explained by the pigeon's discriminating the amount of variability or entropy in localized regions of the display.

Animals↗