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Biomedical subjects

J D Newman

Publications and source records attributed to J D Newman.

At least 19 recordsLinked to original sources
PubMed1992

Enhanced insulin-receptor tyrosine kinase activity associated with chromosomal translocation (1;19) in a pre-B-cell leukemia line.

The gene for the insulin receptor has been assigned to chromosome 19 near the breakpoint of the translocation t(1;19) which occurs in 25% of pre-B-cell leukemias. Insulin receptors in a pre-B-cell leukemia cell line (ACV) with t(1;19) were found to have 2-fold higher affinity for insulin, 5-fold higher basal and insulin-stimulated beta sub-unit autophosphorylation, and 2-fold higher basal and 4-fold higher insulin-stimulated beta sub-unit kinase activity on the synthetic peptide poly(Glu,Tyr), compared to receptors in a B-cell line (ADD) with normal karyotype from the same patient. ACV cells had a novel 13-kb receptor mRNA species and expressed a DNA polymorphism localized to the tyrosine kinase domain of the receptor gene. These findings suggest that t(1;19) in the ACV cell may result in rearrangement of the insulin receptor gene and translation of a receptor with enhanced tyrosine kinase activity.

Blotting, Northern↗
PubMed1992

Cu/Zn superoxide dismutase mRNA and enzyme activity, and susceptibility to lipid peroxidation, increases with aging in murine brains.

To protect against reactive oxygen species, prokaryotic and eukaryotic cells have developed an antioxidant defence mechanism where O2- is converted to H2O2 by superoxide dismutase (Sod), and in a second step, H2O2 is converted to H2O by catalase (Cat) and/or glutathione peroxidase (Gpx). If Sod levels are increased without a concomitant Gpx increase, then the intermediate H2O2 accumulates. This intermediate could undergo the Fenton's reaction, generating hydroxyl radicals which may lead to lipid peroxidation in cells. In this study, we investigate the expression of Sod1, Gpx1 and susceptibility to lipid peroxidation during the aging process in mouse brains. We demonstrate that the mRNA levels and enzyme activity of Sod1 are higher in brains from adult mice compared to neonatal mice. Furthermore, we show that a linear increase in Sod1 mRNA and enzyme activity occurs with aging (1-100 weeks). On the contrary, we find that the mRNA and enzyme activity for Gpx1 does not increase with aging in mouse brains. In addition, our results demonstrate that the susceptibility of murine brains to lipid peroxidation increases with aging. The data in this study are consistent with the notion that reactive oxygen species may contribute to the aging process in mammalian brains. These results are discussed in relation to the normal aging process in mammals, and to the premature aging and mental retardation in Down syndrome.

Aging↗
PubMed1991

Modulation of vocal and nonvocal behavior in adult squirrel monkeys by selective MAO-A and MAO-B inhibition.

The acute effects of monoamine oxidase inhibitors L-deprenyl (0.5-5.0 mg/kg), clorgyline (1.0-10.0 mg/kg), and milacemide (100-400 mg/kg) on the behavior of adult male squirrel monkeys were examined during brief social separations beginning 60 min after subcutaneous drug administration. All three drugs selectively reduced the rate of calling during social separation at doses which did not affect time spent in locomotion, nor the frequency of vigilance-checking. Deprenyl and milacemide, but not clorgyline, produced concurrent decreases in locomotion at the higher doses tested. At threshold doses, clorgyline, but not deprenyl or milacemide, increased call duration and decreased call peak frequency compared to vehicle control values. Plasma levels of MHPG were decreased by an optimal dose of clorgyline but not by deprenyl or milacemide, indicating that substrate specificity was maintained at the drug doses employed. We conclude that different MAO substrates mediate different aspects of vocal and nonvocal behavior in adult male squirrel monkeys.

Acetamides↗
PubMed1991

Biosensors for process control.

Biosensors have been extensively studied during the last 20 years, and a myriad of laboratory biosensors have been developed. Improvements are required in biosensor design and performance before they become widely accepted in industrial process monitoring. However, as the biotechnology industry expands, biosensors may become more acceptable because, despite their limitations, they are the only devices capable of delivering the information required.

Biosensing Techniques↗
PubMed1991

Gender differences in reactivity of adult squirrel monkeys to short-term environmental challenges.

Evidence is presented to show that individual adult squirrel monkeys show gender-specific reactivity profiles to threatening stimuli under laboratory conditions, and that a putative anxiogenic drug, benactyzine hydrochloride, enhances the vocal response to threatening stimuli, but otherwise preserves the relative importance of the stimuli to both males and females. These data support the conclusion that screening of putative anxiolytic drugs in a primate model can be accomplished using efficient, ethologically based testing procedures in the laboratory.

Aggression↗
PubMed1989

Insulin receptor expression in Burkitt lymphoma cell lines.

The specific binding of insulin to 7 different Burkitt lymphoma cell lines containing chromosomal translocations t(8;14), t(8;2) and t(8;22) was markedly decreased when compared to binding to lymphoblastoid cells of normal karyotype derived from Burkitt lymphoma patients or the human IM-9 lymphoblastoid line. The number of insulin-binding sites on intact Burkitt cells was decreased by greater than 90% compared to lymphoblastoid cells, with no change in affinity. This decrease in binding was paralleled by reduced amounts of insulin receptor alpha (Mr 130,000) and beta (Mr 95,000) subunits detected by cell-surface-labelling and insulin receptor mRNA transcripts, indicating that transcription of receptor mRNA is decreased in Burkitt cells compared to lymphoblastoid cells and/or that receptor mRNA is less stable. Burkitt cells displayed negligible insulin-stimulated beta subunit auto-phosphorylation, which could reflect either their decreased number of receptors or a defect in signal transduction. Structural analysis also revealed that the Burkitt cells had an increase in a precursor form (Mr 210,000) of the receptor, suggesting that decreased expression of the receptor may be associated with defective processing. Four Burkitt cell lines with t(8;14) also had reductions of 45-100% in expression of class-1 major histocompatibility (MHC) antigens. The expression of insulin receptors in both Burkitt and lymphoblastoid cells correlated with the expression of class-1 MHC antigens. There was also an inverse correlation between the expression of c-myc and both insulin receptors and class-1 MHC antigens. As the insulin receptor is absent on resting B cells and is induced after cell activation, the decrease in receptor expression on Burkitt cells may reflect their less activated phenotype compared to lymphoblastoid cells.

Burkitt Lymphoma↗
PubMed1989

Induction of the insulin receptor and other differentiation markers by sodium butyrate in the Burkitt lymphoma cell, Raji.

The very low expression of insulin receptors in the Burkitt lymphoma cell Raji was increased 2-fold, 6-fold and 10-fold after 1, 2 and 3 days, respectively, by incubation with the differentiation inducer sodium butyrate. Insulin receptor number was increased without a change in receptor affinity, in association with an increase in the receptor alpha and beta subunits detected after cell-surface labelling and immunoprecipitation. Expression of cell-surface class I and II human leukocyte antigens, the intercellular adhesion molecule-1 and the CD38 leukocyte antigen was also increased, consistent with B cell differentiation. Butyrate effects were not unspecific, as the binding of tumour necrosis factor and growth hormone and the expression of the B cell markers CD20, B5 and CD21 was not increased. The low expression of insulin receptors on Raji cells is therefore a reflection of the less differentiated state of these cells compared to lymphoblastoid cells.

Antigens, Differentiation, B-Lymphocyte↗
PubMed1989

CRH and alpha-helical-CRH modulate behavioral measures of arousal in monkeys.

Several neuropeptides involved in the control of pituitary-adrenal activation have also been shown to have behavioral effects which may be mediated by actions on brain mechanisms independent of pituitary release. The behavioral effects of intraventricular administration of CRH and the synthetic peptide antagonist alpha-helical-CRH were assessed in socially separated squirrel monkeys. Treated monkeys were presented with a sequence of behavioral challenges including undisturbed social separation, presentation of a mirror image, and presentation of a "predator" stimulus. The test sequence was repeated at several time intervals after administration of the peptides. CRH produced dose-related increases in several species-typical measures of arousal including motor activity, vigilance-checking, and marking. Pretreatment with alpha-helical-CRH prevented the increased motor activity but not the marking behavior associated with CRH. When administered alone, alpha-helical-CRH increased vigilance-checking. In addition, alpha-helical-CRH increased aggressive behaviors exhibited at the mirror stimulus. The data provide further support for a central role for CRH in the mediation of both activational and inhibitory behavioral responses to stressful stimuli. These data also suggest both antagonistic and partial agonist effects for alpha-helical-CRH.

Animals↗
PubMed1989

Human thyrotropin receptor subunits characterized by thyrotropin affinity purification and western blotting.

We studied the subunit structure of the human TSH receptor in thyroid tissue from patients with Graves' disease and multinodular goiter by TSH affinity chromatography, immunoprecipitation with Graves' immunoglobulins (Igs), and a modified technique of Western blotting. Human TSH receptor-binding activity was purified about 1,270-fold by sequential affinity chromatography on wheat germ lectin-agarose and TSH-agarose. Analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis of nonreduced affinity-purified receptors eluted in sodium dodecyl sulfate sample buffer revealed three noncovalently linked subunits of 70,000, 50,000, and 35,000 mol wt. When reduced, a major subunit of 25,000 mol wt was identified. When 3 mol/L NaCl was used to elute affinity-purified receptors only the 50,000 mol wt nonreduced subunit was detected. This subunit bound [125I]bovine TSH and was precipitated by Graves' Igs. Modifications to the conventional Western blotting technique enabled thyroglobulin components (approximately 220,000 mol wt), thyroid microsomal antigen (a doublet of approximately 110,000 mol wt), and putative TSH receptor subunits of 70,000 and 50,000 mol wt to be identified in thyroid particulate membranes by Graves' Igs. Blotting of affinity-purified receptors eluted in sodium dodecyl sulfate sample buffer revealed subunits of either 70,000 or 50,000 mol wt, with a minority of Graves' serum samples. We conclude that the nonreduced human TSH receptor is an oligomeric complex comprising three different subunits of 70,000, 50,000, and 35,000 mol wt. The reduced receptor exists as a single subunit of 25,000 mol wt, which may be disulfide linked to form the higher mol wt forms. The 70,000 and 50,000 mol wt subunits contain epitopes that bind Graves' Igs in modified Western blots, thus directly confirming that the human TSH receptor is a target for Graves' Igs.

Autoradiography↗
PubMed1989

Insulin receptor expression in the Burkitt lymphoma cells Daudi and Raji.

The specific binding of insulin to either intact or Triton-solubilized Daudi cells (a Burkitt lymphoma cell line) was reduced by over 95% compared to that to control IM-9 lymphocytes due to a decrease in receptor number without a change in affinity. Analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography revealed that 125I-labeled Daudi cells had reduced amounts (approximately 1/20th) of immunoprecipitable binding (alpha) subunit [mol wt (Mr), 130,000] of the receptor and a relatively abundant 210,000 Mr form not seen in IM-9 cells. The transmembranous (beta) subunit (Mr, 90,000) of the receptor, although not detected by 125I surface labeling, could be phosphorylated and, together with the 210,000 Mr form, exhibited the same 2-fold stimulation of phosphorylation by insulin as that in IM-9 cells. Northern blot hybridization revealed a decrease in Daudi cells of all four major species of insulin receptor mRNA. The Raji cell, another Burkitt lymphoma cell line, also exhibited reduced protein and genetic expression of the insulin receptor, indicating that reduced insulin receptor expression may be representative of other Burkitt lymphoma cell lines.

Blotting, Northern↗
PubMed1988

Role of midline frontolimbic cortex in production of the isolation call of squirrel monkeys.

Since the separation cry of mammals serves to maintain (1) mother-offspring contact and (2) contact between members of a group, it probably ranks as a basic mammalian vocalization. The present study is part of an investigation concerned with identifying the cerebral representation of the separation call in squirrel monkeys. For this purpose, monkeys are tested for their ability to produce spontaneous calls in isolation before and after ablations of different parts of the brain. Because of the subject's auditory and visual isolation, the call emitted during testing is referred to as the isolation call. In a preceding study, it was shown that lesions at the thalamomidbrain junction and in the ventral central gray interfere with the structure and/or production of the call. The present study focuses on the rostral midline limbic cortex, known to be one of the two cortical areas where stimulation elicits vocalization in monkeys. Evidence derived by the process of elimination indicates that the spontaneous call depends on the concerted action of a continuous band of rostral limbic cortex comprising parts of areas 24, 25, and 12. The midline frontal neocortex peripheral to this limbic zone does not appear to be essential for the call.

Animals↗
PubMed1988

Combined opiate/adrenergic receptor blockade enhances squirrel monkey vocalization.

This study provides evidence for the interaction between opiate and noradrenergic neuronal systems on primate vocal behavior. The rate of twitters produced by adult squirrel monkeys was increased in an additive or synergistic manner by the combined administration of the alpha 2 adrenergic antagonist yohimbine and the opiate antagonist naloxone. Similar effects were not demonstrated on the isolation call. In addition, the drug combination led to an increase of autonomic symptoms. The anatomical localization of these findings and mechanism for the production of increased twitters requires further investigation.

Adrenergic alpha-Antagonists↗
PubMed1987

Mediation of separation distress by alpha 2-adrenergic mechanisms in a non-human primate.

This study provides the first behavioral evidence in support of an alpha-adrenergic mechanism underlying imipramine's amelioration of separation distress. The rate of separation-induced vocalization by adult squirrel monkeys was decreased by imipramine and the alpha 2-adrenergic agonist clonidine, and increased by the alpha 2-adrenergic antagonist yohimbine. Yohimbine, but not the alpha 1-antagonist prazosin, reversed the clonidine effect suggesting that drugs acting directly on alpha 2-receptors may have a role in management of separation anxiety.

Adrenergic alpha-Agonists↗
PubMed1987

Activation of phosphoprotein phosphatases by growth hormone sequences with insulin-like activity.

The N-terminal part sequences of pituitary growth hormone, N alpha-acetyl-hGH 7-13 and hGH 6-13, promoted conversion of glycogen synthase b to glycogen synthase a in skeletal muscle and adipose tissue when injected intravenously. The peptides also caused conversion of phosphorylase a to phosphorylase b in liver and adipose tissue, but not in muscle, where the peptides antagonised activation of phosphorylase. Synthase phosphatase activity in muscle and phosphorylase phosphatase activity in liver increased after injection of peptide, with time courses of change similar to those seen for muscle synthase and liver phosphorylase activities. Injection of peptide also decreased both the cyclic AMP dependent and independent synthase kinase activities in muscle. These results show that the insulin-like activities of these peptides on glycogen synthase and phosphorylase involve both increases in protein phosphatase activities and inhibition of protein kinase activities. These results are discussed in relation to the insulin-like activities of growth hormone.

Adipose Tissue↗
PubMed1987

Hexose phosphates as regulators of hepatic glycogen synthase phosphatases.

The activity of glycogen synthase phosphatase from smooth endoplasmic reticulum of liver was stimulated markedly by galactose-6- and fructose-6-phosphates and to a lesser extent by glucose-1- and 2-deoxyglucose-6-phosphates. The synthase phosphatase of liver cytosol showed strong activation by glucose-1-, glucose-6- and fructose-6-phosphates and smaller activation by galactose-6- and 2-deoxyglucose-6-phosphates. Kinetic analysis showed that the activators did not affect the Km for glycogen synthase D, for either enzyme. The mechanism of activation of the two phosphatases by hexose phosphates appears to be by combination of the activator at a specific activator site on the enzyme rather than by substrate modulation. It is concluded that certain hexose phosphates, particularly fructose-6-phosphate and glucose-1-phosphate, can function as regulators of hepatic synthase phosphatase activity, and that this may explain the ability of elevated blood glucose to increase both glycogen synthase I activity and glycogen synthesis in the liver.

Animals↗
PubMed1986

Benactyzine increases alarm call rates in the squirrel monkey.

The effects of benactyzine (0.01-3.0 mg/kg) were examined on the frequency of alarm calls of squirrel monkeys in a laboratory setting. Under baseline conditions, few calls occurred, and neither saline nor a low dose (0.01 mg/kg) of benactyzine increased calling. Higher doses (0.03-3.0 mg/kg) of benactyzine significantly increased call rate (to 1-2 calls per s) in a dose-dependent manner. The rate-increasing effect of benactyzine on alarm calls appears to be related to a central antimuscarinic effect, as it could be partially blocked by 0.01 mg/kg physostigmine, completely blocked by 0.1 mg/kg physostigmine, but was not blocked at all by 0.1 mg/kg neostigmine. Neither of these cholinomimetics increased call rates when given alone. These findings show that benactyzine can increase alarm call rates in squirrel monkeys under defined laboratory conditions, and may serve as a useful pharmacological probe to study neurochemical mechanisms mediating the production of this type of vocalization. In the squirrel monkey, one such mechanism apparently involves a cholinergic substrate.

Animals↗
PubMed1986

An atypical insulin receptor with high affinity for insulin-like growth factors copurified with placental insulin receptors.

Insulin receptors purified from human placenta by sequential affinity chromatography on wheat germ lectin-agarose and insulin coupled to 1,1'-carbonyldiimidazole-activated agarose (CDI-agarose) retained full binding activity but bound a greater than predicted amount of 125I-labeled insulin-like growth factor I (IGF-I). IGF-I and multiplication-stimulating activity (MSA; the rat homologue of IGF-II) were equipotent in displacing either 125I-labeled IGF-I or 125I-labeled MSA from the purified receptors; insulin was 5-15 times more potent. Competitive binding studies indicated that this IGF binding activity could not be explained by cross-reaction with classical insulin receptors or by coelution of IGF-I or IGF-II receptors. Instead, it was due to a minor population of discrete atypical insulin receptors (6-18% total insulin receptors) with moderately high affinity (Kd = 2-4 X 10(-9) M) for IGF-I and MSA. These receptors were not an artifact of insulin-CDI-agarose chromatography, since they were present in wheat germ lectin-agarose-purified preparations and could also be purified from insulin-succinyldiaminodipropylamino-agarose. Affinity labeling with 125I-labeled MSA revealed that these atypical receptors had the same binding subunit (Mr 140,000) as classical insulin and IGF-I receptors. They displayed intermediate reactivity with polyclonal and monoclonal antibodies to the insulin and IGF-I receptors. It is therefore likely that insulin receptors purified by immunoadsorption would also contain atypical insulin receptors. The finding of more than one type of insulin receptor might relate to the slight variations in the cDNA nucleotide sequences and the multiple mRNA species reported for the insulin receptor [Ebina, Y., Ellis, L., Jarnagin, K., Edery, M., Graf, L., Clauser, E., Ou, J.-H., Masiarz, F., Kan, Y. W., Goldfine, I. D., Roth, R. A. & Rutter, W. J. (1985) Cell 40, 747-758].

Affinity Labels↗