Biomedical subjects

A Doan

Publications and source records attributed to A Doan.

9 recordsLinked to original sources

PubMed2000

Presynaptic clustering of mGluR7a requires the PICK1 PDZ domain binding site.

Aggregation of neurotransmitter receptors at pre- and postsynaptic structures is crucial for efficient neuronal communication. In contrast to the wealth of information about postsynaptic specializations, little is known about the molecular organization of presynaptic membrane proteins. We show here that the metabotropic glutamate receptor mGluR7a, which localizes specifically to presynaptic active zones, interacts in vitro and in vivo with PICK1. Coexpression in heterologous systems induces coclustering dependent upon the extreme C terminus of mGluR7a and the PDZ domain of PICK1. mGluR7a and PICK1 localize to excitatory synapses in hippocampal neurons. Furthermore, whereas transfected mGluR7a clusters at presynaptic sites, mGluR7adelta3 lacking the PICK1 binding site targets to axons but does not cluster. These results suggest that PICK1 is a component of the presynaptic machinery involved in mGluR7a aggregation and in modulation of glutamate neurotransmission.

Animals↗

PubMed1999

Coupling of mGluR/Homer and PSD-95 complexes by the Shank family of postsynaptic density proteins.

Shank is a recently described family of postsynaptic proteins that function as part of the NMDA receptor-associated PSD-95 complex (Naisbitt et al., 1999 [this issue of Neuron]). Here, we report that Shank proteins also bind to Homer. Homer proteins form multivalent complexes that bind proline-rich motifs in group 1 metabotropic glutamate receptors and inositol trisphosphate receptors, thereby coupling these receptors in a signaling complex. A single Homer-binding site is identified in Shank, and Shank and Homer coimmunoprecipitate from brain and colocalize at postsynaptic densities. Moreover, Shank clusters mGluR5 in heterologous cells in the presence of Homer and mediates the coclustering of Homer with PSD-95/GKAP. Thus, Shank may cross-link Homer and PSD-95 complexes in the PSD and play a role in the signaling mechanisms of both mGluRs and NMDA receptors.

Adaptor Proteins, Signal Transducing↗

PubMed1998

Homer regulates the association of group 1 metabotropic glutamate receptors with multivalent complexes of homer-related, synaptic proteins.

Homer is a neuronal immediate early gene (IEG) that is enriched at excitatory synapses and binds group 1 metabotropic glutamate receptors (mGluRs). Here, we characterize a family of Homer-related proteins derived from three distinct genes. Like Homer IEG (now termed Homer 1a), all new members bind group 1 mGluRs. In contrast to Homer 1a, new members are constitutively expressed and encode a C-terminal coiled-coil (CC) domain that mediates self-multimerization. CC-Homers form natural complexes that cross-link mGluRs and are enriched at the postsynaptic density. Homer 1a does not multimerize and blocks the association of mGluRs with CC-Homer complexes. These observations support a model in which the dynamic expression of Homer 1a competes with constitutively expressed CC-Homers to modify synaptic mGluR properties.

Amino Acid Sequence↗

PubMed1996

Protein topology of presenilin 1.

Mutations in a gene encoding a multitransmembrane protein, termed presenilin 1 (PS1), are causative in the majority of early-onset cases of AD. To determine the topology of PS1, we utilized two strategies: first, we tested whether putative transmembranes are sufficient to export a protease-sensitive substrate across a lipid bilayer; and second, we examined the binding of antibodies to specific PS1 epitopes in cultured cells selectively permeabilized with the pore-forming toxin, streptolysin-O. We document that the "loop," N-terminal, and C-terminal domains of PS1 are oriented toward the cytoplasm.

Amyloid beta-Protein Precursor↗

PubMed1995

Decision-theoretic refinement planning: a new method for clinical decision analysis.

Clinical decision analysis seeks to identify the optimal management strategy by modelling the uncertainty and risks entailed in the diagnosis, natural history, and treatment of a particular problem or disorder. Decision trees are the most frequently used model in clinical decision analysis, but can be tedious to construct, cumbersome to use, and computationally prohibitive, especially with large, complex decision problems. We present a new method for clinical decision analysis that combines the techniques of decision theory and artificial intelligence. Our model uses a modular representation of knowledge that simplifies model building and enables more fully automated decision making. Moreover, the model exploits problem structures to yield better computational efficiency. As an example we apply our techniques to the problem of management of acute deep venous thrombosis.

Artificial Intelligence↗

PubMed1994

Diurnal expression of Fos in luteinizing hormone-releasing hormone neurons of Syrian hamsters.

The aim of the present study was two-fold: first, to examine the temporal relationship between increased expression of Fos in LHRH neurons of proestrous hamsters and increased plasma levels of LH, FSH, estradiol-17 beta (E2), and progesterone (P4); and second, to establish whether male hamsters, like females, also show diurnal variations in the number of LHRH neurons expressing Fos. Blood samples were collected from proestrous females at 0900 n, 1200 h, 1500 h, and 1800 h and also from males at 0300 h, 0900 h, 1500 h, and 2100 h. RIA of the plasma revealed significant peaks of LH, FSH, and E2 at 1500 h, and of P4 at 1800 h in the females; a significant but smaller peak of LH also occurred at 1500 h in the males. Double-label immunocytochemistry, using antibodies directed against amino acids 127-152 of the human Fos protein and against LHRH, showed that female hamsters expressed Fos in fewer than 10% of their LHRH neurons during the morning and at noon of proestrus but in approximately 41% of these neurons during the late afternoon (1800 h). In contrast, no expression of Fos occurred in LHRH neurons of male hamsters at any time of the day. The finding that the females showed an increase in the number of LHRH neurons expressing Fos after, and not before, the initiation of the preovulatory gonadotropin surge is significant because it does not readily support the hypothesis that this expression of immediate-early genes is in some way associated with the induction of the surge. Instead, the results are consistent with the view that expression of Fos in LHRH neurons reflects either the activation of a mechanism responsible for terminating the surge or, alternatively, the activation of a compensatory mechanism responsible for replenishing depleted neuropeptide stocks.

Animals↗

PubMed1992

Maturation of the hypothalamo-pituitary-gonadal axis of male Syrian hamsters.

Light-microscope immunocytochemistry (ICC) was used to investigate postnatal changes in the morphology of LHRH neurons in the brains of male Syrian hamsters and to relate these changes to more overt maturational developments within the hypothalamo-pituitary-gonadal axis. The animals were maintained under long-day photoperiods (14L:10D), and groups of 6-7 were killed at 10-day intervals from Day 15 to Day 65. Their brains were fixed with 4% paraformaldehyde, sectioned sagittally with a vibratome (75 microns), and processed for ICC using monoclonal LHRH antibody HU4H. Throughout the study period, the hamsters showed a progressive increase in plasma gonadotropin levels, closely followed by an increase in testicular weight and plasma testosterone levels. Histology of the testes revealed that spermatogenesis was already qualitatively completed by Day 35 and quantitative aspects were established by Day 45. Within the brain, LHRH neuronal perikarya were distributed primarily in the medial septal-preoptic area and the diagonal band of Broca; morphologically, these immunopositive neurons were either monopolar or bipolar. The total number of LHRH neurons detected in the areas examined was approximately 440 throughout the developmental period, and the relative proportions of monopolar and bipolar subtypes (86% and 14%, respectively) remained unchanged. In contrast, the area of the perikarya, as determined by autoimage analysis, showed a highly significant age-related increase, both for the monopolar and bipolar neurons. It is suggested that these developmental changes in the LHRH neurons reflect an increase in LHRH synthesis and may, therefore, provide a neuroendocrine trigger for the onset of puberty.

Animals↗

PubMed1991

Immunocytochemical investigation of luteinizing hormone-releasing hormone neurons in Syrian hamsters maintained under long or short days.

Light-microscope immunocytochemistry was used to investigate the LHRH system of adult male Syrian hamsters. Half of the animals were transferred from long to short photoperiods (14L:10D to 6L:18D) for 10 wk, causing plasma gonadotropin levels and the testes to revert to a prepubertal condition. In spite of the marked differences in the reproductive axis between the two groups of hamsters, the number of immunopositive LHRH neurons observed in the preoptic-medial septal area and diagonal band of Broca was approximately 400 in both cases; of these, 87-91% were monopolar and 9-13% were bipolar, regardless of whether the brains were sectioned in a coronal or sagittal plane. These results, therefore, fail to support the hypothesis that photoperiodic changes in the number of LHRH neurons play a major role in controlling the seasonal regression and recrudescence of the reproductive system in the hamster. However, morphometric analysis of the perikarya using an IBAS 2000 automatic image analyzer revealed a photoperiod-related difference. Surprisingly, the perikarya of both monopolar and bipolar LHRH neurons were significantly larger in hamsters that had been maintained on short days, as opposed to long days. These findings, therefore, are in harmony with the view that the inhibitory effect of short days on the reproductive axis is mediated through a suppression of LHRH secretion, which in turn is reflected as an increase in the net content of LHRH within the brain.

Animals↗

PubMedDate not supplied

Decision-theoretic refinement planning in medical decision making: management of acute deep venous thrombosis.

Decision-theoretic refinement planning is a new technique for finding optimal courses of action. The authors sought to determine whether this technique could identify optimal strategies for medical diagnosis and therapy. An existing model of acute deep venous thrombosis of the lower extremities was encoded for analysis by the decision-theoretic refinement planning system (DRIPS). The encoding represented 6,206 possible plans. The DRIPS planner used artificial intelligence techniques to eliminate 5,150 plans (83%) from consideration without examining them explicitly. The DRIPS system identified the five strategies that minimized cost and mortality. The authors conclude that decision-theoretic planning is useful for examining large medical-decision problems.

Algorithms↗