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Biomedical subjects

J A Gally

Publications and source records attributed to J A Gally.

14 recordsLinked to original sources
PubMed2001

Degeneracy and complexity in biological systems.

Degeneracy, the ability of elements that are structurally different to perform the same function or yield the same output, is a well known characteristic of the genetic code and immune systems. Here, we point out that degeneracy is a ubiquitous biological property and argue that it is a feature of complexity at genetic, cellular, system, and population levels. Furthermore, it is both necessary for, and an inevitable outcome of, natural selection.

Animals↗
PubMed2000

Marking synaptic activity in dendritic spines with a calpain substrate exhibiting fluorescence resonance energy transfer.

Excitatory synaptic activity can evoke transient and substantial elevations of postsynaptic calcium. Downstream effects of elevated calcium include the activation of the calcium-dependent protease calpain. We have developed a reagent that identifies dendritic spines in which calpain has been activated. A fusion protein was expressed that contained enhanced yellow and enhanced cyan fluorescent protein (EYFP and ECFP, respectively) linked by a peptide that included the micro-calpain cleavage site from alpha-spectrin. A PDZ-binding site fused to ECFP anchored this protein to postsynaptic densities. The fusion protein exhibited fluorescence resonance energy transfer (FRET), and diminution of FRET by proteolysis was used to localize calpain activity in situ by fluorescence microscopy. Incubation of the fusion protein with calpain in the presence of calcium resulted in the separation of EYFP and ECFP into monomeric fluorophores. In transiently transfected cell lines and dissociated hippocampal neurons, FRET was diminished by raising intracellular calcium levels with an ionophore or with glutamatergic agonists. Calpain inhibitors blocked these changes. Under control conditions, FRET levels in different dendritic spines of cultured neurons and in hippocampal slices were heterogeneous but showed robust decreases upon treatment with glutamatergic agonists. Immunostaining of cultured neurons with antibodies to a spectrin epitope produced by calpain-mediated digestion revealed an inverse correlation between the amount of FRET present at postsynaptic elements and the concentration of spectrin breakdown products. These results suggest that the FRET methodology identifies sites of synaptically induced calpain activity and that it may be useful in analyzing synapses undergoing changes in efficacy.

Amino Acid Sequence↗
PubMed1992

Evidence for gene conversion in genes for cell-adhesion molecules.

The genomic sequences encoding a chicken Ca(2+)-dependent cell adhesion molecule (K-CAM) were recently found to be located approximately 600 base pairs upstream from the translation initiation site of a homologous protein, liver CAM. The sizes of 11 exons of the K-CAM gene are almost identical to those in the L-CAM (liver cell-adhesion molecule) gene with exon-intron junctions occurring at exactly equivalent positions. The sizes and sequences of most introns were, however, much more dissimilar. More detailed comparisons of these two genes reveal that the sequences of the last two exons (exons 15 and 16) are far more alike than are any of the other exons; they are, in fact, almost identical. The introns that separate these exons in the two genes likewise resemble one another far more than do any other corresponding introns. This degree of similarity appears to be far greater than can be accounted for by selection for protein structure, and it strongly suggests that a gene conversion event occurred between these two genes subsequent to their duplication and divergence to perform different biological functions.

Animals↗
PubMed1992

Role of nitric oxide in NMDA-evoked release of [3H]-dopamine from striatal slices.

Evidence that excitatory amino acids act via N-methyl-D-aspartate (NMDA) receptors to evoke the release of catecholamines from axonal terminals and synaptosomes has been used to argue for the presence of pre-synaptic NMDA receptors. NMDA receptor agonists also generate nitric oxide (NO) which rapidly diffuses through neural tissue. We find that exogenously applied NO evokes [3H]-dopamine release from cultured neurons. This release is not blocked by the NMDA antagonist MK-801 nor by tetrodotoxin. Both NG-nitroarginine which inhibits NO synthesis, and hemoglobin which binds extracellular NO, block NMDA-evoked [3H]-dopamine release from striatal slices. A major role of endogenously-synthesized NO may be to evoke neurotransmitter release in local volumes of neural tissue.

Animals↗
PubMed1990

The NO hypothesis: possible effects of a short-lived, rapidly diffusible signal in the development and function of the nervous system.

Several observations suggest that the Ca2(+)-dependent postsynaptic release of nitric oxide (NO) may be important in the formation and function of the vertebrate nervous system. We explore here the hypothesis that the release of NO and its subsequent diffusion may be critically related to three aspects of nervous system function: (i) synaptic plasticity and long-term potentiation in certain regions of the adult nervous system, (ii) the control of cerebral blood flow in such regions, and (iii) the establishment and activity-dependent refinement of axonal projections during the later stages of development. In this paper, we detail and analyze the basic assumptions underlying this NO hypothesis and describe a computer simulation of a minimal version of the hypothesis. In the simulation, a 3-dimensional volume of neuropil is presented with patterned afferent input; NO is produced, diffuses, and is destroyed; and synaptic strengths are determined by a set of synaptic rules based on the correlation of synaptic depolarization and NO levels. According to the hypothesis, voltage-dependent postsynaptic release of this rapidly diffusing substance links the activities of neurons in a local volume of tissue, regardless of whether the neurons are directly connected by synapses. This property is demonstrated in the simulation, and it is this property that is exploited in the hypothesis to account for certain aspects of long-term potentiation and activity-dependent sharpening of axonal arbors.

Aging↗
PubMed1989

Reentrant signaling among simulated neuronal groups leads to coherency in their oscillatory activity.

Recent experiments have revealed tightly synchronized oscillatory discharges in local assemblies of cortical neurons as well as phase coherency of oscillations at distant cortical sites. These findings are consistent with the theory of neuronal group selection, a population theory of brain function that is based on the properties of local groups of neurons. A set of computer simulations shows that cooperative interactions within and among neuronal groups can generate the observed phenomena. In the simulations, oscillations within neuronal groups are generated through local excitatory and inhibitory interactions. Different groups in general oscillate in an uncorrelated fashion. Coherency of the oscillatory activity of different neuronal groups depends crucially on reciprocal reentrant signaling and can reflect the spatial continuity of a stimulus. Separated or discontinuous features of a given stimulus can be transiently associated in a temporally coherent pattern through reentrant signaling between groups in networks responding to different aspects of that stimulus. A simulation of reentrant activity between arrays of neuronal groups selective for oriented lines and pattern motion displays cross-correlations between groups that are responsive to different parts of a stimulus contour if these parts move together. Such coherency among neuronal groups might be used in the discrimination of a stimulus from other stationary or differentially moving elements in a visual scene.

Animals↗
PubMed1969

Deoxyribonuclease IV: a new exonuclease from mammalian tissues.

An exonuclease which specifically degrades double-standard DNA has been isolated from rabbit tissues. The enzyme has an approximate molecular weight of 42,000, requires a divalent metal ion as cofactor, and attacks DNA at the 5'-terminal ends, thereby liberating 5'-mononucleotides. It degrades several synthetic polydeoxynucleotides of single repeating base sequences more rapidly than DNA from natural sources. The specificity of this mammalian enzyme resembles that of several microbial enzymes (phage lambda exonuclease and DNA polymerase) which appear to be required for repair and recombination of DNA.

Animals↗
PubMedDate not supplied

Spatial signaling in the development and function of neural connections.

In the vertebrate central nervous system, afferent axons find their appropriate target structures under the influence of local environmental cues. In many target regions, appropriate patterns of activity in the afferents are also required to establish normal mappings between the source cells and the target region. Specific mappings arise in these targets because temporal contiguity in firing is somehow transformed into spatial contiguity of synaptic contacts. In this article, we propose a theory that utilizes the covariance of a transient diffusive signal produced at active synapses with the firing of presynaptic axon terminals to account for many of these activity-dependent features of vertebrate neuroanatomy. Computer simulations of the growth of axons within a three-dimensional volume of neural tissue reveal the generality of the proposed mechanism in accounting for the self-organization of a broad range of diverse neuroanatomical structures, including those in the cerebral cortex. The proposed mechanism is consistent with detailed anatomical and physiological data, and direct experimental tests of predictions of the theory are suggested.

Animals↗