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Biomedical subjects

R G Phillips

Publications and source records attributed to R G Phillips.

At least 19 recordsLinked to original sources
PubMed2001

Memory retrieval impairment induced by hippocampal CA3 lesions is blocked by adrenocortical suppression.

There is evidence that in rats, partial hippocampal lesions or selective ablation of the CA3 subfield can disrupt retrieval of spatial memory and that hippocampal damage disinhibits hypothalamic-pituitary-adrenocortical (HPA)-axis activity, thereby elevating plasma levels of adrenocorticotropin and corticosterone. Here we report evidence that attenuation of CA3 lesion-induced increases in circulating corticosterone levels with the synthesis inhibitor metyrapone, administered shortly before water-maze retention testing, blocks the impairing effects of the lesion on memory retrieval. These findings suggest that elevated adrenocortical activity is critical in mediating memory retrieval deficits induced by hippocampal damage.

Adrenal Cortex↗
PubMed2001

Gene therapy effectiveness differs for neuronal survival and behavioral performance.

If neuronal gene therapy is to be clinically useful, it is necessary to demonstrate neuroprotection when the gene is introduced after insult. We now report equivalent neuronal protection if calbindin D(28K) gene transfer via herpes simplex virus amplicon vector occurs immediately, 30 min, or 1 h after an excitotoxic insult, but not after a 4 h delay. Behavioral performance was evaluated for immediate and 1 h delay groups using a hippocampal-dependent task. Despite equivalent magnitude and pattern of sparing of neurons with the immediate and 1 h delay approaches, the delay animals took a significantly longer time after insult to return to normal performance.

Animals↗
PubMed2000

Limitations in the neuroprotective potential of gene therapy with Bcl-2.

Considerable attention has focused on the therapeutic transfer of genes with viral vectors into neurons for the purpose of protecting against neurological insults. A number of papers have reported that overexpression of the anti-apoptotic protein Bcl-2 can protect neurons both in vitro and in vivo against a variety of necrotic insults. An emerging literature suggests that the availability of energy tends to modulate a neuron towards dying apoptotically, rather than necrotically, in the aftermath of an insult. This suggests that an anti-apoptotic protein such as Bcl-2 should be minimally protective, at best, against purely energetic insults. In support of this idea, we report that overexpression of Bcl-2 with a herpes simplex viral vector fails to protect hippocampal neurons, either in vitro or in vivo, against the electron transport uncoupler 3-acetylpyridine (3AP). As a positive control, the same vector significantly protected against the excitotoxin kainic acid. This finding supports the view that neurotoxicity induced by 3AP is likely to have only minimal apoptotic facets. On a broader level, it suggests some limitations in the neuroprotective potential of gene therapy with Bcl-2.

Animals↗
PubMed2000

Contributions of postrhinal and perirhinal cortex to contextual information processing.

The role of the postrhinal cortex (POR) and the perirhinal cortex (PER) in processing relational or contextual information was examined with Pavlovian fear conditioning. Rats with electrolytic or neurotoxic lesions of the POR or PER were tested in 2 contextual fear conditioning paradigms. In Experiment 1, electrolytic lesions of the POR or PER produced impairments in contextual fear conditioning but not in conditioning to a phasic auditory conditioned stimulus. Neurotoxic lesions of the POR or PER likewise resulted in anterograde (Experiment 2) and retrograde (Experiment 3) deficits in fear conditioning to the training context in an unsignaled shock paradigm. The results suggest that operations performed on sensory information by the POR and PER are necessary to support contextual learning.

Animals↗
PubMed1999

Wingless signaling leads to an asymmetric response to decapentaplegic-dependent signaling during sense organ patterning on the notum of Drosophila melanogaster.

Wnt and Decapentaplegic cell signaling pathways act synergistically in their contribution to macrochaete (sense organ) patterning on the notum of Drosophila melanogaster. The Wingless-signaling pathway was ectopically activated by removing Shaggy activity (the homologue of vertebrate glycogen synthase kinase 3) in mosaics. Proneural activity is asymmetric within the Shaggy-deficient clone of cells and shows a fixed "polarity" with respect to body axis, independent of the precise location of the clone. This asymmetric response indicates the existence in the epithelium of a second signal, which we suggest is Decapentaplegic. Ectopic expression of Decapentaplegic induces extra macrochaetes only in cells which also receive the Wingless signal. Activation of Hedgehog signaling generates a long-range signal which can promote macrochaete formation in the Wingless activity domain. This signal depends upon decapentaplegic function. Autonomous activation of the Wingless signal response in cells causes them to attenuate or sequester this signal. Our results suggest a novel patterning mechanism which determines sense organ positioning in Drosophila.

Animals↗
PubMed1999

Calbindin D28K gene transfer via herpes simplex virus amplicon vector decreases hippocampal damage in vivo following neurotoxic insults.

Increases in cytoplasmic Ca2+ concentration ([Ca2+]i) can lead to neuron death. Preventing a rise in [Ca2+]i by removing Ca2+ from the extracellular space or by adding Ca2+ chelators to the cytosol of target cells ameliorates the neurotoxicity associated with [Ca2+]i increases. Another potential route of decreasing the neurotoxic impact of Ca2+ is to overexpress one of the large number of constitutive calcium-binding proteins. Previous studies in this laboratory demonstrated that overexpression of the gene for the calcium-binding protein calbindin D28K, via herpes simplex virus (HSV) amplicon vector, increases the survival of hippocampal neurons in vitro following energetic or excitotoxic insults but not following application of sodium cyanide. We now report that in vivo hippocampal infection with the calbindin D28K HSV vector increases neuronal survival in the dentate gyrus after application of the antimetabolite 3-acetylpyridine and increases transsynaptic neuronal survival in area CA3 following kainic acid neurotoxicity. The protective effects of infection with the calbindin D28K vector in an intact brain may prove to be beneficial during changes in Ca2+ homeostasis caused by neurological trauma associated with aging and certain neurological diseases.

Animals↗
PubMed1998

Comparison of ventral subicular and hippocampal neuron spatial firing patterns in complex and simplified environments.

Activity from ventral subicular and hippocampal CA1 neurons was recorded in rats exploring a 4-arm radial maze in which the local and distal cues could be manipulated. Cells from both regions exhibited place fields, although ventral subicular neurons had larger fields than hippocampal cells. Rotation of the local and distal cues in opposite directions produced movement of the place fields in either direction or a complete change in firing pattern. Simplifying the environment also produced changes in place field location. Despite similarities between regions, subiculum fields decreased in size whereas hippocampal fields increased in the simple environment. These findings suggest that subicular cells may receive converging input from several hippocampal neurons and code more complex configurations of the cues.

Analysis of Variance↗
PubMed1998

Fat, plain, but not friendless: self-esteem and peer acceptance of obese pre-adolescent girls.

OBJECTIVES: Poor self-esteem is assumed, but not consistently found, in obese children and adolescents. The aims of this study were a detailed analysis of body weight influences on self-esteem and peer acceptance in pre-adolescent girls. DESIGN: A cross-sectional comparison of girls in four weight (body mass index [BMI]) groups; underweight (< 10%), normal weight (10-85%), overweight (85-95%), and obese (> 95%). MEASURES: Assessments of body weight and height, body shape preference, self-esteem and peer nominations of popularity and attractiveness were collected from 313 girls aged 9y. RESULTS: Obese and overweight girls had significantly lower physical appearance and athletic competence self-esteem than their normal weight peers. Body weight had no impact on girls' rated importance of self-esteem domains. Heavier girls were significantly less likely to be peer nominated as pretty, but did not differ in their popularity. CONCLUSIONS: Prior to adolescence, physical appearance rather than global self-esteem is affected by overweight, and popularity preserved. Further research is required into the mechanisms of peer influence, and its consequences, in obese and overweight young adolescents.

Body Constitution↗
PubMed1997

Genetic relationships between the mutations spade and Sternopleural and the wingless gene in Drosophila development.

In Drosophila melanogaster, there are cases in which gene products contributing to the same developmental event may derive from closely adjacent transcription units and may even share cis-regulatory sequences. Correct recognition of such genomic organization is central to an understanding of developmental mechanisms. The adult phenotypes of combinations between the mutations spade, Sternopleural, and wingless suggest that they are lesions in functionally related genes within the same chromosomal region. wingless mutations fail to complement the recessive mutation spade. The spade mutation, as previously shown, behaves as a lesion in a regulatory site of wingless, sited 5' to the transcription unit, and is concerned with particular postembryonic functions of wingless. While showing wingless-like phenotypes in combination with Sternopleural, even lethal alleles of wingless complement the recessive lethality of Sternopleural alleles. Mutations in Sternopleural increase the severity of wingless phenotypes in many wingless-dependent processes during postembryonic development, and this interaction can occur when the only functional copies of Sp or wg are located in either opposing chromosomes or the same chromosome. This is inconsistent with previous attempts to define Sp as a regulatory allele of wg and explain the phenotypes that result from combinations of Sp and wg by means of transvection. We have analyzed a new EMS-induced allele of Sternopleural that is more severe than the original allele, which also argues for Sp being a separate, mutable genetic locus rather than a regulatory allele of wg. Finally, we have a revertant of Sternopleural (Sp[Rv1]) that behaves as a genetic null allele of wg, but causes ventral-to-dorsal transformations in combination with wg(P), which is not observed in combinations of wg null alleles with wg(P). Because wg(P) is the result of an inversion and because inversions inhibit transvection, the increased severity observed in Sp(Rv1)/wg(P) in comparison to wg(null)/Sp(Rv1) animals cannot be explained by an absence of transvection. Therefore, the two Sternopleural mutations most reasonably define an independent gene located 3' to the wingless gene and having strong functional synergism with it.

Animals↗
PubMed1995

Lesions of the fornix but not the entorhinal or perirhinal cortex interfere with contextual fear conditioning.

The effects of entorhinal cortex lesions, combined entorhinal and perirhinal cortex lesions, and fornix lesions on the conditioning of fear responses (freezing) to contextual stimuli were examined using a conditioning procedure known to produce hippocampal-dependent contextual conditioning. Lesions of the entorhinal and or entorhinal plus perirhinal cortex did not disrupt contextual conditioning, but lesions of the fornix did. None of the lesions affected conditioning to an explicit conditioned stimulus. Given that the entorhinal cortex is the primary linkage between the neocortex and the hippocampus and that the fornix is the primary linkage with subcortical structures, subcortical inputs to and outputs of the hippocampus appear to be sufficient to mediate contextual fear conditioning. As a result, the presumption that neocortical information is required for contextual fear conditioning, and perhaps other hippocampal-dependent functions, should be reevaluated.

Animals↗
PubMed1993

wingless expression mediates determination of peripheral nervous system elements in late stages of Drosophila wing disc development.

We have used conditional wingless genotypes to dissect the role of this gene in late stages of wing disc development. One of these genotypes (wgIL/wg-lacZ) is simultaneously a reporter of wingless transcription and temperature-sensitive for wingless function, and has allowed us to define its pattern of transcription in the absence of wingless activity. The primordia of a subset of the bristles of the notum, which develop in or immediately adjacent to wingless-expressing cells, depend upon wingless activity. The time-course of this contribution and the effect on proneural gene expression together suggest that wingless may regulate the activity of products of the achaete-scute complex in proneural clusters. wingless activity is also required at the presumptive wing margin and is a necessary precondition for the change in proliferation pattern in this region. The involvement of wingless in transducing or mediating positional signals for spatial patterning in imaginal disc development is discussed.

Animals↗
PubMed1992

Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning.

The contribution of the amygdala and hippocampus to the acquisition of conditioned fear responses to a cue (a tone paired with footshock) and to context (background stimuli continuously present in the apparatus in which tone-shock pairings occurred) was examined in rats. In unoperated controls, responses to the cue conditioned faster and were more resistant to extinction than were responses to contextual stimuli. Lesions of the amygdala interfered with the conditioning of fear responses to both the cue and the context, whereas lesions of the hippocampus interfered with conditioning to the context but not to the cue. The amygdala is thus involved in the conditioning of fear responses to simple, modality-specific conditioned stimuli as well as to complex, polymodal stimuli, whereas the hippocampus is only involved in fear conditioning situations involving complex, polymodal events. These findings suggest an associative role for the amygdala and a sensory relay role for the hippocampus in fear conditioning.

Amygdala↗
PubMed1990

The Drosophila segment polarity gene patched is involved in a position-signalling mechanism in imaginal discs.

We demonstrate the role of the segment polarity gene patched (ptc) in patterning in the cuticle of the adult fly. Genetic mosaics of a lethal allele of patched show that the contribution of patched varies in a position-specific manner, defining three regions in the wing where ptc clones, respectively, behave as wild-type cells, affect vein formation, or are rarely recovered. Analysis of twin clones demonstrates that the reduced clone frequency results from a proliferation failure or cell loss. In the region where clones upset venation, they autonomously fail to form veins and also non-autonomously induce ectopic veins in adjacent wild-type cells. In heteroallelic combinations with lethal alleles, two viable alleles produce distinct phenotypes: (1) loss of structures and mirror-image duplications in the region where patched clones fail to proliferate; (2) vein abnormalities in the anterior compartment. We propose that these differences reflect independently mutable functions within the gene. We show the pattern of patched transcription in the developing imaginal wing disc in relation to the expression of certain other reporter genes using a novel double-labelling method combining non-radioactive detection of in situ hybridization with beta-galactosidase detection. The patched transcript is present throughout the anterior compartment, with a stripe of maximal intensity along the A/P compartment border extending into the posterior compartment. We propose that the patched product is a component of a cell-to-cell position-signalling mechanism, a proposal consistent with the predicted structure of the patched protein.

Alleles↗
PubMed1987

Phenocopies induced with antisense RNA identify the wingless gene.

Earlier work suggested that the wingless gene of Drosophila is required for cooperation within discrete groups of cells during development. We show that antisense RNA made from a 3 kb transcript produces wingless mutant phenocopies when injected into wild-type eggs, proving that this transcript executes the wingless function. In the accompanying paper, Rijsewijk et al. report cloning of a Drosophila homolog (Dint-1) of the mouse int-1 gene and show that this gene is identical to wingless+. The partial sequence of the wingless cDNA that we have isolated is identical to part of the complete Dint-1 sequence described by Rijsewijk et al.

Animals↗
PubMed1983

Detection of specific murine anti-tumour immunity and serum factors by the indirect E-rosette augmentation assay.

The spontaneous interaction of sheep erythrocytes and human lymphocytes results in the formation of aggregates known as E-rosettes. The antigen reactivity of murine T-lymphocytes can be detected indirectly by the production of a lymphokine that augments the E-rosette-forming ability of human lymphocytes. An indirect E-rosette augmentation (ERA) assay was used to study cellular reactivity and tumour-related serum reactions in mice bearing methylcholanthrene (MCA)-induced tumours. The assay was used to demonstrate the antigenic specificity of two tumours and to detect blocking factors in tumour-bearer serum. Blocking factors were shown to be tumour-specific and to act on lymphocytes at an early stage before exposure to antigen.

Animals↗