Biomedical subjects
Publications and source records attributed to J L Hicks.
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The ninaC proteins are found in Drosophila photoreceptor cells. Their primary sequences suggest they are kinase/myosin chimeras, but their myosin head-like domain is the most divergent amongst all the myosin-like proteins described to date. To investigate possible roles of the ninaC proteins in cell structure, we examined the ultrastructure of the photoreceptor cells in various ninaC mutants, and tested the ability of the proteins to interact with actin filaments in a myosin-like manner. In flies lacking the larger ninaC protein, p174, an ultrastructural phenotype was evident before eclosion. The axial actin cytoskeleton of the rhabdomeral microvilli appeared either fragmented or as an isolated structure, without linkage to the microvillar membrane. Deletion of the myosin head-like domain or the calmodulin-binding domain of p174 resulted in a similar abnormal cytoskeleton. Breakdown of the rhabdomeres followed, although at different rates depending on the deletion. Lack of the smaller protein, p132, per se did not result in photoreceptor degeneration, but in older flies there was an abnormal accumulation of multivesicular bodies. Moreover, the presence of p132 retarded the degeneration that occurs in the absence of p174, even though the p132 remained outside the rhabdomere. Biochemical studies showed that both ninaC proteins bind actin filaments and cosediment with actin filaments in an ATP-sensitive manner. These results outline structural roles for the ninaC proteins, and are consistent with the notion, suggested by their amino acid sequences, that the proteins are actin-based mechanoenzymes.
Three experiments were performed to test Smith, Ward, and Schumacher's (1993) conformity hypothesis-that people's ideas will conform to examples they are shown in a creative generation task. Conformity was observed in all three experiments; participants tended to incorporate critical features of experimenter-provided examples. However, examination of total output, elaborateness of design, and the noncritical features did not confirm that the conformity effect constrained creative output in any of the three experiments. Increasing the number of examples increased the conformity effect (Experiment 1). Examples that covaried features that are naturally uncorrelated in the real world led to a greater subjective rating of creativity (Experiment 2). A delay between presentation and test increased conformity (Experiment 3), just as models of inadvertent plagiarism would predict. The explanatory power of theoretical accounts such as activation, retrieval blocking, structured imagination, and category abstraction are evaluated.
Calcium signaling within astrocytes in the CNS may play a role comparable to that of electrical signaling within neurons. ATP is a molecule known to produce Ca2+ responses in astrocytes, and has been implicated as a mediator of intercellular Ca2+ signaling in other types of nonexcitable cells. We characterized the signal transduction pathway for ATP-evoked Ca2+ responses in cultured astrocytes from the dorsal spinal cord. Nearly 100% of these astrocytes respond to extracellularly applied ATP, which causes release of Ca2+ from an intracellular pool that is sensitive to thapsigargin and insensitive to caffeine. We found that intracellular administration of IP3 also caused release of Ca2+ from a thapsigargin-sensitive intracellular pool, and that IP3 abolished the response to ATP. The ATP-evoked Ca2+ response was blocked by the IP3 receptor antagonist heparin, applied intracellularly, but not by N-desulfated heparin, which is not an antagonist at these receptors. The Ca2+ response caused by ATP was also blocked by a phospholipase C inhibitor, U-73122, but not by its inactive analog, U-73343. Increases in [Ca2+]i were elicited by intracellular application of activators of heterotrimeric G-proteins, GTP gamma S and AIF4-. On the other hand, [Ca2+], was unaffected by a G-protein inhibitor, GDP beta S, but it did abolish the Ca2+ response to ATP. Pretreating the cultures with pertussis toxin did not affect responses to ATP. Our results indicate that in astrocytes ATP-evoked release of intracellular Ca2+ is mediated by IP3 produced as a result of activating phospholipase C coupled to ATP receptors via a G-protein that is insensitive to pertussis toxin. ATP is known to be released under physiological and pathological circumstances, and therefore signaling via the PLC-IP3 pathway in astrocytes is a potentially important mechanism by which ATP may play a role in CNS function.
ATP has been proposed as a possible chemical mediator of synaptic transmission in the spinal dorsal horn on the basis that it is released in dorsal horn synaptosomes in a Ca(2+)-dependent manner and that its effects mimic those of synaptic inputs to dorsal horn neurons. In the present study we examined the actions of ATP on neurons and glia in cell culture using optical and electrophysiological recording techniques. We found that ATP increased intracellular Ca2+ concentration ([Ca2+]i) in > 99% of astrocytes. In contrast, only 35% of neurons and 20% of oligodendrocytes responded to ATP. The prevalence of the ATP-evoked response in astrocytes led us to characterize the type of receptor mediating the response, the source of Ca2+, and the membrane currents activated by ATP. We found that ADP was approximately equipotent with ATP in increasing [Ca2+]i whereas AMP and adenosine had no effect. In addition, responses to ATP were blocked in a concentration-dependent manner by the P2 purinergic receptor antagonist suramin. Furthermore, as it was found that 2-methylthio-ATP was more potent than ATP and that beta, gamma-methylene-ATP was ineffective, the responses were mediated via the P2 gamma subtype of purinergic receptor. The increase in [Ca2+]i evoked by ATP persisted in extracellular medium with no added Ca2+ and containing EGTA, indicating that this increase was due to release of Ca2+ from intracellular stores. Release of Ca2+ by ATP was blocked by thapsigargin but was unaffected by caffeine. ATP had several effects on membrane current activating inward, outward, and mixed currents despite uniformly causing increases in [Ca2+]i. These observations indicate that ATP has diverse electrophysiological effects on astrocytes as well as increasing [Ca2+]i in these cells. We speculate that ATP released from synaptic terminals in the dorsal horn might act not only on postsynaptic neurons but also on perisynaptic astrocytes. Thus, a physiological role for ATP may be as a neuronal-glial signaling molecule within the spinal dorsal horn.
In September of 1991, all postgraduate general dentistry (PGD) program directors (Advanced Education in General Dentistry [AEGD] and General Practice Residency [GPR] directors [n = 325]) were surveyed to ascertain their opinions of the ideal goals and objectives of PGD programs. The response rate was 81.5 percent (n = 265). The directors rated the relative importance of various PGD program goals and objectives. The average of all the items rated was 3.4 on a scale ranging from 1 = unimportant to 4 = very important. The respondents identified several clinical and didactic subject areas that they considered very important including; infection control, CPR, dental and medical emergencies, diagnosing dentoalveolar trauma, diagnosing oral pathology, and assessment and treatment of patients with medical conditions. They also identified several training areas which were beyond the scope of a PGD program, e.g., research techniques, pediatric sedation, and selected advanced clinical procedures in dentistry (implantology and orthodontics) which require a long time to complete. In general, there was substantial agreement among the directors of different program types and sites as to the relative importance of various program goals. The largest differences were found among directors of programs from different sites, e.g., hospitals versus dental schools as opposed to directors from different program types, e.g., GPR versus AEGD. There is now a need to determine the relationship of these identified idealized goals and differences to program outcomes for the graduates of PGDs.
The local anesthetic-like Na+ channel-blocking drug [3H]PD85639 [alpha-([4-3H]phenyl)-N-[3-(2,6-dimethyl-1-piperizinyl)-alpha-prop yl] [4-3H]benzeneacetamide] binds specifically to receptor sites on Na+ channels in intact synaptosomes and synaptosomal membranes, purified and reconstituted Na+ channels, and type IIA Na+ channel alpha subunits expressed in the transfected Chinese hamster ovary cell line CNaIIA-1. No specific binding was observed in nontransfected CHO-K1 cells, confirming the specificity of binding to Na+ channels. Two classes of binding sites that differed in affinity and dissociation rate were observed in all three preparations. In synaptosomes, the high affinity sites had Kd values of 3-20 nM and a Bmax of approximately 0.2 pmol/mg, whereas the low affinity sites had Kd values of 0.4-20 microM and a Bmax of approximately 5 pmol/mg. Binding of PD85,639 was inhibited by the local anesthetics tetracaine, bupivacaine, and mepivacaine at concentrations in the same range as those that inhibit Na+ channels. Tetracaine did not affect the dissociation rate of PD85,639, consistent with competitive binding of these two drugs at the same receptor site. In contrast, binding of PD85,639 was unaffected by the anticonvulsants phenytoin and carbamazepine, which also inhibit Na+ channels. Veratridine and batrachotoxin, which bind at neurotoxin receptor site 2 on Na+ channels, inhibited specific PD85,639 binding completely. PD85,639 accelerated dissociation of specifically bound batrachotoxin, consistent with an indirect allosteric interaction between these two compounds. Thus, like local anesthetics, PD85,639 inhibits binding of batrachotoxin by an allosteric mechanism. The results indicate that PD85,639 binds specifically to a local anesthetic receptor site on the Na+ channel alpha subunit that is allosterically linked to neurotoxin receptor site 2. PD85,639 may be a useful molecular probe of this important drug receptor site on the Na+ channel.
The ninaC gene encodes two retinal specific proteins (p132 and p174) consisting of a protein kinase domain joined to a domain homologous to the head region of the myosin heavy chain. The putative myosin domain of p174 is linked at the COOH-terminus to a tail which has some similarities to myosin-I tails. In the current report, we demonstrate that the ninaC mutation results in light- and age-dependent retinal degeneration. We also show that ninaC flies display an electrophysiological phenotype before any discernible retinal degeneration indicating that the electrophysiological defect is the primary effect of the mutation. This suggests that ninaC has a role in phototransduction and that the retinal degeneration is a secondary effect resulting from the defect in phototransduction. To examine the requirements for the individual ninaC isoforms, mutant alleles were generated which express only p132 or p174. Elimination of p174 resulted in a ninaC phenotype as strong as the null allele; however, elimination of p132 had little if any effect. As a first step in investigating the basis for the difference in requirements for p174 and p132 we performed immuno-localization at the electron microscopic level and found that the two isoforms display different subcellular distributions in the photoreceptor cells. The p132 protein is restricted primarily to the cytoplasm and p174 to the rhabdomeres, the microvillar structure which is the site of action of many of the steps in phototransduction. This suggests that the p174 myosin-I type tail is the domain responsible for association with the rhabdomeres and that the substrate for the p174 putative kinase may be a rhabdomeric protein important in photo-transduction.
The Drosophila ninaC gene encodes for two head-specific proteins of 132 kDa and 174 kDa. Their predicted amino acid sequences indicate that they may have myosin I and kinase properties. We have: (1) determined the cellular and subcellular distributions of the ninaC proteins in the Drosophila retina by electron microscopic immunocytochemistry with an antibody specific for epitopes shared by both proteins; (2) characterized the ultrastructure of the mutant phenotype. The proteins were detected only in the photoreceptor cells, but were detected in all classes of the compound eye photoreceptors. Within the photoreceptors, they were found in the rhabdomeral microvilli and the cytoplasm adjacent to the rhabdomeres. This distribution coincides with that shown previously for actin filaments. Immunolabelling of tissue from the ninaC P221 mutant, which lacks the 174 kDa protein, and two mutants whose rhabdomeres degenerate, suggests that the 132 kDa protein is present primarily in the cytoplasm adjacent to the rhabdomeres, and that the 174 kDa protein is concentrated in the rhabdomeres. Our ultrastructural analysis showed that the axial cytoskeleton of the rhabdomeral microvilli (which contains filamentous actin) was absent in both the null and P221 mutants. In the photoreceptor cell cytoplasm, the number of multivesicular bodies in the null mutant, but not the P221 mutant, was 3-fold greater in comparison with wild-type.(ABSTRACT TRUNCATED AT 250 WORDS)
Panavia is a modified phosphate ester of dimethacrylate that purportedly forms a strong bond to tooth structure and to metals. The ability of this adhesive to bond orthodontic brackets to enamel was compared to the bond strengths of a no-mix bracket adhesive and a paste/paste autopolymerizing composite resin. Panavia did not form a bond as strong as that achieved by the bracket adhesive but was stronger than the composite resin.
The phototransductive microvilli of arthropod photoreceptors each contain an axial cytoskeleton. The present study shows that actin filaments are a component of this cytoskeleton in Drosophila. Firstly, actin was detected in the rhabdomeral microvilli and in the subrhabdomeral cytoplasm by immunogold labeling with antiactin. Secondly, the rhabdomeres were labeled with phalloidin, indicating the presence of filamentous actin. Finally, the actin filaments were decorated with myosin subfragment-1. The characteristic arrowhead complex formed by subfragment-1 decoration points towards the base of the microvilli, so that the fast growing end of each filament is at the distal end of the microvillus, where it is embedded in a detergent-resistant cap. Each microvillus contains more than one actin filament. Decorated filaments extend the entire length of each microvillus and project into the subrhabdomeral cytoplasm. This organization is comparable to that of the actin filaments in intestinal brush border microvilli. Similar observations were made with the photoreceptor microvilli of the crayfish, Procambarus. Our results provide an indication as to how any myosin that is associated with the rhabdomeres might function.
Two commercial orthodontic adhesives containing fluoride were evaluated in vitro for fluoride release. Fluoride release is critical in preventing both decalcification around orthodontic brackets and the formation of white spot lesions. A paste-type adhesive composite resin and a glass ionomer luting agent were compared to a glass ionomer restorative material to determine fluoride release. The composite resin adhesive released minimal fluoride for only three days and then ceased. The glass ionomer adhesive released fluoride at a similar rate to the glass ionomer restorative material with fluoride release still evident at three months.
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This study investigated the effects of reducing dental clinical requirements. Twenty-seven senior students participated in a modified system in which requirements were reduced to essential experiences, points were awarded for all procedures completed, and a total point requirement was created to ensure comprehensive care. The remaining seniors (N = 97), who operated under the conventional requirement system, served as controls. No significant differences were found between the groups in daily clinic grades, comprehensive examination performance, final senior-year grade point average, or number of procedures completed. A year-end questionnaire on stress and anxiety indicated that the experimental group perceived less stress and anxiety, were significantly more positive about their performance evaluations, and perceived significantly less pressure to complete procedures.
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Although appreciated by most practitioners, the fact that dental infection may be the source of bacteremia without a history of recent dental procedures is occasionally overlooked. The case reported here illustrates what we feel is an example of such a phenomenon. The eradication of the oral foci of infection enhanced the patient's response to therapy and prompted his ultimate recovery.
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This study examines the hypothesis that susceptibility of cattle to high-altitude pulmonary hypertension and heart failure (high mountain disease) is genetically transmitted. Eight offspring of cattle recovered from high mountain disease were considered "susceptible." Eleven offspring of healthy cattle residing at high altitude were considered "resistant." At the resident altitude of 1,524 m, 10-day-old susceptible calves had higher pulmonary arterial pressures than did resistant calves (34 vs.21 mmHg), but at 90 days of age the pressures for the two groups were similar (26 vs. 24 mmHg). After 64 days of exposure to an altitude of 3,048 m, the susceptible calves (87 +/- 7 (SE) vs. 40 +/- 3 mmHg). By 124 days at 3,048 m, all susceptible but none of the resistant calves had developed heart failure. The results indicated that susceptibility to pulmonary hypertension at high altitude was inherited. Susceptible cattle may provide a useful model of human hypoxic pulmonary hypertension.