The expression of a C. elegans neurotransmitter transporter gene (T25B6.7).
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Animals↗
Biomedical subjects
D MacGregor
Publications and source records attributed to D MacGregor.
Immunotherapy of melanoma: targeting defined antigens.
The clinical experience that spontaneous anti-melanoma immune reactivity can occur has stimulated the search for methods to induce this in patients diagnosed with melanoma. Non-specific approaches using a variety of immune stimulants such as BCG or cytokines have met with limited success, as have vaccines derived from tumour cells. More recently, melanoma antigens have been identified that can act as specific targets for immune recognition. Cell surface glycolipids such as the gangliosides GM2 and GD3, can be targeted by antibodies. This has provided the basis for clinical trials with ganglioside vaccines and monoclonal antibody infusions. Antigens recognized by cytotoxic lymphocytes have also been described in the last 5 years. These are peptide antigens derived from intracellular proteins which are present on the cell surface in association with HLA molecules. These antigens include MAGE 1 and 3, tyrosinase, MelanA/MART-1 and gp100. Clinical trials with these have commenced and novel treatment strategies are being developed. Since tumours can be typed for specific antigens and specific immune responses can be measured, the reasons for treatment success or failure can be analysed more effectively than in the past. For example, the emergence of antigen-negative tumour variants can be assessed. This should enable a more systematic approach for developing new immunotherapies for melanoma.
Antigens, Neoplasm↗
The expanding clinical phenotype of the tRNA(Leu(UUR)) A-->G mutation at np 3243 of mitochondrial DNA: diabetic embryopathy associated with mitochondrial cytopathy.
We describe a family which demonstrates and expands the extreme clinical variability now known to be associated with the A-->G transition at nucleotide position 3243 of the mitochondrial DNA. The propositus presented at birth with clinical manifestations consistent with diabetic embryopathy including anal atresia, caudal dysgenesis, and multicystic dysplastic kidneys. His co-twin was normal at birth, but at 3 months of life, presented with intractable seizures later associated with developmental delay. The twins' mother developed diabetes mellitus type I at the age of 20 years and gastrointestinal problems at 22 years. Since age 19 years, the maternal aunt has had recurrent strokes, seizures, mental deterioration and deafness, later diagnosed as MELAS syndrome due to the tRNA(Leu(UUR)) A-->G mutation. A maternal uncle had diabetes mellitus type I, deafness, and normal intellect, and died at 35 years after recurrent strokes. This pedigree expands the known clinical phenotype associated with tRNA(Leu(UUR)) A-->G mutation and raises the possibility that, in some cases, diabetic embryopathy may be due to a mitochondrial cytopathy that affects both the mother's pancreas (and results in diabetes mellitus and the metabolic dysfunction associated with it) and the embryonic/fetal and placental tissues which make the embryo more vulnerable to this insult.
Abnormalities, Multiple↗
Dominant negative mutants of Myc inhibit cooperation of both Myc and adenovirus serotype-5 E1a with Ras.
We have used dominant negative Myc mutants to analyze the Myc and E1a mechanisms of cooperation with Ras. We show that mutants of Myc with an altered basic region (BR; RR366, 367EE) or deletion of the leucine zipper (LZ; delta aa 414-439), changes which modify the DNA binding domain, or with deletions in the Myc amino terminal conserved regions box 1 (dlMB1; delta aa 46-55) and box 2 (dlMB2; delta aa 132-140) inhibit cooperation of wt Myc and activated Ras to transform rat embryo fibroblasts (REF). Expression of the amino terminal 104 aa had no effect whereas wt Myc stimulated focus formation. Mutant dlMB1 cooperated with Ras with one half wt efficiency while dlMB2 was inactive. No mutant tested was toxic during neomycin cotransformation of REF to G418 resistance. Interestingly, these Myc mutants exerted a parallel inhibition of E1a-Ras cooperation to transform REF. This suggests that the Myc-Ras and E1a-Ras cooperation pathways intersect and require common protein factors. A Myc box 2 deletion mutant which is a wt transactivator of the Myc responsive ornithine decarboxylase promoter, but unlike the wt does not repress the adenovirus-2 core promoter (Li et al., 1994, EMBO J., 13:4070-4079), inhibits Myc-Ras and E1a-Ras cooperation. This suggests that a box 2-dependent step, potentially gene repression, is required for both the E1a- and Myc-Ras cooperation mechanisms.
Adenovirus E1A Proteins↗
Metabolism and inactivation of neurotransmitters in nematodes.
The nematode nervous system employs many of the same neurotransmitters as are found in higher animals. The inactivation of neurotransmitters is absolutely essential for the correct functioning of the nervous system. In this article we discuss the various mechanisms used generally in animal nervous systems for synaptic inactivation of neurotransmitters and review the evidence for similar mechanisms operating in parasitic and free-living nematodes. The sequencing of the entire Caenorhabditis elegans genome means that the sequence of nematode genes can be accessed from the C. elegans database (ACeDB) and this wealth of information together with the increasing knowledge of the genetics of this free-living nematode will have great impact on all aspects of nematode neurobiology. The review will provide an insight into how this information may be exploited to identify and characterize target proteins for the development of novel anti-nematode drugs.
Amino Acid Sequence↗
Presence of angiotensin II AT2 receptor binding sites in the adventitia of human kidney vasculature.
1. Angiotensin II (AngII) receptor subtypes in adult human kidney were pharmacologically characterized by in vitro autoradiography using the AngII receptor subtype-selective antagonists, losartan and PD 123319, and the sensitivity to the reducing agent, dithiothreitol. 2. High densities of AngII AT1 receptor binding occur in the glomeruli and the inner stripe of the outer medulla, while a moderate AT1 receptor binding is localized in the proximal convoluted tubules. 3. AT2 receptor binding is observed predominantly in the intrarenal large blood vessels, including the arcuate, inter- and intra-lobular arteries, and in the renal capsule. 4. In the major renal artery, AT1 receptor binding is abundant in the media and adventitia, while AT2 receptor binding is observed mainly in the adventitia. 5. At the light microscopic level using emulsion autoradiography, AT1 receptors are localized in the glomeruli and juxtaglomerular apparatus, as expected. However, in larger renal blood vessels, including the arcuate arteries, inter- and intra-lobular arteries, intense AT2 receptor labelling occurs primarily in the adventitia, while the endothelium and vascular smooth muscle layers contain only low levels of AngII receptor binding. 6. These results indicate that the adult human kidney displays two pharmacologically distinct AngII receptor subtypes, with AT1 predominating in the glomeruli, juxtaglomerular apparatus, proximal tubules and the inner stripe of the outer medulla, while AT2 predominates in the adventitia of the arcuate and interlobular arteries and the renal capsule. The functional significance of AT2 receptor binding sites in the adventitia of adult human kidney vessels remains to be elucidated.
Adult↗
Near threshold photoproduction of eta mesons off the proton.
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Journal Article↗
Down-regulation of vasopressin V1a receptor mRNA in diabetes mellitus in the rat.
1. To investigate the mechanism of hepatic V1a vasopressin receptor down-regulation in streptozotocin-induced diabetes mellitus in the rat, we measured hepatic V1a receptor mRNA by in situ hybridization histochemistry using oligonucleotide probes to the V1a receptor and Northern blotting. 2. Diabetes mellitus caused hyperglycaemia, hyperosmolality and increased plasma vasopressin concentrations (P < 0.01). Hepatocyte V1a receptor mRNA was reduced by 76% in diabetic rats (P < 0.01) and by 53% in insulin-treated diabetic rats (P < 0.01) versus control rats, in parallel with reduced V1a radioligand binding and vasopressin-stimulated inositol phosphates production. There was a similar decrease in hepatic V1a/18S mRNA density ratio in the diabetic and diabetic+insulin groups (both P < 0.05 versus control). 3. These findings suggest that altered V1a mRNA transcription is responsible for the reduced hepatic V1a receptor density in diabetes mellitus.
Animals↗
Regulation of cell proliferation and differentiation by Myc.
Myc is a nuclear phosphoprotein which controls cellular proliferation, most likely by regulating gene activity. The finding that the neuronal model cell line PC12 lacks the Myc DNA binding partner, the Max protein, and the demonstration that Myc is a repressor of gene activity as well as a transactivator, lead to models for Myc action in regulating cell growth.
Adenoviruses, Human↗
Familial Dandy-Walker malformation associated with macrocephaly, facial anomalies, developmental delay, and brain stem dysgenesis: prenatal diagnosis and postnatal outcome in brothers. A new syndrome?
Brothers are reported with an apparently new constellation of manifestations including Dandy-Walker complex (DWC), migrational brain disorder, macrocephaly, and facial anomalies. The first brother presented at birth, the second was detected prenatally with DWC and the pregnancy terminated. Fetal brain histopathology showed DWC associated with brainstem dysgenesis. Inheritance is likely autosomal or X-linked recessive. An extensive review of the differential diagnosis of DWC is provided.
Adult↗
c-Myc represses transcription in vivo by a novel mechanism dependent on the initiator element and Myc box II.
We show that c-Myc, in addition to activating transcription through E-box Myc binding sites (Ems), also represses transcription by a mechanism dependent on initiator (Inr) elements of the basal promoters of susceptible genes. Repression was first observed as a component of c-Myc biphasic regulation of the adenovirus-2 major late promoter (MLP), which contains both Inr and Ems sequences. Two differentiation-specific genes containing Inr, the C/EBP alpha and albumin genes, are repressed through their basal promoters by c-Myc, but are activated by the related B-HLH-LZ factor, USF. Repression requires both the B-HLH-LZ and Myc box II (MBII) domains. Significantly, a MBII deletion mutant which is deficient in repression, but transactivates normally, fails to cooperate with an activated ras gene to transform primary fibroblasts. Thus Myc-dependent transactivation is insufficient for Ras cooperation and the novel transcription repression function is implicated in Ras cooperation as well as the suppression of Inr-dependent genes.
Adenoviridae↗
Quality of toddler-mother attachment in children with Down syndrome: limits to interpretation of strange situation behavior.
Researchers studying social-emotional development have argued that primary attachment relationships, established by the end of the first year of life, are important organizing factors that influence the trajectory of development throughout childhood. Central to this argument is a dimension of "attachment security," along which attachments differ. For normally developing infants and toddlers, attachment security is assessed using the Ainsworth Strange Situation. However, it is not clear that this procedure is appropriate for evaluating attachment security in atypical populations. In this report, 3 samples of children with Down Syndrome (total N = 138) were assessed using the Strange Situation. The procedures were scored according to traditional protocols. Although the 3 samples differed with respect to chronological and developmental age, they showed basic similarity with respect to attachment variables. However, developmentally younger children were more difficult to classify using the standard scoring rules. Scores and classifications for the sample were compared to scores from a sample of normally developing children tested at about 12 months of age. Significant differences with respect to the distributions of cases to classification categories and with respect to the interactive scale scores suggest that the Strange Situation may be measuring different aspects of behavior for children with Down Syndrome, even when they are tested at similar developmental age levels.
Adult↗
Perceived risks of radioactive waste transport through Oregon: results of a statewide survey.
Transportation of hazardous materials, and particularly radioactive wastes, on public highways has become an important risk management issue. The unfavorability of public attitudes regarding hazardous and nuclear wastes signals the potential for strong public opposition to programs for transporting these materials. This paper presents the results of a survey conducted to assess public reactions to a long-term nuclear waste transport program planned to follow a route through a portion of rural Oregon. The survey assessed a number of key risk perception issues, including perceived health and safety risks of nuclear waste transport, relative risks of transport vs. storage at an existing site, trust in state officials, and satisfaction with life in communities along the transport route. The survey identified a number of attitudes and concerns that need to be understood and considered by those in charge of designing and implementing the waste-transportation program.
Data Collection↗
Mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes (MELAS): clinical, radiological, pathological, and genetic observations.
We reviewed 10 patients (5 males, 5 females) with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. The age of symptom onset ranged from 3 months to 12 years. All had lactic acidosis, multiple stroke-like events with secondary neurological deficits, radiological changes of progressive brain infarction, and muscle biopsy showing ragged-red fibers. In patients with earlier onset of symptoms (< 2 yr), involvement tended to be more diffuse, with failure to thrive and early onset of delayed development. Patients whose symptoms appeared later tended to have focal neurological deficits with migraine-like headache, and a rate of cognitive regression reflecting the rapidity of disease progression. Radiological changes included multiple areas of infarction with initial predilection for parietal occipital areas, progressing to generalized atrophy. Pathological findings in muscle biopsies included type 1 fiber predominance, ragged-red fibers, increased intermyofibrillar lipid deposition, and abnormal mitochondria. Four patients showed mitochondrial DNA tRNA mutation at position 3,243. No difference was noted in clinical, radiological, or pathological findings in patients with and without this mutation, suggesting that multiple sites of point mutation may give rise to mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes.
Base Sequence↗
Serotype variation in Bordetella pertussis is governed by cis-acting elements.
Bordetella pertussis contains two genes encoding the serospecific fimbrial subunit proteins 2 and 3 which are assembled into completed fimbriae, which elicit the formation of agglutinating antibodies. Expression of these agglutinogens can vary independently of each other. A gene library from a B. pertussis strain (fimbrial serotype 0.3) was probed with an oligonucleotide probe specific for fimbrial subunit genes. Three homologous genetic loci were identified; an active fim 3 gene, an inactive fim 2 gene and an unknown fim-homologous region. The fim 3 gene carried on a cosmid produced agglutinating fimbrial structures in B. parapertussis and in variants of B. pertussis which had lost the capacity to produce the agglutinogen. This indicated that cis-acting factors are associated with serotype variation in B. pertussis rather than the production of trans-acting repressor molecules.
Blotting, Southern↗
Gene regulation by growth factors.
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Animals↗
Perception of risk from automobile safety defects.
Descriptions of safety engineering defects of the kind that compel automobile manufacturers to initiate a recall campaign were evaluated by individuals on a set of risk characteristic scales that included overall vehicle riskiness, manufacturer's ability to anticipate the defect, importance for vehicle operation, severity of consequences and likelihood of compliance with a recall notice. A factor analysis of the risk characteristics indicated that judgments could be summarized in terms of two composite scales, one representing the uncontrollability of the damage the safety defect might cause and the other representing the foreseeability of the defect by the manufacturer. Motor vehicle defects were found to be highly diverse in terms of the perceived qualities of their risks. Location of individual defects within the factor space was closely associated with perceived riskiness, perceived likelihood of purchasing another car from the same manufacturer, perceived likelihood of compliance with a recall notice, and actual compliance rates.
Adolescent↗