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Biomedical subjects

D Nash

Publications and source records attributed to D Nash.

At least 19 recordsLinked to original sources

Dorsal wing, a locus that affects dorsoventral wing patterning in Drosophila.

The wing imaginal disc is subdivided into a dorsal and a ventral compartments. A new dominant homeotic mutation, Dorsal wing1 (Dlw1), transforms ventral into dorsal compartment in heterozygotes. This phenotype is similar to one of the dominant phenotypes of Polycomb (Pc) mutants. In Pc Dlw+/Pc+ Dlw1 double mutants, the transformation is greatly enhanced. The recessive phenotype of Dlw1 is the opposite to the dominant phenotype. Dlw1/Dlw1 somatic clones induced at any larval stage differentiate only ventral pattern on both wing surfaces. This effect is one of the somatic clone phenotypes of trithorax (trx) lethals. A similar dorsal-to-ventral transformation is observed in Pc Dlw/Dlw clones. Dlw1/Dlw1 clones have no effect elsewhere, except in the dorsal notum, which may differentiate extra macrochaetes. We propose that: (1) Dlw+ is required for the specification of dorsal compartment; (2) some genes of the Polycomb group act as negative regulators of Dlw+, while some genes of the trithorax group act as positive regulators.

Animals

Two solutions to the problem of noise exposure for motorcyclists.

Two solutions to the problem of excessive noise exposure and consequent hearing loss in motorcyclists were investigated and are described. One was an antecedent behaviour-modifying 'prompting' strategy, where a set of earplugs and an advice sheet were provided at the point of sale to consecutive purchasers of new motorcycle crash helmets. Forty-eight riders were recruited but data for analysis were only available in 41. The earplug usage rate was significantly increased from 27% to 83% by this intervention. The second solution involves various aerodynamics and sound-proofing helmet modifications made in an effort to reduce interior noise levels. The only modification which achieved a significant reduction from previously reported average sound levels was the incorporation of a pair of 'standard' earmuffs under the helmet shell. This gave noise levels of 84 dB(A) at 22 m/s (50 mph) and 93 dB(A) at 36 m/s (80 mph), compared to known average values of 95 dB(A) and 107 dB(A), respectively. Both solutions are eminently feasible and desirable, and we hope that the motorcycle industry will act on them.

Adult

The raspberry locus of Drosophila melanogaster includes an inosine monophosphate dehydrogenase like coding sequence.

DNA from the raspberry gene of Drosophila melanogaster has been cloned through P-element tagging of a dysgenically induced lethal allele. A transcribed DNA segment adjacent to the P insert encodes an amino acid sequence that is similar to known inosine monophosphate dehydrogenase (IMPDH) sequences. Further dysgenically induced lethals and all four known spontaneous ras eye-colour mutations have changes in the DNA either within or just upstream from the transcribed region. Identification of IMPDH as a probable product of the ras gene is compatible with the finding of an allele that requires dietary guanosine (GR), since the enzyme mediates the first of two biosynthetic steps leading from inosine monophosphate (IMP) to guanosine monophosphate (GMP). However, other auxotrophic mutants at the locus remain unexplained by the finding. The results further suggest that GMP synthesis from IMP is an essential process, despite the capacity of the fly for salvage synthesis of GMP from GR. Consideration of the phenotypes associated with mutants at the ras locus suggests that IMPDH activity is regulated in a tissue-specific manner.

Alleles

The adenosine2 gene of Drosophila melanogaster encodes a formylglycineamide ribotide amidotransferase.

Drosophila melanogaster genomic DNA spanning an adenosine2 gene rearrangement breakpoint (in cytological map region 26B1-2) was cloned and a composite ade2 base sequence was derived from this DNA and from a corresponding cDNA. Based on genetic evidence, the ade2 gene is thought to encode the purine biosynthetic enzyme formylglycineamide ribotide amidotransferase (FGARAT). The cDNA hybridizes to a 4.8-kb message that encodes a 1354 amino acid polypeptide with extensive similarity to Escherichia coli FGARAT. The D. melanogaster FGARAT amino acid sequence is considerably more like that of the E. coli enzyme than is the FGARAT of B. subtilis, which has two polypeptides with, collectively, 969 amino acids. It is suggested that the taxonomically anomalous similarity between the eukaryotic FGARAT and that from E. coli may indicate horizontal exchange of genetic material. On the basis of substantially greater conservation of sequences shared by all three species compared with those present only in E. coli and D. melanogaster, we suggest that no radical alteration of enzymatic function accompanied the transition between the single-gene and the two-gene state.

Amino Acid Sequence

Gut associated lymphoid tissue in the cotton rat (Sigmodon hispidus) and its response to protein restriction.

We examined age and nutritional related changes in the distribution and size of gut associated lymphoid tissues in the intestinal tract of cotton rats (Sigmodon hispidus). Peyer's patches in the small intestine are prominent, ranging from four to 13, and increase in size (surface area) with age. The average Peyer's patch in the adult cotton rat measured 23.9 mm2. Lymphoid tissue in the cecum was primarily limited to a large aggregate located in the vermiform appendix, which increased in size with age. Age related changes in the number of visible lymphoid follicles in the large intestine were highly significant, increasing from 24.8 in juveniles to 45.1 in adults. Weights of dissectable Peyer's patch tissue in animals consuming a low protein diet were significantly lower in juveniles and greater in subadults compared to those on high protein diets. Relative weights of Peyer's patch tissue averaged 84 to 95% more in low protein-fed animals than in the group on the high quality protein diet. Our results suggest that peripheral lymphoid tissues in wild cotton rats are more resistant to protein deficiencies than other tissues in the body and could be a useful index for assessing nutritional status.

Aging

Genetic analysis of the adenosine3 (Gart) region of the second chromosome of Drosophila melanogaster.

The Gart gene of Drosophila melanogaster is known, from molecular biological evidence, to encode a polypeptide that serves three enzymatic functions in purine biosynthesis. It is located in polytene chromosome region 27D. One mutation in the gene (ade3(1)) has been described previously. We report here forty new ethyl methanesulfonate-induced mutations selected aga!nst a synthetic deficiency of the region from 27C2-9 to ++28B3-4. The mutations were characterized cytogenetically and by complementation analysis. The analysis apparently identifies 12 simple complementation groups. In addition, two segments of the chromosome exhibit complex complementation behavior. The first, the 28A region, gave three recessive lethals and also contains three known visible mutants, spade (spd), Sternopleural (Sp) and wingless (wg); a complex pattern of genetic interaction in the region incorporates both the new and the previously known mutants. The second region is at 27D, where seven extreme semilethal mutations give a complex complementation pattern that also incorporates ade3(1). Since ade3(1) is defective in one of the enzymatic functions encoded in the Gart gene, we assume the other seven also affect the gene. The complexity of the complementation pattern presumably reflects the functional complexity of the gene product. The phenotypic effects of the mutants at 27D are very similar to those described for ade2 mutations, which also interrupt purine biosynthesis.

Adenosine

Drosophila purine auxotrophy: new alleles of adenosine 2 exhibiting a complex visible phenotype.

New mutant alleles of the adenosine2 locus (ade2; 2-17.7) have been isolated using the eye-color phenotype exhibited by the prototype auxotrophic allele ade2 as the screening criterion. The new mutants form a single complementation group, suggesting that they all exhibit purine auxotrophy and defective formylglycineamide ribotide amidotransferase enzyme, like ade2. Tests carried out on particular new alleles confirm these suggestions. The new mutants all exhibit more extreme physical defects than the prototype. They have wing abnormalities like mutants defective in pyrmidine biosynthesis and reduced bristles like those defective in protein synthesis; thus they exhibit the combined visible phenotype of rudimentary wings, rosy eyes, and bobbed bristles. Cytogenetic analysis places the locus in the interband proximal to 26B1-2.

Adenosine

Inhibition of Crimean-Congo hemorrhagic fever viral infectivity yields in vitro by ribavirin.

Ribavirin was evaluated as a potential therapeutic for Crimean-Congo hemorrhagic fever (CCHF). Viral yields for strains of CCHF virus from Europe, Asia, and Africa in African green monkey kidney (Vero) cells were markedly reduced by this drug. Some CCHF viral strains appeared more sensitive than others, but in general, ribavirin doses as low as 5 micrograms/ml caused a transient reduction of viral yields. A further reduction in viral yields was induced by a dose of 25 micrograms/ml, and evidence of viral replication was not demonstrated in cells treated with 50 or 250 micrograms/ml. In contrast, a dose of ribavirin at least 9 times greater was required to induce a comparable inhibitory effect on the yields of Rift Valley fever virus, for which the drug has been shown to inhibit replication in monkeys and rodents.

Animals

Two Drosophila melanogaster mutations block successive steps of de novo purine synthesis.

Drosophila melanogaster purine auxotrophs ade2(1) and ade3(1) have been characterized biochemically. The ade2(1) strain is deficient in the fourth step of the de novo purine synthetic pathway catalyzed by phosphoribosylglycinamidine synthase (phosphoribosylformylglycinamide amidotransferase). The ade3(1) strain is deficient in the previous step catalyzed by phosphoribosylglycinamide formyltransferase (GART). The mutation responsible for the slightly leaky ade3(1) phenotype was characterized further. First, the mutant GART polypeptide was found to be of normal size and present at normal levels. Second, the GART-encoding region of the mutant was cloned, inserted into a yeast-Escherichia coli shuttle vector, and used to transform mutant yeast. Transformants showed very slight in vivo activity when compared to wild type, verifying that the mutation is in the GART coding sequence. Lastly, the region of the gene encoding GART activity from mutant and inbred parental strain flies was completely sequenced. A single base transition was found, leading to the substitution of a serine for a highly conserved glycine. These two mutations provide examples of blocks in the de novo purine synthetic pathway in a whole animal.

Acyltransferases

Heterogeneity of lethals in a "simple" lethal complementation group.

Of 24 ethyl methanesulphonate-induced, recessive-lethal mutations in the region 9E1-9F13 of the X chromosome of Drosophila melanogaster, eight fall into a typically homogeneous lethal complementation group associated with the raspberry (ras) locus. Mutations in this group have previously been shown to be pleiotropic, affecting not only ras but also two other genetic entities, gua 1 and pur 1, which yield auxotrophic mutations.--The eight new mutations have been characterized phenotypically in double heterozygotes with gua 1, pur 1 and ras mutations. Despite their homogeneity in lethal complementation tests, the mutations prove quite diverse. For example, two mutations have little or no effect on eye color in double heterozygotes with ras2. The differences between the lethals are allele-specific and cannot be explained as a trivial outcome of a hypomorphic series.--Taken alone, the lethal complementation studies mask the complexity of the locus and the diversity of its recessive lethal alleles. By extension, we argue that the general use of lethal saturation studies provides an unduly simplified image of genetic organization. We suggest that the reason why recessive lethal mutations rarely present complex complementation patterns is that complex loci tend to produce mutations that affect several subfunctions.

Animals

Three purine auxotrophic loci on the second chromosome of Drosophila melanogaster.

Mutations at three second-chromosomal loci of Drosophila melanogaster have been isolated, mapped, and shown to be purine nucleoside auxotrophs. Two of the loci, adenosine2 and adenosine3, located at map positions 18.4 and 20, respectively, produce mutations which are supplementable with adenine, adenosine, and inosine. Guanosine supplements mutations at the burgundy locus (55.7); this locus was described previously through a pteridine eye-color defect but identified as an auxotrophic locus after the isolation of a new allele, burgua2-1. The mutation ade2-1 also has defective pteridine metabolism.

Adenosine

Increased serum and urinary calcitonin levels in patients with pulmonary disease.

Serum and urinary calcitonin levels were measured in patients with acute and chronic inflammatory diseases of the lung. Using both carboxyl terminal and midportion antisera, the incidence of increased immunoreactive values of this hormone was 68 percent for patients with emphysema, 59 percent for tuberculosis, and 89 percent for acute bacterial pneumonitis. In order to determine the source of the high levels of calcitonin, immunoperoxidase stains were made of sections of human lung; the hormone was found within the bronchial Kultschitzky cell (K cell). This suggests a specific endocrine role for the K cell, and may explain not only the high calcitonin levels in patients with inflammatory lung disease, but also the high levels associated with both carcinoid tumor and small cell carcinoma, which may originate from K cells. It is apparent that moderately high levels of calcitonin in a patient with pulmonary disease cannot always be associated with tumor.

Adult