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Biomedical subjects

D J Andrew

Publications and source records attributed to D J Andrew.

35 records · Page 2Linked to original sources
PubMed1998

Protection of human upper respiratory tract cell lines against sulphur mustard toxicity by glutathione esters.

1. Human and animal lung cells have been used successfully to model the toxic effects of inhaled sulphur mustard (HD). The epithelia of the upper respiratory tract are, however, the primary targets of inhaled HD. The aim of this study was to assess the potential of the mono- and di-isopropyl esters of glutathione (MIPE and DIPE respectively) as cytoprotectants in the human upper respiratory tract cell lines BEAS-2B and RPMI 2650. 2. The optimal concentrations for cytoprotection were shown to be 1.0 mg/ml for both DIPE and MIPE. Both compounds were found to protect cells by pretreatment, slightly less protection was observed in cells simultaneously exposed to sulphur mustard. The greatest protection was shown where MIPE or DIPE were in in situ at the time of exposure to HD. The optimum pre-treatment times were found to be 1 h for MIPE and 2 h for DIPE. Limited protection of cells treated with MIPE or DIPE immediately following HD exposure was also demonstrated. No protection was observed if MIPE or DIPE were not administered immediately following HD exposure. 3. Results suggest that MIPE and DIPE may be effective treatments for exposure to HD by inhalation.

Cell Line↗
PubMed1997

The CRE-binding protein dCREB-A is required for Drosophila embryonic development.

We have previously described the cloning of a cyclic AMP response-element (CRE)-binding protein, dCREB-A, in Drosophila melanogaster that is similar to the mammalian CRE-binding protein CREB. dCREB-A is a member of the bZIP family of transcription factors, shows specific binding to the (CRE), and can activate transcription in cell culture. In this report, we describe the gene structure for dCREB-A, protein expression patterns throughout development and the necessary role for this gene in embryogenesis. The 4.5-kb transcript is encoded in six exons that are distributed over 21 kb of DNA. There are seven start sites and no TATA consensus sequences upstream. The dCREB-A protein is expressed in the nuclei of the embryonic salivary gland, proventriculus and stomadeum. Late in embryogenesis, tracheal cell nuclei and specific nuclei within the segments show staining with anti-dCREB-A antibodies. In adult female ovaries, dCREB-A is expressed in the stage 9 through stage 11 follicle cell nuclei. Null mutations of the dCREB-A gene give rise to animals that no longer express dCREB-A protein and die late in embryogenesis before or at hatching. The absolute requirement of dCREB-A for embryogenesis demonstrates a nonredundant function for a CRE-binding protein that will be useful in studying the role of specific signal transduction cascades in development.

Animals↗
PubMed1997

The Drosophila dCREB-A gene is required for dorsal/ventral patterning of the larval cuticle.

We report on the characterization of the first loss-of-function mutation in a Drosophila CREB gene, dCREB-A. In the epidermis, dCREB-A is required for patterning cuticular structures on both dorsal and ventral surfaces since dCREB-A mutant larvae have only lateral structures around the entire circumference of each segment. Based on results from epistasis tests with known dorsal/ventral patterning genes, we propose that dCREB-A encodes a transcription factor that functions near the end of both the DPP- and SPI-signaling cascades to translate the corresponding extracellular signals into changes in gene expression. The lateralizing phenotype of dCREB-A mutants reveals a much broader function for CREB proteins than previously thought.

Animals↗
PubMed1996

Tubulogenesis in Drosophila: a requirement for the trachealess gene product.

The trachealess (trh) gene of Drosophila is required for embryonic tube formation. In trh mutants, tube-forming cells of the salivary gland, trachea, and filzkörper fail to invaginate to form tubes and remain on the embryo surface. We identified a P-element insertion that disrupts trh function and used the insert to clone and characterize trh. trh is expressed in the salivary duct, trachea, and filzköper primordia, and expression persists in these cells throughout embryogenesis. trh expression in the salivary duct is controlled by the homeotic gene, Sex combs reduced (Scr), and by another salivary gland gene, fork head (fkh). trh is homologous to two transcription factors: the human hypoxia-inducible factor-1 alpha and the Drosophila Single-minded protein.

Amino Acid Sequence↗
PubMed1995

The Sex combs reduced gene of Drosophila melanogaster has multiple transcripts.

The Sex combs reduced (Scr) homeotic gene of Drosophila melanogaster specifies the development of structures within the most posterior head segment, the labium and the most anterior thoracic segment, the prothorax or T1. Here, the structure of Scr and correct sequence of the SCR protein are presented. Scr encodes a 417-amino-acid DNA-binding protein with sequence similarity to the mouse homologues, HOXA5, B5 and C5. The greatest similarity is within the DNA-binding homeodomain (hdm); shorter conserved motifs are found near the N terminus and a region N-terminal to the hdm. As with most of the D. melanogaster homeotic genes, Scr has alternative exons.

Amino Acid Sequence↗
PubMed1994

Setting limits on homeotic gene function: restraint of Sex combs reduced activity by teashirt and other homeotic genes.

Each of the homeotic genes of the HOM or HOX complexes is expressed in a limited domain along the anterior-posterior axis. Each homeotic protein directs the formation of characteristic structures, such as wings or ribs. In flies, when a heat shock-inducible homeotic gene is used to produce a homeotic protein in all cells of the embryo, only some cells respond by altering their fates. We have identified genes that limit where the homeotic gene Sex combs reduced (Scr) can affect cell fates in the Drosophila embryo. In the abdominal cuticle Scr is prevented from inducing prothoracic structures by the three bithorax complex (BX-C) homeotic genes. However, two of the BX-C homeotic genes, Ultrabithorax (Ubx) and abdominal-A (abd-A), have no effect on the ability of Scr to direct the formation of salivary glands. Instead, salivary gland induction by Scr is limited in the trunk by the homeotic gene teashirt (tsh) and in the last abdominal segment by the third BX-C gene, Abdominal-B (AbdB). Therefore, spatial restrictions on homeotic gene activity differ between tissues and result both from the regulation of homeotic gene transcription and from restraints on where homeotic proteins can function.

Animals↗
PubMed1993

Ectopic expression and function of the Antp and Scr homeotic genes: the N terminus of the homeodomain is critical to functional specificity.

The transcription factors encoded by homeotic genes determine cell fates during development. Each homeotic protein causes cells to follow a distinct pathway, presumably by differentially regulating downstream 'target' genes. The homeodomain, the DNA-binding part of homeotic proteins, is necessary for conferring the specificity of each homeotic protein's action. The two Drosophila homeotic proteins encoded by Antennapedia and Sex combs reduced determine cell fates in the epidermis and internal tissues of the posterior head and thorax. Genes encoding chimeric Antp/Scr proteins were introduced into flies and their effects on morphology and target gene regulation observed. We find that the N terminus of the homeodomain is critical for determining the specific effects of these homeotic proteins in vivo, but other parts of the proteins have some influence as well. The N-terminal part of the homeodomain has been observed, in crystal structures and in NMR studies in solution, to contact the minor groove of the DNA. The different effects of Antennapedia and Sex combs reduced proteins in vivo may depend on differences in DNA binding, protein-protein interactions, or both.

Amino Acid Sequence↗
PubMed1992

Downstream of the homeotic genes.

The homeotic genes of Drosophila melanogaster determine which structures form in each of the body segments. Disrupting the function of the homeotic genes causes body parts found in one domain of the animal to be replaced by body parts normally found elsewhere. Each of the homeotic genes encodes a protein, or a closely related family of proteins, which is capable of binding DNA and controlling the transcriptional activities of downstream genes. The homeotic genes are in the middle of a complex regulatory network, and many of the genes that control homeotic expression have been well characterized. However, very little is known about what comes after the homeotic genes, the downstream genes whose activities are regulated by the homeotic genes. Here, we review the known relationships between the homeotic proteins and the few identified target genes. The details of these interactions may be characteristic and may thus guide the search for additional targets.

Animals↗
PubMed1988

Identifying sleep apnea from self-reports.

An apnea score (AS) was developed as a potential screening tool for sleep apnea. This was based on self-report questionnaire responses of 76 sleep disorder center patients and 20 sleep survey volunteers. Twenty volunteers and 23 patients (group I) comprised the initial AS development group. Their questionnaire responses were compared to polysomnographic apnea indexes (AI) and apnea plus hypopnea indexes (AHI). Stepwise multivariate discriminant analysis was used to test whether or not selected group I questionnaire responses could be used to correctly classify respondents into apnea (AI or AHI greater than 5) or nonapnea (AI, AHI less than or equal to 5) groups. Self-reports of "stops breathing during sleep," "loud snoring," and history of adenoidectomy best discriminated normal (AI less than or equal to 5) from apnea (AI greater than 5) cases. The AS derived from group I responses to these three variables was then computed for group II (n = 53). After examination of the AS results, the AS was modified to include just "stops breathing" and "loud snoring" and the AI criterion was raised to 10 per hour. This revised AS correctly identified 100% of the cases with moderate-severe sleep apnea (AI or AHI greater than 40) and 70-76% of all sleep apnea cases with AI or AHI greater than 5. Predictive accuracy was 88% for AI greater than 10. The two questions that comprise the AS should be incorporated into risk appraisal instruments or interviews to screen for sleep apnea.

Adenoidectomy↗
PubMed1987

Fate map of the eye-antennal imaginal disc of the tumorous-head mutant of Drosophila melanogaster.

In specific genetic backgrounds, a mutation in the tuh-3 gene results in the homeotic transformation of head structures to either leg disc derivatives or structures normally found in the extreme posterior end of wild-type animals. The origins of the homeotic structures were mapped to defined positions in the eye-antennal imaginal disc by transplanting abnormal regions of discs isolated from tuh-3 mutants into host mwh;e4 larvae. These metamorphosed implants were removed and differentiated structures were identified. Of 211 successfully recovered implants, 157 gave rise to homeotic tissue: abdominal tergite, male or female external genitalia and/or leg tissue. Transformations to abdominal tergite occurred primarily in cells taken from the eye region of the compound disc. Male and female genitalia arose most often in implants taken from the antennal portion of the disc, although some tissue taken from the lateral region of the eye disc also gave rise to external genitalia. Leg structures came exclusively from implants from the antennal region of the imaginal disc. These results suggest that cells from within specific regions of the eye-antennal compound disc are constrained in their developmental potential. An obvious constraint observed with this mutation is a dorsal/ventral one: Cells from the eye disc, a dorsal structure, primarily gave rise to other dorsal structures, abdominal tergite tissue. Cells from the antennal disc, a ventrally derived structure, primarily gave rise to other ventral structures including genital tissue and distal leg.

Animals↗
PubMed1984

Sequence of the bacteriophage SP01 gene coding for transcription factor 1, a viral homologue of the bacterial type II DNA-binding proteins.

The Bacillus subtilis phage SP01, whose DNA contains 5-hydroxymethyluracil (hmUra) in place of thymine, codes for an abundant, small, basic protein called TF1. TF1 binds preferentially to hydroxymethyluracil-containing DNA and thereby selectively inhibits transcription of such DNA in vitro. The gene for TF1 has been sequenced. We find that this viral protein is a homologue of the ubiquitous bacterial type II DNA-binding proteins. The three-dimensional structure of one of these bacterial proteins has recently been determined. We are able to discern common as well as distinctive features in the amino acid sequence and the three-dimensional structure of the homologous viral protein.

Amino Acid Sequence↗
PubMed1981

Deletion analysis of the tumorous-head (tuh-3) gene in Drosophila melanogaster.

In the presence of the naturally occurring maternal-effect alleles tuh-1h or tuh-1g, the tuh-3 mutant gene can cause the tumorous-head trait or the sac-testis trait. The tuh-3 gene functions as a semidominant in the presence of the tuh-1h maternal effect. Eye-antennal structures are replaced by posterior abdominal tergites and genital structures. If tuh-1h is replaced by its naturally occurring allele tuh-1g, tuh-3 functions as a recessive hypomorph and the defect switches from anterior to posterior structures, with a male genital-disc defect appearing with variable penetrance. Function and regulation of tuh-3+ may better be understood in light of the cytological localization of tuh-3 either adjacent to or as part of the bithorax complex. The tuh-3+ gene product appears to be essential for normal development, at least in the posterior end of the embryo.

Alleles↗