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Biomedical subjects

P A Lawrence

Publications and source records attributed to P A Lawrence.

At least 19 recordsLinked to original sources

Control of Drosophila body pattern by the hunchback morphogen gradient.

Most of the thoracic and abdominal segments of Drosophila are specified early in embryogenesis by the overlapping activities of the hunchback (hb), Krüppel, knirps, and giant gap genes. The orderly expression of these genes depends on two maternal determinants: bicoid, which activates hb transcription anteriorly, and nanos, which blocks translation of hb transcripts posteriorly. Here we provide evidence that the resulting gradient of hb protein dictates where the Krüppel, knirps, and giant genes are expressed by providing a series of concentration thresholds that regulate each gene independently. Thus, hb protein functions as a classical morphogen, triggering several distinct responses as a function of its graded distribution.

Animals

The consequences of ubiquitous expression of the wingless gene in the Drosophila embryo.

The segment polarity gene wingless has an essential function in cell-to-cell communication during various stages of Drosophila development. The wingless gene encodes a secreted protein that affects gene expression in surrounding cells but does not spread far from the cells where it is made. In larvae, wingless is necessary to generate naked cuticle in a restricted part of each segment. To test whether the local accumulation of wingless is essential for its function, we made transgenic flies that express wingless under the control of a hsp70 promoter (HS-wg flies). Uniform wingless expression results in a complete naked cuticle, uniform armadillo accumulation and broadening of the engrailed domain. The expression patterns of patched, cubitus interruptus Dominant and Ultrabithorax follow the change in engrailed. The phenotype of heatshocked HS-wg embryos resembles the segment polarity mutant naked, suggesting that embryos that overexpress wingless or lack the naked gene enter similar developmental pathways. The ubiquitous effects of ectopic wingless expression may indicate that most cells in the embryo can receive and interpret the wingless signal. For the development of the wild-type pattern, it is required that wingless is expressed in a subset of these cells.

Animals

Prolonged faecal excretion of poliovirus in a nurse with common variable hypogammaglobulinaemia.

A nurse with common variable hypogammaglobulinaemia was found to excrete a non-vaccine strain type II poliovirus for almost a year following a bout of gastroenteritis. Attempts were made to halt intestinal carriage of the virus in view of the possible risk of spread to immunocompromised patients and the risk of paralytic poliomyelitis to the patient himself. Three doses of killed Salk vaccine failed to stimulate salivary anti-polio antibodies. Excretion of the virus ceased spontaneously just before oral immunoglobulin containing high titres of antibodies to polio virus was used to halt virus excretion.

Adolescent

Cardiac pacing in children.

Advances in pacemaker technology over the last 25 years have made cardiac pacing in infants and children a safe and practical therapy. Some of the technical challenges encountered with the first permanent pacemaker implantation in children during the early 1960s have been solved with miniaturized generators, lithium batteries, noninvasive programmability, and improved placement techniques. This chapter reports common causes of bradydysrhythmias in children, reviews the indications for permanent pacemaker implantation in children, describes current pacing systems appropriate for children, and identifies nursing implications and potential pacemaker complications unique to children.

Bradycardia

Induction across germ layers in Drosophila mediated by a genetic cascade.

We report an induction process occurring between two germ layers in the Drosophila embryo that involves a cascade of five interacting genes. Two of these, Ultrabithorax and abdominal-A, encode nuclear homeobox proteins; each of them is expressed in one of two adjacent parasegments in the visceral mesoderm and directs expression in its parasegment of a separate target gene, decapentaplegic in parasegment 7 and wingless in parasegment 8. The activity of both target genes is required for normal expression of another homeotic gene, labial, in cells of the adhering midgut epithelium. Their products are putative extracellular proteins, which presumably act as signals between the two germ layers. Positional instruction of this kind may be needed since the endoderm, unlike the mesoderm, appears unsegmented at first as it originates from two primordia near the embryonic poles, outside the realm of segmentation genes.

Animals

Distribution of the wingless gene product in Drosophila embryos: a protein involved in cell-cell communication.

wingless, a segment polarity gene required in every segment for the normal development of the Drosophila embryo, encodes a cysteine-rich protein with a signal peptide. A polyclonal antiserum localizes the wingless protein in approximately the same region of the embryo as the wingless mRNA. The pattern of antigen localization changes rapidly during development. In the extended germband stage, stripes of wingless staining are present in the trunk region just anterior to the parasegment boundary; wingless-expressing cells abut engrailed-expressing cells across that boundary. wingless antigen is seen both inside and outside the cell by electron microscopy: inside the cell, in small membrane-bound vesicles and in multivesicular bodies; outside the cell, close to or on the plasma membrane and associated with material in the intercellular space. The multivesicular bodies containing the wingless protein are occasionally found in engrailed-positive cells, suggesting that the wingless protein behaves as a paracrine signal.

Animals

Pattern formation in the Drosophila embryo: allocation of cells to parasegments by even-skipped and fushi tarazu.

The first sign of metamerization in the Drosophila embryo is the striped expression of pair-rule genes such as fushi tarazu (ftz) and even-skipped (eve). Here we describe, at cellular resolution, the development of ftz and eve protein stripes in staged Drosophila embryos. They appear gradually, during the syncytial blastoderm stage and soon become asymmetric, the anterior margins of the stripes being sharply demarcated while the posterior borders are undefined. By the beginning of germ band elongation, the eve and ftz stripes have narrowed and become very intense at their anterior margins. The development of these stripes in hairy-, runt-, eve-, ftz- and engrailed- embryos is illustrated. In eve- embryos, the ftz stripes remain symmetric and lack sharp borders. Our results support the hypothesis (Lawrence et al. Nature 328, 440-442, 1987) that individual cells are allocated to parasegments with respect to the anterior margins of the eve and ftz stripes.

Animals

Analysis of function of the pair-rule genes hairy, even-skipped and fushi tarazu in mosaic Drosophila embryos.

We report the first attempt of its kind to study genetic interactions using young Drosophila embryos that are mosaic for wildtype and mutant cells. Using nuclear transplantation we make mosaic embryos in which a patch of cells lacks a particular segmentation gene, A. With antibodies, we than look at the expression of another gene that is known to be downstream of gene A, with respect to the cells in the patch. We have examples of patches of hairy cells (where we monitor the effect on fushi tarazu (ftz) expression), even-skipped (monitoring ftz) and ftz (monitoring engrailed and Ultrabithorax). Our main finding is that the dependence of engrailed expression on the ftz gene is strictly cell-autonomous. This result goes some way towards explaining the dependence of Ultrabithorax expression on ftz, a dependence we show to be locally cell-autonomous within parts of parasegments 6 and 8 but non autonomous within parasegment 7.

Animals

Accuracy of nurses in performing capillary blood glucose monitoring.

The accuracy and outcome of capillary blood glucose (CBG) monitoring as routinely performed by nursing staff were assessed. The sample consisted of 160 readings conducted by 93 nursing staff members in four hospitals; 19% of the readings deviated from simultaneous laboratory results by greater than 20%, and deviations resulted in altered responses to standing orders in 26 patients (17%). There was no statistically significant difference between the total variation attributed within and between nurses, possibly indicating that all nurses should be given the same intensity of follow-up training rather than targeting those who perform incorrectly on sample tests. Nurses in the one hospital that required certification before CBG monitoring had significantly less deviation from the laboratory standard than the other three hospitals. Although these data do not provide direct evidence that the certification program increased accuracy, this seems a logical conclusion. More study is needed to determine the most cost-effective type of training and follow-up.

Blood Chemical Analysis

Cell lineage and cell states in the Drosophila embryo.

Much of this essay is a cautionary tale about the inherent difficulty of building theories to explain pattern formation in embryos. In particular, I discuss the relationship between cell state and cell lineage. The idea that embryonic cells can occupy discrete genetic states is an old one but, because of the mass of new information from Drosophila developmental genetics, it has been given new life. I propose an operational definition of a cell state and argue that a true cell state should be propagated faithfully through cell lineage for at least some divisions. The genes involved should have a controlling role and the borders between populations of cells in two different states should be so sharp that cells fall clearly into one state or another.

Animals

Differential regulation of Ultrabithorax in two germ layers of Drosophila.

The homeotic gene Ultrabithorax (Ubx) is expressed in specific parts of Drosophila embryos: in a single metamer in the visceral mesoderm and forming a complex pattern limited to a broad domain in the ectoderm and in the somatic mesoderm. Here we use a linked beta-galactosidase gene to identify cis-acting regulatory sequences. In the visceral mesoderm, correct expression of Ubx depends on localized upstream sequences. In the ectoderm, all galactosidase-positive transformants show the same characteristic pattern. The repeated elements of this basal pattern appear to be a sub-pattern of engrailed (en) expression; they depend on en function as well as on sequences in the Ubx RNA leader. We use a mutant (Haltere-mimic) to show that sequences that normally restrict segmental expression of Ubx in the ectoderm are located downstream from the RNA leader.

Animals

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