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Biomedical subjects

N J Gay

Publications and source records attributed to N J Gay.

At least 73 records · Page 4Linked to original sources
PubMed1998

Getting knotted: a model for the structure and activation of Spätzle.

Sequence analyses show that Spätzle, the Drosophila melanogaster Toll-receptor ligand, shows striking similarity to nerve growth factor and coagulogen. Comparative modelling suggests that Spätzle adopts a cystine-knot fold and forms a dimer that contains a single, intermolecular disulphide bridge. Proteolytically cleaved Spätzle could therefore dimerize and activate the Toll receptor by inducing receptor dimerization.

Amino Acid Sequence↗
PubMed1998

Expression and subcellular distribution of rel/NF kappa B transcription factors in the preimplantation mouse embryo: novel kappa B binding activities in the blastocyst stage embryo.

We describe the expression patterns and subcellular localisation of murine rel/NF kappa B transcription factors and their inhibitors during preimplantation development in the mouse. We find that the known rel and I kappa B proteins are ubiquitously expressed during early murine embryogenesis. The differential persistence of individual rel and I kappa B transcripts in the first cleavage stage embryo and analysis of the 3'UTR suggests that rel and I kappa B protein expression may be regulated at the level of mRNA stability and translation. At the stages of early mouse embryogenesis examined, there was no evidence for strong induction of rel dimer translocation into the nucleus. However, novel kappa B-binding proteins are found in the mouse blastocyst and may provide an alternative mechanism for regulation of gene expression via the kappa B motif in the early mouse embryo.

3' Untranslated Regions↗
PubMed1998

Modeling measles, mumps, and rubella: implications for the design of vaccination programs.

Mathematical models of disease transmission are being used increasingly in the design of population-based vaccination programs. Their use is illustrated in a review of some modeling studies that have implications for the use of measles, mumps, and rubella vaccine. Investigations of vaccination strategy options yield predictions for effectiveness and cost-effectiveness analyses. A quantitative understanding of the factors affecting disease transmission enables the setting of targets for vaccination programs and underpins disease elimination initiatives.

Carrier State↗
PubMed1997

X-ray diffraction and far-UV CD studies of filaments formed by a leucine-rich repeat peptide: structural similarity to the amyloid fibrils of prions and Alzheimer's disease beta-protein.

The development of neuro-degenerative diseases often involves amyloidosis, that is the formation of polymeric fibrillar structures from normal cellular proteins or peptides. For example, in Alzheimer's disease, a 42 amino acid peptide processed from the amyloid precursor protein forms filaments with a beta-sheet structure. Because of this, the structure and dynamics of polymeric peptide filaments is of considerable interest. We showed previously that a 23 amino acid peptide constituting a single leucine-rich repeat (LRRN) polymerises spontaneously in solution to form long filaments of a beta-sheet structure, a property similar to that of Alzheimer's beta-amyloid and prion peptides. Here we report that a variant of LRRN in which a highly conserved asparagine residue is replaced by aspartic acid does not form either filaments or beta structure. By contrast, a variant which replaces this asparagine residue with glutamine forms filaments ultrastructurally indistinguishable from those of LRRN. Electron micrographs of LRRN filaments show that many consist of two interleaved strands which appear to have a ribbon-like morphology. X-ray diffraction patterns from oriented LRRN fibres reveal that they are composed of long beta-sheet arrays, with the interstrand hydrogen bonding parallel to the filament axis. This 'cross-beta' structure is similar to that adopted by beta-amyloid and prion derived fibres. Taken together, these results indicate that the LRR filaments are stabilised by inter- or intra-strand hydrogen bonded interactions comparable to the asparagine ladders of beta-helix proteins or the 'glutamine zippers' of poly-glutamine peptides. We propose that similar stabilising interactions may underlie a number of characterised predispositions to neuro-degenerative diseases that are caused by mutations to amide residues. Our finding that amyloid-like filaments can form from a peptide motif not at present correlated with degenerative disease suggests that a propensity for beta-filament formation is a common feature of protein sub-domains.

Alzheimer Disease↗
PubMed1997

Childhood infection with hepatitis A and B viruses in England and Wales.

Infection with hepatitis B and A viruses during childhood was studied using serum specimens collected from children aged 13 and 14 years by 12 public health laboratories in England and Wales from 1986 to 1995. Six of the 2025 specimens tested for markers of hepatitis B infection showed evidence of earlier resolved infection, one specimen showed evidence of recent infection, and hepatitis B surface antigen (HBsAg) was detected in three specimens. The HBsAg carriage rate of 0.15% (3/2025) was consistent with that expected from vertical transmission before the introduction of antenatal screening and neonatal hepatitis B vaccination, for which the children in our study would not have been eligible. Five of the six children with earlier resolved hepatitis B infection also showed evidence of hepatitis A infection, whose coexistence raises the possibility that both infections were acquired abroad in areas of high endemicity. At present, by adolescence, about one in 200 children has at some time been infected with hepatitis B virus. The current practice of screening pregnant women for HBsAg and selectively vaccinating neonates at high risk of acquiring hepatitis B infection may reduce this rate in the future. Immunisation of all infants against hepatitis B would prevent very few more childhood infections than the current policy. The incidence of hepatitis A infection has fallen in the past decade, suggesting the potential for an epidemic resurgence in the future as more of the population becomes susceptible. The average annual incidence of hepatitis A infection in children aged 0 to 14 years from 1986 to 1995 was 800 per 100 000, fifty times higher than the reported incidence of laboratory confirmed disease in this age group. Most hepatitis A infections in this age group are therefore likely to be subclinical or very mild.

Adolescent↗
PubMed1997

Casein kinase II phosphorylates Ser468 in the PEST domain of the Drosophila IkappaB homologue cactus.

Cactus protein is a Drosophila homologue of the mammalian IkappaB family of cytoplasmic anchor proteins. In unstimulated cells they function to retain rel/NFkappaB transcription factors in the cytoplasm but are rapidly degraded in response to signalling. The destruction of cactus or IkappaBalpha allows the rel/NFkappaB transcription factor to relocalise to the nucleus. Cactus is a phosphoprotein and has in its C-terminus a PEST protein stability domain. In this paper we show that, like mammalian IkappaBalpha, the PEST domain of cactus is phosphorylated by casein kinase II. We have localised the site of modification to a single residue, Ser468, and find no evidence for additional phosphorylation sites. The conservation of these sites in mammalian and invertebrate cytoplasmic anchor proteins suggests that phosphorylation by casein kinase II may play a critical functional role, plausibly in the regulation of constitutive or inducible proteolysis.

Adenosine Triphosphate↗
PubMed1997

Alpha-adaptin, a marker for endocytosis, is expressed in complex patterns during Drosophila development.

A Drosophila cDNA encoding a structural homologue of the mammalian coated vesicle component alpha-adaptin (AP2 adaptor complex) has been cloned and sequenced. The mammalian and invertebrate sequences are highly conserved, especially within the amino terminal region, a domain that mediates interactions with other components within the AP2 complex and with specific receptors tails. Mammalian alpha-adaptins are encoded by two genes; however, Drosophila alpha-adaptin has a single gene locus, within polytene bands 21C2-C3 on the left arm of the chromosome 2, closely adjacent to the paired homeobox gene aristaless. There seem to be at least two Drosophila alpha-adaptin transcripts expressed, plausibly by alternative splicing. One of the transcripts is more abundant during early embryogenesis and may be of maternal origin. We have studied the distribution of the alpha-adaptin protein throughout embryogenesis and at the neuromuscular junction of the third instar larva. During cellularization of the blastoderm embryo, the protein is seen between and ahead of the elongating nuclei, and then redistributes to the cell surface during gastrulation. These observations suggest a role for endocytosis in cellularization and are consistent with the finding that dynamin (the shibire gene product), another component of the endocytic mechanism, is required for cellularization. At later stages of embryogenesis, alpha-adaptin is expressed in complex and dynamic patterns. It is strongly induced in elements of the central and peripheral nervous system (e.g., in neuroblasts, the presumptive stomatogastric nervous system, and the lateral chordotonal sense organs), in the Garland cells, the adult midgut precursors, the antenno-maxillary complex, the endoderm, the fat bodies, and the visceral mesoderm. In the larva, alpha-adaptin is localized at the plasma membrane in the synaptic boutons of the neuromuscular junctions. The cells expressing high levels of alpha-adaptin are known or expected to support high levels of endocytosis; thus, this coated vesicle protein seems to be an excellent marker for endocytic activity. The expression patterns of dynamin, detected in the embryo by in situ hybridization methods, are very similar to those reported here for alpha-adaptin reflecting the likely coordinated expression of endocytic components. Taken together with previous evidence, our results suggest that endosomal vesicle trafficking, membrane recycling, and the regulation of endocytosis play critical roles in the wide range of developmental processes.

Adaptor Protein Complex 2↗
PubMed1997

Sequence and expression of Drosophila myristoyl-CoA: protein N-myristoyl transferase: evidence for proteolytic processing and membrane localisation.

The enzyme N-myristoyl transferase transfers the 14 carbon fatty acid myristate to an N-terminal glycine residue in a small subset of cytoplasmic proteins. Many myristoyl proteins are components of cellular signalling pathways, some of which play important roles during embryonic development, for example protein kinase A. Thus, the function of N-myristoyl transferase is probably essential for embryogenesis and it is of some interest to study the enzyme in an organism with well understood developmental biology. In this paper we report the purification of a processed form of the Drosophila enzyme from peripheral membrane fractions of embryos by affinity chromatography to a protein containing leucine rich repeats. We have also isolated the Drosophila N-myristoyl transferase gene and determined its nucleotide sequence. The predicted amino acid sequence of the Drosophila enzyme is closely related to that of mammalian and fungal N-myristoyl transferases and residues essential for enzyme function are conserved. Our findings indicate that a fraction of Drosophila NMT is bound to the membrane and they are consistent with recent results for the human enzyme. We suggest that N-myristoyl transferase may be recruited to the membrane as part of a translational complex, perhaps by binding to p34 ribosome binding protein, a leucine rich repeat receptor of the microsomal membranes. We have also studied the expression pattern of the gene in the embryo by northern blot analysis and in situ hybridization. The transcripts appear to be uniformly distributed in the pre-cellular embryo but at later stages the RNA is barely detectable with these methods. However, from about stage 14, high levels of transcript are detected in a small number of randomly distributed cells of the central and peripheral nervous system.

Acyltransferases↗
PubMed1997

Epidemiological determinants of pertussis.

In countries with pertussis immunisation programmes, the main epidemiological determinant of the disease is the quality of protection induced by the vaccine and the coverage level achieved. Epidemiological data from England and Wales provide strong evidence that whole-cell pertussis vaccines can give good protection against both clinical disease and transmission of infection, and can generate herd immunity at high coverage levels. Models of pertussis transmission indicate that, even in the absence of waning immunity, the incidence of the disease is likely to increase in older age groups in countries with sustained high coverage. Active surveillance to detect the occurrence of pertussis in adults is required as the ascertainment of such cases through passive clinical reporting systems is low. Comprehensive post-licensing surveillance of the effectiveness of acellular pertussis vaccines will be essential to assess their long-term protection against both clinical disease and transmission of infection, and to determine the optimum boosting strategy.

Humans↗
PubMed1996

Analysis of serological surveys using mixture models: application to a survey of parvovirus B19.

A method for the analysis of age stratified antibody prevalence surveys is developed. The age specific distribution of the quantitative results of serological antibody tests is modelled as a mixture of seropositive and seronegative components. This yields maximum likelihood estimates of the prevalence at each age. The method is illustrated using data from a previously reported survey of antibody to parvovirus B19.

Adolescent↗
PubMed1996

A model of long-term decline in the transmissibility of an infectious disease: implications for the incidence of hepatitis A.

BACKGROUND: The epidemiology of hepatitis A in countries across the world is changing due to improvements in hygiene and living conditions which reduce the transmissibility of the infection. METHODS: A mathematical model is formulated to describe the changes in incidence of a directly transmitted infection produced by a long term decline in its transmissibility. The basic reproduction number, the parameter describing transmissibility, is considered as a function of time. The relationship between the basic reproduction number and the force of infection is derived. RESULTS: Theoretical examples demonstrate that a decline in transmissibility results in an initial decline in the force of infection, but that this may be followed by a substantial resurgence. Resurgences may be possible after several decades of declining incidence, and are most marked following a rapid decline. CONCLUSIONS: Countries which have experienced a rapid decline in the incidence of hepatitis A may be at risk of a resurgence. More detailed mathematical models, informed with data from regular age-stratified serological surveys, should provide the basis for decisions on vaccination policy.

Age Distribution↗
PubMed1996

Hospital admissions attributable to rotavirus infection in England and Wales.

Laboratory reports and data on hospital admissions were used to estimate the number of hospitalizations due to group A rotavirus infection in England and Wales. Between January 1990 and December 1994, there were 75,059 laboratory reports of rotavirus infection, and 66,062 of these were in children <5 years old; rotavirus represented 39% of all pathogens identified in fecal specimens from this age group. Between April 1993 and March 1994, 1904 hospital admissions coded as "infectious intestinal disease" and 2354 coded as "noninfective gastroenteritis" occurred in children <5 in the North Thames region (a health authority representing 13% of the population in England and Wales). By modeling admission and laboratory reporting data, it was estimated that 54% of hospitalizations for intestinal infectious disease and 34% for noninfective gastroenteritis were attributable to rotavirus. By extrapolation of the North Thames data, it was estimated that 17,810 rotavirus-related hospitalizations (5/1000 children <5 years old) occurred in England and Wales during the same period. Effective vaccines have the potential to substantially reduce the number of hospital admissions due to group A rotavirus infection.

Adolescent↗
PubMed1995

Calcium destabilises Drosophila cactus protein and dephosphorylates the dorsal transcription factor.

The Drosophila cactus and dorsal proteins are required for the development of embryonic dorso-ventral polarity and probably also for the innate immune response of the insect. Like their mammalian counterparts (the cytoplasmic anchor protein I kappa B and the rel/NF kappa B transcription factors) cactus and dorsal are regulated at the level of nuclear localisation. We showed previously that increased intra-cellular calcium levels induced by the ionophore ionomycin can activate dorsal/cactus complexes in the Drosophila cell line SL2. In order to study further the activation of dorsal/cactus complexes by calcium, we have prepared a cell line (SLDL) in which dorsal is expressed constitutively. In this paper we show that in SLDL cells ionomycin induces a rapid destruction of cactus and dephosphorylation of dorsal. These results suggest a role for the protein phosphatase calcineurin in calcium mediated activation of dorsal/cactus complexes. They also indicate that in the resting cell constitutive phosphorylation of dorsal is in equilibrium with calcium dependent dephosphorylation.

Amino Acid Sequence↗