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A Ashworth

Publications and source records attributed to A Ashworth.

At least 37 records · Page 2Linked to original sources
PubMed2001

Mutation in Brca2 stimulates error-prone homology-directed repair of DNA double-strand breaks occurring between repeated sequences.

Mutation of BRCA2 causes familial early onset breast and ovarian cancer. BRCA2 has been suggested to be important for the maintenance of genome integrity and to have a role in DNA repair by homology- directed double-strand break (DSB) repair. By studying the repair of a specific induced chromosomal DSB we show that loss of Brca2 leads to a substantial increase in error-prone repair by homology-directed single-strand annealing and a reduction in DSB repair by conservative gene conversion. These data demonstrate that loss of Brca2 causes misrepair of chromosomal DSBs occurring between repeated sequences by stimulating use of an error-prone homologous recombination pathway. Furthermore, loss of Brca2 causes a large increase in genome-wide error-prone repair of both spontaneous DNA damage and mitomycin C-induced DNA cross-links at the expense of error-free repair by sister chromatid recombination. This provides insight into the mechanisms that induce genome instability in tumour cells lacking BRCA2.

Alleles↗
PubMed2001

New complexities for BRCA1 and BRCA2.

A large number of diverse functions have been attributed to the BRCA1 and BRCA2 breast cancer susceptibility genes. Here we review recent progress in the field.

BRCA1 Protein↗
PubMed2001

Microarray and histopathological analysis of tumours: the future and the past?

The excitement surrounding the development of DNA microarray analysis and proteomics has raised questions about the role of these techniques in clinical practice and patient management. But how did the traditional methods of cancer diagnosis and prognosis develop, and how can high-throughput techniques contribute?

DNA, Complementary↗
PubMed2001

A short pseudoautosomal region in laboratory mice.

The pseudoautosomal region (PAR) of mammalian sex chromosomes is a small region of sequence identity that is the site of an obligatory pairing and recombination event between the X and Y chromosomes during male meiosis. During female meiosis, X chromosomes can pair and recombine along their entire length; recombination in the PAR is therefore approximately 10x greater in male meiosis compared with female meiosis. A consequence of the presence of the PAR in two copies in males and females is that genes in the region escape the process of X-inactivation. Although the structure and gene content of the human PAR at Xq/Yq is well understood, the mouse PAR, which appears to be of independent evolutionary origin, is poorly characterized. Here we describe a yeast artificial chromosome (YAC) contig covering the distal part of the mouse X chromosome, which we have used to define the pseudoautosomal boundary, that is, the point of divergence of X-specific and X-Y-identical sequences. In addition, we have investigated the size of the mouse PAR by integrating a unique restriction endonuclease recognition site just proximal to the pseudoautosomal boundary by homologous recombination. Restriction digestion of this modified DNA and pulsed field gel electrophoresis reveal that the PAR in these cells is approximately 700 kb. Thus, the mouse PAR, although small in size, has retained essential sex chromosome pairing functions despite its rapid rate of evolution.

Animals↗
PubMed2001

Breastfeeding and early weaning practices in northeast Brazil: a longitudinal study.

OBJECTIVES: To describe breastfeeding practices from 0 to 12 months of age in 4 small towns that are representative of urban northeast Brazil and to identify factors associated with introduction of other milk in the first month of life. METHODS: From January to August 1998, 364 mothers were interviewed at delivery to ascertain antenatal care; delivery room practices; and their intentions regarding breastfeeding, pacifiers, and introduction of water, teas, and other milk. Their perceptions of home support and the advantages of breastfeeding also were assessed. Thereafter, daily information about feeding practices was collected at twice-weekly home visits. When other milk was started, a second interview was conducted to ascertain initial and current breastfeeding problems and use of a pacifier. Reasons for starting other milk were investigated using 5-point Likert scales. RESULTS: Mothers were positive toward breastfeeding, and 99% breastfed their new infant. Few intended to breastfeed exclusively, and in the first week 80% gave water/tea and 56% used a pacifier. The median duration of exclusive breastfeeding was 0 days, and the median age for starting other milk was 24 days. The median duration of breastfeeding was 65 days for mothers who started other milk within 1 month and 165 days for other mothers. After adjustment for confounding variables, the main factors associated with introduction of other milk within 1 month were pacifier use in the first week (odds ratio [OR], 4.01; 95% confidence interval [CI]: 2.07-7.78), intention to start other milk in the first month (OR, 3.79; 95% CI: 1.74-8.24), giving water/tea in the first week (OR, 3.07; 95% CI: 1.56-6.03), and leaving the maternity ward before breastfeeding was started (OR, 2.59; 95% CI: 1.34-5.04). CONCLUSION: Although breastfeeding is common in this community, it rarely is exclusive and takes place for a relatively short duration. Identification of risk factors for early introduction of other milk offers potential avenues for future intervention, including improvement of breastfeeding support in antenatal and maternity services.

Brazil↗
PubMed2001

Prevalence of anemia in children 6-59 months old in the state of Pernambuco, Brazil.

OBJECTIVE: To determine the prevalence of anemia in children 6-59 months old in Pernambuco, a state in northeastern Brazil, so as to help guide health and nutrition policies there. METHODS: In 1997 a representative sample of 777 young children had their hemoglobin concentration measured. The sampling process was in three stages. First, 18 municipalities were randomly selected to represent the state and its three geographic areas (metropolitan region of Recife, urban interior, and rural interior). Next, using census lists, 45 census sectors were randomly chosen. Finally, 777 children aged 6-59 months old were selected. Blood was collected by venipuncture, and hemoglobin was measured with a portable hemoglobinometer. In the analysis, prevalence was weighted to reflect the census age distribution. RESULTS: The prevalence of anemia among children 6-59 months old was 40.9% for the state as a whole. Prevalence in the metropolitan region of Recife was 39.6%, and it was 35.9% in the urban interior. The rural interior had the highest prevalence, 51.4%. Prevalence was twice as high in children aged 6-23 months as among those 24-59 months old, 61.8% vs. 31.0% (chi 2 = 77.9, P < 0.001). The mean hemoglobin concentrations in the younger and older age groups were 10.4 g/dL (standard deviation (SD) = 1.5) and 11.4 g/dL (SD = 1.4), respectively. There was no statistically significant difference between the sexes in terms of prevalence. CONCLUSIONS: This is the first statewide assessment of anemia prevalence among young children in Brazil. Given the very high prevalence of anemia among the children studied in Pernambuco, especially those in the age group of 6-23 months, public health interventions are needed.

Anemia, Iron-Deficiency↗
PubMed2001

Evaluating the clinical management of severely malnourished children--a study of two rural district hospitals.

BACKGROUND: Severe malnutrition is an important cause of preventable mortality in most South African hospitals. Work recently done in two rural Eastern Cape hospitals supports the literature which shows that many deaths occur as a result of outdated clinical practices and that improving these practices reduces case fatality rates. Rapid assessment of clinical management in paediatric wards is necessary to highlight areas for improvement. OBJECTIVE: To assess the management of severely malnourished children in two rural district hospitals and to recommend improvements for their care. METHODS: Based on draft World Health Organisation (WHO) guidelines for inpatient care of children with severe malnutrition, data collection instruments were developed in conjunction with the district nutrition team to assess the quality of care given to malnourished children in two Mount Frere hospitals, Eastern Cape. Data were collected through retrospective review of case records, with detailed studies of selected cases, structured observations of the paediatric wards, and interviews with ward sisters and doctors. RESULTS: The combined case fatality rate for severe malnutrition was 32%. Inadequate feeding, poor management of rehydration and infection, lack of resources, and a lack of knowledge and motivation among staff were identified as areas that need attention. CONCLUSION: The clinical management of severely malnourished children can be rapidly assessed to highlight areas for improvement. Involving staff in the assessment process has led to their active involvement in improving the management of malnourished children in their hospitals.

Child↗
PubMed2000

Effect of community-based peer counsellors on exclusive breastfeeding practices in Dhaka, Bangladesh: a randomised controlled trial [see commments].

BACKGROUND: Most mothers breastfeed in Bangladesh, but they rarely practise exclusive breastfeeding. Hospital-based strategies for breastfeeding promotion cannot reach them because about 95% have home deliveries. We postulated that with the intervention of trained peer counsellors, mothers could be enabled to breastfeed exclusively for the recommended duration of 5 months. METHODS: 40 adjacent zones in Dhaka were randomised to intervention or control groups. Women were enrolled during the last trimester of pregnancy between February and December, 1996. In the intervention group, 15 home-based counselling visits were scheduled, with two visits in the last trimester, three early postpartum (within 48 h, on day 5, between days 10 and 14), and fortnightly thereafter until the infant was 5 months old. Peer counsellors were local mothers who received 10 days' training. FINDINGS: 363 women were enrolled in each group. Peer counselling significantly improved breastfeeding practices. For the primary outcome, the prevalence of exclusive breastfeeding at 5 months was 202/228 (70%) for the intervention group and 17/285 (6%) for the control group (difference=64%; 95% CI 57%-71%, p>0.0001). For the secondary outcomes, mothers in the intervention group initiated breastfeeding earlier than control mothers and were less likely to give prelacteal and postlacteal foods. At day 4, significantly more mothers in the intervention group breastfed exclusively than controls. INTERPRETATION: Peer counsellors can effectively increase the initiation and duration of exclusive breastfeeding. We recommend incorporation of peer counsellors in mother and child health programmes in developing countries.

Adolescent↗
PubMed2000

BRCA1 and BRCA2.

Explore the source record for details and available documents.

BRCA1 Protein↗
PubMed2000

Expression of sox11 gene duplicates in zebrafish suggests the reciprocal loss of ancestral gene expression patterns in development.

To investigate the role of sox genes in vertebrate development, we have isolated sox11 from zebrafish (Danio rerio). Two distinct classes of sox11-related cDNAs were identified, sox11a and sox11b. The predicted protein sequences shared 75% identity. In a gene phylogeny, both sox11a and sox11b cluster with human, mouse, chick, and Xenopus Sox11, indicating that zebrafish, like Xenopus, has two orthologues of tetrapod Sox11. The work reported here investigates the evolutionary origin of these two gene duplicates and the consequences of their duplication for development. The sox11a and sox11b genes map to linkage groups 17 and 20, respectively, together with other loci whose orthologues are syntenic with human SOX11, suggesting that during the fish lineage, a large chromosome region sharing conserved syntenies with mammals has become duplicated. Studies in mouse and chick have shown that Sox11 is expressed in the central nervous system during development. Expression patterns of zebrafish sox11a and sox11b confirm that they are expressed in the developing nervous system, including the forebrain, midbrain, hindbrain, eyes, and ears from an early stage. Other sites of expression include the fin buds and somites. The two sox genes, sox11a and sox11b, are expressed in both overlapping and distinct sites. Their expression patterns suggest that sox11a and sox11b may share the developmental domains of the single Sox11 gene present in mouse and chick. For example, zebrafish sox11a is expressed in the anterior somites, and zebrafish sox11b is expressed in the posterior somites, but the single Sox11 gene of mouse is expressed in all the somites. Thus, the zebrafish duplicate genes appear to have reciprocally lost expression domains present in the sox11 gene of the last common ancestor of tetrapods and zebrafish. This splitting of the roles of Sox11 between two paralogues suggests that regulatory elements governing the expression of the sox11 gene in the common ancestor of zebrafish and tetrapods may have been reciprocally mutated in the zebrafish gene duplicates. This is consistent with duplicate gene evolution via a duplication-degeneration-complementation process.

Amino Acid Sequence↗
PubMed2000

Endo180, an endocytic recycling glycoprotein related to the macrophage mannose receptor is expressed on fibroblasts, endothelial cells and macrophages and functions as a lectin receptor.

Endo180 was previously characterized as a novel, cell type specific, recycling transmembrane glycoprotein. This manuscript describes the isolation of a full length human Endo180 cDNA clone which was shown to encode a fourth member of a family of proteins comprising the macrophage mannose receptor, the phospholipase A(2) receptor and the DEC-205/MR6 receptor. This receptor family is unusual in that they contain 8-10 C-type lectin carbohydrate recognition domains in a single polypeptide backbone, however, only the macrophage mannose receptor had been shown to function as a lectin. Sequence analysis of Endo180 reveals that the second carbohydrate recognition domain has retained key conserved amino acids found in other functional C-type lectins. Furthermore, it is demonstrated that this protein displays Ca(2+)-dependent binding to N-acetylglucosamine but not mannose affinity columns. In order to characterize the physiological function of Endo180, a series of biochemical and morphological studies were undertaken. Endo180 is found to be predominantly expressed in vivo and in vitro on fibroblasts, endothelial cells and macrophages, and the distribution and post-translational processing in these cells is consistent with Endo180 functioning to internalize glycosylated ligands from the extracellular milieu for release in an endosomal compartment.

Amino Acid Sequence↗
PubMed2000

The caudal neurosecretory system: control and function of a novel neuroendocrine system in fish.

The caudal neurosecretory system (CNSS) of fish was first defined over 70 years ago yet despite much investigation, a clear physiological role has yet to be elucidated. Although the CNSS structure is as yet thought to be confined to piscine species, the secreted peptides, urotensins I and II (UI and UII), have been detected in a number of vertebrate species, most recently illustrated by the isolation of UII in humans. The apparent importance of these peptides, suggested by their relative phylogenetic conservation, is further supported by the complex control mechanisms associated with their secretion. The CNSS in teleosts is known to receive extensive and diverse innervation from the higher central nervous system, with evidence for the presence of cholinergic, noradrenergic, serotonergic, and peptidergic descending inputs. Recent observations also suggest the presence of glucocorticoid receptors in the flounder CNSS, supporting previous evidence for a possible role as a pituitary-independent mechanism controlling cortisol secretion. The most convincing evidence as to a physiological role for the CNSS in fish has stemmed from the direct and indirect influence of the urotensins on osmoregulatory function. Recent advances allowing the measurement of circulating levels of UII in the flounder have supported this. In addition, there is evidence to suggest some seasonal variation in peptide levels supporting the notion that the CNSS may have an integrative role in the control of coordinated changes in the reproductive, osmoregulatory and nutritional systems of migratory euryhaline species.

Amino Acid Sequence↗
PubMed1999

FXY2/MID2, a gene related to the X-linked Opitz syndrome gene FXY/MID1, maps to Xq22 and encodes a FNIII domain-containing protein that associates with microtubules.

Opitz G/BBB syndrome (OS) is a genetically heterogeneous disorder with an X-linked locus and an autosomal locus linked to 22q11.2. OS affects multiple organ systems with often variable severity even between siblings. The clinical features, which include hypertelorism, cleft lip and palate, defects of cardiac septation, hypospadias, and anorectal anomalies, indicate an underlying disturbance of the developing ventral midline of the embryo. The gene responsible for X-linked OS, FXY/MID1, is located on the short arm of the human X chromosome within Xp22.3 and encodes a protein with both an RBCC (RING finger, B-box, coiled coil) and a B30.2 domain. The Fxy gene in mice is also located on the X chromosome but spans the pseudoautosomal boundary in this species. Here we describe a gene closely related to FXY/MID1, called FXY2, which also maps to the X chromosome within Xq22. The mouse Fxy2 gene is located on the distal part of the mouse X chromosome within a region syntenic to Xq22. Analysis of genes flanking both FXY/MID1 and FXY2 (as well as their counterparts in mouse) suggests that these regions may have arisen as a result of an intrachromosomal duplication on an ancestral X chromosome. We have also identified in both FXY2 and FXY/MID1 proteins a conserved fibronectin type III domain located between the RBCC and B30.2 domains that has implications for understanding protein function. The FXY/MID1 protein has previously been shown to colocalize with microtubules, and here we show that the FXY2 protein similarly associates with microtubules in a manner that is dependent on the carboxy-terminal B30.2 domain.

Abnormalities, Multiple↗
PubMed1999

MKP5, a new member of the MAP kinase phosphatase family, which selectively dephosphorylates stress-activated kinases.

Dual-specificity protein tyrosine phosphatases are a burgeoning family of enzymes, some of which, the MKPs, are implicated in the regulation of mitogen-activated protein (MAP) kinases. MKPs have been shown to reverse the activation of the MAP kinases by hydrolyzing phosphothreonine and phosphotyrosine residues present in the substrates. Here we describe the characterization of a novel member of the MKP family, MKP5. The MKP5 gene, which maps to human chromosome 1q32, is expressed tissue-specifically as two transcripts of approximately 3.4 and 2.4 kb in human liver and skeletal muscle. When expressed in mammalian cells, MKP5 blocks the enzymatic activation of MAP kinases with the selectivity p38 approximately JNK/SAPK >> ERK. Immunoprecipitation of endogenous MAP kinases by the catalytically inactive transfected MKP5 demonstrates that it preferentially binds to the p38 and JNK/SAPK kinases. These findings suggest that the selectivity of this phosphatase may be determined at least in part at the level of substrate binding.

Amino Acid Sequence↗
PubMed1999

Alternative splicing of the Drosophila PTEN gene.

Mutations in the human PTEN gene have been identified in a number of different tumour types, and in the hamartomatous polyposis syndromes Cowden disease and Bannayan-Zonana syndrome. The PTEN gene encodes a phosphatase that antagonises phosphoinositide 3-kinase (PI3K) signalling by removing the 3' phosphate from phosphatidylinositol 3, 4,5-trisphosphate (PtdIns (3,4,5)P(3)). Here we show that the PTEN gene is conserved in the invertebrate Drosophila melanogaster and demonstrate that the gene undergoes alternative splicing.

Alternative Splicing↗