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Biomedical subjects

S Beck

Publications and source records attributed to S Beck.

At least 91 records · Page 5Linked to original sources
PubMed1997

Chromosomal localization, gene structure and transcription pattern of the ORFX gene, a homologue of the MHC-linked RING3 gene.

We have mapped the human ORFX gene to chromosome 9q34 and determined its complete gene structure. Comparison with RING3, the human MHC-linked homologue on 6p21.3, shows the two gene structures to be highly conserved but with an approximate threefold expansion in the ORFX introns. RING3 and ORFX are found to be ubiquitously expressed in human adult and foetal tissues. Evidence suggests that the two genes may have arisen from an ancient duplication in a common ancestral chromosome.

Adult↗
PubMed1997

Dominant-negative cyclin-selective ubiquitin carrier protein E2-C/UbcH10 blocks cells in metaphase.

Destruction of mitotic cyclins by ubiquitin-dependent proteolysis is required for cells to complete mitosis and enter interphase of the next cell cycle. In clam eggs, this process is catalyzed by a cyclin-selective ubiquitin carrier protein, E2-C, and the cyclosome/anaphase promoting complex (APC), a 20S particle containing cyclin-selective ubiquitin ligase activity. Here we report cloning a human homolog of E2-C, UbcH10, which shares 61% amino acid identity with clam E2-C and can substitute for clam E2-C in vitro. Dominant-negative clam E2-C and human UbcH10 proteins, created by altering the catalytic cysteine to serine, inhibit the in vitro ubiquitination and destruction of cyclin B in clam oocyte extracts. When transfected into mammalian cells, mutant UbcH10 inhibits the destruction of both cyclin A and B, arrests cells in M phase, and inhibits the onset of anaphase, presumably by blocking the ubiquitin-dependent proteolysis of proteins responsible for sister chromatid separation. Thus, E2-C/UbcH10-mediated ubiquitination is involved in both cdc2 inactivation and sister chromatid separation, processes that are normally coordinated during exit from mitosis.

Amino Acid Sequence↗
PubMed1997

Estimating the burden of disease in an English region.

BACKGROUND: Health Authorities seeking to make appropriate investments in health care require information about the nature of the burden of disease in their populations. The World Bank instrument called DALY-Disability Adjusted Life Year-has been used in the South and West Region to measure this burden. METHOD: The burden of disease caused by a selection of diseases has been calculated using DALYs, which combine premature mortality and disability. An estimate of the total burden has been estimated by ICD chapter. RESULTS: Premature mortality accounts for 52 per cent of the burden of disease and disability 48 per cent. Mental illness, for which its DALY value is largely derived from disability not premature mortality, contributes the third largest component of the total burden, after heart disease and cancer. DISCUSSION: DALYs can be calculated using UK data, and, with an appreciation of the theoretical issues which surround the calculations, can be used to describe the burden of disease in a population. Although designed to assist investment decisions in developing countries, the DALY is likely to be valuable in established market economies.

Algorithms↗
PubMed1997

The effect of human cytomegalovirus on selected functions of peripheral blood monocytes.

The effect of in vitro infection of human cytomegalovirus (HCMV) on various monocyte functions relevant to antimicrobial defence mechanisms has been investigated: the phagocytic activity of monocytes, the release of lysozyme and intracellular concentration of acid phosphatase, and the release of the cytokines interleukin-1 (IL-1), IL-6, and tumour necrosis factor-alpha (TNF-alpha). HCMV significantly inhibited the release of lysozyme and intracellular concentration of acid phosphatase. Regarding the phagocytic activity and the release of cytokines, there was considerable variation in the HCMV effect among the different blood donors tested. There was no clear tendency in the observed results; both stimulation and inhibition were seen. The HCMV-specific pp65 was detected in the nucleus of about 1% of the monocytes 3 h after infection and HCMV-specific IE antigens were found in about 0.1% of the monocytes 2 days postinfection. No E- or L-gene expression was observed and no infectious virus was produced in the monocytes. Our results indicate that HCMV infection may influence monocyte functions in spite of no productive infection of these cells.

Cytomegalovirus↗
PubMed1997

The chromosome 6 sequencing project at the Sanger Centre.

Chromosome 6 is probably best known for encoding the major histocompatibility complex (MHC) which is essential to the human immune response. In addition, it has been shown to be associated with many diseases such Schizophrenia, Diabetes, Arthritis, Haemochromatosis, Narcolepsy, Epilepsy, Retinitis Pigmentosa, Deafness, Ovarian Cancer, and many more. Chromosome 6 is about 180 Mb in size and is estimated to encode around 3500 genes of which only about 10% are currently known. It is our aim to map, sequence and annotate the entire chromosome in close collaboration with the chromosome 6 community.

Chromosomes, Human, Pair 6↗
PubMed1997

The Chromosome 6 database at the Sanger Centre.

The Sanger Centre Chromosome 6 Database (6ace) has been developed as the primary means of release of annotated sequencing and mapping information for human chromosome 6 from the Sanger Centre. It is also being used to curate global data from published and unpublished external sources. The rationale behind the development of 6ace is described, together with information as to how to access the database.

Base Sequence↗
PubMed1997

Characterization of recombination in the HLA class II region.

Studies of linkage disequilibrium across the HLA class II region have been useful in predicting where recombination is most likely to occur. The strong associations between genes within the 85-kb region from DQB1 to DRB1 are consistent with low frequency of recombination in this segment of DNA. Conversely, a lack of association between alleles of TAP1 and TAP2 (approximately 15 kb) has been observed, suggesting that recombination occurs here with relatively high frequency. Much of the HLA class II region has now been sequenced, providing the tools to undertake detailed analysis of recombination. Twenty-seven families containing one or two recombinant chromosomes within the 500-kb interval between the DPB1 and DRB1 genes were used to determine patterns of recombination across this region. SSCP analysis and microsatellite typing yielded identification of 127 novel polymorphic markers distributed throughout the class II region, allowing refinement of the site of crossover in 30 class II recombinant chromosomes. The three regions where recombination was observed most frequently are as follows: the 45-kb interval between HLA-DNA and RING3 (11 cases), the 50-kb interval between DQB3 and DQB1 (6 cases), and an 8.8-kb segment of the TAP2 gene (3 cases). Six of the 10 remaining recombinants await further characterization, pending identification of additional informative markers, while four recombinants were localized to other intervals (outliers). Analysis of association between markers flanking HLA-DNA to RING3 (45 kb), as well as TAP1 to TAP2 (15 kb), by use of independent CEPH haplotypes indicated little or no linkage disequilibrium, supporting the familial recombination data. A notable sequence motif located within a region associated with increased rates of recombination consisted of a (TGGA)12 tandem repeat within the TAP2 gene.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Coping with the inexorable rise in medical admissions: evaluating a radical reorganisation of acute medical care in a Scottish district general hospital.

OBJECTIVE: To describe radical changes in acute medical care in a district general hospital and assess their impact on staff and patients. DESIGN: A before and after comparison of structure, process and outcome indicators in the year preceding and following reorganisation. SETTING: The Adult Medicine Clinical Directorate of the Royal Alexandra Hospital in Paisley, Scotland. SUBJECTS: Staff in the Medical Directorate and a random sample of 400 patients. INTERVENTIONS: The main stimulus for reorganisation was the pressure caused by a relatively steep rise in admissions. In response, the six existing general medical wards were converted into a 38-bed Medical Admissions Unit and five more specialised wards. A new acute receiving rota allowed each consultant to concentrate almost exclusively on acute receiving for one week at a time. RESULTS: The boarding of patients in non-medical wards was eliminated through improved bed management. The needs of patients became better matched to the specialism of their consultant. The cardiologist's share of in-patients with cardiological problems rose from 34% of 2,877 cases to 58% of 3,085 cases (p < 0.001) and the respiratory physicians' share of respiratory in-patients grew from 53% of 1,281 cases to 67% of 1,287 cases (p < 0.001). After the reorganisation, medical staff had significantly fewer concerns about losing track of patients (p < 0.01) or about boarding (p < 0.01), however, concern about 'blocked beds' became greater (p < 0.05). Nurses reported more time for health promotion (p < 0.01) but also a rise in stress (p < 0.05). More patients reported that staff had time to explain their treatment (85/109 (79%) before, 93/105 (89%) after, p < 0.05) and a higher proportion felt ready for discharge (91/108 (84%) before, 99/106 (93%) after, p < 0.05). CONCLUSIONS: Radical reorganisation of medical care in response to rising acute medical admissions is achievable and may lead to improvements in care.

Adult↗
PubMed1996

Human cytomegalovirus suppression of and latency in early hematopoietic progenitor cells.

Bone marrow cells (BMC) are involved in the pathogenesis of human cytomegalovirus++ (HCMV) infections, and the hematopoietic cells are probable sites of HCMV latency in healthy donors. In vitro studies have indicated both a direct inhibitory effect of HCMV on proliferation and differentiation of myeloid bone marrow progenitors and an impairment of bone marrow stroma cell function by HCMV. The purpose of the present study was to establish whether the suppressing effect could be limited to subsets of immature CD34+ BMC and to investigate the role of immature cell populations as possible sites of HCMV latency. CD34+ cells from healthy HCMV-seropositive and -seronegative donors were sorted according to the expression of HLA-DR (CD34+ HLA-DR+ and CD34+ HLA-DR- cells). The progenitor growth of hematopoietic progenitor cells from seronegative donors was examined by colony and single-cell assays after in vitro infection with HCMV. To determine the susceptibility of the CD34+ cells to HCMV infection in vitro and in vivo, cells of both subsets from seronegative and seropositive donors were analyzed for the presence of HCMV DNA by polymerase chain reaction. HCMV infection in vitro inhibited the interleukin-1alpha (IL-1alpha)-, IL-3-, granulocyte colony-stimulating factor-, granulocyte-macrophage colony-stimulating factor-, and stem cell factor-induced proliferation in single-cell assays of CD34+ HLA-DR- cells by 34%. In contrast, the colony growth of the CD34+ HLA-DR+ subset was suppressed in cells from only 3 of the 8 donors. However, in vitro HCMV infection of the CD34+ HLA-DR+ progenitor cells inhibited the proliferation of all donors tested when hematopoietic growth factors were used individually to promote progenitor growth. In addition, the formation of burst-forming units-erythroid and colony-forming units-granulocyte, erythrocyte, monocyte, megakaryocyte was reduced 40% to 60% by HCMV in vitro. In contrast, the growth of high proliferative potential colony-forming cells was not inhibited after in vitro HCMV infection. Furthermore, HCMV DNA was detected in both CD34+ HLA-DR- and CD34+ HLA-DR+ progenitors from in vitro-infected HCMV-seronegative donors and cells from HCMV-seropositive donors. Taken together, the early progenitors defined as CD34+ HLA-DR- and CD34+ HLA-DR+ are directly suppressed in their proliferation by HCMV in vitro, and hematopoietic stem cells are also sites of HCMV latency in healthy HCMV-seropositive donors.

Adult↗
PubMed1996

Direct growth suppression of myeloid bone marrow progenitor cells but not cord blood progenitors by human cytomegalovirus in vitro.

Recently, considerable interest has arisen as to use cord blood (CB) as a source of hematopoietic stem cells for allogenic transplantation when bone marrow (BM) from a familial HLA-matched donor is not available. Because human cytomegalovirus (HCMV) has been shown to inhibit the proliferation of BM progenitors in vitro, it was important to examine whether similar effect could be observed in HCMV-infected CB cells. Therefore, the effect of HCMV challenge on the proliferation of myeloid progenitors from BM and CB was compared using both mononuclear cells (MNC) and purified CD34+ cells. A clinical isolate of HCMV inhibited the colony formation of myeloid BM progenitors responsive to granulocyte-macrophage colony-stimulating factor (CSF), granulocyte-CSF, macrophage-CSF, interleukin-3 (IL-3) and the combination of IL-3 and stem cell factor (SCF). In contrast, colony growth of CB progenitors was not affected. In addition, HCMV inhibited directly the growth of purified BM CD34+ cells responsive to IL-3 and SCF in single cell assay by 40%, wheras the growth of CD34+ progenitors obtained from CB was not suppressed. The HCMV lower matrix structural protein pp65 and HCMV DNA were detected in both CB and BM CD34+ cells after in vitro challenge. However, neither immediate early (IE)-mRNA nor IE proteins were observed in infected cells. Cell cyclus examination of BM and CB CD34+ cells revealed that 25.7% of BM progenitors were in S + G2/ M phase wheras only 10.7% of the CB progenitors. Thus, a clinical isolate of HCMV directly inhibited the proliferation of myeloid BM progenitors in vitro wheras CB progenitors were not affected. This difference in the susceptibility of CB and BM cells to HCMV may partly be caused by the slow cycling rate of naive CB progenitors compared to BM progenitors at the time of infection.

Adult↗
PubMed1996

Evolutionary dynamics of non-coding sequences within the class II region of the human MHC.

About 40% (350 kb) of the human MHC class II region has been sequenced and a coordinated effort to sequence the entire MHC is underway. In addition to the coding information (22 genes/pseudogenes), the non-coding sequences reveal novel information on the organisation and evolution of the MHC as demonstrated here by the example of a 200 kb contig that has been analysed for local and global features. In conjunction with cross-species comparisons, our results present new evidence on the structure of isochores, the evolutionary dynamics of repeat-mediated recombination and its effect on certain MHC encoded genes, and a higher than average degree of natural polymorphism that has implications for sequencing the human genome. We also report the finding of a class I-related pseudogene (HLA-ZI) in the middle of the class II region, which provides the first direct evidence for DNA exchange between these two related regions in man.

Amino Acid Sequence↗
PubMed1996

Reevaluation of synaptic relationships of cerebellar terminals in the ventral lateral nucleus of the rhesus monkey thalamus based on serial section analysis and three-dimensional reconstruction.

Terminals of cerebellar afferents (CB) to different regions of the ventral lateral nucleus (VL) of the rhesus monkey thalamus were labeled with wheat germ agglutinin-horseradish peroxidase following injections into the dentate nucleus. Synaptic relationships of 17 CB with projection neuron dendrites (PNd) and local circuit neuron dendrites (LCNd) were analyzed in serial ultrathin sections from dorsal and ventral VL regions, which are known to differ cytoarchitecturally and functionally. Three terminals were reconstructed using three-dimensional (3D) computer image analysis techniques to obtain volumetric and planar measurements. CB in the ventral VL were often flat and elongated with synaptic vesicles arranged in clusters. Each CB was engaged with one PNd and one to four LCNd. A single bouton formed 8-50 synaptic contacts, with those on PNd outnumbering the ones on LCNd 4.1:1. Only some CB in the ventral VL were engaged in complex synaptic arrangements such as triads and serial synapses. Most CB in the dorsal VL displayed a roundish shape and numerous uniformly distributed synaptic vesicles. They formed 5-25 synaptic contacts with a 3:1 ratio of contacts on PNd compared with those on LCNd. CB in the dorsal VL participated in a variety of complex synaptic arrangements. Two types of triads were found: classic with CB, PNd and LCNd, and unconventional with CB and two LCNd. CB were also involved in serial synapses with two LCNd or LCNd and another PNd, and serial sequential synapses with two LCNd and a PNd. Three glomerulus-like structures were encountered in the dorsal VL. 3D reconstruction and volumetric measurements revealed that synaptic contacts formed by CB on PNd had varying shapes and sizes (0.022-0.274 microns2). Synapses formed on LCNd were larger (0.09-0.407 microns2). The total area of all active zones of a single CB on LCNd was either equal to or about 40% smaller than that of synapses on PNd. The entire active zone area comprised 1-1.6% of the total CB surface area and did not seem to correlate with the volume. Synaptic contacts formed by associated LCNd on PNd in complex arrangements were usually small (0.021-0.044 micron2). The results suggest that: synapses formed by CB on PNd and LCNd, and synapses formed by LCNd on PNd may differ in strength; a variety of different circuits participate in the processing of cerebellar afferent information in the primate VL; and these circuits differ in functionally different VL subdivisions.

Animals↗
PubMed1996

Six new polymorphic microsatellite markers used for the integration of genetic and physical maps of human chromosome 7.

We report the isolation and characterization of six new polymorphic dinucleotide repeat microsatellite markers (D7S1491, D7S1492, D7S1493, D7S1494, D7S1495, and D7S1496), their integration into the genetic map of human chromosome 7 by analysis of 40 CEPH (Centre d'Etude du Polymorphisme Humain) pedigrees, and their use for integration of physical and genetic maps of this chromosome.

Alleles↗
PubMed1996

Divergent intron arrangement in the MB1/LMP7 proteasome gene pair.

We sequenced the human MB1 gene from a cosmid clone mapping to chromosome 14q11.2-12. The gene spans about 6 kilobases and contains three exons and two introns. There was no evidence of an alternative leader exon, which is a characteristic of the major histocompatibility complex (MHC)-encoded LMP7 gene, the closest relative of MB1, with which it shares 67% amino acid identity. Conceptual translation of the 5' end of the gene calls for a cleaved leader sequence of 59 amino acids, consistent with western blot data. None of the MB1 gene's three exons were coincident with any of the six exons in LMP7. In contrast, in the delta-encoding gene and its counterpart, the MHC-encoded LMP2 gene (59% amino acid identity), all six exons are arranged at equivalent positions in respect to the coding frame. The unique structure of MB1 implies a separate origin or different selection pressures acting at this particular locus. DNA repeat analysis provides information on the minimum time of separation of the MB1/LMP7 pair of genes.

Base Sequence↗
PubMed1996

MHCDB: database of the human MHC (release 2).

The second release of the human major histocompatibility complex (MHC) database is now publicly available. It contains an updated physical map and considerably more genomic sequence. cDNA sequences of all current alleles are accessible as individual sequence entries. The variability of different genes is displayed graphically as static and dynamic images accessible from the database. Known disease-serotype associations have also been incorporated, together with data from the MHCPEP database of eluted peptides.

Databases, Factual↗
PubMed1996

Cloning of contiguous genomic fragments from human chromosome 21 harbouring three trefoil peptide genes.

A group of small peptides with a typical cysteine-rich domain (termed trefoil motif or P-domain) is abundantly expressed at mucosal surfaces of specific normal and neoplastic tissues. Their association with the maintenance of surface integrity was suggested. The first known human trefoil peptide (pS2) was isolated from breast cancer cells (MCF7). Its oestrogen-inducible gene, and the human homologue to the porcine spasmolytic peptide gene (hSP/SML1) appear synchronously expressed in healthy stomach mucosa and several carcinomas of the gastrointestinal tract. Both genes were shown to be localised at 21q22.3. A new trefoil peptide from human intestinal mucosa (hITF/hP1.B) and its gene were described recently. By using suitable oligonucleotide primers and PCR and isolating large (110-250 kb) genomic recombinants cloned in the bacterial artificial chromosome (BAC) system, we present a genomic region from chromosome band 21q22.3 cloned in contiguous sequences and encoding all three members of human P-domain/trefoil peptides proving a physical linkage of all three trefoil peptide genes. Such genomic sequences will provide useful experimental material for analysis of gene regulation, for gene modification experiments and for establishing transgenic cells or animals.

Base Sequence↗