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S D Brown

Publications and source records attributed to S D Brown.

At least 19 recordsLinked to original sources
PubMed1998

Cloning of a novel member of the low-density lipoprotein receptor family.

A gene encoding a novel transmembrane protein was identified by DNA sequence analysis within the insulin-dependent diabetes mellitus (IDDM) locus IDDM4 on chromosome 11q13. Based on its chromosomal position, this gene is a candidate for conferring susceptibility to diabetes. The gene, termed low-density lipoprotein receptor related protein 5 (LRP5), encodes a protein of 1615 amino acids that contains conserved modules which are characteristic of the low-density lipoprotein (LDL) receptor family. These modules include a putative signal peptide for protein export, four epidermal growth factor (EGF) repeats with associated spacer domains, three LDL-receptor (LDLR) repeats, a single transmembrane spanning domain, and a cytoplasmic domain. The encoded protein has a unique organization of EGF and LDLR repeats; therefore, LRP5 likely represents a new category of the LDLR family. Both human and mouse LRP5 cDNAs have been isolated and the encoded mature proteins are 95% identical, indicating a high degree of evolutionary conservation.

Amino Acid Sequence↗
PubMed1998

Isolation and characterization of LRP6, a novel member of the low density lipoprotein receptor gene family.

A novel member of the low density lipoprotein receptor (LDLR) gene family has been identified and characterized. This gene, termed LDL receptor-related protein 6 (LRP6), encodes a transmembrane protein which has 71% identity and is structurally similar to the protein encoded by LRP5, a proposed candidate gene for type 1 diabetes located on human chromosome 11q13. LRP6 maps to human chromosome 12p11-p13. Mouse Lrp6 encodes a protein that has 98% identity to human LRP6 and maps to chromosome 6. Unlike other members of the LDLR family, LRP6 and LRP5 display a unique pattern of four epidermal growth factor (EGF) and three LDLR repeats in the extracellular domain. The cytoplasmic domain of LRP6 is not similar to other members of the LDLR family, while comparison with LRP5 reveals proline-rich motifs that may mediate protein-protein interactions. Thus, it is likely that LRP6 and LRP5 comprise a new class of the LDLR family.

Amino Acid Sequence↗
PubMed1998

Structure of the Drosophila DNA topoisomerase I gene and expression of messages with different lengths in the 3' untranslated region.

The nucleotide sequence of the Drosophila DNA topoisomerase I gene (top1) has been determined. Structurally, top1 consists of eight exons and seven introns. The top1 coding region contains a new class of opa repeats, encoding clusters of serine residues instead of glutamine repeats usually seen in Drosophila genes of the neurogenic loci. A unique feature of top1 is the developmental switch of its transcripts: a heterogeneous population of transcripts ranging from 3.8 to 4.2kb seen maximally at 0-2h of embryogenesis and a 5.2-kb transcript maximal at 6-12h of embryonic development. The transcripts expressed in the 0-2-h embryo have been shown as maternal storage products specific to ovarian tissues. RACE analysis shows that whereas the 6-12-h transcripts have a single site for polyadenylation, there are at least 12 different sites for poly(A) addition to the 0-2-h transcripts. An additional intron specific for the maternal storage transcripts appears in some of the 0-2-h transcripts. No significant heterogeneity at the 5' end of the top1 transcripts is seen. Sequence searches have revealed a number of regulatory sequences for potential translational control in the 3' untranslated region.

Animals↗
PubMed1998

Mouse models of genetic disease: new approaches, new paradigms.

The mouse mutant resource is a valuable tool for gene function studies in the post-genomics era. However, despite a seemingly large catalogue of mouse mutants, it is recognized that we have access to mutations at only a small fraction of the total number of mouse genes. There is a phenotype gap that needs to be narrowed by the implementation of large-scale, systematic mutagenesis programmes in the mouse. Both genotype-driven and phenotype-driven approaches can be employed to recover new mouse mutations. Genotype-driven approaches include large-scale genome-wide mutagenesis by gene trapping in embryonic stem cells. For genotype-driven approaches, the initial focus is on the characterization of the mutational change to the genome. Identification of the mutated gene is relatively trivial, but the genotype-driven route provides little indication of the likely phenotypic outcome of the mutation. In contrast, phenotype-driven approaches employ mutagenesis procedures that emphasize the recovery of novel phenotypes without prior assumptions about the underlying gene or pathway that has been disrupted--although identifying the underlying gene may not be trivial. One phenotype-driven approach includes chemical mutagenesis using N-ethyl-N-nitrosourea (ENU). ENU mutagenesis programmes are increasingly being brought to bear on increasing the breadth and depth of the mouse mutant resource, and in so doing narrowing the phenotype gap.

Animals↗
PubMed1998

Mouse mutagenesis-systematic studies of mammalian gene function.

The mouse will play a pivotal role in mammalian gene function studies as we enter the post-genomics era. The challenge is to develop systematic, genome-wide mutagenesis approaches to the study of gene function. The current mouse mutant resource has been an important source of human genetic disease models. However, despite an apparently large catalogue of mouse mutations, we have access to mutations at only a small fraction of the likely total number of mammalian genes-there is a phenotype gap that needs to be filled by the establishment of new mutagenesis programmes. Two routes, genotype- and phenotype-driven, can be used for the recovery of novel mouse mutations. For the former, gene trap embryonic stem cell libraries appear set to deliver a large number of mutations around the mouse genome. The advantage of genotype-driven approaches is the ease of identification of the mutated locus; the disadvantage that a priori assumptions have to be made concerning the function and likely phenotype of the mutated gene. In contrast, phenotype-driven mutagenesis emphasizes the recovery of novel phenotypes. One phenotype-driven approach that will play an important role in expanding the mouse mutant resource employs the mutagen N-ethyl-N-nitrosourea (ENU). The phenotype-driven route makes no assumptions about the underlying genes involved, and ENU mutagenesis programmes can be expected to play a significant role in uncovering novel pathways and genes; the disadvantage is that the identification of the mutant gene is still not trivial. Together, the complementary routes of genotype- and phenotype-driven mutagenesis will provide a much enlarged catalogue of mouse mutations and phenotypes for future gene function studies.

Animals↗
PubMed1998

Susceptibility to RPR 106,972, quinupristin/dalfopristin and erythromycin among recent clinical isolates of enterococci, staphylococci and streptococci from North American medical centres.

An orally administered streptogramin (RPR 106,972) and a parenteral streptogramin (quinupristin/dalfopristin) were evaluated against a collection of 2481 recent clinical isolates of gram-positive cocci. The isolates were gathered from ten North American medical centres during the winter months of 1996-1997. In spite of minor differences, both streptogramins had essentially identical spectra of activity which included many erythromycin-resistant isolates. Previously proposed interpretative criteria for quinupristin/dalfopristin disc diffusion susceptibility tests were confirmed.

Academic Medical Centers↗
PubMed1998

Comparison of brain temperature with bladder and rectal temperatures in adults with severe head injury.

OBJECTIVE: The purpose of this study was to compare brain temperature (Tbr) with conventional indicators of core body temperature (i.e., rectal temperature [Tre] and bladder temperature [Tbl]), in adults with severe head injury. METHODS: The relationships between Tbr and Tbl and between Tbr and Tre are described in terms of differences in temperature in eight patients with severe head injury. INSTRUMENTATION: Brain tissue temperature was measured every minute, with a thermocouple embedded 2 cm from the tip of a ventriculostomy catheter used to measure intracranial pressure. Tbl was measured with a thermistor embedded in a bladder catheter, and Tre was measured with a thermistor in a rectal probe. RESULTS: Tbr was usually greater than Tbl and Tre. The average difference between Tbr and Tbl for each patient ranged from 0.32 to 1.9 degrees C, with standard deviations of the difference ranging from 0.30 to 0.80 degrees C. The average difference between Tbr and Tre for each patient ranged from 0.1 to 2.0 degrees C, with standard deviations of the difference ranging from 0.32 to 1.08 degrees C. In the majority of patients, the differences (Tbr - Tbl and Tbr - Tre) were greater at temperatures outside of the normal temperature range (Tbr < or =36 degrees C and >38 degrees C). CONCLUSION: Tbl and Tre often underrepresent Tbr after traumatic brain injury, particularly when the patient is hypo- or hyperthermic.

Adolescent↗
PubMed1998

A high-resolution microsatellite map of the mouse genome.

The European Collaborative Interspecific Backcross (EUCIB) resource was constructed for the purposes of high-resolution genetic mapping of the mouse genome (). The large Mus spretus/C57BL/6 backcross of 982 progeny has a genetic resolution of 0.3 cM at the 95% confidence level ( approximately 500 kb in the mouse genome). We have used the EUCIB mapping resource to develop a genome-wide high-resolution genetic map incorporating 3368 microsatellites. The microsatellites are distributed among 2302 genetically separated bins with 1.46 markers per bin on average. Average bin separation is 0.61 cM. This high-resolution genetic map will aid the construction of a robust physical map of the mouse genome.

Animals↗
PubMed1998

PMX-622 (polymyxin B-dextran 70) does not alter in vitro activities of 11 antimicrobial agents.

Because of its capacity to neutralize the lethality of gram-negative bacterial endotoxic lipopolysaccharides, PMX-622 (polymyxin B bound to dextran 70) is being developed for possible adjunctive therapy of gram-negative sepsis. In this study, it was determined that the in vitro antimicrobial activity of PMX-622 was minimal and that it does not interfere with the in vitro antimicrobial activity of 11 antibiotics commonly used to treat gram-negative infections.

Anti-Bacterial Agents↗
PubMed1998

Antipneumococcal activities of a ketolide (HMR 3647), a streptogramin (quinupristin-dalfopristin), a macrolide (erythromycin), and a lincosamide (clindamycin).

Four different compounds belonging to the macrolide-lincosamide-streptogramin B (MLSb) class of antimicrobial agents were tested against 611 Streptococcus pneumoniae strains. The ketolide (HMR 3647, previously RU66647) and the streptogramin (quinupristin-dalfopristin) were both active against pneumococci with high-level MLSb resistance (clindamycin-resistant strains) as well as those with low-level macrolide resistance (clindamycin-susceptible strains).

Anti-Bacterial Agents↗
PubMed1998

In vitro antimicrobial activity of MSI-78, a magainin analog.

MSI-78 is a cationic peptide with broad-spectrum antimicrobial activity and is being developed as a topical agent. We compared the in vitro activity of MSI-78 with those of ofloxacin and other antibiotics against fresh clinical isolates. Based on MIC distribution statistics, strains for which the MSI-78 MIC was < or = 64 micro/ml were assumed to be susceptible for purposes of this report. Of 411 aerobic isolates tested, 91% were susceptible to MSI-78, compared to 91% for ofloxacin and 92% for ciprofloxacin. Only enterococci consistently required > or = 64 microg of MSI-78/ml for inhibition. MSI-78 demonstrated bactericidal activity equivalent to that of ofloxacin. Of 61 anaerobes, 97% were susceptible to MSI-78. Of 10 isolates of Candida albicans, 3 were inhibited by MSI-78 at 24 h. Further studies of this compound appear to be warranted.

Anti-Infective Agents↗
PubMed1998

In vitro activities of clinafloxacin against contemporary clinical bacterial isolates from 10 North American centers.

Clinafloxacin was more active than ciprofloxacin against 4,213 aerobic and facultative anaerobic bacterial isolates from 10 medical centers, as tested by broth microdilution and disk diffusion methods. The percentage of 201 anaerobes susceptible to clinafloxacin by broth microdilution was comparable to cefoxitin. Our data support the proposed disk diffusion interpretive criteria for aerobic bacteria with 5-microg clinafloxacin disks.

Anti-Infective Agents↗
PubMed1998

In vitro activities of the ketolide HMR 3647 against recent gram-positive clinical isolates and Haemophilus influenzae.

The ketolide HMR 3647 (previously RU 66647) was evaluated against 2, 563 recent clinical isolates of gram-positive pathogens and 200 Haemophilus influenzae isolates. HMR 3647 was active against macrolide-resistant streptococci, including pneumococci, but was not active against macrolide- or lincosamide-resistant staphylococci. Against H. influenzae, the potency of HMR 3647 was similar to that of azithromycin.

Anti-Bacterial Agents↗
PubMed1998

Shaker-1 mutations reveal roles for myosin VIIA in both development and function of cochlear hair cells.

The mouse shaker-1 locus, Myo7a, encodes myosin VIIA and mutations in the orthologous gene in humans cause Usher syndrome type 1B or non-syndromic deafness. Myo7a is expressed very early in sensory hair cell development in the inner ear. We describe the effects of three mutations on cochlear hair cell development and function. In the Myo7a816SB and Myo7a6J mutants, stereocilia grow and form rows of graded heights as normal, but the bundles become progressively more disorganised. Most of these mutants show no gross electrophysiological responses, but some did show evidence of hair cell depolarisation despite the disorganisation of their bundles. In contrast, the original shaker-1 mutants, Myo7ash1, had normal early development of stereocilia bundles, but still showed abnormal cochlear responses. These findings suggest that myosin VIIA is required for normal stereocilia bundle organisation and has a role in the function of cochlear hair cells.

Animals↗