Biomedical subjects
Publications and source records attributed to J L Wood.
[structure: see text] Three different approaches to the carbocyclic core of CP-263,114 are presented that illustrate a strategic evolution from an oxy-Cope rearrangement to variants of the Wharton fragmentation.
[reaction: see text] Assembly of the carbocyclic core of CP-263,114 has been accomplished efficiently and in high yield. Key steps include a phenolic oxidation/intramolecular Diels-Alder sequence, tandem radical cyclization, and the late-stage fragmentation of a densely functionalized isotwistane skeleton.
[see structure]. Studies toward the total synthesis of marine diterpenoids isolated from Acanthella sp., e.g., kalihinol A, are described. Efficient construction of the functionalized trans-decalin core (11) is achieved through intramolecular Diels-Alder cyclization followed by diastereoselective epoxidation and aziridination.
Recent efforts in our laboratories have resulted in a synthetic approach toward C2'-alkylated K252a analogues via extension of a K252a cyclofuranosylation strategy. The bis-indole-N-glycosidic coupling of 6-N-(3,4-dimethoxybenzyl)-staurosporinone (21) with a number of highly functionalized carbohydrates has given access to previously unattainable, biologically relevant analogues.
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[reaction: see text] The complete carbocyclic skeleton of ingenol is assembled via a route that employs ring-closing metathesis (RCM) to close the strained "inside-outside" BC ring system (i.e., 24 --> 25).
The neurotransmitter serotonin controls a wide range of biological systems, including its own synthesis and release. As the rate-limiting enzyme in serotonin biosynthesis, tryptophan hydroxylase (TPH) is a potential target for this autoregulation. Using the serotonergic neuron-like CA77 cell line, we have demonstrated that treatment with a 5-hydroxytryptamine autoreceptor agonist, CGS 12066A, can lower TPH mRNA levels and promoter activity. We reasoned that this repression might involve inhibition of MAP kinases, since 5-HT1 receptors can increase mitogen-activated protein (MAP) kinase phosphatase levels. To test this hypothesis, we first showed that the TPH promoter can be activated 20-fold by mitogen-activated extracellular-signal regulated kinase kinase kinase (MEKK), an activator of MAP kinases. This activation was then blocked by CGS 12066A. The maximal MAP kinase and CGS repression regulatory region was mapped to between -149 and -45 base pairs upstream of the transcription start site. The activation by MEKK appears to be cell-specific, because MEKK did not activate the TPH promoter in nonneuronal cell lines. At least part, but not all, of the MAP kinase responsiveness was mapped to an inverted CCAAT box that binds the transcription factor NF-Y. These data suggest a model for the autoregulation of serotonin biosynthesis by repression of MAP kinase stimulation of the TPH promoter.
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A matched case-control study was made of 100 thoroughbred horses which were coughing and 148 control horses which were free of clinical signs of respiratory tract disease. The variables identified by multivariable conditional logistic regression as being significantly associated with coughing included age (the risk decreased with age), the stage of training (horses in early training were at greatest risk), the time since the last race (horses that had never raced were at greatest risk) and the time since they were last transported (horses transported more than 14 days previously were more likely to cough than those transported within the last week). The coughing horses were significantly more likely to have high scores for upper and lower tracheal mucus and pharyngeal lymphoid hyperplasia. In addition, the tracheal aspirates of the coughing horses had increased odds of neutrophilia and were more likely to have intracellular bacteria than the control horses. However, a considerable proportion of the control horses had cytological and/or endoscopic evidence of airway inflammation.
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In order to investigate the role of infectious agents in the aetiology of lower respiratory tract disease in Thoroughbred racehorses, a matched case-control study was conducted. Cases were identified by the presence of coughing, and were compared to a control population matched on time of sample collection and location within the same training establishment. Tracheal wash samples were collected from 100 cases and 148 controls. Case horses were more likely than controls to have endoscopic and cytological evidence of airway inflammation. There was no significant association between serological evidence of infection by commonly implicated respiratory viruses and coughing. Similarly, mycoplasma were rarely isolated and were not associated with disease. In contrast, there was a strong association between isolation of greater than a total of 10(3) colony-forming units/ml of tracheal wash and coughing. Individual bacterial species associated with disease included Streptococcus zooepidemicus, Streptococcus pneumoniae, Streptococcus suis, Streptococcus sanguis, Pasteurella spp and Bordetella bronchiseptica. This study provides evidence of the role of bacterial infection in the aetiology of lower respiratory tract inflammation in racehorses. However, in 58% of cases, few or no bacteria were isolated. Hence, at the time of identification of disease, there was no evidence of viral, bacterial or mycoplasmal infection in the majority of coughing horses. The aetiology of the signs observed in these horses requires further investigation.
[reaction: see text] Two complementary strategies for the synthesis of the diazonamide A bisaryl quaternary center are described. The first strategy relies upon an extremely facile tandem cyclopropanation/ring-opening sequence, which has proven amenable to chiral catalysis to provide enantioenriched material. The second strategy relies upon a more concise alkylation route ideal for material advancement.
Protein kinases have proved to be largely resistant to the design of highly specific inhibitors, even with the aid of combinatorial chemistry. The lack of these reagents has complicated efforts to assign specific signalling roles to individual kinases. Here we describe a chemical genetic strategy for sensitizing protein kinases to cell-permeable molecules that do not inhibit wild-type kinases. From two inhibitor scaffolds, we have identified potent and selective inhibitors for sensitized kinases from five distinct subfamilies. Tyrosine and serine/threonine kinases are equally amenable to this approach. We have analysed a budding yeast strain carrying an inhibitor-sensitive form of the cyclin-dependent kinase Cdc28 (CDK1) in place of the wild-type protein. Specific inhibition of Cdc28 in vivo caused a pre-mitotic cell-cycle arrest that is distinct from the G1 arrest typically observed in temperature-sensitive cdc28 mutants. The mutation that confers inhibitor-sensitivity is easily identifiable from primary sequence alignments. Thus, this approach can be used to systematically generate conditional alleles of protein kinases, allowing for rapid functional characterization of members of this important gene family.
Hip dysplasia (malformation of the coxofemoral joint) in dogs is a major health problem for which the British Veterinary Association (BVA) had set up a control scheme in 1965. Based on scoring nine components of the radiographs of both the left and right joints, the degree of hip joint malformation is now quantified by an overall hip score (a measure of the condition of the hip joint). The hip scores of 1258 flat-coated retrievers and 1566 Newfoundlands (registered with The Kennel Club in the United Kingdom) were analysed after merging with Kennel Club pedigree data for 19036 flat-coated retrievers registered by 1995 and 14336 Newfoundlands registered by 1997. The merged data included the animal's identity, date of birth, sex and hip scores and also similar records for the dog's relatives including the hip score if the relative had been tested. In recent years, breeding has been increasingly from tested parents. There has been some reduction in offspring hip scores - presumably because breeders avoided breeding from males with very high scores. However, a much greater reduction in offspring hip score would be achieved by stricter science-based selection of potential sires and dams. Regression modelling quantified the positive relationship between offspring and parental hip scores. The genetic heritability of hip scores was large and significant in both breeds (particularly from dams). The breeders in UK tended to use healthy sires for breeding but they have taken less care in selecting dams. Our regression models emphasise the need for both sires and dams, particularly dams, to be healthy with very small hip scores.
Hip dysplasia (malformation of the hip joint) is an important health problem in dogs. The condition and the control scheme for Gordon Setters was organised by the British Veterinary Association (BVA) and the Kennel Club before 1976 and use hip scores. Our analyses of hip dysplasia in Gordon Setters used both hip scores and the scores for the nine components (which collectively defined the hip score). The scores for all nine components were available for 732 females and 420 males. These clinical data were merged with the Kennel Club pedigree database (animal's identity, date of birth, and also similar data for its parents, including hip scores if the parent had been tested). Regression models showed strong positive relationships between offspring and parental hip scores as well as for some component scores. The heritability of hip dysplasia (assessed using both hip scores and the major components) was significant, particularly from dams. Our research emphasizes the need for both sires and dams--particularly dams, to have zero or small hip scores. Tested parents have been used increasingly in recent years, but greater reduction in offspring hip score will require stricter selection of potential breeding stock. The models reported here provide quantitative predictions of likely health benefits from selective breeding.
Young Thoroughbred racehorses (222 yearlings entering training and 246 2-year-old horses already in training) from eight flat-training yards in Newmarket, UK were used to monitor serological responses to vaccination with an inactivated influenza virus vaccine. Blood samples taken prior to and after vaccination were tested by single radial haemolysis (SRH) to determine antibody titres (expressed as area of haemolysis in mm(2)). Prior to vaccination, yearlings had mean antibody titres (64+/-4 mm(2)) that were approximately half of those of 2-year-olds (115+/-3 mm(2)) and 89% of yearlings and 73% of 2-year-olds had SRH titres <140 mm(2). Extrapolation from experimental and field studies suggests that these levels would not protect against homologous influenza virus infection. Both age-groups showed anamnestic responses to vaccination resulting in similar peak mean titres ( approximately 160+/-2mm(2)) with 67% of yearlings and 73% of 2-year-olds achieving levels > or =140 mm(2). A second dose of vaccine administered a month after the first in yearlings did not increase the mean titre but 75% of horses had levels of antibody > or =140 mm(2). The vaccination history in the official passport of yearlings showed that 23% had no record of previous vaccination and were probably fully susceptible to infection. For yearlings entering training, the important predictors from multiple-regression analyses of SRH titres prior to vaccination were "Time since last vaccination," "Total number of previous vaccines" and "Age at first vaccination." In 2-year-olds and following two doses of vaccine in yearlings, there was no significant relationship between these factors and SRH titre.
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OBJECTIVE: To establish a model for inheritance of gluten-sensitive enteropathy (GSE) in Irish Setters. ANIMALS: 44 dogs of a 6-generation family of Irish Setters with GSE and 7 healthy Irish Setters. PROCEDURE: Phenotype of each dog was determined after oral administration of gluten in the weaning diet, using morphometric evaluation of jejunal biopsies (all generations) and measurement of small intestinal permeability by use of a lactulose-rhamnose permeation test (generations 1, 2, and 3). Overall probability for each of 4 genetic models of inheritance (autosomal recessive, autosomal dominant, sex-linked recessive, and sex-linked dominant) accounting for segregation of partial villus atrophy within the entire family was calculated. RESULTS: The autosomal recessive model was most tenable and was 56,250 times more likely to account for segregation of partial villus atrophy than the autosomal dominant model, assuming disease prevalence of 0.8%. Both sex-linked models were untenable. These conclusions were robust to the error attached to estimation of disease prevalence. High intestinal permeability without morphometric jejunal abnormalities in 4 of 20 dogs in the 3 youngest generations suggested heterogeneity of lesions associated with GSE. CONCLUSIONS: Genetic transmission of GSE is under the control of a single major autosomal recessive locus.