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J Beasley

Publications and source records attributed to J Beasley.

At least 19 recordsLinked to original sources
PubMed2003

Mouse models of human cancer web-based resources.

The Mouse Models of Human Cancers Consortium (MMHCC) is a collaborative program designed to derive and characterize mouse models of human malignancies. To enhance information and resource exchange among the MMHCC investigators and other cancer research scientists, the NCI Center for Bioinformatics (NCICB, http://ncicb.nci.nih.gov/) has developed web-based resources that are freely available to the cancer research community. These resources include a website (http://emice.nci.nih.gov) and databases for cancer models (http://cancermodels.nci.nih.gov) and cancer images (http://cancerimages.nci.nih.gov).

Animals↗
PubMed2001

Cerulenin mimics effects of leptin on metabolic rate, food intake, and body weight independent of the melanocortin system, but unlike leptin, cerulenin fails to block neuroendocrine effects of fasting.

Cerulenin and a related compound, C75, have recently been reported to reduce food intake and body weight independent of leptin through a mechanism hypothesized, like leptin, to involve hypothalamic nutrition-sensitive neurons. To assess whether these inhibitors act through mechanisms similar to mechanisms engaged by leptin, ob/ob and Ay (agouti) mice, as well as fed and fasted wild-type mice, were treated with cerulenin. Like leptin, cerulenin reduced body weight and food intake and increased metabolic rate in ob/ob mice, and cerulenin produced the same effects in wild-type mice, whereas lithium chloride, at doses that produce conditioned taste aversion, reduced metabolic rate. However, in contrast to leptin, cerulenin did not prevent effects of fasting on plasma corticosterone or hypothalamic levels of neuropeptide Y, agouti-related peptide, pro-opiomelanocortin, or cocaine- and amphetamine-related peptide mRNA. Also, in contrast to leptin, cerulenin was highly effective to reduce body weight in Ay mice, in which obesity is caused by blockade of the melanocortin receptor. These data demonstrate that cerulenin produces metabolic effects similar to effects of leptin, but through mechanisms that are independent of, or down-stream from, both leptin and melanocortin receptors.

Animals↗
PubMed2000

The use of peptides in Diogenesis: a novel approach to drug discovery and phenomics.

The Diogenesis Process is an integrated drug discovery platform that allows target validation, partner identification, and the identification of small molecule drug candidates for protein:protein interactions. Diogenesis utilizes the well-established methods of peptide display, synthetic and recombinant peptide production, in vitro biochemical and cell-based testing to form a universal drug discovery engine with distinct advantages over competing protocols. The process creates a library of diverse peptides, and selects rare and unique binders that identify and simplify surface "hot spots" on protein targets through which target activity can be regulated. In many cases, these peptide "Surrogates" have the minimal sequence and structural information needed to induce a change in the biological activity of the target; in pharmacological terms, only after inducing agonism or antagonism. The use of Surrogates in hot spot identification also allows subdivision of rather large surface domains into smaller domains that alone, or in combination with another subdomain, offers sufficient territory for modification of target activity. These Surrogates, in turn, provide the necessary ligands to develop appropriate Site Directed Assays (SDAs) for each essential subdomain. The SDAs provide the screening mode for finding competitive small molecules by high throughput screening. The other arm of the Diogenesis system is an application in the new area of "Phenomics." This part of the discovery process is a form of phenotypic analysis of genomic information that has also been referred to as "functional" genomics. Phenomics, done via the Diogenesis system, uses peptide Surrogates as modifiers of the activity of, and identifiers of the partners of, gene products of known and unknown function. Actually, in many instances, the same Surrogate isolated for use in Phenomics will be used to create SDAs for discovery of small molecule drug candidates. In this simple fashion, the two applications of Diogenesis are integrated to provide savings in research time and money.

Amino Acid Sequence↗
PubMed2000

Apoptosis in factor-dependent haematopoietic cells is linked to calcium-sensitive mitochondrial rearrangements and cytoskeletal modulation.

Apoptosis in murine haematopoietic interleukin (IL)3-dependent cell lines is induced within 6-8 h by IL-3 withdrawal. Direct introduction of cytochrome c by electroporation induces apoptosis within 2 h and was inhibited by caspase inhibitors, such as Z-VADfmk and Z-Dfmk. We report here that apoptosis induced by IL-3 withdrawal was refractory to these inhibitors but was accompanied by striking redistribution of mitochondria, which aggregated into an area associated with centrioles without loss of Deltapsim. Both mitochondrial redistribution and apoptosis were inhibited by the calcium ionophore, ionomycin. Nocodozole, an inhibitor of microtubule assembly, also induced apoptosis, which was unaffected by caspase inhibitors. Although nocodozole did not alter mitochondrial distribution, it significantly reduced Deltapsim, and both reduction of Deltapsim and apoptosis were inhibited by ionomycin. Oligomycin, which inhibits the mitochondrial FoF1 ATPase, similarly induced apoptosis, which was unaffected by caspase inhibitors but was inhibited by ionomycin. Further, oligomycin stimulated the novel formation and release of surface membrane-derived vesicles containing mitochondria with intact Deltapsim; ionomycin also inhibited their production. In all these conditions, Bcl-2 protected cells from apoptosis. Our studies show that apoptosis induced by three very different agents shares insensitivity to caspase inhibitors, suppression by ionomycin and effects on mitochondria, which all appear to be linked to cytoskeletal/microtubule activity. They suggest that microtubules and the cytoskeleton play an important role in apoptosis through mechanisms affecting mitochondria but which are independent of cytochrome c release.

Animals↗
PubMed2000

Adrenalectomy reverses obese phenotype and restores hypothalamic melanocortin tone in leptin-deficient ob/ob mice.

In genetically obese leptin-deficient ob/ob mice, adrenalectomy reverses or attenuates the obese phenotype. Relative to lean controls, ob/ob mice also exhibit decreased hypothalamic proopiomelanocortin (POMC) mRNA and increased hypothalamic agouti-related peptide (AGRP) mRNA and neuropeptide Y (NPY) mRNA. It has been hypothesized that this profile of hypothalamic gene expression contributes to the obese phenotype caused by leptin deficiency. To assess if reversal of obese phenotype by adrenalectomy entails normalization of hypothalamic gene expression, male wild-type and ob/ob mice were adrenalectomized (with saline supplementation) or sham adrenalectomized at 2 months of age. Mice were sacrificed 2 weeks after adrenalectomy, during which time food intake and body weight were monitored daily. After sacrifice, hypothalamic gene expression was assessed by Northern blot analysis as well as in situ hybridization. In wild-type mice, adrenalectomy significantly decreased AGRP mRNA but did not significantly influence POMC or NPY mRNA. In ob/ob mice, adrenalectomy reduced the levels of plasma glucose, serum insulin and corticosterone, and food intake toward or below wild-type levels, and it restored hypothalamic POMC and AGRP mRNA but not NPY mRNA to wild-type levels. These studies suggest that adrenalectomy reverses or attenuates the obese phenotype in ob/ob mice, in part by restoring hypothalamic melanocortin tone toward wild-type levels. These studies also demonstrate that factors other than leptin may play a major role in regulating hypothalamic melanocortin function.

Adrenalectomy↗
PubMed1998

Adrenal neuropeptide Y mRNA but not preproenkephalin mRNA induction by stress is impaired by aging in Fischer 344 rats.

Relatively few molecular markers of stress have been studied in aged individuals. Interactions of age and stress on adrenal neuropeptide Y (NPY) and preproenkephalin (ppENK) expression have not been reported. The purpose of these studies was to characterize the adrenal NPY and ppENK responses to stress using a common stressor, physical restraint for 2 h, in Fischer 344 rats at 7, 16 and 23 months of age. Northern blot techniques were used to evaluate induction by stress of adrenal NPY mRNA and adrenal ppENK mRNA. Two humoral responses to stress, serum glucose and corticosterone, were measured to corroborate that a stress response occurred. We observed that the induction by stress of adrenal NPY mRNA is impaired with age but the stress-induced elevation of adrenal ppENK mRNA, blood glucose, and corticosterone show no evidence of age-related impairments.

Adrenal Glands↗
PubMed1997

A modified citrulline assay of NOS activity in rat brain homogenates does not detect direct effects of halothane on the kinetics of NOS activity.

An improved citrulline radioassay of nitric oxide synthase (NOS) activity was developed to study the direct effects of the volatile anesthetic (VA) halothane on the enzyme kinetics of neuronal NOS derived from different regions of the rat central nervous system (CNS). The Vmax of NOS in both soluble cytosolic and membrane bound particulate fractions varied across regions with greatest activity in the cerebellum and least in the spinal cord. In contrast, the Km was not different across regions or in the cytosolic and particulate fractions. Halothane at 0.5, 1, 2 or 3% delivered concentration had no effect on either kinetic parameter of NOS in any of the regions studied indicating that the VAs have no direct effects on NOS activity.

Animals↗
PubMed1996

Identifying the physiological electron transfer site of cytochrome c peroxidase by structure-based engineering.

A technique was developed to evaluate whether electron transfer (ET) complexes formed in solution by the cloned cytochrome c peroxidase [CcP(MI)] and cytochromes c from yeast (yCc) and horse (hCc) are structurally similar to those seen in the respective crystal structures. Site-directed mutagenesis was used to convert the sole Cys of the parent enzyme (Cys 128) to Ala, and a Cys residue was introduced at position 193 of CcP(MI), the point of closest contact between CcP(MI) and yCc in the crystal structure. Cys 193 was then modified with a bulky sulfhydryl reagent, 3-(N-maleimidylpropionyl)-biocytin (MPB), to prevent yCc from binding at the site seen in the crystal. The MPB modification has no effect on overall enzyme structure but causes 20-100-fold decreases in transient and steady-state ET reaction rates with yCc. The MPB modification causes only 2-3-fold decreases in ET reaction rates with hCc, however. This differential effect is predicted by modeling studies based on the crystal structures and indicates that solution phase ET complexes closely resemble the crystalline complexes. The low rate of catalysis of the MPB-enzyme was constant for yCc in buffers of 20-160 mM ionic strength. This indicates that the low affinity complex formed between CcP(MI) and yCc at low ionic strength is not reactive in ET.

Animals↗
PubMed1995

Pulmonary arteriole hypertrophy in broilers with pulmonary hypertension syndrome (ascites).

Two experiments were conducted to determine the effect of low ventilation or cool temperature environments on pulmonary arteriole hypertrophy. Male broilers were maintained under control or low ventilation conditions in Experiment 1, whereas male broiler breeder by-product chicks were exposed to cool temperature conditions in Experiment 2. Birds were randomly selected for histological evaluation of lung tissue in both experiments. In Experiment 1, birds that had pulmonary hypertension syndrome (PHS+) exhibited a greater degree of inflammation of lung tissue at 5 and 7 wk of age than controls or birds that did not have PHS (PHS-). These PHS+ birds also had higher numbers of cartilaginous osseous nodules at 3 and 7 wk of age than controls. Morphometric analyses revealed that PHS+ birds in Experiment 1 had a thicker medial layer associated with 100 to 200 microns diameter pulmonary arterioles at 7 wk of age, and 50 to 100 microns arterioles at 3 and 7 wk of age than PHS- or control birds. In Experiment 2, PHS+ birds exhibited a thicker medial layer in pulmonary arterioles at 7 wk of age than did PHS- birds, but there were no differences in medial layer thickness at 5 wk of age nor were there differences in the degree of inflammation or amount of osseous nodule formation between PHS+ and PHS- birds at 5 and 7 wk of age. Thus, pulmonary arteriole hypertrophy was observed in birds having PHS in response to both low ventilation and cool temperature environments and this hypertrophy occurred with or without a coincident inflammatory response in lung tissue.

Animals↗
PubMed1992

Mental impairment in the West Midlands.

The case records of 55 people from the West Midlands (UK) fulfilling the Mental Health Act 1983 criteria for mental impairment or severe mental impairment, were studied. Most were young men with mild mental retardation. 73 per cent were resident in (or on leave from) mental handicap hospitals, and 27 per cent resident in special hospitals. 29 per cent were subject to a Restriction Order. Most had lived in hospital for more than six years. The commonest problem behaviours were aggression, property offences and inappropriate or offending sexual behaviour. 31 per cent were mentally ill or had a past history of mental illness. A diverse range of services appears necessary to meet the needs of this group of people.

Adolescent↗
PubMed1987

Day-case ligation of patent ductus arteriosus in premature infants.

Over a 3-year period patent ductus arterious (PDA) ligation was performed on a day-case transfer basis on 45 premature infants. The overall survival rate was 93%. We would recommend this practice as an alternative to surgery in the neonatal intensive care unit.

Ductus Arteriosus, Patent↗
PubMed1986

Craniofacial surgery.

Craniofacial surgery is concerned with the treatment of congenital and acquired conditions affecting the head, face and jaws (Tessier, 1971a). Previously these were treated individually by plastic, neurological and faciomaxillary surgeons. This type of surgery was associated with a high risk of morbidity and mortality (Goldin, 1975). Following the pioneering work of Dr Paul Tessier in Paris during the mid-1960s, using a multidisciplinary team approach has allowed for more radical treatment of these abnormalities with an acceptable morbidity rate within established craniofacial units (Munro, 1975).

Adolescent↗
PubMed1976

Another example of an antibody reacting optimally with p red cells.

An antibody is described that reacted strongly with red cells of the p(Tj(a-)) phenotype and moderately to strongly with cord red cells of the P2 phenotype. The antibody failed to react, or reacted very weakly, with red cells of the P1k and phenotypes and with the red cells of five children of a p individual, ahd reacted weakly with occasional red cell samples from adults of the P2 phenotype. These results suggest that the antibody does not detect a product of the p gene but instead detects a P system precursor substance. In p individuals this P system precursor substance is not altered by the p genes. In individuals of the P1 or P2 phenocursor substance is not altered by the p genes. In individuals of the P1 or P2 phenotype this precursor substance is apparently converted to P1 and/or P antigens by the P1 or P2 genes.

Aged↗