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Biomedical subjects

A Best

Publications and source records attributed to A Best.

29 records · Page 2Linked to original sources
PubMed1995

A 68-kDa kinase and NADPH oxidase component p67phox are targets for Cdc42Hs and Rac1 in neutrophils.

Cdc42Hs and Rac1 are members of the Ras superfamily of small molecular weight (p21) GTP binding proteins. Cdc42Hs induces filopodia formation in Swiss 3T3 fibroblasts while Rac1 induces membrane ruffling. Rac1 also activates superoxide production by the components (cytochrome b, p40phox, p67phox, and p47phox) of the neutrophil oxidase. To isolate target proteins involved in these signaling pathways, we have probed proteins from neutrophil cytosol immobilized on nitrocellulose with Cdc42Hs labeled with [gamma-32P]GTP. Cdc42Hs probe detected binding protein(s) of 66-68 kDa in neutrophil cytosol. Rac1 probe also detected the 66-68-kDa proteins, suggesting the possibility that p67phox may be a binding protein for both of these p21 proteins. Indeed, Cdc42Hs and Rac1 were found to bind specifically to purified recombinant p67phox but not the other oxidase components. A 68-kDa Cdc42Hs binding protein was purified from neutrophil cytosol and found to be related to the recently described p65pak kinase from brain. These results suggest that the p68 kinase and p67phox are targets for Cdc42Hs and Rac1 in neutrophils.

Brain↗
PubMed1995

The Ras-related protein Cdc42Hs and bradykinin promote formation of peripheral actin microspikes and filopodia in Swiss 3T3 fibroblasts.

The Ras-related protein Cdc42 plays a role in yeast cell budding and polarity. Two related proteins, Rac1 and RhoA, promote formation in mammalian cells of membrane ruffles and stress fibers, respectively, which contain actin microfilaments. We now show that microinjection of the related human Cdc42Hs into Swiss 3T3 fibroblasts induced the formation of peripheral actin microspikes, determined by staining with phalloidin. A proportion of these microspikes was found to be components of filopodia, as analyzed by time-lapse phase-contrast microscopy. The formation of filopodia was also found to be promoted by Cdc42Hs microinjection. This was followed by activation of Rac1-mediated membrane ruffling. Treatment with bradykinin also promoted formation of microspikes and filopodia as well as subsequent effects similar to that seen upon Cdc42Hs microinjection. These effects of bradykinin were specifically inhibited by prior microinjection of dominant negative Cdc42HsT17N, suggesting that bradykinin acts by activating cellular Cdc42Hs. Since filopodia have been ascribed an important sensory function in fibroblasts and are required for guidance of neuronal growth cones, these results indicate that Cdc42Hs plays an important role in determining mammalian cell morphology.

Actin Cytoskeleton↗
PubMed1994

Breakpoint cluster region gene product-related domain of n-chimaerin. Discrimination between Rac-binding and GTPase-activating residues by mutational analysis.

The breakpoint cluster region gene product (Bcr) is a GTPase-activating protein (GAP) for members of the Rho family, Cdc42Hs, and Rac1, as is the brain protein n-chimaerin. At least 15 proteins have sequence identity to the GAP domain (150 amino acid residues) of Bcr. The widespread occurrence of proteins that possess sequence identity to the Bcr-related GAP domain makes it especially important to understand its structure/function relationships. Amino acid sequence alignment of these proteins reveals three blocks of conservation in the GAP domain. Here, we present a mutational analysis of this domain using n-chimaerin sequences. Ten mutations were constructed (at least two in each of the blocks of conservation), expressed as glutathione S-transferase fusion proteins in Escherichia coli, and purified. Seven of the mutants, including deletions, still possessed GAP activity for Rac1. Three of the mutants had no Rac1-GAP activity but were still able to bind Rac1. IC50 values obtained from competition experiments suggest that n-chimaerin and the mutants with no GAP activity bound Rac1 with similar apparent binding constants. Thus, this mutant analysis allows discrimination between Rac1-binding and Rac1 GTPase- activating residues.

Amino Acid Sequence↗
PubMed1993

A novel functional target for tumor-promoting phorbol esters and lysophosphatidic acid. The p21rac-GTPase activating protein n-chimaerin.

Phorbol esters are potent tumor promoters widely used for investigating mechanisms of cell transformation with protein kinase C (PKC) generally considered as being their only protein target. Lysophosphatidic acid (LPA) can act as a mitogen, affecting cell shape and the actin cytoskeleton. There is no identified functional target for LPA. We have isolated a cDNA encoding a protein n-chimaerin that is a high affinity phorbol ester receptor and a p21rac-GTPase activating protein (rac-GAP). p21rac is a member of the ras superfamily of small molecular weight GTP-binding proteins, which stimulates actin microfilament formation in Swiss 3T3 cells and superoxide production by the neutrophil oxidase. We now show that the rac-GAP activity of n-chimaerin is stimulated by phosphatidylserine (PS) and phosphatidic acid (PA) and that phorbol esters can synergize with PS and PA. LPA, in contrast, was found to inhibit n-chimaerin. The phospholipid/phorbol ester modulation of the rac-GAP activity requires the PKC-like cysteine-rich domain of n-chimaerin. Thus, n-chimaerin is a novel functional target (distinct from PKC) for both phorbol esters and LPA. These data suggest that the physiological role of n-chimaerin is to link events initiating at the cell surface/membrane with p21rac effector pathways.

Animals↗
PubMed1993

Factor structure of the Motivation Assessment Scale.

The Motivation Assessment Scale (MAS) was developed to provide clinical information on four hypothesized functions that may control problem behaviour in persons with developmental disabilities. The original four-factor structure of the MAS was based on face validity, with the items being grouped in terms of each of the hypothesized functions. Validation of the scale was provided in terms of correlations between teacher ratings of eight children on the MAS and ranking of the controlling variables from functional analogue tests. In this study, staff in residential facilities rated 60 residents and teachers in schools rated 96 students on the MAS. The target behaviour rated for both samples was self-injury, with the institutional sample engaging in the behaviour more than 15 times an hour and the school sample, less than 15 times an hour. The results of factor analyses, with varimax rotation, provided a conceptually meaningful factor structure with the institutional sample, but not with the school sample. The 16 MAS items resolved into four factors that were conceptually related to four conditions that may maintain problem behaviour (i.e. sensory, escape, attention and tangible). The results suggested that the original MAS has a robust factor structure and may be clinically useful in predicting the controlling functions of problem behaviours, if the target behaviours occur at a rate no less than 15 responses per hour.

Adult↗
PubMed1991

Quack doctors of the NHS?

Management consultants have been called 'charlatans' who only tell you what you already know. But this pessimistic view obscures several inherent paradoxes which managers should be aware of when they use outside experts. Ardha Best and Brian Bloomfield examine the role of consultants in the field of information technology.

Consultants↗
PubMed1989

Vitamin supplementation in pregnancy.

The aim of the study was to investigate the extent and determinants of vitamin supplementation in early pregnancy. Some 246 women were recruited in the antenatal clinics of a major teaching hospital and asked to complete a brief questionnaire relating to sources of advice and details of diet and vitamin supplementation during the index pregnancy. Further information was abstracted from routine antenatal records. A total of fifty-seven women (23%) took some form of vitamin supplement during the index pregnancy. Factors which affected supplementation included advice received from diverse sources and whether or not the women took iron supplements. Somewhat surprisingly, supplementation was not affected by age, social class or reproductive history.

Adolescent↗
PubMed1982

[Various periodical and aperiodical variations of heart infarct mortality in the DRG].

On the basis of 66.900 cases of death from ischaemic heart disease from 1970 to 1974, patient aged 70 years and younger, total statistics, an average quotient for the house/clinic-relation was calculated. The variations of the house/clinic-relation observed are subdivided into 3 stable periods: 24-hour periodicity, season periodicity and weekday periodicity (socially conditioned). These periods are superimposed by aperiodical influences. The relations between increased house/clinic-relation of the cases of death from ischaemic heart disease and the increased influences of the geomagnetic field as well as geomagnetic tempests (SSC). Here a significant positive connection for the indicators of activity as well as for the SSC was the result. One can issue from the fact that, the higher the ratio is the more unfavourable conditions for a specialised therapy of the complications of the ischaemic heart disease are existing. The cases in question in this phenomenon are new chronobiological knowledges which have a direct relation to the medical practice. Instances are given for the practical use in the prevention of complications of the ischaemic heart disease.

Aged↗
PubMed1976

[Surgical treatment of malignant melanoma (author's transl)].

The primary lesion is widely excised under a general anesthetic. The resulting defect is covered by a free graft. Prophylactic lymph-node dissection seems to be reasonable for stage-I melanoma with deep invasion (microstage III-V) according to recent investigations. Stage II is an absolute indication. Stage III patients received an individual palliative therapy. The value of additional measures is not yet clearly defined.

Germany, West↗