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Biomedical subjects

C R Brown

Publications and source records attributed to C R Brown.

At least 73 records · Page 4Linked to original sources
PubMed1997

Fibromyalgia.

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Diagnosis, Differential↗
PubMed1997

Guide to evaluation of permanent impairment of the temporomandibular joint. American Academy of Head, Neck and Facial Pain; American Academy of Orofacial Pain; American Academy of Pain Management; American College of Prosthodontists; American Equilibration Society and Society of Occlusal Studies; American Society of Maxillofacial Surgeons; American Society of Temporomandibular Joint Surgeons; International College of Cranio-mandibular Orthopedics; Society for Occlusal Studies.

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Ankylosis↗
PubMed1996

Tumour necrosis factor alpha causes retention of activated glucocorticoid receptor within the cytoplasm of A549 cells.

Glucocorticosteroids are the most effective therapy for the suppression of airway inflammation. Classically, ligand binding to the inactive cytosolic receptor (GR) causes a conformational change enabling nuclear translocation of the active GR and alteration in the transcriptional response. We have investigated GR-transcription factor interactions within the cytoplasm where many transcription factors are localized prior to activation. Active DNA binding GR complexes were found within the cytoplasm of human lung epithelial cells (A549). Stimulation by dexamethasone (1 microM) caused translocation of active GR into the nucleus and inhibition of RANTES release. Coincubation of cells with dexamethasone and TNF alpha (1 ng/ml) or PMA (0.1 microM) prevented RANTES release and the translocation of activated GR to the nucleus without affecting GR levels as detected by western blotting. These results suggest that a major site of pro-inflammatory cytokine action may be within the cytoplasm of steroid-responsive cells acting via prevention of the GR translocation into the nucleus.

Blotting, Western↗
PubMed1996

Molecular chaperones and the centrosome. A role for TCP-1 in microtubule nucleation.

Molecular chaperones play an important role in facilitating the proper maturation of many newly synthesized proteins. Here we provide evidence that molecular chaperones also participate in regulating the assembly of the microtubule cytoskeleton. Via indirect immunofluorescence analysis, both hsp 73 and TCP-1 localized within the centrosome in interphase and mitotic cells. These proteins, along with the centrosome-specific protein, pericentrin, were also present within an enriched preparation of centrosomes. Because the centrosome serves as an initiation site for microtubule growth, we examined the ability of cells to regrow their microtubule network in the presence of hsp 73 or TCP-1 specific antibodies. Purified tubulin and GTP were added to cells following the depolymerization and extraction of cellular microtubules. Microtubules were observed to nucleate off the centrosome using this system, even in the presence of anti-hsp 73 antibodies. Incubation with anti-TCP-1 antibodies, however, blocked microtubule regrowth off the centrosome. Similarly, anti-TCP-1 antibodies microinjected into living cells first treated with nocodazole also inhibited the regrowth of the microtubule network following removal of the microtubule poison. Our results complement earlier genetic studies in yeast implicating a role for TCP-1 in microtubule mediated processes, and may help to explain the previously reported mitotic and meiotic abnormalities associated with TCP-1 mutations.

Amino Acid Sequence↗
PubMed1996

Molecular chaperones and the centrosome. A role for HSP 73 in centrosomal repair following heat shock treatment.

In the accompanying paper (Brown, C. R., Doxsey, S. J., Hong-Brown, L. W., Martin, R. L., and Welch, W. J. (1996) J. Biol. Chem. 271, 824-832) two molecular chaperones, hsp 73 and TCP-1, were shown to be integral components of the centrosome. Here we show that heat shock treatment adversely affects both the structure and function of the centrosome, and that hsp 73 plays a role in the repair of the organelle. After heat shock treatment, the centrosome could not be identified via indirect immunofluorescence and cells were unable to support microtubule regrowth. During recovery from heat shock, a strong correlation between the return of staining of three centrosomal antigens (hsp 73, TCP-1, and pericentrin) and the recovery of microtubule regrowth properties was found. Incubation of cells with glycerol, a protein protective agent, prevented the heat induced alterations in the structure/function of the centrosome. Likewise, the recovery of the structure and function of the centrosome after heat shock treatment was significantly accelerated in cells first made thermotolerant. We provide evidence that this process is related to the levels of hsp 73 since: 1) microinjection of hsp 73 antibody blocked centrosomal reassembly and microtubule regrowth abilities following heat shock; and 2) microinjection of purified hsp 73 protein prior to heat shock treatment accelerated both the repair and function of the organelle, similar to that observed for thermotolerant cells.

Antigens↗
PubMed1996

Mortality in near-term ostrich embryos during artificial incubation.

1. The ostrich industry in South Africa (and elsewhere) experiences a high rate of embryo mortality during artificial incubation of eggs. Most of this mortality takes place in the last l0-l4 d of incubation. 2. We carried out post-mortem examinations on 111 embryos that died within this period to assess the causes of this mortality. 3. Malpositioning and severe oedema were the predominant symptoms of dead-in shell embryos with 55% being malpositioned and 41% showing severe oedema. Of these, 22 embryos (24%) showed both symptoms. Malpositioning generally results from incorrect setting of the eggs or inadequate turning and oedema was significantly correlated with the amount of water lost from the eggs which in turn was correlated with egg size. 4. Myopathy, gross lesions of internal organs, haemorrhage, bacterial infections and congenital deformities were found in less than 10% of chicks examined for these symptoms.

Animals↗
PubMed1996

Influence of molecular and chemical chaperones on protein folding.

Protein folding inside the cell involves the participation of accessory components known as molecular chaperones. In addition to their active participation in the folding process, molecular chaperones serve as a type of 'quality control system', recognizing, retaining and targeting misfolded proteins for their eventual degradation. It is now known that a number of human diseases arise as a consequence of specific point mutations or deletions within genes encoding essential proteins. In many cases these mutations/deletions are not so severe as to totally destroy the biological activity of the particular gene product. Rather, the mutations often result in only subtle folding abnormalities which lead to the newly synthesized protein being retained at the endoplasmic reticulum by the actions of the cellular quality control system. In this short review article we discuss our recent studies showing that the protein folding defect associated with the most common mutation in patients with cystic fibrosis can be overcome by a novel strategy. As shown in the paper by Brown et al in this issue (Brown et al 1996), a number of different low molecular weight compounds, all known to stabilize proteins in their native conformation, are effective in rescuing the processing defect of the mutant cystic fibrosis transmembrane conductance regulator protein. We then discuss how these same compounds, which we now call chemical chaperones, also may prove to be effective in correcting a number of other protein folding abnormalities which constitute the underlying basis of a large number of different human diseases.

Humans↗
PubMed1996

Chemical chaperones correct the mutant phenotype of the delta F508 cystic fibrosis transmembrane conductance regulator protein.

Mutations in the cystic fibrosis transmembrane conductance regulator protein (CFTR) often result in a failure of the protein to be properly processed at the level of the endoplasmic reticulum (ER) and subsequently transported to the plasma membrane. The folding defect associated with the most common CFTR mutation (delta F508) has been shown to be temperature sensitive. Incubation of cells expressing delta F508 CFTR at lower growth temperatures results in the proper processing of a portion of the mutant CFTR protein. Under these conditions, the mutant protein can move to the plasma membrane where it functions, similar to the wild-type protein, in mediating chloride transport. We set out to identify other methods, which like temperature treatment, would rescue the folding defect associated with the delta F508 CFTR mutation. Here we show that treatment of cells expressing the delta F508 mutant with a number of low molecular weight compounds, all known to stabilize proteins in their native conformation, results in the correct processing of the mutant CFTR protein and its deposition at the plasma membrane. Such compounds included the cellular osmolytes glycerol and trimethylamine N-oxide, as well as deuterated water. Treatment of the delta F508 CFTR-expressing cells with any one of these compounds, which we now refer to as 'chemical chaperones', restored the ability of the mutant cells to exhibit forskolin-dependent chloride transport, similar to that observed for the cells expressing the wild-type CFTR protein. We suggest that the use of 'chemical chaperones' may prove to be effective for the treatment of cystic fibrosis, as well as other genetic diseases whose underlying basis involves defective protein folding and/or a failure in normal protein trafficking events.

3T3 Cells↗
PubMed1996

Some blood chemical, electrolyte and mineral values from young ostriches.

Haematocrit, plasma osmolality and plasma calcium, inorganic phosphorus and magnesium concentrations were measured in 10 healthy ostrich chicks at 2-weekly intervals between 8 and 26 weeks of age. Plasma sodium, potassium and zinc concentrations were measured in an additional 50 chicks between 2 and 6 months of age. With the exception of calcium, blood constituents did not change significantly with age. Overall, haematocrit was lower and phosphorus and magnesium were slightly higher than previously measured for adults, which is consistent with previous measurements for chicks.

Age Factors↗