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M Noble

Publications and source records attributed to M Noble.

At least 19 recordsLinked to original sources
PubMed1992

Crystal structure of a Src-homology 3 (SH3) domain.

The Src-homologous SH3 domain is a small domain present in a large number of proteins that are involved in signal transduction, such as the Src protein tyrosine kinase, or in membrane-cytoskeleton interactions, but the function of SH3 is still unknown (reviewed in refs 1-3). Here we report the three-dimensional structure at 1.8 A resolution of the SH3 domain of the cytoskeletal protein spectrin expressed in Escherichia coli. The domain is a compact beta-barrel made of five antiparallel beta-strands. The amino acids that are conserved in the SH3 sequences are located close to each other on one side of the molecule. This surface is rich in aromatic and carboxylic amino acids, and is distal to the region of the molecule where the N and C termini reside and where SH3 inserts into the alpha-spectrin chain. We suggest that a protein ligand binds to this conserved surface of SH3.

Amino Acid Sequence↗
PubMed1992

The differentiation of glial cell progenitor populations following transplantation into non-repairing central nervous system glial lesions in adult animals.

The non-repairing nature of the locally x-irradiated ethidium bromide (EB)-induced demyelinating white matter lesion has been further validated by showing that injections of two cultures which promote host remyelination of EB lesions in normal tissue do not do so in x-irradiated lesions. The behaviour of an oncogene-immortalized glial cell line and a growth-factor-expanded glial progenitor population have been examined following transplantation into the non-repairing EB lesion. Our studies indicate that the selected glial cell populations were each capable of establishing glial environments around demyelinated axons. Extensive oligodendrocyte remyelination with little astrocytic presence was observed in lesions transplanted with growth-factor-expanded optic nerve progenitors, while less extensive oligodendrocyte remyelination with the establishment of astrocyte-like cells was found in lesions transplanted with ts A58-SV40T immortalized glial cells. Prolonged expansion of both populations resulted in a loss of differentiation to normal glial phenotypes.

Animals↗
PubMed1992

Development and regeneration in the O-2A lineage: studies in vitro and in vivo.

This brief review discusses selected aspects of our studies on the control of division and differentiation of the glial precursor cells which give rise to oligodendrocytes. For more extensive reviews on this topic, the reader is referred to recent reviews by Raff (1989), Richardson et al. (1991), Noble (1991) and Noble et al. (1991).

Aging↗
PubMed1992

Adjuvant radiotherapy in high stage transitional cell carcinoma of the renal pelvis and ureter.

This review was undertaken to assess the influence of adjuvant radiation therapy on failure patterns and survival in high stage transitional cell carcinoma of the renal pelvis or ureter. Ninety-four patients with transitional cell carcinoma of the renal pelvis or ureter were retrospectively reviewed. Twenty-six had American Joint Commission stage T3 or T4 N0/+, M0 disease and underwent curative resections (median follow-up 13.5 months, range 3-311). Local failure was defined as recurrence in the tumor bed, regional nodes, or ureteral stump. Time to recurrence and survival were calculated from the time of pathologic diagnosis. Variables associated with local failure, distant metastasis, and survival were analyzed using univariate and multivariate analysis. Seventeen received surgery only, nine received adjuvant radiation therapy (median dose 50 Gy). Local failure occurred in 9 of 17 without and 1 of 9 with adjuvant radiation therapy (p = 0.07). Actuarial 5-year local control was 34% without and 88% with adjuvant radiation therapy. Cox step-wise regression confirmed adjuvant radiation therapy (p = 0.006) and grade (p = 0.006) as significantly associated with local failure. No patients with low grade lesions suffered local failure either with or without adjuvant radiation therapy. High grade lesions had an local failure rate of 15% with and 71% without adjuvant radiation therapy. Metastatic disease occurred in 4 of 9 and 8 of 17 with and without radiation therapy. No significant factors influencing distant failure were identified. Five-year actuarial survival was 44% with and 24% without adjuvant radiation therapy. The survival differences were not statistically significant on univariate or multivariate analysis. High staged transitional cell carcinoma of the renal pelvis or ureter has a substantial local failure risk after surgery alone. Adjuvant radiation therapy markedly reduces this risk but has no impact on distant disease which occurs in approximately 50%. Effective adjuvant therapy will require effective systemic therapy in addition to adjuvant radiation therapy.

Aged↗
PubMed1992

The O-2A(adult) progenitor cell: a glial stem cell of the adult central nervous system.

Systematic comparison of the properties of oligodendrocyte-type-2 astrocyte (O-2A) progenitor cells derived from optic nerves of perinatal and adult rats has revealed that these two populations differ in many fundamental properties. In particular, O-2A(perinatal) progenitor cells are rapidly dividing cells capable of generating large numbers of oligodendrocytes over a relatively short time span. Oligodendrocyte differentiation generally occurs synchronously in all members of a clone, thus leading to elimination of that clone from the pool of dividing cells. However, some O-2A(perinatal) progenitors are also capable of giving rise to O-2A(adult) progenitors. These latter cells express many of the characteristics of stem cells of adult animals, including the capacity to undergo asymmetric division and differentiation. We suggest that precursors which function during early development give rise to terminally differentiated end-stage cells and to a second generation of precursors with properties more appropriate for later developmental stages. It is this second generation of precursors which express the properties of stem cells in adult animals, and we therefore further suggest that our work offers novel insights into the possible developmental origin of stem cells.

Animals↗
PubMed1992

In vitro analysis of the origin and maintenance of O-2Aadult progenitor cells.

We have been studying the differing characteristics of oligodendrocyte-type-2 astrocyte (O-2A) progenitors isolated from optic nerves of perinatal and adult rats. These two cell types display striking differences in their in vitro phenotypes. In addition, the O-2Aperinatal progenitor population appears to have a limited life-span in vivo, while O-2Aadult progenitors appear to be maintained throughout life. O-2Aperinatal progenitors seem to have largely disappeared from the optic nerve by 1 mo after birth, and are not detectable in cultures derived from optic nerves of adult rats. In contrast, O-2Aadult progenitors can first be isolated from optic nerves of 7-d-old rats and are still present in optic nerves of 1-yr-old rats. These observations raise two questions: (a) From what source do O-2Aadult progenitors originate; and (b) how is the O-2Aadult progenitor population maintained in the nerve throughout life? We now provide in vitro evidence indicating that O-2Aadult progenitors are derived directly from a subpopulation of O-2Aperinatal progenitors. We also provide evidence indicating that O-2Aadult progenitors are capable of prolonged self renewal in vitro. In addition, our data suggests that the in vitro generation of oligodendrocytes from O-2Aadult progenitors occurs primarily through asymmetric division and differentiation, in contrast with the self-extinguishing pattern of symmetric division and differentiation displayed by O-2Aperinatal progenitors in vitro. We suggest that O-2Aadult progenitors express at least some properties of stem cells and thus may be able to support the generation of both differentiated progeny cells as well as their own continued replenishment throughout adult life.

Aging↗
PubMed1992

Cooperation between PDGF and FGF converts slowly dividing O-2Aadult progenitor cells to rapidly dividing cells with characteristics of O-2Aperinatal progenitor cells.

We have shown previously that oligodendrocyte-type-2 astrocyte (O-2A) progenitor cells isolated from adult rat optic nerves can be distinguished in vitro from their perinatal counterparts on the basis of their much slower rates of division, differentiation, and migration when grown in the presence of cortical astrocytes or PDGF. This behavior is consistent with in vivo observations that there is only a modest production of oligodendrocytes in the adult CNS. As such a behavior is inconsistent with the likely need for a rapid generation of oligodendrocytes following demyelinating damage to the mature CNS, we have been concerned with identifying in vitro conditions that allow O-2Aadult progenitor cells to generate rapidly large numbers of progeny cells. We now provide evidence that many slowly dividing O-2Aadult progenitor cells can be converted to rapidly dividing cells by exposing adult optic nerve cultures to both PDGF and bFGF. In addition, these O-2Aadult progenitor cells appear to acquire other properties of O-2Aperinatal progenitor cells, such as bipolar morphology and high rate of migration. Although many O-2Aadult progenitor cells in cultures exposed to bFGF alone also divide rapidly, these cells are multipolar and migrate little in vitro. Oligodendrocytic differentiation of O-2Aadult progenitor cells, which express receptors for bFGF in vitro, is almost completely inhibited in cultures exposed to bFGF or bFGF plus PDGF. As bFGF and PDGF appear to be upregulated and/or released after injury to the adult brain, this particular in vitro response of O-2Aadult progenitor cells to PDGF and bFGF may be of importance in the generation of large numbers of new oligodendrocytes in vivo following demyelination.

Animals↗
PubMed1992

The quantification of fluorescent emission from biological samples using analysis of polarization.

The quantification of fluorescent emission from biological specimens can only be carried out in cellular regions where the relationship between fluorophore concentration and fluorescent emission is linear. Using a confocal scanning laser microscope, we show that quantification of fluorescent emission from biological samples labelled with fluorescein and fluorescein analogues mounted in a viscous medium can be readily achieved. Where the distribution of fluorophore is highly localized, for example in cells labelled for immunofluorescence analysis, we demonstrate that analysis of fluorescence depolarization can identify regions in which fluorophore concentration exceeds the range in which the relationship to fluorescent emission is linear. We also demonstrate that, under the conditions examined, depth-dependent effects, fading and quenching are either small enough to be ignored or can be corrected for mathematically when quantifying fluorescent emission.

Animals↗
PubMed1992

Specific expression of N-acetylaspartate in neurons, oligodendrocyte-type-2 astrocyte progenitors, and immature oligodendrocytes in vitro.

To test the specificity of N-acetylaspartate (NAA) as a neuronal marker for proton nuclear magnetic resonance (1H NMR) spectroscopy, purified and characterized cultured cells were analyzed for their NAA content using both 1H NMR and HPLC. Cell types studied included cerebellar granule neurons, type-1 astrocytes, meningeal cells, oligodendrocyte-type-2 astrocyte (O-2A) progenitor cells, and oligodendrocytes. A high concentration of NAA was found in extracts of cerebellar granule neurons (approximately 12 nmol/mg of protein), whereas NAA remained undetectable in purified type-1 astrocytes, meningeal cells, and mature oligodendrocytes. However, twice the neuronal level of NAA was found in O-2A progenitors grown in vitro. In addition significant levels of NAA were also detected in cultures of immature oligodendrocytes. Our data partly support previous suggestions that NAA may be a useful neuronal marker for 1H NMR spectroscopic examination of the adult brain. However, they also raise the further possibility that alterations of NAA associated with some specific brain disorders, particularly disorders seen in newborn and young children, may reflect abnormalities in the development of oligodendroglia or their precursors.

Animals↗
PubMed1992

From chance to choice in the generation of neural cell lines.

Despite the central importance of cell lines in contemporary studies in cellular and molecular biology, many areas of potential investigation remain impeded by the limited number of lines available and by the difficulty in generating new lines of interest. Thus, there has been a constant pressure to develop improved methods for obtaining cell lines of particular interest. This review examines some of the problems associated with in vitro approaches to cell line generation. In addition, two different ways in which transgenic animals can be used to overcome the limitations of in vitro production of cell lines are discussed. In the first approach, specific promoters are utilized to target expression of immortalizing genes to cells of interest. The second approach is concerned with development of a strain of transgenic animals (the H-2KbtsA58 transgenic mouse) designed to obviate the need for identification of cell-type specific promoters, and in which it is theoretically possible to directly generate conditionally immortal cell lines from any tissue of the body by simple dissection and growth of cells in appropriate tissue culture conditions. Finally, approaches are also discussed in which investigations on the control of precursor differentiation have been applied so as to bypass the need for expression of activated immortalizing oncogenes in the generation of large quantities of conditionally immortalized cells with the capacity to undergo normal differentiation in vitro and in vivo.

Animals↗
PubMed1991

Platelet-derived growth factor is mitogenic for O-2Aadult progenitor cells.

We report that platelet-derived growth factor (PDGF) is a potent mitogen for oligodendrocyte type-2 astrocyte (O-2A) progenitor cells derived from the optic nerves of adult rats. Moreover, O-2Aadult progenitors cultured in PDGF express the range of properties we have described previously for O-2Aadult progenitors cultured in the presence of type-1 astrocytes. Similarly, previous studies have demonstrated that PDGF is able to mimic the influence of type-1 astrocytes on O-2Aperinatal progenitors. Specifically, O-2Aadult progenitors and O-2Aperinatal progenitors exposed to PDGF express differences in average cell cycle time (59 +/- 5 h for O-2Aadult progenitors versus 20 +/- 6 h for O-2Aperinatal progenitors), average rate of migration (4.1 +/- 0.6 microns h-1 versus 24.6 +/- 5.4 microns h-1), morphology (unipolar versus bipolar), and antigenic phenotype (04+ vimentin- versus 04- vimentin+). Thus, our present results indicate that a single signalling molecule secreted by type-1 astrocytes produces markedly different cellular behaviours in two related O-2A progenitor populations.

Animals↗
PubMed1991

The pathogenesis of demyelinating disease: insights from cell biology.

Cellular and humoral immune mechanisms have been implicated in the pathogenesis of human and experimental demyelinating diseases of the CNS. How these interact in the complex sequence of events that culminates in phagocytosis of myelin by macrophages has yet to be resolved. The relationship between leakage of the blood-brain barrier and demyelination, the reason why recurrent inflammatory demyelination occurs--seemingly in the absence of an antigen-specific immune response--and the lack of effective remyelination all require explanation if a coherent account of immunologically mediated demyelination is to be achieved. One approach to these problems is to study in vitro the developmental and cellular biology of oligodendrocytes--the glial cells responsible for the synthesis and maintenance of CNS myelin. This provides experimental opportunities not offered by more direct investigation of the intact nervous system, but carries the clear disadvantage that observations made in vitro cannot necessarily be extrapolated to humans.

Animals↗
PubMed1991

The cellular measurement of time.

This review describes three biological processes in which there is evidence for single cells being able to measure elapsed time. We describe the work that has led to this view, and review more recent work that has provided new insights into possible mechanisms for the measurement of time.

Animals↗