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PL Myers 《Canadian Metallurgical Quarterly》1997,8(6):701-707
Over the next decade, the impact of library synthesis will play a major role in shortening the lead optimization phase of drug discovery. The prognosis for combinatorial chemistry to discover fundamentally different new classes of therapeutically active small molecules against some of the more difficult biological targets is less certain. Expectations are high because the technology potentially allows us to sample available drug space by synthesizing all possible small molecule ligands (variously estimated to be between 10(30)-10(50) compounds). Some caution is advised, however, since, despite recent increases in high-throughput screening of substantially greater numbers of synthetic compounds and natural products, we are not routinely finding a plethora of new structures. The outcome may be that combinational chemistry offers us the ability to work faster on finding ligands for well-established tractable targets, such as G-protein-coupled receptors, ion channels or proteases, rather than, say, the more complex protein-protein interactions which from the majority of targets in signal transduction pathways. 相似文献
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PL Hurd 《Canadian Metallurgical Quarterly》1997,54(5):1309-1315
Cichlids of the species Nannacara anomala employ several colour displays during fights which do not seem to signal either fighting ability or motivation. How should these colour displays be interpreted when winning is reliably predicted by weight asymmetries? Medial Line colour displays were associated with, and predicted, tail-beating, while Vertical Bar colour displays were associated with mouth-wrestling. I suggest that these colour displays are used to facilitate the transmission of assessment information within a fight, and that they are an example of cooperative signalling between opponents. The results support the idea that the structure of fights contains strong cooperative aspects.Copyright 1997 The Association for the Study of Animal Behaviour1997The Association for the Study of Animal Behaviour 相似文献
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The subunit compositions of the NR1 C2 exon-containing N-methyl-D-aspartate (NMDA) receptors of adult mammalian forebrain were determined by using a combination of immunoaffinity chromatography and immunoprecipitation studies with NMDA receptor subunit-specific antibodies. NMDA receptors were solubilised by sodium deoxycholate, pH 9, and purified by anti-NR1 C2 antibody affinity chromatography. The purified receptor subpopulation showed immunoreactivity with anti-NR1 C2, anti-NR1 N1, anti-NR1 C2', anti-NR2A, and anti-NR2B NMDA receptor antibodies. The NR1 C2-receptor subpopulation was subjected to immunoprecipitation using anti-NR2B antibodies and the resultant immune pellets analysed by immunoblotting where anti-NR1 C2, anti-NR1 C2', anti-NR2A, and anti-NR2B immunoreactivities were all found. Quantification of the immunoblots showed that 46% of the NR1 C2 immunoreactivity was associated with the NR2B subunit. Of this, 87% (i.e., 40% of total) were NR1 C2/NR2B receptors and 13% (6% of total) were NR1 C2/NR2A/NR2B, thus identifying the triple combination as a minor receptor subset. These results demonstrate directly, for the first time, the coexistence of the NR2A and NR2B subunits in native NMDA receptors. They show the coexistence of two splice forms of the NR1 subunit, i.e., NR1 C2 and NR1 C2', in native receptors and, in addition, they imply an NMDA receptor subpopulation containing four types of NMDA receptor subunit, NR1 C2, NR1 C2', NR2A, and NR2B, which, in accord with molecular size determinations, predicts that the NMDA receptor is at least tetrameric. These results are the first quantitative study of NMDA receptor subtypes and demonstrate molecular heterogeneity for both the NR1 and the NR2 subunits in native forebrain NMDA receptors. 相似文献
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PL Spath 《Canadian Metallurgical Quarterly》1997,71(19):78-79
Early in the decade, health care discovered a powerful patient care management tool: the clinical path. Leaders in the field latched onto paths as the solution to cost and quality dilemmas, but they overlooked the importance of the underlying principles of quality management. Beyond Clinical Paths, a new book from American Hospital Publishing, focuses on the issues critical to successful quality improvement through clinical paths. The following excerpt by the book's editor, Patrice L. Spath, sets the stage for a new approach to clinical quality. 相似文献
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Effects of TCDD on Ah receptor, ARNT, EGF, and TGF-alpha expression in embryonic mouse urinary tract
Lipoprotein(a) [Lp(a)] biogenesis was examined in primary cultures of hepatocytes isolated from mice transgenic for both human apolipoprotein(a) [apo(a)] and human apoB. Steady-state and pulse-chase labeling experiments demonstrated that newly synthesized human apo(a) had a prolonged residence time (approximately 60 min) in the endoplasmic reticulum (ER) before maturation and secretion. Apo(a) was inefficiently secreted by the hepatocytes and a large portion of the protein was retained and degraded intracellularly. Apo(a) exhibited a prolonged and complex folding pathway in the ER, which included incorporation of apo(a) into high molecular weight, disulfide-linked aggregates. These folding characteristics could account for long ER residence time and inefficient secretion of apo(a). Mature apo(a) bound via its kringle domains to the hepatocyte cell surface before appearing in the culture medium. Apo(a) could be released from the cell surface by apoB-containing lipoproteins. These studies are consistent with a model in which the efficiency of post-translational processing of apo(a) strongly influences human plasma Lp(a) levels, and suggest that cell surface assembly may be one pathway of human Lp(a) production in vivo. Transgenic mouse hepatocytes thus provide a valuable model system with which to study factors regulating human Lp(a) biogenesis. 相似文献
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PL Gabbott BG Dickie RR Vaid AJ Headlam SJ Bacon 《Canadian Metallurgical Quarterly》1997,377(4):465-499
This paper is a light microscopical study describing the detailed morphology and quantitative distribution of local circuit neurones in areas 25, 32, and 24b of the medial prefrontal cortex (mPFC) in the rat. Cortical interneurones were identified immunocytochemically by their expression of calretinin (CR), parvalbumin (PV), and calbindin D-28k (CB) immunoreactivity. Neurones immunoreactive for gamma-aminobutyric acid (GABA) were also investigated, as were interneurones containing reduced nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase activity. Several distinct classes of CR+, PV+, and CB+ neurones were identified; the most frequent were: bipolar/bitufted CR+ cells in upper layer 3; multipolar PV+ neurones in layers 3 and 5; and bitufted/multipolar CB+ neurones in lower layer 3. CB+ neurones resembling Martinotti and neurogliaform cells were also present in layers 5/6. The morphologies and depth distributions of each cell type were consistent across the three areas of mPFC studied. Seven classes of diaphorase-reactive mPFC neurone are described; these cells were composed about 0.8% of the total neurone population and had a peak distribution located in mid- to lower layer 5 in each area. In areas 32 and 25, three defined bands of diffuse NADPH diaphorase staining were located in layer 2 and in upper and deep layer 5. Diaphorase reactivity was very infrequently colocalised with either CR, PV, or CB immunoreactivities. The numerical densities of neurones (N(V), number of cells per mm3) in each layer were calculated stereologically. The mean total neuronal N(V) estimate for areas 25, 32, and 24b was 51,603 +/- 3,324 (mean +/- S.D.; n = 8). Significant interareal differences were detected. From cortical thickness data and neuronal N(V) estimates, the absolute number of neurones under 1 mm2 of cortical surface (N(C)) have been derived. The mean N(C) value for areas 25, 32, and 24b was 57,328 +/- 7,505 neurones. In immunolabelled Nissl-stained sections, CR+ neurones constituted an overall 4.0%, PV+ cells 5.6%, and CB+ 3.4% of the total neurone populations in mPFC. GABA+ cells represented a mean of 16.2% (14.8-17.2%) of neurones in areas 25, 32 and 24b. The absolute numbers of CR+, PV+, CB+, and GABA+ neurones within individual layers in a column of cortex under 1 mm2 of cortical surface (N(L)) have also been derived, with significant interareal differences in N(L) values being detected. The data provide the structural basis for a qualitative and quantitative definition of local cortical circuits in the rat mPFC. 相似文献
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