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81.
82.
P S Charifson J P Bowen S D Wyrick A J Hoffman M Cory A T McPhail R B Mailman 《Journal of medicinal chemistry》1989,32(9):2050-2058
Conformational studies on a series of 1-phenyl-, 4-phenyl-, and 1-benzyl-1,2,3,4-tetrahydroisoquinolines that possess an identical substituent pattern to the prototypical D1 dopamine receptor antagonist SCH23390 [(R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5- tetrahydro-1H-3-benzazepine (1)] were performed with use of molecular mechanics calculations [MM2(85), with newly developed aromatic halide bending and torsional parameters that are now incorporated into MM2(87)], single-crystal X-ray analysis, and high-field NMR spectroscopy. The synthesis and biological testing of compounds 2-7 has been previously reported. The test compounds were compared both quantitatively and graphically to compound 1. Calculations on both the free-base and protonated forms of each compound were carried out. To insure that conformation space was adequately sampled, the test compounds were energy minimized from different starting geometries; ring inversion of the heterocycle was employed, as were dihedral driver calculations on the phenyl or benzyl rings. For N-methyl-6-chloro-7-hydroxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline (2), it was determined that the torsion angle tau(C8a-C1-C12-C17) had energy minima at approximately 60 degrees and 240 degrees. This finding was corroborated by NMR studies that indicated a dramatic upfield chemical shift of ArH8 after ring cyclization. The nitrogen lone pair or hydrogen vector was approximately orthogonal to the plane of the substituted aromatic ring in the tetrahydroisoquinolines; this explained the upfield chemical shift of the vicinal chiral proton (H1). In all instances, the 6-membered heterocyclic ring in the energy-minimized structures preferred the half-chair conformation with the phenyl rings pseudo-equatorial. Distance comparisons of the proposed pharmacophoric atoms (Cl, N, O, centroid of the phenyl or benzyl ring) showed that the phenyl or benzyl centroid to ammonium H distance, Cl to N distance, and distance of the nitrogen above or below the plane of the isoquinoline aromatic ring are the distances most highly correlated with biological activity (r = 0.82, 0.75, 0.81, respectively). Resolution and single-crystal X-ray analysis of compound 2 showed the most active enantiomer to possess the S absolute configuration, in contrast to the benzazepine (R)-1. Least-squares fitting of the energy-minimized structures with SYBYL molecular modeling software showed (S)-(+)-2, rather than (R)-(-)-2, gave a better fit to (R)-1. Volume determinations derived from SYBYL multifit analyses aided in receptor mapping to qualitatively describe areas of "active" pharmacophore space as well as areas of "inactive" substituent space.(ABSTRACT TRUNCATED AT 400 WORDS) 相似文献
83.
CD14, a lipopolysaccharide (LPS) receptor, is present on the surface membrane of phagocytic leukocytes; it is also present in a soluble form in serum. Recently published results confer to this molecule novel functions that are linked to T-cell activation and to apoptosis. We report here that we have defined and characterized a novel lymphocyte population in human peripheral blood, a population that expresses an intracellular antigen detectable with MO2, a monoclonal antibody directed against the human CD14 molecule. This population is composed primarily of CD8-positive T-cells. We found surprisingly that this novel MO2-positive population of lymphocytes was greatly enhanced in asymptomatic, untreated HIV-positive individuals. 相似文献
84.
85.
Tezak Z Prandini P Boscaro M Marin A Devaney J Marino M Fanin M Trevisan CP Park J Tyson W Finkel R Garcia C Angelini C Hoffman EP Pegoraro E 《Human mutation》2003,21(2):103-111
Complete laminin alpha2 (LAMA2) deficiency causes approximately half of congenital muscular dystrophy (CMD) cases. Many loss-of-function mutations have been reported in these severe, neonatal-onset patients, but only single missense mutations have been found in milder CMD with partial laminin alpha2 deficiency. Here, we studied nine patients diagnosed with CMD who showed abnormal white-matter signal at brain MRI and partial deficiency of laminin alpha2 on immunofluorescence of muscle biopsy. We screened the entire 9.5 kb laminin alpha2 mRNA from patient muscle biopsy by direct capillary automated sequencing, single strand conformational polymorphism (SSCP), or denaturing high performance liquid chromatography (DHPLC) of overlapping RT-PCR products followed by direct sequencing of heteroduplexes. We identified laminin alpha2 sequence changes in six of nine CMD patients. Each of the gene changes identified, except one, was novel, including three missense changes and two splice-site mutations. The finding of partial laminin alpha2 deficiency by immunostaining is not specific for laminin alpha2 gene mutation carriers, with only two patients (22%) showing clear causative mutations, and an additional three patients (33%) showing possible mutations. The clinical presentation and disease progression was homogeneous in the laminin alpha2-mutation positive and negative CMD patients. 相似文献
86.
87.
Gerald R. Buzzell Armando Menndez-Pelez Roger A. Hoffman Carmen Rodríguez Isaac Antolin 《Anatomical record (Hoboken, N.J. : 2007)》1994,240(1):52-58
Background: The porphyrin concentrations of the Harderian glands of Syrian hamsters show marked sexual differences, with male levels being much lower than those of females. Porphyrinogenesis is inhibited by androgens, so orchidectomy leads to elevated male porphyrin concentrations; however, a number of other procedures (some of which also lower androgen levels) prevent this. We studied the effects of short-day photoperiods and melatonin on Harderian porphyrin concentrations. Methods: Intact, castrated, or pinealectomized hamsters of both sexes were exposed to long-day or short-day photoperiods. Intact or castrated hamsters were given melatonin injections in the morning or the afternoon, or were given beeswax pellets containing melatonin. After a variable period, Harderian glands were dissected and porphyrins were measured. Results: Prolonged short-day exposure (13 weeks) led to increased Harderian porphyrin concentrations and this rise was prevented by pinealectomy. The rise in Harderian porphyrins following short-day exposure was small, compared with that following castration. Short-day photoperiods also prevented the rise in porphyrin levels associated with castration and this effect was prevented by removal of the pineal. Melatonin injections, whether given in the morning or in the afternoon, had no effect on Harderian porphyrin concentration of castrated male hamsters. Continuous release melatonin pellets reduced the postcastrational rise in porphyrin levels in one experiment, while having no effect in another. In female hamster, neither short photoperiods nor melatonin pellets influenced Harderian porphyrin concentrations. Conclusions: These results suggested that a factor from the pineal gland helps maintain the low levels of porphyrin which are characteristic of male Harderian glands, despite the decrease in androgen levels which typically results from exposure to short days. Morning and afternoon injections of melatonin and continuous release melatonin pellets failed to resolve the question of whether this pineal factor is melatonin. Our results demonstrated that low male and high female porphyrin levels are maintained in Syrian hamsters, despite seasonal variations in the hormonal milieu, suggesting that these sexual differences are important for the (still unestablished) function of the Harderian glands in this species. © 1994 Wiley-Liss, Inc. 相似文献
88.
P M Hoffman D S Robbins M T Nolte C J Gibbs D C Gajdusek 《The New England journal of medicine》1978,299(13):680-685
To test the hypothesis that host resistance factors may be abnormal in Guamanians in whom amyotrophic lateral sclerosis and Parkinsonism-dementia develop, cellular immunity was evaluated in both diseases and compared to that of Guamanians with other nervous-system diseases, normal adult Guamanians and non-Guamanians with amyotrophic lateral sclerosis and Parkinsonism. Diminished responses to skin-test antigens, lymphopenia, diminished per cent and total T cells and, less frequently, decreased mitogen responses were seen in Guamanian patients with amytorophic lateral sclerosis and Parkinsonism-dementia but not in the other patient or normal groups. Guamanian patients with amyotrophic lateral sclerosis and diminished cellular immunity had an increased frequency of HLA-Bw35 (P less than 0.005) and shorter mean duration of disease (P less than 0.05) than those with normal cellular immunity. In Parkinsonism dementia diminished cellular immunity was less strongly associated with HLA-BW35 (P less than 0.05) and was not associated with differences in duration of disease. Normal Guamanians and those with other nervous-system diseases showed no association of diminished cellular immunity with HLA-Bw35. The association appeared disease-related, with onset concomitant with the neurologic expression of Guamanian amyotrophic lateral sclerosis and Parkinsonism-dementia. 相似文献
89.
U Thathamangalam K Chandrasekaran J C Hoffman V W McFarland C Parott C A Smith D T Simmons P T Mora 《Virology》1986,155(1):132-147
In most murine cells transformed by the SV40 virus, virtually all of the cellular phosphoprotein p53 is in a complex with the SV40 T antigen. Here, we report that, in SV40-infected T-antigen-positive Balb 3T12 mouse cells, most (approximately 80%) of the p53 is not in complex. Complex formation was determined by measuring the amounts of [35S]methionine-labeled p53 which coprecipitated with T antigen when using monoclonal antibody to T antigen. The amount of complex formation was expressed as a percentage of total p53 present, measured by the amount of p53 precipitated with the monoclonal antibody to the p53. The values were confirmed by Western blotting procedure, in which the steady-state levels of the proteins were measured. In these measurements after complete precipitation with antibody to T antigen, the residual p53 in the supernatant was precipitated by antibody to p53, and this amount was denoted as free p53. There was no significant difference seen between the [35S]methionine-labeled tryptic peptides of complexed and the free p53 (or between complexed and free T antigens) as determined by two-dimensional gel electrophoresis and chromatography. Virus rescue experiments and retransformation by the rescued virus showed that there was no mutation in the SV40 DNA coding for the T antigen which could account for the lack of complex formation. Both p53 and T antigen were underphosphorylated in cells which exhibited reduced complex formation. Tumorigenicity in syngeneic mice and anchorage-independent cell growth in culture of various cloned mouse cells with or without T antigen expression was compared. The changes in the biologic properties were explainable solely on the basis of known or expected effects of expression of the T antigen and were independent of complex formation or of absence of complex formation between p53 and T antigen. 相似文献
90.
Comparison of detection of antibody to the acquired immune deficiency syndrome virus by enzyme immunoassay, immunofluorescence, and Western blot methods. 总被引:7,自引:16,他引:7
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D Gallo J L Diggs G R Shell P J Dailey M N Hoffman J L Riggs 《Journal of clinical microbiology》1986,23(6):1049-1051
There was 100% agreement between enzyme immunoassay (EIA) (Abbott Laboratories), Western blot, and indirect immunofluorescence (IF) when these three methods were used to measure antibody to the acquired immune deficiency syndrome (AIDS) virus in sera from 142 high-risk individuals, indicating that IF was a sensitive alternative method for detecting antibody to this agent. Thirty-two (64%) of 50 EIA-positive plasma specimens from a blood bank and 6 (21%) of 28 EIA-positive sera from alternative testing sites were negative by IF. In addition, two EIA-negative sera from the latter group were positive by IF. Western blotting agreed with IF on those 40 specimens which gave discrepant results by EIA and IF. The IF method was determined to be equal to Western blotting in sensitivity and specificity for detection of AIDS antibody, and it was found to be useful for confirming positive EIA results, especially in specimens from individuals in low-risk groups. 相似文献