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Biomedical subjects

H Robinson

Publications and source records attributed to H Robinson.

At least 91 records · Page 5Linked to original sources
PubMed1990

NMR studies on the binding of antitumor drug nogalamycin to DNA hexamer d(CGTACG).

The interactions between a novel antitumor drug nogalamycin with the self-complementary DNA hexamer d(CGTACG) have been studied by 500 MHz two dimensional proton nuclear magnetic resonance spectroscopy. When two nogalamycins are mixed with the DNA hexamer duplex in a 2:1 ratio, a symmetrical complex is formed. All non-exchangeable proton resonances (except H5' & H5") of this complex have been assigned using 2D-COSY and 2D-NOESY methods at pH 7.0. The observed NOE cross peaks are fully consistent with the 1.3 A resolution x-ray crystal structure (Liaw et al., Biochemistry 28, 9913-9918, 1989) in which the elongated aglycone chromophore is intercalated between the CpG steps at both ends of the helix. The aglycone chromophore spans across the GC Watson-Crick base pairs with its nogalose lying in the minor groove and the aminoglucose lying in the major groove of the distorted B-DNA double helix. The binding conformation suggests that specific hydrogen bonds exist in the complex between the drug and guanine-cytosine bases in both grooves of the helix. When only one drug per DNA duplex is present in solution, there are three molecular species (free DNA, 1:1 complex and 2:1 complex) in slow exchange on the NMR time scale. This equilibrium is temperature dependent. At high temperature the free DNA hexamer duplex and the 1:1 complex are completely destabilized such that at 65 degrees C only free single-stranded DNA and the 2:1 complex co-exist. At 35 degrees C the equilibrium between free DNA and the 1:1 complex is relatively fast, while that between the 1:1 complex and the 2:1 complex is slow. This may be rationalized by the fact that the binding of nogalamycin to DNA requires that the base pairs in DNA open up transiently to allow the bulky sugars to go through. A separate study of the 2:1 complex at low pH showed that the terminal GC base pair is destabilized.

Base Sequence↗
PubMed1990

Cyclic diguanylic acid behaves as a host molecule for planar intercalators.

Cyclic ribodiguanylic acid, c-(GpGp), is the endogenous effector regulator of cellulose synthase. Its three-dimensional structure from two different crystal forms (tetragonal and trigonal) has been determined by X-ray diffraction analysis at 1 A resolution. In both crystal forms, two independent c-(GpGp) molecules associate with each other to form a self-intercalated dimer. A hydrated cobalt ion is found to coordinate to two N7 atoms of adjacent guanines, forcing these two guanines to destack with a large dihedral angle (32 degrees), in the dimer of the tetragonal form. This metal coordination mechanism may be relevant to that of the anticancer drug cisplatin. Moreover, c-(GpGp) exhibits unusual spectral properties not seen in any other cyclic dinucleotide. It interacts with planar organic intercalator molecules in ways similar to double helical DNA. We propose a cage-like model consisting of a tetrameric c-(GpGp) aggregate in which a large cavity ('host') is generated to afford a binding site for certain planar intercalators ('guests').

Cyclic GMP↗
PubMed1990

Molecular modelling studies on the binding of phenylurea inhibitors to the D 1 protein of photosystem II.

A hypothetical molecular model of part of the D 1 protein of photosystem II, based on the analogous portion of the L subunit of the Rhodopseudomonas viridis reaction centre, has been used to study the binding of an extended hydrophobic phenylurea inhibitor (N,N-dimethyl-carbamoyl)4-amino-4'-chloro-trans-stilbene) (I) to the QB site. The inhibitor was fitted by eye into a cleft in the site, and a limited part of the inhibitor/D 1 complex was energy minimized. The gross orientation of the inhibitor placed the dimethylurea moiety towards the predicted binding domain of the plastoquinone head group, and the stilbene moiety directed along the quinone isoprenoid side chain binding domain, suggesting a similar pathway of approach of the two molecules from the membrane into the binding site. Binding interactions of the inhibitor included hydrogen bonds to the side chain hydroxyl of ser 264 and the peptide carbonyl group of ala 251, with the side chain hydroxyl of ser 268 as an alternative ligand. Numerous hydrophobic contacts were also possible. Although phenylureas do not bind to reaction centres of Rp. viridis, many of the binding interactions to D 1 could also be detected in Rp. viridis. However, the beta-CH2, and delta-CO2- groups of glu 212 in Rp. viridis are located in the corresponding region of D 1 occupied by the dimethylurea moiety of the inhibitor in our model of its binding to D 1. This may explain why diuron (DCMU) does not bind to Rp. viridis reaction centres.

Amino Acid Sequence↗
PubMed1990

Agnathia malformation complex associated with a cystic distention of the oral cavity and hydranencepahly.

A fetus with a severe variant of the agnathia malformation complex (AMC) was delivered following prenatal diagnostic evaluation with ultrasonography. The constellation of anomalies that accompanied the agnathia included holoprosencephaly, hydranencephaly, situs inversus, and polysplenia. Recently, several authors have reported the association between the agnathia, holoprosencephaly, and situs inversus. We present evidence which suggests that, when hydranencephaly is also present, this may represent the most severe variant of the AMC. Our case is presented, the literature is reviewed, and a hypothesis regarding the embryopathologic mechanism is discussed.

Abnormalities, Multiple↗
PubMed1989

Antitumor drug nogalamycin binds DNA in both grooves simultaneously: molecular structure of nogalamycin-DNA complex.

The three-dimensional molecular structures of the complexes between an interesting antitumor drug, nogalamycin, and two DNA hexamers, d[CGT(pS)ACG] and d[m5CGT(pS)Am5CG], were determined at high resolution by X-ray diffraction analyses. Two nogalamycins bind to the DNA double helix in a 2:1 ratio with the aglycon chromophore intercalated between the CpG steps at both ends of the helix. The nogalose and aminoglucose sugars lie in the minor and major grooves, respectively, of the distorted B-DNA double helix. The binding of nogalamycin to DNA requires that the base pairs in DNA open up transiently to allow the bulky sugars to go through. Specific hydrogen bonds are found in the complex between the drug and guanine bases. We suggest that nogalamycin may prefer GC sequences embedded in a stretch of AT sequences.

DNA↗
PubMed1989

Autoradiographic study of the attrition of migrating schistosomula in the skin of mice. I. Mice immunized with highly X-irradiated Schistosoma mansoni cercariae.

The migratory pattern in naive mice of Schistosoma mansoni cercariae X-irradiated with OkR, 12kR, or 48rR has been investigated with compressed organ autoradiography. Three groups of 69 mice each were infected with 75Se-labelled cercariae. The skin at the site of infection, as well as the entire lungs and liver were removed from infected mice daily from 1-21d, on 24d, and on 28d; tissues were then processed for autoradiography. Autoradiographic analysis of migratory patterns showed that the schistosomula derived from nonattenuated cercariae passed quickly from the skin to the lungs and at a moderate rate from the lungs to the liver. Schistosomula derived from 12kR-irradiated cercariae were delayed in passing from the skin to the lungs and from the lungs to the liver, so that many remained in the lungs and died there, while only a few died in the skin or liver. Schistosomula derived from 48kR-irradiated cercariae remained mainly in the skin, rarely reached the lungs and were never found in the liver. This study indicates that immunization with 48kR-irradiated cercariae will cause no significant lesions in the lungs or liver.

Animals↗
PubMed1988

Histologic analysis of placental tissue in first trimester abortions.

The value of histologic evaluation in the analysis of material from first trimester abortions is not completely defined. We prospectively analyzed placenta and decidua from 75 first trimester, spontaneous abortions to ascertain if morphologic features were predictive of karyotype. The histologic features analyzed included hydropic villus change, villus fibrosis, villus scalloping with trophoblastic invaginations, atypical stromal cells, aggregates of lymphocytes in placenta or decidua, and acute inflammation of placenta or decidua. Normal karyotypes were observed in 44 cases and abnormal karyotypes were demonstrated in 31. The presence of villus scalloping with trophoblastic invagination was significantly associated with abnormal karyotypes, particularly triploidy, and the demonstration of acute inflammation was seen significantly more often in cases with normal karyotypes. We conclude that histology can provide only a suggestion as to the likelihood of an abnormal karyotype; the findings are not specific enough to obviate the need for karyotyping in the individual case.

Abortion, Spontaneous↗
PubMed1988

Rheumatic disease in the Nuu-Chah-Nulth native Indians of the Pacific Northwest.

The Nuu-Chah-Nulth are a tribe of 2,300 Pacific Northwest native Indians. A retrospective study has identified 157 requiring referral to rheumatologists over 15 years. Rheumatoid arthritis (RA) was found in 23, systemic lupus erythematosus (SLE) in 8, sacroiliitis 5, and Reiter's syndrome 1. Overlap syndromes with combinations of RA, SLE, scleroderma and polymyositis were seen in 9. Other rheumatic disorders included osteoarthritis 10, soft tissue rheumatism 14, and musculoskeletal complaints of known etiology (trauma, infection, neoplasm) 12. The remaining 75 patients suffered from periodic weather dependent joint swelling (52) or polyarthralgia (23) which were sometimes accompanied by features of systemic connective tissue disease. These findings are compared with rheumatic disease in other North American Indians.

Antibodies, Antinuclear↗
PubMed1986

Preventive screening for the fragile X syndrome.

In an Australian population of 1.2 million, we screened 1977 intellectually handicapped persons, who were identified through the public schools and sheltered workshops, for the X-linked semidominant fragile X syndrome. We excluded 527 because they had another known diagnosis. The remaining 1450 were offered chromosomal analysis. Of the 1117 who consented (77 percent), an additional 196 were excluded, and among the 921 who were tested cytogenetically, 40 probands were found. Prevalence rates for persons with an intellectual handicap and the fragile X syndrome in the public school population were 1:2610 for males and 1:4221 for females. Family studies identified 84 women who were either obligate carriers or at high risk of being carriers, who were under the age of 35 and had no children. These women were given genetic counseling, and the availability of antenatal diagnosis was explained to them. If each of these 84 women had two children, 27 of their sons would have an intellectual handicap. We recommend cytogenetic screening for the fragile X syndrome in all currently identified intellectually handicapped people, followed by routine screening of children newly identified as intellectually handicapped in the school system.

Australia↗
PubMed1986

Fetal intravascular transfusion for severe erythroblastosis: effects on haematology and survival.

Since February 1984, 8 fetuses (including a set of hydropic twins) with severe erythroblasts in the second trimester have received intravascular transfusions guided by ultrasound. These transfusions were associated with a decreasing fetal reticulocytosis, a decreasing proportion of circulating fetal haemoglobin and a decreasing mean fetal red corpuscular volume. All infants were born alive at an average of 5.5 weeks after the first transfusion; 3 infants died, including the hydropic twins and another with lethal congenital anomalies. All 5 survivors required simple transfusions for up to 54 days after birth because of prolonged bone marrow suppression. In severe erythroblastosis in the second trimester, direct intravascular transfusion using ultrasound guidance promises to improve fetal outcome.

Blood Transfusion, Intrauterine↗
PubMed1986

Lower Purkinje cell counts in the cerebella of four autistic subjects: initial findings of the UCLA-NSAC Autopsy Research Report.

As part of an autopsy research project, the brains of four autistic subjects were examined and compared with those of three comparison subjects without CNS pathology and one with phenytoin toxicity. The cerebellum was selected for initial investigation because pathognomonic symptoms and neurophysiological measures suggest that pathology may exist in the cerebellar-vestibular axis in certain patients. Total Purkinje cell counts were significantly lower in the cerebellar hemisphere and vermis of each autistic subject than in the comparison subjects.

Adolescent↗