Search PubMed⌕ Search

Biomedical subjects

A B Smith

Publications and source records attributed to A B Smith.

At least 109 records · Page 6Linked to original sources
PubMed1995

Killing of trypanosomes by the human haptoglobin-related protein.

African trypanosomes cause disease in humans and animals. Trypanosoma brucei brucei affects cattle but not humans because of its sensitivity to a subclass of human high density lipoproteins (HDLs) called trypanosome lytic factor (TLF). TLF contains two apolipoproteins that are sufficient to cause lysis of T. b. brucei in vitro. These proteins were identified as the human haptoglobin-related protein and paraoxonase-arylesterase. An antibody to haptoglobin inhibited TLF activity. TLF was shown to exhibit peroxidase activity and to be inhibited by catalase. These results suggest that TLF kills trypanosomes by oxidative damage initiated by its peroxidase activity.

Amino Acid Sequence↗
PubMed1995

A combined morphological and molecular phylogeny for sea urchins (Echinoidea: Echinodermata).

Phylogenetic relationships of higher taxa of echinoids have been investigated using a 163 character morphological data base and molecular sequences from large and small subunit (LSU and SSU) ribosomal RNA (rRNA) genes. The complete SSU rRNA gene has been sequenced for 21 taxa, with representatives from nine of the 14 extant orders of Echinoidea. Partial LSU sequences, representing the first 400 base pairs (b.p.) from the 5' end were also sequenced for three taxa to complement an existing data base of ten taxa. The two molecular sequences provided a total of 371 variable sites, of which 143 were phylogenetically informative (compared to 145 phylogenetically informative sites from morphological data). Morphological, LSU and SSU data have been analysed separately and together. Morphological and SSU sequence data generate topologies that are not significantly in conflict (under Templeton's test), but the strong signal pairing arbaciids with clypeasteroids in the LSU derived tree marks the LSU sequence data as anomalous for this taxon. A 'total evidence' approach derived a tree very similar in topology to that derived from morphological data. Rooted on the stem group echinoid Archaeocidaris, our total evidence tree suggested relationships of higher taxa as follows: Cidaroida (Phormosomatidae (Echinothuriidae (Diadematidae ((Spatangoida (Clypeasteroida, Cassiduloida)) ((Calycina, Arbacioida) (Stomopneustidae (Glyphocidaridae (Temnopleuridae (Echinometridae (Echinidae, Stronglyocentridae)))))))))). Phylogenetic analyses run both with and without key fossil taxa yielded slightly different topologies. It is important to include fossil taxa in a phylogenetic analysis where there are long stem-group branches or where the crown group is highly derived.

Animals↗
PubMed1995

Production and oxidation of indole by Haemophilus influenzae.

During growth in high concentrations of iron nitrate, H. influenzae produces compounds reactive in biochemical assays for hydroxamates. Mixing experiments established that nitrate was responsible for inducing these compounds. Analysis by 1H and 13C NMR and high resolution mass spectrometry identified the active species as 2,2-bis(3'-indolyl)indoxyl. Bacterial production of the latter compound has been previously observed only in Pseudomonas aureofaciens. A mutant defective in the production of 2,2-bis(3'-indolyl)indoxyl was constructed by marker insertion. The formation of indole and 2,2-bis (3'-indolyl)indoxyl was quantitated by reverse-phase high pressure liquid chromatography during growth in high concentrations of nitrate. The mutant produced high concentrations of indole, but only minimal amounts of 2,2-bis(3'-indolyl)indoxyl, and also proved to be defective in nitrate reduction. These data suggest that indole may function as an electron donor for nitrate reductase in H. influenzae.

Chromatography, High Pressure Liquid↗
PubMed1995

Design and synthesis of nonpeptide peptidomimetic inhibitors of renin.

The desire to replace the amide backbone of renin inhibitors with a new scaffold led us to explore vinylogous amides (enaminones). An initial attempt proved unsuccessful, a result explained after the fact via docking experiments. Based on this lesson, we designed a different vinylogous amide scaffold which incorporated one or more pyrrolinone rings into the backbone. Three of the four compounds gave IC50S in the 0.6 to 18 microM range. These compounds did not inhibit HIV-1 protease. Taken together, the results reported herein provide insights into the role of hydrogen bonding and steric interactions for binding to renin.

Drug Design↗
PubMed1994

Peptide synthesis catalyzed by an antibody containing a binding site for variable amino acids.

Monoclonal antibodies, induced with a phosphonate diester hapten, catalyzed the coupling of p-nitrophenyl esters of N-acetyl valine, leucine, and phenylalanine with tryptophan amide to form the corresponding dipeptides. All possible stereoisomeric combinations of the ester and amide substrates were coupled at comparable rates. The antibodies did not catalyze the hydrolysis of the dipeptide product nor hydrolysis or racemization of the activated esters. The yields of the dipeptides ranged from 44 to 94 percent. The antibodies were capable of multiple turnovers at rates that exceeded the rate of spontaneous ester hydrolysis. This achievement suggests routes toward creating a small number of antibody catalysts for polypeptide syntheses.

Antibodies, Catalytic↗
PubMed1994

Tremorgenic indole alkaloids potently inhibit smooth muscle high-conductance calcium-activated potassium channels.

Tremorgenic indole alkaloids produce neurological disorders (e.g., staggers syndromes) in ruminants. The mode of action of these fungal mycotoxins is not understood but may be related to their known effects on neurotransmitter release. To determine whether these effects could be due to inhibition of K+ channels, the interaction of various indole diterpenes with high-conductance Ca(2+)-activated K+ (maxi-K) channels was examined. Paspalitrem A, paspalitrem C, aflatrem, penitrem A, and paspalinine inhibit binding of [125I]charybdotoxin (ChTX) to maxi-K channels in bovine aortic smooth muscle sarcolemmal membranes. In contrast, three structurally related compounds, paxilline, verruculogen, and paspalicine, enhanced toxin binding. As predicted from the binding studies, covalent incorporation of [125I]ChTX into the 31-kDa subunit of the maxi-K channel was blocked by compounds that inhibit [125I]ChTX binding and enhanced by compounds that stimulate [125I]ChTX binding. Modulation of [125I]ChTX binding was due to allosteric mechanisms. Despite their different effects on binding of [125I]ChTX to maxi-K channels, all compounds potently inhibited maxi-K channels in electrophysiological experiments. Other types of voltage-dependent or Ca(2+)-activated K+ channels examined were not affected. Chemical modifications of paxilline indicate a defined structure-activity relationship for channel inhibition. Paspalicine, a deshydroxy analog of paspalinine lacking tremorgenic activity, also potently blocked maxi-K channels. Taken together, these data suggest that indole diterpenes are the most potent nonpeptidyl inhibitors of maxi-K channels identified to date. Some of their pharmacological properties could be explained by inhibition of maxi-K channels, although tremorgenicity may be unrelated to channel block.

Allosteric Regulation↗
PubMed1994

Effect of chelate treatments on kidney, bone and brain lead levels of lead-intoxicated mice.

The effects of chelating agent treatment with meso-2,3-dimercaptosuccinic acid (DMSA), Na2CaEDTA, Na2ZnEDTA, and Na3ZnDTPA on the organ lead levels of lead-loaded mice have been determined. At 1 mmol/kg/day i.p., all caused reductions in the lead levels of the kidney after four injections, but only Na2CaEDTA produced a significant reduction in brain lead. All chelating agents caused significant reductions in kidney and brain lead levels when administered at a daily dose of 1 mmol/kg/day for eight days, but only DMSA reduced the bone lead level. In animals given 50 mg Pb/kg or 100 mg Pb/kg, the administration of Na2CaEDTA or DMSA at 1 mmol/kg/day x 8 produced significant reductions in kidney, bone and brain lead levels, but DMSA produced greater reductions of bone lead in both groups and of kidney lead in the group given 100 mg Pb/kg. An examination of published data describing the effect of chelating agent treatment on brain lead levels indicates that DMSA produces a reduction in brain lead levels under all conditions examined to date.

Animals↗
PubMed1994

Vectorially oriented membrane protein monolayers: profile structures via x-ray interferometry/holography.

X-ray interferometry/holography was applied to meridional x-ray diffraction data to determine uniquely the profile structures of a single monolayer of an integral membrane protein and a peripheral membrane protein, each tethered to the surface of a solid inorganic substrate. Bifunctional, organic self-assembled monolayers (SAMs) were utilized to tether the proteins to the surface of Ge/Si multilayer substrates, fabricated by molecular beam epitaxy, to facilitate the interferometric/holographic x-ray structure determination. The peripheral membrane protein yeast cytochrome c was covalently tethered to the surface of a sulfhydryl-terminated 11-siloxyundecanethiol SAM via a disulfide linkage with residue 102. The detergent-solubilized, photosynthetic reaction center integral membrane protein was electrostatically tethered to the surface of an analogous amine-terminated SAM. Optical absorption measurements performed on these two tethered protein monolayer systems were consistent with the x-ray diffraction results indicating the reversible formation of densely packed single monolayers of each fully functional membrane protein on the surface of the respective SAM. The importance of utilizing the organic self-assembled monolayers (as opposed to Langmuir-Blodgett) lies in their ability to tether specifically both soluble peripheral membrane proteins and detergent-solubilized integral membrane proteins. The vectorial orientations of the cytochrome c and the reaction center molecules were readily distinguishable in the profile structure of each monolayer at a spatial resolution of 7 A.

Amines↗
PubMed1994

Cadmium mobilization by monoaralkyl- and monoalkyl esters of meso-2,3-dimercaptosuccinic acid and by a dithiocarbamate.

Syntheses and relative cadmium mobilizing properties are described for three new monoaralkyl esters (HOOCCH(SH)CH(SH)COOR, where R = phenylethyl ((CH2)2C6H5), MPhEDMS; R = 3-phenylpropyl ((CH2)3C6H5), MPhPDMS; and R = 2-phenoxyethyl ((CH2)2OC6H5). MPhOEDMS) of meso-2,3-dimercaptusuccinic acid. These were prepared by the reaction of the corresponding alcohol with meso-2,3-dimercaptosuccinic acid (DMSA) in aqueous HCl. When administered intraperitoneally to cadmium-loaded mice at 0.50 mmol/kg/day for four consecutive days, all induced significant reductions in the whole body cadmium levels. MPhEDMS, 60%; MPhPDMS, 66%; and MPhOEDMS, 58% in comparison with control levels. At the same dosage monoisoamyl meso-2,3-dimercaptosuccinate (Mi-ADMS) and a dithiocarbamate, sodium N-benzyl-4-O-(beta-D-galactopyranosyl)-D-glucamine-N-carbodithioate++ + (BLDTC) induced reductions of 65% and 57%, respectively. Hepatic and renal cadmium were also depleted significantly, while brain cadmium levels were unchanged. These compounds induced a significant reduction in the cadmium levels of the spleen, and one, MPhOEDMS, produced a 10% decrease in pancreatic cadmium. The manner in which the later injections removed smaller fractions of the total body cadmium is consistent with a bodily distribution of these compounds by which they are concentrated primarily in the kidneys and the liver, with much smaller amounts reaching other organs. It is proposed that these compounds enter renal and hepatic cells through an anion transport system.

Animals↗
PubMed1994

Cancer mortality patterns among female and male workers employed in a cable manufacturing plant during World War II.

A cohort mortality study was conducted among 9028 (3042 women, 5986 men) workers potentially exposed to chlorinated naphthalenes (chloracnegens structurally similar to dioxins) and asbestos in the manufacture of Navy cable during World War II. Based on mortality through December 31, 1985, standardized mortality ratios (SMRs) for all cancers was 1.03 in women (95% confidence interval [CI] = 0.9 to 1.17) and 1.18 in men (95% CI = 1.10 to 1.26). There were no significant elevations in causes of death hypothesized a prior to be associated with chlorinated naphthalene exposure (malignant neoplasms [MN] of connective tissue, liver, and lymphatic and hematopoietic organs). An excess of MN of the connective tissue was suggested for workers with over 1 year of exposure and 25 years of latency (SMR = 3.54; 95% CI = 0.97 to 9.07). Among cancer sites not hypothesized to be related a priori, three showed concordant excesses among both genders (MN of stomach; rectum; and trachea, bronchus, and lung). No significant elevations occurred in hormonally related cancers among women. Cancer mortality among 460 individuals with chloracne (431 men, 29 women) was similar to that of the entire cohort, although the chloracne subcohort showed significant excesses in two rare causes of death (MN of esophagus, SMR = 3.26; "benign and unspecified neoplasms," SMR = 4.93). Use of county referent rates decreased SMRs for stomach, rectal, and buccal cavity cancer, suggesting a role for nonoccupational risk factors. It is difficult to draw conclusions about carcinogenicity of chlorinated naphthalenes because of study limitations, most importantly, concomitant asbestos exposure and the relatively short duration of exposure to chlorinated naphthalenes among most of the cohort.

Acne Vulgaris↗
PubMed1993

meso-2,3-dimercaptosuccinic acid monoalkyl esters: effects on mercury levels in mice.

Seven monoesters of meso-2,3-dimercaptosuccinic acid (DMSA) were evaluated for relative activities in mobilizing and promoting excretion of mercury in mercury-laden mice. Compounds assessed were the ethyl (M-EDMS), n-propyl (Mn-PDMS), isopropyl (Mi-PDMS), n-butyl (Mn-BDMS), isobutyl (Mi-BDMS), n-amyl (Mn-ADMS), and isoamyl (Mi-ADMS) esters. 2,3-Dimercaptopropane-1-sulfonate (DMPS) and DMSA were used as positive controls. After the first oral dose of each compound at 0.5 mmol/kg, DMSA and DMPS reduced the corporal mercury burden 16% and 24%, respectively, compared to controls, while the monoesters effected reductions of 35% (M-EDMS) to 49% (Mi-ADMS). After the second treatment at the same dose, the respective reductions produced by DMSA and DMPS were 24% and 38%, and those conferred by the monoesters ranged from 52% (M-EDMS) to 61% (Mn-BDMS). Determination of the comparative dose-response relationships of DMSA and Mi-ADMS on corporal and renal mercury concentrations revealed the monoester to be more active than DMSA on both parameters at each dose used. The cumulative amount of mercury excreted in urine by control mice over a 3-day period was 7.08 micrograms; this was increased 22%, 85%, and 94% by daily i.p. injections of DMSA, DMPS, and Mi-ADMS, respectively, at a daily dose of 0.1 mmol/kg. The respective cumulative 3-day totals recovered in feces from control mice and from mice treated with DMSA, DMPS, and Mi-ADMS were 9.76, 8.21, 10.44, and 11.73 micrograms. Parallel daily measurements of retained whole body radioactivity from 203Hg in mice were in good agreement with the values calculated from the excretion data.

Animals↗
PubMed1993

Effect of cromakalim on micturition function in rats.

Although many studies investigating the effect of cromakalim on bladder contractility exist, thus far, there are no published studies investigating its effect on micturition function in conscious rats. We measured the effect of cromakalim i.v. on urine output, frequency, volume of each micturition, and blood pressure in saline-diuresed and non-diuresed rats. In saline-diuresed rats cromakalim produced significant decreases in urine output (0.1 mg/kg, 32%; 0.3 mg/kg, 46%; 1.0 mg/kg, 68%) and average frequency (0.1 mg/kg, 36%; 0.3 mg/kg, 51%; 1.0 mg/kg, 70%) in the first 3 hours. At 3-6 hours after administration of cromakalim there were rebound increases in both urine output (0.1 mg/kg, 290%; 0.3 mg/kg, 373%; 1.0 mg/kg, 538%), and frequency (0.1 mg/kg, 147%; 0.3 mg/kg, 181%; 1.0 mg/kg, 314%) and by 6-12 hours the effects of cromakalim on micturition function were gone. Mean arterial pressure dropped to 50% of control immediately after cromakalim administration in saline-diuresed rats and began to return to control levels after 3 hours. Cromakalim produced similar results in non-diuresed rats. The decrease in urine output 0-3 hours after cromakalim administration may have been a consequence of cromakalim's profound decrease in blood pressure that occurred during that time.

Administration, Oral↗
PubMed1993

Design and synthesis of sulfur-free cyclic hexapeptides which contain the RGD sequence and bind to the fibrinogen GP IIb/IIIa receptor. A conformation-based correlation between propensity for imide formation and receptor affinity.

The Arg-Gly-Asp (RGD) sequence is the key recognition site in many adhesive interactions. To probe the structural and conformational requirements for potential antithrombotic agents, we have designed and synthesized three cyclic hexapeptides (1, 5 and 6) containing the RGD sequence. In the ELISA GP IIb/IIIa-fibrinogen receptor assay, 1, 5 and 6 bound with IC50 values of 1, 0.1 and 0.016 microM, respectively. All three peptides completely displaced fibrinogen from the receptor. No potent, sulfur-free cyclic hexapeptide had heretofore been described as a fibrinogen receptor antagonist. The enhanced binding affinity of 6, distinguished by the presence of two D-amino acids, is likely to reflect an increased conformational resemblance to the natural peptide ligands. Cyclization of H-Asp(OFm)-DSer-Phe-DPhe-Arg-Gly-OH with DPPA and NaHCO3 in DMF to afford 6 was attended by subsequent aspartimide formation with generation of 9-fluorenylmethanol. Interestingly, imide formation was not observed with any of the three linear hexapeptides (3, 8 and 9), with the all-L-cyclic peptide 1, nor with 5, which contains only Ser-1 in the D-configuration. The observed imide formation led us to use catalytic transfer hydrogenation rather than piperidine to remove the 9-fluorenylmethyl ester protecting group at the beta-carbonyl of aspartic acid. Further investigation revealed that imide formation was minimized by careful exclusion of water, reducing dissolution of NaHCO3. Thus the distinguishing conformational features of 6 express themselves both in receptor affinity and chemical propensity toward imide formation.

Amino Acid Sequence↗
PubMed1993

Fluid style.

Explore the source record for details and available documents.

Adenoidectomy↗
PubMed1992

Comparative variation of morphological and molecular evolution through geologic time: 28S ribosomal RNA versus morphology in echinoids.

The comparatively good fossil record of post-Palaeozoic echinoids allows rates of morphological change to be estimated over the past 260 million years and compared with rates of molecular evolution. Parsimony analysis of morphological data, based predominantly on skeletal characteristics, and parsimony, distance and maximum likelihood analyses of molecular data, from the first 380 bases from the 5' end of the 28S rRNA molecule, for 10 species of echinoid produce congruent phylogenies. The molecular sequence chosen is demonstrably far from saturation and sister groups have divergence times ranging from about 15 to 260 Ma. Parsimony analysis allows the great majority of molecular and morphological apomorphies to be placed in one of 18 independent geological time intervals, providing a direct measure of rates of evolution for periods in the geological past. Because most molecular fixed point mutations in our sequences cannot be polarized unambiguously by outgroup comparison (making the outgroup states effectively random), distance and parsimony analyses both tend spuriously to root the echinoid tree on the longest internal branch. A topology identical to that derived from morphological data is, however, obtained using Maximum Likelihood and also parsimony analysis where outgroup rooting is restricted to more conserved regions. This is taken as the correct topology for assessing rates of evolution. Overall, both morphological and molecular changes show a moderately strong correlation with time elapsed, but a weaker correlation with one another. Statistically significant differences in evolutionary rate are found between some, but not all, pair-wise comparisons of sister lineages for both molecular and morphological data. The molecular clock rate for echinaceans is three times faster than that for cidaroids and irregular echinoids. Spearman's rank correlation test, which requires only relative magnitude of changes to be known, suggests that morphological change has a slightly better correlation with time than does molecular change, averaged over all ten species. However, when just echinaceans are considered an extremely good correlation is found between the number of molecular changes and time elapsed, whereas morphological change remains poorly correlated. Thus, molecular rates approximate to a clocklike model within restricted echinoid clades, but vary significantly between clades. Averaging results over all echinoids produces a correlation that is no better than the correlation between morphological change and time elapsed.

Animals↗
PubMed1992

Mobilization of lead in mice by administration of monoalkyl esters of meso-2,3-dimercaptosuccinic acid.

The following six monoalkyl esters of meso-2,3-dimercaptosuccinic acid (DMSA) were synthesized and evaluated for relative activities in mobilizing lead from kidneys and brains of lead-bearing mice: n-propyl (Mn-PDMS), i-propyl (Mi-PDMS), n-butyl (Mn-BDMS), i-butyl (Mi-BDMS), n-amyl (Mn-ADMS) and i-amyl meso-2,3-dimercaptosuccinate (Mi-ADMS). DMSA was used as a positive control. When each was administered intraperitoneally (i.p.) as a single dose of 2.0 mmol/kg, DMSA lowered the kidney lead concentration 52%, while the monoesters effected reductions of 54-75%. Mn-ADMS was toxic at this dose. DMSA lowered the brain lead level 20% when given as a single dose, while the monoesters conferred reductions of 64-87%. When given as 5 daily i.p. injections at 0.5 mmol/kg, DMSA reduced the kidney lead concentration 45%, while the monoesters caused reductions of 56-73%. DMSA lowered the brain lead concentration 35% on the 5-day treatment regimen, while the monoesters evoked reductions of 59-75%. Mi-ADMS was equally effective when given orally or i.p. The i.p. LD50 value of this analog in mice is 3.0 mmol/kg, a value which lies between the reported LD50 doses of DMSA (16.0 mmol/kg) and dimercaprol (1.1 mmol/kg). It is suggested that the ability of these monoesters to cross cell membranes may account for their superiority to DMSA in mobilizing brain lead in this animal model.

Animals↗
PubMed1992

Mortality among workers exposed to polychlorinated biphenyls.

On the basis of evidence from animal studies, polychlorinated biphenyls (PCBs) are considered potentially carcinogenic to humans. However, the results of studies in human populations exposed to PCBs have been inconsistent. The authors conducted a retrospective cohort analysis (1957-1986) comparing the mortality of 3,588 electrical capacitor manufacturing workers with known exposure to PCBs with age-, sex-, and calendar time-specific mortality rates for all whites in the United States. Proportional hazards modeling was also performed to examine the association between cumulative PCB exposure and site-specific cancer mortality. All-cause mortality (192 deaths observed, 283.3 expected) and total cancer mortality (54 deaths observed, 63.7 expected) were lower than expected. More deaths were observed than expected for malignant melanoma (8 observed, less than 2.0 expected) and cancer of the brain and nervous system (5 observed, 2.8 expected). The average estimated cumulative dose for the cases of brain cancer (22.9 units) was greater than for other workers (12.9 units), but the 95% confidence intervals around this difference were broad. The risk of malignant melanoma was not related to cumulative PCB exposure. These results provide some evidence of an association between employment at this plant and malignant melanoma and cancer of the brain. The possibility that the results are due to chance, bias, or confounding cannot be excluded.

Brain Neoplasms↗