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PubMed1996

High-resolution NMR of biological solids.

Solid-state NMR experiments have recently provided a number of biochemical insights: motionally averaged 2H lineshapes have shown that the motion of a backbone loop protecting a protein binding site is not ligand gated; isotropic 13C chemical shifts of freeze-quenched enzyme-ligand intermediates have revealed mechanistic details of reaction pathways; multiple heteronuclear distance determinations have characterized the binding-site geometry of a 46 kDa noncrystalline enzyme complex; and homonuclear recoupling experiments have established that insoluble amyloid fibrils form a pleated beta sheet.

Animals↗
PubMed1994

Thiopyrano[2,3,4-cd]indoles as 5-lipoxygenase inhibitors: synthesis, biological profile, and resolution of 2-[2-[1-(4-chlorobenzyl)-4-methyl-6-[(5-phenylpyridin-2-yl)methoxy]-4,5 -dihydro-1H-thiopyrano[2,3,4-cd]indol-2-yl]ethoxy]butanoic acid.

Leukotriene biosynthesis inhibitors have potential as new therapies for asthma and inflammatory diseases. The recently disclosed thiopyrano[2,3,4-cd]indole class of 5-lipoxygenase (5-LO) inhibitors has been investigated with particular emphasis on the side chain bearing the acidic functionality. The SAR studies have shown that the inclusion of a heteroatom (O or S) in conjunction with an alpha-ethyl substituted acid leads to inhibitors of improved potency. The most potent inhibitor prepared contains a 2-ethoxybutanoic acid side chain. This compound, 14d (2-[2-[1-(4-chlorobenzyl)-4-methyl-6-[(5-phenylpyridin-2-yl)methox y]- 4,5-dihydro-1H-thiopyrano[2,3,4-cd]indol-2-yl]ethoxy]-butanoic acid, L-699,333), inhibits 5-HPETE production by human 5-LO and LTB4 biosynthesis by human PMN leukocytes and human whole blood (IC50s of 22 nM, 7 nM and 3.8 microM, respectively). The racemic acid 14d has been shown to be functionally active in a rat pleurisy model (inhibition of LTB4, ED50 = 0.65 mg/kg, 6 h pretreatment) and in the hyperreactive rat model of antigen-induced dyspnea (50% inhibition at 2 and 4 h pretreatment; 0.5 mg/kg po). In addition, 14d shows excellent functional activity against antigen-induced bronchoconstriction in the conscious squirrel monkey [89% inhibition of the increase in RL and 68% inhibition in the decrease in Cdyn (0.1 mg/kg, n = 3)] and in the conscious sheep models of asthma (iv infusion at 2.5 micrograms/kg/min). Acid 14d is highly selective as an inhibitor of 5-LO activity when compared to the inhibition of human 15-LO, porcine 12-LO and ram seminal vesicle cyclooxygenase (IC50 > 5 microM) or competition in a FLAP binding assay (IC50 > 10 microM). Resolution of 14d affords 14g, the most potent diastereomer, which inhibits the 5-HPETE production of human 5-LO and LTB4 biosynthesis of human PMN leukocytes and human whole blood with IC50s of 8 nM, 4 nM, and 1 microM respectively. The in vitro and in vivo profile of 14d is comparable to that of MK-0591, which has showed biochemical efficacy in inhibiting ex vivo LTB4 biosynthesis and urinary LTE4 excretion in clinical trials.

Animals↗
PubMed1981

Phencyclidine metabolism: resolution, structure, and biological activity of the isomers of the hydroxy metabolite, 4-phenyl-4-(1-piperidinyl)cyclohexanol.

One of the major biotransformation pathways in the metabolism of phencyclidine is hydroxylation at C-4 of the cyclohexane ring to give 4-phenyl-4-(1-piperidinyl)cyclohexanol (1). Since the latter compound can exist as cis and trans isomers and the synthetic mixture has been reported to be biologically active, it was of interest to separate the isomers, test them for biological activity, and determine their ratio as metabolic products of phencyclidine. The synthetic mixture of 1 was separated by TLC and the individual isomers were characterized by 13C and 1H NMR and MS analyses. Preliminary testing of the isomers in the mouse rotarod assay indicates that the trans isomer (1b) is only slightly more active then the cis isomer (1a). Both isomers produced seizure activity and lethality at doses required to produce maximal ataxia.

Animals↗
PubMed1998

Improved dilute bicelle solutions for high-resolution NMR of biological macromolecules.

Dissolving biological macromolecules in dilute bicelle solutions, which form oriented liquid crystals in the presence of a magnetic field, permits measurement of anisotropic spin interactions such as dipolar couplings [Tjandra, N. and Bax, A., Science, 278, 1111-1114]. However, the lifetimes and temperature ranges of orientation for these samples are critically dependent on sample composition and experimental conditions. This paper demonstrates that doping dilute bicelle solutions with small amounts of charged amphiphiles substantially improves the stability and degree of alignment, as well as extends the temperature range of orientation for these systems. An explanation of the dependence of bicelle aggregation on sample composition is proposed based on the DLVO theory of colloids.

Colloids↗
PubMed1992

Stereochemical studies of chiral H-1 antagonists of histamine: the resolution, chiral analysis, and biological evaluation of four antipodal pairs.

The resolution of the H-1 antihistamines chloropheniramine, dimethindene, carbinoxamine, and mebrophenhydramine is described. The optical purity of antipodal products is investigated by chiral HPLC (use of alpha 1-acid glycoprotein and beta-cyclodextrin columns) and NMR (spectra of beta-cyclodextrin inclusion complexes). Configurational relationships among the group are reviewed and assignments are confirmed and extended by circular dichroism evidence. Affinity constants of antipodal pairs for guinea pig ileum and cerebellum sites, determined by gut bath and binding experiments respectively, are reported together with some in vivo tests in man for central effects. Results are discussed in terms of configurational requirements for activity and variations in antipodal potency ratios within the group.

Animals↗
PubMed1992

Image contrast in high-resolution electron microscopy of biological macromolecules: TMV in ice.

It is shown that the contrast in high-resolution electron micrographs of biological macromolecules, illustrated by a study of TMV in ice, falls considerably below the level which should theoretically be attained. The factors which contribute to the low contrast include radiation damage, inelastic scattering, specimen movement and charging. Future progress depends on improved understanding of their contributions and relative importance. Contrast is defined as the amplitude of a particular Fourier component extracted from an image in comparison to that expected by extrapolation from separate electron or X-ray diffraction measurements. The fall in contrast gets worse with increased resolution and is particularly serious at 10 A and beyond for specimens embedded in vitreous ice, a method of specimen preparation which is otherwise particularly desirable because of the expectation that the embedded molecules should be well preserved in a near-native environment. This low contrast at high resolution is the principal limitation to atomic-resolution structure determination by electron microscopy. In spite of good progress in the direction of better images, it remains a major problem which prevents electron microscopy from becoming a simple and rapid method for biological atomic structure determination.

Bacteriorhodopsins↗
PubMedDate not supplied

Investigation of biological systems by high resolution 2-mm wave band ESR.

The application of high resolution ESR to the investigation of various biological systems is discussed. The advantages of the technique in the study of structural, conformational and dynamic characteristics have been exemplified by spin-labeled human serum albumin, egg lysozyme, liposome membranes, inverted micelles, alpha-chymotrypsin, cotton fiber and cellulose. The polarity of the microenvironment and the mechanism of molecular mobility of the objects under study have been determined. The combination of high resolution and saturation transfer techniques has been shown to give a detailed analysis of very slow molecular motions in biological objects. Peroxide radicals in biosystems have been identified from their ESR spectra at the 2-mm wave band.

Biopolymers↗
PubMed1975

Development of methodology for low exposure, high resolution electron microscopy of biological specimens.

Specimen damage resulting from inelastic scattering is one of the factors that limits high-resolution electron microscopy of biological specimens. We have, therefore, sought to develop a method to record images of periodic objects at a reduced electron exposure in order to preserve high-resolution structural detail. The resulting image will tend increasingly to be a statistically noisy one, as the electron exposure is reduced to lower and lower values. Construction of a statistically defined image from such data is possible by spatial averaging of the electron signals from a large number of identical unit cells. In this paper, we have first investigated the theory pertaining to the attainable resolution as a function of the electron exposure, the magnification, and several other relevant parameters. In addition, we report experimental results obtained with a commercial image intensifier and with nuclear track photographic emulsion, both of which are highly sensitive recording devices. Usable images can be recorded and processed at exposures in the image plane as low as 10(-3) electron/micron2 (1.6 x 10(-14) coulomb/cm2).

Electrons↗
PubMed1985

A new model for the resolution of cultural and biological inheritance in the presence of temporal trends: application to systolic blood pressure.

A contemporary path model for the resolution of cultural and biological inheritance is extended to incorporate temporal variation in family resemblance. Specifically, the genetic and environmental effects, like all other parameters of the model, are allowed to vary over an individual's age according to some specific mathematical functions. In the computer program BETREND a library of such functions is incorporated. Data on systolic blood pressure in 542 Japanese-American nuclear families were analyzed. This new methodology detected significant temporal variation in cultural inheritance, a result that was not found previously by using static models which could only distinguish between adult and childhood heritabilities. Cultural heritability, estimated to be 10% at birth, increases to a maximum of 28% at age 36, at which time it declines until it eventually reaches 10% at age 49. Although not statistically significant, there was some evidence for temporal trends in genetic heritability as well. Ignoring trends, the genetic heritability was estimated as .30. On the other hand, trends in sibling environment were clearly nonsignificant. This model provides an objective method of testing the significance of temporal trends in familial resemblance by using multifactorial models, of resolving varying gene expression and transient environmental effects as possible sources of generating the observed temporal variation, and of estimating continuous changes in heritability with age.

Adolescent↗
PubMed1989

Scanning tunneling microscopy with applications to biological surfaces.

Each major advance in the field of microscopy has eventually been translated into major advances in the biological and medical sciences. The scanning tunneling microscope (STM) offers exciting new ways of imaging biological surfaces with resolution to the sub-molecular scale. Rigid, conductive surfaces can readily be imaged with the STM with atomic resolution. Unfortunately, few biological surfaces are sufficiently conductive or rigid enough to be examined directly with the STM. At present, non-conductive surfaces can be examined in two ways: 1) Sufficiently thin molecular layers attached to conductive substrates so that tunneling can occur through the molecules; or 2) coating or replicating non-conductive surfaces with metal layers so as to make them conductive, then imaging with the STM. We present images of biological and organic molecules obtained with these techniques that demonstrate the possibilities and limitations of each. Future advances leading to atomic resolution STM of biological surfaces depend on significant progress in the art and science of making biomaterials compatible with the restrictions of the instrument.

Biocompatible Materials↗
PubMedDate not supplied

Determination of surface topography of biological specimens at high resolution by scanning tunnelling microscopy.

Although techniques are available for the determination of the three-dimensional structure of biological specimens, for example scanning electron microscopy, they all have some serious drawback, such as low resolution, the requirement for crystals or for the sample to be analysed in a high vacuum. In an attempt to develop a technique for high-resolution three-dimensional structure analysis of non-crystalline biological material, we have tested the applicability of scanning tunnelling microscopy (STM), a method that has been used successfully in the analysis of metal and semiconductor surface structures. We report here that scanning tunnelling electron microscopy can be used to determine the surface topography of biological specimens at atmospheric pressure and room temperature, giving a vertical resolution of the order of 1 A. Our results show that quantum mechanical tunnelling of electrons through biological material is possible provided that the specimen is deposited on a conducting surface.

Atmospheric Pressure↗
PubMed1990

Cold stage design for high resolution electron microscopy of biological materials.

Both the number and range of applications of cryotechniques in transmission electron microscopy are increasing rapidly. In some cases, most notably the determination of protein structure by electron crystallography, progress has been limited by the performance of commercially available cryo stages. We review the design and performance criteria for stages which will be necessary for wide applicability in high resolution studies of biological specimens. The important criteria include an operating temperature below -140 degrees C with a low rate of contamination of the specimen, ability to tilt to 60 degrees, and perhaps most important, good resolution as judged by an effective modulation transfer function of 0.8 at 0.35 nm. Most applications also require an effective cryotransfer system. Up until now, most work in high resolution electron crystallography has been accomplished with laboratory-built stages which meet some, but not all, of these criteria. The availability of cold stages which fully meet criteria will allow the rapid expansion of high resolution studies by electron microscopy in structural biology.

Cryopreservation↗
PubMed1997

High resolution imaging of native biological sample surfaces using scanning probe microscopy.

The possibility of acquiring high resolution topographs using scanning probe microscopes under physiological conditions allows the observation of biomolecules at work. Progress has recently been made in imaging protein-DNA complexes, individual oligomers and protein arrays. Scanning probe microscopes are now tools that complement X-ray crystallography and electron microscopy.

Bacterial Outer Membrane Proteins↗
PubMed1989

Ultrahigh resolution scanning electron microscopy of biological materials.

In recent years, several ultrahigh resolution scanning electron microscopes (SEM) were successively developed. They were all equipped with a field emission electron gun and an objective lens with a short focal length, and showed a resolution better than 1 nm. With such instrument, not only intracellular structures but also virus, bacteriophages, and biological macromolecules were clearly observed. With improvement of the instrumental resolution, some unexpected problems came to the fore in the area of specimen preparation. The first is the metal coating of the specimen, because coated metal particles are plainly seen as rounded "pebbles" at very high magnifications. For observations at the high magnifications, therefore, uncoated and not conductively stained specimens were used. The second problem is contamination by the electron beam. This problem is complicated and remains unsolved. Although the ultra-high resolution scanning electron microscopy has just begun, it will surely open new research fields in biomedicine.

Animals↗
PubMed1992

Ultrahigh-resolution scanning electron microscopy of biological materials.

The age of ultrahigh-resolution scanning electron microscopy (SEM) began in 1985, when the UHS-T1, with a resolution of 0.5 nm, was developed. Commercial instruments of the same or similar types followed rapidly. As instrumental resolution progressed, conventional specimen preparation methods became inadequate, and a number of new techniques were devised. In this paper, detailed procedures for these preparation methods such as the CC plate method and heavy metal impregnation are described, together with precautions recommended for achieving ultrahigh-resolution. Some applications of the method to biological specimens are also reported. Morphological identification of immunoglobulins prepared from human blood was attempted, and although the identification was not completely successful this technique may yet come to be of use in the clinical examination of allergic or infectious diseases. SEM images of complement, Clq, proteoglycan and the helical structure of double stranded DNA are shown, as also is the visualization of immunolabelled cell-surface receptors.

Carbon↗