Comparative study of normal and branched alkane monolayer films adsorbed on a solid surface. II. Dynamics.

The dynamics of monolayer films of the n-alkane tetracosane (n-C24H52) and the branched alkane squalane (C30H62) adsorbed on graphite have been studied by quasielastic and inelastic neutron scattering and molecular dynamics (MD) simulations. Both molecules have 24 carbon atoms along their carbon backbone, and squalane has an additional six methyl side groups symmetrically placed along its length. The authors' principal objective has been to determine the influence of the side groups on the dynamics of the squalane monolayer and thereby assess its potential as a nanoscale lubricant. To investigate the dynamics of these monolayers they used both the disk chopper spectrometer (DCS) and the high flux backscattering spectrometer (HFBS) at the National Institute of Standards and Technology. These instruments made it possible to study dynamical processes such as molecular diffusive motions and vibrations on very different time scales: 1-40 ps (DCS) and 0.1-4 ns (HFBS). The MD simulations were done on corresponding time scales and were used to interpret the neutron spectra. The authors found that the dynamics of the two monolayers are qualitatively similar on the respective time scales and that there are only small quantitative differences that can be understood in terms of the different masses and moments of inertia of the two molecules. In the course of this study, the authors developed a procedure to separate out the low-frequency vibrational modes in the spectra, thereby facilitating an analysis of the quasielastic scattering. They conclude that there are no major differences in the monolayer dynamics caused by intramolecular branching. It remains to be seen whether this similarity in monolayer dynamics also holds for the lubricating properties of these molecules in confined geometries.

Vibrations of micro-eV energies in nanocrystalline microstructures.

The phonon density of states of nanocrystalline bcc Fe and nanocrystalline fcc Ni3Fe were measured by inelastic neutron scattering in two different ranges of energy. As has been reported previously, the nanocrystalline materials showed enhancements in their phonon density of states at energies from 2 to 15 meV, compared to control samples composed of large crystals. The present measurements were extended to energies in the micro-eV range, and showed significant, but smaller, enhancements in the number of modes in the energy range from 5 to 18 microeV. These modes of micro-eV energies provide a long-wavelength limit that bounds the fraction of modes at milli-eV energies originating with the cooperative dynamics of the nanocrystalline microstructure.

Intramolecular diffusive motion in alkane monolayers studied by high-resolution quasielastic neutron scattering and molecular dynamics simulations.

Molecular dynamics simulations of a tetracosane (n-C24H50) monolayer adsorbed on a graphite basal-plane surface show that there are diffusive motions associated with the creation and annihilation of gauche defects occurring on a time scale of approximately 0.1-4 ns. We present evidence that these relatively slow motions are observable by high-energy-resolution quasielastic neutron scattering (QNS) thus demonstrating QNS as a technique, complementary to nuclear magnetic resonance, for studying conformational dynamics on a nanosecond time scale in molecular monolayers.

The inverse relationship between protein dynamics and thermal stability.

Protein powders that are dehydrated or mixed with a glassy compound are known to have improved thermal stability. We present elastic and quasielastic neutron scattering measurements of the global dynamics of lysozyme and ribonuclease A powders. In the absence of solvation water, both protein powders exhibit largely harmonic motions on the timescale of the measurements. Upon partial hydration, quasielastic scattering indicative of relaxational processes appears at sufficiently high temperature. When the scattering spectrum are analyzed with the Kohlrausch-Williams-Watts formalism, the exponent beta decreases with increasing temperature, suggesting that multiple relaxation modes are emerging. When lysozyme was mixed with glycerol, its beta values were higher than the hydrated sample at comparable temperatures, reflecting the viscosity and stabilizing effects of glycerol.

Molecular dynamics of solid-state lysozyme as affected by glycerol and water: a neutron scattering study.

Glycerol has been shown to lower the heat denaturation temperature (T(m)) of dehydrated lysozyme while elevating the T(m) of hydrated lysozyme (. J. Pharm. Sci. 84:707-712). Here, we report an in situ elastic neutron scattering study of the effect of glycerol and hydration on the internal dynamics of lysozyme powder. Anharmonic motions associated with structural relaxation processes were not detected for dehydrated lysozyme in the temperature range of 40 to 450K. Dehydrated lysozyme was found to have the highest T(m) by. Upon the addition of glycerol or water, anharmonicity was recovered above a dynamic transition temperature (T(d)), which may contribute to the reduction of T(m) values for dehydrated lysozyme in the presence of glycerol. The greatest degree of anharmonicity, as well as the lowest T(d), was observed for lysozyme solvated with water. Hydrated lysozyme was also found to have the lowest T(m) by. In the regime above T(d), larger amounts of glycerol lead to a higher rate of change in anharmonic motions as a function of temperature, rendering the material more heat labile. Below T(d), where harmonic motions dominate, the addition of glycerol resulted in a lower amplitude of motions, correlating with a stabilizing effect of glycerol on the protein.

A view of dynamics changes in the molten globule-native folding step by quasielastic neutron scattering.

In order to understand the changes in protein dynamics that occur in the final stages of protein folding, we have used neutron scattering to probe the differences between a protein in its folded state and the molten globule states. The internal dynamics of bovine alpha-lactalbumin (BLA) and its molten globules (MBLA) have been examined using incoherent, quasielastic neutron scattering (IQNS). The IQNS results show length scale dependent, pico-second dynamics changes on length scales from 3.3 to 60 A studied. On shorter-length scales, the non-exchangeable protons undergo jump motions over potential barriers, as those involved in side-chain rotamer changes. The mean potential barrier to local jump motions is higher in BLA than in MBLA, as might be expected. On longer length scales, the protons undergo spatially restricted diffusive motions with the diffusive motions being more restricted in BLA than in MBLA. Both BLA and MBLA have similar mean square amplitudes of high frequency motions comparable to the chemical bond vibrational motions. Bond vibrational motions thus do not change significantly upon folding. Interestingly, the quasielastic scattering intensities show pronounced maxima for both BLA and MBLA, suggesting that "clusters" of atoms are moving collectively within the proteins on picosecond time scales. The correlation length, or "the cluster size", of such atom clusters moving collectively is dramatically reduced in the molten globules with the correlation length being 6.9 A in MBLA shorter than that of 18 A in BLA. Such collective motions may be important for the stability of the folded state, and may influence the protein folding pathways from the molten globules.

Use of transgenic animals for carcinogenicity testing: considerations and implications for risk assessment.

Advances in genetic engineering have created opportunities for improved understanding of the molecular basis of carcinogenesis. Through selective introduction, activation, and inactivation of specific genes, investigators can produce mice of unique genotypes and phenotypes that afford insights into the events and mechanisms responsible for tumor formation. It has been suggested that such animals might be used for routine testing of chemicals to determine their carcinogenic potential because the animals may be mechanistically relevant for understanding and predicting the human response to exposure to the chemical being tested. Before transgenic and knockout mice can be used as an adjunct or alternative to the conventional 2-year rodent bioassay, information related to the animal line to be used, study design, and data analysis and interpretation must be carefully considered. Here, we identify and review such information relative to Tg.AC and rasH2 transgenic mice and p53+/- and XPA-/- knockout mice, all of which have been proposed for use in chemical carcinogenicity testing. In addition, the implications of findings of tumors in transgenic and knockout animals when exposed to chemicals is discussed in the context of human health risk assessment.

Joint deformity and dysfunction: a basic review of underlying mechanisms.

Five common examples of joint deformity or dysfunction were presented. In each case, abnormal biomechanics were caused by or associated with arthritis or arthrosis due to advanced age or overused joints. The principles described for each example can be applied to essentially all synovial joints in the body. Understanding the underlying pathologic and biomechanical mechanisms that cause joint dysfunction can enhance treatment and patient education programs.

An electromyographic study of the hip abductor muscles as subjects with a hip prosthesis walked with different methods of using a cane and carrying a load.

BACKGROUND AND PURPOSE: Certain methods of carrying handheld loads or using a cane can reduce the demands placed on the hip abductor (HA) muscles and the loads on the underlying prosthetic hip. In certain conditions, unusually large forces from the HA muscles may contribute to premature loosening of a prosthetic hip. The purpose of this study was to examine HA use by measuring the amplitude of the electromyographic (EMG) signal from the HA muscles as subjects carried a load and simultaneously used a cane. SUBJECTS: Twenty-four active subjects (mean age = 63.3 years, SD = 10.7, range = 40-86) with a unilateral prosthetic hip were tested. METHODS: The HA muscle surface EMG activity was analyzed as subjects carried loads weighing 5%, 10%, or 15% of body weight held by either their contralateral or ipsilateral arm relative to their prosthetic hip. They simultaneously used a cane with their free hand. RESULTS: The contralateral cane and ipsilateral load conditions produced HA muscle EMG activity that was approximately 40% less than the EMG activity produced while walking without carrying a load or using a cane. CONCLUSION AND DISCUSSION: People who are in danger of premature loosening of their prosthetic hip should, if possible, avoid carrying loads. If a load must be carried, however, then the contralateral cane and ipsilateral load condition appears to minimize the loads placed on the prosthetic hip due to HA muscle activity.

Hip abductor muscle activity as subjects with hip prostheses walk with different methods of using a cane.

BACKGROUND AND PURPOSE: Using a cane held contralateral to a prosthetic hip is presumed to be an effective way to reduce the demands on the hip abductor (HA) muscles and, therefore, the forces on the implant. In this study, surface electromyographic (EMG) activity was measured from the HA muscles to test this notion. SUBJECTS: Twenty-four active subjects (9 female, 15 male) with unilateral prosthetic hips were tested. The subjects, aged 40 to 86 years (mean = 63.3, SD = 10.7), were not regular cane users. METHODS: Surface EMG activity and cane force were analyzed while the subjects walked with the cane held (1) contralateral to the prosthesis (CL-CANE), (2) ipsilateral to the prosthesis (IL-CANE), and (3) contralateral to the prosthesis with instructions for the subject to push with a "near-maximal effort" (CL-CANE+). RESULTS: Only the following conditions showed a change in HA muscle EMG activity as compared with not using a cane: CL-CANE = -31.1%, CL-CANE+ = -42.3%. CONCLUSION AND DISCUSSION: Holding the cane contralateral to the prosthetic hip appears to be an effective method of reducing demands on the HA muscles.

Topics in cancer risk assessment.

The estimation of carcinogenic risks from exposure to chemicals has become an integral part of the regulatory process in the United States within the past decade. With it have come considerable controversy and debate over the scientific merits and shortcomings of the methods and their impact on risk management decisions. In this paper we highlight selected topics of current interest in the debate. As an indication of the level of public concern, we note the major recent reports on risk assessment from the National Academy of Sciences and the U.S Environmental Protection Agency's proposed substantial revisions to its Guidelines for Carcinogen Risk Assessment. We identify and briefly frame several key scientific issues in cancer risk assessment, including the growing recognition of the importance of understanding the mode of action of carcinogenesis in experimental animals and in humans, the methodologies and challenges in quantitative extrapolation of cancer risks, and the question of how to assess and account for human variability in susceptibility to carcinogens. In addition, we discuss initiatives in progress that may fundamentally alter the carcinogenesis testing paradigm.

Accounting for susceptibility in risk assessment: current practice and new directions.

Differences in susceptibility between individuals can lead to variability in response to chemical exposures which in turn modify the risk of illness. As a means of exploring the basis for such differences in susceptibility, a project was undertaken to determine what data were available on the range of response variability for several health effects: neurotoxicity, reproductive/developmental toxicity, pulmonary toxicity, and cancer. In addition, modeling approaches for characterizing response variability were examined and evaluated. The main goal of this effort was to determine whether human response variability was adequately accounted for in the current risk assessment procedures for human health effects. The conclusions of the project were that few data are available, both because variability has rarely been the primary focus of study, and because data are not usually reported in such a way that response variability can be determined. Several recommendations were made to facilitate better characterization of interindividual variability, including the study of variability in available human data (e.g. the NHANES database) and allowing greater access to raw data from epidemiologic studies. In addition, the identification of relevant biomarkers, improved understanding of sources of variability, interaction of chemical effects with other exposures or pre-existing disease, and retrospective evaluations of risk assessments were recommended. It is hoped that these recommendations will stimulate research on susceptibility and response variability and encourage the reporting of data in a way that facilitates analysis of interindividual variability in response.

Hip abductor muscle activity in persons with a hip prosthesis while carrying loads in one hand.

BACKGROUND AND PURPOSE: Carrying loads in one hand may result in the hip abductor (HA) muscles needing to generate large forces. For a person with a prosthetic hip, these forces may contribute to loosening of the implant. In this study, surface electromyography (EMG) was used to estimate the relative demands placed on the HA muscles as persons with a prosthetic hip carried loads in one hand. SUBJECTS: Twenty-five active subjects (9 female, 16 male) with a prosthetic hip participated. Subjects were aged 40 to 86 years (mean = 63.7, SD = 10.7). METHODS: Surface EMG data from the HA muscles (primarily the gluteus medius) were analyzed during mid-stance as subjects carried loads weighing 5%, 10%, and 15% of their body weight. Loads were carried in the hand opposite the side of the prosthetic hip (contralaterally held loads) or in the hand on the same side as the prosthetic hip (ipsilaterally held loads). RESULTS: Results showed that the contralaterally held loads produced greater HA muscle EMG activity levels than no-load walking. The ipsilaterally held loads produced lower HA muscle EMG activity levels than no-load walking. CONCLUSION AND DISCUSSION: These EMG data, in addition to calculations using a simple biomechanical model, suggest that persons should use caution or avoid carrying loads in the hand on the side contralateral to their prosthetic hip.

Mammary gland neoplasia.

Determining how findings of chemically induced carcinogenic effects in rodents can properly be interpreted for human health poses a continuing challenge to the risk assessment community. One approach begins by comparing and contrasting carcinogenic process in rodents and humans, identifying biologically significant similarities and differences and gaps in scientific knowledge and understanding. Russo and Russo (in this issue) use just such an approach to evaluate the current state of scientific understanding of the comparative mechanisms of mammary tumorigenesis in humans and rodents, particularly the role of reproductive hormones. This commentary describes the basis for this review and suggests some of the implications the report may have for human health risk assessment and for future research.

An electromyographic analysis of the hip abductors during load carriage: implications for hip joint protection.

Decreasing the relative force demands on the hip abductor muscles may reduce hip joint forces. The purpose of this study was to use surface electromyography (EMG) to determine the relative demand on the hip abductor muscles as subjects walked and carried single hand-held loads of multiple weights. Thirty healthy, college-aged subjects carried single hand-held loads by their side. The loads weighed between 3 and 30% of body weight. Loads were carried in a position either ipsilateral or contralateral to a given hip side. Normalized EMG (%EMG) was collected during the middle stance phase of walking. The amount of %EMG remained statistically equal to or less than the no-load EMG baseline for all ipsilateral-held loads and greater than the no-load EMG for all contralateral-held loads above 3% body weight. Load positions and weights that generated %EMG levels less than or equal to the no-load baseline most likely offer a degree of hip joint protection for persons with hip disability.

Long-term correlates of childhood sexual abuse in adult survivors.

Empirical research demonstrates a relationship between history of child sexual abuse and numerous psychological, interpersonal, and behavioral problems in adults. Long-term correlates and theoretical conceptualizations of these sequelae are described.