Predictions of structural elements for the binding of Hin recombinase with the hix site of DNA

Molecular dynamics simulations were coupled with experimental data from biochemistry and genetics to generate a theoretical structure for the binding domain of Hin recombinase complexed with the hix site of DNA. The theoretical model explains the observed sequence specificity of Hin recombinase and leads to a number of testable predictions concerning altered sequence selectivity for various mutants of protein and DNA. Combining molecular dynamics simulations with constraints based on current knowledge of protein structure leads to a theoretical structure of the binding domain of Hin recombinase with the hix site of DNA. The model offers a mechanistic explanation of the presently known characteristics of Hin and predicts the effects of specific mutations of both protein and DNA. The predictions can be tested by currently feasible experiments that should lead to refinements in and improvements on the current theoretical model. Because current experimental and theoretical methods are all limited to providing only partial information about protein-DNA interactions, we believe that this approach of basing molecular simulations on experimental knowledge and using the results of these simulations to design new, more precise experimental tests will be of general utility. These results provide additional evidence for the generality of the helix-turn-helix motif in DNA recognition and stabilization of proteins on DNA

Linking the National Medical Expenditure Survey with the National Health Interview Survey: analysis of field trials

[by Nancy A. Mathiowetz and E. Patrick Ward]."September 1987."Includes bibliographical references

The Cannell Legacy

Charles Cannell engineered the study of Interviewer-respondent interaction. He created conceptual frameworks for understanding the interviewing process and its impact on data quality. He invented methods for observing and recording interview interaction. He pioneered the use of randomized experiments in the survey context. He amalgamated insights from clinical and social psychology, sociology, group dynamics, as well as research on verbal and nonverbal communication to inform his work. This interdisciplinary approach has broadly influenced both interviewing research and practice. In this paper, we review Cannell’s many contributions to the field and his enduring legacy

The Cannell Legacy

Charles Cannell engineered the study of Interviewer-respondent interaction. He created conceptual frameworks for understanding the interviewing process and its impact on data quality. He invented methods for observing and recording interview interaction. He pioneered the use of randomized experiments in the survey context. He amalgamated insights from clinical and social psychology, sociology, group dynamics, as well as research on verbal and nonverbal communication to inform his work. This interdisciplinary approach has broadly influenced both interviewing research and practice. In this paper, we review Cannell’s many contributions to the field and his enduring legacy

The Cannell Legacy

Charles Cannell engineered the study of Interviewer-respondent interaction. He created conceptual frameworks for understanding the interviewing process and its impact on data quality. He invented methods for observing and recording interview interaction. He pioneered the use of randomized experiments in the survey context. He amalgamated insights from clinical and social psychology, sociology, group dynamics, as well as research on verbal and nonverbal communication to inform his work. This interdisciplinary approach has broadly influenced both interviewing research and practice. In this paper, we review Cannell’s many contributions to the field and his enduring legacy

The Cannell Legacy

Charles Cannell engineered the study of Interviewer-respondent interaction. He created conceptual frameworks for understanding the interviewing process and its impact on data quality. He invented methods for observing and recording interview interaction. He pioneered the use of randomized experiments in the survey context. He amalgamated insights from clinical and social psychology, sociology, group dynamics, as well as research on verbal and nonverbal communication to inform his work. This interdisciplinary approach has broadly influenced both interviewing research and practice. In this paper, we review Cannell’s many contributions to the field and his enduring legacy

Group Vibrational Mode Assignments as a Broadly Applicable Tool for Characterizing Ionomer Membrane Structure as a Function of Degree of Hydration

Infrared spectra of Nafion, Aquivion, and the 3M membrane were acquired during total dehydration of fully hydrated samples. Fully hydrated exchange sites are in a sulfonate form with a C₃V local symmetry. The mechanical coupling of the exchange site to a side chain ether link gives rise to vibrational group modes that are classified as C₃V modes. These mode intensities diminish concertedly with dehydration. When totally dehydrated, the sulfonic acid form of the exchange site is mechanically coupled to an ether link with no local symmetry. This gives rise to C₁ group modes that emerge at the expense of C₃V modes during dehydration. Membrane IR spectra feature a total absence of C₃V modes when totally dehydrated, overlapping C₁ and C₃V modes when partially hydrated, and a total absence of C₁ modes when fully hydrated. DFT calculated normal mode analyses complemented with molecular dynamics simulations of Nafion with overall λ (λ_(Avg)) values of 1, 3, 10, 15 and 20 waters/exchange site, were sectioned into sub-cubes to enable the manual counting of the distribution of λ_(local) values that integrate to λ_(Avg) values. This work suggests that at any state of hydration, IR spectra are a consequence of a distribution of λ_(local) values. Bond distances and the threshold value of λ_(local), for exchange site dissociation, were determined by DFT modelling and used to correlate spectra to manually counted λ_(local) distributions

On-resin N-methylation of cyclic peptides for discovery of orally bioavailable scaffolds.

Backbone N-methylation is common among peptide natural products and has a substantial impact on both the physical properties and the conformational states of cyclic peptides. However, the specific impact of N-methylation on passive membrane diffusion in cyclic peptides has not been investigated systematically. Here we report a method for the selective, on-resin N-methylation of cyclic peptides to generate compounds with drug-like membrane permeability and oral bioavailability. The selectivity and degree of N-methylation of the cyclic peptide was dependent on backbone stereochemistry, suggesting that conformation dictates the regiochemistry of the N-methylation reaction. The permeabilities of the N-methyl variants were corroborated by computational studies on a 1,024-member virtual library of N-methyl cyclic peptides. One of the most permeable compounds, a cyclic hexapeptide (molecular mass = 755 Da) with three N-methyl groups, showed an oral bioavailability of 28% in rat

Multi-centre parallel arm randomised controlled trial to assess the effectiveness and cost-effectiveness of a group-based cognitive behavioural approach to managing fatigue in people with multiple sclerosis

Abstract (provisional) Background Fatigue is one of the most commonly reported and debilitating symptoms of multiple sclerosis (MS); approximately two-thirds of people with MS consider it to be one of their three most troubling symptoms. It may limit or prevent participation in everyday activities, work, leisure, and social pursuits, reduce psychological well-being and is one of the key precipitants of early retirement. Energy effectiveness approaches have been shown to be effective in reducing MS-fatigue, increasing self-efficacy and improving quality of life. Cognitive behavioural approaches have been found to be effective for managing fatigue in other conditions, such as chronic fatigue syndrome, and more recently, in MS. The aim of this pragmatic trial is to evaluate the clinical and cost-effectiveness of a recently developed group-based fatigue management intervention (that blends cognitive behavioural and energy effectiveness approaches) compared with current local practice. Methods This is a multi-centre parallel arm block-randomised controlled trial (RCT) of a six session group-based fatigue management intervention, delivered by health professionals, compared with current local practice. 180 consenting adults with a confirmed diagnosis of MS and significant fatigue levels, recruited via secondary/primary care or newsletters/websites, will be randomised to receive the fatigue management intervention or current local practice. An economic evaluation will be undertaken alongside the trial. Primary outcomes are fatigue severity, self-efficacy and disease-specific quality of life. Secondary outcomes include fatigue impact, general quality of life, mood, activity patterns, and cost-effectiveness. Outcomes in those receiving the fatigue management intervention will be measured 1 week prior to, and 1, 4, and 12 months after the intervention (and at equivalent times in those receiving current local practice). A qualitative component will examine what aspects of the fatigue management intervention participants found helpful/unhelpful and barriers to change. Discussion This trial is the fourth stage of a research programme that has followed the Medical Research Council guidance for developing and evaluating complex interventions. What makes the intervention unique is that it blends cognitive behavioural and energy effectiveness approaches. A potential strength of the intervention is that it could be integrated into existing service delivery models as it has been designed to be delivered by staff already working with people with MS. Service users will be involved throughout this research. Trial registration: Current Controlled Trials ISRCTN7651747