Two center multipole expansion method: application to macromolecular systems

We propose a new theoretical method for the calculation of the interaction energy between macromolecular systems at large distances. The method provides a linear scaling of the computing time with the system size and is considered as an alternative to the well known fast multipole method. Its efficiency, accuracy and applicability to macromolecular systems is analyzed and discussed in detail.Comment: 23 pages, 7 figures, 1 tabl

Effects of digital engagement on the quality of life of older people

It is often asserted that older people's quality of life (QOL) is improved when they adopt information and communication technology (ICT) such as the Internet, mobile phones and computers. Similar assumptions are made about older people's use of ICT-based care such as telecare and telehealth. To examine the evidence around these claims, we conducted a scoping review of the academic and grey literature, coving the period between January 2007 and August 2014. A framework analysis approach, based on six domains of QOL derived from the ASCOT and WHOQOL models, was adopted to deductively code and analyse relevant literature. The review revealed mixed results. Older people's use of ICT in both mainstream and care contexts has been shown to have both positive and negative impacts on several aspects of QOL. Studies which have rigorously assessed the impact of older people's use of ICT on their QOL mostly demonstrate little effect. A number of qualitative studies have reported on the positive effects for older people who use ICT such as email or Skype to keep in touch with family and friends. Overall, the review unearthed several inconsistencies around the effects of older people's ICT use on their QOL, suggesting that implicit agreement is needed on the best research methods and instrumentation to adequately describe older people's experiences in today's digital age. Moreover, the available evidence does not consider the large number of older people who do not use ICT and how non-use affects QOL

Computational modeling to elucidate molecular mechanisms of epigenetic memory

How do mammalian cells that share the same genome exist in notably distinct phenotypes, exhibiting differences in morphology, gene expression patterns, and epigenetic chromatin statuses? Furthermore how do cells of different phenotypes differentiate reproducibly from a single fertilized egg? These are fundamental problems in developmental biology. Epigenetic histone modifications play an important role in the maintenance of different cell phenotypes. The exact molecular mechanism for inheritance of the modification patterns over cell generations remains elusive. The complexity comes partly from the number of molecular species and the broad time scales involved. In recent years mathematical modeling has made significant contributions on elucidating the molecular mechanisms of DNA methylation and histone covalent modification inheritance. We will pedagogically introduce the typical procedure and some technical details of performing a mathematical modeling study, and discuss future developments.Comment: 36 pages, 4 figures, 2 tables, book chapte

The case for investment in technology to manage the global costs of dementia

Worldwide growth in the number of people living with dementia will continue over the coming decades and is already putting pressure on health and care systems, both formal and informal, and on costs, both public and private. One response could be to make greater use of digital and other technologies to try to improve outcomes and contain costs. We were commissioned to examine the economic case for accelerated investment in technology that could, over time, deliver savings on the overall cost of care for people with dementia. Our short study included a rapid review of international evidence on effectiveness and cost-effectiveness of technology, consideration of the conditions for its successful adoption, and liaison with people from industry, government, academic, third sector and other sectors, and people with dementia and carers. We used modelling analyses to examine the economic case, using the UK as context. We then discussed the roles that state investment or action could play, perhaps to accelerate use of technology so as to deliver both wellbeing and economic benefits

Client-Driven Advocacy and Psychiatric Disability: A Model for Social Work Practice

This paper presents an innovative advocacy model designed to assist people coping with psychiatric disabilities to fulfill their basic living needs. The model emphasizes the importance of clients defining their own needs for advocacy and then, with the support and assistance of an advocate, taking direct action to fulfill these needs. The model is elaborated in terms of its basic attributes, the interlocking roles of both clients and advocates, the importance of the advocacy relationship, and seven core processes of advocacy. The authors conclude with a discussion of possible effects of introducing the model into social work practice in mental health settings

Nucleoid-associated proteins shape the global protein occupancy and transcriptional landscape of a clinical isolate of Vibrio cholerae.

UNLABELLED: Vibrio cholerae, the causative agent of the diarrheal disease cholera, poses an ongoing health threat due to its wide repertoire of horizontally acquired elements (HAEs) and virulence factors. New clinical isolates of the bacterium with improved fitness abilities, often associated with HAEs, frequently emerge. The appropriate control and expression of such genetic elements is critical for the bacteria to thrive in the different environmental niches they occupy. H-NS, the histone-like nucleoid structuring protein, is the best-studied xenogeneic silencer of HAEs in gamma-proteobacteria. Although H-NS and other highly abundant nucleoid-associated proteins (NAPs) have been shown to play important roles in regulating HAEs and virulence in model bacteria, we still lack a comprehensive understanding of how different NAPs modulate transcription in V. cholerae. By obtaining genome-wide measurements of protein occupancy and active transcription in a clinical isolate of V. cholerae, harboring recently discovered HAEs encoding for phage defense systems, we show that a lack of H-NS causes a robust increase in the expression of genes found in many HAEs. We further found that TsrA, a protein with partial homology to H-NS, regulates virulence genes primarily through modulation of H-NS activity. We also identified few sites that are affected by TsrA independently of H-NS, suggesting TsrA may act with diverse regulatory mechanisms. Our results demonstrate how the combinatorial activity of NAPs is employed by a clinical isolate of an important pathogen to regulate recently discovered HAEs. IMPORTANCE: New strains of the bacterial pathogen Vibrio cholerae, bearing novel horizontally acquired elements (HAEs), frequently emerge. HAEs provide beneficial traits to the bacterium, such as antibiotic resistance and defense against invading bacteriophages. Xenogeneic silencers are proteins that help bacteria harness new HAEs and silence those HAEs until they are needed. H-NS is the best-studied xenogeneic silencer; it is one of the nucleoid-associated proteins (NAPs) in gamma-proteobacteria and is responsible for the proper regulation of HAEs within the bacterial transcriptional network. We studied the effects of H-NS and other NAPs on the HAEs of a clinical isolate of V. cholerae. Importantly, we found that H-NS partners with a small and poorly characterized protein, TsrA, to help domesticate new HAEs involved in bacterial survival and in causing disease. A proper understanding of the regulatory state in emerging isolates of V. cholerae will provide improved therapies against new isolates of the pathogen

No Beginning and No End: A Study of the Emergency Room as a Social System

http://deepblue.lib.umich.edu/bitstream/2027.42/50883/1/106.pd

Optimal Reaction Coordinates

The dynamic behavior of complex systems with many degrees of freedom is often analyzed by projection onto one or a few reaction coordinates. The dynamics is then described in a simple and intuitive way as diffusion on the associated free energy pro le. In order to use such a picture for a quantitative description of the dynamics one needs to select the coordinate in an optimal way so as to minimize non-Markovian effects due to the projection. For equilibrium dynamics between two boundary states (e.g., a reaction) the optimal coordinate is known as the committor or the pfold coordinate in protein folding studies. While the dynamics projected on the committor is not Markovian, many important quantities of the original multidimensional dynamics on an arbitrarily complex landscape can be computed exactly. Here we summarize the derivation of this result, discuss different approaches to determine and validate the committor coordinate and present three illustrative applications: protein folding, the game of chess, and patient recovery dynamics after kidney transplant

Stochastic tuning of gene expression enables cellular adaptation in the absence of pre-existing regulatory circuitry

Cells adapt to familiar changes in their environment by activating predefined regulatory programs that establish adaptive gene expression states. These hard-wired pathways, however, may be inadequate for adaptation to environments never encountered before. Here, we reveal evidence for an alternative mode of gene regulation that enables adaptation to adverse conditions without relying on external sensory information or genetically predetermined cis-regulation. Instead, individual genes achieve optimal expression levels through a stochastic search for improved fitness. By focusing on improving the overall health of the cell, the proposed stochastic tuning mechanism discovers global gene expression states that are fundamentally new and yet optimized for novel environments. We provide experimental evidence for stochastic tuning in the adaptation of Saccharomyces cerevisiae to laboratory-engineered environments that are foreign to its native gene-regulatory network. Stochastic tuning operates locally at individual gene promoters, and its efficacy is modulated by perturbations to chromatin modification machinery

Stereochemical errors and their implications for molecular dynamics simulations

<p>Abstract</p> <p>Background</p> <p>Biological molecules are often asymmetric with respect to stereochemistry, and correct stereochemistry is essential to their function. Molecular dynamics simulations of biomolecules have increasingly become an integral part of biophysical research. However, stereochemical errors in biomolecular structures can have a dramatic impact on the results of simulations.</p> <p>Results</p> <p>Here we illustrate the effects that chirality and peptide bond configuration flips may have on the secondary structure of proteins throughout a simulation. We also analyze the most common sources of stereochemical errors in biomolecular structures and present software tools to identify, correct, and prevent stereochemical errors in molecular dynamics simulations of biomolecules.</p> <p>Conclusions</p> <p>Use of the tools presented here should become a standard step in the preparation of biomolecular simulations and in the generation of predicted structural models for proteins and nucleic acids.</p