Evaluating evolution as a learning algorithm

We interpret the Moran model of natural selection and drift as an algorithm for learning features of a simplified fitness landscape, specifically genotype superiority. This algorithm's efficiency in extracting these characteristics is evaluated by comparing it to a novel Bayesian learning algorithm developed using information-theoretic tools. This algorithm makes use of a communication channel analogy between an environment and an evolving population. We use the associated channel-rate to determine an informative population-sampling procedure. We find that the algorithm can identify genotype superiority faster than the Moran model but at the cost of larger fluctuations in uncertainty

An Agent-Based Model of Signal Transduction in Bacterial Chemotaxis

We report the application of agent-based modeling to examine the signal transduction network and receptor arrays for chemotaxis in Escherichia coli, which are responsible for regulating swimming behavior in response to environmental stimuli. Agent-based modeling is a stochastic and bottom-up approach, where individual components of the modeled system are explicitly represented, and bulk properties emerge from their movement and interactions. We present the Chemoscape model: a collection of agents representing both fixed membrane-embedded and mobile cytoplasmic proteins, each governed by a set of rules representing knowledge or hypotheses about their function. When the agents were placed in a simulated cellular space and then allowed to move and interact stochastically, the model exhibited many properties similar to the biological system including adaptation, high signal gain, and wide dynamic range. We found the agent based modeling approach to be both powerful and intuitive for testing hypotheses about biological properties such as self-assembly, the non-linear dynamics that occur through cooperative protein interactions, and non-uniform distributions of proteins in the cell. We applied the model to explore the role of receptor type, geometry and cooperativity in the signal gain and dynamic range of the chemotactic response to environmental stimuli. The model provided substantial qualitative evidence that the dynamic range of chemotactic response can be traced to both the heterogeneity of receptor types present, and the modulation of their cooperativity by their methylation state

Processes of Change in an Asthma Self-Care Intervention

The final version of this paper has been published in Qualitative Health Research, Vol. 23 (10), October 2013 by SAGE Publications Ltd, All rights reserved. © It is available at: http://qhr.sagepub.com/content/23/10/1419.longIn this article, we present a qualitative exploration of the psychological and communication processes that occur within an intervention to improve self-care for people with asthma. In the context of a primary-care-based trial of the intervention, we collected data at three time points for 21 patients, comprising 2 audiotaped consultations (nurse and patient together) and individual semistructured interviews 3 months after the second consultation. Using framework analysis, we identified both psychological processes (illness understanding, affective response to asthma, and reasoned motivation) and patientGÇôprovider interactions (active patient involvement and individual tailoring). We use these findings to extend and refine the pre-existing theoretical model of behavior change underpinning the intervention, in particular with relation to patientGÇôprovider interaction processes. We conclude that it is important for developers and providers of asthma self-care interventions to attend to the style of delivery as well as the behavior change techniques involved

Therapeutic concentrations of glucagon-like peptide-1 in cerebrospinal fluid following cell-based delivery into the cerebral ventricles of cats

<p>Abstract</p> <p>Background</p> <p>Neuropeptides may have considerable potential in the treatment of acute and chronic neurological diseases. Encapsulated genetically engineered cells have been suggested as a means for sustained local delivery of such peptides to the brain. In our experiments, we studied human mesenchymal stem cells which were transfected to produce glucagon-like peptide-1 (GLP-1).</p> <p>Methods</p> <p>Cells were packed in a water-permeable mesh bag containing 400 polymeric microcapsules, each containing 3000 cells. The mesh bags were either transplanted into the subdural space, into the brain parenchyma or into the cerebral ventricles of the cat brain. Mesh bags were explanted after two weeks, and cell viability, as well as GLP-1 concentration in the cerebrospinal fluid (CSF), was measured.</p> <p>Results</p> <p>Viability of cells did not significantly differ between the three implantation sites. However, CSF concentration of GLP-1 was significantly elevated only after ventricular transplantation with a maximum concentration of 73 pM (binding constant = 70 pM).</p> <p>Conclusions</p> <p>This study showed that ventricular cell-based delivery of soluble factors has the capability to achieve concentrations in the CSF which may become pharmacologically active. Despite the controversy about the pharmacokinetic limitations of ventricular drug delivery, there might be a niche in this for encapsulated cell biodelivery of soluble, highly biologically-effective neuropeptides of low molecular weight like GLP-1.</p

Advance Care Planning as a Shared Endeavor: Completion of ACP Documents in a Multidisciplinary Cancer Program

Objective—We examined the roles of oncology providers in advance care planning (ACP) delivery in the context of a multidisciplinary cancer program. Methods—Semi-structured interviews were conducted with 200 women with recurrent and/or metastatic breast or gynecologic cancer. Participants were asked to name providers they deemed important in their cancer care and whether they had discussed and/or completed ACP documentation. Evidence of ACP documentation was obtained from chart reviews. Results—Fifty percent of participants self-reported completing an advance directive (AD) and 48.5% had named a healthcare power of attorney (HPA), 38.5% had completed both, and 39.0% had completed neither document. Among women who self-reported completion of the documents, only 24.0% and 14.4% of women respectively had documentation of an AD and HPA in their chart. Completion of an AD was associated with number (adjusted odds ratio [AOR] = 1.49) and percentage (AOR = 6.58) of providers with whom the participant had a conversation about end-of-life decisions. Participants who named a social worker or nurse practitioner were more likely to report having completed an AD. Participants who named at least one provider in common (e.g., named the same oncologist) were more likely to have comparable behaviors related to naming a HPA (AOR = 1.13, p = 0.011) and completion of an AD (AOR = 1.06, p = 0.114). Conclusions—Despite the important role of physicians in facilitating ACP discussions, involvement of other staff was associated with a greater likelihood of completion of ACP documentation. Patients may benefit from opportunities to discuss ACP with multiple members of their cancer care team

Amyloid-beta transporter expression at the blood-CSF barrier is age-dependent

<p>Abstract</p> <p>Background</p> <p>Age is the major risk factor for many neurodegenerative diseases, including Alzheimer's disease (AD). There is an accumulation of amyloid-beta peptides (Aβ) in both the AD brain and the normal aging brain. Clearance of Aβ from the brain occurs via active transport at the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB). With increasing age, the expression of the Aβ efflux transporters is decreased and the Aβ influx transporter expression is increased at the BBB, adding to the amyloid burden in the brain. Expression of the Aβ transporters at the choroid plexus (CP) epithelium as a function of aging was the subject of this study.</p> <p>Methods</p> <p>This project investigated the changes in expression of the Aβ transporters, the low density lipoprotein receptor-related protein-1 (LRP-1), P-glycoprotein (P-gp), LRP-2 (megalin) and the receptor for advanced glycation end-products (RAGE) at the BCSFB in Brown-Norway/Fischer rats at ages 3, 6, 9, 12, 20, 30 and 36 months, using real time RT-PCR to measure transporter mRNA expression, and immunohistochemistry (IHC) to measure transporter protein in isolated rat CP.</p> <p>Results</p> <p>There was an increase in the transcription of the Aβ efflux transporters, LRP-1 and P-gp, no change in RAGE expression and a decrease in LRP-2, the CP epithelium influx transporter, at the BCSFB with aging. Decreased Aβ42 concentration in the CP, as measured by quantitative IHC, was associated with these Aβ transporter alterations.</p> <p>Conclusions</p> <p>Age-dependent alterations in the CP Aβ transporters are associated with a decrease in Aβ42 accumulation in the CP, and are reciprocal to the changes seen in these transporters at the BBB, suggesting a possible compensatory role for the BCSFB in Aβ clearance in aging.</p

Temporal course of cerebrospinal fluid dynamics and amyloid accumulation in the aging rat brain from three to thirty months

<p>Abstract</p> <p>Background</p> <p>Amyloid accumulation in the brain parenchyma is a hallmark of Alzheimer's disease (AD) and is seen in normal aging. Alterations in cerebrospinal fluid (CSF) dynamics are also associated with normal aging and AD. This study analyzed CSF volume, production and turnover rate in relation to amyloid-beta peptide (Aβ) accumulation in the aging rat brain.</p> <p>Methods</p> <p>Aging Fischer 344/Brown-Norway hybrid rats at 3, 12, 20, and 30 months were studied. CSF production was measured by ventriculo-cisternal perfusion with blue dextran in artificial CSF; CSF volume by MRI; and CSF turnover rate by dividing the CSF production rate by the volume of the CSF space. Aβ40 and Aβ42 concentrations in the cortex and hippocampus were measured by ELISA.</p> <p>Results</p> <p>There was a significant linear increase in total cranial CSF volume with age: 3-20 months (<it>p </it>< 0.01); 3-30 months (<it>p </it>< 0.001). CSF production rate increased from 3-12 months (<it>p </it>< 0.01) and decreased from 12-30 months (<it>p </it>< 0.05). CSF turnover showed an initial increase from 3 months (9.40 day^-1) to 12 months (11.30 day^-1) and then a decrease to 20 months (10.23 day^-1) and 30 months (6.62 day^-1). Aβ40 and Aβ42 concentrations in brain increased from 3-30 months (<it>p </it>< 0.001). Both Aβ42 and Aβ40 concentrations approached a steady state level by 30 months.</p> <p>Conclusions</p> <p>In young rats there is no correlation between CSF turnover and Aβ brain concentrations. After 12 months, CSF turnover decreases as brain Aβ continues to accumulate. This decrease in CSF turnover rate may be one of several clearance pathway alterations that influence age-related accumulation of brain amyloid.</p

Consumption caught in the cash nexus.

During the last thirty years, ‘consumption’ has become a major topic in the study of contemporary culture within anthropology, psychology and sociology. For many authors it has become central to understanding the nature of material culture in the modern world but this paper argues that the concept is, in British writing at least, too concerned with its economic origins in the selling and buying of consumer goods or commodities. It is argued that to understand material culture as determined through the monetary exchange for things - the cash nexus - leads to an inadequate sociological understanding of the social relations with objects. The work of Jean Baudrillard is used both to critique the concept of consumption as it leads to a focus on advertising, choice, money and shopping and to point to a more sociologically adequate approach to material culture that explores objects in a system of models and series, ‘atmosphere’, functionality, biography, interaction and mediation

Issues in the Pharmacokinetics of Trichloroethylene and Its Metabolites

Much progress has been made in understanding the complex pharmacokinetics of trichloroethylene (TCE). Qualitatively, it is clear that TCE is metabolized to multiple metabolites either locally or into systemic circulation. Many of these metabolites are thought to have toxicologic importance. In addition, efforts to develop physiologically based pharmacokinetic (PBPK) models have led to a better quantitative assessment of the dosimetry of TCE and several of its metabolites. As part of a mini-monograph on key issues in the health risk assessment of TCE, this article is a review of a number of the current scientific issues in TCE pharmacokinetics and recent PBPK modeling efforts with a focus on literature published since 2000. Particular attention is paid to factors affecting PBPK modeling for application to risk assessment. Recent TCE PBPK modeling efforts, coupled with methodologic advances in characterizing uncertainty and variability, suggest that rigorous application of PBPK modeling to TCE risk assessment appears feasible at least for TCE and its major oxidative metabolites trichloroacetic acid and trichloroethanol. However, a number of basic structural hypotheses such as enterohepatic recirculation, plasma binding, and flow- or diffusion-limited treatment of tissue distribution require additional evaluation and analysis. Moreover, there are a number of metabolites of potential toxicologic interest, such as chloral, dichloroacetic acid, and those derived from glutathione conjugation, for which reliable pharmacokinetic data is sparse because of analytical difficulties or low concentrations in systemic circulation. It will be a challenge to develop reliable dosimetry for such cases