A Boolean Model of the Gene Regulatory Network Underlying Mammalian Cortical Area Development

The cerebral cortex is divided into many functionally distinct areas. The emergence of these areas during neural development is dependent on the expression patterns of several genes. Along the anterior-posterior axis, gradients of Fgf8, Emx2, Pax6, Coup-tfi, and Sp8 play a particularly strong role in specifying areal identity. However, our understanding of the regulatory interactions between these genes that lead to their confinement to particular spatial patterns is currently qualitative and incomplete. We therefore used a computational model of the interactions between these five genes to determine which interactions, and combinations of interactions, occur in networks that reproduce the anterior-posterior expression patterns observed experimentally. The model treats expression levels as Boolean, reflecting the qualitative nature of the expression data currently available. We simulated gene expression patterns created by all possible networks containing the five genes of interest. We found that only of these networks were able to reproduce the experimentally observed expression patterns. These networks all lacked certain interactions and combinations of interactions including auto-regulation and inductive loops. Many higher order combinations of interactions also never appeared in networks that satisfied our criteria for good performance. While there was remarkable diversity in the structure of the networks that perform well, an analysis of the probability of each interaction gave an indication of which interactions are most likely to be present in the gene network regulating cortical area development. We found that in general, repressive interactions are much more likely than inductive ones, but that mutually repressive loops are not critical for correct network functioning. Overall, our model illuminates the design principles of the gene network regulating cortical area development, and makes novel predictions that can be tested experimentally.     

Measures of Quality of Care for People with HIV: A Scoping Review of Performance Indicators for Primary Care

The healthcare of people with HIV is transitioning from specialty care to the primary healthcare (PHC) system. However, many of the performance indicators used to measure the quality of HIV care pre-date this transition. The goal of this work was to examine how existing HIV care performance indicators measure the comprehensive and longitudinal care offered in a PHC setting. A scoping review consisting of peer-reviewed and grey literature searches was performed. Two reviewers evaluated study eligibility and indicators in documents meeting inclusion criteria were extracted into a database. Indicators were matched to a PHC performance measurement framework to determine their applicability for evaluating quality of care in the PHC setting. The literature search identified 221 publications, of which 47 met inclusion criteria. 1184 indicators were extracted and removal of duplicates left 558 unique indicators. A majority of the 558 indicators fell under the ‘secondary prevention’ (12%) and ‘care of chronic conditions’ (33%) domains when indicators were matched to the PHC performance framework. Despite the imbalance, nearly all performance domains in the PHC framework were populated by at least one indicator with significant concentrations in domains such as patient-provider relationship, patient satisfaction, population and community characteristics, and access to care. Existing performance frameworks for the care of people with HIV provide a comprehensive set of indicators that align well with a PHC performance framework. Nonetheless, some important elements of care, such as patient-reported outcomes, are poorly covered by existing indicators. Advancing our understanding of how the experience of care for people with HIV is impacted by changes in health services delivery, specifically more care within the PHC system, will require performance indicators to capture this aspect of HIV care.     

Estimating the number of genetic elements that defer senescence inDrosophila

Summary Although many different physiological and biochemical changes characterize the process of senescence, little is understood of the genetic elements that determine its age of onset. We provide here the first estimates of the number of genetic factors that extend longevity inDrosophila melanogaster. Life span was measured in F₁, F₂ and backcrosses of true-breeding long and short-lived stocks ofD. melanogaster, established by selection. Estimates of the number of effective factors delaying senescence range from about 0.3 to 1.5, indicating control by a single factor. The distribution of longevity shows this to arise as selection acts on the short-lived parental stock. Life span is extended at the cost of early fecundity.     

Competition between solution and cell surface receptors for ligand. Dissociation of hapten bound to surface antibody in the presence of solution antibody.

We present a joint theoretical and experimental study on the effects of competition for ligand between receptors in solution and receptors on cell surfaces. We focus on the following experiment. After ligand and cell surface receptors equilibrate, solution receptors are introduced, and the dissociation of surface bound ligand is monitored. We derive theoretical expressions for the dissociation rate and compare with experiment. In a standard dissociation experiment (no solution receptors present) dissociation may be slowed by rebinding, i.e., at high receptor densities a ligand that dissociates from one receptor may rebind to other receptors before separating from the cell. Our theory predicts that rebinding will be prevented when S much greater than N2Kon/(16 pi 2D a4), where S is the free receptor site concentration in solution, N the number of free surface receptor sites per cell, Kon the forward rate constant for ligand-receptor binding in solution, D the diffusion coefficient of the ligand, and a the cell radius. The predicted concentration of solution receptors needed to prevent rebinding is proportional to the square of the cell surface receptor density. The experimental system used in these studies consists of a monovalent ligand, 2,4-dinitrophenyl (DNP)-aminocaproyl-L-tyrosine (DCT), that reversibly binds to a monoclonal anti-DNP immunoglobulin E (IgE). This IgE is both a solution receptor and, when anchored to its high affinity Fc epsilon receptor on rat basophilic leukemia (RBL) cells, a surface receptor. For RBL cells with 6 x 10(5) binding sites per cell, our theory predicts that to prevent DCT rebinding to cell surface IgE during dissociation requires S much greater than 2,400 nM. We show that for S = 200-1,700 nM, the dissociation rate of DCT from surface IgE is substantially slower than from solution IgE where no rebinding occurs. Other predictions are also tested and shown to be consistent with experiment.     

Base compositional structure of genomes

We model the base compositional structure of the human and Escherichia coli genomes. Three particular properties are first quantified: (1) There is a significant tendency for any region of either genome to have a strand-symmetric base composition. (2) The variation in base composition from region to region, within each genome, is very much larger than expected from common homogeneous stochastic models. (3) A given local base composition tends to persist over a scale of at least kilobases (E. coli) or tens of kilobases (human). Multidomain stochastic models from the literature are reviewed and sharpened. In particular, quantitative measurements of the third property lead us to suggest a significant shift in the style of domain models, in which the variation of A+T content with position is modeled by a random walk with frequent small steps rather than with large quantum jumps. As an application, we suggest a way to reduce the amount of computation in the assembly of large sequences from sequences of randomly chosen fragments.