A Computational Approach to Estimating Nondisjunction Frequency in Saccharomyces cerevisiae.

Errors segregating homologous chromosomes during meiosis result in aneuploid gametes and are the largest contributing factor to birth defects and spontaneous abortions in humans. Saccharomyces cerevisiae has long served as a model organism for studying the gene network supporting normal chromosome segregation. Measuring homolog nondisjunction frequencies is laborious, and involves dissecting thousands of tetrads to detect missegregation of individually marked chromosomes. Here we describe a computational method (TetFit) to estimate the relative contributions of meiosis I nondisjunction and random-spore death to spore inviability in wild type and mutant strains. These values are based on finding the best-fit distribution of 4, 3, 2, 1, and 0 viable-spore tetrads to an observed distribution. Using TetFit, we found that meiosis I nondisjunction is an intrinsic component of spore inviability in wild-type strains. We show proof-of-principle that the calculated average meiosis I nondisjunction frequency determined by TetFit closely matches empirically determined values in mutant strains. Using these published data sets, TetFit uncovered two classes of mutants: Class A mutants skew toward increased nondisjunction death, and include those with known defects in establishing pairing, recombination, and/or synapsis of homologous chromosomes. Class B mutants skew toward random spore death, and include those with defects in sister-chromatid cohesion and centromere function. Epistasis analysis using TetFit is facilitated by the low numbers of tetrads (as few as 200) required to compare the contributions to spore death in different mutant backgrounds. TetFit analysis does not require any special strain construction, and can be applied to previously observed tetrad distributions

Network Mendelian randomization: using genetic variants as instrumental variables to investigate mediation in causal pathways.

BACKGROUND: Mendelian randomization uses genetic variants, assumed to be instrumental variables for a particular exposure, to estimate the causal effect of that exposure on an outcome. If the instrumental variable criteria are satisfied, the resulting estimator is consistent even in the presence of unmeasured confounding and reverse causation. METHODS: We extend the Mendelian randomization paradigm to investigate more complex networks of relationships between variables, in particular where some of the effect of an exposure on the outcome may operate through an intermediate variable (a mediator). If instrumental variables for the exposure and mediator are available, direct and indirect effects of the exposure on the outcome can be estimated, for example using either a regression-based method or structural equation models. The direction of effect between the exposure and a possible mediator can also be assessed. Methods are illustrated in an applied example considering causal relationships between body mass index, C-reactive protein and uric acid. RESULTS: These estimators are consistent in the presence of unmeasured confounding if, in addition to the instrumental variable assumptions, the effects of both the exposure on the mediator and the mediator on the outcome are homogeneous across individuals and linear without interactions. Nevertheless, a simulation study demonstrates that even considerable heterogeneity in these effects does not lead to bias in the estimates. CONCLUSIONS: These methods can be used to estimate direct and indirect causal effects in a mediation setting, and have potential for the investigation of more complex networks between multiple interrelated exposures and disease outcomes

A Formative Evaluation of the Children, Youth, and Families at Risk Coaching Model

In this article, we describe the results of a formative evaluation of a coaching model designed to support recipients of funding through the Children, Youth, and Families at Risk (CYFAR) initiative. Results indicate that CYFAR coaches draw from a variety of types of coaching and that CYFAR principle investigators (PIs) are generally satisfied with the coaches\u27 methods. Areas in which PIs would like to see changes to the coaching model include amount of technical coaching and amount of help with specific CYFAR funding requirements. We review strategies for incorporating this feedback into practice and discuss implications for CYFAR and for Extension in general

Applying Coaching Strategies to Support Youth- and Family-Focused Extension Programming

In this article, we describe how a peer-coaching model has been applied to support community-based Extension programming through the Children, Youth, and Families at Risk (CYFAR) initiative. We describe the general approaches to coaching that have been used to help with CYFAR program implementation, evaluation, and sustainability efforts; we discuss strategies coaches use to maintain effective relationships with CYFAR stakeholders; and we review common characteristics of effective coaches. Finally, we discuss implications that coaching strategies might have for Extension programming in general and present future directions for research and practice related to peer coaching

Warped Tachyonic Inflation in Type IIB Flux Compactifications and the Open-String Completeness Conjecture

We consider a cosmological scenario within the KKLT framework for moduli stabilization in string theory. The universal open string tachyon of decaying non-BPS D-brane configurations is proposed to drive eternal topological inflation. Flux-induced `warping' can provide the small slow-roll parameters needed for successful inflation. Constraints on the parameter space leading to sufficient number of e-folds, exit from inflation, density perturbations and stabilization of the Kahler modulus are investigated. The conditions are difficult to satisfy in Klebanov-Strassler throats but can be satisfied in T^3 fibrations and other generic Calabi-Yau manifolds. This requires large volume and magnetic fluxes on the D-brane. The end of inflation may or may not lead to cosmic strings depending on the original non-BPS configuration. A careful investigation of initial conditions leading to a phenomenologically viable model for inflation is carried out. The initial conditions are chosen on the basis of Sen's open string completeness conjecture. We find time symmetrical bounce solutions without initial singularities for k=1 FRW models which are correlated with an inflationary period. Singular big-bang/big-crunch solutions also exist but do not lead to inflation. There is an intriguing correlation between having an inflationary universe in 4 dimensions and 6 compact dimensions or a big-crunch singularity and decompactification.Comment: 43 pages, 9 figures. v3: Typos correcte

On the symmetry of the vacuum in theories with spontaneous symmetry breaking

We review the usual account of the phenomena of spontaneous symmetry breaking (SSB), pointing out the common misunderstandings surrounding the issue, in particular within the context of quantum field theory. In fact, the common explanations one finds in this context, indicate that under certain conditions corresponding to the situation called SSB, the vacuum of the theory does not share the symmetries of the Lagrangian. We explain in detail why this statement is incorrect in general, and in what limited set of circumstances such situation could arise. We concentrate on the case of global symmetries, for which we found no satisfactory exposition in the existing literature, and briefly comment on the case of gauge symmetries where, although insufficiently publicized, accurate and complete descriptions exist. We briefly discuss the implications for the phenomenological manifestations usually attributed to the phenomena of spontaneous symmetry breaking, analyzing which might be affected by our analysis and which are not. In particular we describe the mass generation mechanism in a fully symmetric scheme (i.e., with a totally symmetric vacuum), and briefly discuss the implications of this analysis to the problem of formation of topological defects in the early universe

Gene Profiling of Aortic Valve Interstitial Cells under Elevated Pressure Conditions: Modulation of Inflammatory Gene Networks

The study aimed to identify mechanosensitive pathways and gene networks that are stimulated by elevated cyclic pressure in aortic valve interstitial cells (VICs) and lead to detrimental tissue remodeling and/or pathogenesis. Porcine aortic valve leaflets were exposed to cyclic pressures of 80 or 120 mmHg, corresponding to diastolic transvalvular pressure in normal and hypertensive conditions, respectively. Linear, two-cycle amplification of total RNA, followed by microarray was performed for transcriptome analysis (with qRT-PCR validation). A combination of systems biology modeling and pathway analysis identified novel genes and molecular mechanisms underlying the biological response of VICs to elevated pressure. 56 gene transcripts related to inflammatory response mechanisms were differentially expressed. TNF-α, IL-1α, and IL-1β were key cytokines identified from the gene network model. Also of interest was the discovery that pentraxin 3 (PTX3) was significantly upregulated under elevated pressure conditions (41-fold change). In conclusion, a gene network model showing differentially expressed inflammatory genes and their interactions in VICs exposed to elevated pressure has been developed. This system overview has detected key molecules that could be targeted for pharmacotherapy of aortic stenosis in hypertensive patients

Rendering an Account: An Open-State Archive in Postgraduate Supervision

The paper begins with a brief account of the transformation of research degree studies under the pressures of global capitalism and neo-liberal governmentality. A parallel transformation is occurring in the conduct of research through the use of information and communication technologies. Yet the potential of ICTs to shape practices of surveillance or to produce new student-supervisor relations and enhance the processes of developing the dissertation has received almost no critical attention. As doctoral supervisor and student, we then describe the features and uses of a web-based open state archive of the student's work-in-progress, developed by the student and accessible to his supervisor. Our intention was to encourage more open conversations between data and theorising, student and supervisor, and ultimately between the student and professional community. However, we recognise that relations of accountability, as these have developed within a contemporary "audit revolution" (Power, 1994, 1997) in universities, create particular "lines of visibility" (Munro, 1996). Thus while the open-state archive may help to redefine in less managerial terms notions of quality, transparency, flexibility and accountability, it might also make possible greater supervisory surveillance. How should we think about the panoptical potential of this archive? We argue that the diverse kinds of interactional patterns and pedagogical intervention it encourages help to create shifting subjectivities. Moreover, the archive itself is multiple, in bringing together an array of diverse materials that can be read in various ways, by following multiple paths. It therefore constitutes a collage, which we identify as a mode of cognition and of accounting distinct from but related to argument and narrative. As a more "open" text (Iser, 1978) it has an indeterminacy which may render it less open to abuse for the technologies of managerial accountability

On D3-brane Potentials in Compactifications with Fluxes and Wrapped D-branes

We study the potential governing D3-brane motion in a warped throat region of a string compactification with internal fluxes and wrapped D-branes. If the Kahler moduli of the compact space are stabilized by nonperturbative effects, a D3-brane experiences a force due to its interaction with D-branes wrapping certain four-cycles. We compute this interaction, as a correction to the warped four-cycle volume, using explicit throat backgrounds in supergravity. This amounts to a closed-string channel computation of the loop corrections to the nonperturbative superpotential that stabilizes the volume. We demonstrate for warped conical spaces that the superpotential correction is given by the embedding equation specifying the wrapped four-cycle, in agreement with the general form proposed by Ganor. Our approach automatically provides a solution to the problem of defining a holomorphic gauge coupling on wrapped D7-branes in a background with D3-branes. Finally, our results have applications to cosmological inflation models in which the inflaton is modeled by a D3-brane moving in a warped throat.Comment: 45 pages, 1 figure; v2: added reference, clarified notatio