Computation of the intervals of uncertainties about the parameters found for identification

A modeling method to calculate the intervals of uncertainty for parameters found by identification is described. The region of confidence and the general approach to the calculation of these intervals are discussed. The general subprograms for determination of dimensions are described. They provide the organizational charts for the subprograms, the tests carried out and the listings of the different subprograms

Characterization of the Darboux point for particular classes of problems

A minimal sufficient condition for global optimality involving the Darboux point, analogous to the minimal sufficient condition of local optimality involving the conjugate point, is presented. The Darboux point is then characterized for optimal control problems with linear dynamics, cost functionals with a general terminal state term and an integrand quadratic in the state and control, and general terminal conditions. The Darboux point is shown to be the supremum of a sequence of conjugate points. If the terminal state term is quadratic, along with a scalar quadratic boundary condition, then the Darboux point is also the time at which the Riccati matrix becomes unbounded, giving a characterization of the unboundedness of the Riccati matrix at points which are not in general conjugate points.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45212/1/10957_2004_Article_BF01268173.pd

The Darboux point

A theory of global optimality based upon the Darboux-point concept is developed. A definition is proposed for the Darboux point, and the Darboux point is shown to exist on nonglobally optimal trajectories under relatively general conditions. A mutually exclusive classification of Darboux points is noted, and several properties are proved for one of these classes (the Type-1 Darboux point). Numerous examples are included to illustrate the Darboux-point definition and properties.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45205/1/10957_2004_Article_BF00932789.pd

NP-hardness of Deciding Convexity of Quartic Polynomials and Related Problems

We show that unless P=NP, there exists no polynomial time (or even pseudo-polynomial time) algorithm that can decide whether a multivariate polynomial of degree four (or higher even degree) is globally convex. This solves a problem that has been open since 1992 when N. Z. Shor asked for the complexity of deciding convexity for quartic polynomials. We also prove that deciding strict convexity, strong convexity, quasiconvexity, and pseudoconvexity of polynomials of even degree four or higher is strongly NP-hard. By contrast, we show that quasiconvexity and pseudoconvexity of odd degree polynomials can be decided in polynomial time.Comment: 20 page

Polarized secretion of Leukemia Inhibitory Factor

<p>Abstract</p> <p>Background</p> <p>The direction of cytokine secretion from polarized cells determines the cytokine's cellular targets. Leukemia inhibitory factor (LIF) belongs to the interleukin-6 (IL-6) family of cytokines and signals through LIFR/gp130. Three factors which may regulate the direction of LIF secretion were studied: the site of stimulation, signal peptides, and expression levels. Stimulation with IL-1β is known to promote IL-6 secretion from the stimulated membrane (apical or basolateral) in the human intestinal epithelial cell line Caco-2. Since LIF is related to IL-6, LIF secretion was also tested in Caco-2 following IL-1β stimulation. Signal peptides may influence the trafficking of LIF. Two isoforms of murine LIF, LIF-M and LIF-D, encode different signal peptides which have been associated with different locations of the mature protein in fibroblasts. To determine the effect of the signal peptides on LIF secretion, secretion levels were compared in Madin-Darby canine kidney (MDCK) clones which expressed murine LIF-M or LIF-D or human LIF under the control of an inducible promoter. Low and high levels of LIF expression were also compared since saturation of the apical or basolateral route would reveal specific transporters for LIF.</p> <p>Results</p> <p>When Caco-2 was grown on permeable supports, LIF was secreted constitutively with around 40% secreted into the apical chamber. Stimulation with IL-1β increased LIF production. After treating the apical surface with IL-1β, the percentage secreted apically remained similar to the untreated, whereas, when the cells were stimulated at the basolateral surface only 20% was secreted apically. In MDCK cells, an endogenous LIF-like protein was detected entirely in the apical compartment. The two mLIF isoforms showed no difference in their secretion patterns in MDCK. Interestingly, about 70% of murine and human LIF was secreted apically from MDCK over a 400-fold range of expression levels within clones and a 200,000-fold range across clones.</p> <p>Conclusion</p> <p>The site of stimulation affected the polarity of LIF secretion, while, signal peptides and expression levels did not. Exogenous LIF is transported in MDCK without readily saturated steps.</p

Efficient Generation of Germ Line Transmitting Chimeras from C57BL/6N ES Cells by Aggregation with Outbred Host Embryos

Genetically modified mouse strains derived from embryonic stem (ES) cells have become essential tools for functional genomics and biomedical research. Large scale mutagenesis projects are producing libraries of mutant C57BL/6 (B6) ES cells to enable the functional annotation of every gene of the mouse genome. To realize the utility of these resources, efficient and accessible methods of generating mutant mice from these ES cells are necessary. Here, we describe a combination of ICR morula aggregation and a chemically-defined culture medium with widely available and accessible components for the high efficiency generation of germline transmitting chimeras from C57BL/6N ES cells. Together these methods will ease the access of the broader biomedical research community to the publicly available B6 ES cell resources

Histone H1 Depletion Impairs Embryonic Stem Cell Differentiation

Pluripotent embryonic stem cells (ESCs) are known to possess a relatively open chromatin structure; yet, despite efforts to characterize the chromatin signatures of ESCs, the role of chromatin compaction in stem cell fate and function remains elusive. Linker histone H1 is important for higher-order chromatin folding and is essential for mammalian embryogenesis. To investigate the role of H1 and chromatin compaction in stem cell pluripotency and differentiation, we examine the differentiation of embryonic stem cells that are depleted of multiple H1 subtypes. H1c/H1d/H1e triple null ESCs are more resistant to spontaneous differentiation in adherent monolayer culture upon removal of leukemia inhibitory factor. Similarly, the majority of the triple-H1 null embryoid bodies (EBs) lack morphological structures representing the three germ layers and retain gene expression signatures characteristic of undifferentiated ESCs. Furthermore, upon neural differentiation of EBs, triple-H1 null cell cultures are deficient in neurite outgrowth and lack efficient activation of neural markers. Finally, we discover that triple-H1 null embryos and EBs fail to fully repress the expression of the pluripotency genes in comparison with wild-type controls and that H1 depletion impairs DNA methylation and changes of histone marks at promoter regions necessary for efficiently silencing pluripotency gene Oct4 during stem cell differentiation and embryogenesis. In summary, we demonstrate that H1 plays a critical role in pluripotent stem cell differentiation, and our results suggest that H1 and chromatin compaction may mediate pluripotent stem cell differentiation through epigenetic repression of the pluripotency genes