Heck reactions of Crotonaldehyde and Organocatalytic, asymmetric Mannich reactions of N-Boc and related imines

This thesis is divided into two major parts. The first part deals with the development of conditions for a Heck reaction to introduce aryl and vinyl substituents to the beta-position of crotonaldehyde and related alpha,beta-unsaturated aldehydes. The reaction provides very fast (<1 h) access to the desired beta,beta-disubstituted, alpha,beta-unsaturated aldehydes in typically good to very high yields. The methodology is furthermore employed in shortening the formerly lengthy synthesis of enantiopure Florhydral. The second and larger part concerns the development of the chemistry of N-Boc, N-Cbz, N Fmoc, and N-Bz-imines in proline-catalyzed Mannich reactions of unmodified aldehydes and ketones. The reactions are usually good to high in yield and with high to excellent levels of enantioselectivity. It also describes the first use of acetaldehyde as donor in an organocatalyzed reaction, leading to defined single-addition products of extremely high enantiopurity. Finally, the newly developed methodology was employed to synthesize the side chain of paclitaxel (taxol), and the semisynthesis thereof is presented

The Emergence of Insight in Problem Solving

This paper relates the notion of insight in problem solving to the current debate concerning epistemological and ontological emergence. The psychological school that stresses the relevance of insight for solving certain types of problems has been Gestalt theory. In classical Gestaltist writings, however, there is not much information about the question of whether or not insights are wholes with emergent properties. It is only in the more recent literature that this question is formulated. The present paper provides examples of insight problems (section I). Then it shows how insight was characterized in Gestalt theoretical writings, in particular by K. Duncker (II), and how this relates to the philosophical debate on emergence (III). After presenting two stances in research on problem solving that resemble the positions arguing for epistemological and ontological emergence (IV), I conclude with suggesting an alternative by complementing the basic part-whole framework with bidirectional processes found in perceptual reversals of ambiguous figures (V). In so doing I suggest to understand insight as ‘intersight,’ which is not an emergent whole, but a hinge or switch that mediates between two or more part-whole structures (here: problem and solution).This paper relates the notion of insight in problem solving to the current debate concerning epistemological and ontological emergence. The psychological school that stresses the relevance of insight for solving certain types of problems has been Gestalt theory. In classical Gestaltist writings, however, there is not much information about the question of whether or not insights are wholes with emergent properties. It is only in the more recent literature that this question is formulated. The present paper provides examples of insight problems (section I). Then it shows how insight was characterized in Gestalt theoretical writings, in particular by K. Duncker (II), and how this relates to the philosophical debate on emergence (III). After presenting two stances in research on problem solving that resemble the positions arguing for epistemological and ontological emergence (IV), I conclude with suggesting an alternative by complementing the basic part-whole framework with bidirectional processes found in perceptual reversals of ambiguous figures (V). In so doing I suggest to understand insight as ‘intersight,’ which is not an emergent whole, but a hinge or switch that mediates between two or more part-whole structures (here: problem and solution)

Interaction of a Mammalian Virus with Host RNA Silencing Pathways: A Dissertation

In the complex relationships of mammalian viruses with their hosts, it is currently unclear as to what role RNA silencing pathways play during the course of infection. RNA silencing-based immunity is the cornerstone of plant and invertebrate defense against viral pathogens, and examples of host defense mechanisms and numerous viral counterdefense mechanisms exist. Recent studies indicate that RNA silencing might also play an active role in the context of a mammalian virus infection. We show here that a mammalian virus, human adenovirus, interacts with RNA silencing pathways during infection, as the virus produces microRNAs (miRNAs) and regulates the expression of Dicer, a key component of RNA silencing mechanisms. Our work demonstrates that adenovirus encodes two miRNAs within the loci of the virus-associated RNA I (VA RNA I). We find that one of these miRNAs, miR-VA “g”, enters into a functional, Argonaute-2 (Ago-2)-containing silencing complex during infection. Currently, the cellular or viral target genes for these miRNAs remain unidentified. Inhibition of the function of the miRNAs during infection did not affect viral growth in a highly cytopathic cell culture model. However, studies from other viruses implicate viral miRNAs in the establishment of latent or chronic infections. Additionally, we find that adenovirus infection leads to the reduced expression of Dicer. This downregulation does not appear to be dependent on the presence of VA RNA or its associated miRNAs. Rather, Dicer levels appear to inversely correlate with the level of viral replication, indicating that another viral gene product is responsible for this activity. Misregulation of Dicer expression does not appear to influence viral growth in a cell culture model of infection, and also does not lead to gross changes in the pool of cellular miRNAs. Taken together, our results demonstrate that RNA silencing pathways are active participants in the process of infection with human adenovirus. The production of viral miRNAs and the regulation of cellular Dicer levels during infection implicate RNA silencing mechanisms in both viral fitness as well as potential host defense strategies

Plasma N-Terminal Pro-Brain Natriuretic Peptide as Prognostic Marker in Fatal Cardial Decompensation with Sunitinib Malate Therapy

A 74-year-old man with metastatic renal cell carcinoma and a history of cardiac failure was treated with sunitinib malate. MUGA echocardiography could not detect a relevant change in the ejection fraction although the clinical situation of the patient worsened dramatically. The only parameter to hint at the deteriorated cardiac function was plasma N-terminal pro-brain natriuretic peptide (BNP). Finally, the patient died after only one cycle of sunitinib treatment. We propose to prospectively include BNP for the early detection of cardiovascular decompensation in high-risk patients. Future studies concerning the relevance of BNP in drug-related cardiotoxicity are urgently needed. Copyright (C) 2010 S. Karger AG, Base

Dynamic multifactor hubs interact transiently with sites of active transcription in Drosophila embryos.

The regulation of transcription requires the coordination of numerous activities on DNA, yet how transcription factors mediate these activities remains poorly understood. Here, we use lattice light-sheet microscopy to integrate single-molecule and high-speed 4D imaging in developing Drosophila embryos to study the nuclear organization and interactions of the key transcription factors Zelda and Bicoid. In contrast to previous studies suggesting stable, cooperative binding, we show that both factors interact with DNA with surprisingly high off-rates. We find that both factors form dynamic subnuclear hubs, and that Bicoid binding is enriched within Zelda hubs. Remarkably, these hubs are both short lived and interact only transiently with sites of active Bicoid-dependent transcription. Based on our observations, we hypothesize that, beyond simply forming bridges between DNA and the transcription machinery, transcription factors can organize other proteins into hubs that transiently drive multiple activities at their gene targets.Editorial noteThis article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter)

Towards adjoint-based inversion of time-dependent mantle convection with non-linear viscosity

We develop and study an adjoint-based inversion method for the simultaneous recovery of initial temperature conditions and viscosity parameters in time-dependent mantle convection from the current mantle temperature and historic plate motion. Based on a realistic rheological model with temperature-dependent and strain-rate-dependent viscosity, we formulate the inversion as a PDE-constrained optimization problem. The objective functional includes the misfit of surface velocity (plate motion) history, the misfit of the current mantle temperature, and a regularization for the uncertain initial condition. The gradient of this functional with respect to the initial temperature and the uncertain viscosity parameters is computed by solving the adjoint of the mantle convection equations. This gradient is used in a pre-conditioned quasi-Newton minimization algorithm. We study the prospects and limitations of the inversion, as well as the computational performance of the method using two synthetic problems, a sinking cylinder and a realistic subduction model. The subduction model is characterized by the migration of a ridge toward a trench whereby both plate motions and subduction evolve. The results demonstrate: (1) for known viscosity parameters, the initial temperature can be well recovered, as in previous initial condition-only inversions where the effective viscosity was given; (2) for known initial temperature, viscosity parameters can be recovered accurately, despite the existence of trade-offs due to ill-conditioning; (3) for the joint inversion of initial condition and viscosity parameters, initial condition and effective viscosity can be reasonably recovered, but the high dimension of the parameter space and the resulting ill-posedness may limit recovery of viscosity parameters

Space shuttle food system summary, 1981-1986

All food in the Space Shuttle food system was precooked and processed so it required no refrigeration and was either ready-to-eat or could be prepared for consumption by simply adding water and/or heating. A gun-type water dispenser and a portable, suitcase-type heater were used to support this food system during the first four missions. On STS-5, new rehydratable packages were introduced along with a needle-injection water dispenser that measured the water as it was dispensed into the packages. A modular galley was developed to facilitate the meal preparation process aboard the Space Shuttle. The galley initially flew on STS-9. A personal hygiene station, a hot or cold water dispenser, a convection oven, and meal assembly areas were included in the galley

Patterning the insect eye: from stochastic to deterministic mechanisms

While most processes in biology are highly deterministic, stochastic mechanisms are sometimes used to increase cellular diversity, such as in the specification of sensory receptors. In the human and Drosophila eye, photoreceptors sensitive to various wavelengths of light are distributed randomly across the retina. Mechanisms that underlie stochastic cell fate specification have been analysed in detail in the Drosophila retina. In contrast, the retinas of another group of dipteran flies exhibit highly ordered patterns. Species in the Dolichopodidae, the "long-legged" flies, have regular alternating columns of two types of ommatidia (unit eyes), each producing corneal lenses of different colours. Individual flies sometimes exhibit perturbations of this orderly pattern, with "mistakes" producing changes in pattern that can propagate across the entire eye, suggesting that the underlying developmental mechanisms follow local, cellular-automaton-like rules. We hypothesize that the regulatory circuitry patterning the eye is largely conserved among flies such that the difference between the Drosophila and Dolichopodidae eyes should be explicable in terms of relative interaction strengths, rather than requiring a rewiring of the regulatory network. We present a simple stochastic model which, among its other predictions, is capable of explaining both the random Drosophila eye and the ordered, striped pattern of Dolichopodidae.Comment: 24 pages, 4 figure

Africa : the new frontier for global strategy scholars

Context matters in the global strategy literature. We discuss how Africa, as a setting that received limited attention in the past, offers opportunity to challenge existing theory, and develop new insights. The overall goal is to ask: What will the field of global strategic management look like once we have engaged with Africa in a similar manner as we have done with other emerging economies? We also introduce the papers published in this special issue and highlight directions for future research