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    Sachsenhausen Concentration Camp

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    Time Course of the Increase in the Myocardial Slow Inward Current after a Photochemically Generated Concentration Jump of Intracellular cAMP

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    Voltage-clamped atrial trabeculae from bullfrog hearts were exposed to membrane-permeant photolyzable o-nitrobenzyl esters of cAMP and cGMP. UV flashes produced intracellular concentration jumps of cAMP or cGMP. With the cAMP derivative, flashes resulted in an increased slow inward current (Isi), producing a broadened action potential. The Isi reached a maximum 10-30 sec after the flash and decreased over the next 60-300 sec. The first increases were observable within 150 msec; this value is an upper limit imposed by the instrumentation. Responses to flashes lasted longer at higher drug concentrations and in the presence of the phosphodiesterase inhibitor papaverine; effects of flashes developed and decreased faster at higher temperature. Although the amplitude of the Isi was increased, its waveform and voltage sensitivity were not affected. Intracellular concentration jumps of cAMP failed to affect the muscarinic K+ conductance. There were no observable effects of cGMP concentration jumps. The data confirm (i) that cAMP regulates the Isi and (ii) that the 5- to 10-sec delay between application of ß-agonists and the onset of positive inotropic effects, observed in previous studies, has been correctly ascribed to events prior to the interaction between cAMP and protein kinase

    The role of type 4 phosphodiesterases in generating microdomains of cAMP: Large scale stochastic simulations

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    Cyclic AMP (cAMP) and its main effector Protein Kinase A (PKA) are critical for several aspects of neuronal function including synaptic plasticity. Specificity of synaptic plasticity requires that cAMP activates PKA in a highly localized manner despite the speed with which cAMP diffuses. Two mechanisms have been proposed to produce localized elevations in cAMP, known as microdomains: impeded diffusion, and high phosphodiesterase (PDE) activity. This paper investigates the mechanism of localized cAMP signaling using a computational model of the biochemical network in the HEK293 cell, which is a subset of pathways involved in PKA-dependent synaptic plasticity. This biochemical network includes cAMP production, PKA activation, and cAMP degradation by PDE activity. The model is implemented in NeuroRD: novel, computationally efficient, stochastic reaction-diffusion software, and is constrained by intracellular cAMP dynamics that were determined experimentally by real-time imaging using an Epac-based FRET sensor (H30). The model reproduces the high concentration cAMP microdomain in the submembrane region, distinct from the lower concentration of cAMP in the cytosol. Simulations further demonstrate that generation of the cAMP microdomain requires a pool of PDE4D anchored in the cytosol and also requires PKA-mediated phosphorylation of PDE4D which increases its activity. The microdomain does not require impeded diffusion of cAMP, confirming that barriers are not required for microdomains. The simulations reported here further demonstrate the utility of the new stochastic reaction-diffusion algorithm for exploring signaling pathways in spatially complex structures such as neurons

    Chemotaxis von Seeigel-Spermien - kinetische Messungen intrazellulärer Botenstoffe

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    The egg-petide resact induces a chemotactical response of sperm from sea urchin Arbacia punctulata. By bindig to a receptor-guanylylcyclase on the flagellar membrane resact activates a signaling-cascade. This leads to an increase in cGMP-/cAMP-concentration, Ca2+^{2+}- concentration an pH. The sequence and thereby the causal relations of the single physiological reactions were unkown before. In order to reveal the sequence of the signaling events I have established two methods which allowed time-resolved measurements (e.g. in millisecond time-scale) of the physiological reactions. The quenched-flow-method was used to detect the time-course of the cGMP-/cAMP-concentration. Therefore it was combined with cGMP-/cAMP-sensitive Radioimmunoassays. The stopped-flow-method was used to record the timecourse of the Ca2+^{2+}- or pH-sensitive fluorescence-indicators. Both methods enabled me to measure for the first time the sequence of the physiological reactions. The measurements showed, that resact induces a fast and high increase of the cGMP-concentration. The cGMP-concentration starts rising within the first 25 ms and reaches its half-maximal concentration within 200 ms. A cGMP-increase is already induced at picomolar resact-concentrations whereas a cAMP-increase is only induced by nanomolar resactconcentrations. Furthermore the cAMP-increase is slighter and slower compared to the cGMP-increase. Arround 250 ms after the stimulation with resact the Ca2+^{2+}-concentration increases. This Ca2+^{2+}- signal can be devided in an „early“ and a „late“ Ca2+^{2+}-signal. While the early Ca2+^{2+}-signal can be already triggered by single resact-molecules the late Ca2+^{2+}-signal is less sensitive to the eggpetide. The early Ca2+^{2+}-signal is either directly or through other signaling events triggered by cGMP. The cAMP-increase is – at least in the presence of the PDE-inhibitor IBMX – slower than the late Ca2+^{2+}-signal. Therby cAMP could only trigger the late Ca2+^{2+}-signal. In contrast to the late Ca2+^{2+}-signal the early Ca2+^{2+}-signal is induced at the same time as the resact-induced change of the swimming-behavior. Thus the early Ca2+^{2+}-signal represents the crucial reaction in the resact-induced signaling-cascade. Like the early Ca2+^{2+}-signal, the pH responds to resact-concentrations over more than 6 orders of magnitude. The delay of the pH-change is only at high resact-concentrations faster than the delay of the Ca2+^{2+}-signal. At low resact-concentrations the pH increases after the Ca2+^{2+}-concentration. Contrary to other publications, this results shows that the pH-increase does not trigger the Ca2+^{2+}-increase

    Justice for War Criminals: The Trials of Nazi Concentration Camp Guards at Dachau

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    This paper will seek to explore whether or not Nazi war criminals tasked with manning and staffing the various concentration and death camps were in any way entitled to due process of law upon their capture and trial. This concept is debated among international Holocaust scholars and often discussed with purely apodictic arguments based upon a lack of understanding of military law. This paper will discuss in detail the rights, liberties, and treatment of Nazi war criminals after World War II in relation to the trials of concentration camp guards. It will also necessarily explore and explicate the misunderstood military legal environment in which these trials occurred as well as identify the international and domestic laws upon which these trials were based. By drawing upon primary source documents like memoranda, trial records, and other notes by officials and parties involved in trying these war criminals, this paper will argue that Nazi concentration camp guards were not entitled to due process nor could they claim any rights independently of those charitably granted them by their captors. This paper will reference the flawed conceptions of international law held by dissenting scholars and juxtapose them with the letter of the law at the time of the trials. This will serve as proof that the concentration camp guards were afforded the proper rights and will also present a cogent and strong argument that promotes understanding of a complex military legal system while simultaneously refuting and quantifying the rights of the concentration camp guards in question

    Concentration Camp Form

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    Two sided form with all lines left blank. Top left of front side begins with \u27Konzentrationslager\u27: Information Provided by Michael D. Bulmash: Two sided concentration camp personal form that asks individuals name, address, military history, party affiliations, criminal record, etc.https://digital.kenyon.edu/bulmash/2367/thumbnail.jp

    The Cell Density Factor CMF Regulates the Chemoattractant Receptor cAR1 in Dictyostelium

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    Starving Dictyostelium cells aggregate by chemotaxis to cAMP when a secreted protein called conditioned medium factor (CMF) reaches a threshold concentration. Cells expressing CMF antisense mRNA fail to aggregate and do not transduce signals from the cAMP receptor. Signal transduction and aggregation are restored by adding recombinant CMF. We show here that two other cAMP-induced events, the formation of a slow dissociating form of the cAMP receptor and the loss of ligand binding, which is the first step of ligand-induced receptor sequestration, also require CMF. Vegetative cells have very few CMF and cAMP receptors, while starved cells possess ~40,000 receptors for CMF and cAMP. Transformants overexpressing the cAMP receptor gene cAR1 show a 10-fold increase of [3H]cAMP binding and a similar increase of [125I]CMF binding; disruption of the cAR1 gene abolishes both cAMP and CMF binding. In wild-type cells, downregulation of cAR1 with high levels of cAMP also downregulates CMF binding, and CMF similarly downregulates cAMP and CMF binding. This suggests that the cAMP binding and CMF binding are closely linked. Binding of ~200 molecules of CMF to starved cells affects the affinity of the majority of the cAR1 cAMP receptors within 2 min, indicating that an amplifying mechanism allows one activated CMF receptor to regulate many cARs. In cells lacking the G-protein β subunit, cAMP induces a loss of cAMP binding, but not CMF binding, while CMF induces a reduction of CMF binding without affecting cAMP binding, suggesting that the linkage of the cell density-sensing CMF receptor and the chemoattractant cAMP receptor is through a G-protein.

    Computational modelling suggests dynamic interactions between Ca2+, IP3 and G protein-coupled modules are key to robust Dictyostelium aggregation

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    Under conditions of starvation, Dictyostelium cells begin a programme of development during which they aggregate to form a multicellular structure by chemotaxis, guided by propagating waves of cyclic AMP that are relayed robustly from cell to cell. In this paper, we develop and analyse a new model for the intracellular and extracellular cAMP dependent processes that regulate Dictyostelium migration. The model allows, for the first time, a quantitative analysis of the dynamic interactions between calcium, IP(3) and G protein-dependent modules that are shown to be key to the generation of robust cAMP oscillations in Dictyostelium cells. The model provides a mechanistic explanation for the transient increase in cytosolic free Ca(2+) concentration seen in recent experiments with the application of the calmodulin inhibitor calmidazolium (R24571) to Dictyostelium cells, and also allows elucidation of the effects of varying both the conductivity of stretch-activated channels and the concentration of external phosphodiesterase on the oscillatory regime of an individual cell. A rigorous analysis of the robustness of the new model shows that interactions between the different modules significantly reduce the sensitivity of the resulting cAMP oscillations to variations in the kinetics of different Dictyostelium cells, an essential requirement for the generation of the spatially and temporally synchronised chemoattractant cAMP waves that guide Dictyostelium aggregation