Cell non-autonomous regulation of hepatic IGF-1 and neonatal growth by Kinase Suppressor of Ras 2 (KSR2)

Individuals with poor postnatal growth are at risk for cardiovascular and metabolic problems as adults. Here we show that disruption of the molecular scaffold Kinase Suppressor of Ras 2 (KSR2) causes selective inhibition of hepatic GH signaling in neonatal mice with impaired expression of IGF-1 and IGFBP3. ksr2−/− mice are normal size at birth but show a marked increase in FGF21 accompanied by reduced body mass, shortened body length, and reduced bone mineral density (BMD) and content (BMC) first evident during postnatal development. However, disrupting FGF21 in ksr2−/− mice does not normalize mass, length, or bone density and content in fgf21−/−ksr2−/− mice. Body length, BMC and BMD, but not body mass, are rescued by infection of two-day-old ksr2−/− mice with a recombinant adenovirus encoding human IGF-1. Relative to wild-type mice, GH injections reveal a significant reduction in JAK2 and STAT5 phosphorylation in liver, but not in skeletal muscle, of ksr2−/− mice. However, primary hepatocytes isolated from ksr2−/− mice show no reduction in GH-stimulated STAT5 phosphorylation. These data indicate that KSR2 functions in a cell non-autonomous fashion to regulate GH-stimulated IGF-1 expression in the liver of neonatal mice, which plays a key role in the development of body length

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of the closed control loop. Similar observations can also be made for the model given by (4). The basic conclusion is that in this example with a parabolic PDE fairly acceptable behavior of the control loop (at least from the aspect of its stability) could be obtained for model (3) only if the order of the reduced approximating model was « > 7, and for model (4) if it was n > 3. But, in practice, those orders are usually too high and our next task is to find a reduced model with a possible lowest order but which will be capable of reproducing instability in the loop at the same K^ as the real distributed process. The solution can be found in the field of the Fade approximation, i.e., with the help of the nonminimum phase transfer function given by (5). The problem is solved by moving the positive zero of the transfer function G^ais) from the position, _ 4 to the right of the position, 4/f, Therefore, the lowest-order reduced model which is (from the aspect of the stability) capable of reproducing the behaviour of the control loop containing a real distributed plant described with parabolic PDE is the following nonminimum phase model, (17) Conclusions The dynamics of spatially distributed processes is described by PDE in the time domain, and by the transcendental transfer function in the i-domain. Therefore, the model is of infinite order and for the purpose of control system design such models must, as a rule, be reduced. In the process of reduction the objectives of the model are important. It has been shown that some models, although good for the reproduction of the process (open loop) dynamics, are completely unacceptable as a basis for designing control systems because they cannot reproduce the basic possibility of instability of the whole control system. An original analytical solution is given for the maximum control gain K^ of the P controller in output feedback control of the heat conduction process through homogeneous continuum described by a parabolic PDE. This solution for Kc was confirmed numerically. We have proposed the selection of a zero position for a simple nonminimum phase dynamic system that makes it possible to obtain a model with the same properties (from the aspect of reproducing instabilities) as the real distributed process. For this class of problems this is the simplest solution. The ideas (and methods) proposed in this work are also directed to the question of control system synthesis for other systems with distributed parameters. The example given here with the P controller can also be extended both to other classical distributed processes and to other controller structures as well. Reference

Measurement of the reaction rates in 232Th samples irradiated by 4 GeV deuterons and secondary neutrons

Section VI. Fundamental Problems of Nuclear Power Engineerin