Tissue compatibility of poly(hydroxypropylglutamate)-prazosin conjugates

Biocompatibility of an injectable biodegradable drug delivery system for prazosin was investigated in Sprague-Dawley rats by histological studies after subcutaneous injection ofpoly(hydroxypropyl glutamate)-prazosin (PHPG-prazosin) conjugate particles. The studies showed that (1) the acute inflammatory response to this injectable biodegradable polymeric prodrug system was mild and of only short duration, (2) the chronic inflammation was minimal to zero, (3) the fibrous capsule could be seen starting from 7 days and became more prominent at longer time periods, (4) a collagen network was formed into the injection site after 21 days, (5) the macrophages and foreign giant cells reacted to the globules of conjugate particles, and (6) no adverse reactions were identified. Focal inflammation and the formation of the fibrous capsule around the injection site were the significant histological findings in the histopathological studies. Therefore, it is concluded that the biodegradable injectable PHPG-prazosin carbamate polymeric prodrug system is tissue biocompatible

Statistics of correlated percolation in a bacterial community

Signal propagation over long distances is a ubiquitous feature of multicellular communities, but cell-to-cell variability can cause propagation to be highly heterogeneous. Simple models of signal propagation in heterogenous media, such as percolation theory, can potentially provide a quantitative understanding of these processes, but it is unclear whether these simple models properly capture the complexities of multicellular systems. We recently discovered that in biofilms of the bacterium Bacillus subtilis, the propagation of an electrical signal is statistically consistent with percolation theory, and yet it is reasonable to suspect that key features of this system go beyond the simple assumptions of basic percolation theory. Indeed, we find here that the probability for a cell to signal is not independent from other cells as assumed in percolation theory, but instead is correlated with its nearby neighbors. We develop a mechanistic model, in which correlated signaling emerges from cell division, phenotypic inheritance, and cell displacement, that reproduces the experimentally observed correlations. We find that the correlations do not significantly affect the spatial statistics, which we rationalize using a renormalization argument. Moreover, the fraction of signaling cells is not constant in space, as assumed in percolation theory, but instead varies within and across biofilms. We find that this feature lowers the fraction of signaling cells at which one observes the characteristic power-law statistics of cluster sizes, consistent with our experimental results. We validate the model using a mutant biofilm whose signaling probability decays along the propagation direction. Our results reveal key statistical features of a correlated signaling process in a multicellular community. More broadly, our results identify extensions to percolation theory that do or do not alter its predictions and may be more appropriate for biological systems.P50 GM085764 - NIGMS NIH HHS; Howard Hughes Medical Institute; R01 GM121888 - NIGMS NIH HHSPublished versio

Partial entropy in finite-temperature phase transitions

It is shown that the von Neumann entropy, a measure of quantum entanglement, does have its classical counterpart in thermodynamic systems, which we call partial entropy. Close to the critical temperature the partial entropy shows perfect finite-size scaling behavior even for quite small system sizes. This provides a powerful tool to quantify finite-temperature phase transitions as demonstrated on the classical Ising model on a square lattice and the ferromagnetic Heisenberg model on a cubic lattice.Comment: 4 pages, 6 figures, Revised versio

Effects of assembly and mutations outside the active site on the functional pH dependence of Escherichia coli aspartate transcarbamylase

Electrostatics are central to the function and regulation of Escherichia coli aspartate transcarbamylase, and modeling has suggested that long range electrostatic effects are likely to be important (Glackin, M. P., McCarthy, M. P., Mallikarachchi, D., Matthew, J. B., and Allewell, N. M. (1989) Proteins Struct. Funct. Genet. 5, 66-77; Oberoi, H., Trikha, J., Yuan, X., and Allewell, N. M. (1995) Proteins Struct. Funct. Genet., in press). To investigate this possibility from an experimental standpoint, we have examined the effects both of assembly and of removing ionizable and polar side chains outside the active site (Glu-50, Tyr-165, and Tyr-240) on the pH dependence of the kinetic parameters of aspartate transcarbamylase. The holoenzyme (c6r6) assembles from three regulatory dimers (r2) and two catalytically active trimers (c3). pH dependences of the enzyme kinetic parameters suggest that the mechanisms of productive binding of L-Asp to the binary complexes of the catalytic subunit (c3) and holoenzyme (c6r6) with carbamyl phosphate are different. In contrast, the Michaelis complex appears similar for both c3 and c6r6, except for pK shifts of ~1 pH unit. Results also indicate that the catalytic mechanism of the holoenzyme does not involve reverse protonation, as has recently been proposed for the catalytic trimer (Turnbull, J. L., Waldrop, G. L., and Schachman, H. K. (1992) Biochemistry 31, 6562-6569). The tyrosines at positions 165 and 240 are part of a cluster of interactions that links the catalytic subunits in the T state (the c1:c4 interface) and which is disrupted in the T → R transition. The effects of mutating the two Tyr residues are quite different: Y240F has higher than wild-type activity and affinity over the entire pH range, while Y165F has activity and affinity an order of magnitude lower than wild-type. Removal of the regulatory subunits from Y165F increases activity and affinity and restores the pH dependence of the wild-type catalytic subunit. Like Y165F, E50A has low activity and affinity over the entire pH range. Linkage analysis indicates that there is long range energetic coupling among the active site, the c:r subunit interfaces, and residue Y165. The substantial quantitative difference between Y165F and Y240F, both of which are at the c1:c4 interface about 14-16 Å from the closest active site, demonstrates specific path dependence, as opposed to general distance dependence, of interactions between this interface and the active site

Microgrid Stability Controller Based on Adaptive Robust Total SMC

This paper presents a microgrid stability controller (MSC) in order to provide existing distributed generation units (DGs) the additional functionality of working in islanding mode without changing their control strategies in grid-connected mode and to enhance the stability of the microgrid. Microgrid operating characteristics and mathematical models of the MSC indicate that the system is inherently nonlinear and time-variable. Therefore, this paper proposes an adaptive robust total sliding-mode control (ARTSMC) system for the MSC. It is proved that the ARTSMC system is insensitive to parametric uncertainties and external disturbances. The MSC provides fast dynamic response and robustness to the microgrid. When the system is operating in grid-connected mode, it is able to improve the controllability of the exchanged power between the microgrid and the utility grid, while smoothing the DGs’ output power. When the microgrid is operating in islanded mode, it provides voltage and frequency support, while guaranteeing seamless transition between the two operation modes. Simulation and experimental results show the effectiveness of the proposed approach

Generalized convexities and generalized gradients based on algebraic operations

AbstractIn this paper, we investigate properties of generalized convexities based on algebraic operations introduced by Ben Tal [A. Ben Tal, On generalized means and generalized convex functions, J. Optim. Theory Appl. 21 (1977) 1–13] and relations between these generalized convexities and generalized monotonicities. We also discuss the (h,φ)-generalized directional derivative and gradient, and explore the relation between this gradient and the Clarke generalized gradient. Definitions of some generalized averages of the values of a generalized convex function at n equally spaced points based on the algebraic operations are also presented and corresponding results are obtained. Finally, the (φ,γ)-convexity is defined and some properties of (φ,γ)-convex functions are derived

Background modelling for γ\gamma-ray spectroscopy with INTEGRAL/SPI

The coded-mask spectrometer-telescope SPI on board the INTEGRAL observatory records photons in the energy range between 20 and 8000 keV. A robust and versatile method to model the dominating instrumental background (BG) radiation is difficult to establish for such a telescope in the rapidly changing space environment. From long-term monitoring of SPI's Germanium detectors, we built up a spectral parameter data base, which characterises the instrument response as well as the BG behaviour. We aim to build a self-consistent and broadly applicable BG model for typical science cases of INTEGRAL/SPI, based on this data base. The general analysis method for SPI relies on distinguishing between illumination patterns on the 19-element Germanium detector array from BG and sky in a maximum likelihood framework. We illustrate how the complete set of measurements, even including the exposures of the sources of interest, can be used to define a BG model. We apply our method to different science cases, including point-like, diffuse, continuum, and line emission, and evaluate the adequacy in each case. From likelihood values and the number of fitted parameters, we determine how strong the impact of the unknown BG variability is. We find that the number of fitted parameters, i.e. how often the BG has to be re-normalised, depends on the emission type (diffuse with many observations over a large sky region, or point-like with concentrated exposure around one source), and the spectral energy range and bandwidth. A unique time scale, valid for all analysis issues, is not applicable for INTEGRAL/SPI, but must and can be inferred from the chosen data set. We conclude that our BG modelling method is usable in a large variety of INTEGRAL/SPI science cases, and provides nearly systematics-free and robust results.Comment: 11 pages, 2 appendix pages, 9 figures, 4 appendix figures, 4 tables; based on the work of Diehl et al. (2018), Siegert (2017), and Siegert (2013

A subcutaneous adipose tissue-liver signalling axis controls hepatic gluconeogenesis.

The search for effective treatments for obesity and its comorbidities is of prime importance. We previously identified IKK-ε and TBK1 as promising therapeutic targets for the treatment of obesity and associated insulin resistance. Here we show that acute inhibition of IKK-ε and TBK1 with amlexanox treatment increases cAMP levels in subcutaneous adipose depots of obese mice, promoting the synthesis and secretion of the cytokine IL-6 from adipocytes and preadipocytes, but not from macrophages. IL-6, in turn, stimulates the phosphorylation of hepatic Stat3 to suppress expression of genes involved in gluconeogenesis, in the process improving glucose handling in obese mice. Preliminary data in a small cohort of obese patients show a similar association. These data support an important role for a subcutaneous adipose tissue-liver axis in mediating the acute metabolic benefits of amlexanox on glucose metabolism, and point to a new therapeutic pathway for type 2 diabetes