Quantitative assessment of cell fate decision between autophagy and apoptosis

Abstract Autophagy and apoptosis are cellular processes that regulate cell survival and death, the former by eliminating dysfunctional components in the cell, the latter by programmed cell death. Stress signals can induce either process, and it is unclear how cells ‘assess’ cellular damage and make a ‘life’ or ‘death’ decision upon activating autophagy or apoptosis. A computational model of coupled apoptosis and autophagy is built here to analyze the underlying signaling and regulatory network dynamics. The model explains the experimentally observed differential deployment of autophagy and apoptosis in response to various stress signals. Autophagic response dominates at low-to-moderate stress; whereas the response shifts from autophagy (graded activation) to apoptosis (switch-like activation) with increasing stress intensity. The model reveals that cytoplasmic Ca2+ acts as a rheostat that fine-tunes autophagic and apoptotic responses. A G-protein signaling-mediated feedback loop maintains cytoplasmic Ca2+ level, which in turn governs autophagic response through an AMP-activated protein kinase (AMPK)-mediated feedforward loop. Ca2+/calmodulin-dependent kinase kinase β (CaMKKβ) emerges as a determinant of the competing roles of cytoplasmic Ca2+ in autophagy regulation. The study demonstrates that the proposed model can be advantageously used for interrogating cell regulation events and developing pharmacological strategies for modulating cell decisions

Traffic Equations and Granular Convection

We investigate both numerically and analytically the convective instability of granular materials by two dimensional traffic equations. In the absence of vibrations the traffic equations assume two distinctive classes of fixed bed solutions with either a spatially uniform or nonuniform density profile. The former one exists only when the function V(\rho) that monitors the relaxation of grains assumes a cut off at the closed packed density, \rho_c, with V(\rho_c)=0, while the latter one exists for any form of V. Since there is little difference between the uniform and nonuniform solution deep inside the bed, the convective instability of the bulk may be studied by focusing on the stability of the uniform solution. In the presence of vibrations, we find that the uniform solution bifurcates into a bouncing solution, which then undergoes a supercritical bifurcation to the convective instability. We determine the onset of convection as a function of control parameters and confirm this picture by solving the traffic equations numerically, which reveals bouncing solutions, two convective rolls, and four convective rolls. Further, convective patterns change as the aspect ratio changes: in a vertically long container, the rolls move toward the surface, and in a horizontally long container, the rolls move toward the walls. We compare these results with those reported previously with a different continuum model by Hayakawa, Yue and Hong[Phys. Rev. Lett. 75,2328, 1995]. Finally, we also present a derivation of the traffic equations from Enskoq equation.Comment: 34 pages, 10 figure

Probing the isospin dependent mean field and nucleon nucleon cross section in the medium by the nucleon emissions

We study the isospin effects of the mean field and two-body collision on the nucleon emissions at the intermediate energy heavy ion collisions by using an isospin dependent transport theory. The calculated results show that the nucleon emission number $N_{n}$ depends sensitively the isospin effect of nucleon nucleon cross section and weakly on the isospin dependent mean field for neutron-poor system in higher beam energy region . In particular, the correlation between the medium correction of two-body collision and the momentum dependent interaction enhances the dependence of nucleon emission number $N_{n}$ on the isospin effect of nucleon nucleon cross section. On the contrary, the ratio of the neutron proton ratio of the gas phase to the neutron proton ratio of the liquid phase, i.e., the degree of isospin fractionation $_{b}/_{b}$ depends sensitively on the isospin dependent mean field and weakly on the isospin effect of two-body collision for neutron-rich system in the lower beam energy region. In this case, $N_{n}$ and $_{b}/_{b}$ are the probes for extracting the information about the isospin dependent nucleon nucleon cross section in the medium and the isospin dependent mean field,respectively.Comment: 4 pages,4 figure

Hand problems among endourologists.

BACKGROUND AND PURPOSE: Endourology has evolved rapidly for the management of both benign and malignant disease of the upper urinary tract. Limited data exist, however, on the occupational hazards posed by complex endourologic procedures. The aim of this study was to determine the prevalence and possible causes of hand problems among endourologists who routinely perform flexible ureteroscopy compared with controls. MATERIALS AND METHODS: An online computer survey targeted members of the Endourological Society and psychiatrists in academic and community settings. A total of 600 endourologists and 578 psychiatrists were contacted by e-mail. Invited physicians were queried regarding their practice settings and symptoms of hand pain, neuropathy, and/or discomfort. RESULTS: Survey responses were obtained from 122 (20.3%) endourologists and 74 (12.8%) psychiatrists. Of endourologists, 61% were in an academic setting and 70% devoted their practice to endourology. Endourologists were in practice for a mean 13 years, performing 4.5 ureteroscopic cases per week with a mean operative time of 50 minutes. Hand/wrist problems were reported by 39 (32%) endourologists compared with 14 (19%) psychiatrists (P=0.0486, relative risk [RR]=1.69). Surgeons who preferred counterintuitive ureteroscope deflection were significantly more likely to have problems (56%) compared with intuitive users (27%) (RR 2.07, P=0.0139) or those with no preference (26%) (RR 2.15, P=0.0451). Overall, most respondents (85%) with hand/wrist problems needed either medical or surgical intervention. CONCLUSIONS: Hand and wrist problems are very common among endourologists. Future studies are needed to develop more ergonomic platforms and thereby reduce the endourologist\u27s exposure to these occupational hazards

Exact expression for the diffusion propagator in a family of time-dependent anharmonic potentials

We have obtained the exact expression of the diffusion propagator in the time-dependent anharmonic potential $V(x,t)={1/2}a(t)x^2+b\ln x$. The underlying Euclidean metric of the problem allows us to obtain analytical solutions for a whole family of the elastic parameter a(t), exploiting the relation between the path integral representation of the short time propagator and the modified Bessel functions. We have also analyzed the conditions for the appearance of a non-zero flow of particles through the infinite barrier located at the origin (b<0).Comment: RevTex, 19 pgs. Accepted in Physical Review

Stratification Instability in Granular Flows

When a mixture of two kinds of grains differing in size and shape is poured in a vertical two-dimensional cell, the mixture spontaneously stratifies in alternating layers of small and large grains, whenever the large grains are more faceted than the small grains. Otherwise, the mixture spontaneously segregates in different regions of the cell when the large grains are more rounded than the small grains. We address the question of the origin of the instability mechanism leading to stratification using a recently proposed set of equations for surface flow of granular mixtures. We show that the stable solution of the system is a segregation solution due to size (large grains tend to segregate downhill near the substrate and small grains tend to segregate uphill) and shape (rounded grains tend to segregate downhill and more faceted grains tend to segregate uphill). As a result, the segregation solution of the system is realized for mixtures of large-rounded grains and small-cubic grains with the large-rounded grains segregating near the bottom of the pile. Stability analysis reveals the instability mechanism driving the system to stratification as a competition between size-segregation and shape-segregation taking place for mixtures of large-cubic grains and small-rounded grains. The large-cubic grains tend to size-segregate at the bottom of the pile, while at the same time, they tend to shape-segregate near the pouring point. Thus, the segregation solution becomes unstable, and the system evolves spontaneously to stratification.Comment: 10 pages, 10 figures, http://polymer.bu.edu/~hmakse/Home.htm

Hydrodynamic Description of Granular Convection

We present a hydrodynamic model that captures the essence of granular dynamics in a vibrating bed. We carry out the linear stability analysis and uncover the instability mechanism that leads to the appearance of the convective rolls via a supercritical bifurcation of a bouncing solution. We also explicitly determine the onset of convection as a function of control parameters and confirm our picture by numerical simulations of the continuum equations.Comment: 14 pages, RevTex 11pages + 3 pages figures (Type csh

An analog of glibenclamide selectively enhances autophagic degradation of misfolded α1-antitrypsin Z

The classical form of α1-antitrypsin deficiency (ATD) is characterized by intracellular accumulation of the misfolded variant α1-antitrypsin Z (ATZ) and severe liver disease in some of the affected individuals. In this study, we investigated the possibility of discovering novel therapeutic agents that would reduce ATZ accumulation by interrogating a C. elegans model of ATD with high-content genome-wide RNAi screening and computational systems pharmacology strategies. The RNAi screening was utilized to identify genes that modify the intracellular accumulation of ATZ and a novel computational pipeline was developed to make high confidence predictions on repurposable drugs. This approach identified glibenclamide (GLB), a sulfonylurea drug that has been used broadly in clinical medicine as an oral hypoglycemic agent. Here we show that GLB promotes autophagic degradation of misfolded ATZ in mammalian cell line models of ATD. Furthermore, an analog of GLB reduces hepatic ATZ accumulation and hepatic fibrosis in a mouse model in vivo without affecting blood glucose or insulin levels. These results provide support for a drug discovery strategy using simple organisms as human disease models combined with genetic and computational screening methods. They also show that GLB and/or at least one of its analogs can be immediately tested to arrest the progression of human ATD liver disease.</div