Membrane channel hypothesis of lysosomal permeabilization by beta-amyloid

Alzheimer's disease (AD) is the most common cause of dementia affecting millions of people. Neuronal death in AD is initiated by oligomeric amyloid-β (Aβ) peptides. Recently, we proposed the amyloid degradation toxicity hypothesis, which explains multiple major observations associated with AD - such as autophagy failure and a decreased metabolism. According to the hypothesis, the key event in the cellular toxicity of amyloid is the formation of non-selective membrane channels in lysosomal membranes by amyloid fragments that are produced by the digestion of Aβ previously absorbed by endocytosis. Electrophysiological data suggest that amyloid-formed channels have different sizes, which can be explained by the fact that barrel-shaped amyloid aggregates which create channels can consist of different number of monomers. To estimate the ability of channels to leak molecules of various molecular weights, we modeled the channels as saline-filled cylinders in non-conductive membranes that pass spheres with a density of average globular proteins. As a basis, we used the conductance distribution taken from the previously published experimental dataset, in which single channels with a conductance reaching one nanosiemens were registered. Our calculations show that channels with a giant conductance can allow for passing macromolecules such as lysosomal cathepsins implicated in the activation of apoptosis. The formation of giant channels is disproportionally promoted in an acidic environment. Also, amyloid fragments leaking from permeabilized lysosomes can reach the internal leaflet of the plasma membrane and permeabilize it. We conclude that while dissipation of the proton gradient by any - even the smallest amyloid channel - readily explains lysosomal failure, the relatively rare events of lysosomal permeabilization to large macromolecules can be an alternative mechanism of cellular death induced by exposure to Aβ.

Power and Thermal Efficiency Optimization of an Irreversible Steady-Flow Lenoir Cycle

Using finite time thermodynamic theory, an irreversible steady-flow Lenoir cycle model is established, and expressions of power output and thermal efficiency for the model are derived. Through numerical calculations, with the different fixed total heat conductances (UT) of two heat exchangers, the maximum powers (Pmax), the maximum thermal efficiencies (ηmax), and the corresponding optimal heat conductance distribution ratios (uLP(opt)) and (uLη(opt)) are obtained. The effects of the internal irreversibility are analyzed. The results show that, when the heat conductances of the hot- and cold-side heat exchangers are constants, the corresponding power output and thermal efficiency are constant values. When the heat source temperature ratio (τ) and the effectivenesses of the heat exchangers increase, the corresponding power output and thermal efficiency increase. When the heat conductance distributions are the optimal values, the characteristic relationships of P-uL and η-uL are parabolic-like ones. When UT is given, with the increase in τ, the Pmax, ηmax, uLP(opt), and uLη(opt) increase. When τ is given, with the increase in UT, Pmax and ηmax increase, while uLP(opt) and uLη(opt) decrease.

Tempered Fractional Equations for Quantum Transport in Mesoscopic One-Dimensional Systems with Fractal Disorder

New aspects of electron transport in quantum wires with Lévy-type disorder are described. We study the weak scattering and the incoherent sequential tunneling in one-dimensional quantum systems characterized by a tempered Lévy stable distribution of spacing between scatterers or tunneling barriers. The generalized Dorokhov–Mello–Pereyra–Kumar equation contains the tempered fractional derivative on wire length. The solution describes the evolution from the anomalous conductance distribution to the Dorokhov function for a long wire. For sequential tunneling, average values and relative fluctuations of conductance and resistance are calculated for different parameters of spatial distributions. A tempered Lévy stable distribution of spacing between barriers leads to a transition in conductance scaling.

Can One Define the Conductance of Amino Acids?

We studied the electron-transport properties of ten different amino acids and one dimer (di-methionine) using the mechanically controlled break-junction (MCBJ) technique. For methionine and cysteine, additional measurements were performed with the scanning tunneling microscope break-junction (STM-BJ) technique. By means of a statistical clustering technique, we identified several conductance groups for each of the molecules considered. Ab initio calculations revealed that the observed broad conductance distribution stems from the possibility of various binding geometries which can be formed during stretching combined with a multitude of possible conformational changes. The results suggest that it would be helpful to explore different experimental techniques such as recognition tunneling and conditions to help identify the nature of amino-acid-based junctions even further, for example, with the goal to establish a firm platform for their unambiguous recognition by tunneling break-junction experiments.

Effect of connection on transport between scale free networks

Using numerical simulations, we investigate the effects of the connectivity and topologies of network on the quality of transport between connected scale free networks. Hence, the flow as the electrical conductance between connected networks is calculated. It is found that the conductance distribution between networks follow a power law [Formula: see text] where [Formula: see text] is the exponent of the global Network of network, we show that the transport in the symmetric growing preferential attachment connection is more efficient than the symmetric static preferential attachment connection. Furthermore, the differences of transport and networks communications properties in the different cases are discussed.