Inhibition of Serine Protease Activity Protects Against High Fat Diet-Induced Inflammation and Insulin Resistance.

Recent evidence suggests that enhanced protease-mediated inflammation may promote insulin resistance and result in diabetes. This study tested the hypothesis that serine protease plays a pivotal role in type 2 diabetes, and inhibition of serine protease activity prevents hyperglycemia in diabetic animals by modulating insulin signaling pathway. We conducted a single-center, cross-sectional study with 30 healthy controls and 57 patients with type 2 diabetes to compare plasma protease activities and inflammation marker between groups. Correlations of plasma total and serine protease activities with variables were calculated. In an in-vivo study, LDLR-/- mice were divided into normal chow diet, high-fat diet (HFD), and HFD with selective serine protease inhibition groups to examine the differences of obesity, blood glucose level, insulin resistance and serine protease activity among groups. Compared with controls, diabetic patients had significantly increased plasma total protease, serine protease activities, and also elevated inflammatory cytokines. Plasma serine protease activity was positively correlated with body mass index, hemoglobin A1c, homeostasis model assessment-insulin resistance index (HOMA-IR), tumor necrosis factor-α, and negatively with adiponectin concentration. In the animal study, administration of HFD progressively increased body weight, fasting glucose level, HOMA-IR, and upregulated serine protease activity. Furthermore, in-vivo serine protease inhibition significantly suppressed systemic inflammation, reduced fasting glucose level, and improved insulin resistance, and these effects probably mediated by modulating insulin receptor and cytokine expression in visceral adipose tissue. Our findings support the serine protease may play an important role in type 2 diabetes and suggest a rationale for a therapeutic strategy targeting serine protease for clinical prevention of type 2 diabetes

Full Counting Statistics of a Superconducting Beam Splitter

We study the statistics of charge transport in a mesoscopic three-terminal device with one superconducting terminal and two normal-metal terminals. We calculate the full distribution of transmitted charges into the two symmetrically biased normal terminals. In a wide parameter range, we find large positive crosscorrelations between the currents in the two normal arms. We also determine the third cumulant that provides additional information on the statistics not contained in the current noise.Comment: 5 pages, 2 figures, revtex

Full counting statistics of Andreev scattering in an asymmetric chaotic cavity

We study the charge transport statistics in coherent two-terminal double junctions within the framework of the circuit theory of mesoscopic transport. We obtain the general solution of the circuit-theory matrix equations for the Green's function of a chaotic cavity between arbitrary contacts. As an example we discuss the full counting statistics and the first three cumulants for an open asymmetric cavity between a superconductor and a normal-metal lead at temperatures and voltages below the superconducting gap. The third cumulant shows a characteristic sign change as a function of the asymmetry of the two quantum point contacts, which is related to the properties of the Andreev reflection eigenvalue distribution.Comment: 8 pages, 4 figure

Self-consistent Approach to Off-Shell Transport

The properties of two forms of the gradient expanded Kadanoff--Baym equations, i.e. the Kadanoff--Baym and Botermans-Malfliet forms, suitable to describe the transport dynamics of particles and resonances with broad spectral widths, are discussed in context of conservation laws, the definition of a kinetic entropy and the possibility of numerical realization. Recent results on exact conservations of charge and energy-momentum within Kadanoff-Baym form of quantum kinetics based on local coupling schemes are extended to two cases relevant in many applications. These concern the interaction via a finite range potential, and, relevant in nuclear and hadron physics, e.g. for the pion--nucleon interaction, the case of derivative coupling.Comment: 35 pages, submitted to issue of Phys. Atom. Nucl. dedicated to S.T. Belyaev on the occasion of his 80th birthday. Few references are adde

Finite-element theory of transport in ferromagnet-normal metal systems

We formulate a theory of spin dependent transport of an electronic circuit involving ferromagnetic elements with non-collinear magnetizations which is based on the conservation of spin and charge current. The theory considerably simplifies the calculation of the transport properties of complicated ferromagnet-normal metal systems. We illustrate the theory by considering a novel three terminal device.Comment: revised paper, accepted for publication in Phys. Rev. Let

Full Current Statistics in Diffusive Normal-Superconductor Structures

We study the current statistics in normal diffusive conductors in contact with a superconductor. Using an extension of the Keldysh Green's function method we are able to find the full distribution of charge transfers for all temperatures and voltages. For the non-Gaussian regime, we show that the equilibrium current fluctuations are enhanced by the presence of the superconductor. We predict an enhancement of the nonequilibrium current noise for temperatures below and voltages of the order of the Thouless energy E_Th=D/L^2. Our calculation fully accounts for the proximity effect in the normal metal and agrees with experimental data. We demonstrate that the calculation of the full current statistics is in fact simpler than a concrete calculation of the noise.Comment: 4 pages, 2 figures (included

Structure of the Protein Phosphatase 2A Holoenzyme

SummaryProtein Phosphatase 2A (PP2A) plays an essential role in many aspects of cellular physiology. The PP2A holoenzyme consists of a heterodimeric core enzyme, which comprises a scaffolding subunit and a catalytic subunit, and a variable regulatory subunit. Here we report the crystal structure of the heterotrimeric PP2A holoenzyme involving the regulatory subunit B′/B56/PR61. Surprisingly, the B′/PR61 subunit has a HEAT-like (huntingtin-elongation-A subunit-TOR-like) repeat structure, similar to that of the scaffolding subunit. The regulatory B′/B56/PR61 subunit simultaneously interacts with the catalytic subunit as well as the conserved ridge of the scaffolding subunit. The carboxyterminus of the catalytic subunit recognizes a surface groove at the interface between the B′/B56/PR61 subunit and the scaffolding subunit. Compared to the scaffolding subunit in the PP2A core enzyme, formation of the holoenzyme forces the scaffolding subunit to undergo pronounced conformational rearrangements. This structure reveals significant ramifications for understanding the function and regulation of PP2A

Full Counting Statistics of Superconductor--Normal-Metal Heterostructures

The article develops a powerful theoretical tool to obtain the full counting statistics. By a slight extension of the standard Keldysh method we can access immediately all correlation functions of the current operator. Embedded in a quantum generalization of the circuit theory of electronic transport, we are able to study the full counting statistics of a large class of two-terminal contacts and multi-terminal structures, containing superconductors and normal metals as elements. The practical use of the method is demonstrated in many examples.Comment: 35 pages, contribution to "Quantum Noise", ed. by Yu.V. Nazarov and Ya.M. Blanter, minor changes in text, references adde

Universal Statistics of Transport in Disordered Conductors

In low temperature limit, we study electron counting statistics of a disordered conductor. We derive an expression for the distribution of charge transmitted over a finite time interval by using a result from the random matrix theory of quasi one dimensional disordered conductors. In the metallic regime, we find that the peak of the distribution is Gaussian and shows negligible sample to sample variations. We also find that the tails of the distribution are neither Gaussian nor Poisson and exhibit strong sample to sample variations.Comment: 11 pages, REVTEX3.0, MIT-CMT-HL940