Protease inhibitors targeting coronavirus and filovirus entry.

In order to gain entry into cells, diverse viruses, including Ebola virus, SARS-coronavirus and the emerging MERS-coronavirus, depend on activation of their envelope glycoproteins by host cell proteases. The respective enzymes are thus excellent targets for antiviral intervention. In cell culture, activation of Ebola virus, as well as SARS- and MERS-coronavirus can be accomplished by the endosomal cysteine proteases, cathepsin L (CTSL) and cathepsin B (CTSB). In addition, SARS- and MERS-coronavirus can use serine proteases localized at the cell surface, for their activation. However, it is currently unclear which protease(s) facilitate viral spread in the infected host. We report here that the cysteine protease inhibitor K11777, ((2S)-N-[(1E,3S)-1-(benzenesulfonyl)-5-phenylpent-1-en-3-yl]-2-{[(E)-4-methylpiperazine-1-carbonyl]amino}-3-phenylpropanamide) and closely-related vinylsulfones act as broad-spectrum antivirals by targeting cathepsin-mediated cell entry. K11777 is already in advanced stages of development for a number of parasitic diseases, such as Chagas disease, and has proven to be safe and effective in a range of animal models. K11777 inhibition of SARS-CoV and Ebola virus entry was observed in the sub-nanomolar range. In order to assess whether cysteine or serine proteases promote viral spread in the host, we compared the antiviral activity of an optimized K11777-derivative with that of camostat, an inhibitor of TMPRSS2 and related serine proteases. Employing a pathogenic animal model of SARS-CoV infection, we demonstrated that viral spread and pathogenesis of SARS-CoV is driven by serine rather than cysteine proteases and can be effectively prevented by camostat. Camostat has been clinically used to treat chronic pancreatitis, and thus represents an exciting potential therapeutic for respiratory coronavirus infections. Our results indicate that camostat, or similar serine protease inhibitors, might be an effective option for treatment of SARS and potentially MERS, while vinyl sulfone-based inhibitors are excellent lead candidates for Ebola virus therapeutics

Stability, Gain, and Robustness in Quantum Feedback Networks

This paper concerns the problem of stability for quantum feedback networks. We demonstrate in the context of quantum optics how stability of quantum feedback networks can be guaranteed using only simple gain inequalities for network components and algebraic relationships determined by the network. Quantum feedback networks are shown to be stable if the loop gain is less than one-this is an extension of the famous small gain theorem of classical control theory. We illustrate the simplicity and power of the small gain approach with applications to important problems of robust stability and robust stabilization.Comment: 16 page

Approaches for advancing scientific understanding of macrosystems

The emergence of macrosystems ecology (MSE), which focuses on regional- to continental-scale ecological patterns and processes, builds upon a history of long-term and broad-scale studies in ecology. Scientists face the difficulty of integrating the many elements that make up macrosystems, which consist of hierarchical processes at interacting spatial and temporal scales. Researchers must also identify the most relevant scales and variables to be considered, the required data resources, and the appropriate study design to provide the proper inferences. The large volumes of multi-thematic data often associated with macrosystem studies typically require validation, standardization, and assimilation. Finally, analytical approaches need to describe how cross-scale and hierarchical dynamics and interactions relate to macroscale phenomena. Here, we elaborate on some key methodological challenges of MSE research and discuss existing and novel approaches to meet them

Plasma Panel Sensors for Particle and Beam Detection

The plasma panel sensor (PPS) is an inherently digital, high gain, novel variant of micropattern gas detectors inspired by many operational and fabrication principles common to plasma display panels (PDPs). The PPS is comprised of a dense array of small, plasma discharge, gas cells within a hermetically-sealed glass panel, and is assembled from non-reactive, intrinsically radiation-hard materials such as glass substrates, metal electrodes and mostly inert gas mixtures. We are developing the technology to fabricate these devices with very low mass and small thickness, using gas gaps of at least a few hundred micrometers. Our tests with these devices demonstrate a spatial resolution of about 1 mm. We intend to make PPS devices with much smaller cells and the potential for much finer position resolutions. Our PPS tests also show response times of several nanoseconds. We report here our results in detecting betas, cosmic-ray muons, and our first proton beam tests.Comment: 2012 IEEE NS

Evolution of superconductivity in isovalent Te-substituted KxFe2-ySe2 crystals

We report the evolution of superconductivity and the phase diagram of the KxFe2-ySe2-zTez (z=0-0.6) crystals grown by a simple one-step synthesis. No structural transition is observed in any crystals, while lattice parameters exhibit a systematic expansion with Te content. The Tc exhibits a gradual decrease with increasing Te content from Tconset = 32.9 K at z = 0 to Tconset = 27.9 K at z = 0.5, followed by a sudden suppression of superconductivity at z = 0.6. Upon approaching a Te concentration of 0.6, the shielding volume fraction decreases and eventually drops to zero. Simultaneously, hump positions in r-T curve shift to lower temperatures. These results suggest that isovalent substitution of Te for Se in KxFe2-ySe2 crystals suppresses the superconductivity in this system.Comment: 10 pages, 1 table, 8 figure

LNK suppresses interferon signaling in melanoma.

LNK (SH2B3) is a key negative regulator of JAK-STAT signaling which has been extensively studied in malignant hematopoietic diseases. We found that LNK is significantly elevated in cutaneous melanoma; this elevation is correlated with hyperactive signaling of the RAS-RAF-MEK pathway. Elevated LNK enhances cell growth and survival in adverse conditions. Forced expression of LNK inhibits signaling by interferon-STAT1 and suppresses interferon (IFN) induced cell cycle arrest and cell apoptosis. In contrast, silencing LNK expression by either shRNA or CRISPR-Cas9 potentiates the killing effect of IFN. The IFN-LNK signaling is tightly regulated by a negative feedback mechanism; melanoma cells exposed to IFN upregulate expression of LNK to prevent overactivation of this signaling pathway. Our study reveals an unappreciated function of LNK in melanoma and highlights the critical role of the IFN-STAT1-LNK signaling axis in this potentially devastating disease. LNK may be further explored as a potential therapeutic target for melanoma immunotherapy

Measuring Shear-Induced Adhesion of Gecko-Inspired Fibrillar Arrays Using Scanning Probe Techniques

The natural ability of geckos and spiders to climb almost all surfaces using the compliant, nano‐structured components on their feet provides motivation for making bio‐inspired adhesives. The goal of the studies in this paper is to create an analytical technique for improving the ability to characterize dry adhesives modeled after these biological systems. The technique described herein uses a scanning probe microscope to manipulate a flat test surface in contact with biomimetic fibrillar arrays while monitoring the adhesion forces. Adhesion forces were measured after both normal contact and shear‐induced contact between the nano‐structured fibrils and the test surface. Results confirm that the adhesion forces are higher for bio‐inspired adhesives after a shear‐induced contact. Variations in these forces can be measured across the sample with micrometer‐scale lateral resolution. This method of analysis can be extended to evaluate bio‐inspired dry adhesives with realistic mechanisms of attachment utilized in robotic and similar applications of these materials

Harnessing Tunable Scanning Probe Techniques to Measure Shear Enhanced Adhesion of Gecko-Inspired Fibrillar Arrays

The hierarchical arrays of mesoscale to nanoscale fibrillar structures on a gecko’s foot enable the animal to climb surfaces of varying roughness. Adhesion force between the fibrillar structures and various surfaces is maximized after the gecko drags its foot in one direction, which has also been demonstrated to improve the adhesion forces of artificial fibrillar arrays. Essential conditions that influence the magnitude of these interactions include the lateral distance traveled and velocity between the contacting surfaces, as well as the velocity at which the two surfaces are subsequently separated. These parameters have, however, not been systematically investigated to assess the adhesion properties of artificial adhesives. We introduce a systematic study that investigates these conditions using a scanning probe microscope to measure the adhesion forces of artificial adhesives through a process that mimics the mechanism by which a gecko climbs. The measured adhesion response was different for arrays of shorter and longer fibrils. These results from 9000 independent measurements also provide further insight into the dynamics of the interactions between fibrillar arrays and contacting surfaces. These studies establish scanning probe microscopy techniques as a versatile approach for measuring a variety of adhesion properties of artificial fibrillar adhesives