A bioavailable cathepsin S nitrile inhibitor abrogates tumor development

BACKGROUND: Cathepsin S has been implicated in a variety of malignancies with genetic ablation studies demonstrating a key role in tumor invasion and neo-angiogenesis. Thus, the application of cathepsin S inhibitors may have clinical utility in the treatment of cancer. In this investigation, we applied a cell-permeable dipeptidyl nitrile inhibitor of cathepsin S, originally developed to target cathepsin S in inflammatory diseases, in both in vitro and in vivo tumor models.

METHODS: Validation of cathepsin S selectivity was carried out by assaying fluorogenic substrate turnover using recombinant cathepsin protease. Complete kinetic analysis was carried out and true K i values calculated. Abrogation of tumour invasion using murine MC38 and human MCF7 cell lines were carried out in vitro using a transwell migration assay. Effect on endothelial tube formation was evaluated using primary HUVEC cells. The effect of inhibitor in vivo on MC38 and MCF7 tumor progression was evaluated using cells propagated in C57BL/6 and BALB/c mice respectively. Subsequent immunohistochemical staining of proliferation (Ki67) and apoptosis (TUNEL) was carried out on MCF7 tumors.

RESULTS: We confirmed that this inhibitor was able to selectively target cathepsin S over family members K, V, L and B. The inhibitor also significantly reduced MC38 and MCF7 cell invasion and furthermore, significantly reduced HUVEC endothelial tubule formation in vitro. In vivo analysis revealed that the compound could significantly reduce tumor volume in murine MC38 syngeneic and MCF7 xenograft models. Immunohistochemical analysis of MCF7 tumors revealed cathepsin S inhibitor treatment significantly reduced proliferation and increased apoptosis.

CONCLUSIONS: In summary, these results highlight the characterisation of this nitrile cathepsin S inhibitor using in vitro and in vivo tumor models, presenting a compound which may be used to further dissect the role of cathepsin S in cancer progression and may hold therapeutic potential.

The use of binary mixtures of 1-butyl-1-methylpyrrolidinium bis{(trifluoromethyl)sulfonyl}imide and aliphatic nitrile solvents as electrolyte for supercapacitors

Abstract The development of high voltage electrolytes is one of the key aspects for increasing both energy and power density of electrochemical double layer capacitors (EDLCs). The usage of blends of ionic liquids and organic solvents has been considered as a feasible strategy since these electrolytes combine high usable voltages and good transport properties at the same time. In this work, the ionic liquid 1-butyl-1-methylpyrrolidinium bis{(trifluoromethyl)sulfonyl}imide ([Pyrr14][TFSI]) was mixed with two nitrile-based organic solvents, namely butyronitrile and adiponitrile, and the resulting blends were investigated regarding their usage in electrochemical double layer capacitors. Both blends have a high electrochemical stability, which was confirmed by prolonged float tests at 3.2 V, as well as, good transport properties. In fact, the butyronitrile blend reaches a conductivity of 17.14 mS·cm−1 and a viscosity of 2.46 mPa·s at 20 °C, which is better than the state-of-the-art electrolyte (1 mol·dm−3 of tetraethylammonium tetrafluoroborate in propylene carbonate).

Binary Mixtures of 1-Butyl-1-Methylpyrrolidinium Bis{(trifluoromethyl)Sulfonyl}Imide and Aliphatic Nitrile Solvents As Electrolyte for Electrochemical Double Layer Capacitors (Invited).

Electrochemical double layer capacitors (EDLCs), also known as supercapacitors, are promising energy storage devices, especially when considering high power applications [1]. EDLCs can be charged and discharged within seconds [1], feature high power (10 kW·kg-1) and an excellent cycle life (>500,000 cycles). All these properties are a result of the energy storage process of EDLCs, which relies on storing energy by charge separation instead of chemical redox reactions, as utilized in battery systems. Upon charging, double layers are forming at the electrode/electrolyte interface consisting of the electrolyte’s ions and electric charges at the electrode surface.In state-of-the-art EDLC systems activated carbons (AC) are used as active materials and tetraethylammonium tetrafluoroborate ([Et4N][BF4]) dissolved in organic solvents like propylene carbonate (PC) or acetonitrile (ACN) are commonly used as the electrolyte [2]. These combinations of materials allow operative voltages up to 2.7 V - 2.8 V and an energy in the order of 5 Wh·kg-1[3]. The energy of EDLCs is dependent on the square of the operative voltage, thus increasing the usable operative voltage has a strong effect on the delivered energy of the device [1]. Due to their high electrochemical stability, ionic liquids (ILs) were thoroughly investigated as electrolytes for EDLCs, as well as, batteries, enabling high operating voltages as high as 3.2 V - 3.5 V for the former [2]. While their unique ionic structure allows the usage of neat ILs as electrolyte in EDLCs, ILs suffer from low conductivity and high viscosity increasing the intrinsic resistance and, as a result, a lower power output of the device. In order to overcome this issue, the usage of blends of ionic liquids and organic solvents has been considered a feasible strategy as they combine high usable voltages, while still retaining good transport properties at the same time.In our recent work the ionic liquid 1-butyl-1-methylpyrrolidinium bis{(trifluoromethyl)sulfonyl}imide ([Pyrr14][TFSI]) was combined with two nitrile-based organic solvents, namely butyronitrile (BTN) and adiponitrile (ADN), and the resulting blends were investing regarding their usage in electrochemical double layer capacitors [4,5]. Firstly, the physicochemical properties were investigated, showing good transport properties for both blends, which are similar to the state-of-the-art combination of [Et4N][BF4] in PC. Secondly, the electrochemical properties for EDLC application were studied in depth revealing a high electrochemical stability with a maximum operative voltage as high as 3.7 V. In full cells these high voltage organic solvent based electrolytes have a good performance in terms of capacitance and an acceptable equivalent series resistance at cut-off voltages of 3.2 and 3.5 V. However, long term stability tests by float testing revealed stability issues when using a maximum voltage of 3.5 V for prolonged time, whereas at 3.2 V no such issues are observed (Fig. 1).Considering the obtained results, the usage of ADN and BTN blends with [Pyrr14][TFSI] in EDLCs appears to be an interesting alternative to state-of-the-art organic solvent based electrolytes, allowing the usage of higher maximum operative voltages while having similar transport properties to 1 mol∙dm-3 [Et4N][BF4] in PC at the same time.

Tailoring Magnetic, Mechanical and Dielectric Properties of Magnetorheological Elastomers based on Natural Rubber and Iron by Magnetic Field Assisted Curing for Possible Applications

If magnetism is universal in nature, magnetic materials are ubiquitous. A life without magnetism is unthinkable and a day without the influence of a magnetic material is unimaginable. They find innumerable applications in the form of many passive and active devices namely, compass, electric motor, generator, microphone, loud speaker, maglev train, magnetic resonance imaging, data recording and reading, hadron collider etc. The list is endless. Such is the influence of magnetism and magnetic materials in ones day to day life. With the advent of nanoscience and nanotechnology, along with the emergence of new areas/fields such as spintronics, multiferroics and magnetic refrigeration, the importance of magnetism is ever increasing and attracting the attention of researchers worldwide. The search for a fluid which exhibits magnetism has been on for quite some time. However nature has not bestowed us with a magnetic fluid and hence it has been the dream of many researchers to synthesize a magnetic fluid which is thought to revolutionize many applications based on magnetism. The discovery of a magnetic fluid by Jacob Rabinow in the year 1952 paved the way for a new branch of Physics/Engineering which later became magnetic fluids. This gave birth to a new class of material called magnetorheological materials. Magnetorheological materials are considered superior to electrorheological materials in that magnetorheology is a contactless operation and often inexpensive.Most of the studies in the past on magnetorheological materials were based on magnetic fluids. Recently the focus has been on the solid state analogue of magnetic fluids which are called Magnetorheological Elastomers (MREs). The very word magnetorheological elastomer implies that the rheological properties of these materials can be altered by the influence of an external applied magnetic field and this process is reversible. If the application of an external magnetic field modifies the viscosity of a magnetic fluid, the effect of external magnetic stimuli on a magnetorheological elastomer is in the modification of its stiffness. They are reversible too. Magnetorheological materials exhibit variable stiffness and find applications in adaptive structures of aerospace, automotive civil and electrical engineering applications. The major advantage of MRE is that the particles are not able to settle with time and hence there is no need of a vessel to hold it. The possibility of hazardous waste leakage is no more with a solid MRE. Moreover, the particles in a solid MRE will not affect the performance and durability of the equipment. Usually MR solids work only in the pre yield region while MR fluids, typically work in the post yield state. The application of an external magnetic field modifies the stiffness constant, shear modulus and loss modulus which are complex quantities. In viscoelastic materials a part of the input energy is stored and released during each cycle and a part is dissipated as heat. The storage modulus G′ represents the capacity of the material to store energy of deformation, which contribute to material stiffness. The loss modulusG′′ represents the ability of the material to dissipate the energy of deformation. Such materials can find applications in the form of adaptive vibration absorbers (ATVAs), stiffness tunable mounts and variable impedance surfaces. MREs are an important material for automobile giants and became the focus of this research for eventual automatic vibration control, sound isolation, brakes, clutches and suspension systems

Synthesis, Characterization and Properties of Conductive Elastomeric Composites Based on Polypyrrole and Short Nylon-6 Fiber

The search for new materials especially those possessing special properties continues at a great pace because of ever growing demands of the modern life. The focus on the use of intrinsically conductive polymers in organic electronic devices has led to the development of a totally new class of smart materials. Polypyrrole (PPy) is one of the most stable known conducting polymers and also one of the easiest to synthesize. In addition, its high conductivity, good redox reversibility and excellent microwave absorbing characteristics have led to the existence of wide and diversified applications for PPy. However, as any conjugated conducting polymer, PPy lacks processability, flexibility and strength which are essential for industrial requirements. Among various approaches to making tractable materials based on PPy, incorporating PPy within an electrically insulating polymer appears to be a promising method, and this has triggered the development of blends or composites. Conductive elastomeric composites of polypyrrole are important in that they are composite materials suitable for devices where flexibility is an important parameter. Moreover these composites can be moulded into complex shapes.

Rheology of bituminous mastics and mortars containing crumb rubber from tyres: a novel dry-hybrid technology

This report studied the effect of crumb rubber in the asphalt mixture. The mixtures were also having limestone filler as a modifier. Mastic and mortar (mastic-fine aggregate system) mixture having different quantities of crumb rubber and limestone filler modifiers have been tested in order to find the best rutting resistance combination with an acceptable stiffness. The rheological tests on bituminous mastics and mortars have done in the laboratories in Nottingham Transport Engineering Centre (NTEC) and University of Bologna (DICAM). In the second chapter, an extensive literature review about the binders, additives, asphalt mixtures, various modelling and testing methods have been reviewed. In the third chapter, the physical and rheological properties of the binders have been investigated using both traditional devices and DSRs. The forth chapter is dedicated to finding the behaviour of the modified mastics (Binder-modifier system) with different combinations. Five different combinations of crumb rubber and limestone filler mastic tested with various methods using Dynamic Shear Rheometers. In the fifth chapter, in order to find the effect of the modifiers in the rheological properties of the complete asphalt mixture, the fine aggregates added to the same mastic combinations. In this phase, the behaviour of the system so-called mortar; binder, rubber, filler and fine aggregates) has been studied using the DSR device and the traditional tests. The results show that using fine crumb rubber reduces the thermo sensibility of the mastic (Binder Bitumen System) and improves its elasticity. Limestone filler in the other hand increases the mixture stiffness at high Frequencies. Another important outcome of this research was that the rheological properties of the mortars were following the same trend of the mastics, therefore study the rheological properties of the mastic gives an upright estimation of the mortar.

Real, rubber or virtual: The vision of “one’s own” body as a means for pain modulation. A narrative review

In the last few years a branch of pain research has been focussing on the modulatory effects of the vision of the body on pain perception. So, for instance, the vision of one’s own real body has been proven to induce analgesic effects. On the other hand, bodily illusions such as the rubber hand illusion have provided new tools for the study of perceptual processes during altered body ownership states. Recently, new paradigms of body ownership made use of a technology that is going places both in clinical and in experimental settings, i.e. virtual reality. While the vision of one’s own real body has been proven to yield compelling analgesic effects, slightly more controversial are those attributed to the vision of “owned” dummy bodies. This review will discuss the studies that examined the effects on pain perception of the vision of the own body, with or without body ownership illusions.

BETA-GA2O3: A TRANSPARENT CONDUCTIVE OXIDE FOR POTENTIAL RESISTIVE SWITCHING APPLICATIONS

Thesis (Ph.D.)--University of Washington, 2016-08

Diketonylpyridinium cations as a support of new ionic liquid crystals and ion-conductive materials: analysis of counter-ion effects

Ionic liquid crystals (ILCs) allow the combination of the high ionic conductivity of ionic liquids (ILs) with the supramolecular organization of liquid crystals (LCs). ILCs salts were obtained by the assembly of long-chained diketonylpyridinium cations of the type [HOO^(R(n)pyH)] + and BF_(4)^(-) , ReO_(4)^(-), NO_(3)^(-), CF_(3)SO_(3)^(-), CuCl_(4)^(2-) counter-ions. We have studied the thermal behavior of five series of compounds by differential scanning calorimetry (DSC) and hot stage polarized light optical microscopy (POM). All materials show thermotropic mesomorphism as well as crystalline polymorphism. X-ray diffraction of the [HOO^(R(12)pyH)][ReO_(4)] crystal reveals a layered structure with alternating polar and apolar sublayers. The mesophases also exhibit a lamellar arrangement detected by variable temperature powder X-ray diffraction. The CuCl_(4)^(2-) salts exhibit the best LC properties followed by the ReO_(4)^(-) ones due to low melting temperature and wide range of existence. The conductivity was probed for the mesophases in one species each from the ReO_(4)^(-) , and CuCl_(4)^(2-) families, and for the solid phase in one of the non-mesomorphic Cl^(-) salts. The highest ionic conductivity was found for the smectic mesophase of the ReO_(4)^(-) containing salt, whereas the solid phases of all salts were dominated by electronic contributions. The ionic conductivity may be favored by the mesophase lamellar structure.

[3 + 2]-Cycloadditions of nitrile ylides after photoactivion of vinyl azides under flow conditions

The photodenitrogenation of vinyl azides to 2H-azirines by using a photoflow reactor is reported and compared with thermal formation of 2H-azirines. Photochemically, the ring of the 2H-azirines was opened to yield the nitrile ylides, which underwent a [3 + 2]-cycloaddition with 1,3-dipolarophiles. When diisopropyl azodicarboxylate serves as the dipolarophile, 1,3,4-triazoles become directly accessible starting from the corresponding vinyl azide. © 2013 Cludius-Brandt et al.

Periodic emission of droplets from an oscillating electrified meniscus of a low-viscosity, highly conductive liquid

The generation of identical droplets of controllable size in the micrometer range is a problem of much interest owing to the numerous technological applications of such droplets. This work reports an investigation of the regime of periodic emission of droplets from an electrified oscillating meniscus of a liquid of low viscosity and high electrical conductivity attached to the end of a capillary tube, which may be used to produce droplets more than ten times smaller than the diameter of the tube. To attain this periodic microdripping regime, termed axial spray mode II by Juraschek and Röllgen [R. Juraschek and F. W. Röllgen, Int. J. Mass Spectrom. 177, 1 (1998)], liquid is continuously supplied through the tube at a given constant flow rate, while a dc voltage is applied between the tube and a nearby counter electrode. The resulting electric field induces a stress at the surface of the liquid that stretches the meniscus until, in certain ranges of voltage and flow rate, it develops a ligament that eventually detaches, forming a single droplet, in a process that repeats itself periodically. While it is being stretched, the ligament develops a conical tip that emits ultrafine droplets, but the total mass emitted is practically contained in the main droplet. In the parametrical domain studied, we find that the process depends on two main dimensionless parameters, the flow rate nondimensionalized with the diameter of the tube and the capillary time, q, and the electric Bond number BE, which is a nondimensional measure of the square of the applied voltage. The meniscus oscillation frequency made nondimensional with the capillary time, f, is of order unity for very small flow rates and tends to decrease as the inverse of the square root of q for larger values of this parameter. The product of the meniscus mean volume times the oscillation frequency is nearly constant. The characteristic length and width of the liquid ligament immediately before its detachment approximately scale as powers of the flow rate and depend only weakly on the applied voltage. The diameter of the main droplets nondimensionalized with the diameter of the tube satisfies dd≈(6/π)1/3(q/f)1/3, from mass conservation, while the electric charge of these droplets is about 1/4 of the Rayleigh charge. At the minimum flow rate compatible with the periodic regimen, the dimensionless diameter of the droplets is smaller than one-tenth, which presents a way to use electrohydrodynamic atomization to generate droplets of highly conducting liquids in the micron-size range, in marked contrast with the cone-jet electrospray whose typical droplet size is in the nanometric regime for these liquids. In contrast with other microdripping regimes where the mass is emitted upon the periodic formation of a narrow capillary jet, the present regime gives one single droplet per oscillation, except for the almost massless fine aerosol emitted in the form of an electrospray.

Microfabricated elastomer tactile sensors for robotic fingertip systems

Tactile sensing is an important aspect of robotic systems, and enables safe, dexterous robot-environment interaction. The design and implementation of tactile sensors on robots has been a topic of research over the past 30 years, and current challenges include mechanically flexible “sensing skins”, high dynamic range (DR) sensing (i.e.: high force range and fine force resolution), multi-axis sensing, and integration between the sensors and robot. This dissertation focuses on addressing some of these challenges through a novel manufacturing process that incorporates conductive and dielectric elastomers in a reusable, multilength-scale mold, and new sensor designs for multi-axis sensing that improve force range without sacrificing resolution. A single taxel was integrated into a 1 degree of freedom robotic gripper for closed-loop slip detection. Manufacturing involved casting a composite silicone rubber, polydimethylsiloxane (PDMS) filled with conductive particles such as carbon nanotubes, into a mold to produce microscale flexible features on the order of 10s of microns. Molds were produced via microfabrication of silicon wafers, but were limited in sensing area and were costly. An improved technique was developed that produced molds of acrylic using a computer numerical controlled (CNC) milling machine. This maintained the ability to produce microscale features, and increased the sensing area while reducing costs. New sensing skins had features as small as 20 microns over an area as large as a human hand. Sensor architectures capable of sensing both shear and normal force sensing with high dynamic range were produced. Using this architecture, two sensing modalities were developed: a capacitive approach and a contact resistive approach. The capacitive approach demonstrated better dynamic range, while the contact resistive approach used simpler circuitry. Using the contact resistive approach, normal force range and resolution were 8,000 mN and 1,000 mN, respectively, and shear force range and resolution were 450 mN and 100 mN, respectively. Using the capacitive approach, normal force range and resolution were 10,000 mN and 100 mN, respectively, and shear force range and resolution were 1,500 mN and 50 mN, respectively.

Taraxacum koksaghyz Rodin as an alternative source of natural rubber and inulin; agronomic advances and genetic linkage map

126 p. El contenido del capítulo 3 está sujeto a confidencialidad.

Leaf anatomy of rubber-tree clones

A seringueira é uma planta de fácil reconhecimento por ser lenhosa, de porte mediano a grande, que apresenta um padrão característico de desfolha e reenfolhamento e, sobretudo, pela produção de látex. O objetivo do trabalho foi efetuar um estudo anatômico e morfológico foliar, comparando os clones RRIM 600 e GT 1 de seringueira &91;Hevea brasiliensis (Wild. ex Adr. de Juss.) Muell.- Arg&93;, desenvolvidos sob as mesmas condições edáficas e climáticas, para obtenção de informações que possam fornecer subsídios para correlações com dados fisiológicos e também diferenciar os clones em relação ao conteúdo de fibras, espessamento de tecidos do parênquima paliçádico e do parênquima lacunoso, caracterização anatômica do pecíolo, número e tamanho de estômatos e fornecer dados referentes a morfologia foliolar. Foram realizadas secções transversais na região do mesófilo, nervura central e pecíolo, seguindo-se os métodos usuais de preparação de lâminas permanentes. Foram realizadas análises biométricas de extensões de tecidos dos parênquimas paliçádico e lacunoso e contagem do número de células do parênquima lacunoso. Paralelamente foram realizadas análises biométricas para aferições de estômatos. Não houve diferenças para a altura das células epidérmicas, altura e número de camadas do parênquima lacunoso e para o comprimento e para a maior largura do limbo foliolar. Porém houve variação para a espessura das células do parênquima paliçádico, sendo que GT 1 apresentou maior espessura em relação a RRIM 600. GT1 apresentou maior número de estômatos em relação a RRIM 600, porém com menor tamanho. GT1 apresentou maior diâmetro da nervura central da folha e do pecíolo e maior quantidade de fibras de esclerênquima que RRIM 600.

Microclimate, development and productivity of robusta coffee shaded by rubber trees and at full sun.

Existem poucos estudos sobre arborização de café conilon com seringueira. Objetivou-se avaliar o microclima, desenvolvimento e produtividade do cafeeiro conilon cultivado a pleno sol e sob sombreamento proporcionado pela seringueira. O experimento foi composto por uma lavoura de café conilon (Coffea canephora), cultivada a pleno sol e outra lavoura de café consorciada com seringueira (Hevea brasiliensis). A seringueira e o cafeeiro foram plantados no sentido Leste/Oeste, em Jaguaré, Espírito Santo, Brasil. Avaliou-se a luminosidade, temperatura e umidade relativa do ar, concentração foliar de nutrientes, medição dos internódios dos ramos plagiotrópicos e ortotrópicos, área foliar, índice relativo de clorofila, e a produtividade do cafeeiro. O sombreamento influenciou diretamente no microclima, reduzindo a temperatura do ar no verão e no inverno e aumentando a umidade relativa. A luminosidade no verão teve uma redução media de 905 lumens ft-2 ao longo de todo dia, equivalente a 72,49%, e no inverno de 1665 lumens ft-2, equivalente a 88,04%. O sombreamento proporcionou maior estiolamento dos ramos plagiotrópicos e ortotrópicos, bem como maior expansão foliar. A concentração foliar de Fe e Mn foram maiores no cafeeiro arborizado. A clorofila b e total estimada foram maior no cafeeiro cultivado a pleno sol. O denso sombreamento oferecido pela seringueira nas condições estudadas proporcionou perdas na produtividade do cafeeiro, contudo, ocorre a formação da seringueira.