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"Mawatari, Kazuma"
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Interleukin-31 promotes fibrosis and T helper 2 polarization in systemic sclerosis
Systemic sclerosis (SSc) is a chronic multisystem disorder characterized by fibrosis and autoimmunity. Interleukin (IL)-31 has been implicated in fibrosis and T helper (Th) 2 immune responses, both of which are characteristics of SSc. The exact role of IL-31 in SSc pathogenesis is unclear. Here we show the overexpression of IL-31 and IL-31 receptor A (IL-31RA) in dermal fibroblasts (DFs) from SSc patients. We elucidate the dual role of IL-31 in SSc, where IL-31 directly promotes collagen production in DFs and indirectly enhances Th2 immune responses by increasing pro-Th2 cytokine expression in DFs. Furthermore, blockade of IL-31 with anti-IL-31RA antibody significantly ameliorates fibrosis and Th2 polarization in a mouse model of SSc. Therefore, in addition to defining IL-31 as a mediator of fibrosis and Th2 immune responses in SSc, our study provides a rationale for targeting the IL-31/IL-31RA axis in the treatment of SSc.
Systemic sclerosis (SSc) disease involves multisystem fibrosis and autoimmunity with limited treatment options. Here the authors demonstrate that IL-31 and IL-31RA are overexpressed in dermal fibroblasts from SSc patients and show that fibrosis and cytokine release can be reduced upon blocking of IL-31/IL-31RA.
Journal Article
Nanofluidic optical diffraction interferometry for detection and classification of individual nanoparticles in a nanochannel
Detection and classification of nanoparticles in flow at a single particle resolution are becoming extremely important with the progress in materials chemistry, life science, and nanotechnology. Interferometric light scattering has been widely used as a highly sensitive nanoparticle detection technique. However, its application to flow cytometric analyses is challenging, because precise fluidic control and complicated optical system are inevitable for accurate measurement of individual nanoparticles in flow. Here, we report the development of nanofluidic optical diffraction interferometry (NODI) which utilizes optical diffraction by a single nanochannel as a reference light for interferometric light scattering detection of nanoparticles in the nanochannel. Our method detected individual gold nanoparticles as small as 20 nm in diameter in flow by a simple optical system. Furthermore, by introducing a dual-wavelength measurement system, four types of gold and silver nanoparticles with 40–60 nm in diameter were discriminated based on their interferometric signals. Using a support vector machine (SVM) algorithm, classification of individual nanoparticles was achieved with over 70% accuracy. Our simple yet sensitive detection method will be widely used for the quantification and characterization of various nanoparticles.
Journal Article
Characterization of optical diffraction by single nanochannel for aL–fL sample detection in nanofluidics
Nanofluidics which integrates analytical systems in 101–103 nm space provides ultra-sensitive analyses at a single-cell and single-molecule level. One of the key technologies for nanofluidics is the ultra-sensitive detection method; however, the ultra-small volume at aL–fL scale makes it challenging. Recently, we have developed a non-fluorescent molecule detection method for nanofluidics called photo-thermal optical diffraction (POD) which utilizes the photo-thermal effect of target molecules and optical diffraction by a single nanochannel. To improve the performance of such diffraction-based detection methods, the design and optimization of optical diffraction are essential. However, it is unknown whether the optical diffraction by a single nanochannel follows general diffraction theory because liquid properties change in the ultra-small space. In this study, we elucidated optical diffraction by a single nanochannel from theoretical calculations and experiments. Our experiments revealed the effect of channel size, channel position, and solvents in the nanochannel, which showed good agreement with proposed theoretical calculations. We also revealed no or little change of refractive index of water in the nanochannel compared with that in the bulk. Finally, we confirmed that the POD signal was proportional to the diffracted light intensity, and the calculated limit of detection of POD was 7.0 × 10–7 RIU in a detection volume of 0.23 fL. Our theoretical calculations and experimental results can be widely applied to the design and optimization of detection methods using optical diffraction by nanochannels and nanostructures.
Journal Article
Single-cell-level protein analysis revealing the roles of autoantigen-reactive B lymphocytes in autoimmune disease and the murine model
Despite antigen affinity of B cells varying from cell to cell, functional analyses of antigen-reactive B cells on individual B cells are missing due to technical difficulties. Especially in the field of autoimmune diseases, promising pathogenic B cells have not been adequately studied to date because of its rarity. In this study, functions of autoantigen-reactive B cells in autoimmune disease were analyzed at the single-cell level. Since topoisomerase I is a distinct autoantigen, we targeted systemic sclerosis as autoimmune disease. Decreased and increased affinities for topoisomerase I of topoisomerase I-reactive B cells led to anti-inflammatory and pro-inflammatory cytokine production associated with the inhibition and development of fibrosis, which is the major symptom of systemic sclerosis. Furthermore, inhibition of pro-inflammatory cytokine production and increased affinity of topoisomerase I-reactive B cells suppressed fibrosis. These results indicate that autoantigen-reactive B cells contribute to the disease manifestations in autoimmune disease through their antigen affinity.
Journal Article
Nano-bubble Valve
Valve technology is one of the important elements in micro or nanofluidic control. Many valve technologies have been realized for microfluidic control, by which the applications of microfluidic devices have expanded. However, valve technology for nanofluidic control (nanovalves) is still challenging due to the ultrasmall size (100 nm scale) of the nanochannels. We propose a novel nanovalve that utilizes nanobubbles. The entire nanochannel surface is made hydrophobic by surface modification. Nanobubbles are generated by light and removed in the nanochannels. The basic principle of nanobubble generation and removal was confirmed, and the valve function was confirmed by the introduction/cessation of pure water, which led to a change in the concentration of a fluorescent solution after mixing with the pure water. As a result, the high performance (70 ms response time and 400 kPa pressure capacity) of this simple nanovalve was demonstrated.
Journal Article
Metal-Free Fabrication of Fused Silica Extended Nanofluidic Channel to Remove Artifacts in Chemical Analysis
In microfluidics, especially in nanofluidics, nanochannels with functionalized surfaces have recently attracted attention for use as a new tool for the investigation of chemical reaction fields. Molecules handled in the reaction field can reach the single–molecule level due to the small size of the nanochannel. In such surroundings, contamination of the channel surface should be removed at the single–molecule level. In this study, it was assumed that metal materials could contaminate the nanochannels during the fabrication processes; therefore, we aimed to develop metal-free fabrication processes. Fused silica channels 1000 nm-deep were conventionally fabricated using a chromium mask. Instead of chromium, electron beam resists more than 1000 nm thick were used and the lithography conditions were optimized. From the results of optimization, channels with 1000 nm scale width and depth were fabricated on fused silica substrates without the use of a chromium mask. In nanofluidic experiments, an oxidation reaction was observed in a device fabricated by conventional fabrication processes using a chromium mask. It was found that Cr6+ remained on the channel surfaces and reacted with chemicals in the liquid phase in the extended nanochannels; this effect occurred at least to the micromolar level. In contrast, the device fabricated with metal-free processes was free of artifacts induced by the presence of chromium. The developed fabrication processes and results of this study will be a significant contribution to the fundamental technologies employed in the fields of microfluidics and nanofluidics.
Journal Article
Development of a pressure-driven nanofluidic control system and its application to an enzymatic reaction
A novel air-pressure-based nanofluidic control system was developed and its performance was examined. We found that the flow in a 100 nm scale nanochannel on a chip (called an extended nanospace channel) could be controlled within the pressure range of 0.003-0.4 MPa, flow rate range of 0.16-21.2 pL/min, and residence time range of 24 ms-32.4 s by using the developed nanofluidic control system. Furthermore, we successfully demonstrated an enzyme reaction in which the fluorogenic substrate TokyoGreen-β-galactoside (TG-β-gal) was hydrolyzed to the fluorescein derivative TokyoGreen (TG) and β-galactose by the action of β-galactosidase enzyme as a calalyst in a Y-shaped extended nanospace channel. The parameters for the reaction kinetics, such as K m, V max and k cat, were estimated for the nanofluidic reaction, and these values were compared with the results of bulk and microfluidic reactions. A comparison showed that the enzyme reaction rate in the Y-shaped extended nanospace channel increased by a factor of about two compared with the rates in the bulk and micro spaces. We thought that this nanospatial property resulted from the activated protons of water molecules in the extended nanospace. This assumption was supported by the result that the pH dependence of the maximum enzyme activity in the Y-shaped extended nanospace channel was slightly different from that in the bulk and micro spaces.
Journal Article
Extended-Nanofluidic Devices and the Unique Liquid Properties - Invited Paper
Microfluidic devices are downscaling to 10-100 nm space, which we call extended-nano space. Because the extended-nano space is a space to bridge isolated molecules and normal bulk fluid, new solution chemistry can be expected. However, it was difficult to investigate due to the ultra-small space. Our group developed fundamental technologies for the extended-nano fluidics such as nanofabrication and bonding for glass substrates, aL-fL pressure driven fluidic control, partial surface modification, and single molecule detection. Based on these technologies, many unique liquid properties were found such as viscosity increase, enhanced proton mobility, lower dielectric constant. In addition, the liquid property changes depended on channel size, channel shape, and kinds of liquid. New analytical and energy devices are created utilizing the unique properties in the extended-nano space. In this talk, fundamental technologies and unique liquid properties found in this space are mainly presented, which would have impact not only on chemistry and biology but also on semiconductor industry.
Journal Article
Transport of a Micro Liquid Plug in a Gas-Phase Flow in a Microchannel
Micro liquid droplets and plugs in the gas-phase in microchannels have been utilized in microfluidics for chemical analysis and synthesis. While higher velocities of droplets and plugs are expected to enable chemical processing at higher efficiency and higher throughput, we recently reported that there is a limit of the liquid plug velocity owing to splitting caused by unstable wetting to the channel wall. This study expands our experimental work to examine the dynamics of a micro liquid plug in the gas phase in a microchannel. The motion of a single liquid plug, 0.4–58 nL in volume, with precise size control in 39- to 116-m-diameter hydrophobic microchannels was investigated. The maximum velocity of the liquid plug was 1.5 m/s, and increased to 5 m/s with splitting. The plug velocity was 20% of that calculated using the Hagen-Poiseuille equation. It was found that the liquid plug starts splitting when the inertial force exerted by the fluid overcomes the surface tension, i.e., the Weber number (ratio of the inertial force to the surface tension) is higher than 1. The results can be applied in the design of microfluidic devices for various applications that utilize liquid droplets and plugs in the gas phase.
Journal Article