Simultaneous targeting of CD14 and factor XIa by a fusion protein consisting of an anti-CD14 antibody and the modified second domain of bikunin improves survival in rabbit sepsis models.

Severe sepsis is a complex, multifactorial, and rapidly progressing disease characterized by excessive inflammation and coagulation following bacterial infection. To simultaneously suppress pro-inflammatory and pro-coagulant responses, we genetically engineered a novel fusion protein (MR1007) consisting of an anti-CD14 antibody and the modified second domain of bikunin, and evaluated the potential of MR1007 as an anti-sepsis agent. Suppressive effects of MR1007 on lipopolysaccharide (LPS)-induced inflammatory responses were assessed using peripheral blood mononuclear cells or endothelial cells. Its inhibitory activity against the coagulation factor XIa was assessed using a purified enzyme and a chromogenic substrate. Anticoagulant activity was assessed using human or rabbit plasma. Anti-inflammatory and anti-coagulant effects and/or survival benefits were evaluated in an endotoxemia model and a cecal ligation and puncture model. MR1007 inhibited LPS-induced cytokine production in peripheral blood mononuclear cells and endothelial cells, inhibited factor XIa, and exhibited anticoagulant activity. In an endotoxemia model, 0.3-3mg/kg MR1007 suppressed pro-inflammatory and pro-coagulant responses in a dose-dependent manner; at a dose of 3mg/kg, the protein improved survival even when administered 8h after the LPS injection. In addition, 10mg/kg MR1007 administered 2h post cecal ligation and puncture improved survival. However, MR1007 administered at doses up to 30mg/kg did not increase ear bleeding time or bacterial counts in the cecal ligation and puncture model. Thus, simultaneous targeting of CD14 and factor XIa improves survival in the rabbit endotoxemia and sepsis models and represents a promising approach for the treatment of severe sepsis.

Waveguide-mode interference lithography technique for high contrast subwavelength structures in the visible region.

We explore possibilities of waveguide-mode interference lithography (WMIL) technique for high contrast subwavelength structures in the visible region. Selecting an appropriate waveguide-mode, we demonstrate high contrast resist mask patterns for the first time. TM1 mode in the waveguide is shown to be useful for providing a three-dimensional structure whose cross section is checkerboard pattern. Applying our WMIL technique, we demonstrate 1D, 2D and 3D subwavelength resist patterns that are widely used for the fabrication of metamteterials in the visible region. In addition to the resist patterns, we demonstrate a resonance at 1.9 eV for a split tube structure experimentally.

Saturated absorption spectroscopy of acetylene molecules with an optical nanofiber.

We performed saturated absorption spectroscopy of acetylene (C2H2) ν1 + ν3 band transitions with an optical nanofiber (ONF). Owing to high-intensity light around the ONF, we observed a Lamb dip at relatively low-power laser (~10 mW) without a cavity. Our results showed that the simple ONF spectrometer is advantageous for performing saturation absorption spectroscopy and serves as a practical low-cost wavelength reference in the optical fiber communication band.

Precise intensity correlation measurement for atomic resonance fluorescence from optical molasses.

We measured the intensity correlation of true thermal light scattered from cold atoms in an optical molasses. Using a single-mode fiber as a transverse mode filter, measurement with maximally high spatial coherence was realized, allowing us to observe ideal photon bunching with unprecedented precision. The measured intensity correlation functions showed a definite bimodal structure with fast damped oscillation from the maximum value of 2.02(3) and slow monotonic decay toward unity. The oscillation can be understood as an interference between elastic and inelastic scattering fields in resonance fluorescence.

A novel antiplatelet antibody therapy that induces cAMP-dependent endocytosis of the GPVI/Fc receptor gamma-chain complex.

Platelet adhesion to vascular subendothelium, mediated in part by interactions between collagen and glycoprotein VI (GPVI) complexed with Fc receptor gamma-chain, is crucial for thrombus formation. Antiplatelet therapy benefits patients with various thrombotic and ischemic diseases, but the safety and efficacy of existing treatments are limited. Recent data suggest GPVI as a promising target for a novel antiplatelet therapy, for example, GPVI-specific Abs that deplete GPVI from the surface of platelets. Here, we characterized GPVI-specific auto-Abs (YA-Abs) from the first reported patient with ongoing platelet GPVI deficiency caused by the YA-Abs. To obtain experimentally useful human GPVI-specific mAbs with characteristics similar to YA-Abs, we generated human GPVI-specific mouse mAbs and selected 2 representative mAbs, mF1201 and mF1232, whose binding to GPVI was inhibited by YA-Abs. In vitro, mF1201, but not mF1232, induced human platelet activation and GPVI shedding, and mF1232 inhibited collagen-induced human platelet aggregation. Administration of mF1201 and mF1232 to monkeys caused GPVI immunodepletion with and without both significant thrombocytopenia and GPVI shedding, respectively. When a human/mouse chimeric form of mF1232 (cF1232) was labeled with a fluorescent endocytosis probe and administered to monkeys, fluorescence increased in circulating platelets and surface GPVI was lost. Loss of platelet surface GPVI mediated by cF1232 was successfully reproduced in vitro in the presence of a cAMP-elevating agent. Thus, we have characterized cAMP-dependent endocytosis of GPVI mediated by a human GPVI-specific mAb as what we believe to be a novel antiplatelet therapy.

Holographic storage of multiple coherence gratings in a Bose-Einstein condensate.

We demonstrate superradiant conversion between a two-mode collective atomic state and a single-mode light field in an elongated cloud of Bose-condensed atoms. Two off-resonant write beams induce superradiant Raman scattering, producing two independent coherence gratings with different wave vectors in the cloud. By applying phase-matched read beams after a controllable delay, the gratings can be selectively converted into the light field also in a superradiant way. Because of the large optical density and the small velocity width of the condensate, a high conversion efficiency of >70% and a long storage time of >120 micros were achieved.

Mirror magneto-optical trap using circularly polarized light-emitting optical fibers.

A fiber-optic mirror magneto-optical trap (mirror-MOT) that uses a pair of circularly polarized light-emitting optical fibers as an optical access is demonstrated. The fiber is fabricated so that a length of birefringence fiber, designed to be a quarter wave retarder at both wavelengths of 780 and 852 nm, is attached directly onto a polarization-maintaining normal fiber. The polarization states of light emitted from the fibers are sufficiently circular for the operation of a mirror-MOT with 87Rb atoms. The mirror-MOT is able to capture approximately the same number of atoms obtainable with a conventional mirror-MOT. The technique makes it possible to fabricate a compact MOT apparatus by introducing the optical fibers directly into an ultrahigh-vacuum chamber.

Increased cytotoxicity of soluble Fas ligand by fusing isoleucine zipper motif.

Fas (CD95) ligand (FasL) has the ability to induce apoptosis in Fas-expressing glioma cells by binding to Fas. Several molecular species have been designed to be soluble Fas ligands for therapeutic purposes. We successfully constructed a chimeric soluble FasL by fusing an isoleucine zipper motif for self-oligomerization and a FLAG sequence to the extracellular domain of the human Fas ligand (FIZ-shFasL). The cytotoxic effect of FIZ-shFasL on Jurkat cells was equivalent to that of membrane-bound FasL and approximately 10-fold stronger than that of agonistic anti-Fas antibody (CH-11). Flow cytometric analysis demonstrated that the differential Fas expression of human brain tumor cell lines partially correlated with levels of apoptosis through FIZ-shFasL. The upper limit of FIZ-shFasL for safe systemic administration to rat is estimated as below 2 microg/ml in plasma concentration. FIZ-shFasL could be applicable as a therapeutic agent for cancer.