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Dedicator of cytokinesis 3 (DOCK3) is an atypical member of the guanine nucleotide exchange factors (GEFs) and plays important roles in neurite outgrowth. DOCK3 forms a complex with Engulfment and cell motility protein 1 (Elmo1) and effectively activates Rac1 and actin dynamics. In this study, we screened 462,169 low-molecular-weight compounds and identified the hit compounds that stimulate the interaction between DOCK3 and Elmo1, and neurite outgrowth in vitro. Some of the derivatives from the hit compound stimulated neuroprotection and axon regeneration in a mouse model of optic nerve injury. Our findings suggest that the low-molecular-weight DOCK3 activators could be a potential therapeutic candidate for treating axonal injury and neurodegenerative diseases including glaucoma.

Activation of neurotrophic factor signaling is a promising therapy for neurodegeneration. However, the transient nature of ligand-dependent activation limits its effectiveness. In this study, we solved this problem by inventing a system that forces membrane localization of the intracellular domain of Tropomyosin receptor kinase B (iTrkB), which results in constitutive activation without ligands. Our system overcomes the small size limitation of the genome packaging in adeno-associated virus (AAV) and allows high expression of the transgene. Using AAV-mediated gene therapy into the eyes, we demonstrated that iTrkB expression enhances neuroprotection in mouse models of glaucoma and stimulates robust axon regeneration after optic nerve injury. In addition, iTrkB expression in the retina was also effective in an optic tract transection model, in which the injury site is near the superior colliculus. Regenerating axons successfully formed pathways to their brain targets, resulting in partial recovery of visual behaviour. Our system may be also applicable to other trophic factor signaling and lead to a significant advance in the field of gene therapy for neurotrauma and neurodegenerative disorders including glaucoma.

Activation of neurotrophic factor signaling is a promising therapy for neurodegeneration. However, limited availability of both ligands and receptors permits only transient activation. In this study, we conquered this problem by inventing a new system that forces membrane localization of the intracellular domain of neurotrophin receptor TrkB, which results in constitutive activation without ligands. Our new system overcomes the small size limitation of the genome packaging in adeno-associated virus and allows high expression of the transgene. Single gene therapy using the modified form of TrkB enhances neuroprotection in mose models of glaucoma, and stimulates robust axon regeneration after optic nerve injury. Our system may be also applicable to other trophic factor signaling and lead to a significant advance in the field of gene therapy for neurodegenerative disorders.

The DOCK-D (dedicator of cytokinesis D) family proteins are atypical guanine nucleotide exchange factors that regulate Rho GTPase activity. The family consists of Zizimin1 (DOCK9), Zizimin2 (DOCK11), and Zizimin3 (DOCK10). Functions of the DOCK-D family proteins are presently not well-explored, and the role of the DOCK-D family in neuroinflammation is unknown. In this study, we generated three mouse lines in which DOCK9 (DOCK9(−/−)), DOCK10 (DOCK10(−/−)), or DOCK11 (DOCK11(−/−)) had been deleted and examined the phenotypic effects of these gene deletions in MOG(35–55) peptide-induced experimental autoimmune encephalomyelitis, an animal model of the neuroinflammatory disorder multiple sclerosis. We found that all the gene knockout lines were healthy and viable. The only phenotype observed under normal conditions was a slightly smaller proportion of B cells in splenocytes in DOCK10(−/−) mice than in the other mouse lines. We also found that the migration ability of macrophages is impaired in DOCK10(−/−) and DOCK11(−/−) mice and that the severity of experimental autoimmune encephalomyelitis was ameliorated only in DOCK10(−/−) mice. No apparent phenotype was observed for DOCK9(−/−) mice. Further investigations indicated that lipopolysaccharide stimulation up-regulates DOCK10 expression in microglia and that microglial migration is decreased in DOCK10(−/−) mice. Up-regulation of C–C motif chemokine ligand 2 (CCL2) expression induced by activation of Toll-like receptor 4 or 9 signaling was reduced in DOCK10(−/−) astrocytes compared with WT astrocytes. Taken together, our findings suggest that DOCK10 plays a role in innate immunity and neuroinflammation and might represent a potential therapeutic target for managing multiple sclerosis.

A reagent generated from TMSN3/KMnO4/BnEt3NCl was found to promote an SH2′ radical azidation of a bromo silyl enol ether to furnish an azido silyl enol ether via olefin transposition. With the present azidation protocol, a new synthetic approach to agelastatin A, a potent antitumor marine alkaloid, has been established.

To determine the effectiveness of a single or a combination of topical neurotrophic factors (NFs) in protecting retinal ganglion cells (RGCs) in the rat optic nerve crush (ONC) model, the left ONC was performed to induce the death of the RGCs in adult Sprague-Dawley rats. The NFs studied were tauroursodeoxycholic acid (TUDCA), citicoline, neurotrophin-4 (NT-4), combined TUDCA/citicoline (Doublet-1), combined TUDCA/NT-4 (Doublet-2), combined TUDCA/citicoline/NT-4 (Triplet), and PBS. After 2 weeks, the number of RGCs was determined by Brn3a immunostaining. The optic nerves were immunostained for anti-Growth Associated Protein-43(GAP-43) and -200kD neurofilament heavy antibody to study optic nerve regeneration. Two weeks after the ONC, the densities of RGCs in all treated eyes were significantly higher than that of the PBS treated eyes. In the Triplet group, the number of RGC axons after ONC was significantly higher than that in all of the single treatment groups and the number of TUNEL positive cells was significantly reduced and the number of GAP-43 immunopositive axons was significantly greater than those in the PBS group. Neovascularization was observed only in the Doublet-1 group. We conclude that the combination of the three NFs was the most effective way to protect RGCs after the ONC.

A reagent generated from TMSN

This paper proposes highly reliable coding methods for applications in two extreme conditions. n-out-of-8 level cell (nLC) is proposed for archival applications which require significantly long data-retention time with small write/erase cycle. On the other hand, for applications with large write/erase cycle and short data-retention time (enterprise application, etc.), universal asymmetric coding (UAC) is proposed. nLC reduces the number of memory states to improve the reliability with low cost overhead. In 7LC, the bit-error rate (BER) reduction will be 79% after 1k-year data retention while seven memory states are efficiently used out of eight states. By considering nLC with error-correcting codes (ECCs), the optimum number of cell levels (n) can be determined to minimize the bit-cost with given acceptable data-retention time. In UAC, the coding method is changed according to the write/erase cycle and data-retention time to keep the BER low. As a result, BER is reduced by 52% at maximum, compared with the original random pattern.

Packet classification is an essential function in Internet routers that provides advanced network services such as virtual private networks (VPNs) and quality of service (QoS). Decision tree-based packet classification algorithms such as HiCuts and HyperCuts allow the tradeoff between storage and throughput in the experimental result with the real life rulesets. However, the memory consumption of these algorithms remains high when high throughput is required. In this paper, we propose the tree data structure whose storage is small maintaining high throughput. It is based on the two ideas: The first is to use Level Ordered Unary Degree Sequence (LOUDS) which is a succinct representation of a tree structure. A general tree of n nodes is usually represented in pointer form, requiring 64n bits in 64-bit architecture, whereas LOUDS requires 2n+o(n) bits. Because LOUDS can access any child node from its parent one in constant time, the tree traversal is fast. The second is reducing the information contained in the tree node. This also reduces storage requirements without affecting search speed. The proposed data structure requires up to approximately one ninth less memory than pointer-formed tree, and the time complexity of a packet classification is equivalent to the pointer-formed tree.

Fatty acyl-AMP ligases (FAALs) activate fatty acids as acyladenylates, and subsequently catalyze their transfer onto the acyl carrier proteins (ACPs) of polyketide synthases (PKSs) or nonribosomal peptide synthetases to produce lipidic metabolites. Myxococcus xanthus contains a polyketide biosynthesis gene cluster in which putative FAAL (FtpD) and ACP (FtpC) genes are located close to a type III PKS (FtpA) gene. Here we describe the characterization of these three proteins in vitro. FtpD adenylated stearic acid and produced stearoyl-FtpC. The stearoyl moiety was then transferred to FtpA. When extender substrates (malonyl-CoA and methylmalonyl-CoA) were added to the reaction, the alkylresorcinol 5-heptadecyl-4-methyl-benzene-1,3-diol was synthesized. Further in vitro analysis indicated that FtpA produces an alkylresorcylic acid as the direct product, and that this decarboxylates to alkylresorcinol nonenzymatically. This is the first report of a FAAL supplying a long-chain fatty acyl-ACP starter substrate to a type III PKS.

Aberrant CpG island methylation contributes to the pathogenesis of various malignancies. However, little is known about the association of epigenetic abnormalities with multistep tumorigenic events in adult T cell leukemia/lymphoma (ATLL). To determine whether epigenetic abnormalities induce the progression of ATLL, we analyzed the methylation profiles of the SHP1, p15, p16, p73, HCAD, DAPK, hMLH-1, and MGMT genes by methylation specific PCR assay in 65 cases with ATLL patients. The number of CpG island methylated genes increased with disease progression and aberrant hypermethylation in specific genes was detected even in HTLV-1 carriers and correlated with progression to ATLL. The CpG island methylator phenotype (CIMP) was observed most frequently in lymphoma type ATLL and was also closely associated with the progression and crisis of ATLL. The high number of methylated genes and increase of CIMP incidence were shown to be unfavorable prognostic factors and correlated with a shorter overall survival by Kaplan-Meyer analysis. The present findings strongly suggest that the multistep accumulation of aberrant CpG methylation in specific target genes and the presence of CIMP are deeply involved in the crisis, progression, and prognosis of ATLL, as well as indicate the value of CpG methylation and CIMP for new diagnostic and prognostic biomarkers.

We developed a method for simulating birefringence of an annealed ingot of MgF2 single crystal for lithography optics. This method provides the optical path difference caused by crystal symmetry and residual stress existing in the crystal. The method consists of the residual stress analysis and the birefringence analysis. The residual stres analysis comprises the heat conduction analysis and the elastic thermal stress analysis. The heat conduction analysis provides the temperature distribution during ingot annealing and the elastic thermal stress analysis provides the residual stress after annealing by using the result of the heat conduction analysis. Because there exists no experimental data on the inelastic behavior of MgF2 single crystal, the residual stress was estimated with the elastic thermal stress analysis by assuming a stress-free temperature, by which the inelastic behavior could be treated approximately. The finite element method was applied to both the heat conduction analysis and the elastic thermal stress analysis. In these analyses, the temperature dependence of material properties and the crystal anisotropy were taken into account. In the birefringence analysis, the distributions of optical path difference were calculated by an approximate method using the result of the residual stress analysis. This approximate method uses the average stress along the wave normal and is equivalent to the exact method in case of low stress dealt with the present study. In this analysis, it is possible to consider both the intrinsic birefringence and the stress birefringence in any crystal orientation.

Packet filtering is a function to determine whether a packet is allowed to forward or not by applying rules to a packet. Filtering packets can improve security and performance. Linear search is the simplest and a storage-efficient algorithm. The time to filter a packet grows linearly with the number of rules. If an action list which stores actions (allow or drop) for all manner of packet headers is pre-computed from a rule set, routers can filter a packet in constant time. The list is called Direct Accessible Filter (DAF) in this paper. However, DAF requires large storage. This paper proposes DAF using succinct data structures which are low storage requirement and support fast query. We apply succinct representation techniques to DAF and aim at low storage requirement. Theoretical and experimental results show that DAF using succinct data structure enjoys low storage requirement and constant search speed.

Inverse spin Hall effect (ISHE) allows the conversion of pure spin current into charge current in nonmagnetic materials (NM) due to spin-orbit interaction (SOI). In ferromagnetic materials (FM), SOI is known to contribute to anomalous Hall effect (AHE), anisotropic magnetoresistance (AMR), and other spin-dependent transport phenomena. However, SOI in FM has been ignored in ISHE studies in spintronic devices, and the possibility of "self-induced ISHE" in FM has never been explored until now. In this paper, we demonstrate the experimental verification of ISHE in FM. We found that the spin-pumping-induced spin current in permalloy (Py) film generates a transverse electromotive force (EMF) in the film itself, which results from the coupling of spin current and SOI in Py. The control experiments ruled out spin rectification effect and anomalous Nernst effect as the origin of the EMF., Comment: 28 page, 5 figures, supplemental information (To appear in Physical Review B (Regular Article))

Application-aware solid-state drives (SSDs) with 2 adaptive coding schemes to improve reliability are presented. In NAND flash memory, a direct reliability trade-off exists between write/erase (W/E) cycle and data-retention (DR) time. Thus, SSDs can be used for applications that have long DR time and low W/E cycles, or short DR time with high W/E cycles. The n-out-of-8 level cell (nLC) scheme is proposed for low-cost, long-term, archive storage which is indispensable to preserve human digital data. nLC eliminates the memory states of the Triple-Level Cell (TLC) NAND flash memory from 8 to 7...4 levels. Universal asymmetric coding (UAC) is also proposed for cloud/security camera/enterprise storage environments which require high endurance but shorter DR time. Both nLC and UAC optimize coding based on the applications' required W/E cycle and DR. Bit-error rates (BERs) are improved by 79% and 52% with nLC and UAC, respectively.

Spin pumping enables the vertical transport of pure spin current through Al in a Pd/Al/Ni80Fe20(Py) trilayer film, in which the Py acts as a spin battery. The spin current injected into the Al flows through the Al to reach the Pd, resulting in the generation of electromotive forces due to the inverse spin Hall effect in the Pd. The electromotive forces decreased with increasing thickness of the Al layer. A simple model based on the theory by Tserkovnyak et al., [Phys. Rev. B, 66, 224403 (2002)] allows an estimation of the spin coherence of the perpendicular spin transport in the Al of 61 nm. This comparatively short coherence is attributed to a reduction in spin pumping efficiency because of the roughness of the Al/Py interface., Comment: 22pages, 4 figures (To appear in Scientific Reports)

We developed an analysis system for simulating birefringence of an annealed ingot of CaF 2 single crystal caused by the residual stress after annealing process. In the residual stress calculation, we can select either the elastic thermal stress analysis using a stress-free temperature or more exact stress analysis considering creep deformation. When we use the residual stress calculated from the creep deformation analysis of a CaF 2 ingot, we can obtain reasonable results in comparison with the experimental results.

We developed an analysis system for simulating birefringence of an annealed ingot of CaF 2 single crystal caused by the residual stress after annealing process. The analysis system comprises the heat conduction analysis that provides the temperature distribution during the ingot annealing, the stress analysis to calculate the residual stress after ingot annealing, and the birefringence analysis of an annealed ingot induced by the residual stress. In the residual stress calculation, we can select either the elastic thermal stress analysis using the assumption of a stress-free temperature or more exact stress analysis considering the time-dependent nonlinear behavior of a material called creep. When we use the residual stress calculated from the creep deformation analysis of a CaF 2 ingot, we can obtain reasonable results both for the optical path difference values and for its distributions in comparison with the experimental results.

In this study, the temperature dependence of the spin Hall angle of palladium (Pd) was experimentally investigated by spin pumping. A Ni80Fe20/Pd bilayer thin film was prepared, and a pure spin current was dynamically injected into the Pd layer. This caused the conversion of the spin current to a charge current owing to the inverse spin Hall effect. It was found that the spin Hall angle varies as a function of temperature, whereby the value of the spin Hall angle increases to ca. 0.02 at 123 K., 17pages, 3figures

A 2 : 1 mixture of NCS and Ph(3)P successfully promoted the anti-dichlorination of olefins to provide corresponding dichlorides, serving as a molecular chlorine surrogate generated in situ.

We report a significant lowering of the Schottky barrier height (SBH) in nickel (Ni)/rubrene devices by the insertion of a tetrafluoro-tetracyanoquinodimethane (F4TCNQ), molybdenum trioxide (MoO3), or tetracyanoquinodimethane (TCNQ) layers at the device junction. Devices with F4TCNQ and MoO3 layers show ohmic-like characteristics, whereas the device with the TCNQ layer shows a low SBH (0.26 eV). The SBH of Ni/rubrene device without the acceptor layers is 0.56 eV. We explain the SBH lowering by the electron accepting properties of the thin layers. Such layers can be used to fabricate molecular spintronics devices with ohmic contacts for effective electrical spin injection.