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We developed an orally active and blood-brain-barrier-permeable benzofuran analogue (8, MDR-1339) with potent antiaggregation activity. Compound 8 restored cellular viability from Aβ-induced cytotoxicity but also improved the learning and memory function of AD model mice by reducing the Aβ aggregates in the brains. Given the high bioavailability and brain permeability demonstrated in our pharmacokinetic studies, 8 will provide a novel scaffold for an Aβ-aggregation inhibitor that may offer an alternative treatment for AD.

The spoke-type permanent magnet synchronous motor (PMSM) is a motor built using nonrare earth elements, which feature low flux density. It has a flux concentrated structure of permanent magnet arrangement to improve power density. Further, the torque in the spoke-type PMSM is composed of a magnetic torque component from the permanent magnets and a reluctance torque arising from the inductance difference between the d - and q -axis. This paper analyzed the d - and q -axes inductances that affect the reluctance torque depending on the magnitude of the applied current and the current phase angle of the spoke-type PMSM at base speed. We also derived the variation of the d - and q - axis inductances, which is shown at the operation speed region. Accordingly, the variation of the current phase angle for generating the maximum output power is analyzed. Based on the above results, we predicted the variation in the driving mode of the spoke-type PMSM, and subsequently verified the prediction experimentally.

This paper contains the results of actually applying to motor development the 3-D printing technology, which is one of noteworthy technologies to lead industries in the future. The current level of 3-D printing technology was identified, synchronous reluctance motor was designed and fabricated on the basis of the technology, and experiment was carried out to verify the design and fabrication. The comparative analysis between the existing model and the proposed model was carried out by finite element method analysis and experiment, and it shows the possibility that 3-D printing technology can be applied to the motor industry.

Pantograph must be correctly attached to catenary to continuously supply stable power to railway vehicle, and the device used here is Auxiliary Air Compressor (ACM). The existing ACM used the DC motor that included commutator and brush. Since maintenance and repair by mechanical friction are essential for the DC motor, BLDC motor studies have been conducted to improve this. A three-phase BLDC motor does 120° two-phase commutation through hall sensors in general. However, since hall sensor is vulnerable to heat and can run only when all three sensors work normally, sensorless control method has been studied to solve this. Using back EMF Zero Crossing Point (ZCP) detection method, this paper will introduce a stable switching sensing method that has a noncommutation area in a low speed zone.

This paper deals with the effects of welding, which is done to fix the stator stack, on a motor in case of fabricating a prototype motor that is manufactured in a small quantity. In the case of a small motor, the stator is designed and fabricated with the segmented core as a way to raise the fill factor of winding wire to the utmost within a limited size. In case of fabrication by welding both inside and outside of the stator in order to fix the segmented-core stator, the effects of stack are ignored, and the eddy current loss occurs. This paper performed the no-load test on an IPM-type BLDC motor for driving the suction fan of a vacuum cleaner, which was manufactured by using a segmented-core stator. As a result of the test, it was found that input power more than expected was supplied. To analyze the effects of welding by using the finite element analysis method and verify them experimentally, a stator was re-manufactured by bonding, and input power supplied during the no-load test was compared.

Since an existing 3-phase inner rotor torque actuator (TA) has severe torque ripples, it is not appropriate for a gimbal system that requires precise position control. Therefore, a coreless TA is considered to eliminate the core causing torque ripples. In order to compensate for several problems (e.g., problems of production structures and output degradation) when a coreless type is used, the final 2-phase outer rotor is proposed for the low vibration and high power TA in the gimbal system. To control the 2-phase TA applied to such the gimbal system, special inverter control methods, such as bi-directional drive for tilting control and control for output torque improvement, are required. The 2-phase 3-leg inverter is free of DC capacitor voltage unbalance compared to the 2-leg inverter, and is economical because it uses less power switches than the 4-leg inverter. Therefore, the 2-phase 3-leg inverter is applied to drive the 2-phase outer rotor coreless TA of a hybrid gimbal system, and it is verified through simulation.

Auxiliary air compressor(ACM) applied to railroad cars is a device which controls amount of compressed air in order that pantographs can be mounted correctly on the roof of an electric train. Existing ACMs consist of dc motors and brushes wear out due to friction with a commutator. Therefore, continuous maintenance is required. However, three phase BLDC motors have higher power density compared to dc motors and the machine maintenance is not needed because electric commutation is possible. The three phase generally uses hall sensors to get position information and this enables the accurate control. This paper suggests an algorithm that compensates the errors occurred when the hall sensors have a breakdown for stable operation.

Amyloid-β (Aβ) protein causes neurotoxicity and its abnormal aggregation into amyloid is a pathological hallmark of Alzheimer's disease (AD). Cellular proteins able to interact with Aβ or its precursor, AβPP (amyloid-β protein precursor), may regulate Aβ production and neurotoxicity. We identified a brain-enriched type I transmembrane protein, tomoregulin (TR), that directly binds Aβ and Aβ oligomers (AβO). TR co-immunoprecipitated with Aβ and AβO in cultured cells and co-localized with amyloid plaques and intraneuronal Aβ in the 5xFAD AD mouse model. TR was also enriched in astrocytic processes reactive to amyloid plaques. Surface plasmon resonance spectroscopy studies showed that the extracellular domain of TR binds to AβO with a high affinity (KD = 76.8 nM). Electron paramagnetic resonance spectroscopy also demonstrated a physical interaction between spin-labeled Aβ and the TR extracellular domain in solution. Furthermore, TR also interacted with AβPP and enhanced its cleavage by α-secretase. Both cellular expression of TR and application of recombinant TR extracellular domain protected N2a neurons from AβO-induced neuronal death. These data provide first evidence that neuronal and astrocytic expression of TR is intimately related to Aβ metabolism and toxicity, and could be neuroprotective through its direct interaction with Aβ andAβPP.

Precise 3D spatial mapping of cells and their connections within living tissues is required to fully understand developmental processes and neural activities. Zebrafish embryos are relatively small and optically transparent, making them the vertebrate model of choice for live in vivo imaging. However, embryonic brains cannot be imaged in their entirety by confocal or two-photon microscopy due to limitations in optical range and scanning speed. Here, we use light-sheet fluorescence microscopy to overcome these limitations and image the entire head of live transgenic zebrafish embryos. We simultaneously imaged cranial neurons and blood vessels during embryogenesis, generating comprehensive 3D maps that provide insight into the coordinated morphogenesis of the nervous system and vasculature during early development. In addition, blood cells circulating through the entire head, vagal and cardiac vasculature were also visualized at high resolution in a 3D movie. These data provide the foundation for the construction of a complete 4D atlas of zebrafish embryogenesis and neural activity.

Glycosylation with O-linked β-N-acetylglucosamine (O-GlcNAc) is one of the protein glycosylations affecting various intracellular events. However, the role of O-GlcNAcylation in neurodegenerative diseases such as Alzheimer's disease (AD) is poorly understood. Mitochondrial adenosine 5′-triphosphate (ATP) synthase is a multiprotein complex that synthesizes ATP from ADP and Pi. Here, we found that ATP synthase subunit α (ATP5A) was O-GlcNAcylated at Thr432 and ATP5A O-GlcNAcylation was decreased in the brains of AD patients and transgenic mouse model, as well as Aβ-treated cells. Indeed, Aβ bound to ATP synthase directly and reduced the O-GlcNAcylation of ATP5A by inhibition of direct interaction between ATP5A and mitochondrial O-GlcNAc transferase, resulting in decreased ATP production and ATPase activity. Furthermore, treatment of O-GlcNAcase inhibitor rescued the Aβ-induced impairment in ATP production and ATPase activity. These results indicate that Aβ-mediated reduction of ATP synthase activity in AD pathology results from direct binding between Aβ and ATP synthase and inhibition of O-GlcNAcylation of Thr432 residue on ATP5A.

The clinical benefit of current anticancer regimens for lung cancer therapy is still limited due to moderate efficacy, drug resistance, and recurrence. Therefore, the development of effective anticancer drugs for first-line therapy and for optimal second-line treatment is necessary. Because the 90-kDa molecular chaperone heat shock protein (Hsp90) contributes to the maturation of numerous mutated or overexpressed oncogenic proteins, targeting Hsp90 may offer an effective anticancer therapy. Here, we investigated antitumor activities and toxicity of a novel deguelin-derived C-terminal Hsp90 inhibitor, designated L80. L80 displayed significant inhibitory effects on the viability, colony formation, angiogenesis-stimulating activity, migration, and invasion of a panel of non-small cell lung cancer cell lines and their sublines with acquired resistance to paclitaxel with minimal toxicity to normal lung epithelial cells, hippocampal cells, vascular endothelial cells, and ocular cells. Biochemical analyses and molecular docking simulation revealed that L80 disrupted Hsp90 function by binding to the C-terminal ATP-binding pocket of Hsp90, leading to the disruption of the interaction between hypoxia-inducible factor (HIF)-1α and Hsp90, downregulation of HIF-1α and its target genes, including vascular endothelial growth factor (VEGF) and insulin-like growth factor 2 (IGF2), and decreased the expression of various Hsp90 client proteins. Consistent with these in vitro findings, L80 exhibited significant antitumor and antiangiogenic activities in H1299 xenograft tumors. These results suggest that L80 represents a novel C-terminal Hsp90 inhibitor with effective anticancer activities with minimal toxicities.

This paper discusses the analysis and simulation method and the test method for a two-degree-of-freedom (2-DOF) actuator torque. The previous studies on the analysis of 2-DOF motor’s tilting torque were carried out only by finite element method (FEM), not by analytic method. This paper describes the operating principles of and the processes of inducing a tilting torque and a holding torque both of which exist only in special purpose electric machines. This allowed us to establish a design process. By overcoming the limits of the 3-D FEM, this paper introduced the 2-D model analysis by considering a real coil shape. Finally, this paper manufactured and tested the 2-DOF actuator to verify the introduced analytic analysis method.

Amyloid-β (Aβ) peptide is central to the development of brain pathology in Alzheimer disease (AD) patients. Association with receptors for advanced glycation end-products (RAGE) enables the transport of Aβ peptide from circulating blood to human brain, and also causes the activation of the NF-κB signaling pathway. Here we show that two β-strands of RAGE participate in the interaction with Aβ peptide. Serial deletion analysis of the RAGE V domain indicates that the third and eighth β-strands are required for interaction with Aβ peptide. Site-directed mutagenesis of amino acids located in the third and eighth β-strands abolish the interaction of RAGE with Aβ peptide. Wild-type RAGE activates the NF-κB signaling pathway in response to Aβ peptide treatment, while a RAGE mutant defective in Aβ binding does not. Furthermore, use of peptide for the third β-strand or a RAGE monoclonal antibody that targets the RAGE-Aβ interaction interface inhibited transport of the Aβ peptide across the blood brain barrier in a mice model. These results provide information crucial to the development of RAGE-derived therapeutic reagents for Alzheimer disease.

Glutaminyl cyclase (QC) has been implicated in the formation of toxic amyloid plaques by generating the N-terminal pyroglutamate of β-amyloid peptides (pGlu-Aβ) and thus may participate in the pathogenesis of Alzheimer’s disease (AD). We designed a library of glutamyl cyclase (QC) inhibitors based on the proposed binding mode of the preferred substrate, Aβ3E−42. An in vitro structure–activity relationship study identified several excellent QC inhibitors demonstrating 5- to 40-fold increases in potency compared to a known QC inhibitor. When tested in mouse models of AD, compound 212 significantly reduced the brain concentrations of pyroform Aβ and total Aβ and restored cognitive functions. This potent Aβ-lowering effect was achieved by incorporating an additional binding region into our previously established pharmacophoric model, resulting in strong interactions with the carboxylate group of Glu327 in the QC binding site. Our study offers useful insights in designing novel QC inhibitors as a potential tre...

This paper intends to verify, through actual fabrication and test, that 3D printing technology, which is one of the top 10 most promising future technologies, can be grafted onto motor industry. A complicated rotor geometry of SynRM, a non-rare earth motor, was designed and fabricated, using 3D printing technology. This paper tried to test the validity of its research by FEM analysis and load test in comparison with the existing SynRMs.

Development of a simple, non-invasive early diagnosis platform of Alzheimer's disease (AD) using blood is urgently required. Recently, PiB-PET imaging has been shown to be powerful to quantify amyloid-β plaque loads leading to pathophysiological alterations in AD brains. Thus, there has been a need for serum biomarkers reflecting PiB-PET imaging data as an early diagnosis platform of AD. Here, using LC-MS/MS analysis coupled with isobaric tagging, we performed comprehensive proteome profiling of serum samples from cognitively normal controls, mild cognitive impairment (MCI), and AD patients, who were selected using PiB-PET imaging. Comparative analysis of the proteomes revealed 79 and 72 differentially expressed proteins in MCI and AD, respectively, compared to controls. Integrated analysis of these proteins with genomic and proteomic data of AD brain tissues, together with network analysis, identified three biomarker candidates representing the altered proteolysis-related process in MCI or AD: proprotein convertase subtilisin/kexin type 9 (PCSK9), coagulation factor XIII, A1 polypeptide (F13A1), and dermcidin (DCD). In independent serum samples of MCI and AD, we confirmed the elevation of the candidates using western blotting and ELISA. Our results suggest that these biomarker candidates can serve as a potential non-invasive early diagnosis platform reflecting PiB-PET imaging for MCI and AD.

Alzheimer's disease (AD) in the early stages is characterized by memory impairment, which may be attributable to synaptic dysfunction. Oxidative stress, mitochondrial dysfunction, and Ca2+dysregulation are key factors in the pathogenesis of AD, but the causal relationship between these factors and synaptic dysfunction is not clearly understood. We found that in the hippocampus of an AD mouse model (Tg2576), mitochondrial Ca2+handling in dentate granule cells was impaired as early as the second postnatal month, and this Ca2+dysregulation caused an impairment of post-tetanic potentiation in mossy fiber-CA3 synapses. The alteration of cellular Ca2+clearance in Tg2576 mice is region-specific within hippocampus because in another region, CA1 pyramidal neuron, no significant difference in Ca2+clearance was detected between wild-type and Tg2576 mice at this early stage. Impairment of mitochondrial Ca2+uptake was associated with increased mitochondrial reactive oxygen species and depolarization of mitochondrial membrane potential. Mitochondrial dysfunctions in dentate granule cells and impairment of post-tetanic potentiation in mossy fiber-CA3 synapses were fully restored when brain slices obtained from Tg2576 were pretreated with antioxidant, suggesting that mitochondrial oxidative stress initiates other dysfunctions. Reversibility of early dysfunctions by antioxidants at the preclinical stage of AD highlights the importance of early diagnosis and antioxidant therapy to delay or prevent the disease processes.

One of the major hallmarks of Alzheimer's disease (AD) is the extracellular deposition of amyloid-β (Aβ) as senile plaques in specific brain regions. Clearly, an understanding of the cellular processes underlying Aβ deposition is a crucial issue in the field of AD research. Recent studies have found that accumulation of intraneuronal Aβ (iAβ) is associated with synaptic deficits, neuronal death, and cognitive dysfunction in AD patients. In this study, we found that Aβ deposits had several shapes and sizes, and that iAβ occurred before the formation of extracellular amyloid plaques in the subiculum of 5XFAD mice, an animal model of AD. We also observed pyroglutamate-modified Aβ (N3pE-Aβ), which has been suggested to be a seeding molecule for senile plaques, inside the Aβ plaques only after iAβ accumulation, which argues against its seeding role. In addition, we found that iAβ accumulates in calcium-binding protein (CBP)-free neurons, induces neuronal death, and then develops into senile plaques in 2-4-month-old 5XFAD mice. These findings suggest that N3pE-Aβ-independent accumulation of Aβ in CBP-free neurons might be an early process that triggers neuronal damage and senile plaque formation in AD patients. Our results provide new insights into several long-standing gaps in AD research, namely how Aβ plaques are formed, what happens to iAβ and how Aβ causes selective neuronal loss in AD patients.

Activated microglia and reactive astrocytes are commonly found in and around the senile plaque, which is the central pathological hallmark of Alzheimer's disease. Astrocytes respond to neuronal activity through the release of gliotransmitters such as glutamate,d-serine, and ATP. However, it is largely unknown whether and how gliotransmitters affect neuronal functions. In this study, we explored the effect of a gliotransmitter, ATP, on neurons damaged by β-amyloid peptide (Aβ). We found that Aβ1-42(Aβ42) increased the release of ATP in cultures of primary astrocytes and U373 astrocyte cell line. We also found that exogenous ATP protected Aβ42-mediated reduction in synaptic molecules, such as NMDA receptor 2A and PSD-95, through P2 purinergic receptors and prevented Aβ42-induced spine reduction in cultured primary hippocampal neurons. Moreover, ATP prevented Aβ42-induced impairment of long-term potentiation in acute hippocampal slices. Our findings suggest that Aβ-induced release of gliotransmitter ATP plays a protective role against Aβ42-mediated disruption of synaptic plasticity.

Alzheimer's disease (AD) is the fastest growing neurodegenerative disease in the elderly population, and the search for therapeutic targets and diagnostic AD biomarkers is an exigent issue. Because amyloid-β (Aβ) aggregation constitutes the epicenter of AD pathology, Aβ-binding proteins that regulate Aβ aggregation, such as transthyretin (TTR), have attracted much attention. TTR binds to Aβ, prevents its aggregation, and consequently inhibits Aβ-induced cellular toxicity. Decreased TTR levels in cerebrospinal fluid (CSF) from AD patients suggest that TTR is a biomarker of AD. But, studies on TTR as a biomarker have focused on CSF; no study has evaluated peripheral levels of TTR in AD. Here, we examined the relationship between serum TTR levels and AD. We measured TTR levels in serum samples from 90 nondemented controls and 111 AD patients and observed significantly lower serum TTR levels in AD (p < 0.001). Notably, females in the control group had lower serum TTR levels compared with male in the control (p = 0.006), while no difference in gender was noted in the AD group. There were no age-related changes in serum TTR levels. Thus, this study demonstrates a clear negative correlation between serum TTR levels and AD, suggesting that TTR is not only involved in AD pathological process but also suggested as possible peripheral biomarker for AD diagnosis in serum level.

The molecular pathogenesis of disorders arising from protein mis-folding and aggregation is difficult to elucidate, involving a complex ensemble of intermediates whose toxicity depends upon their state of progression along distinct processing pathways. To address the complex mis-folding and aggregation that initiates the toxic cascade resulting in Alzheimer's disease, we have developed a TOAC spin-labeled Aβ peptide to observe its isoform-dependent interaction with the apoE protein. While most individuals carry the E3 isoform of apoE, approximately 15% of humans carry the E4 isoform, which is recognized as the most significant genetic determinant for Alzheimer's. ApoE is consistently associated with the amyloid plaque marker for Alzheimer's disease. A vital question centers on the influence of the two predominant isoforms, E3 and E4, on Aβ peptide processing and hence Aβ toxicity. We employed EPR spectroscopy of incorporated spin labels to investigate the interaction of apoE with the toxic oligomeric species of Aβ in solution. EPR spectra of the spin labeled side chain report on side chain and backbone dynamics, as well as the spatial proximity of spins in an assembly. Our results indicate oligomer binding involves the C-terminal domain of apoE, with apoE3 reporting a much greater response through this conformational marker. Coupled with SPR binding measurements, apoE3 displays a higher affinity and capacity for the toxic Aβ oligomer. These findings support the hypothesis that apoE polymorphism and Alzheimer's risk can largely be attributed to the reduced ability of apoE4 to function as a clearance vehicle for the toxic form of Aβ.

The protease BACE1 (beta-site APP-cleaving enzyme 1) is essential for the generation of amyloid beta (Abeta) from amyloid precursor protein (APP). Although BACE1 is expressed primarily in neurons, which are a principal source of Abeta in the brain, the mechanism that underlies basal expression of BACE1 in neurons has not been studied thoroughly. In the present study, we found that endogenous BACE1 expression was mediated by constitutive JAK2/STAT1 activation in neurons. Inhibition of the JAK2/STAT1 signaling pathway, using AG490 (a JAK2 inhibitor), a dominant-negative form of STAT1, and SOCS1 and SOCS3 overexpression, reduced levels of BACE1 promoter activity, expression of endogenous BACE1, and generation of Abeta. These results were recapitulated in the SH-SY5Y neuronal cell line, primary cultured neurons, and mouse brains. Therefore, we propose that constitutive JAK2/STAT1 activation mediates endogenous BACE1 expression in neurons and that inhibition of JAK2/STAT1 signaling abrogates basal levels of BACE1 expression and Abeta generation.

Small beta-amyloid (Abeta) 1-42 aggregates are toxic to neurons and may be the primary toxic species in Alzheimer's disease (AD). Methods to reduce the level of Abeta, prevent Abeta aggregation, and eliminate existing Abeta aggregates have been proposed for treatment of AD. A tricyclic pyrone named CP2 is found to prevent cell death associated with Abeta oligomers. We studied the possible mechanisms of neuroprotection by CP2. Surface plasmon resonance spectroscopy shows a direct binding of CP2 with Abeta42 oligomer. Circular dichroism spectroscopy reveals monomeric Abeta42 peptide remains as a random coil/alpha-helix structure in the presence of CP2 over 48 h. Atomic force microscopy studies show CP2 exhibits similar ability to inhibit Abeta42 aggregation as that of Congo red and curcumin. Atomic force microscopy closed-fluid cell study demonstrates that CP2 disaggregates Abeta42 oligomers and protofibrils. CP2 also blocks Abeta fibrillations using a protein quantification method. Treatment of 5x familial Alzheimer's disease mice, a robust Abeta42-producing animal model of AD, with a 2-week course of CP2 resulted in 40% and 50% decreases in non-fibrillar and fibrillar Abeta species, respectively. Our results suggest that CP2 might be beneficial to AD patients by preventing Abeta aggregation and disaggregating existing Abeta oligomers and protofibrils.

The SbetaC gene is conditionally expressed a 99-residue carboxy terminal fragment, C99, of amyloid precursor protein in MC65 cells and causes cell death. Consequently, MC65 cell line was used to identify inhibitors of toxicity related to intracellular amyloid beta (Abeta) oligomers. Compounds that reduce the level of Abeta peptides, prevent Abeta aggregation, or eliminate existing Abeta aggregates may be used in the treatment of Alzheimer's disease (AD). Previously, we found that a tricyclic pyrone (TP) molecule, compound 1, prevents MC65 cell death and inhibits Abeta aggregation. Hence various TPs containing heterocycle at C7 side chain and a nitrogen at position 2 or 5 were synthesized and their MC65 cell protective activities evaluated. TPs containing N3'-adenine moiety such as compounds 1 and 11 are most active with EC(50) values of 0.31 and 0.35 microM, respectively. EC(50) values of tricyclic N5-analog, pyranoisoquinolinone 13, and N2-analog, pyranopyridinone 20, are 2.49 and 1.25 microM, respectively, despite the lack of adenine moiety. Further investigation of tricyclic N2- and N5-analogs is warranted.

Background The receptor for advanced glycation end products (RAGE) has been found to interact with amyloid β (Aβ). Although RAGE does not have any kinase motifs in its cytosolic domain, the interaction between RAGE and Aβ triggers multiple cellular signaling involved in Alzheimer’s disease (AD). However, the mechanism of signal transduction by RAGE remains still unknown. Therefore, identifying binding proteins of RAGE may provide novel therapeutic targets for AD. Results In this study, we identified p38-regulated/activated protein kinase (PRAK) as a novel RAGE interacting molecule. To investigate the effect of Aβ on PRAK mediated RAGE signaling pathway, we treated SH-SY5Y cells with monomeric form of Aβ. We demonstrated that Aβ significantly increased the phosphorylation of PRAK as well as the interaction between PRAK and RAGE. We showed that knockdown of PRAK rescued mTORC1 inactivation induced by Aβ treatment and decreased the formation of Aβ-induced autophagosome. Conclusions We provide evidence that PRAK plays a critical role in AD pathology as a key interactor of RAGE. Thus, our data suggest that PRAK might be a potential therapeutic target of AD involved in RAGE-mediated cell signaling induced by Aβ. Electronic supplementary material The online version of this article (doi:10.1186/s13024-016-0068-5) contains supplementary material, which is available to authorized users.

Amyloid precursor protein generates the secreted amyloid precursor protein alpha, which protects hippocampal neurons from ischemic injury and facilitates neuronal survival and synaptogenesis in the developing nervous system. Here, we examined whether platelet-derived growth factor regulates the generation of secreted amyloid precursor protein alpha during the neuronal differentiation of hippocampal precursor cells, HiB5. We showed that platelet-derived growth factor promoted amyloid precursor protein production and secreted amyloid precursor protein alpha secretion. These effects of platelet-derived growth factor were diminished by the PI3K-specific inhibitor wortmannin and the protein kinase C-specific inhibitor GF109203X, suggesting the involvement of the PI3K and protein kinase C-signaling pathway. Furthermore, the conditioned media enriched with secreted amyloid precursor protein alpha promoted the survival of HiB5 cells during neuronal differentiation. These results suggest that the neurotrophic effect of platelet-derived growth factor is mediated in part via upregulation of the expression and release of secreted amyloid precursor protein alpha.

Ternary Ti-Zr-N thin films were synthesized by rf-reactive sputtering in Ar–N2 plasma. Effects of the substrate temperature in the sputtering process on the microstructures of Ti-Zr-N thin films were investigated using SEM, TEM, XRD and AES techniques. The hardness of the Ti-Zr-N film increases as the substrate temperature in reactive sputtering increases. The reactive sputtered Ti-Zr-N film is characterized as polycrystalline in nature with two dominant orientations of (111) and (200). A substrate temperature of 300°C is suggested for getting a densely packed film structure with the highest hardness.

Recent evidence suggests that tau aggregates are not only neurotoxic, but also propagate in neurons acting as a seed for native tau aggregation. Prion-like tau transmission is now considered as an important pathogenic mechanism driving the progression of tau pathology in the brain. However, prion-like tau species have not been clearly characterized. To identify infectious tau conformers, here we prepared diverse tau aggregates and evaluated the effect on inducing intracellular tau-aggregation. Among tested, tau dimer containing P301L-mutation is identified as the most infectious form to induce tau pathology. Biochemical analysis reveals that P301L-tau dimer is covalently cross-linked with a disulfide bond. The relatively small and covalently cross-linked tau dimer induced tau pathology efficiently in primary neurons and also in tau-transgenic mice. So far, the importance of tau disulfide cross-linking has been overlooked in the study of tau pathology. Here our results suggested that tau disulfide cross-linking might play critical role in tau propagation by producing structurally stable and small tau conformers.

Receptor for advanced glycation end products (RAGE) is known to be involved in the transportation of amyloid β (Aβ) peptides and causes the accumulation of Aβ in the brain. Moreover, recent studies suggest that the interactions between RAGE and Aβ peptides may be the culprit behind Alzheimer's disease (AD). Inhibitors of the RAGE-Aβ interactions would not only prevent the accumulation of toxic Aβ in the brain, and but also block the progress of AD, therefore, have the potential to provide a 'disease-modifying therapy'. In this study, we have developed a series of 6-phenoxy-2-phenylbenzoxazole analogs as novel inhibitors of RAGE. Among these derivatives, we found several effective inhibitors that block the RAGE-Aβ interactions without causing significant cellular toxicity. Further testing showed that compound 48 suppressed Aβ induced toxicity in mouse hippocampal neuronal cells and reduced Aβ levels in the brains of a transgenic mouse model of AD after oral administration.

Beta-amyloid (Aβ), a major pathological hallmark of Alzheimer's disease (AD), is derived from amyloid precursor protein (APP) through sequential cleavage by β-secretase and γ-secretase enzymes. APP is an integral membrane protein and plays a key role in the pathogenesis of AD; however, the biological function of APP is still unclear. The present study shows that APP is rapidly degraded by the ubiquitin-proteasome system (UPS) in the CHO cell line in response to endoplasmic reticulum (ER) stress, such as calcium ionophore, A23187, induced calcium influx. Increased levels of intracellular calcium by A23187 induces polyubiquitination of APP, causing its degradation. A23187-induced reduction of APP is prevented by the proteasome inhibitor MG132. Furthermore, an increase in levels of the endoplasmic reticulum-associated degradation (ERAD) marker, E3 ubiquitin ligase HRD1, proteasome activity and decreased levels of the deubiquitinating enzyme USP25 were observed during ER stress. In addition, we found that APP interacts with USP25. These findings suggest that acute ER stress induces degradation of full-length APP via the ubiquitin-proteasome proteolytic pathway.

The nature of the association between ischemic stroke and Alzheimer's disease (AD) at the cellular and molecular level is still unknown. We evaluated the effect of ischemic neuronal insults on the regulation of amyloid precursor protein (APP) processing. We used an in vitro model of cerebral ischemia (oxygen-glucose deprivation) to evaluate the effect of ischemic neuronal insults on the amyloidogenic and non-amyloidogenic pathways using human neuroblastoma cell line and primary cultured cells of transgenic mice which expressed human APP (Tg2576). Ischemic neuronal insults increased the production of Abeta in Tg2576 primary culture cells compared to controls. A disintegrin and metalloprotease 10 (ADAM 10) was markedly increased in early stage of ischemic insults, which was followed by decreased level of ADAM 10 expression in later stage. The protein and mRNA expression of beta-site cleavage enzyme (BACE) and BACE activity was not significantly different between the group of ischemic insults and control. By contrast, the activity of gamma-secretase was significantly increased after 4 h of ischemic insults, as compared to controls. The present study showed that the ischemic neuronal insults increased the production of Abeta by influencing APP metabolism, which may link the role of ischemic insults to the pathogenesis of AD.

Interfering effects of NO and SO2 gases on CO2 sensing performance of the solid state galvanic cell, Pt, O2, CO2, Na2CO3–BaCO3ǀǀNa+ǀǀNa2Ti6O13–TiO2, O2, Pt were investigated at 673 K and 773 K. In the interfering gases concentration ranges of 50–150 ppm NO and 5–15 ppm SO2, exposure to NO gas guaranteed a recovery of electromotive force (EMF) from the relatively small EMF deviation. However, SO2 gas remarkably degraded the performance of the sensor arising from the formation of sulfate on the sensing electrode. Na2CO3–SnO2, Na2CO3–SnO2–Cu, and Na2CO3–SnO2–CuO were heat-treated and adopted as filter materials adjacent to the sensing electrode. The EMF response of the CO2 sensors with filters was compared in terms of filter efficiency. Among them, Na2CO3–SnO2–CuO filter showed the most promising characteristics in suppressing NO and SO2 gas interference.

Practical small-sized thick film CO2 sensor with self-heater was fabricated with Na β -Alumina (NBA), Na2Ti6O13-TiO2, and Na2CO3 as a solid electrolyte, reference electrode, and a sensing electrode, respectively. The measured EMF from the sensor followed the Nernstian behavior with CO2 concentration change in the range of 400 to 600∘C (350–580 mW power consumption). However, in the aspect of stability, densification of the NBA thick film and prevention of Na2CO3 evaporation were needed. In this study, an Al2O3 porous layer deposited on Na2CO3 was effective in improving the durability during operation of the sensor. It is thought that Al2O3 suppresses evaporation of Na2CO3.

An assumed strain finite strip method(FSM) using the non-periodic B-spline for a shell is presented. In the present method, the shape function based on the non-periodic B-splines satisfies the Kronecker delta properties at the boundaries and allows to introduce interior supports in much the same way as in a conventional finite element formulation. In the formulation for a shell, the geometry of the shell is defined by non-periodic B3-splines without any tangential vectors at the ends and the penalty function method is used to incorporate the drilling degrees of freedom. In this study, new assumed strain fields using the non-periodic B-spline function are proposed to overcome the locking problems. The strip formulated in this way does not posses any spurious zero energy modes. The versatility and accuracy of the new approach are demonstrated through a series of numerical examples.

A new approach for the CTE on the basis of Ashelby.s cutting and welding process was made for the analysis of the thermal expansion behaviors of Al-Si alloys and composites. In this theoretical approach, it was considered that relaxation of residual stress could create an elastoplastic zone in the matrix around a particle during cooling. A comparison of the measured CTEs with the calculated ones for the Al-Si-SiCp and Al-Si-Al2O3 composite systems was performed in terms of the volume percent and the size of reinforced phases. The calculated results revealed that the linear CTE of the both composite depends on the size of the reinforce phases, especially at the composite systems with a low volume percent of the reinforce phases. The increase in the volume percentages of Al2O3, SiCp and Si phase lowers the linear CTEs of the systems. The measured CTEs was deviated less than about ten percents from the calculated ones at composites with a high volume percent. The deviations of the CTEs of reinforced phases are about 4 - 6 vol% from real composite systems.

A recent clinical study showed that statins, which are inhibitors of cholesterol biosynthesis pathway, reduced the prevalence of Alzheimer's disease (AD). Animal studies that have employed high cholesterol diet indicate significant relationship between cholesterol level and senile plaque deposition. Here, we investigated the effects of lovastatin on beta-amyloid production and senile plaque deposition in an animal model of AD (Tg2576 mice). As expected, lovastatin treatment reduced plasma cholesterol level in both male and female mice. However, lovastatin enhanced the amounts of beta-amyloid and other beta-secretase derived peptides in females, but not in males. Likewise, lovastatin increased the number of plaques in the hippocampus and cortex of females, but not in males. Lovastatin did not change the amounts of full-length or alpha-secretase processed amyloid precursor protein (APP), or presenilin 1 (PS1) in either sex. Thus, lovastatin lowers cholesterol level in both genders, but enhances beta-amyloid production and senile plaque deposition only in brains of female Tg2576 mice. Our results suggest that low plasma cholesterol levels might be a risk factor for AD in females.

Neurons, but not astrocytes, are known as the major source of Abeta, because astrocytes express low levels of putative beta-secretase (BACE). Astrocytes near senile plaque cores show enhanced levels of BACE protein expression, however, suggesting that astrocytes can contribute to Abeta production under pathological conditions. To investigate factors that stimulate BACE protein expression in astrocytes, we tested the effects of interleukin-1beta (IL-1beta) and interferon-gamma (IFN-gamma) on BACE protein expression in U373MG astrocytoma cells and primary astrocyte cultures from Tg2576 mouse brains. BACE protein expression and sAPPbeta production were dramatically increased, without changes in holo APP levels, following IFN-gamma treatment in both cell types. AG490, which is a blocker of IFN-gamma-induced STAT signaling, decreased IFN-gamma-induced BACE protein expression and sAPPbeta production in a dose-dependent manner. These results show that astrocytes are capable of expressing BACE and producing sAPPbeta in response to certain stimulating factors, and IFN-gamma is one such factor.

The unequally spaced non-periodic B-spline finite strip method (FSM) is presented. The motivation to investigate the irregularly spaced interior nodes in the longitudinal direction of strip is to generalize the concept ofnon-periodic B-spline FSM and to improve the general accuracy of the stress evaluation in the region of high stress gradients. In the present paper, the unequally spaced non-periodic B3-spline series with multiple knots at the boundary are introduced for the interpolation of displacement and description of geometry in the formulation of isoparametric spline FSM. The use of multiple knots at the boundary makes the shape function satisfy the Kronecker delta properties at the boundary. The unequally spaced B-spline FSM is applied to the stress-reduced shell problem with six degrees of freedom per node. The main purpose of this study is to find a way of ensuring that the geometry of strip is appropriately approximated when the interior nodes of the strip are not regularly spaced along the longitudinal direction. Some numerical results have been compared with those of the previous studies to evaluate the accuracy and efficiency of this method.