BAFF and APRIL as osteoclast-derived survival factors for myeloma cells: a rationale for TACI-Fc treatment in patients with multiple myeloma.
Explore the source record for details and available documents.
B-Cell Activating Factor↗
Biomedical subjects
A Nakano
Publications and source records attributed to A Nakano.
Yeast Golgi apparatus--dynamics and sorting.
The yeast Saccharomyces cerevisiae is one of the best-studied organisms to understand molecular mechanisms of membrane traffic, but as far as the organization of the Golgi apparatus is concerned, yeast is only just beginning to yield clues about how dynamic and flexible the organelle is.
Endoplasmic Reticulum↗
Unexpected delayed rupture of the vertebral-posterior inferior cerebellar artery aneurysms following closed head injury.
Subarachnoid haemorrhage secondary to closed head injury is rarely associated with traumatic aneurysms of the posterior circulation. We report two cases of ruptured vertebral-posterior inferior cerebellar artery (VA-PICA) pseudoaneurysms following closed head injuries. In each case, there was no associated penetrating injury or skull fracture. The first patient was kicked followed by disturbed consciousness. The computerized tomography (CT) scan on admission and cerebral angiography on the 11th day after the trauma revealed a massive subarachnoid haemorrhage (SAH) with pan-ventricular haemorrhage and an aneurysm of the right PICA near its origin. Further ruptures occurred on the 12th, 15th, and 66th day, and he died on the 69th day. The second patient complained of persistent headache and nausea following a fight on the previous day. A CT scan and angiography on the 1st day after the trauma showed posterior fossa SAH with fourth ventricular blood and a tiny protrusion of the left VA-PICA. On the 14th day, repeated angiography revealed a remarkable growth of the aneurysm, followed by the second rupture. The repair of the VA-PICA junction was urgently performed with successful exclusion of the aneurysm. To our knowledge, only eight cases of traumatic aneurysms located at the VA or the PICA near its origin have been reported. When intraventricular blood is found with massive subarachnoid blood or with posterior fossa SAH, this ominous complication should be considered. Traumatic VA-PICA pseudoaneurysms are curable by refined microsurgical techniques, if diagnosed in time.
Adult↗
Gene transfer of Fc-fusion cytokine by in vivo electroporation: application to gene therapy for viral myocarditis.
Among a number of techniques for gene transfer in vivo, the direct injection of plasmid DNA into muscle is simple, inexpensive and safe. Although combining direct DNA injection with in vivo electroporation increases the efficiency of gene transfer into muscle, applications of this method have remained limited because of the relatively low expression level. To overcome this problem, we developed a plasmid vector that expresses a secretory protein as a fusion protein with the noncytolytic immunoglobulin Fc portion and used it for electroporation-mediated viral interleukin 10 (vIL-10) expression in vivo. The fusion cytokine vIL-10/mutFc was successfully expressed and the peak serum concentration of vIL-10 was almost 100-fold (195 ng/ml) higher than with a non-fusion vIL-10 expression plasmid. The expressed fusion cytokine suppressed the phytohemagglutinin-induced IFN-gamma production by human peripheral blood mononuclear cells and decreased the mortality in a mouse viral myocarditis model as effectively as vIL-10 expression. These results demonstrate that the transfer of plasmid DNA expressing a noncytolytic Fc-fusion cytokine is useful to deliver enhanced levels of cytokine without altering general biological activities. This simple and efficient system should provide a new approach to gene therapy for human diseases and prove very useful for investigating the function of newly discovered secretory protein genes.
Animals↗
Directly linked dehydropurpurin-porphyrin dyads from Ag(I)-promoted oxidation of meso-phenylethynyl substituted zinc(II) porphyrins.
Ag(I)-promoted oxidation of (5,15-diaryl-10-phenylethynyl-porphyrinato)zinc(II) complexes in CHCl3 gave directly linked 12,13-dehydropurpurin-porphyrin dyads, the structures of which were revealed by X-ray analysis.
Journal Article↗
Significance of cadmium concentrations in blood and hair as an indicator of dose 15 years after the reduction of environmental exposure to cadmium.
To evaluate the significance of cadmium (Cd) concentrations in blood (B-Cd) and hair (H-Cd) as an indicator of dose, a cross-sectional study was performed on 40 residents in a Cd-polluted area, Nagasaki Prefecture, Japan, in 1996. In the study area, soil replacement of Cd-polluted rice fields ended in 1981. B-Cd and H-Cd were significantly higher in the study population than in the control subjects. B-Cd was positively correlated with urinary Cd (U-Cd) (Spearman r=0.50, P=0.06 for males and r=0.72, P=0.0001 for females), while H-Cd was weakly or moderately correlated with U-Cd. After adjustment for gender using logistic regression analysis, log(B-Cd) and log(U-Cd), but not log(H-Cd), were significantly associated with the prevalence of increased urinary beta2-microglobulin (P for trend <0.05). These findings suggest that B-Cd is a good indicator of cumulative dose many years after the reduction of environmental exposure to Cd. H-Cd may be weakly or moderately correlated with body burden.
Adult↗
Ara6, a plant-unique novel type Rab GTPase, functions in the endocytic pathway of Arabidopsis thaliana.
Ara6 of Arabidopsis thaliana is a novel member of the Rab/Ypt GTPase family with unique structural features. It resembles Rab5 GTPases best, but lacks a large part of the C-terminal hypervariable region and the cysteine motif, and instead harbors an extra stretch of amino acid residues containing myristoylation and palmitoylation sites at the N-terminus. Ara6 is tightly associated with membranes and is expressed constitutively. In contrast, the conventional Rab5 ortholog, Ara7, is highly expressed only in actively dividing cells. Examination of green fluorescent protein (GFP)-tagged proteins indicates that both Ara6 and Ara7 are distributed on a subpopulation of endosomes and suggests their roles in endosomal fusion. The endosomal localization of Ara6 requires N-terminal fatty acylation, nucleotide binding and the C-terminal amino acid sequence coordinately. Proteins similar to Ara6 are found only in higher plants and thus represent a novel class of Rab GTPases regulating endocytic function in a plant- specific manner.
Amino Acid Sequence↗
Activation of the Ras-cAMP signal transduction pathway inhibits the proteasome-independent degradation of misfolded protein aggregates in the endoplasmic reticulum lumen.
Many kinds of misfolded secretory proteins are known to be degraded in the endoplasmic reticulum (ER). Dislocation of misfolded proteins from the ER to the cytosol and subsequent degradation by the proteasome have been demonstrated. Using the yeast Saccharomyces cerevisiae, we have been studying the secretion of a heterologous protein, Rhizopus niveus aspartic proteinase-I (RNAP-I). Previously, we found that the pro sequence of RNAP-I is important for the folding and secretion, and that Deltapro, a mutated derivative of RNAP-I in which the entire region of the pro sequence is deleted, forms gross aggregates in the yeast ER. In this study, we show that the degradation of Deltapro occurs independently of the proteasome. Its degradation was not inhibited either by a potent proteasome inhibitor or in a proteasome mutant. We also show that neither the export from the ER nor the vacuolar proteinase is required for the degradation of Deltapro. These results raise the possibility that the Deltapro aggregates are degraded in the ER lumen. We have isolated a yeast mutant in which the degradation of Deltapro is delayed. We show that the mutated gene is IRA2, which encodes a GTPase-activating protein for Ras. Because Ira2 protein is a negative regulator of the Ras-cAMP pathway, this result suggests that hyperactivation of the Ras-cAMP pathway inhibits the degradation of Deltapro. Consistently, down-regulation of the Ras-cAMP pathway in the ira2 mutant suppressed the defect of the degradation of Deltapro. Thus, the Ras-cAMP signal transduction pathway seems to control the proteasome-independent degradation of the ER misfolded protein aggregates.
Aspartic Acid Endopeptidases↗
Coupling length scales for multiscale atomistics-continuum simulations: atomistically induced stress distributions in Si/Si3N4 nanopixels.
A hybrid molecular-dynamics (MD) and finite-element simulation approach is used to study stress distributions in silicon/silicon-nitride nanopixels. The hybrid approach provides atomistic description near the interface and continuum description deep into the substrate, increasing the accessible length scales and greatly reducing the computational cost. The results of the hybrid simulation are in good agreement with full multimillion-atom MD simulations: atomic structures at the lattice-mismatched interface between amorphous silicon nitride and silicon induce inhomogeneous stress patterns in the substrate that cannot be reproduced by a continuum approach alone.
Journal Article↗
Modified windmill porphyrin arrays: coupled light-harvesting and charge separattion, conformational relaxation in the S1 state, and S2-S2 energy transfer.
The architecture of windmill hexameric zinc(II) -porphyrin array 1 is attractive as a light-harvesting functional unit in view of its three-dimensionally extended geometry that is favorable for a large cross-section of incident light as well as for a suitable energy gradient from the peripheral porphyrins to the meso-meso-linked diporphyrin core. Three core-modified windmill porphyrin arrays 2-4 were prepared for the purpose of enhancing the intramolecular energy-transfer rate and coupling these arrays with a charge-separation functional unit. Bisphenylethynylation at the meso and meso' positions of the diporphyrin core indeed resulted in a remarkable enhancement in the intramolecular S1-S1 energy transfer in 2 with tau=2 approximately 3 ps, as revealed by femtosecond time-resolved transient absorption spectroscopy. The fluorescence lifetime of the S2 state of the peripheral porphyrin energy donor determined by the fluorescence up-conversion method was 68 fs, and thus considerably shorter than that of the reference monomer (150 fs), suggesting the presence of the intramolecular energy-transfer channel in the S2 state manifold. Such a rapid energy transfer can be understood in terms of large Coulombic interactions associated with the strong Soret transitions of the donor and acceptor. Picosecond time-resolved fluorescence spectra and transient absorption spectra revealed conformational relaxation of the S1 state of the diporphyrin core with tau = 25 ps. Upon photoexcitation of models 3 and 4, which bear a naphthalenetetracarboxylic diimide or a meso-nitrated free-base porphyrin attached to the modified diporphyrin core as an electron acceptor, a series of photochemical processes proceeded, such as the collection of the excitation energy at the diporphyrin core, the electron transfer from the S1 state of the diporphyrin to the electron acceptor, and the electron transfer from the peripheral porphyrins to the diporphyrin cation radical, which are coupled to provide a fully charge-separated state such as that in the natural photosynthetic reaction center. The overall quantum yield for the full charge separation is better in 4 than in 3 owing to the slower charge recombination associated with smaller reorganization energy of the porphyrin acceptor.
Journal Article↗
Obtusifoliol 14alpha-demethylase (CYP51) antisense Arabidopsis shows slow growth and long life.
Obtusifoliol 14alpha-demethylase is a plant orthologue of sterol 14alpha-demethylase (CYP51) essential in sterol biosynthesis. We have prepared CYP51 antisense Arabidopsis in order to shed light on the sterol and steroid hormone biosynthesis in plants. Arabidopsis putative CYP51 cDNA (AtCYP51) was obtained from Arabidopsis expressed sequence tag (EST) library and its function was examined in a yeast lanosterol 14alpha-demethylase (Erg11) deficient mutant. A recombinant AtCYP51 protein fused with a yeast Erg11 signal-anchor peptide was able to complement the erg11 mutation, which confirmed AtCYP51 to be a functional sterol 14alpha-demethylase. AtCYP51 was then used to generate transgenic Arabidopsis by transforming with pBI vector harboring AtCYP51 in the antisense direction under CaMV35S promoter. The resulting transgenic plants were decreased in accumulation of AtCYP51 mRNA and increased in the amount of endogenous obtusifoliol. They showed a semidwarf phenotype in the early growth stage and a longer life span than control plants. This newly found phenotype is different from previously characterized brassinosteroid (BR)-deficient campesterol biosynthesis mutants.
Amino Acid Sequence↗
Cytokine gene therapy for myocarditis by in vivo electroporation.
Cytokines are important pathophysiologic and pathogenic factors in cardiovascular disorders, including viral myocarditis. We attempted to treat viral myocarditis with cytokine gene therapy by transferring an inhibitory cytokine, IL-1 receptor antagonist (IL-1ra) or viral IL-10 (vIL-10), by in vivo electroporation, a new method for gene transfer into muscle. Four-week-old male DBA/2 mice were inoculated intraperitoneally with 10 PFU of encephalomyocarditis virus. Immediately after virus inoculation, an expression plasmid carrying IL-1ra or vIL-10 was injected into tibialis anterior muscles followed by electroporation. Serum levels of IL1ra and vIL-10 reached 10.5 and 2.3 ng/ml, respectively, on day 5, when gene expression reached its peak. Histopathological examination showed that myocardial cellular infiltration was improved in mice treated with IL-1ra or vIL-10 compared with the control group. On day 14 after the onset of myocarditis, transfer of IL1ra or vIL-10 expression plasmid had significantly improved the survival rates of the animals. The expression of TNF-alpha was decreased to 0.60-fold (p < 0.005) and inducible nitric oxide synthase (iNOS) 0.43-fold (p < 0.005) by IL-1ra treatment, and the expression of IFN-gamma in the heart was decreased to 0.35-fold (p < 0.05), and iNOS 0.21-fold (p < 0.005), by vIL-10 relative to the controls. These results show that gene therapy with IL-1ra or vIL-10 expression plasmid was effective in the treatment of viral myocarditis, and in vivo electroporation may be a useful method by which to deliver cytokine therapy in cardiovascular diseases.
Animals↗
Purification, crystallization and preliminary X-ray diffraction analysis of the yeast Sec12Deltap protein, a guanine nucleotide-exchange factor involved in vesicle transport.
Sec12 is a guanine nucleotide-exchange factor (GEF) of the GTP-binding protein Sar1. Its GEF activity on Sar1 makes it a key element in vesicle budding from the endoplasmic reticulum to the Golgi apparatus in yeast. Sec12 is an integral membrane glycoprotein of 70 kDa. A 38.5 kDa N-cytoplasmic domain (Sec12Deltap) has been expressed in Saccharomyces cerevisiae and in Escherichia coli, purified to homogeneity and crystallized. Two crystal forms were obtained. Crystal form I belongs to space group P6(2)/P6(4), with unit-cell parameters a = b = 191.7, c = 53.3 A, gamma = 120 degrees, and diffracts to 2.6 A resolution. Crystal form II belongs to space group P1, with unit-cell parameters a = 52.6, b = 53.0, c = 116.8 A, alpha = 98.0, beta = 97.4, gamma = 93.4 degrees, and diffracts to 2.0 A resolution.
Crystallization↗
Solitary plasmacytoma with VEGF overproduction: report of a patient with polyneuropathy.
Explore the source record for details and available documents.
Bone Neoplasms↗
Rer1p, a retrieval receptor for endoplasmic reticulum membrane proteins, is dynamically localized to the Golgi apparatus by coatomer.
Rer1p, a yeast Golgi membrane protein, is required for the retrieval of a set of endoplasmic reticulum (ER) membrane proteins. We present the first evidence that Rer1p directly interacts with the transmembrane domain (TMD) of Sec12p which contains a retrieval signal. A green fluorescent protein (GFP) fusion of Rer1p rapidly cycles between the Golgi and the ER. Either a lesion of coatomer or deletion of the COOH-terminal tail of Rer1p causes its mislocalization to the vacuole. The COOH-terminal Rer1p tail interacts in vitro with a coatomer complex containing alpha and gamma subunits. These findings not only give the proof that Rer1p is a novel type of retrieval receptor recognizing the TMD in the Golgi but also indicate that coatomer actively regulates the function and localization of Rer1p.
Amino Acid Motifs↗
Mitochondrial ATP-sensitive K+ channels play a role in cardioprotection by Na+-H+ exchange inhibition against ischemia/reperfusion injury.
OBJECTIVES: The possible role of the ATP-sensitive potassium (KATP) channel in cardioprotection by Na+-H+ exchange (NHE) inhibition was examined. BACKGROUND: The KATP channel is suggested to be involved not only in ischemic preconditioning but also in some pharmacological cardioprotection. METHODS: Infarction was induced by 30-min coronary occlusion in rabbit hearts in situ or by 30-min global ischemia in isolated hearts. Myocardial stunning was induced by five episodes of 5-min ischemia/5-min reperfusion in situ. In these models, the effects of NHE inhibitors (cariporide and ethylisopropyl-amiloride [EIPA]) and the changes caused by KATP channel blockers were assessed. In another series of experiments, the effects of EIPA on mitochondrial KATP (mito-KATP) and sarcolemmal KATP (sarc-KATP) channels were examined in isolated cardiomyocvtes. RESULTS: Cariporide (0.6 mg/kg) reduced infarct size in situ by 40%, and this effect was abolished by glibenclamide (0.3 mg/kg), a nonselective KATP channel blocker. In vitro, 1 microM cariporide limited infarct size by 90%, and this effect was blocked by 5-hydroxydecanoate (5-HD), a mito-KATP channel blocker but not by HMR1098, a sarc-KATP channel blocker. Infarct size limitation by 1 microM EIPA was also prevented by 5-HD. Cariporide attenuated regional contractile dysfunction by stunning, and this protection was abolished by glibenclamide and 5-HD. Ethylisopropyl amiloride neither activated the mito-KATP channel nor enhanced activation of this channel by diazoxide, a KATP channel opener. CONCLUSIONS: Opening of the mito-KATP channel contributes to cardioprotection by NHE inhibition, though the interaction between NHE and this KATP channel remains unclear.
Animals↗
Compound heterozygosity for a recurrent 16.5-kb Alu-mediated deletion mutation and single-base-pair substitutions in the ABCC6 gene results in pseudoxanthoma elasticum.
Pseudoxanthoma elasticum (PXE) is a systemic heritable disorder affecting the elastic structures in the skin, eyes, and cardiovascular system, with considerable morbidity and mortality. Recently, mutations in the ABCC6 gene (also referred to as "MRP6" or "eMOAT") encoding multidrug-resistance protein 6 (MRP6), a putative transmembrane ABC transporter protein of unknown function, have been disclosed. Most of the genetic lesions delineated thus far consist of single-base-pair substitutions resulting in nonsense, missense, or splice-site mutations. In this study, we examined four multiplex families with PXE inherited in an autosomal recessive pattern. In each family, the proband was a compound heterozygote for a single-base-pair-substitution mutation and a novel, approximately 16.5-kb deletion mutation spanning the site of the single-base-pair substitution in trans. The deletion mutation was shown to extend from intron 22 to intron 29, resulting in out-of-frame deletion of 1,213 nucleotides from the corresponding mRNA and causing elimination of 505 amino acids from the MRP6 polypeptide. The deletion breakpoints were precisely the same in all four families, which were of different ethnic backgrounds, and haplotype analysis by 13 microsatellite markers suggested that the deletion had occurred independently. Deletion breakpoints within introns 22 and 29 were embedded within AluSx repeat sequences, specifically in a 16-bp segment of DNA, suggesting Alu-mediated homologous recombination as a mechanism.
ATP-Binding Cassette Transporters↗
Grain Boundaries in Gallium Arsenide Nanocrystals Under Pressure: A Parallel Molecular-Dynamics Study.
Structural transformation in gallium arsenide nanocrystals under pressure is studied using molecular-dynamics simulations on parallel computers. It is found that the transformation from fourfold to sixfold coordination is nucleated on the nanocrystal surface and proceeds inwards with increasing pressure. Inequivalent nucleation of the high-pressure phase at different sites leads to inhomogeneous deformation of the nanocrystal. This results in the transformed nanocrystal having grains of different orientations separated by grain boundaries. A new method based on microscopic transition paths is introduced to uniquely characterize grains and deformations.
Journal Article↗