The first detection of a Clar's hydrocarbon, 2,6,10-tri-tert-butyltriangulene: a ground-state triplet of non-Kekulé polynuclear benzenoid hydrocarbon.
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Journal Article↗
Biomedical subjects
J Inoue
Publications and source records attributed to J Inoue.
Lipopolysaccharide stimulates the MyD88-independent pathway and results in activation of IFN-regulatory factor 3 and the expression of a subset of lipopolysaccharide-inducible genes.
Bacterial lipopolysaccharide (LPS) triggers innate immune responses through Toll-like receptor (TLR) 4, a member of the TLR family that participates in pathogen recognition. TLRs recruit a cytoplasmic protein, MyD88, upon pathogen recognition, mediating its function for immune responses. Two major pathways for LPS have been suggested in recent studies, which are referred to as MyD88-dependent and -independent pathways. We report in this study the characterization of the MyD88-independent pathway via TLR4. MyD88-deficient cells failed to produce inflammatory cytokines in response to LPS, whereas they responded to LPS by activating IFN-regulatory factor 3 as well as inducing the genes containing IFN-stimulated regulatory elements such as IP-10. In contrast, a lipopeptide that activates TLR2 had no ability to activate IFN-regulatory factor 3. The MyD88-independent pathway was also activated in cells lacking both MyD88 and TNFR-associated factor 6. Thus, TLR4 signaling is composed of at least two distinct pathways, a MyD88-dependent pathway that is critical to the induction of inflammatory cytokines and a MyD88/TNFR-associated factor 6-independent pathway that regulates induction of IP-10.
Adaptor Proteins, Signal Transducing↗
Numerical analysis of spectra of the Frobenius-Perron operator of a noisy one-dimensional mapping: toward a theory of stochastic bifurcations.
A different method to detect the stochastic bifurcation point of a one-dimensional mapping in the presence of noise is proposed. This method analyzes the eigenvalues and eigenfunctions of the noisy Frobenius-Perron operator. The invariant density or the eigenfunction of the eigenvalue 1 of the operator possesses "static" information of the noisy one-dimensional dynamics while the other eigenvalues and eigenfunctions have "dynamic" information. Clear bifurcation phenomena have been observed in a noisy sine-circle map and both stochastic saddle-node and period-doubling bifurcation points have been successfully defined in terms of the eigenvalues.
Journal Article↗
Image restoration using the Q-Ising spin glass.
We investigate static and dynamic properties of gray-scale image restoration by making use of the Q-Ising spin glass model, whose ladder symmetry allows us to take in account the distance between two spins. We thus give an explicit expression of the Hamming distance between the original and restored images as a function of the hyperparameters in the mean field limit. Finally, numerical simulations for real-world pictures are carried out to prove the efficiency of our model.
Journal Article↗
TAK1 is a ubiquitin-dependent kinase of MKK and IKK.
TRAF6 is a signal transducer that activates IkappaB kinase (IKK) and Jun amino-terminal kinase (JNK) in response to pro-inflammatory mediators such as interleukin-1 (IL-1) and lipopolysaccharides (LPS). IKK activation by TRAF6 requires two intermediary factors, TRAF6-regulated IKK activator 1 (TRIKA1) and TRIKA2 (ref. 5). TRIKA1 is a dimeric ubiquitin-conjugating enzyme complex composed of Ubc13 and Uev1A (or the functionally equivalent Mms2). This Ubc complex, together with TRAF6, catalyses the formation of a Lys 63 (K63)-linked polyubiquitin chain that mediates IKK activation through a unique proteasome-independent mechanism. Here we report the purification and identification of TRIKA2, which is composed of TAK1, TAB1 and TAB2, a protein kinase complex previously implicated in IKK activation through an unknown mechanism. We find that the TAK1 kinase complex phosphorylates and activates IKK in a manner that depends on TRAF6 and Ubc13-Uev1A. Moreover, the activity of TAK1 to phosphorylate MKK6, which activates the JNK-p38 kinase pathway, is directly regulated by K63-linked polyubiquitination. We also provide evidence that TRAF6 is conjugated by the K63 polyubiquitin chains. These results indicate that ubiquitination has an important regulatory role in stress response pathways, including those of IKK and JNK.
Adaptor Proteins, Signal Transducing↗
A conserved imprinting control region at the HYMAI/ZAC domain is implicated in transient neonatal diabetes mellitus.
Transient neonatal diabetes mellitus (TNDM) is associated with intra-uterine growth retardation, dehydration and a lack of insulin. Some TNDM patients exhibit paternal uniparental disomy (UPD) of chromosome 6q24, where at least two imprinted genes, HYMAI and ZAC, have so far been characterized. Here we show that the differentially methylated CpG island that partially overlaps mZac1 and mHymai at the syntenic mouse locus is a likely imprinting control region (ICR) for the approximately 120--200 kb domain. The region is unmethylated in sperm but probably methylated in oocytes, a difference that persists between parental alleles throughout pre- and post-implantation development. We also show that within this ICR, there is a region that exhibits a high degree of homology between mouse and human. Using a reporter expression assay, we demonstrate that this conserved region acts as a strong transcriptional repressor when methylated. Finally, we provide in vivo evidence that in the majority of TNDM patients with a normal karyotype, there is a loss of methylation within the highly homologous region. We propose that this ICR regulates expression of imprinted genes within the domain; epigenetic or genetic mutations of this region probably result in TNDM, possibly by affecting expression of ZAC in the pancreas and/or the pituitary.
Alleles↗
Effects of stimulus intensity on sound localization in the horizontal and upper-hemispheric median plane.
Sound lateralization ability with headphones is known to be affected by stimulus intensity. However, there have been few studies on sound localization with loudspeakers in free field from the standpoint of stimulus intensity. The aim of this study is to obtain basic data for the tests with normal hearing and hearing-impaired subjects, and for the fitting of a hearing aid. The author investigated the relationship between stimulus intensities and sound localization ability of the broadband noise and pure tone bursts delivered in the horizontal and upper-hemispheric median planes. Subjects were ten volunteers, 5 males and 5 females, at the age of 18-19 years, with normal hearing. The results showed well how subjects perceived directions at all stimulus intensities. The percentage of correct response (%correct) for broadband noise stimuli was maximum at the intensity from 40 to 70 dB SPL (sound pressure level), and was minimum at 0 to 20 dB SPL in both the horizontal plane and the upper-hemispheric median plane. At lower stimulus intensity, examinee could not judge the direction, even if they could hear the stimuli. For pure tone bursts stimuli in the upper-hemispheric median plane, %correct was low irrespective of stimulus intensity.
Acoustic Stimulation↗
Proteolytic activation of SREBPs during adipocyte differentiation.
A member of sterol regulatory element-binding protein (SREBP) family, SREBP-1, is a key regulator of adipocyte differentiation. Expression of the SREBP-1 gene is induced during adipocyte differentiation, but proteolytic activation of the synthesized precursor form of SREBP-1 has not been well analyzed. The proteolytic processing of SREBPs is severely suppressed in sterol loaded culture cells. Here we report that a splicing isoform, SREBP-1a, is predominantly expressed in 3T3-L1 preadipocytes and adipocytes, and that the nuclear active form of SREBP-1 protein increases in adipocyte differentiation. We further show that the amount of nuclear SREBP-2 protein also increases despite no increase in SREBP-2 mRNA, suggesting that proteolytic cleavage of SREBPs is induced in lipid loaded adipocytes. Northern blot analyses reveal that mRNA levels for SREBP cleavage-activating protein (SCAP), Site-1 protease (S1P), and Site-2 protease (S2P), which participate in the proteolytic processing of SREBPs, are relatively unaffected in adipogenesis. These results demonstrate that SREBP-2 appears to promote adipocyte differentiation as well as SREBP-1 and that the proteolytic activation of SREBPs may be induced by an as-yet unidentified mechanism in lipid loaded adipocytes.
3T3 Cells↗
Mice containing a human chromosome 21 model behavioral impairment and cardiac anomalies of Down's syndrome.
Trisomy 21 (Ts21) is the most common live-born human aneuploidy; it results in a constellation of features known as Down's syndrome (DS). Ts21 is the most frequent cause of congenital heart defects and the leading genetic cause of mental retardation. To investigate the gene dosage effects of an extra copy of human chromosome 21 (Chr 21) on various phenotypes, we used microcell-mediated chromosome transfer to create embryonic stem (ES) cells containing Chr 21. ES cell lines retaining Chr 21 as an independent chromosome were used to produce chimeric mice with a substantial contribution from Chr 21-containing cells. Fluorescence in situ hybridization and PCR-based DNA analysis revealed that Chr 21 was substationally intact but had sustained a small deletion. The freely segregating Chr 21 was lost during development in some tissues, resulting in a panel of chimeric mice with various mosaicism as regards retention of the Chr 21. These chimeric mice showed a high correlation between retention of Chr 21 in the brain and impairment in learning or emotional behavior by open-field, contextual fear conditioning and forced swim tests. Hypoplastic thymus and cardiac defects, i.e. double outlet right ventricle and riding aorta, were observed in a considerable number of chimeric mouse fetuses with a high contribution of Chr 21. These chimeric mice mimic a wide variety of phenotypic traits of DS, revealing the utility of mice containing Chr 21 as unique models for DS and for the identification of genes responsible for DS.
Animals↗
Segregation of TRAF6-mediated signaling pathways clarifies its role in osteoclastogenesis.
Signals emanating from the receptor for interleukin-1 (IL-1), lipopolysaccharide (LPS) or osteoclast differentiation factor/receptor activator of NF kappa B ligand (ODF/RANKL) stimulate transcription factors AP-1 through mitogen-activated protein kinase (MAPK) activation and NF kappa B through I kappa B kinase (IKK) activation. These kinases are thought to be activated by tumor necrosis factor receptor-associated factor 6 (TRAF6). However, molecular mechanisms by which TRAF6 activates various downstream kinases remain to be elucidated. We identified functional domains of TRAF6 under physiological conditions established by appropriate expression of TRAF6 mutants in TRAF6-deficient cells. In IL-1 and LPS signaling pathways, the RING finger and first zinc finger domains are not required for NF kappa B activation but are required for full activation of MAPK. However, IL-1 and LPS signals utilize distinct regions within the zinc finger domains of TRAF6 to activate NF kappa B. Furthermore, the RING finger domain is not required for differentiation of splenocytes to multinuclear osteoclasts, but is essential for osteoclast maturation. Thus, TRAF6 plays essential roles in both the differentiation and maturation of osteoclasts by activating various kinases via its multiple domains.
Animals↗
Loss of cortical and thalamic neuronal tenascin-C expression in a transgenic mouse expressing exon 1 of the human Huntington disease gene.
A transgenic mouse containing the first exon of the human Huntington's disease (HD) gene has revealed a variety of behavioral and pathophysiological anomalies reminiscent of certain aspects of human Huntington's disease (HD). The present study has found that expression of the extracellular matrix glycoprotein tenascin-C appears to be unaffected in astroglial cells in wild-type and R6/2 transgenic mice that express the mutant huntingtin protein but that it is conspicuously absent in two neuronal populations within the cerebral cortex and thalamus of the R6/2 mice. Loss of tenascin-C expression begins between the fourth and eighth postnatal weeks, coincidental with the onset of abnormal behavioral phenotype and the appearance of intranuclear inclusion bodies and neuropil aggregates. By 12 weeks, R6/2 mice exhibit a complete absence of tenascin-C neuronal immunolabeling, a disappearance of cRNA probe-positive neurons across discrete cytoarchitectonic regions of the dorsal thalamus (e.g., the ventromedial, parafascicular, lateral posterior, and posterior thalamic groups) and frontal cortex, and an accompanying thalamic astrogliosis. The loss of neuronal tenascin-C expression includes structures that are known to send converging excitatory axonal projections to the caudate-putamen, the structure that is most at risk for neurodegeneration in HD. Altered neuronal expression of tenascin-C in R6/2 mice implicates altered transcriptional activities of the mutant huntingtin protein. The abnormal biochemistry and possibly abnormal activity of thalamostriate and corticostriate projection neurons may also affect abnormal neuronal activities in their primary connectional target, the neostriatum, which is severely compromised in HD.
Animals↗
Phase I/II study of intravenous nedaplatin and intraarterial cisplatin with transcatheter arterial embolization for patients with locally advanced uterine cervical carcinoma.
BACKGROUND: Nedaplatin, a platinum analog with less renal toxicity and similar efficacy for cervical carcinoma, recently has been shown to have a synergistic effect on cervical carcinoma lines in combination with cisplatin. To determine the clinical efficacy of this combination in patients with cervical carcinoma, the authors conducted a Phase I/II study of intravenous nedaplatin and intraarterial cisplatin combined with transcatheter arterial embolization (TAE). METHODS: Eligibility criteria were as follows: cervical carcinoma (Stages IB2-IV; International Federation of Gynecology and Obstetrics), 16-70 years of age, performance status between 0 and 2, and adequate bone marrow, renal, and hepatic function. Nedaplatin (40-70 mg/m2) was administered intravenously on Day 1 followed by intraarterial administration of cisplatin (70 mg/m2) on Day 3 via both uterine arteries by using the Seldinger method. This then was followed by TAE. This course of treatment was repeated every 3 weeks for 3 cycles. RESULTS: Patient data were as follows: age 37-68 (median, 55 years) and Stages IB2:4, IIA:3, IIB:2, IIIA:1, IIIB:3, IVA:2 carcinoma. The response to therapy was defined by magnetic resonance imaging as follows: partial response in 60% (9 of 15) of patients, complete response in 40% (6 of 15) of patients, and an overall response rate of 100% (95% confidence interval, 78-100%). Myelosuppression was manageable. Grade 3/4 renal toxicity was observed in 2 patients who received 70 mg/m2 of nedaplatin. Thirteen patients received radical hysterectomy, 1 patient received lymph node sampling, and 11 patients received adjuvant radiotherapy or chemotherapy. CONCLUSIONS: The maximum tolerable dose was 70 mg/m2 nedaplatin, and the dose-limiting toxicity was renal toxicity. The recommended dose was 60 mg/m2 nedaplatin intravenously followed by 70 mg/m2 cisplatin intraarterially. Intravenous nedaplatin followed by intraarterial cisplatin with TAE appears to be very effective for locally advanced cervical carcinoma.
Adult↗
Construction of 700 human/mouse A9 monochromosomal hybrids and analysis of imprinted genes on human chromosome 6.
As an in vitro assay system for the identification of human imprinted genes, a library of human/mouse A9 monochromosomal hybrids containing a single, intact bsr-tagged human chromosome of known parental origin, derived from normal human fibroblasts, has been previously generated by microcell-mediated chromosome transfer (MMCT). To supplement this assay system, we constructed additional 700 A9 monochromosomal hybrids, using a pSTneo or pPGKneo selection marker. To validate the A9 hybrids, we screened them with chromosome-specific polymorphic markers, and identified the hybrids containing either human chromosome 6, 7, 14, 18, or 21 of known parental origin. Matching paternal and maternal chromosome pairs of A9 hybrids were identified for chromosomes 6, 7, 14, and 18. The paternal-specific expression of ZAC (zinc finger protein, which regulates apoptosis and cell cycle arrest) and HYMAI (hydatidiform mole-associated and imprinted transcript), and the maternal-specific methylation of a CpG island within an imprinted domain on human chromosome 6q24, were maintained in A9 hybrids. For an example, we profiled the expression of expressed sequence tags (ESTs) and the methylation of CpG islands in the 300-kb imprinted domain around 6q24, which may be associated with cancers and transient neonatal diabetes mellitus (TNDM). Thus, the 700 A9 hybrids should be useful for various aspects of imprinting studies.
Animals↗
Mammalian homologue of E. coli Ras-like GTPase (ERA) is a possible apoptosis regulator with RNA binding activity.
BACKGROUND: ERA (Escherichia coli Ras-like protein) is an E. coli GTP binding protein that is essential for proliferation. A DNA database search suggests that homologous sequences with ERA exist in various organisms including human, mouse, Drosophila, Caenorhabditis elegans and Antirrhinum majus. However, the physiological function of eukaryotic ERA-like proteins is not known. RESULTS: We have cloned cDNAs encoding the entire coding region of a human homologue (H-ERA) and a mouse homologue (M-ERA) of ERA. The mammalian homologue of ERA consists of a typical GTPase/GTP-binding domain and a putative K homology (KH) domain, which is known as an RNA binding domain. We performed transfection experiments with wild-type H-ERA or various H-ERA mutants. H-ERA possessing the amino acid substitution mutation into the GTPase domain induced apoptosis of HeLa cells, which was blocked by Bcl-2 expression. Deletion of the C-terminus, which contains a part of the KH domain, alleviated apoptosis by the H-ERA mutant, suggesting the importance of this domain in the function of H-ERA. We have also shown the RNA binding activity of H-ERA by pull-down experiments using RNA homopolymer immobilized on beads or recombinant H-ERA proteins. CONCLUSION: Our data suggest that H-ERA plays an important role in the regulation of apoptotic signalling with its GTPase/GTP binding domain.
Amino Acid Sequence↗
The novel calpain inhibitor SJA6017 improves functional outcome after delayed administration in a mouse model of diffuse brain injury.
A principal mechanism of calcium-mediated neuronal injury is the activation of neutral proteases known as calpains. Proteolytic substrates for calpain include receptor and cytoskeletal proteins, signal transduction enzymes and transcription factors. Recently, calpain inhibitors have been shown to provide benefit in rat models of focal head injury and focal cerebral ischemia. The present study sought to investigate, in experiment 1, the time course of calpain-mediated cytoskeletal injury in a mouse model of diffuse head injury by measuring the 150- and 145-kDa alpha-spectrin breakdown products (SBDP). Secondly, in experiment 2, we examined the effect of early (20 min postinjury) administration of the novel calpain inhibitor SJA6017 on functional outcome measured 24 h following injury and its effect on posttraumatic alpha-spectrin degradation. Lastly, in experiment 3, we examined the effect of delayed (4 or 6 h postinjury) administration of SJA6017 on 24-h postinjury functional outcome. In experiment 1, isoflurane-anesthetized male CF-1 mice (18-22 g) were subjected to a 750 g-cm weight drop-induced injury and were sacrificed for SBDP analysis at postinjury times of 30 min, and 1, 2, 6, 24 and 48 h (plus sham). In experiments 2 and 3, mice were injured as described, and delivered a single tail vein injection of either SJA6017 (0.3, 1, or 3 mg/kg) or vehicle (administered immediately, 4 or 6 h postinjury [3 mg/kg]). Functional outcome was evaluated in both studies, and, in experiment 2, 24-h postinjury assessment of SBDPs was determined. Following injury, the level of SBDP 145 was significantly different from sham at 24 and 48 h in cortical and at 24 h in the hippocampal tissues and at 48 h in the striatum. Immediate postinjury administration of SJA6017 resulted in a dose-related improvement in 24-h functional outcome (p < 0.05 at 3 mg/kg). Significance was maintained after a 4-h delay of the 3 mg/kg, but was lost after a 6-h delay. Despite improvement in functional outcome at 24 h, SJA6017 did not reduce spectrin breakdown in cortical or hippocampal tissues. These results support a role for calpain-mediated neuronal injury and the potential for a practical therapeutic window for calpain inhibition following traumatic brain injury. However, measurements of regional spectrin degradation may not be the most sensitive marker for determining the effects of calpain inhibition.
Animals↗
The TOL plasmid pWW0 xylN gene product from Pseudomonas putida is involved in m-xylene uptake.
The upper operon of the TOL plasmid pWW0 of Pseudomonas putida encodes a set of enzymes involved in the conversion of toluene and xylenes to their carboxylic acid derivatives. The last gene of the upper operon, xylN, encodes a 465-amino-acid polypeptide which exhibits significant sequence similarity to FadL, an outer membrane protein involved in fatty acid transport in Escherichia coli. To analyze the role of the xylN gene product, xylN on TOL plasmid pWW0 was disrupted by inserting a kanamycin resistance gene, and the phenotypes of P. putida harboring the wild-type and xylN mutant TOL plasmids were characterized. The growth of P. putida harboring the wild-type TOL plasmid was inhibited by a high concentration of m-xylene, while that of P. putida harboring the xylN mutant TOL plasmid was not. The apparent K(s) value for the oxidation of m-xylene in intact cells of the xylN mutant was fourfold higher than that of the wild-type strain, although the TOL catabolic enzyme activities in cell extracts from the two strains were almost identical. We therefore presume that the xylN gene product is a porin involved in the transport of m-xylene and its analogues across the outer membrane. Western blot analysis confirmed the localization of XylN in the outer membrane.
Bacterial Outer Membrane Proteins↗
Occurrences of candidiasis in a Fisher's lovebird and a budgerigar.
Two cage birds, a two-month-old Fisher's lovebird (Agapornis fischeri) and a one-year-old budgerigar (Melopsittacus undulatus), manifested clinical symptoms with general weakness, loss of appetite and ruffled feathers, then died. Pathological findings revealed a large quantity of yellowish-white pseudomembrane on the mucosal membrane of the esophagus and crop in these two birds. Histopathologically, blastospores (5.5 microm long x 3.4 microm wide) and pseudohyphae were detected in the lesions of conspicuous parakeratosis and moderate acanthosis in the stratified squamous epithelium. These two birds were diagnosed as having had candidiasis.
Animals↗
Decline in the positive rate of human T-lymphotropic virus type-1 (HTLV-1) antibodies among blood donors in Nagasaki.
OBJECTIVE: The aim of this study was to clarify the trend of the HTLV-1 seroprevalence rate among blood donors. METHODS: Samples were screened by the particle agglutination test for HTLV-1 antibodies. MATERIALS: Serum from blood donors was screened. RESULTS: The positive rate of HTLV-1 antibodies among blood donors decreased from 13.14 to 0.81 % over the years from 1928 to 1983. CONCLUSION: A decline over the years in the positive rate of HTLV-1 antibodies among blood donors was revealed.
Adolescent↗