Showing papers by "Osaka University published in 2007"
TL;DR: An overview of the status of the terahertz technology, its uses and its future prospects are presented in this article, with a focus on the use of the waveband in a wide range of applications.
Abstract: Research into terahertz technology is now receiving increasing attention around the world, and devices exploiting this waveband are set to become increasingly important in a very diverse range of applications. Here, an overview of the status of the technology, its uses and its future prospects are presented.
5,512 citations
University of Vermont1, University of Minnesota2, University of Texas at Austin3, Hong Kong University of Science and Technology4, Osaka University5, University of Queensland6, Griffith University7, University of Illinois at Chicago8, IBM9, Nanjing University10, Imperial College London11, University of Salford12
TL;DR: This paper presents the top 10 data mining algorithms identified by the IEEE International Conference on Data Mining (ICDM) in December 2006: C4.5, k-Means, SVM, Apriori, EM, PageRank, AdaBoost, kNN, Naive Bayes, and CART.
Abstract: This paper presents the top 10 data mining algorithms identified by the IEEE International Conference on Data Mining (ICDM) in December 2006: C4.5, k-Means, SVM, Apriori, EM, PageRank, AdaBoost, kNN, Naive Bayes, and CART. These top 10 algorithms are among the most influential data mining algorithms in the research community. With each algorithm, we provide a description of the algorithm, discuss the impact of the algorithm, and review current and further research on the algorithm. These 10 algorithms cover classification, clustering, statistical learning, association analysis, and link mining, which are all among the most important topics in data mining research and development.
4,944 citations
TL;DR: The findings highlight the unexpected role of homeostatic level of p62, which is regulated by autophagy, in controlling intracellular inclusion body formation, and indicate that the pathologic process associated with autophagic deficiency is cell-type specific.
2,018 citations
TL;DR: Using this method, evidence that overexpression of a dominant negative form of Rab7 prevented the fusion of autophagosomes with lysosomes is provided, suggesting that Rab7 is involved in this step.
Abstract: During the process of autophagy, autophagosomes undergo a maturation process consisting of multiple fusions with endosomes and lysosomes, which provide an acidic environment and digestive function to the interior of the autophagosome. Here we found that a fusion protein of monomeric red-fluorescence protein and LC3, the most widely used marker for autophagosomes, exhibits a quite different localization pattern from that of GFP-LC3. GFP-LC3 loses fluorescence due to lysosomal acidic and degradative conditions but mRFP-LC3 does not, indicating that the latter can label the autophagic compartments both before and after fusion with lysosomes. Taking advantage of this property, we devised a novel method for dissecting the maturation process of autophagosomes. mRFP-GFP tandem fluorescent-tagged LC3 (tfLC3) showed a GFP and mRFP signal before the fusion with lysosomes, and exhibited only the mRFP signal subsequently. Using this method, we provided evidence that overexpression of a dominant negative form of Rab7 prevented the fusion of autophagosomes with lysosomes, suggesting that Rab7 is involved in this step. This method will be of general utility for analysis of the autophagosome maturation process.
1,967 citations
TL;DR: The role of NF-κB in TLR signaling pathways has been discussed in this article, where the authors review recent progress in their understanding of the role and potential implications for molecular medicine.
1,822 citations
TL;DR: Whether prostate cancer is driven by inflammation, and if so, to develop new strategies to prevent the disease, is determined by developing new experimental animal models coupled with classical Epidemiological studies, genetic epidemiological studies and molecular pathological approaches.
Abstract: About 20% of all human cancers are caused by chronic infection or chronic inflammatory states. Recently, a new hypothesis has been proposed for prostate carcinogenesis. It proposes that exposure to environmental factors such as infectious agents and dietary carcinogens, and hormonal imbalances lead to injury of the prostate and to the development of chronic inflammation and regenerative 'risk factor' lesions, referred to as proliferative inflammatory atrophy (PIA). By developing new experimental animal models coupled with classical epidemiological studies, genetic epidemiological studies and molecular pathological approaches, we should be able to determine whether prostate cancer is driven by inflammation, and if so, to develop new strategies to prevent the disease.
1,504 citations
TL;DR: Results indicate that constitutive autophagy in the heart under baseline conditions is a homeostatic mechanism for maintaining cardiomyocyte size and global cardiac structure and function, and that upregulation of autophagic in failing hearts is an adaptive response for protecting cells from hemodynamic stress.
Abstract: Autophagy, an evolutionarily conserved process for the bulk degradation of cytoplasmic components, serves as a cell survival mechanism in starving cells. Although altered autophagy has been observed in various heart diseases, including cardiac hypertrophy and heart failure, it remains unclear whether autophagy plays a beneficial or detrimental role in the heart. Here, we report that the cardiac-specific loss of autophagy causes cardiomyopathy in mice. In adult mice, temporally controlled cardiac-specific deficiency of Atg5 (autophagy-related 5), a protein required for autophagy, led to cardiac hypertrophy, left ventricular dilatation and contractile dysfunction, accompanied by increased levels of ubiquitination. Furthermore, Atg5-deficient hearts showed disorganized sarcomere structure and mitochondrial misalignment and aggregation. On the other hand, cardiac-specific deficiency of Atg5 early in cardiogenesis showed no such cardiac phenotypes under baseline conditions, but developed cardiac dysfunction and left ventricular dilatation one week after treatment with pressure overload. These results indicate that constitutive autophagy in the heart under baseline conditions is a homeostatic mechanism for maintaining cardiomyocyte size and global cardiac structure and function, and that upregulation of autophagy in failing hearts is an adaptive response for protecting cells from hemodynamic stress.
1,390 citations
TL;DR: It is found that Bim is essential for ER stress-induced apoptosis in a diverse range of cell types both in culture and within the whole animal.
1,335 citations
TL;DR: It is shown that adipose tissue of obese mice is hypoxic and that local adipose tissues hypoxia dysregulates the production of adipocytokines, and the results suggest that hypoperfusion and Hypoxia in adipose organs underlie the dysregulated production of fat-derived secretory factors and metabolic syndrome in obesity.
Abstract: Obesity is linked to a variety of metabolic disorders, such as insulin resistance and atherosclerosis. Dysregulated production of fat-derived secretory factors, adipocytokines, is partly responsible for obesity-linked metabolic disorders. However, the mechanistic role of obesity per se to adipocytokine dysregulation has not been fully elucidated. Here, we show that adipose tissue of obese mice is hypoxic and that local adipose tissue hypoxia dysregulates the production of adipocytokines. Tissue hypoxia was confirmed by an exogenous marker, pimonidazole, and by an elevated concentration of lactate, an endogenous marker. Moreover, local tissue hypoperfusion (measured by colored microspheres) was confirmed in adipose tissue of obese mice. Adiponectin mRNA expression was decreased, and mRNA of C/EBP homologous protein (CHOP), an endoplasmic reticulum (ER) stress-mediated protein, was significantly increased in adipose tissue of obese mice. In 3T3-L1 adipocytes, hypoxia dysregulated the expression of adipocytokines, such as adiponectin and plasminogen activator inhibitor type-1, and increased the mRNAs of ER stress marker genes, CHOP and GRP78 (glucose-regulated protein, 78 kD). Expression of CHOP attenuated adiponectin promoter activity, and RNA interference of CHOP partly reversed hypoxia-induced suppression of adiponectin mRNA expression in adipocytes. Hypoxia also increased instability of adiponectin mRNA. Our results suggest that hypoperfusion and hypoxia in adipose tissues underlie the dysregulated production of adipocytokines and metabolic syndrome in obesity.
1,179 citations
TL;DR: It is shown that localization of mouse Np95 to replicating heterochromatin is dependent on the presence of hemi-methylated DNA and the link between Np 95 and Dnmt1 establishes key steps of the mechanism for epigenetic inheritance of DNA methylation.
Abstract: DNA methyltransferase (cytosine-5) 1 (Dnmt1) is the principal enzyme responsible for maintenance of CpG methylation and is essential for the regulation of gene expression, silencing of parasitic DNA elements, genomic imprinting and embryogenesis. Dnmt1 is needed in S phase to methylate newly replicated CpGs occurring opposite methylated ones on the mother strand of the DNA, which is essential for the epigenetic inheritance of methylation patterns in the genome. Despite an intrinsic affinity of Dnmt1 for such hemi-methylated DNA, the molecular mechanisms that ensure the correct loading of Dnmt1 onto newly replicated DNA in vivo are not understood. The Np95 (also known as Uhrf1 and ICBP90) protein binds methylated CpG through its SET and RING finger-associated (SRA) domain. Here we show that localization of mouse Np95 to replicating heterochromatin is dependent on the presence of hemi-methylated DNA. Np95 forms complexes with Dnmt1 and mediates the loading of Dnmt1 to replicating heterochromatic regions. By using Np95-deficient embryonic stem cells and embryos, we show that Np95 is essential in vivo to maintain global and local DNA methylation and to repress transcription of retrotransposons and imprinted genes. The link between hemi-methylated DNA, Np95 and Dnmt1 thus establishes key steps of the mechanism for epigenetic inheritance of DNA methylation.
1,179 citations
TL;DR: Results indicate that Tim4 and Tim1 are phosphatidylserine receptors for the engulfment of apoptotic cells, and may also be involved in intercellular signalling in which exosomes are involved.
Abstract: During programmed cell death in multicellular organisms, a large number of cells are engulfed by macrophages, thus avoiding the release of noxious materials from the dying cells. These 'apoptotic' cells expose phosphatidylserine (PS) on their surface as an 'eat-me' signal. Miyanishi et al. show that the receptors Tim4 and Tim1 are implicated in phagocyte recognition of PS, while Park et al. show that the BAI1 protein is a receptor for PS in mammalian macrophages. Apoptotic cells expose phosphatidylserine as an 'eat-me' signal for macrophages. This paper shows that the receptors Tim4 and Tim1 are implicated in phagocyte recognition of phosphatidylserine. In programmed cell death, a large number of cells undergo apoptosis, and are engulfed by macrophages to avoid the release of noxious materials from the dying cells1,2. In definitive erythropoiesis, nuclei are expelled from erythroid precursor cells and are engulfed by macrophages. Phosphatidylserine is exposed on the surface of apoptotic cells3 and on the nuclei expelled from erythroid precursor cells4; it works as an ‘eat me’ signal for phagocytes5,6. Phosphatidylserine is also expressed on the surface of exosomes involved in intercellular signalling7. Here we established a library of hamster monoclonal antibodies against mouse peritoneal macrophages, and found an antibody that strongly inhibited the phosphatidylserine-dependent engulfment of apoptotic cells. The antigen recognized by the antibody was identified by expression cloning as a type I transmembrane protein called Tim4 (T-cell immunoglobulin- and mucin-domain-containing molecule; also known as Timd4)8. Tim4 was expressed in Mac1+ cells in various mouse tissues, including spleen, lymph nodes and fetal liver. Tim4 bound apoptotic cells by recognizing phosphatidylserine via its immunoglobulin domain. The expression of Tim4 in fibroblasts enhanced their ability to engulf apoptotic cells. When the anti-Tim4 monoclonal antibody was administered into mice, the engulfment of apoptotic cells by thymic macrophages was significantly blocked, and the mice developed autoantibodies. Among the other Tim family members, Tim1, but neither Tim2 nor Tim3, specifically bound phosphatidylserine. Tim1- or Tim4-expressing Ba/F3 B cells were bound by exosomes via phosphatidylserine, and exosomes stimulated the interaction between Tim1 and Tim4. These results indicate that Tim4 and Tim1 are phosphatidylserine receptors for the engulfment of apoptotic cells, and may also be involved in intercellular signalling in which exosomes are involved.
TL;DR: The worldwide Protein Data Bank (wwPDB) is the international collaboration that manages the deposition, processing and distribution of the PDB archive, a repository for the coordinates and related information for more than 38 000 structures, including proteins, nucleic acids and large macromolecular complexes that have been determined using X-ray crystallography, NMR and electron microscopy techniques.
Abstract: The worldwide Protein Data Bank (wwPDB) is the international collaboration that manages the deposition, processing and distribution of the PDB archive. The online PDB archive is a repository for the coordinates and related information for more than 38 000 structures, including proteins, nucleic acids and large macromolecular complexes that have been determined using X-ray crystallography, NMR and electron microscopy techniques. The founding members of the wwPDB are RCSB PDB (USA), MSD-EBI (Europe) and PDBj (Japan) [H.M. Berman, K. Henrick and H. Nakamura (2003) Nature Struct. Biol., 10, 980]. The BMRB group (USA) joined the wwPDB in 2006. The mission of the wwPDB is to maintain a single archive of macromolecular structural data that are freely and publicly available to the global community. Additionally, the wwPDB provides a variety of services to a broad community of users. The wwPDB website at http://www.wwpdb.org/ provides information about services provided by the individual member organizations and about projects undertaken by the wwPDB.
TL;DR: Results indicate that the Atg12-Atg5 conjugate is a ubiquitin-protein ligase (E3)-like enzyme for Atg8-PE conjugation reaction, distinctively promoting protein-lipid conjugations.
San Francisco General Hospital1, University of Michigan2, National Jewish Health3, Cornell University4, University of California, San Francisco5, Tulane University6, Vanderbilt University7, University of Chicago8, University of Alabama at Birmingham9, University of Washington10, Emory University11, Mayo Clinic12, University of California, Los Angeles13, University of Iowa14, University College Dublin15, Osaka University16, University of Pittsburgh17, University of Ulsan18, University of Freiburg19
TL;DR: An international effort to summarize the current state of knowledge regarding acute exacerbations of IPF is presented, and proposed diagnostic criteria include subjective worsening over 30 days or less, new bilateral radiographic opacities, and the absence of infection or another identifiable etiology.
Abstract: The natural history of idiopathic pulmonary fibrosis (IPF) has been characterized as a steady, predictable decline in lung function over time. Recent evidence suggests that some patients may experience a more precipitous course, with periods of relative stability followed by acute deteriorations in respiratory status. Many of these acute deteriorations are of unknown etiology and have been termed acute exacerbations of IPF. This perspective is the result of an international effort to summarize the current state of knowledge regarding acute exacerbations of IPF. Acute exacerbations of IPF are defined as acute, clinically significant deteriorations of unidentifiable cause in patients with underlying IPF. Proposed diagnostic criteria include subjective worsening over 30 days or less, new bilateral radiographic opacities, and the absence of infection or another identifiable etiology. The potential pathobiological roles of infection, disordered cell biology, coagulation, and genetics are discussed, and future research directions are proposed.
TL;DR: The XIS is an X-ray imaging spectrometer system, consisting of state-of-the-art charge-coupled devices (CCDs) optimized for Xray detection, camera bodies, and control electronics as mentioned in this paper.
Abstract: The XIS is an X-ray Imaging Spectrometer system, consisting of state-of-the-art charge-coupled devices (CCDs) optimized for X-ray detection, camera bodies, and control electronics. Four sets of XIS sensors are placed at the focal planes of the grazing-incidence, nested thin-foil mirrors (XRT: X-Ray Telescope) onboard the Suzaku satellite. Three of the XIS sensors have front-illuminated CCDs, while the other has a back-illuminated CCD. Coupled with the XRT, the energy range of 0.2–12keV with energy resolution of 130eV at 5.9keV, and a field of view of 18 � ×18 �
Massachusetts Institute of Technology1, Goddard Space Flight Center2, Kyoto University3, Nagoya University4, University of Tokyo5, Osaka University6, Ehime University7, University of Cambridge8, Hiroshima University9, Carnegie Mellon University10, Max Planck Society11, University of Miyazaki12, Franklin W. Olin College of Engineering13, Rutgers University14, Tokyo Metropolitan University15, Kobe University16, Stanford University17, Tokyo Institute of Technology18, Rikkyo University19, Kogakuin University20, Tokyo University of Science21, University of Wisconsin-Madison22, Kanazawa University23, Nihon University24, Pennsylvania State University25, European Space Research and Technology Centre26, Yale University27, Saitama University28, Chuo University29, University of Leicester30, Nihon Fukushi University31, Aoyama Gakuin University32, Iwate University33
TL;DR: In this paper, the authors summarized the spacecraft, in-orbit performance, operations, and data processing that are related to observations of the Suzaku X-ray observatory, including high-sensitivity wide-band Xray spectroscopy.
Abstract: High-sensitivity wide-band X-ray spectroscopy is the key feature of the Suzaku X-ray observatory, launched on 2005 July 10. This paper summarizes the spacecraft, in-orbit performance, operations, and data processing that are related to observations. The scientific instruments, the high-throughput X-ray telescopes, X-ray CCD cameras, non-imaging hard X-ray detector are also described.
Bradley University1, University of Tartu2, National Institutes of Health3, University of California4, Pontifical Catholic University of Chile5, University of Louisville6, University of Latvia7, Pennsylvania State University8, Slovak Academy of Sciences9, University of San Carlos10, University of Malta11, Ghent University12, Clemson University13, Laval University14, University of Buenos Aires15, Osaka University16, Illinois State University17, National Autonomous University of Mexico18, University of Brasília19, University of Western Australia20, University of Lima21, Boğaziçi University22, University of Kassel23, York University24, University of Queensland25, Åbo Akademi University26, Al Akhawayn University27, University of Hawaii at Manoa28, University of Catania29, University of Otago30, University of Dhaka31, Chemnitz University of Technology32, Knox College33, Comenius University in Bratislava34, University of Rijeka35, University of Malaya36, Vilnius University37, American University of Beirut38, Kwangju Health College39, University of Salzburg40, Utrecht University41, National Computerization Agency42, City University of Hong Kong43, University of Idaho44, University of Zimbabwe45, University of Lisbon46, University of Central Lancashire47, Loyola Marymount University48, University of KwaZulu-Natal49, University of Granada50, University of Botswana51, Babeș-Bolyai University52, University of Cyprus53, University of Belgrade54, KPMG55, University of Montpellier56, University of Zurich57, University of Alabama58, Baylor University59, Queen's University Belfast60, University of Ljubljana61, University of Haifa62, University of La Serena63, Florida Atlantic University64, University of California, Davis65, University of Dar es Salaam66, Ramapo College67, Cyprus College68, Middle East Technical University69, Nicolaus Copernicus University in Toruń70, University of the South Pacific71, Vrije Universiteit Brussel72, University at Albany, SUNY73, University of the Aegean74, University of Lethbridge75, University of Vienna76, University of Hong Kong77, Yuan Ze University78, Charles University in Prague79, Chonnam National University80, Indian Institutes of Technology81
TL;DR: The Big Five Inventory (BFI) is a self-report measure designed to assess the high-order personality traits of Extraversion, Agreeableness, Conscientiousness, Neuroticism, and Openness as discussed by the authors.
Abstract: The Big Five Inventory (BFI) is a self-report measure designed to assess the high-order personality traits of Extraversion, Agreeableness, Conscientiousness, Neuroticism, and Openness. As part of the International Sexuality Description Project, the BFI was translated from English into 28 languages and administered to 17,837 individuals from 56 nations. The resulting cross-cultural data set was used to address three main questions: Does the factor structure of the English BFI fully replicate across cultures? How valid are the BFI trait profiles of individual nations? And how are personality traits distributed throughout the world? The five-dimensional structure was robust across major regions of the world. Trait levels were related in predictable ways to self-esteem, sociosexuality, and national personality profiles. People from the geographic regions of South America and East Asia were significantly different in openness from those inhabiting other world regions. The discussion focuses on limitations of t...
TL;DR: It is suggested that inhibiting the IL-1R–Myd88 pathway in vivo could block the damage from acute inflammation that occurs in response to sterile cell death, and do so in a way that might not compromise tissue repair or host defense against pathogens.
Abstract: Dying cells stimulate inflammation, and this response is thought to contribute to the pathogenesis of many diseases. Very little has been known, however, about how cell death triggers inflammation. We found here that the acute neutrophilic inflammatory response to cell injury requires the signaling protein myeloid differentiation primary response gene 88 (Myd88). Analysis of the contribution of Myd88-dependent receptors to this response revealed only a minor reduction in mice doubly deficient in Toll-like receptor 2 (Tlr2) and Tlr4 and normal responses in mice lacking Tlr1, Tlr3, Tlr6, Tlr7, Tlr9, Tlr11 or the interleukin-18 receptor (IL-18R). However, mice lacking IL-1R showed a markedly reduced neutrophilic inflammatory response to dead cells and tissue injury in vivo as well as greatly decreased collateral damage from inflammation. This inflammatory response required IL-1alpha, and IL-1R function was required on non-bone-marrow-derived cells. Notably, the acute monocyte response to cell death, which is thought to be important for tissue repair, was much less dependent on the IL-1R-Myd88 pathway. Also, this pathway was not required for the neutrophil response to a microbial stimulus. These findings suggest that inhibiting the IL-1R-Myd88 pathway in vivo could block the damage from acute inflammation that occurs in response to sterile cell death, and do so in a way that might not compromise tissue repair or host defense against pathogens.
TL;DR: The aged-rejuvenation-glue-liquid (ARGL) shear band model has been proposed for metallic glasses based on small-scale molecular dynamics simulations up to 20,000 atoms and thermomechanical analysis as mentioned in this paper.
Abstract: The aged-rejuvenation-glue-liquid (ARGL) shear band model has been proposed for metallic glasses (Acta Mater. 54 (2006) 4293), based on small-scale molecular dynamics simulations up to 20,000 atoms and thermomechanical analysis. The model predicts the existence of a critical lengthscale � 10 nm, above which melting could occur in shear-alienated glass. Large-scale molecular dynamics simulations with up to 5 million atoms have directly verified this prediction. When the applied stress exceeds the glue traction (computed separately before in a shear cohesive zone, or an amorphous-amorphous ‘‘generalized stacking fault energy’’ calculation), we indeed observe maturation of the shear band embryo into bona fide shear crack, accompanied by melting. In contrast, when the applied stress is below the glue traction, the shear band embryo does not propagate, becomes diffuse, and eventually dies. Thus this all-important quantity, the glue traction which is a property of shearalienated glass, controls the macroscopic yield point of well-aged glass. We further suggest that the disruption of chemical short-range order (‘‘chemical softening’’) governs the glue traction microscopically. Catastrophic thermal softening occurs only after chemical alienation and softening in our simulation, after the shear band embryo has already run a critical length. [doi:10.2320/matertrans.MJ200769]
King's College1, Carlos III Health Institute2, King's College London3, Georgia Regents University4, Baylor College of Medicine5, Osaka University6, Southern General Hospital7, University of Naples Federico II8, Tel Aviv University9, Icahn School of Medicine at Mount Sinai10, St Thomas' Hospital11, Royal College of Nursing12, Emory University13, Fukuoka University14, North Tyneside General Hospital15, Royal Free Hospital16, University of Kent17
TL;DR: NMSS can be used to assess the frequency and severity of NMS in PD patients across all stages in conjunction with the recently validated non‐motor questionnaire.
Abstract: Non-motor symptoms (NMS) in Parkinson's disease (PD) are common, significantly reduce quality of life and at present there is no validated clinical tool to assess the progress or potential response to treatment of NMS. A new 30-item scale for the assessment of NMS in PD (NMSS) was developed. NMSS contains nine dimensions: cardiovascular, sleep/fatigue, mood/cognition, perceptual problems, attention/memory, gastrointestinal, urinary, sexual function, and miscellany. The metric attributes of this instrument were analyzed. Data from 242 patients mean age 67.2 +/- 11 years, duration of disease 6.4 +/- 6 years, and 57.3% male across all stages of PD were collected from the centers in Europe, USA, and Japan. The mean NMSS score was 56.5 +/- 40.7, (range: 0-243) and only one declared no NMS. The scale provided 99.2% complete data for the analysis with the total score being free of floor and ceiling effect. Satisfactory scaling assumptions (multitrait scaling success rate >95% for all domains except miscellany) and internal consistency were reported for most of the domains (mean alpha, 0.61). Factor analysis supported the a prori nine domain structure (63% of the variance) while a small test-retest study showed satisfactory reproducibility (ICC > 0.80) for all domains except cardiovascular (ICC = 0.45). In terms of validity, the scale showed modest association with indicators of motor symptom severity and disease progression but a high correlation with other measures of NMS (NMSQuest) and health-related quality of life measure (PDQ-8) (both, rS = 0.70). In conclusion, NMSS can be used to assess the frequency and severity of NMS in PD patients across all stages in conjunction with the recently validated non-motor questionnaire.
TL;DR: This new biomimetic model may provide a broadly applicable 3D culture system to study the effect of microenvironmental conditions on tumor malignancy in vitro and in vivo.
Abstract: Microenvironmental conditions control tumorigenesis and biomimetic culture systems that allow for in vitro and in vivo tumor modeling may greatly aid studies of cancer cells' dependency on these conditions. We engineered three-dimensional (3D) human tumor models using carcinoma cells in polymeric scaffolds that recreated microenvironmental characteristics representative of tumors in vivo. Strikingly, the angiogenic characteristics of tumor cells were dramatically altered upon 3D culture within this system, and corresponded much more closely to tumors formed in vivo. Cells in this model were also less sensitive to chemotherapy and yielded tumors with enhanced malignant potential. We assessed the broad relevance of these findings with 3D culture of other tumor cell lines in this same model, comparison with standard 3D Matrigel culture and in vivo experiments. This new biomimetic model may provide a broadly applicable 3D culture system to study the effect of microenvironmental conditions on tumor malignancy in vitro and in vivo.
TL;DR: RIG-I is a cytoplasmic sensor of HCV and is governed by RD interactions that are shared with LGP2 as an on/off switch controlling innate defenses, which may have therapeutic implications for immune regulation.
Abstract: RIG-I is an RNA helicase containing caspase activation and recruitment domains (CARDs). RNA binding and signaling by RIG-I are implicated in pathogen recognition and triggering of IFN-alpha/beta immune defenses that impact cell permissiveness for hepatitis C virus (HCV). Here we evaluated the processes that control RIG-I signaling. RNA binding studies and analysis of cells lacking RIG-I, or the related MDA5 protein, demonstrated that RIG-I, but not MDA5, efficiently binds to secondary structured HCV RNA to confer induction of IFN-beta expression. We also found that LGP2, a helicase related to RIG-I and MDA5 but lacking CARDs and functioning as a negative regulator of host defense, binds HCV RNA. In resting cells, RIG-I is maintained as a monomer in an autoinhibited state, but during virus infection and RNA binding it undergoes a conformation shift that promotes self-association and CARD interactions with the IPS-1 adaptor protein to signal IFN regulatory factor 3- and NF-kappaB-responsive genes. This reaction is governed by an internal repressor domain (RD) that controls RIG-I multimerization and IPS-1 interaction. Deletion of the RIG-I RD resulted in constitutive signaling to the IFN-beta promoter, whereas RD expression alone prevented signaling and increased cellular permissiveness to HCV. We identified an analogous RD within LGP2 that interacts in trans with RIG-I to ablate self-association and signaling. Thus, RIG-I is a cytoplasmic sensor of HCV and is governed by RD interactions that are shared with LGP2 as an on/off switch controlling innate defenses. Modulation of RIG-I/LGP2 interaction dynamics may have therapeutic implications for immune regulation.
TL;DR: Tocilizumab monotherapy was generally well tolerated and provided radiographic benefit in patients with RA and improved signs and symptoms.
Abstract: Objective To evaluate the ability of tocilizumab (a humanised anti-IL-6 receptor antibody) monotherapy to inhibit progression of structural joint damage in patients with RA. Methods In a multi-centre, x ray reader-blinded, randomised, controlled trial, 306 patients with active RA of Results Patients had a mean disease duration of 2.3 years and a disease activity score in 28 joints of 6.5 at baseline. Mean total modified Sharp score (TSS) was 29.4, which was very high despite the relatively short disease duration. At week 52, the tocilizumab group showed statistically significantly less radiographic change in TSS (mean 2.3; 95% CI 1.5 to 3.2) than the DMARD group (mean 6.1; 95% CI 4.2 to 8.0; p Conclusion Tocilizumab monotherapy was generally well tolerated and provided radiographic benefit in patients with RA.
TL;DR: The direct oxidative coupling of benzoic acids with internal alkynes proceeds efficiently in the presence of a rhodium/copper catalyst system under air to afford the corresponding isocoumarin derivatives via divinylation and subsequent cyclization.
TL;DR: In this article, the authors have focused on the mechanisms of the one-electron redox reactions of organic compounds during the TiO2 photocatalytic reactions and on the development of TiO 2-based materials.
Abstract: Titanium dioxide (TiO2) has been extensively investigated for the photocatalytic purification of air and water. In this article, we have focused on the mechanisms of the one-electron redox reactions of organic compounds during the TiO2 photocatalytic reactions and on the development of TiO2-based materials. It was clearly demonstrated that the adsorption dynamics of substrates and intermediates, the electronic interaction between TiO2 and adsorbates, and the band structure and morphology of TiO2 nanomaterials are crucial factors for establishing efficient photocatalytic reaction systems. The TiO2-based hybrid nanoparticles with various functional materials, such as polyoxometalates (POMs) and cyclodextrins (CDs), have been fabricated on the basis of the mechanistic aspects. New experimental methods, such as two-color two-laser flash photolysis and single-molecule fluorescence techniques, for the investigation of the TiO2 photocatalytic reactions have been demonstrated.
TL;DR: The performance of this approach is illustrated by imaging the surface of a particularly challenging alloy system and successfully identifying the three constituent atomic species silicon, tin and lead, even though these exhibit very similar chemical properties and identical surface position preferences that render any discrimination attempt based on topographic measurements impossible.
Abstract: Dynamic force microscopy, which works by detecting the interaction force between the oscillating tip of an atomic force microscope (AFM) and a surface, has been refined to the extent that it can achieve true atomic resolution of insulator, semiconductor and metal surfaces. In a landmark publication in this issue this technique has been used to perform the chemical identification of individual atoms in a multi-element system. The method involves precise quantification of short-range chemical forces between the probed atoms and the AFM tip, and provides a robust and general recognition tool suitable for both cryogenic and room temperature environments. The cover shows a topographic image of a surface alloy made up of silicon (red), tin (blue), and lead atoms (green) in equal proportions on a silicon (111) substrate. This atomic identification method is relevant to a wide range of research areas such as catalysis, materials science and semiconductor technology. Scanning probe microscopy is a versatile and powerful method that uses sharp tips to image, measure and manipulate matter at surfaces with atomic resolution1,2. At cryogenic temperatures, scanning probe microscopy can even provide electron tunnelling spectra that serve as fingerprints of the vibrational properties of adsorbed molecules3,4,5 and of the electronic properties of magnetic impurity atoms6,7, thereby allowing chemical identification. But in many instances, and particularly for insulating systems, determining the exact chemical composition of surfaces or nanostructures remains a considerable challenge. In principle, dynamic force microscopy should make it possible to overcome this problem: it can image insulator, semiconductor and metal surfaces with true atomic resolution8,9,10, by detecting and precisely measuring11,12,13 the short-range forces that arise with the onset of chemical bonding between the tip and surface atoms14,15 and that depend sensitively on the chemical identity of the atoms involved. Here we report precise measurements of such short-range chemical forces, and show that their dependence on the force microscope tip used can be overcome through a normalization procedure. This allows us to use the chemical force measurements as the basis for atomic recognition, even at room temperature. We illustrate the performance of this approach by imaging the surface of a particularly challenging alloy system and successfully identifying the three constituent atomic species silicon, tin and lead, even though these exhibit very similar chemical properties and identical surface position preferences that render any discrimination attempt based on topographic measurements impossible.
TL;DR: Gain- and loss-of-function studies in Arabidopsis indicated that AHK1 is a positive regulator of drought and salt stress responses and abscisic acid (ABA) signaling, and cytokinin clearly mediates stress responses because it was required for CRE1 to function as a negative regulator of osmotic stress.
Abstract: In plants, multistep component systems play important roles in signal transduction in response to environmental stimuli and plant growth regulators. Arabidopsis contains six nonethylene receptor histidine kinases, and, among them, AHK1/ATHK1, AHK2, AHK3, and CRE1 were shown to be stress-responsive, suggesting their roles in the regulation of plant response to abiotic stress. Gain- and loss-of-function studies in Arabidopsis indicated that AHK1 is a positive regulator of drought and salt stress responses and abscisic acid (ABA) signaling. Microarray analysis of the ahk1 mutant revealed a down-regulation of many stress- and/or ABA-inducible genes, including AREB1, ANAC, and DREB2A transcription factors and their downstream genes. These data suggest that AHK1 functions upstream of AREB1, ANAC, and DREB2A and positively controls stress responses through both ABA-dependent and ABA-independent signaling pathways. In addition, AHK1 plays important roles in plant growth because the ahk1 ahk2 ahk3 triple mutant showed further reduced growth. Unlike AHK1, loss-of-function analysis of ahk2, ahk3, and cre1 implied that the stress-responsive AHK2, AHK3, and CRE1 act as negative regulators in ABA signaling. AHK2 and AHK3 also negatively control osmotic stress responses in Arabidopsis because ahk2, ahk3, and ahk2 ahk3 mutants were strongly tolerant to drought and salt stress due to up-regulation of many stress- and/or ABA-inducible genes. Last, cytokinin clearly mediates stress responses because it was required for CRE1 to function as a negative regulator of osmotic stress.
TL;DR: Protective immunity to pneumocystis, but not to candida, required dectin-1 for the production of antifungal reactive oxygen species, and wild-type and dectIn-1-knockout mice were equally susceptible to candidA infection.
Abstract: Dectin-1 is a C-type lectin involved in the recognition of beta-glucans found in the cell walls of fungi. We generated dectin-1-deficient mice to determine the importance of dectin-1 in the defense against pathogenic fungi. In vitro, beta-glucan-induced cytokine production from wild-type dendritic cells and macrophages was abolished in cells homozygous for dectin-1 deficiency ('dectin-1-knockout' cells). In vivo, dectin-1-knockout mice were more susceptible than wild-type mice to pneumocystis infection, even though their cytokine production was normal. However, pneumocystis-infected dectin-1-knockout macrophages did show defective production of reactive oxygen species. In contrast to those results, wild-type and dectin-1-knockout mice were equally susceptible to candida infection. Thus, dectin-1 is required for immune responses to some fungal infections, as protective immunity to pneumocystis, but not to candida, required dectin-1 for the production of antifungal reactive oxygen species.
TL;DR: The hard X-ray detector (HXD) on board Suzaku as discussed by the authors was designed to achieve an extremely low in-orbit background based on a combination of new techniques, including the concept of well-type active shield counter.
Abstract: The Hard X-ray Detector (HXD) on board Suzaku covers a wide energy range from 10 keV to 600 keV by combination of silicon PIN diodes and GSO scintillators. The HXD is designed to achieve an extremely low in-orbit background based on a combination of new techniques, including the concept of well-type active shield counter. With an effective area of 142 cm at 20 keV and 273 cm at 150 keV, the background level at the sea level reached ∼ 1×10 cts s cm keV at 30 keV for the PIN diodes, and ∼ 2×10 cts s cm keV at 100 keV, and ∼ 7×10 cts s cm keV at 200 keV for the phoswich counter. Tight active shielding of the HXD results in a large array of guard counters surrounding the main detector parts. These anti-coincidence counters, made of ∼4 cm thick BGO crystals, have a large effective area for sub-MeV to MeV γ-rays. They work as an excellent γ-ray burst monitor with limited angular resolution ( ∼ 5). The on-board signal-processing system and the data transmitted to the ground are also described.
TL;DR: It is shown that, in dorsal-zone-depleted mice, the dorsal domain of the olfactory bulb was devoid of glomerular structures, although second-order neurons were present in the vacant areas, which indicates that aversive information is received in the ofactory bulb by separate sets ofglomeruli, those dedicated for innate and those for learned responses.
Abstract: The mammalian olfactory system mediates various responses, including aversive behaviours to spoiled foods and fear responses to predator odours. In the olfactory bulb, each glomerulus represents a single species of odorant receptor. Because a single odorant can interact with several different receptor species, the odour information received in the olfactory epithelium is converted to a topographical map of multiple glomeruli activated in distinct areas in the olfactory bulb. To study how the odour map is interpreted in the brain, we generated mutant mice in which olfactory sensory neurons in a specific area of the olfactory epithelium are ablated by targeted expression of the diphtheria toxin gene. Here we show that, in dorsal-zone-depleted mice, the dorsal domain of the olfactory bulb was devoid of glomerular structures, although second-order neurons were present in the vacant areas. The mutant mice lacked innate responses to aversive odorants, even though they were capable of detecting them and could be conditioned for aversion with the remaining glomeruli. These results indicate that, in mice, aversive information is received in the olfactory bulb by separate sets of glomeruli, those dedicated for innate and those for learned responses.