Development of NIR Bioimaging Systems

Abstract. Fluorescence bioimaging is one of the most important technologies in the biomedical field. The most serious issue concerning current fluorescence bioimaging systems is the use of short wavelength light, UV or VIS, for the excitation of phosphors such as fluorescent proteins or quantum dots. The authors propose a fluorescence bioimaging system excited by near infrared light using rare-earth doped ceramic nanophosphors. The requirements for the nanophosphors are a designed emission scheme under the near infrared excitation, a controlled size between 10 and 200 nm and surface modification of the particles with a biofunctional polymer, which prevents particle agglomeration and non-specific interaction to nontargeting substances and gives them a specific interaction for the targeted objects. The preparation of the bioimaging probe and demonstrative imaging work are reported

Point mutation of tyrosine 759 of the IL-6 family cytokine receptor, gp130, augments collagen-induced arthritis in DBA/1J mice

<p>Abstract</p> <p>Background</p> <p>Knock-in mice (gp130F759) with a Y759F point mutation in gp130, a signal transducing receptor subunit shared by members of the IL-6 cytokine family, show sustained activation of STAT3, enhanced acute-phase or immune responses, and autoimmune arthritis. We conducted a detailed analysis of collagen-induced arthritis (CIA) in gp130F759 with a DBA/1J background (D/J.gp130F759).</p> <p>Methods</p> <p>We backcrossed gp130F759 to C57BL/6 and DBA/1J, and compared the pathologic changes, including occurrence of arthritis, in the two distinct genetic backgrounds. We analyzed CIA in D/J.gp130F759 and investigated the effects of methotrexate (MTX) on CIA.</p> <p>Results</p> <p>C57BL/6 background gp130F759 mice, but not D/J.gp130F759, spontaneously developed polyarthritis and glomerulonephritis. On the other hand, keratitis of the eyes only developed in D/J.gp130F759, indicating the influence of genetic background on disease development in gp130F759 mice. Resistance of the DBA/1J background against spontaneous arthritis urged us to examine CIA in D/J.gp130F759. CIA in D/J.gp130F759 was more severe, with greater bone destruction, than the control mice. After collagen immunization, splenomegaly and serum levels of rheumatoid factor and anti-DNA antibody were augmented in D/J.gp130F759. Bio-Plex analysis of serum cytokines revealed increased IL-12p40 and PDGF-BB before immunization, and increased levels of IFN-γ, IL-17, TNF-α, IL-9, and MIP-1β 8 days after the booster dose. IL-6 and PDGF-BB in D/J.gp130F759 showed distinct kinetics from the other cytokines; higher levels were observed after arthritis development. MTX partially attenuated the development of arthritis and inhibited bone destruction in D/J.gp130F759, with reduction of anti-type II collagen antibody levels, suggesting that MTX mainly affects antigen-specific immune responses in CIA.</p> <p>Conclusion</p> <p>The Tyr-759 point mutation of the IL-6 family cytokine receptor subunit, gp130, caused autoimmune disease, and this was also influenced by the genetic background. CIA in D/J.gp130F759 is useful for evaluating drugs in a relatively short period because sustained activation of STAT3 may enhance the disease symptoms.</p

Association between shift work and the risk of death from biliary tract cancer in Japanese men

Background: There is increasing evidence suggesting that shift work involving night work may increase cancer risk. Methods: We examined the association between working rotating shifts and the risk of death from biliary tract cancer among Japanese men who participated in the Japan Collaborative Cohort Study. Of the 46, 395 men recruited, 22, 224 men aged 40-65 at baseline (1988-1990) who reported working full-time or were self-employed were included in the present analysis. The study subjects were followed through December 31, 2009. Information regarding occupation and lifestyle factors was collected using a self-administered questionnaire. Cox proportional hazard models were used to estimate the hazard ratio (HR) and 95 % confidence interval (CI) for the risk of death from biliary tract cancer in relation to shift work. Results: During a mean 17-year follow-up, we observed 94 biliary tract cancer deaths, including 23 deaths from gallbladder cancer and 71 deaths from extrahepatic bile duct cancer. Overall, shift work was associated with a statistically non-significant increase in the risk of biliary tract cancer, with an HR of 1.50 (95 % CI: 0.81-2.77), among rotating shift workers. When the analysis was limited to extrahepatic bile duct cancer, a significant association appeared, with a multivariable-adjusted HR of 1.93 (95 % CI: 1.00-3.72) for rotating shift workers. Conclusion: Our data indicate that shift work may be associated with increased risk of death from extrahepatic bile duct cancer in this cohort of Japanese men. The association with gallbladder cancer remains unclear because of the small number of deaths

Asymmetric nature of two subunits of RAD18, a RING-type ubiquitin ligase E3, in the human RAD6A–RAD18 ternary complex

RAD18, a RING-type ubiquitin ligase (E3) that plays an essential role in post-replication repair, possesses distinct domains named RING, UBZ, SAP and the RAD6-binding domain (R6BD) and forms a dimer. RAD6, an ubiquitin-conjugating enzyme (E2), stably associates with R6BD in the C-terminal portion. In this study, we established a method to distinguish between the two subunits of RAD18 by introduction of different tags, and analyzed mutant complexes. Our results, surprisingly, demonstrate that RAD6A and RAD18 form a ternary complex, RAD6A–(RAD18)2 and the presence of only one R6BD in the two RAD18 subunits is sufficient for ternary complex formation and the ligase activity. Interestingly, ligase activity of a mutant dimer lacking both R6BDs is not restored even with large amounts of RAD6A added in solution, suggesting a requirement for precise juxtaposition via interaction with R6BD. We further show that mutations in both subunits of either RING or SAP, but not UBZ, strongly reduce ligase activity, although inactivation in only one of two subunits is without effect. These results suggest an asymmetric nature of the two RAD18 subunits in the complex

PD-1 and LAG-3 inhibitory co-receptors act synergistically to prevent autoimmunity in mice

A new mouse model of spontaneous autoimmune disease reveals an important role for the inhibitory co-receptor LAG-3 in suppressing autoimmunity

Role of Transient Receptor Potential Vanilloid 1 in Inflammation and Autoimmune Diseases

Transient receptor potential vanilloid 1 (TRPV1), a non-selective cation channel, is a receptor activated by high temperatures and chemical agonists such as the vanilloids and protons. Because of these properties, TRPV1 has emerged as a polymodal nocisensor of nociceptive afferent neurons. TRPV1 is thought to be a central transducer of hyperalgesia and a prime target for controlling pain pharmacologically because it is a point where many proalgesic pathways converge and it is upregulated and sensitized by inflammation and injury. However, whether TRPV1 agonists promote or inhibit inflammation remains unclear. We recently demonstrated that SA13353 (1-[2-(1-adamantyl)ethyl]-1-pentyl-3-[3-(4-pyridyl)propyl]urea), a novel TRPV1 agonist, inhibits tumor necrosis factor-a production by the activation of capsaicin-sensitive afferent neurons and reduces the severity of symptoms in kidney injury, lung inflammation, arthritis, and encephalomyelitis. These results suggest that TRPV1 agonists may act as anti-inflammatories in certain inflammatory and autoimmune conditions in vivo. Given the potential deleterious effects of inhibiting the population of channels with a protective function, caution should be taken in the use of potent TRPV1 antagonists as a general strategy to treat inflammation. Further studies are required to clarify the role of TRPV1 and neuropeptides, which are released because of TRPV1 activation in inflammation and autoimmune diseases