SF-10 induces cell-mediated immunity

We reported previously that intranasal instillation of a synthetic human pulmonary surfactant with a carboxy vinyl polymer as a viscosity improver, named SF-10, shows potent adjuvanticity for humoral immunity in mice and cynomolgus monkeys. SF-10 effectively induces influenza hemagglutinin vaccine (HAv)-specific IgA in nasal and lung washes and IgG in sera with their neutralizing activities. Since CD8+ T cell-mediated protection is an important requirement for adaptive immunity, we investigated in this study the effects of SF-10 with antigen on local and systemic cell-mediated immunity. Nasal instillation of ovalbumin, a model antigen, combined with SF-10 efficiently delivered antigen to mucosal dendritic and epithelial cells and promoted cross-presentation in antigen presenting cells, yielding a high percentage of ovalbumin-specific cytotoxic T lymphocytes in the nasal mucosa, compared with ovalbumin alone. Nasal immunization of HAv-SF-10 also induced HAv-specific cytotoxic T lymphocytes and upregulated granzyme B expression in splenic CD8+ T cells with their high cytotoxicity against target cells pulsed with HA peptide. Furthermore, nasal vaccination of HAv-SF-10 significantly induced higher cytotoxic T lymphocytes-mediated cytotoxicity in the lungs and cervical lymph nodes in the early phase of influenza virus infection compared with HAv alone. Protective immunity induced by HAv-SF-10 against lethal influenza virus infection was partially and predominantly suppressed after depletion of CD8+ and CD4+ T cells (induced by intraperitoneal injection of the corresponding antibodies), respectively, suggesting that CD4+ T cells predominantly and CD8+ T cells partially contribute to the protective immunity in the advanced stage of influenza virus infection. These results suggest that SF-10 promotes effective antigen delivery to antigen presenting cells, activates CD8+ T cells via cross-presentation, and induces cell-mediated immune responses against antigen

Oral vaccination with influenza hemagglutinin combined with human pulmonary surfactant-mimicking synthetic adjuvant SF-10 induces efficient local and systemic immunity compared with nasal and subcutaneous vaccination and provides protective immunity in mice

We reported previously that a synthetic mucosal adjuvant SF-10, which mimics human pulmonary surfactant, delivers antigen to mucosal dendritic cells in the nasal cavity and promotes induction of humoral and cellular immunity. The aim of the present study was to determine the effects of oral administration of antigen combined with SF-10 (antigen-SF-10) on systemic and local immunity. Oral administration of ovalbumin, a model antigen, combined with SF-10 enhanced ovalbumin uptake into intestinal antigen presenting MHC II+CD11c+ cells and their CD11b+CD103+ and CD11b+CD103- subtype dendritic cells, which are the major antigen presenting subsets of the intestinal tract, more efficiently compared to without SF-10. Oral vaccination with influenza hemagglutinin vaccine (HAv)-SF-10 induced HAv-specific IgA and IgG in the serum, and HAv-specific secretory IgA and IgG in bronchoalveolar lavage fluid, nasal washes, gastric extracts and fecal material; their levels were significantly higher than those induced by subcutaneous HAv or intranasal HAv and HAv-SF-10 vaccinations. Enzyme-linked immunospot assay showed high numbers of HAv-specific IgA and IgG antibody secreting cells in the gastrointestinal and respiratory mucosal lymphoid tissues after oral vaccination with HAv-SF-10, but no or very low induction following oral vaccination with HAv alone. Oral vaccination with HAv-SF-10 provided protective immunity against severe influenza A virus infection, which was significantly higher than that induced by HAv combined with cholera toxin. Oral vaccination with HAv-SF-10 was associated with unique cytokine production patterns in the spleen after HAv stimulation; including marked induction of HAv-responsive Th17 cytokines (e.g., IL-17A and IL-22), high induction of Th1 cytokines (e.g., IL-2 and IFN-γ) and moderate induction of Th2 cytokines (e.g., IL-4 and IL-5). These results indicate that oral vaccination with HAv-SF-10 induces more efficient systemic and local immunity than nasal or subcutaneous vaccination with characteristically high levels of secretory HAv-specific IgA in various mucosal organs and protective immunity

Effects of galactic magnetic field on the UHECR correlation studies with starburst galaxies

We estimate the biases caused by the coherent deflection of cosmic rays due to the Galactic magnetic field (GMF) in maximum-likelihood analysis for searches of ultrahigh-energy cosmic ray (UHECR) sources in the literature. We simulate mock event datasets with a set of assumptions for the starburst galaxy (SBG) source model (arXiv:1801.06160), coherent deflection by a GMF model (arXiv:1204.3662,arXiv:1210.7820), and mixed-mass composition (arXiv:1901.03338); we then conduct a maximum-likelihood analysis without accounting for the GMF in the same manner as previous studies. We find that the anisotropic fraction $f_{\rm ani}$ is estimated systematically lower than the true value. We estimate the true parameters which are compatible with the best-fit parameters reported in (arXiv:1801.06160), and find that except for a narrow region with a large anisotropic fraction and small separation angular scale a wide parameter space is still compatible with the experimental results. We also develop a maximum-likelihood method that takes into account the GMF model and confirm in the MC simulations that we can estimate the true parameters within a 1$\sigma$ contour under the ideal condition that we know the event-by-event mass and the GMF

Induction of systemic and mucosal immunity and maintenance of its memory against influenza A virus by nasal vaccination using a new mucosal adjuvant SF-10 derived from pulmonary surfactant in young cynomolgus monkeys

Induction of systemic and mucosal immunity and maintenance of its memory was investigated in 12 young male cynomolgus monkeys after intranasal instillation of flu vaccine using a new mucosal adjuvant SF-10 derived from pulmonary surfactant constituents. Split-product of influenza virus A/California/7/2009(H1N1)pdm hemagglutinin vaccine (HAv) at 15 μg with or without SF-10 and the adjuvant alone were instilled intranasally three times every 2 weeks. SF-10-adjuvanted HAv (SF-10-HAv) elicited significantly higher HAv-specific IgG and hemagglutinin inhibition (HI) titers in serum and HAv-specific secretory IgA and its neutralizing activities in nasal washes compared with HAv antigen and SF-10 alone. Significant cross-neutralizing activities of nasal washes after the third vaccination to several other H1N1 and H3N2 strains were observed. HI titers in serum and neutralizing activities in nasal washes reached peak levels at 6 weeks after initial vaccination, then gradually decreased after 10 weeks and returned to the baseline levels at 36 weeks. A single intranasal revaccination of SF-10-HAv at 36 weeks rapidly and significantly increased both immunity in serum and nasal washes compared with naïve monkeys. Revaccination by one or two doses achieved almost maximal immunity at 2 or 4 weeks after instillation. Statistically significant adverse effects (e.g., body weight loss, elevated body temperature, nasal discharge, change in peripheral blood leukocyte and platelet counts) were not observed for 2 weeks after vaccination of SF-10-HAv, HAv or SF-10 and also during the experimental period. These results in young monkey model suggest the potential of clinical use SF-10 for intranasal flu vaccine

Supravalvular thrombus after pulmonary artery banding and fontan procedure evaluated by multidetector-row computed tomography

SummaryThe mechanisms responsible for thromboembolic events in children with congenital heart disease have not yet been fully elucidated. Furthermore, establishment of long-term anticoagulation therapy in Fontan patients remains controversial. Here, we report the case of a 9-year-old boy who presented with hemiparesis due to a thromboembolic stroke; the boy had previously undergone staged pulmonary artery banding and Fontan procedure. Cardiac multidetector-row computed tomography (MDCT) clearly showed the supravalvular thrombus at the roofed (blind) pulmonary valve and circulatory stasis, which could be considered a possible source of the thrombus. Follow-up CT examination showed that the thrombus disappeared, but the circulatory stasis remained. Therefore, because the risk of thrombus formation was not eliminated, anticoagulation therapy was continued for the patient. Our case indicates the possible application of cardiac MDCT for providing insight into the hemodynamic mechanisms responsible for the thromboembolic events in children with congenital heart disease

New Function of Autophagy in C. jejuni Invasion

Campylobacter jejuni is a leading cause of food-borne disease worldwide. The pathogenicity of C. jejuni is closely associated with the internalization process in host epithelial cells, which is related to a host immune response. Autophagy indicates a key role in the innate immune system of the host to exclude invasive pathogens. Most bacteria are captured by autophagosomes and degraded by autophagosome-lysosome fusion in host cells. However, several pathogens, such as Salmonella and Shigella, avoid and/or escape autophagic degradation to establish infection. But autophagy involvement as a host immune response to C. jejuni infection has not been clarified. This study revealed autophagy association in C. jejuni infection. During infection, C. jejuni activated the Rho family small GTPase Rac1 signaling pathway, which modulates actin remodeling and promotes the internalization of this pathogen. In this study, we found the LC3 contribution to C. jejuni invasion signaling via the Rac1 signaling pathway. Interestingly, during C. jejuni invasion, LC3 was recruited to bacterial entry site depending on Rac1 GTPase activation just at the early step of the infection. C. jejuni infection induced LC3-II conversion, and autophagy induction facilitated C. jejuni internalization. Also, autophagy inhibition attenuated C. jejuni invasion step. Moreover, Rac1 recruited LC3 to the cellular membrane, activating the invasion of C. jejuni. Altogether, our findings provide insights into the new function of LC3 in bacterial invasion. We found the interaction between the Rho family small GTPase, Rac1, and autophagy-associated protein, LC3

CFTR associated diarrhea in VP-infection

Vibrio parahaemolyticus is a foodborne bacterium that causes acute gastroenteritis through the consumption of contaminated, raw, or undercooked seafood. Cystic fibrosis transmembrane conductance regulator (CFTR) is a well-characterized chloride channel that regulates several other ion channels and transporters to maintain water homeostasis in the gut lumen. Also, CFTR is a main target of bacterial infection-associated diarrhea. Hence, the aim of this study was to clarify the contribution of CFTR in V. parahaemolyticus-induced diarrhea in a mouse model of intestinal loop fluid accumulation, with CFTR inhibitors and a CFTR knockout model. The results indicated that CFTR plays a critical role in fluid accumulation in response to V. parahaemolyticus infection. We also investigated the inflammatory association in CFTR-mediated V. parahaemolyticus-induced fluid secretion with cyclooxygenase inhibitors and found that fluid accumulation was decreased by inhibition of cyclooxygenase 2 produced by neutrophils. These findings suggest that V. parahaemolyticus-inducing infiltration and activation of neutrophils also participated in CFTR mediated fluid secretion. This study reveals an important relationship between V. parahaemolyticus-induced diarrhea and inflammation in a mouse model

National survey of the association of depressive symptoms with the number of off duty and on-call, and sleep hours among physicians working in Japanese hospitals: a cross sectional study

<p>Abstract</p> <p>Background</p> <p>Physicians' mental health may be adversely affected by the number of days of work and time spent on-call, and improved by sleep and days-off. The aim of this study was to determine the associations of depressive symptoms with taking days of off duty, hours of sleep, and the number of days of on-call and overnight work among physicians working in Japanese hospitals.</p> <p>Methods</p> <p>A cross-sectional study as a national survey was conducted by mail. The study population was 10,000 randomly selected physicians working in hospitals who were also members of the Japan Medical Association (response rate 40.5%). Self-reported anonymous questionnaire was sent to assess the number of days off-duty, overnight work, and on-calls, and the average number of sleep hours on days not working overnight in the previous one month. Depressive state was determined by the Japanese version of the Quick Inventory of Depressive Symptomatology. Logistic regression analysis was used to explore the associations between depressive symptoms and the studied variables.</p> <p>Results</p> <p>Among the respondents, 8.3% of men and 10.5% of women were determined to be depressed. For both men and women, depressive state was associated with having no off-duty days and averaging less than 5 hours of sleep on days not doing overnight work. Depressive state was positively associated with being on-call more than 5 days per month for men, and more than 8 days per month for women, and was negatively associated with being off-duty more than 8 days per month for men.</p> <p>Conclusion</p> <p>Some physicians need some support to maintain their mental health. Physicians who do not take enough days-off, who reduced sleep hours, and who have certain number of days on-calls may develop depressive symptoms.</p

Enantiomer-selective Anti-influenza Activity of Bakuchiol

Background: Novel therapeutic approaches against influenza are required. Bakuchiol is a phenolic isoprenoid found in Babchi seeds. Results: Bakuchiol enantiomer-selectively inhibited influenza A viral infection and growth and activated the Nrf2 pathway. Conclusion: Bakuchiol showed novel enantiomer-selective anti-influenza viral activity. Significance: The study of bakuchiol will contribute to the development of novel approaches to influenza therapy