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Getah virus (GETV), an arthropod-borne virus transmitted by mosquitoes, has been isolated from several animals. GETV infection in horses shows clinical signs such as fever, rash, and edema in the leg. Noma horses are one of the eight Japanese native horses. The present study aimed to clarify the occurrence of GETV infection in Noma horses. Serum samples collected from Noma horses were analyzed using a virus neutralization test and enzyme-linked immunosorbent assay and showed that the anti-GETV antibody titers in the samples collected in 2017 were significantly higher than those collected in 2012. We concluded that a seroconversion of anti-GETV antibodies was occurred in the Noma horse population around 2012, providing evidence of the GETV epidemic in Japan circa 2012.

Runt-related transcription factor (RUNX) transcription factors are essential regulators of diverse developmental processes. In mammals, there are three RUNX genes, RUNX1, RUNX2, and RUNX3. All RUNX proteins contain a highly conserved DNA-binding domain, called the runt-homology domain (RHD), which is responsible for DNA-binding and interaction with a partner, core binding factor subunit β (CBFβ). They regulate transcription of target genes, involving hematopoietic differentiation, cell cycle regulation, p53 pathways, and so on. From our previous studies, we assume that compensation mechanism is present among the RUNX family members. RUNX plays pivotal roles in leukemogenesis and inhibition of RUNX has now been widely recognized as a novel strategy in anti-leukemic therapies. However, common mechanism via RUNX in diverse acute myeloid leukemia (AML) remains elusive. Here, we demonstrate that targeting RUNX-nuclear factor of activated T cells 2 (NFATC2) axis is an effective strategy to suppress drug-resistant (DR)-acute promyelocytic leukemia (APL) cells. Silencing of RUNX and NFATC2 in DR-APL cells suppressed cell growth and induced apoptotic cell death. Next, by RNA-seq analysis of several AML patient cohorts, we confirmed that a strong positive correlation between RUNX family (RUNX1,2,3: Pan RUNX) and NFAT family (NFATC1,2,3,4, NFAT5: Pan NFAT) exists not only in APL but also in all hematopoietic malignancies and that AML forms the Pan RUNX high-Pan NFAT high expression cluster. Inspection of the NFATC1-3 promoter revealed the RUNX binding sequence, and direct transcriptionally regulation of NFATC1-3 by RUNX family was confirmed in both chromatin immunoprecipitation (ChIP)-seq analysis and dual luciferase reporter assay. We believe that RUNX-NFAT axis could be an important target in diverse AML. Next, considering the well-established role of RUNX and NFATC2 in T cell immunity, we also apply targeting RUNX-NFATC2 strategy to suppress T cell activation and xenogeneic graft-versus-host disease (GVHD).The expansion of donor T cells requires IL-2, and aGVHD has been defined as a Th1-mediated disease. It is now well known that RUNX, especially RUNX1 and RUNX3 , are highly expressed in T cells, and directly regulate Th1 cytokine genes. As immunosuppressive approach for the prevention or treatment of aGVHD, calcineurin inhibitors, cyclosporine A and tacrolimus, inhibit GVHD by preventing the activation of NFAT, and steroid inhibits transcription of proinflammatory genes. We suppose that targeting RUNX can downregulate NFAT and also cytokine genes in T cell. RUNX1 knockdown and PanRUNX knockdown led to deceased NFATC2 and cytokine gene expression in cytokine-producing Jurkat cell line. It was also confirmed that by inhibiting the RUNX family and suppressing the NFATC2 family at the transcriptional level, the amount of the total NFATC family was significantly reduced compared with the drug that suppresses the nuclear translocation of NFATc2.The importance of RUNX-NFATC2 axis in T cell immunity was also exactly confirmed by the rescue experiments. Finally, to achieve "cluster regulation of RUNX (CROX)" strategy, we have been developing a novel RUNX inhibitor: chlorambucil-conjugated pyrrole-imidazole (PI) polyamides (Chb-M') that targets consensus RUNX-binding sequences, and specifically inhibits binding of RUNX family members. So, Chb-M' can switch off the RUNX target genes efficiently. In diverse AML including APL, core binding factor (CBF)-AML, mixed lineage leukemia (MLL)-rearranged AML, and AML-M0 and so on, Chb-M' was remarkably effective, and suppressed the expression of NFAT family in the protein level and induced apoptotic cell death. ChbM' also had a prominent effect in the AMLPDX model.The importance of RUNX-NFAT axis in AML was confirmed by the pharmacological rescue experiments using phorbol 12-myristate 13-acetate (PMA) and Ionomycin stimulation. Chb-M' also suppressed NFATC2 and cytokine gene expression in peripheral blood mononuclear cells (PBMC) and ameliorated GVHD for xenogeneic GVHD mouse model by transplanting human PBMC into immunodeficient mice. Taken together, we show RUNX could be a novel therapeutic target against diverse AML and GVHD through targeting RUNX-NFAT axis. Disclosures No relevant conflicts of interest to declare.

Phylogenetic analysis of respiratory syncytial virus (RSV) group B genotype BA strains from the 2002-2003 to 2009-2010 seasons collected in Niigata, Japan, revealed four distinct clusters, designated new BA genotypes BA7, BA8, BA9, and BA10. These new genotypes were not associated with large outbreaks in the community.

Oseltamivir has been used for treatment of influenza A and B infections, but recent reports documented that it was less active against the latter. We compared the effectiveness of oseltamivir in children between laboratory confirmed influenza A and B over 4 influenza seasons from 2001 to 2005 in a pediatric clinic in Japan. Among 1,848 patients screened, 299 influenza A and 209 influenza B patients were administered oseltamivir (treated groups), and 28 influenza A and 66 influenza B patients were assigned as non-treated groups. The duration of fever, defined as period when patients had the maximum temperature higher than 37.5 degrees C in three-time measurements in a day after the clinic visit, was evaluated among the four groups. In uni-variate analysis, the duration of fever was shorter for treated group than non-treated for influenza A (1.8 +/- 0.9 days vs 2.6 +/- 1.3 days, p0.01), but it was not significant for influenza B (2.4 +/- 1.3 days vs 2.8 +/- 1.2 days, p = 0.9). The fever duration was longer in treated influenza B than A patients (p0.01). Multi-variate analysis indicated younger age (6 years old) and higher body temperature at the clinic visit prolonged the duration of fever. Adjusted average duration of fever indicated that oseltamivir was effective for both types, but more effective on influenza A, and the benefit increased for younger children. Our data provide evidence that oseltamivir is beneficial for influenza infections, but the effectiveness is differed by type and age.

In recent years, a dramatic increase of amantadine-resistant influenza A has occurred globally, but limited data have been available on the clinical course of patients developed amantadine-resistant viruses. We compared fever reduction between patients who developed resistance or remained sensitive in a pediatric clinic in Niigata, Japan, from 2000 to 2006. A total of 2,802 clinical samples were collected from patients who visited the pediatric outpatient clinic with influenza like illness during the seven influenza epidemic seasons. Patients were divided into 4 groups and analyzed for the fever reduction after amantadine treatment: emerged amantadine-resistant (n = 15); amantadine-sensitive (n = 35); patients administered no antiviral drugs (n = 42); and oseltamivir-treated patients (n = 320), which served as references. All 4 groups showed alleviation of fever up to day 3. The amantadine-resistant group had a significant recurrence of fever on day 4 and/or 5, and as a consequence, the course of illness was prolonged. Considering the pattern of fever, recurrent and persistent patterns were found significantly at higher rates in children with emerged resistant virus compared to other groups, and the age tended to be younger in amantadine-resistant compared to amantadine-sensitive group (3.9 +/- 3.0 vs 6.7 +/- 4.1 years old, n.s.). Therefore, we concluded that younger children were prone to develop amantadine-resistance after treatment and showed a significant recurrence of fever on day 4 and/or 5, and the course of illness was consequently prolonged.

Objective:To evaluate the antibody response to influenza vaccines in nursing home residents and healthcare workers (HCWs) and its relation to residents' functional and chronic disease status during four successive seasons.Design:Before-after study.Setting:Nine nursing homes during the 1998-1999 season and two during the 1999-2000, 2000-2001, and 2001-2002 seasons.Participants:Two hundred fifty-nine residents and 79 HCWs during the 1998-1999 season; 180 and 71, respectively, during the 1999-2000 season; 162 and 71, respectively, during the 2000-2001 season; and 153 and 79, respectively, during the 2001-2002 season.Results:Multivariate analysis indicated that the mean fold increase in the geometric mean titers (GMTs) of hemagglutination inhibition (HI) antibodies and the response rate (the proportion of vaccinées resulting in a significant, at least fourfold increase in antibody titer) were good and no significant differences occurred for almost all strains in both residents and HCWs. The GMTs of HI antibodies and the protection rate (the proportion of participants with HI antibody titers & 40) were increased in both residents and HCWs, but were significantly lower for almost all strains in residents than in HCWs. Furthermore, multivariate analysis indicated that subdivision of residents into three groups by level of daily activities and into four groups according to underlying diseases revealed only minor differences in immune responses.Conclusions:Antibody responses to the influenza vaccine were lower in residents than in HCWs. However, residents showed similar antibody responses regardless of their level of daily activity or underlying diseases.

To study the molecular epidemiology of respiratory syncytial virus (RSV) in a community, children with acute respiratory symptoms at a pediatric outpatient clinic in Niigata, Japan, were analyzed over three seasons from November 2001 to July 2004. Of 499 nasopharyngeal aspirate specimens, 185 (37.1%) were RSV positive, and only 8 (4.5%) of 177 patients were shown by the reverse transcription (RT)-PCR method to be reinfected. RSV infection occurred beginning in the early winter, and the rates declined in the spring. The predominant subgroup changed from A to B and returned to A over the three seasons. Phylogenetic analysis also revealed that multiple genotypes cocirculated each year, with genotype GA5 of subgroup A predominating in the 2001-2002 and the 2003-2004 seasons. A new genotype of subgroup B (named BA, according to the nomenclature for viruses) with a 60-nucleotide insertion in the second variable region of the attachment glycoportein protein was predominant as an emerging strain in the 2002-2003 season, but this was not associated with new epidemiological or clinical features, unlike the cases of disease caused by other genotypes in the other seasons. In conclusion, our molecular analysis of RSV confirms that multiple genotypes cocirculate each year and that the genotype predominating may shift with the season. Support for determination of the genotype by RT-PCR as an effective tool for characterization of RSV circulation patterns in the community is provided.

In this letter, we report the first infrared spectrum of C(76)(2-). This multiply charged anion has been studied in an electrodynamic ion trap held at room temperature using tunable infrared radiation from a free-electron laser. Resonant vibrational excitation is found to cause electron detachment and the resulting singly negatively charged as well as the remaining doubly charged parent ion are monitored as a function of IR wavelength in an experimental scheme that we term infrared multiphoton electron detachment spectroscopy. The obtained IR spectra are contrasted to computed vibrational spectra using density functional theory. The dianionic molecule retains its overall symmetry (i.e., D(2) point group) with a (1)A(1) ground state with respect to the neutral fullerene. Spectral shifts of characteristic tangential modes relative to the neutral cage are shown to originate from the excess charge density.

This article, by regarding the relative number of affirmative bits on an arbitrary finite sequence of bits as the truth value, defines a new multivalued logic system such that the set of logic formulae forms a Boolean algebra in contrast to other non-Boolean multivalued logic systems, which we call a Boolean multivalued logic system. This article also, for demonstrating compactly that the Boolean properties (in contrast to other multivalued logic systems) simplify multivalued inferences in flexible styles, shows several intuitively-understandable examples tracing biotic diversity such that, on the proposed logic system, we can easily handle semantic inferences verifying values of all bits of each logic formula, inductive inferences counting the relative numbers of affirmative bits for determination of truth values, and deductive inferences syntactically narrowing ranges of truth values.

Background The spread of influenza viruses in a community are influenced by several factors, but no reports have focused on the relationship between the incidence of influenza and characteristics of small neighborhoods in a community. We aimed to clarify the relationship between the incidence of influenza and neighborhood characteristics using GIS and identified the type of small areas where influenza occurs frequently or infrequently. Methods Of the 19,077 registered influenza cases, we analyzed 11,437 influenza A and 5,193 influenza B cases that were diagnosed by the rapid antigen test in 66-86 medical facilities in Isahaya City, Japan, from 2004 to 2008. We used the commercial geodemographics dataset, Mosaic Japan to categorize and classify each neighborhood. Furthermore, we calculated the index value of influenza in crude and age adjusted rates to evaluate the incidence of influenza by Mosaic segmentation. Additional age structure analysis was performed to geodemographics segmentation to explore the relationship between influenza and family structure. Results The observed number of influenza A and B patients in the neighborhoods where young couples with small children lived was approximately 10-40% higher than the expected number (p < 0.01) during all seasons. On the contrary, the number of patients in the neighborhoods of the aging society in a rural area was 20-50% lower than the expected number (p < 0.01) during all seasons. This tendency was consistent after age adjustment except in the case of influenza B, which lost significance in higher incidence areas, but the overall results indicated high transmission of influenza in areas where young families with children lived. Conclusions Our analysis indicated that the incidence of influenza A and B in neighborhood groups is related to the family structure, especially the presence of children in households. Simple statistical analysis of geodemographics data is an effective method to understand the differences in the incidence of influenza among neighborhood groups, and it provides a valuable basis for community strategies to control influenza.

A total of 1,041 human influenza A virus isolates were collected at a clinic in Niigata, Japan, during eight influenza seasons from 2000 to 2007. The H3N2 subtype accounted for 75.4% of the isolates, and the rest were H1N1. Extremely high rates of amantadine-resistant strains of H3N2 subtype were observed in 2005/2006 (100%) and 2006/2007 (79.4%), while amantadine-resistant strains of H1N1 subtype were only detected in 2006/2007 (48.2%). Sequence and phylogenetic analysis of the HA1 subunit of the hemagglutinin (HA) gene revealed a characteristic linear trunk in the case of H3N2 viruses and a multi-furcated tree in the case of H1N1 and showed a higher sequence diversity among H3N2 strains than H1N1 strains. Mutations in the HA1 from both subtypes were mainly found in the globular region, and only one-third of these were retained for two or more successive years. Higher diversity of H3N2 viruses was mainly attributable to a higher fixation rate of non-synonymous mutations and to a lesser extent to a higher nucleotide substitution rate than for H1N1. Our analysis showed evidence of four positively selected sites in the HA1 of H1 and five sites in that of H3, four of which were novel. Finally, acquisition or loss of N-glycosylation sites was shown to contribute to the evolution of influenza A virus, especially in the case of H3N2, which had a higher tendency to acquire new glycosylation sites.

Summary Objectives Due to high vaccine coverage in Niigata, we had no outbreaks of measles from 1997 to 2003 but an opportunity to study the role of sporting events in the propagation of an epidemic was experienced in the spring of the latter year. Methods Mandatory measles case reports were requested from all high schools in Niigata, which covered a school year, date of onset, club activity, vaccination status, and hospitalization. Results With national marathon and kendo (Japanese fencing) meetings for high school students, measles outbreaks occurred at 27 high schools with 192 patients (186 students and 6 teachers) in Niigata. Of 64 unvaccinated patients, 14 (21.9%) were hospitalized and 6 (6.2%) of 97 vaccinated patients. Mostly single cases were encountered at high schools in which index cases had a vaccination history, whereas at a high school in which index cases had no vaccination history, the total number of cases per school increased, mostly within more than 3 cases ( p Conclusion We conclude that sporting events, even if outdoors, might be a risk factor for measles infections. Appropriate actions to control outbreaks should be performed promptly in collaboration with related personnel and institutions.

The possible west-east spread of influenza across Europe during the influenza seasons of the previous few years was mapped in 2004 using data from the European Influenza Surveillance Scheme

Background: Human metapneumoviruses (hMPVs) are recognized as a leading cause of respiratory infections in young infants in many countries. The objective of this study was to identify links between hMPV and influenza virus infections among children with influenza-like illness. Method: This study was conducted in 2 influenza seasons (2002-2003 and 2003-2004) at 2 pediatric outpatient clinics in Niigata city, Japan. Nasopharyngeal swabs or aspirates were collected from influenza-like illness patients, and hMPV and influenza were detected by reverse transcription-polymerase chain reaction (RT-PCR). A nucleotide sequence of 352 nucleotides segment of the F gene was performed. Results: A total of 765 influenza viruses and 84 hMPV were identified from 1498 nasopharyngeal swabs or aspirates by virus isolation and RT-PCR, respectively. hMPV-positive rates in patients with influenza-like illness were 5.7 and 5.2% in the 2002-2003 and 2003-2004 seasons, respectively. Epidemic curves of influenza and hMPV patients showed similar patterns with peaks in February in 2 influenza seasons. hMPV infections occurred frequently in infants and school children. Approximately 46% of hMPV patients were coinfected with influenza A viruses, but those coinfected cases were not clinically distinct from the others. No coinfection with influenza B viruses was found. Phylogenetic analysis of the hMPV fusion gene sequences revealed that 2 distinct hMPV cocirculated and that completely identical strains in subgroup A were observed over 2 years. Conclusions: HMPV plays an important pathogenic role in patients with influenza-like illness in winter seasons, often in coinfections with influenza A viruses.