85–23, revised 1985) and the national laws on Protection of Anima

85–23, revised 1985) and the national laws on Protection of Animals were followed. A total of 109 female NOD mice were analysed. First, 62 female NOD mice were litter-matched and randomized after weaning into four groups (groups A1–D1; Fig. S1). As

a control group, female NOD mice in group A1 (n = 16) were not mated. In the remaining groups, female NOD were mated at age 10 weeks to male NOD mice (group B1, n = 15) representing MHC identical mating, male CByB6F1/J mice (group C1, n = 16) representing MHC haploidentical mating or male C57BL/6J mice (group D1, n = 15), representing fully MHC mismatched mating. For pairings, two male mice were used in each group. To analyse the effect of later gestation, a second set of 47 female NOD mice were litter-matched and randomized after weaning into three groups: control unmated females (n = 16, group A2); females mated at

age 13 weeks to three male Ulixertinib NOD mice (n = 16, group B2); and females mated at age 13 weeks to three male CByB6F1/J mice (n = 15, group C2). For the mating, two female and one male mouse were housed together in one cage for a median time of 14 days [interquartile range (IQR), 14–17 days]. Subsequently, 45 of 46 females mated at 10 weeks of age and 29 of 31 females mated at 13 weeks of age delivered altogether 610 pups. The number of pups per litter ranged between four and 13 (median, 9; IQR, 7–10), and the offspring numbers were distributed equally between the different mating groups (Fig. S1). All pups remained with their dam for the weaning period of median 21 days (IQR, 21–23 days). All female Adriamycin order NOD mice were followed to overt diabetes or until the age of 28 weeks. Inositol monophosphatase 1 Urine glucose levels were measured twice weekly using urine glucose sticks (Diastix, Bayer HealthCare LLC, Mishawaka, IN, USA), beginning at 10 weeks of age. The diagnosis of diabetes was defined as two consecutive urine glucose values > 5·5 mmol/l and blood glucose levels > 13·9 mmol/l (Glucometer Elite,

Bayer Diagnostics GmbH, Munich, Germany). Venous blood was obtained at age 10 weeks (prior to the mating) and 16 weeks (after weaning), and diabetes onset or 30 weeks for the measurement of insulin autoantibodies. In group C1, splenocytes from two diabetic mice at diabetes onset and two non-diabetic mice at the end of observation were collected to look for lymphocyte chimerism. Antibodies to insulin were detected using a radiobinding assay, as described previously [14]. All measurements were performed on coded samples that were operator-blinded. The upper limit of normal was determined from the 99th centile values obtained in sera from BALB/c and C57BL/6 female mice. The assay is represented as laboratory B in the animal models of Diabetes Workshop [15]. In order to analyse if cells with paternal genome alleles migrated during gestation from the fetus to the dam and persisted, staining and flow cytometry for MHC class I molecules was performed on the collected splenocytes.

The information summarized in Table 1 is indeed going to rapidly

The information summarized in Table 1 is indeed going to rapidly evolve with the exponential increase of community level genome-wide surveys of the microorganisms inhabiting the various microenvironments of the human body (i.e., gut, skin, oral mucosa, and urogenital tract) [23], their environmental reservoir [24], and the human populations living in different geographic regions [6, 8]. Understanding the prevalence and distribution of microbial eukaryotes in addition to prokaryotic

microorganisms in the human body may have important consequences for human health. While current studies of the human mycobiota focus mainly on pathogens or opportunistic fungi, most resident microbial eukaryotes do not cause infections, and are instead either beneficial or commensal. Elucidating community-wide changes in the human mycobiota, LDK378 nmr rather than only the presence or absence

of specific taxa, will be crucial to understanding the cause of, and potential treatment for, several multifaceted polymicrobial diseases [25]. Immune responses to fungi require PRRs, such as TLRs, C-type lectin receptors, and the galectin family of proteins [26-28] to trigger intracellular signaling cascades that initiate and direct innate and adaptive immune responses check details [29]. By sensing conserved molecular structures on fungi, namely the PAMPs, PRRs promote the activation of the immune system and the clearance of fungi, with specific immune responses generated depending on the cell type involved. In a recent review [30], we highlighted the roles and mechanisms of dectin-1, dectin-2, and DC-SIGN in orchestrating antifungal to immunity, exploring how these PRRs help maintain homeostasis between potential disease-causing organisms and resident microbial populations. Indeed, the immune system does not remain ignorant of commensal, passenger (transient), or opportunistic fungi, and sensing these different fungi through PRRs serve to ensure that

both the symbiotic host–microbial relationship and a homeostatic balance between tolerogenic and proinflammatory immune responses are maintained. In light of this, tissue homeostasis and its possible breakdown in fungal infections and diseases play a fundamental role. A number of seminal reviews have addressed the importance of both resistance — the ability to limit microbial burden — and tolerance — the ability to limit the host damage caused by an uncontrolled response — as mechanisms of immune responses to fungi and the reader is directed to these for more in-depth information about specific immune mechanisms [31-34]. Monocytes, macrophages, neutrophils as well as epithelial and endothelial cells [35], mostly contribute to the antifungal innate immune response through phagocytosis and direct pathogen killing. By contrast, uptake of fungi by DCs promotes the differentiation of naïve T cells into effector Th-cell subtypes (Fig. 1).

PTEN protein was present heterogeneously in 42 cases and homogene

PTEN protein was present heterogeneously in 42 cases and homogeneously in 18

cases. In homogeneous glioblastomas, no correlation was found between PTEN protein expression and the Carfilzomib datasheet LOH of the gene. Surprisingly, in the heterogeneous glioblastomas, LOH was found significantly more frequently (P < 0.001) in PTEN-positive areas (81%) than in PTEN-negative ones (35.7%). In general, molecular results of frozen tissue were representative of the tumour. Only two cases of methylation of the PTEN promoter were identified. A significant difference was found for overall survival for LOH10q23 status (P = 0.005) and for homogeneous vs. heterogeneous tumours (P = 0.014). The expression of PTEN protein does not correlate with the abnormalities of the LOH of the gene. Interestingly, patients with glioblastomas presenting either LOH of 10q23 or heterogeneous PTEN expression have a poorer prognosis. "
“In the CNS, primary tumors with rhabdoid components are classified as atypical teratoid/rhabdoid tumor, rhabdoid meningioma or rhabdoid glioblastoma. The authors present a young adult patient with supratentorial rhabdoid tumor incidentally found after head trauma as a small pre-existing lesion

in the parahippocampal gyrus. Pembrolizumab purchase MRI demonstrated an area of hypointensity on T1-weighted images and hyperintensity on T2-weighted and fluid attenuated inversion recovery images. A serial MR scan revealed no change 3 months after the initial examination but drastic changes at 6 months. As the tumor and accompanying intratumoral hemorrhage enlarged rapidly, resection of the tumor was performed. Histopathology Org 27569 revealed that the main component of the tumor was typical rhabdoid cells with some necrotic areas. There were also pathological features consistent with oligoastrocytoma. The specimen had neither vascular

proliferation usually seen in high-grade glioma nor the meningothelial pattern that suggests meningioma. Immunohistochemical findings revealed that cells were strongly positive for vimentin, epithelial membrane antigen and INI-1 antibody throughout the specimen. Further, monosomy 22 was detected by fluorescence in situ hybridization. The tumor was finally thought to be an unclassifiable primitive rhabdoid tumor with oligoastrocytoma that arose in the CNS. The patient died within 5 months of detection of the tumor, regardless of surgical resection, radiotherapy and chemotherapy. “
“Institut de Neurociències, Department of Cell Biology, Physiology and Immunology and Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Universitat Autònoma de Barcelona, Barcelona, Spain Auditory Neurophysiology Unit, Institute of Neuroscience of Castilla y León, University of Salamanca, Salamanca, Spain Dithiocarb (diethyldithiocarbamate, DEDTC) belongs to the group of dithiocarbamates and is the main metabolite of disulphiram, a drug of choice for the treatment of alcohol dependence.

[1, 4, 10] Taken together these data indicate that the duration/s

[1, 4, 10] Taken together these data indicate that the duration/strength of TCR ligation check details results in a progressive reinforcement of expression programmes that are downstream of the TCR signal. Fixation of epigenetic modifications and or the expression of unique transcription factors are a likely mechanism for preserving the exhausted state in the absence of antigen (Fig. 1b). Indeed, gene expression profiling studies demonstrate the preservation of many effector transcriptional programmes including persistent down-regulation of several on-off-on genes (Fig. 1b). Consistent with this idea, we have recently reported on preservation of acquired epigenetic modifications at the PD-1 locus

regulatory regions in virus-specific

CD8 T cells during chronic viral infection.[27] Our data demonstrated that the transient up-regulation of PD-1 expression in functional virus-specific CD8 T cells Selleckchem GSK2118436 was coupled to chromatin accessibility, permissive histone modifications, and acquisition of an unmethylated transcriptional regulatory region at the peak of acute viraemia. Following clearance of the acute viral infection, the PD-1 transcriptional regulatory region regained the DNA methylation programme and became less sensitive to DNase challenge. Importantly, the repressive transcriptional programme was not reacquired in virus-specific CD8 T cells during chronic infection of mice and humans.[27] To our surprise, the permissive epigenetic transcriptional programme at the PD-1 locus was retained in PD-1lo cells following reduction in chronic viral load. Preservation of the permissive transcriptional programme facilitated enhanced re-expression of PD-1 relative to functional memory cells that contained the repressive programme at the PD-1 locus.[27] The kinetic analysis of epigenetic regulation of PD-1 during acute and chronic infections as well as analysis of effector molecule regulation during CD4 and CD8 T-cell memory cell differentiation

have set the stage for further analysis of the enzymes that catalyse the epigenetic modifications Niclosamide and their specificity determinates. Further scrutiny of gene regulatory mechanisms related to the identification and function of phenotypically distinct effector and memory T-cell subsets is necessary. Undoubtedly such studies will further clarify when memory cells are generated and how progressive changes in phenotype and function are obtained. Specifically, analysis of epigenetic modifications will provide a snapshot of the differentiation status of effector and memory T cells. Epigenetic profiling of antigen-specific CD4 and CD8 memory T cells will immediately benefit vaccine development as it will provide a novel parameter for identifying poised expression programmes aiding in the assessment of T-cell memory quality.

This technology is particularly applicable to nephrology, in whic

This technology is particularly applicable to nephrology, in which the genetic basis of multiple disorders has been identified, but single-gene testing remains impractical given broad, overlapping clinical phenotypes. We describe two cases of nephronophthisis mutations identified via whole exome sequencing. Case Report: The first, a case of a 29 year

old female Maraviroc cell line who was diagnosed with juvenile nephronophthisis on renal biopsy at 14 years old. She subsequently underwent deceased-donor kidney transplantation at 18years. She is a product of consanguineous parents. Her mother and brother also have end stage renal failure. The family underwent single-gene testing of the UMOD gene, as a possible autosomal dominant cause of their renal failure, with no pathologic mutation identified. Our patient subsequently underwent whole R788 cost exome sequencing, as part of a research cohort of Australian patients investigated for a genetic cause for their kidney disease. Sequencing revealed a novel homozygous splice-site mutation within NPHP1 (NM_000272.3:c.1884+1G>T).The second is a case of a 3 year old boy who presented with hepatosplenomegaly

and renal failure at 18 months old, and is now dialysis dependent. He had no significant family history. Whole exome sequencing tuclazepam identified a reported homozygous missense mutation within NPHP3 (NM_153240.4:c.1928C>T:p.Pro643Leu). Conclusions: We have utilised massively parallel sequencing to identify both a novel and known nephronophthisis mutation in separate cases, and importantly these findings have guided treatment, transplantation and family planning for these patients. These experiences highlight the benefits of utilising this technology to

identify a genetic diagnosis in patients with renal disease. 203 ASSESSMENT OF MEDICATION AWARENESS AND THE UTILITY OF MEDICATION CARDS IN CHRONIC HAEMODIALYSIS PATIENTS H NANDAKOBAN, YM KUANG, M SURANYI, A MAKRIS Renal Unit, Liverpool Hospital, Sydney, NSW, Australia Aim: To determine the factors contributing to medication awareness for chronic haemodialysis (HD) patients and determine the utility of medication cards in improving medication awareness. Background: Patients on HD often have several chronic health issues and are subject to polypharmacy. Errors in medication prescription and ingestion can lead to morbidity. There is little information about prescribed medication understanding in HD patients. Medication cards may improve patient understanding of their medications.

IgA antibody response to both antigens did differ in Mtb-infected

IgA antibody response to both antigens did differ in Mtb-infected and non-infected subjects. Moreover, there was a positive correlation between the level of IFN-γ induced by the specific antigens and the level of serum IgA against ESAT-6/CFP-10 and Rv2031 in healthy Mtb-infected U0126 mouse subjects. These results encourage further follow-up studies on the specific roles of IgA antibody and its subclasses in the progression of Mtb infection and of the immunodiagnostic test using additional antigens in population under various epidemiological settings of the disease. ML designed the study, participated in data collection, data analysis and drafted the manuscript. GA participated in designing the study, data

collection, analysis and write-up. GMD participated in designing the study, data analysis and interpretation and write-up. GM participated in designing the study and write-up. KF produced the recombinant antigens for the study and write-up. TO participated in selleck chemicals llc designing of the study, the writing up of the manuscript, and supervised antigen production and its QC. GB involved in designing of the study and critically revised the manuscript. FA involved in designing the study and write-up of the manuscript and critically revised the manuscript. All authors read and approved the final manuscript. ML is the guarantor of the manuscript. We are grateful to study participants, Afar Regional and Amibara District Health

Bureau, Dubti hospital, Meleka Werer Health Centres. We would like to thank nurse Gezahegn Getachew, staff of Melka Werer Health Centre, for his assistances in physical and clinical examinations. We would like to thank Mr. Sisay Dessie, Mr. Girma Kebede and Ms

Kokobe Gebre-Michael for their technical assistance. We would like to thank staff of Dubti hospital for their technical and clinical examinations of patients suspected of PTB. We would also like to thank staff of Armauer Hansen Research Institute for their cooperation during selleck chemicals laboratory work. The study was financially supported by Norwegian Programme for Development, Research and Education, NUFU (NUFU PRO-2007/10198) as well as the Research Council of Norway. “
“The pathogenesis of vitiligo is still controversial. The purpose of this study was to gain insight into the nature of lymphoid cells infiltrating depigmented areas of skin in vitiligo. Immunochemical procedures were carried out in biopsies from 20 patients with active lesions to search for cells expressing CD1a, CD2, CD3, CD4, CD5, CD8, CD20, CD25, CD30, CD56, CD68 and CD79a. Results indicate that early lesions are infiltrated mainly by dendritic cells, whereas older lesions display significantly lower proportions of these cells and increased percentages of mature T cells. This finding might suggest that the autoimmune reactivity towards melanocyte antigens might be T cell-dependent and antigen-driven.

01 (95% CI 0 70–1 44; P=0 97), respectively, compared with the 15

01 (95% CI 0.70–1.44; P=0.97), respectively, compared with the 1513 A and −762 T alleles. Polymorphisms at the 1513 locus had a statistically significant association with P2X7 variants

and tuberculosis susceptibility, while the −762 locus allele variants were not significantly associated with P2X7 variants and tuberculosis susceptibility. Tuberculosis is a major cause of morbidity and mortality worldwide, especially in Asia and Africa. Genetic variability, combined with environmental factors, are expected to contribute to the risk of developing active tuberculosis (Cooke & Hill, 2001). Human P2X7, which encodes the P2X7 receptor, has been cloned and mapped to human chromosome 12q24 and linked to tuberculosis susceptibility (Buell et al., 1998). The MEK inhibitor P2X7 receptor is a ligand-gated cation channel that is highly expressed on human and murine macrophages (Nicke

et al., 1998; Gu et al., 2001). The activation of P2X7 by adenosine Compound Library chemical structure triphosphate (ATP) causes the immediate opening of a cation-selective channel, allowing the influx of Ca2+ and Na+ and the efflux of K+. This initiates a number of downstream signaling events, including caspase activation, resulting in apoptosis and phospholipase D (PLD) activation, which promotes phagosome–lysosome fusion, resulting in mycobacteria death (Humphreys et al., 2000; Kusner & Barton, 2001; Coutinho-Silva et al., 2003). P2X7 is highly polymorphic and several single nucleotide polymorphisms (SNPs) that

lead to loss of receptor function have been described (Fernando et al., 2005; Shemon et al., 2006). The most common is the 1513AC polymorphism, resulting in a glutamic acid to alanine substitution at position 496. This substitution results in the expression of a nonfunctional P2X7 receptor in macrophages from subjects homozygous for the 1513 C allele and patients heterozygous at this locus have impaired P2X7 receptor function. Additionally, the −762TC SNP Adenosine triphosphate in the P2X7 promoter region has been shown to be protective against tuberculosis in a Gambian population (Li et al., 2002). However, there is no evidence that the −762 C allele has functional consequences for gene expression. Several studies have looked at associations between the P2X7 gene 1513 and −762 loci allele variants and susceptibility to tuberculosis; however, these analyses have yielded mixed results depending on the population studied, in part due to the lack of adequate statistical power, selection bias or population diversity. Because a metaanalysis may overcome some of these methodological difficulties, a systematic review of the literature using metaanalysis was carried out as a means of providing a quantitative estimate on the association between P2X7 polymorphisms and susceptibility tuberculosis. To the best of our knowledge, no metaanalysis of the literature exploring the relationship between P2X7 gene polymorphisms and susceptibility to tuberculosis has been carried out to date.

pneumoniae is the use of LAB as carriers of different pneumococca

pneumoniae is the use of LAB as carriers of different pneumococcal antigens. In previous studies we have demonstrated that immunization with PppA, expressed learn more as a wall-anchored protein on the surface of L. lactis, was able to induce cross-protective immunity against different pneumococcal serotypes, afforded protection against both systemic and respiratory pneumoccocal challenges, and induced

protective immunity in adult and infant mice [16]. Additionally, on the basis of previous studies, we have demonstrated that the nasal route is the best alternative for protection against a pneumococcal infection using L. lactis as adjuvant [14,15] and as antigen delivery vehicle [16,31]. This agrees with the findings of other researchers HDAC inhibitor who demonstrated the convenience of the nasal route for the immunization of mucosae against respiratory pathogens [32,33]. In this work we have assessed new immunization strategies using an inactivated recombinant bacterium by itself and in association with a probiotic strain. Analysis of the immunostimulatory properties of non-viable LAB strains showed that they depend upon the strain used, although

there is evidence indicating that viable bacteria are more effective for mucosal immunostimulation. In most cases, heat-killed strains were assessed in which differences in immunostimulation might be associated with heat-induced alteration of epitopes [34]. In order to conserve the structure of the PppA expressed in the surface of L. lactis, death was carried out by chemical inactivation. The inactivated strain proved to be effective for the induction of high levels of specific IgA and IgG antibodies in BAL and of IgG in the serum of the vaccinated young mice, which

were higher than those obtained with the live vaccine. The association of the live and dead vaccines with the probiotic increased specific anti-PppA antibodies, reaching maximum values in the D-LL + Lc (N) group. The increase in IgA and IgG anti-PppA is of fundamental importance at the lung level, because while IgA prevents pathogen attachment to epithelial cells, during thus reducing colonization, IgG would exert protection at the alveolar level, promoting phagocytosis and preventing local dissemination of the pneumococcus and its passage into blood [35]. We demonstrated that the vaccine-induced humoral immune response was increased in all assessed groups at both the lung and systemic compartments, although the highest levels of specific antibodies were obtained when the vaccine, dead or live, was associated with the probiotic. This was coincident with the increase in IL-4 in the lung compartment, indicating activation of the Th2 cell population, which enhanced the humoral immune response. Recent reports have shown that certain lactobacilli improved the specific antibody response after vaccination against some viral and bacterial pathogens [21,36]. In addition, L.

We conclude that cellular differentiation of pre-BI cells to a pr

We conclude that cellular differentiation of pre-BI cells to a pre-BII-like stage, induced by the removal of IL-7, is delayed, but not inhibited by the doxycycline-induced overexpression

of Myc and Pim1, as judged by the retarded loss of c-kit expression, the retarded loss of clonability on stromal cells in the presence of IL-7 and by the slower gain of CD25. Furthermore, CH5424802 cell line acquisition of IgM on the surface or intracellularly is blocked. It appears that the Myc-single and the Pim1/Myc-double-transduced cells are arrested in differentiation before sIgM+ immature B cells. Transplantation of Pim1/Myc-double-overexpressing pre-BI cells in doxycycline-fed Rag1−/− recipient mice (Fig. 3) led to a marked expansion of CD19+ B-lineage cells in selleck chemicals vivo. In two separate experiments, the transplanted pre-B cells were kept either for 4 weeks (Fig. 3A–C) or for 8 weeks (Fig. 3D) in doxycycline-fed mice, followed each by a 4-week period without doxycycline in the drinking water. At 4 weeks, high numbers of transplanted cells overexpressing Pim1 and Myc were detected in BM, spleen and

peritoneum. At 8 weeks, the transplanted pre-B cells could also be detected in the swollen lymph nodes of the animals (data not shown). FACS analysis of the phenotypes of B lineage cells showed that spleens of doxycycline-induced mice, which harbored Pim1/Myc overexpressing B cells contained 100-fold higher numbers of pre-B cells, up to 6-fold higher numbers of immature IgM+ B cells, and up to twice the numbers of mature B cells than spleens of doxycycline-uninduced mice (Fig. 3B and C). The expanded number of cells detected after 8 weeks in BM, spleen, peritoneum and lymph nodes in the presence of doxycycline were, in majority, CD93+IgM− pre-B

cells (data not shown). Removal of doxycycline from the drinking water from transplanted mice 4 or 8 weeks after transplantation resulted in the disappearance of the previously expanded numbers of pre-B-, immature, and the slightly increased numbers of mature B cells from the spleen to normal numbers seen in uninduced mice (Fig. 3A, B and D). In a separate experiment, the capacities of Pim1/Myc-overexpressing pre-B cells to proliferate ex MycoClean Mycoplasma Removal Kit vivo after expansion in vivo were tested (Fig. 3E and F). These Pim1/Myc-overexpressing IgM− pre-B cells isolated from spleen and LNs of mice fed for 8 weeks with doxycycline could be propagated in vitro without IL-7 and OP9 cells in the presence, but not in the absence of doxycycline. Upon removal of doxycycline from these ex vivo cultures, the cells terminated proliferation and acquired IgM on their surface (Fig. 3F). The reasons for this oncogene-dependent inhibition of IgM expression are presently under detailed investigation.

3b-2, b-3) (17) We also found that clustering of RILP in the per

3b-2, b-3) (17). We also found that clustering of RILP in the perinuclear regions was disrupted and diffused by the expression

of Rab7T22N. Collectively, our data demonstrate that Rab7 is vital for recruiting RILP to phagosomes during the maturation process, but not for recruiting CD63. How M.tb escapes the effects of the bactericidal components within the phagosome while still acquiring nutrients for growth is very important question. It has been suggested that mycobacterial phagosomes arrest their maturation at an early stage and completely avoid fusion with lysosomes (18, 19). However, we have shown the localization of CD63 (Fig. 2) and LAMP-2 (4) on M.tb phagosomes in macrophages. It Selleck Doxorubicin has been proposed that phagolysosome biogenesis is achieved by a series of fusions with heterogeneous lysosomes (20). This model is supported by a report demonstrating the existence of sub-populations of lysosomes in macrophages (6). Our previous and current studies demonstrating the alternative localization of lysosomal markers on M.tb phagosomes further support this model. From these observations, it seems that dissociation

of Rab7 from M.tb phagosomes selectively inhibits fusion with harmful lysosomes despite continued fusion with non-microbicidal lysosomes. In conclusion, based on our findings we propose the following model for M.tb-induced inhibition of phagolysosome biogenesis: Early M.tb phagosomes are capable of recruiting Rab7 and can potentially fuse with lysosomes. RILP is also recruited to M.tb phagosomes, which form the Rab7-RILP-dynein/dynactin protein complex followed by promotion of selleck chemicals llc phagolysosome biogenesis. However, viable M.tb is able to release Rab7 from phagosomes, resulting in inhibition of further fusion with lysosomal vesicles and disassembly of the RILP-phagosome complex. This causes the blocking of subsequent phagolysosome biogenesis. over On the other hand, non-microbicidal vesicles expressing CD63 and/or LAMP-2 continuously fuse with M.tb phagosomes

despite Rab7 dissociation, and this fusion would support the acquisition of nutrients for mycobacterial proliferation within the phagosome. We thank Drs. Toshi Nagata and Masato Uchijima (Hamamatsu University School of Medicine, Hamamatsu, Japan) for their helpful discussion. M.tb strain H37Rv was kindly provided by Dr. Isamu Sugawara (Research Institute of Tuberculosis, Tokyo, Japan). This work was supported in part by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science, COE Research and Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science and Technology of Japan, Health and Labor Science Research Grants for Research into Emerging and Reemerging Infectious Diseases from the Ministry of Health, Labor and Welfare of Japan, and the United States-Japan Cooperative Medical Science Committee.