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1.  Effects of campaign for postpartum vaccination on seronegative rate against rubella among Japanese women 
BMC Infectious Diseases  2014;14:152.
Japan experienced two rubella outbreaks in the past decade (2004 and 2012 – 2013), resulting in 10 and 20 infants with congenital rubella syndrome (CRS), respectively. This study was performed to determine whether the seronegative rate was lower in multiparous women than in primiparous women in Japan.
Hemagglutination inhibition (HI) test results during pregnancy were analyzed retrospectively in 11048 primiparous and 9315 multiparous women who gave birth at six hospitals in northern Japan in the 5-year study period (January 2008 through December 2012). Women with HI titer <  1:8 were defined as susceptible to rubella.
The seronegative rate was significantly lower in multiparous than primiparous women aged 30 – 31 years (2.3% [22/967] vs. 4.5% [66/1454], P  =  0.0036), 36 – 37 years (3.4% [55/1601] vs. 5.7% [79/1389], P  =  0.0030), and overall women (3.8% [350/9315] aged 34.7  ±  5.2 vs. 5.4% [597/11048] for 33.2  ±  5.9, P  <  0.001). The susceptible fraction size did not differ largely according to hospital, ranging from 3.5% to 6.3%. Those for each year did not change markedly; 4.5% [150/3369], 5.2% [221/4268], 4.4% [195/4412], 4.6% [186/4056], and 4.6% [195/4258] for 2008, 2009, 2010, 2011, and 2012, respectively. Those for teenagers were consistently high: 22.7% [5/22], 20.7% [6/29], 20.6% [7/34], 13.0% [3/23], and 23.5% [4/17] for 2008, 2009, 2010, 2011, and 2012, respectively.
The seronegative rate was significantly lower in multiparous than primiparous women. However, Japanese rubella vaccination programs were insufficient to eliminate CRS.
PMCID: PMC3994452  PMID: 24650141
Congenital rubella syndrome; Outbreak; Vaccine
2.  Positively charged cholesterol–recombinant human gelatins foster the cellular uptake of proteins and murine immune reactions 
Recombinant human gelatins with defined molecular weights were modified with cholesterol to make them amphiphilic in nature. We investigated the feasibility of these modified human gelatins acting as a carrier of antigenic proteins for inducing cellular immunity. The aim of this study was to synthesize novel and effective compounds for vaccine delivery in vivo.
Two types of cholesterol-modified gelatin micelles, anionic cholesterol-modified gelatin (aCMG) and cationic-cholesterol modified gelatin (cCMG), were synthesized using different cholesterol derivatives such as the cholesterol-isocyanate (Ch-I) for aCMG and amino-modified cholesterol for cCMG. One was anionic and the other cationic, and therefore they differed in terms of their zeta potential. The aCMG and cCMG were characterized for their size, zeta potential, and in their ability to form micelles. Cytotoxicity was also evaluated. The modified human gelatins were then investigated as a carrier of antigenic proteins for inducing cellular immunity both in vitro in DC 2.4 cells, a murine dendritic cell line, as well as in vivo. The mechanism of entry of the polymeric micelles into the cells was also evaluated.
It was found that only cCMG successfully complexed with the model antigenic protein, fluorescein-isothiocyanate ovalbumin (OVA) and efficiently delivered and processed proteins in DC 2.4 cells. It was hypothesized that cCMG enter the cells predominantly by a caveolae-mediated pathway that required tyrosine kinase receptors on the cell surface. Animal testing using mice showed that the cationic cholesterol-modified gelatin complexed with OVA produced significantly high antibody titers against OVA: 2580-fold higher than in mice immunized with free OVA.
Conclusively, cCMG has shown to be very effective in stimulating an immune response due to its high efficiency, stability, and negligible cytotoxicity.
PMCID: PMC3471541  PMID: 23091385
recombinant human gelatin; cholesterol; micelle; protein delivery; caveolae pathway; receptor-mediated endocytosis
3.  Indomethacin Analogues that Enhance Doxorubicin Cytotoxicity in Multidrug Resistant Cells without Cox Inhibitory Activity 
ACS Medicinal Chemistry Letters  2011;2(5):353-357.
Conformationally restricted indomethacin analogues were designed and prepared from the corresponding 2-substituted indoles, which were synthesized by a one-pot isomerization/enamide-ene metathesis as the key reaction. Conformational analysis by calculations, NMR studies, and X-ray crystallography suggested that these analogues were conformationally restricted in the s-cis or the s-trans form due to the 2-substituent as expected. Their biological activities on cyclooxygenase-1 (COX-1) inhibition, cyclooxygenase-2 (COX-2) inhibition, and modulation of MRP-1-mediated multidrug resistance (MDR) are described. Some of these indomethacin analogues enhanced doxorubicin cytotoxicity, although they do not have any COX inhibitory activity, which suggests that the MDR-modulating effect of an NSAID can be unassociated with its COX-inhibitory activity. This may be an entry into the combination chemotherapy of doxorubicin with a MDR modulator.
PMCID: PMC4017980  PMID: 24900317
Cancer; conformation analysis; cytotoxicity; drug design; nitrogen heterocycles
4.  Effects of Ligands on Unfolding of the Amyloid β-Peptide Central Helix: Mechanistic Insights from Molecular Dynamics Simulations 
PLoS ONE  2012;7(1):e30510.
Polymerization of the amyloid β-peptide (Aβ), a process which requires that the helical structure of Aβ unfolds beforehand, is suspected to cause neurodegeneration in Alzheimer's disease. According to recent experimental studies, stabilization of the Aβ central helix counteracts Aβ polymerization into toxic assemblies. The effects of two ligands (Dec-DETA and Pep1b), which were designed to bind to and stabilize the Aβ central helix, on unfolding of the Aβ central helix were investigated by molecular dynamics simulations. It was quantitatively demonstrated that the stability of the Aβ central helix is increased by both ligands, and more effectively by Pep1b than by Dec-DETA. In addition, it was shown that Dec-DETA forms parallel conformations with β-strand-like Aβ, whereas Pep1b does not and instead tends to bend unwound Aβ. The molecular dynamics results correlate well with previous experiments for these ligands, which suggest that the simulation method should be useful in predicting the effectiveness of novel ligands in stabilizing the Aβ central helix. Detailed Aβ structural changes upon loss of helicity in the presence of the ligands are also revealed, which gives further insight into which ligand may lead to which path subsequent to unwinding of the Aβ central helix.
PMCID: PMC3264620  PMID: 22291970
5.  Unfolding of the Amyloid β-Peptide Central Helix: Mechanistic Insights from Molecular Dynamics Simulations 
PLoS ONE  2011;6(3):e17587.
Alzheimer's disease (AD) pathogenesis is associated with formation of amyloid fibrils caused by polymerization of the amyloid β-peptide (Aβ), which is a process that requires unfolding of the native helical structure of Aβ. According to recent experimental studies, stabilization of the Aβ central helix is effective in preventing Aβ polymerization into toxic assemblies. To uncover the fundamental mechanism of unfolding of the Aβ central helix, we performed molecular dynamics simulations for wild-type (WT), V18A/F19A/F20A mutant (MA), and V18L/F19L/F20L mutant (ML) models of the Aβ central helix. It was quantitatively demonstrated that the stability of the α-helical conformation of both MA and ML is higher than that of WT, indicating that the α-helical propensity of the three nonpolar residues (18, 19, and 20) is the main factor for the stability of the whole Aβ central helix and that their hydrophobicity plays a secondary role. WT was found to completely unfold by a three-step mechanism: 1) loss of α-helical backbone hydrogen bonds, 2) strong interactions between nonpolar sidechains, and 3) strong interactions between polar sidechains. WT did not completely unfold in cases when any of the three steps was omitted. MA and ML did not completely unfold mainly due to the lack of the first step. This suggests that disturbances in any of the three steps would be effective in inhibiting the unfolding of the Aβ central helix. Our findings would pave the way for design of new drugs to prevent or retard AD.
PMCID: PMC3049775  PMID: 21408230
6.  What is the role of regulatory T cells in the success of implantation and early pregnancy? 
The immune system is well controlled by the balance between immunostimulation and immunoregulation. CD4+CD25+ regulatory T (Treg) cells and an enzyme called indoleamine-2, 3-dioxygenase (IDO) mediate maternal tolerance of the allogeneic fetus. Treg cells, therefore, may prevent early pregnancy loss due to maternal ‘rejection.’
The latest understanding of tolerance during pregnancy is reviewed.
Results and conclusions
Recent data show that CD4+CD25+ Treg cells play essential roles in the induction and maintenance of tolerance, and that they augment the IDO activity in dendritic cells and macrophages. Therefore, CD4+CD25+ Treg cells and IDO enzyme may cooperate in the induction of tolerance during pregnancy. Treg deficiency is associated with very early post-implantation loss and spontaneous abortion in animal models, and low Treg levels are associated with recurrent miscarriages in humans.
PMCID: PMC3454956  PMID: 17668314
CD4+CD25+ regulatory T cell; CTLA-4; Decidua; IDO; Miscarriage; Preeclampsia
7.  A murine model of autosomal dominant neurohypophyseal diabetes insipidus reveals progressive loss of vasopressin-producing neurons 
Journal of Clinical Investigation  2003;112(11):1697-1706.
Familial neurohypophyseal diabetes insipidus (FNDI) is an autosomal dominant disorder caused by mutations in the arginine vasopressin (AVP) precursor. The pathogenesis of FNDI is proposed to involve mutant protein–induced loss of AVP-producing neurons. We established murine knock-in models of two different naturally occurring human mutations that cause FNDI. A mutation in the AVP signal sequence [A(–1)T] is associated with a relatively mild phenotype or delayed presentation in humans. This mutation caused no apparent phenotype in mice. In contrast, heterozygous mice expressing a mutation that truncates the AVP precursor (C67X) exhibited polyuria and polydipsia by 2 months of age and these features of DI progressively worsened with age. Studies of the paraventricular and supraoptic nuclei revealed induction of the chaperone protein BiP and progressive loss of AVP-producing neurons relative to oxytocin-producing neurons. In addition, Avp gene products were not detected in the neuronal projections, suggesting retention of WT and mutant AVP precursors within the cell bodies. In summary, this murine model of FNDI recapitulates many features of the human disorder and demonstrates that expression of the mutant AVP precursor leads to progressive neuronal cell loss.
PMCID: PMC281642  PMID: 14660745

Results 1-7 (7)