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1.  IL1RAPL1 knockout mice show spine density decrease, learning deficiency, hyperactivity and reduced anxiety-like behaviours 
Scientific Reports  2014;4:6613.
IL-1 receptor accessory protein-like 1 (IL1RAPL1) is responsible for nonsyndromic intellectual disability and is associated with autism. IL1RAPL1 mediates excitatory synapse formation through trans-synaptic interaction with PTPδ. Here, we showed that the spine density of cortical neurons was significantly reduced in IL1RAPL1 knockout mice. The spatial reference and working memories and remote fear memory were mildly impaired in IL1RAPL1 knockout mice. Furthermore, the behavioural flexibility was slightly reduced in the T-maze test. Interestingly, the performance of IL1RAPL1 knockout mice in the rotarod test was significantly better than that of wild-type mice. Moreover, IL1RAPL1 knockout mice consistently exhibited high locomotor activity in all the tasks examined. In addition, open-space and height anxiety-like behaviours were decreased in IL1RAPL1 knockout mice. These results suggest that IL1RAPL1 ablation resulted in spine density decrease and affected not only learning but also behavioural flexibility, locomotor activity and anxiety.
PMCID: PMC4196104  PMID: 25312502
2.  Is d-aspartate produced by glutamic-oxaloacetic transaminase-1 like 1 (Got1l1): a putative aspartate racemase? 
Amino Acids  2014;47:79-86.
d-Aspartate is an endogenous free amino acid in the brain, endocrine tissues, and exocrine tissues in mammals, and it plays several physiological roles. In the testis, d-aspartate is detected in elongate spermatids, Leydig cells, and Sertoli cells, and implicated in the synthesis and release of testosterone. In the hippocampus, d-aspartate strongly enhances N-methyl-d-aspartate receptor-dependent long-term potentiation and is involved in learning and memory. The existence of aspartate racemase, a candidate enzyme for d-aspartate production, has been suggested. Recently, mouse glutamic-oxaloacetic transaminase 1-like 1 (Got1l1) has been reported to synthesize substantially d-aspartate from l-aspartate and to be involved in adult neurogenesis. In this study, we investigated the function of Got1l1 in vivo by generating and analyzing Got1l1 knockout (KO) mice. We also examined the enzymatic activity of recombinant Got1l1 in vitro. We found that Got1l1 mRNA is highly expressed in the testis, but it is not detected in the brain and submandibular gland, where d-aspartate is abundant. The d-aspartate contents of wild-type and Got1l1 KO mice were not significantly different in the testis and hippocampus. The recombinant Got1l1 expressed in mammalian cells showed l-aspartate aminotransferase activity, but lacked aspartate racemase activity. These findings suggest that Got1l1 is not the major aspartate racemase and there might be an as yet unknown d-aspartate-synthesizing enzyme.
PMCID: PMC4282708  PMID: 25287256
Glutamic-oxaloacetic transaminase-1 like 1; d-Aspartate; Knockout mice; Testis; Hippocampus; Recombinant protein expression
3.  IL1RAPL1 Associated with Mental Retardation and Autism Regulates the Formation and Stabilization of Glutamatergic Synapses of Cortical Neurons through RhoA Signaling Pathway 
PLoS ONE  2013;8(6):e66254.
Interleukin-1 receptor accessory protein-like 1 (IL1RAPL1) is associated with X-linked mental retardation and autism spectrum disorder. We found that IL1RAPL1 regulates synapse formation of cortical neurons. To investigate how IL1RAPL1 controls synapse formation, we here screened IL1RAPL1-interacting proteins by affinity chromatography and mass spectroscopy. IL1RAPL1 interacted with Mcf2-like (Mcf2l), a Rho guanine nucleotide exchange factor, through the cytoplasmic Toll/IL-1 receptor domain. Knockdown of endogenous Mcf2l and treatment with an inhibitor of Rho-associated protein kinase (ROCK), the downstream kinase of RhoA, suppressed IL1RAPL1-induced excitatory synapse formation of cortical neurons. Furthermore, we found that the expression of IL1RAPL1 affected the turnover of AMPA receptor subunits. Insertion of GluA1-containing AMPA receptors to the cell surface was decreased, whereas that of AMPA receptors composed of GluA2/3 was enhanced. Mcf2l knockdown and ROCK inhibitor treatment diminished the IL1RAPL1-induced changes of AMPA receptor subunit insertions. Our results suggest that Mcf2l-RhoA-ROCK signaling pathway mediates IL1RAPL1-dependent formation and stabilization of glutamatergic synapses of cortical neurons.
PMCID: PMC3681934  PMID: 23785489
4.  Presence of Viral Genome in Urine and Development of Hematuria and Pathological Changes in Kidneys in Common Marmoset (Callithrix jacchus) after Inoculation with Dengue Virus 
Pathogens  2013;2(2):357-363.
Common marmosets (Callithrix jacchus) developed high levels of viremia, clinical signs including fever, weight loss, a decrease in activity and hematuria upon inoculation with dengue virus (DENV). Presence of DENV genome in urine samples and pathological changes in kidneys were examined in the present study. Levels of DENV genome were determined in 228 urine samples from 20 primary DENV-inoculated marmosets and in 56 urine samples from four secondary DENV-inoculated marmosets. DENV genome was detected in 75% (15/20) of marmosets after primary DENV infection. No DENV genome was detected in urine samples from the marmosets with secondary infection with homologous DENV (0%, 0/4). Two marmosets demonstrated hematuria. Pathological analysis of the kidneys demonstrated non-suppressive interstitial nephritis with renal tubular regeneration. DENV antigen-positive cells were detected in kidneys. In human dengue virus infections, some patients present renal symptoms. The results indicate that marmosets recapitulate some aspects of the involvement of kidneys in human DENV infection, and suggest that marmosets are potentially useful for the studies of the pathogenesis of DENV infection, including kidneys.
PMCID: PMC4235723  PMID: 25437039
dengue virus; animal model; marmoset; urine; hematuria; kidney
5.  Safery Guidelines for PDT in The Field of Otorhinolaryngology and Head and Neck Disorders 
Laser Therapy  2012;21(1):54-59.
PMCID: PMC3944598  PMID: 24610983
6.  Allele frequency of antiretroviral host factor TRIMCyp in wild-caught cynomolgus macaques (Macaca fascicularis) 
A recent study showed that the frequency of an antiretroviral factor TRIM5 gene-derived isoform, TRIMCyp, in cynomolgus macaques (Macaca fascicularis) varies widely according to the particular habitat examined. However, whether the findings actually reflect the prevalence of TRIMCyp in wild cynomolgus macaques is still uncertain because the previous data were obtained with captive monkeys in breeding and rearing facilities. Here, we characterized the TRIM5 gene in cynomolgus macaques captured in the wild, and found that the frequency of the TRIMCyp allele was comparable to those in captive monkeys. This suggests that the previous results with captive monkeys do indeed reflect the natural allele frequency and that breeding and rearing facilities may not affect the frequency of TRIM5 alleles. Interestingly, the prevalence of a minor haplotype of TRIMCyp in wild macaques from the Philippines was significantly lower than in captive ones, suggesting that it is advantageous for wild monkeys to possess the major haplotype of TRIMCyp. Overall, our results add to our understanding of the geographic and genetic prevalence of cynomolgus macaque TRIMCyp.
PMCID: PMC3430983  PMID: 22969754
cynomolgus monkey; TRIM5α; TRIMCyp; genetic diversity; host factor
7.  Molecular mechanism of parallel fiber-Purkinje cell synapse formation 
The cerebellum receives two excitatory afferents, the climbing fiber (CF) and the mossy fiber-parallel fiber (PF) pathway, both converging onto Purkinje cells (PCs) that are the sole neurons sending outputs from the cerebellar cortex. Glutamate receptor δ2 (GluRδ2) is expressed selectively in cerebellar PCs and localized exclusively at the PF-PC synapses. We found that a significant number of PC spines lack synaptic contacts with PF terminals and some of residual PF-PC synapses show mismatching between pre- and postsynaptic specializations in conventional and conditional GluRδ2 knockout mice. Studies with mutant mice revealed that in addition to PF-PC synapse formation, GluRδ2 is essential for synaptic plasticity, motor learning, and the restriction of CF territory. GluRδ2 regulates synapse formation through the amino-terminal domain, while the control of synaptic plasticity, motor learning, and CF territory is mediated through the carboxyl-terminal domain. Thus, GluRδ2 is the molecule that bridges synapse formation and motor learning. We found that the trans-synaptic interaction of postsynaptic GluRδ2 and presynaptic neurexins (NRXNs) through cerebellin 1 (Cbln1) mediates PF-PC synapse formation. The synaptogenic triad is composed of one molecule of tetrameric GluRδ2, two molecules of hexameric Cbln1 and four molecules of monomeric NRXN. Thus, GluRδ2 triggers synapse formation by clustering four NRXNs. These findings provide a molecular insight into the mechanism of synapse formation in the brain.
PMCID: PMC3505014  PMID: 23189042
glutamate receptor δ2; motor learning; neurexin; parallel fiber; Purkinje cell; synapse formation
8.  Long-Term Persistent GBV-B Infection and Development of a Chronic and Progressive Hepatitis C-Like Disease in Marmosets 
It has been shown that infection of GB virus B (GBV-B), which is closely related to hepatitis C virus, develops acute self-resolving hepatitis in tamarins. In this study we sought to examine longitudinally the dynamics of viral and immunological status following GBV-B infection of marmosets and tamarins. Surprisingly, two of four marmosets but not tamarins experimentally challenged with GBV-B developed long-term chronic infection with fluctuated viremia, recurrent increase of alanine aminotransferase and plateaued titers of the antiviral antibodies, which was comparable to chronic hepatitis C in humans. Moreover, one of the chronically infected marmosets developed an acute exacerbation of chronic hepatitis as revealed by biochemical, histological, and immunopathological analyses. Of note, periodical analyses of the viral genomes in these marmosets indicated frequent and selective non-synonymous mutations, suggesting efficient evasion of the virus from antiviral immune pressure. These results demonstrated for the first time that GBV-B could induce chronic hepatitis C-like disease in marmosets and that the outcome of the viral infection and disease progression may depend on the differences between species and individuals.
PMCID: PMC3267178  PMID: 22319510
GBV-B; HCV; marmoset; tamarin; hepatitis C
9.  Predisposition for borderline personality disorder with comorbid major depression is associated with that for polycystic ovary syndrome in female Japanese population 
Polycystic ovary syndrome (PCOS) is a common lifestyle-related endocrinopathy in women of reproductive age and is associated with several mental health problems. We examined the genotypic distributions of IRS-1 Gly972Arg and CYP11B2 -344T/C, which were previously described as influencing PCOS, and assayed the serum levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), in a set of female patients with borderline personality disorder (BPD) with comorbid major depressive disorder (MDD) (n = 50) and age-matched control subjects (n = 100), to investigate the predisposition for BPD with MDD. The results showed that the patients were more frequently IRS-1 972Arg variant allele carriers (P = 0.013; OR 6.68; 95% CI = 1.30–34.43) and homozygous for the CYP11B2 −344C variant allele (P = 0.022; OR = 3.32; 95% CI = 1.18–9.35) than the control subjects. The IL-6 level was significantly higher in the patients than in the controls (P < 0.0001). There was no significant difference in the serum TNF-α level between patients with BPD with MDD and the healthy comparison group (P = 0.5273). In conclusion, the predisposition for BPD with MDD is associated with that for PCOS, in the female Japanese population. An elevated serum IL-6 level is considered to be a possible biomarker of BPD with MDD.
PMCID: PMC3215522  PMID: 22090801
borderline personality disorder; depression; polycystic ovary syndrome; genetic polymorphism; insulin resistance
10.  Characterization of Natural Killer Cells in Tamarins: A Technical Basis for Studies of Innate Immunity 
Natural killer (NK) cells are capable of regulating viral infection without major histocompatibility complex restriction. Hepatitis C is caused by chronic infection with hepatitis C virus (HCV), and impaired activity of NK cells may contribute to the control of the disease progression, although the involvement of NK cells in vivo remains to be proven. GB virus B (GBV-B), which is genetically most closely related to HCV, induces acute and chronic hepatitis upon experimental infection of tamarins. This non-human primate model seems likely to be useful for unveiling the roles of NK cells in vivo. Here we characterized the biological phenotypes of NK cells in tamarins and found that depletion of the CD16+ subset in vivo by administration of a monoclonal antibody significantly reduced the number and activity of NK cells.
PMCID: PMC3112332  PMID: 21713119
CD16; cynomolgus monkey; tamarin; NK cell
11.  The C-terminus of interferon gamma receptor beta chain (IFNγR2) has antiapoptotic activity as a Bax inhibitor 
Cancer biology & therapy  2009;8(18):1771-1786.
Bax is a pro-apoptotic protein that mediates intrinsic cell-death signaling. Using a yeast-based functional screening approach, we identified interferon gamma receptor beta chain (IFNγR2) as a new Bax suppressor. IFNγR2 is a component of the IFNγ receptor complex along with the IFNγR alpha chain (IFNγR1). Upon IFNγ binding, a conformational change in the receptor complex occurs that activates the Jak2/STAT1 signaling cascade. We found that the C-terminal region (amino acids 296–337) of IFNγR2 (IFNγR2296-337) contains a novel Bax inhibitory domain. This portion does not contain the Jak2-binding domain; therefore, the antiapoptotic function of IFNγR2 is independent of JAK/STAT signaling. IFNγR2296-337 rescued human cells from apoptosis induced by overexpression of Bax but not Bak. Overexpression of IFNγR2 (wild type and IFNγR2296-337) rescued cells from etopo-side and staurosporine, which are known to induce Bax-mediated cell death. Interestingly, IFNγR2 inhibited apoptosis induced by the BH3-only protein Bim-EL, suggesting that IFNγR2 inhibits Bax activation through a BH3-only protein. Bax and IFNγR2 were co-immunoprecipitated from cell lysates prepared from HEK293 and DAMI cells. Furthermore, direct binding of purified recombinant proteins of Bax and IFNγR2 was also confirmed. Addition of recombinant Bcl-2 protein to cell lysates significantly reduced the interaction of IFNγR2 and Bax, suggesting that Bcl-2 and IFNγR2 bind a similar domain of Bax. We found that the C-terminal fragment (cytoplasmic domain) of IFNγR2 is expressed in human cancer cell lines of megakaryocytic cancer (DAMI), breast cancer (MDA-MD-468), and prostate cancer (PC3 cells). The presence of the C-terminal fragment of IFNγR2 may confer on cancer cells resistance to apoptotic stresses. Our discovery of the anti-Bax activity of the cytoplasmic domain of IFNγR2 may shed new light on the mechanism of how cell death is controlled by IFNγ and Bax.
PMCID: PMC2927208  PMID: 19657228
interferon gamma receptor beta chain (IFNγR2); Bcl-2 associated protein X (Bax); apoptosis; cytosolic IFNγR2; antiapoptotic protein; Bcl-2 family of proteins; interferon gamma (IFNγ)
12.  Study of the outcome of suicide attempts: characteristics of hospitalization in a psychiatric ward group, critical care center group, and non-hospitalized group 
BMC Psychiatry  2010;10:4.
The allocation of outcome of suicide attempters is extremely important in emergency situations. Following categorization of suicidal attempters who visited the emergency room by outcome, we aimed to identify the characteristics and potential needs of each group.
The outcomes of 1348 individuals who attempted suicide and visited the critical care center or the psychiatry emergency department of the hospital were categorized into 3 groups, "hospitalization in the critical care center (HICCC)", "hospitalization in the psychiatry ward (HIPW)", or "non-hospitalization (NH)", and the physical, mental, and social characteristics of these groups were compared. In addition, multiple logistic analysis was used to extract factors related to outcome.
The male-to-female ratio was 1:2. The hospitalized groups, particularly the HICCC group, were found to have biopsychosocially serious findings with regard to disturbance of consciousness (JCS), general health performance (GAS), psychiatric symptoms (BPRS), and life events (LCU), while most subjects in the NH group were women who tended to repeat suicide-related behaviors induced by relatively light stress. The HIPW group had the highest number of cases, and their symptoms were psychologically serious but physically mild. On multiple logistic analysis, outcome was found to be closely correlated with physical severity, risk factor of suicide, assessment of emergent medical intervention, and overall care.
There are different potential needs for each group. The HICCC group needs psychiatrists on a full-time basis and also social workers and clinical psychotherapists to immediately initiate comprehensive care by a medical team composed of multiple professionals. The HIPW group needs psychological education to prevent repetition of suicide attempts, and high-quality physical treatment and management skill of the staff in the psychiatric ward. The NH group subjects need a support system to convince them of the risks of attempting suicide and to take a problem-solving approach to specific issues.
PMCID: PMC2821663  PMID: 20064269
13.  Footprint Analysis of the RAG Protein Recombination Signal Sequence Complex for V(D)J Type Recombination 
Molecular and Cellular Biology  1998;18(1):655-663.
We have studied the interaction between recombination signal sequences (RSSs) and protein products of the truncated forms of recombination-activating genes (RAG) by gel mobility shift, DNase I footprinting, and methylation interference assays. Methylation interference with dimethyl sulfate demonstrated that binding was blocked by methylation in the nonamer at the second-position G residue in the bottom strand and at the sixth- and seventh-position A residues in the top strand. DNase I footprinting experiments demonstrated that RAG1 alone, or even a RAG1 homeodomain peptide, gave footprint patterns very similar to those obtained with the RAG1-RAG2 complex. In the heptamer, partial methylation interference was observed at the sixth-position A residue in the bottom strand. In DNase I footprinting, the heptamer region was weakly protected in the bottom strand by RAG1. The effects of RSS mutations on RAG binding were evaluated by DNA footprinting. Comparison of the RAG-RSS footprint data with the published Hin model confirmed the notion that sequence-specific RSS-RAG interaction takes place primarily between the Hin domain of the RAG1 protein and adjacent major and minor grooves of the nonamer DNA.
PMCID: PMC121532  PMID: 9418911
14.  Photodynamic Therapy for Head and Neck Cancer 
Photodynamic therapy (PDT) is a recently developed treatment involving the use of a photosensitizer and low power light, usually from a laser, to selectively destroy tumor cells. At present, we perform PDT for head and neck cancer using argon or excimer dye lasers with hematoporphyrin derivative as a photosensitizer. This study attempted to assess the utility and safety of PDT and to investigate the long-term outcome. All 24 patients had squamous cell carcinoma: 15 with laryngeal, 5 with lingual or oral, and 4 with pharyngeal cancer and were treated by PDT. Data were obtained from records from February 1988 through April 1995. After PDT, 12 of 15 laryngeal cancer patients were classified as having a complete remission (CR), as were 2 of the 5 lingual or oral and one of the 4 pharyngeal cancer patients. The patients were followed for 8 to 153 months. The longest duration of CR in patients treated by PDT alone was 148 months. Photosensitivity was experienced by all patients, but required no treatment. Liver, kidneys, and bone marrow showed no abnormal values. There were no clinically relevant adverse reactions, and patients with severe complications due to other types of treatment and elderly patients were also treated safely with this therapy.
PMCID: PMC2362549  PMID: 18493416

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