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1.  Serum zinc value in patients with hepatitis virus-related chronic liver disease: association with the histological degree of liver fibrosis and with the severity of varices in compensated cirrhosis 
The relationships between the serum mineral concentrations and the endoscopic findings of esophageal varices have been poorly investigated. In this study, we investigated hepatitis virus-positive patients who had undergone a liver biopsy (n = 576) and 75 patients with compensated cirrhosis in order to evaluate the association of the zinc value with the severity of liver fibrosis and esophageal varices. The mean zinc values decreased with the progression of fibrosis (METAVIR score; F0–1: 71.3 ± 11.3, F2: 68.9 ± 11.7, F3: 66.3 ± 11.8, F4: 63.9 ± 15.0). In the hepatitis virus-related compensated cirrhosis, the mean zinc value decreased with the severity of varices (patients without varices: 66.3 ± 12.6, patients with low-risk varices: 62.5 ± 13.7, patients with high-risk varices: 55.6 ± 13.0). The zinc value was significantly lower in patients with varices than in those without varices (59.3 ± 13.6 vs 66.3 ± 12.6, p<0.05). The zinc value was also significantly lower in the patients with a high risk of bleeding than in those with a low risk (55.6 ± 13.0 vs 64.6 ± 13.1, p<0.01). These findings suggest that the zinc value is not only an indicator of an abnormal metal metabolism, but is also a simple parameter associated with hepatitis virus-related various conditions, including the degree of liver fibrosis and the severity of esophageal varices in compensated cirrhosis.
PMCID: PMC4186381  PMID: 25320463
liver cirrhosis; zinc; esophageal varices; biomarker; metabolism
2.  An Increased Ratio of Glycated Albumin to HbA1c Is Associated with the Degree of Liver Fibrosis in Hepatitis B Virus-Positive Patients 
Background. In hepatitis B virus- (HBV-) positive patients, the relationship between the metabolic variables and histological degree of liver fibrosis has been poorly investigated. Methods. A total of 176 HBV-positive patients were assessed in whom the ratios of glycated albumin-to-glycated hemoglobin (GA/HbA1c) were calculated in order to investigate the relationship with the degree of liver fibrosis. Results. The GA/HbA1c ratio increased in association with the severity of fibrosis (METAVIR scores: F0-1: 2.61 ± 0.24, F2: 2.65 ± 0.24, F3: 2.74 ± 0.38, and F4: 2.91 ± 0.63). The GA/HbA1c ratios were inversely correlated with four variables of liver function: the prothrombin time (PT) percentage (P < 0.0001), platelet count (P < 0.0001), albumin value (P < 0.0001), and cholinesterase value (P < 0.0001). The GA/HbA1c ratio was positively correlated with two well-known markers of liver fibrosis, FIB-4 (P < 0.0001) and the AST-to-platelet ratio index (APRI) (P < 0.0001). Furthermore, the GA/HbA1c showed better correlations with two variables of liver function (PT percentage and cholinesterase value) than did FIB-4 and with all four variables than did the APRI. Conclusion. The GA/HbA1c ratio is associated with the degree of liver fibrosis in HBV-positive patients.
PMCID: PMC3947677  PMID: 24693282
3.  Thrombocytopenia in pegylated interferon and ribavirin combination therapy for chronic hepatitis C 
Journal of Gastroenterology  2013;49(8):1253-1263.
This study aimed to examine the therapeutic effect and prognostic indicators of pegylated interferon (PEG-IFN) and ribavirin (RBV) combination therapy in thrombocytopenic patients with chronic hepatitis C, hepatitis C virus (HCV)-related cirrhosis, and those who underwent splenectomy or partial splenic embolization (PSE).
Of 326 patients with HCV-related chronic liver disease (252 with genotype 1b and 74 with genotype 2a/2b) treated with PEG-IFN/RBV, 90 were diagnosed with cirrhosis.
Regardless of the degree of thrombocytopenia, the administration rate was significantly higher in the splenectomy/PSE group compared to the cirrhosis group. However, in patients with genotype 1b, the sustained virological response (SVR) rate was significantly lower in the cirrhosis and the splenectomy/PSE groups compared to the chronic hepatitis group. No cirrhotic patients with platelets less than 80,000 achieved an SVR. Patients with genotype 2a/2b were more likely to achieve an SVR than genotype 1b. Prognostic factors for SVR in patients with genotype 1b included the absence of esophageal and gastric varices, high serum ALT, low AST/ALT ratio, and the major homo type of the IL28B gene. Splenectomy- or PSE-facilitated induction of IFN in patients with genotype 2a/2b was more likely to achieve an SVR by an IFN dose maintenance regimen. Patients with genotype 1b have a low SVR regardless of splenectomy/PSE. In particular, patients with a hetero/minor type of IL28B did not have an SVR.
Splenectomy/PSE for IFN therapy should be performed in patients expected to achieve a treatment response, considering their genotype and IL28B.
PMCID: PMC4124258  PMID: 24065124
IFN therapy; IL28B; Partial splenic embolization; Splenectomy; Thrombocytopenia
4.  Serum levels of soluble platelet endothelial cell adhesion molecule-1 and vascular cell adhesion molecule-1 are decreased in subjects with autism spectrum disorder 
Molecular Autism  2013;4:19.
Adhesion molecules, such as platelet-endothelial adhesion molecule-1 (PECAM-1), platelet selectin (P-selectin), endothelial selectin (E-selectin), intracellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1), are localized on the membranes of activated platelets and leukocytes and on the vascular endothelium. Recently, we measured serum levels of soluble (s) forms of adhesion molecules in adults,18 to 26 years old, with autism spectrum disorder (ASD) and observed low levels of sPECAM-1 and sP-selectin. A subsequent study showed a similar result in children two to four years old with ASD. However, information about school age (five to seventeen years old) ASD subjects is required to determine whether adhesion molecules are also reduced in individuals with ASD in this age range.
Twenty-two subjects with high-functioning ASD and 29 healthy age-matched controls were recruited. ELISA was used for sPECAM-1, and a suspension array system was used for sP-selectin, sE-selectin, sICAM-1 and sVCAM-1 measurements. We found that serum levels of sPECAM-1 (U = 91.0, P<0.0001 by Mann–Whitney U test) and sVCAM-1 (U = 168.0, P = 0.0042) were significantly lower in ASD subjects than in controls. Subsequently, we examined the correlations between serum levels of either sPECAM-1 or sVCAM-1 and clinical variables including Autism Diagnostic Interview - Revised subscores and our previous cytokine profile data from the same ASD subjects. However, we did not find any significant correlations between them.
The present results, taken together with previous results, suggest that sPECAM-1 may play a role in the generation and development of ASD, beginning in childhood and lasting until adulthood.
PMCID: PMC3695876  PMID: 23773279
Autism; Human serum; Adhesion molecules; Platelet-endothelial adhesion molecule-1; Platelet selectin; Endothelial selectin; Intracellular adhesion molecule-1; Vascular cell adhesion molecule-1
5.  Enzymes in the glutamate-glutamine cycle in the anterior cingulate cortex in postmortem brain of subjects with autism 
Molecular Autism  2013;4:6.
Accumulating evidence suggests that dysfunction in the glutamatergic system may underlie the pathophysiology of autism. The anterior cingulate cortex (ACC) has been implicated in autism as well as in glutamatergic neurotransmission. We hypothesized that alterations in the glutamate-glutamine cycle in the ACC might play a role in the pathophysiology of autism.
We performed Western blot analyses for the protein expression levels of enzymes in the glutamate-glutamine cycle, including glutamine synthetase, kidney-type glutaminase, liver-type glutaminase, and glutamate dehydrogenases 1 and 2, in the ACC of postmortem brain of individuals with autism (n = 7) and control subjects (n = 13).
We found that the protein levels of kidney-type glutaminase, but not those of the other enzymes measured, in the ACC were significantly lower in subjects with autism than in controls.
The results suggest that reduced expression of kidney-type glutaminase may account for putative alterations in glutamatergic neurotransmission in the ACC in autism.
PMCID: PMC3621600  PMID: 23531457
Autism; Glutamate; Glutaminase; Glutamate-glutamine cycle; Anterior cingulate cortex
6.  Vldlr overexpression causes hyperactivity in rats 
Molecular Autism  2012;3:11.
Reelin regulates neuronal positioning in cortical brain structures and neuronal migration via binding to the lipoprotein receptors Vldlr and Lrp8. Reeler mutant mice display severe brain morphological defects and behavioral abnormalities. Several reports have implicated reelin signaling in the etiology of neurodevelopmental and psychiatric disorders, including autism, schizophrenia, bipolar disorder, and depression. Moreover, it has been reported that VLDLR mRNA levels are increased in the post-mortem brain of autistic patients.
We generated transgenic (Tg) rats overexpressing Vldlr, and examined their histological and behavioral features.
Spontaneous locomotor activity was significantly increased in Tg rats, without detectable changes in brain histology. Additionally, Tg rats tended to show performance deficits in the radial maze task, suggesting that their spatial working memory was slightly impaired. Thus, Vldlr levels may be involved in determining locomotor activity and memory function.
Unlike reeler mice, patients with neurodevelopmental or psychiatric disorders do not show striking neuroanatomical aberrations. Therefore, it is notable, from a clinical point of view, that we observed behavioral phenotypes in Vldlr-Tg rats in the absence of neuroanatomical abnormalities.
PMCID: PMC3533969  PMID: 23110844
Hyperactivity; Neurodevelopmental disorder; Psychiatric disorder; Reelin; Transgenic rat; Vldlr
7.  Investigation of the serum levels of anterior pituitary hormones in male children with autism 
Molecular Autism  2011;2:16.
The neurobiological basis of autism remains poorly understood. The diagnosis of autism is based solely on behavioural characteristics because there are currently no reliable biological markers. To test whether the anterior pituitary hormones and cortisol could be useful as biological markers for autism, we assessed the basal serum levels of these hormones in subjects with autism and normal controls.
Using a suspension array system, we determined the serum levels of six anterior pituitary hormones, including adrenocorticotropic hormone and growth hormone, in 32 drug-naive subjects (aged 6 to 18 years, all boys) with autism, and 34 healthy controls matched for age and gender. We also determined cortisol levels in these subjects by enzyme-linked immunosorbent assay. Serum levels of adrenocorticotropic hormone, growth hormone and cortisol were significantly higher in subjects with autism than in controls. In addition, there was a significantly positive correlation between cortisol and adrenocorticotropic hormone levels in autism.
Our results suggest that increased basal serum levels of adrenocorticotropic hormone accompanied by increased cortisol and growth hormone may be useful biological markers for autism.
PMCID: PMC3215952  PMID: 22011527
8.  Association of Transcription Factor Gene LMX1B with Autism 
PLoS ONE  2011;6(8):e23738.
Multiple lines of evidence suggest a serotoninergic dysfunction in autism. The role of LMX1B in the development and maintenance of serotoninergic neurons is well known. In order to examine the role, if any, of LMX1B with autism pathophysiology, a trio-based SNP association study using 252 family samples from the AGRE was performed. Using pair-wise tagging method, 24 SNPs were selected from the HapMap data, based on their location and minor allele frequency. Two SNPs (rs10732392 and rs12336217) showed moderate association with autism with p values 0.018 and 0.022 respectively in transmission disequilibrium test. The haplotype AGCGTG also showed significant association (p = 0.008). Further, LMX1B mRNA expressions were studied in the postmortem brain tissues of autism subjects and healthy controls samples. LMX1B transcripts was found to be significantly lower in the anterior cingulate gyrus region of autism patients compared with controls (p = 0.049). Our study suggests a possible role of LMX1B in the pathophysiology of autism. Based on previous reports, it is likely to be mediated through a seretoninergic mechanism. This is the first report on the association of LMX1B with autism, though it should be viewed with some caution considering the modest associations we report.
PMCID: PMC3162001  PMID: 21901133
9.  Decreased expression of axon-guidance receptors in the anterior cingulate cortex in autism 
Molecular Autism  2011;2:14.
Axon-guidance proteins play a crucial role in brain development. As the dysfunction of axon-guidance signaling is thought to underlie the microstructural abnormalities of the brain in people with autism, we examined the postmortem brains of people with autism to identify any changes in the expression of axon-guidance proteins.
The mRNA and protein expression of axon-guidance proteins, including ephrin (EFN)A4, eEFNB3, plexin (PLXN)A4, roundabout 2 (ROBO)2 and ROBO3, were examined in the anterior cingulate cortex and primary motor cortex of autistic brains (n = 8 and n = 7, respectively) and control brains (n = 13 and n = 8, respectively) using real-time reverse-transcriptase PCR (RT-PCR) and western blotting. Real-time RT-PCR revealed that the relative expression levels of EFNB3, PLXNA4A and ROBO2 were significantly lower in the autistic group than in the control group. The protein levels of these three genes were further analyzed by western blotting, which showed that the immunoreactive values for PLXNA4 and ROBO2, but not for EFNB3, were significantly reduced in the ACC of the autistic brains compared with control brains.
In this study, we found decreased expression of axon-guidance proteins such as PLXNA4 and ROBO2 in the brains of people with autism, and suggest that dysfunctional axon-guidance protein expression may play an important role in the pathophysiology of autism.
PMCID: PMC3177773  PMID: 21859478
10.  Plasma Cytokine Profiles in Subjects with High-Functioning Autism Spectrum Disorders 
PLoS ONE  2011;6(5):e20470.
Accumulating evidence suggests that dysregulation of the immune system is involved in the pathophysiology of autism spectrum disorders (ASD). The aim of the study was to explore immunological markers in peripheral plasma samples from non-medicated subjects with high-functioning ASD.
Methodology/Principal Findings
A multiplex assay for cytokines and chemokines was applied to plasma samples from male subjects with high-functioning ASD (n = 28) and matched controls (n = 28). Among a total of 48 analytes examined, the plasma concentrations of IL-1β, IL-1RA, IL-5, IL-8, IL-12(p70), IL-13, IL-17 and GRO-α were significantly higher in subjects with ASD compared with the corresponding values of matched controls after correction for multiple comparisons.
The results suggest that abnormal immune responses as assessed by multiplex analysis of cytokines may serve as one of the biological trait markers for ASD.
PMCID: PMC3103577  PMID: 21647375
11.  Utility of Subjective Sleep Assessment Tools for Healthy Preschool Children: A Comparative Study Between Sleep Logs, Questionnaires, and Actigraphy 
Journal of Epidemiology  2010;20(2):143-149.
Sleep pattern is an important factor in a child’s mental, behavioural and physical status. To evaluate the sleep patterns of children, subjective tools such as sleep logs and questionnaires are still widely used in addition to objective methods of sleep assessment. Despite the established correlation between subjective and objective sleep variables, the characteristic features of subjective assessment have not been elucidated.
To investigate the characteristics of parental sleep assessment (daily sleep log and brief questionnaire) in preschool children, a 7-day actigraphic sleep study was conducted in 48 healthy 5-year-old children.
Sleep schedule variables in the parental reports generally correlated well with actigraphic assessment of sleep patterns; however, sleep periods were longer in parental reports than in actigraphic recordings. Although the daily sleep log was better correlated with actigraphy, the brief questionnaire showed a good correlation with sleep pattern on weekday actigraphic assessments. Parental reports recorded fewer than 10% of the night wakings recorded by actigraphy.
Subjective sleep assessments remain useful, although their utility depends on the purpose and size of the study in question. However, knowledge of the potential biases and characteristics of such assessments is essential for correct interpretation of the data.
PMCID: PMC3900813  PMID: 20139658
actigraphy; sleep log; questionnaire; preschool child; sleep pattern; subjective sleep assessment; parental report
12.  Destruction of Dopaminergic Neurons in the Midbrain by 6-Hydroxydopamine Decreases Hippocampal Cell Proliferation in Rats: Reversal by Fluoxetine 
PLoS ONE  2010;5(2):e9260.
Non-motor symptoms (e.g., depression, anxiety, and cognitive deficits) in patients with Parkinson disease (PD) precede the onset of the motor symptoms. Although these symptoms do not respond to pharmacological dopamine replacement therapy, their precise pathological mechanisms are currently unclear. The present study was undertaken to examine whether the unilateral 6-hydroxydopamine (6-OHDA) lesion to the substantia nigra pars compacta (SNc), which represents a model of long-term dopaminergic neurotoxicity, could affect cell proliferation in the adult rat brain. Furthermore, we examined the effects of the selective serotonin reuptake inhibitor (SSRI) fluoxetine and the selective noradrenaline reuptake inhibitor maprotiline on the reduction in cell proliferation in the subgranular zone (SGZ) by the unilateral 6-OHDA lesion.
Methodology/Principal Findings
A single unilateral injection of 6-OHDA into the rat SNc resulted in an almost complete loss of tyrosine hydroxylase (TH) immunoreactivity in the striatum and SNc, as well as in reductions of TH-positive cells and fibers in the ventral tegmental area (VTA). On the other hand, an injection of vehicle alone showed no overt change in TH immunoreactivity. A unilateral 6-OHDA lesion to SNc significantly decreased cell proliferation in the SGZ ipsilateral to the 6-OHDA lesion, but not in the contralateral SGZ or the subventricular zone (SVZ), of rats. Furthermore, subchronic (14 days) administration of fluoxetine (5 mg/kg/day), but not maprotiline significantly attenuated the reduction in cell proliferation in the SGZ by unilateral 6-OHDA lesion.
The present study suggests that cell proliferation in the SGZ of the dentate gyrus might be, in part, under dopaminergic control by SNc and VTA, and that subchronic administration of fluoxetine reversed the reduction in cell proliferation in the SGZ by 6-OHDA. Therefore, SSRIs such as fluoxetine might be potential therapeutic drugs for non-motor symptoms as well as motor symptoms in patients with PD, which might be associated with the reduction in cell proliferation in the SGZ.
PMCID: PMC2822849  PMID: 20174647
13.  Crystal structure of A3B3 complex of V-ATPase from Thermus thermophilus 
The EMBO Journal  2009;28(23):3771-3779.
Vacuolar-type ATPases (V-ATPases) exist in various cellular membranes of many organisms to regulate physiological processes by controlling the acidic environment. Here, we have determined the crystal structure of the A3B3 subcomplex of V-ATPase at 2.8 Å resolution. The overall construction of the A3B3 subcomplex is significantly different from that of the α3β3 sub-domain in FoF1-ATP synthase, because of the presence of a protruding ‘bulge' domain feature in the catalytic A subunits. The A3B3 subcomplex structure provides the first molecular insight at the catalytic and non-catalytic interfaces, which was not possible in the structures of the separate subunits alone. Specifically, in the non-catalytic interface, the B subunit seems to be incapable of binding ATP, which is a marked difference from the situation indicated by the structure of the FoF1-ATP synthase. In the catalytic interface, our mutational analysis, on the basis of the A3B3 structure, has highlighted the presence of a cluster composed of key hydrophobic residues, which are essential for ATP hydrolysis by V-ATPases.
PMCID: PMC2775895  PMID: 19893485
crystal structure; FoF1; proton pump; rotary motor; V-ATPase
14.  Perinatal Asphyxia Reduces Dentate Granule Cells and Exacerbates Methamphetamine-Induced Hyperlocomotion in Adulthood 
PLoS ONE  2008;3(11):e3648.
Obstetric complications have been regarded as a risk factor for schizophrenia later in life. One of the mechanisms underlying the association is postulated to be a hypoxic process in the brain in the offspring around the time of birth. Hippocampus is one of the brain regions implicated in the late-onset dopaminergic dysfunction associated with hypoxic obstetric complications.
Methodology/Principal Findings
We used an animal model of perinatal asphyxia, in which rat pups were exposed to 15 min of intrauterine anoxia during Cesarean section birth. At 6 and 12 weeks after birth, the behavior of the pups was assessed using a methamphetamine-induced locomotion test. In addition, the histopathology of the hippocampus was examined by means of stereology. At 6 weeks, there was no change in the methamphetamine-induced locomotion. However, at 12 weeks of age, we found an elevation in methamphetamine-induced locomotor activity, which was associated with an increase of dopamine release in the nucleus accumbens. At the same age, we also found a reduction of the dentate granule cells of the hippocampus.
These results suggest that the dopaminergic dysregulation after perinatal asphyxia is associated with a reduction in hippocampal dentate granule cells, and this may partly contribute to the pathogenesis of schizophrenia.
PMCID: PMC2572851  PMID: 18985150
15.  Molecular mechanism of ligand recognition by membrane transport protein, Mhp1 
The EMBO Journal  2014;33(16):1831-1844.
The hydantoin transporter Mhp1 is a sodium-coupled secondary active transport protein of the nucleobase-cation-symport family and a member of the widespread 5-helix inverted repeat superfamily of transporters. The structure of Mhp1 was previously solved in three different conformations providing insight into the molecular basis of the alternating access mechanism. Here, we elucidate detailed events of substrate binding, through a combination of crystallography, molecular dynamics, site-directed mutagenesis, biochemical/biophysical assays, and the design and synthesis of novel ligands. We show precisely where 5-substituted hydantoin substrates bind in an extended configuration at the interface of the bundle and hash domains. They are recognised through hydrogen bonds to the hydantoin moiety and the complementarity of the 5-substituent for a hydrophobic pocket in the protein. Furthermore, we describe a novel structure of an intermediate state of the protein with the external thin gate locked open by an inhibitor, 5-(2-naphthylmethyl)-L-hydantoin, which becomes a substrate when leucine 363 is changed to an alanine. We deduce the molecular events that underlie acquisition and transport of a ligand by Mhp1.
PMCID: PMC4195764  PMID: 24952894
five helix inverted repeat superfamily; hydantoin; membrane transport; Mhp1; molecular recognition; nucleobase-cation-symport, NCS1, family
16.  FGF receptor genes and breast cancer susceptibility: results from the Breast Cancer Association Consortium 
Agarwal, D | Pineda, S | Michailidou, K | Herranz, J | Pita, G | Moreno, L T | Alonso, M R | Dennis, J | Wang, Q | Bolla, M K | Meyer, K B | Menéndez-Rodríguez, P | Hardisson, D | Mendiola, M | González-Neira, A | Lindblom, A | Margolin, S | Swerdlow, A | Ashworth, A | Orr, N | Jones, M | Matsuo, K | Ito, H | Iwata, H | Kondo, N | Hartman, M | Hui, M | Lim, W Y | T-C Iau, P | Sawyer, E | Tomlinson, I | Kerin, M | Miller, N | Kang, D | Choi, J-Y | Park, S K | Noh, D-Y | Hopper, J L | Schmidt, D F | Makalic, E | Southey, M C | Teo, S H | Yip, C H | Sivanandan, K | Tay, W-T | Brauch, H | Brüning, T | Hamann, U | Dunning, A M | Shah, M | Andrulis, I L | Knight, J A | Glendon, G | Tchatchou, S | Schmidt, M K | Broeks, A | Rosenberg, E H | van't Veer, L J | Fasching, P A | Renner, S P | Ekici, A B | Beckmann, M W | Shen, C-Y | Hsiung, C-N | Yu, J-C | Hou, M-F | Blot, W | Cai, Q | Wu, A H | Tseng, C-C | Van Den Berg, D | Stram, D O | Cox, A | Brock, I W | Reed, M W R | Muir, K | Lophatananon, A | Stewart-Brown, S | Siriwanarangsan, P | Zheng, W | Deming-Halverson, S | Shrubsole, M J | Long, J | Shu, X-O | Lu, W | Gao, Y-T | Zhang, B | Radice, P | Peterlongo, P | Manoukian, S | Mariette, F | Sangrajrang, S | McKay, J | Couch, F J | Toland, A E | Yannoukakos, D | Fletcher, O | Johnson, N | Silva, I dos Santos | Peto, J | Marme, F | Burwinkel, B | Guénel, P | Truong, T | Sanchez, M | Mulot, C | Bojesen, S E | Nordestgaard, B G | Flyer, H | Brenner, H | Dieffenbach, A K | Arndt, V | Stegmaier, C | Mannermaa, A | Kataja, V | Kosma, V-M | Hartikainen, J M | Lambrechts, D | Yesilyurt, B T | Floris, G | Leunen, K | Chang-Claude, J | Rudolph, A | Seibold, P | Flesch-Janys, D | Wang, X | Olson, J E | Vachon, C | Purrington, K | Giles, G G | Severi, G | Baglietto, L | Haiman, C A | Henderson, B E | Schumacher, F | Le Marchand, L | Simard, J | Dumont, M | Goldberg, M S | Labrèche, F | Winqvist, R | Pylkäs, K | Jukkola-Vuorinen, A | Grip, M | Devilee, P | Tollenaar, R A E M | Seynaeve, C | García-Closas, M | Chanock, S J | Lissowska, J | Figueroa, J D | Czene, K | Eriksson, M | Humphreys, K | Darabi, H | Hooning, M J | Kriege, M | Collée, J M | Tilanus-Linthorst, M | Li, J | Jakubowska, A | Lubinski, J | Jaworska-Bieniek, K | Durda, K | Nevanlinna, H | Muranen, T A | Aittomäki, K | Blomqvist, C | Bogdanova, N | Dörk, T | Hall, P | Chenevix-Trench, G | Easton, D F | Pharoah, P D P | Arias-Perez, J I | Zamora, P | Benítez, J | Milne, R L
British Journal of Cancer  2014;110(4):1088-1100.
Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium.
Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression.
Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95% confidence interval=1.02–1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2.
Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2.
PMCID: PMC3929867  PMID: 24548884
breast cancer; SNP; FGF receptors; susceptibility; disease subtypes
17.  Key Dynamics of Conserved Asparagine in a Cryptochrome/Photolyase Family Protein by FTIR Spectroscopy† 
Biochemistry  2010;49(41):8882-8891.
Cryptochromes (Crys) and photolyases (Phrs) are flavoproteins that contain an identical cofactor (flavin adenine dinucleotide, FAD) within the same protein architecture, but whose physiological functions are entirely different. In this study, we investigated light-induced conformational changes of a cyanobacterium Cry/Phr-like protein (SCry-DASH) with UV–visible and Fourier transform infrared (FTIR) spectroscopy. We developed a system to measure light-induced difference spectra under the concentrated conditions. In the presence of reducing agent, SCry-DASH showed photoreduction to the reduced form, and we identified a signal unique for an anionic form in the process. Difference FTIR spectra enabled us to assign characteristic FTIR bands to the respective redox forms of FAD. An asparagine residue, which anchors the FAD embedded within the protein is conserved in not only the cyanobaterial protein, but also in Phrs and other Crys including the mammalian clock-related Crys. By characterizing an asparagine-to-cysteine (N392C) mutant of SCry-DASH, which mimics an insect specific Cry, we identified structural changes of the carbonyl group of this conserved asparagine upon light-irradiation. We also found that the N392C mutant is stabilized in the anionic form. We did not observe a signal from protonated carboxylic acid residues during the reduction process, suggesting that the carboxylic acid moiety would not be directly involved as a proton donor to FAD in the system. These results are in contrast to plant specific Crys represented by Arabidopsis thaliana Cry1 which carry Asp at the position. We discuss potential roles for this conserved asparagine position and functional diversity in the Cry/Phr frame.
PMCID: PMC4329311  PMID: 20828134
18.  FTIR Study of the Photoactivation Process of Xenopus (6-4) Photolyase† 
Biochemistry  2012;51(29):5774-5783.
Photolyases (PHRs) are blue-light activated DNA repair enzymes that maintain genetic integrity by reverting UV-induced photoproducts into normal bases. The FAD chromophore of PHRs has four different redox states: oxidized (FADox), anion radical (FAD•−), neutral radical (FADH•) and fully reduced (FADH−). We combined difference Fourier-transform infrared (FTIR) spectroscopy with UV-visible spectroscopy to study the detailed photoactivation process of Xenopus (6-4) PHR. Two photons produce the enzymatically active, fully reduced PHR from oxidized FAD: FADox is converted to semiquinone via light-induced one-electron and one-proton transfers, and then to FADH− by light-induced one-electron transfer. We successfully trapped FAD•− at 200 K, where electron transfer occurs, but proton transfer does not. UV-visible spectroscopy following 450-nm illumination of FADox at 277 K defined the FADH•/FADH− mixture and allowed calculation of difference FTIR spectra among the four redox states. The absence of a characteristic C=O stretching vibration indicated that the proton donor is not a protonated carboxylic acid. Structural changes in Trp and Tyr are suggested from UV-visible and FTIR analysis of FAD•− at 200 K. Spectral analysis of amide-I vibrations revealed structural perturbation of the protein’s β-sheet during initial electron transfer (FAD•− formation), transient increase in α-helicity during proton transfer (FADH• formation) and reversion to the initial amide-I signal following subsequent electron transfer (FADH− formation). Consequently, in (6-4) PHR, unlike cryptochrome-DASH, formation of enzymatically active FADH− did not perturb α-helicity. Protein structural changes in the photoactivation of (6-4) PHR are discussed on the basis of the present FTIR observations.
PMCID: PMC4329314  PMID: 22747528
19.  An unusual cause of spontaneous bacterial peritonitis due to Campylobacter fetus with alcoholic liver cirrhosis 
BMJ Case Reports  2013;2013:bcr2012008406.
A 40-year-old man with severe alcoholic liver cirrhosis with a 2-day history of fatigue and abdominal pain was admitted. He reported eating sushi and sliced raw chicken a few days previously. His abdomen was distended, with shifting dullness. Based on the patient's history, physical examination and the results of abdominocentesis, he was diagnosed as having spontaneous bacterial peritonitis; blood and ascitic fluid cultures were positive for Campylobacter fetus. The patient was started on treatment with cefotaxime, which was switched after 1 week to ampicillin for an additional 3 weeks. The patient was successfully treated with the 4-week course of intravenous antibiotic therapy.
PMCID: PMC3603790  PMID: 23417384
20.  Spatiotemporal abnormality dynamics of the pale grass blue butterfly: three years of monitoring (2011–2013) after the Fukushima nuclear accident 
Long-term monitoring of the biological impacts of the radioactive pollution caused by the Fukushima nuclear accident in March 2011 is required to understand what has occurred in organisms living in the polluted areas. Here, we investigated spatial and temporal changes of the abnormality rate (AR) in both field-caught adult populations and laboratory-reared offspring populations of the pale grass blue butterfly, Zizeeria maha, which has generation time of approximately one month. We monitored 7 localities (Fukushima, Motomiya, Hirono, Iwaki, Takahagi, Mito, and Tsukuba) every spring and fall over 3 years (2011–2013).
The adult ARs of these localities quickly increased and peaked in the fall of 2011, which was not observed in non-contaminated localities. In the offspring generation, the total ARs, which include deaths at the larval, prepupal, and pupal stages and morphological abnormalities at the adult stage, peaked either in the fall of 2011 or in the spring of 2012, with much higher levels than those of the parent field populations, suggesting that high incidence of deaths and abnormalities might have occurred in the field populations. Importantly, the elevated ARs of the field and offspring populations settled back to a normal level by the fall of 2012 and by the spring of 2013, respectively. Similar results were obtained not only in the spatiotemporal dynamics of the number of individuals caught per minute but also in the temporal dynamics of the correlation coefficient between the adult abnormality rate and the ground radiation dose or the distance from the Power Plant.
These results demonstrated an occurrence and an accumulation of adverse physiological and genetic effects in early generations, followed by their decrease and leveling off at a normal level, providing the most comprehensive record of biological dynamics after a nuclear accident available today. This study also indicates the importance of considering generation time and adaptive evolution in evaluating the biological impacts of artificial pollution in wild organisms.
Electronic supplementary material
The online version of this article (doi:10.1186/s12862-015-0297-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4335452
Adaptive evolution; Fukushima nuclear accident; Long-term monitoring; Pale grass blue butterfly; Radioactive contamination
21.  Pertussis outbreak in university students and evaluation of acellular pertussis vaccine effectiveness in Japan 
Recent studies worldwide have reported increasing numbers of adults diagnosed with Bordetella pertussis despite receiving childhood vaccinations. This study describes a pertussis outbreak at a university medical faculty campus and examines the effectiveness of diphtheria, tetanus, and pertussis (DTaP) vaccination completed during infancy in Japan.
After the outbreak, self-administered questionnaires and serum samples were collected from students on campus to determine the incidence of pertussis and underlying diseases. Pertussis was diagnosed on the basis of clinical criteria and serum anti-pertussis toxin antibody levels. Using data collected from 248 first and second grade students who had submitted copies of their vaccination records, we evaluated the effectiveness of DTaP vaccination in infancy against adult pertussis.
Questionnaire responses were obtained from 636 students (of 671 registered students; 95% response rate). Of 245 students who reported a continuous cough during the outbreak period, 84 (attack rate: 13.2%) were considered “probable” pertussis cases that met clinical criteria. The outbreak occurred mainly in first and second grade students in the Faculty of Medicine. Of 248 students who provided vaccination records, 225 had received 4 DTaP doses (coverage: 90.7%); the relative risk of the complete vaccination series compared to those with fewer than 4 doses or no doses for probable cases was 0.48 (95% confidence interval: 0.24-0.97).
Waning protection was suspected due to over time. Booster vaccination for teenagers and development of highly efficacious pertussis vaccines are needed.
Electronic supplementary material
The online version of this article (doi:10.1186/s12879-015-0777-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4323135  PMID: 25656486
Pertussis; Outbreak; Vaccine effectiveness
22.  Septic thrombophlebitis of the superior mesenteric vein with bacteraemia caused by Bacteroides fragilis and Streptococcus intermedius as a complication of diverculitis 
BMJ Case Reports  2013;2013:bcr2013008661.
A 68-year-old Japanese man with alcoholic liver cirrhosis was admitted to our hospital because of fever and haematemesis. On day 3, his blood culture became positive for Gram-negative bacilli and Gram-positive cocci, and contrast-enhanced abdominal CT revealed acute septic thrombophlebitis of the superior mesenteric vein with caecal diverculitis. Antimicrobial therapy with ampicillin–sulbactam and anticoagulant therapy were started and the blood culture grew Bacteroides fragilis and Streptococcus intermedius. On hospital day 7, the patient's condition began to improve in response to the therapy, therefore, the ampicillin–sulbactam and anticoagulant therapy was continued for 42 days. The patient was discharged home on hospital day 45. B fragilis bacteraemia of unknown source should caution the physician to search for an intra-abdominal focus, such as thrombosis of the portal vein or mesenteric vein.
PMCID: PMC3604454  PMID: 23389727
23.  Identification of an Interaction between VWF rs7965413 and Platelet Count as a Novel Risk Marker for Metabolic Syndrome: An Extensive Search of Candidate Polymorphisms in a Case-Control Study 
PLoS ONE  2015;10(2):e0117591.
Although many single nucleotide polymorphisms (SNPs) have been identified to be associated with metabolic syndrome (MetS), there was only a slight improvement in the ability to predict future MetS by the simply addition of SNPs to clinical risk markers. To improve the ability to predict future MetS, combinational effects, such as SNP—SNP interaction, SNP—environment interaction, and SNP—clinical parameter (SNP × CP) interaction should be also considered. We performed a case-control study to explore novel SNP × CP interactions as risk markers for MetS based on health check-up data of Japanese male employees. We selected 99 SNPs that were previously reported to be associated with MetS and components of MetS; subsequently, we genotyped these SNPs from 360 cases and 1983 control subjects. First, we performed logistic regression analyses to assess the association of each SNP with MetS. Of these SNPs, five SNPs were significantly associated with MetS (P < 0.05): LRP2 rs2544390, rs1800592 between UCP1 and TBC1D9, APOA5 rs662799, VWF rs7965413, and rs1411766 between MYO16 and IRS2. Furthermore, we performed multiple logistic regression analyses, including an SNP term, a CP term, and an SNP × CP interaction term for each CP and SNP that was significantly associated with MetS. We identified a novel SNP × CP interaction between rs7965413 and platelet count that was significantly associated with MetS [SNP term: odds ratio (OR) = 0.78, P = 0.004; SNP × CP interaction term: OR = 1.33, P = 0.001]. This association of the SNP × CP interaction with MetS remained nominally significant in multiple logistic regression analysis after adjustment for either the number of MetS components or MetS components excluding obesity. Our results reveal new insight into platelet count as a risk marker for MetS.
PMCID: PMC4315519  PMID: 25646961
24.  Genome-wide association analysis in East Asians identifies breast cancer susceptibility loci at 1q32.1, 5q14.3 and 15q26.1 
Nature genetics  2014;46(8):886-890.
In a three-stage genome-wide association study among East Asian women including 22,780 cases and 24,181 controls, we identified three novel genetic loci associated with breast cancer risk, including rs4951011 at 1q32.1 (in intron 2 of the ZC3H11A gene, P = 8.82 × 10−9), rs10474352 at 5q14.3 (near the ARRDC3 gene, P = 1.67 × 10−9), and rs2290203 at 15q26.1 (in intron 14 of the PRC1 gene, P = 4.25 × 10−8). These associations were replicated in European-ancestry populations including 16,003 cases and 41,335 controls (P = 0.030, 0.004, and 0.010, respectively). Data from the ENCODE project suggest that variants rs4951011 and rs10474352 may be located in an enhancer region and transcription factor binding sites, respectively. This study provides additional insights into the genetics and biology of breast cancer.
PMCID: PMC4127632  PMID: 25038754
25.  Intracellular Concentrations of 65 Species of Transcription Factors with Known Regulatory Functions in Escherichia coli 
Journal of Bacteriology  2014;196(15):2718-2727.
The expression pattern of the Escherichia coli genome is controlled in part by regulating the utilization of a limited number of RNA polymerases among a total of its approximately 4,600 genes. The distribution pattern of RNA polymerase changes from modulation of two types of protein-protein interactions: the interaction of core RNA polymerase with seven species of the sigma subunit for differential promoter recognition and the interaction of RNA polymerase holoenzyme with about 300 different species of transcription factors (TFs) with regulatory functions. We have been involved in the systematic search for the target promoters recognized by each sigma factor and each TF using the newly developed Genomic SELEX system. In parallel, we developed the promoter-specific (PS)-TF screening system for identification of the whole set of TFs involved in regulation of each promoter. Understanding the regulation of genome transcription also requires knowing the intracellular concentrations of the sigma subunits and TFs under various growth conditions. This report describes the intracellular levels of 65 species of TF with known function in E. coli K-12 W3110 at various phases of cell growth and at various temperatures. The list of intracellular concentrations of the sigma factors and TFs provides a community resource for understanding the transcription regulation of E. coli under various stressful conditions in nature.
PMCID: PMC4135669  PMID: 24837290

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