An atlas of combinatorial transcriptional regulation in mouse and man.

Combinatorial interactions among transcription factors are critical to directing tissue-specific gene expression. To build a global atlas of these combinations, we have screened for physical interactions among the majority of human and mouse DNA-binding transcription factors (TFs). The complete networks contain 762 human and 877 mouse interactions. Analysis of the networks reveals that highly connected TFs are broadly expressed across tissues, and that roughly half of the measured interactions are conserved between mouse and human. The data highlight the importance of TF combinations for determining cell fate, and they lead to the identification of a SMAD3/FLI1 complex expressed during development of immunity. The availability of large TF combinatorial networks in both human and mouse will provide many opportunities to study gene regulation, tissue differentiation, and mammalian evolution.

Plasma dehydroepiandrosterone sulfate levels in patients with major depressive disorder correlate with remission during treatment with antidepressants.

OBJECTIVE: We attempted to investigate whether dehydroepiandrosterone sulfate (DHEA-S) levels are associated with remission of major depressive disorder by assessing scores on the 17-Item Structured Interview Guide for the Hamilton Depression before and after antidepressant treatment. METHODS: Plasma DHEA-S levels in 24 patients diagnosed with major depressive disorder on the basis of Diagnostic and Statistical Manual of Mental Disorders, fourth edition (text revision) before and after antidepressant treatment, and 24 healthy, gender-matched, and age-matched controls were measured using a radioimmunoassay kit. RESULTS: Plasma DHEA-S levels in patients were significantly higher than those in healthy controls. In patients who achieved remission after antidepressant treatment, plasma DHEA-S levels significantly declined compared with the levels before treatment. A significant correlation was observed between changes in DHEA-S levels and Absence of Depressive and Anxious Mood scores, which are calculated from the 2-Item Structured Interview Guide for the Hamilton Depression rating as follows: severity of depressive mood and anxiety in patients before and after antidepressant treatment. CONCLUSIONS: These findings suggest that plasma DHEA-S levels can be used as a putative indicator of the state of remission in patients with major depressive disorder. Copyright © 2014 John Wiley & Sons, Ltd.

Antigenic variation among recent Japanese isolates of bovine coronaviruses belonging to phylogenetically distinct genetic groups.

Bovine coronaviruses (BCoVs) isolated in Japan consist of four genetic groups, as determined by phylogenetic analysis using the polymorphic region (aa 456-592) of the S glycoprotein gene. Japanese field isolates of BCoV, reference Kakegawa strain, and vaccine strain 66/H were analyzed for their antigenic properties by indirect immunofluorescence and neutralization testing. There were no significant differences observed among these BCoVs in direct immunofluorescence tests. However, antigenic differences were observed between BCoVs in the neutralization tests, although there was no clear indication of a distinct serotype. A monoclonal antibody, 4H4, against the Kakegawa strain belonging to group 1 lacked significant neutralizing activity for viruses of groups 2, 3, and 4. Therefore, we speculate that the genetic differences between these groups may have altered their antigenicity. Analysis of mutant viruses resistant to neutralization by 4H4 revealed that the antigenic site of the Kakegawa strain maps to amino acid position 284 of the S glycoprotein. This site is not homologous to a known antigenic site (aa 528) of the Quebec strain belonging to group 1, and it is not located in the conformational domain comprising domain I (aa 351-403) and domain II (aa 517-621). This amino acid constitutes a neutralization epitope of BCoV, which is distinct from aa 528 of the Quebec strain. These results indicate antigenic evolution of BCoV between the genetic groups circulating in Japan.

Effectiveness of low-dose milnacipran for a patient suffering from pain disorder with delusional disorder (somatic type) in the orofacial region.

Glossodynia is chronic pain localized around the tongue, with no perceivable organic abnormalities. In the fields of oral and maxillofacial surgery, it is categorized as an oral psychosomatic disease. In contrast, psychiatric nosology classifies glossodynia as a pain disorder among somatoform disorders, per the DSM-IV. The patient was a 71-year-old woman who developed symptoms of glossodynia, specifically a sore tongue. In the decade before she presented to us, she had had bizarre symptoms of oral cenesthopathy such as the sensation that her teeth had become 'limp and floppy' and that she needles in her mouth. Treatment was attempted using several psychotropic drugs, but no satisfactory response was noted. Because the patient was referred to our outpatient clinic, we tried psychotropic therapy again. Additionally, valproic acid, tandospirone and sertraline were administered (in this order), but the patient still showed no response. However, when sertraline was changed to milnacipran, all symptoms disappeared in a short period. We suggest that a small dose of milnacipran can be effective for controlling oral cenesthopathy as well as glossodynia.

Molecular epidemiology of Salmonella enterica serovar typhimurium isolates from cattle in hokkaido, Japan: evidence of clonal replacement and characterization of the disseminated clone.

The molecular epidemiology of 545 Salmonella enterica serovar Typhimurium isolates collected between 1977 and 2009 from cattle in Hokkaido, Japan, was investigated using pulsed-field gel electrophoresis (PFGE). Nine main clusters were identified from 116 PFGE patterns. Cluster I comprised 248 isolates, 243 of which possessed a sequence specific to definitive phage type 104 (DT104) or U302. The cluster I isolates were dominant in 1993 to 2003, but their numbers declined beginning in 2004. Beginning in 2002, an increase was observed in the number of cluster VII isolates, consisting of 21 PFGE patterns comprising 165 isolates. A total of 116 isolates representative of the 116 PFGE profiles were analyzed by multilocus variable-number tandem-repeat analysis (MLVA). Other than two drug-sensitive isolates, 19 isolates within cluster VII were classified in the same cluster by MLVA. Among the cluster VII isolates, an antibiotic resistance type showing resistance to ampicillin, chloramphenicol, streptomycin, sulfonamides, tetracycline, kanamycin, cefazolin, and sulfamethoxazole-trimethoprim and a resistance type showing resistance to ampicillin, streptomycin, sulfonamides, tetracycline, and kanamycin were found in 23 and 125 isolates, respectively. In the 19 isolates representative of cluster VII, the bla(TEM-1) gene was found on a Salmonella serotype Typhimurium virulence plasmid, which was transferred to Escherichia coli by electroporation along with resistance to two to four other antimicrobials. Genomic analysis by subtractive hybridization and plasmid analysis suggested that the bla(TEM-1)-carrying virulence plasmid has a mosaic structure composed of elements of different origin. These results indicate an emerging multidrug-resistant S. Typhimurium clone carrying a virulence-resistance plasmid among cattle in Hokkaido, Japan.

Detection of a novel bovine papillomavirus type 11 (BPV-11) using xipapillomavirus consensus polymerase chain reaction primers.

Polymerase chain reaction-based bovine papillomavirus (BPV) detection methods using a combination of two primer sets, subAup/subAdw and subBup/subBdw, have enabled the broad-spectrum detection of most characterized BPV types. These methods were used to detect the partial L1 nucleotide sequence of BPV types from 167 cutaneous warts in cattle. Three potentially new viruses were detected using subBup/subBdw primer sets. The partial nucleotide sequences of these viruses were most similar to BPV-4, -6 and -9. Whole genome sequencing of one sample defines a new BPV type in the genus Xipapillomavirus, designated BPV-11.

The effects of acute treatment with tandospirone, diazepam, and placebo on driving performance and cognitive function in healthy volunteers.

OBJECTIVE: To assess the effects of two anxiolytics, diazepam and tandospirone, on driving performance from methodological viewpoints taking frequent rear-end collisions into account. METHODS: In this double-blinded, three-way crossover trial, 18 healthy males received acute doses of 20 mg tandospirone (TSP), 5 mg diazepam (DZP), and placebo (PCB). The subjects were administered three driving tasks-road tracking, car following, and harsh braking-performed using a driving simulator and three cognitive tasks-Wisconsin Card Sorting Test, Continuous Performance Test, and N-back test-at baseline and at 1 and 4 h post-dosing. The Stanford Sleepiness Scale scores were also assessed. RESULTS: DZP nonsignificantly increased the percent change of brake reaction time (BRT) as compared to PCB at 4 h post-dosing. TSP nonsignificantly decreased the percent change of BRT as compared to PCB. Consequently, there was a significant difference in the percent change of BRT between DZP and TSP at 4 h post-dosing. For the remaining tasks, no statistically significant effects of treatment were observed. CONCLUSIONS: Acute doses of DZP significantly impaired the harsh-braking performance as compared to acute doses of TSP. These findings suggest that TSP may be used more safely in patients' driving activities.

A case of dementia with Lewy bodies that temporarily showed symptoms similar to Creutzfeldt-Jakob disease.

We discuss a case of a 67-year-old male with dementia with Lewy bodies (DLB) that was initially suspected as Creutzfeldt-Jakob disease (CJD) or another type of encephalopathy, because he showed rapidly progressive deterioration, myoclonus, gait disturbance and a decline in activities of daily living. The present study describes a clinically atypical case with probable DLB and reviews similar cases in the literature, and we propose a rapidly progressive clinical subtype of DLB.

Phylogenetic and antigenic analysis of bovine parainfluenza virus type 3 isolated in Japan between 2002 and 2019.

Bovine parainfluenza virus type 3 (BPIV3) is one of the most important viral respiratory pathogens of cattle. In addition to the classical BPIV3 genotype A (BPIV3a), new genetic groups, genotype B (BPIV3b) and C (BPIV3c), have been identified and isolated in certain parts of the world. The present study aimed to investigate the genetic and antigenic characteristics of BPIV3 circulating in Japan. Seventy-three BPIV3 field strains were isolated from nasal samples of cattle between 2002 and 2019. Phylogenetic analysis of the phosphoprotein and hemagglutinin-neuraminidase genes showed that the isolates clustered into two genotypes, BPIV3a (49 %) and BPIV3c (51 %). The BPIV3a strains had more wide genetic variation than the rest of the genotypes. Additionally, new variants were obtained and designated them tentatively as subgroup 4 of the BPIV3a. The first Japanese BPIV3c was isolated in 2012, but here the BPIV3c NM2 strain was isolated from a sample collected four years earlier than the previous report. The antigenicity of ten BPIV3 strains including all three genotypes was assessed with a viral cross-neutralization test. Anti-sera against BPIV3a and BPIV3b cross-reacted well with both homologous and heterologous viruses. On the other hand, anti-sera against BPIV3c had reduced cross-reactivity to the heterologous viruses. Overall, our findings showed that genetically and antigenically divergent BPIV3 is prevalent in cattle in Japan. These results could provide a reference for molecular epidemiological characterization of BPIV3 and vaccine development.

Application of a Photocatalyst as an Inactivator of Bovine Coronavirus.

Bovine coronavirus (BCoV), a major causative pathogen of bovine enteric and respiratory diseases and a zoonotic pathogen transmissible between animals and humans, has led to severe economic losses in numerous countries. BCoV belongs to the genus Betacoronavirus, which is a model of a pathogen that is threatening human health and includes severe acute respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-2, and Middle East respiratory syndrome coronavirus. This study aimed to determine whether photocatalytic material effectively reduces CoVs in the environment. Using the film adhesion method of photocatalytic materials, we assessed its antiviral activity and the effect of visible light irradiation according to methods defined by the International Organization for Standardization. Consequently, photocatalytic material was found to have antiviral activity, reducing the viral loads by 2.7 log TCID50 (tissue culture infective dose 50)/0.1 mL (500 lux), 2.8 log TCID50/0.1 mL (1000 lux), and 2.4 log TCID50/0.1 mL (3000 lux). Hence, this photocatalytic material might be applicable not only to reducing CoVs in the cattle breeding environment but also perhaps in other indoor spaces, such as offices and hospital rooms. To our knowledge, this study is the first to evaluate the antiviral activity of a photocatalytic material against CoV.

Salmonella enterica serotype Typhimurium DT104 ArtA-dependent modification of pertussis toxin-sensitive G proteins in the presence of [32P]NAD.

Salmonella enterica serotype Typhimurium (S. Typhimurium) definitive phage type (DT) 104 has become a widespread cause of human and other animal infections worldwide. The severity of clinical illness in S. Typhimurium DT104 outbreaks suggests that this strain possesses enhanced virulence. ArtA and ArtB - encoded by a prophage in S. Typhimurium DT104 - are homologues of components of pertussis toxin (PTX), including its ADP-ribosyltransferase subunit. Here, we show that exposing DT104 to mitomycin C, a DNA-damaging agent, induced production of prophage-encoded ArtA/ArtB. Pertussis-sensitive G proteins were labelled in the presence of [(32)P]NAD and ArtA, and the label was released by HgCl(2), which is known to cleave cysteine-ADP-ribose bonds. ADP-dependent modification of G proteins was markedly reduced in in vitro-synthesized ArtA(6Arg-Ala) and ArtA(115Glu-Ala), in which alanine was substituted for the conserved arginine at position 6 (necessary for NAD binding) and the predicted catalytic glutamate at position 115, respectively. A cellular ADP-ribosylation assay and two-dimensional electrophoresis showed that ArtA- and PTX-induced ADP-ribosylation in Chinese hamster ovary (CHO) cells occur with the same type of G proteins. Furthermore, exposing CHO cells to the ArtA/ArtB-containing culture supernatant of DT104 resulted in a clustered growth pattern, as is observed in PTX-exposed CHO cells. Hydrogen peroxide, an oxidative stressor, also induced ArtA/ArtB production, suggesting that these agents induce in vivo synthesis of ArtA/ArtB. These results, taken together, suggest that ArtA/ArtB is an active toxin similar to PTX.

Distribution of neurofibrillary tangles in diffuse neurofibrillary tangles with calcification.

AIMS: In this study, the appearance and distribution of neurofibrillary tangles (NFT) in diffuse neurofibrillary tangles with calcification (DNTC) were investigated neuropathologically in order to elucidate the detailed distribution pattern in this disease. METHODS: The distribution of NFT in six cases neuropathologically diagnosed as DNTC (two men and four women) was studied using Gallyas-Braak silver stain. The age at death ranged from 56 to 73, with an average of 63.5 +/- 7.5 years. RESULTS: NFT were seen throughout the cerebral cortex, and were especially marked in the temporal and limbic cortices. The distribution pattern of NFT in the limbic lobe was similar to that in Alzheimer's disease as reported in the previous studies. In the temporal lobe, more NFT were distributed in the anterior than in the posterior area, which was confirmed in all six cases. The temporal pole showed the highest density of NFT including ghost tangles. CONCLUSIONS: The diffuse appearance of NFT in the cerebral cortex with the highest severity in the temporal pole was found to be a neuropathological characteristic of DNTC.

Phylogenetic studies of bovine coronaviruses isolated in Japan.

Molecular analysis of the polymorphic region of the bovine coronavirus (BCoV)-S gene using recent Japanese field isolates and reference strains revealed that the 148 isolates collected from 1999 to 2008 from 13 prefectures, covering all regions of Japan (Hokkaido, Tohoku, Kanto, Chubu, Kinki, Chugoku, Shikoku, and Kyusyu region) and divided into 3 clusters, show distinctive divergence from the prototype enteric BCoV strains. Almost all isolates after 2005 were clustered into group 4, and there was no regional specificity in these clusters. To differentiate the genotypes without sequencing, a simple technique-reverse transcriptase-polymerase chain reaction/restriction fragment length polymorphism analysis (RT-PCR/RFLP)-was developed. The availability of a simple and easy diagnostic assay will enable larger epidemiological studies of BCoV.

Relationship between three serotonin receptor subtypes (HTR3A, HTR2A and HTR4) and treatment-resistant schizophrenia in the Japanese population.

The proportion of treatment-resistant schizophrenia (TRS) has been estimated as 20-40% in the schizophrenic patients. Genetic factors are considered to be involved in the development of this condition. Serotonin subtypes are hypothesized to be the candidate genes. In the present study, single marker and haplotype analyses between several mutations of serotonin receptor subtypes (HTR2A, HTR3A and HTR4) and TRS (TRS=101, NON-TRS=239) were performed to determine a possible relationship with the development of TRS. Additionally, we also compared the daily neuroleptic dosage among each genotype. No significant association was observed between TRS and each allele, genotype, and haplotype. However, the daily neuroleptic dosage that patients had been receiving during their maintenance therapy was significantly higher in patients with the T/T genotype of HTR3A polymorphism (rs1062613, p=0.041). The present results support further research to examine the relationship between HTR3A polymorphism and the development of TRS in the Japanese population.

The effects of acute treatment with paroxetine, amitriptyline, and placebo on driving performance and cognitive function in healthy Japanese subjects: a double-blind crossover trial.

OBJECTIVE: To assess the effects of antidepressants on driving performance from a different methodological viewpoint in light of the recent traffic accidents. METHODS: In this double-blinded, 3-way crossover trial, 17 healthy males received acute doses of 10 mg paroxetine, 25 mg amitriptyline, and placebo. The subjects were administered three driving tasks--road tracking, car following, and harsh braking--performed using a driving simulator and three cognitive tasks--Wisconsin Card Sorting Test, Continuous Performance Test, and N-back test at baseline and at 1 h and 4 h post-dosing. The Stanford Sleepiness Scale scores were also assessed. RESULTS: At 4 h post-dosing, amitriptyline significantly impaired road-tracking and car-following performance, reduced driver vigilance, and caused subjective somnolence. Paroxetine impaired neither driving performance nor cognitive function. CONCLUSIONS: Acute doses of amitriptyline significantly impaired driving performance in the context of driving on crowded urban roads at relatively low speeds. This setting is important with respect to skills necessary for daily driving and may be difficult to measure in actual driving tests. This simulator-based study replicated the results of previous studies and could be considered complementary to them. This method may enable easy and safe screening of the driving hazard potential of drugs.

An association between serotonin receptor 3B gene (HTR3B) and treatment-resistant schizophrenia (TRS) in a Japanese population.

Genetic factors are thought to be involved in the development of treatment-resistant schizophrenia (TRS). Since several antipsychotic drugs inhibit the release of neurotransmitters via the serotonin receptors 3 (5-HT3), a dysfunction of this kind of receptor might be associated with the development of TRS. Thus, single-marker and haplotype analyses of the tag-single nucleotide polymorphisms (SNPs) of the 5-HT3B subunit gene (HTR3B) were performed in TRS (n = 101) and non-TRS (n = 244) patients. The deletion allele at the 3 bp-insertion/deletion polymorphism site (-100_-102delAAG) located in the putative HTR3B promoter region is significantly more frequent in the TRS group than the insertion allele by a single-marker comparison (p = 0.031). In addition, luciferase promoter assays showed that the deletion allele exhibited significantly higher transcriptional activity than the insertion allele in COS7 cells (p < 0.05). These results suggest that HTR3B is involved in the development of TRS in the Japanese population.

A long-term animal experiment indicating persistent infection of bovine coronavirus in cattle.

A long-term animal experiment involving inoculation with bovine coronavirus (BCoV) was conducted to verify its persistent infection in cattle. Three colostrum-deprived Holstein calves were housed separately in individual rooms of a high-containment facility and inoculated with the BCoV strain Kumamoto/1/07. Until the end of the experiment (1,085, 700 and 280 days, respectively), viral RNAs were detected sporadically by RT-PCR and nested PCR from plasma, nasal discharge, and feces. Seroconversion and titer changes were validated by hemagglutination inhibition tests and neutralization tests. Among the samples, nasal discharge showed a higher viral positivity than feces, which seemed to be associated with positive detection in the plasma. These data demonstrate the existence of persistent infection of BCoV in the respiratory tissues of cattle.

Association of SOX10 with schizophrenia in the Japanese population.

BACKGROUND: Microarray studies of schizophrenic brains revealed decreases in the expression of myelin and oligodendrocyte-related genes. Of these genes, sex-determining region Y-box 10 (SOX10) is a major transcription factor modulating the expression of proteins involved in neurogenesis and myelination. The SOX10 gene is located on chromosome 22q13.1, a region repeatedly reported to show positive signals in linkage studies on schizophrenia. OBJECTIVE: This study was conducted to clarify the exact role of SOX10 in the pathophysiology of schizophrenia. METHODS: We performed an association analysis of SOX10 in a Japanese population of 915 schizophrenic patients and 927 controls. Genotyping was carried out using polymerase chain reaction restriction fragment length polymorphism. MAIN RESULTS: One single nucleotide polymorphism of the SOX10 gene (rs139,887) was selected as a haplotype tag single nucleotide polymorphism using 96 controls. A significant association was observed in the genotype and allelic frequency of this single nucleotide polymorphism between schizophrenic patients and controls (P=0.025 and P=0.009, respectively). Especially, a significant association was found in male patients, but not female patients. We also performed a mutational search of the whole coding region, branch site, and promoter region of SOX10 in 96 schizophrenic patients, but no potential functional polymorphisms were detected. CONCLUSION: This study suggests that the SOX10 gene is related to the development of schizophrenia in the Japanese population.

Association study between the transferrin gene and schizophrenia in the Japanese population.

Several lines of evidence, including diffusion tensor imaging and microarray studies, indicate that abnormalities in myelination play an important role in the pathophysiology of schizophrenia. Of myelin and oligodendrocyte-related genes, a significant decrease in the mRNA levels of transferrin in schizophrenics has been reported by both microarray and quantitative polymerase chain reaction studies. We performed an association analysis of the transferrin gene in a Japanese population of 384 schizophrenic patients and 384 controls. Six single nucleotide polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism and a TaqMan assay. No significant differences in genotype, allele, or haplotype frequencies of the six single nucleotide polymorphisms were observed between schizophrenic patients and controls. The present results suggest that the transferrin gene is not related to the development of schizophrenia in the Japanese population.

The 2',3'-cyclic nucleotide 3'-phosphodiesterase and oligodendrocyte lineage transcription factor 2 genes do not appear to be associated with schizophrenia in the Japanese population.

Several lines of evidence suggest that disturbance of myelin-related genes is associated with the etiology of schizophrenia. Recently, the 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP) gene and the oligodendrocyte lineage transcription factor 2 (OLIG2) gene were reported to be related to the development of schizophrenia, based on the results of genetic association and microarray studies. In the present study, no significant association with schizophrenia was observed by single-marker or haplotype analysis for 6 tag SNPs of these genes (759 cases, 757 controls). These findings suggest that CNP and OLIG2 are unlikely to be related to the development of schizophrenia in the Japanese population.