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author:("akata, S")
1.  Distinct Cell Clusters Touching Islet Cells Induce Islet Cell Replication in Association with Over-Expression of Regenerating Gene (REG) Protein in Fulminant Type 1 Diabetes 
PLoS ONE  2014;9(4):e95110.
Background
Pancreatic islet endocrine cell-supporting architectures, including islet encapsulating basement membranes (BMs), extracellular matrix (ECM), and possible cell clusters, are unclear.
Procedures
The architectures around islet cell clusters, including BMs, ECM, and pancreatic acinar-like cell clusters, were studied in the non-diabetic state and in the inflamed milieu of fulminant type 1 diabetes in humans.
Result
Immunohistochemical and electron microscopy analyses demonstrated that human islet cell clusters and acinar-like cell clusters adhere directly to each other with desmosomal structures and coated-pit-like structures between the two cell clusters. The two cell-clusters are encapsulated by a continuous capsule composed of common BMs/ECM. The acinar-like cell clusters have vesicles containing regenerating (REG) Iα protein. The vesicles containing REG Iα protein are directly secreted to islet cells. In the inflamed milieu of fulminant type 1 diabetes, the acinar-like cell clusters over-expressed REG Iα protein. Islet endocrine cells, including beta-cells and non-beta cells, which were packed with the acinar-like cell clusters, show self-replication with a markedly increased number of Ki67-positive cells.
Conclusion
The acinar-like cell clusters touching islet endocrine cells are distinct, because the cell clusters are packed with pancreatic islet clusters and surrounded by common BMs/ECM. Furthermore, the acinar-like cell clusters express REG Iα protein and secrete directly to neighboring islet endocrine cells in the non-diabetic state, and the cell clusters over-express REG Iα in the inflamed milieu of fulminant type 1 diabetes with marked self-replication of islet cells.
doi:10.1371/journal.pone.0095110
PMCID: PMC3997392  PMID: 24759849
2.  Diagnostic criteria for acute‐onset type 1 diabetes mellitus (2012): Report of the Committee of Japan Diabetes Society on the Research of Fulminant and Acute‐onset Type 1 Diabetes Mellitus 
Abstract
Type 1 diabetes is a disease characterized by destruction of pancreatic β‐cells, which leads to absolute deficiency of insulin secretion. Depending on the manner of onset and progression, it is classified as fulminant, acute‐onset or slowly progressive type 1 diabetes. Here, we propose the diagnostic criteria for acute‐onset type 1 diabetes mellitus. Among the patients who develop ketosis or diabetic ketoacidosis within 3 months after the onset of hyperglycemic symptoms and require insulin treatment continuously after the diagnosis of diabetes, those with anti‐islet autoantibodies are diagnosed with ‘acute‐onset type 1 diabetes mellitus (autoimmune)’. In contrast, those whose endogenous insulin secretion is exhausted (fasting serum C‐peptide immunoreactivity <0.6 ng/mL) without verifiable anti‐islet autoantibodies are diagnosed simply with ‘acute‐onset type 1 diabetes mellitus’. Patients should be reevaluated after certain periods in case their statuses of anti‐islet autoantibodies and/or endogenous insulin secretory capacity are unknown.
doi:10.1111/jdi.12119
PMCID: PMC4025242  PMID: 24843746
Criteria; Diagnosis; Type 1 diabetes
3.  MicroRNA-33b downregulates the differentiation and development of porcine preadipocytes 
Molecular Biology Reports  2014;41:1081-1090.
Sterol regulatory element binding transcription factor (SREBF) is a key transcription regulator for lipid homeostasis. MicroRNA-33b (miR-33b) is embedded in intron 16 of porcine SREBF1 and is conserved among most mammals. Here, we investigated the effect of miR-33b on adipocyte differentiation and development in porcine subcutaneous pre-adipocytes (PSPA). PSPA were transiently transfected with miR-33b, and adipose differentiation was then induced. Delayed adipose differentiation and decreased lipid accumulation were observed in miR-33b-transfected PSPA. Computational predictions suggested that miR-33b may target early B cell factor 1 (EBF1), an adipocyte activator of lipogenesis regulators such as CCAAT-enhancer binding protein alpha (C/EBPα) and peroxisome proliferator-activated receptor gamma (PPARγ). Both gene and protein expression of EBF1 were downregulated in miR-33b-transfected PSPA, followed by considerable decreases in the expression of C/EBPα and PPARγ and their downstream lipogenic genes. However, miR-33b transfection did not markedly affect mRNA and protein expression of SREBF1. We also investigated differences in the expression of miR-33b and lipogenic genes in subcutaneous fat tissues between 5-month-old crossbred gilts derived from Landrace (lean-type) and Meishan (fatty-type) boars. Landrace-derived crossbred gilts expressed more miR-33b and less lipogenic genes than did gilts derived from Meishan. Our results suggest that miR-33b affected the differentiation and development of PSPA by attenuating the lipogenic gene expression cascade through EBF1 to C/EBPα and PPARγ. The differential expression of miR-33b observed in crossbred gilts may in part account for differences in lipogenic gene expression and the fat:lean ratio between pig breeds.
Electronic supplementary material
The online version of this article (doi:10.1007/s11033-013-2954-z) contains supplementary material, which is available to authorized users.
doi:10.1007/s11033-013-2954-z
PMCID: PMC3929038  PMID: 24398549
Adipocyte; Gene expression; Lipogenesis; MicroRNA; PPAR; SREBF
4.  Physiological Characterization of an Anaerobic Ammonium-Oxidizing Bacterium Belonging to the “Candidatus Scalindua” Group 
Applied and Environmental Microbiology  2013;79(13):4145-4148.
The phylogenetic affiliation and physiological characteristics (e.g., Ks and maximum specific growth rate [μmax]) of an anaerobic ammonium oxidation (anammox) bacterium, “Candidatus Scalindua sp.,” enriched from the marine sediment of Hiroshima Bay, Japan, were investigated. “Candidatus Scalindua sp.” exhibits higher affinity for nitrite and a lower growth rate and yield than the known anammox species.
doi:10.1128/AEM.00056-13
PMCID: PMC3697556  PMID: 23584767
5.  Effectiveness of a Multimodal Community Intervention Program to Prevent Suicide and Suicide Attempts: A Quasi-Experimental Study 
PLoS ONE  2013;8(10):e74902.
Background
Multilevel and multimodal interventions have been suggested for suicide prevention. However, few studies have reported the outcomes of such interventions for suicidal behaviours.
Methods
We examined the effectiveness of a community-based multimodal intervention for suicide prevention in rural areas with high suicide rates, compared with a parallel prevention-as-usual control group, covering a total of 631,133 persons. The effectiveness was also examined in highly populated areas near metropolitan cities (1,319,972 persons). The intervention started in July 2006, and continued for 3.5 years. The primary outcome was the incidence of composite outcome, consisting of completed suicides and suicide attempts requiring admission to an emergency ward for critical care. We compared the rate ratios (RRs) of the outcomes adjusted by sex, age group, region, period and interaction terms. Analyses were performed on an intention-to-treat basis and stratified by sex and age groups.
Findings
In the rural areas, the overall median adherence of the intervention was significantly higher. The RR of the composite outcome in the intervention group decreased 7% compared with that of the control group. Subgroup analyses demonstrated heterogeneous effects among subpopulations: the RR of the composite outcome in the intervention group was significantly lower in males (RR = 0.77, 95% CI 0.59–0.998, p = 0.0485) and the RR of suicide attempts was significantly lower in males (RR = 0.39, 95% CI 0.22–0.68, p = 0.001) and the elderly (RR = 0.35, 95% CI 0.17–0.71, p = 0.004). The intervention had no effect on the RR of the composite outcome in the highly populated areas.
Interpretation
Our findings suggest that this community-based multimodal intervention for suicide prevention could be implemented in rural areas, but not in highly populated areas. The effectiveness of the intervention was shown for males and for the elderly in rural areas.
Trial Registration
ClinicalTrials.gov NCT00737165 UMIN Clinical Trials Registry UMIN000000460
doi:10.1371/journal.pone.0074902
PMCID: PMC3794031  PMID: 24130673
6.  Rhabdom evolution in butterflies: insights from the uniquely tiered and heterogeneous ommatidia of the Glacial Apollo butterfly, Parnassius glacialis 
The eye of the Glacial Apollo butterfly, Parnassius glacialis, a ‘living fossil’ species of the family Papilionidae, contains three types of spectrally heterogeneous ommatidia. Electron microscopy reveals that the Apollo rhabdom is tiered. The distal tier is composed exclusively of photoreceptors expressing opsins of ultraviolet or blue-absorbing visual pigments, and the proximal tier consists of photoreceptors expressing opsins of green or red-absorbing visual pigments. This organization is unique because the distal tier of other known butterflies contains two green-sensitive photoreceptors, which probably function in improving spatial and/or motion vision. Interspecific comparison suggests that the Apollo rhabdom retains an ancestral tiered pattern with some modification to enhance its colour vision towards the long-wavelength region of the spectrum.
doi:10.1098/rspb.2012.0475
PMCID: PMC3396891  PMID: 22628477
vision; colour; motion; compound eye; photoreceptor; opsin
7.  A Novel Splicing Variant of Peroxisome Proliferator-Activated Receptor-γ (Pparγ1sv) Cooperatively Regulates Adipocyte Differentiation with Pparγ2 
PLoS ONE  2013;8(6):e65583.
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that regulate expression of a number of genes associated with the cellular differentiation and development. Here, we show the abundant and ubiquitous expression of a newly identified splicing variant of mouse Pparγ (Pparγ1sv) that encodes PPARγ1 protein, and its importance in adipogenesis. The novel splicing variant has a unique 5′-UTR sequence, relative to those of Pparγ1 and Pparγ2 mRNAs, indicating the presence of a novel transcriptional initiation site and promoter for Pparγ expression. Pparγ1sv was highly expressed in the white and brown adipose tissues at levels comparable to Pparγ2. Pparγ1sv was synergistically up-regulated with Pparγ2 during adipocyte differentiation of 3T3-L1 cells and mouse primary cultured preadipocytes. Inhibition of Pparγ1sv by specific siRNAs completely abolished the induced adipogenesis in 3T3-L1 cells. C/EBPβ and C/EBPδ activated both the Pparγ1sv and Pparγ2 promoters in 3T3-L1 preadipocytes. These findings suggest that Pparγ1sv and Pparγ2 synergistically regulate the early stage of the adipocyte differentiation.
doi:10.1371/journal.pone.0065583
PMCID: PMC3686765  PMID: 23840343
8.  Genome-wide association study of coronary artery disease in the Japanese 
A new understanding of the genetic basis of coronary artery disease (CAD) has recently emerged from genome-wide association (GWA) studies of common single-nucleotide polymorphisms (SNPs), thus far performed mostly in European-descent populations. To identify novel susceptibility gene variants for CAD and confirm those previously identified mostly in populations of European descent, a multistage GWA study was performed in the Japanese. In the discovery phase, we first genotyped 806 cases and 1337 controls with 451 382 SNP markers and subsequently assessed 34 selected SNPs with direct genotyping (541 additional cases) and in silico comparison (964 healthy controls). In the replication phase, involving 3052 cases and 6335 controls, 12 SNPs were tested; CAD association was replicated and/or verified for 4 (of 12) SNPs from 3 loci: near BRAP and ALDH2 on 12q24 (P=1.6 × 10−34), HLA-DQB1 on 6p21 (P=4.7 × 10−7), and CDKN2A/B on 9p21 (P=6.1 × 10−16). On 12q24, we identified the strongest association signal with the strength of association substantially pronounced for a subgroup of myocardial infarction cases (P=1.4 × 10−40). On 6p21, an HLA allele, DQB1*0604, could show one of the most prominent association signals in an ∼8-Mb interval that encompasses the LTA gene, where an association with myocardial infarction had been reported in another Japanese study. CAD association was also identified at CDKN2A/B, as previously reported in different populations of European descent and Asians. Thus, three loci confirmed in the Japanese GWA study highlight the likely presence of risk alleles with two types of genetic effects – population specific and common – on susceptibility to CAD.
doi:10.1038/ejhg.2011.184
PMCID: PMC3283177  PMID: 21971053
coronary artery disease; gene; association study; Japanese
9.  Report of the Committee of the Japan Diabetes Society on the Research of Fulminant and Acute‐onset Type 1 Diabetes Mellitus: New diagnostic criteria of fulminant type 1 diabetes mellitus (2012) 
Abstract
We have revised a part of the diagnostic criteria for fulminant type 1 diabetes. The new criteria were set both to express the essence of this disease of rapid increase of patients' blood glucose and to be highly sensitive to reduce the misdiagnosis. After analyzing the data of 382 patients with newly‐diagnosed fulminant type 1 diabetes, we adopted the glycated hemoglobin (HbA1c) level of 8.7% (National Glycohemoglobin Standardization Program [NGSP] value). The new criterion indicates 100% of sensitivity and the best value by receiver operating characteristic curve analysis. In addition, we added a comment that ‘This value (HbA1c <8.7% in NGSP) is not applicable for patients with previously diagnosed glucose intolerance’ in the new criteria and also a comment that ‘Association with human leukocyte antigen DRB1*04:05‐DQB1*04:01 is reported’ as a related finding. We did not revise the screening criteria and the other part of the diagnostic criteria, because they are still reliable.
doi:10.1111/jdi.12024
PMCID: PMC4015434  PMID: 24843620
Criteria; Diagnosis; Fulminant
10.  Development of a fine thermocouple-needle system for real-time feedback of thermal tumour ablation margin 
The British Journal of Radiology  2011;84(1008):1139-1141.
Thermal tumour ablation techniques such as radiofrequency (RF) ablation are applied for radical removal of local tumours as an easier, less invasive alternative to surgical resection. A serious drawback of thermal ablation, however, is that the ablation area cannot be accurately assessed during the procedure. To achieve real-time feedback and exact and safe ablation, a superfine thermocouple-needle system (TNS) comprising a 0.25-mm diameter thermocouple embedded in a 22-G, 15-cm-long needle was devised and efficacy was tested in vitro using porcine livers (n = 15) and in vivo using rabbit back muscles (n = 2) and livers (n = 3). A 17-gauge RF electrode with a 2 cm active tip was used for ablation. The TNS was inserted 1 cm from the active tip of the RF electrode and liver temperature around the electrode was measured concurrently. The RF current was cut off when the temperature reached 60°C or after 5 min at ≥50°C. Porcine livers and rabbit back muscles were then cut along a plane passing through the axes of the electrode and the TNS. In rabbit livers, contrast-enhanced CT was performed to evaluate ablation areas. Ablation areas in cut surfaces of porcine livers exhibited well-defined discoloured regions and the TNS tip precisely pinpointed the margin of the ablation area. Contrast-enhanced CT of rabbit livers showed the TNS tip accurately located at the margin of areas without contrast enhancement. These results indicate that the TNS can accurately show ablation margins and that placing the TNS tip at the intended ablation margin permits exact thermal ablation.
doi:10.1259/bjr/81796498
PMCID: PMC3473833  PMID: 21937618
11.  Type 1 Diabetes and Interferon Therapy 
Diabetes Care  2011;34(9):2084-2089.
OBJECTIVE
Interferon therapy can trigger induction of several autoimmune diseases, including type 1 diabetes. To assess the clinical, immunologic, and genetic characteristics of type 1 diabetes induced by interferon therapy, we conducted a nationwide cross-sectional survey.
RESEARCH DESIGN AND METHODS
Clinical characteristics, anti-islet autoantibodies, and HLA-DR typing were examined in 91 patients for whom type 1 diabetes developed during or shortly after interferon therapy.
RESULTS
Median age at the onset of type 1 diabetes was 56 (interquartile range 48–63) years and mean ± SD BMI was 20.8 ± 2.7 kg/m2. The time period from the initiation of interferon therapy to type 1 diabetes onset in patients receiving pegylated interferon and ribavirin was significantly shorter than that in patients with nonpegylated interferon single therapy (P < 0.05). Anti-islet autoantibodies were detected in 94.5% of patients at diabetes onset. Type 1 diabetes susceptibility HLA-DRs in the Japanese population, DR4 and DR9, were also associated with interferon treatment–related type 1 diabetes. Furthermore, the prevalence of HLA-DR13 was significantly higher in interferon treatment–related type 1 diabetes than in healthy control subjects (odds ratio 3.80 [95% CI 2.20–7.55]; P < 0.0001) and classical type 1 diabetes (2.15 [1.17–3.93]; P < 0.05).
CONCLUSIONS
Anti-islet autoantibodies should be investigated before and during interferon therapy to identify subjects at high risk of type 1 diabetes. Stronger antiviral treatment may induce earlier development of type 1 diabetes. Furthermore, patients who develop interferon-induced type 1 diabetes are genetically susceptible.
doi:10.2337/dc10-2274
PMCID: PMC3161293  PMID: 21775762
12.  Alternative Reproductive Tactics in the Shell-Brooding Lake Tanganyika Cichlid Neolamprologus brevis 
Alternative reproductive tactics (ARTs) are found in several Lake Tanganyika shell-brooding cichlids. Field studies were conducted in the Wonzye population to examine reproductive ecology and ARTs in the Lake Tanganyika shell-brooding cichlid Neolamprologus brevis. We discovered that this fish occurred in both rocky- and sandy-bottom habitats, but in rocky habitats, brood-caring females exclusively occurred in shell-patches that another cichlid species created. All N. brevis of both sexes in the patches were sexually mature, whereas immature males and females with unripe eggs were found frequently in sandy-bottom habitats. Males in sandy-bottom habitats were smaller, but fed more frequently and were in better somatic condition than males in the patches. Similar tendency was found in females. This indicates that N. brevis uses different habitats depending on the stage of its life history, with migration from sandy-bottom habitats to the shell-patches for reproduction. Males in the patches exhibited different behavior patterns: floating above the patches and lying in the patches. The former was larger, more aggressive, and invested less in gonads (relative to body size) than the latter. These results accord with those of other shell-brooding Lake Tanganyika cichlids with ARTs, and they therefore suggest the presence of ARTs in N. brevis.
doi:10.1155/2012/193235
PMCID: PMC3408672  PMID: 22888463
13.  RIG-I– and MDA5-Initiated Innate Immunity Linked With Adaptive Immunity Accelerates β-Cell Death in Fulminant Type 1 Diabetes 
Diabetes  2011;60(3):884-889.
OBJECTIVE
The contribution of innate immunity responsible for aggressive β-cell destruction in human fulminant type 1 diabetes is unclear.
RESEARCH DESIGN AND METHODS
Islet cell expression of Toll-like receptors (TLRs), cytoplasmic retinoic acid–inducible gene I (RIG-I)-like receptors, downstream innate immune markers, adaptive immune mediators, and apoptotic markers was studied in three autopsied pancreata obtained 2 to 5 days after onset of fulminant type 1 diabetes.
RESULTS
RIG-I was strongly expressed in β-cells in all three pancreata infected with enterovirus. Melanoma differentiation–associated gene-5 was hyperexpressed in islet cells, including β- and α-cells. TLR3 and TLR4 were expressed in mononuclear cells that infiltrated islets. Interferon (IFN)-α and IFN-β were strongly expressed in islet cells. Major histocompatibility complex (MHC)-class I, IFN-γ, interleukin-18, and CXC motif ligand 10 were expressed and colocalized in affected islets. CD11c+ MHC-class II+ dendritic cells and macrophage subsets infiltrated most islets and showed remarkable features of phagocytosis of islet cell debris. CD4+ forkhead box P3+ regulatory T cells were not observed in and around the affected islets. Mononuclear cells expressed the Fas ligand and infiltrated most Fas-expressing islets. Retinoic acid–receptor responder 3 and activated caspases 8, 9, and 3 were preferentially expressed in β-cells. Serum levels of IFN-γ were markedly increased in patients with fulminant type 1 diabetes.
CONCLUSIONS
These findings demonstrate the presence of specific innate immune responses to enterovirus infection connected with enhanced adoptive immune pathways responsible for aggressive β-cell toxicity in fulminant type 1 diabetes.
doi:10.2337/db10-0795
PMCID: PMC3046849  PMID: 21289206
14.  CT-guided radiofrequency liver tumour ablation: use of a two-step coaxial system with a fine guide needle wire unit for high-risk cases 
The British Journal of Radiology  2010;83(996):1077-1079.
Accurate radiofrequency (RF) needle targeting to liver lesions under CT guidance is technically difficult and generally requires multiple needle manipulations, which carries potential risk. This approach is hardly applicable for precariously located lesions or for patients who have difficulty holding their breath. The aim of this study was to develop a novel two-step coaxial system to facilitate CT-guided RF ablation in difficult cases. The study group comprised 11 patients with 12 hepatic lesions. The coaxial system consisted of two parts: a 21-gauge pencil-tip guide needle wire (GNW) unit comprising a 150-mm-long needle segment and a 250-mm-long wire segment; and a 140-mm-long outer cannula with its stylet, which accepts a 17-gauge RF electrode needle. The GNW was inserted until the route of the GNW was confirmed to be positioned correctly. The cannula with the stylet was then advanced along the GNW. Lesions were successfully accessed using the GNW, even in patients who could not hold their breath, and manipulation was feasible within the limited space of the CT gantry. The light GNW also facilitated step-by-step CT-guided angular manipulations, unlike heavy RF electrodes, which are unstable during hands-free use unless deeply inserted. Therefore, this system enabled sequential ablations of large tumours by ensuring three different routes in advance by using the GNW. Insertion of the cannula along the GNW was simple. In conclusion, the two-step coaxial system enabled CT-guided RF tumour ablation to be performed in cases conventionally contraindicated owing to high risk of serious complications.
doi:10.1259/bjr/21804442
PMCID: PMC3473614  PMID: 21088092
15.  CFH, VEGF, and PEDF genotypes and the response to intravitreous injection of bevacizumab for the treatment of age-related macular degeneration 
We determined whether there is an association between complement factor H (CFH), high-temperature requirement A-1 (HTRA1), vascular endothelial growth factor (VEGF), and pigment epithelium-derived factor (PEDF) genotypes and the response to treatment with a single intravitreous injection of bevacizumab for age-related macular degeneration (AMD). Eighty-three patients with exudative AMD treated by bevacizumab injection were genotyped for three single nucleotide polymorphisms (SNPs; rs800292, rs1061170, rs1410996) in the CFH gene, a rs11200638-SNP in the HTRA1 gene, three SNPs (rs699947, rs1570360, rs2010963) in the VEGF gene, and four SNPs (rs12150053, rs12948385, rs9913583, rs1136287) in the PEDF gene using a TaqMan assay. The CT genotype (heterozygous) of CFH-rs1061170 was more frequently represented in nonresponders in vision than TT genotypes (nonrisk allele homozygous) at the time points of 1 and 3 months, while there was no CC genotype (risk allele homozygous) in our study cohort (p = 7.66 × 10−3, 7.83 × 10−3, respectively). VEGF-rs699947 was also associated with vision changes at 1 month and PEDF-rs1136287 at 3 months (p = 5.11 × 10−3, 2.05 × 10−2, respectively). These variants may be utilized for genetic biomarkers to estimate visual outcomes in the response to intravitreal bevacizumab treatment for AMD.
doi:10.1007/s12177-010-9055-1
PMCID: PMC3148139  PMID: 21811649
Age-related macular degeneration; Bevacizumab; Complement factor H; Genetic biomarker; High-temperature requirement A-1; Pigment epithelium-derived factor; Vascular endothelial growth factor
16.  Regulation of flagellar motility by the conserved flagellar protein CG34110/Ccdc135/FAP50 
Molecular Biology of the Cell  2011;22(7):976-987.
This study reports the function of a conserved flagellar protein CG34110, which has highly conserved orthologues in species containing motile cilia. It appears to represent a novel regulatory protein located on the outer doublet microtubules of the axoneme across a broad range of species.
Eukaryotic cilia and flagella are vital sensory and motile organelles. The calcium channel PKD2 mediates sensory perception on cilia and flagella, and defects in this can contribute to ciliopathic diseases. Signaling from Pkd2-dependent Ca2+ rise in the cilium to downstream effectors may require intermediary proteins that are largely unknown. To identify these proteins, we carried out genetic screens for mutations affecting Drosophila melanogaster sperm storage, a process mediated by Drosophila Pkd2. Here we show that a new mutation lost boys (lobo) encodes a conserved flagellar protein CG34110, which corresponds to vertebrate Ccdc135 (E = 6e-78) highly expressed in ciliated respiratory epithelia and sperm, and to FAP50 (E = 1e-28) in the Chlamydomonas reinhardtii flagellar proteome. CG34110 localizes along the fly sperm flagellum. FAP50 is tightly associated with the outer doublet microtubules of the axoneme and appears not to be a component of the central pair, radial spokes, dynein arms, or structures defined by the mbo waveform mutants. Phenotypic analyses indicate that both Pkd2 and lobo specifically affect sperm movement into the female storage receptacle. We hypothesize that the CG34110/Ccdc135/FAP50 family of conserved flagellar proteins functions within the axoneme to mediate Pkd2-dependent processes in the sperm flagellum and other motile cilia.
doi:10.1091/mbc.E10-04-0331
PMCID: PMC3069022  PMID: 21289096
17.  Identification of a second gene associated with variation in vertebral number in domestic pigs 
BMC Genetics  2011;12:5.
Background
The number of vertebrae in pigs varies and is associated with body size. Wild boars have 19 vertebrae, but European commercial breeds for pork production have 20 to 23 vertebrae. We previously identified two quantitative trait loci (QTLs) for number of vertebrae on Sus scrofa chromosomes (SSC) 1 and 7, and reported that an orphan nuclear receptor, NR6A1, was located at the QTL on SSC1. At the NR6A1 locus, wild boars and Asian local breed pigs had the wild-type allele and European commercial-breed pigs had an allele associated with increased numbers of vertebrae (number-increase allele).
Results
Here, we performed a map-based study to define the other QTL, on SSC7, for which we detected genetic diversity in European commercial breeds. Haplotype analysis with microsatellite markers revealed a 41-kb conserved region within all the number-increase alleles in the present study. We also developed single nucleotide polymorphisms (SNPs) in the 450-kb region around the QTL and used them for a linkage disequilibrium analysis and an association study in 199 independent animals. Three haplotype blocks were detected, and SNPs in the 41-kb region presented the highest associations with the number of vertebrae. This region encodes an uncharacterized hypothetical protein that is not a member of any other known gene family. Orthologs appear to exist not only in mammals but also birds and fish. This gene, which we have named vertnin (VRTN) is a candidate for the gene associated with variation in vertebral number. In pigs, the number-increase allele was expressed more abundantly than the wild-type allele in embryos. Among candidate polymorphisms, there is an insertion of a SINE element (PRE1) into the intron of the Q allele as well as the SNPs in the promoter region.
Conclusions
Genetic diversity of VRTN is the suspected cause of the heterogeneity of the number of vertebrae in commercial-breed pigs, so the polymorphism information should be directly useful for assessing the genetic ability of individual animals. The number-increase allele of swine VRTN was suggested to add an additional thoracic segment to the animal. Functional analysis of VRTN may provide novel findings in the areas of developmental biology.
doi:10.1186/1471-2156-12-5
PMCID: PMC3024977  PMID: 21232157
18.  Living on the wedge: female control of paternity in a cooperatively polyandrous cichlid 
Theories suggest that, in cooperatively breeding species, female control over paternity and reproductive output may affect male reproductive skew and group stability. Female paternity control may come about through cryptic female choice or female reproductive behaviour, but experimental studies are scarce. Here, we show a new form of female paternity control in a cooperatively polyandrous cichlid fish (Julidochromis transcriptus), in which females prefer wedge-shaped nesting sites. Wedge-shaped sites allowed females to manipulate the siring success of the group member males by spawning the clutch at the spot where the large males were just able to enter and fertilize the outer part of the clutch. Small males fertilized the inner part of the clutch, protected from the large aggressive males, leading to low male reproductive skew. Small males provided more brood care than large males. Multiple paternity induced both males to provide brood care and reduced female brood care accordingly. This is, to our knowledge, the first documented case in a species with external fertilization showing female mating behaviour leading to multiple male paternity and increased male brood care as a result.
doi:10.1098/rspb.2009.1175
PMCID: PMC2821345  PMID: 19726479
female paternity control; reproductive skew; cooperative polyandry; sexual conflict; brood care; Julidochromis transcriptus
19.  HA-tagging of Putative Flagellar Proteins in Chlamydomonas reinhardtii Identifies a Novel Protein of Intraflagellar Transport Complex B 
Proteomic analysis of flagella from the green alga Chlamydomonas reinhardtii has identified over 600 putative flagella proteins. The genes encoding nine of these not previously characterized plus the previously described PACRG protein were cloned, inserted into a vector adding a triple-HA tag to the C-terminus of the gene product, and transformed into C. reinhardtii. Expression was confirmed by western blotting. Indirect immunofluorescence located all ten fusion proteins in the flagellum; PACRG was localized to a subset of outer doublet microtubules. For some proteins, additional signal was observed in the cell body. Among the latter was FAP232-HA, which showed a spotted distribution along the flagella and an accumulation at the basal bodies. This pattern is characteristic for intraflagellar transport (IFT) proteins. FAP232-HA co-localized with the IFT protein IFT46 and co-sedimented with IFT particles in sucrose gradients. Furthermore, it co-immunoprecipitated with IFT complex B protein IFT46, but not with IFT complex A protein IFT139. We conclude that FAP232 is a novel component of IFT complex B and rename it IFT25. Homologues of IFT25 are encoded in the genomes of a subset of organisms that assemble cilia or flagella; C. reinhardtii IFT25 is 37% identical to the corresponding human protein. Genes encoding IFT25 homologues are absent from the genomes of organisms that lack cilia and flagella and, interestingly, also from those of Drosophila melanogaster and Caenorhabditis elegans, suggesting that IFT25 has a specialized role in IFT that is not required for the assembly of cilia or flagella in the worm and fly.
doi:10.1002/cm.20369
PMCID: PMC2922027  PMID: 19382199
flagellar proteome; FAP134; cilia; placental protein pp25; small heat-shock-like protein beta-11 (HSPB11); FAP173; PACRG
20.  Adiponectin Upregulates Ferritin Heavy Chain in Skeletal Muscle Cells 
Diabetes  2009;58(1):61-70.
OBJECTIVE—Adiponectin is an adipocyte-derived protein that acts to reduce insulin resistance in the liver and muscle and also inhibits atherosclerosis. Although adiponectin reportedly enhances AMP-activated protein kinase and inhibits tumor necrosis factor-α action downstream from the adiponectin signal, the precise physiological mechanisms by which adiponectin acts on skeletal muscles remain unknown.
RESEARCH DESIGN AND METHODS—We treated murine primary skeletal muscle cells with recombinant full-length human adiponectin for 12 h and searched, using two-dimensional electrophoresis, for proteins upregulated more than threefold by adiponectin compared with untreated cells.
RESULTS—We found one protein that was increased 6.3-fold with adiponectin incubation. MALDI-TOF (matrix-assisted laser desorption/ionization−top of flight) mass spectrometric analysis identified this protein as ferritin heavy chain (FHC). When murine primary skeletal muscle cells were treated with adiponectin, IκB-α phosphorylation was observed, suggesting that adiponectin stimulates nuclear factor (NF)-κB activity. In addition, FHC upregulation by adiponectin was inhibited by NF-κB inhibitors. These results suggest NF-κB activation to be involved in FHC upregulation by adiponectin. Other NF-κB target genes, manganese superoxide dismutase (MnSOD) and inducible nitric oxide synthase (iNOS), were also increased by adiponectin treatment. We performed a reactive oxygen species (ROS) assay using CM-H2DCFDA fluorescence and found that ROS-reducing effects of adiponectin were abrogated by FHC or MnSOD small-interfering RNA induction.
CONCLUSIONS—We have demonstrated that adiponectin upregulates FHC in murine skeletal muscle tissues, suggesting that FHC elevation might partially explain how adiponectin protects against oxidative stress in skeletal muscles.
doi:10.2337/db07-0690
PMCID: PMC2606894  PMID: 18931039
21.  A community intervention trial of multimodal suicide prevention program in Japan: A Novel multimodal Community Intervention program to prevent suicide and suicide attempt in Japan, NOCOMIT-J 
BMC Public Health  2008;8:315.
Background
To respond to the rapid surge in the incidence of suicide in Japan, which appears to be an ongoing trend, the Japanese Multimodal Intervention Trials for Suicide Prevention (J-MISP) have launched a multimodal community-based suicide prevention program, NOCOMIT-J. The primary aim of this study is to examine whether NOCOMIT-J is effective in reducing suicidal behavior in the community.
Methods/DesignThis study is a community intervention trial involving seven intervention regions with accompanying control regions, all with populations of statistically sufficient size. The program focuses on building social support networks in the public health system for suicide prevention and mental health promotion, intending to reinforce human relationships in the community. The intervention program components includes a primary prevention measures of awareness campaign for the public and key personnel, secondary prevention measures for screening of, and assisting, high-risk individuals, after-care for individuals bereaved by suicide, and other measures. The intervention started in July 2006, and will continue for 3.5 years. Participants are Japanese and foreign residents living in the intervention and control regions (a total of population of 2,120,000 individuals).
Discussion
The present study is designed to evaluate the effectiveness of the community-based suicide prevention program in the seven participating areas.
Trial registration
UMIN Clinical Trials Registry (UMIN-CTR) UMIN000000460.
doi:10.1186/1471-2458-8-315
PMCID: PMC2551615  PMID: 18793423
22.  Serial six year quantitative angiographic follow up in asymptomatic patients following successful coronary angioplasty 
Heart  2004;90(10):1179-1182.
Objective: To evaluate long term (six years) lumen changes after balloon angioplasty by using quantitative coronary angiography.
Methods: Complete serial quantitative coronary angiography (before and after angioplasty and at six months, three years, and six years) was performed in 100 patients with successful angioplasty and without subsequent repeated revascularisation. In all, 198 dilated segments were compared with 395 non-dilated segments that were obtained from non-target arteries of study patients.
Results: From six months to three years after angioplasty, minimum lumen diameter (MLD) increased significantly by 0.13 (0.28) (mean (SD)) mm in dilated segments and decreased significantly by 0.04 (0.27) mm in non-dilated segments. From three years to six years, MLD remained stable in dilated segments but decreased further (by 0.04 (0.28) mm) in non-dilated segments. Consequently, the ΔMLD between six months and six years was larger in dilated segments than in non-dilated segments (0.12 (0.32) v −0.08 (0.34); p < 0.001). Further, ΔMLD from six months to six years correlated positively with the percentage diameter stenosis (DS) at six months in each group (dilated segments r  =  0.47, p < 0.0001; non-dilated segments r  =  0.49, p < 0.0001). Multivariate analysis showed that the only independent predictor of ΔMLD over six years for each group was the DS at six months.
Conclusions: Lesion regression occurs within the first three years after angioplasty and reaches a plateau thereafter. Moreover, the stenosis severity at six months predicts the magnitude of late regression after angioplasty.
doi:10.1136/hrt.2003.022772
PMCID: PMC1768508  PMID: 15367518
coronary angioplasty; regression
23.  PEDE (Pig EST Data Explorer) has been expanded into Pig Expression Data Explorer, including 10 147 porcine full-length cDNA sequences 
Nucleic Acids Research  2006;35(Database issue):D650-D653.
We formerly released the porcine expressed sequence tag (EST) database Pig EST Data Explorer (PEDE; ), which comprised 68 076 high-quality ESTs obtained by using full-length-enriched cDNA libraries derived from seven tissues. We have added eight tissues and cell types to the EST analysis and have integrated 94 555 additional high-quality ESTs into the database. We also fully sequenced the inserts of 10 147 of the cDNA clones that had undergone EST analysis; the sequences and annotation of the cDNA clones were stored in the database. Further, we constructed an interface that can be used to perform various searches in the database. The PEDE database is the primary resource of expressed pig genes that are supported by full-length cDNA sequences. This resource not only enables us to pick cDNA clones of interest for a particular analysis, but it also confirms and thus contributes to the sequencing integrity of the pig genome, which is now being compiled by an international consortium (). PEDE has therefore evolved into what we now call ‘Pig Expression Data Explorer’.
doi:10.1093/nar/gkl954
PMCID: PMC1751553  PMID: 17145712
24.  PEDE (Pig EST Data Explorer): construction of a database for ESTs derived from porcine full-length cDNA libraries 
Nucleic Acids Research  2004;32(Database issue):D484-D488.
We generated the PEDE (Pig EST Data Explorer; http://pede.dna.affrc.go.jp/) database using se quences assembled from porcine 5′ ESTs from oligo-capped full-length cDNA libraries. Thus far we have performed EST analysis of various organs (thymus, spleen, uterus, lung, liver, ovary and peripheral blood mononuclear cells) and assembled 68 076 high-quality sequences into 5546 contigs and 28 461 singlets. PEDE provides a search interface for getting results of homology searches and enables users to obtain information on sequence data and cDNA clones of interest. Single-nucleotide polymorphisms detected through comparison of the EST sequences are classified by origin (western and oriental breeds) and are searchable in the database. This database system can accelerate analyses of livestock traits and yields information that can lead to new applications in pigs as model systems for medical research.
doi:10.1093/nar/gkh037
PMCID: PMC308771  PMID: 14681463
25.  A Single-Center, Open-Label, Randomized, Parallel-Group Study Assessing the Differences Between an Angiotensin II Receptor Antagonist and an Angiotensin-Converting Enzyme Inhibitor in Hypertensive Patients with Congestive Heart Failure: The Research for Efficacy of Angiotensin II Receptor Antagonist in Hypertensive Patients with Congestive Heart Failure Study 
Background: Angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) have been used to treat congestive heart failure (CHF). According to a MEDLINE search, however, few studies are available on the clinical differences between ARBs and ACEIs in CHF.
Objective: To examine the clinical differences between an ARB (candesartan cilexetil) and an ACEI (lisinopril) in the treatment of CHF, we investigated exercise capacity, ventricular function, and neurohormonal levels in hypertensive patients with CHF before and after treatment with these agents.
Methods: Patients with symptoms of CHF (New York Heart Association functional class II–III and left ventricular ejection fraction [LVEF] ≤45%) complicated by hypertension (systolic blood pressure [BP] ≥140 mm Hg or diastolic BP ≥90 mm Hg) were eligible for this single-center, open-label, randomized, parallel-group study. They were given either the ARB or the ACEI for 24 weeks. A cardiopulmonary exercise test and echocardiography were performed. Clinical findings and cardiac events in addition to the CHF symptoms were investigated. Neurohormonal levels were measured before and after 24 weeks of treatment with the study drug. The primary end point of this study was exercise capacity, which was measured using peak oxygen consumption (VO2).
Results: Forty-two patients with CHF were enrolled and 38 (28 men, 10 women; mean [SD] age, 69.0 [8.2] years) completed the study. None of these patients had definite progression of the CHF symptoms. In the ARB-treated patients, mean (SD) peak VO2 (mL/min/kg) and LVEF (%) increased from 14.1 (2.9) to 15.3 (3.4) and from 34.4 (9.5) to 41.8 (9.5), respectively. In the ACEI group, the peak VO2 did not change, but the LVEF (%) increased from 34.2 (10.2) to 40.4 (13.0). However, the differences between ARB and ACEI were not clarified because of the possibility of a small sample size.
Conclusions: Although this study was not powered to show differences in efficacy between the ARB and ACEI in this study, our findings suggest that both ARB and ACEI had beneficial effects in hypertensive patients with CHF. Some unidentified differences in hemodynamic characteristics were found between the ARB and the ACEI groups.
doi:10.1016/S0011-393X(03)00020-1
PMCID: PMC4053004  PMID: 24944358
renin–angiotensin system; congestive heart failure; cardiopulmonary exercise test; neurohormone

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