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1.  A Case of Mild Encephalopathy with a Reversible Splenial Lesion Associated with G5P[6]Rotavirus Infection 
Case Reports in Pediatrics  2013;2013:197163.
We report a case of mild encephalopathy with a reversible splenial lesion (MERS) associated with acute gastroenteritis caused by rotavirus (RV) infection. The patient (male, 4 years and 3 months old) was admitted to our hospital for diarrhea and afebrile seizures. Head MRI revealed a hyperintense signal in the splenium of the corpus callosum on DWI and a hypointense signal on the ADC-map. After awakening from sedation, the patient's disturbance of consciousness improved. On day 5 after admission of the illness, the patient was discharged from the hospital in a good condition. Electroencephalography on day 2 after admission was normal. On day 8 of admission, head MRI revealed that the splenial lesion had disappeared. RV antigen-positive stools suggested that RV had caused MERS. This RV genotype was considered to be G5P[6]; it may have spread to humans as a strain reassortment through substitution of porcine RV into human RV gene segments. This extremely rare genotype was detected first in Japan and is not covered by existing vaccines; this is the first sample isolated from encephalopathy patients. Few reports have investigated RV genotypes in encephalopathy; we believe that this case is valuable for studying the relationship between genotypes and clinical symptoms.
doi:10.1155/2013/197163
PMCID: PMC3845239  PMID: 24324908
2.  Structure of the human-heart fatty-acid-binding protein 3 in complex with the fluorescent probe 1-anilinonaphthalene-8-sulphonic acid 
Journal of Synchrotron Radiation  2013;20(Pt 6):923-928.
The crystal structure of human-heart-type fatty-acid-binding protein in complex with anilinonaphthalene-8-sulfonate was solved at 2.15 Å resolution revealing the detailed binding mechanism of the fluorescent probe 1-anilinonaphthalene-8-sulfonate.
Heart-type fatty-acid-binding protein (FABP3), which is a cytosolic protein abundantly found in cardiomyocytes, plays a role in trafficking fatty acids throughout cellular compartments by reversibly binding intracellular fatty acids with relatively high affinity. The fluorescent probe 1-anilinonaphthalene-8-sulfonate (ANS) is extensively utilized for examining the interaction of ligands with fatty-acid-binding proteins. The X-ray structure of FABP3 was determined in the presence of ANS and revealed the detailed ANS-binding mechanism. Furthermore, four water molecules were clearly identified in the binding cavity. Through these water molecules, the bound ANS molecule forms indirect hydrogen-bond interactions with FABP3. The adipocyte-type fatty-acid-binding protein (FABP4) exhibits 67% sequence identity with FABP3 and its crystal structure is almost the same as that of FABP3. However, FABP4 can bind with a higher affinity to ANS than FABP3. To understand the difference in their ligand specificities, a structural comparison was performed between FABP3–ANS and FABP4–ANS complexes. The result revealed that the orientation of ANS binding to FABP3 is completely opposite to that of ANS binding to FABP4, and the substitution of valine in FABP4 to leucine in FABP3 may result in greater steric hindrance between the side-chain of Leu115 and the aniline ring of ANS.
doi:10.1107/S0909049513021298
PMCID: PMC3795557  PMID: 24121341
X-ray structure; FABP3–ANS complex; human-heart fatty-acid-binding protein
3.  Utilization of Stiff Culm Trait of Rice smos1 Mutant for Increased Lodging Resistance 
PLoS ONE  2014;9(7):e96009.
Although the introduction of semi-dwarf trait into rice has led to improved lodging resistance making it capable of supporting high grain yield, lodging still remains a concern when attempting to further increase the grain yield of rice. However, improving the lodging resistance in rice by depending on the semi-dwarf trait alone is possible only up to a certain limit, beyond which other traits may be needed for reinforcement. To search for alternative traits relating to high lodging resistance, we identified 9 rice mutant lines possessing improved culm strength. To evaluate whether such lines can be useful for breeding lodging resistant rice, small organ size1 (smos1) mutant having increased lodging resistance but low tiller number and low grain yield, was chosen as a representative for a breeding trial. smos1 was crossed with ST-4 (from the Stock rice collection of Nagoya University Togo field #4), a cultivar with high tiller number and high grain yield, and from their progeny, LRC1 (lodging resistance candidate-1) was selected. Although the low tiller number trait of smos1 was not fully reversed in LRC1, this was compensated by an increase in grain weight per panicle, thereby resulting in high grain yield per plant. This important attribute of LRC1 was further enhanced by the improved lodging resistance trait inherited from smos1. Such improved lodging resistance in LRC1 and smos1 was revealed to be mainly due to increased culm diameter and culm thickness, which led to a high section modulus (SM) value, a parameter defining the physical strength of the culm. Since smos1 possesses high breaking-type lodging resistance which is different from semi-dwarf plants with high bending-type lodging resistance, an alternative approach of using thick culm lines for the creation of rice with increased lodging resistance is hereby proposed.
doi:10.1371/journal.pone.0096009
PMCID: PMC4079509  PMID: 24987959
4.  The prospects and challenges of universal vaccines for influenza 
Trends in microbiology  2013;21(7):350-358.
Vaccination is the most effective way to reduce the impact of epidemic as well as pandemic influenza. However, the licensed inactivated influenza vaccine induces strain-specific immunity and must be updated annually. When novel viruses appear, matched vaccines are not likely to be available in time for the first wave of a pandemic. Yet, the enormous diversity of influenza A viruses in nature makes it impossible to predict which subtype or strain will cause the next pandemic. Several recent scientific advances have generated renewed enthusiasm and hope for universal vaccines that will induce broad protection from a range of influenza viruses.
doi:10.1016/j.tim.2013.04.003
PMCID: PMC3700639  PMID: 23685068
Influenza virus; Universal vaccine
5.  Split luciferase complementation assay to detect regulated protein-protein interactions in rice protoplasts in a large-scale format 
Rice  2014;7(1):11.
Background
The rice interactome, in which a network of protein-protein interactions has been elucidated in rice, is a useful resource to identify functional modules of rice signal transduction pathways. Protein-protein interactions occur in cells in two ways, constitutive and regulative. While a yeast-based high-throughput method has been widely used to identify the constitutive interactions, a method to detect the regulated interactions is rarely developed for a large-scale analysis.
Results
A split luciferase complementation assay was applied to detect the regulated interactions in rice. A transformation method of rice protoplasts in a 96-well plate was first established for a large-scale analysis. In addition, an antibody that specifically recognizes a carboxyl-terminal fragment of Renilla luciferase was newly developed. A pair of antibodies that recognize amino- and carboxyl- terminal fragments of Renilla luciferase, respectively, was then used to monitor quality and quantity of interacting recombinant-proteins accumulated in the cells. For a proof-of-concept, the method was applied to detect the gibberellin-dependent interaction between GIBBERELLIN INSENSITIVE DWARF1 and SLENDER RICE 1.
Conclusions
A method to detect regulated protein-protein interactions was developed towards establishment of the rice interactome.
doi:10.1186/s12284-014-0011-8
PMCID: PMC4077619  PMID: 24987490
Interactome; Split luciferase complementation; Regulated protein-protein interactions
6.  Pedestrian counting with grid-based binary sensors based on Monte Carlo method 
SpringerPlus  2014;3:299.
Abstract
In this paper, we propose a method for estimating the number of pedestrians walking in opposite directions, as in cases of a shopping street or a sidewalk in a downtown area. The proposed method utilizes a compound-eye sensor that is constructed by placing two binary sensors for the pedestrians’ movement direction and multiple binary sensors for the vertical direction of the pedestrians’ movement direction. A number of Monte Carlo simulations about the movement of pedestrians are conducted, and the output history of the compound-eye sensor is obtained in each simulation. The simulation scenario with a small difference of the output history of the compound-eye sensor is selected to estimate the number of pedestrians. Evaluation results show that in the field whose width is 8 [m] the relative error in the proposed method is the smallest by using 2×8 binary sensors.
doi:10.1186/2193-1801-3-299
PMCID: PMC4079898  PMID: 24995154
Pedestrian counting; Monte Carlo method; Binary sensor; Sensor network
7.  Gibberellin deficiency pleiotropically induces culm bending in sorghum: an insight into sorghum semi-dwarf breeding 
Scientific Reports  2014;4:5287.
Regulation of symmetrical cell growth in the culm is important for proper culm development. So far, the involvement of gibberellin (GA) in this process has not yet been demonstrated in sorghum. Here, we show that GA deficiency resulting from any loss-of-function mutation in four genes (SbCPS1, SbKS1, SbKO1, SbKAO1) involved in the early steps of GA biosynthesis, not only results in severe dwarfism but also in abnormal culm bending. Histological analysis of the bent culm revealed that the intrinsic bending was due to an uneven cell proliferation between the lower and upper sides of culm internodes. GA treatment alleviated the bending and dwarfism in mutants, whereas the GA biosynthesis inhibitor, uniconazole, induced such phenotypes in wild-type plants— both in a concentration-dependent manner, indicating an important role of GA in controlling erectness of the sorghum culm. Finally, we propose that because of the tight relationship between GA deficiency-induced dwarfism and culm bending in sorghum, GA-related mutations have unlikely been selected in the history of sorghum breeding, as could be inferred from previous QTL and association studies on sorghum plant height that did not pinpoint GA-related genes.
doi:10.1038/srep05287
PMCID: PMC4055941  PMID: 24924234
8.  Postoperative Deep Surgical-Site Infection after Instrumented Spinal Surgery: A Multicenter Study 
Global Spine Journal  2013;3(2):95-102.
A retrospective survey revealed 37 cases (1.1%) of deep surgical-site infection (SSI) among 3,462 instrumented spinal surgeries between 2004 and 2008. Excluding 8 patients who were unclassifiable, we categorized 29 patients into 3 groups of similar backgrounds—thoracolumbar degenerative disease (the DEG group; n = 15), osteoporotic vertebral collapse (the OVC group; n = 10), and cervical disorders (the cervical group; n = 4)—and investigated the key to implant salvage. Final respective implant retention rates for the groups were 40, 0, and 100%, with the OVC group having the worst rate (p < 0.01). In the DEG group with early infection, those whose implants were retained had lower body temperatures, lower white blood cell counts, and a lower rate of discharge at the time of SSI diagnosis (p < 0.05). Implant retention may be affected by initial spinal pathology. In the DEG group, debridement before drainage may be advantageous to implant salvage.
doi:10.1055/s-0033-1343072
PMCID: PMC3854595  PMID: 24436857
surgical-site infection; spinal surgery; spinal instrumentation; treatment
9.  A Panel of Serum Biomarkers Differentiates IgA Nephropathy from Other Renal Diseases 
PLoS ONE  2014;9(5):e98081.
Background and Objectives
There is increasing evidence that galactose-deficient IgA1 (Gd-IgA1) and Gd-IgA1-containing immune complexes are important for the pathogenesis of IgA nephropathy (IgAN). In the present study, we assessed a novel noninvasive multi-biomarker approach in the diagnostic test for IgAN.
Materials and Methods
We compared serum levels of IgA, IgG, Gd-IgA1, Gd-IgA1-specific IgG and Gd-IgA1-specific IgA in 135 IgAN patients, 79 patients with non-IgAN chronic kidney disease (CKD) controls and 106 healthy controls. Serum was collected at the time of kidney biopsy from all IgAN and CKD patients.
Results
Each serum marker was significantly elevated in IgAN patients compared to CKD (P<0.001) and healthy controls (P<0.001). While 41% of IgAN patients had elevated serum Gd-IgA1 levels, 91% of these patients exhibited Gd-IgA1-specific IgG levels above the 90th percentile for healthy controls (sensitivity 89%, specificity 92%). Although up to 25% of CKD controls, particularly those with immune-mediated glomerular diseases including lupus nephritis, also had elevated serum levels of Gd-IgA1-specific IgG, most IgAN patients had elevated levels of Gd-IgA1-specific antibody of both isotypes. Serum levels of Gd-IgA1-specific IgG were associated with renal histological grading. Furthermore, there was a trend toward higher serum levels of Gd-IgA1-specific IgG in IgAN patients with at least moderate proteinuria (≥1.0 g/g), compared to patients with less proteinuria.
Conclusions
Serum levels of Gd-IgA1-specific antibodies are elevated in most IgAN patients, and their assessment, together with serum levels of Gd-IgA1, improves the specificity of the assays. Our observations suggest that a panel of serum biomarkers may be helpful in differentiating IgAN from other glomerular diseases.
doi:10.1371/journal.pone.0098081
PMCID: PMC4032235  PMID: 24858067
10.  Sequence analysis on the information of folding initiation segments in ferredoxin-like fold proteins 
Background
While some studies have shown that the 3D protein structures are more conservative than their amino acid sequences, other experimental studies have shown that even if two proteins share the same topology, they may have different folding pathways. There are many studies investigating this issue with molecular dynamics or Go-like model simulations, however, one should be able to obtain the same information by analyzing the proteins’ amino acid sequences, if the sequences contain all the information about the 3D structures. In this study, we use information about protein sequences to predict the location of their folding segments. We focus on proteins with a ferredoxin-like fold, which has a characteristic topology. Some of these proteins have different folding segments.
Results
Despite the simplicity of our methods, we are able to correctly determine the experimentally identified folding segments by predicting the location of the compact regions considered to play an important role in structural formation. We also apply our sequence analyses to some homologues of each protein and confirm that there are highly conserved folding segments despite the homologues’ sequence diversity. These homologues have similar folding segments even though the homology of two proteins’ sequences is not so high.
Conclusion
Our analyses have proven useful for investigating the common or different folding features of the proteins studied.
doi:10.1186/1472-6807-14-15
PMCID: PMC4055915  PMID: 24884463
Folding initiation segment prediction; Sequence analysis; Inter-residue average distance statistics; Evolutionarily conserved folding; Ribosomal protein S6; Procarboxypeptidase A2; U1A Spliceosomal protein; mt-Acylphosphatase
11.  TGR5 signalling inhibits the production of pro-inflammatory cytokines by in vitro differentiated inflammatory and intestinal macrophages in Crohn's disease 
Immunology  2013;139(1):19-29.
Bile acids (BAs) play important roles not only in lipid metabolism, but also in signal transduction. TGR5, a transmembrane receptor of BAs, is an immunomodulative factor, but its detailed mechanism remains unclear. Here, we aimed to delineate how BAs operate in immunological responses via the TGR5 pathway in human mononuclear cell lineages. We examined TGR5 expression in human peripheral blood monocytes, several types of in vitro differentiated macrophages (Mϕs) and dendritic cells. Mϕs differentiated with macrophage colony-stimulating factor and interferon-γ (Mγ-Mϕs), which are similar to the human intestinal lamina propria CD14+ Mϕs that contribute to Crohn's disease (CD) pathogenesis by production of pro-inflammatory cytokines, highly expressed TGR5 compared with any other type of differentiated Mϕ and dendritic cells. We also showed that a TGR5 agonist and two types of BAs, deoxycholic acid and lithocholic acid, could inhibit tumour necrosis factor-α production in Mγ-Mϕs stimulated by commensal bacterial antigen or lipopolysaccharide. This inhibitory effect was mediated by the TGR5–cAMP pathway to induce phosphorylation of c-Fos that regulated nuclear factor-κB p65 activation. Next, we analysed TGR5 levels in lamina propria mononuclear cells (LPMCs) obtained from the intestinal mucosa of patients with CD. Compared with non-inflammatory bowel disease, inflamed CD LPMCs contained more TGR5 transcripts. Among LPMCs, isolated CD14+ intestinal Mϕs from patients with CD expressed TGR5. In isolated intestinal CD14+ Mϕs, a TGR5 agonist could inhibit tumour necrosis factor-α production. These results indicate that TGR5 signalling may have the potential to modulate immune responses in inflammatory bowel disease.
doi:10.1111/imm.12045
PMCID: PMC3634536  PMID: 23566200
bile acid; Crohn's disease; intestinal macrophage; TGR5; tumour necrosis factor α
12.  On and Off Retinal Circuit Assembly by Divergent Molecular Mechanisms 
Science (New York, N.Y.)  2013;342(6158):10.1126/science.1241974.
Direction-selective responses to motion can be to the onset (On) or cessation (Off) of illumination. Here, we show that the transmembrane protein semaphorin 6A and its receptor plexin A2 are critical for achieving radially symmetric arborization of On starburst amacrine cell (SAC) dendrites and normal SAC stratification in the mouse retina. Plexin A2 is expressed in both On and Off SACs; however, semaphorin 6A is expressed in On SACs. Specific On-Off bistratified direction-selective ganglion cells in semaphorin 6A−/− mutants exhibit decreased tuning of On directional motion responses. These results correlate the elaboration of symmetric SAC dendritic morphology and asymmetric responses to motion, shedding light on the development of visual pathways that use the same cell types for divergent outputs.
doi:10.1126/science.1241974
PMCID: PMC3863450  PMID: 24179230
13.  Super-Resolution Imaging of PDMS Nanochannels by Single-Molecule Micelle-Assisted Blink Microscopy 
The journal of physical chemistry. B  2013;117(16):4406-4411.
Single-molecule super-resolution microscopy is an emerging technique for nanometer-scale fluorescence imaging, but in vitro single-molecule imaging protocols typically require a constant supply of reagents, and such transport is restricted in constrained geometries. In this paper, we develop Single-Molecule Micelle-Assisted Blink (MAB) microcopy to enable sub-diffraction-limit imaging of nanochannels with better than 40-nm accuracy. The method, based on micelles and thiol-related photoswitching, is used to measure nanochannels formed in polydimethyl-siloxane (PDMS) through tensile cracking. These conduits are reversibly size-adjustable from a few nanometers up to a micron, and enable filtering of small particles and linearization of DNA. Unfortunately, conventional techniques cannot be used to measure widths, characterize heterogeneities or discover porosity in situ. We overcome the access barriers by using sodium dodecyl sulfate (SDS), an ionic surfactant, to facilitate delivery of Cy5 dye and beta-mercaptoethanol reducing agent in the confined geometry. These SDS micelles and admicelles have the further benefit of slowing diffusion of Cy5 to improve localization accuracy. We use MAB microscopy to measure nanochannel widths, to reveal heterogeneity along channel lengths and between different channels in the same device, and to probe biologically relevant information about the nano-environment, such as solvent accessibility.
doi:10.1021/jp307635v
PMCID: PMC3637843  PMID: 23256598
Fluorescence; diffraction limit; microfluidics; photoswitching; atomic force microscopy
14.  Diagnosis and management of intestinal Behçet’s disease  
Abstract
Behçet’s disease (BD) is a chronic relapsing disease with multiple organ system involvement characterized clinically by oral and genital aphthae, cutaneous lesions, and ophthalmological, neurological, and/or gastrointestinal manifestations. Little clinical evidence is available regarding the management of patients with intestinal BD, despite recognition that the presence of intestinal lesions is a poor prognostic factor, causing perforation and massive bleeding. Many recent case reports have suggested that anti-tumor necrosis factor alpha (TNF)α monoclonal antibodies (mAbs) are effective in patients with intestinal BD. Adalimumab, a fully human anti-TNFα mAb, has been approved in Japan for the treatment of intestinal BD. Here, we review the pathogenesis, diagnosis and management of intestinal BD, including evidence of the efficacy of anti-TNFα mAbs.
doi:10.1007/s12328-014-0488-0
PMCID: PMC4037558  PMID: 24883128
Intestinal Behçet’s disease; Anti-TNFα mAb; Trisomy 8; Adalimumab
15.  Safety analysis of two different regimens of uracil–tegafur plus leucovorin as adjuvant chemotherapy for high-risk stage II and III colon cancer in a phase III trial comparing 6 with 18 months of treatment: JFMC33-0502 trial 
Purpose
The JFMC33-0502 trial is a phase III clinical study designed to determine the most appropriate duration of postoperative adjuvant chemotherapy with uracil–tegafur (UFT) plus leucovorin in patients with stage IIB or III colon cancer. We report the interim results of preplanned safety analyses.
Methods
Patients with stage IIB or III colon cancer who had undergone curative resection were randomly assigned to receive UFT (300 mg/m2) plus leucovorin (75 mg/day) for 6 months (control group, 4 weeks of treatment followed by a 1-week rest, five courses) or for 18 months (study group, 5 days of treatment followed by a 2-day rest, 15 courses). Treatment status and safety were evaluated.
Results
A total of 1,071 patients were enrolled, and 1,063 were included in safety analyses. Treatment completion rate at 6 months was 74.0 % in the control group and 76.7 % in the study group. Treatment completion rate in the study group at 18 months was 56.0 %. The overall incidence of adverse events (AEs) was 75.3 % in the control group and 77.6 % in the study group. The incidences of grade 3 or higher AEs were low in both groups. During the first 6 months, the incidences of the subjective AEs were significantly lower in the study group.
Conclusions
Oral UFT plus leucovorin given by either dosage schedule is a very safe regimen for adjuvant chemotherapy. In particular, 5 days of treatment followed by a 2-day rest was a useful treatment option from the viewpoint of toxicity even when given for longer than 6 months.
Electronic supplementary material
The online version of this article (doi:10.1007/s00280-014-2461-5) contains supplementary material, which is available to authorized users.
doi:10.1007/s00280-014-2461-5
PMCID: PMC4032639  PMID: 24744162
Colon cancer; Adjuvant chemotherapy; Uracil–tegafur (UFT); Leucovorin; Treatment duration
16.  Sweetened Beverages, Coffee, and Tea and Depression Risk among Older US Adults 
PLoS ONE  2014;9(4):e94715.
Sweetened beverages, coffee, and tea are the most consumed non-alcoholic beverages and may have important health consequences. We prospectively evaluated the consumption of various types of beverages assessed in 1995–1996 in relation to self-reported depression diagnosis after 2000 among 263,923 participants of the NIH-AARP Diet and Health Study. Odds ratios (OR) and 95% confidence intervals (CI) were derived from multivariate logistic regressions. The OR (95% CI) comparing ≥4 cans/cups per day with none were 1.30 (95%CI: 1.17–1.44) for soft drinks, 1.38 (1.15–1.65) for fruit drinks, and 0.91 (0.84–0.98) for coffee (all P for trend<0.0001). Null associations were observed for iced-tea and hot tea. In stratified analyses by drinkers of primarily diet versus regular beverages, the ORs were 1.31 (1.16–1.47) for diet versus 1.22 (1.03–1.45) for regular soft drinks, 1.51 (1.18–1.92) for diet versus 1.08 (0.79–1.46) for regular fruit drinks, and 1.25 (1.10–1.41) for diet versus 0.94 (0.83–1.08) for regular sweetened iced-tea. Finally, compared to nondrinkers, drinking coffee or tea without any sweetener was associated with a lower risk for depression, adding artificial sweeteners, but not sugar or honey, was associated with higher risks. Frequent consumption of sweetened beverages, especially diet drinks, may increase depression risk among older adults, whereas coffee consumption may lower the risk.
doi:10.1371/journal.pone.0094715
PMCID: PMC3990543  PMID: 24743309
17.  Efficacy of the anti–IL-6 receptor antibody tocilizumab in neuromyelitis optica 
Neurology  2014;82(15):1302-1306.
Objective:
To evaluate the safety and efficacy of a humanized anti–interleukin-6 receptor antibody, tocilizumab (TCZ), in patients with neuromyelitis optica (NMO).
Methods:
Seven patients with anti–aquaporin-4 antibody (AQP4-Ab)-positive NMO or NMO spectrum disorders were recruited on the basis of their limited responsiveness to their current treatment. They were given a monthly injection of TCZ (8 mg/kg) with their current therapy for a year. We evaluated the annualized relapse rate, the Expanded Disability Status Scale score, and numerical rating scales for neurogenic pain and fatigue. Serum levels of anti-AQP4-Ab were measured with AQP4-transfected cells.
Results:
Six females and one male with NMO were enrolled. After a year of TCZ treatment, the annualized relapse rate decreased from 2.9 ± 1.1 to 0.4 ± 0.8 (p < 0.005). The Expanded Disability Status Scale score, neuropathic pain, and general fatigue also declined significantly. The ameliorating effects on intractable pain exceeded expectations.
Conclusion:
Interleukin-6 receptor blockade is a promising therapeutic option for NMO.
Classification of evidence:
This study provides Class IV evidence that in patients with NMO, TCZ reduces relapse rate, neuropathic pain, and fatigue.
doi:10.1212/WNL.0000000000000317
PMCID: PMC4001188  PMID: 24634453
18.  Functionally Distinct Effects of the C-Terminal Regions of IKKε and TBK1 on Type I IFN Production 
PLoS ONE  2014;9(4):e94999.
Inhibitor of κB kinase ε (IKKε) and TANK binding kinase 1 (TBK1), so-called non-canonical IKKs or IKK-related kinases, are involved in the cellular innate immunity by inducing type I IFNs. Two kinases commonly phosphorylate transcription factors IRF3 and IRF7 in type I IFN production pathway. In contrast to TBK1, underlying mechanisms of IKKε activation and regions required for activation of downstream molecules are poorly understood. In this study, we investigated regions of IKKε required for the activation of type I IFN promoter specially, by focusing on the C-terminal region. To show the functional significance of the IKKε C-terminal region on type I IFN production, we employed various mutant forms of IKKε and compared to corresponding region of TBK1. We identified the specific regions and residues of IKKε involved in the activation of downstream signaling. Interestingly, corresponding region and residues are not required for activation of downstream signaling by TBK1. The results highlight the importance of the C-terminal region in the functional activity of IKKε in innate immune response and also the difference in activation mechanisms between IKKε and the closely related TBK1.
doi:10.1371/journal.pone.0094999
PMCID: PMC3983252  PMID: 24722368
19.  Long-Term Effects of Goshajinkigan in Prevention of Diabetic Complications: A Randomized Open-Labeled Clinical Trial 
Objective. This clinical trial was designed to investigate whether goshajinkigan reduces the onset of diabetic complications or not. Materials and Methods. A total of 332 type 2 diabetic mellitus patients were registered from 9 clinical centers from March 2000 to August 2007. Patients were randomly assigned to take goshajinkigan extract powder, 2.5 grams for 3 times a day or no kampo therapy, additionally to the regular treatment. The primary endpoints were the onset of macrovascular diseases or progression of nephropathy or retinopathy. Statistical analysis was performed by the intention-to-treat method. Results. After 5 years of observation, 116 patients were submitted to analysis. Among them, no macrovascular events were observed in both groups. Although 43 participants had upstaging of retinopathy or nephropathy in total, there was no significant difference between goshajinkigan group and control group. Deterioration of ankle reflex was suppressed in goshajinkigan group. Also glycated hemoglobin, and fasting plasma glucose were decreased in the goshajinkigan group. Conclusion. Although the power of analysis was too low to demonstrate any effects of goshajinkigan on the progression of macrovascular diseases, retinopathy or nephropathy, goshajinkigan may be beneficial for diabetic neuropathy and glycemic control.
doi:10.1155/2014/128726
PMCID: PMC4000675  PMID: 24812564
20.  Association between Self-Reported General and Mental Health and Adverse Outcomes: A Retrospective Cohort Study of 19 625 Scottish Adults 
PLoS ONE  2014;9(4):e93857.
Objective
Self-reported general health and mental health are independent predictors of all-cause mortality. This study examines whether they are also independent predictors of incident cancer, coronary heart disease and psychiatric hospitalisation.
Methods
We conducted a retrospective, population cohort study by linking the 19 625 Scottish adults who participated in the Scottish Health Surveys 1995–2003, to hospital admissions, cancer registration and death certificate records. We conducted Cox proportional hazard models adjusting for potential confounders including age, sex, socioeconomic status, alcohol, smoking status, body mass index, hypertension and diabetes.
Results
Poor general health was reported by 1215 (6.2%) participants and was associated with cancer registrations (adjusted Hazard Ratio [HR] 1.30, 95% CI 1.10, 1.55), coronary heart disease events (adjusted HR 2.30, 95% CI 1.86, 2.84) and psychiatric hospitalisations (adjusted HR 2.42, 95% CI 1.65, 3.56). There was evidence of dose relationships and the associations remained significant after adjustment for mental health. 3172 (16%) participants had poor mental health (GHQ ≥4). After adjustment for general health, the associations between poor mental health and coronary heart disease events (adjusted HR 1.36, 95% CI 1.13, 1.63) and all-cause death (adjusted HR 1.38, 95% CI 1.23, 1.55) became non-significant, but mental health remained associated with psychiatric hospitalisations (fully adjusted HR 2.02, 95% CI 1.48, 2.75).
Conclusion
Self-reported general health is a significant predictor of a range of clinical outcomes independent of mental health. The association between mental health and non-psychiatric outcomes is mediated by general health but it is an independent predictor of psychiatric outcome. Individuals with poor general health or mental health warrant close attention.
doi:10.1371/journal.pone.0093857
PMCID: PMC3976324  PMID: 24705574
21.  Low-dose interleukin-2 therapy restores regulatory T cell homeostasis in patients with chronic graft-versus-host disease 
Science translational medicine  2013;5(179):179ra43.
CD4+FoxP3+ regulatory T cells (Tregs) play a central role in the maintenance of immune tolerance after allogeneic hematopoietic stem cell transplantation. We recently reported that daily administration of low-dose IL-2 induces selective expansion of functional Treg and clinical improvement of chronic graft-versus-host disease (GVHD). To define the mechanisms of action of IL-2 therapy we examined the immunologic effects of this treatment on homeostasis of CD4 T cell subsets after transplant. We first demonstrate that chronic GVHD is characterized by constitutive phosphorylation of Stat5 in conventional CD4 T cells (Tcon) associated with elevated levels of IL-7 and IL-15 and relative functional deficiency of IL-2. IL-2 therapy resulted in the selective increase of Stat5 phosphorylation in Treg and decrease of pStat5 in Tcon. Over an eight-week period, IL-2 therapy induced a series of changes in Treg homeostasis, including increased proliferation, increased thymic export and enhanced resistance to apoptosis. Low-dose IL-2 had minimal effects on Tcon. These findings define the mechanisms whereby low-dose IL-2 therapy restores the homeostasis of CD4 T cell subsets and promotes the re-establishment of immune tolerance.
doi:10.1126/scitranslmed.3005265
PMCID: PMC3686517  PMID: 23552371
22.  Benefits of skin biopsy of senile hemangioma in intravascular large B-cell lymphoma: A case report and review of the literature 
Oncology Letters  2014;7(6):2003-2006.
Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of B-cell lymphoma characterized by selective growth of clonal B-cells in the lumen of the small vessels of various organs including the liver, spleen, lungs, skin, brain, and kidney. An 86-year-old male presented with weight loss, fever and night sweats (known as B symptoms). Blood examination revealed pancytopenia, high lactate dehydrogenase and high soluble interleukin-2 receptor, suggesting hematopoietic malignancy. However, there were no abnormal hematopoietic cells in the peripheral blood. No lymph node swelling was identified on examination by whole-body computed tomography scan. Therefore, IVLBCL was suspected, and random skin biopsies and a skin biopsy from a senile hemangioma were carried out. A small number of large atypical lymphoid cells resided in the small blood vessels in the deep dermis and subcutaneous tissue of the random skin biopsies, and numerous atypical lymphoid cells were identified in the small vessels of the senile hemangioma. These results suggest the usefulness of skin biopsy from senile hemangiomas in the diagnosis of IVLBCL.
doi:10.3892/ol.2014.2017
PMCID: PMC4049734  PMID: 24932279
intravascular large B-cell lymphoma; senile hemangioma; skin biopsy; CD20
23.  Lack of Association between Intact/Deletion Polymorphisms of the APOBEC3B Gene and HIV-1 Risk 
PLoS ONE  2014;9(3):e92861.
Objective
The human APOBEC3 family of proteins potently restricts HIV-1 replication APOBEC3B, one of the family genes, is frequently deleted in human populations. Two previous studies reached inconsistent conclusions regarding the effects of APOBEC3B loss on HIV-1 acquisition and pathogenesis. Therefore, it was necessary to verify the effects of APOBEC3B on HIV-1 infection in vivo.
Methods
Intact (I) and deletion (D) polymorphisms of APOBEC3B were analyzed using PCR. The syphilis, HBV and HCV infection rates, as well as CD4+ T cell counts and viral loads were compared among three APOBEC3B genotype groups (I/I, D/I, and D/D). HIV-1 replication kinetics was assayed in vitro using primary cells derived from PBMCs.
Results
A total of 248 HIV-1-infected Japanese men who have sex with men (MSM) patients and 207 uninfected Japanese MSM were enrolled in this study. The genotype analysis revealed no significant differences between the APOBEC3B genotype ratios of the infected and the uninfected cohorts (p = 0.66). In addition, HIV-1 disease progression parameters were not associated with the APOBEC3B genotype. Furthermore, the PBMCs from D/D and I/I subjects exhibited comparable HIV-1 susceptibility.
Conclusion
Our analysis of a population-based matched cohort suggests that the antiviral mechanism of APOBEC3B plays only a negligible role in eliminating HIV-1 in vivo.
doi:10.1371/journal.pone.0092861
PMCID: PMC3965477  PMID: 24667791
24.  Serum heat shock protein 47 levels are elevated in acute interstitial pneumonia 
Background
Heat shock protein (HSP) 47, a collagen-specific molecular chaperone, is involved in the processing and/or secretion of procollagen. We hypothesized that HSP47 could be a useful marker for fibrotic lung disease. The aim of this study was to evaluate serum levels of HSP47 in patients with various idiopathic interstitial pneumonias (IIPs).
Methods
Subjects comprised 9 patients with acute interstitial pneumonia (AIP), 12 with cryptogenic organizing pneumonia (COP), 16 with nonspecific interstitial pneumonia (NSIP), 19 with idiopathic pulmonary fibrosis (IPF), and 19 healthy adult volunteers.
Results
Patients with AIP had serum HSP47 levels that were significantly higher than those of COP, NSIP or IPF patients and those of healthy volunteers. In contrast, serum levels of HSP47 among patients with COP, NSIP, IPF, and healthy volunteers did not differ significantly. Receiver operating characteristic curves revealed that the cut-off level for HSP47 that resulted in the highest diagnostic accuracy for discriminating between AIP and COP, NSIP, IPF, and healthy controls was 859.3 pg/mL. The sensitivity, specificity, and diagnostic accuracy were 100.0%, 98.5%, and 98.7%, respectively.
Conclusion
The present results demonstrate that, among patients with various IIPs, serum levels of HSP47 were elevated specifically in patients with AIP.
doi:10.1186/1471-2466-14-48
PMCID: PMC3994423  PMID: 24650086
Heat shock protein 47; Acute interstitial pneumonia; Idiopathic interstitial pneumonia
25.  Serum heat shock protein 47 levels are elevated in acute exacerbation of idiopathic pulmonary fibrosis 
Cell Stress & Chaperones  2013;18(5):581-590.
Little is known about the pathophysiology of acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF). Heat shock protein 47 (HSP47), a collagen-specific molecular chaperone, is essential for biosynthesis and secretion of collagen molecules. Previous studies in experimental animal fibrosis models have shown that downregulation of HSP47 expression reduces collagen production and diminishes fibrosis progression. In this study, serum HSP47 levels were evaluated to elucidate pathogenic differences involving HSP47 between AE-IPF and stable (S)-IPF. Subjects comprised 20 AE-IPF and 33 S-IPF patients. Serum levels of HSP47, Krebs von den Lungen-6 (KL-6), surfactant protein (SP)-A, SP-D, and lactate dehydrogenase (LDH) were measured. Immunohistochemical analysis of lung HSP47 expression was determined in biopsy and autopsy tissues diagnosed as diffuse alveolar damage (DAD) and usual interstitial pneumonia (UIP). Serum levels of HSP47 were significantly higher in AE-IPF than in S-IPF patients, whereas serum levels of KL-6, SP-A, and SP-D did not differ significantly. Receiver operating characteristic curves revealed that HSP47 was superior for discriminating AE-IPF and S-IPF. The cutoff for HSP47 resulting in the highest diagnostic accuracy was 559.4 pg/mL; sensitivity, specificity, and diagnostic accuracy were 100.0 %, 93.9 %, and 96.2 %, respectively. Immunohistochemical analysis revealed that pulmonary HSP47 expression was greater in DAD than UIP tissues. Serum HSP47 was significantly higher in AE-IPF than in S-IPF patients, suggesting that underlying fibrogenic mechanisms involving HSP47 differ in the two conditions.
doi:10.1007/s12192-013-0411-5
PMCID: PMC3745258  PMID: 23435730
Acute exacerbation of idiopathic pulmonary fibrosis; Heat shock protein 47; Krebs von den Lungen-6; Surfactant protein A; Surfactant protein D

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