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1.  Regulation of cargo-selective endocytosis by dynamin 2 GTPase-activating protein girdin 
The EMBO Journal  2014;33(18):2098-2112.
In clathrin-mediated endocytosis (CME), specificity and selectivity for cargoes are thought to be tightly regulated by cargo-specific adaptors for distinct cellular functions. Here, we show that the actin-binding protein girdin is a regulator of cargo-selective CME. Girdin interacts with dynamin 2, a GTPase that excises endocytic vesicles from the plasma membrane, and functions as its GTPase-activating protein. Interestingly, girdin depletion leads to the defect in clathrin-coated pit formation in the center of cells. Also, we find that girdin differentially interacts with some cargoes, which competitively prevents girdin from interacting with dynamin 2 and confers the cargo selectivity for CME. Therefore, girdin regulates transferrin and E-cadherin endocytosis in the center of cells and their subsequent polarized intracellular localization, but has no effect on integrin and epidermal growth factor receptor endocytosis that occurs at the cell periphery. Our results reveal that girdin regulates selective CME via a mechanism involving dynamin 2, but not by operating as a cargo-specific adaptor.
doi:10.15252/embj.201488289
PMCID: PMC4195775  PMID: 25061227
clathrin-mediated endocytosis; dynamin; girdin; GTPase-activating protein; selective endocytosis
2.  Progression of cerebellar chronic encapsulated expanding hematoma during late pregnancy after gamma knife radiosurgery for arteriovenous malformation 
Surgical Neurology International  2014;5(Suppl 16):S575-S579.
Background:
The etiology and appropriate management strategy of chronic encapsulated expanding hematoma during pregnancy after gamma knife radiosurgery for arteriovenous malformation (AVM) remain unclear.
Case Description:
A 34-year-old female developed chronic encapsulated expanding hematoma during late pregnancy, after angiographic disappearance of cerebellar AVM following two courses of gamma knife radiosurgery. The present case implicates pregnancy as a potential promoter of growth and enlargement of chronic encapsulated expanding hematoma, which may become life-threatening and require surgical intervention.
Conclusion:
Immediate surgical management after delivery may be associated with a favorable outcome, so close follow-up management and patient education are very important in women planning pregnancy.
doi:10.4103/2152-7806.148054
PMCID: PMC4287896  PMID: 25593781
Arteriovenous malformation; gamma knife; pregnancy; radiosurgery
3.  Regulation of cargo-selective endocytosis by dynamin 2 GTPase-activating protein girdin 
The EMBO Journal  2014;33(18):2098-2112.
In clathrin-mediated endocytosis (CME), specificity and selectivity for cargoes are thought to be tightly regulated by cargo-specific adaptors for distinct cellular functions. Here, we show that the actin-binding protein girdin is a regulator of cargo-selective CME. Girdin interacts with dynamin 2, a GTPase that excises endocytic vesicles from the plasma membrane, and functions as its GTPase-activating protein. Interestingly, girdin depletion leads to the defect in clathrin-coated pit formation in the center of cells. Also, we find that girdin differentially interacts with some cargoes, which competitively prevents girdin from interacting with dynamin 2 and confers the cargo selectivity for CME. Therefore, girdin regulates transferrin and E-cadherin endocytosis in the center of cells and their subsequent polarized intracellular localization, but has no effect on integrin and epidermal growth factor receptor endocytosis that occurs at the cell periphery. Our results reveal that girdin regulates selective CME via a mechanism involving dynamin 2, but not by operating as a cargo-specific adaptor.
doi:10.15252/embj.201488289
PMCID: PMC4195775  PMID: 25061227
clathrin-mediated endocytosis; dynamin; girdin; GTPase-activating protein; selective endocytosis
4.  Whole-Genome Sequence of Mycobacterium kyorinense 
Genome Announcements  2014;2(5):e01062-14.
We report here the first draft genome sequence of Mycobacterium kyorinense, which was described in 2009 and exhibits significant pathogenicity to humans.
doi:10.1128/genomeA.01062-14
PMCID: PMC4200164  PMID: 25323726
5.  Factors affecting discontinuation of initial treatment with paroxetine in panic disorder and major depressive disorder 
Objective
The aims of the present study were to analyze the association between discontinuation of paroxetine (PAX) and the genetic variants of the polymorphism in the serotonin transporter gene-linked polymorphic region (5-HTTLPR) in Japanese patients with panic disorder (PD) and major depressive disorder (MDD).
Methods
The 5-HTTLPR genotype was determined by polymerase chain reaction method. PAX plasma concentration was measured by high-performance liquid chromatography to confirm adherence.
Results
When comparing between the PD and MDD patients with the chi-square test and Fisher’s exact test, the PD patients had a significant and higher discontinuation rate due to non-adherence than did the MDD patients (13.5% [7/52] versus 0% [0/88], respectively; P<0.001). MDD patients had a significant and higher discontinuation rate due to untraceability than PD patients (12.5% [11/88] versus 1.9% [1/52]; P=0.032). Multilogistic regression revealed a tendency for the long/short and short/short genotypes to affect discontinuation due to adverse effects in PD patients (25.0% versus 6.3%, respectively; P=0.054).
Conclusion
The results indicate that the 5-HTTLPR genotype might contribute to the discontinuation of initial PAX treatment due to adverse effects in PD patients.
doi:10.2147/NDT.S68670
PMCID: PMC4174019  PMID: 25258536
paroxetine; discontinuation; panic disorder; major depressive disorder
6.  The expression status of CD133 is associated with the pattern and timing of primary glioblastoma recurrence 
Neuro-Oncology  2013;15(9):1151-1159.
Background
Glioblastoma carries a poor prognosis primarily because of its high rate of recurrence. The ability to predict the recurrence pattern and timing would be highly useful for determining effective treatment strategies. We examined the correlation between prognostic factors and the pattern of recurrence in patients with primary glioblastoma. In particular, we examined whether there was a correlation between the expression of CD133 and glioblastoma recurrence.
Methods
We retrospectively analyzed 112 patients with primary glioblastoma. The timing and pattern (local or distant) of the initial recurrence were obtained from medical records. To identify factors predictive of recurrence, we examined CD133 expression by Western blots and immunohistochemistry, clinical (age, sex, KPS, Ki67 labeling index, surgery, ventricular entry) and genetic (IDH1, 7p, 9p, 10q, MGMT) factors.
Results
Of the 112 patients, 99 suffered recurrence. The first recurrence was local in 77 patients and distant in 22 patients. Among the factors to predict the pattern of recurrence, CD133 expression was significantly higher in distant than in local recurrence. Of the factors to predict the timing of recurrence, high CD133 expression was associated with shorter time to distant recurrence in both univariate and multivariate analyses (P = .0011 and P = .038, respectively).
Conclusions
The expression of CD133 may be a predictor of the pattern and timing of recurrence of primary glioblastoma.
doi:10.1093/neuonc/not066
PMCID: PMC3748916  PMID: 23658323
glioblastoma; CD133; distant recurrence; local recurrence; stem cells
8.  Activated Cdc42-Bound IQGAP1 Determines the Cellular Endocytic Site 
Molecular and Cellular Biology  2013;33(24):4834-4843.
Recruitment of specific molecules to a specific membrane site is essential for communication between specialized membranous organelles. In the present study, we identified IQGAP1 as a novel GDP-bound-Rab27a-interacting protein. We found that IQGAP1 interacts with GDP-bound Rab27a when it forms a complex with GTP-bound Cdc42. We also found that IQGAP1 regulates the endocytosis of insulin secretory membranes. Silencing of IQGAP1 inhibits both endocytosis and the glucose-induced redistribution of endocytic machinery, including Rab27a and its binding protein coronin 3. These processes can also be inhibited by disruption of the trimeric complex with dominant negative IQGAP1 and Cdc42. These results indicate that activation of Cdc42 in response to the insulin secretagogue glucose recruits endocytic machinery to IQGAP1 at the cell periphery and regulates endocytosis at this membrane site.
doi:10.1128/MCB.00895-13
PMCID: PMC3889562  PMID: 24100016
9.  Isolation, Structure Determination, and Anti-HIV Evaluation of Tigliane-type Diterpenes and Biflavonoid from Stellera chamaejasme 
Journal of natural products  2013;76(5):852-857.
Five novel tigliane-type diterpenes, stelleracins A–E (3–7), a novel flavanone dimer, chamaeflavone A (8), and six known compounds were isolated from roots of Stellera chamaejasme. Their structures were elucidated by extensive spectroscopic analyses. The isolated compounds were evaluated for anti-HIV activity in MT4 cells. New compounds 3–5 showed potent anti-HIV activity (EC90 0.00056–0.0068 μM) and relatively low or no cytotoxicity (IC50 4.4–17.2 μM). These new compounds represent promising new leads for development into anti-AIDS clinical trial candidates.
doi:10.1021/np300815t
PMCID: PMC3715147  PMID: 23611151
10.  Identification of prognostic factors for the nonoperative treatment of stiff shoulder 
International Orthopaedics  2013;37(5):859-864.
Purpose
This study evaluated prognostic factors for the nonoperative treatment of stiff shoulder.
Methods
Between June 2005 and May 2010, 497 stiff shoulders treated at our institute were included in this study. Multivariable analysis for recovery with Cox proportional hazard model was performed. The chief determining variable was pathogenesis (idiopathic, diabetic, post-traumatic) and confounding variables were age (49 or less, 50–59, 60 and above), sex, onset to visit interval (three months or less, four months or more), and external rotation (under 0°, 0° or more) or forward flexion (less than 90°, 90° or more) or internal rotation on the first visit.
Results
There were 356 idiopathic, 61 diabetic, and 80 post-traumatic stiff shoulders. Hazard ratio (HR) and 95 % confidence interval (CI) for recovery (lower HR means poor prognosis) was 0.54 (0.36–0.96) in the diabetic group (p = 0.007), and 0.92 (0.67–1.25) in the post-traumatic group (p = 0.58) compared with the idiopathic group. A positive correlation was observed in ages of 60 or over (HR 1.46, 95 % CI 0.86–1.65, p-value 0.02) and external rotation under 0° on the first visit (0.71, 0.53–0.96, 0.03). No correlations were observed in sex (p = 0.78) or onset to visit interval (p = 0.99). Similar results were obtained when forward flexion or internal rotation was used as a confounding variable.
Conclusions
Diabetes mellitus and severely restricted joint motion on the first visit were poor prognostic factors and ages of 60 or over was a better prognostic factor.
doi:10.1007/s00264-013-1859-8
PMCID: PMC3631491  PMID: 23503671
11.  Burden of Total and Cause-Specific Mortality Related to Tobacco Smoking among Adults Aged ≥45 Years in Asia: A Pooled Analysis of 21 Cohorts 
PLoS Medicine  2014;11(4):e1001631.
Wei Zheng and colleagues quantify the burden of tobacco-smoking-related deaths for adults in Asia.
Please see later in the article for the Editors' Summary
Background
Tobacco smoking is a major risk factor for many diseases. We sought to quantify the burden of tobacco-smoking-related deaths in Asia, in parts of which men's smoking prevalence is among the world's highest.
Methods and Findings
We performed pooled analyses of data from 1,049,929 participants in 21 cohorts in Asia to quantify the risks of total and cause-specific mortality associated with tobacco smoking using adjusted hazard ratios and their 95% confidence intervals. We then estimated smoking-related deaths among adults aged ≥45 y in 2004 in Bangladesh, India, mainland China, Japan, Republic of Korea, Singapore, and Taiwan—accounting for ∼71% of Asia's total population. An approximately 1.44-fold (95% CI = 1.37–1.51) and 1.48-fold (1.38–1.58) elevated risk of death from any cause was found in male and female ever-smokers, respectively. In 2004, active tobacco smoking accounted for approximately 15.8% (95% CI = 14.3%–17.2%) and 3.3% (2.6%–4.0%) of deaths, respectively, in men and women aged ≥45 y in the seven countries/regions combined, with a total number of estimated deaths of ∼1,575,500 (95% CI = 1,398,000–1,744,700). Among men, approximately 11.4%, 30.5%, and 19.8% of deaths due to cardiovascular diseases, cancer, and respiratory diseases, respectively, were attributable to tobacco smoking. Corresponding proportions for East Asian women were 3.7%, 4.6%, and 1.7%, respectively. The strongest association with tobacco smoking was found for lung cancer: a 3- to 4-fold elevated risk, accounting for 60.5% and 16.7% of lung cancer deaths, respectively, in Asian men and East Asian women aged ≥45 y.
Conclusions
Tobacco smoking is associated with a substantially elevated risk of mortality, accounting for approximately 2 million deaths in adults aged ≥45 y throughout Asia in 2004. It is likely that smoking-related deaths in Asia will continue to rise over the next few decades if no effective smoking control programs are implemented.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, more than 5 million smokers die from tobacco-related diseases. Tobacco smoking is a major risk factor for cardiovascular disease (conditions that affect the heart and the circulation), respiratory disease (conditions that affect breathing), lung cancer, and several other types of cancer. All told, tobacco smoking kills up to half its users. The ongoing global “epidemic” of tobacco smoking and tobacco-related diseases initially affected people living in the US and other Western countries, where the prevalence of smoking (the proportion of the population that smokes) in men began to rise in the early 1900s, peaking in the 1960s. A similar epidemic occurred in women about 40 years later. Smoking-related deaths began to increase in the second half of the 20th century, and by the 1990s, tobacco smoking accounted for a third of all deaths and about half of cancer deaths among men in the US and other Western countries. More recently, increased awareness of the risks of smoking and the introduction of various tobacco control measures has led to a steady decline in tobacco use and in smoking-related diseases in many developed countries.
Why Was This Study Done?
Unfortunately, less well-developed tobacco control programs, inadequate public awareness of smoking risks, and tobacco company marketing have recently led to sharp increases in the prevalence of smoking in many low- and middle-income countries, particularly in Asia. More than 50% of men in many Asian countries are now smokers, about twice the prevalence in many Western countries, and more women in some Asian countries are smoking than previously. More than half of the world's billion smokers now live in Asia. However, little is known about the burden of tobacco-related mortality (deaths) in this region. In this study, the researchers quantify the risk of total and cause-specific mortality associated with tobacco use among adults aged 45 years or older by undertaking a pooled statistical analysis of data collected from 21 Asian cohorts (groups) about their smoking history and health.
What Did the Researchers Do and Find?
For their study, the researchers used data from more than 1 million participants enrolled in studies undertaken in Bangladesh, India, mainland China, Japan, the Republic of Korea, Singapore, and Taiwan (which together account for 71% of Asia's total population). Smoking prevalences among male and female participants were 65.1% and 7.1%, respectively. Compared with never-smokers, ever-smokers had a higher risk of death from any cause in pooled analyses of all the cohorts (adjusted hazard ratios [HRs] of 1.44 and 1.48 for men and women, respectively; an adjusted HR indicates how often an event occurs in one group compared to another group after adjustment for other characteristics that affect an individual's risk of the event). Compared with never smoking, ever smoking was associated with a higher risk of death due to cardiovascular disease, cancer (particularly lung cancer), and respiratory disease among Asian men and among East Asian women. Moreover, the researchers estimate that, in the countries included in this study, tobacco smoking accounted for 15.8% of all deaths among men and 3.3% of deaths among women in 2004—a total of about 1.5 million deaths, which scales up to 2 million deaths for the population of the whole of Asia. Notably, in 2004, tobacco smoking accounted for 60.5% of lung-cancer deaths among Asian men and 16.7% of lung-cancer deaths among East Asian women.
What Do These Findings Mean?
These findings provide strong evidence that tobacco smoking is associated with a substantially raised risk of death among adults aged 45 years or older throughout Asia. The association between smoking and mortality risk in Asia reported here is weaker than that previously reported for Western countries, possibly because widespread tobacco smoking started several decades later in most Asian countries than in Europe and North America and the deleterious effects of smoking take some years to become evident. The researchers note that certain limitations of their analysis are likely to affect the accuracy of its findings. For example, because no data were available to estimate the impact of secondhand smoke, the estimate of deaths attributable to smoking is likely to be an underestimate. However, the finding that nearly 45% of the global deaths from active tobacco smoking occur in Asia highlights the urgent need to implement comprehensive tobacco control programs in Asia to reduce the burden of tobacco-related disease.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001631.
The World Health Organization provides information about the dangers of tobacco (in several languages) and about the WHO Framework Convention on Tobacco Control, an international instrument for tobacco control that came into force in February 2005 and requires parties to implement a set of core tobacco control provisions including legislation to ban tobacco advertising and to increase tobacco taxes; its 2013 report on the global tobacco epidemic is available
The US Centers for Disease Control and Prevention provides detailed information about all aspects of smoking and tobacco use
The UK National Health Services Choices website provides information about the health risks associated with smoking
MedlinePlus has links to further information about the dangers of smoking (in English and Spanish)
SmokeFree, a website provided by the UK National Health Service, offers advice on quitting smoking and includes personal stories from people who have stopped smoking
Smokefree.gov, from the US National Cancer Institute, offers online tools and resources to help people quit smoking
doi:10.1371/journal.pmed.1001631
PMCID: PMC3995657  PMID: 24756146
12.  Overexpression of MET is a new predictive marker for anti-EGFR therapy in metastatic colorectal cancer with wild-type KRAS 
Purpose
Since the KRAS mutation is not responsible for all metastatic colorectal cancer (mCRC) patients with resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibody (MoAb) therapy, new predictive and prognostic factors are actively being sought.
Methods
We retrospectively evaluated the efficacy of anti-EGFR MoAb-based therapies in 91 patients with mCRC according to KRAS, BRAF, and PIK3CA mutational status as well as PTEN and MET expression.
Results
In the patient group with wild-type KRAS, the presence of BRAF mutation or PIK3CA mutations was associated with lower disease control rate (DCR), shorter progression-free survival (PFS), and shorter overall survival. Patients with MET overexpression also showed lower DCR and shorter PFS when compared with patients with normal MET expression. In a separate analysis, 44 patients harboring wild-type KRAS tumors were sorted into subgroups of 25 patients without abnormality in three molecules (BRAF, PIK3CA and MET) and 19 patients with abnormality in at least one of these three molecules. The former group showed significantly higher DCR and longer PFS following anti-EGFR therapy than the latter group.
Conclusions
Our data point to the usefulness of MET overexpression, in addition to BRAF and PIK3CA mutations, as a new predictive marker for responsiveness to anti-EGFR MoAbs in mCRC patients with wild-type KRAS. This study also suggests that application of multiple biomarkers is more effective than the use of a single marker in selecting patients who might benefit from anti-EGFR therapy.
Electronic supplementary material
The online version of this article (doi:10.1007/s00280-014-2401-4) contains supplementary material, which is available to authorized users.
doi:10.1007/s00280-014-2401-4
PMCID: PMC3965831  PMID: 24500024
Colorectal cancer; BRAF; PIK3CA; PTEN; MET; Anti-EGFR therapy
13.  Proteasome inhibitor MG132 induces NAG-1/GDF15 expression through the p38 MAPK pathway in glioblastoma cells 
The expression of nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1) is regulated by the p53 and Egr-1 tumor suppressor pathways. Many anti-cancer drugs and chemicals induce NAG-1 expression, but the mechanisms are not fully understood. Transgenic mice expressing human NAG-1 are resistant to intestinal and prostate cancer, suggesting that NAG-1 is a tumor suppressor. Proteasome inhibitors exhibit anti-glioblastoma activities in preclinical studies. Here, we show that the proteasome inhibitors MG132 and bortezomib induced NAG-1 expression and secretion in glioblastoma cells. MG132 increased NAG-1 expression through transcriptional and post-transcriptional mechanisms. At the transcriptional level, the induction of NAG-1 required the −133 to +41 bp region of the promoter. At post-transcriptional levels, MG132 stabilized NAG-1 mRNA by increasing the half-life from 1.5 h to > 8 h. Because of the dramatic increase in mRNA stability, this is likely the major contributor to MG132-mediated NAG-1 induction. Further probing into the mechanism revealed that MG132 increased phosphorylation of the p38 MAPK pathway. Consequently, inhibiting p38 phosphorylation blocked activation of the NAG-1 promoter and decreased mRNA stability, indicating that p38 MAPK activation mediates both MG132-dependent promoter activation and mRNA stabilization of NAG-1. We propose that the induction of NAG-1 by p38 MAPK is a potential contributor to the anti-glioblastoma activity of proteasome inhibitors.
doi:10.1016/j.bbrc.2012.11.137
PMCID: PMC3558552  PMID: 23261467
NAG-1/GDF15; MG132; glioblastoma; p38 MAPK
14.  Association of body mass index and risk of death from pancreas cancer in Asians: findings from the Asia Cohort Consortium 
Objective
We aimed to examine the association between BMI and the risk of death from pancreas cancer in a pooled analysis of data from the Asia Cohort Consortium.
Methods
The data for this pooled-analysis included 883,529 men and women from 16 cohort studies in Asian countries. Cox proportional-hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for pancreas cancer mortality in relation to BMI. Seven predefined BMI categories (<18.5, 18.5–19.9, 20.0–22.4, 22.5–24.9, 25.0–27.4, 27.5–29.9, ≥30) were used in the analysis, with BMI of 22.5–24.9 serving as the reference group. The multivariable analyses were adjusted for known risk factors, including age, smoking, and history of diabetes.
Results
We found no statistically significant overall association between each BMI category and risk of death from pancreas cancer in all Asians, and obesity was unrelated to mortality risk in both East Asians and South Asians. Age, smoking, and history of diabetes did not modify the association between BMI and risk of death from pancreas cancer. In planned subgroup analyses among East Asians, an increased risk of death from pancreas cancer among those with a BMI<18.5 was observed for individuals with a history of diabetes; HR = 2.01(95%CI: 1.01–4.00) (p for interaction=0.07).
Conclusion
The data do not support an association between BMI and risk of death from pancreas cancer in these Asian populations.
doi:10.1097/CEJ.0b013e3283592cef
PMCID: PMC3838869  PMID: 23044748
body mass index; insulin resistance; obesity; overweight; pancreatic cancer
15.  Association of the Hermansky–Pudlak syndrome type 4 (HPS4) gene variants with cognitive function in patients with schizophrenia and healthy subjects 
BMC Psychiatry  2013;13:276.
Background
The Hermansky–Pudlak Syndrome Type 4 (HPS4) gene, which encodes a subunit protein of the biogenesis of lysosome-related organelles complex (BLOC)-3, which is involved in late endosomal trafficking, is associated with schizophrenia; however, its clinical relevance in schizophrenia remains unknown. The purpose of the present study was to investigate whether HPS4 is associated with cognitive functions in patients with schizophrenia and healthy controls and with the clinical profiles of patients with schizophrenia.
Methods
We investigated the association of variants of HPS4 with clinical symptoms and cognitive function in Japanese patients with schizophrenia (n = 240) and age-matched healthy control subjects (n = 240) with single nucleotide polymorphisms (SNP)- or haplotype-based linear regression. We analyzed five tagging SNPs (rs4822724, rs61276843, rs9608491, rs713998, and rs2014410) of HPS4 and 2–5 locus haplotypes of these five SNPs. The cognitive functions of patients and healthy subjects were evaluated with the Brief Assessment of Cognition in Schizophrenia, Japanese-language version, and the patients were assessed for their symptomatology with the Positive and Negative Symptom Scale (PANSS).
Results
In patients with schizophrenia, rs713998 was significantly associated with executive function under the dominant genetic model (P = 0.0073). In healthy subjects, there was a significant association between working memory and two individual SNPs under the recessive model (rs9608491: P = 0.001; rs713998: P = 0.0065) and two haplotypes (rs9608491-713998: P = 0.0025; rs61276843-9608491-713998: P = 0.0064). No significant association was found between HPS4 SNPs and PANSS scores or premorbid IQ, as measured by the Japanese version of the National Adult Reading Test.
Conclusions
These findings suggested the involvement of HPS4 in the working memory of healthy subjects and in the executive function deficits in schizophrenia.
doi:10.1186/1471-244X-13-276
PMCID: PMC3819706  PMID: 24168225
HPS4; Cognition; Working memory; Executive function; BACS; rs9608491; rs713998
16.  Effectiveness of Variable-Gain Kalman Filter Based on Angle Error Calculated from Acceleration Signals in Lower Limb Angle Measurement with Inertial Sensors 
The wearable sensor system developed by our group, which measured lower limb angles using Kalman-filtering-based method, was suggested to be useful in evaluation of gait function for rehabilitation support. However, it was expected to reduce variations of measurement errors. In this paper, a variable-Kalman-gain method based on angle error that was calculated from acceleration signals was proposed to improve measurement accuracy. The proposed method was tested comparing to fixed-gain Kalman filter and a variable-Kalman-gain method that was based on acceleration magnitude used in previous studies. First, in angle measurement in treadmill walking, the proposed method measured lower limb angles with the highest measurement accuracy and improved significantly foot inclination angle measurement, while it improved slightly shank and thigh inclination angles. The variable-gain method based on acceleration magnitude was not effective for our Kalman filter system. Then, in angle measurement of a rigid body model, it was shown that the proposed method had measurement accuracy similar to or higher than results seen in other studies that used markers of camera-based motion measurement system fixing on a rigid plate together with a sensor or on the sensor directly. The proposed method was found to be effective in angle measurement with inertial sensors.
doi:10.1155/2013/398042
PMCID: PMC3825052  PMID: 24282442
17.  Treatment of, and Candida utilis biomass production from shochu wastewater; the effects of maintaining a low pH on DOC removal and feeding cultivation on biomass production 
SpringerPlus  2013;2:514.
Shochu wastewater (SW; alcoholic distillery wastewater) contains large amounts of organic compounds (25,000 – 60,000 COD mg/L), nitrogen (1,000 – 6,000 T-N mg/L), and phosphorus (500 – 1,000 T-P mg/L). Despite its high nutrient content, SW is highly perishable, which limits its utilization for animal feed and fertilizer. Therefore, SW is mainly treated by methane fermentation. On the other hand, a feed yeast, Candida utilis, can utilize various organic compounds and be utilized as a yeast extract source and animal feed. We previously bred a mutant, C. utilis UNA1, that accumulates a large amount of nitrogen. Here, we investigated the use of C. utilis UNA1 to treat highly concentrated SW. With fed-batch cultivation using a 5-L jar fermenter, controlling pH at 5.0 with H2SO4, 62.9% of DOC, 38.4% of DTN, and 44.5% of DTP were stably removed from non-diluted barley shochu wastewater (BSW), and about 16.7 kg of freeze-dried yeast biomass was obtained. The yeast sludge biomass generated from BSW contains about 60% crude protein. Furthermore, using H2SO4 to control pH increased the sulfur content of wastewater, which increased the methionine composition of yeast sludge biomass.
doi:10.1186/2193-1801-2-514
PMCID: PMC3797912  PMID: 24156090
Candida utilis; Shochu wastewater; Treatment; Biomass production; Amino acid composition
18.  Experimental Evaluation of Balance Prediction Models for Sit-to-Stand Movement in the Sagittal Plane 
Evaluation of balance control ability would become important in the rehabilitation training. In this paper, in order to make clear usefulness and limitation of a traditional simple inverted pendulum model in balance prediction in sit-to-stand movements, the traditional simple model was compared to an inertia (rotational radius) variable inverted pendulum model including multiple-joint influence in the balance predictions. The predictions were tested upon experimentation with six healthy subjects. The evaluation showed that the multiple-joint influence model is more accurate in predicting balance under demanding sit-to-stand conditions. On the other hand, the evaluation also showed that the traditionally used simple inverted pendulum model is still reliable in predicting balance during sit-to-stand movement under non-demanding (normal) condition. Especially, the simple model was shown to be effective for sit-to-stand movements with low center of mass velocity at the seat-off. Moreover, almost all trajectories under the normal condition seemed to follow the same control strategy, in which the subjects used extra energy than the minimum one necessary for standing up. This suggests that the safety considerations come first than the energy efficiency considerations during a sit to stand, since the most energy efficient trajectory is close to the backward fall boundary.
doi:10.1155/2013/592328
PMCID: PMC3804152  PMID: 24187580
19.  Reconstitution of dynamic microtubules with Drosophila XMAP215, EB1, and Sentin 
The Journal of Cell Biology  2012;199(5):849-862.
XMAP215msps and the EB1–Sentin duo act individually and cooperatively to accelerate microtubule growth and increase rescue events but also to promote frequent catastrophes.
Dynamic microtubules (MTs) are essential for various intracellular events, such as mitosis. In Drosophila melanogaster S2 cells, three MT tip-localizing proteins, Msps/XMAP215, EB1, and Sentin (an EB1 cargo protein), have been identified as being critical for accelerating MT growth and promoting catastrophe events, thus resulting in the formation of dynamic MTs. However, the molecular activity of each protein and the basis of the modulation of MT dynamics by these three factors are unknown. In this paper, we showed in vitro that XMAP215msps had a potent growth-promoting activity at a wide range of tubulin concentrations, whereas Sentin, when recruited by EB1 to the growing MT tip, accelerated growth and also increased catastrophe frequency. When all three factors were combined, the growth rate was synergistically enhanced, and rescue events were observed most frequently, but frequent catastrophes restrained the lengthening of the MTs. We propose that MT dynamics are promoted by the independent as well as the cooperative action of XMAP215msps polymerase and the EB1–Sentin duo.
doi:10.1083/jcb.201206101
PMCID: PMC3514792  PMID: 23185033
20.  Radiation-Induced Microbleeds after Cranial Irradiation: Evaluation by Phase-Sensitive Magnetic Resonance Imaging with 3.0 Tesla 
Yonago Acta medica  2013;56(1):7-12.
Background
Although there are many reports regarding radiation-induced microbleeds, its frequency, relation to dose and latency after radiation are not fully elucidated. The purpose of this study was to evaluate the frequency, latency, patient factors and dose relation of radiation-induced microbleeds after cranial irradiation using phase-sensitive magnetic resonance imaging (PSI) at 3.0 T.
Methods
Retrospective evaluation of 34 patients (age range, 13–78 years; mean, 49 years; follow-up period, 3–169 months; mean 29 months) who had undergone cranial irradiation using magnetic resonance (MR) imaging including PSI was performed. Twenty-three patients received high-dose irradiation (44–60 Gy), and 11 patients received 24–30 Gy whole brain irradiation. When microbleeds were detected on MR imaging in these high-dose irradiation patients, dose distribution maps were reproduced by reviewing the clinical records. Then the irradiated areas were divided into 6 radiation-dose classes: regions > 55 Gy, 45–55 Gy, 35–45 Gy, 25–35 Gy, 15–25 Gy and 5–15 Gy. The frequency of microbleeds in each radiation-dose class was analyzed.
Results
Microbleeds were detected in 7 (21%) of 34 patients on T2-weighted imaging, whereas they were detected in 16 (47%) of the 34 patients on PSIs. The frequency of microbleeds was higher than previously reported. The latency of radiation-induced microbleeds after radiation was 3 months to 9 years (mean, 33 months). In high-dose irradiation patients, the frequency of microbleeds significantly was associated with radiation dose. There were no foci that were observed in regions that had received < 25 Gy.
Conclusion
Radiation-induced microbleeds occurred more frequently in the present study than has been previously reported. PSI can be used to detect these vascular changes earlier than other conventional MR imaging techniques.
PMCID: PMC3760491  PMID: 24031146
cranial irradiation; magnetic resonance imaging; radiation injury; ; 
21.  Physical and Mental Factors Associated with Obesity in Individuals with Mental Disorders Attending Psychiatric Day-Care Facilities 
Yonago Acta medica  2013;56(1):1-6.
Background
Individuals with mental disorders have increased rates of obesity and metabolic syndrome. Here we evaluated factors influencing obesity in individuals with mental disorders who were attending psychiatric day-care facilities on an outpatient basis.
Methods
The subjects (n = 108) were outpatients attending hospital-based rehabilitation programs. We assessed body fat, weight, height, waist circumference, body mass index (BMI), blood pressure, Geriatric Depression Scale-15 (GDS) scores, frequency of day-care visits, satisfaction with body shape, physical comorbidity and lifestyle habits. Lifestyle habits were evaluated using Breslow's health index based on health-related choices.
Results
The subjects were divided into 2 groups: obese group (BMI ≥ 25 kg/m2) and non-obese group (BMI < 25 kg/m2). The physical parameters and attributes of both groups were compared, and factors related to BMI were statistically analyzed. The prevalence of obesity was 47.2% in all patients, 42.4% in males and 54.8% in females. Weight, waist circumference, body fat and systolic and diastolic blood pressure were significantly higher in the obese group than in the non-obese group. Body fat, waist circumference, systolic blood pressure and diastolic blood pressure exhibited significant positive correlations with BMI, whereas the frequency of day-care visits, satisfaction with body shape, GDS score and Breslow's health index exhibited significant negative correlations with BMI.
Conclusion
The present results showed that the prevalence of obesity was high in outpatients with mental disorders. Improvement in lifestyle choices is necessary to prevent obesity and the onset of metabolic syndrome in such patients.
PMCID: PMC3760492  PMID: 24031145
Breslow’s health index; metabolic syndrome; mental disorder; obesity; psychiatric day-care facility
22.  Tiam1 interaction with the PAR complex promotes talin-mediated Rac1 activation during polarized cell migration 
The Journal of Cell Biology  2012;199(2):331-345.
The PAR complex targets Tiam1 to adhesions, where it interacts with talin to promote adhesion-induced Rac1 activation, cell spreading, and migration.
Migrating cells acquire front-rear polarity with a leading edge and a trailing tail for directional movement. The Rac exchange factor Tiam1 participates in polarized cell migration with the PAR complex of PAR3, PAR6, and atypical protein kinase C. However, it remains largely unknown how Tiam1 is regulated and contributes to the establishment of polarity in migrating cells. We show here that Tiam1 interacts directly with talin, which binds and activates integrins to mediate their signaling. Tiam1 accumulated at adhesions in a manner dependent on talin and the PAR complex. The interactions of talin with Tiam1 and the PAR complex were required for adhesion-induced Rac1 activation, cell spreading, and migration toward integrin substrates. Furthermore, Tiam1 acted with talin to regulate adhesion turnover. Thus, we propose that Tiam1, with the PAR complex, binds to integrins through talin and, together with the PAR complex, thereby regulates Rac1 activity and adhesion turnover for polarized migration.
doi:10.1083/jcb.201202041
PMCID: PMC3471226  PMID: 23071154
23.  Mycobacterium kyorinense Infection  
Emerging Infectious Diseases  2013;19(3):508-510.
doi:10.3201/eid1903.12-0591
PMCID: PMC3647647  PMID: 23750358
pneumonia; lymphadenitis; arthritis; Mycobacterium celatum; rpoB; rifampin; mutation; bacteria
24.  DNA methylation-mediated silencing of nonsteroidal anti-inflammatory drug-activated gene (NAG-1/GDF15) in glioma cell lines 
Nonsteroidal anti-inflammatory drug-activated gene, NAG-1, a transforming growth factor-β member, is involved in tumor progression and development. The association between NAG-1 expression and development and progression of glioma has not been well defined. Glioblastoma cell lines have lower basal expression of NAG-1 than other gliomas and normal astrocytes. Most primary human gliomas have very low levels of NAG-1 expression. NAG-1 basal expression appeared to inversely correlate with tumor grade in glioma. Aberrant promoter hypermethylation is a common mechanism for silencing of tumor suppressor genes in cancer cells. In glioblastoma cell lines, NAG-1 expression was increased by the demethylating agent, 5-aza-2’-deoxycytidine. To investigate whether the NAG-1 gene was silenced by hypermethylation in glioblastoma, we examined DNA methylation status using genomic bisulfite sequencing. The NAG-1 promoter was densely methylated in several glioblastoma cell lines as well as in primary oligodendroglioma tumor samples, which have low basal expression of NAG-1. DNA methylation at two specific sites (−53 and +55 CpG sites) in the NAG-1 promoter was strongly associated with low NAG-1 expression. The methylation of the NAG-1 promoter at the −53 site blocks Egr-1 binding and thereby suppresses Nag-1 induction. Treatment of cells with low basal NAG-1 expression with NAG-1 inducer also did not increase NAG-1. Incubation with a demethylation chemical increased Nag-1 basal expression and subsequent incubation with a NAG-1 inducer increased NAG-1 expression. We concluded from these data that methylation of specific promoter sequences causes transcriptional silencing of the NAG-1 locus in glioma and may ultimately contribute to tumor progression.
doi:10.1002/ijc.26082
PMCID: PMC3133861  PMID: 21437897
NAG-1; GDF15; glioblastoma; DNA methylation
25.  MAML1 Enhances the Transcriptional Activity of Runx2 and Plays a Role in Bone Development 
PLoS Genetics  2013;9(1):e1003132.
Mastermind-like 1 (MAML1) is a transcriptional co-activator in the Notch signaling pathway. Recently, however, several reports revealed novel and unique roles for MAML1 that are independent of the Notch signaling pathway. We found that MAML1 enhances the transcriptional activity of runt-related transcription factor 2 (Runx2), a transcription factor essential for osteoblastic differentiation and chondrocyte proliferation and maturation. MAML1 significantly enhanced the Runx2-mediated transcription of the p6OSE2-Luc reporter, in which luciferase expression was controlled by six copies of the osteoblast specific element 2 (OSE2) from the Runx2-regulated osteocalcin gene promoter. Interestingly, a deletion mutant of MAML1 lacking the N-terminal Notch-binding domain also enhanced Runx2-mediated transcription. Moreover, inhibition of Notch signaling did not affect the action of MAML1 on Runx2, suggesting that the activation of Runx2 by MAML1 may be caused in a Notch-independent manner. Overexpression of MAML1 transiently enhanced the Runx2-mediated expression of alkaline phosphatase, an early marker of osteoblast differentiation, in the murine pluripotent mesenchymal cell line C3H10T1/2. MAML1−/− embryos at embryonic day 16.5 (E16.5) had shorter bone lengths than wild-type embryos. The area of primary spongiosa of the femoral diaphysis was narrowed. At E14.5, extended zone of collagen type II alpha 1 (Col2a1) and Sox9 expression, markers of chondrocyte differentiation, and decreased zone of collagen type X alpha 1 (Col10a1) expression, a marker of hypertrophic chondrocyte, were observed. These observations suggest that chondrocyte maturation was impaired in MAML1−/− mice. MAML1 enhances the transcriptional activity of Runx2 and plays a role in bone development.
Author Summary
To identify new molecules involved in bone and cartilage development and/or homeostasis, we utilized approximately 10,000 arrayed and addressable cDNA clones, which allowed systematic, efficient, and unbiased screening of cDNAs encoding factors that could activate critical bone differentiation activity via activation of Runx2, master regulator of bone development. We analyzed MAML1−/− mice to investigate the role of MAML1 in bone development. MAML1−/− embryos at embryonic day 14.5 and 16.5 had shorter bone lengths than wild-type embryos. The area of primary spongiosa of the femoral diaphysis was narrowed, indicated that chondrocyte maturation was impaired. This revealed that MAML1 plays an important role in proper bone development and may provide us with a new basis for identifying potential therapeutic targets for bone diseases.
doi:10.1371/journal.pgen.1003132
PMCID: PMC3542067  PMID: 23326237

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