Low Dose of Curcumin Combined with Exercise Synergistically Induces Beige Adipocyte Formation in Mice.

Curcumin (Cur) has various biological effects, including anti-obesity and anti-diabetic properties. However, the molecular mechanisms by which Cur exerts these effects remain unclear. In addition, high doses of Cur have been administered in most animal and human trials to date, due mainly to the poor water solubility of native Cur and its low oral bioavailability. In our previous study, we demonstrated that a highly bioavailable Cur formulation (4.5 mg/kg) induces the formation of beige adipocytes in inguinal white adipose tissue (iWAT) in mice. In the present study, to enhance Cur-mediated beige adipocyte formation and reduce the required functional Cur dose, we investigated whether a low dose of Cur combined with exercise synergistically induced beige adipocyte formation. Cur (1.5 mg Cur/kg, daily) combined with exercise for 4 wk significantly induced beige adipocyte formation in iWAT in mice. This effect was associated with the elevation of interleukin-6 level following subsequent Cur administration combined with exercise. These results indicate that exercise combined with Cur synergistically enhances biological activity and reduces the required Cur dose. These findings suggest that Cur could be used as a dietary supplement during exercise to enhance exercise-mediated health benefits.

Combination of Exercise and Intake of Amino Acid Mixture Synergistically Induces Beige Adipocyte Formation in Mice.

Exercise combined with dietary factors may have significant effects on the suppression of body fat accumulation. Several trials suggest that amino acid mixtures containing alanine, arginine, and phenylalanine (ARF) combined with exercise can significantly reduce body fat accumulation in overweight adults and high-fat diet-induced obesity in mice. We therefore hypothesized that combining ARF and exercise would significantly induce beige adipocyte formation and that this would contribute to reducing body weight, whereas administration of ARF or exercise alone would not. Administration of ARF (1 g/kg body weight, daily) combined with exercise (5 sessions per week) for 4 wk significantly induced formation of beige adipocytes in inguinal white adipose tissue (iWAT) in mice, although ARF or exercise alone did not. Metabolomic analysis showed that plasma lactate concentration was significantly elevated in the exercise+ARF group relative to the exercise group. Furthermore, lactate dehydrogenase B, which increases redox stress by converting lactate to pyruvate in iWAT and triggers induction of uncoupling protein 1 expression was significantly upregulated in iWAT of the exercise+ARF group. These findings demonstrate the unique effect of ARF combined with exercise for inducing beige adipocyte formation, which may be associated with the suggested lactate-mediated pathway. Appropriate mixtures of amino acids could be used as a dietary supplement before exercise and contributed to increasing energy expenditures.

TC10, a Rho family GTPase, is required for efficient axon regeneration in a neuron-autonomous manner.

Intracellular signaling pathways that promote axon regeneration are closely linked to the mechanism of neurite outgrowth. TC10, a signaling molecule that acts on neurite outgrowth through membrane transport, is a member of the Rho family G proteins. Axon injury increases the TC10 levels in motor neurons, suggesting that TC10 may be involved in axon regeneration. In this study, we tried to understand the roles of TC10 in the nervous system using TC10 knock-out mice. In cultured hippocampal neurons, TC10 ablation significantly reduced axon elongation without affecting ordinary polarization. We determined a role of TC10 in microtubule stabilization at the growth cone neck; therefore, we assume that TC10 limits axon retraction and promotes in vitro axon outgrowth. In addition, there were no notable differences in the size and structure of brains during prenatal and postnatal development between wild-type and TC10 knock-out mice. In motor neurons, axon regeneration after injury was strongly suppressed in mice lacking TC10 (both in conventional and injured nerve specific deletion). In retinal ganglion cells, TC10 ablation suppressed the axon regeneration stimulated by intraocular inflammation and cAMP after optic nerve crush. These results show that TC10 plays an important role in axon regeneration in both the peripheral and central nervous systems, and the role of TC10 in peripheral axon regeneration is neuron-intrinsic.

Phosphatase of regenerating liver sensitizes MET to functional activation by hepatocyte growth factor.

Phosphatase of regenerating liver (PRL) is overexpressed in metastatic cancers and actively drives their malignant progression. Many studies on cultured cancer cells have implied PRL overexpression as a stimulant for cellular signaling involved in cell proliferation. However, its role in the tightly adhered and polarized epithelial cells remains largely uncharacterized. In this study, we show that inducible expression of PRL in MDCK normal epithelial cells sensitized MET, the receptor for hepatocyte growth factor (HGF), to functional activation by HGF. We found that PRL expression amplified tyrosine phosphorylation levels of various proteins, among which MET was identified to be the most abundant. This phosphorylation occurred selectively at Y1234/1235 in the activation loop of MET, whereas phosphorylation of Y1349 in the effector-binding site, which is directly involved in downstream signaling, was almost undetectable. Consistently, PRL overexpression by itself did not cause observable alterations at the cellular level. However, when cells were stimulated with HGF, phosphorylation of Y1349 was much more strongly induced in PRL-expressing cells than in control cells. This resulted in robust cell scattering and tubulogenesis, even with low levels of HGF. Collectively, these results demonstrate a unique role of PRL in regulating MET function, which is known to be crucial for remodeling of epithelial tissues and malignant progression of cancers.

Inhibited autonomy for promoting physical health: qualitative analysis of narratives from persons living with severe mental illness.

BACKGROUND: Autonomy is a key factor in the reduction of inequitable physical healthcare among people with severe mental illness compared with the general population.AimsTo clarify the critical mechanism underlying autonomy in physical health promotion based on the perspectives of people with severe mental illness. METHOD: We employed a conventional content analysis of narrative data from the Healthy Active Lives in Japan (HeAL Japan) workshop meetings. RESULTS: 'Inhibited autonomy' was extracted as a central component and shaped by the users' experiences, both in a healthcare setting and in real life. This component emerged based on the lack of an empowerment mechanism in psychiatric services. CONCLUSIONS: A barrier to the encouragement of autonomy in physical health promotion was found in current psychiatric services. An effective strategy should be explored to foster an empowerment mechanism in psychiatric and mental health services.Declaration of interestNone.

Involvement of the Mab21l1 gene in calvarial osteogenesis.

The Mab-21 gene family is crucial for animal development. A deficiency in the Mab-21 genes associates with several defects, including skeletal malformation in mice and humans. In this study, we observed that mice lacking Mab21l1 displayed an unclosed fontanelle, suggesting impaired calvarial bone development. Cells isolated from the calvaria of these mice showed a greater osteoblast differentiation potential as evidenced by the abundance of mineralized bone nodules and higher expression levels of osteogenic markers than wild-type cells. Mab21l1-/- osteoblasts also expressed higher levels of adipocyte genes and interferon-regulated genes at early stages of osteogenesis. Rankl/Opg expression levels were also higher in Mab21l1-/- osteoblasts than in wild-type cells. These data suggest that Mab21l1 is involved in either the regulation of mesenchymal cell proliferation and differentiation or the balance between bone formation and resorption. An alteration in these regulatory machineries, therefore, may lead to insufficient bone formation, causing the bone phenotype in Mab21l1-/- mice.

[Curriculum of the New Certificate Psychiatrist System of the Japanese Board of Psychiatry-What Items are Applied Each Year for Three Years, and How Training Psychiatrists are Evaluated-].

The new certificate psychiatrist system of the Japanese Board of Psychiatry is discussed from the viewpoint of the improvement of the current certificate psychiatrist system. In the new system, training items are applied each year for three years. Actually general items and particular disease items of the current training book are rearranged in the new sys- tem. The results of training psychiatrists are evaluated multi-dimensionally and two-way com- municatively. The instructing doctor evaluates the performance of training psychiatrists at the time of completing the program at all training hospitals and gives some feedback to the psy- chiatrists. Staff with multiple occupations also evaluate the training psychiatrists. The training psychiatrists also evaluate the instructing doctors and training program. The program man- agement committee of each basic training hospital collaborates with the training committee of the cooperative training hospitals to examine and evaluate the training results, and improve the program.

The septum transversum mesenchyme induces gall bladder development.

The liver, gall bladder, and ventral pancreas are formed from the posterior region of the ventral foregut. After hepatic induction, Sox17+/Pdx1+ pancreatobiliary common progenitor cells differentiate into Sox17+/Pdx1- gall bladder progenitors and Sox17-/Pdx1+ ventral pancreatic progenitors, but the cell-extrinsic signals that regulate this differentiation process are unknown. This study shows that the septum transversum mesenchyme (STM) grows in the posterior direction after E8.5, becoming adjacent to the presumptive gall bladder region, to induce gall bladder development. In this induction process, STM-derived BMP4 induces differentiation from common progenitor cells adjacent to the STM into gall bladder progenitor cells, by maintaining Sox17 expression and suppressing Pdx1 expression. Furthermore, the STM suppresses ectopic activation of the liver program in the posterior region of the ventral foregut following hepatic induction through an Fgf10/Fgfr2b/Sox9 signaling pathway. Thus, the STM plays pivotal roles in gall bladder development by both inductive and suppressive effects.

Profile measurement of concave spherical mirror and a flat mirror using a high-speed nanoprofiler.

Ultraprecise aspheric mirrors that offer nanofocusing and high coherence are indispensable for developing third-generation synchrotron radiation and X-ray free-electron laser sources. In industry, the extreme ultraviolet (wavelength: 13.5 nm) lithography used for high-accuracy aspheric mirrors is a promising technology for fabricating semiconductor devices. In addition, ultraprecise mirrors with a radius of curvature of less than 10 mm are needed in many digital video instruments. We developed a new type of nanoprofiler that traces the normal vector of a mirror's surface. The principle of our measuring method is that the normal vector at each point on the surface is determined by making the incident light beam on the mirror surface and the reflected beam at that point coincide, using two sets of two pairs of goniometers and one linear stage. From the acquired normal vectors and their coordinates, the three-dimensional shape is calculated by a reconstruction algorithm. The characteristics of the measuring method are as follows: the profiler uses the straightness of laser light without using a reference surface. Surfaces of any shape can be measured, and there is no limit on the aperture size. We calibrated this nanoprofiler by considering the system error resulting from the assembly error and encoder scale error, and evaluated the performance at the nanometer scale. We suppressed the effect of random errors by maintaining the temperature in a constant-temperature room within ±0.01°C. We measured a concave spherical mirror with a radius of curvature of 400 mm and a flat mirror and compared the results with those obtained using a Fizeau interferometer. The profiles of the mirrors were consistent within the range of system errors.

Teratogenic factors affect transcription factor expression.

Chemical compounds are produced every day, many with adverse effects on human health, and hence it is vital to predict the risks to humans simply, rapidly, and accurately. Teratogens have a serious impact on fetal development. This has been studied mainly by phenotypic analysis of experimental animals. However, since phenotypes can vary within different species, we established a new evaluation system based on our recent finding that teratogens influence Hox gene expression in mice. Similarly to the Hox gene expression changes, the expression patterns of several transcription factors involved in development, including the Dlx, Irx, Sall, and T-box families, were altered after 6 h of exposure to retinoic acid (RA) or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The expression changes in Dlx4, Dlx6, Irx5, Sall2, Sall3, Sall4, Tbx10, and Tbx22 were linked to teratogen-induced phenotypes, and our results indicate that expression changes in developmental transcription factors can help to predict teratogenic risk.

Relationship between quantitative electroencephalogram and interferon-α-induced depression in chronic hepatitis C patients.

BACKGROUND: Quantitative electroencephalogram (qEEG) changes in chronic hepatitis C patients treated with interferon-α (IFN-α) have previously been reported. However, whether IFN-α-induced depression is related to changes in qEEG during IFN-α treatment remains unclear. METHOD: Fifty chronic hepatitis C patients were enrolled and IFN-α was administered intramuscularly at 9 × 10(6) IU daily for the first 4 weeks and then 3 times a week for the next 20 weeks. Serial EEGs obtained before and at 4 weeks after treatment were assessed. The absolute power for each frequency band was determined using qEEG techniques. Differences in the rate of change in absolute power for each of 6 frequency bands (δ, θ1, θ2, α1, α2 and ß) were assessed between patients with and without major depression using the Mann-Whitney U test. When significant differences in the rate of change in absolute power for each frequency band were observed, differences in the rate of change were also assessed between patients with and without psychological complications using the Mann-Whitney U test. RESULTS: Major depression due to psychological complications during IFN-α treatment was reported in 10 out of 50 patients. In the θ1 band, the difference in the rate of change was demonstrated to be significant (p = 0.0036). Moreover, at the central, frontal, parietal, and temporal locations, the rates of change were also significantly different. CONCLUSION: In IFN-α-treated chronic hepatitis C patients who were diagnosed with major depression, qEEG changes were more obvious and widely distributed.

Mab21l2 is essential for embryonic heart and liver development.

During mouse embryogenesis, proper formation of the heart and liver is especially important and is crucial for embryonic viability. In this study, we showed that Mab21l2 was expressed in the trabecular and compact myocardium, and that deletion of Mab21l2 resulted in a reduction of the trabecular myocardium and thinning of the compact myocardium. Mab21l2-deficient embryonic hearts had decreased expression of genes that regulate cell proliferation and apoptosis of cardiomyocytes. These results show that Mab21l2 functions during heart development by regulating the expression of such genes. Mab21l2 was also expressed in the septum transversum mesenchyme (STM). Epicardial progenitor cells are localized to the anterior surface of the STM (proepicardium), and proepicardial cells migrate onto the surface of the heart and form the epicardium, which plays an important role in heart development. The rest of the STM is essential for the growth and survival of hepatoblasts, which are bipotential progenitors for hepatocytes and cholangiocytes. Proepicardial cells in Mab21l2-deficient embryos had defects in cell proliferation, which led to a small proepicardium, in which α4 integrin expression, which is essential for the migration of proepicardial cells, was down-regulated, suggesting that defects occurred in its migration. In Mab21l2-deficient embryos, epicardial formation was defective, suggesting that Mab21l2 plays important roles in epicardial formation through the regulation of the cell proliferation of proepicardial cells and the migratory process of proepicardial cells. Mab21l2-deficient embryos also exhibited hypoplasia of the STM surrounding hepatoblasts and decreased hepatoblast proliferation with a resultant loss of defective morphogenesis of the liver. These findings demonstrate that Mab21l2 plays a crucial role in both heart and liver development through STM formation.

Relationships between exploratory eye movement dysfunction and clinical symptoms in schizophrenia.

AIM: Many psychophysiological tests have been widely researched in the search for a biological marker of schizophrenia. The exploratory eye movement (EEM) test involves the monitoring of eye movements while subjects freely view geometric figures. Suzuki et al. (2009) performed discriminant analysis between schizophrenia and non-schizophrenia subjects using EEM test data; consequently, clinically diagnosed schizophrenia patients were identified as having schizophrenia with high probability (73.3%). The aim of the present study was to investigate the characteristics of schizophrenia patients who were identified as having schizophrenia on EEM discriminant analysis (SPDSE) or schizophrenia patients who were identified as not having schizophrenia on EEM discriminant analysis (SPDNSE). METHODS: The data for the 251 schizophrenia subjects used in the previous discriminant-analytic study were analyzed, and the demographic or symptomatic characteristics of SPDSE and SPDNSE were investigated. As for the symptomatic features, a factor analysis of the Brief Psychiatric Rating Scale (BPRS) rating from the schizophrenia subjects was carried out. RESULTS: Five factors were found for schizophrenia symptoms: excitement/hostility; negative symptoms; depression/anxiety; positive symptoms; and disorganization. SPDSE had significantly higher factor scores for excitement/hostility, negative symptoms and disorganization than SPDNSE. Furthermore, the BPRS total score for the SPDSE was significantly higher than that for the SPDNSE. CONCLUSION: SPDSE may be a disease subtype of schizophrenia with severe symptoms related to excitement/hostility, negative symptoms and disorganization, and EEM parameters may detect this subtype. Therefore, the EEM test may be one of the contributors to the simplification of the heterogeneity of schizophrenia.

[Survey on the actual condition of psychiatrists and psychiatric services in Japan. (Part 1): Basic data on number and distribution of psychiatrists].

BACKGROUND: To ensure that psychiatric services adequately meet the needs of the Japanese people, planning a prospective design based on a needs analysis is required. Presently, the distribution of medical resources in Japan is skewed and the priorities of psychiatric services are unclear. OBJECTIVE: To determine the current status of psychiatric services. METHOD: The definition of a psychiatrist was determined by qualified specialists of the Japanese Society for Psychiatry and Neurology (JSPN). Of the 11,169 candidates who applied for the specialist psychiatry examination, 246 were excluded due to a lack of personal information and 4 due to refusal. The remaining 10,919 agreed to allow the verification of their personal data. This study was conducted with the approval of the JSPN. The total number of psychiatrists, their demographic backgrounds, the number of psychiatrists by prefecture, and the number of psychiatrists in each secondary medical care block in Japan were calculated. RESULTS: Of the 10,919 psychiatrists included in this analysis, 2,124 were female and 8,790 were male. Approximately 90% were < 65 years old, and 42% were < 45 years old. Their primary work places were as follows: psychiatric hospitals (n = 5,233, 47.9%); university departments of psychiatry (n=1,353, 12.4%); general hospitals (n = 1,064, 9.7%); psychiatric clinics (n = 2,456, 22.5%); nonpsychiatric clinics (n = 687, 6.3%); and nonclinical work places such as basic science departments (n = 124, 1.1%). The number of psychiatrists per 100,000 inhabitants in each prefecture was determined. The highest numbers of psychiatrists were from Kochi (13.20), Tokyo (12.76), and Tokushima (12.24), and the lowest numbers were from Ibaraki (5.34), Aomori (5.36), and Saitama (5.67). The number of psychiatrists per 100,000 inhabitants in Kochi was 1.48 per area (100 km square), and Tokyo showed the highest at 75.99 psychiatrists per area, followed by Osaka and Kanagawa. The five Tohoku prefectures and Hokkaido had the fewest psychiatrists per area. CONCLUSION: For planning the future management of psychiatric services, continuous investigation of the actual number of psychiatrists and the status of psychiatric services in Japan is required with the constant cooperation of the JSPN.

[Survey on the actual condition of psychiatrists and psychiatric services in Japan. (Part 2): Change in geographical working area and setting of each psychiatrist].

BACKGROUND: The shortage of psychiatrists has recently become a public concern; however, the reason for this shortage has not been clearly discussed or explained on the basis of real data. We assumed that it is not only due to the lack of the absolute number of psychiatrists, but also due to an imbalance in their distribution in geographical working areas and settings. OBJECTIVE: To evaluate the change in distribution of Japanese psychiatrists. METHOD: We analyzed the change in the geographical working area and setting of each psychiatrist from September 2006 to March 2009 using data obtained from psychiatrists who applied for the Board Certification Examination of the Japanese Psychiatric Association. Our data included 6,881 psychiatrists. RESULTS: With regard to the geographical working area, the number of psychiatrists in ordinance-designated cities (urban areas) increased by 2.2%, whereas that in other areas decreased by 3.0%. On examination of work settings, we noted a 16.0% decrease in the number of psychiatric departments in general hospitals and a 20.0% increase in the number of psychiatric clinics. Surprisingly, more than 10% of middle-aged psychiatrists (10.3% of 36 45-year-olds and 12.2% of 46-55-year olds) who worked in general hospitals moved to clinics. CONCLUSION: The present study revealed that, although psychiatrists did not tend to move from rural to urban areas, they showed a tendency to move from general hospitals to psychiatric clinics.

Influence of teratogenic factors on mouse 39 hox gene expression.

In normal development, each gene correctly expresses under temporal and spatial regulation. Teratogenic agents among environmental contaminants induce aberrated gene expression and consequently lead to congenital malformations. Therefore, it is urgent to identify molecular markers for the detection of teratogenic agents' effects.We analyzed mouse 39 hox gene expression in teratogenic factor exposed embryos. We found that 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) and retinoic acid (RA) affected differentially expression of hox. Unlike the RA-effects, TCDD led to broad repression of all hox loci. This different effect was also detected in miRNAs (microRNAs) expression in hox loci. Our results indicate that this irregular hox expression is a cause of congenital malformation, and suggest that monitoring of all hox expression works as a marker for environmental contaminants, including teratogenic effects.