Prmt7 is required for the osteogenic differentiation of mesenchymal stem cells via modulation of BMP signaling.

Arginine methylation, which is catalyzed by protein arginine methyltransferases (Prmts), is known to play a key role in various biological processes. However, the function of Prmts in osteogenic differentiation of mesenchymal stem cells (MSCs) has not been clearly understood. In the current study, we attempted to elucidate a positive role of Prmt7 in osteogenic differentiation. Prmt7-depleted C3H/10T1/2 cells or bone marrow mesenchymal stem cells (BMSCs) showed the attenuated expression of osteogenic specific genes and Alizarin red staining compared to the wild-type cells. Furthermore, we found that Prmt7 deficiency reduced the activation of bone morphogenetic protein (BMP) signaling cascade, which is essential for the regulation of cell fate commitment and osteogenesis. Taken together, our data indicate that Prmt7 plays important regulatory roles in osteogenic differentiation.

Inonotus obliquus upregulates muscle regeneration and augments function through muscle oxidative metabolism.

Skeletal muscle wasting related to aging or pathological conditions is critically associated with the increased incidence and prevalence of secondary diseases including cardiovascular diseases, metabolic syndromes, and chronic inflammations. Much effort is made to develop agents to enhance muscle metabolism and function. Inonotus obliquus (I. obliquus; IO) is a mushroom popularly called chaga and has been widely employed as a folk medicine for inflammation, cardiovascular diseases, diabetes, and cancer in Eastern Europe and Asia. However, its effect on muscle health has not been explored. Here, we aimed to investigate the beneficial effect of IO extract in muscle regeneration and metabolism. The treatment of IO in C2C12 myoblasts led to increased myogenic differentiation and alleviation of dexamethasone-induced myotube atrophy. Network pharmacological analysis using the identified specific chemical constituents of IO extracts predicted protein kinase B (AKT)-dependent mechanisms to promote myogenesis and muscle regeneration. Consistently, IO treatment resulted in the activation of AKT, which suppressed muscle-specific ubiquitin E3 ligases induced by dexamethasone. IO treatment in mice improved the regeneration of cardiotoxin-injured muscles accompanied by elevated proliferation and differentiation of muscle stem cells. Furthermore, it elevated the mitochondrial content and muscle oxidative metabolism accompanied by the induction of peroxisome proliferator-activated receptor γ coactivator α (PGC-1α). Our current data suggest that IO is a promising natural agent in enhancing muscle regenerative capacity and oxidative metabolism thereby preventing muscle wasting.

PRMT7 ablation in cardiomyocytes causes cardiac hypertrophy and fibrosis through ß-catenin dysregulation.

Angiotensin II (AngII) has potent cardiac hypertrophic effects mediated through activation of hypertrophic signaling like Wnt/ß-Catenin signaling. In the current study, we examined the role of protein arginine methyltransferase 7 (PRMT7) in cardiac function. PRMT7 was greatly decreased in hypertrophic hearts chronically infused with AngII and cardiomyocytes treated with AngII. PRMT7 depletion in rat cardiomyocytes resulted in hypertrophic responses. Consistently, mice lacking PRMT7 exhibited the cardiac hypertrophy and fibrosis. PRMT7 overexpression abrogated the cellular hypertrophy elicited by AngII, while PRMT7 depletion exacerbated the hypertrophic response caused by AngII. Similar with AngII treatment, the cardiac transcriptome analysis of PRMT7-deficient hearts revealed the alteration in gene expression profile related to Wnt signaling pathway. Inhibition of PRMT7 by gene deletion or an inhibitor treatment enhanced the activity of ß-catenin. PRMT7 deficiency decreases symmetric dimethylation of ß-catenin. Mechanistic studies reveal that methylation of arginine residue 93 in ß-catenin decreases the activity of ß-catenin. Taken together, our data suggest that PRMT7 is important for normal cardiac function through suppression of ß-catenin activity.

Aronia Upregulates Myogenic Differentiation and Augments Muscle Mass and Function Through Muscle Metabolism.

Black chokeberry or aronia (the fruit of Aronia melanocarpa) has been reported to having pharmacological activities against metabolic syndrome, such as hypertension, obesity, diabetes, and pro-inflammatory conditions. However, the effects of aronia on myogenic differentiation and muscle homoeostasis are uncharacterized. In this study, we investigated the effects of aronia (black chokeberry) on myogenic differentiation and muscle metabolic functions in young mice. Aronia extract (AR) promotes myogenic differentiation and elevates the formation of multinucleated myotubes through Akt activation. AR protects dexamethasone (DEX)-induced myotube atrophy through inhibition of muscle-specific ubiquitin ligases mediated by Akt activation. The treatment with AR increases muscle mass and strength in mice without cardiac hypertrophy. AR treatment enhances both oxidative and glycolytic myofibers and muscle metabolism with elevated mitochondrial genes and glucose metabolism-related genes. Furthermore, AR-fed muscle fibers display increased levels of total OxPHOS and myoglobin proteins. Taken together, AR enhances myogenic differentiation and improves muscle mass and function, suggesting that AR has a promising potential as a nutraceutical remedy to intervene in muscle weakness and atrophy.

Inducible Prmt1 ablation in adult vascular smooth muscle leads to contractile dysfunction and aortic dissection.

Vascular smooth muscle cells (VSMCs) have remarkable plasticity in response to diverse environmental cues. Although these cells are versatile, chronic stress can trigger VSMC dysfunction, which ultimately leads to vascular diseases such as aortic aneurysm and atherosclerosis. Protein arginine methyltransferase 1 (Prmt1) is a major enzyme catalyzing asymmetric arginine dimethylation of proteins that are sources of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase. Although a potential role of Prmt1 in vascular pathogenesis has been proposed, its role in vascular function has yet to be clarified. Here, we investigated the role and underlying mechanism of Prmt1 in vascular smooth muscle contractility and function. The expression of PRMT1 and contractile-related genes was significantly decreased in the aortas of elderly humans and patients with aortic aneurysms. Mice with VSMC-specific Prmt1 ablation (smKO) exhibited partial lethality, low blood pressure and aortic dilation. The Prmt1-ablated aortas showed aortic dissection with elastic fiber degeneration and cell death. Ex vivo and in vitro analyses indicated that Prmt1 ablation significantly decreased the contractility of the aorta and traction forces of VSMCs. Prmt1 ablation downregulated the expression of contractile genes such as myocardin while upregulating the expression of synthetic genes, thus causing the contractile to synthetic phenotypic switch of VSMCs. In addition, mechanistic studies demonstrated that Prmt1 directly regulates myocardin gene activation by modulating epigenetic histone modifications in the myocardin promoter region. Thus, our study demonstrates that VSMC Prmt1 is essential for vascular homeostasis and that its ablation causes aortic dilation/dissection through impaired myocardin expression.

Response Enhancement of Pt-AlGaN/GaN HEMT Gas Sensors by Thin AlGaN Barrier with the Source-Connected Gate Configuration at High Temperature.

AlGaN/GaN HEMT hydrogen gas sensors were optimized by AlGaN barrier thickness in the gate-source connected configuration demonstrated high response and robust stability up to 500 °C. First, we found that the hydrogen sensing performance of a conventional normally-on HEMT-based sensor was enhanced when zero voltage was applied on the gate in comparison with a floating-gate condition due to a reduced level of the base current. In the next step, to take advantage of the response increase by VGS = 0 V, a new type of sensor with a source-connected gate (SCG) was fabricated to utilize the normally-on operation of the GaN HEMT sensor as a two-terminal device. AlGaN barrier thickness was thinned by the dry-etching process to gain higher transconductance at a zero-gate bias with the reduction of the distance from the 2DEG channel to the AlGaN surface, thereby significantly improve the hydrogen response. The SCG GaN sensor with an ultra-thin AlGaN barrier (9 nm) exhibited responses of 85% and 20% at 200 and 500 °C, respectively, onto 4%-hydrogen gas, which demonstrates a promising ability for harsh environment applications.

PRMT7 deficiency causes dysregulation of the HCN channels in the CA1 pyramidal cells and impairment of social behaviors.

HCN channels regulate excitability and rhythmicity in the hippocampal CA1 pyramidal cells. Perturbation in the HCN channel current (Ih) is associated with neuropsychiatric disorders, such as autism spectrum disorders. Recently, protein arginine methyltransferase 7 (PRMT7) was shown to be highly expressed in the hippocampus, including the CA1 region. However, the physiological function of PRMT7 in the CA1 neurons and the relationship to psychiatric disorders are unclear. Here we showed that PRMT7 knockout (KO) mice exhibit hyperactivity and deficits in social interaction. The firing frequency of the CA1 neurons in the PRMT7 KO mice was significantly higher than that in the wild-type (WT) mice. Compared with the WT CA1 neurons, the PRMT7 KO CA1 neurons showed a more hyperpolarized resting potential and a higher input resistance, which were occluded by the Ih-current inhibitor ZD7288; these findings were consistent with the decreased Ih and suggested the contribution of Ih-channel dysfunction to the PRMT7 KO phenotypes. The HCN1 protein level was decreased in the CA1 region of the PRMT7 KO mice in conjunction with a decrease in the expression of Shank3, which encodes a core scaffolding protein for HCN channel proteins. A brief application of the PRMT7 inhibitor DS437 did not reproduce the phenotype of the PRMT7 KO neurons, further indicating that PRMT7 regulates Ih by controlling the channel number rather than the open probability. Moreover, shRNA-mediated PRMT7 suppression reduced both the mRNA and protein levels of SHANK3, implying that PRMT7 deficiency might be responsible for the decrease in the HCN protein levels by altering Shank3 expression. These findings reveal a key role for PRMT7 in the regulation of HCN channel density in the CA1 pyramidal cells that may be amenable to pharmacological intervention for neuropsychiatric disorders.

High-Sensitivity Hydrogen Sensor Based on AlGaN/GaN Heterojunction Field-Effect Transistor.

We have developed a Pd-functionalized hydrogen gas sensor based on a recessed AlGaN/GaN heterostructure field-effect transistor. The AlGaN barrier layer under the Pd catalyst was partially etched to enhance its sensitivity. Both low-power consumption and high sensitivity were achieved by employing a recessed structure. Sensor characterization was carried out at the temperature range from room temperature to 250 °C, among which the best sensing characteristics were observed at 200 °C. A sensitivity of 380% with a response time of 0.25 s was achieved at a bias voltage of 0.3 V at 200 °C under a hydrogen exposure concentration of 4%. The standby power consumption was only 2 µW for the sensing area of 100×28 µm² due to the low standby current, which was caused by the recessed AlGaN barrier layer.

PRMT7 methylates and suppresses GLI2 binding to SUFU thereby promoting its activation.

Cellular senescence is implicated in aging or age-related diseases. Sonic hedgehog (Shh) signaling, an inducer of embryonic development, has recently been demonstrated to inhibit cellular senescence. However, the detailed mechanisms to activate Shh signaling to prevent senescence is not well understood. Here, we demonstrate that Protein arginine methyltransferase 7 (PRMT7) promotes Shh signaling via GLI2 methylation which is critical for suppression of cellular senescence. PRMT7-deficient mouse embryonic fibroblasts (MEFs) exhibited a premature cellular senescence with accompanied increase in the cell cycle inhibitors p16 and p21. PRMT7 depletion results in reduced Shh signaling activity in MEFs while PRMT7 overexpression enhances GLI2-reporter activities that are sensitive to methylation inhibition. PRMT7 interacts with and methylates GLI2 on arginine residues 225 and 227 nearby a binding region of SUFU, a negative regulator of GLI2. This methylation interferes with GLI2-SUFU binding, leading to facilitation of GLI2 nuclear accumulation and Shh signaling. Taken together, these data suggest that PRMT7 induces GLI2 methylation, reducing its binding to SUFU and increasing Shh signaling, ultimately leading to prevention of cellular senescence.

Methylation determines the extracellular calcium sensitivity of the leak channel NALCN in hippocampal dentate granule cells.

The sodium leak channel NALCN is a key player in establishing the resting membrane potential (RMP) in neurons and transduces changes in extracellular Ca2+ concentration ([Ca2+]e) into increased neuronal excitability as the downstream effector of calcium-sensing receptor (CaSR). Gain-of-function mutations in the human NALCN gene cause encephalopathy and severe intellectual disability. Thus, understanding the regulatory mechanisms of NALCN is important for both basic and translational research. This study reveals a novel mechanism for NALCN regulation by arginine methylation. Hippocampal dentate granule cells in protein arginine methyltransferase 7 (PRMT7)-deficient mice display a depolarization of the RMP, decreased threshold currents, and increased excitability compared to wild-type neurons. Electrophysiological studies combined with molecular analysis indicate that enhanced NALCN activities contribute to hyperexcitability in PRMT7-/- neurons. PRMT7 depletion in HEK293T cells increases NALCN activity by shifting the dose-response curve of NALCN inhibition by [Ca2+]e without affecting NALCN protein levels. In vitro methylation studies show that PRMT7 methylates a highly conserved Arg1653 of the NALCN gene located in the carboxy-terminal region that is implicated in CaSR-mediated regulation. A kinase-specific phosphorylation site prediction program shows that the adjacent Ser1652 is a potential phosphorylation site. Consistently, our data from site-specific mutants and PKC inhibitors suggest that Arg1653 methylation might modulate Ser1652 phosphorylation mediated by CaSR/PKC-delta, leading to [Ca2+]e-mediated NALCN suppression. Collectively, these data suggest that PRMT7 deficiency decreases NALCN methylation at Arg1653, which, in turn, decreases CaSR/PKC-mediated Ser1652 phosphorylation, lifting NALCN inhibition, thereby enhancing neuronal excitability. Thus, PRMT7-mediated NALCN inhibition provides a potential target for the development of therapeutic tools for neurological diseases.

SGTb regulates a surface localization of a guidance receptor BOC to promote neurite outgrowth.

Neuritogenesis is a critical event for neuronal differentiation and neuronal circuitry formation during neuronal development and regeneration. Our previous study revealed a critical role of a guidance receptor BOC in a neuronal differentiation and neurite outgrowth. However, regulatory mechanisms for BOC signaling pathway remain largely unexplored. In the current study, we have identified Small glutamine-rich tetratricopeptide repeat (TPR)-containing b (SGTb) as a BOC interacting protein through yeast two-hybrid screening. Like BOC, SGTb is highly expressed in brain and P19 embryonal carcinoma (EC) cells differentiated into neuronal cells. BOC and SGTb proteins co-precipitate in mouse brain and differentiated P19 EC cells. Furthermore, BOC and SGTb co-localize in neurites and especially are concentrated at the tip of neurites in various neuronal cells. SGTb depletion attenuates neuronal differentiation of P19 cells through reduction of the surface level of BOC. Additionally, SGTb depletion causes BOC localization at neurite tip, coinciding with decreased p-JNK levels critical for actin cytoskeleton remodeling. The overexpression of SGTb or BOC restores JNK activation in BOC or SGTb-depleted cells, respectively. Finally, SGTb elevates the level of surface-resident BOC in BOC-depleted cells, restoring JNK activation. Taken together, our data suggest that SGTb interacts with BOC and regulates its surface level and consequent JNK activation, thereby promoting neuronal differentiation and neurite outgrowth.

Cardiac specific PRMT1 ablation causes heart failure through CaMKII dysregulation.

Dysregulation of Ca2+/calmodulin-dependent protein kinase (CaMK)II is closely linked with myocardial hypertrophy and heart failure. However, the mechanisms that regulate CaMKII activity are incompletely understood. Here we show that protein arginine methyltransferase 1 (PRMT1) is essential for preventing cardiac CaMKII hyperactivation. Mice null for cardiac PRMT1 exhibit a rapid progression to dilated cardiomyopathy and heart failure within 2 months, accompanied by cardiomyocyte hypertrophy and fibrosis. Consistently, PRMT1 is downregulated in heart failure patients. PRMT1 depletion in isolated cardiomyocytes evokes hypertrophic responses with elevated remodeling gene expression, while PRMT1 overexpression protects against pathological responses to neurohormones. The level of active CaMKII is significantly elevated in PRMT1-deficient hearts or cardiomyocytes. PRMT1 interacts with and methylates CaMKII at arginine residues 9 and 275, leading to its inhibition. Accordingly, pharmacological inhibition of CaMKII restores contractile function in PRMT1-deficient mice. Thus, our data suggest that PRMT1 is a critical regulator of CaMKII to maintain cardiac function.

Black ginseng activates Akt signaling, thereby enhancing myoblast differentiation and myotube growth.

BACKGROUND: Black ginseng (BG) has greatly enhanced pharmacological activities relative to white or red ginseng. However, the effect and molecular mechanism of BG on muscle growth has not yet been examined. In this study, we investigated whether BG could regulate myoblast differentiation and myotube hypertrophy. METHODS: BG-treated C2C12 myoblasts were differentiated, followed by immunoblotting for myogenic regulators, immunostaining for a muscle marker, myosin heavy chain or immunoprecipitation analysis for myogenic transcription factors. RESULTS: BG treatment of C2C12 cells resulted in the activation of Akt, thereby enhancing heterodimerization of MyoD and E proteins, which in turn promoted muscle-specific gene expression and myoblast differentiation. BG-treated myoblasts formed larger multinucleated myotubes with increased diameter and thickness, accompanied by enhanced Akt/mTOR/p70S6K activation. Furthermore, the BG treatment of human rhabdomyosarcoma cells restored myogenic differentiation. CONCLUSION: BG enhances myoblast differentiation and myotube hypertrophy by activating Akt/mTOR/p70S6k axis. Thus, our study demonstrates that BG has promising potential to treat or prevent muscle loss related to aging or other pathological conditions, such as diabetes.

A Sonic hedgehog coreceptor, BOC regulates neuronal differentiation and neurite outgrowth via interaction with ABL and JNK activation.

Neurite outgrowth is a critical step for neurogenesis and remodeling synaptic circuitry during neuronal development and regeneration. An immunoglobulin superfamily member, BOC functions as Sonic hedgehog (Shh) coreceptor in canonical and noncanonical Shh signaling in neuronal development and axon outgrowth/guidance. However signaling mechanisms responsible for BOC action during these processes remain unknown. In our previous studies, a multiprotein complex containing BOC and a closely related protein CDO promotes myogenic differentiation through activation of multiple signaling pathways, including non-receptor tyrosine kinase ABL. Given that ABL and Jun. N-terminal kinase (JNK) are implicated in actin cytoskeletal dynamics required for neurogenesis, we investigated the relationship between BOC, ABL and JNK during neuronal differentiation. Here, we demonstrate that BOC and ABL are induced in P19 embryonal carcinoma (EC) cells and cortical neural progenitor cells (NPCs) during neuronal differentiation. BOC-depleted EC cells or Boc-/- NPCs exhibit impaired neuronal differentiation with shorter neurite formation. BOC interacts with ABL through its putative SH2 binding domain and seems to be phosphorylated in an ABL activity-dependent manner. Unlike wildtype BOC, ABL-binding defective BOC mutants exhibit impaired JNK activation and neuronal differentiation. Finally, Shh treatment enhances JNK activation which is diminished by BOC depletion. These data suggest that BOC interacts with ABL and activates JNK thereby promoting neuronal differentiation and neurite outgrowth.

Protein arginine methylation facilitates KCNQ channel-PIP2 interaction leading to seizure suppression.

KCNQ channels are critical determinants of neuronal excitability, thus emerging as a novel target of anti-epileptic drugs. To date, the mechanisms of KCNQ channel modulation have been mostly characterized to be inhibitory via Gq-coupled receptors, Ca(2+)/CaM, and protein kinase C. Here we demonstrate that methylation of KCNQ by protein arginine methyltransferase 1 (Prmt1) positively regulates KCNQ channel activity, thereby preventing neuronal hyperexcitability. Prmt1+/- mice exhibit epileptic seizures. Methylation of KCNQ2 channels at 4 arginine residues by Prmt1 enhances PIP2 binding, and Prmt1 depletion lowers PIP2 affinity of KCNQ2 channels and thereby the channel activities. Consistently, exogenous PIP2 addition to Prmt1+/- neurons restores KCNQ currents and neuronal excitability to the WT level. Collectively, we propose that Prmt1-dependent facilitation of KCNQ-PIP2 interaction underlies the positive regulation of KCNQ activity by arginine methylation, which may serve as a key target for prevention of neuronal hyperexcitability and seizures.

Prmt7 Deficiency Causes Reduced Skeletal Muscle Oxidative Metabolism and Age-Related Obesity.

Maintenance of skeletal muscle function is critical for metabolic health and the disruption of which exacerbates many chronic diseases such as obesity and diabetes. Skeletal muscle responds to exercise or metabolic demands by a fiber-type switch regulated by signaling-transcription networks that remains to be fully defined. Here, we report that protein arginine methyltransferase 7 (Prmt7) is a key regulator for skeletal muscle oxidative metabolism. Prmt7 is expressed at the highest levels in skeletal muscle and decreased in skeletal muscles with age or obesity. Prmt7(-/-) muscles exhibit decreased oxidative metabolism with decreased expression of genes involved in muscle oxidative metabolism, including PGC-1α. Consistently, Prmt7(-/-) mice exhibited significantly reduced endurance exercise capacities. Furthermore, Prmt7(-/-) mice exhibit decreased energy expenditure, which might contribute to the exacerbated age-related obesity of Prmt7(-/-) mice. Similarly to Prmt7(-/-) muscles, Prmt7 depletion in myoblasts also reduces PGC-1α expression and PGC-1α-promoter driven reporter activities. Prmt7 regulates PGC-1α expression through interaction with and activation of p38 mitogen-activated protein kinase (p38MAPK), which in turn activates ATF2, an upstream transcriptional activator for PGC-1α. Taken together, Prmt7 is a novel regulator for muscle oxidative metabolism via activation of p38MAPK/ATF2/PGC-1α.

Monitoring the quality of medicines: results from Africa, Asia, and South America.

Monitoring the quality of medicines plays a crucial role in an integrated medicines quality assurance system. In a publicly available medicines quality database (MQDB), the U.S. Pharmacopeial Convention (USP) reports results of data collected from medicines quality monitoring (MQM) activities spanning the period of 2003-2013 in 17 countries of Africa, Asia, and South America. The MQDB contains information on 15,063 samples collected and tested using Minilab® screening methods and/or pharmacopeial methods. Approximately 71% of the samples reported came from Asia, 23% from Africa, and 6% from South America. The samples collected and tested include mainly antibiotic, antimalarial, and antituberculosis medicines. A total of 848 samples, representing 5.6% of total samples, failed the quality test. The failure proportion per region was 11.5%, 10.4%, and 2.9% for South America, Africa, and Asia, respectively. Eighty-one counterfeit medicines were reported, 86.4% of which were found in Asia and 13.6% in Africa. Additional analysis of the data shows the distribution of poor-quality medicines per region and by therapeutic indication as well as possible trends of counterfeit medicines.

Cdo suppresses canonical Wnt signalling via interaction with Lrp6 thereby promoting neuronal differentiation.

Canonical Wnt signalling regulates expansion of neural progenitors and functions as a dorsalizing signal in the developing forebrain. In contrast, the multifunctional co-receptor Cdo promotes neuronal differentiation and is important for the function of the ventralizing signal, Shh. Here we show that Cdo negatively regulates Wnt signalling during neurogenesis. Wnt signalling is enhanced in Cdo-deficient cells, leading to impaired neuronal differentiation. The ectodomains of Cdo and Lrp6 interact via the Ig2 repeat of Cdo and the LDLR repeats of Lrp6, and the Cdo Ig2 repeat is necessary for Cdo-dependent Wnt inhibition. Furthermore, the Cdo-deficient dorsal forebrain displays stronger Wnt signalling activity, increased cell proliferation and enhanced expression of the dorsal markers and Wnt targets, Pax6, Gli3, Axin2. Therefore, in addition to promoting ventral central nervous system cell fates with Shh, Cdo promotes neuronal differentiation by suppression of Wnt signalling and provides a direct link between two major dorsoventral morphogenetic signalling pathways.

TGF-ß-activated kinase 1 (TAK1) and apoptosis signal-regulating kinase 1 (ASK1) interact with the promyogenic receptor Cdo to promote myogenic differentiation via activation of p38MAPK pathway.

p38MAPK plays an essential role in the transition of myoblasts to differentiated myotubes through the activation of MyoD family transcription factors. A promyogenic cell surface molecule, Cdo, promotes myogenic differentiation mainly through activation of the p38MAPK pathway. Two MAP3Ks, TAK1 and ASK1, can activate p38MAPK via MKK6 in various cell systems. Moreover TAK1 has been shown to promote myogenic differentiation via p38MAPK activation. In this study, we hypothesized that TAK1 and ASK1 might function as MAP3Ks in Cdo-mediated p38MAPK activation during myoblast differentiation. Both ASK1 and TAK1 were expressed in myoblasts and interacted with the cytoplasmic tail of Cdo and a scaffold protein, JLP. The depletion of TAK1 or ASK1 in C2C12 cells decreased myoblast differentiation, whereas overexpression of TAK1 or ASK1 in C2C12 cells enhanced myotube formation. In agreement with this, overexpression of ASK1 or TAK1 resulted in enhanced p38MAPK activation, and their knockdown inhibited p38MAPK in C2C12 cells. Overexpression of TAK1 or ASK1 in Cdo(-/-) myoblasts and Cdo-depleted C2C12 cells restored p38MAPK activation as well as myotube formation. Furthermore, ASK1 and TAK1 compensated for each other in p38MAPK activation and myoblast differentiation. Taken together, these findings suggest that ASK1 and TAK1 function as MAP3Ks in Cdo-mediated p38MAPK activation to promote myogenic differentiation.

Dermatitis among farmers engaged in peri-urban aquatic food production in Hanoi, Vietnam.

OBJECTIVE: To assess whether exposure to wastewater is a risk factor for dermatitis (eczema) among farmers engaged in peri-urban aquatic food production in Hanoi, Vietnam. METHODS: A cross-sectional study with two follow-ups was conducted from April to December 2005 in two peri-urban communes in Hanoi, one using wastewater and another using river, rain and well water for aquatic food production. In each commune, 100 households were randomly selected and adult household members engaged in farming field work were interviewed in three surveys. Farmers who reported skin problems at the time of interviews were examined and treated by a dermatologist. Data were analysed for one farmer per household. RESULTS: The overall prevalence of dermatitis from 592 interviews was 6.3%. The commune which used wastewater had a much higher overall prevalence of dermatitis (10.4%) than the commune that did not (2.1%; P-value < 0.001). Multivariable logistic regression analyses showed that occupational wastewater contact was an important risk factor for dermatitis (odds ratio [OR] 3.0; 95% confidence interval [CI] 1.1-7.7). Duration of daily wastewater contact was not significantly associated with dermatitis. Aquaculture work in the wet season carried an increased risk of dermatitis in both communes (OR 2.8; 95% CI 1.02-7.6). The use of personal protective measures during field work and washing hands and feet after work did not reduce the risk for dermatitis. However, observations showed that these practices were applied in such a way that they were unlikely to provide effective protection against wastewater contact. CONCLUSION: Contact with wastewater is an important risk factor for dermatitis among farmers engaged in wastewater-fed peri-urban aquatic food production. Additional studies should test preventive and mitigating measures such as improved personal protection and hygiene.