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Patients’ suffering from large or deep wounds caused by traumatic and/or thermal injuries have significantly lower chances of recapitulating lost skin function through natural healing. We tested whether enhanced unfolded protein response (UPR) by expression of a UPR transcriptional activator, X-box-binding protein 1 (XBP1) can significantly promote wound repair through stimulating growth factor production and promoting angiogenesis. In mouse models of a second-degree thermal wound, a full-thickness traumatic wound, and a full-thickness diabetic wound, the topical gene transfer of the activated form of XBP1 (spliced XBP1, XBP1s) can significantly enhance re-epithelialization and increase angiogenesis, leading to rapid, nearly complete wound closure with intact regenerated epidermis and dermis. Overexpression of XBP1s stimulated the transcription of growth factors in fibroblasts critical to proliferation and remodeling during wound repair, including platelet-derived growth factor BB, basic fibroblast growth factor, and transforming growth factor beta 3. Meanwhile, the overexpression of XBP1s boosted the migration and tube formation of dermal microvascular endothelial cells in vitro. Our functional and mechanistic investigations of XBP1-mediated regulation of wound healing processes provide novel insights into the previously undermined physiological role of the UPR in skin injuries. The finding opens an avenue to developing potential XBP1-based therapeutic strategies in clinical wound care protocols.

The endoplasmic reticulum (ER)–tethered, liver-enriched stress sensor CREBH is processed in response to increased energy demands or hepatic stress to release an amino-terminal fragment that functions as a transcription factor for hepatic genes encoding lipid and glucose metabolic factors. Here, we discovered that the carboxyl-terminal fragment of CREBH (CREBH-C) derived from membrane-bound, full-length CREBH was secreted as a hepatokine in response to fasting or hepatic stress. Phosphorylation of CREBH-C mediated by the kinase CaMKII was required for efficient secretion of CREBH-C through exocytosis. Lipoprotein lipase (LPL) mediates the lipolysis of circulating triglycerides for tissue uptake and is inhibited by a complex consisting of angiopoietin-like (ANGPTL) 3 and ANGPTL8. Secreted CREBH-C blocked the formation of ANGPTL3-ANGPTL8 complexes, leading to increased LPL activity in plasma and metabolic tissues in mice. CREBH-C administration promoted plasma triglyceride clearance and partitioning into peripheral tissues and mitigated hypertriglyceridemia and hepatic steatosis in mice fed a high-fat diet. Individuals with obesity had higher circulating amounts of CREBH-C than control individuals, and human CREBH loss-of-function variants were associated with dysregulated plasma triglycerides. These results identify a stress-induced, secreted protein fragment derived from CREBH that functions as a hepatokine to stimulate LPL activity and triglyceride homeostasis.

Plasma application systems can be classified as an inductive-coupled plasma (ICP) system and a capacitive coupled plasma (CCP) system. Generally, a voltage-source-type pulse generator (VST-PG) is utilized in ICP systems. The VST-PG has the intrinsic problem of spike currents and voltage ringing in CCP systems. A filter inductor and damping circuit have been employed to mitigate this problem. However, this solution degrades the dynamic performance and increases the system cost, particularly for a CCP system with a large power rating. This article proposes a current-source-type pulse generator (CST-PG) to solve the problem of current spike and voltage ringing in a CCP system. The proposed circuit structure provides the output voltage and current waveform of the enhanced waveform fidelity. In the proposed system, two current sources of different scales are connected in parallel to generate the output current with high precision. The entire system consists of four major functional blocks: a bias current generator, a bias current modulator, a slope current generator, and a slope current modulator. The proposed solution also employs a SiC mosfet -type power semiconductor switch of 1200 V/90 A to meet the fast transient requirement. The proposed converter system successfully satisfies the specification of an output voltage of 1.6 kV and an output current of 35 A with a fundamental frequency of 100 kHz. The experimental validation result confirms the superior performance of CST-PG with a reduced crest factor of 1.12 for a laboratory prototype.

This paper introduces a novel method to reduce the voltage stress experienced by 320 V/1 kW/13.56 MHz electrical variable capacitor (EVC) circuits with an asymmetrical switch configuration applied in the impedance matching circuits of RF plasma systems. The proposed method employs a symmetrical switch configuration in place of the asymmetrical switch configuration in each of the capacitor legs in an EVC circuit. The symmetrical switch configuration reduces the voltage stress in the EVC circuit due to symmetrical charging and discharging modes. As a result, the proposed circuit can be used in etching systems. The major idea is verified by simulation and experimental results, which successfully demonstrate that the voltage stress on the switch of an EVC circuit is reduced by more than 35%.

This paper proposes a current source-type pulse generator circuit to improve load voltage waveforms by solving the voltage ringing problem of capacitively coupled plasma systems. The voltage source-type pulse power supplies used in the plasma industry have short-circuit currents and voltage ringing problems with capacitively coupled plasma loads. The current source-type pulse generator proposed in this paper can solve these problems. The proposed circuit consists of four detailed circuits: bias current generator, bias current modulator, slope current generator, and slope current modulator. They form two constant currents at the DC link, and output two pulse currents to the load. These output currents contribute to generating the plasma load voltage required by the capacitively coupled plasma process. The proposed circuit is verified by a PLECS simulator and a laboratory-scale hardware system. To check the improvement of the output waveform, a voltage source-type pulse generator and the current source-type pulse generator are tested under the same experimental conditions. The results are represented by load voltage and current waveforms. In addition, the entire system of the current source-type pulse generator is designed and verified by simulation and experimental results. The resulting output waveforms meet the process requirements, and the obtained results demonstrate that the proposed current source-type pulse generator circuit can be suitably used for capacitively coupled plasma loads.

Insulin resistance is a major phenotype observed in nonalcoholic steatohepatitis (NASH), the advanced stage of nonalcoholic fatty liver disease (NAFLD). Insulin resistance in NASH is characterized by reductions in whole body, hepatic, and adipose tissue insulin sensitivity. The mechanisms underlying hepatic insulin resistance is primarily associated with hepatic glucose production (HGP) rate. Hepatic insulin resistance can also be a consequence or a driving factor of hepatic lipid accumulation by increasing free fatty acid synthesis, delivery, and catabolism. The common method to assess hepatic insulin resistance is to measure hepatic glucose production (HGP) using isotope tracer distribution technique. However, non-radioactive approaches have been developed to assess hepatic insulin resistance in the context of NASH. In this chapter, we describe the methods to evaluate hepatic insulin resistance in animal models of NASH by examining insulin sensitivity and glucose tolerance as well as the key molecules in hepatic insulin signaling pathways.

Summary The rs58542926C >T (E167K) variant of the transmembrane 6 superfamily member 2 gene (TM6SF2) is associated with increased risks for nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D). Nevertheless, the role of the TM6SF2 rs58542926 variant in glucose metabolism is poorly understood. We performed a sex-stratified analysis of the association between the rs58542926C >T variant and T2D in multiple cohorts. The E167K variant was significantly associated with T2D, especially in males. Using an E167K knockin (KI) mouse model, we found that male but not the female KI mice exhibited impaired glucose tolerance. As an ER membrane protein, TM6SF2 was found to interact with inositol-requiring enzyme 1 α (IRE1α), a primary ER stress sensor. The male Tm6sf2 KI mice exhibited impaired IRE1α signaling in the liver. In conclusion, the E167K variant of TM6SF2 is associated with glucose intolerance primarily in males, both in humans and mice., Graphical abstract, Highlights • The TM6SF2 E167K variant is significantly associated with T2D, primarily in males • Male, but not female, Tm6sf2 KI mice exhibited impaired glucose tolerance • IRE1α signaling is attenuated in the liver of male Tm6sf2 KI mice • IDE and LIPIN1 were dysregulated in the liver of male KI mice but not the females, Physiology; Molecular physiology; Diabetology; Genomics

Betaine-homocysteine methyltransferase (BHMT) catalyzes the transfer of methyl-groups from betaine to homocysteine (Hcy) producing methionine and dimethylgycine. In this work, we characterize Bhmt wildtype (WT) and knockout (KO) mice that were fully backcrossed to a C57Bl6/J background. Consistent with our previous findings, Bhmt KO mice had decreased body weight, fat mass and adipose tissue weight compared to WT. Histological analyses and gene expression profiling indicate that adipose browning was activated in KO mice and contributed to the adipose atrophy observed. BHMT is not expressed in adipose tissue but is abundant in liver, thus, a signal must be originating from the liver that modulates adipose tissue. We found that, in Bhmt KO mice, homocysteine-induced endoplasmic reticulum (ER) stress, with activation of hepatic transcription factor cyclin AMP response element binding protein (CREBH), mediated an increase in hepatic and plasma concentrations of fibroblast growth factor 21 (FGF21), which is known to induce adipose browning. CREBH binds to the promoter regions of FGF21 to activate its expression. Taken together, our data indicate that deletion of a single gene in one-carbon metabolism modifies adipose biology and energy metabolism. It would be interesting to determine whether people with functional polymorphisms in BHMT exhibit a similar adipose atrophy phenotype.

Objective The endoplasmic reticulum (ER)-resident E3 ligase HRD1 and its co-activator Sel1L are major components of ER-associated degradation (ERAD) machinery. Here, we investigated the molecular mechanism and functional significance underlying the circadian regulation of HRD1/Sel1L-mediated protein degradation program in hepatic energy metabolism. Methods Genetically engineered animal models as well as gain- and loss-of-function studies were employed to address the circadian regulatory mechanism and functional significance. Gene expression, transcriptional activation, protein–protein interaction, and animal metabolic phenotyping analyses were performed to dissect the molecular network and metabolic pathways. Results Hepatic HRD1 and Sel1L expression exhibits circadian rhythmicity that is controlled by the ER-tethered transcriptional activator CREBH, the nuclear receptor peroxisome proliferator-activated receptor α (PPARα), and the core clock oscillator BMAL1 in mouse livers. HRD1/Sel1L mediates polyubiquitination and degradation of the CREBH protein across the circadian cycle to modulate rhythmic expression of the genes encoding the rate-limiting enzymes or regulators in fatty acid (FA) oxidation, triglyceride (TG) lipolysis, lipophagy, and gluconeogenesis. HRD1 liver-specific knockout (LKO) mice displayed increased expression of the genes involved in lipid and glucose metabolism and impaired circadian profiles of circulating TG, FA, and glucose due to overproduction of CREBH. The circadian metabolic activities of HRD1 LKO mice were inversely correlated with those of CREBH KO mice. Suppressing CREBH overproduction in the livers of HRD1 LKO mice restored the diurnal levels of circulating TG and FA of HRD1 LKO mice. Conclusion Our work revealed a key circadian-regulated molecular network through which the E3 ubiquitin ligase HRD1 and its co-activator Sel1L regulate hepatic circadian metabolism., Graphical abstract Image 1, Highlights • The E3 ubiquitin ligase HRD1 and its co-factor Sel1L are regulated by the circadian clock. • HRD1-mediated protein degradation program integrates hepatic energy metabolism with circadian rhythm. • HRD1/Sel1L mediates circadian degradation of CREBH to regulate hepatic lipid and glucose homeostasis. • BMAL1, CREBH, and PPARα coordinate to control rhythmic expression of HRD1/Sel1L.

Autophagy, a lysosomal degradative pathway in response to nutrient limitation, plays an important regulatory role in lipid homeostasis upon energy demands. Here, we demonstrated that the endoplasmic reticulum–tethered, stress-sensing transcription factor cAMP-responsive element-binding protein, hepatic-specific (CREBH) functions as a major transcriptional regulator of hepatic autophagy and lysosomal biogenesis in response to nutritional or circadian signals. CREBH deficiency led to decreased hepatic autophagic activities and increased hepatic lipid accumulation upon starvation. Under unfed or during energy-demanding phases of the circadian cycle, CREBH is activated to drive expression of the genes encoding the key enzymes or regulators in autophagosome formation or autophagic process, including microtubule-associated protein 1B-light chain 3, autophagy-related protein (ATG)7, ATG2b, and autophagosome formation Unc-51 like kinase 1, and the genes encoding functions in lysosomal biogenesis and homeostasis. Upon nutrient starvation, CREBH regulates and interacts with peroxisome proliferator–activated receptor α (PPARα) and PPARγ coactivator 1α to synergistically drive expression of the key autophagy genes and transcription factor EB, a master regulator of lysosomal biogenesis. Furthermore, CREBH regulates rhythmic expression of the key autophagy genes in the liver in a circadian-dependent manner. In summary, we identified CREBH as a key transcriptional regulator of hepatic autophagy and lysosomal biogenesis for the purpose of maintaining hepatic lipid homeostasis under nutritional stress or circadian oscillation.—Kim, H., Williams, D., Qiu, Y., Song, Z., Yang, Z., Kimler, V., Goldberg, A., Zhang, R., Yang, Z., Chen, X., Wang, L., Fang, D., Lin, J. D., Zhang, K. Regulation of hepatic autophagy by stress-sensing transcription factor CREBH.

This paper introduces a novel method to reduce the capacitance variable time experienced by Vacuum Variable Capacitor (VVC) circuit of 320V/1kW/13.56MHz having a vacuum variable capacitor applied in impedance matching circuit of RF plasma system. The method replaces vacuum variable capacitor with a novel Electrical Variable Capacitor (EVC) employing a power electronics technology in order to reduce the capacitance variable time. The proposed idea successfully reduces the capacitance variable time in the VVC owing to fast switching action of power semiconductor switch and can be applied in the impedance matching circuit of high-power and high-frequency RF plasma system. The proposed circuit topology is effectively supported by experiment which has verified that the capacitance variable time of the EVC is maintained below 150us.

Bacterial endotoxin can induce inflammatory and metabolic changes in the host. In this study, we revealed a molecular mechanism by which a stress-inducible, liver-enriched transcription factor, cAMP-responsive element-binding protein hepatic-specific (CREBH), modulates lipid profiles to protect the liver from injuries upon the bacterial endotoxin lipopolysaccharide (LPS). LPS challenge can activate CREBH in mouse liver tissues in a toll-like receptor (TLR)/MyD88-dependent manner. Upon LPS challenge, CREBH interacts with TNF receptor-associated factor 6 (TRAF6), an E3 ubiquitin ligase that functions as a key mediator of TLR signaling, and this interaction relies on MyD88. Further analysis demonstrated that TRAF6 mediates K63-linked ubiquitination of CREBH to facilitate CREBH cleavage and activation. CREBH directly activates expression of the gene encoding Apolipoprotein A4 (ApoA4) under LPS challenge, leading to modulation of high-density lipoprotein (HDL) in animals. CREBH deficiency led to reduced production of circulating HDL and increased liver damage upon high-dose LPS challenge. Therefore, TLR/MyD88-dependent, TRAF6-facilitated CREBH activation represents a mammalian hepatic defense response to bacterial endotoxin by modulating HDL.

The circadian clock orchestrates diverse physiological processes critical for health and disease. CREB, hepatocyte specific (CREBH) is a liver-enriched, endoplasmic reticulum (ER)–tethered transcription factor known to regulate the hepatic acute phase response and energy homeostasis under stress conditions. We demonstrate that CREBH is regulated by the circadian clock and functions as a circadian regulator of hepatic lipid metabolism. Proteolytic activation of CREBH in the liver exhibits typical circadian rhythmicity controlled by the core clock oscillator BMAL1 and AKT/glycogen synthase kinase 3β (GSK3β) signaling pathway. GSK3β-mediated phosphorylation of CREBH modulates the association between CREBH and the coat protein complex II transport vesicle and thus controls the ER-to-Golgi transport and subsequent proteolytic cleavage of CREBH in a circadian manner. Functionally, CREBH regulates circadian expression of the key genes involved in triglyceride (TG) and fatty acid (FA) metabolism and is required to maintain circadian amplitudes of blood TG and FA in mice. During the circadian cycle, CREBH rhythmically regulates and interacts with the hepatic nuclear receptors peroxisome proliferator–activated receptor α and liver X receptor α as well as with the circadian oscillation activator DBP and the repressor E4BP4 to modulate CREBH transcriptional activities. In conclusion, these studies reveal that CREBH functions as a circadian-regulated liver transcriptional regulator that integrates energy metabolism with circadian rhythm.

Obesity or a high-fat diet represses the endoribonuclease activity of inositol-requiring enzyme 1α (IRE1α), a transducer of the unfolded protein response (UPR) in cells under endoplasmic reticulum (ER) stress. An impaired UPR is associated with hepatic steatosis and non-alcoholic fatty liver disease (NAFLD), which is caused by lipid accumulation in the liver. Here, we found that IRE1α was critical to maintaining lipid homeostasis in the liver by repressing the biogenesis of microRNAs (miRNAs) that regulate lipid mobilization. In mice fed normal chow, the endoribonuclease function of IRE1α processed a subset of precursor miRNAs in the liver, including those of the miR-200 and miR-34 families, such that IRE1α promoted their degradation through the process of regulated IRE1-dependent decay (RIDD). A high-fat diet in mice or hepatic steatosis in patients was associated with the S-nitrosylation of IRE1α and inactivation of its endoribonuclease activity. This resulted in an increased abundance of these miRNA families in the liver and, consequently, a decreased abundance of their targets, which included peroxisome proliferator-activated receptor α (PPARα) and the deacetylase sirtuin 1 (SIRT1), regulators of fatty acid oxidation and triglyceride lipolysis. IRE1α deficiency exacerbated hepatic steatosis in mice. The abundance of the miR-200 and miR-34 families was also increased in cultured, lipid-overloaded hepatocytes and in the livers of patients with hepatic steatosis. Our findings reveal a mechanism by which IRE1α maintains lipid homeostasis through its regulation of miRNAs, a regulatory pathway distinct from the canonical IRE1α-UPR pathway under acute ER stress.

Cyclic AMP-responsive element-binding protein 3-like 3, hepatocyte specific (CREBH), is a hepatic transcription factor that functions as a key regulator of energy homeostasis. Here, we defined a regulatory CREBH posttranslational modification process, namely, lysine-specific acetylation, and its functional involvement in fasting-induced hepatic lipid metabolism. Fasting induces CREBH acetylation in mouse livers in a time-dependent manner, and this event is critical for CREBH transcriptional activity in regulating hepatic lipid homeostasis. The histone acetyltransferase PCAF-mediated acetylation and the deacetylase sirtuin-1-mediated deacetylation coexist to maintain CREBH acetylation states under fasting conditions. Site-directed mutagenesis and functional analyses revealed that the lysine (K) residue at position 294 (K294) within the bZIP domain of the CREBH protein is the site where fasting-induced acetylation/deacetylation occurs. Introduction of the acetylation-deficient (K294R) or acetylation-mimicking (K294Q) mutation inhibited or enhanced CREBH transcriptional activity, respectively. Importantly, CREBH acetylation at lysine 294 was required for the interaction and synergy between CREBH and peroxisome proliferator-activated receptor α (PPARα) in activating their target genes upon fasting or glucagon stimulation. Introduction of the CREBH lysine 294 mutation in the liver leads to hepatic steatosis and hyperlipidemia in animals under prolonged fasting. In summary, our study reveals a molecular mechanism by which fasting or glucagon stimulation modulates lipid homeostasis through acetylation of CREBH.

Background & Aims Hepatic fibrosis, featured by the accumulation of excessive extracellular matrix in liver tissue, is associated with metabolic disease and cancer. Inhalation exposure to airborne particulate matter in fine ranges (PM 2.5 ) correlates with pulmonary dysfunction, cardiovascular disease, and metabolic syndrome. In this study, we investigated the effect and mechanism of PM 2.5 exposure on hepatic fibrogenesis. Methods Both inhalation exposure of mice and in vitro exposure of specialized cells to PM 2.5 were performed to elucidate the effect of PM 2.5 exposure on hepatic fibrosis. Histological examinations, gene expression analyses, and genetic animal models were utilized to determine the effect and mechanism by which PM 2.5 exposure promotes hepatic fibrosis. Results Inhalation exposure to concentrated ambient PM 2.5 induces hepatic fibrosis in mice under the normal chow or high-fat diet. Mice after PM 2.5 exposure displayed increased expression of collagens in liver tissues. Exposure to PM 2.5 led to activation of the transforming growth factor β-SMAD3 signaling, suppression of peroxisome proliferator-activated receptor γ, and expression of collagens in hepatic stellate cells. NADPH oxidase plays a critical role in PM 2.5 -induced liver fibrogenesis. Conclusions Exposure to PM 2.5 exerts discernible effects on promoting hepatic fibrogenesis. NADPH oxidase mediates the effects of PM 2.5 exposure on promoting hepatic fibrosis.

Circadian rhythms play crucial roles in orchestrating diverse physiological processes that are critical for health and disease. Dysregulated circadian rhythms are closely associated with various human metabolic diseases, including type 2 diabetes, cardiovascular disease, and non-alcoholic fatty liver disease. Modern lifestyles are frequently associated with an irregular circadian rhythm, which poses a significant risk to public health. While the central clock has a set periodicity, circadian oscillators in peripheral organs, particularly in the liver, can be entrained by metabolic alterations or stress cues. At the molecular level, the signal transduction pathways that mediate stress responses interact with the key determinants of circadian oscillation to maintain metabolic homeostasis under physiological or pathological conditions. In the liver, a number of nuclear receptors or transcriptional regulators, which are regulated by metabolites, hormones, the circadian clock, or environmental stressors, serve as direct links between stress responses and circadian metabolism. In this review, we summarize recent advances in the understanding of the interactions between stress responses (endoplasmic reticulum stress response, oxidative stress response, and inflammatory responses) and circadian metabolism, and the role of these interactions in the development of metabolic diseases. Keywords: Stress response, Circadian metabolism, Metabolic disease, Non-alcoholic fatty liver disease (NAFLD), Hepatic lipid metabolism

Lipid metabolism is tightly regulated by nuclear receptors, transcription factors, and cellular enzymes. In this study, we demonstrated that the liver-enriched transcription factor CREBH (cAMP-responsive element binding protein, hepatocyte specific) and peroxisome proliferator-activated receptor α (PPARα) function as binary transcriptional activators to regulate lipid metabolism by activating fibroblast growth factor 21 (FGF21), a hepatic hormone that regulates whole-body energy homeostasis. Gain- and loss-of-function studies indicated that CREBH regulates triglyceride and fatty acid metabolism in animals under fasting or on an atherogenic high-fat (AHF) diet. CREBH and PPARα act as interactive trans-activators that regulate each other for their expression. Activated CREBH protein interacts with PPARα to form a functional complex upon fasting or the AHF diet, and both factors are required for induction of the metabolic hormone FGF21. The CREBH-PPARα complex was found to bind to integrated CRE-PPAR-responsive element-binding motifs in the FGF21 gene promoter. Whereas CREBH and PPARα function in synergy to activate FGF21 gene expression, PPARα relies on CREBH to exert its trans-activation effect on FGF21. Supporting the key role of CREBH in regulating FGF21, infusion of recombinant FGF21 protein can reverse hypertriglyceridemia and hypoketonemia and partially rescue nonalcoholic steatohepatitis developed in the CREBH-null mice after the AHF diet. Our study demonstrated a transcriptional regulatory axis of CREBH-PPARα-FGF21 in maintaining lipid homeostasis under metabolic stress. The functional relationship between CREBH and PPARα in regulating FGF21 may represent an important transcriptional coactivation mechanism that orchestrates the processes of energy supply upon metabolic alteration.

Background & Aims The mitochondrial nicotinamide adenine dinucleotide (NAD) kinase (NADK2, also called MNADK) catalyzes phosphorylation of NAD to yield NADP. Little is known about the functions of mitochondrial NADP and MNADK in liver physiology and pathology. We investigated the effects of reduced mitochondrial NADP by deleting MNADK in mice. Methods We generated MNADK knockout (KO) mice on a C57BL/6NTac background; mice with a wild-type Mnadk gene were used as controls. Some mice were placed on an atherogenic high-fat diet (16% fat, 41% carbohydrate, and 1.25% cholesterol supplemented with 0.5% sodium cholate) or given methotrexate intraperitoneally. We measured rates of fatty acid oxidation in primary hepatocytes using radiolabeled palmitate and in mice using indirect calorimetry. We measured levels of reactive oxygen species in mouse livers and primary hepatocytes. Metabolomic analyses were used to quantify serum metabolites, such as amino acids and acylcarnitines. Results The KO mice had metabolic features of MNADK-deficient patients, such as increased serum concentrations of lysine and C10:2 carnitine. When placed on the atherogenic high-fat diet, the KO mice developed features of nonalcoholic fatty liver disease and had increased levels of reactive oxygen species in livers and primary hepatocytes, compared with control mice. During fasting, the KO mice had a defect in fatty acid oxidation. MNADK deficiency reduced the activation of cAMP-responsive element binding protein-hepatocyte specific and peroxisome proliferator–activated receptor alpha, which are transcriptional activators that mediate the fasting response. The activity of mitochondrial sirtuins was reduced in livers of the KO mice. Methotrexate inhibited the catalytic activity of MNADK in hepatocytes and in livers in mice with methotrexate injection. In mice given injections of methotrexate, supplementation of a diet with nicotinamide riboside, an NAD precursor, replenished hepatic NADP and protected the mice from hepatotoxicity, based on markers such as increased level of serum alanine aminotransferase. Conclusion MNADK facilitates fatty acid oxidation, counteracts oxidative damage, maintains mitochondrial sirtuin activity, and prevents metabolic stress-induced non-alcoholic fatty liver disease in mice.

Osteoclasts (OCs) are responsible for bone resorption in inflammatory joint diseases. Monocyte chemotactic protein-1 (MCP-1) has been shown to induce differentiation of monocytes to OC precursors, but nothing is known about the underlying mechanisms. Here, we elucidate how MCPIP, induced by MCP-1, mediates this differentiation. Knockdown of MCPIP abolished MCP-1-mediated expression of OC markers, tartrate-resistant acid phosphatase, and serine protease cathepsin K. Expression of MCPIP induced p47(PHOX) and its membrane translocation, reactive oxygen species formation, and induction of endoplasmic reticulum (ER) stress chaperones, up-regulation of autophagy marker, Beclin-1, and lipidation of LC3, and induction of OC markers. Inhibition of oxidative stress attenuated ER stress and autophagy, and suppressed expression of OC markers. Inhibition of ER stress by a specific inhibitor or by knockdown of IRE1 blocked autophagy and induction of OC markers. ER stress inducers, tunicamycin and thapsigargin, induced expression of OC markers. Autophagy inhibition by 3'-methyladenine, LY294002, wortmannin or by knockdown of Beclin-1 or Atg 7 inhibited MCPIP-induced expression of OC markers. These results strongly suggest that MCP-1-induced differentiation of OC precursor cells is mediated via MCPIP-induced oxidative stress that causes ER stress leading to autophagy, revealing a novel mechanistic insight into the role of MCP-1 in OCs differentiation.

MCP-1-induced protein (MCPIP, also known as ZC3H12A) has recently been uncovered to act as a negative regulator of inflammation. Expression of MCPIP was elevated in the ventricular myocardium of patients with ischemic heart failure. However, the role of MCPIP in the development of post-infarct cardiac inflammation and remodeling is unknown. The objective of the present study was to investigate whether MCPIP exerts an inhibitory effect on the cardiac inflammatory response and adverse remodeling after myocardial infarction (MI). Mice with cardiomyocyte-specific expression of MCPIP and their wild-type littermates (FVB/N) were subjected to permanent ligation of left coronary artery. The levels of MCPIP were significantly increased in the ischemic myocardium and sustained for 4 weeks after MI. Acute infarct size was comparable between groups. However, constitutive overexpression of MCPIP in the murine heart resulted in improved survival rate, decreased cardiac hypertrophy, less of fibrosis and scar formation, and better cardiac performance at 28 days after MI, along with a markedly reduced monocytic cell infiltration, less cytokine expression, decreased caspase-3/7 activities and apoptotic cell death compared to the wild-type hearts. Cardiomyocyte-specific expression of MCPIP also attenuated activation of cardiac NF-κB signaling and expression of inflammation-associated microRNAs (miR-126, -146a, -155, and -199a) when compared with the post-infarct wild-type hearts. In vitro, MCPIP expression suppressed hypoxia-induced NF-κB-luciferase activity in cardiomyocytes. In conclusion, MCPIP expression in the ischemic myocardium protects against adverse cardiac remodeling and dysfunction following MI by modulation of local myocardial inflammation, possibly through mitigating NF-κB signaling and suppressing inflammation-associated microRNA expression.

Novel methods for initial position estimation during start-up are presented for interior permanent magnet synchronous machine drives. The magnet cavities in the IPMSM rotor create a sizable difference in the inductances of the two orthogonal rotor axes. This spatial saliency based on the rotor position makes it possible to use persistent, rotating or pulsating vector, carrier frequency image tracking techniques to reliably identify and track the orientation of the d and q axes even when the rotor is at standstill. However, additional details in the saliency image must be used to identify the polarization of the magnets in order to distinguish the north and south poles. The magnet polarity is identified by using magnetic saturation effects on the saliency image to uniquely identify the magnet pole polarity being tracked. Carrier currents for both rotating and pulsating voltage carrier injection are derived by using IPM machine model including saturation and verified by measured carrier current components. Experimental results show that the proposed algorithms are capable of reliable and fast initial position estimation including the polarity at standstill.

This paper presents an improved method to estimate rotor motion states for an interior permanent-magnet machine drive. This approach is based on the estimation of a saliency-based electromotive force (EMF) in the stationary reference frame using a state filter. The spatial information obtained from the estimated saliency-based EMF is used in an observer to estimate the motor motion states. By using the commanded torque as a feedforward input to the observer, the motion state estimation has zero-phase lag, providing a very-high-bandwidth estimate.

We adopted simplified pneumatic pressurization system in polishing process to remove quilting effect. Optimized air pressure was investigated by FEM analysis and fabrication of 25 nm rms surface without quilting effect was experimentally verified.

This paper proposes a PMSM torque control method considering DC-link voltage variations and friction torque. For EV/HEV applications, a two-dimensional look-up table (2D-LUT) is used for a current reference generation due to its stable and robust torque control performance. Conventionally, this 2D-LUT is established by a flux-torque table to overcome DC-link voltage variations. However, the flux table establishment is more complex than the speed table establishment. Moreover, one flux data reflects several speed conditions in variable DC-link voltage, friction torque cannot be considered by using the flux table. In this paper, a speed-torque 2D-LUT is used for a current reference generation. With this table, PMSM torque control is well achieved regardless of DC-link voltage variations by the proposed control method. Also, friction torque is compensated by a novel compensation block described on this paper.

This paper describes Utility Interactive PV(UIPV) system that is able to improve peak-cut characteristic without major alteration of power circuit structure which adds energy storage device like batteries and alters software application algorithm. A new power circuit and application algorithm has been simulated to prove this.

A bumpless position/speed estimation method which uses only a low-resolution position sensor is presented for low cost permanent magnet machine (PMSM) drives. By integrating methods, i.e. using a speed reference for zero speed startup, a low resolution Hall sensor for low speed acceleration, and back-EMF for high speed operation, the rotor position can be estimated and controlled over the entire speed range. In order to achieve bumpless transitions, the three techniques are combined with a crossover function based on the speed reference. The proposed method can be used in applications with unpredictable variation in loads, such as horizontal drum washing machines.

This paper presents a synchronous frame current regulator for salient-pole AC machines, which is insensitive to both parameters and synchronous frequencies. The transformation from stationary to synchronous frame is known to produce a frame-dependent cross-coupling term, which results in degradation in current response at high speeds and is represented as an asymmetric pole in the complex vector form of such systems. The asymmetric pole close to right half plane (RHP) in the complex vector s-domain cannot be perfectly canceled by parameter-based design of PI controllers due to parameter variation. Complex vector design synchronous frame PI current regulator with a virtually translated asymmetric pole is shown in this paper to reduce the parameter sensitivity and to improve disturbance rejection. The current regulator with the virtually translated pole have been analyzed in complex vector form for nonsalient-pole AC machine and in scalar form for salient-pole AC machines. It has been shown to yield comparable performances in both cases. This paper includes experimental verification of the performance of the proposed current regulator for an IPMSM.

This paper presents a virtual translation technique for current regulation for AC machines. A virtual physical parameter is employed to effectively translate the system pole to achieve fast and robust dynamics. Applying this technique to conventional synchronous frame current regulators reduces parameter sensitivity and improves robustness. The current controllers are redesigned in the virtually translated system. Current regulators adopting the technique have been analyzed in complex vector form for symmetric AC machines and in scalar form for salient-pole AC machines. Several current regulators using this technique have been experimentally evaluated for different operating conditions in an IPMSM drive.

This paper presents a comparison of carrier signal injection methods for sensorless torque and motion control of interior permanent magnet synchronous machine (IPMSM) drives. Rotor position can be identified at standstill and higher speeds by using one of two spatial saliency based high frequency carrier signal injection methods: rotating vector in the stationary frame or pulsating vector in the estimated rotor frame. Carrier currents for both rotating and pulsating voltage carrier injection are derived by using an IPMSM model for high frequency. An appropriate carrier signal extraction and a spatial saliency tracking scheme for both injection methods are developed for robust sensorless control. By interfering with the spatial saliency, saturation-induced saliencies act as disturbances to the rotor position estimation. Modeling, measurement, and analysis of the undesirable saturation-induced saliencies are presented for both carrier signal injection methods.