Micro-Shaping of Pure Aluminum in Long-Duration Wire Electrochemical Micromachining Using Bipolar Nanosecond Pulses.

With the increasing application of three-dimensional pure aluminum microstructures in micro-electromechanical systems (MEMS) and for fabricating terahertz components, high-quality micro-shaping of pure aluminum has gradually attracted attention. Recently, high-quality three-dimensional microstructures of pure aluminum with a short machining path have been obtained through wire electrochemical micromachining (WECMM), owing to its sub-micrometer-scale machining precision. However, machining accuracy and stability decrease owing to the adhesion of insoluble products on the surface of the wire electrode in long-duration WECMM, which limits the application of pure aluminum microstructures with a long machining path. In this study, the bipolar nanosecond pulses are used to improve the machining accuracy and stability in long-duration WECMM of pure aluminum. A negative voltage of -0.5 V was considered appropriate based on experimental results. Compared with the traditional WECMM using unipolar pulses, the machining accuracy of the machined micro-slit and the duration of stable machining were significantly improved in long-duration WECMM using bipolar nanosecond pulses.

Research on Integral Fabrication and Inner Surface Metallization of the High-Frequency Terahertz Hollow-Core Metal Rectangular Waveguide Cavity by a Combined Process Based on Wire Electrochemical Micromachining and Electrochemical Deposition.

With the development of fabrication technology for terahertz rectangular cavity devices, the fabrication process of integral terahertz waveguide cavities has received much attention because of its beneficial effect on improving the transmission of terahertz signals. However, smaller feature sizes, higher dimensional accuracy, and more stringent requirements for cavity surface roughness and edge radius make it difficult to manufacture terahertz waveguide cavities with a high operating frequency by using existing micro-manufacturing technology. At the same time, the smaller feature size also makes it more difficult to realize uniform metallization on the inner surface of a terahertz waveguide cavity. In this paper, a new and improved combined manufacturing process based on wire electrochemical micromachining and electrochemical deposition is proposed to realize the integral fabrication and uniform metallization of the inner surface of a high-frequency terahertz metal rectangular waveguide cavity. A detailed description and analysis of this combined process are carried out, together with corresponding experimental investigations. An integral 1.7 THz hollow-core metal rectangular waveguide cavity with an end-face size of 165.9 µm × 88.3 µm, an edge radius of less than 10 µm, an internal bottom surface roughness of less than 0.10 µm, and an internal side surface roughness of less than 0.40 µm was manufactured, and high-quality metallization of its inner surface was also achieved.

Electrochemical Deposition of Pure-Nickel Microstructures with Controllable Size.

Pure nickel microstructures have been widely used in MEMS and have great application potential as a sacrificial mandrel for fabricating terahertz micro-cavity components. The performance of MEMS and terahertz micro-cavity components can be significantly improved through the use of high-quality pure nickel microstructures. Up to now, microfabrication techniques, such as laser micromachining, wire electrical-discharge machining, and cold-spray additive manufacturing, have been used to machine various types of such microstructures. However, huge challenges are involved in using these micromachining techniques to fabricate pure-nickel microstructures with controllable size and good dimensional accuracy, surface roughness, and edge radius. In this paper, taking the example of a pure-nickel rectangular mandrel that corresponds to the size of the end face of a 1.7-THz rectangular waveguide cavity, the machining processes for the electrochemical deposition of pure-nickel microstructures with controllable size, high dimensional accuracy, and good surface roughness and edge radius are discussed systematically. This proposed method can be used to manufacture various types of high-quality pure-nickel microstructures.

A Naringin- and Icariin-Contained Herbal Formula, Gushukang, Ameliorated Aged Osteoporosis of Aged Mice with High Calcium Intake.

Traditional herbal formula Gushukang (GSK) was clinically applied to treat primary osteoporosis and showed osteoprotective effect in ovariectomized rodent animals and regulatory action on calcium transporters. This study aimed to determine if GSK could ameliorate aged osteoporosis by modulating serum level of calciotropic hormones and improving calcium balance. 18-month-old male mice were orally administered with either GSK (0.38[Formula: see text]g/kg body weight) or calcitriol (1[Formula: see text][Formula: see text]g/kg body weight) combined with high calcium diet (HCD, 1.2% Ca) for 60 days. The aged mice fed with normal calcium diet (NCD, 0.6% Ca) were a negative control. Trabecular bone and cortical bone properties as well as calcium balance were determined. Treatment with GSK significantly increased 25(OH)D and 1,25-(OH)2D levels in serum, moreover, it markedly attenuated trabecular bone micro-architectural deteriorations and elevated trabecular bone mass as well as strengthened cortical bone mechanical properties shown by the increase in maximal bending load and elastic modulus. Calcium balance, including urinary Ca excretion, fecal Ca level and net calcium retention, was remarkably improved by GSK, which up-regulated TRPV6 expression in duodenum and TRPV5 expression in kidney and down-regulated claudin-14 expression in duodenum and kidney. Additionally, 1-OHase and 24-OHase expression was significantly decreased (vs. NCD group) and increased (vs. HCD group), respectively, in kidney of GSK- and calcitriol-treated mice. Taken together, this study demonstrated the ameliorative effects of Gushukang on aged osteoporosis by effectively stimulating vitamin D production and improving calcium balance of aged mice with high dietary calcium supplement.

Genome-wide translational reprogramming of genes important for myocyte functions in overload-induced heart failure.

Genome-wide changes in gene translational efficiency during the development of heart failure are poorly understood. We tested the hypothesis that aberrant changes in translational efficiency of cardiac genes are associated with the development of myocyte decompensation in response to persistent stress stimuli. We demonstrated that chronic pressure overload in mice resulted in a genome-wide reprogramming of translational efficiency, with >50% of the translatome exhibiting decreased translational efficiencies during the transition from myocardial compensation to decompensation. Importantly, these translationally repressed genes included those involved in angiogenesis and energy metabolism. Moreover, we showed that the stress-induced translational reprogramming was accompanied by persistent activation of the eukaryotic initiation factor 2α (eIF2α)-mediated stress response pathway. Counteracting the endogenous eIF2α functions by cardiac-specific overexpression of an eIF2α-S51A mutant ameliorated the development of myocyte decompensation, with concomitant improvements in translation of cardiac functional genes and increases in angiogenic responses. These data suggest that the mismatch between transcription and translation of the cardiac genes with essential functions may represent a novel molecular mechanism underlying the development of myocyte decompensation in response to chronic stress stimuli, and the eIF2α pathway may be a viable therapeutic target for recovering the optimal translation of the repressed cardiac genes.

Inhibition of nucleolar stress response by Sirt1: A potential mechanism of acetylation-independent regulation of p53 accumulation.

The mammalian Sirt1 deacetylase is generally thought to be a nuclear protein, but some pilot studies have suggested that Sirt1 may also be involved in orchestrating nucleolar functions. Here, we show that nucleolar stress response is a ubiquitous cellular reaction that can be induced by different types of stress conditions, and Sirt1 is an endogenous suppressor of nucleolar stress response. Using stable isotope labeling by amino acids in cell culture approach, we have identified a physical interaction of between Sirt1 and the nucleolar protein nucleophosmin, and this protein-protein interaction appears to be necessary for Sirt1 inhibition on nucleolar stress, whereas the deacetylase activity of Sirt1 is not strictly required. Based on the reported prerequisite role of nucleolar stress response in stress-induced p53 protein accumulation, we have also provided evidence suggesting that Sirt1-mediated inhibition on nucleolar stress response may represent a novel mechanism by which Sirt1 can modulate intracellular p53 accumulation independent of lysine deacetylation. This process may represent an alternative mechanism by which Sirt1 regulates functions of the p53 pathway.

Gushukang exerts osteopreserve effects by regulating vitamin D and calcium metabolism in ovariectomized mice.

Calcium homeostasis plays vital roles in the management of bone health. Traditional herbal formula Gushukang (GSK) was clinically applied to treat primary osteoporosis. This study aimed to explore the osteoprotective effects of GSK and its roles in maintaining calcium homeostasis in ovariectomized (OVX) mice. The OVX mice were orally treated with low (0.38 g/kg), middle (0.76 g/kg) and high (1.52 g/kg) dose of GSK for 8 weeks. GSK treatment dramatically increased serum calcium level and decreased urinary calcium excretion as well as enhanced calcium content in bone of OVX mice. Serum level of 25-hydroxyvitamin D was significantly increased in OVX mice with exposure to GSK. Treatment with GSK improved bone mass and micro-structure of trabecular bone at distal metaphysis of femur and proximal metaphysis of tibia in OVX mice shown by safranin O staining and micro-CT measurement. GSK treatment at all doses up-regulated mRNA expression of calcium-binding protein-28k and vitamin D receptor in kidney of OVX mice, and dose-dependently decreased mRNA expression of claudin-14 and elevated mRNA expression of claudin-16 in duodenum of OVX mice. Taken together, GSK exerted beneficial effects on trabecular bone of OVX mice by improving calcium homeostasis via regulating paracellular calcium absorption in duodenum and transcellular calcium reabsorption in kidney.

Stage-dependent effects of exogenous TRAIL on atherogenesis: role of ER stress-mediated sensitization of macrophage apoptosis.

Deletion of the gene of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in apolipoprotein E-deficient (ApoE-/-) mice increased atherosclerosis. However, the effect of TRAIL at a supra-physiological level on early atherogenesis is unknown. ApoE-/- mice were divided into Early (high-fat diet with concomitant TRAIL treatment for 4 weeks) and Late (high-fat diet for 16 weeks with TRAIL being given during the last 4 weeks) groups. It was found that TRAIL stimulated atherogenesis in the Early group but not in the Late group. TRAIL did not change the intra-plaque macrophage content in Early group, but decreased it in the Late group. In cultured macrophages, induction of endoplasmic reticulum (ER) stress increased death receptor 5 (DR5) expression and TRAIL-induced apoptosis, which were mediated by the transcription factor CCAAT/enhancer-binding protein homologous protein (CHOP). The expression levels of CHOP, 78 kDa glucose-regulated protein (GRP78) and DR5 were all elevated in the Late group. TRAIL treatment in vivo also increased intra-plaque apoptotic only in Late lesions. Moreover, the chemical chaperone 4-phenylbutyrate blocked the development of ER stress and upregulation of DR5 in Late lesions in vivo. In conclusion, TRAIL at a supra-physiological level has a stimulatory effect on early atherogenesis, but not in the advanced lesions. The differential effects of TRAIL may be related to differences in ER stress, DR5 expression, and the sensitivity of macrophage apoptosis in response to TRAIL in early versus advanced lesions. The results presented here raise the possibility that treatment with exogenous TRAIL as a therapeutic agent may be detrimental in patients with increased risk of atherosclerosis.

The antioxidant compound tert-butylhydroquinone activates Akt in myocardium, suppresses apoptosis and ameliorates pressure overload-induced cardiac dysfunction.

Tert-butylhydroquinone (TBHQ) is an antioxidant compound which shows multiple cytoprotective actions. We evaluated the effects of TBHQ on pathological cardiac remodeling and dysfunction induced by chronic overload. Pressure overload was created by transverse aortic constriction (TAC) in male C57BL/6 mice. TBHQ was incorporated in the diet and administered for 4 weeks. TBHQ treatment prevented left ventricular dilatation and cardiac dysfunction induced by TAC, and decreased the prevalence of myocardial apoptosis. The beneficial effects of TBHQ were associated with an increase in Akt activation, but not related to activations of Nrf2 or AMP-activated protein kinase. TBHQ-induced Akt activation was accompanied by increased phosphorylation of Bad, glycogen synthase kinase-3ß (GSK-3ß) and mammalian target of rapamycin (mTOR). Mechanistically, we showed that in cultured H9c2 cells and primary cardiac myocytes, TBHQ stimulated Akt phosphorylation and suppressed oxidant-induced apoptosis; this effect was abolished by wortmannin or an Akt inhibitor. Blockade of the Akt pathway in vivo accelerated cardiac dysfunction, and abrogated the protective effects of TBHQ. TBHQ also reduced the reactive aldehyde production and protein carbonylation in stressed myocardium. We suggest that TBHQ treatment may represent a novel strategy for timely activation of the cytoprotective Akt pathway in stressed myocardium.

Cytotoxin-induced NADPH oxides activation: roles in regulation of cell death.

Numerous studies have shown that a variety of cytotoxic agents can activate the NADPH oxidase system and induce redox-dependent regulation of cellular functions. Cytotoxin-induced NADPH oxidase activation may either exert cytoprotective actions (e.g., survival, proliferation, and stress tolerance) or cause cell death. Here we summarize the experimental evidence showing the context-dependent dichotomous effects of NADPH oxidase on cell fate under cytotoxic stress conditions and the potential redox signaling mechanisms underlying this phenomenon. Clearly, it is difficult to create a unified paradigm on the toxicological implications of NADPH oxidase activation in response to cytotoxic stimuli. We suggest that interventional strategies targeting the NADPH oxidase system to prevent the adverse impacts of cytotoxins need to be contemplated in a stimuli- and cell type-specific manner.

TRB3 gene silencing alleviates diabetic cardiomyopathy in a type 2 diabetic rat model.

OBJECTIVE: Tribbles 3 (TRB3) is associated with insulin resistance, an important trigger in the development of diabetic cardiomyopathy (DCM). We sought to determine whether TRB3 plays a major role in modulating DCM and the mechanisms involved. RESEARCH DESIGN AND METHODS: The type 2 diabetic rat model was induced by high-fat diet and low-dose streptozotocin. We evaluated the characteristics of type 2 DCM by serial echocardiography and metabolite tests, Western blot analysis for TRB3 expression, and histopathologic analyses of cardiomyocyte density, lipids accumulation, cardiac inflammation, and fibrosis area. We then used gene silencing to investigate the role of TRB3 in the pathophysiologic features of DCM. RESULTS: Rats with DCM showed severe insulin resistance, left ventricular dysfunction, aberrant lipids deposition, cardiac inflammation, fibrosis, and TRB3 overexpression. We found that the silencing of TRB3 ameliorated metabolic disturbance and insulin resistance; myocardial hypertrophy, lipids accumulation, inflammation, fibrosis, and elevated collagen I-to-III content ratio in DCM rats were significantly decreased. These anatomic findings were accompanied by significant improvements in cardiac function. Furthermore, with TRB3 gene silencing, the inhibited phosphorylation of Akt was restored and the increased phosphorylation of extracellular signal-regulated kinase 1/2 and Jun NH(2)-terminal kinase in DCM was significantly decreased. CONCLUSIONS: TRB3 gene silencing may exert a protective effect on DCM by improving selective insulin resistance, implicating its potential role for treatment of human DCM.