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Supplementary Fig. S1 from Chk1 and Chk2 are differentially involved in homologous recombination repair and cell cycle arrest in response to DNA double-strand breaks induced by camptothecins

Camptothecins (CPT) activate S or G2-M arrest and the homologous recombination (HR) repair pathway in tumor cells. In this process, both checkpoint kinases 1 and 2 (Chk1 and Chk2, respectively) are activated, but their differential roles, especially in the coordination of checkpoint and repair control, and potential clinic relevance remain to be fully elucidated. In this study, the repairable double-strand breaks were induced in human colon cancer HCT116 cells by 1-h exposure to 25 or 100 nmol/L CPT and its novel derivative chimmitecan. The cellular disposal of double-strand breaks was reflected as the progressive dispersal of γ-H2AX foci, reduction of “comet” tails, dynamic activation of RAD51-mediated HR repair, and reversible G2-M arrest. In this model, the differential kinetics of Chk1 and Chk2 activation was characterized by the progressively increased phosphorylation of Chk2 until 72 h, the degradation of Chk1, and the disappearance of phosphorylated Chk1 48 h after drug removal. Using RNA interference, we further showed that Chk2 was essential to G2-M arrest, whereas Chk1 was mainly required for HR repair in CPT-treated HCT116 cells. Moreover, Chk2, rather than Chk1, predominated over the control of cell survival in this model. The differential roles of Chk1 and Chk2 in regulating HR repair and G2-M phase arrest were also confirmed in HT-29 colon cancer cells. Together, these findings systematically dissect the differential roles of Chk1 and Chk2 in a favorable model pursuing CPT-driven DNA damage responses, providing critical evidence to further explore checkpoint modulation, especially Chk2 inhibition as a therapeutic strategy in combination with CPT. [Mol Cancer Ther 2008;7(6):1440–9]

Supplementary Fig Legends from Chk1 and Chk2 are differentially involved in homologous recombination repair and cell cycle arrest in response to DNA double-strand breaks induced by camptothecins

Since the 21st century, the development of automotive and home appliance industries has greatly contributed to the prosperity of the plastics industry, which has led to an increasing demand for molding molds. In the production process, the molds will be impacted, worn and corroded, especially in the production of plastic products made of PVC, fluoroplastics and flame retardant ABS, etc. The molds will be corroded by the corrosive gases generated such as hydrogen chloride, hydrogen fluoride and sulfur dioxide, which requires plastic molds to have a certain degree of corrosion resistance while ensuring strong toughness.S136 SUP is a modified martensitic stainless steel based on S136 from ASSAB, Sweden, which has fine-tuned the content ratio of some elements to ensure a certain strength and high toughness at the same time. The chemical composition, heat treatment and microstructure of the steel have a certain influence on its corrosion resistance, and the tempering temperature of the heat treatment has a greater influence on the corrosion resistance of martensitic stainless steel. Therefore, in this paper, the microstructure and corrosion resistance of S136 SUP at different tempering temperatures are explored and studied.

A majority of cancers fail to respond to immunotherapy due to the immunosuppressive tumor microenvironment (TME), and metabolic regulation of the TME has been a promising strategy to improve immunotherapy. Lactate is a key metabolic player in tumor immune response since its excess secretion aggravates tumor immune escape by favoring the polarization of tumor-associated macrophages (TAMs) to an immunosuppressive phenotype meanwhile impeding the tumor infiltration of the cytotoxic T lymphocyte. Here, we proposed a metabolic reprogramming mechanism to ameliorate tumor immunosuppression by using lonidamine and syrosingopine incorporated liposomes (L@S/L) to regulate lactate production and efflux. Concretely, lonidamine reduced lactate production by affecting the glycolytic metabolic pathway while syrosingopine decreased lactate efflux by inhibiting the key protein expression of the lactate transporter MCT-4. Consequently, both the drugs synergistically normalize the pH of the TME to overcome the tumor immunosuppressive microenvironment.

Serrated chip is a typical characteristic of high-speed cutting. It is an important aspect of high-speed cutting mechanism, and has significant influence on cutting force, cutting temperature and t...

In this work, the same formulations of Nano-Silica/intumescent fire retardant polypropylene nanocomposites were prepared via a novel vane extruder and a tri-screw extruder, which represented elongational flow field and shearing flow field, respectively. Not only the synergistic combustion mechanisms of Kissinger method and Flynn-Wall-Ozawa method were revealed, but also the combustion effect and efficiency were compared. Both two methods proved specimens that processed by TE exhibited higher thermal stability. The smaller aggregates of physical initial Nano-Silica, the better dispersivity of aggregates in specimens that processed by VE. Such property broke the compactness degree of char layer.

The association between high-dose or low-dose sodium-glucose cotransporter 2 (SGLT2) inhibitors and various cardiovascular and respiratory serious adverse events (SAE) is unclear. Our meta-analysis aimed to define the association between high-dose or low-dose SGLT2 inhibitors and 86 kinds of cardiovascular SAE and 58 kinds of respiratory SAE. We included large cardiorenal outcome trials of SGLT2 inhibitors. Meta-analysis was conducted and stratified by the dose of SGLT2 inhibitors (high dose or low dose) to synthesize risk ratio (RR) and 95% confidence interval (CI). We included 9 trials. Compared with placebo, SGLT2 inhibitors used at high dose or low dose were associated with the decreased risks of 6 kinds of cardiovascular SAE [eg, bradycardia (RR, 0.60; 95% CI, 0.41-0.89), atrial fibrillation (RR, 0.79; 95% CI, 0.69-0.92), and hypertensive emergency (RR, 0.34; 95% CI, 0.15-0.78)] and 6 kinds of respiratory SAE [eg, asthma (RR, 0.59; 95% CI, 0.37-0.93), chronic obstructive pulmonary disease (RR 0.77, 95% CI 0.62-0.96), and sleep apnea syndrome (RR 0.37, 95% CI 0.17-0.81)]. SGLT2 inhibitors used at high dose or low dose did not show significant associations with 132 other cardiopulmonary SAE. For any outcome of interest, the subgroup difference according to the dose of SGLT2 inhibitors was not significant (Psubgroup0.05). SGLT2 inhibitors used at whether high dose or low dose are associated with the decreased risks of 12 cardiopulmonary disorders (eg, bradycardia, atrial fibrillation, hypertensive emergency, asthma, chronic obstructive pulmonary disease, and sleep apnea syndrome). These findings may suggest the potential efficacy of high- or low-dose SGLT2 inhibitors for the prevention and treatment of these cardiopulmonary disorders.

Abdominal aortic aneurysm (AAA) is characterized by aorta dilation due to wall degeneration, which mostly occurs in elderly males. Vascular aging is implicated in degenerative vascular pathologies, including AAA. Cyclic nucleotide phosphodiesterases, by hydrolyzing cyclic nucleotides, play critical roles in regulating vascular structure remodeling and function. Cyclic nucleotide phosphodiesterase 1C (PDE1C) expression is induced in dedifferentiated and aging vascular smooth muscle cells (SMCs), while little is known about the role of PDE1C in aneurysm. We observed that PDE1C was not expressed in normal aorta but highly induced in SMC-like cells in human and murine AAA. In mouse AAA models induced by Angiotensin II or periaortic elastase, PDE1C deficiency significantly decreased AAA incidence, aortic dilation, and elastin degradation, which supported a causative role of PDE1C in AAA development in vivo. Pharmacological inhibition of PDE1C also significantly suppressed preestablished AAA. We showed that PDE1C depletion antagonized SMC senescence in vitro and/or in vivo, as assessed by multiple senescence biomarkers, including senescence-associated β-galactosidase activity, γ-H2AX foci number, and p21 protein level. Interestingly, the role of PDE1C in SMC senescence in vitro and in vivo was dependent on Sirtuin 1 (SIRT1). Mechanistic studies further showed that cAMP derived from PDE1C inhibition stimulated SIRT1 activation, likely through a direct interaction between cAMP and SIRT1, which leads to subsequent up-regulation of SIRT1 expression. Our findings provide evidence that PDE1C elevation links SMC senescence to AAA development in both experimental animal models and human AAA, suggesting therapeutical significance of PDE1C as a potential target against aortic aneurysms.

Arterial calcification predicts accelerated restenosis after angioplasty and stenting. We studied the effects of calcification on neointimal hyperplasia after balloon injury in the rat carotid. Arterial calcification was induced by subcutaneous injection of vitamin D3 or by adventitial application of calcium chloride. After balloon catheter injury, neointimal hyperplasia was significantly increased in rats with medial calcification compared with controls. Neointimal cell proliferation in calcified arteries as assessed by proliferating cell nuclear antigen (PCNA) staining was also higher. In calcified arteries, bone morphogenetic protein 2 (BMP-2)levels were increased at the time of injury suggesting a possible explanation for the altered responses. In vascular smooth muscle cells (SMCs) grown under calcifying conditions , stimulation with BMP-2 significantly increased cell proliferation, however, this did not occur in those grown under non-calcifying conditions. These data suggest that neointimal hyperplasia is accelerated in calcified arteries and that this may be due in part to increased BMP-2 expression in medial SMCs. Treatments aimed at inhibiting restenosis in calcified arteries may differ from those that work in uncalcified vessels.

In the field of polymer processing, disperse phase exhibited better dispersion and distribution performance in elongational field rather than shearing field. This property commonly brought a better functional feature for polymer composites. It could also be applied to Nano-ZnO/IFR synergetic flame retarded polypropylene/ ethylene-propylene-diene monomer composites. An experiment was designed to study the mechanism of improving flame retardant properties. In the experiment, the same formulas of composites were extruded by vane extruder (represents elongational field) and three-screw extruder (represents shearing field). Then Kissinger method and Flynn-Wall-Ozawa method were used to mutually proved that Nano-ZnO with better dispersion condition catalysed a more intense esterification of IFR in the whole thermal degradation process.

Vascular calcification is a pathologic response to mineral imbalances and is prevalent in atherosclerosis, diabetes mellitus, and chronic kidney disease. When located in the media, it is highly associated with increased cardiovascular morbidity and mortality, particularly in patients on dialysis. Vascular calcification is tightly regulated and controlled by a series of endogenous factors. In the present study, we assess the effects of lysosomal and endosomal inhibition on calcification in vascular smooth muscle cells (VSMCs) and aortic rings. We observed that lysosomal function was increased in VSMCs cultured in calcification medium containing 3.5 mM inorganic phosphate (Pi) and 3 mM calcium (Ca2+) for 7 days. We also found that the lysosomal marker lysosome-associated membrane protein 2 was markedly increased and colocalized with osteogenic markers in calcified aortas from vitamin D3-treated rats. Interestingly, both the lysosomal inhibitor chloroquine and the endosomal inhibitor dynasore dose-dependently enhanced Pi + Ca2+-mediated VSMC calcification. Inhibition of lysosomal and endosomal function also promoted osteogenic transformation of VSMCs. Additionally, lysosome inhibition increased Pi-induced medial calcification of aortic rings ex vivo. These data suggest that the endosome-lysosome system may play a protective role in VSMC and medial artery calcification.

A new prediction model was proposed to give the critical cutting condition of serrated chip in high speed machining, including cutting speed, depth of cut, and rake angle. Firstly, a critical criterion of serrated chip in high speed machining was obtained through the linear stability analysis of balance equations of continuum mechanics for primary deformation zone, which considers the influence of compression stress through stress equivalent. Secondly, the model of deformation in the primary deformation zone was proposed to build the corresponding relationships between the cutting conditions and the deformation conditions based on the model of parallel boundary shear zone. Lastly, the critical cutting condition of serrated chip in high speed machining can be predicted by combining the critical criterion and the calculation of deformation conditions in the primary deformation zone. For the validation of model, the critical cutting conditions of serrated chip on AISI 1045 steel were predicted and an orthogonal cutting experiment was performed for comparing with the prediction results. The comparison shows that the prediction results agree well with that of experiment. Therefore, the proposed model is available. This is very useful for the optimization of cutting parameters and precision control of high speed machining.

In multi-wire sawing, reducing the wire wear loss and increasing wire consumption are the common means to avoid the risk of saw wire breakage because the worn saw wire experiences a complex process with strength degradation and surface damage. So, it is urgent and necessary to give a reliable wire wear loss in theory. This paper focused on the surface topography and fracture strength of worn wire with different wire wear loss. Furthermore, the saw wire maximum safety wear loss model was presented based on the experimental results. By observing the surface topography of the worn saw wire, the dented traces were distributed on the whole surface and a few grooves with large depth were shown in the local zone. The cross-sections of the worn saw wires with different wear loss were circular. In addition, its fracture strength of the wore saw wires was not reduced with the increasing of the saw wire wear loss. On the contrary, the fracture strength of the wire with large wear loss was improved by hardening in comparison with fresh saw wire. This phenomenon suggested that surface damages did not affect the fracture strength of saw wire under the experimental condition. Furthermore, fracture photograph of the fracture test samples was divided into the crack propagation zone and final fracture zone. By analyzing these fracture topography, almost all the crack propagation zones were circular and its diameter was about 48.27 μm. It is not correlated with the amount of wear loss. However, the shape became non-circular in some samples with large depth damage on the surface. By summarizing these results, the model and calculation method of the maximum safety wear loss of saw wire were established, which could provide the theoretical basis for the determining the maximum safety wear loss.

Vascular calcification is highly prevalent in patients with diabetes mellitus and chronic kidney disease. When located in the media, arterial calcification is strongly associated with increased cardiovascular morbidity and mortality. The second messenger cyclic nucleotides cAMP and cGMP, controlled by distinct cyclic nucleotide phosphodiesterase (PDE) isozymes, play important regulatory roles in a variety of human diseases. Using a qPCR PDE array, we found that PDE10A was the most highly induced among all PDE genes in a rat model of medial artery calcification. PDE10A expression was markedly increased in calcified arteries from rats with chronic kidney disease and in tibial arteries from patients with peripheral artery disease. Interestingly, it co-localized with osteogenic markers in these specimens. In vitro , PDE10A knockdown using siRNA, and inhibition with a synthetic inhibitor markedly reduced osteogenic transformation and calcification of vascular SMC exposed to high phosphate levels. Aortic rings from PDE10A knockout mice showed significantly less Pi-induced medial calcification than those from wild-type controls. Deficiency of PDE10A also reduced medial calcification in a mouse medial calcification model in vivo . Mechanistic studies to elucidate the signaling alterations invoked by PDE10A are ongoing. These findings suggest that PDE10A plays a crucial role in the development of medial artery calcification, and that targeting it may provide a novel therapeutic strategy for reducing medial calcification and improving outcomes in patients with PAD.

Laser shock processing is a new kind of technology to improve the physical and mechanical properties of the metal surface. It uses the high-amplitude stress wave produced by the interaction of short-pulse laser and material, to make the material produce the compressive residual stress and refinement internal structure, and lead to the improved hardness and strength of material. In this paper, the simulation of laser shocking process with square spot of Titanium alloy plate was carried out through ABAQUS. The influences of the shock time, laser energy, plate thickness and spot size on the strengthening are investigated from the view of residual stress. The results show that: There are the compression residual stress in the workpiece surface after laser shcok processing, and its amplitude is about 300-400Mpa. With the increase of shock time, the surface residual stress increases, the area and depth of strengthening zone also increase. The strengthening area becomes a circular, while the distribution of residual stress becomes unhomogeneous. The surface residual stress increases as the laser energy increasing, but the amplitude is smaller. The plate thickness does not affect the amplitude of the surface residual stress. When the shock pressure is constant, surface residual stress does not change with the spot size. However, if the laser energy is constant, due to the shock pressure will decrease with the increase of spot size. Therefore, there should be an optimized spot size when the strengthening effectiveness and efficiency are both considered.

Rationale: Neointimal hyperplasia characterized by abnormal accumulation of vascular smooth muscle cells (SMCs) is a hallmark of occlusive disorders such as atherosclerosis, postangioplasty restenosis, vein graft stenosis, and allograft vasculopathy. Cyclic nucleotides are vital in SMC proliferation and migration, which are regulated by cyclic nucleotide phosphodiesterases (PDEs). Objective: Our goal is to understand the regulation and function of PDEs in SMC pathogenesis of vascular diseases. Methods and Results: We performed screening for genes differentially expressed in normal contractile versus proliferating synthetic SMCs. We observed that PDE1C expression was low in contractile SMCs but drastically elevated in synthetic SMCs in vitro and in various mouse vascular injury models in vivo. In addition, PDE1C was highly induced in neointimal SMCs of human coronary arteries. More importantly, injury-induced neointimal formation was significantly attenuated by PDE1C deficiency or PDE1 inhibition in vivo. PDE1 inhibition suppressed vascular remodeling of human saphenous vein explants ex vivo. In cultured SMCs, PDE1C deficiency or PDE1 inhibition attenuated SMC proliferation and migration. Mechanistic studies revealed that PDE1C plays a critical role in regulating the stability of growth factor receptors, such as PDGF receptor β (PDGFRβ) known to be important in pathological vascular remodeling. PDE1C interacts with low-density lipoprotein receptor–related protein-1 and PDGFRβ, thus regulating PDGFRβ endocytosis and lysosome-dependent degradation in an low-density lipoprotein receptor–related protein-1–dependent manner. A transmembrane adenylyl cyclase cAMP-dependent protein kinase cascade modulated by PDE1C is critical in regulating PDGFRβ degradation. Conclusions: These findings demonstrated that PDE1C is an important regulator of SMC proliferation, migration, and neointimal hyperplasia, in part through modulating endosome/lysosome-dependent PDGFRβ protein degradation via low-density lipoprotein receptor–related protein-1.

In view of the cooling difficulty in complex injection mold, the difference between conventional cooling channels and Conformal Cooling Channels (CCC) is researched. CCC is superior to conventional cooling channels on cooling effect according to the simulation analysis of plastic flow based on Autodesk Moldflow Insight software. Considered the manufacturing difficulty of CCC, an approach which uses three-dimensional printing and investment casting is put forward in the end.

The research of the simulation for high speed cutting is usually based on 2D modeling by now, and the 3D simulation is few. Because the cutting process is a 3D deformation of workpiece, it's badly in need of the research on 3D finite element simulation of cutting process for further reveal the mechanism of high speed cutting. The 3D simulation of inclined cutting of hardened 45 steel (45HRC) is carried out base on ABAQUS. The forming process of serrated chip is simulated by adopting the Johnson-cook material modeling and separation criterion of shear failure. The change of chip morphology, chip flow angle and deformation coefficient of width under different rake angle and cutting depth are analyzed. The results show that the segment degree of chip becomes larger with the decrease of rake angle and increase of cutting depth. The chip flow angle is not effected by rake angle and its value is approximately equal to tool cutting edge inclination angle, an it increases with the increase of cutting depth. The deformation coefficient of width increase with the decrease of rake angle and increase of cutting depth.

This article states the error factors in parts of data acquisition and data processing of reverse engineering, and gives optimization suggestions in practical applications. It provides a more practical method for manufacturing products closer to the samples.

Under the condition of cutting speed 10-300m/min, rake angle -10°、0°、10°and cutting depths 0.05mm、0.1mm and 0.2mm, the experiment study of adiabatic shear serrated chip and surface roughness are carried out. The influence of cutting condition on serrated chip is analyzed through the metallographic observation of obtained chip. By the measurement of finished surface, the influenc of cutting condition and adiabatic shear on surface roughness is also investigated. The rusults show that the reason lead to serrated chip in high speed cutting of Ti6Al4V is adiabatic shear, not the periodic fracture.The adiabatic shear serrated chip is easier appear and the degree of segment is more large under the condition of higher cutting speed, larger cutting depth and smaller rake angle. The surface roughness is smaller when the cutting speed is higher, cutting depth is larger, and rake angle is smaller.

A major role of automotive engineers is to improve fuel efficiency and vehicle safety. However, it is very difficult to improve both of these requirements at the same time. So they deal with the design of structural reinforcements in hopes to improve the crush strength, but minimize the weight of the automobile body. Forming simulation has been playing increasingly important role in this field to save time and cost and the accuracy of the simulation argued against the real life results. In this paper The Auto Center pillar reinforce plate is studied by finite element method, and forming process is optimized according to full flow simulation. The simulation shows that the FEM can make the tryout process better to get high success rate and shorter time.

Phosphodiesterase 3A (PDE3A) is a major regulator of cAMP in cardiomyocytes. PDE3 inhibitors are used for acute treatment of congestive heart failure, but are associated with increased incidence of arrhythmias and sudden death with long-term use. We previously reported that chronic PDE3A downregulation or inhibition induced myocyte apoptosis in vitro. However, the cardiac protective effect of PDE3A has not been demonstrated in vivo in disease models. In this study, we examined the role of PDE3A in regulating myocardial function and survival in vivo using genetically engineered transgenic mice with myocardial overexpression of the PDE3A1 isozyme (TG). TG mice have reduced cardiac function characterized by reduced heart rate and ejection fraction (52.5 ± 7.8% vs. 83.9 ± 4.7%) as well as compensatory expansion of left ventricular diameter (4.19 ± 0.19 mm vs. 3.10 ± 0.18 mm). However, there was no maladaptive increase of fibrosis and apoptosis in TG hearts compared to wild type (WT) hearts, and the survival rates also remained the same. The diminution of cardiac contractile function is very likely attributed to a decrease in beta-adrenergic receptor (β-AR) response in TG mice. Importantly, the myocardial infarct size (4.0 ± 1.8% vs. 24.6 ± 3.8%) and apoptotic cell number (1.3 ± 1.0% vs. 5.6 ± 1.5%) induced by ischemia/reperfusion (I/R) injury were significantly attenuated in TG mice. This was associated with decreased expression of inducible cAMP early repressor (ICER) and increased expression of anti-apoptotic protein BCL-2. To further verify the anti-apoptotic effects of PDE3A1, we performed in vitro apoptosis study in isolated adult TG and WT cardiomyocytes. We found that the apoptotic rates stimulated by hypoxia/reoxygenation or H2O2 were indeed significantly reduced in TG myocytes, and the differences between TG and WT myocytes were completely reversed in the presence of the PDE3 inhibitor milrinone. These together indicate that PDE3A1 negatively regulates β-AR signaling and protects against I/R injury by inhibiting cardiomyocyte apoptosis.

A method for building the constitutive relationship based on the J-C model and hardness is presented through considering the influence of hardness on the yield strength and the tensile strength. A constitutive relationship of hardened AISI 1045 is built by this method and the adiabatic shear critical cutting conditions of three kinds of hardness AISI 1045 steel are prediction through a model building by the linear pertubation analysis which considering the influence of compression stress of the primary shear zone, the cutting conditions and the constitutive relationship. For proving the prediction results, some orthogonal cutting experiments are performed to get the critical cutting conditions of adiabatic shear. The comparison shows that the prediction results are consistent with that of experiments.

Majority of automobile and appliance components are made by deep drawing sheet metal process. So these growing needs demand a new design methodology based on metal forming simulation. With the help of metal forming simulation we can identify the problem areas and solutions can be validated. The aim of this research is to develop techniques that would reduce the amount of time spent during the tool qualifying stage. In this paper the draw tools on Automobile outer clutch shell surface are designed by the precise die surface at different dimensions and draw processes is analyzed with appropriate simulation parameters. From this we got the most reliable results. The compression with the tryout part shows that the simulation process can accurately predict the formability problems.

The ultimate goal of the metal forming industry is to form components made of a specific material into a required shape without experiencing wrinkling, bifurcation and spring-back. This study is devoted to develop the whole process by making rules of precision for specific part geometry. For inner clutch shell a computer simulation system and the general procedure of dynamic simulation in sheet metal forming are presented. Finally compute all simulation results with reference to the original part property and recommend the appropriate process flow to produce the part, the comparison with tryout results shows that the formality simulation of thick panel with precise die face is reliable and accurate.

In the hot stamping process, die gap may affect cooling efficiency of the die and the condition of stress-strain. When other conditions are same, die gap were taken for 0.9t, t, 1.1 t, 1.2 t, t is sheetthickness. Temperature field and thickness distribution of the parts are simulated by ANSYS/LS-DYNA module, it is discovered that the distribution of temperature and thickness is uniform when the die gap is 1t and 1.1t. Finally, an experimental is designed to verify the simulation accuracy.

In the finishing machining, processing parameters directly affects the quality of machined surface. While the micro topography of the surface maps with the fractal dimensions. The paper researched the relation between processing parameters and fractal dimensions through the experiments in order to obtain the relationship. Through the design of orthogonal rotation experiment, determine the experimental parameters. Then measure the experimental sample for the surface and calculate the fractal dimensions using the box counting method. In the end, obtain the functional relation of processing parameters and fractal dimensions by regression method. The results show that the specific processing parameters of the surface can predict the fractal dimension by this formula. And this provides reference for selection of processing parameters.

Cyclic nucleotide phosphodiesterase 1C (PDE1C) represents a major phosphodiesterase activity in human myocardium, but its function in the heart remains unknown. Using genetic and pharmacological approaches, we studied the expression, regulation, function, and underlying mechanisms of PDE1C in the pathogenesis of cardiac remodeling and dysfunction. PDE1C expression is up-regulated in mouse and human failing hearts and is highly expressed in cardiac myocytes but not in fibroblasts. In adult mouse cardiac myocytes, PDE1C deficiency or inhibition attenuated myocyte death and apoptosis, which was largely dependent on cyclic AMP/PKA and PI3K/AKT signaling. PDE1C deficiency also attenuated cardiac myocyte hypertrophy in a PKA-dependent manner. Conditioned medium taken from PDE1C-deficient cardiac myocytes attenuated TGF-β-stimulated cardiac fibroblast activation through a mechanism involving the crosstalk between cardiac myocytes and fibroblasts. In vivo, cardiac remodeling and dysfunction induced by transverse aortic constriction, including myocardial hypertrophy, apoptosis, cardiac fibrosis, and loss of contractile function, were significantly attenuated in PDE1C-knockout mice relative to wild-type mice. These results indicate that PDE1C activation plays a causative role in pathological cardiac remodeling and dysfunction. Given the continued development of highly specific PDE1 inhibitors and the high expression level of PDE1C in the human heart, our findings could have considerable therapeutic significance.

Cardiac fibroblasts become activated and differentiate to smooth muscle-like myofibroblasts in response to hypertension and myocardial infarction (MI), resulting in extracellular matrix (ECM) remodeling, scar formation and impaired cardiac function. cAMP and cGMP-dependent signaling have been implicated in cardiac fibroblast activation and ECM synthesis. Dysregulation of cyclic nucleotide phosphodiesterase (PDE) activity/expression is also associated with various diseases and several PDE inhibitors are currently available or in development for treating these pathological conditions. The objective of this study is to define and characterize the specific PDE isoform that is altered during cardiac fibroblast activation and functionally important for regulating myofibroblast activation and ECM synthesis. We have found that Ca(2+)/calmodulin-stimulated PDE1A isoform is specifically induced in activated cardiac myofibroblasts stimulated by Ang II and TGF-β in vitro as well as in vivo within fibrotic regions of mouse, rat, and human diseased hearts. Inhibition of PDE1A function via PDE1-selective inhibitor or PDE1A shRNA significantly reduced Ang II or TGF-β-induced myofibroblast activation, ECM synthesis, and pro-fibrotic gene expression in rat cardiac fibroblasts. Moreover, the PDE1 inhibitor attenuated isoproterenol-induced interstitial fibrosis in mice. Mechanistic studies revealed that PDE1A modulates unique pools of cAMP and cGMP, predominantly in perinuclear and nuclear regions of cardiac fibroblasts. Further, both cAMP-Epac-Rap1 and cGMP-PKG signaling was involved in PDE1A-mediated regulation of collagen synthesis. These results suggest that induction of PDE1A plays a critical role in cardiac fibroblast activation and cardiac fibrosis, and targeting PDE1A may lead to regression of the adverse cardiac remodeling associated with various cardiac diseases.

Objectives: Clinical studies demonstrate associations between arterial calcification and adverse outcomes in patients with peripheral arterial disease. The causal relationship between calcification and ischemia, however, remains unclear. This study aims to evaluate the effects of arterial calcification on functional recovery and limb perfusion following acute limb ischemia in a murine model. Methods: Arterial calcification was induced in 64 Sprague-Dawley rats using Vitamin D 3 . A control group of 32 rats received vehicle only. After 2 weeks, to allow for calcification, unilateral hindlimb ischemia was induced by ligation and excision of the superficial femoral artery. At weekly intervals, functional and ischemia status were evaluated in a blinded manner and laser Doppler perfusion imaging was performed. Results: Calcium assay demonstrated greater arterial calcification in the superficial femoral arteries (0.1 vs. 17.0, P < .01) of Vitamin D 3 injected animals. Rats injected with Vitamin D3 showed significantly worse Tarlov, Ischemia, Modified Ischemia, and Total Ischemia scores at each post-operative time point (Week 1: 16.6 vs. 14.5 P Conclusions: Vitamin D3 induced calcification is associated with decreased perfusion and worse functional recovery in a rat model of hindlimb ischemia. Future research aimed at understanding the relationship between vitamin D 3 , arterial calcification, and lower extremity ischemia may help to improve outcomes in patients with PAD.

The thin-walled blade of aero engine has low stiffness, during machining, it easily generates deflection due to the milling force, but because high accuracy of such component is required, the prediction of the deflection exactly becomes extremely important. Therefore, this paper analyzes the milling process, and simplifies it reasonably. The deformation of the blade is predicted based on ABAQUS using FEM, and then the machining deflection curves of the blade is got. The result is analyzed soon afterwards, and deflection law is summarized. Finally, an experiment has been designed. The reliability of the method of predicting deflection is proved by comparing the measurement results and the simulation ones.

This paper has done CAE analysis of hot stamping, and optimized the water-cooled system which takes the degree of uniform temperature of blank as the objective function of optimization. The aim is to find a method of optimizing hot stamping mold cooling system based on ANSYS Parametric Design Language (APDL) with ANSYS Mechanical/LS-DYNA software and lay the foundation for designing hot stamping mold. And the work mainly consists of three sections, building parametric finite element model, simulating the process of quenching and optimizing the location parameters and radiuses of each coolant duct. Finally, contrast the optimal result with the initial result and get the conclusion, and moreover, point out the future work.

Background Medial artery calcification develops in diabetes, chronic kidney disease, and as part of the aging process. It is associated with increased morbidity and mortality in vascular patients. Bone morphogenetic proteins (BMPs) have previously been implicated in the initiation and progression of vascular calcification. We thus evaluated whether dorsomorphin homologue 1 (DMH1), a highly selective BMP inhibitor, could attenuate vascular calcification in vitro and in an organ culture model of medial calcification. Methods Confluent human aortic smooth muscle cells (SMCs) were cultured in calcification medium containing 3.0 mM inorganic phosphate (Pi) for 7 days with or without DMH1. Medial calcification was assessed using an aortic organ culture model. Calcification was visualized by alizarin red S staining, and calcium concentration was assessed by an o -cresolphthalein complexone calcium assay. Osteogenic cell and vascular SMC markers were determined by Western blot, quantitative reverse transcription polymerase chain reaction, and immunohistochemical staining. Results DMH1 reduced Pi-induced calcium deposition in human SMCs. It also antagonized human recombinant BMP2-induced calcium accumulation. Western blot further revealed that DMH1 was able to block Pi-mediated upregulation of the osteoblast markers osterix and alkaline phosphatase and downregulation of the SMC markers smooth muscle myosin heavy chain and SM22α as well as p-Smad1/5/8, suggesting that DMH1 may regulate SMC osteogenic differentiation through the BMP/Smad1/5/8 signaling pathway. Finally, using an ex vivo aortic ring organ culture model, we observed that DMH1 reduces Pi-induced aortic medial calcification. Conclusions The selective BMP inhibitor DMH1 can inhibit calcium accumulation in vascular SMCs and arterial segments exposed to elevated phosphate levels. Such small molecules may have clinical utility in reducing medial artery calcification in our population of vascular patients.

A mathematical model of fractal interpolation surface is introuduced in this paper. A calculation to fractal dimension of the messy point data is proposed and used to get appropriate vertical scale factor to construct precise blank residue model. Fractal dimensions of different fractal interpolation surfaces with different vertical scale factor are different. The relationship between vertical scale factor and fractal dimension is obtained through calculating fractal dimensions of tested surfaces which are created by fractal interpolation with different vertical scale factor.

The research status of 2-D machining of cutting edge and flanging edge of automobile die are reviewed, and the key factor that influences the cycle and cost is pointed out. According to the characteristic of NC machine command and the particular requirement of cutter location precision during cutting, a new spiral interpolation algorithm is presented based on the in-depth analysis of pre-interpolation. The influences of the height of die edges, the length of cutter’s side blade and holder collision are all considered during interpolation, which make the upper cutter blade used as much as possible without any holder collision. Finally, the high-efficient auto NC machining of 3-D die edges is realized.

In order to enhance the processing efficency of complex cavity surfaces by using iso-scallop height method, a subdivision method based on the improved image direction information measure is proposed in this paper. According to the relationship between maximum cutting bandwidth and cutting direction in the theory of iso-scallop height, the method constructed an optimal cutting direction angle field image in the u-v system of parameters firstly; and then an improved direction information measure definition which combined with the characters of the angle field image was proposed; Finally, the subdivision boundary for mold cavity surface was identified by using the direction measure as the edge characteristic index. Experimental results indicate that the proposed method demonstrates good performance in distinguishing and extracting boundary points of surface subdivision.

Orthogonal cutting experiments of hardness AISI1045 steel( HRC45) are performed. The change of chip formation and cutting force with cutting conditions are investigated through metallurgical observation, and the critical cutting speed of adiabatic shear of AISI1045 steel at different cutting depths and rake angles are given. In addition, the saw-frequency and space length of serrated chip and the influence of serrated chip on cutting force are also studied. The critical cutting speed decreases with the increase of cutting depth, but increases with the increase of rake angle. The saw-frequency of serrated chip is found to be independent of the cutting depth, and increases with the increase of cutting speed and rake angle. The cutting force decreases with the increase of cutting speed and rake angle, but increases with the increase of cutting depth, and there isn’t a sudden change of cutting force at the onset of adiabatic shear.

Hot stamping is a process which simultaneously forms and quenches the hot blanks at the austenization temperature (900-1200 °C) to produce full martensitic Ultra High Strength (UHS) steel structure. Automobile manufacturers use hot stamping to produce many car frame components which can decrease the total weight of the car and increase the car safety. The aim of this paper is to simulate the thermo-mechanical process of the hot stamping which consists of FEA simulations by using Abaqus/Explicit. The process includes too steps: heating of the blank to 900°C, and simultaneous punching and quenching process to increase the tensile strength of the material. The objectives of the FEA simulation are to obtain thermo-mechanical properties of the material and to predict strength of the steel as the product of hot stamping. The results of this simulation will be the values of maximum Von Mises stress and nodal temperature of the blank, the punch reaction force, and also the prediction of the yield strength and tensile strength of the material which will be compared to the yield strength and tensile strength of the available steel alloy data.