BMP-2 induces ATF4 phosphorylation in chondrocytes through a COX-2/PGE2 dependent signaling pathway

SummaryObjectiveBone morphogenic protein (BMP)-2 is approved for fracture non-union and spine fusion. We aimed to further dissect its downstream signaling events in chondrocytes with the ultimate goal to develop novel therapeutics that can mimic BMP-2 effect but have less complications.MethodsBMP-2 effect on cyclooxygenase (COX)-2 expression was examined using Real time quantitative PCR (RT-PCR) and Western blot analysis. Genetic approach was used to identify the signaling pathway mediating the BMP-2 effect. Similarly, the pathway transducing the PGE2 effect on ATF4 was investigated. Immunoprecipitation (IP) was performed to assess the complex formation after PGE2 binding.ResultsBMP-2 increased COX-2 expression in primary mouse costosternal chondrocytes (PMCSC). The results from the C9 Tet-off system demonstrated that endogenous BMP-2 also upregulated COX-2 expression. Genetic approaches using PMCSC from ALK2fx/fx, ALK3fx/fx, ALK6−/−, and Smad1fx/fx mice established that BMP-2 regulated COX-2 through activation of ALK3–Smad1 signaling. PGE-2 EIA showed that BMP-2 increased PGE2 production in PMCSC. ATF4 is a transcription factor that regulates bone formation. While PGE2 did not have significant effect on ATF4 expression, it induced ATF4 phosphorylation. In addition to stimulating COX-2 expression, BMP-2 also induced phosphorylation of ATF4. Using COX-2 deficient chondrocytes, we demonstrated that the BMP-2 effect on ATF4 was COX-2-dependent. Tibial fracture samples from COX-2−/− mice showed reduced phospho-ATF4 immunoreactivity compared to wild type (WT) ones. PGE2 mediated ATF4 phosphorylation involved signaling primarily through the EP2 and EP4 receptors and PGE2 induced an EP4-ERK1/2-RSK2 complex formation.ConclusionsBMP-2 regulates COX-2 expression through ALK3–Smad1 signaling, and PGE2 induces ATF4 phosphorylation via EP4-ERK1/2-RSK2 axis

Low-Power Pulse-Triggered Flip-Flop Design With Conditional Pulse-Enhancement Scheme

In this paper, a novel low-power pulse-triggered flip-flop (FF) design is presented. First, the pulse generation control logic, an AND function, is removed from the critical path to facilitate a faster discharge operation. A simple two-transistor AND gate design is used to reduce the circuit complexity. Second, a conditional pulse-enhancement technique is devised to speed up the discharge along the critical path only when needed. As a result, transistor sizes in delay inverter and pulse-generation circuit can be reduced for power saving. Various postlayout simulation results based on UMC CMOS 90-nm technology reveal that the proposed design features the best power-delay-product performance in seven FF designs under comparison. Its maximum power saving against rival designs is up to 38.4%. Compared with the conventional transmission gate-based FF design, the average leakage power consumption is also reduced by a factor of 3.52

Low complexity dual-mode pulse generator designs

Two novel low complexity dual-mode pulse generator designs suitable for FFs with triggering mode control are presented. The proposed designs successfully integrate XOR/OR (AND/XNOR) functions into a unified pass transistor logic (PTL) module to provide control on single- or double-edge operations. The designs use as few as 8 transistors each and ingeniously avoid the signal degradation problem inherent in most PTL circuits. As the only dual-mode designs so far, the proposed designs also outperform rival single-mode designs in both aspects of circuit complexity and power consumption

A Low Complexity Dual-Mode Pulse-Triggered Flip-Flop Design Based on Unified AND/XNOR Logic

A dual mode pulse triggered flip flop design supporting functional versatility is presented A low complexity unified logic module consisting of only five transistors for dual mode pulse generation is devised using pass transistor logic (PTL) Potential threshold voltage loss problem is successfully resolved to ensure the signal integrity Despite the extra logic for dual mode operations the circuit complexity of the proposed design is comparable to those of the single mode designs Simulations in different process corners and switching activities prove the competitive per tormance of proposed design against various single mode design

A Low Complexity Low Power Signal Transition Detector Design for Self-Timed Circuits

A novel signal transition detector design using as few as 8 transistors is presented The proposed design cleverly exploits the property of a specific Internal state transition to mitigate the voltage degradation problem by employing only one extra transistor It is thus capable of supporting level intact output signals and eliminating DC power consumption in the trailing buffer The proposed design. featuring. low circuit complexity and low power consumption. is considered useful for applications in self-timed circuits Simulation results show that. when compared with other pass transistor logic based counterpart designs as much as 46% savings in power and 28% in area can be achieved by the proposed desig

Low Power Pulse Generator Design Using Hybrid Logic

A low power pulse generator design using hybrid logic realization of a 3-input NAND gate is presented. The hybrid logic approach successfully shortens the critical path along the discharging transistor stack and thus reduces the short circuit power consumption during the pulse generation. The combination of pass transistor and full CMOS logic styles in one NAND gate design also helps minimize the required transistor size, which alleviates the loading capacitance of clock tree as well. Simulation results reveal that, compared with prior work, our design can achieve 20.5% and 23% savings respectively in power and circuit area

A novel high-speed and energy efficient 10-transistor full adder design

In this paper, we propose a novel full adder design using as few as ten transistors per bit. Compared with other lowgate-count full adder designs using pass transistor logic, the proposed design features lower operating voltage, higher computing speed and lower energy (power delay product) operation. The design adopts inverter buffered XOR/XNOR designs to alleviate the threshold voltage loss problem commonly encountered in pass transistor logic design. This problem usually prevents the full adder design from operating in low supply voltage or cascading directly without extra buffering. The proposed design successfully embeds the buffering circuit in the full adder design and the transistor count is minimized. The improved buffering helps the design operate under lower supply voltage compared with existing works. It also enhances the speed performance of the cascaded operation significantly while maintaining the performance edge in energy consumption. For performance comparison, both dc and performances of the proposed design against various full adder designs are evaluated via extensive HSPICE simulations. The simulation results, based on TSMC 2P4M 0.35-mu m process models, indicate that the proposed design has the lowest working V-dd And highest working frequency among all designs using ten transistors. It also features the lowest energy consumption per addition among these designs. In addition, the performance edge of the proposed design in both speed and energy consumption becomes even more significant as the word length of the adder increases

Development and validation of a short form of the Fugl-Meyer motor scale in patients with stroke.

Contains fulltext : 52394.pdf (publisher's version ) (Closed access)BACKGROUND AND PURPOSE: The 50-item Fugl-Meyer motor scale (FM) is commonly used in outcome studies. However, the lengthy administration time of the FM keeps it from being widely accepted for routine clinical use. We aimed to develop a short form of the FM (the S-FM) with sound psychometric properties for stroke patients. METHODS: The FM was administered to 279 patients. It was then simplified based on expert opinions and the results of Rasch analysis. The psychometric properties (including Rasch reliability, concurrent validity, predictive validity, and responsiveness) of the S-FM were examined and were compared with those of the FM. The concurrent validity and responsiveness of the S-FM were further validated in a sample from the Netherlands. RESULTS: We selected 6 items for each subscale to construct a 12-item S-FM. The S-FM demonstrated high Rasch reliability, high concurrent validity with the original scale, moderate responsiveness, and moderate predictive validity with the comprehensive activities of daily living function. The S-FM also showed sufficient concurrent validity and responsiveness on the Dutch sample. CONCLUSIONS: Our results provide strong evidence that the psychometric properties of the S-FM are comparable with those of the FM. The S-FM contains only 12 items, making it a very efficient measure for assessing the motor function of stroke patients in both clinical and research settings

Diabetes exacerbates angiographic coronary lesion progression in subjects with metabolic syndrome independent of CRP levels

Background: Metabolic syndrome is gaining more attention as a special cluster of cardiovascular risks. However, its role, with or without diabetes, in predicting atherosclerosis progression, remains largely undetermined. We investigated the predictors for angiographic coronary atherosclerosis progression in patients with metabolic syndrome and angina pectoris. Methods: Patients with metabolic syndrome and angina pectoris who underwent repeat coronary angiograms and had serum samples at the time of first catheterization were enrolled for analysis (N=113). A modified Gensini scoring system was used to define CAD progression between the index and follow-up angiograms. Those who had significant angiographic progression of coronary disease were classified as the progression group (N=42) and those who did not as the non-progression group (N=71). Results: There were more cases of diabetes mellitus (52% vs. 31%, p=0.040) in the CAD progression group. The progression group also had higher baseline fasting blood glucose (150 +/- 73 vs. 117 +/- 46 mg/dl, p=0.010) but similar LDL cholesterol (114 +/- 38 vs. 109 +/- 33 mg/dl, p=0.421) than the non-progression group. In terms of inflammatory markers, there was no difference in hs-CRP (p=0.208), MCP-1 (p=0.514), or sCD40L (p-0.549) between the groups. In binary logistic regression, diabetes mellitus remained a significant predictor of CAD progression (OR 2.43, p=0.030) for patients with metabolic syndrome and angina pectoris, but hs-CRP and LDL-C were not. Conclusion: Diabetes mellitus, but not inflammatory marker hs-CRP or LDL-C, is a significant predictor of angiographic CAD progression in patients with metabolic syndrome and angina pectoris. (c) 2007 Elsevier B.V. All rights reserved