The technological novelty of inventions signals economic potential while simultaneously indicating considerable technological and market risks. We speculate that unlike early-stage venture capital ...(VC) investors, late-stage public investors will interpret technological novelty as a signal of high risks. Consequently, they will hesitate to promptly invest in high-tech start-ups with such inventions, thereby slowing the initial public offering speed of the start-ups. Based on a sample of 408 VC-backed healthcare start-ups founded between 1990 and 2010, we find support for our hypothesis. We also find that the negative effect of technological novelty of inventions can be relieved when the technology is characterised by conventionality, when the founder is also the inventor, or when the start-up is backed by premium VC investors.
This paper presents a distributed adaptive neural tracking consensus control strategy for a class of stochastic nonlinear multiagent systems with whole state time delays, input and output constrains. ...The considered systems are involved in the existence of whole state delays and stochastic disturbances, which makes the controller design more difficult and complex. Firstly, time delays are related to unknown dynamic interactions with the whole states of the agent systems, and novel Lyapunov-Krasovskii functionals are constructed. Secondly, the smooth asymmetric saturation nonlinearity is given based on Gaussian error function, output constraints are achieved via barrier Lyapunov functions, and neural networks are utilized to deal with the completely unknown nonlinearities and stochastic disturbances. Then, based on Lyapunov stability theory, a delay-independent adaptive controller is developed via Lyapunov-Krasovskii functionals and backstepping technique, and it reduces the complexity of learning parameters. It is proved that the proposed approximation-based controller can guarantee that all closed-loop signals are cooperatively semi-globally uniformly ultimately bounded (CSGUUB), and the tracking errors between the followers and the leaders eventually converge to a small neighbourhood around the origin. Finally, simulation studies are carried out, and the simulation results verify the correctness and effectiveness of the proposed strategy.
Periodontitis is characterized by alveolar bone destruction and is one of the most common chronic oral diseases. Inflammatory cytokines released by pyroptosis, which can be triggered by oxidative ...stress, are critical in the development of periodontitis. This study aims to clarify whether oxidative stress causes osteoblast dysfunction by inducing pyroptosis in the process of periodontitis. We found that treatment with lipopolysaccharide (LPS) led to NLRP3 inflammasome-mediated pyroptosis of MG63 cells as well as decreased cell migration. Of note, LPS stimulation increased LDH release in a time- and dose-dependent manner. However, inhibition of reactive oxygen species with N-acetyl-L-cysteine attenuated oxidative stress-mediated pyroptosis and improved migration injury in osteoblasts treated with LPS. Further, inhibition of the NLRP3 inflammasome with MCC950 improved osteoblast migration and restored the expression of osteogenic differentiation-related proteins such as COL 1, RUNX 2 and ALP. In conclusion, oxidative stress caused by LPS induces pyroptosis in osteoblasts, leading to osteogenic dysfunction.
The incidence of diabetic osteoporosis is increasing. This article evaluates the effect of combination treatment with the hypoglycemic drug exendin-4 (Ex-4) and the vitamin D analog eldecalcitol ...(ED-71) on improving diabetic osteoporosis and explores the relevant mechanism of action.
Micro-CT, HE staining, immunohistochemistry, qPCR and ELISA were used to evaluate the impact of Ex-4 and ED-71 on bone formation and macrophage polarization in a mouse model of diabetic osteoporosis in vivo. Immunofluorescence, flow cytometry and qPCR were used to characterize the polarization type of macrophages treated with Ex-4 and ED-71 in vitro. A co-culture system of BMSCs and macrophages was established. Subsequently, crystal violet staining, alkaline phosphatase staining and alizarin red staining were used to evaluate the migration and osteogenesis differentiation of BMSCs.
Ex-4 combined with ED-71 significantly reduced blood glucose levels and enhanced bone formation in mice with diabetic osteoporosis. In addition, Ex-4 synergized with ED-71 to induce the polarization of macrophages into M2 through the PI3K/AKT pathway. Macrophages treated with the combination of Ex-4 and ED-71 can significantly induce the osteogenic differentiation of BMSCs.
Ex-4 synergized with ED-71 to reduce blood glucose levels significantly. And this combination therapy can synergistically induce osteogenic differentiation of BMSCs by promoting M2 macrophages polarization, thereby improving diabetic osteoporosis. Therefore, the combination of Ex-4 and ED-71 may be a new strategy for the treatment of diabetic osteoporosis.
In order to solve the coordinated optimization problem of distributed generation (DG), on‐load tap changer (OLTC) and capacitor banks, a dynamic reactive power optimization (DRPO) method based on ...fuzzy time clustering is proposed. In the method, fuzzy time clustering algorithm is used to cluster the static optimal switching sequence of OLTC and capacitor banks. The time decoupling of control variables is realized and it meets the constraints of the maximum switching times. Next, the influencing factors of DG reactive power limit are analysed. Considering the control ability of OLTC, capacitor banks and DG in voltage and reactive power optimization, a coordinated optimization method is proposed. Since the adjustment of OLTC tap position directly affects the voltage and reactive power distribution of the whole line, the switching time and tap position of OLTC are determined based on the static optimization results of each time and fuzzy time clustering algorithm. Then, the switching time of capacitor banks is determined by fuzzy time clustering algorithm. At last, the switching capacity of capacitor banks and DG reactive power are jointly optimized to get the final control scheme. The proposed method demonstrated good performance in the modified IEEE33 node system and two actual power grid examples.
Periodontitis is a major chronic oral disease that is accelerated by activation of the NLRP3 inflammasome and the resulting pyroptosis. According to recent studies, active vitamin D and its analogs ...have been reported to have great anti-inflammatory effects. However, the anti-inflammatory mechanism of a newly found vitamin D analog, eldecalcitol (ED-71), is still unclear. This study investigates whether ED-71 could protect human gingival fibroblasts (HGFs) from LPS-induced pyroptosis and, if so, determine its underlying mechanism.
After HGFs were treated with LPS alone or with LPS and ED-71, their viability was measured by CCK8 assay. The degrees of inflammation and pyroptosis were measured via LDH assay, H
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assay, fluorescent staining, flow cytometry, and Western blots. Intracellular ROS, Hoechst 33,342, and PI stains were assessed with a fluorescence microscope. ROS inhibitor NAC, NLRP3 inhibitor MCC950, and Nrf2 inhibitor ML385 were added to further clarify the mechanism.
LPS induced cytotoxicity in HGFs, as shown by CCK8 assay. LPS also increased intracellular ROS, H
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levels, release of LDH, and expression of the pyroptosis-related proteins NLRP3, caspase-1, and IL-1β. NAC and MCC950 reduced LPS-induced NLRP3, caspase-1, and IL-1β. Pretreatment with ED-71 effectively inhibited the LPS-induced pyroptosis and was associated with activation of the Nrf2/HO-1 signaling pathway. This beneficial effect of ED-71 was suppressed by ML385.
This study demonstrates the therapeutic effect of ED-71 on LPS-induced NLRP3 inflammasome-dependent pyroptosis in HGFs and further reveals that ED-71 can inhibit pyroptosis by activating the Nrf2/HO-1 pathway. Our results thus suggest that ED-71 is a potential candidate for the treatment of periodontitis.
The W9 peptide has been shown to act as a receptor activator for nuclear factor-κB ligand (RANKL) antagonist and tumor necrosis factor (TNF)-α antagonist, which can promote bone formation and inhibit ...bone resorption. Studies on the W9 peptide at the cellular level have mainly focused on osteoblasts, and little research on the mechanism by which the W9 peptide regulates osteoclasts has been reported, which was the aim of this work. In this study, a rat mandibular defect model was established in vivo and implanted with hydrogel containing the W9 peptide for 2 weeks and 4 weeks, and histochemical staining was used to evaluate the formation of new bone and the changes in osteoclasts. RAW264.7 cells were cultured in vitro for osteoclast induction, and different concentrations of W9 peptide were added. Tartrate resistant acid phosphatase staining, monodansylcadaverine staining, TdT-mediated dUTP Nick-End Labeling assay, real-time PCR and Western blot were used to detect osteoclast differentiation, autophagy and apoptosis. Our results showed that the W9 peptide could reduce osteoclastogenesis and osteoclast activity induced by RANKL, and these effects were partly due to the inhibition of osteoclast autophagy. On the other hand, the W9 peptide could promote mature osteoclast apoptosis, in which autophagy might play an antagonistic role. Taken together, these results suggest that the W9 peptide inhibits osteoclastogenesis and osteoclast activity by downregulating osteoclast autophagy and promoting osteoclast apoptosis. Our results will benefit the development and application of new small molecule peptides for the treatment of bone resorption diseases.
Rheumatoid arthritis (RA) is a chronic, progressive, and systemic inflammatory joint disease characterized by synovial inflammation and joint damage. Abnormal activation of fibroblast-like ...synoviocytes is an initial event of synovial inflammation and joint damage, which can significantly aggravate the progression of RA. Clinical studies have shown that synovitis may be associated with pyroptosis. Therefore, this study is mainly aim for exploring the underlying mechanisms of relationship between inflammation and pyroptosis during synovitis. A cell model of synovitis was constructed by stimulating synovial fibroblasts RSC-364 cells with lipopolysaccharide (LPS). In vitro, we found that LPS can induce pyroptosis of synovial fibroblasts through NOD-like receptor pyrin domain-3/caspase-1/gasdermin D and caspase-3/gasdermin E two signaling pathways, and these two signaling pathways can promote each other. In addition, NF-κB signaling pathway, as the upstream of these two pathways, is involved in regulating the pyroptosis of synovial fibroblast. These results suggest that pyroptosis may be triggered during the occurrence of RA. We hope to provide a new perspective for the study of RA and a new therapeutic target for clinical treatment of RA.
The well-developed unified power flow controller (UPFC) has demonstrated its capability in providing voltage support and improving power system stability. The objective of this paper is to ...demonstrate the capability of the UPFC in mitigating oscillations in a wind farm integrated power system by employing eigenvalue analysis and dynamic time-domain simulation approaches. For this purpose, a power oscillation damping controller (PODC) of the UPFC is designed for damping oscillations caused by disturbances in a given interconnected power system, including the change in tie-line power, the changes of wind power outputs, and others. Simulations are carried out for two sample power systems, i.e., a four-machine system and an eight-machine system, for demonstration. Numerous eigenvalue analysis and dynamic time-domain simulation results confirm that the UPFC equipped with the designed PODC can effectively suppress oscillations of power systems under various disturbance scenarios.
Droop control is widely used in multi-terminal flexible DC (VSC-MTDC) transmission systems by virtue of the advantage of multi-station cooperative unbalanced power dissipation, however, the essence ...of the droop control strategy is to change the DC current to realize the unbalanced power dissipation, and the resulting DC voltage deviation will affect the normal operation of the system. Firstly, this paper theoretically analyses the working characteristics of the conventional droop control and proposes a control method to realize the quasi-differential-free regulation of DC voltage by translating the droop curve. Second, according to the power margin of the converter station, the feedforward compensation amount of each converter station is reasonably set to avoid the power impact on the converter station. Finally, for the problem that the actual value of DC voltage still deviates from the rated value, a control strategy containing secondary regulation of DC voltage is proposed to further restore the DC voltage to the initial value on the basis of ensuring the effect of power regulation, which improves the stability of the operation of the VSC-MTDC system. The final simulation results verify the effectiveness of the proposed method.
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