A Modeling and Analysis Study Reveals That CaMKII in Synaptic Plasticity Is a Dominant Affecter in CaM Systems in a T286 Phosphorylation-Dependent Manner

NMDAR-dependent synaptic plasticity in the hippocampus consists of two opposing forces: long-term potentiation (LTP), which strengthens synapses and long-term depression (LTD), which weakens synapses. LTP and LTD are associated with memory formation and loss, respectively. Synaptic plasticity is controlled at a molecular level by Ca²⁺-mediated protein signaling. Here, Ca²⁺ binds the protein, calmodulin (CaM), which modulates synaptic plasticity in both directions. This is because Ca²⁺-bound CaM activates both LTD-and LTP-inducing proteins. Understanding how CaM responds to Ca²⁺ signaling and how this translates into synaptic plasticity is therefore important to understanding synaptic plasticity induction. In this paper, CaM activation by Ca²⁺ and calmodulin binding to downstream proteins was mathematically modeled using differential equations. Simulations were monitored with and without theoretical knockouts and, global sensitivity analyses were performed to determine how Ca²⁺/CaM signaling occurred at various Ca²⁺ signals when CaM levels were limiting. At elevated stimulations, the total CaM pool rapidly bound to its protein binding targets which regulate both LTP and LTD. This was followed by CaM becoming redistributed from low-affinity to high-affinity binding targets. Specifically, CaM was redistributed away from LTD-inducing proteins to bind the high-affinity LTP-inducing protein, calmodulin-dependent kinase II (CaMKII). In this way, CaMKII acted as a dominant affecter and repressed activation of opposing CaM-binding protein targets. The model thereby showed a novel form of CaM signaling by which the two opposing pathways crosstalk indirectly. The model also found that CaMKII can repress cAMP production by repressing CaM-regulated proteins, which catalyze cAMP production. The model also found that at low Ca²⁺ stimulation levels, typical of LTD induction, CaM signaling was unstable and is therefore unlikely to alone be enough to induce synaptic depression. Overall, this paper demonstrates how limiting levels of CaM may be a fundamental aspect of Ca²⁺ regulated signaling which allows crosstalk among proteins without requiring directly interaction.     

The Role of Hydrogen Sulfide in the Development and Progression of Lung Cancer

Lung cancer is one of the 10 most common cancers in the world, which seriously affects the normal life and health of patients. According to the investigation report, the 3-year survival rate of patients with lung cancer is less than 20%. Heredity, the environment, and long-term smoking or secondhand smoke greatly promote the development and progress of the disease. The mechanisms of action of the occurrence and development of lung cancer have not been fully clarified. As a new type of gas signal molecule, hydrogen sulfide (H₂S) has received great attention for its physiological and pathological roles in mammalian cells. It has been found that H₂S is widely involved in the regulation of the respiratory system and digestive system, and plays an important role in the occurrence and development of lung cancer. H₂S has the characteristics of dissolving in water and passing through the cell membrane, and is widely expressed in body tissues, which determines the possibility of its participation in the occurrence of lung cancer. Both endogenous and exogenous H₂S may be involved in the inhibition of lung cancer cells by regulating mitochondrial energy metabolism, mitochondrial DNA integrity, and phosphoinositide 3-kinase/protein kinase B co-pathway hypoxia-inducible factor-1α (HIF-1α). This article reviews and discusses the molecular mechanism of H₂S in the development of lung cancer, and provides novel insights for the prevention and targeted therapy of lung cancer.     

恒速偏频激光陀螺系统静基座初始对准中等效东向陀螺漂移估计

以单轴恒速偏频激光陀螺系统为研究对象,在分析IMU传感器误差的基础上,建立了合理有效的静基座初始对准滤波器模型。针对系统连续旋转运行的特性,提出了简洁适用的滤波器估计误差检验方法,利用自主设计的原理样机验证了恒速偏频技术的实际可行性,对滤波算法进行了实验测试。实验结果表明,初始对准滤波算法能够稳定有效地估计IMU传感器误差,且等效东陀螺漂移估计精度优于0.0004(°)/h,该系统具有很高的工程应用潜力。     

Pancreatic β-cell signaling: toward better understanding of diabetes and its treatment

Pancreatic β-cells play a central role in the maintenance glucose homeostasis by secreting insulin, a key hormone that regulates blood glucose levels. Dysfunction of the β-cells and/or a decrease in the β-cell mass are associated closely with the pathogenesis and pathophysiology of diabetes mellitus, a major metabolic disease that is rapidly increasing worldwide. Clarification of the mechanisms of insulin secretion and β-cell fate provides a basis for the understanding of diabetes and its better treatment. In this review, we discuss cell signaling critical for the insulin secretory function based on our recent studies.     

Anti-rheumatoid arthritis effects of Xanthii Fructus by affecting the PI3K-AKT signaling pathway based on TMT-labeled quantitative proteomics

Rheumatoid arthritis is a systemic autoimmune disease characterized by chronic symmetrical multiple arthritis. Current traditional counter-therapies are expensive and have side effects. Xanthii Fructus has effects in expelling wind and cold, draining the nasal orifice, and removing wind and dampness. However, its mechanism of action against rheumatoid arthritis is unknown. In this paper, the mechanism of the anti- rheumatoid arthritis effect of Xanthii Fructus is studied by proteomics. The experimental results show that it could significantly reduce serum inflammatory factor levels, alleviate joint edema, improve vasodilation and congestion, and significantly reduce the number of inflammatory cells. Proteomics results show that the PI3K-AKT signaling pathway is the key pathway for Xanthii Fructus to treat rheumatoid arthritis. In this study, we obtained a new understanding of the mechanism of Xanthii Fructus in the treatment of rheumatoid arthritis, which provided a theoretical basis for its prevention and treatment and laid the foundation for further research.     

Separating equilibria in a continuous-time bargaining model with two-sided uncertainty

In this paper, we analyze the class of all smooth separating sequential equilibria in a continuous-time bargaining model with two-sided uncertainty. Trade between players occurs whenever there is surplus to be shared and delay is used to signal their valuations. When the buyer and the seller have a common discount rate, we show that the final outcome is unique among all these equilibria: the difference between the highest possible buyer's valuation and the lowest possible seller's valuation always narrows down at a rate exactly equal to the discount rate. When their discount rates differ, the more patient side always reveals his valuation first in the unique smooth separating equilibrium. Received: November 1997/Final version: December 1999     

A C2‐continuous high‐resolution upwind convection scheme

A bounded upwinding scheme for numerical solution of hyperbolic conservation laws and Navier–Stokes equations is presented. The scheme is based on convection boundedness criterion and total variation diminishing stability criteria and developed by employing continuously differentiable functions. The accuracy of the scheme is verified by assessing the error and observed convergence rate on 1‐D benchmark test cases. A comparative study between the new scheme and conventional total variation diminishing/convection boundedness criterion‐based upwind schemes to solve standard nonlinear hyperbolic conservation laws is also accomplished. The scheme is then examined in the simulation of Newtonian and non‐Newtonian fluid flows of increasing complexity; a satisfactory agreement has been observed in terms of the overall behavior. Finally, the scheme is used to study the hydrodynamics of a gas‐solid flow in a bubbling fluidized bed. Copyright © 2013 John Wiley & Sons, Ltd.     

Design and Synthesis of New Benzo[d]oxazole-Based Derivatives and Their Neuroprotective Effects on β-Amyloid-Induced PC12 Cells

A series of novel synthetic substituted benzo[d]oxazole-based derivatives (5a–5v) exerted neuroprotective effects on β-amyloid (Aβ)-induced PC12 cells as a potential approach for the treatment of Alzheimer’s disease (AD). In vitro studies show that most of the synthesized compounds were potent in reducing the neurotoxicity of Aβ_25-35-induced PC12 cells at 5 μg/mL. We found that compound 5c was non-neurotoxic at 30 μg/mL and significantly increased the viability of Aβ_25-35-induced PC12 cells at 1.25, 2.5 and 5 μg/mL. Western blot analysis showed that compound 5c promoted the phosphorylation of Akt and glycogen synthase kinase (GSK-3β) and decreased the expression of nuclear factor-κB (NF-κB) in Aβ_25-35-induced PC12 cells. In addition, our findings demonstrated that compound 5c protected PC12 cells from Aβ_25-35-induced apoptosis and reduced the hyperphosphorylation of tau protein, and decreased the expression of receptor for AGE (RAGE), β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1), inducible nitric oxide synthase (iNOS) and Bcl-2-associated X protein/B-cell lymphoma 2 (Bax/Bcl-2) via Akt/GSK-3β/NF-κB signaling pathway. In vivo studies suggest that compound 5c shows less toxicity than donepezil in the heart and nervous system of zebrafish.