Inflammation and autophagy are two critical cellular processes. The relationship between these two processes is complex and includes the suppression of inflammation by autophagy. However, the ...signaling mechanisms that relieve this autophagy-mediated inhibition of inflammation to permit a beneficial inflammatory response remain unknown. We find that LPS triggers p38α mitogen-activated protein kinase (MAPK)-dependent phosphorylation of ULK1 in microglial cells. This phosphorylation inhibited ULK1 kinase activity, preventing it from binding to the downstream effector ATG13, and reduced autophagy in microglia. Consistently, p38α MAPK activity is required for LPS-induced morphological changes and the production of IL-1β by primary microglia in vitro and in the brain, which correlates with the p38α MAPK-dependent inhibition of autophagy. Furthermore, inhibition of ULK1 alone was sufficient to promote an inflammatory response in the absence of any overt inflammatory stimulation. Thus, our study reveals a molecular mechanism that enables the initial TLR4-triggered signaling pathway to inhibit autophagy and optimize inflammatory responses, providing new understanding into the mechanistic basis of the neuroinflammatory process.
Small molecule JAK inhibitors have emerged as a major therapeutic advancement in treating autoimmune diseases. The discovery of isoform selective JAK inhibitors that traditionally target the ...catalytically active site of this kinase family has been a formidable challenge. Our strategy to achieve high selectivity for TYK2 relies on targeting the TYK2 pseudokinase (JH2) domain. Herein we report the late stage optimization efforts including a structure-guided design and water displacement strategy that led to the discovery of BMS-986165 (11) as a high affinity JH2 ligand and potent allosteric inhibitor of TYK2. In addition to unprecedented JAK isoform and kinome selectivity, 11 shows excellent pharmacokinetic properties with minimal profiling liabilities and is efficacious in several murine models of autoimmune disease. On the basis of these findings, 11 appears differentiated from all other reported JAK inhibitors and has been advanced as the first pseudokinase-directed therapeutic in clinical development as an oral treatment for autoimmune diseases.
We have fabricated CsPbBr3 perovskite quantum dots (QDs) in a multi‐component borate glass by melt‐quenching technique. Transmission electron microscopy (TEM) reveals a cubic phase CsPbBr3 crystal ...for QDs. As the treatment temperature or the treatment time duration increases, the photoluminescence (PL) peak shifts to long wavelength in the range of 510 to 525 nm, and the full width at half‐maximum varies in the range of 24 to 18 nm. The absorption edge shifts to low energy side in the range of 2.54 to 2.41 eV. The different photoluminescence excitation spectra (PLE) reflect the change of microstructure for different samples. The PL peak wavelength and line‐shape are independent of excitation wavelength. These results of spectra show typical exciton emission characteristics. As treatment conditions strengthens, photoluminescence quantum yield (PLQY) first increases and then decreases, having the best PLQY 86.9%. Bi‐exponential fitting curves show that short lifetime τ1 continuously decreases. Long lifetime τ2, weight for long lifetime component, and average lifetime τavg first increase and then decrease. The PLQY values are affected by both τ1 and τ2, which are relative to the crystal quality in the interior and the surface of QDs, respectively. The high PLQY value corresponds to medium treatment condition, which is attributed to a balanced effect of crystal quality in interior and the surface of QDs.
High PLQY values and luminescence lifetimes for different treatment conditions.
Model abstraction for finite state automata is beneficial to reduce the complexity of discrete-event systems (DES), enhances the readability and facilitates the control synthesis and verification of ...DES. Supremal quasi-congruence computation is an effective way for reducing the state space of DES. Effective algorithms on the supremal quasi-congruence relation have been developed based on the graph theory. This paper proposes a new approach to translate the supremal quasi-congruence computation into a satisfiability (SAT) problem that determines whether there exists an assignment for Boolean variables in the state-to-coset allocation matrix. If the result is satisfied, then the supremal quasi-congruence relation exists and the minimum equivalence classes is obtained. Otherwise, it indicates that there is no such supremal quasi-congruence relation, and a new set of observable events needs to be modified or reselected for the original system model. The satisfiability problem on the computation of supremal quasi-congruence relation is solved by different methods, which are respectively implemented by mixed integer linear programming (MILP) in MATLAB, binary linear programming (BLP) in CPLEX, and a SAT-based solver (Z3Py). Compared with the MILP and BLP methods, the SAT method is more efficient and stable. The computation time of model abstraction for large-scale systems by Z3Py solver is significantly reduced.
Glass fiber with different content and different kinds of compatibilizers were used to prepare glass fiber-reinforced polypropylene (GFRP) composites. β-nucleating agent with different content was ...used to prepare β-polypropylene (PP), after which the toughness, crystallization ability and heat resistance were all enhanced. Differential scanning calorimetry (DSC) and wide-angle X-ray diffraction (WAXD) showed that the crystallite degree and crystallization ability were all greatly improved and β-PP was in dominant position. At last, both β-nucleating agent and glass fiber were used to modify the PP composites (β-GFRP). The formation of β-form PP made the matrix softer, which was beneficial for energy absorption and enhancement of toughness. The tensile strength, flexural strength and flexural modulus were improved dramatically, which were attributed to the coeffect of framework structure of GF and β-form PP.
Axonal injury is a common cause of neurological dysfunction. Unfortunately, in contrast to axons from the peripheral nervous system, the limited capacity of regeneration of central nervous system ...(CNS) axons is a major obstacle for functional recovery in patients suffering neurological diseases that involve the subcortical white matter. Urokinase-type plasminogen activator (uPA) is a serine proteinase that upon binding to the urokinase-type plasminogen activator receptor (uPAR) catalyzes the conversion of plasminogen into plasmin on the cell surface. uPAR expression increases after an injury, and signaling through uPAR promotes tissue remodeling. However, it is yet unknown whether uPA binding to uPAR has an effect on axonal recovery in the CNS. Here, we used in vitro and in vivo models of CNS axonal injury to test the hypothesis that uPA binding to uPAR promotes axonal regeneration in the CNS. We found that newly formed growth cones from axons re-emerging from an axonal injury express uPAR and that binding of uPA to this uPAR promotes axonal recovery by a mechanism that does not require the generation of plasmin. Our data indicate that the binding of recombinant uPA or endogenous uPA to uPAR induces membrane recruitment and activation of β1 integrin via the low density lipoprotein receptor-related protein-1 (LRP1), which leads to activation of the Rho family small GTPase Rac1 and Rac1-induced axonal regeneration. Our results show that the uPA/uPAR/LRP1 system is a potential target for the development of therapeutic strategies to promote axonal recovery following a CNS injury.
The rise of global value chains (GVCs) characterized by the so-called "outsourcing", "fragmentation production", and "trade in tasks" has been considered one of the most important phenomena for the ...21st century trade. GVCs also can play a decisive role in trade policy making. However, due to the increasing complexity and sophistication of international production networks, especially in the equipment manufacturing industry, conventional trade statistics and the corresponding trade indicators may give us a distorted picture of trade. This paper applies various network analysis tools to the new GVC accounting system proposed by Koopman et al. (2014) and Wang et al. (2013) in which gross exports can be decomposed into value-added terms through various routes along GVCs. This helps to divide the equipment manufacturing-related GVCs into some sub-networks with clear visualization. The empirical results of this paper significantly improve our understanding of the topology of equipment manufacturing-related GVCs as well as the interdependency of countries in these GVCs that is generally invisible from the traditional trade statistics.
ZnO is a promising thermoelectric material for high-temperature applications; however, the strong correlation between the electrical and thermal transport properties has limited their simultaneous ...optimization to achieve superior thermoelectric performance. In this work, defect engineering was applied to solve this problem. The results revealed that by eliminating the intrinsic acceptor defects at the grain boundaries, the Schottky barrier disappeared, which led to a huge increase in the Hall mobility. Meanwhile, an increased solid solution of the trivalent dopant Al was achieved to increase the carrier concentration. The increased Hall mobility and carrier concentration gave rise to a maximum electrical conductivity (σ310K) of 1.9 × 105 S m−1, showing a metallic-like behavior. Owing to the ultrahigh σ with moderate Seebeck coefficient, a maximum power factor of 8.2 × 10−4 W m−1 K−2 was obtained at 980 K. Moreover, by introducing large numbers of lattice defects in the grains, the lattice thermal conductivity was simultaneously decreased. Therefore, the multiple-doped ZnO ceramic with defect engineering of both grains and grain boundaries optimized the electrical and thermal transport properties in a relatively independent way which provided a new and effective route to optimize the performance of the ZnO-based thermoelectric materials.
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YNbO4 phosphors with various Er3+ and Yb3+ concentrations were synthesized via a traditional high-temperature solid-state reaction method. Their crystal structure was investigated by means of X-ray ...diffraction (XRD) and Rietveld refinements, and it was confirmed that the obtained samples exist in monoclinic phase. The Er3+ and Yb3+ concentration-dependent up-conversion (UC) luminescence was studied under 1550 nm excitation. By inspecting the dependence of UC intensity on the laser working current, it was found that four-photon and three-photon population processes were co-existent for generating the green UC emissions in the samples with higher Yb3+ concentrations. In addition, it was observed that the temperature sensing properties of YNbO4: Er3+/Yb3+ phosphors were sensitive to both Er3+ and Yb3+ doping concentrations. Furthermore, based on the obtained temperature response of the UC luminescence phosphors, 1550 nm laser-irradiation-induced thermal effect was studied, and it was discovered that the sample temperature was very sensitive to the doping concentrations of Er3+ and Yb3+ and the excitation power.
Yb3+/Tm3+ and Yb3+/Er3+ co-doped NaLuF4 crystals were synthesized by a facile hydrothermal method. The optical temperature sensing properties of Tm3+ based upon its two thermally coupled energy ...levels 3F2, 3 and 3H4 were systematically investigated by means of fluorescence intensity ratio (FIR) technique. The 980 nm laser-induced thermal effect on Tm3+ doped NaLuF4 crystals was studied by using Er3+ doped sample as thermal probe. The temperature sensitivity of Tm3+ in NaLuF4: Yb3+/Tm3+ crystals shows a nonlinear dependence on temperature, and the maximum value is about 0.00045 K−1 at 600 K. The accuracy and reliability of the optical thermometry based on Tm3+ in NaLuF4: Yb3+/Tm3+ crystals has been checked by using Yb3+/Er3+ co-doped sample as temperature sensing unit. The results demonstrate that NaLuF4: Yb3+/Tm3+ crystals have good sensing stability and may have potential application for the optical thermometry.
The optical temperature sensing properties of Tm3+ were systematically investigated, and NaLuF4: Yb3+/Er3+ crystals were adopted as a thermal probe to monitor the laser-induced thermal effect and to verify the accuracy of the temperature detection for Tm3+ in NaLuF4: Yb3+/Tm3+ crystals. Display omitted
•Yb3+/Tm3+ and Yb3+/Er3+ co-doped NaYF4 were prepared by a microwave hydrothermal route.•Temperature sensing properties of Tm3+ doped sample were systematically investigated.•Thermal effect was studied by time scanning upconversion spectra.•Accuracy and reliability of the optical thermometry based on Tm3+ in as-obtained sample has been checked.•As-prepared NaLuF4: Yb3+/Tm3+ crystals are promising sensing materials for application in optical thermometer.
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