(2014) Autophagy facilitates TLR4-and TLR3-triggered migration and invasion of lung cancer cells through the promotion of TRAF6 ubiquitination, Autophagy, 10:2, 257-268,

Am ain remaining challengei np rotein engineering is how to recombine beneficial substitutions. Systematic recombinations tudies show that poorly performing variants are usually obtained after recombination of 3t o4beneficial substitutions. This limits researchers in exploiting nature's potential in generatingb etter enzymes. TheC omputer-assisted Recombination (CompassR)s trategy provides as election guide for beneficial substitutionst hat can be recombined to gradually improvee nzyme performance by analysis of the relative free energy of folding (DDG fold ). The performance of CompassR was evaluated by analysis of 84 recombinantsl ocated on 13 positions of Bacillus subtilis lipase A. The finally obtainedv ariant F17S/V54K/D64N/D91Eh ad a 2.7-fold improved specific activity in 18.3 %( v/v) 1-butyl-3methylimidazolium chloride ([BMIM][Cl]). In essence,t he de-ductedC ompassR rule allows recombination of beneficial substitutions in an iterative manner and empowers researchers to generate bettere nzymes in atime-efficient manner.

Lung ischemia-reperfusion (I/R) injury remains one of the most common complications after various cardiopulmonary surgeries. The inflammation response triggered by the released damage-associated molecular patterns (DAMPs) aggravates lung tissue damage. However, little is known about the role of autophagy in the pathogenesis of lung I/R injury. Here, we report that a variety of inflammation-related and autophagy-associated genes are rapidly upregulated, which facilitate the inflammation response in a minipig lung I/R injury model. Left lung I/R injury triggered inflammatory cytokine production and activated the autophagy flux as evidenced in crude lung tissues and alveolar macrophages. This was associated with the release of DAMPs, such as high mobility group protein B1 (HMGB1) and heat shock protein 60 (HSP60). Indeed, treatment with recombinant HMGB1 or HSP60 induced autophagy in alveolar macrophages, whereas autophagy inhibition by knockdown of ATG7 or BECN1 markedly reduced DAMPtriggered production of inflammatory cytokines including IL-1β, TNF and IL12 in alveolar macrophages. This appeared to be because of decreased activation of MAPK and NF-κB signaling. Furthermore, knockdown of ATG7 or BECN1 inhibited Lys63 (K63)-linked ubiquitination of TNF receptor-associated factor 6 (TRAF6) in DAMP-treated alveolar macrophages. Consistently, treatment with 3-MA inhibited K63-linked ubiquitination of TRAF6 in I/R-injured lung tissues in vivo. Collectively, these results indicate that autophagy triggered by DAMPs during lung I/R injury amplifies the inflammatory response through enhancing K63-linked ubiquitination of TRAF6 and activation of the downstream MAPK and NF-κB signaling.

Current therapeutic strategies such as angiogenic therapy and anti-inflammatory therapy for treating myocardial infarction have limited success. An effective approach may benefit from resolution of excessive inflammation combined with enhancement of angiogenesis. Here, we developed a microRNA-21-5p delivery system using functionalized mesoporous silica nanoparticles (MSNs) with additional intrinsic therapeutic effects. These nanocarriers were encapsulated into an injectable hydrogel matrix (Gel@MSN/miR-21-5p) to enable controlled on-demand microRNA-21 delivery triggered by the local acidic microenvironment. In a porcine model of myocardial infarction, we demonstrated that the released MSN complexes notably inhibited the inflammatory response by inhibiting the polarization of M1 macrophage within the infarcted myocardium, while further microRNA-21-5p delivery by MSNs to endothelial cells markedly promoted local neovascularization and rescued at-risk cardiomyocytes. The synergy of anti-inflammatory and proangiogenic effects effectively reduced infarct size in a porcine model of myocardial infarction.

Brain-derived neurotrophic factor (BDNF) plays an important role in nervous system development and function and it is well established that BDNF is involved in the pathogenesis of a wide range of psychiatric disorders. Recently, numerous studies have associated the DNA methylation level of BDNF promoters with certain psychiatric phenotypes. In this review, we summarize data from current literature as well as from our own analysis with respect to the correlation of BDNF methylation changes with psychiatric disorders and address questions about whether DNA methylation related to the BDNF can be useful as biomarker for specific neuropsychiatric disorders.

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An experiment was conducted to investigate the influence of Zn supplementation on the performance, antioxidant status, and immune responses of broilers challenged with Eimeria tenella. A total of 384 male broilers (1 d old) were assigned to 8 treatments consisting of 8 replicates of 6 chicks each. A basal corn-soybean meal diet (29.6 mg of Zn/kg) was supplemented with methionine hydroxyl analog-Zn chelate at 0, 20, 40, and 60 mg/kg of diet. At 21 d of age, birds were orally gavaged with 1.5 × 10(4) sporulated E. tenella oocysts. Dietary Zn supplementation had no effect on growth performance of either the challenged or nonchallenged birds. Activities of Cu-Zn superoxide dismutase and glutathione peroxidase were increased (P < 0.001) with increasing Zn levels in both the challenged and nonchallenged groups. Lipid peroxidation tended to be reduced (P = 0.08) at Zn inclusion of 20 and 40 mg/kg. In vitro lymphocyte proliferation responses to mitogen concanavalin A and LPS were not influenced by dietary Zn or challenge. The main effects of Zn level and challenge were significant for secretory IgA on d 28 (P < 0.01) and 35 (P < 0.001). During both periods, secretory IgA of birds receiving dietary Zn supplementation was higher (P < 0.05) than that of those receiving no Zn supplementation. Birds fed Zn supplementation excreted fewer oocysts in the excreta than those receiving no Zn supplement (P < 0.001). Results indicated that organic Zn supplementation reduced oxidative stress and improved some immune responses irrespective of whether birds were healthy or challenged with E. tenella.

Acquiring the fundamental understanding of electrochemical processes occurring at the complex electrode–liquid interface is a grand challenge in catalysis. Herein, to gain theoretical insights into the experimentally observed potential-dependent activity and selectivity for the CO2 reduction reaction (CO2RR) on the popular single-iron-atom catalyst, we performed ab initio molecular dynamics (AIMD) simulation, constrained MD sampling, and thermodynamic integration to acquire the free energy profiles for the proton and electron transfer processes of CO2 at different potentials. We have demonstrated that the adsorption of CO2 is significantly coupled with the electron transfer from the substrate while the further protonation does not show distinct charge variation. This strongly suggests that CO2 adsorption is potential-dependent and optimizing the electrode potential is vital to achieve the efficient activated adsorption of CO2. We further identified a linear scaling relationship between the reaction free energy (ΔG) and the potential for key elementary steps of CO2RR and HER, of which the slope is adsorbate-specific and not as simple as 1 eV per volt as suggested by the traditional computational hydrogen electrode (CHE) model. The derived scaling relationship can reproduce the experimental onset potential (U onset) of CO2RR, potential of the maximal CO2-to-CO Faraday efficiency (FECO), and potential where FECO = FEH2. This suggests that our state-of-the-art model could precisely interpret the activity and selectivity of CO2RR/HER on the Fe-N4-C catalyst under different electrode potentials. In general, our study not only provides an innovative insight into the theoretical explanation of the origin of the solvation effect from the perspective of charge transfer but also emphasizes the critical role of electrode potential in the theoretical consideration of catalytic activity, which offers a profound understanding of the electrochemical environment and bridges the gap between theoretical predictions and experimental results.