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Toll-like receptors (TLRs) are a family of pattern recognition receptors (PRRs) that modulate innate immune responses and play essential roles in the pathogenesis of heart diseases. Although important, the molecular mechanisms controlling cardiac TLR genes expression have not been clearly addressed. This study examined the expression pattern of Tlr1, Tlr2, Tlr3, Tlr4, Tlr5, Tlr6, Tlr7, Tlr8, and Tlr9 in normal and disease-stressed mouse hearts. Our results demonstrated that the expression levels of cardiac Tlr3, Tlr7, Tlr8, and Tlr9 increased with age between neonatal and adult developmental stages, whereas the expression of Tlr5 decreased with age. Furthermore, pathological stress increased the expression levels of Tlr2, Tlr4, Tlr5, Tlr7, Tlr8, and Tlr9. Hippo-YAP signaling is essential for heart development and homeostasis maintenance, and YAP/TEAD1 complex is the terminal effector of this pathway. Here we found that TEAD1 directly bound genomic regions adjacent to Tlr1, Tlr2, Tlr3, Tlr4, Tlr5, Tlr6, Tlr7, and Tlr9. In vitro, luciferase reporter data suggest that YAP/TEAD1 repression of Tlr4 depends on a conserved TEAD1 binding motif near Tlr4 transcription start site. In vivo, cardiomyocyte-specific YAP depletion increased the expression of most examined TLR genes, activated the synthesis of pro-inflammatory cytokines, and predisposed the heart to lipopolysaccharide stress. In conclusion, our data indicate that the expression of cardiac TLR genes is associated with age and activated by pathological stress and suggest that YAP/TEAD1 complex is a default repressor of cardiac TLR genes. [ABSTRACT FROM AUTHOR]

Deformation of fan blades after shot peening is investigated. A finite element analysis (FEA) model of deformation induced by compressive residual stress (CRS) reveals that the difference in CRS between blade back and blade basin is the main cause of deformation. An FEA model of the influence of shot peening parameters on residual stress shows that to minimize deformation, the parameters should be optimized to give a CRS in the blade back −80 MPa to −50 MPa greater than that in the blade basin. An experimental study shows that the optimized parameters greatly reduce blade deformation caused by shot peening. [Display omitted] • The finite element model for deformation caused by residual stress and the model of shot peening are established. • The residual stress difference between blade back and blade basin caused the fan blade deformation. • The shot peening parameters are optimized to reduce deformation and verified by experiments. [ABSTRACT FROM AUTHOR]

• Novel sulfonamide derivatives containing dithiocarbamate moiety were synthesized as potent PKM2 activators. • Compound 8k has good PKM2 activation potency (AC 50 = 56 nM). • Compound 8k has great anti-proliferation activities on 6 tumor cell lines (IC 50 = 0.28 ~ 1.86 µM). • Compound 8k could effectively inhibit the colony formation of MCF7 cells. • Compound 8k could reduce the PKM2 nuclear localization and block the downstream signaling pathways of PKM2. Pyruvate kinase M2 isoform (PKM2) plays a key role in cancer progression through both metabolic and non-metabolic functions, thus it is recognized as a potential target for cancer diagnosis and treatment. In this study, we discovered a sulfonamide-dithiocarbamate compound 8a as a novel PKM2 activator from a random screening of an in-house compound library. Then, a series of lead compound 8a analogs were designed and synthesized for screening as potent PKM2 activators. Among them, compound 8b (AC 50 = 0.136 µM) and 8k (AC 50 = 0.056 µM) showed higher PKM2 activation activities than positive control NZT (AC 50 = 0.228 µM), and they (IC 50 < 1 µM) exhibited more significant anti-proliferative activities against human tumor cell lines than NZT (IC 50 > 10 µM). Especially, compound 8k inhibited the proliferation of multiple cancer cells, but showed little toxicity on normal cells. In addition, we found that compound 8k inhibit the colony formation of MCF7 cells. Western blot analysis demonstrated that 8k could reduce PKM2 nuclear localization and block the downstream signaling pathway of PKM2, resulting in suppression of tumor cell proliferation. Overall, compound 8k may be a promising candidate for further mechanistic investigation of PKM2 and cancer therapy. [ABSTRACT FROM AUTHOR]

The traditional efficiency analysis method of hydraulic system generally neglects the influence of mechanical nonlinearity, which causes great difference between theoretical efficiency optimization and actual application. This will reduce the energy-saving effect. In this paper, the electro-hydraulic servo steering system (EHSSS) of heavy vehicles is taken as the research object. Considering both mechanical nonlinearity and hydraulic nonlinearity of the steering system, this paper establishes the efficiency model of the EHSSS. In order to achieve the efficiency analysis of this nonlinear model, an efficiency analysis method in quasi-steady state condition is proposed. The theoretical analysis is consistent with the experimental results in four different single-side loading conditions, so the validity of the model and method is verified. Then, based on the above model and method, the system efficiency spectrums are obtained in different operating conditions. The efficiency of the EHSSS with strong nonlinearity is not only related to the equivalent load but also the steering angle. The results show that the efficiency is the highest in the maximum equivalent load conditions and at left or right end points. In addition, this paper obtains the efficiency curves of steering system in different speeds, hydraulic parameters and structural parameters. The method presented in this paper takes into account the effect of mechanical nonlinearity on the efficiency, which provides theoretical guidance for further efficiency improvement of electro-hydraulic steering system. • An analysis method in quasi-steady state condition is proposed to study EHSSS efficiency with nonlinear components. • The efficiency model of EHSSS was established with this method and verified by experiments. • The influences of key parameters on EHSSS efficiency were obtained, which can guide energy saving design of EHSSS. [ABSTRACT FROM AUTHOR]

Brown adipose tissue (BAT) is the primary non-shivering thermogenesis organ in mammals, which plays essential roles in maintaining the body temperature of infants. Although the development of BAT during embryogenesis has been well addressed in rodents, how BAT grows after birth remains unknown. Using mouse interscapular BAT (iBAT) as an example, we studied the cellular and molecular mechanisms that regulate postnatal BAT growth. By analyzing the developmental dynamics of brown adipocytes (BAs), we found that BAs size enlargement partially accounts for iBAT growth. By investigating the BAs cell cycle activities, we confirmed the presence of proliferative BAs in the neonatal mice. Two weeks after birth, most of the BAs exit cell cycle, and the further expansion of the BAT was mainly due to lipogenesis-mediated BAs volume increase. Microscopy and fluorescence-activated cell sorting analyses suggest that most BAs are mononuclear and diploid. Based on the developmental dynamics of brown adipocytes, we propose that the murine iBAT has two different growth phases between birth and weaning: increase of BAs size and number in the first two weeks, and BAs size enlargement thereafter. In summary, our data demonstrate that both lipogenesis and proliferation of BAs contribute to postnatal iBAT growth in mice. [ABSTRACT FROM AUTHOR]

While membrane technology has shown promising separation applications, efficient separation of viscous organic liquids remains a great challenge as they can readily adhere to and foul membranes, leading to severely declined permeation flux and even failure of the membranes. Herein, a unique grafted-liquid lubrication strategy is introduced for the first time by covalently grafting highly flexible polydimethylsiloxane (PDMS) brushes onto membranes to tackle the above challenge. The PDMS polymer brush featuring extremely low glass transition temperature (T g : 127 °C) is rotationally dynamic at room temperature and acts as a liquid-like lubrication layer, which can both reduce the foulant adhesion and promote liquid slippage at the membrane-liquid interface. As a result, a remarkably improved permeation flux and superior antifouling ability towards highly viscous organic liquids (i.e., crude oil) are achieved for the PDMS-brush lubricated membrane compared with conventional solid membranes of similar surface structure and wettability. It is believed that the grafted-liquid lubrication strategy will open a promising avenue for developing high-performance membranes dealing with viscous liquids. Image 1 • A unique grafted-liquid lubrication strategy for membrane modification is reported. • The grafted-liquid lubricated membrane shows markedly enhanced permeability towards highly viscous oils. • The membrane exhibits superior antifouling ability. • The membrane enables fast separation of crude oil-water mixture. [ABSTRACT FROM AUTHOR]

Multi-drug resistance (MDR) remains the main culprit for the low survival rate of advanced colorectal cancer (CRC). Photothermal-therapy (PPT) is effective to kill MDR tumor cells, but fails to completely eradicate tumors. In this study, we prepared a nanocomposite based on gold nanorod core with triple layer coating (GNRs/mSiO 2 /PHIS/TPGS/DOX) to combat multidrug resistant (MDR) colorectal cancer via multi-strategies. We first synthesized the mesoporous silica-coated gold nanorods (GNRs/mSiO 2), and loaded with antitumor drug doxorubicin (DOX) to realize a combination of chemo- and photothermal-therapy. To reverse DOX resistance, pH responsive poly-histidine (PHIS) was conjugated on GNRs/mSiO 2 to increase drug intracellular accumulation via efficient endo/lysosome escape; d -α-tocopherol polyethylene glycol 1000 succinate (TPGS) was then assembled on the surface of the particles to realize drug intracellular retention by inhibition P-glycoprotein. The results showed that the nanocomposite exhibited a highly efficient photothermal conversion in the NIR region, a pH and NIR triggered drug release profile and an increment of DOX intracellular accumulation and cytotoxicity on MDR SW620/Ad300 cells. Most importantly, the nanocomposite showed the most potent antitumor efficacy without obvious systemic toxicity comparing to other control groups with either chemo- or photothermal therapy alone on SW620/Ad300 tumor bearing mice. Altogether, the successful preparation of the nanocomposite and its potent efficacy might provide evidence for the future design and develop of nano-therapeutic system in the treatment of MDR colorectal cancer. Image 1 • The nanocomposite realized a combination of chemo- and photothermal-therapy for completely eradicating tumors. • The nanocomposite induces endo/lysosome escape and release P-gp inhibitor TPGS simultaneously. • The nanocomposite showed potent in vivo antitumor efficacy against drug resistant colon tumor. [ABSTRACT FROM AUTHOR]

Capacitive deionization (CDI) based on the principle of electrochemical double layers has emerged as a prospective water treatment technology to challenge the water scarcity. Herein, a novel integrated CDI electrode comprised of large-scale and vertically aligned Co(OH) 2 nanosheets on the GP matrix (Co(OH) 2 @GP) has been prepared successfully via a facile hydrothermal strategy for the first time. The texture analyses such as TEM, SEM, XPS, XRD and N 2 adsorption indicated that well-grown and interconnected Co(OH) 2 nanosheets on the GP matrix ensured the electrode a high specific surface area (207.62 m2/g) and superior open pore network. The electrochemical performance investigated by the CV, EIS and GC techniques revealed that the Co(OH) 2 @GP electrode combing the merits of Co(OH) 2 nanomaterial and GP efficiently obtained the amazing specific capacitance of 411.02 F/g, good electric conductivity and favourable cyclability. Moreover, the CDI behaviour of Co(OH) 2 @GP electrode evaluated by the batch mode experiments in the 300 mg/L of NaCl solution demonstrated an ultrahigh salt removal capacity of 48.21 mg/g and excellent regeneration ability. The highly simplified electrode processing, free binder and outstanding CDI performance render the Co(OH) 2 @GP electrode a promising candidate in the highly efficient CDI application. Unlabelled Image • Capacitive deionization (CDI) has emerged as a promising technology to challenge the water scarcity. • A novel integrated Co(OH) 2 @GP-based CDI electrode by the in situ growth strategy has been proposed. • The Co(OH) 2 @GP electrode achieved an ultrahigh salt removal capacity of 48.21 mg/g and excellent regeneration performance. • The salt removal capacity is much higher than the widely used graphene materials. [ABSTRACT FROM AUTHOR]

Introduction: Shortly after acute myocardial infarction, innate immure response is initiated to recruit leukocytes into the injured myocardium. Toll-like receptors (TLRs), which recognize the death associated patterns (DAMPs) are crucial components of the innate immune system. Hippo-YAP signaling pathway is required for cardiac repair, however, whether YAP regulates cardiac repair by orchestrating innate immune response is unknown. Hypothesis: Transient activation of YAP with modified RNA is sufficient to reduce cardiomyocyte necrosis and cardiac inflammation after ischemia reperfusion stress Methods: In this study, we transiently activated YAP with active YAP modified RNA (aYAP modRNA) in the myocardium in a mouse ischemia reperfusion model. In short term studies, hearts were collected for histology and inflammation analysis one or two days after IR. In long term studies, mouse heart function was measured at three different time points. At the end of the long term study, hearts were collected for scar size measurement and histology analysis. We used cultured cardiomyocytes (CM) to study the molecular mechanism of YAP regulation of innate immune. Results: Two days after IR, aYAP modRNA treated mice had more CM proliferation, less cardiomyocytes (CMs) necrosis, less neutrophils infiltration and lower serum troponin T level. One month after IR, Yap modRNA treated mice had better heart function, reduced scar size and hypertrophic remodeling. Whole genome scale gene expression analysis showed that TLR signaling pathway was regulated by YAP/TEAD1. Depletion of Yap in the mouse heart increased the expression of Tlr2 and Tlr4. YAP modRNA treatment reduced the expression of Tlr2 and Tlr4 in the myocardium. In vitro data showed that activation of YAP was sufficient to abolish TLR4 activation induced CM necrosis. Conclusions: Our findings show that aYAP modRNA is sufficient to boost cardiac repair by reducing CM necrosis and cardiac inflammatory response. Mechanically, YAP suppresses CM necrosis and cardiac inflammation by regulating the TLR4 signaling. [ABSTRACT FROM AUTHOR]