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Strong CO adsorption and facile CO dimerization are the key challenges in electrochemical CO 2 reduction towards multi-carbon (C 2+) products. We recently showed that CoPc immobilized on a single-walled carbon nanotube can selectively reduce CO 2 to methanol. This is enabled through molecular strain, which dramatically improves the CO adsorption energy to CoPc, which in turn facilitates methanol formation. We now examine the extended Phthalocyanine (Pc Ex) dual atom catalyst (DAC), which is intrinsically strained and contains two catalyst centers, making it a candidate for reducing CO to C 2+ products. Using Quantum Mechanics (QM), we screened 20 elements embedded in the Pc Ex , seeking catalysts with weak hydrogen binding, strong CO binding, and facile CO dimerization. We identified Fe, Ru, Co, and Ir as the best performers and subsequently evaluated the entire CO to C 2 H 4 mechanism (9 steps) using each of these elements as catalysts. In terms of limiting potential and overall exergonicity, we identified CoPc Ex as the best catalyst, followed by IrPc Ex. We then examined the full CO to C 2 H 4 mechanism on the bimetallic IrCoPc Ex catalyst using grand canonical QM to obtain the reaction energetics as a function of applied potential. We conclude that the bimetallic IrCoPc Ex is most promising for efficiently converting CO to ethylene. [Display omitted] • High throughput screening with quantum mechanics to predict dual atom catalysts for converting CO to ethylene. • Explored how varying catalyst identity in an extended phthalocyanine platform affects the CO to ethylene reaction mechanism. • The bimetallic Ir-Co catalyst is predicted to convert CO to ethylene most efficiently. [ABSTRACT FROM AUTHOR]

Highlights • An uncertain model is presented for the random vibration of a subsea pipeline. • The spatial variation of ground motions is considered. • The unilateral contact relationship between the pipeline and seabed is considered. • Propagations of the randomness and modelling uncertainties are investigated. Abstract Based on a nonparametric modelling approach, this paper presents a random vibration analysis of a subsea pipeline subjected to spatially varying ground motions. The earthquake-induced ground motions are modelled as nonstationary random processes and their spatial variations are considered. The modelling uncertainties of the subsea pipeline are taken into account using a random matrix theory, while the unilateral contact relationship between the pipeline and seabed is also considered. Thus, an uncertain computational model for the subsea pipeline subjected to a random earthquake is established, and the corresponding solutions are calculated using Monte Carlo simulation (MCS). In order to highlight the contribution of the unilateral contact effect to random responses of pipelines, comparative studies are performed between the unilateral and permanent contact models. In numerical examples, the possible convergence problems in the present computational model are firstly studied to determine the optimal numbers of reduced modes and MCS samples. Then influences of the randomness in the earthquake and modelling uncertainties in the pipeline are investigated qualitatively through three representative cases. The different propagations of randomness and modelling uncertainties in the unilateral and permanent models are also examined and discussed. It is concluded that the randomness of the earthquake and modelling uncertainties of the pipeline have significant influences on the statistical characteristics of earthquake responses of the pipeline. [ABSTRACT FROM AUTHOR]

In this paper, a frequency domain method is proposed for the nonstationary seismic analysis of long-span structures subjected to random ground motions considering the wave passage effect. Based on the correlation analysis theory and fast Fourier transform (FFT), a semi-analytical solution is derived for the evolutionary power spectral density of the random response of long-span structures in the frequency domain. The expression of this solution indicates that the evolutionary property of nonstationary random responses can be determined completely by the modulation function of random ground motions, and hence the solution has clear physical interpretations. For slowly varying modulation functions, the FFT can be implemented with a small sampling frequency, so the present method is very efficient within a given accuracy. In numerical examples, nonstationary random responses of a long-span cable stayed bridge to random ground motions with the wave passage effect are studied by the present method, and comparisons are made with those of the pseudo excitation method (PEM) to verify the present method. Then the accuracy and efficiency of the present method with different sampling frequencies are compared and discussed. Finally, the influences of the apparent velocity of the seismic waves on nonstationary random responses are investigated. [ABSTRACT FROM AUTHOR]

A computational framework is presented to calculate the reliability of subsea pipelines subjected to a random earthquake. This framework takes full account of the physical features of pipelines and the earthquake, and also retains high computing precision and efficiency. The pipeline and the seabed are modelled as a Timoshenko beam and a Winkler foundation, respectively, while the unilateral contact effect between them is considered. The random earthquake is described by its power spectrum density function and its spatial variation is considered. After suitable discretizations in the spatial domain by the finite element method and the time domain by the Newmark integration method, the dynamic unilateral contact problem is derived as a linear complementarity problem (LCP). Subset Simulation (SS), which is an advanced Monte Carlo simulation approach, is used to estimate the reliability of pipelines. By means of numerical examples, the accuracy and robustness of SS are demonstrated by comparing with the direct Monte Carlo simulation (DMCS). Then a sensitivity analysis of the reliability and a failure analysis are performed to identify the influential system parameters. Finally, failure probabilities of subsea pipelines are assessed for three typical cases, namely, with and without the unilateral contact effect, with different grades of spatial variations and with different free spans. The influences of these effects or parameters on the reliability are discussed qualitatively. [ABSTRACT FROM AUTHOR]

Telomerase is aberrantly expressed in many cancers and plays an important role in the development of cellular immortality and oncogenesis, which makes it a potential cancer therapeutic target for drug discovery. Here, we constructed a firefly luciferase reporter driven by the human telomerase reverse trancriptase ( hTERT ) gene promoter to screen for inhibitory compounds. Compound 5c was discovered and shown to significantly inhibit the promoter activity of hTERT gene. Furthermore, five analogs of compound 5c were synthesized, and compound 8b was shown to be a more potent inhibitor of hTERT gene promoter activity and subsequent expression of hTERT mRNA and protein. The viability of HeLa cells was inhibited by a knockdown of hTERT gene expression, and the same effect was also observed by treating with compound 8b . Moreover, our results indicated that compound 8b induced apoptosis of HeLa cells, and activated caspase-9 and caspase-3 enzymes. Taken together, these results suggested that compound 8b down-regulates the expression of hTERT and induces mitochondrial-dependent apoptosis. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract The transcription factor forkhead box O 3A (FOXO3A) is a tumor suppressor that promotes cell cycle arrest and apoptosis. Piperlongumine (PL), a plant alkaloid, is known to selectively kill tumor cells while sparing normal cells. However, the mechanism of PL-induced cancer cell death is not fully understood. We report here that an association of FOXO3A with the pro-apoptotic protein BIM (also known as BCL2-like 11, BCL2L11) has a direct and specific function in PL-induced cancer cell death. Using HeLa cells stably expressing a FOXO3A-GFP fusion protein and several other cancer cell lines, we found that PL treatment induces FOXO3A dephosphorylation and nuclear translocation and promotes its binding to the BIM gene promoter, resulting in the up-regulation of BIM in the cancer cell lines. Accordingly, PL inhibited cell viability and caused intrinsic apoptosis in a FOXO3A-dependent manner. Of note, siRNA-mediated FOXO3A knockdown rescued the cells from PL-induced cell death. In vivo, the PL treatment markedly inhibited xenograft tumor growth, and this inhibition was accompanied by the activation of the FOXO3A-BIM axis. Moreover, PL promoted FOXO3A dephosphorylation by inhibiting phosphorylation and activation of Akt, a kinase that phosphorylates FOXO3A. In summary, our findings indicate that PL activates the FOXO3A-BIM apoptotic axis by promoting dephosphorylation and nuclear translocation of FOXO3A via Akt signaling inhibition. These findings uncover a critical mechanism underlying the effects of PL on cancer cells. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract The autophagy-lysosome pathway plays a central role in cellular homeostasis by regulating the cellular degradative machinery. The transcription factor EB (TFEB) regulates the biogenesis and function of both lysosomes and autophagosomes, and enhancement of TFEB function has emerged as an attractive therapeutic strategy for lysosome-related disorders. However, little is known about the role of TFEB activation in regulating the cellular fate. Here, we describe that clomiphene citrate (CC), a selective estrogen receptor modulator, promotes nuclear translocation of TFEB and increases lysosomal biogenesis in HeLa and MDA-MB-231 cells. Treatment with CC inhibits cell viability and causes apoptosis by increasing the release of proteases cathepsin B (CatB) and cathepsin D (CatD) from lysosomes into the cytosol. In contrast, knockdown of TFEB rescues the cells from CC-induced cell death. Furthermore, CC-induced TFEB activation also enhances the autophagy flux in HeLa cells. Knockdown of autophagy-related gene 7 (ATG7) significantly decreases the CC-induced CatB and CatD release and cell death, suggesting that autophagy contributes to the lysosomal membrane permeabilization (LMP) caused by CC. Altogether, these findings have broad implications for our understanding of TFEB function and provide new insights into CC pharmacological therapy. [ABSTRACT FROM AUTHOR]

Abstract The design of sub-wavelength structure with full-spectrum near-unity solar absorption is a long-sought-after goal of crucial importance for optoelectronic materials and technology. To date, numerous attempts to tackle this problem consisted either of using stronger absorption-but narrowband or the broader spectrum-but moderate light trapping mechanisms. Herein, a novel strategy that achieves perfect absorption for solar energy in the full-spectrum range of the sun's radiance is presented by the thin-film refractory metal resonators. This impressive absorption mainly stems from the cooperative effect of strong plasmonic resonances and the intrinsic broadband spectral responses by the refractory metals, such as Ti, V, W, etc. The full-spectrum weighted solar absorption efficiency is exceeding 98%, showing a near-unity light trapping for the sun's radiation. Moreover, excellent thermal emitting with the spectral averaged efficiency ~ 91% is achieved in the wavelength range (280–4000 nm) by the W-based absorber, suggesting a platform for near-perfect blackbody emitting source. More importantly, the investigations on achieving full-spectrum solar absorbers and thermal emitters provide new insight on the mechanism and philosophy for the design. Just like the proverb, in order to catch bandits, the first thing is to catch the ringleader. As for the purpose of achieving full-spectrum near-unity absorbers or radiators, the key point is to perfectly trap or excite the solar/thermal power in the main distribution ranges for the sunlight or the blackbody radiation. Accordingly, these attractive properties and findings suggest that the investigation and the related full-spectrum solar absorbers and blackbody radiator might have promising applications in the fields related to energy harvesting and conversion. Graphical abstract fx1 Highlights • A feasible way is demonstrated for achieving full-spectrum thin-film solar absorbers. • The averaged solar absorption efficiency η A is > 98% for the sunlight (280–4000 nm). • Near-perfect thermal emitter with similar properties to the ideal blackbody radiator is demonstrated. • The key important factor for designing near-unity full-spectrum absorber/ emitter is obtained. [ABSTRACT FROM AUTHOR]

Abstract Experiments have been undertaken and for the first time, we have identified that a new cardiac glycoside (CG) isolated from Helleborus thibetanus Franch. a plant endemic to China, bears potent anti-cancer activity. We have named it as HTF-1. By using in vitro cell models, we have found that HTF-1 induces apoptosis against several types of cancer cells in a concentration- and time-dependent manner. It is able to inhibit cancer cell in proliferation, migration and invasion. HTF-1 causes S cell cycle arrest. Further-on, we have identified that HTF-1 triggers caspase-9 dependent apoptosis pathway and double strand DNA breaks (DSBs). Additionally, HTF-1 activates JNK, but suppresses ERK and PI3K-Akt-mTOR pathways. Collectively, the above-mentioned mechanisms contribute to the anti-cancer activity of HTF-1. It is rare to discover novel anti-cancer CG during the past couple of decades. We believe that our work will enrich the understanding of CGs; also, pave the way for natural product-based anti-cancer drug development. Graphical abstract Image 1 Highlights • HTF-1, a newly isolated cardiac glycoside from Helleborus thibetanus Franch., bears potent in vitro anti-cancer activity. • HTF-1 inhibits cancer cell in proliferation, migration and invasion; additionally, it causes S cell cycle arrest. • HTF-1 triggers caspase-9 dependent apoptosis pathway and double strand DNA breaks. • Mechanistically, HTF-1 activates JNK, but suppresses ERK and PI3K-Akt-mTOR pathways. [ABSTRACT FROM AUTHOR]

Autophagy is emerging as a critical response of normal and cancer cells to environmental changes and plays an important role in cell metabolism and maintenance of damaged organelles. Transmembrane prostate androgen-induced protein (TMEPAI) is a pro-tumorigenic factor with high expression in tumor cells. In this study, we showed that depletion of TMEPAI leads to lysosomal labilization and inhibits autophagy. Further study showed that the inhibition of autophagy induced by the depletion of TMEPAI is involved in regulation of Beclin-1. Depletion of TMEPAI increases the sensitivity of cancer cells to chemotherapeutic drugs. Our study reveals the role of TMEPAI in promoting lysosome stability and autophagy, which might be used as a target for cancer chemotherapeutic treatment. [ABSTRACT FROM AUTHOR]