TIF1γ and SMAD4 regulation in colorectal cancer: impact on cell proliferation and liver metastasis.

We investigated the effects of transcriptional intermediary factor 1γ (TIF1γ) and SMAD4 on the proliferation and liver metastasis of colorectal cancer (CRC) cells through knockdown of TIF1γ and/or SMAD4 and knockdown of TIF1γ and/or restoration of SMAD4 expression. Furthermore, we examined TIF1γ and SMAD4 expression in human primary CRC and corresponding liver metastatic CRC specimens. TIF1γ promoted but SMAD4 inhibited the proliferation of CRC cells by competitively binding to activated SMAD2/SMAD3 complexes and then reversely regulating c-Myc, p21, p27, and cyclinA2 levels. Surprisingly, both TIF1γ and SMAD4 reduced the liver metastasis of all studied CRC cell lines via inhibition of MEK/ERK pathway-mediated COX-2, Nm23, uPA, and MMP9 expression. In patients with advanced CRC, reduced TIF1γ or SMAD4 expression was correlated with increased invasion and liver metastasis and was a significant, independent risk factor for recurrence and survival after radical resection. Patients with advanced CRC with reduced TIF1γ or SAMD4 expression had higher recurrence rates and shorter overall survival. TIF1γ and SMAD4 competitively exert contrasting effects on cell proliferation but act complementarily to suppress the liver metastasis of CRC via MEK/ERK pathway inhibition. Thus, reduced TIF1γ or SMAD4 expression in advanced CRC predicts earlier liver metastasis and poor prognosis.

Unraveling the rapid ion migration in perovskite solar cells by circuit-switched transient photoelectric technique.

Ion migration activated by illumination is a critical factor responsible for the performance decline and stability degradation of perovskite solar cells (PSCs). While ion migration has been widely believed to be much slower than charge transport, recent research suggests that, despite the lack of understanding of the mechanism, it may also be involved in a series of rapid photoelectric responses of PSCs. Here, we report an improved circuit-switched transient photoelectric technique with nanosecond temporal resolution, which enables quantitative characterization of ion migration dynamics in PSCs across a fairly broad time window. Specifically, ion migration occurring within microseconds after illumination (corresponding to a diffusion length of ∼10-7 cm) is unambiguously identified. In conjunction with the composition engineering protocol, we justify that it arises from the short-range migration of halide anions and organic cations around the contact/perovskite interface. The rapid ion migration kinetics revealed in this work strongly complement the well-established ion migration model, which offers new insights into the mechanism of ion-carrier interaction in PSC devices.

Sirtuin 6 Deacetylates Apoptosis-Associated Speck-Like Protein (ASC) to Inhibit Endothelial Cell Pyroptosis in Atherosclerosis.

Endothelial cell dysfunction is the main pathology of atherosclerosis (AS). Sirtuin 6 (SIRT6), a deacetylase, is involved in AS progression. This study aimed to investigate the impacts of SIRT6 on the pyroptosis of endothelial cells and its underlying mechanisms. ApoE-/- mice were fed a high-fat diet (HFD) to establish the AS mouse model, atherosclerotic lesions were evaluated using oil red O staining, and blood lipids and inflammatory factors were measured using corresponding kits. Human umbilical vein endothelial cells (HUVECs) were treated with oxidized low-density lipoprotein (ox-LDL) to establish the cell model, and pyroptosis was evaluated by flow cytometry, ELISA, and western blot. Immunoprecipitation (IP), co-IP, western blot, and immunofluorescence were used to detect the molecular mechanisms. The results showed that SIRT6 expression was downregulated in the blood of HFD-induced mice and ox-LDL-induced HUVECs. Overexpression of SIRT6 reduced atherosclerotic lesions, blood lipids, and inflammation in vivo and suppressed pyroptosis of HUVECs in vitro. Moreover, SIRT6 interacted with ASC to inhibit the acetylation of ASC, thus, reducing the interaction between ASC and NLRP3. Moreover, SIRT6 inhibits endothelial cell pyroptosis in the aortic roots of mice by deacetylating ASC. In conclusion, SIRT6 deacetylated ASC to inhibit its interaction with NLRP3 and then suppressed pyroptosis of endothelial cells, thus, decelerating the progression of AS. The findings provide new insights into the function of SIRT6 in AS.

MicroRNA-188-5p inhibits hepatocellular carcinoma proliferation and migration by targeting forkhead box N2.

BACKGROUND: This study aimed to identify the biological functions, expression modes, and possible mechanisms underlying the relationship between metastatic human hepatocellular carcinoma (HCC) and MicroRNA-188-5p (miR-188) dysregulation using cell lines. METHODS: A decrease in miR-188 was detected in low and high metastatic HCC cells compared to that in normal hepatic cells and non-invasive cell lines. Gain- and loss-of-function experiments were performed in vitro to investigate the role of miR-188 in cancer cell (Hep3B, HepG2, HLF, and LM3) proliferation and migration. RESULTS: miR-188 mimic transfection inhibited the proliferation of metastatic HLF and LM3 cells but not non-invasive HepG2 and Hep3B cells; nonetheless, miR-188 suppression promoted the growth of HLF and LM3 cells. miR-188 upregulation inhibited the migratory rate and invasive capacity of HLF and LM3, rather than HepG2 and Hep3B cells, whereas transfection of a miR-188 inhibitor in HLF and LM3 cells had the opposite effects. Dual-luciferase reporter assays and bioinformatics prediction confirmed that miR-188 could directly target forkhead box N2 (FOXN2) in HLF and LM3 cells. Transfection of miR-188 mimics reduced FOXN2 levels, whereas miR-188 inhibition resulted in the opposite result, in HLF and LM3 cells. Overexpression of FOXN2 in HLF and LM3 cells abrogated miR-188 mimic-induced downregulation of proliferation, migration, and invasion. In addition, we found that miR-188 upregulation impaired tumor growth in vivo. CONCLUSIONS: In summary, this study showed thatmiR-188 inhibits the proliferation and migration of metastatic HCC cells by targeting FOXN2.

Low-Temperature Preparation of High-Quality Perovskite Polycrystalline Films via Crystallization Kinetics Engineering.

Preparation of lead halide perovskite polycrystalline films at a low annealing temperature is highly restricted by their intrinsically large crystallization activation energy, which hinders the conversion of the precursors/intermediates to perovskites and yields as-prepared polycrystals with tiny grain sizes and terrible crystal quality. Herein, we demonstrate through in-situ, real-time spectroscopic studies that both the nucleation and crystal growth kinetics can be improved without the need for a high annealing temperature by treating the film with thiourea, as accounted for by the reduced activation energy. As a consequence, the thiourea-treated perovskite polycrystalline film exhibits larger grain sizes and greater crystallinity than the untreated one. More importantly, owing to the synergistic effect of the promoted crystallization kinetics and the passivation of surface defects, the low-temperature prepared films treated with thiourea even present more prominent photophysical properties than those fabricated by using the conventional high-temperature method. The strategy of crystallization kinetics engineering proposed in this work paves the way for fabricating high-quality perovskite polycrystalline films in a low-temperature manner.

Design, synthesis and neuraminidase inhibitory activity of 4-methyl-5-(3-phenylacryloyl) thiazoles.

A series of 4-methyl-5-(3-phenylacryloyl)thiazoles based on chalcones were designed, synthesized and evaluated for their influenza neuraminidase (NA) inhibitory activity in vitro. A preliminary structure-activity relationship (SAR) analysis showed that thiazoles bearing amide had greater potency. It also showed that mono-hydroxyl group at 4-position on phenyl ring was more effective than other electron-releasing groups or electron-withdraw groups. Compounds A2 and A26 were more potent against NA with IC50 values of 8.2 ± 0.5 µg/mL and 6.2 ± 1.4 µg/mL, respectively. Molecular docking study demonstrated that thiazoles skeleton was benefit for the NA inhibitory activity.

Mesoporous TiO2 layer suppresses ion accumulation in perovskite solar cells.

Ion accumulation in perovskite solar cells can be highly suppressed by a mesoporous TiO2 layer. This is evidenced by the decrease of the ion-related electrostatic potential with increasing the thickness of the mesoporous layer, accounted for by the electron population in the shallow trap states of the TiO2 nanocrystals.

A Novel Integrated Pharmacokinetic-Pharmacodynamic Model to Evaluate Combination Therapy and Determine In Vivo Synergism.

Understanding pharmacokinetic (PK)-pharmacodynamic (PD) relationships is essential in translational research. Existing PK-PD models for combination therapy lack consideration of quantitative contributions from individual drugs, whereas interaction factor is always assigned arbitrarily to one drug and overstretched for the determination of in vivo pharmacologic synergism. Herein, we report a novel generic PK-PD model for combination therapy by considering apparent contributions from individual drugs coadministered. Doxorubicin (Dox) and sorafenib (Sor) were used as model drugs whose PK data were obtained in mice and fit to two-compartment model. Xenograft tumor growth was biphasic in mice, and PD responses were described by three-compartment transit models. This PK-PD model revealed that Sor (contribution factor = 1.62) had much greater influence on overall tumor-growth inhibition than coadministered Dox (contribution factor = 0.644), which explains the mysterious clinical findings on remarkable benefits for patients with cancer when adding Sor to Dox treatment, whereas there were none when adding Dox to Sor therapy. Furthermore, the combination index method was integrated into this predictive PK-PD model for critical determination of in vivo pharmacologic synergism that cannot be correctly defined by the interaction factor in conventional models. In addition, this new PK-PD model was able to identify optimal dosage combination (e.g., doubling experimental Sor dose and reducing Dox dose by 50%) toward much greater degree of tumor-growth inhibition (>90%), which was consistent with stronger synergy (combination index = 0.298). These findings demonstrated the utilities of this new PK-PD model and reiterated the use of valid method for the assessment of in vivo synergism. SIGNIFICANCE STATEMENT: A novel pharmacokinetic (PK)-pharmacodynamic (PD) model was developed for the assessment of combination treatment by considering contributions from individual drugs, and combination index method was incorporated to critically define in vivo synergism. A greater contribution from sorafenib to tumor-growth inhibition than that of coadministered doxorubicin was identified, offering explanation for previously inexplicable clinical observations. This PK-PD model and strategy shall have broad applications to translational research on identifying optimal dosage combinations with stronger synergy toward improved therapeutic outcomes.

Influence of the MACl additive on grain boundaries, trap-state properties, and charge dynamics in perovskite solar cells.

Grain boundary trap passivation in perovskite films has become one of the most effective strategies for suppressing the charge recombination and enhancing the photovoltaic performance of perovskite solar cells, whereas the relevant trap-state properties and the charge carrier dynamics need to be further clarified. In this work, the CH3NH3Cl (MACl) additive is introduced into the MAI:PbI2 precursor solution to obtain perovskite films comprising various grain sizes with distinct grain boundaries and trap-state properties. The influence of grain boundary traps passivated with the MACl additive on trap-state properties and charge carrier transport/recombination dynamics is systematically studied with time-resolved spectroscopic and transient photoelectric characterization. Specifically, the MACl amount determines the content of the PbI2 residual in the final perovskite, leading to photoluminescence quenching induced by charge transfer. The trap-state distribution result reveals that the deep-level traps at the grain boundaries as the main sources of charge recombination centers are dramatically passivated. Low-temperature photoluminescence spectroscopy distinguishes and compares the trap-state emission related to different perovskite phases. Transient photoelectric measurements including photovoltage decay and charge extraction further demonstrate that the boundary trap passivation can effectively promote charge transport and inhibit charge recombination in devices treated with the optimized MACl amount. As a result, the corresponding device possesses superior photovoltaic parameters to the control device. This work proposes a systematic understanding of the grain boundary trap passivation strategy and provides a new insight into the development of high-performance perovskite solar cells.

Network-Based Driving Force of National Economic Development: A Social Capital Perspective.

Network science has been widely applied in theoretical and empirical studies of global value chain (GVC), and many related articles have emerged, forming many more mature and complete analytical frameworks. Among them, the GVC accounting method based on complex network theory is different from the mainstream economics in both research angle and content. In this paper, we build up global industrial value chain network (GIVCN) models based on World Input-Output Database, introduce the theoretical framework of Social Capital, and define the network-based indicators with economic meanings. Second, we follow the econometric framework to analyze the hypothesis and test whether it is true. Finally, we study how the three types of capital constituted by these indicators interact with each other, and discuss their impact on the social capital (economic development level, i.e., GDP). The results prove that the structural capital (industrial status) has a positive impact on the social capital; the relational capital (industrial correlation) has a positive impact on both social capital and structural capital; the cognitive capital (industrial structure) has a small impact on the social capital, structural capital, and relational capital.

Auxin acts as a downstream signaling molecule involved in hydrogen sulfide-induced chilling tolerance in cucumber.

MAIN CONCLUSION: This report proves a cross talk between H2S and IAA in cold stress response, which has presented strong evidence that IAA acts as a downstream signal mediating the H2S-induced stress tolerance in cucumber seedlings. We evaluated changes in endogenous hydrogen sulfide (H2S) and indole-3-acetic acid (IAA) emission systems, and the interactive effect of exogenous H2S and IAA on chilling tolerance in cucumber seedlings. The results showed that chilling stress increased the activity and relative mRNA expression of L-/D-cysteine desulfhydrase (L-/D-CD), which in turn induced the accumulation of endogenous H2S. Similarly, the endogenous IAA system was triggered by chilling stress. We found that 1.0 mM sodium hydrosulfide (NaHS, an H2S donor) significantly enhanced the activity of flavin monooxygenase (FMO) and relative expression of FMO-like proteins (YUCCA2), which in turn elevated endogenous IAA levels in cucumber seedlings. However, IAA had little effects on activities of L-/D-CD and endogenous H2S levels. H2S-induced IAA production accompanied by increase in chilling tolerance, as shown by the decrease in stress-induced electrolyte leakage (EL) and reactive oxygen species (ROS) accumulation, and increase in gene expressions and enzyme activities of photosynthesis. 1-naphthylphthalamic acid (NPA, an IAA polar transport inhibitor) declined H2S-induced chilling tolerance and defense genes' expression. However, scavenging of H2S had a little effect on IAA-induced chilling tolerance. These results suggest that IAA acting as a downstream signaling molecule is involved in the H2S-induced chilling tolerance in cucumber seedlings.

Large mechanical squeezing beyond 3dB of hybrid atom-optomechanical systems in a highly unresolved sideband regime.

We propose a scheme for the generation of strong mechanical squeezing beyond 3dB in hybrid atom-optomechanical systems in the highly unresolved sideband (HURSB) regime where the decay rate of cavity is much larger than the frequency of the mechanical oscillator. The system is formed by two two-level atomic ensembles and an optomechanical system with cavity driven by two lasers with different amplitudes. In the HURSB regime, the squeezing of the movable mirror can not be larger than 3dB if no atomic ensemble or only one atomic ensemble is put into the optomechanical system. However, if two atomic ensembles are put into the optomechanical system, the strong mechanical squeezing beyond 3dB is achieved even in the HURSB regime. Our scheme paves the way toward the implementation of strong mechanical squeezing beyond 3dB in hybrid atom-optomechanical systems in experiments.

Large and robust mechanical squeezing of optomechanical systems in a highly unresolved sideband regime via Duffing nonlinearity and intracavity squeezed light.

We propose a scheme to generate strong and robust mechanical squeezing in an optomechanical system in the highly unresolved sideband (HURSB) regime with the help of the Duffing nonlinearity and intracavity squeezed light. The system is formed by a standard optomechanical system with the Duffing nonlinearity (mechanical nonlinearity) and a second-order nonlinear medium (optical nonlinearity). In the resolved sideband regime, the second-order nonlinear medium may play a destructive role in the generation of mechanical squeezing. However, it can significantly increase the mechanical squeezing (larger than 3dB) in the HURSB regime when the parameters are chosen appropriately. Finally, we show the mechanical squeezing is robust against the thermal fluctuations of the mechanical resonator. The generation of large and robust mechanical squeezing in the HURSB regime is a combined effect of the mechanical and optical nonlinearities.

Identification of free fatty acid receptor 2 agonists using virtual screening.

Structure- and ligand-based virtual-screening methods (docking, 2D- and 3D-similarity searching) were analyzed for their effectiveness in virtual screening against FFAR2. To evaluate the performance of these methods, retrospective virtual screening was performed. Statistical quality of the methods was evaluated by BEDROC and RIE. The results revealed that electrostatic similarity search protocol using EON (ET combo) outperformed all other protocols with outstanding enrichment of >95% in top 1% and 2% of the dataset with an AUC of 0.958. Interestingly, the hit lists that are obtained from different virtual-screening methods are generally highly complementary to hits found from electrostatic similarity searching. These results suggest that considering electrostatic similarity searching first increases the chance of identifying more (and more diverse) active compounds from a virtual-screening campaign. Accordingly, prospective virtual screening using electrostatic similarity searching was used to identify novel FFAR2 ligands. The discovered compounds provide new chemical matter starting points for the initiation of a medicinal chemistry campaign.

Bioassay of ferulic acid derivatives as influenza neuraminidase inhibitors.

Four series of ferulic acid derivatives were designed, synthesized, and evaluated for their neuraminidase (NA) inhibitory activities against influenza virus H1N1 in vitro. The pharmacological results showed that the majority of the target compounds exhibited moderate influenza NA inhibitory activity, which was also better than that of ferulic acid. The two most potent compounds were 1m and 4a with IC50 values of 12.77 ± 0.47 and 12.96 ± 1.34 µg/ml, respectively. On the basis of the biological results, a preliminary structure-activity relationship (SAR) was derived and discussed. Besides, molecular docking was performed to study the possible interactions of compounds 1p, 2d, 3b, and 4a with the active site of NA. It was found that the 4-OH-3-OMe group and the amide group (CON) of ferulic acid amide derivatives were two key pharmacophores for NA inhibitory activity. It is meaningful to further modify the natural product ferulic acid to improve its influenza NA inhibitory activity.

Charge carrier recombination dynamics in a bi-cationic perovskite solar cell.

The compositional engineering is of great importance to tune the electrical and optical properties of perovskite and improve the photovoltaic performance of perovskite solar cells. The exploration of the corresponding photoelectric conversion processes, especially the carrier recombination dynamics, will contribute to the optimization of the devices. In this work, perovskite with mixed methylammonium (MA) and formamidinium (FA) as organic cations, MA0.4FA0.6PbI3, is fabricated to study the influence of the bi-cation on the charge carrier recombination dynamics. X-ray diffraction analysis indicates the existence of the MAPbI3-FAPbI3 phase segregation in the bi-cationic perovskite crystal. The time-resolved photoluminescence dynamics presents a relatively fast carrier recombination process ascribed to the charge transfer from MAPbI3 to FAPbI3 in the bi-cationic perovskite film. The carrier recombination dynamics investigated by transient photovoltage measurements reveals a biphasic trap-assisted carrier recombination mechanism in the bi-cationic device, which involves carrier recombination in the MAPbI3 phase and FAPbI3 phase, respectively. The ultimate presentation of the carrier recombination process is closely related to the charge transfer between the two perovskite phases.

Design, synthesis and biological evaluation of honokiol derivatives as influenza neuraminidase inhibitors.

Honokiol, a natural polyphenol, which was reported to have satisfactory influenza neuraminidase (NA) inhibitory activity, was structurally modified. Twenty-three compounds were synthesized and the ortho-effects in the epoxidation and hydrolyzation reactions were studied. The derivatives were evaluated for NA inhibitory activity and the benzoylhydrazone derivatives showed much better anti-NA activity than honokiol. Structure-activity relationship analysis suggested that the polyphenols exhibited better anti-NA activity than monophenols and biphenols. Furthermore, probable binding mode of drug with target revealed that the most active compound had much stronger interactions with the active site of NA than honokiol suggesting the potent anti-influenza virus activity.

Integrity of Membrane Structures in Giant Unilamellar Vesicles as Assay for Antioxidants and Prooxidants.

We have attempted to evaluate, on the basis of optical microscopy for a single giant unilamellar vesicle (GUV), the potency of antioxidants in protecting GUV membranes from oxidative destruction. Photosensitized membrane budding of GUVs prepared from soybean phosphatidylcholine with chlorophyll a (Chl a) and ß-carotene (ß-Car) as photosensitizer and protector, respectively, were followed by microscopic imaging. A dimensionless entropy parameter, ΔE, as derived from the time-resolved microscopic images, was employed to describe the evolution of morphological variation of GUVs. As an indication of membrane instability, the budding process showed three successive temporal regimes as a common feature: a lag phase prior to the initiation of budding characterized by LP (in s), a budding phase when ΔE increased with a rate of kΔE (in s-1), and an ending phase with morphology stabilized at a constant ΔEend (dimensionless). We show that the phase-associated parameters can be objectively obtained by fitting the ΔE-t kinetics curves to a Boltzmann function and that all of the parameters are rather sensitive to ß-Car concentration. As for the efficacy of these parameters in quantifying the protection potency of ß-Car, kΔE is shown to be most sensitive for ß-Car in a concentration regime of biological significance of <1 × 10-7 M, whereas LP and ΔEend are more sensitive for ß-Car concentrations exceeding 1 × 10-7 M. Furthermore, based on the results of GUV imaging and fluorescence and Raman spectroscopies, we have revealed for different phases the mechanistic interplay among 1O2* diffusion, PC-OOH accumulation, Chl a and/or ß-Car consumption, and the morphological variation. The developed assay should be valuable for characterizing the potency of antioxidants or prooxidants in the protection or destruction of the membrane integrity of GUVs.

Bioengineered NRF2-siRNA Is Effective to Interfere with NRF2 Pathways and Improve Chemosensitivity of Human Cancer Cells.

The nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a transcription factor in the regulation of many oxidative enzymes and efflux transporters critical for oxidative stress and cellular defense against xenobiotics. NRF2 is dysregulated in patient osteosarcoma (OS) tissues and correlates with therapeutic outcomes. Nevertheless, research on the NRF2 regulatory pathways and its potential as a therapeutic target is limited to the use of synthetic small interfering RNA (siRNA) carrying extensive artificial modifications. Herein, we report successful high-level expression of recombinant siRNA against NRF2 in Escherichia coli using our newly established noncoding RNA bioengineering technology, which was purified to >99% homogeneity using an anion-exchange fast protein liquid chromatography method. Bioengineered NRF2-siRNA was able to significantly knock down NRF2 mRNA and protein levels in human OS 143B and MG63 cells, and subsequently suppressed the expression of NRF2-regulated oxidative enzymes [heme oxygenase-1 and NAD(P)H:quinone oxidoreductase 1] and elevated intracellular levels of reactive oxygen species. In addition, recombinant NRF2-siRNA was effective to sensitize both 143B and MG63 cells to doxorubicin, cisplatin, and sorafenib, which was associated with significant downregulation of NRF2-targeted ATP-binding cassette (ABC) efflux transporters (ABCC3, ABCC4, and ABCG2). These findings support that targeting NRF2 signaling pathways may improve the sensitivity of cancer cells to chemotherapy, and bioengineered siRNA molecules should be added to current tools for related research.

Energy transfer mechanism dominated by the doping location of activators in rare-earth upconversion nanoparticles.

Research on the energy transfer mechanism of rare-earth-doped upconversion nanoparticles (UCNPs) has been an important area due to the increasing demand for tuning multicolor emission and enhancing the upconversion efficiency; however, because of large energy mismatch, many lanthanide activators, such as Eu3+, cannot realize highly efficient near infrared-to-visible upconversion by simple codoping of Yb3+. Therefore, introduction of other ions to assist the energy transfer process is required. Herein, we prepared core-shell nanoparticles with different doping locations to investigate the upconversion energy transfer mechanism. The upconversion luminescence (UCL) of core-shell nanoparticles was investigated by steady-state luminescence and time-resolved luminescence spectra. The UCL behaviors in these different multi-activator core-shell nanoparticles were observed. The results revealed different energy transfer channels influenced by the doping location of activators. This study may open up new avenues of structure design for fine-tuning of multicolor UCL for specific applications.