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.

Electric dipole polarizabilities and tune-out wavelengths for 23S1 and 33S1 states of Be2.

The electric dipole polarizabilities and the tune-out wavelengths for the n3S1 (n = 2, 3) states of Be2+ are determined through the application of the relativistic full-configuration-interaction approach. Our calculations directly integrate the mass shift operator into the Dirac-Coulomb-Breit Hamiltonian and further assess the quantum electrodynamics (QED) correction to the dynamic dipole polarizabilities using perturbation theory. The results reveal that the static electric dipole polarizability of the 23S1 and 33S1 states, as well as the 93 nm tune-out wavelength of the 23S1 state and the 238 nm tune-out wavelength of the 33S1 state, exhibits a high sensitivity to QED correction, which exceeds 80 ppm, providing a sensitive test for atomic structure theory.

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.