Synthesis and biological evaluation of C-4 substituted phenoxazine-bearing hydroxamic acids with potent class II histone deacetylase inhibitory activities.

Class II histone deacetylases (HDACs) are considered as potential targets to treat Alzheimer's disease (AD). Previously, C-3 substituted phenothiazine-containing compounds with class II HDAC-inhibiting activities was found to promote neurite outgrowth. This study replaced phenothiazine moiety with phenoxazine that contains many C-3 and C-4 substituents. Some resulting compounds bearing the C-4 substituent on a phenoxazine ring displayed potent class II HDAC inhibitory activities. Structure-activity relationship (SAR) of these compounds that inhibited HDAC isoenzymes was disclosed. Molecular modelling analysis demonstrates that the potent activities of C-4 substituted compounds probably arise from π-π stacked interactions between these compounds and class IIa HDAC enzymes. One of these, compound 7d exhibited the most potent class II HDAC inhibition (IC50= 3-870 nM). Notably, it protected neuron cells from H2O2-induced neuron damage at sub-µM concentrations, but with no significant cytotoxicity. These findings show that compound 7d is a lead compound for further development of anti-neurodegenerative agents.

Suppression and Revival of Superconducting Phase Coherence in Monolayer FeSe/SrTiO3.

Monolayer FeSe grown on SrTiO3 (FeSe/STO) is an interfacial high-temperature superconductor distinctively different from bulk FeSe. However, the superconducting phase coherence of the interface is challenging to probe due to its fragility in the atmosphere. Here, we perform in situ mutual inductance under ultrahigh vacuum on FeSe/STO in combination with band mapping by angle-resolved photoemission spectroscopy. We find that even though the monolayer shows a gap-closing temperature above 50 K, no diamagnetism is visible down to 5 K. This is the case for few-layer FeSe/STO until it exceeds a critical number of five layers, where diamagnetism suddenly appears. The suppression of diamagnetism in the monolayer is also lifted by depositing a top FeTe layer. However, Tc and superfluid density both decrease with thicker FeTe, suggesting unconventional electron pairing and phase coherence competition. Our observation may be understood by a scenario in which the interfacial superconducting phase coherence is highly anisotropic.

Spatially homogeneous few-cycle compression of Yb lasers via all-solid-state free-space soliton management.

The high power and variable repetition-rate of Yb femtosecond lasers makes them very attractive for ultrafast science. However, for capturing sub-200 fs dynamics, efficient, high-fidelity and high-stability pulse compression techniques are essential. Spectral broadening using an all-solid-state free-space geometry is particularly attractive, as it is simple, robust and low-cost. However, spatial and temporal losses caused by spatio-spectral inhomogeneities have been a major challenge to date, due to coupled space-time dynamics associated with unguided nonlinear propagation. In this work, we use all-solid-state free-space compressors to demonstrate compression of 170 fs pulses at a wavelength of 1030nm from a Yb:KGW laser to ∼9.2 fs, with a highly spatially homogeneous mode. This is achieved by ensuring that the nonlinear beam propagation in periodic layered Kerr media occurs in spatial soliton modes, and by confining the nonlinear phase through each material layer to less than 1.0 rad. A remarkable spatio-spectral homogeneity of ∼0.87 can be realized, which yields a high efficiency of >50% for few-cycle compression. The universality of the method is demonstrated by implementing high-quality pulse compression under a wide range of laser conditions. The high spatiotemporal quality and the exceptional stability of the compressed pulses are further verified by high-harmonic generation. Our predictive method offers a compact and cost-effective solution for high-quality few-cycle-pulse generation from Yb femtosecond lasers, and will enable broad applications in ultrafast science and extreme nonlinear optics.

[Baicalein enhances the gap junction in the TM4 Sertoli cells of mice].

OBJECTIVE: To investigate the effect of baicalein on the gap junction intercellular communication (GJIC) in the TM4 Sertoli cells of the mouse testis and its related mechanism. METHODS: We measured the cytotoxicity of different concentrations of baicalein on the TM4 Sertoli cells in the mouse testis by MTT, detected the fluorescence transfer of the TM4 Sertoli cells by parachute assay, and determined the expression of the protein connexin 43 ( Cx43) in the baicalein-treated cells by Western blot and immunofluorescence assay. RESULTS: Baicalein produced no obvious cytotoxicity on the TM4 Sertoli cells at the concentration below 60 µmol/L but significantly increased their GJIC at 0-20 µmol/L (P < 0.01). Western blot and immunofluorescence assay showed that 0-20 µmol/L baicalein remarkably elevated the expression of Cx43 in the TM4 cells (P < 0.01) and on the membrane of the TM4 cells. CONCLUSION: Baicalein at the concentration of 0-20 µmol/L can significantly enhance GJIC in mouse TM4 Sertoli cells by increasing the expression of the Cx43 protein.

Antibiotic heliomycin and its water-soluble 4-aminomethylated derivative provoke cell death in T24 bladder cancer cells by targeting sirtuin 1 (SIRT1).

Bladder cancer is one of the most frequent cancers among males, and a poor survival rate reflects problems with aggressiveness and chemo-resistance. Accumulating evidence indicates that SIRT1 is involved in bladder cancer tumorigenesis and is positively associated with chemo-resistance and poor prognosis. We recently synthesized water-soluble chemical derivatives of heliomycin, an antibiotic from Streptomyces resistomycificus, and demonstrated that they possess anticancer properties. In this present study, we used the cellular thermal shift assay (CETSA) in T24 bladder cancer cells to show that heliomycin (designated compound (H1)) and its 4-(tert-butylamino)methyl derivative (HD2) directly engaged with SIRT1 in the native cellular environment, whereas another derivative (HD3) did not. Upon binding, heliomycin downregulated SIRT1 protein expression without altering its transcript level, and subsequently induced autophagy. Interestingly, the derivative (HD2) triggered apoptosis. The interaction between SIRT1 protein and heliomycin or its derivatives was also speculated by a molecular docking simulation, suggesting heliomycin (H1) and derivative (HD2) acting with the different binding modes to SIRT1. Given the increased water-solubility, hydrogen bonds were found on Ala262 and Ile347 residues in the docked complex of derivative (HD2) to produce more steady interaction and initiate signaling pathways that were not observed in the case of heliomycin. Meanwhile, it is evident that derivative (HD3) did not engage with SIRT1 by CETSA or molecular docking studies, nor did it downregulate SIRT1 expression. Taken together, these findings clearly show that SIRT1 is targeted and downregulated by heliomycin and its water-soluble 4-aminomethylated derivative (HD2) possibly through autophagic and/or proteasomal degradation, leading to cell death and growth suppression of T24 bladder cancer cells.

Bis(chloroacetamidino)-Derived Heteroarene-Fused Anthraquinones Bind to and Cause Proteasomal Degradation of tNOX, Leading to c-Flip Downregulation and Apoptosis in Oral Cancer Cells.

Anthraquinone-based intercalating compounds, namely doxorubicin and mitoxantrone, have been used clinically based on their capacity to bind DNA and induce DNA damage. However, their applications have been limited by side effects and drug resistance. New-generation anthraquinone derivatives fused with different heterocycles have been chemically synthesized and screened for higher anticancer potency. Among the compounds reported in our previous study, 4,11-bis(2-(2-chloroacetamidine)ethylamino)anthra[2,3-b]thiophene-5,10-dione dihydrochloride (designated 2c) was found to be apoptotic, but the direct cellular target responsible for the cytotoxicity remained unknown. Here, we report the synthesis and anticancer properties of two other derivatives, 4,11-bis(2-(2-chloroacetamidine)ethylamino)naphtho[2,3-f]indole-5,10-dione dihydrochloride (2a) and 4,11-bis(2-(2-chloroacetamidine)ethylamino)-2-methylanthra[2,3-b]furan-5,10-dione dihydrochloride (2b). We sought to identify and validate the protein target(s) of these derivatives in oral cancer cells, using molecular docking simulations and cellular thermal shift assays (CETSA). Our CETSA results illustrate that these derivatives targeted the tumor-associated NADH oxidase (tNOX, ENOX2), and their direct binding downregulated tNOX in p53-functional SAS and p53-mutated HSC-3 cells. Interestingly, the compounds targeted and downregulated tNOX to reduce SIRT1 deacetylase activity and increase Ku70 acetylation, which triggers c-Flip ubiquitination and induces apoptosis in oral cancer cells. Together, our data highlight the potential value of these heteroarene-fused anthraquinones in managing cancer by targeting tNOX and augmenting apoptosis.

Oxygen Adsorption Induced Superconductivity in Ultrathin FeTe Film on SrTiO3(001).

The phenomenon of oxygen incorporation-induced superconductivity in iron telluride (Fe1+yTe, with antiferromagnetic (AFM) orders) is intriguing and quite different from the case of FeSe. Until now, the microscopic origin of the induced superconductivity and the role of oxygen are far from clear. Here, by combining in situ scanning tunneling microscopy/spectroscopy (STM/STS) and X-ray photoemission spectroscopy (XPS) on oxygenated FeTe, we found physically adsorbed O2 molecules crystallized into c (2/3 × 2) structure as an oxygen overlayer at low temperature, which was vital for superconductivity. The O2 overlayer were not epitaxial on the FeTe lattice, which implied weak O2 -FeTe interaction but strong molecular interactions. The energy shift observed in the STS and XPS measurements indicated a hole doping effect from the O2 overlayer to the FeTe layer, leading to a superconducting gap of 4.5 meV opened across the Fermi level. Our direct microscopic probe clarified the role of oxygen on FeTe and emphasized the importance of charge transfer effect to induce superconductivity in iron-chalcogenide thin films.

High temperature superconductivity at FeSe/LaFeO3 interface.

Enormous enhancement of superconducting pairing temperature (Tg) to 65 K in FeSe/SrTiO3 has made it a spotlight. Despite the effort of interfacial engineering, FeSe interfaced with TiOx remains the unique case in hosting high Tg, hindering a decisive understanding on the general mechanism and ways to further improving Tg. Here we constructed a new high-Tg interface, single-layer FeSe interfaced with FeOx-terminated LaFeO3. Large superconducting gap and diamagnetic response evidence that the superconducting pairing can emerge near 80 K, highest amongst all-known interfacial superconductors. Combining various techniques, we reveal interfacial charge transfer and strong interfacial electron-phonon coupling (EPC) in FeSe/LaFeO3, showing that the cooperative pairing mechanism works beyond FeSe-TiOx. Intriguingly, the stronger interfacial EPC than that in FeSe/SrTiO3 is likely induced by the stronger interfacial bonding in FeSe/LaFeO3, and can explain the higher Tg according to recent theoretical calculations, pointing out a workable route in designing new interfaces to achieve higher Tg.

[Effects of binary coverage on soil water content in apple orchards during low-water-consumption growth period]. / äºŒå ƒè¦†ç›–å¯¹è‹¹æžœæ ‘ä½Žè€—æ°´ç”Ÿè‚²æœŸåœŸå£¤æ°´åˆ†çš„å½±å“.

To investigate the effects of intercropped rape and film mulching on soil water content in dryland apple orchards during the low-water consumption period on the Loess Plateau, soil water content and soil water storage were measured with in situ field observations. The results showed that at the sprout period of apple trees, mean water content in 0-200 cm soil layer under apple trees with film mulching + intercropping 50% width rape (PR1) and apple trees with film mulching + intercropping 100% width rape (PR2) treatments increased by 7.9% and 6.9% compared with the control (apple trees without film mulching+row clearing), respectively. At the blossom period of apple trees, mean soil water content under these two treatments increased by 3.5% and 6.9%, respectively. At the sprout period of apple trees, soil water competition between apple trees and rape occurred in both PR1 and PR2 treatments, with the competition being most severe at the boundaries. At the sprout period, competition in the PR1 treatment was less intense than that in the PR2 treatment. At the blossom period, competition in the PR1 treatment was not obvious, but the competition in the PR2 treatment was significant. Moreover, at the sprout and blossom period, a low-soil-water-content zone was observed in the PR2 treatment. Compared with the control, both PR1 and PR2 treatments increased soil water storage in 0-80 cm layer, and soil water was not deficit in the 0-200 cm layer. In conclusion, the implementation of PR1 model is conducive to improve soil water availability in the dryland apple orchard on the Loess Plateau during the low-water consumption period.