Surface Activation by Single Ru Atoms for Enhanced High-Temperature CO2 Electrolysis.

Cathodic CO2 adsorption and activation is essential for high-temperature CO2 electrolysis in solid oxide electrolysis cells (SOECs). However, the component of oxygen ionic conductor in the cathode displays limited electrocatalytic activity. Herein, stable single Ruthenium (Ru) atoms are anchored on the surface of oxygen ionic conductor (Ce0.8 Sm0.2 O2-δ , SDC) via the strong covalent metal-support interaction, which evidently modifies the electronic structure of SDC surface for favorable oxygen vacancy formation and enhanced CO2 adsorption and activation, finally evoking the electrocatalytic activity of SDC for high-temperature CO2 electrolysis. Experimentally, SOEC with the Ru1 /SDC-La0.6 Sr0.4 Co0.2 Fe0.8 O3-δ cathode exhibits a current density as high as 2.39 A cm-2 at 1.6 V and 800 °C. This work expands the application of single atom catalyst to the high-temperature electrocatalytic reaction in SOEC and provides an efficient strategy to tailor the electronic structure and electrocatalytic activity of SOEC cathode at the atomic scale.

Propofol exerts anti-anhedonia effects via inhibiting the dopamine transporter.

Lasker's award-winning drug propofol is widely used in general anesthesia. The recreational use of propofol is reported to produce a well-rested feeling and euphoric state; yet, the neural mechanisms underlying such pleasant effects remain unelucidated. Here, we report that propofol actively and directly binds to the dopamine transporter (DAT), but not the serotonin transporter (SERT), which contributes to the rapid relief of anhedonia. Then, we predict the binding mode of propofol by molecular docking and mutation of critical binding residues on the DAT. Fiber photometry recording on awake freely moving mice and [18F] FP-CIT-PET scanning further establishes that propofol administration evokes rapid and lasting dopamine accumulation in nucleus accumbens (NAc). The enhanced dopaminergic tone drives biased activation of dopamine-receptor-1-expressing medium spiny neurons (D1-MSNs) in NAc and reverses anhedonia in chronically stressed animals. Collectively, these findings suggest the therapeutic potential of propofol against anhedonia, which warrants future clinical investigations.

Official tenure and governance effectiveness of China's basic pension insurance system: An inverted U-shaped curve.

Objectives: Based on incentive theory of motivation, this paper aims to estimate China's basic pension insurance's annual efficiency and inter-period efficiency changes from 2015 to 2019 and further examine the relationship between official tenure and basic pension insurance governance performance. Methods: The DEA-BCC model was used to evaluate the operating efficiency of basic pension insurance in 31 provinces of China. And four panel Tobit models were constructed to examine the heterogeneous linkages between officials' tenure and governance efficiency in different regions of China. Results: The results showed that there was an inverted U-shaped relationship between the official tenure and the governance efficiency of basic pension insurance. The younger an official was in his current position, the more apparent the inverted U-shaped relationship between the tenure of an official and the governance efficiency of basic pension insurance. We also found that localized government officials showed better governance efficiency of basic pension insurance. However, as the term of office of officials increased, the governance efficiency of non-localized officials showed a steeper negative effect. Conclusion: This study firstly reveals a significant relationship between the characteristics of officials and the operation of China's basic pension insurance system, which is a complement to the study of China's basic pension systems.

DNA-PK Inhibitor Peposertib Amplifies Radiation-Induced Inflammatory Micronucleation and Enhances TGFß/PD-L1 Targeted Cancer Immunotherapy.

Radiotherapy is the most widely used cancer treatment and improvements in its efficacy and safety are highly sought-after. Peposertib (also known as M3814), a potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor, effectively suppresses the repair of radiation-induced DNA double-strand breaks (DSB) and regresses human xenograft tumors in preclinical models. Irradiated cancer cells devoid of p53 activity are especially sensitive to the DNA-PK inhibitor, as they lose a key cell-cycle checkpoint circuit and enter mitosis with unrepaired DSBs, leading to catastrophic consequences. Here, we show that inhibiting the repair of DSBs induced by ionizing radiation with peposertib offers a powerful new way for improving radiotherapy by simultaneously enhancing cancer cell killing and response to a bifunctional TGFß "trap"/anti-PD-L1 cancer immunotherapy. By promoting chromosome misalignment and missegregation in p53-deficient cancer cells with unrepaired DSBs, DNA-PK inhibitor accelerated micronuclei formation, a key generator of cytosolic DNA and activator of cGAS/STING-dependent inflammatory signaling as it elevated PD-L1 expression in irradiated cancer cells. Triple combination of radiation, peposertib, and bintrafusp alfa, a fusion protein simultaneously inhibiting the profibrotic TGFß and immunosuppressive PD-L1 pathways was superior to dual combinations and suggested a novel approach to more efficacious radioimmunotherapy of cancer. IMPLICATIONS: Selective inhibition of DNA-PK in irradiated cancer cells enhances inflammatory signaling and activity of dual TGFß/PD-L1 targeted therapy and may offer a more efficacious combination option for the treatment of locally advanced solid tumors.

Measurement and Evaluation of the Operating Efficiency of China's Basic Pension Insurance: Based on Three-Stage DEA Model.

PURPOSE: This paper aims to measure the operating efficiency of China's basic pension insurance from 2014 to 2019 in 31 provinces. METHODS: The three-stage DEA model was used to evaluate the operating efficiency of basic pension insurance in 31 provinces. RESULTS: On the whole, the operating efficiency of China's basic pension insurance was at a high level, but there was still room for improvement. GDP, urbanization level and scale of government public expenditure had a positive impact on the operating efficiency of regional basic pension insurance. In contrast, the old-age dependency ratio had a significant negative effect. There were noticeable regional differences in the operating efficiency of China's basic pension insurance, which showed a pattern of Central (0.742) >Eastern (0.689) >Western (0.505) after removing the influence of environmental variables. CONCLUSION: This study systematically analyzes the impact of external environmental regulations on China's basic pension insurance's operating efficiency and provides decision-making references for further improving the operating efficiency of China's basic pension insurance. In order to further optimize the allocation of basic endowment insurance, this paper proposes the following countermeasures and suggestions: (1) broaden investment channels and improve the investment efficiency; (2) increase supervision of social security departments and strengthen information disclosure; (3) unify the management of social basic pension insurance.

Highly efficient nano-Fe/Cu bimetal-loaded mesoporous silica Fe/Cu-MCM-41 for the removal of Cr(VI): Kinetics, mechanism and performance.

Zero valent iron (Fe0) can reduce Cr(VI) in water, where Fe0 and Fe(Ⅱ) are possible electron donors, but passivation and aggregation easily occur to Fe0. To improve the performance of Fe0, a new hybridization strategy of Fe/Cu bimetal and silica-based mesoporous molecular sieve MCM-41 for the removal of Cr(VI) from water has been proposed. The results show that the two-dimensional mesoporous structure of MCM-41 can provide skeleton support for Fe0, improve the mass transfer rate, and overcome the aggregation bottleneck of Fe0. The Cr(VI) removal rate reached 98.98% (pH = 2) after 40 min. The analytical results revealed Cr(VI) removal process: Cr(VI) adsorbed onto Fe/Cu-MCM-41 by electrostatic attraction and other molecular inter-atomic forces. The second metal, Cu, can inhibit the passivation of Fe0 and promote Fe(Ⅱ)through the formation of Fe/Cu battery, thereby promoting the electron transfer. The resulting Cr(Ⅲ) is precipitated as FeCr2O4 and CrxFe1-x(OH)3.

The F-Box Protein CG5003 Regulates Axon Pruning and the Integrity of the Drosophila Mushroom Body.

Protein homeostasis serves as an important step in regulating diverse cellular processes underlying the function and development of the nervous system. In particular, the ubiquitination proteasome system (UPS), a universal pathway mediating protein degradation, contributes to the development of numerous synaptic structures, including the Drosophila olfactory-associative learning center mushroom body (MB), thereby affecting associated function. Here, we describe the function of a newly characterized Drosophila F-box protein CG5003, an adaptor for the RING-domain type E3 ligase (SCF complex), in MB development. Lacking CG5003 ubiquitously causes MB γ axon pruning defects and selective CG5003 expression in pan-neurons leads to both γ axon and α/ß lobe abnormalities. Interestingly, change in CG5003 expression in MB neurons does not cause any abnormalities in axons, suggesting that CG5003 functions in cells extrinsic to MB to regulate its development. Mass spectrum analysis indicates that silencing CG5003 expression in all neurons affects expression levels of proteins in the cell and structural morphogenesis, transcription regulator activity, and catalytic activity. Our findings reinforce the importance of UPS and identify a new factor in regulating neuronal development as exemplified by the synaptic structure MB.

Configuration Analysis of Influencing Factors of Technical Efficiency Based on DEA and fsQCA: Evidence from China's Medical and Health Institutions.

PURPOSE: This paper aims to measure the technical efficiency of China's medical and health institutions from 2012 to 2017 and outline the path to achieve high-quality development. METHODS: The DEA-Malmquist was used to evaluate the total factor productivity of medical and health institutions in 31 provinces. A fuzzy set Qualitative Comparative Analysis (fsQCA) was used for configuration analysis of determinants affecting technical efficiency. RESULTS: The average total factor productivity (TFP) of those institutions was 0.965, namely TFP declined averagely by 3.5% annually. The efficiency change and the technical change were 0.998 and 0.967, respectively. The realization paths of high technical efficiency are composed of high fatality rate and high financial allocation-led, high population density and high GDP-led. Low dependency ratio and low financial allocation-led, low fatality rate and low financial allocation-led are the main reasons for low technical efficiency. CONCLUSION: Due to advanced medical technology and economic development, major cities like Beijing, Shanghai, and Guangdong have attracted a large number of high-level health personnel, achieving long-term and stable health business growth. Hubei, Anhui, and Sichuan also have made rapid development of health care through appropriate financial subsidies and policy supports. The technical changes in Qinghai, Yunnan, and Inner Mongolia are higher than the national average, but the operation and management level of the medical and health institutions is relatively weak. Henan, Jiangxi, and Heilongjiang have a prominent performance in the efficiency change, but the technical change is weaker than the national average.

Fabrication of the magnetic mesoporous silica Fe-MCM-41-A as efficient adsorbent: performance, kinetics and mechanism.

Antibiotics are emerging pollutants and increasingly present in aquaculture and industrial wastewater. Due to their impact on the environment and health, their removal has recently become a significant concern. In this investigation, we synthesized nano zero-valent iron-loaded magnetic mesoporous silica (Fe-MCM-41-A) via precipitation and applied the adsorption of oxytetracycline (OTC) from an aqueous solution. The effects of competing ions such as Na+, Ca2+ and Cu2+ on the adsorption process under different pH conditions were studied in depth to providing a theoretical basis for the application of nanomaterials. The characterization of the obtained material through transmission electron microscopy demonstrates that the adsorbent possesses hexagonal channels, which facilitate mass transfer during adsorption. The loaded zero-valent iron made the magnetic, and was thus separated under an applied magnetic field. The adsorption of OTC onto Fe-MCM-41-A is rapid and obeys the pseudo-second-order kinetic model, and the maximum adsorption capacity of OTC is 625.90 mg g-1. The reaction between OTC and Fe-MCM-41-A was inner complexation and was less affected by the Na+. The effect of Ca2+ on the adsorption was small under acidic and neutral conditions. However, the promotion effect of Ca2+ increased by the increase of pH. Cu2+ decreased the removal efficiencies continuously and the inhibitory effects decrease varied with the increase of pH. We propose that surface complexing, ion-exchange, cationic π-bonding, hydrogen bonding, and hydrophobicity are responsible for the adsorption of OTC onto Fe-MCM-41-A.

Therapeutic Implications of p53 Status on Cancer Cell Fate Following Exposure to Ionizing Radiation and the DNA-PK Inhibitor M3814.

Inhibition of DNA double-strand break (DSB) repair in cancer cells has been proposed as a new therapeutic strategy for potentiating the anticancer effects of radiotherapy. M3814 is a novel, selective pharmacologic inhibitor of the serine/threonine kinase DNA-dependent protein kinase (DNA-PK), a key driver of nonhomologous end-joining, one of the main DSB-repair pathways, currently under clinical investigation. Here, we show that M3814 effectively blocks the repair of radiation-induced DSBs and potently enhances p53 phosphorylation and activation. In p53 wild-type cells, ataxia telangiectasia-mutated (ATM) and its targets, p53 and checkpoint kinase 2 (CHK2), were more strongly activated by combination treatment with M3814 and radiation than by radiation alone, leading to a complete p53-dependent cell-cycle block and premature cell senescence. Cancer cells with dysfunctional p53 were unable to fully arrest their cell cycle and entered S and M phases with unrepaired DNA, leading to mitotic catastrophe and apoptotic cell death. Isogenic p53-null/wild-type A549 and HT-1080 cell lines were generated and used to demonstrate that p53 plays a critical role in determining the response to ionizing radiation and M3814. Time-lapse imaging of cell death and measuring apoptosis in panels of p53 wild-type and p53-null/mutant cancer lines confirmed the clear differences in cell fate, dependent on p53 status. IMPLICATIONS: Our results identify p53 as a possible biomarker for response of cancer cells to combination treatment with radiation and a DNA-PK inhibitor and suggest that p53 mutation status should be considered in the design of future clinical trials. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/17/12/2457/F1.large.jpg.

Removal of tetracycline from aqueous solution by MCM-41-zeolite A loaded nano zero valent iron: Synthesis, characteristic, adsorption performance and mechanism.

In this study, nano zero valent iron (NZVI) modified MCM-41-zeolite A (Fe-MCM-41-A) composite as a novel adsorbent was prepared by precipitation method and applied for tetracycline (TC) removal from aqueous solution. The adsorbent was characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared (FT-IR) spectroscopy, X-ray photoelectron spectroscopy (XPS) and N2-BET analysis. Hysteresis loops indicated that the sample has a desirable magnetic property and can be separated quickly. Adsorption studies were carried out to evaluate its potential for TC removal. Results showed that the optimal Fe-MCM-41-A dosage, initial pH and reaction time at initial TC concentration of 100mgL-1 solution are 1gL-1, pH=5, and 60 min respectively, at which the removal efficiency of TC was 98.7%. The TC adsorption results fitted the Langmuir isotherm model very well and the adsorption process could be described by a pseudo-second-order kinetic model. A maximum TC adsorption capacity of 526.32mgg-1 was achieved. This study demonstrates that Fe-MCM-41-A is a promising and efficient material for TC adsorption from aqueous solution.

Aurora A Kinase Inhibition Selectively Synergizes with Histone Deacetylase Inhibitor through Cytokinesis Failure in T-cell Lymphoma.

PURPOSE: Aurora A kinase (AAK) is expressed exclusively during mitosis, and plays a critical role in centrosome duplication and spindle formation. Alisertib is a highly selective AAK inhibitor that has demonstrated marked clinical activity of alisertib across a spectrum of lymphomas, though particularly in patients with T-cell lymphoma (TCL). We sought to compare and contrast the activity of alisertib in preclinical models of B-cell lymphoma (BCL) and TCL, and identify combinations worthy of clinical study. High-throughput screening of pralatrexate, the proteasome inhibitor (ixazomib), and the histone deacetylase (HDAC) inhibitor (romidepsin) revealed that only romidepsin synergized with alisertib, and only in models of TCL. We discovered that the mechanism of synergy between AAK inhibitors and HDAC inhibitors appears to be mediated through cytokinesis failure. EXPERIMENTAL DESIGN: A high-throughput screening approach was used to identify drugs that were potentially synergistic in combination with alisertib. Live-cell imaging was used to explore the mechanistic basis for the drug: drug interaction between alisertib and romidepsin. An in vivo xenograft TCL model was used to confirm in vitro results. RESULTS: In vitro, alisertib exhibited concentration-dependent cytotoxicity in BCL and TCL cell lines. Alisertib was synergistic with romidepsin in a T-cell-specific fashion that was confirmed in vivo. Live-cell imaging demonstrated that the combination treatment resulted in profound cytokinesis failure. CONCLUSIONS: These data strongly suggest that the combination of alisertib and romidepsin is highly synergistic in TCL through modulation of cytokinesis and merits clinical development.

BmCREC is an endoplasmic reticulum (ER) resident protein and required for ER/Golgi morphology.

Silkworm posterior silkgland is a model for studying intracellular trafficking. Here, using this model, we identify several potential cargo proteins of BmKinesin-1 and focus on one candidate, BmCREC. BmCREC (also known as Bombyx mori DNA supercoiling factor, BmSCF) was previously proposed to supercoil DNA in the nucleus. However, we show here that BmCREC is localized in the ER lumen. Its C-terminal tetrapeptide HDEF is recognized by the KDEL receptor, and subsequently it is retrogradely transported by coat protein I (COPI) vesicles to the ER. Lacking the HDEF tetrapeptide of BmCREC or knocking down COPI subunits results in decreased ER retention and simultaneously increased secretion of BmCREC. Furthermore, we find that BmCREC knockdown markedly disrupts the morphology of the ER and Golgi apparatus and leads to a defect of posterior silkgland tube expansion. Together, our results clarify the ER retention mechanism of BmCREC and reveal that BmCREC is indispensable for maintaining ER/Golgi morphology.

New insights into the mechanism for chromosome alignment in metaphase.

During mitosis, duplicated sister chromatids are properly aligned at the metaphase plate of the mitotic spindle before being segregated into two daughter cells. This requires a complex process to ensure proper interactions between chromosomes and spindle microtubules. The kinetochore, the proteinaceous complex assembled at the centromere region on each chromosome, serves as the microtubule attachment site and powers chromosome movement in mitosis. Numerous proteins/protein complexes have been implicated in the connection between kinetochores and dynamic microtubules. Recent studies have advanced our understanding on the nature of the interface between kinetochores and microtubule plus ends in promoting and maintaining their stable attachment. These efforts have demonstrated the importance of this process to ensure accurate chromosome segregation, an issue which has great significance for understanding and controlling abnormal chromosome segregation (aneuploidy) in human genetic diseases and in cancer progression.

The MRN-CtIP pathway is required for metaphase chromosome alignment.

Faithful duplication of the genome in S phase followed by its accurate segregation in mitosis is essential to maintain genomic integrity. Recent studies have suggested that proteins involved in DNA transactions are also required for whole-chromosome stability. Here we demonstrate that the MRN (Mre11, Rad50, and Nbs1) complex and CtIP are required for accurate chromosome segregation. Depletion of Mre11 or CtIP, antibody-mediated inhibition of Mre11, or small-molecule inhibition of MRN using mirin results in metaphase chromosome alignment defects in Xenopus egg extracts. Similarly, loss of MRN function adversely affects spindle assembly around DNA-coated beads in egg extracts. Inhibition of MRN function in mammalian cells triggers a metaphase delay and disrupts the RCC1-dependent RanGTP gradient. Addition of the Mre11 inhibitor mirin to egg extracts and mammalian cells reduces RCC1 association with mitotic chromosomes. Thus, the MRN-CtIP pathway contributes to Ran-dependent mitotic spindle assembly by modulating RCC1 chromosome association.

CENP-E--dependent BubR1 autophosphorylation enhances chromosome alignment and the mitotic checkpoint.

How the state of spindle microtubule capture at the kinetochore is translated into mitotic checkpoint signaling remains largely unknown. In this paper, we demonstrate that the kinetochore-associated mitotic kinase BubR1 phosphorylates itself in human cells and that this autophosphorylation is dependent on its binding partner, the kinetochore motor CENP-E. This CENP-E-dependent BubR1 autophosphorylation at unattached kinetochores is important for a full-strength mitotic checkpoint to prevent single chromosome loss. Replacing endogenous BubR1 with a nonphosphorylatable BubR1 mutant, as well as depletion of CENP-E, the BubR1 kinase activator, results in metaphase chromosome misalignment and a decrease of Aurora B-mediated Ndc80 phosphorylation at kinetochores. Furthermore, expressing a phosphomimetic BubR1 mutant substantially reduces the incidence of polar chromosomes in CENP-E-depleted cells. Thus, the state of CENP-E-dependent BubR1 autophosphorylation in response to spindle microtubule capture by CENP-E is important for kinetochore function in achieving accurate chromosome segregation.

Formin mDia3: A novel target for Aurora B kinase.

Stable attachment of kinetochores to spindle microtubules is essential for accurate chromosome segregation. We have shown that a kinetochore-associated formin protein, mDia3, contributes to the generation of stable kinetochore-microtubule attachment. The published report reviewed here shows an essential role of mDia3 in achieving metaphase chromosome alignment, and this function is directly regulated by Aurora B phosphorylation. Aurora B is a central component during the capture of spindle microtubules by kinetochores, in which it selectively eliminates incorrect attachments by phosphorylating a group of microtubule binding proteins at kinetochores to reduce their microtubule binding affinity. Here, we discuss the roles of Aurora B kinase and its substrates in achieving proper kinetochore-microtubule attachment.

Characterization of kinesin-like proteins in silkworm posterior silk gland cells.

Kinesins are microtubule-based motors involved in various intracellular transports. Neurons, flagellated cells, and pigment cells have been traditionally used as model systems to study the cellular functions of kinesins. Here, we report silkworm posterior silkgland (PSG), specialized cells with an extensive endomembrane system for intracellular transport and efficient secretion of fibroin, as a novel model for kinesin study. To investigate kinesin-driven intracellular transport in PSG cells, we cloned five silkworm kinesin-like proteins (KLPs), BmKinesin-1, BmKinesin-6, BmKinesin-7, BmKinesin-13, and BmKinesin-14A. We determined their expression patterns by relative real-time PCR and western blotting. Immunofluorescence microscopy verified their colocalization with microtubules. By combining pull-down assays, LC-MS/MS, and western blotting analysis, we identified many potential cargoes of BmKinesin-1 in PSG, including fibroin-containing granules and exuperantia-associated ribonucleoprotein (RNP) complexes. Moreover, BmKinesin-13 overexpression disrupted the microtubule network in BmN cells, which is consistent with a role of Kinesin-13 in regulating microtubule dynamics in other organisms. On the basis of these results, we concluded that PSG might have advantages in elucidating mechanisms of intracellular transport in secretory tissues and could serve as a potential model for kinesin studies.