Knockdown of phosphatases of regenerating liver-1 prolongs the lifespan of Caenorhabditis elegans via activating DAF-16/FOXO.

Phosphatases of regenerating liver (PRLs) are dual-specificity protein phosphatases. The aberrant expression of PRLs threatens human health, but their biological functions and pathogenic mechanisms are unclear yet. Herein, the structure and biological functions of PRLs were investigated using the Caenorhabditis elegans (C. elegans). Structurally, this phosphatase in C. elegans, named PRL-1, consisted of a conserved signature sequence WPD loop and a single C(X)5 R domain. Besides, by Western blot, immunohistochemistry and immunofluorescence staining, PRL-1 was proved to mainly express in larval stages and express in intestinal tissues. Afterward, by feeding-based RNA-interference method, knockdown of prl-1 prolonged the lifespan of C. elegans but also improved their healthspan, such as locomotion, pharyngeal pumping frequency, and defecation interval time. Furthermore, the above effects of prl-1 appeared to be taken without acting on germline signaling, diet restriction pathway, insulin/insulin-like growth factor 1 signaling pathway, and SIR-2.1 but through a DAF-16-dependent pathway. Moreover, knockdown of prl-1 induced the nuclear translocation of DAF-16, and upregulated the expression of daf-16, sod-3, mtl-1, and ctl-2. Finally, suppression of prl-1 also reduced the ROS. In conclusion, suppression of prl-1 enhanced the lifespan and survival quality of C. elegans, which provides a theoretical basis for the pathogenesis of PRLs in related human diseases.

Ultrafast and Low-Power 2D Bi2O2Se Memristors for Neuromorphic Computing Applications.

Memristors that emulate synaptic plasticity are building blocks for opening a new era of energy-efficient neuromorphic computing architecture, which will overcome the limitation of the von Neumann bottleneck. Layered two-dimensional (2D) Bi2O2Se, as an emerging material for next-generation electronics, is of great significance in improving the efficiency and performance of memristive devices. Herein, high-quality Bi2O2Se nanosheets are grown by configuring mica substrates face-down on the Bi2O2Se powder. Then, bipolar Bi2O2Se memristors are fabricated with excellent performance including ultrafast switching speed (<5 ns) and low-power consumption (<3.02 pJ). Moreover, synaptic plasticity, such as long-term potentiation/depression (LTP/LTD), paired-pulse facilitation (PPF), and spike-timing-dependent plasticity (STDP), are demonstrated in the Bi2O2Se memristor. Furthermore, MNIST recognition with simulated artificial neural networks (ANN) based on conductance modification could reach a high accuracy of 91%. Notably, the 2D Bi2O2Se enables the memristor to possess ultrafast and low-power attributes, showing great potential in neuromorphic computing applications.

Computational Study on the Effect of Inactivating/Activating Mutations on the Inhibition of MEK1 by Trametinib.

Activation of the mitogen-activated protein kinase (MAPK) signaling pathway regulated by human MAP kinase 1 (MEK1) is associated with the carcinogenesis and progression of numerous cancers. In addition, two active mutations (P124S and E203K) have been reported to enhance the activity of MEK1, thereby eventually leading to the tumorigenesis of cancer. Trametinib is an MEK1 inhibitor for treating EML4-ALK-positive, EGFR-activated, and KRAS-mutant lung cancers. Therefore, in this study, molecular docking and molecular dynamic (MD) simulations were performed to explore the effects of inactive/active mutations (A52V/P124S and E203K) on the conformational changes of MEK1 and the changes in the interaction of MEK1 with trametinib. Moreover, steered molecular dynamic (SMD) simulations were further utilized to compare the dissociation processes of trametinib from the wild-type (WT) MEK1 and two active mutants (P124S and E203K). As a result, trametinib had stronger interactions with the non-active MEK1 (WT and A52V mutant) than the two active mutants (P124S and E203K). Moreover, two active mutants may make the allosteric channel of MEK1 wider and shorter than that of the non-active types (WT and A52V mutant). Hence, trametinib could dissociate from the active mutants (P124S and E203K) more easily compared with the WT MEK1. In summary, our theoretical results demonstrated that the active mutations may attenuate the inhibitory effects of MEK inhibitor (trametinib) on MEK1, which could be crucial clues for future anti-cancer treatment.

Rational Design of Phosphorescent Iridium(III) Complexes for Selective Glutathione Sensing and Amplified Photodynamic Therapy.

It is a huge challenge to avoid irreversible damage to normal tissues during irradiation in photodynamic therapy (PDT) for cancer. An effective strategy is to develop smart photosensitizers, which exhibit amplified generation of reactive oxygen species (ROS) through triggering specific reaction in the tumor microenvironment. In this work, we designed a class of glutathione (GSH)-activatable photosensitizers (Ir1 and Ir4) based on an effective strategy of GSH-induced nucleophilic substitution reaction. The addition of GSH, induced changes in both phosphorescence intensity and lifetime of photosensitizers with high sensitivity. Importantly, the amount of singlet oxygen generated was increased significantly by GSH-induced activation reaction. Hence, the photosensitizers can selectively distinguish cancer cells from normal cells through luminescence and lifetime imaging, and can amplify PDT effects in cancer cells, owing to the evidently higher level of GSH compared to normal cells. This work presents a novel paradigm for GSH-amplified PDT against cancer cells and provides a new avenue for smart-responsive theranostic systems that can avoid nonspecific damage to normal cells.

The Application of Bilayer Heterogeneous MOFs in pH and Heat-Triggered Systems for Controllable Fragrance Release.

To facilitate the integration of a fragrance encapsulation system into different products to achieve effective releases, a dual-responsive release system with pH and thermal trigger control is designed in this work. A series of ZIF-8 (M) and bilayer ZIF-8-on-ZIF-8 (MM) materials are synthesized by a solvent method at room temperature. The fragrance is encapsulated into the ZIFs by dynamic adsorption or in situ encapsulation combined dynamic adsorption. The fragrance loading contributed by dynamic adsorption was as high as 80%. The fragrance loaded in the double-layer MM host was almost twice that of the monolayer host M due to the stronger electrostatic interaction between MM and vanillin. In the pH and thermal trigger response release experiments, the second MOF layer in the MM host, as a controlled entity, greatly improved the load and kinetic equilibrium time of vanillin, and realized the controlled release of guest molecules. The developed dual-responsive release system in this work exhibits great potential in daily chemical products.

Environmental remediation of Pb-Cd contaminated soil with organic phosphonic acids-saponin: Conditions, effectiveness, ecological risk and recovery.

Soil washing is a rapid and efficient method for heavy metals removal. In this study, a kind of novel environmentally friendly eluent is proposed, consisting of ethylenediamine tetra methylene phosphonic acid and saponin (E-S). In a response surface optimization design (RSOD), the operating parameters were optimized and ecological effects were investigated. Additionally, soil microbial diversity and composition were discussed. Finally, an optimal method for chelator recovery was presented. The single-factor and RSOD results showed that E-S had higher remediation efficiency for Pb-Cd contaminated soil with the best parameters of duration 240 min, temperature 40 °C, E/S ratio 1:1. Under these operating conditions, the removal rates of Pb and Cd were (72.2 ± 0.5)% and (61.2 ± 0.4)% for the artificially contaminated soil and (69.2 ± 0.1)% and (65.2 ± 0.2)% for in situ contaminated soil, respectively. The contents of Pb and Cd decreased from 562.36 mg/kg to 180.41 mg/kg and 80.96 mg/kg to 27.2 mg/kg respectively, and the soil ecological risk indexes reduced from 32% to 24% for Pb and 36%-27% for Cd. Owing to the efficient enrichment of Stenotrophomonas in soil, E-S has a potential of simultaneous removal effect on organic pollutants as well. Furthermore, the results revealed that E-S can be effectively recovered (>95%) by sodium sulfide precipitation.

Citric acid-based deep eutectic solvent (CA-DES) as a new soil detergent for the removal of cadmium from coking sites.

In order to solve the problem of soil pollution caused by excess heavy metals, cadmium (Cd), a novel soil-washing agent organic chelating acid-based deep eutectic solvent (OCA-DES), was investigated for the removal of Cd from the contaminated soil of coking plant. Four kinds of OCA-DES were prepared by mixing choline chloride (Ch-Cl) with four organic chelating acids (citric acid, oxalic acid, tartaric acid, and malic acid), respectively, to compare their washing efficiency of Cd from soil. The effects of washing operation conditions on the Cd removal efficiency were investigated. Side effects of citric acid-based deep eutectic solvent (CA-DES) on soil were analyzed using scanning electron microscopy (SEM), X-ray diffraction (XRD), and Fourier transform infrared (FTIR). The results showed that CA-DES had the best Cd removal efficiency and could reach as high as 93.75%, under ideal conditions. CA-DES mainly washed extractable and reducible Cd. The CA-DES washing process has less side effects on soil and hardly eroded the soil or changed the mineral structure of the soil. The main roles of CA-DES washing Cd include (1) hydrogen bonds capturing Cd; (2) the carboxyl group(-COOH) forming soluble chelate with Cd; and (3) releasing H+ ions in exchange for Cd. This study demonstrates that CA-DES, a novel soil-washing agent, has excellent removal of cadmium from soil and is environment-friendly.

Hybrid Aerogel Triboelectric Nanogenerator Based on the Synergistic Effect of Solid-Solid/Gas-Solid Triboelectricity and Piezoelectric Polarization.

Aerogels, due to their unique interconnected 3D networks, and large number of air-filled pores, extend the structural characteristics and physicochemical properties of the nanoscale to the macro level. However, aerogels made from a single component can hardly meet the needs of multifunctional energy harvesting/supply situations. Here, a BaTiO3-based hybrid aerogel (BTO HA) with 3D network structure was prepared. When the BTO HA is used as the electrode of triboelectric nanogenerator (BTO HA-TENG), high electrical output performances were obtained, which is due to the synergistic effect of solid-solid contact electrifications between the two electrification layers, the gas-solid contact electrifications between the inner surface of BTO HA and the air filled in the aerogel pores, and the piezoelectricity of the doped BaTiO3 nanoparticles. The BTO HA-TENG exhibited excellent fatigue resistance and structural stability after 12,000 cycles of alternatively contact/separation tests, and it can not only provide stable power supply for commercial capacitors, drive small mobile electronic devices but also can be used as a self-powered sensor to monitor human motion signals. Compared with traditional TENGs depending on surface charge transfer, the BTO HA-TENG exhibited its unique advantage that it can generate and transfer triboelectric charges by 3D volume, which boost TENGs' electrical output performances.

Ultralight, Elastic, Hybrid Aerogel for Flexible/Wearable Piezoresistive Sensor and Solid-Solid/Gas-Solid Coupled Triboelectric Nanogenerator.

Aerogels have been attracting wide attentions in flexible/wearable electronics because of their light weight, excellent flexibility, and electrical conductivity. However, multifunctional aerogel-based flexible/wearable electronics for human physiological/motion monitoring, and energy harvest/supply for mobile electronics, have been seldom reported yet. In this study, a kind of hybrid aerogel (GO/CNT HA) based on graphene oxide (GO) and carboxylated multiwalled carbon nanotubes (CMWCNTs) is prepared which can not only used as piezoresistive sensors for human motion and physiological signal detections, but also as high performance triboelectric nanogenerator (TENG) coupled with both solid-solid and gas-solid contact electrifications (CE). The repeatedly loading-unloading tests with 20 000 cycles exhibit its high and ultrastable piezoresistive sensor performances. Moreover, when the obtained aerogel is used as the electrode of a TENG, high electric output performance is produced due to the synergistic effect of solid-solid, and gas-solid interface CEs (3D electrification: solid-solid interface CE between the two solid electrification layers; gas-solid interface CE between the inner surface of GO/CNT HA and the air filled in the aerogel pores). This kind of aerogel promises good applications for human physiological/motion monitoring and energy harvest/supply in flexible/wearable electronics such as piezoresistive sensors and flexible TENG.

The Effects of Congruence Between Person and Environment on Innovation Performance in Ports.

The projected growth and rapid technological development in maritime transportation will create demand for a newly skilled and motivated workforce in the port sector. Thus, it is important for ports to attract, recruit and retain talented employees to promote innovation and enhance competitive advantages. This manuscript focuses on the welfare and talent of port staff from the perspective of person-environment (P-E) fit. Using polynomial regression with response surface analysis, this study explores the effect of P-E fit on job satisfaction, work engagement and innovation performance, and bootstrapping is applied to confirm the mediating roles of job satisfaction and work engagement in the relationship between P-E fit and innovation performance. Results show that (1) need-supply (N-S) fit and demands-abilities (D-A) fit improved port employees' job satisfaction, work engagement and innovation performance, and the impacts on work engagement and innovation performance show an inverted "U" and "U" shape, respectively; (2) D-A fit is more important when job satisfaction plays a mediating role; and (3) N-S fit makes a greater contribution when work engagement mediates the effect of P-E fit on the innovation performance. These findings contribute to P-E fit research as well as to human resource management practices in ports.

Discovery of small molecule inhibitors through pharmacophore modeling, molecular docking, molecular dynamics simulation and experimental validation against myeloid cell leukemia-1 (Mcl-1).

Myeloid cell leukemia-1 (Mcl-1) protein is a family of Bcl-2 (B cell lymphoma 2) rich proteases of the most common increase threshold for genetic aberrations observed in human cancer, including lung, breast, pancreatic, cervical, and ovarian cancers as well as leukemia and lymphoma. Mcl-1 is recognized as an attractive drug target in number of diseases, including cancer. In the present study we surveyed and collected queries compounds from PDB database of Mcl-1 protein and generated pharmacophore-based models adapted to screen the drug-like compounds from FDA approved database. The 206 best lead molecules from pharmacophore-screening were further evaluated by molecular docking, molecular dynamics simulation, MM-GBSA calculation, as well as experimental validation. Two hits, ZINC00601272 and ZINC00002166, showed the best docking scores, which showed a tendency to inhibit cell viability of HL60 and K562 leukemia cells with Mcl-1 expressions. Conclusively, the present study provides structural information of Mcl-1 inhibitors for next generations of cancer therapeutics through computational and experimental validation approach.Communicated by Ramaswamy H. Sarma.

Conformational Changes of Glutamine 5'-Phosphoribosylpyrophosphate Amidotransferase for Two Substrates Analogue Binding: Insight from Conventional Molecular Dynamics and Accelerated Molecular Dynamics Simulations.

Glutamine 5'-phosphoribosylpyrophosphate amidotransferase (GPATase) catalyzes the synthesis of phosphoribosylamine, pyrophosphate, and glutamate from phosphoribosylpyrophosphate, as well as glutamine at two sites (i.e., glutaminase and phosphoribosylpyrophosphate sites), through a 20 Å NH3 channel. In this study, conventional molecular dynamics (cMD) simulations and enhanced sampling accelerated molecular dynamics (aMD) simulations were integrated to characterize the mechanism for coordination catalysis at two separate active sites in the enzyme. Results of cMD simulations illustrated the mechanism by which two substrate analogues, namely, DON and cPRPP, affect the structural stability of GPATase from the perspective of dynamic behavior. aMD simulations obtained several key findings. First, a comparison of protein conformational changes in the complexes of GPATase-DON and GPATase-DON-cPRPP showed that binding cPRPP to the PRTase flexible loop (K326 to L350) substantially effected the formation of the R73-DON salt bridge. Moreover, only the PRTase flexible loop in the GPATase-DON-cPRPP complex could remain closed and had sufficient space for cPRPP binding, indicating that binding of DON to the glutamine loop had an impact on the PRTase flexible loop. Finally, both DON and cPRPP tightly bonded to the two domains, thereby inducing the glutamine loop and the PRTase flexible loop to move close to each other. This movement facilitated the transfer of NH3 via the NH3 channel. These theoretical results are useful to the ongoing research on efficient inhibitors related to GPATase.

Structure-based virtual screening of natural products as potential stearoyl-coenzyme a desaturase 1 (SCD1) inhibitors.

Stearyl coenzyme A desaturase enzyme 1 (SCD1) is a key enzyme that catalyzes the conversion of saturated fatty acids (SFA) into monounsaturated fatty acids (MUFA) and plays a vital role in lipid metabolism of tumor cells. SCD1 is overexpressed in a variety of malignant tumors, and its related inhibitors showed significant anti-tumor activity in vitro and in vivo experiments, which is a new target for tumor therapy. The focus of this study is to identify novel SCD1 inhibitors from natural products through computer simulations. First, 176,602 compounds from natural product databases were virtually screened. By molecular dynamics (MD) simulations, the ligand-protein interactions of 5 compounds with high docking manifestation were analyzed accurately. Then, MM-GBSA and MM-PBMA methods were used to verify the results. Finally, ADMET prediction was performed for the 5 compounds. As a result, two natural products with potential inhibition towards SCD1 were identified, which had the excellent docking manifestation, binding mode within SCD1 pocket and stability during molecular dynamics simulation. This study provides a meaningful model for the development and optimization of new inhibitors and anti-tumor drugs targeting SCD1.

How oncogenic mutations activate human MAP kinase 1 (MEK1): a molecular dynamics simulation study.

Approximately 30% of all types of human cancers possess a constitutively activated the mitogen-activated protein kinase (MAPK) signaling pathway while MAP kinase 1 (MEK1) is a critical component of this pathway. It has been reported mutations could improve the activity of MEK1 to result in cell proliferation and transformation, which is a known oncogenic event in various cancer types. In this study, eight molecular dynamics simulations, molecular mechanics Poisson-Boltzmann surface area (MM-PBSA), combined with protein structure network were performed to explore the mechanism that mutations activate MEK1. Protein structure networks and hydrogen bonds analysis demonstrated that active mutations broke the interaction between activation segments (residues 216-222) and C-helix (residues 105-121) in MEK1, leading to it transform inactive form to active form. Moreover, hydrogen bond analysis and MM-PBSA calculation indicated that activating mutations decrease the binding affinity between MEK1 and inhibitor to reduce the inhibitory effect of inhibitors. In addition, some active mutations cause structural changes in the Pro-rich loop (residues 261-268) of MEK1. These changes may stabilize the interaction between the MEK1 mutants and the ligands by increasing the number of exposed hydrophobic residues in the active site of MEK1. Our results may provide useful theoretical evidences for the mechanism underlying the role of human MEK1 in human cancers.Communicated by Ramaswamy H. Sarma.

De Novo Design of Polymeric Carrier to Photothermally Release Singlet Oxygen for Hypoxic Tumor Treatment.

Intratumoral hypoxia extremely limits the clinic applications of photodynamic therapy (PDT). Endoperoxides allow thermally releasing singlet oxygen (1O2) in a defined quantity and offer promising opportunities for oxygen-independent PDT treatment of hypoxic tumors. However, previous composite systems by combining endoperoxides with photothermal reagents may result in unpredicted side effects and potential harmful impacts during therapy in vivo. Herein, we de novo design an all-in-one polymer carrier, which can photothermally release 1O2. The strategy has been demonstrated to effectively enhance the production of 1O2 and realize the photodamage in vitro, especially in hypoxic environment. Additionally, the polymer carrier accumulates into tumor after intravenous injection via the enhanced permeation and retention effects and accelerates the oxygen-independent generation of 1O2 in tumors. The oxidative damage results in good inhibitory effect on tumor growth. Realization of the strategy in vivo paves a new way to construct photothermal-triggered oxygen-independent therapeutic platform for clinical applications.

Oxygen self-sufficient NIR-activatable liposomes for tumor hypoxia regulation and photodynamic therapy.

The inherent hypoxic environment in tumors severely resists the efficacy of photodynamic therapy. To address this problem, herein, the strategy of using oxygen self-sufficient liposomes (denoted as CaO2/B1/NH4HCO3 lipo), which contained aza-BODIPY dye (B1) and CaO2 nanoparticles in the hydrophobic layer and NH4HCO3 in the hydrophilic cavity, was presented to overcome hypoxia-associated photodynamic resistance. Under near-infrared (NIR) irradiation, NIR-absorbable B1 was activated to induce hyperthermia and further triggered the decomposition of NH4HCO3. Subsequently, with the aid of NH4HCO3 and CaO2 nanoparticles, oxygen was rapidly and self-sufficiently generated, during which clean by-products were produced. Furthermore, the increased amount of oxygen promoted the singlet oxygen production in the presence of B1, which served as a photosensitizer because of the heavy atom effect. The oxygen self-sufficient system improved the anticancer efficiency and alleviated the hypoxic environment in vivo, which demonstrated a valuable attempt to regulate intratumoral hypoxia and overcome the limitation of current photodynamic therapy systems. To our knowledge, this highlights the first example of using NIR light to activate CaO2 nanoparticle-containing liposomes for the modulation of the hypoxic environment in tumors.

Phosphorescent iridium(iii) complexes: a versatile tool for biosensing and photodynamic therapy.

This article highlights the utilization of phosphorescent iridium(iii) complexes for biosensing and photodynamic therapy. Comments on the effectiveness of these complexes in biological applications are included. Challenges and potential solutions are also discussed for further development and exploitation.

Luminescent ion pairs with tunable emission colors for light-emitting devices and electrochromic switches.

Most recently, stimuli-responsive luminescent materials have attracted increasing interest because they can exhibit tunable emissive properties which are sensitive to external physical stimuli, such as light, temperature, force, and electric field. Among these stimuli, electric field is an important external stimulus. However, examples of electrochromic luminescent materials that exhibit emission color change induced by an electric field are limited. Herein, we have proposed a new strategy to develop electrochromic luminescent materials based on luminescent ion pairs. Six tunable emissive ion pairs (IP1-IP6) based on iridium(iii) complexes have been designed and synthesized. The emission spectra of ion pairs (IPs) show concentration dependence and the energy transfer process is very efficient between positive and negative ions. Interestingly, IP6 displayed white emission at a certain concentration in solution or solid state. Thus, in this contribution, UV-chip (365 nm) excited light-emitting diodes showing orange, light yellow and white emission colors were successfully fabricated. Furthermore, IPs displayed tunable and reversible electrochromic luminescence. For example, upon applying a voltage of 3 V onto the electrodes, the emission color of the solution of IP1 near the anode or cathode changed from yellow to red or green, respectively. Color tunable electrochromic luminescence has also been realized by using other IPs. Finally, a solid-film electrochromic switch device with a sandwiched structure using IP1 has been fabricated successfully, which exhibited fast and reversible emission color change.

Rational design of a luminescent nanoprobe for hypoxia imaging in vivo via ratiometric and photoluminescence lifetime imaging microscopy.

A luminescent nanoprobe has been designed for detection of oxygen. The nanoprobe exhibits high sensitivity, selectivity and excellent reversibility, and has been employed for hypoxia imaging in vitro and in vivo by ratiometric and photoluminescence lifetime imaging techniques.