Chemical modification of proteins in living cells permits valuable glimpses into the molecular interactions that underpin dynamic cellular events. While genetic engineering methods are often ...preferred, selective labeling of endogenous proteins in a complex intracellular milieu with chemical approaches represents a significant challenge. In this study, we report novel diazocoumarin compounds that can be photoactivated by visible (430–490 nm) and near-infrared light (800 nm) irradiation to photo-uncage reactive carbene intermediates, which could subsequently undergo an insertion reaction with concomitant fluorescence “turned on”. With these new molecules in hand, we have developed a new approach for rapid, selective, and fluorogenic labeling of endogenous protein in living cells. By using CA-II and eDHFR as model proteins, we demonstrated that subcellular localization of proteins can be precisely visualized by live-cell imaging and protein levels can be reliably quantified in multiple cell types using flow cytometry. Dynamic protein regulations such as hypoxia-induced CA-IX accumulation can also be detected. In addition, by two-photon excitation with an 800 nm laser, cell-selective labeling can also be achieved with spatially controlled irradiation. Our method circumvents the cytotoxicity of UV light and obviates the need for introducing external reporters with “click chemistries”. We believe that this approach of fluorescence labeling of endogenous protein by bioorthogonal photoirradiation opens up exciting opportunities for discoveries and mechanistic interrogation in chemical biology.
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IJS, KILJ, NUK, PNG, UL, UM
Study of flexible nanodielectric materials (FNDMs) with high permittivity is one of the most active academic research areas in advanced functional materials. FNDMs with excellent dielectric ...properties are demonstrated to show great promise as energy‐storage dielectric layers in high‐performance capacitors. These materials, in common, consist of nanoscale particles dispersed into a flexible polymer matrix so that both the physical/chemical characteristics of the nanoparticles and the interaction between the nanoparticles and the polymers have crucial effects on the microstructures and final properties. This review first outlines the crucial issues in the nanodielectric field and then focuses on recent remarkable research developments in the fabrication of FNDMs with special constitutents, molecular structures, and microstructures. Possible reasons for several persistent issues are analyzed and the general strategies to realize FNDMs with excellent integral properties are summarized. The review further highlights some exciting examples of these FNDMs for power‐energy‐storage applications.
Recent progress in the development of flexible nanodielectric materials (FNDMs) with high dielectric permittivity is highlighted. Particular focus is given to increasing the energy density of various FNDMs. Key issuses in the synthesis, structure, and dielectric properties of nanodielectrics are reviewed. Some long‐standing problems and topics that warrant further investigation are also addressed.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The literature has confirmed that when managers increase profits through earnings management, the readability of annual reports may be reduced Lo (2017), Ye (2018). Whether this conclusion is ...suitable for Chinese corporate social responsibility (CSR) reports, however, is still unclear. Based on the panel data of 5083 Chinese non-financial listed companies from 2010 to 2019, this paper adopts multiple linear regression to investigate the impact of earnings management on the readability of Chinese CSR reports. The results show that: (1) There is a significant negative correlation between earnings management and the readability of Chinese CSR reports, with the readability of Chinese annual reports as a mediating variable. (2) The negative effect is more significant when companies are not punished for violations, when the internal control index is low, when companies lack ISO14001 certification and when companies do not have independent third-party authentication for Chinese CSR reports. (3) When earnings management just exceeds zero, the readability of Chinese CSR reports decreases. (4) The economic consequences of reducing the readability of Chinese CSR reports are that financing costs are increased and environmental performance is decreased. To improve the quality of information disclosure of listed companies, the recommendations are as follows: First, the government should issue CSR reporting standards to reduce the manipulation of Chinese CSR reports. Second, Chinese CSR reports disclosed by listed companies must be audited by independent third parties to enhance the credibility of the information. Third, the company needs to strengthen its external and internal supervision to reduce the manipulation space for the readability of Chinese CSR reports. This study extends the negative relationship between earnings management and the readability from annual reports to Chinese CSR reports. To prevent investors from detecting earnings management, the readability of Chinese CSR reports may be reduced. At the same time, the study has definitely added value to the existing literature in the domain of CSR.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In this paper, an estimation of distribution algorithm (EDA)-based memetic algorithm (MA) is proposed for solving the distributed assembly permutation flow-shop scheduling problem (DAPFSP) with the ...objective to minimize the maximum completion time. A novel bi-vector-based method is proposed to represent a solution for the DAPFSP. In the searching phase of the EDA-based MA (EDAMA), the EDA-based exploration and the local-search-based exploitation are incorporated within the MA framework. For the EDA-based exploration phase, a probability model is built to describe the probability distribution of superior solutions. Besides, a novel selective-enhancing sampling mechanism is proposed for generating new solutions by sampling the probability model. For the local-search-based exploitation phase, the critical path of the DAPFSP is analyzed to avoid invalid searching operators. Based on the analysis, a critical-path-based local search strategy is proposed to further improve the potential solutions obtained in the EDA-based searching phase. Moreover, the effect of parameter setting is investigated based on the Taguchi method of design-of-experiment. Suitable parameter values are suggested for instances with different scales. Finally, numerical simulations based on 1710 benchmark instances are carried out. The experimental results and comparisons with existing algorithms show the effectiveness of the EDAMA in solving the DAPFSP. In addition, the best-known solutions of 181 instances are updated by the EDAMA.
To assess survival of treatment patterns based on concurrent chemoradiotherapy (CCRT) in patients with stage IIB cervical squamous cell carcinoma (CSCC).
Patients with stage IIB CSCC receiving CCRT ...were investigated from June 2012 to June 2019 in Guangxi Medical University Cancer Hospital. Baseline characteristics and treatment patterns were described. Survival between treatment patterns were compared using Kaplan-Meier methods.
A total of 232 patients were included: 39.7% of patients received CCRT alone, 6.5% of patients received neoadjuvant chemotherapy (NACT) + CCRT, 45.6% of patients received CCRT + adjuvant chemotherapy (AC), and 8.2% of patients received NACT + CCRT + AC. CCRT + AC showed similar overall survival (OS; hazard ratio HR = 0.95, 95% confidence interval CI: 0.41-2.17; P = 0.894) and locoregional-free survival (LRFS; HR = 2.39, 95% CI: 0.45-12.63; P = 0.303) compared with CCRT. However, CCRT + AC had a worse distant metastasis-free survival (DMFS; HR = 5.39, 95% CI: 1.14-25.57; P = 0.034). After propensity score matching, CCRT + AC had comparable OS (HR = 0.89, 95% CI: 0.29-2.70; P = 0.833), LRFS (HR = 3.26, 95% CI: 0.30-35.38; P = 0.331), and DMFS (HR = 4.80, 95% CI: 0.55-42.26; P = 0.157) compared to CCRT.
AC did not improve survival in patients with stage IIB CSCC receiving CCRT.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In this research, we systematically investigated the reaction mechanism and electrocatalytic properties of transition metal anchored two-dimensional (2D) porphine-fused sheets (TM-Por) as novel ...single-atom catalysts (SACs) for the electrochemical nitrogen reduction reaction (eNRR) under ambient conditions. Using high-throughput screening and first-principles calculations based on the density functional theory (DFT) method, three eNRR catalyst candidates,
i.e.
Mo-Por, Tc-Por, and Nb-Por, were screened out, with the eNRR onset potentials on them being −0.36, −0.53, and −0.74 V, respectively. Furthermore, these catalyst candidates all have good stability and selectivity. Analyzing the band structures found that these catalyst candidates all are metallic, which is needed for good electrocatalysts.
Ab initio
molecular dynamics (AIMD) simulations show that these catalyst candidates have good stability at 500 K. It is hoped that our work will open up new possibilities for the experimental synthesis of electrochemical ammonia catalysts.
Thirty transition metal atoms were embedded into porphine-fused sheets (TM-Por) to form single-atom catalysts for eNRR under ambient conditions. Three TM-Por (TM = Mo, Tc, Nb) catalysts were predicted with excellent catalytic performance.
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•The relative abundance of core ARGs increased following the pandemic.•Tigecycline- and meropenem-resistant bacteria proliferated following the outbreak.•Human skin was found to be ...the presumed main source of public transit air.•Potential health risks due to airborne bacteria increased during the pandemic.
Antimicrobial resistance is recognized as one of the greatest public health concerns. It is becoming an increasingly threat during the COVID-19 pandemic due to increasing usage of antimicrobials, such as antibiotics and disinfectants, in healthcare facilities or public spaces. To explore the characteristics of airborne antibiotic resistome in public transport systems, we assessed distribution and health risks of airborne antibiotic resistome and microbiome in railway stations before and after the pandemic outbreak by culture-independent and culture-dependent metagenomic analysis. Results showed that the diversity of airborne antibiotic resistance genes (ARGs) decreased following the pandemic, while the relative abundance of core ARGs increased. A total of 159 horizontally acquired ARGs, predominantly confering resistance to macrolides and aminoglycosides, were identified in the airborne bacteria and dust samples. Meanwhile, the abundance of horizontally acquired ARGs hosted by pathogens increased during the pandemic. A bloom of clinically important antibiotic (tigecycline and meropenem) resistant bacteria was found following the pandemic outbreak. 251 high-quality metagenome-assembled genomes (MAGs) were recovered from 27 metagenomes, and 86 genera and 125 species were classified. Relative abundance of ARG-carrying MAGs, taxonomically assigned to genus of Bacillus, Pseudomonas, Acinetobacter, and Staphylococcus, was found increased during the pandemic. Bayesian source tracking estimated that human skin and anthropogenic activities were presumptive resistome sources for the public transit air. Moreover, risk assessment based on resistome and microbiome data revealed elevated airborne health risks during the pandemic.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) urgently needs an effective cure. 3CL protease (3CL
pro
) ...is a highly conserved cysteine proteinase that is indispensable for coronavirus replication, providing an attractive target for developing broad-spectrum antiviral drugs. Here we describe the discovery of myricetin, a flavonoid found in many food sources, as a non-peptidomimetic and covalent inhibitor of the SARS-CoV-2 3CL
pro
. Crystal structures of the protease bound with myricetin and its derivatives unexpectedly revealed that the pyrogallol group worked as an electrophile to covalently modify the catalytic cysteine. Kinetic and selectivity characterization together with theoretical calculations comprehensively illustrated the covalent binding mechanism of myricetin with the protease and demonstrated that the pyrogallol can serve as an electrophile warhead. Structure-based optimization of myricetin led to the discovery of derivatives with good antiviral activity and the potential of oral administration. These results provide detailed mechanistic insights into the covalent mode of action by pyrogallol-containing natural products and a template for design of non-peptidomimetic covalent inhibitors against 3CL
pro
s, highlighting the potential of pyrogallol as an alternative warhead in design of targeted covalent ligands.
Fuziline, an aminoalcohol‐diterpenoid alkaloid derived from Aconiti lateralis radix preparata, has been reported to have a cardioprotective activity in vitro. However, the potential mechanism of ...fuziline on myocardial protection remains unknown. In this study, we aimed to explore the efficacy and mechanism of fuziline on isoproterenol (ISO)‐induced myocardial injury in vitro and in vivo. As a result, fuziline effectively increased cell viability and alleviated ISO‐induced apoptosis. Meanwhile, fuziline significantly decreased the production of ROS, maintained mitochondrial membrane potential (MMP) and blocked the release of cytochrome C, suggesting that fuziline could play the cardioprotective role through restoring the mitochondrial function. Fuziline also could suppress ISO‐induced endoplasmic reticulum (ER) stress via the PERK/eIF2α/ATF4/Chop pathway. In addition, using ROS scavenger NAC could decrease ISO‐induced apoptosis and block ISO‐induced ER stress, while PERK inhibitor GSK2606414 did not reduce the production of ROS, indicating that excess production of ROS induced by ISO triggered ER stress. And fuziline protected against ISO‐induced myocardial injury by inhibiting ROS‐triggered ER stress. Furthermore, fuziline effectively improved cardiac function on ISO‐induced myocardial injury in rats. Western blot analysis also showed that fuziline reduced ER stress‐induced apoptosis in vivo. Above these results demonstrated that fuziline could reduce ISO‐induced myocardial injury in vitro and in vivo by inhibiting ROS‐triggered ER stress via the PERK/eIF2α/ATF4/Chop pathway.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
In this paper, an effective estimation of distribution algorithm (EDA) is proposed to solve the distributed permutation flow-shop scheduling problem (DPFSP). First, the earliest completion factory ...rule is employed for the permutation based encoding to generate feasible schedules and calculate the schedule objective value. Then, a probability model is built for describing the probability distribution of the solution space, and a mechanism is provided to update the probability model with superior individuals. By sampling the probability model, new individuals can be generated among the promising search region. Moreover, to enhance the local exploitation, some local search operators are designed based on the problem characteristics and utilized for the promising individuals. In addition, the influence of parameter setting of the EDA is investigated based on the Taguchi method of design of experiments, and a suitable parameter setting is suggested. Finally, numerical simulations based on 420 small-sized instances and 720 large-sized instances are carried out. The comparative results with some existing algorithms demonstrate the effectiveness of the proposed EDA in solving the DPFSP. In addition, the new best-known solutions for 17 out of 420 small instances and 589 out of 720 large instances are found.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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