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Funding Information: Xuelan Hou thanks for the scholarship by the China Scholarship Council , No. 201706250038 ; Yongdan Li acknowledges the financial supports from various funding agencies in China for their support to his research when he worked as a full professor in Tianjin University, China. Publisher Copyright: © 2022 The Author(s) Construction of Z-scheme graphitic carbon nitride-titanium dioxide nanotubes (C3N4-TNT) has been known useful to optimize the band structure for improving photon capture and for accelerating charge carrier separation and transfer rate in photoelectrochemical water splitting (PECWS) cells. However, the reported operating potential window in a PECWS cell, often in 0 – 1.23 VRHE (volt versus reversible hydrogen electrode) plus its overpotential, is too narrow to understand the C3N4-TNT electrode. Herein, a broad potential window of −0.5 − 2.5 VRHE is applied to C3N4-TNT@Ti and recorded via the polarization test under chopped sunlight to analyze the effect of both electrons from external electrical circuit and photons from simulated sunlight. In 0 – 2.5 VRHE, the potential enhances the photocurrent density. For example, at 1.6 VRHE, the C3N4-TNT sample exhibits 1.8-time higher photocurrent density than that of pure TNT. In −0.5 − 0 VRHE, i.e., both samples do not give photo-current response. In addition, for advanced water oxidation/reduction beyond WS to oxygen/hydrogen, a large potential window will be expected. Further, the light capture ability, the charge carrier recombination rate, and the electron flow path through the C3N4-TNT junction without and with reverse/forward potentials are discussed to elucidate the effect of the applied potential.

Elevator safety is closely related to public safety. Overspeed governor is a crucial part of the elevator safety system. Its inspection and calibration involve the measurement of tripping velocity. The frequently-used contact-type measurement method has risks. This paper proposes a non-contact image-recognizing measurement method by the camera, which includes the processes of rotor centre recognition, feature points matching, and tripping switches recognition. The velocity curve can be obtained by feature points displacement based on the rotor centre. Tripping switches recognition can determine the electrical and mechanical tripping velocities in the speed curve. The experimental results demonstrate that the proposed method has no significant difference from the common contact-type measurement method, while it significantly eliminates the risks of physical damage and improves measurement safety. Moreover, this paper proposes the deduction and calculation of measurement uncertainty decided by camera performance. Due to the enhancement of measuring safety, the proposed method will have further application in the field of elevator inspection. Practical application: The research on tripping velocity measurement for overspeed governor in this paper is principally based on image recognition with the help of a camera. The experiment result indicates that the proposed method is capable of completing the speed measurement for the overspeed governor without contact. The proposed method significantly mitigates the risks of physical damage and improves measurement safety rather than the contact-type measurement method. The proposed non-contact image-recognizing method can substitute for the existing contact-type method and contributes to the inspection, maintenance, and management of elevators, which will have further application prospects.

Phagocytic ability of macrophage is responsible for tuberculosis infection. Nicotine has been shown to attenuate the phagocytic ability of macrophage; however, the underlying mechanism remains unclear. Here, we demonstrated that nicotine increased the message RNA (mRNA) and protein expression of signal regulatory protein alpha (SIRPα) and enhanced the stability of SIRPα mRNA in macrophage. Nicotine decreased the expression of microRNA (miR)-296-3p, which directly targeted the 3′-untranslated region (3′-UTR) of SIRPα mRNA in macrophage. Furthermore, nicotine inhibited the phagocytic ability of macrophage by regulating the miR-296-3p–SIRPα axis. Moreover, nicotine decreased miR-296-3p expression via increasing c-Myc expression in macrophage. Together, we found that nicotine attenuate the phagocytic ability of macrophage by regulating the c-Myc-miR-296-3p–SIRPα signal.

Funding Information: This work has been funded by the Academy of Finland Project (Grant No. 348403), the Start-up Funding offered by Ningbo University of Technology to J.Y., and the Start-up Package of T10108 Professorship offered by Aalto University to Y.L. Q.Q. and P.Y. acknowledge financial support from the China Scholarship Council (Grant Nos. 201906150134 and 202006120046). Publisher Copyright: © 2022 The Authors. Published by American Chemical Society. Nonaqueous redox flow batteries (NARFBs) hold potential application as an electricity energy storage for intermittent renewable energy and can operate with high voltage and energy density. However, their further development is impeded by lack of a proper membrane. Herein, a flexible freestanding anionic metal-organic framework (MOF)-based membrane is prepared through a solution casting method, with an anionic MOF (UiO-66-SO3Li) and polyvinylidene fluoride. The prepared membrane shows an impressive ionic selectivity (37.6) of Li+ to N-(ferrocenylmethyl)-N,N-dimethyl-N-ethylammonium (Fc1N112+) ions and high ionic conductivity. Benefiting from the unique micropore structure of MOF and the anionic transport channels of Li+ across the membrane, the resultant Li-based hybrid NARFB delivers a high-capacity retention (99.95% per cycle) over 500 cycles with a well-assembled stable interphase after long time lithium plating/stripping, which decreases the voltage efficiency during the cycling. Calculations reveal that the membrane easily desolvates Li+ in the unique micropore structure of MOF before Li deposition occurs, which suppresses parasitic reaction and accelerates Li uniform deposition. This work provides a viable method to design bifunctional NARFB membranes which achieve ion sieving and ion exchange functions.

Pyruvate is an important energy substance during early embryonic development of mammals. However, the underlying mechanisms of pyruvate during early embryonic development in pigs and its role in zygotic genome activation (ZGA) are not fully understood. Here, based on a previous RNA-seq dataset of porcine early embryos, we found that pyruvate metabolism-related genes started to be expressed at the 4-cell stage and that pyruvate metabolism-related genes were correlated with porcine ZGA marker genes. To determine the function of pyruvate in porcine embryos, in vitro fertilization (IVF) embryos were cultured in PZM-3 medium (control group); modified PZM-3 medium that only contains pyruvate and lactate plus salts (+P group); or modified PZM-3 medium lacking pyruvate (-P group). The 4-cell arrest rate at 72 h was significantly increased in the -P group compared to the +P group (P 0.05). In addition, we observed that the reactive oxygen species (ROS) level was significantly increased and that the adenosine triphosphate (ATP) level was significantly (P 0.05) decreased in the -P group compared to the +P group. Moreover, the expression of ZGA marker genes and SIRT1 protein in embryos was significantly decreased in the -P group compared to the +P group (P 0.05). Furthermore, the acetylation level of H3K9 was significantly decreased (P 0.05) and the methylation level of H3K9 was significantly increased (P 0.05) in the -P group compared to the +P group. In summary, our findings demonstrate that pyruvate affects early embryonic development in pigs by promoting ZGA and reducing oxidative stress levels.

Methicillin-resistant Staphylococcus aureus (MRSA) has been developing rapidly in recent years. It poses a severe peril to global health care, and the new strategies to against the MRSA is urgently needed. Sortase A (SrtA) regulates the anchoring of many surface proteins. Compounds repress Staphylococcus aureus (S. aureus) cysteine transpeptidase SrtA are considered adequate potent virulence inhibitors. Then, we describe the identification of an effective SrtA inhibitor, cyanidin chloride, a bioflavonoid compound isolated from various plants. It has a reversible inhibitory effect on SrtA activity at an IC50 of 21.91 μg/mL. As a SrtA inhibitor, cyanidin chloride antagonizes SrtA-related virulence phenotypes due to its breadth and specificity, including fibrinogen adhesion, A549 cell invasion, biofilm formation, and surface protein (SpA) anchoring. Subsequently, molecular docking and fluorescence quenching revealed that SrtA and cyanidin chloride had robust mutual affinity. Further mechanistic studies revealed that Arg-197, Gly-167, and Sep-116 were the key-binding sites mediating the interaction between SrtA and cyanidin chloride. Notably, a significant therapeutic effect of cyanidin chloride in vivo was also observed on the mouse pneumonia model induced by MRSA. In conclusion, our study indicates that cyanidin chloride potentially represents a new candidate SrtA inhibitor for S. aureus and potentially be developed as a new antivirulence agent.

Aims The main purpose of this study was to study the therapeutical effect of oroxylin A glucuronide (OAG) on methicillin-resistant Staphylococcus aureus (MRSA). Methods and results By substrate peptide reaction-based fluorescence resonance energy transfer (FRET) screening, we identified that OAG was an efficient inhibitor of Sortase A (SrtA) with an IC50 of 45.61 μg mL−1, and achieved efficacy in the treatment of Staphylococcus aureus (S. aureus) infections. We further demonstrated that OAG inhibited the adhesion of the S. aureus to fibrinogen, the surface protein A anchoring and diminished biofilm formation. Results obtained from fluorescence quenching assay elucidated a direct interaction between OAG and SrtA. Employing molecular dynamics simulations, we proved that OAG binds to the binding sites of R197, G192, E105, and V168 in the SrtA. Notably, OAG exhibited a robust therapeutic effect in a MRSA-induced pneumonia model. Conclusions We identified that OAG as a novel class of reversible inhibitors of SrtA, combats MRSA-induced Infections.

Background: The influencing factors on the prognosis of patients with testicular cancer (TC) remains unclear. We aimed to explore the clinical influencing factors of overall survival (OS) and cancer-specific survival (CSS) of Testicular Cancer (TC) patients and to build the nomograms. Methods: Within the Surveillance, Epidemiology, and End Results (SEER) database, 7718 TC patients diagnosed between 2004 and 2018 were included and their clinical data were assessed. The data were randomly divided into training and validation cohorts in a ratio of 7:3 to construct the prediction models. Prognosis information including 3-, 5-, and 10-year OS and CSS rates were recorded. In this study, the Kaplan-Meier method was used to draw the survival curve and variables with PResults: A total of 7718 patients were included in the prognostic model. In the multivariate Cox regression model, older age at diagnosis, without surgery, regional lymph node involvement (N1, N2, N3 and NX), with chemotherapy and larger tumor size were independent predictors of poor prognosis factors for OS and CSS in TC patients. The C-indexes were 0.75 (95% confidence interval [CI]: 0.72- 0.78) for OS and 0.82 (95% CI: 0.79- 0.85) for CSS, indicating that the prognosis of testicular cancer patients had a good predictive effect. Based on the nomogram, in the verification group, the AUC values of the 3-, 5-, and 10-year OS were 0.799, 0.757; 0.725, and 0.827, 0.823, and 0.825 for 3, 5, and 10- years CSS, respectively. The differences in the OS and CSS between the real observation and the forecast were quite constant according to the calibration curves. The models were validated in the validation cohort, which also demonstrated the models had good reliability for prognostication. Conclusions: Clinical factors including age at diagnosis, surgery conditions, N Stage, chemotherapy conditions and tumor size were good predictors for OS and CSS in TC. Our predictive nomogram may play an important role in predicting 3-, 5-, and 10-year outcomes in patients with TC.

Antimicrobial resistance (AMR) is a global, multifaceted crisis that poses significant challenges to the successful eradication of devastating pathogens, particularly methicillin-resistant Staphylococcus aureus (MRSA), a persistent superbug that causes devastating infections. The scarcity of new antibacterial drugs is obvious, and antivirulence strategies that reduce the pathogenicity of bacteria by weakening their virulence have become the subject of intense investigation. Alpha-hemolysin (Hla), a cytolytic pore-forming toxin, has a pivotal role in S. aureus pathogenesis. Here, we demonstrated that echinatin, a natural compound isolated from licorice, effectively inhibited the hemolytic activity of MRSA at 32 μg/mL. In addition, echinatin did not interfere with bacterial growth and had no significant cytotoxicity at the inhibitory concentration of S. aureus hemolysis. Heptamer formation tightly correlated with Hla-mediated cell invasion, whereas echinatin did not affect deoxycholic acid-induced oligomerization of Hla. Echinatin affected hemolytic activity through indirect binding to Hla as confirmed by the neutralization assay and cellular thermal shift assay (CETSA). Furthermore, qRT–PCR and western blot analyses revealed that echinatin suppressed Hla expression at both the mRNA and protein levels as well as the transcript levels of Agr quorum-sensing system-related genes. Additionally, when echinatin was added to a coculture system of A549 cells and S. aureus, it significantly reduced cell damage. Importantly, echinatin exhibited a significant therapeutic effect in an MRSA-induced mouse pneumonia model. In conclusion, the present findings demonstrated that echinatin significantly inhibits the hemolysin effect and may be a potential candidate compound for combating drug-resistant MRSA infections.

The mountain area is faced with complex conditions such as vertical and horizontal valleys, complex geological topography, many earthquake fault zones, high seismic intensity, fragile ecology, and changeable climate. The traditional concrete bridges have a heavy weight, high consumption of sand and gravel materials, large structural dimensions of steel box composite bridges, high steel consumption, and poor overall horizontal performance of steel plate composite beams, which are not suitable for mountain construction conditions. Therefore, based on the construction environment and application requirements of highway bridges in mountainous areas, the structural scheme of steel box-steel plate composite beam is put forward in this paper, and the design of a 25 m–50 m standard-span steel box-steel plate composite beam is studied. The results show that the steel box-steel plate composite beam structure scheme is adopted, which has excellent mechanical characteristics of steel box girder and simple structure of steel plate girder. It has the mechanical characteristics of “balanced transverse force and excellent longitudinal force”, so it is a reasonable choice for small radius curved beam bridge in a mountainous area, so it is a reasonable choice for small radius curved beam bridge in a mountainous area. The steel box-steel plate composite beam adopts the integrated technology of manufacture, transportation and installation, which can better meet the road transport conditions in the mountain area. The longitudinal assembly of the manufacturing unit as the installation unit can ensure the rapid and high-precision installation of the construction site, and the assembly construction of the bridge in the mountain area has been realized. The technical and economic comparison shows that the mechanical performance of steel box-steel plate composite beam is similar to that of steel box beam and obviously better than that of steel plate girder. The steel consumption and construction period of steel box-steel plate composite beam are similar to that of steel plate girder, and are significantly less than that of the steel box girder. Therefore, the steel box-steel plate composite beam is a good choice for mountain bridge construction.

Lenvatinib is a tyrosine kinase receptor inhibitor that inhibits vascular and endothelial growth factor receptor kinase activity. This study evaluated the bioequivalence and safety of lenvatinib with Lenvima® . The fasting and postprandial groups were two independent trials. Subjects were randomly divided into two sequences at a ratio of 1:1 for two-cycle crossover administration. Subjects took 10 mg lenvatinib or Lenvima® once per cycle. The wash-out period was 14 days. Detected the plasma drug concentrations and assessed the bioequivalence of two drugs. Besides, we evaluated the safety of the drugs throughout the trial. In the fasting state, the GMRs of Cmax, AUC0-t, and AUC0-∞ were 99.89%, 102.98% and 103.19%, respectively. The 90% CIs were all within 80%-125%. In the postprandial state, the GMRs of Cmax, AUC0-t, and AUC0-∞ were 98.96%, 94.25% and 95.27%, respectively. The 90% CIs were all within 80%-125%. All results met the bioequivalence criteria. Both drugs had good safety and tolerance in this trial. This study showed that lenvatinib and Lenvima® had similar bioequivalence and safety in healthy Chinese subjects under fasting and postprandial conditions. This trial is registered at the Chinese Clinical Trial website (http://www.chinadrugtrials.org.cn/index.html # CTR20191172)

In the fields of optics and photonics, phase-only spatial light modulators (SLMs) play an increasingly important role in wave-front engineering. However, the SLMs are subject to wavefront distortion arising from the imperfection in the birefringence effect and physical structure of modulators. This paper presents a simple self-interference phase calibration method applicable to liquid-crystal SLM. We build a interferometric imaging system basing on the Pancharatnam-phase-shifting to measure the phase distribution of a light beam coming from SLMs. Two types of phase modulation errors of SLMs can be characterized in the measurement process: the erroneous gamma curve and shape aberration. The former belongs to dynamic phase distortion and is measured through a four-step Pancharatnam phase shifting interference, which allows a one-shot recording of interference pattern via a polarization camera; the latter represents static phase distortion and is extracted from the interference between light waves coming from different regions of the SLM panel by using Zernike polynomial fitting. Our method has the advantages of high-precision pixel-wise phase correction and robustness against environmental disturbance, and thus can facilitate the applications of SLM in the optical field manipulation.

Funding Information: This work was supported with the start-up package of T10108 professorship offered by Aalto University. Q. Qiu, J. Long, P. Yao J. Wang and X. Li acknowledge the financial support from the China Scholarship Council (Grant No. 201906150134, 202101010001, 202006120046, 202106120279 and 202106440120). Z.-Z. Pan acknowledges the financial support of the Academy of Finland (Grant No. 324414). Publisher Copyright: © 2023 The Authors Lithium oxygen battery (LOB) is a highly promising energy storage device for the next generation electric vehicles due to its high theoretical energy density. However, many challenges hinder its practical application. The electrochemical performances, such as discharge capacity, discharge and charge overpotentials, power density and stability are all far from satisfactory. In recent years, a great progress has been made and numerous works on cathode materials have been published. This article focuses on the state-of-the-art of LOB cathode materials and the reaction mechanism happens on the cathode. The principles of cathode reactions are summarized and the requirements for cathode materials are discussed. The performance of LOBs with carbon-based and carbon free cathode materials are described. The approaches on improving the cathode performance via temperature increase, material surface engineering, texture optimization and oxygen vacancy regulation are elaborated. A perspective on the research trend on the cathode catalyst is finally proposed.

Funding Information: The financial support from National Natural Science Foundation of China under contract number 22075205 and the support of Tianjin Municipal Science and Technology Commission under contract number 19JCYBJC21700 are gratefully acknowledged. The work has been also supported by the Program of Introducing Talents to the University Disciplines under file number B06006, and the Program for Changjiang Scholars and Innovative Research Teams in Universities under file number IRT 0641. Publisher Copyright: © 2022 The Royal Society of Chemistry A thin yttria stabilized zirconia (YSZ)/gadolinia doped ceria (GDC) bi-layer membrane is fabricated through the slurry spin coating technique and used as an electrolyte of a solid oxide fuel cell with La0.6Sr0.4Co0.2Fe0.8O3−δ as the cathode. The viscosity of the YSZ slurry is controlled by adding ethanol in the terpineol solvent, which shows a negligible effect on the thickness but a remarkable influence on the porosity of the YSZ film. The thickness of the YSZ layer increases with the YSZ content in the slurry. The YSZ films are pre-sintered at various temperatures, and the one sintered at 1200 °C has a moderate interaction with the GDC slurry, forming a 10 μm-thick YSZ/GDC bilayer with a low porosity and a low ohmic resistance. The corresponding single cell shows a maximum power density of 1480 mW cm−2 at 750 °C.

The advantage of oncolytic viruses (OV) in cancer therapy is their dual effect of directly killing tumours while prompting anti-tumour immune response. Oncolytic parapoxvirus ovis (ORFV) and other OVs are thought to induce apoptosis, but apoptosis, being the immunogenically inert compared to other types of cell death, does not explain the highly inflamed microenvironment in OV-challenged tumors. Here we show that ORFV and its recombinant therapeutic derivatives are able to trigger tumor cell pyroptosis via Gasdermin E (GSDME). This effect is especially prominent in GSDME-low tumor cells, in which ORFV-challenge pre-stabilizes GSDME by decreasing its ubiquitination and subsequently initiates pyroptosis. Consistently, GSDME depletion reduces the proportion of intratumoral cytotoxic T lymphocytes, pyroptotic cell death and the success of tumor ORFV virotherapy. In vivo, the OV preferentially accumulates in the tumour upon systemic delivery and elicits pyroptotic tumor killing. Consequentially, ORFV sensitizes immunologically ‘cold’ tumors to checkpoint blockade. This study thus highlights the critical role of GSDME-mediated pyroptosis in oncolytic ORFV-based antitumor immunity and identifies combinatorial cancer therapy strategies.

Vector-borne flaviviruses, including tick-borne encephalitis virus (TBEV), Zika virus (ZIKA), West Nile virus (WNV), yellow fever virus (YFV), dengue virus (DENV), and Japanese encephalitis virus (JEV), pose a growing threat to public health worldwide, and have evolved complex mechanisms to overcome host antiviral innate immunity. However, the underlying mechanisms of flavivirus structural proteins to evade host immune response remain elusive. Here we show that TBEV structural proteins, including pre-membrane (prM), envelope, and capsid proteins, could inhibit type I interferon (IFN-I) production. Mechanically, TBEV prM interacted with both MDA5 and MAVS and interfered with the formation of MDA5-MAVS complex, thereby impeded the nuclear translocation and dimerization of IRF3 to inhibit RLR antiviral signaling. ZIKA and WNV prM was also demonstrated to interact with both MDA5 and MAVS, while dengue virus serotype 2 (DENV2) and YFV prM associated only with MDA5 or MAVS to suppress IFN-I production. In contrast, JEV prM could not suppress IFN-I production. Overexpression of TBEV and ZIKA prM significantly promoted the replication of Sendai virus. Our findings reveal the immune evasion mechanisms of flavivirus prM, which may contribute to understanding flavivirus pathogenicity, therapeutic intervention and vaccine development.Author SummaryAll flaviviruses must overcome the antiviral innate immunity to infect vertebrate host. The non-structural proteins of flaviviruses are mainly responsible for viral replication and host innate immune escape, and the structural proteins are involved in the virus assembly, which are potential targets for prevention and treatment of flaviviral infections. Whether flavivirus structural proteins participate in host innate immune escape remains to be determined. Here, we found that tick-borne encephalitis virus structural proteins precursor membrane (prM), capsid, and envelope proteins can antagonize type I interferon production, in which prM interacts with both MDA5 and MAVS to inhibit RLR antiviral signaling. Additionally, Zika virus and West Nile virus prMs also interact with both MDA5 and MAVS, while dengue virus serotype 2 and yellow fever virus prMs associate only with MDA5 or MAVS to suppress type I interferon production. In contrast, Japanese encephalitis virus prM cannot antagonize type I interferon production. Our findings reveal that flavivirus prM inhibits type I interferon production via interacting with MDA5 and/or MAVS in a species-dependent manner, which may contribute to understanding flavivirus pathogenicity, therapeutic intervention, and vaccine development.

The alkali metal heat pipes are the critical heat transfer elements in heat pipe cooled reactors. However, there are instabilities in heat pipes such as geyser boiling, resulting in temperature oscillation and even threatening the reactor safety. This work developed a coupled neutronic and thermal-mechanical analysis method to analyze the effects of geyser boiling and heat pipe temperature oscillations on the critical parameters, e.g., temperature and stress, during reactor operation. The megawatt heat pipe reactor MegaPower was chosen as an application case. The simulations show that the heat pipe temperature oscillation leads to the same frequency oscillation of the temperature and stress in the solid-state core. Besides, the temperature amplitudes are significantly reduced by shortening the oscillation period. Reducing the oscillation period from 60 s to 15 s reduced the temperature amplitude of the fuel pellet center from 22℃ to 5℃. Furthermore, the stress oscillation in the core may lead to material fatigue or even failure for a long period of operation, which is highly undesired. This work can provide valuable data and references for the safety design of heat pipe reactors.

Copper is vital for various life processes, whereas severely toxic at excess level. Intracellular copper homeostasis is strictly controlled by a set of transporters and chaperones encoded by the copper homeostasis genes. Increasing evidence has shown that copper is usually overloaded in multiple malignancies, including pancreatic cancer, which has an extremely poor prognosis. Recently, silencing the SLC31A1 gene, which encodes a major transmembrane copper transporter (CTR1), has been demonstrated to be an effective means for reducing the malignant degree of pancreatic cancer by downregulating the cellular copper levels. Herein, we utilized tetrahedral framework nucleic acids (tFNAs) as vehicles to overcome the biological barriers for delivering small molecular RNAs and efficiently transferred two kinds of CTR1 mRNA-targeted RNA therapeutics, siCTR1 or miR-124, into PANC-1 cells. Both therapeutic tFNAs, termed t-siCTR1 and t-miR-124, prevented copper intake more effective than the free RNA therapeutics via efficiently suppressing the expression of CTR1, thereby significantly attenuating the progression of PANC-1 cells. In this study, therapeutic tFNAs are constructed to target metal ion transporters for the first time, which may provide an effective strategy for future treatment of other metal metabolism disorders.

Background: Vector-borne flaviviruses, including tick-borne encephalitis virus (TBEV), Zika virus (ZIKA), West Nile virus (WNV), yellow fever virus (YFV), dengue virus (DENV), and Japanese encephalitis virus (JEV), pose a growing threat to public health worldwide, and have evolved complex mechanisms to overcome host antiviral innate immunity. However, the underlying mechanisms of flavivirus structural proteins to evade host immune response remain elusive. Results: We show that TBEV structural protein, pre-membrane (prM) protein, could inhibit type I interferon (IFN-I) production. Mechanically, TBEV prM interacted with both MDA5 and MAVS and interfered with the formation of MDA5-MAVS complex, thereby impeding the nuclear translocation and dimerization of IRF3 to inhibit RLR antiviral signaling. ZIKA and WNV prM was also demonstrated to interact with both MDA5 and MAVS, while dengue virus serotype 2 (DENV2) and YFV prM associated only with MDA5 or MAVS to suppress IFN-I production. In contrast, JEV prM could not suppress IFN-I production. Overexpression of TBEV and ZIKA prM significantly promoted the replication of TBEV and Sendai virus. Conclusion: Our findings reveal the immune evasion mechanisms of flavivirus prM, which may contribute to understanding flavivirus pathogenicity, therapeutic intervention and vaccine development.

Methicillin-resistant Staphylococcus aureus (MRSA) is a zoonotic antibiotic-resistant pathogen that negatively impacts society from medical, veterinary, and societal standpoints. The search for alternative therapeutic strategies and innovative anti-infective agents is urgently needed. Among the pathogenic mechanisms of Staphylococcus aureus (S. aureus), sortase A is a virulence factor of great concern because it is highly linked with the ability of MRSA to invade the host. In this study, we identified that rhodionin, a natural compound of flavonoid glucosides, effectively inhibited the activity of SrtA without affecting the survival and growth of bacteria, and its half maximal inhibitory concentration (IC

Methicillin-resistant

Meat is the main source of protein nutrition for humans. However, given the increasing population and environmental pressure, a shortage of meat is expected in the future. The preparation of plant-based (meat) products using existing processing methods represents a breakthrough to solve the shortage of traditional animal meat in the future, and texture is a key issue determining whether plant-based (meat) products can replace traditional animal meat. Therefore, this review highlights recent progress in the texture of plant-based (meat) products. First, the texture changes in plant-based (meat) products were reviewed based on components (proteins, starch, lipids, food additives) and processing methods (processing factors, instrumental factors). Then, the current methods used to analyze the texture of plant-based (meat) products were summarized based on sensory evaluation and instrumental analysis (mechanical analysis, spectral analysis, and image analysis). Finally, this review outlined methods to improve the texture quality of plant-based (meat) products and analytical evaluation methods and provided an outlook on future research priorities.

Drug-resistant bacteria was the third leading cause of death worldwide in 2019, which sounds like a cautionary note for global public health. Therefore, developing novel strategies to combat Methicillin-resistant Staphylococcus aureus (MRSA) infections is the need of the hour. Caseinolytic protease P (ClpP) represents pivotal microbial degradation machinery in MRSA involved in bacterial homeostasis and pathogenicity, considered an ideal target for combating S. aureus infections. Herein, we identified a natural compound, hinokiflavone, that inhibited the activity of ClpP of MRSA strain USA300 with an IC(50) of 34.36 μg/mL. Further assays showed that hinokiflavone reduced the virulence of S. aureus by inhibiting multiple virulence factors expression. Results obtained from cellular thermal transfer assay (CETSA), thermal shift assay (TSA), local surface plasmon resonance (LSPR) and molecular docking (MD) assay enunciated that hinokiflavone directly bonded to ClpP with confirmed docking sites, including SER-22, LYS-26 and ARG-28. In vivo, the evaluation of anti-infective activity showed that hinokiflavone in combination with vancomycin effectively protected mice from MRSA-induced fatal pneumonia, which was more potent than vancomycin alone. As mentioned above, hinokiflavone, as an inhibitor of ClpP, could be further developed into a promising adjuvant against S. aureus infections.

We conducted a phase I bioequivalence trial in healthy Chinese subjects in the fasting and postprandial states. The goal of this trial was to compare the pharmacokinetics and safety of the test preparation Cefaclor granule (Disha Pharmaceutical Group Co., Ltd.) and the reference preparation Cefaclor suspension (Ceclor®, Eli Lilly and Company). In this trial, 24 subjects were selected in the fasting and postprandial states, respectively. Enrolled subjects randomly accepted a single dose of 0.125 g Cefaclor granule or Cefaclor suspension. The washout period was set as 2 days. Blood samples were collected within 8 h after administration in the fasting state and within 10 h after administration in the postprandial state. Plasma concentrations were determined by Liquid chromatography-tandem mass spectrometry (LC-MS/MS). Pharmacokinetic parameters (AUC, Cmax) were used to evaluate bioequivalence of the two drugs. In the fasting trial, the geometric mean ratios (90% confidence intervals CIs) for Cmax, AUC0-t, and AUC0-∞ were 93.01% (85.96%–100.63%), 97.92% (96.49%–99.38%) and 97.95% (96.52%–99.41%), respectively. The GMR (90% CIs) for Cmax, AUC0-t, and AUC0-∞ in postprandial state were 89.27% (81.97%–97.22%), 97.31% (95.98%–98.65%) and 97.31% (95.93%–98.71%), respectively. The 90% CIs of AUC and Cmax in the fasting and postprandial states were within the 80–125% bioequivalence range. Therefore, Cefaclor granule and Cefaclor suspension were bioequivalent and displayed similar safety profiles. Furthermore, food intake affected the pharmacokinetic parameters of both drugs.

This study aimed to identify hibifolin as a sortase A (SrtA) inhibitor and to determine whether it could attenuate the virulence of methicillin-resistant Staphylococcus aureus (MRSA). We employed a fluorescence resonance energy transfer (FRET) assay to screen a library of natural molecules to identify compounds that inhibit SrtA activity. Fluorescence quenching assay and molecular docking were performed to verify the direct binding interaction between SrtA and hibifolin. The pneumonia model was established using C57BL/6J mice by MRAS nasal administration for evaluating the effect of hibifolin on the pathogenicity of MRSA. Herein, we found that hibifolin was able to inhibit SrtA activity with an IC

Funding Information: This work was supported by the National Key Research and Development Program of China ( 2022YFB4101800 ). The financial support from the National Natural Science Foundation of China under contract number 22075205 is gratefully acknowledged. The work has been also supported by the Program of Introducing Talents to the University Disciplines under file number B06006 , and the Program for Changjiang Scholars and Innovative Research Teams in Universities under file number IRT 0641 . Publisher Copyright: © 2023 The Authors Photocatalytic N-formylation of amines with CO2 is a promising strategy to convert CO2 into value-added chemicals sustainably. In this work, a black TiO2-supported Cu photocatalyst is prepared through a solvothermal method for the N-formylation of N-methylaniline with NaBH4 as the reducing agent. Cu nanoparticles and oxygen vacancies are formed on the surface of the photocatalyst after reduction with H2, which decreases the band-gap energy and promotes the separation of photogenerated electrons and holes, thereby improving the photocatalytic activity remarkably. A 100 % conversion is achieved after 9 h radiation, and the yield of N-methylformanilide reaches 81 %. Both the amount of NaBH4 and the pressure of CO2 show important influences on the activity and selectivity of the photocatalytic process, and the carbon and hydrogen in the aldehyde group are from CO2 and NaBH4, respectively. The photocatalyst also shows promising cycling durability.

DNA self-assembled nanostructures have been considered as effective vehicles for biomolecule delivery because of their excellent biocompatibility, cellular permeability, noncytotoxicity, and small size. Here, we report an efficient antiviral strategy with self-assembled tetrahedral framework nucleic acids (tFNAs) delivering small interfering RNA (t-siRNA) to silence classical swine fever virus (CSFV) gene in porcine host cells. In this study, two previously reported siRNAs, C3 and C6, specifically targeting the CSFV genome were selected and modified on tFNAs, respectively, and termed t-C3 and t-C6. Results indicate that t-C3 and t-C6 can inhibit the viral proliferation of CSFV in kidney derived porcine cells, PK-15, effectively and that inhibition was markedly stronger than free siRNA-C3 or siRNA-C6 only. In addition, the DNA nanostructure also has high cargo-carrying capacity, allowing to deliver multiple functional groups. To improve the antiviral ability of tFNAs, a dual-targeting DNA nanostructure t-C3-C6 was constructed and used to silence the CSFV gene in porcine host cells. This study found that t-C3-C6 can inhibit the viral release and replication, exhibiting outstanding anti-CSFV capabilities. Therefore, these dual-targeting tFNAs have great potential in virus therapy. This strategy not only provides a novel method to inhibit CSFV replication in porcine cells but also verifies that tFNAs are effective tools for delivery of antiviral elements, which have great application potential.

MWW derivatives zeolite of MCM-22 with 3D layer structure, MCM-56 with partial disordered layer, MCM-36 with pillared layer and ITQ-2 with delaminated layer were prepared by hydrothermal synthesis and further modification to investigate the effect of acidic and interlayer structure on the catalytic performance of ethane dehydroaromatization and ethylene aromatization. With the retention of the MWW structure and confirmation of the intercalation or delamination efficiency, it was found that the increased exposed half-cup pocket and aluminum site on the external MWW layer structure can improve the xylene selectivity and catalytic stability. Although the amounts of total and strong acid site of H-form ITQ-2, MCM-36, MCM-56 are lower than those of MCM-22, the ratio of Lewis(L)/Bronsted(B) acid sites increases, which indicates that the exposed tri-coordinated framework aluminum in the half-cup pocket of external surface generated by exfoliation and pillaring can acted as the L acid sites. After loading Zn species, the strong acid amount and L acid sites amount are improved by the interaction between the loaded Zn species and MWW framework aluminum. The impregnated Zn species exist on the MWW zeolite with the state of ZnO and ZnAl2O4. The Zn species play roles of both ethane dehydrogenation and ethylene aromatization. The strong B acid sites play an important role for the oligomerization and aromatization of light olefins, while the excess amount of strong acid sites causes the increasing of cracking step which favors for light olefins production.

SARS-CoV-2, the causative agent of the COVID-19 pandemic, undergoes continuous evolution, highlighting an urgent need for development of novel antiviral therapies. Here we show a quantitative mass spectrometry-based succinylproteomics analysis of SARS-CoV-2 infection in Caco-2 cells, revealing dramatic reshape of succinylation on host and viral proteins. SARS-CoV-2 infection promotes succinylation of several key enzymes in the TCA, leading to inhibition of cellular metabolic pathways. We demonstrated that host protein succinylation is regulated by viral nonstructural protein (NSP14) through interaction with sirtuin 5 (SIRT5); overexpressed SIRT5 can effectively inhibit virus replication. We found succinylation inhibitors possess significant antiviral effects. We also found that SARS-CoV-2 nucleocapsid and membrane proteins underwent succinylation modification, which was conserved in SARS-CoV-2 and its variants. Collectively, our results uncover a regulatory mechanism of host protein posttranslational modification and cellular pathways mediated by SARS-CoV-2, which may become antiviral drug targets against COVID-19.

Hypopharyngeal squamous cell carcinoma (HSCC) is one of the high mortality cancers with a poor prognosis, which is driving the development of new chemotherapeutic agents. We identified the anticancer effects of a natural compound, solamargine (SM), on FaDU cells and explored its mechanism in terms of non-coding RNA. It was observed that SM inhibited the proliferation of FaDU cells with an IC50 of 5.17 μM. High-throughput sequencing data revealed that lncRNA HOXA11-AS was significantly downregulated in cells co-incubated with SM. Further assays demonstrated that SM-induced downregulation of lncRNA HOXA11-AS showed important implications for apoptosis. Given the properties of HOXA11-AS as a miR-155 sponge, we further confirmed that SM upregulated the expression of miR-155 in FaDU cells. C-Myc is a transcription factor that regulates cell differentiation and apoptosis, whose mRNA is considered to be targeted by miR-155. We showed that c-Myc expression was downregulated by SM and accompanied by increased apoptosis, which was consistent with the findings of transcriptome sequencing. Furthermore, SM administration suppressed xenograft tumor growth in a xenograft mouse model in vivo. In the light of the aforementioned findings, our results suggested that SM downregulated the expression of HOXA11-AS, which in turn induces apoptosis by downregulating c-Myc in FaDU, providing evidence for the anticancer effect of SM on HSCC and uncovering the effect of SM on non-coding RNAs as, at least partly, a mechanism of action.

Due to increasing antibiotic resistance, targeting bacterial virulence factors is now gaining further interest as an alternative strategy to develop novel classes of anti-infective agents. The critical role of α-hemolysin (Hla), an indispensable virulence determinant, in the pathogenicity of Staphylococcus aureus renders this virulence factor an appealing target for effective therapeutic applications. Herein, we identified a natural compound schisandraone, as an effective Hla inhibitor, which could inhibit Hla production and thus hemolytic activity in a dose-dependent manner without affecting the growth of S. aureus. We also found that the addition of schisandrone could down-regulate the transcriptional levels of the hla, agrA and RNAIII and significantly alleviated Hla-mediated injury of A549 cells co-cultured with S. aureus. In vivo studies further suggested that schisandrone combined with antibiotic ceftiofur exhibited a significant therapeutic effect on S. aureus infection. These findings revealed the role of schisandrone in inhibiting the activity of Hla and we believe that it is a promising anti-virulence candidate to combat MRSA pneumonia.

Antimicrobial resistance (AMR) poses a major threat to human health globally. Staphylococcus aureus is recognized as a cause of disease worldwide, especially methicillin-resistant S. aureus (MRSA) and vancomycin-resistant S. aureus (VRSA). The enzyme sortase A (SrtA), present on the cell surface of S. aureus, plays a key role in bacterial virulence without affecting the bacterial viability, and SrtA-deficient S. aureus strains do not affect the growth of bacteria. Here, we found that punicalagin, a natural compound, was able to inhibit SrtA activity with a very low half maximal inhibitory concentration (IC(50)) value of 4.23 μg/mL, and punicalagin is a reversible inhibitor of SrtA. Moreover, punicalagin has no distinct cytotoxicity toward A549, HEK293T, or HepG2 cells at a much higher concentration than the IC(50) detected by MTT [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide] assays. In addition, punicalagin visibly attenuated the virulence-related phenotype of SrtA in vitro by decreasing adhesion of S. aureus to fibrinogen, reducing the ability of protein A (SpA) displayed on the surface of the bacteria and biofilm formation. Fluorescence quenching elucidated the interaction between punicalagin and SrtA. Molecular docking further implied that the inhibitory activity lay in the bond between punicalagin and SrtA residues LYS190, TYR187, ALA104, and GLU106. In In vivo studies, we surprisingly found that punicalagin had a more effective curative effect combined with cefotaxime when mice were infected with pneumonia caused by MRSA. Essentially, punicalagin, a therapeutic compound targeting SrtA, demonstrates great potential for combating MRSA infections.

Summary Search for resource-efficient materials in vast compositional spaces is an outstanding challenge in creating environmentally stable perovskite semiconductors. We demonstrate a physics-constrained sequential learning framework to subsequently identify the most stable alloyed organic-inorganic perovskites. We fuse data from high-throughput degradation tests and first-principle calculations of phase thermodynamics into an end-to-end Bayesian optimization algorithm using probabilistic constraints. By sampling just 1.8% of the discretized CsxMAyFA1−x−yPbI3 (MA, methylammonium; FA, formamidinium) compositional space, perovskites centered at Cs0.17MA0.03FA0.80PbI3 show minimal optical change under increased temperature, moisture, and illumination with >17-fold stability improvement over MAPbI3. The thin films have 3-fold improved stability compared with state-of-the-art multi-halide Cs0.05(MA0.17FA0.83)0.95Pb(I0.83Br0.17)3, translating into enhanced solar cell stability without compromising conversion efficiency. Synchrotron-based X-ray scattering validates the suppression of chemical decomposition and minority phase formation achieved using fewer elements and a maximum of 8% MA. We anticipate that this data fusion approach can be extended to guide materials discovery for a wide range of multinary systems.

Afatinib is an oral, irreversible ErbB family blocker. It binds covalently to the kinase domains of epidermal growth factor (EGFR), HER2 and HER4, resulting in irreversible inhibition of tyrosine kinase autophosphorylation. Our trial compared the bioequivalence and safety between afatinib produced by Chia Tai Tianqing Pharmaceutical Group Co., Ltd. and GiotrifHealthy Chinese subjects (N = 36) were randomly divided into two groups at a ratio of 1:1. There was a single dose per period of afatinib and GiotrifThe geometric mean ratios (GMRs) of CThis study showed that afatinib was bioequivalent to GiotrifThis trial is registered at the Chinese Clinical Trial website ( http://www.chinadrugtrials.org.cn/index.html # CTR20171160).

The resistance of Staphylococcus aureus ( S. aureus ) to various antibiotics has increased dramatically, and thus the development of new anti-infective drugs with new targets is urgently needed to combat resistance. Caseinolytic peptidase P (ClpP) is a casein hydrolase that has been shown to regulate a variety of important virulence factors in S. aureus .

Background Calcium ions (Ca2+) participates in various intracellular signal cascades and especially plays a key role in pathways relevant to cancer cells. Mitochondrial metabolism stimulated by calcium overload can trigger the opening of the mitochondrial permeability transition pore (MPTP), which leads to cancer cell death. Methods Herein, a mitochondrial pathway for tumour growth inhibition was built via the double-activation of MPTP channel. Fe2+ doped covalent organic frameworks (COF) was synthesised and applied as template to grow CaCO3 shell. Then O2 was storaged into Fe2+ doped COF, forming O2-FeCOF@CaCO3 nanocomposite. After modification with folic acid (FA), O2-FeCOF@CaCO3@FA (OFCCF) can target breast cancer cells and realize PDT/Ca2+ overload synergistic treatment. Results COF can induce the production of 1O2 under 650 nm irradiation for photodynamic therapy (PDT). Low pH and hypoxia in tumour microenvironment (TME) can activate the nanocomposite to release oxygen and Ca2+. The released O2 can alleviate hypoxia in TME, thus enhancing the efficiency of COF-mediated PDT. Abundant Ca2+ were released and accumulated in cancer cells, resulting in Ca2+ overload. Notably, the reactive oxygen species (ROS) and Ca2+ overload ensure the sustained opening of MPTP, which leads to the change of mitochondria transmembrane potential, the release of cytochrome c (Cyt c) and the activation of caspases 3 for cancer cell apoptosis. Conclusion This multifunctional nanosystem with TME responded abilities provided a novel strategy for innovative clinical cancer therapy. Graphical Abstract