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Cisplatin resistance is a major therapeutic challenge in advanced head and neck squamous cell carcinoma (HNSCC). Here, we aimed to investigate the key signaling pathway for cisplatin resistance in HNSCC cells. Vomeronasal type-1 receptor 5 (VN1R5) was identified as a cisplatin resistance-related protein and was highly expressed in cisplatin-resistant HNSCC cells and tissues. The long noncoding RNA (lncRNA) lnc-POP1-1 was confirmed to be a downstream target induced by VN1R5. VN1R5 transcriptionally regulated lnc-POP1-1 expression by activating the specificity protein 1 (Sp1) transcription factor via the cyclic AMP (cAMP)/protein kinase A (PKA) pathway. VN1R5 promoted cisplatin resistance in HNSCC cells in a lnc-POP1-1-dependent manner. Mechanistically, lnc-POP1-1 bound to the minichromosome maintenance deficient 5 (MCM5) protein directly and decelerated MCM5 degradation by inhibiting ubiquitination of the MCM5 protein, which facilitated the repair of DNA damage caused by cisplatin. In summary, we identified the cisplatin resistance-related protein VN1R5 and its downstream target lnc-POP1-1. Upon upregulation by VN1R5, lnc-POP1-1 promotes DNA repair in HNSCC cells through interaction with MCM5 and deceleration of its degradation.

Acute kidney injury (AKI) is a serious complication in critically ill patients. Accumulating evidences indicated that macrophages play an important pro-inflammatory role in AKI and isoliquiritigenin (ISL) can inhibit macrophagic inflammation, but its role in AKI and the underlying mechanism are unknown. The present study aims to investigate the renoprotective effect of ISL on AKI and the role of Formyl peptide receptors 2 (FPR2) in this process. In this study, cisplatin-induced AKI model and lipopolysaccharide-induced macrophage inflammatory model were employed to perform the in vivo and in vitro experiments. The results showed that ISL strongly relieved kidney injury and inhibited renal inflammation in vivo and suppress macrophagic inflammatory response in vitro. Importantly, it was found that FPR2 was significantly upregulated compared to the control group in AKI and LPS-induced macrophage, whereas it was strongly suppressed by ISL. Interestingly, overexpression of FPR2 with transfection of pcDNA3.1-FPR2 effectively reversed the anti-inflammatory effect of ISL in macrophage, suggesting that FPR2 may be the potential target for ISL to prevent inflammation and improve kidney injury of AKI. Take together, these findings indicated that ISL improved cisplantin-induced kidney injury by inhibiting FPR2 involved macrophagic inflammation, which may provide a potential therapeutic option for AKI.

Aims: This research explored the effect of exogenous abscisic acid (ABA) treatment on sugar metabolism in tomato fruits, and provided theoretical basis for the regulation of ABA on the growth and development of tomato fruits. Study Design: The whole tomato plant was treated by spraying with 50 mg·L-1 ABA. Spraying distilled water was as the control. Place and Duration of Study: College of Biological Science and Technology, between February 2019 and March 2020. Methodology: The contents of soluble sugar in tomato fruits were measured with HPLC (High performance liquid chromatography). The enzyme extraction and activities were followed the biochemical method. Results: Exogenous ABA treatment reduced the weight and transverse meridians of the fruit at the ripening stage, but increased the contents of fructose, glucose and sucrose in the fruit. At the same time, it also increased the activities of acid invertase, neutral invertase, and sucrose phosphate synthase at the ripening stage. Conclusions: Exogenous ABA treatment was beneficial to the accumulation of sugar in tomato fruit and improved tomato quality. Therefore, it could be applied to tomato production.

All-solid-state batteries are intensively investigated, although their performance is not yet satisfactory for large-scale applications. In this context, the combination of Li10GeP2S12 solid electrolyte and LiNi1-x-yCoxMnyO2 positive electrode active materials is considered promising despite the yet unsatisfactory battery performance induced by the thermodynamically unstable electrode|electrolyte interface. Here, we report electrochemical and spectrometric studies to monitor the interface evolution during cycling and understand the reactivity and degradation kinetics. We found that the Wagner-type model for diffusion-controlled reactions describes the degradation kinetics very well, suggesting that electronic transport limits the growth of the degradation layer formed at the electrode|electrolyte interface. Furthermore, we demonstrate that the rate of interfacial degradation increases with the state of charge and the presence of two oxidation mechanisms at medium (3.7 V vs. Li+/Li < E vs. Li+/Li) and high (E ≥ 4.2 V vs. Li+/Li) potentials. A high state of charge (>80%) triggers the structural instability and oxygen release at the positive electrode and leads to more severe degradation.

Mitogen-activated protein kinase-interacting kinases (MNKs) and provirus integration in maloney murine leukemia virus kinases (PIMs) are downstream enzymes of cell proliferation signaling pathways associated with the resistance of tyrosine kinase inhibitors. MNKs and PIMs have complementary effects to regulate cap-dependent translation of oncoproteins. Dual inhibitors of MNKs and PIMs have not been developed. We developed a novel 4,6-disubstituted pyrido[3,2-d]pyrimidine compound 21o with selective inhibition of MNKs and PIMs. The IC50's of 21o to inhibit MNK1 and MNK2 are 1 and 7 nM and those to inhibit PIM1, PIM2, and PIM3 are 43, 232, and 774 nM, respectively. 21o inhibits the growth of myeloid leukemia K562 and MOLM-13 cells with GI50's of 2.1 and 1.2 μM, respectively. 21o decreases the levels of p-eIF4E and p-4EBP1, the downstream products of MNKs and PIMs, as well as cap-dependent proteins c-myc, cyclin D1, and Mcl-1. 21o inhibits the growth of MOLM-13 cell xenografts without causing evident toxicity. 21o represents an innovative dual MNK/PIM inhibitor with a good pharmacokinetic profile.

An efficient synthesis of indolo[2,1-a]benzazepinones through rhodium-catalyzed cascade reactions of 2-arylindoles with allyl alcohols has been developed. This work expands the scope of products that are available through C-H activation/intramolecular annulation reactions of 2-arylindoles in organic synthesis.

The Rh(III)-catalyzed dual directing group assisted C-H activation/annulation of 3-arylisoxazolones with propargyl alcohols has been developed, which expands the application scope of isoxazolones in organic synthesis. This protocol also worked well with 3-aryl-1,4,2-dioxazol-5-ones to produce synthetically and biologically important 4-arylisoquinolones.

Molecules bearing separate π-electron donor (D) and acceptor (A) groups that undergo face-to-face D/A interactions have been utilized to develop thermally activated delayed fluorescence (TADF) mate...

NAC (NAM, ATAF1/2, CUC2) transcription factors play important roles in plant growth, development, and responses to abiotic stress. In this study, we cloned an NAC2 subfamily transcription factor gene (SlNAC7) from the halophyte Suaeda liaotungensis K., and conducted a series of studies to determine the characteristics and functions of this gene. The SlNAC7 coding region contains 1719 base pairs that encode a 573 amino acid long protein. SlNAC7 is expressed in the roots, stems, and leaves of S. liaotungensis, with the highest expression in the leaves. We found that SlNAC7 expression can be induced by drought, salt, cold, and abscisic acid. Transient expression in onion epidermal cells revealed that SlNAC7 is located in both the nucleus and cytoplasm. A transcriptional activation experiment in yeast showed that the transcriptional activation domain of SlNAC7 is located at the C terminus. When SlNAC7 was transformed into Arabidopsis under the control of a CaMV 35S promoter its overexpression was found to enhance the ability of transgenic plants to resist drought, salt, and cold stress. Moreover, these plants showed multiple changes in growth characteristics and physiological and biochemical indices in response to different stresses, as well as the upregulation of numerous stress-related genes. We have thus characterized a new halophyte-derived NAC transcription factor, SlNAC7, which can regulate plant growth and physiological and biochemical changes under adverse conditions by regulating the expression of stress-related genes, thereby enhancing plant stress resistance. SlNAC7 is a promising candidate for breeding new varieties of stress-tolerant crops.

Fe4N nanopowders were prepared using specially-made high-pressure gas-solid reaction equipment, and their composition, morphology, and magnetic properties were analyzed by X-ray diffraction (XRD), transmission electron microscopy (TEM), and vibrating sample magnetometry (VSM). An average particle size of 35 nm was obtained at 0.4 MPa, an ammonia-to-hydrogen ratio of 3:1, 623 K, in an ammonia solution for 2 h. The hysteresis loop displayed a thin and narrow shape at 673 K during VSM tests. The saturation magnetization (Ms) reached 169.80 emu/g.

Two new Schiff base copper(II) complexes, [Cu2L2] (I) and [Cu2L(NCNCN)2]n (II), where L is the dianionic form of N,N'-bis(5-fluorosalicylidene)-1,3-propanediamine (H2L), were synthesized and characterized by elemental analyses, infrared and electronic spectroscopy, and single crystal X-ray determinations (CIF files CCDC. nos. 2000415 (I) and 2000416 (II)). Complex I is a phenolate bridged dinuclear copper(II) compound. Complex II is a phenolate and dicyanoamide bridged polynuclear copper(II) compound. In both complexes, the Cu atoms are in square pyramidal coordination. The Schiff base ligand coordinates to the Cu atoms through the phenolate O and imino N atoms. The Schiff base H2L and the two complexes showed high selectivity and antimicrobial activities against a number of the bacteria and fungi.

A new copper(II) complex [Cu(L 1 )(NCS)(CH 3 OH)] ( 1 ) and a new zinc(II) complex [ZnCl 2 (HL 2 )]·CH 3 OH ( 2 ), derived from 4-bromo- N' -(pyridin-2-ylmethylene)benzohydrazide (HL 1 ) and 4-methoxy- N' -(pyridin-2-ylmethylene)benzohydrazide (HL 2 ), were prepared and characterized by elemental analysis, IR and UV-Vis spectroscopy and single crystal X-ray diffraction. The hydrazone HL 1 coordinates to the Cu atom in enolate form, while the hydrazone HL 2 coordinates to the Zn atom in carbonyl form. Single crystal structural analyses indicate that the hydrazones coordinate to the metal atoms through the pyridine N, imino N, and enolate/carbonyl O atoms. The Cu atom in complex 1 is in square pyramidal coordination, and the Zn atom in complex 2 is in trigonal-bipyramidal coordination. The inhibitory effects of the complexes on Jack bean urease were studied, which show that the copper complex has strong activity on urease.

During the quantitative analysis of NaCl, NaOH, and β-phenylethylamine (PEA) in water samples, the highly overlapped spectra of NaCl, NaOH, and PEA resulted in poor concentration prediction. Meanwhile, the original spectral data of the natural water usually contain noise and interference spectra which will definitely affect the prediction accuracy. Hence, a new quantitative analysis method, which was based on ultraviolet (UV) spectroscopy coupled with partial least squares (PLS) and net analyte preprocessing (NAP), was developed. Firstly, the PLS regression models of the calibration set were constructed by using 15 single component samples, 9 binary component samples and 25 ternary component samples. In addition, the independent test set was built up based on 34 samples to validate the prediction performance of the PLS regression models. The relative errors of prediction (REP) were both less than 3.1% for NaCl, NaOH, and PEA. And the correlation coefficients (Rpred 2 ) of the PLS-1 and PLS-2 models were both not less than 0.98 for NaCl, NaOH, and PEA. Finally, the PLS models coupled with NAP algorithm were successfully used to make the quantitative determination of NaCl, NaOH, and PEA added into the natural water, and the mean recovery rates of NaCl, NaOH, and PEA were satisfactory (95-102%). Therefore, UV spectroscopy coupled with PLS models and NAP algorithm can be considered as an effective method to determine the concentration of NaCl, NaOH and PEA in the natural water

Unstable electrode/solid-state electrolyte interfaces and internal lithium dendrite penetration hamper the applications of solid-state lithium-metal batteries (SSLMBs), and the underlying mechanisms are not well understood. Herein, in situ optical microscopy provides insights into the lithium plating/stripping processes in a gel polymer electrolyte and reveals its dynamic evolution. Spherical lithium deposits evolve into moss-like and branch-shaped lithium dendrites with increasing current densities. Remarkably, the on-site-formed solid electrolyte interphase (SEI) shell on the lithium dendrite is distinctly captured after lithium stripping. Inducing an on-site-formed SEI shell with an enhanced modulus to wrap the lithium precipitation densely and uniformly can regulate dendrite-free behaviors. An in-depth understanding of lithium dendrite evolution and its functional SEI shell will aid in the optimization of SSLMBs.

Calcium ion (Ca2+) is an indispensable second messenger in living organisms. The impaired Ca2+ handling can induce many diseases. In this paper, we developed a simple and effective method to encapsulate a coumarin-based Ca2+ probe ((E)-2-hydroxy-N′-((7-hydroxy-2-oxo-2H-chromen-8-yl)methylene)-2-phenylacetohydrazide, CPM) into nanoparticles (NPs), and CPM NPs with blue fluorescence were obtained, whose maximum excitation and maximum emission wavelengths were characterized at 365 nm and 450 nm, respectively. The CPM NPs show significant fluorescence enhancement toward Ca2+ over other metal ions, with a limit of determination (LOD) of 0.04 μM. To optimize the optical property of the NPs, CPM and curcumin, which were introduced as the Forster resonance energy transfer (FRET) donor and acceptor, respectively, were co-encapsulated, and bright green CPM@Cur NPs with large stokes shift and narrow emission band width were constructed. Due to their low cytotoxicity and excellent stability, CPM NPs and CPM@Cur NPs were further successfully used to discriminate the primary aortic smooth muscle cells isolated from mice with abnormal Ca2+ homeostasis from their littermate controls. It is worth noting that CPM@Cur NPs exhibit stronger fluorescence signal and diminished background interference, which make them have great potential in the Ca2+ monitoring during biological processes. This strategy opens a new way to synthesize NPs with high brightness and has a potential application prospect in composite sensing and intracellular imaging.

Emerging evidence has implicated poly-(ADP-ribose) polymerase 1 (PARP-1), a transcriptional coregulator, in a variety of inflammatory diseases. In the current study, the role of PARP-1 in neuropathic pain and the underlying mechanisms were investigated. Neuropathic pain was determined by assessing the paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) following lumbar 5 spinal nerve ligation (SNL) in male rates. Western blotting, qRT-PCR, immunohistochemistry, chromatin immunoprecipitation (ChIP), and Co-IP assays were performed to elucidate the mechanisms. The results showed that SNL resulted in a significant increase in the expression and activation of PARP-1 in the ipsilateral L4/5 dorsal root ganglia (DRG) and spinal dorsal horn, which occurred on day one, reached peak on day 7, and persisted more than 2 weeks after surgery. Double immunofluorescence staining revealed that PARP-1 was expressed exclusively in DRG A-type and C-type neurons. In the spinal cord, PARP-1 mainly colocalized with the neuronal marker NeuN and the astrocytic marker GFAP specifically in the superficial lamina. Prior intrathecal (i.t.) injection of PJ-34, a PARPs inhibitor, or Tiq-A, a specific PARP-1 inhibitor, dose-dependently prevented the reductions in PWT and PWL following SNL. Established neuropathic pain-like hypersensitivity was also attenuated with i.t. injection of PJ-34 and Tiq-A starting on day 7 following SNL, a timepoint at which neuropathic pain was fully established. SNL-induced mechanical allodynia and thermal hyperalgesia were also alleviated by i.t. injection of PARP-1 siRNA following a reduction in PARP-1 expression in the dorsal horn. Moreover, the SNL-induced increases in TNF-α protein and mRNA in the dorsal horn and DRG were dramatically suppressed by i.t. injection of Tiq-A or PARP-1 siRNA. The i.t. lipopolysaccharide (LPS)-induced increase in the production of TNF-α in the dorsal horn was also inhibited by prior to i.t. injection of PARP-1 siRNA. Results of ChIP assay showed that SNL-induced PARP-1 activation promoted the binding of NF-κB p65 with the TNF-α promoter in the dorsal horn and that PARP-1 inhibition reduced this binding and suppressed TNF-α expression. Co-IP assay revealed that SNL caused a significant increase in the level of histone H1 poly(ADP)–ribosylation. Together, these results indicate that PARP-1-regulated TNF-α expression in the DRG and spinal dorsal horn following SNL contributes to the development and maintenance of neuropathic pain. Targeting PARP-1 might be a promising therapeutic strategy for the treatment of the chronic pain.

Aims It has been reported that allopregnanolone (APα) promotes the neurogenesis of the neural progenitor cells (NPCs) in the subventricular zone (SVZ) and prevents the decrease of dopaminergic neurons in 6‐hydroxydopamine (6‐OHDA)‐treated mice by binding to γ‐aminobutyric acid A receptor (GABAAR) and then opening voltage‐gated L‐type Ca2+ channel, but the underlying mechanisms remain elusive. The aim of this study was to explore the possible involvement of GABAAR and calcium/calmodulin‐dependent protein kinase II delta 3 (CaMKIIδ3) in this process. Methods 6‐OHDA‐treated mice and primary cultured midbrain cells were administrated with APα and GABAAR antagonist bicuculline (Bic), and the proliferation and differentiation of NPCs, the tyrosine hydroxylase (TH)‐positive neurons and their fibers, the expression levels of CaMKIIδ3 and brain‐derived neurotrophic factor (BDNF), and motor functions were measured using ELISA, immunohistochemical staining, real‐time RT‐PCR, Western blot, and behavioral test. Results Allopregnanolone significantly promoted the phosphorylation of cytoplasmic CaMKIIδ3 and its nuclear translocation by binding to GABAAR, which, in turn, increased the expression levels of BDNF. This may account for the findings that the exogenous APα enhanced the proliferation and differentiation of NPCs, and ameliorated the nigrostriatal system and behavioral performance in 6‐OHDA‐treated mice. Conclusions Allopregnanolone may directly activate GABAAR, which, in turn, enhance the proliferation and differentiation of NPCs via upregulating the expression levels of CaMKIIδ3, and finally contribute to the restoration of dopaminergic neurons in 6‐OHDA‐treated mice., APα significantly promotes the phosphorylation of cytoplasmic CaMKIIδ3 and its nuclear translocation by binding to GABAAR, which, in turn, increases the expression levels of cell cycle protein and BDNF. This may account for the findings that APα enhances the proliferation and differentiation of NPCs, and ameliorates the deficiency of dopaminergic neurons in 6‐OHDA‐treated mice and primary cultured midbrain cells.

The photocatalytic conversion of CO2 to energy-rich CH4 solar fuel is an ideal strategy for future energy generation as it can resolve global warming and the imminent energy crisis concurrently. Ho...

Purpose Chronic kidney disease (CKD) is a global nephrotic syndrome characterized by chronic inflammation, oxidative stress and fibrosis in the kidney. Isoliquiritigenin (ISL), a flavonoid from licorice, has historically been reported to inhibit innate immune responses to inflammation and fibrosis in vivo. However, the effect of ISL on CKD progression is largely unknown.

Hydrogen sulfide (H(2)S), a plant gasotransmitter, functions in the plant response to cadmium (Cd) stress, implying a role for cysteine desulfhydrase in producing H(2)S in this process. Whether d-CYSTEINE DESULFHYDRASE (DCD) acts in the plant Cd response remains to be identified, and if it does, how DCD is regulated in this process is also unknown. Here, we report that DCD-mediated H(2)S production enhances plant Cd tolerance in Arabidopsis (Arabidopsis thaliana). When subjected to Cd stress, a dcd mutant accumulated more Cd and reactive oxygen species and showed increased Cd sensitivity, whereas transgenic lines overexpressing DCD had decreased Cd and reactive oxygen species levels and were more tolerant to Cd stress compared with wild-type plants. Furthermore, the expression of DCD was stimulated by Cd stress, and this up-regulation was mediated by a Cd-induced transcription factor, WRKY13, which bound to the DCD promoter. Consistently, the higher Cd sensitivity of the wrky13-3 mutant was rescued by the overexpression of DCD. Together, our results demonstrate that Cd-induced WRKY13 activates DCD expression to increase the production of H(2)S, leading to higher Cd tolerance in plants.

The urgent demands for high-energy-density rechargeable batteries promote a flourishing development of Li metal anode. However, the uncontrollable dendrites growth and serious side reactions severely limit its commercial application. Herein, an artificial LiF-rich solid electrolyte interphase (SEI) is constructed at molecular-level using one-step photopolymerization of hexafluorobutyl acrylate based solution, where the LiF is in situ generated during photopolymerization process (denoted as PHALF). The LiF-rich layer comprised flexible polymer matrix and inorganic LiF filler not only ensures intimate contact with Li anode and adapts volume fluctuations during cycling but also regulates Li deposition behavior, enabling it to suppress the dendrite growth and block side reactions between the electrolyte and Li metal. Accordingly, the PHALF-Li anode presents superior stable cycling performance over 500 h at 1 mA·cm−2 for 1 mA·h·cm−2 without dendrites growth in carbonate electrolyte. The work provides a novel approach to design and build in situ artificial SEI layer for high-safety and stable Li metal anodes.

In recent years, peptide/protein drugs have attracted considerable attention owing to their superior targeting and therapeutic effect and fewer side effects compared with chemical drugs. Oral administration modality with enhanced patient compliance is increasingly being recognized as an ideal route for peptide/protein delivery. However, the limited permeation efficiency and low oral bioavailability of peptide/protein drugs significantly hinder therapeutic advances. To address these problems, various nano and microscale delivery platforms have been developed, which offer significant advantages in oral peptide/protein delivery. In this review, we briefly introduce the transport mechanisms of oral peptide/protein delivery and the primary barriers to this delivery process. We also highlight the recent advances in various nano and microscale delivery platforms designed for oral peptide/protein delivery. We then summarize the existing strategies used in these delivery platforms to improve the oral bioavailability and permeation efficiency of peptide/protein therapeutics. Finally, we discuss the major challenges faced when nano and microscale systems are used for oral peptide/protein delivery. This review is expected to provide critical insight into the design and development of oral peptide/protein delivery systems with significant therapeutic advances.

A structure-determined gold-levonorgestrel nanocluster, Au10(C21H27O2)10 (Au10NC), has been obtained via solvent induced crystal transformation from Au8(C21H27O2)8 (Au8NC), accompanied by a fluorescence color change from green to yellow. A cationic polymer, poly(allylamine hydrochloride) (PAH), was chosen to assemble with Au10NC to prepare monodisperse and stable particles (Au10NC-PAH) with an increased quantum yield of 49.8%. The as-fabricated Au10NC-PAH realized effective antibody-mediated actin imaging and sustained drug release.

Objective The objective of this open-label, randomized study was to compare dose-dense paclitaxel plus carboplatin (PCdd) with dose-dense epirubicin and cyclophosphamide followed by paclitaxel (ECdd-P) as an adjuvant chemotherapy for early triple-negative breast cancer (TNBC). Methods We included Chinese patients with high recurrence risk TNBC who underwent primary breast cancer surgery. They were randomly assigned to receive PCdd [paclitaxel 150 mg/m2 on d 1 and carboplatin, the area under the curve, (AUC)=3 on d 2] or ECdd-P (epirubicin 80 mg/m2 divided in 2 d and cyclophosphamide 600 mg/m2 on d 1 for 4 cycles followed by paclitaxel 175 mg/m2 on d 1 for 4 cycles) every 2 weeks with granulocyte colony-stimulating factor (G-CSF) support. The primary endpoint was 3-year disease-free survival (DFS); the secondary endpoints were overall survival (OS) and safety. Results The intent-to-treat population included 143 patients (70 in the PCdd arm and 73 in the ECdd-P arm). Compared with the ECdd-P arm, the PCdd arm had significantly higher 3-year DFS [93.9% vs. 79.1%; hazard ratio (HR)=0.310; 95% confidence interval (95% CI), 0.137-0.704; log-rank, P=0.005] and OS (98.5% vs. 92.9%; HR=0.142; 95% CI, 0.060-0.825; log-rank, P=0.028). Worse neutropenia (grade 3/4) was found in the ECdd-P than the PCdd arm (47.9% vs. 21.4%, P=0.001). Conclusions PCdd was superior to ECdd-P as an adjuvant chemotherapy for early TNBC with respect to improving the 3-year DFS and OS. PCdd also yielded lower hematological toxicity. Thus, PCdd might be a preferred regimen for early TNBC patients with a high recurrence risk.

Survival data have shown little therapeutic improvement in pancreatic ductal adenocarcinoma (PDAC) over the past several decades, mostly due to aggressive growth and resistance to therapy. Glutathione (GSH) depletion in PDAC may serve as a strategy to suppress tumour malignancy and sensitize tumour cells to therapy. Herein, novel l-cysteine-based poly(disulfide amide) polymers were fabricated to deliver a histone methyltransferase G9a inhibitor (UNC0638) that can simultaneously block GSH biosynthesis and clear cellular GSH levels in PDAC. The optimal UNC0638 nanodrug (NPUNC0638) had the desired particle size, reasonable drug loading capacity, and GSH-controlled drug release. Moreover, compared to UNC0638 alone, NPUNC0638 showed better efficacy in inhibiting cell viability, arresting the cell cycle, inducing apoptosis, and suppressing the invasion and self-renewal capacity of PDAC cells. Furthermore, NPUNC0638 was found to be tumour-specific and well tolerated with no apparent toxicity to vital organs and haematopoietic stem and progenitor cells. Additionally, treatment with NPUNC0638 provided favourable outcomes in the PDAC xenograft model. Therefore, this work presents a potent drug delivery platform to overcome the GSH-induced malignant potential of PDAC.

A novel donor (D)–spiro-acceptor (A) emitter, namely 10-phenyl-10H-spiro[acridine-9,9′-fluorene]-2′,4′,7′-tricarbonitrile (SAF-3CN), was synthesized for high efficiency, yellowish green third-generation thermally activated delayed fluorescence (TADF) organic light-emitting diodes (OLEDs). The CN-modulation of the fluorene was adopted for the modification of the singlet state with minor modifications of the triplet state. Compared to the reference material 10-phenyl-10H-spiro[acridine-9,9′-fluorene]-2′,7′-dicarbonitrile (ACRFLCN), the electron-withdrawing –CN substituent on the C4 site of the fluorene results in a sufficiently small singlet–triplet energy gap (ΔEST) and obvious TADF characteristics of SAF-3CN in the doped films. Encouragingly, the device performance achieves an external quantum efficiency (EQE) of 19.4% and small roll-off, which is better than that of ACRFLCN and closer to the best performance in this system.

Vitamin A and its precursor (β-carotene) have been linked with cancer incidence and mortality. However, the relationship between vitamin A and the prognosis of hepatocellular-carcinoma (HCC) is still unknown. Therefore, we investigated whether dietary intakes of vitamin A, retinol, and β-carotene were associated with survival in patients with HCC who participated in the Guangdong Liver Cancer Cohort (GLCC) study. Patients aged 18-80 years with a diagnosis of incident Primary Liver Cancer (PLC) were enrolled within one month of diagnosis prior to cancer treatment at the Sun Yat-sen University Cancer Center. Dietary information one year before diagnosis of HCC was obtained using a 79-item, validated semiquantitative food frequency questionnaire (FFQ). We restricted the present analysis to 877 HCC patients enrolled in the GLCC between September, 2013 and April, 2017 who had completed FFQ. Cox proportional hazard regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CIs) for overall and HCC-specific survival. After a median follow-up of 797 days, 384 deaths were documented, 343 of which died from HCC. The multivariable-adjusted HRs (95% CI) of overall and HCC-specific survival for the highest versus the lowest quartile were 0.70 (0.53-0.94) and 0.68 (0.50-0.92) for vitamin A, and 0.72 (0.54-0.96) and 0.69 (0.51-0.94) for β-carotene, respectively. However, no significant association of dietary retinol intakes with survival outcomes was observed. Our observations suggest that higher prediagnostic dietary intakes of vitamin A and β-carotene were associated with improved overall and HCC-specific survival.

Background Osteoporosis is a chronic bone metabolism disorder affecting millions of the world population. The RANKL/RANK/OPG signaling pathway has been confirmed to be the main regulator of osteoporosis. It is of great interest to identify appropriate therapeutic agents that can regulate the RANKL/RANK/OPG pathway. Baicalin (BA) is a well-known traditional Chinese medicine formula against various inflammatory diseases with a proven role of the RANKL/RANK/OPG pathway regulation. However, the potential effect of BA on osteoporosis and the mechanisms underlying this remain unclear. In the present study, we aimed to evaluate the efficacy of BA in the prevention of dexamethasone (DEX)-induced osteoporosis in zebrafish. Methods In this study, growth and development changes of zebrafish and calcein staining were assessed with a micrograph. The expression levels of RANKL and OPG and transcription factors in response to DEX induction and BA administration were evaluated by Western blotting and qRT-PCR. In addition, the intermolecular interactions of BA and RANKL were investigated by molecular docking. Results Results show that BA enhances the growth and development of dexamethasone (DEX)-induced osteoporosis in zebrafish larvae. Calcein staining and calcium and phosphorus determination revealed that BA ameliorates mineralization of DEX-induced osteoporosis zebrafish larvae. BA also regulates the expression of RANKL and OPG and hampers the changes in gene expression related to bone formation and resorption under the induction of DEX in zebrafish. It can be inferred by molecular docking that BA may interact directly with the extracellular domain of RANKL. Conclusion The findings, herein, reveal that BA ameliorates DEX-induced osteoporosis by regulation of the RANK/RANKL/OPG signaling pathway.

A series of five new fluoro-substituted aroylhydrazones were prepared and structurally characterized by elemental analysis, IR, UV-Vis and 1H NMR spectroscopy, as well as single crystal X-ray diffraction. The compounds were evaluated for their antibacterial (Bacillus subtilis, Staphylococcus aureus, Escherichia coli, and Pseudomonas fluorescence) and antifungal (Candida albicans and Aspergillus niger) activities by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) method. The biological assay indicated that the presence of the electron-withdrawing groups in the aroylhydrazones improved their antimicrobial activities.

We prospected a novel arylesterase LggEst from the probiotics Lacticaseibacillus rhamnosus GG by genome mining strategy, and characterized the enzymatic properties in detail. Biochemical characterization revealed that arylesterase LggEst presented high activity at a wide range of temperatures from 25 to 65 °C with maximum activity at 50 °C. LggEst maintained high activity in the pH range from 5.5 to 7.5 with optimum pH of 6.5. LggEst might efficiently hydrolyze a series of aryl substrates p-nitrophenyl esters with different acyl chain lengths. LggEst displayed the Vmax from 2.8 to 77.3 μmol min−1 mg−1 protein and the kcat from 1.8 to 48.8 s−1 with the highest catalytic activity on pNPC6. The KM of LggEst on different substrates varied significantly from 4.9 μM to 5.6 mM with the highest affinity on pNPC10. LggEst exhibited the preference for medium- and long-chain p-nitrophenyl esters. LggEst showed remarkable thermostability at 45 °C. LggEst could be tolerant of several organic solvents at the concentration of 10% and DMSO and methanol at the concentration of 20%. Catalytic activity of LggEst was improved by 12% in the presence of 20% ethylene glycol. LggEst was resistant to high concentrations of sodium citrate and sodium chloride. Notably, enzymatic activity of LggEst was significantly enhanced in the presence of 0.1% sodium deoxycholate at high temperatures.

Background: Our previous study indicates that Brucea javanica oil (BJO) is beneficial for treatment of ulcerative colitis (UC), and that quassinoids in particular brusatol are bioactive components. However, it is still uncertain whether or not other components in BJO, such as oleic acid and fatty acids, have anti-UC effect.Purpose: The present study aimed to compare the anti-UC effects between brusatol-enriched BJO (BE-BJO) and brusatol-free BJO (BF-BJO), and to explore the effects and mechanisms of BE-BJO on colon inflammation and intestinal epithelial barrier function.Methods: Balb/C mice received 3% (wt/vol) DSS for one weeks to establish the UC model. Different doses of BE-BJO, BF-BJO or BJO were treated. Body weight and colon length were measured. Disease activity index (DAI) and histological analysis were evaluated. The levels of pro-inflammatory cytokines in the colon tissues were measured by enzyme linked immunosorbent assay (ELISA). The expressions of tight junction proteins were tested to investigate the intestinal epithelial barrier function. The effects of BE-BJO on NF-κB and RhoA/ROCK pathways were studied.Results: BE-BJO alleviated DSS-induced loss of body weight, increase of DAI and shortening of colon, whereas BF-BJO did not have these protective effects. BE-BJO treatment improved the morphology of colon tissue, inhibited the production and release of pro-inflammatory cytokines including TNF-α、 IFN-γ、 IL-6 and IL-1β in the colon tissue, as well as reversed the decreased expressions of ZO-1, Occludin, Claudin-1and E-cadherin induced by DSS, but augmented Claudin-2 expression. Mechanistically, BE-BJO repressed phosphorylation of NF-κB subunit p65, suppressed RhoA activation, downregulated ROCK, and prevented phosphorylation of myosin light chain (MLC) in DSS-treated mice.Conclusions: This work demonstrated that BE-BJO could ameliorate DSS-induced UC by preventing colon inflammation and enhancing intestinal epithelial barrier function, probably via suppression of NF-κB and RhoA/ROCK signaling pathways. These findings confirm that quassinoids are active compounds from BJO and suggest the therapeutic potential of quassinoids and BE-BJO in the treatment of UC.

Doxorubicin- (DOX-) induced cardiotoxicity is associated with oxidative stress and cardiomyocyte apoptosis. The adaptor protein p66Shc regulates the cellular redox status and determines cell susceptibility to apoptosis. This study is aimed at investigating the involvement of sirtuin 1- (SIRT1-) mediated p66Shc inhibition in DOX-induced redox signalling and exploring the possible protective mechanisms of berberine (Ber) against DOX-triggered cardiac injury in rats and a cultured H9c2 cell line. Our results showed that the Ber pretreatment markedly increased CAT, SOD, and GSH-PX activities, decreased the levels of MDA, and improved the electrocardiogram and histopathological changes in the myocardium in DOX-treated rats (in vivo). Furthermore, Ber significantly ameliorated the DOX-induced oxidative insult and mitochondrial damage by adjusting the levels of intracellular ROS, ΔΨm, and [Ca2+]m in H9c2 cells (in vitro). Importantly, the Ber pretreatment increased SIRT1 expression following DOX exposure but downregulated p66Shc. Consistent with the results demonstrating the SIRT1-mediated inhibition of p66Shc expression, the Ber pretreatment inhibited DOX-triggered cardiomyocyte apoptosis and mitochondrial dysfunction. After exposing H9c2 cells to DOX, the increased SIRT1 expression induced by Ber was abrogated by a SIRT1-specific inhibitor (EX527) or the use of siRNA against SIRT1. Accordingly, SIRT1 inhibition significantly abrogated the suppression of p66Shc expression and protection of Ber against DOX-induced oxidative stress and apoptosis. These results suggest that Ber protects the heart from DOX injury through SIRT1-mediated p66Shc suppression, offering a novel mechanism responsible for the protection of Ber against DOX-induced cardiomyopathy.

Nanocomposite films were synthesized by introducing phosphotungstic acid (PWA) into the poly (vinylpyrrolidone and methyl acrylate) (P (VP(N-vinylpyrrolidone)coMA(methyl acrylate))). FT-IR curves illustrated that non-covalent bond interaction was built between PWA particles and organic matrixes. In combination the results of SEM, TG-DTA and DSC, it was conducted that the ratio of functional groups of VP had a critical effect on the surface morphology, thermal stability of the hybrid films. Irradiated with ultraviolet light, the transparent thin hybrid films change from colorless to blue. Stored in air, the hybrid films could recover colorless gradually. The analysis of kinetics told us that higher VP content within the different systems always accompanied more superior photochromic performance, faster coloring and fading speed. Appearance of W5+ in ESR spectra indicated that the photo-reduction process between PWA and copolymer matrix occurred.

This study was designed to explore the pharmacokinetic regularity of the plasma concentration, tissue distribution and excretion of orcinol glucoside from aqueous extracts of raw and processed Curculigo orchioides Gaertn., Hypoxidaceae. The experiment first used an ultrahigh-performance liquid chromatography-tandem mass spectrometry approach with multiple reaction monitoring and a positive mode to separate orcinol glucoside from naringin to obtain the plasma concentration curves, bar graph of tissue distribution and excretion curves. These results might be beneficial for reasonable clinical application of C. orchioides and for further development of its wine and salt-processing mechanism. Keywords: Excretion, Plasma concentration, Tissue distribution, Wine-processing technology

Metallic lithium affords the highest theoretical capacity and lowest electrochemical potential and is viewed as a leading contender as an anode for high-energy-density rechargeable batteries. However, the poor wettability of molten lithium does not allow it to spread across the surface of lithiophobic substrates, hindering the production and application of this anode. Here we report a general chemical strategy to overcome this dilemma by reacting molten lithium with functional organic coatings or elemental additives. The Gibbs formation energy and newly formed chemical bonds are found to be the governing factor for the wetting behavior. As a result of the improved wettability, a series of ultrathin lithium of 10–20 μm thick is obtained together with impressive electrochemical performance in lithium metal batteries. These findings provide an overall guide for tuning the wettability of molten lithium and offer an affordable strategy for the large-scale production of ultrathin lithium, and could be further extended to other alkali metals, such as sodium and potassium., Molten lithium cannot spread onto the lithiophobic substrate, hindering the production and application of lithium metal anodes. Here, the authors show a general chemical strategy to tune the wettability by forming new chemical bonds through the reactions with various organic coatings or elemental additives.

We report here the rare observation of a one-dimensional coordination polymer, {[Zn5(bit)4Cl6]·2(CH3CN)}n (1, Hbit = 1-methyl-2-(1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazole), having one mode of binding for the polytopic ligand and three different polyhedra, tetrahedron, square-base pyramid, and octahedron, for the metal node. The formation process of 1 involves the in situ decarboxylation of Hbitc (5-(1-methyl-1H-benzo[d]imidazol-2-yl)-1H-1,2,3-triazole-4-carboxylic acid) to Hbit. Apart from one bridging μ2-Cl, all the other chlorine atoms act as a terminal ligand to complete the polyhedra. While 1 is almost insoluble in most organic solvent, electrospray ionization mass spectrometry of its ultrasound-treated DMSO suspension found the two main species [Zn(bit)]+ at 0 eV and [Zn2(bit)3]+ at elevated in-source energies. Density functional theory calculation suggests a potential formation process involving the sequence: [Zn(bit)]+→ [Zn2(bit)3]+ + [Zn2(bit)2Cl]+ → [Zn3(bit)4Cl2]+. The luminescence intensity e...

Novel visible-light photochromic composites were synthesized by introducing PMoA into ZnO-nanotubes fabricated through a hydrothermal synthesis method. Characterization methods revealed that both o...

Toughening of brittle epoxy (EP) resins is important to widen their applications. In this work, both polysulfone (PSF) as thermoplastic toughening agent and graphene oxide (GO) as nanofiller toughening agent are employed to toughen diglycidyl ether of bisphenol-A (DEGBA) epoxy resin. PSF and GO are added to EP via melt blending and solvent mixing method, respectively. Pure epoxy resin is brittle with a fracture toughness ( K I C ) of ca. 0.99 MPa . m 0.5 . Dual toughening by the simultaneous addition of PSF and GO significantly enhances the fracture toughness of the epoxy resin. The GO/PSF/EP ternary nanocomposite with 5 phr PSF and 0.2 phr GO shows the maximum value of ca. 1.88 MPa . m 0.5 with an increase of 89.90% in K I C compared to that of neat epoxy. Meanwhile, the elongation at break is also greatly enhanced by the addition of PSF and GO. Moreover, the tensile strength , Young's modulus and thermal stability are slightly enhanced and glass transition temperature is maintained after PSF and GO are introduced into EP resin. The current strategy of using both PSF and GO as dual toughening agents is promising for effectively toughening epoxy resins without sacrificing tensile and thermal properties.

This paper aims to obtain rare earth magnesium alloy with good adhesion and corrosion resistance. The work was concerned with the electrochemical behaviors of Co(II), Mg(II), Pr(III) on Pt and Cu e...

Two new sesquiterpenoid glycosides as dihydrophaseic acid 4′-O-[6″-O-(4″′-hydroxy-3″′, 5″′-dimethoxy) benzoyl)]-β-D-glucopyranoside (1) and dihydrophaseic acid 4′-O-[6″-O-(3″′-methoxy- 4″′-hydroxy)...

Two novel donor-σ-π-σ-acceptor-type dispiro molecules-10-phenyl-10H-dispiro-acridine-9,9'-anthracene-10',9''-fluorene-2'',7''-dicarbo-nitrile (DiSAAF) and dispiro-fluorene-9,9'-anthracene-10',9''-quinolino[3,2,1-kl]phenoxazine-2,7-dicarbonitrile (DiSFAQ)-with excellent thermal stability are designed and synthesized. Both materials exhibit blocked long-range intramolecular charge transfer but show intermolecular charge-transfer emission in the film state. Their photophysical and thermal properties then are fully investigated and a maximum external quantum efficiency of 21.7% of the red phosphorescent device is achieved by DiSAAF.

Accumulating evidence shows that genetic polymorphism of the vitamin D receptor (VDR) gene is associated with intervertebral disc degeneration (IDD), implying that VDR may be involved in the pathogenesis of IDD. However, the exact relationship between VDR and IDD remains unknown. The aim of this study was to investigate the age-dependent expression of VDR in rat intervertebral discs and to determine the effect of VDR on oxidative stress-induced cell apoptosis of the annulus fibrosus (AF) and the underlying mechanism. Sprague-Dawley rats were subjected to magnetic resonance imaging (MRI) and CT scans at young (2-3 months), adult (6-7 months), and old (14-15 months) ages. The images revealed age-related degeneration of the lumbar intervertebral discs and endplates. Immunohistochemistry demonstrated positive expression of VDR in the AF. The expression level of VDR in aged rats was significantly reduced compared with that in the young and adult animals and exhibited a negative correlation to IDD severity. Western blot analysis further demonstrated that the amount of VDR protein was significantly decreased in severe degenerative discs. AF cells were also isolated from young rat lumbar discs and subjected to different concentrations of hydrogen peroxide (H2O2) for various amounts of time. The results revealed that H2O2 inhibited the viability of AF cells and induced mitochondrial pathway apoptosis. However, pretreatment of AF cells with 10-7 and 10-8 M 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] effectively increased cell viability, increased mitochondrial membrane potential, decreased the level of reactive oxygen species, increased mitochondrial ATP content, reserved the activity of key enzymes in the oxidative respiratory chain, and thus protected the mitochondria from H2O2-induced damage. Whereas, siRNA knock-down of VDR abolished the protective effects of 1,25(OH)2D3. Moreover, 1,25(OH)2D3 inhibited H2O2-induced autophagy of AF cells through inhibition of the mTOR/p70S6K signal pathway. Our study demonstrated that decreased expression of VDR may play a role in age-related intervertebral disc degeneration in rats and that activation of VDR ameliorates oxidative stress-induced apoptosis in AF cells by preserving mitochondrial functions.

SiOx-based anodes have received intensive attention with the effort on increasing the energy density of lithium-ion batteries (LIBs) for applications such as electric and hybrid electric vehicles. To ensure the security and energy density of LIBs, it is prerequisite to address the cell deformation arising from the huge volume variation of SiOx-based anodes during battery operation. We herein reported the compacted SiOx/G/C granules constructed by the interfacial adhesion between SiOx nanoparticles and thin-layer graphite under the collaborative auxiliary of binder pitch, which contributes to preserving intact conduction pathway and structure integrity of anodes during the repeated lithiation/delithiation process. The as-prepared SiOx/G/C granules deliver superior cycling stability, high initial Coulombic efficiency and good rate capability. In particular, low deformation (13.7% thickness expansion), which is comparable with that of graphite anodes, could be attained in high capacity SiOx/G/C anode (653 mA h g−1). The excellent properties of SiOx/G/C anodes, especially in maintaining structure integrity and lowering deformation, provide insights into the rational design of high capacity electrode materials with huge volume variation.

Background The pathophysiology of genetic hypercalciuric stone-forming rats parallels that of human idiopathic hypercalciuria. In this model, all animals form calcium phosphate stones. We previously found that chlorthalidone, but not potassium citrate, decreased stone formation in these rats. Methods To test whether chlorthalidone and potassium citrate combined would reduce calcium phosphate stone formation more than either medication alone, four groups of rats were fed a fixed amount of a normal calcium and phosphorus diet, supplemented with potassium chloride (as control), potassium citrate, chlorthalidone (with potassium chloride to equalize potassium intake), or potassium citrate plus chlorthalidone. We measured urine every 6 weeks and assessed stone formation and bone quality at 18 weeks. Results Potassium citrate reduced urine calcium compared with controls, chlorthalidone reduced it further, and potassium citrate plus chlorthalidone reduced it even more. Chlorthalidone increased urine citrate and potassium citrate increased it even more; the combination did not increase it further. Potassium citrate, alone or with chlorthalidone, increased urine calcium phosphate supersaturation, but chlorthalidone did not. All control rats formed stones. Potassium citrate did not alter stone formation. No stones formed with chlorthalidone, and rats given potassium citrate plus chlorthalidone had some stones but fewer than controls. Rats given chlorthalidone with or without potassium citrate had higher bone mineral density and better mechanical properties than controls, whereas those given potassium citrate did not. Conclusions In genetic hypercalciuric stone-forming rats, chlorthalidone is superior to potassium citrate alone or combined with chlorthalidone in reducing calcium phosphate stone formation and improving bone quality.

Configurations, stabilities and adsorption mechanisms of ground-state MonN and MonN2 (n = 1–8) clusters are calculated by using the density functional method within the PBE level. Evidently...

The structures and electronic properties of ferrous nitride–fulminic acid (FeN–HCNO) clusters are investigated by using PW91 functional. The results reveal that the Fe atom of an FeN molecule prefe...

In this study, the thermal decomposition of NH4HSO4 (ABS) on two typical V2O5/TiO2 catalysts (0.5 wt% and 4.5 wt% vanadia loadings) was studied. The vanadium-density-dependent decomposition process of ABS was verified using thermogravimetric analysis followed by IR and XPS investigations. The vanadium density strongly influences the interaction between the ABS and catalyst surface, thus changing the decomposition process of the ABS-related surface species. For the 0.5 wt% V2O5/TiO2 catalyst, the bidentate SO42− species that formed from the interaction between the ABS and TiO2 support have higher thermal stability than those of pure ABS (ca. 330 °C). The decomposition temperature of these species was above 350 °C. Meanwhile, the remaining NH4+ has lower thermal stability, which started at ca. 250 °C. By contrast, for the 4.5 wt% V2O5/TiO2 catalyst, the ABS was deposited on the catalyst surface probably through a VOSO4 analogous structure rather than being bonded to the TiO2 sites, such that the decomposition process of the ABS was very similar to that of pure ABS with only a slight decomposition delay. This study suggests that different regeneration strategies for ABS deactivation should be adopted depending on the vanadia loadings of the V2O5/TiO2 catalysts.

Bacillus thuringiensis BMB181 (Bt BMB181), with high melanin production, is an ideal candidate for industrial scale production of light-stable insecticides. However, its melanogenic pathways remain unclear. In the present study, we demonstrated that Bt BMB181 failed to produce melanin after treatment with mesotrione, an inhibitor of 4-hydroxyphenylpyruvate dioxygenase in the homogentisic acid pathway of melanin synthesis. Heterologous expression experiments suggested that homogentisate-1,2-dioxygenase (HmgA) in Bt BMB171 functions normally, yet HmgA in Bt BMB181 had lost its activity, at least partly. Using the CRISPR-Cas9 system, the hmgA gene in Bt BMB171 was knocked out and the mutant strain gained the ability to produce melanin. Furthermore, the complemented strain reverted to the wild-type phenotype. In addition, overexpression of its own hmgA gene in Bt BMB181 also resulted in failure to produce the pigment. BLAST results indicated that the amino acid alteration (G272E) in HmgA of Bt BMB181 was caused by a single point mutation (815G→ A). The enzyme activity of purified HmgA171 was more than 10-fold higher than that of HmgA181. Finally, we determined that the mutation in hmgA was responsible for melanin accumulation in Bt BMB181. Our results provided new insights into the synthesis and regulation of melanin production in B.thuringiensis and will promote its future industrial application.

The type VI secretion system (T6SS) is a double-tubular toxin-injection nanomachine widely found in gram-negative human and plant pathogens. The current model depicts that the T6SS spear-like Hcp tube is powered by the contraction of an outer sheath to drill through the envelope of a neighboring cell, achieving cytosol to cytosol delivery. However, gram-positive bacteria seem to be impenetrable to such T6SS action. Here we report that a plant pathogen Acidovorax citrulli (AC) deploys a highly potent T6SS to kill a range of bacteria including Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis, and Mycobacterium smegmatis as well as fungal species including Candida albicans and Pichia pastoris. Using bioinformatic and biochemical assays, we identified a group of T6SS effectors and characterized one effector RhsB that is critical for interspecies interaction. We report that RhsB contains a conserved YD-repeat domain and a C-terminal nuclease domain. Toxicity of RhsB was neutralized by its downstream immunity proteins through direct interaction. RhsB was cleaved at the C-terminal end and a catalytic mutation within the internal aspartic protease abolished such cleavage. Collectively, the T6SS of AC displays potent activities to penetrate the cell envelope barriers of gram-positive and fungal species, highlighting the greatly expanded capabilities of T6SS in modulating microbiome compositions in complex environments.