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Recent studies indicate mammalian target of rapamycin (mTOR) may play an important role in PCa progression and drug resistance. Here, we investigated the effects of a novel mTORC1/C2 dual inhibitor, AZD2014, on naive and docetaxel (Doc)‐pre‐treated castration‐resistant PCa (CRPC) cells and explored its therapeutic potential in CRPCs. In the current study, AZD2014 has a greater inhibitory effect against 4EBP1 and AKT phosphorylation than rapamycin in CRPC cells and prevented the feedback activation of AKT signalling. Importantly, AZD2014 suppressed CRPC cell growth in vitro by suppressing proliferation, apoptosis, cell cycle arrest at G1 phase and autophagy to a greater extent than rapamycin. Moreover, AZD2014 was more efficacious than rapamycin in inhibiting migration, invasion and EMT progression in Doc‐sensitive and Doc‐resistant CRPC cells. Overall, AZD2014 showed significant antitumour effects. Thereby, the current study highlights a reliable theoretical basis for the clinical application of AZD2014 in both Doc‐sensitive and Doc‐resistant CRPCs.

The development of low-cost, highly active and stable electrocatalysts for the oxygen evolution reaction (OER) is desirable and challenging. In this work, we report nickel foam (NF) supported low-crystalline NiCoFe nanosheet array electrocatalysts derived from NiCo layered double hydroxide via spontaneous cation exchange reaction. Driven by the redox properties of NiCo layered double hydroxide and iron salt precursors, the entire cation exchange reaction process is completed without extra energy input. The chemical composition and catalytic properties of the as-prepared NiCoFe/NF catalysts are strongly dependent on the valence state of the Fe cation in the iron salt precursors. The NiCoFe/NF–FeSO4 catalyst with FeSO4 as the iron salt precursor exhibits satisfactory OER activity with a much lower overpotential of 293 mV to reach a current density of 100 mA cm−2 as compared with NiCoFe/NF–Fe2(SO4)3 (η100 = 333 mV), NiCo/NF (η100 = 425 mV) and commercial RuO2 (η100 = 399 mV) catalysts. Moreover, NiCoFe/NF–FeSO4 also exhibits impressive long-term durability for the OER. The current density remains nearly unchanged during the 95 h of continuous OER test, demonstrating a promising application in actual industrial water electrolysis. These findings indicate that the iron ion valence states in the iron salt precursors have a significant impact on the composition of the catalysts and thus affect their catalytic performances. This work is instructive for the rational design and preparation of highly efficient Earth-abundant electrocatalysts for the OER.

Background. Previous studies have demonstrated that various circular RNAs are involved in the malignant proliferation of cancers, such as liver cancer, lung cancer, breast cancer, and others. The potential role of circular RNAs in glioblastoma, however, is still uncertain. In this study, we aimed to study the potential role of hsa_circ_01844 in glioblastoma. Methods. Using reverse transcription-polymerase chain reaction (RT-PCR) method, hsa_circ_01844 expression was measured in five glioblastoma samples and five normal brain samples. To evaluate the potential function of hsa_circ_01844 in glioblastoma, hsa_circ_01844 was overexpressed in glioblastoma cell lines (U251 and U87 cells). Using these two cell lines, in vitro experiments including the flow cytometry assay, 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay, Transwell assay, and cell apoptosis assay were performed to investigate the role of hsa_circ_01844 in glioblastoma. Student t test and one-way analysis of variance were used for statistical analysis. Results. The expression of circular RNA hsa_circ_01844 was lower in glioblastoma tissues when compared with the normal brain tissues by RT-PCR method (0.034 ± 0.036 vs. 1.630 ± 0.891, P

The increasingly severe issue of antibiotic-induced pollution greatly stimulates the development of high-performance advanced adsorbents. In this contribution, a novel Fe-centered metal–organic aerogel (Fe-MOA) was synthesized through the use of bio-based ligand 2,5-furandicarboxylic acid (FDCA). Various characterization techniques including FT-IR, XPS, SEM, TEM, EDX and N2 adsorption–desorption analysis verified the successful preparation of the Fe-MOA with a hierarchically meso and macroporous network structure. The Fe-MOA was subsequently used as an adsorbent for the removal of tetracycline (TC) in aqueous solution. And the results suggested that the Fe-MOA exhibited an unprecedented adsorption capacity for TC with the record value of 1023 mg g−1. The adsorption equilibrium and isotherm data agreed well with the pseudo-second-order and Freundlich models, respectively. The mechanism investigations showed that the ultrahigh adsorption capability was synergistically driven by multiple affinities including electrostatic interaction, hydrogen bonding, surface complexation and π–π interactions between the conjugated groups in TC and the furan rings of the Fe-MOA. The recycling adsorption experiment results showed that the Fe-MOA retained 80% of the 1st-cycle adsorption capacity after being reused for 5 cycles, demonstrating the excellent reusability of Fe-MOA. Compared with other adsorbents, the ultrahigh TC adsorption capacity and excellent recycling performance make the Fe-MOA a favorable adsorbent candidate for TC pollution, highlighting the significant potential for solving practical TC-related pollution issues.

Mitochondrial dysfunction is a hallmark of cancer cells and targeting cancer mitochondria has emerged as a promising anti-cancer therapy. Previously, we repurposed chlorambucil by conjugating it to a mitochondrial targeting triphenylphosphonium (TPP) group to design Mito-Chlor, a novel agent that acts on mitochondria DNA (mtDNA). Herein, we show that Mito-Chlor, but not chlorambucil, inhibits the nascent transcription of mtDNA. Clustering analysis of transcriptomic profile of our Bru-seq database led to the identification of another mitochondrial transcription inhibitor SQD1, which inhibits the proliferation of MIA PaCa-2 cells with an IC(50) of 1.3 μM. Interestingly, Mito-Chlor reduces expression of mitochondrial proteins, interferes with mitochondria membrane potential, and impairs oxidative phosphorylation while SQD1 does not. Both compounds increased cellular and mitochondrial reactive oxygen species and stimulated similar signaling pathways in response to oxidative stress. As mitochondrial transcription inhibitors and redox modulators, SQD1 and Mito-Chlor are promising for the treatment of pancreatic cancer by blocking mitochondrial function.

Layered nickel-rich cathodes generally suffer from their unstable surface because of lithium impurities. Thus, building an interface with both high electrochemical stability and electroactivity is ...

Selective autophagy is a subcellular process whereby cytoplasmic materials are selectively sequestered into autophagosomes for subsequent delivery to the vacuole for degradation and recycling. Arabidopsis (Arabidopsis thaliana) NBR1 (next to BRCA1 gene 1 protein; AtNBR1) has been proposed to function as a selective autophagy receptor in plants, whereby AtNBR1 anchors the ubiquitinated targets to autophagosomes for degradation. However, the specific cargos of AtNBR1 remain elusive. We previously showed that Arabidopsis exocyst subunit EXO70 family protein E2 (AtExo70E2), a marker for exocyst-positive organelle (EXPO), colocalized with the autophagosome marker Arabidopsis autophagy-related protein8 (AtATG8) and was delivered to the vacuole for degradation upon autophagic induction. Here, through multiple analyses, we demonstrate that AtNBR1 is a selective receptor for AtExo70E2 during autophagy in Arabidopsis. First, two novel loss-of-function nbr1 CRISPR mutants (nbr1-c1 and nbr1-c2) showed an early-senescence phenotype under short-day growth conditions. Second, during autophagic induction, the vacuolar delivery of AtExo70E2 or EXPO was significantly reduced in nbr1 mutants compared to wild-type plants. Third, biochemical and recruitment assays demonstrated that AtNBR1 specifically interacted and recruited AtExo70E2 or its EXPO to AtATG8-positive autophagosomes in a ubiquitin-associated (UBA)-independent manner during autophagy. Taken together, our data indicate that AtNBR1 functions as a selective receptor in mediating vacuolar delivery of AtExo70E2 or EXPO in a UBA-independent manner in plant autophagy.

This study aimed at identifying antioxidant and anti-inflammatory peptides derived from the in vitro gastrointestinal digestion of germinated and heated (microwave and boiling) foxtail millet. The protein digest fraction containing low-molecular-weight peptides (

The development of non-precious metal catalysts for the electrochemical oxygen evolution reaction (OER) is especially important for the water electrolysis process. Herein, a two-dimensional (2D) ultrathin hybrid Co–NiFe layered double hydroxide (LDH) is synthesized via a facile hydrothermal method. In 1.0 M KOH electrolyte, Co–NiFe LDH exhibits remarkable activities for OER. At the current density of 10 mA cm−2, it only needs an overpotential of 278 mV, which is ca. 50 mV and 20 mV lower than those for NiFe LDH (328 mV) and RuO2 catalysts (298 mV), respectively. In addition, Co–NiFe LDH also shows impressive long-term stability for OER. Besides the stable morphology and crystal structure, the potential is always kept at 1.50 V and shows almost no attenuation during the 20 h of durability test. Changes in the electronic structure of LDH due to introduction of Co ions, as well as the large specific surface area facilitate the mass/electron transfer and the oxygen bubbles release, and thus lead to the enhanced catalytic properties for OER. This work can be informative not only for understanding the role of physical and electronic structures on OER but also for designing high-performance non-precious metal OER electrocatalysts.

A series of PdmAg/C electrocatalysts (m being the atomic Pd/Ag ratio, m = 0.05, 0.1, 0.5, 1.0) for both ethanol and methanol oxidation reactions (EOR and MOR) are prepared via a facile co-reduction method. The morphologies and crystal structures are characterized by transmission electron microscopy techniques (TEM) and X-ray diffraction (XRD). Cyclic voltammetry (CV) and chronoamperometry (CA) techniques are applied to explore the catalytic performance of the PdmAg/C electrocatalysts for EOR and MOR in alkali medium. Our findings show that the catalytic performance of the PdmAg/C electrocatalysts rests with m and Pd0.5Ag/C has the highest activity among the PdmAg/C electrocatalysts. Furthermore, the activities of the PdmAg/C electrocatalysts are associated with the potential scope of CV curves. When Pd0.5Ag/C is tested in a relatively wide potential scope (−1.0 to 0.5 V), the current density of EOR is ca. 9.39 times higher than that tested in the narrow potential scope (−1.0 to 0.1 V). The improvement is ascribed to the promotion effects of Ag oxide formed at relatively high potential, that is, the synergistic effects between Ag oxide and Pd contribute to the improvement in the catalytic properties of Pd.

Anti-epidermal growth factor receptor (EGFR) therapy–associated cutaneous toxicity is a syndrome characterized by papulopustular rash, local inflammation, folliculitis and microbial infection, resulting in a decrease in quality of life and dose interruption. However, no effective clinical intervention is available for this adverse effect. Here, we report the atrophy of dermal white adipose tissue (dWAT), a highly plastic adipose tissue with various skin-specific functions, correlates with rash occurrence and exacerbation in a murine model of EGFR inhibitor-induced rash. The reduction in dWAT is due to the inhibition of adipogenic differentiation by defects in peroxisome proliferator-activated receptor γ (PPARγ) signaling, and increased lipolysis by the induced expression of the lipolytic cytokine IL6. The activation of PPARγ by rosiglitazone maintains adipogenic differentiation and represses the transcription of IL6, eventually improving skin functions and ameliorating the severity of rash without altering the antitumor effects. Thus, activation of PPARγ represents a promising approach to ameliorate cutaneous toxicity in patients with cancer who receive anti-EGFR therapy.Graphical abstract

Excessive apoptosis of chondrocytes and degradation of the extracellular matrix (ECM) contribute to the typical pathological characteristics of osteoarthritis (OA). Various studies have reported that tetramethylpyrazine (TMP) protects against multiple disorders by inhibiting inflammation and oxidative stress. The present study investigated the effects of TMP on chondrocytes and evaluated the associated mechanisms. To determine the effect of TMP on OA and the underlying mechanisms, chondrocytes were incubated with TMP and IL‑1β or thapsigargin (TG) Western blotting assays were performed to examine the expression levels of endoplasmic reticulum (ER) stress proteins, and TUNEL staining, fluorescence immunostaining and reverse transcription‑quantitative PCR were used to determine the apoptosis levels, and catabolic and inflammatory factors. It was found that TMP protected chondrocytes by suppressing IL‑1β‑induced expression of glucose‑regulated protein 78 (GRP78) and CHOP (an apoptotic protein). TMP regulated the TG‑mediated upregulated expression of GRP78 and CHOP in the chondrocytes of rats, as well as markedly suppressed levels of ER stress‑triggered inflammatory cytokines (TNF‑α and IL‑6). Furthermore, TMP modulated TG‑induced changes in ECM catabolic metabolism in rat chondrocytes. Collectively, TMP alleviated ER‑stress‑activated apoptosis and related inflammation in chondrocytes, indicating that it has therapeutic potential for the treatment of OA.

To understand the enhanced protection mechanism of CoCrNiAlY–YSZ–LaMgAl11O19 double-layer ceramic coating with aluminum plating, a finite element simulation method was used to simulate the distribution of thermal stress in the coating in all directions. The results show that in the air exposure of the un-aluminized coating, high temperature causes a large radial thermal stress on the surface of the LaMgAl11O19 (LMA) layer, and it increases with the increase in temperature, which is the main reason for the initiation of axial cracks. After arc aluminum plating, the aluminum plating layer effectively inhibited the volume shrinkage of the coating through good adhesion to the coating and internal diffusion; the thermal stress of the coating was considerably reduced; and the CoCrNiAlY–YSZ–LMA coating had an effective enhancement and protection effect. However, there was still a certain amount of shear thermal stress inside the LMA layer, the top of the crack, and the bottom of the crack. This thermal stress caused the initiation of radial microcracks in the LMA layer, which also becomes a risk point for the failure of the aluminum coating.

The freshness and color quality of postharvest tea leaves can be markedly prolonged and retained by proper preservation measures. Here, we investigated the dynamic changes of chlorophyll and its derivatives in postharvest tea leaves under different low-temperature treatments using natural withering as a control. Chlorophyll decomposition was found closely related with chlorophyllide, pheophorbide, and pheophytin. Low-temperature withering could slow chlorophyll degradation in postharvest tea leaves via significant inhibition on the enzyme activity and gene expression of Mg-dechelatase, chlorophyllase, and pheophorbide a oxygenase. At the initial stage of withering, a significant increase was observed in the chlorophyll content, expression of chlorophyll-synthesis-related enzymes (such as glutamyl-tRNA synthetase, etc.), and chlorophyll synthase activity in newly picked tea leaves. Moreover, an obvious decrease was found in the content of l-glutamate as the foremost precursor substance of chlorophyll synthesis. Hence, our findings revealed that the chlorophyll synthesis reaction was induced by the light-dehydration-stress in the initial withering of tea leaves. This study provides a theoretical basis for exploring preservation technology in actual green tea production.

Background Benign prostatic hyperplasia (BPH) is the most common urological disease in elderly men, but the underlying pathophysiological mechanisms are complex and not fully understood. Phosphodiesterase type 5 inhibitors (PDE5-Is) used to treat BPH could upregulate the cyclic guanosine monophosphate (cGMP)-dependent protein kinase G (PKG) signaling, which was shown to blunt inflammation in the prostate. Our previous findings indicate that CD8+ T cells promote the proliferation of BPH epithelial cells (BECs) in low androgen conditions through secretion of CCL5; however, the role of the cGMP/PKG pathway in the process is unclear. Methods Paraffin-embedded tissues were used for expression quantity of CD8+ T cells, CCL5, cyclin D1, and PDE5 protein by immunohistology in prostate specimens which were/were not treated with finasteride 5 mg daily for at least 6 months before surgery. BPH-1 cells were cocultured with or without CD8 + T cells or PDE5-Is in low androgen conditions for 4 days. The conditioned media, BPH-1 cells, and CD8 + T cells were harvested for the subsequent experiments. The quantitative polymerase chain reaction was used for assaying the level of messenger RNA expression of CCL5. CCL5 in the conditioned media was detected by the enzyme-linked immunosorbent assay. The effect of PDE5-Is on cocultured BPH-1/CD8 + T-cell proliferation was detected by the cell counting kit-8. A high-fat diet (HFD)-induced prostatic hyperplasia rat model was used to investigate the effect of cGMP/PKG activation in CD8 + T cells in vivo. Results CD8+ T-cell infiltration into human BPH tissues was positively correlated with the expression of CCL5, cyclin D1, and PDE5, whereas in an HFD-induced prostatic hyperplasia rat model, the activation of the cGMP/PKG signaling by a PDE5-I could suppress the CD8 + T-cell infiltration and the CCL5 and cyclin D1 expression. Furthermore, the activation of the cGMP/PKG pathway inhibited CCL5 secretion by CD8 + T cells by downregulating nuclear factor-κB p65 phosphorylation, which reduced the growth of BPH-1 through CCL5/STAT5/CCND1 signaling. Conclusions Our results indicate that the upregulation of the cGMP/PKG/p65 signaling reduces CCL5 secretion in CD8 + T cells, which in turn decreases the proliferation of BECs in low androgen conditions, suggesting that the combination of 5α reductase inhibitors lowering androgen levels and PDE5-Is may be a novel, more effective treatment for BPH patients.

Surface Al-doped LiNi0.5Co0.2Mn0.3O2 (523) single crystals with a diameter of 2–4 μm were synthesized by using Ni-Co-Mn hydroxide precursor and combined with further Al3+ coating/annealing operations. Al contents in the surface and the bulk structures of product particles were about 1.05% and 0.02%, respectively. XPS, XRD, and HRTEM results confirm that the Al element exist as a dopant within the layered structures of 523 surface. Coin cell testing of the as-prepared 523 cathode were taken under different voltage ranges of 3.0–4.3 V, 3.0–4.4 V, and 3.0–4.5 V, with corresponding 100 cycles capacity retentions of 91.2%, 74.0%, and 67.8% at 25 °C, and 43.1%, 40.1%, and 31.6% at 55 °C. The capacity degradation rate was mainly associated with the interfacial structure instabilities of 523 materials under different voltage ranges, which have been investigated by electrochemical impedance spectroscopy (EIS) and XPS.

Background Chemotherapy with Docetaxel (Doc) is efficient in a subset of prostate cancer (PCa) cases; however, most patients ultimately develop resistance to Docetaxel. The tumor immune microenvironment and secreted cytokines play a substantial role in development of resistance to chemotherapy. Our previous study has demonstrated that CD4+ T cells in prostate tumor microenvironment contribute to PCa progression; meanwhile, we found increased CD4+ T‐cell infiltration in tumor area after Doc treatment; however, their effects on PCa chemosensitivity remain unclear. Here, we aim to explore the role and mechanisms of CD4+ T cells in PCa chemotherapy sensitivity. Methods CD4+ T‐cell infiltration in Doc‐treated paraffin‐embedded specimens from transurethral resection of prostate, radical prostatectomy, or bone metastasis was detected by immunohistochemistry. The castration‐resistant PCa cell lines—C4‐2 and CWR22RV1, and CD4+ T‐cell lines—HH and Molt‐3 were used in the coculture system. After coculture with the lymphocytes, PCa cell chemosensitivity was detected by cell counting kit‐8, terminal deoxynucleotidyl transferase dUTP nick‐end labeling assays, and Western blot analysis. Various cell cytokines were determined by cytokine arrays and reverse‐transcription polymerase chain reaction. The recombinant human C‐C motif chemokine ligand 5 (CCL5) was added to PCa cells for further confirming its effects and anti‐CCL5 antibody was used for neutralization. S3I‐201, a signal transducer and activator of transcription 3 (STAT3) inhibitor, was added to the coculture system to detect STAT3 role in chemosensitivity. Tumor xenografts in nude mice were used for confirming effects of CD4+ T cells in vivo study. Results We found more infiltrated CD4+ T cells in human PCa lesions than in the adjacent noncancerous tissues after Doc treatment. In vitro cell line study confirmed that CD4+ T cells increase the PCa Doc resistance. Quantative polymerase chain reaction and cytokine arrays indicated that after coculture with PCa, CD4+ T cells could secrete large amounts of CCL5. Moreover, CCL5 stimulation enhanced PCa resistance to Doc, and anti‐CCL5 antibody could partly reverse this process. We found that CD4+ T cells could activate P‐STAT3 signaling via secreting CCL5 and adding a STAT3 inhibitor can reverse the chemoresistance. In vivo mouse model with xenografted 22RV1 cells and CD4+ T cells also confirmed the in vitro results. Conclusions Together, our results indicate that infiltrating CD4+ T cells could promote PCa chemotherapy resistance via modulation of the CCL5/STAT3 signaling pathway.

Phytoexcretion is a novel strategy to remediate cadmium (Cd) pollution by leaf excretion in tall fescue (Festuca arundinacea), which involves the processes of Cd leaf excretion, root-to-leaf translocation, and root uptake. A hydroponic experiment was designed to investigate a series of 11 zinc (Zn) concentrations on Cd leaf excretion in tall fescue under 75 μM Cd stress. The results showed that the promotions of Zn on Cd leaf excretion, root-to-leaf translocation, and leaf accumulation were concentration-dependent in tall fescue. Zn treatments at 90 and 135 μM resulted in the highest Cd leaf excretion with 118.1 and 123.6 mg/kg of Cd excretion amount and 27.0 and 26.6% of excretion ratio, which were 2.6 and 2.7 fold of the control (15 μM of Zn), respectively. Cd leaf excretion was decreased when Zn treatments reached 180 μM, which could be toxic to plants as indicated by the decline of plant biomass. Zn also promoted leaf Cd accumulation and Cd translocation from roots to leaves and reached the highest at 90 and 180 μM respectively. Root Cd accumulation decreased with the increase of Zn concentrations, but the total plant Cd uptake did not decrease significantly until Zn concentration reached 90 μM. Our results indicate that 90 μM of Zn treatment can be served as the threshold to promote Cd leaf excretion and improve the efficiency of Cd phytoexcretion in tall fescue.

Irrational land-use can accelerate soil erosion by deteriorating soil structure and depleting soil nutrients, especially profoundly alter soil organic carbon (C), total nitrogen (N), total phosphorus (P) contents and stocks. However, it remains unknown how soil C, N, P stoichiometry patterns are affected by land-use type and soil erosion. This study was carried out to examine the soil C:N:P stoichiometry patterns in woodland (WL), upland (UL), and paddy (PD) at soil depths of 0–10, 10–20, and 20–30 cm under collapsed gully erosion (CGE) and sheet erosion (SE) conditions in lateritic red soil region. Compared to WL, C content and stock decreased by 19.1–31.9 g kg−1 and 12.8–31.7 Mg ha−1, but P content and stock increased by 4.9–7.4 g kg−1 and 6.7–9.9 Mg ha−1 in UL soil at 0–30 cm, resulting in a decrease in C:N, C:P and N:P ratios by 8.6–14.8, 23.0–28.6 and 0.7–1.0, respectively. In addition, N, P contents and stocks increased by −0.04–1.8 g kg−1, 4.1–10.5 g kg−1 and 1.8–1.1 Mg ha−1, 7.0–8.2 Mg ha−1 in PD soil at 0–30 cm, resulting in a decrease in the ratio of C:N, C:P and N:P by 8.1–10.6, 20.7–26.0 and 0.6–0.8, respectively. Furthermore, C, N, P contents, stocks and C:N ratio in UL and PD soils were more significant under SE than CGE condition with, while it was opposite trend in WL at 0–30 cm depth. Soil C, N, P contents and stocks significantly decreased with soil depth, while no significant changes were detected on their stoichiometric ratio. Soil porosity and texture had significant contribution to C, N and P stoichiometry by PCA and RDA analysis. Our results demonstrate that the intensive agricultural practices changing soil porosity and texture under SE condition led to more pronounced differences of soil C, N, P and their stoichiometric ratios in lateritic red soil region.

Biofilm growth is a widespread mechanism that protects bacteria against harsh environments, antimicrobials, and immune responses. These types of conditions challenge chronic colonizers such as Helicobacter pylori but it is not fully understood how H. pylori biofilm growth is defined and its impact on H. pylori survival. To provide insights into H. pylori biofilm growth properties, we characterized biofilm formation on abiotic and biotic surfaces, identified genes required for biofilm formation, and defined the biofilm-associated gene expression of the laboratory model H. pylori strain G27. We report that H. pylori G27 forms biofilms with a high biomass and complex flagella-filled 3D structures on both plastic and gastric epithelial cells. Using a screen for biofilm-defective mutants and transcriptomics, we discovered that biofilm cells demonstrated lower transcripts for TCA cycle enzymes but higher ones for flagellar formation, two type four secretion systems, hydrogenase, and acetone metabolism. We confirmed that biofilm formation requires flagella, hydrogenase, and acetone metabolism on both abiotic and biotic surfaces. Altogether, these data suggest that H. pylori is capable of adjusting its phenotype when grown as biofilm, changing its metabolism, and re-shaping flagella, typically locomotion organelles, into adhesive structures.

Redox modulators have been developed as an attractive approach to treat cancer. Herein, we report the synthesis, identification, and biological evaluation of a quinazolinedione reactive oxygen species (ROS) inducer, QD394, with significant cytotoxicity in pancreatic cancer cells. QD394 shows a transcriptomic profile remarkably similar to napabucasin, a cancer stemness inhibitor. Both small molecules inhibit STAT3 phosphorylation, increase cellular ROS, and decrease the GSH/GSSG ratio. Moreover, QD394 causes an iron- and ROS-dependent, GPX4 mediated cell death, suggesting ferroptosis as a major mechanism. Importantly, QD394 decreases the expression of LRPPRC and PNPT1, two proteins involved in mitochondrial RNA catabolic processes and both negatively correlated with the overall survival of pancreatic cancer patients. Pharmacokinetics-guided lead optimization resulted in the derivative QD394-Me, which showed improved plasma stability and reduced toxicity in mice compared to QD394. Overall, QD394 and QD394-Me represent novel ROS-inducing drug-like compounds warranting further development for the treatment of pancreatic cancer.

Vesicle trafficking between the membrane-bound organelles in plant cells plays crucial roles in the precise transportation of various materials, and thus supports cell proliferation and cellular polarization. Conventionally, plant prevacuolar compartments (PVCs), identified as multivesicular bodies (MVBs), play important roles in both the secretory pathway as intermediate compartments and the endocytic pathway as late endosomes. In recent years, the PVC/MVBs have been proposed to play important roles in both protein vacuolar delivery and unconventional secretion, but several important questions on the new regulators and environmental cues that coordinate the PVC/MVB–organelle membrane interactions and their biological significances remain. In this review, we first summarize the identity and nature of the plant PVC/MVBs, and then we present an update on our current understanding on the interaction of PVC/MVBs with other organelles in the plant endomembrane system with focus on the vacuole, autophagosome, and plasma membrane (PM) in plant development and stress responses. Finally, we raise some open questions and present future perspectives in the study of PVC/MVB–organelle interactions and associated biological functions.

Greenhouse vegetable production is one of the major non-point source (NPS) pollution due to its high fertilizer input and low nutrient use efficiency. Excessive salt and nutrient accumulation in the topsoil is responsible for the NPS pollution in greenhouse vegetable production. This study was designed to investigate the effects of turfgrass intercropping on NPS pollution in greenhouse sweet pepper production. The results showed that the pollution discharges via both surface runoff and leaching were significantly reduced by turfgrass intercropping. The reduction of pollution was associated with the capacity of turfgrass species in the absorption and accumulation of salts and nitrate. Paspalum vaginatum with preferential accumulations of nitrate and salts performed best results in the alleviation of soil salinity and NPS pollution. Paspalum vaginatum-intercropping decreased 51.2% of nitrate and 23.9% of electrical conductivity in the soil, 71.8% of total nitrogen, 54.9% of ammonia-nitrogen, 67.0% of nitrate-nitrogen, 68.8% of total phosphorus, 68.2% of phosphates, and 73.2% of potassium in the surface runoff, and 64.1% of total nitrogen, 53.4% of ammonia-nitrogen, 67.0% of nitrate-nitrogen, 44.3% of total phosphorus, 54.8% of phosphates, and 32.9% of potassium in the leachate. These results indicated that Paspalum vaginatum-intercropping could be a clean and sustainable solution to prevent NPS pollution in greenhouse vegetable production.

Inhibition of proteasome activity blocks the degradation of dysfunctional proteins and induces cancer cell death due to cellular stress. Thus, proteasome inhibitors represent an attractive class of anticancer agents, and bortezomib, carfilzomib and ixazomib have been FDA-approved to treat multiple myeloma. However, cancer cells acquire resistance to these inhibitors through point mutations in the proteasome catalytic subunit or induction of alternative compensatory mechanisms. In this study, we identified a quinolin-chlorobenzothioate, QCBT7, as a new proteasome inhibitor showing cytotoxicity in a panel of cancer cell lines. QCBT7 is a more stable derivative of quinoline-8-thiol that targets the regulatory subunit instead of the catalytic subunit of the proteasome. QCBT7 caused the accumulation of ubiquitylated proteins in the cancer cells, indicating its proteasome inhibitory activity. Additionally, QCBT7 increased the expression of a set of genes (PFKFB4, CHOP, HMOX1 and SLC7A11) at both nascent RNA and protein levels, similarly to the known proteasome inhibitors MG132 and ixazomib. Together, QCBT7 induces proteasome inhibition, hypoxic response, endoplasmic reticulum stress and glycolysis, finally leading to cell death. Importantly, we have identified PFKFB4 as a potential biomarker of proteasome inhibitors that can be used to monitor treatment response.

LiCoO2 nano-particles precursor was synthesized through a mixed-alkalis (LiOH-NaOH) hydrothermal reaction, and finally sintered into LiCoO2 nanobricks with a sickness of ~300 nm. This LiCoO2 nanobrick cathode delivered a specific capacity of 131.8 mAh g−1 at 1 C between 3.0 and 4.2 V and 90% capacity retention after 100 cycles. Those synthesized LiCoO2 nanobricks were further treated by surface Al3+ doping to achieve much enhanced 4.5 V lithium storage capability and cycling stability. EIS results showed the surface Al3+ doping operation can signification decrease the charge-transfer resistances of the LiCoO2 cathodes for both before and after cyclings.

Protein folding in the endoplasmic reticulum is an oxidative process that relies on protein disulfide isomerase (PDI) and endoplasmic reticulum oxidase 1 (ERO1). Over 30% of proteins require the chaperone PDI to promote disulfide bond formation. PDI oxidizes cysteines in nascent polypeptides to form disulfide bonds and can also reduce and isomerize disulfide bonds. ERO1 recycles reduced PDI family member PDIA1 using a FAD cofactor to transfer electrons to oxygen. ERO1 dysfunction critically affects several diseases states. Both ERO1 and PDIA1 are overexpressed in cancers and implicated in diabetes and neurodegenerative diseases. Cancer-associated ERO1 promotes cell migration and invasion. Furthermore, the ERO1-PDIA1 interaction is critical for epithelial-to-mesenchymal transition. Co-expression analysis of ERO1A gene expression in cancer patients demonstrated that ERO1A is significantly upregulated in lung adenocarcinoma (LUAD), glioblastoma and low-grade glioma (GBMLGG), pancreatic ductal adenocarcinoma (PAAD), and kidney renal papillary cell carcinoma (KIRP) cancers. ERO1Α knockdown gene signature correlates with knockdown of cancer signaling proteins including IGF1R, supporting the search for novel, selective ERO1 inhibitors for the treatment of cancer. In this review, we explore the functions of ERO1 and PDI to support inhibition of this interaction in cancer and other diseases.

Reduced graphene oxide (RGO) supported PtmAu electrocatalysts with different atomic Pt/Au ratios (m = 0.5–2.0) are prepared via co-reduction of H2PtCl6 and HAuCl4. The catalysts are comprehensively characterized through TEM, XRD and XPS. The catalytic behaviors of the PtmAu catalysts toward methanol oxidation reaction (MOR) in alkaline electrolyte are investigated via cyclic voltammetry (CV) and chronoamperometry (CA) techniques. Results show that methanol oxidation currents on the PtmAu catalysts are higher than that on pure Pt catalyst, suggesting that the introduction of Au in Pt catalyst can significantly promote the catalytic properties of Pt. Among the PtmAu catalysts, Pt1.0Au/RGO shows the highest mass-specific activity (MSA) and intrinsic activity (IA). The MSA and IA of Pt1.0Au/RGO is 0.72 A mg−1Pt+Au and 105.4 A m−2Pt, which are ca. 2.40 and 3.56 times those of Pt/RGO (0.30 A mg−1Pt+Au and 29.6 A m−2Pt), respectively. CO stripping voltammograms and CV curves suggest that the improved electrocatalytic properties of the PtmAu/RGO catalysts are especially attributed to the decreased CO formation rather than the facile removal of CO on the surface of Pt. The findings of this work have potential applications in understanding the mechanism of MOR and designing highly effective Pt-based anodic catalysts of direct methanol fuel cells.

Fungal community and non-volatile metabolites changes during the pile-fermentation are key factors to organoleptic qualities of dark green tea. However, the correlation between fungal succession and non-volatile compounds has never been satisfactorily explained. The purpose of the present study was to investigate fungal succession and its correlation with flavor compounds by multi-omics. Illumina Miseq sequencing of ITS1 region was conducted to analyze the fungal succession, a total of 78 OTUs which consisted of one phyla, nine classes, 15 orders, 26 families, 37 genera were identified, with Ascomycota as dominant phyla. Cluster analysis and non-metric multidimensional scaling of samples demonstrated the distribution of OTUs in multi-dimensional space, the pile-fermentation process of dark green tea can be divided into four periods according to the generated trajectory of fungal population, S0, S1-S3, S4-S5, and S6. Aspergillus is the dominant genus. Penicillium, Cyberlindnera, Debaryomyces, Candida, Thermomyces, Rasamsonia, Thermoascus, and Byssochlamys appear in different periods. three alkaloids, seven catechins, nine amino acids, five organic acids, five flavones and flavonoid glycosides were identified by UPLC-QTOF-MS/MS, and the contents were all decreasing. Caffeine, EGC, EGCG, L-theanine, kaempferitrin, L-phenylalanine, gallic acid, and myricetin-3-O-galactoside are important ingredients which contribute to the flavor of dark green tea. This study demonstrated the fungal succession, non-volatile flavor compounds and their relationships during pile-fermentation of dark green tea, and provides new insights into evaluating pivotal role of fungal succession in the manufacturing process of dark green tea.

The composition distribution around grain boundaries of low-chromium ferritic stainless steels was investigated by the techniques of three-dimensional atom probe and focused ion beam. It was found that Cr atoms segregated largely (up to as much as 22.4 at.%) at grain boundaries with co-segregation of other solute atoms in the absence of Cr-carbides precipitation. The co-segregation induced the formation of a Cr-depleted zone (down to only 9.3 at.%) leading to intergranular corrosion. Based on the new mechanism, a novel concept of reducing or even preventing the grain boundary segregation to prevent intergranular corrosion at the level of dynamics/thermodynamics was proposed.

Volatile compounds are important contributors to dark tea quality. However, the aroma formation during the key processing pile-fermentation remains unclear. Herein, a total of 46 compounds including 17 alcohols, nine ketones, eight alkenes, five aldehydes, four esters, one heterocyclic oxygen, one alkane, and one pyranoid were identified by GC-MS. At the end of pile-fermentation, alcohols and aldehydes decreased by 21.2% and 12.9% respectively, while ketones and alkenes increased by 40.3% and 11.5% respectively, esters doubled compared to the initial period. PLS-DA analysis demonstrated that the characteristic aroma components were mainly ionone, linalool and its oxides (floral, citrus-like, fruity), safranal (woody, herbal and spice), β-cyclocitral, β-terpinene, limonene (fruity), trans-2-hexenyl hexanoate (fragrance) and roses oxide (rose). Importantly, Pearson correlation analysis demonstrated microbial communities and volatile compounds were highly correlated (|r|>0.7, p

Arabidopsis glucuronokinase (AtGlcAK), as a member of the GHMP kinases family, is implicated in the de novo synthesis of UDP-glucuronic acid (UDP-GlcA) by the myo-inositol oxygenation pathway. In this study, two T-DNA insertion homozygous mutants of AtGlcAK, atglcak-1 and atglcak-2, were identified. AtGlcAK was highly expressed in roots and flowers. There was reduced primary root elongation and lateral root formation in atglcak mutants under osmotic stress. The atglcak mutants displayed enhanced stomatal opening in response to abscisic acid (ABA), elevated water loss and impaired drought tolerance. Under water stress, the accumulation of reducing and soluble sugars was reduced in atglcak mutants, and the metabolism of glucose and sucrose was affected by the synthetic pathway of UDP-GlcA. Furthermore, a reduced level of starch in atglcak mutants was observed under normal conditions. The phylogenetic analysis suggested that GlcAK was conserved in numerous dicots and monocots plants. In short, AtGlcAK mutants displayed hypersensitivity to ABA and reduced root development under water stress, rendering the plants more susceptible to drought stress.

Lectin receptor-like kinases (LecRKs) are a class of membrane proteins found in higher plants. They play important roles in defense against of pathogens, perception of insect feeding, and stress tolerance. LecRK-VII.1 (AT4G04960) is one member of the LecRK family, which contains a conserved lectin domain and a kinase domain. In this study, the lecrk-VII.1 mutants (lecrk-VII.1-1 and lecrk-VII.1-2) showed increased seed germination rates and primary root length compared to ecotype Columbia-0 (Col-0) when treated with different concentrations of NaCl and methyl jasmonate (MeJA). To further confirm the possible role of LecRK-VII.1 in salt and jasmonic acid (JA) responses, we performed a comparative proteomic analysis of Arabidopsis Col-0 and lecrk-VII.1-1 mutant seedlings. In total, 312 proteins were differentially expressed of which 75 were related to stress responses including salt stress and JA response. Among them, decreased expressions of lipoxygenase (LOX) and annexin were confirmed by RT-PCR analyses. Activity of LOX was accordingly reduced in lecrk-VII.1 mutants. These results provide some valuable data to understand the role of LecRK-VII.1 in the response to salt stress and MeJA. In order to understand the role of LecRK-VII.1 in the response to salt stress and MeJA, we studied the phenotypes and expression patterns between the lecrk-VII.1 mutants and wild type. Comparative proteomic analysis of differentially expressed proteins of the lecrk-VII.1 mutants and wild type in Arabidopsis was performed.

The endoplasmic reticulum (ER) is the major site for protein folding in eukaryotic cells. ER homeostasis is essential for the development of an organism, whereby the unfolded protein response (UPR) within the ER is precisely regulated. ER‐phagy is a newly identified selective autophagic pathway for removal of misfolded or unfolded proteins within the ER in mammalian cells. Sec62, a component of the translocon complex, was recently characterized as an ER‐phagy receptor during the ER stress recovery phase in mammals. In this study, we demonstrated that the Arabidopsis Sec62 (AtSec62) is required for plant development and might function as an ER‐phagy receptor in plants. We showed that AtSec62 is an ER‐localized membrane protein with three transmembrane domains (TMDs) with its C‐terminus facing to the ER lumen. AtSec62 is required for plant development because atsec62 mutants display impaired vegetative growth, abnormal pollen and decreased fertility. atsec62 mutants are sensitive towards tunicamycin (TM)‐induced ER stress, whereas overexpression of AtSec62 subsequently enhances stress tolerance during the ER stress recovery phase. Moreover, YFP‐AtSec62 colocalizes with the autophagosome marker mCh‐Atg8e in ring‐like structures upon ER stress induction. Taken together, these data provide evidence for the pivotal roles of AtSec62 in plant development and ER‐phagy., Endoplasmic reticulum (ER) is the major site for protein synthesizing and folding. In this study, we illustrated an ER membrane localized protein, a component of Sec translocon, is critical for keeping ER homeostasis under ER stress condition in Arabidopsis.

Chronic tubulointerstitial injury impacts the prognosis of focal segmental glomerulosclerosis (FSGS). We found that the level of versican V1 was increased in tubular cells of FSGS patients. Tubular cell–derived versican V1 induced proliferation and collagen synthesis by activating the CD44/Smad3 pathway in fibroblasts. Both urine C3a and suPAR were increased and bound to the tubular cells in FSGS patients. C3a promoted the transcription of versican by activating the AKT/β-catenin pathway. C3aR knockout decreased the expression of versican in Adriamycin-treated (ADR-treated) mice. On the other hand, suPAR bound to integrin β6 and activated Rac1, which bound to SRp40 at the 5′ end of exon 7 in versican pre-mRNA. This binding inhibited the 3′-end splicing of intron 6 and the base-pair interactions between intron 6 and intron 8, leading to the formation of versican V1. Cotreatment with ADR and suPAR specifically increased the level of versican V1 in tubulointerstitial tissues and caused more obvious interstitial fibrosis in mice than treatment with only ADR. Altogether, our results show that C3a and suPAR drive versican V1 expression in tubular cells by promoting transcription and splicing, respectively, and the increases in tubular cell–derived versican V1 induce interstitial fibrosis by activating fibroblasts in FSGS.

Cadmium (Cd) contamination of the soil is one of the most serious environmental problems of agricultural production. Phytoremediation has attracted increasing attention because it can safely remove the soil contaminates via plant uptake, accumulations and plant harvesting. However, the high Cd toxicity to plant tissues and treatment of the large amount of hazardous plant residues from phytoremediation have limited its commercial implementation. Here we show that the leaves of the tall fescue (Festuca arundinacea) can excrete Cd out to avoid Cd toxicity in plant tissues. Cd specific fluorescence spectroscopy with laser confocal scanning microscope, screening electron microscope with energy dispersive spectroscopy and guttation fluids analysis confirmed that leaf hydathodes were the pathway of Cd excretion in tall fescue. Element analysis showed that Cd was preferentially excreted out when compared to the ion nutrients. The amount of leaf Cd excretion was linearly increased in response to the Cd stress period. The phytoremediation efficiency was evaluated to remove 14.4% of soil Cd annually by the leaf Cd excretion in our experimental system. These findings indicate that a novel strategy of Cd phytoexcretion based on washing-off and collection of leaf surface Cd is feasible to avoid Cd toxic in plant tissues and the high treatment cost of hazardous plant residues.

Tubulointerstitial fibrosis impacts renal prognosis of focal segmental glomerulosclerosis (FSGS). Based on transcriptomic analysis, we found that the level of LOC105375913 was increased in tubular cells of FSGS patients. C3a induced the expression of LOC105375913, which promoted the expression of fibronectin and collagen I in tubular cells. Silence of snail reversed the level of fibronectin and collagen I in cells overexpressing LOC105375913. MiR-27b was predicted and confirmed to regulate the expression of snail in tubular cells, and LOC105375913 contained the response element of miR-27b. The competitive binding between LOC105375913 and miR-27b increased the level of snail and promoted fibrogenesis in tubular cells. Upstream, p38 and XBP-1s regulated the expression of LOC105375913. Inhibition of p38 or silence of XBP-1s decreased the level of LOC105375913, and suppressed the expression of snail, fibronectin and collagen I in tubular cells treated with C3a. Overexpression of LOC105375913 decreased the level of miR-27b, increased the level of snail and caused tubulointerstitial fibrosis in mice. In conclusion, the activation of C3a/p38/XBP-1s pathway induces the expression of LOC105375913 in tubular cells, and LOC105375913 increases the level of snail and induces tubulointerstitial fibrosis through competitive binding of miR-27b in tubular cells of FSGS patients.

The recently reported superconductivity 9-15 K in Nd0.8Sr0.2NiO2/SrTiO3 heterostructures that were fabricated by a soft-chemical topotactic reduction approach based on precursor Nd0.8Sr0.2NiO3 thin films deposited on SrTiO3 substrates, has excited an immediate surge of research interest. To explore an alternative physical path instead of chemical reduction for realizing superconductivity in this compound, using pulsed laser deposition, we systematically fabricated 63 Nd0.8Sr0.2NiOx (NSNO) thin films at a wide range of oxygen partial pressures on various different oxide substrates. Transport measurements did not find any signature of superconductivity in all the 63 thin-film samples. With reducing the oxygen content in the NSNO films by lowering the deposition oxygen pressure, the NSNO films are getting more resistive and finally become insulating. Furthermore, we tried to cap a 20-nm-thick amorphous LaAlO3 layer on a Nd0.8Sr0.2NiO3 thin film deposited at a high oxygen pressure of 150 mTorr to create oxygen vacancies on its surface and did not succeed in higher conductivity either. Our experimental results together with the recent report on the absence of superconductivity in synthesized bulk Nd0.8Sr0.2NiO2 crystals suggest that the chemical reduction approach could be unique for yielding superconductivity in NSNO/SrTiO3 heterostructures. However, SrTiO3 substrates could be reduced to generate oxygen vacancies during the chemical reduction process as well, which may thus partially contribute to conductivity., Comment: 8 pages, 5 figures; Accepted in Rare Metals

Microparticles are sub-micron, membrane-bound particles released from virtually all cells and which are present in the circulation. In several autoimmune disorders their amount and composition in the circulation is altered. Microparticle surface protein expression has been explored as a differentiating tool in autoimmune disorders where the clinical pictures can overlap. Here, we examine the utility of a novel lipid-based marker&mdash, microparticle cholesterol, present in all microparticles regardless of cellular origin&mdash, to distinguish between rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). We first isolated a series of microparticle containing lipoprotein deficient fractions from patient and control plasma. There were no significant differences in the size, structure or protein content of microparticles isolated from each group. Compared to controls, both patient groups contained significantly greater amounts of platelet and endothelial cell-derived microparticles. The cholesterol content of microparticle fractions isolated from RA patients was significantly greater than those from either SLE patients or healthy controls. Our data indicate that circulating non-lipoprotein microparticle cholesterol, which may account for 1&ndash, 2% of measured cholesterol in patient samples, may represent a novel differentiator of disease, which is independent of cellular origin.

A simple, rapid, and highly selective trace matrix solid phase dispersion (MSPD) technique, coupled with ultra-performance liquid chromatography–ultraviolet detection, was proposed for extracting flavonoids from orange fruit peel matrices. Molecular sieve SBA-15 was applied for the first time as a solid support in trace MSPD. Parameters, such as the type of dispersant, mass ratio of the sample to the dispersant, grinding time, and elution pH, were optimized in detail. The optimal extraction conditions involved dispersing a powdered fruit peel sample (25 mg) into 25 mg of SBA-15 and then eluting the target analytes with 500 μL of methanol. A satisfactory linearity ( r 2 > 0.9990) was obtained, and the calculated limits of detection reached 0.02–0.03 μg/mL for the compounds. The results showed that the method developed was successfully applied to determine the content of flavonoids in complex fruit peel matrices.

Greenhouse vegetable production contributes 60% of the economic value of the world vegetable industry. However, the secondary soil salinization and nitrate accumulation in vegetable products have become critical concerns in greenhouse vegetable production system. Here we show that cauliflower intercropped with five turfgrass species not only reduces the salinity stress and nitrate accumulation of cauliflower but also improves cauliflower curd quality. Effect of soil salinity control and cauliflower nitrate reduction was associated with the capacity of salt and nitrate uptake and accumulation of turfgrass species. Paspalum vaginatum performed the most significant effects on soil salinity control, reduced 37.8% of nitrate content, increased 50.7% of vitamin C and 21.1% of soluble protein contents in cauliflower curd. Our results demonstrated that intercropping with Paspalum vaginatum could provide a significant help for the sustainable development in the intensive greenhouse vegetable production.

How phytoplankton responded spatiotemporally to the co-occurrence of multiple variables is of central importance for ecosystem management. In this study, extensive investigations in the Pearl River estuary (PRE), southern China, between 1974 and 2017 revealed a strong anthropogenic effect on the environmental drivers of phytoplankton dynamics (in terms of chlorophyll a). The empirical cause-and-effect chain summarized as human activity → hydrology → nutrient → chlorophyll may constitute fundamental quantitative tools for predicting effects of coastal eutrophication. Change in subaqueous topography induced by human stress resulted in shoal-trough instability, which unexpectedly shifted nutrient dynamics across the entire regions. Over time, dissolved inorganic nitrogen (DIN) and phosphorus (PO4) increased, as did the molar N/P ratio (DIN/PO4), indicating that phytoplankton growth was potentially phosphate-limited in most PRE. The adsorption of phosphorus by sediment particles was stronger than that of nitrogen. The quantification of phytoplankton drivers demonstrated the importance of river-tide dynamics, which incorporated the interplay between environmental variables. Particularly, the influence of riverine input varied over time and site, affecting hydrological control variables and nutrient limitations. Our structural equation modelling results (p

The intergranular corrosion behavior of the low-chromium ferritic stainless steel without Cr-carbide precipitation was investigated by the methods of qualitative and quantitative corrosion testing and microstructural analysis. The intergranular corrosion susceptibility of the aged stainless steels can be attributed to the Cr-depleted zone formation induced by Cr-C co-segregation to grain boundaries before Cr-carbide nucleation. The change of intergranular corrosion morphology after aging at 450 °C from discontinuous (aged for 2 h) to semi-continuous (aged for 20 h) and to continuous (aged for 200 h) is discussed in detail.