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Incompressible dipping substrata are commonly encountered in engineering practice. Compared to horizontal underlying strata, the inclined underlying stratum increase the risk of collapse of embankments reinforced with columns because it weakens the restraint of the column base. The objective of this study is to investigate the effectiveness of geosynthetics on improving the embankment stability when the underlying stratum is inclined. The influence of geosynthetic tensile stiffness on the ultimate surcharge and failure mechanism is studied. A deep-seated failure with column tilting occurs when the geosynthetic tensile stiffness is low, whereas a lateral sliding occurs when the geosynthetic tensile stiffness is high. To illustrate the contribution of geosynthetics, the distribution of the lateral pressures acting on the columns is analyzed.

It is widely accepted that lysosomes are essential for cell homeostasis, and autophagy plays an important role in tumor development. Here, we found FV-429, a synthetic flavonoid compound, inhibited autophagy flux, promoted autophagosomes accumulation, and inhibited lysosomal degradation in T-cell malignancies. These effects were likely to be achieved by lysosomal dysregulation. The destructive effects of FV-429 on lysosomes resulted in blockage of lysosome-associated membrane fusion, lysosomal membrane permeabilization (LMP), and cathepsin-mediated caspase-independent cell death (CICD). Moreover, we initially investigated the effects of autophagy inhibition by FV-429 on the therapeutic efficacy of chemotherapy and found that FV-429 sensitized cancer cells to chemotherapy agents. Our findings suggest that FV-429 could be a potential novel autophagy inhibitor with notable antitumor efficacy as a single agent.

Caffeic acid (CA), a derivative of cinnamic acid, exists in various vegetables and fruits. Natural compounds as beneficial antioxidants play an important role in the research of Alzheimer's disease (AD). In this study, we evaluated the effects of CA against AD using the C. elegans models of AD. We found that CA significantly alleviated Aβ-induced toxicity, increased lifespan, decreased body paralysis, and improved reproductive defects. Also, CA treatment increased resistance to heat and oxidative stress in N2 and CL4176. Moreover, reactive oxygen species (ROS) levels and polyglutamine (polyQ40) aggregate formation were reduced. Furthermore, the mechanistic studies revealed that CA activated transcription factor DAF-16 and its downstream targets SOD-3 and GST-4 to protect against Aβ toxicity. Also, the heat shock proteins hsf-1 and hsp-16.2 mRNA were up-regulated in CL4176. Moreover, CA activated the mRNA expression of lgg-1. Lastly, the KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis of RNA-seq data revealed that there was a significant change in the metabolism-related pathways. Overall, these results suggested an underlying mechanism of action of CA in treating AD at an organism level.

By summarizing 187 relevant research articles published in 2019, the review is focused on the research progress of physicochemical processes for wastewater treatment. This review divides into two sections, physical processes and chemical processes. The physical processes section includes three sub-sections, that is, adsorption, granular filtration, and dissolved air flotation, whereas the chemical processes section has five sub-sections, that is, coagulation/flocculation, advanced oxidation processes, electrochemical, capacitive deionization, and ion exchange. PRACTITIONER POINTS: Totally 187 research articles on wastewater treatment have been reviewed and discussed. The review has two major sections with eight sub-topics.

As apex predators, marine mammals play a key role in maintaining community structure and functioning in marine ecosystems. Hence, a decline in marine mammal populations may have negative effects on...

Cutaneous T-cell lymphoma (CTCL) is characterized by a heterogeneous group of extranodal non-Hodgkin lymphomas, in which monoclonal T lymphocytes infiltrate the skin. LW-213, a derivative of wogonin, was found to induce cell apoptosis in chronic myeloid leukemia (CML). In this study, we investigated the effects of LW-213 on CTCL cells and the underlying mechanisms. We showed that LW-213 (1–25 μM) dose-dependently inhibited human CTCL cell lines (Hut-102, Hut-78, MyLa, and HH) with IC(50) values of around 10 μM, meanwhile it potently inhibited primary leukemia cells derived from peripheral blood of T-cell lymphoma patients. We revealed that LW-213-induced apoptosis was accompanied by ROS formation and the release of calcium from endoplasmic reticulum (ER) through IP(3)R-1channel. LW-213 selectively activated CHOP and induced apoptosis in Hut-102 cells via activating PERK–eIF2α–ATF4 pathway. Interestingly, the degree of apoptosis and expression of ER stress-related proteins were alleviated in the presence of either N-acetyl cysteine (NAC), an ROS scavenger, or 2-aminoethyl diphenylborinate (2-APB), an IP(3)R-1 inhibitor, implicating ROS/calcium-dependent ER stress in LW-213-induced apoptosis. In NOD/SCID mice bearing Hut-102 cell line xenografts, administration of LW-213 (10 mg/kg, ip, every other day for 4 weeks) markedly inhibited the growth of Hut-102 derived xenografts and prolonged survival. In conclusion, our study provides a new insight into the mechanism of LW-213-induced apoptosis, suggesting the potential of LW-213 as a promising agent against CTCL.

This study focuses on the stability of stone column-supported and geosynthetic-reinforced embankments on soft soil. An upper-bound limit state plasticity failure discretization scheme (known as discontinuity layout optimization (DLO)), which determines the embankment stability without pre-assuming a slip surface, is used. The relationships between the stability of stone column-supported and geosynthetic-reinforced embankments and various influencing parameters, including the soil strength, geometric configuration, reinforcement strength, and area replacement ratio, are analysed. It is found that geosynthetics provide a significant contribution to embankment stability. Two failure mechanisms of geosynthetics (i.e., rupture failure and bond failure) are revealed and the effect of geosynthetics on embankment stability is governed by the failure mode. The application of stone columns mitigates the risk of geosynthetic failure. To provide an analytical solution for primary design in engineering practice, an approach based on the limit equilibrium method is proposed. Validations are performed with the DLO solution to demonstrate the accuracy and reliability of the developed analytical approach.

Anthropogenic activities can adversely impact biogeochemical processes essential for maintaining ecosystem health in semi-enclosed bays. However, the influence of anthropogenic contaminants such as potentially toxic elements on microbial communities that regulate biogeochemical cycles in semi-enclosed bays is poorly understood. We determined the concentrations of four potentially toxic elements (Cu, Zn, Pb, and As) in sediments from a typical tropical semi-enclosed bay in Guangdong, China. Source apportionment using Pearson's correlation analysis revealed that aquaculture activities were probably the primary source of Cu, Zn, and Pb. Using high-throughput sediment DNA sequencing, we found that Proteobacteria was the dominant phylum in sediments. There was no evidence suggesting site-specific variation in microbial function even though sediments adjacent to aquaculture discharge points had higher microbial diversity. In contrast, pollutant-specific variations were observed; for example, Zn and Pd showed potential adverse effects on the environmental information processing function, while As showed a negative correlation with metabolic function. Based on different environmental characteristics, future research should consider the impact of multiple factors on the bacterial community in aquaculture systems.

Antibiotics are widely consumed in the intensive mariculture industry. A better understanding of the effect of antibiotics on intergenerational antibiotic resistance in organisms is urgent since intergenerational transmission is crucial for the spread of antibiotic resistance genes (ARGs) in the environment. Herein, marine medaka (Oryzias melastigma) chronically exposed to low doses of sulfamethazine (SMZ) hormetically affected the progeny, characterized by increased richness and diversity of fecal microbiota and intestinal barrier-related gene up-regulation. Progeny immunity was modulated and caused by genetic factors due to the absence of significant SMZ accumulation in F1 embryos. In addition, some of the top genera in the progeny were positively correlated with immune diseases, while the expression of some immune-related genes, such as TNFα, IL1R2, and TLR3 changed significantly. This further indicated that the host selection caused by changes in progeny immunity was probably the primary determinant of progeny intestinal microbial colonization. Metagenomic analysis revealed that Proteobacteria represented the primary carriers of ARGs, while parental SMZ exposure facilitated the distribution and enrichment of multiple ARGs involved in the antibiotic inactivation in the progeny by promoting the diversity of Gammaproteobacteria and Bacteroidetes, further illustrating that antibiotic selection pressure persisted even if the offspring were not exposed. Therefore, SMZ induced hormesis in the progeny at the expense of increasing antibiotic resistance. Collectively, these findings provide a comprehensive overview of the intergenerational effect of antibiotics and serve as a reminder that the ARG transmission induced by the intergenerational impact of antibiotics on organisms should not be ignored.

The modern society greatly utilizes automobiles to fulfill the requirements of transport, and it is logically necessary to research the most efficient joinery method arrangements to construct automobiles. In the contemporary stage of joinery technology, the three mainstream methods are bolting, riveting and welding, and among these joinery methods, bolting could be used for cylinder head and cylinder block, riveting might be the most suitable means for aluminum alloy and steel in vehicle., and welding would be most appropriate for doors, bottom plates and body assemblies. These different methods have various advantages and disadvantages in their applications, as their theories and principles are all but the same. This paper also discussed the methods of joinery that should be used in parts of the automobile body and the future expectation of more novel connection methods that would appear to replace traditional ones.

Background. The association between sleep disturbance and the menstruation in the young women population has been scarcely studied. The aim of this study is to assess the association between sleep status and phase of the menstrual cycle in healthy, young, ovulating women. Methods. This cross-sectional study used the data collected from healthy young, ovulating Chinese females from September to December 2018. The association was analyzed by using linear regression and binary logistic analyses. Results. 2260 women aged 17 to 30 were included in the analysis. The average sleep duration of the respondents was 7.24 hours ( SD = 0.92 ). 61.7% of them admitted that they were accompanied by at least one of sleep symptoms including difficulty initiating sleep, difficulty maintaining sleep, dreaminess, early morning awakening, and somnolence. Sleep quality was significantly associated with dysmenorrhea (OR 95 % CI = 1.74 [1.40-2.17], P < 0.001 ) and self-awareness menstrual regularity (OR 95 % CI = 1.29 [1.06-1.56], P = 0.011 ). Conclusion. This study found that poor sleep quality is significantly associated with dysmenorrhea and self-awareness menstrual irregularity among healthy, young, ovulating, Chinese females.

Panax ginseng is a valuable traditional Chinese medicine in Northeast China. Ginsenoside, the active component of ginseng, has not been investigated much for its effects on aging and its underlying mechanism(s) of action. Here, we investigated the effects of total ginsenoside (TG), a mixture of the primary active ginsenosides from Panax ginseng, on the lifespan of Caenorhabditis elegans (C. elegans). We found that TG extended the lifespan of C. elegans and reduced lipofuscin accumulation. Moreover, TG increased the survival of C. elegans in response to heat and oxidative stress via the reduction of ROS. Next, we used RNA-seq to fully define the antiaging mechanism(s) of TG. The KEGG pathway analysis showed that TG can prolong the lifespan and is involved in the longevity regulating pathway. qPCR showed that TG upregulated the expression of nrh-80, daf-12, daf-16, hsf-1 and their downstream genes. TG also reduced the fat accumulation and promoted lipid metabolism. Moreover, TG failed to extend the lifespan of daf-16 and hsf-1 mutants, highlighting their role in the antiaging effects of TG in C. elegans. The four main constitution of TG were then confirmed by HPLC and included ginsenoside Re, Rg1, Rg2 and Rd. Of the ginsenosides, only ginsenoside Rd prolonged the lifespan of C. elegans to levels comparable to TG. These findings provided mechanistic insight into the antiaging effects of ginsenoside in C. elegans.

Excavations may cause excessive ground movements, resulting in potential damage to laterally adjacent tunnels. The aim of this investigation is to present a simple assessment technique using a multivariate adaptive regression splines (MARS) model, which can map the nonlinear interactions between the influencing factors and the maximum horizontal deformation of tunnels. A high-quality case history in Tianjin, China, is presented to illustrate the effect of excavation on the tunnel deformation and to validate the FEM. The hypothetical data produced by the FEM provide a basis for developing the proposed MARS model. Based on the proposed model, the independent and coupled effects of the input variables (i.e. the normalized buried depth of tunnels Ht/He, the normalized horizontal distance between tunnels and retaining structures Lt/He, and the maximum horizontal displacement of retaining structures, δRmax) on the tunnel response are analysed. The prediction precision and accuracy of the MARS model are validated via the artificial data and the collected case histories.

Mitotic catastrophe of cancer cells induced by drugs is characterized by low dosage and low toxicity, representing a significant advantage in the cancer treatment. Effective therapeutic options are limited for T-cell malignancies patients who are still treated by high-dose multiagent chemotherapy, potentially followed by hematopoietic stem cell transplantation, highlighting the urgency for identification of more effective anti-T-cell malignancies drugs. The use of antineoplastic drugs which induced tumor cell mitotic catastrophe would be a new strategy for cancer therapy. Nevertheless, there is still no effective mitotic catastrophe agent in T-cell malignancies. Our study showed that nonlethal dosage (ND) of GL-V9 (5-hydroxy-8-methoxy-2-phenyl-7-(4-(pyrrolidin-1-yl) butoxy) 4 H-chromen-4-one) (2 µM), a potential anticancer drug, not only attenuated cell growth and survival, but also arrested the cell cycle in G2/M phase and induced multipolar spindles, nuclear alterations (micronucleation and multinucleation), which are the most prominent morphological characteristics of mitotic catastrophe, in T-cell malignancies cell lines including Jurkat, HuT-102, and HuT-78. Moreover, ND GL-V9 could trigger DNA damage, and significantly influence several mitosis-associated proteins. Besides, results showed that ND GL-V9 increased the activity of senescence-associated β-galactosidase (SA-β-Gal) following the induction of mitotic catastrophe in Jurkat and HuT-102 cells with intact p53, while causing apoptosis in p53-deficient HuT-78 cells. We concluded that the anti-T-cell malignancies effects of ND GL-V9 and clarified the precise regulation in the process of mitosis under the action of GL-V9 in T-cell malignancies. Our data provided new evidence for the study of T-cell malignancies treatment associated with mitotic catastrophe and cellular senescence induction.

Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell neoplasm characterized by an uncontrolled proliferation of moderately and well differentiated cells of the granulocytic lineage. LW-213, a newly synthesized flavonoid compound, was found to exert antitumor effects against breast cancer through inducing G2/M phase arrest. We investigated whether LW-213 exerted anti-CML effects and the underlying mechanisms. We showed that LW-213 inhibited the growth of human CML cell lines K562 and imatinid-resistant K562 (K562r) in dose- and time-dependent manners with IC50 values at the low μmol/L levels. LW-213 (5, 10, 15 μM) caused G2/M phase arrest of K562 and K562r cells via reducing the activity of G2/M phase transition-related proteins Cyclin B1/CDC2 complex. LW-213 treatment induced apoptosis of K562 and K562r cells via inhibiting the expression of CDK9 through lysosome degradation, thus leading to the suppression of RNAPII phosphorylation, down-regulation of a short-lived anti-apoptic protein MCL-1. The lysosome inhibitor, NH4Cl, could reverse the anti-CML effects of LW-213 including CDK9 degradation and apoptosis. LW-213 treatment also degraded the downstream proteins of BCR-ABL1, such as oncoproteins AKT, STAT3/5 in CML cells, which was blocked by NH4Cl. In primary CML cells and CD34+ stem cells, LW-213 maintained its pro-apoptotic activity. In a K562 cells-bearing mice model, administration of LW-213 (2.5, 5.0 mg/kg, ip, every other day for 4 weeks) dose-dependently prolonged the survival duration, and significantly suppressed huCD45+ cell infiltration and expression of MCL-1 in spleens. Taken together, our results demonstrate that LW-213 may be an efficient agent for CML treatment.

Small interfering RNA(siRNA) has been proved to be a powerful tool for silencing target gene in cells, raising the possibility that siRNA can be employed as a therapy for treating cancers and other genetic diseases. However, siRNA transfection has the limitation due to the difficulty in the delivery of siRNA to target cells and tissues. To explore an efficient biocompatible siRNA delivery system, cationic diphenylalanine vesicles(CDPVs) were constructed to transfer survivin siRNA to human ovarian cancer cells. The morphology of CDPVs was characterized by scanning electron microscopy(SEM) and the distribution of survivin siRNA was characterized by confocal laser scanning microscopy, which reveal that diphenylalanine and the survivin siRNA were successfully co-delivered. After co-incubation for 48 h, the CDPVs/siRNA exhibited enhanced tumor cell growth inhabitation and apoptosis inducted in human SK-OV-3 ovarian carcinoma cells. Overall, CDPVs is an efficient siRNA delivery system and has a promising prospect for cancer therapy.

Alzheimer’s disease(AD) is a neurodegenerative disorder characterized by the deposition of β-amyloid peptide(Aβ) in the brain tissues, and an imbalance in the oxidant-antioxidant system. Compounds with antioxidant activity and the ability to inhibit Aβ aggregation therefore potentially treat AD. In this study, we designed an iron-porphyrin containing bifunctional peptide(BP, Deuterohemin-AlaHisThrValGluLysLeuProPhePheAsp) based on natural microperoxidase-11(MP-11) and typical β-sheet breaker LPFFD(iAβ5p). This BP substantially reduced the aggregation of Aβ and caused oligomer disassembly, by binding Aβ with affinity constant of 9.07 μmol/L. Furthermore, it showed a neuroprotective effect on Aβ25—35 induced toxicity in SH-SY5Y cells, and significantly alleviated Aβ-induced paralysis and extended lifespan in Aβ1—42 transgenic C. elegans(CL4176). It also showed a potent peroxidase activity of 20.8 U/mg, and scavenged free radicals both in vitro and in vivo. In addition, BP up-regulated the levels of hsp16.2, hsp16.41, and hsp12.6 mRNAs to 183.26%, 160.16%, and 162.64% respectively, and down-regulated that of hsp70 to 36.76% in C. elegans. Taken together, the synthetic BP inhibited Aβ aggregation and showed antioxidant activity, indicating the therapeutic potential of novel peptide drugs against AD.

Microplastics and antibiotics widely coexist in the aquatic environment, especially in mariculture regions. However, antibiotics adsorbed on microplastics and their role in the colonization of microorganisms on microplastics are poorly understood. Therefore, in-situ aging experiments were conducted to investigate the impact of antibiotics and microplastics co-occurrence on microorganisms and assess their potential risks to human health. Results showed that antibiotics were adsorbed selectively on microplastics, with 29 investigated antibiotics (n = 40) detected in surrounding water but only 6 investigated antibiotics were adsorbed on microplastics. The concentration of antibiotics accumulated on microplastics was controlled by microplastic types and environmental conditions. For example, aged polypropylene (PP) had more developed pore structures resulting in higher adsorption of antibiotics than other microplastic types. High-throughput sequencing showed higher diversity and distinct composition of microorganisms attached to the microplastics than the surrounding water. Opportunistic pathogenic bacteria such as Mycobacterium possessed positive relationships with tetracycline and doxycycline on aged microplastics, which showed adsorbed antibiotics on aged microplastics could benefit some specific pathogens colonized on the microplastics and spread into unaffected ecosystems, marine organisms even humans. The health risk quotient (HQ) implied the potential human health risk of consuming commercial seafood polluted by antibiotics and microplastic loaded with antibiotics. This study revealed the interaction of antibiotics and microorganisms with aged microplastics in aquaculture systems, providing a novel insight into their synergistic effects on ecological and human health.

Embankment stability issues present design and research challenges to geotechnical engineers. Current design methodologies for the stability of embankments on columns are mainly evaluated ...

BackgroundThe positive transcription elongation factor b (P-TEFb) kinase activity is involved in the process of transcription. Cyclin-dependent kinase 9 (CDK9), a core component of P-TEFb, regulates the process of transcription elongation, which is associated with differentiation and apoptosis in many cancer types. Wogonin, a natural CDK9 inhibitor isolated fromScutellaria baicalensis.This study aimed to investigate the involved molecular mechanisms of wogonin on anti- chronic myeloid leukemia (CML) cells.Materials and methodsmRNA and protein levels were analysed by RT-qPCR and western blot. Flow cytometry was used to assess cell differentiation and apoptosis. Cell transfection, immunofluorescence analysis and co-immunoprecipitation (co-IP) assays were applied to address the potential regulatory mechanism of wogonin. KU-812 cells xenograftNOD/SCIDmice model was used to assess and verify the mechanism in vivo.ResultsWe reported that the anti-CML effects in K562, KU-812 and primary CML cells induced by wogonin were regulated by P-TEFb complex. We also confirmed the relationship between CDK9 and erythroid differentiation via knockdown the expression of CDK9. For further study the mechanism of erythroid differentiation induced by wogonin, co-IP experiments were used to demonstrate that wogonin increased the binding between GATA-1 and FOG-1 but decreased the binding between GATA-1 and RUNX1, which were depended on P-TEFb. Also, wogonin induced apoptosis and decreased the mRNA and protein levels of MCL-1 in KU-812 cells, which is the downstream of P-TEFb. In vivo studies showed wogonin had good anti-tumor effects in KU-812 xenograftsNOD/ SCIDmice model and decreased the proportion of human CD45+cells in spleens of mice. We also verified that wogonin exhibited anti-CML effects through modulating P-TEFb activity in vivo.ConclusionsOur study indicated a special mechanism involving the regulation of P-TEFb kinase activity in CML cells, providing evidences for further application of wogonin in CML clinical treatment.

Caffeic acid (CA), a derivative of cinnamic acid, exists in various vegetables and fruits. Natural compounds as beneficial antioxidants play an important role in the research of Alzheimer's disease (AD). In this study, we evaluated the effects of CA against AD using the C. elegans models of AD. We found that CA significantly alleviated Aβ-induced toxicity, increased lifespan, decreased body paralysis, and improved reproductive defects. Also, CA treatment increased resistance to heat and oxidative stress in N2 and CL4176. Moreover, reactive oxygen species (ROS) levels and polyglutamine (polyQ40) aggregate formation were reduced. Furthermore, the mechanistic studies revealed that CA activated transcription factor DAF-16 and its downstream targets SOD-3 and GST-4 to protect against Aβ toxicity. Also, the heat shock proteins hsf-1 and hsp-16.2 mRNA were up-regulated in CL4176. Moreover, CA activated the mRNA expression of lgg-1. Lastly, the KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis of RNA-seq data revealed that there was a significant change in the metabolism-related pathways. Overall, these results suggested an underlying mechanism of action of CA in treating AD at an organism level.

T-cell malignancies are still difficult to treat due to a paucity of plans that target critical dependencies. Drug-induced cellular senescence provides a permanent cell cycle arrest during tumorigenesis and cancer development, particularly when combined with senolytics to promote apoptosis of senescent cells, which is an innovation for cancer therapy. Here, our research found that wogonin, a well-known natural flavonoid compound, not only had a potential to inhibit cell growth and proliferation but also induced cellular senescence in T-cell malignancies with nonlethal concentration. Transcription activity of senescence-suppression human telomerase reverse transcriptase (hTERT) and oncogenic C-MYC was suppressed in wogonin-induced senescent cells, resulting in the inhibition of telomerase activity. We also substantiated the occurrence of DNA damage during the wogonin-induced aging process. Results showed that wogonin increased the activity of senescence-associated β-galactosidase (SA-β-Gal) and activated the DNA damage response pathway mediated by p53. In addition, we found the upregulated expression of BCL-2 in senescent T-cell malignancies because of the antiapoptotic properties of senescent cells. Following up this result, we identified a BCL-2 inhibitor Navitoclax (ABT-263), which was highly effective in decreasing cell viability and inducing apoptotic cell death in wogonin-induced senescent cells. Thus, the “one-two punch” approach increased the sensibility of T-cell malignancies with low expression of BCL-2 to Navitoclax. In conclusion, our research revealed that wogonin possesses potential antitumor effects based on senescence induction, offering a better insight into the development of novel therapeutic methods for T-cell malignancies.

In this technical note, the seismic bearing capacity coefficients of shallow foundations placed on soft ground reinforced by stone columns are evaluated based on the upper-bound theorem of...

The US Centers for MedicareMedicaid Services proposed in 2019 that glycated hemoglobin ATen patient EDTA-whole blood specimens were distributed to 318 and 336 laboratories in the 2018 and 2019 PT events organized by Shanghai Center for Clinical Laboratory (SCCL). HbAHbAThe AL (in NGSP unit) of ±6% or ±7% for PT evaluation of HbA

Background Although targeting histone deacetylases (HDACs) may be an effective strategy for core binding factor‐acute myeloid leukemia (CBF‐AML) harboring t(8;21) or inv(16), HDAC inhibitors are reported to be limited by drug‐resistant characteristic. Our purpose is to evaluate the anti‐leukemia effects of Baicalein on CBF‐AML and clarify its underlying mechanism. Methods Enzyme activity assay was used to measure the activity inhibition of HDACs. Rhodamine123 and RT‐qPCR were employed to evaluate the distribution of drugs and the change of ATP‐binding cassette (ABC) transporter genes. CCK8, Annexin V/PI, and FACS staining certified the effects of Baicalein on cell growth, apoptosis, and differentiation. Duolink and IP assay assessed the interaction between HDAC‐1 and ubiquitin, HSP90 and AML1‐ETO, and Ac‐p53 and CBFβ‐MYH11. AML cell lines and primary AML cells‐bearing NOD/SCID mice models were used to evaluate the anti‐leukemic efficiency and potential mechanism of Baicalein in vivo. Results Baicalein showed HDAC‐1/8 inhibition to trigger growth suppression and differentiation induction of AML cell lines and primary AML cells. Although the inhibitory action on HDAC‐1 was mild, Baicalein could induce the degradation of HDAC‐1 via ubiquitin proteasome pathway, thereby upregulating the acetylation of Histone H3 without promoting ABC transporter genes expression. Meanwhile, Baicalein increased the acetylation of HSP90 and lessened its connection to AML1/ETO, consequently leading to degradation of AML1‐ETO in t(8;21)q(22;22) AML cells. In inv(16) AML cells, Baicalein possessed the capacity of apoptosis induction accompanied with p53‐mediated apoptosis genes expression. Moreover, CBFβ‐MYH11‐bound p53 acetylation was restored via HDAC‐8 inhibition induced by Baicalein contributing the diminishing of survival of CD34+ inv(16) AML cells. Conclusions These findings improved the understanding of the epigenetic regulation of Baicalein, and warrant therapeutic potential of Baicalein for CBF‐AML., Baicalein shows HDAC1/8 inhibition without promoting ABC transporter genes expression.2. Baicalein exerts therapeutic effect in CBF‐AML.3. The inhibition of HDAC1/8 could be potential therapeutic target for CBF‐AML treatment.

The combination of selenium and pillararenes to prepare selenium-containing pillararene-based biomaterials is of great significance for the development of biomedicine. Herein, using a covalent self-assembly strategy, we successfully developed new diselenium-containing ultrathin polymer nanocapsules based on lateral cross-linked pillararenes. The new system exhibited a very potent anticancer effect; additionally, the incorporation of the cleavable redox diselenium bond into the polymer nanocapsules provided a smart nanocarrier for drug delivery. Moreover, the polymer nanocapsules were developed for anticancer drug targeting delivery by loading an anticancer drug and introducing the tumor-penetrating peptide RGD through the host-guest interaction strategy. The targeting DOX-loaded diselenium-containing polymer nanocapsules exhibited enhanced stability, self-anticancer effect, targeted delivery and controlled drug release, resulting in effective combined inhibition of tumor progression.

Levels of serum sodium (Na) are widely determined in clinical laboratories. Accordingly, sodium quantification must be performed using reliable methods. Herein are reported the results of the evaluation of a new inductively coupled plasma mass spectrometry (ICP-MS) method for sodium quantification.Serum samples were diluted 100 × by 0.3% ultrapure nitric acid, and germanium (Ge) was used as an internal standard. Sodium calibration solutions with different concentrations were added to serum matrix solutions. The serum sodium concentration was calculated according to the standards addition method. The analytical performance of the method, as well as a comparison with other sodium method, was investigated.The correlation coefficients (r) between the measured Na/Ge ratios and the analyte concentration ratios were all 0.9999. Intra- and between-assay coefficients of variation (CVs) were 0.64% and 0.57%, respectively, and the total CV was 0.67%. The trueness of the method was verified by measuring a certified reference material, SRM 956d. The new ICP-MS method was compared with the 2017 and 2018 External Quality Assessment Scheme for Reference Laboratories in Laboratory Medicine (RELA). The results were well correlated with those obtained by the routine indirect ion selective electrode (ISE) method: sodium (ICP-MS, mmol/L) = 0.9895 × sodium (ISE, mmol/L) + 1.3049 (r = 0.9914, n = 40). The mean deviation between the results of the ICP-MS method and the indirect ISE method was -0.15%.The new ICP-MS method proved to be accurate, reliable, simple, and fast and may be used as a candidate reference method for setting target values in the standardization of serum sodium measurements.

The river-sea transport of microplastic with complex environmental conditions and diverse driving factors has received growing attention in the estuary. This research investigated the vertical distribution of microplastics in the water column and surface sediments and explored the effect of tidal variation on the transport of microplastics in Jiulong Estuary and Xiamen Bay, China. Results show that the microplastics in the estuary (630 ± 515 μm) was significantly larger than that in the bay (344 ± 420 μm, p0.01). Low-density microplastics are present in the whole water column, while high-density microplastics was apt to accumulate in the bottom water and surface sediment suggesting biofouling and material density of microplastics synergistic affect its vertical distribution. Every 1-2 h high-frequency samples collected in a whole tide found the increase of fine size (45-300 μm) and decrease of large size (300 μm) in the flood tide, which implied fine microplastics were easily driven into the estuary from the bay at flood tide than large microplastics. The abundance of microplastics in the sediments decreased in the fast-rising and fast-falling period implies the tide influences the fragmentation and resuspension of microplastics in the estuary. Finally, the flux of microplastics entering Xiamen Bay was 53.5 t/month in the moderate flow month were estimated based on the abundance of different water layers instead of floating microplastics in the surface water.

Decreasing bone marrow (BM) microvessel density and circulating angiogenic cytokine levels are promising strategies for the treatment of relapsed and resistant acute myeloid leukemia (AML). Previous studies have reported that wogonoside could inhibit the progression of AML and suppress angiogenesis in a solid tumor, but the correlation of these two effects was ignored. In this research, we determined whether wogonoside could inhibit angiogenesis in this hematologic malignancy. We found that wogonoside could inhibit tumor growth and progression, and prolong the survival of nude mice inoculated with U937/MDR. Besides, reducing BM angiogenesis might cause therapeutic effect against resistant AML. Therefore, coculture between AML cells and BM stromal cells was established to imitate their crosstalk. Then, the effect of wogonoside on BM angiogenesis was tested in vitro and in vivo. We found that wogonoside could suppress microvessel formation in the chicken chorioallantoic membrane assay model and matrigel plug assay. The mechanism research revealed that wogonoside could block the JAK2-STAT3 pathway in AML cells and stromal cells to break their positive feedback. We detected several cytokines related to AML or angiogenesis and found that secreted interleukin-8 was a significant angiogenic cytokine to induce BM angiogenesis. These findings supported that new diagnostics and promising treatment strategies could be developed in relapsed and resistant AML patients.

Extensive research has investigated the bearing capacity of footings placed on leveled ground improved by deep mixed (DM) columns. However, few studies have focused on the effects of the embedment on the bearing capacity of footings on ground reinforced with DM columns. In geotechnical engineering practice underestimation of the limit load has occurred in China because of the increased use of conventional design methods for reinforced ground with embedment. In this investigation, a numerical model using a rigorous limit analysis tool, known as discontinuity layout optimization (DLO), is established. An equivalent area model is employed with an appropriate stress concentration ratio. Subsequently, a set of design charts of bearing capacity coefficients is produced with a special focus on the bearing capacity coefficient Nq and the failure mechanism. The results show that three failure patterns exist in the composite ground reinforced by DM columns. For cases without embedment, the bearing capacity coefficient Nc increases with the area replacement ratio to a certain value due to the occurrence of general shear failure mechanism. The bearing capacity coefficient Nγ decreases with the area replacement ratio, as the equivalent frictional strength of the reinforced region is reduced. When the embedment is considered, the failure mechanism of composite foundation has a significant influence on the coefficient Nq. Specifically, increase of column length leads to a larger value of Nq when block failure is observed. When a general shear failure pattern occurs, the effect of additional column lengths on the coefficient Nq can be neglected.

This investigation aimed to develop a simplified semi-empirical method of assessing the deformation of tunnels laterally adjacent to excavations. A finite element analysis using the hardening soil model with small-strain stiffness (HSS model) was performed to study the influence of the excavation depth, the horizontal displacements of retaining structures, and the relative tunnel locations on the responses of existing tunnels. A simplified model was developed based on the numerical results, and a database comprising 14 case histories was collected. Comparisons were made with the generated artificial data and the collected case histories to demonstrate the accuracy of the proposed model.

Acute myeloid leukaemia (AML) comprises a range of disparate genetic subtypes, involving complex gene mutations and specific molecular alterations. Post‐translational modifications of specific proteins influence their translocation, stability, aggregation and even leading disease progression. Therapies that target to post‐translational modification of specific proteins in cancer cells represent a novel treatment strategy. Non‐homogenous subcellular distribution of PLSCR1 is involved in the primary AML cell differentiation. However, the nuclear translocation mechanism of PLSCR1 remains poorly understood. Here, we leveraged the observation that nuclear translocation of PLSCR1 could be induced during wogonoside treatment in some primary AML cells, despite their genetic heterogeneity that contributed to the depalmitoylation of PLSCR1 via acyl protein thioesterase 1 (APT‐1), an enzyme catalysing protein depalmitoylation. Besides, we found a similar phenomenon on another AML‐related protein, N‐RAS. Wogonoside inhibited the palmitoylation of small GTPase N‐RAS and enhanced its trafficking into Golgi complex, leading to the inactivation of N‐RAS/RAF1 pathway in some primary AML cells. Taken together, our findings provide new insight into the mechanism of wogonoside‐induced nuclear translocation of PLSCR1 and illuminate the influence of N‐RAS depalmitoylation on its Golgi trafficking and RAF1 signalling inactivation in AML.

Tumor necrosis factor alpha (TNFα) is a complicated cytokine which is involved in proliferation and differentiation of acute myelogenous leukemia (AML) cells through a poorly understood mechanism. Mechanistic studies indicate that TNFα induced binding of PI3K subunit p85α to N-terminal truncated nuclear receptor RXRα (tRXRα) proteins, and activated AKT. The activated PI3K/AKT pathway negatively regulated differentiation of AML cells through the upregulation of c-Myc. In addition, TNFα also induced activation of nuclear factor κB (NF-κB), a nuclear transcription factor which was shown to promote cell proliferation. The present study demonstrates that oroxylin A, a natural compound isolated from Scutellariae radix, sensitizes leukemia cells to TNFα and markedly enhances TNFα-induced growth inhibition and differentiation of AML cell including human leukemia cell lines and primary AML cells. Activation of PI3K/AKT pathway could be inhibited by oroxylin A through inhibiting expression of tRXRα in NB4 and HL-60-resistant cells. Furthermore, we found that oroxylin A inhibited the activation of NF-κB and the DNA binding activity by TNFα proved by EMSA in these two AML cell lines. Moreover, in vivo studies showed that treatment with oroxylin A in combination with TNFα decreased AML cell population and prolonged survival in NOD/SCID mice with xenografts of primary AML cells. Overall, our results indicate that oroxylin A is able to inhibit the negative effects of TNFα for AML therapy, suggesting that combination of oroxylin A and TNFα have the potential to delay growth or eliminate the abnormal leukemic cells, thus representing a promising strategy for AML treatment.

// Le Shen 1, * , Lu-Lu Zhang 2, * , Hui Li 1 , Xiao Liu 1 , Xiao-Xuan Yu 1 , Po Hu 1 , Hui Hui 1 , Qing-Long Guo 1 and Shuai Zhang 3 1 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, People’s Republic of China 2 Department of Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, People’s Republic of China 3 Department of Thoracic Surgery, Nanjing Medical University Affiliated Cancer Hospital, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Cancer Institute of Jiangsu Province, Nanjing 210009, People’s Republic of China * These authors have contributed equally to this work Correspondence to: Shuai Zhang, email: Dr_zhangshuai@163.com Qing-Long Guo, email: anticancer_drug@163.com Hui Hui, email: moyehh@163.com Keywords: oroxylin A, tregs, TGF-β1, NF-κB Received: January 23, 2017 Accepted: March 22, 2017 Published: April 19, 2017 ABSTRACT Oroxylin A (OA), a naturally occurring monoflavonoid isolated from Scutellariae radix , has previously been reported to inhibit the proliferation of several cancer cell lines. CD4 + CD25 + Foxp3 + regulatory T cells (Tregs) play an important role in maintenance of immunologic self-tolerance. Tregs also increase in cancer and take part in suppressing antitumor immune responses. Here, we explored how OA affected the Tregs in lung cancer environment and the involved underlying mechanism. It is found that OA reversed the generation of Tregs induced by H460 lung cancer cells co-culture. Furthermore, in vivo , OA reduced tumor formation rate and attenuated Foxp3 expression in tumor-infiltrating lymphocytes. We also found that transforming growth factor-β1 (TGF-β1) neutralizing antibody reversed the enhancement of Treg number and expression of p-Smad3ˎp-p38ˎp-JNKˎp-ERK1/2 in the co-culture model. Moreover, OA reduced the secretion of TGF-β1 and down-regulated the activation of NF-κB signaling in H460 cells. OA also inhibited Treg activity by a direct inhibition of the T cells’ response to TGF-β1. In conclusion, our study demonstrated that OA inhibits the generation of Tregs in lung cancer environment by inhibiting the T cells’ response to TGF-β1 and decreasing the secretion of TGF-β1 in lung cancer cells via NF-κB signaling.

Cutaneous T-cell lymphomas (CTCLs) represent a rare form of non-Hodgkin lymphomas characterized by an accumulation of malignant CD4+ T cells in the skin. TP53 genetic alteration is one of the most prevalent genetic abnormalities in CTCLs. Therefore, it is a promising target for innovative therapeutic approaches. We found that p53 could physically interact with histone deacetylase (HDAC) 1 and HDAC8, and was subsequently deacetylated to lose its function in CTCL cells, and the p53 downstream apoptosis-associated genes were repressed. Thus, the anti-CTCL activity displayed by HDAC inhibitors depends on p53 status. However, recent studies have reported that HDAC inhibitors could induce a wide variety of drug-resistant characteristics in cancer cells by regulating ATP-binding cassette transporters. Moreover, we discovered that Baicalein, a natural product, exhibited an inhibitory effect on HDAC1 and HDAC8. Though the inhibition of HDAC1 was mild, Baicalein could induce the degradation of HDAC1 through the ubiquitin proteasome pathway, thereby markedly upregulating the acetylation of histone H3 without promoting ATP-binding cassette transporter gene expression. In terms of the mechanism, Baicalein showed better growth inhibition than traditional HDAC inhibitors in CTCLs. This study indicates a special mechanism of HDAC1 and HDAC8 and p53 in T-cell lymphoma cells and identifies a potential and safe natural HDAC inhibitor for the treatment of CTCLs.

T-cell malignancies are characterized by the excessive proliferation of hematopoietic precursor cells of T-cell lineage lymphocytes in the bone marrow. Previous studies suggest that T-cell malignancies are usually accompanied by highly activated PI3K/AKT signaling which confers the ability of cancer cells to proliferate and survive. Here, we found that GL-V9, a newly synthesized flavonoid compound, had a potent to inhibit the activation of AKT1 and induce the cell apoptosis in T-cell malignancies including cell lines and primary lymphoblastic leukemia. Results showed that GL-V9-induced degradation of AKT1 blocked PI3K/AKT1 signaling and the degradation of AKT1 could be reversed by NH4Cl, an inhibitor of lysosomal function. Inhibiting AKT1 promoted dephosphorylation of FOXO3A and its nuclear translocation. We further demonstrated that GL-V9-induced apoptosis effects were dependent on the binding of FOXO3A to the BIM promoter, resulting in the production of BH3-only protein BIM. Moreover, GL-V9 showed a more persistent and stronger apoptosis induction effects than pharmacologic PI3K inhibitor. The in vivo studies also verified that GL-V9 possessed the anti-tumor effects by reducing the leukemic burden in T-ALL-bearing BALB/c nude mice. In conclusion, our study provides a new insight into the mechanism of GL-V9-induced apoptosis, suggesting the potency of GL-V9 to be a promising agent against T-cell malignancies.

Semi-enclosed bays are used for critical economic activities such as ports, aquaculture, and human settlement due to their topography and ocean connectivity. However, the role of these geomorphological characteristics on the accumulation of chlorinated organic pollutants in semi-enclosed bays is poorly understood. We investigated the spatiotemporal distribution and potential ecological risk of organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) in sediments from Shantou Bay, a semi-enclosed bay. The ∑PCB concentration was 258-1297 ng g-1 and 59.6-651 ng g-1 in the dry season and wet season, respectively. Sediments collected downstream and upstream the aquaculture farms had significantly lower DDT concentrations than those collected close to the aquaculture discharge points. The ratio of DDT and its metabolites indicated that there was possible fresh input of DDTs into Shantou Bay. However, no significant spatial trend was observed in the PCB profiles. The concentrations of PCBs and OCPs in Shantou Bay were above the China Marine Sediment Quality Class I suggesting remediation was essential to ensure the aquatic systems could be safely used for fisheries, swimming, or as marine protected areas. Furthermore, the potential ecological risk of DDTs was high as it exceeded the effects thresholds at all sites. Seasonal variations in human activities, resuspension of historical contaminants due to physical oceanographic, climatic and hydrological factors, and contaminant trapping probably contributed to the changes in organic pollutant distribution in the semi-enclosed bay.

Soil deposits inevitably affect the seismic performance of underground structures, and underground tunnels are commonly constructed on sites composed of layered soil deposits. In this study, dynamic centrifuge tests and numerical modelling are conducted to enhance the fundamental understanding of the kinematic soil-tunnel interaction for tunnels constructed in layered soils that consist of muddy clay and silty clay. The site seismic response and tunnel seismic performance between the centrifuge and numerical modelling are compared. The acceleration time histories, amplification factors of the input motions, and the Fourier spectra between free field and structural field are experimentally and numerically investigated. For comparative purposes, parametric studies of tunnels in a single muddy clay and a single silty clay using verified numerical modelling are carried out. In addition, the dynamic bending moment and axial forces obtained by centrifuge and numerical modelling are compared with the solutions predicted by analytical methods in prior studies.

Ferulic acid (FA) is a naturally-occurring well-known potent antioxidant and free radical scavenger. FA supplementation is an effective strategy to delay aging, but the underlying mechanism remains unknown. In the present study, we examined the effects of FA on lifespan extension and its mechanism of FA in Caenorhabditis elegans (C. elegans). Results suggested that FA increased the lifespan of C. elegans, rather than altering the growth of E. coli OP50. Meanwhile, FA promoted the healthspan of C. elegans by improving locomotion and reducing fat accumulation and polyQ aggregation. FA increased the resistance to heat and oxidative stress through reducing ROS. The upregulating of the expression of the hlh-30, skn-1, and hsf-1 were involved in the FA-mediated lifespan extension. Furthermore, FA treatment had no impact on the lifespan of daf-2, hlh-30, skn-1, and hsf-1 mutants, confirming that insulin/IGF-1 signaling pathway and multiple longevity mechanisms were associated with the longevity mechanism of FA. We further found that mitochondrial signaling pathway was modulation involved in FA-mediated lifespan extension. With the results from RNA-seq results and mutants lifespan assay. These findings contribute to our knowledge of the lifespan extension and underlying mechanism of action of FA in C. elegans.

Indo-Pacific humpback (Sousa chinensis) dolphins are primarily exposed to chlorinated organic contaminants through the consumption of contaminated fish. We assessed the potential risk of chlorinated organic contaminants to Indo-Pacific humpback dolphins by determining the concentration of 21 organochlorine pesticides (OCPs) and 28 polychlorinated biphenyls (PCBs) in 14 fish species collected from the South China Sea coastal waters. The results of the study showed that bioaccumulation of OCPs and PCBs was influenced by sampling location, fish species, and fish niche. The average ∑DDT (Dichlorodiphenyltrichloroethane) concentration was 3 times higher in benthopelagic fish (488 ng/g) compared to pelagic-neritic fish (155 ng/g) from Jiangmen, whereas an opposite pattern of the lower DDTs concentration in benthopelagic and demersal fish compared to pelagic fish from Zhuhai (p 100), except Xiamen and Qinzhou. A highest average ∑DDT concentration was observed Qinzhou. This study showed that fish consumption might pose a health risk to Indo-Pacific humpback dolphins. However, further studies are required to determine the contribution of fish niche to the overall risk.

Naphthenic acids (NAs) originate from bitumen and are considered a major contributor to acute toxicity in oil sands process-affected water (OSPW) produced from bitumen extraction processes. To reclaim oil sands tailings and remediate OSPW, in-pit fluid fine tailings can be water-capped as end pit lakes (EPL). Addressing NAs present in OSPW, either through removal, dilution or degradation, is an objective for oil sands reclamation. EPLs can remediate NAs through degradation or dilution or both. To assess and understand degradation potential, Chlorella kessleri and Botryococcus braunii were tested for their tolerance to, and ability to biodegrade, three model NAs (cyclohexanecarboxylic acid, cyclohexaneacetic acid, and cyclohexanebutyric acid). Water sourced from the industry's first EPL, the Base Mine Lake (BML), was used alone as an inoculum or co-cultured with C. kessleri to biodegrade cyclohexanecarboxylic acid and cyclohexanebutyric acid. All cultures metabolized the model compounds via β-oxidation. Biodegradation by the co-culture of C. kessleri and BML inoculum was most effective and rapid: the cyclohexaneacetic acid generated from cyclohexanebutyric acid could be further degraded by the co-culture, while the cyclohexaneacetic acid generated could not be consumed by pure algal cultures or BML inoculum alone. Adding C. kessleri greatly increased the diversity of the microbial community in the BML inoculum; many known hydrocarbon and NA degraders were identified from the 16S rRNA gene sequencing from this co-culture. This more diverse microbial community could have potential for EPL remediation.

Currently, tailings ponds are used to contain oil sands process-affected water (OSPW) and fluid fine tailings (FFT) generated from the Alberta oil sands mining operations. In 2016, the gove...

Accelerating the dewatering of oil sands tailings is a crucial challenge to the oil sands industry. Fresh tailings (15–20% by weight solids) and mature tailings (30–35% by weight solids) de...

The application of MgFe 2 O 4 as microwave (MW) absorber and catalyst to removal p-nitrophenol (PNP) in soil has been investigated, including the catalytic performance, removal route, and reaction mechanisms. Five types of MgFe 2 O 4 nanoparticles were synthesized with chemical co-precipitation (M 1 , M 1–1 , and M 1–2 ), gel combustion (M 2 ), and reverse micelle (M 3 ) methods, respectively, and characterized by FTIR, XRD, and SEM technologies. The results showed that the chemical co-precipitation of MgFe 2 O 4 (M 1 , calcined at 600 °C for 2 h) with higher O–H and H–O–H contents and higher Mg 2+ /Fe 3+ occupying tetrahedral sites had the highest catalytic performance for PNP degradation. The enhancement of MW catalytic performance was attributed to the significant increased and hypodispersion of “hot spots” on MgFe 2 O 4 surface (>1000 °C) and the generation of various active species ( OH and O 2 − ). Water and oxygen molecular as active species donors played an important role in the catalytic process. The main degradation products were phenol, hydroquinone, 1,2,4-trihydroxybenzene, and dihydroxynitrobenzene. Three stages were occurred in the MW catalytic process. A part of PNP was firstly thermal desorbed from soil with soil temperature increasing, and PNP was further catalytically oxidized by OH and O 2 − species from the disassociation of water and oxygen. Parts of PNP and its decomposed products were directly encapsulated in soil by thermal stabilization.