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Photothermal therapy (PTT) has gained extensive interest in tumor treatments due to its non-invasive and low-toxic nature. However, the currently available photothermal agents (PTAs) mostly show unsatisfactory photothermal conversion efficiency (PCE). Besides, as a local cancer treatment modality, PTT fails to inhibit metastasis of tumors. To address these issues, in this study, two aza-boron-dipyrromethene (aza-BODIPY)-based organic photothermal agents (OPTAs), Fc-aza-BODIPY and TPA-aza-BODIPY, were rationally coined by introducing two strong electron-donating ferrocene (Fc) moieties and two triphenylamine (TPA) rotors, which could boost intramolecular photo-induced electron transfer (PET) and molecular rotation respectively, thereby improving the PCE of aza-BODIPY dyes. After encapsulation of hydrophobic Fc-aza-BODIPY (or TPA-aza-BODIPY) and quercetin with biodegradable PLGA and DSPE-mPEG2000, the resulting nanoparticles (FAQ NPs and TAQ NPs) showed excellent optical properties with PCE of ∼72.0% and ∼79.7% and specific tumor accumulations through enhanced permeability and retention (EPR) effects. Consequently, these two NPs possessed prominent antitumor effects under 880 nm laser irradiation. Moreover, both FAQ NPs and TAQ NPs loaded with quercetin could inhibit tumor metastasis efficiently. These two multifunctional nanomaterials integrating OPTAs and anti-metastasis agents constructed a cooperative treatment program, which may provide a potential opportunity for future clinical cancer treatment.

Herein, we fabricate a multifunctional molecular prodrug BAC where the chemotherapeutical agent camptothecin (CPT) is linked with a boron dipyrromethene (BODIPY)-based photosensitizer by an azobenzene chain which is sensitive to over-expressed azoreductase in hypoxic tumor cells. This prodrug was further loaded into biodegradable monomethoxy poly(ethylene glycol)-b-poly(caprolactone) (mPEG-b-PCL) to improve its solubility and tumor accumulation. The formed BAC nanoparticles (BAC NPs) can destroy aerobic tumor cells with relatively short distance from blood vessels by photodynamic therapy (PDT) under illumination. The PDT action inevitably leads to consumption of O

Tyrosine phosphorylation of secretion machinery proteins is a crucial regulatory mechanism for exocytosis. However, the participation of protein tyrosine phosphatases (PTPs) in different exocytosis stages has not been defined. Here we demonstrated that PTP-MEG2 controls multiple steps of catecholamine secretion. Biochemical and crystallographic analyses revealed key residues that the interactions between govern the PTP-MEG2 and NSF-pY83 site, specify PTP-MEG2 substrate selectivity and modulate the fusion of catecholamine-containing vesicles. Unexpectedly, delineation of PTP-MEG2 mutants along with the NSF binding interface revealed that PTP-MEG2 controls the fusion pore opening through non-NSF dependent mechanisms. Utilizing bioinformatics search and biochemical and electrochemical screening approaches, we discovered that PTP-MEG2 regulates the opening and extension of the fusion pore by dephosphorylating the DYNAMIN2-pY125 and MUNC18-1-pY145 site. Further structural and biochemical analysis confirmed the interaction of PTP-MEG2 with MUNC18-1-pY145 or DYNAMIN2-pY125 through a distinct structural basis compared with that of the NSF-pY83 site. Our studies extended mechanistic insights in complex exocytosis processes.HIGHLIGHTSPTP-MEG2 regulates multiple steps of exocytosis.A crystal structure of the PTP-MEG2/phosphor-NSF-pY83 segment was obtained.Functional delineation of the PTP-MEG2/NSF interface led to the discovery of new PTP-MEG2 substrates.PTP-MEG2 regulates fusion pore opening and extension through the DYNAMIN2-pY125 site and MUNC18-1 pY145 site.The distinct structural basis of the recognition of substrates by PTP-MEG2 allows selective inhibitor design.

Genomic sequencing analysis of tumors provides potential molecular therapeutic targets for precision medicine. However, identifying a key driver gene or mutation that can be used for hepatocellular carcinoma (HCC) treatment remains difficult. Here, we performed whole-exome sequencing on genomic DNA obtained from six pairs of HCC and adjacent tissues and identified two novel somatic mutations of UBE2S (p. Gly57Ala and p. Lys63Asn). Predictions of the functional effects of the mutations showed that two amino-acid substitutions were potentially deleterious. Further, we observed that wild-type UBE2S, especially in the nucleus, was significantly higher in HCC tissues than that in adjacent tissues and closely related to the clinicopathological features of patients with HCC. Functional assays revealed that overexpression of UBE2S promoted the proliferation, invasion, metastasis, and G1/S phase transition of HCC cells in vitro, and promoted the tumor growth significantly in vivo. Mechanistically, UBE2S interacted with TRIM28 in the nucleus, both together enhanced the ubiquitination of p27 to facilitate its degradation and cell cycle progression. Most importantly, the small-molecule cephalomannine was found by a luciferase-based sensitive high-throughput screen (HTS) to inhibit UBE2S expression and significantly attenuate HCC progression in vitro and in vivo, which may represent a promising strategy for HCC therapy.

BackgroundSomatic mutations are involved in hepatocellular carcinoma (HCC) progression, but the genetic mechanism associated to hepatocarcinogenesis remains poorly understood. We report that Eyes absent homolog 2 (EYA2) suppresses the HCC progression, while EYA2(A510E) mutation identified by exome sequencing attenuates the tumor-inhibiting effect of EYA2.MethodsWhole-exome sequencing was performed on six pairs of human HCC primary tumors and matched adjacent tissues. Focusing on EYA2, expression level of EYA2 in human HCC samples was evaluated by quantitative real-time PCR, western blot and immunohistochemistry. Loss- and gain-of-function studies, hepatocyte-specific deletion of EYA2 (Eya2−/−) in mice and RNA sequencing analysis were used to explore the functional effect and mechanism of EYA2 on HCC cell growth and metastasis. EYA2 methylation status was evaluated using Sequenom MassARRAY and publicly available data analysis.ResultsA new somatic mutation p.Ala510Glu of EYA2 was identified in HCC tissues. The expression of EYA2 was down-regulated in HCC and associated with tumor size (P = 0.001), Barcelona Clinic Liver Cancer stage (P = 0.016) and tumor differentiation (P = 0.048). High level of EYA2 was correlated with a favorable prognosis in HCC patients (P = 0.003). Results from loss-of-function and gain-of-function experiments suggested that knockdown of EYA2 enhanced, while overexpression of EYA2 attenuated, the proliferation, clone formation, invasion, and migration of HCC cells in vitro. Delivery of EYA2 gene had a therapeutic effect on inhibition of orthotopic liver tumor in nude mice. However, EYA2(A510E) mutation led to protein degradation by unfolded protein response, thus weakening the inhibitory function of EYA2. Hepatocyte-specific deletion of EYA2 in mice dramatically promoted diethylnitrosamine-induced HCC development. EYA2 was also down-regulated in HCC by aberrant CpG methylation. Mechanically, EYA2 combined with DACH1 to transcriptionally regulate SOCS3 expression, thus suppressing the progression of HCC via SOCS3-mediated blockade of the JAK/STAT signaling pathway.ConclusionsIn our study, we identified and validated EYA2 as a tumor suppressor gene in HCC, providing a new insight into HCC pathogenesis.

BackgroundEarly studies have unveiled multiple regulatory functions of circular RNAs (circRNAs); however, accurate detection and quantification of circRNAs, especially in understudied organisms, is unsolved yet.ResultsIn this study, we developed a new reference-free method, namely Cirit, to de novo detect circRNAs with sequence support from the next generation sequencing (NGS) transcriptome. The Cirit showed remarkable performance in accurate detection and quantification of circRNAs via comparing with current methods from different aspects. Using Cirit, we detected 28,813 nonredundant human circRNAs from 91 transcriptome datasets, as well as 2,385 circRNAs from four understudied organisms. Subsequent analyses found that the majority of human circRNAs expressed spatiotemporally; only a very small portion of circRNAs were back-splice junction (BSJ)-consistent (maximally 5.17%) or sequence-consistent (under 2%). Furthermore, circRNA genesis were relatively flexible that only about 60% of human circRNAs used the canonical GT-AG pattern for back-splice. The inconsistent expression of circRNAs challenges their roles as precise transcriptional regulators.ConclusionsIn summary, the reference-free method provides a straightforward and universal way for reliable circRNA research. It will largely boost the successful rate in designing highly specific probes to monitor circRNA behavior in cell. In particular, it brings circRNA research to the organisms that have no genome or draft genome.

Public concern regarding silver nanoparticles (AgNPs) in the environment has been increasing since they can cause adverse effects in some aquatic species. However, few data are actually available on the effects of AgNPs on the germ cells. In the present study, we used the zebrafish ovarian follicle as a model to assess the potentially adverse effects of AgNPs on oocyte maturation (germinal vesicle breakdown, GVBD) in vitro. Similar to the maturation inducing hormone (17α, 20β-dihydroxy-4-pregnen-3-one), AgNPs induced GVBD, and reduced the total cyclic adenosine monophosphate (cAMP) concentration in zebrafish ovarian follicles. The results from transmission electron microscope observation and Hoechst 33342 staining clearly indicated that AgNPs induced apoptosis in ovarian follicle cells surrounding the oocyte. Similar to AgNPs, AgNO3 also induced GVBD, decreased cAMP concentration and induced apoptosis of ovarian follicle cells. However, the results from gene expression analysis showed that transcript levels of oxidative stress related genes were more sensitive to AgNPs than AgNO3. Further more, H2O2 has an ability to induce zebrafish oocytes maturation by induction of apoptosis in ovarian follicle cells. Taken together, the results from our study indicated that oxidative stress appeared to be one of important mechanisms in AgNP induced apoptosis in ovarian follicle cells, which further triggered the GVBD.

The Chinese mitten crab (

Molecular dynamics simulations have been performed on the aqueous solutions of poly(vinyl methyl ether) (PVME) at various concentrations. Both radial and spatial distribution functions are used to investigate the detailed hydration structures. The structures of water are found to get increasingly concentrated when polymers are introduced and the water motions are severely hindered by the polymer matrix. At low concentrations, larger populations of tt conformers in meso dyads than those at higher concentrationsare found and this phenomenon is believed to be due to the increasing in bonding of water molecule to two ether oxygens in meso dyad. At higher concentrations, the size and conformations of polymers are quite similar to those in bulk. A transition of hydrogen bond fractions between PVME and water at around the concentration of 0.3 is observed and this value is perfectly in agreement with the results of conformational analysis and Raman spectra. Second neighbor hydrogen bond statistics revealed the domination of complicated hydrogen bond networks at low concentrations, but single hydrogen bonds as well as isolated clusters composed of 2-4 water molecules are usual around each polymer repeat unit.

The slow diffusion reaction of octacyanometallate [MoV(CN)8]3–, lanthanide ions (Gd–Lu), and 1,10-phenanthroline (phen) in CH3CN/H2O has yielded eight isostructural one-dimensional chains, [LnIII(phen)2(H2O)MoV(CN)8]2[(n-C4H9)4N](NO3)·2CH3CN·4H2O (Ln = Gd(1), Tb(2), Dy(3), Ho(4), Er(5), Tm(6), Yb(7), Lu(8)), in which [LnIII(phen)2(H2O)]3+ and [MoV(CN)8]3– units are linked alternatively through cyanide groups, generating left- and right-handed helices. Interestingly, 1–8 undergo a resolvation–recrystallization process upon prolonging the diffusion-reaction time, together with the valence change from V to IV of Mo center and structural dimensionalities switching from helical chains to trinuclear clusters, (Hphen)2.5[LnIII0.5(phen)(H2O)][MoIV(CN)8]·1.5CH3CN (Ln = Gd(9), Tb(10), Dy(11), Ho(12), Er(13), Tm(14), Yb(15), Lu(16)). Magnetic studies of 1–16 revealed the typical effects induced by single-ion magnetic anisotropy and/or the population of low-lying excited states, and 11 and 13 showed extraordinary fie...

Solution culture experiments were conducted to investigate the effect of wastewater nitrogen levels and NH

Slow diffusion reactions of Ln3+ (Ln = Ce, Eu, Tb) ions, pyrazine, and the [W(CN)8]3– unit at 0 °C produced three discrete coordination compounds [Ln(H2O)5(CH3CN)2][W(CN)8]·0.5pyrazine·CH3CN·2H2O [Ln = Ce (1), Eu (2)] and [Tb(H2O)6(CH3CN)2][W(CN)8]·pyrazine·2CH3CN·3H2O (3). Single crystal X-ray diffraction analysis revealed that compounds 1 and 2 are isomorphous and adopt a rare centrosymmetric tetranuclear square unit, while compound 3 exhibits an ion-pair moiety, in which unique tetramer water clusters (H2O)4 are involved. The presence of different types of hydrogen-bonding interactions is responsible for the formation of three-dimensional supramolecular networks. The isolations of compounds 1–3 provide a further insight into the effect of temperatures on constructions and structures of the lanthanide(III)-pyrazine-octacyanotungstate(V) system.

Distribution of residual stress in hot rolled low carbon martensite high-strength steel strip was measured by means of blind-hole method in the steel before and after tempering. The hot rolled low carbon martensite high-strength steel strip was tempered at 450°C, 500°C, 550°C or 600°C. Before tempering, the value of the residual stress along the width direction is maximum at the edge, intermediate at the center, minimum at the 1/4 of the strip. The figure of the residual stress distribution along the width direction is like the shape of the letter M. Residual stress of the strip is reduced after tempering. When tempering at 450°C or 500°C, evolution of residual stress is caused by changes of thermal stress. Distribution of residual stress becomes gentle. With tempering temperature increasing, distribution of residual stress is reversed, because evolution of thermal stress and phase transition stress changes in different time.

Background/Aims: We previously demonstrated the safety and efficacy of low-dose, short-interval target vessel regional chemotherapy (TVRCLDSI) delivered through the hepatic artery with transarterial embolization (TAE) in patients with advanced gastric cancer (AGC). The present study aimed to compare the efficacy of TAE + TVRCLDSI with that of standard TAE + TVRC in AGC patients with liver metastases who failed to respond to first- or second-line systemic chemotherapy. Methods: This study recruited a total of 58 GC patients with liver metastases after failure of first- or second-line systemic chemotherapy. Twenty-eight patients were assigned to the TAE + TVRCLDSI group and 30 patients to the TAE + TVRC group. The primary end point was overall survival (OSTVRC), which was defined as the time from the initiation of TVRC until the last follow-up or death. Results: OSTVRC, time to progression (TTP) until appearance of intra- and extrahepatic metastases, and overall TTP and treatment periods in the TAE + TVRCLDSI group were all significantly longer than in the TAE + TVRC group (all p < 0.001). Conclusion: TAE + TVRCLDSI had a higher efficacy and safety, which was reflected by OS rates, progression-free survival rates, longer duration of treatment and milder side effects compared to standard TAE + TVRC.

Photochromic materials are now anticipated as promising candidates for erasable memory media of the next generation because organic materials are easy to tailor. Density Functional calculations at the B3LYP/6-311+G(d,p)//HF/3-21G and partly at the B3LYP/6-311++G(3df,3pd)//B3LYP/6-31G(d) levels were carried out for thermal irreversibility study of the titled compounds, a kind of photochromic materials which undergo cyclization and cycloreversion reactions. Eighteen configurations were characterized for both the cis and the trans forms of three diarylethene-type compounds. Among them, six were transition states. The results from the relative energy barriers and from the normal coordinate analyses of the imaginary frequencies show that Woodward–Hoffman principle about disrotatory and conrotatory mechanisms is valid for the thermal irreversibility study on the compounds. The thermal irreversibility of changing phenyl to thiophenyl groups in stilbene, of introducing methyl groups on central carbons that were responsible for the electrocyclic reaction was discussed. The applicability of Irie’s rule was investigated.

The reaction of Sm3+ ion with [M(CN)8]3− (M = W, Mo) units in the presence of the chelated ligand phen has isolated two octacyanometalate-based assemblies [Sm(phen)(DMF)5][M(CN)8]·CH3OH·H2O (M = Mo, 1; W, 2). Single crystal X-ray diffraction analysis revealed that both compounds are isostructural and the structure consists of Sm3+ centers and [M(CN)8]3− units linked alternatively to generate a one-dimensional (1D) zigzag chain. The chains are further connected together through hydrogen-bonding and π-π stack interactions to form a 3D supramolecular network. The magnetic results revealed that the ferromagnetic interactions were observed between Sm(III) and M(V) centers in both compounds.

The 1,1′-binaphthol-based dimers with p-phenylenebis(2-ethynyl) spacer, (+)-6 and (+)-2, were synthesized as chiral host compounds. 1H NMR, UV-vis, and fluorescent titration were used to evaluate the enantiomeric recognition abilities of the chiral host dimers toward the guest amine 7 and α-amino acid ester 8. The chiral BINOL-based dimers were found to have good enantiomeric recognition ability. The computer simulation of the host–guest complex molecules was carried out to describe the conformational changes of both naphthyl ring in the molecule of chiral host dimer after complexation with the guest molecule. Chirality 13:595–600, 2001. © 2001 Wiley-Liss, Inc.

The crystal structure of the title compound, (C12H12N2)(C12H11N2)[Mo(CN)8]·4H2O, consists of 4,4'-(ethene-1,2-di-yl)dipyridinium and 4-[2-(pyridin-4-yl)ethen-yl]pyridinium cations disordered over the same site, an [Mo(CN)8](3-) anion and four water mol-ecules of crystallization. The eight-coordinate [Mo(CN)8](3-) unit exhibits a slightly distorted square-anti-prismatic geometry. In the structure, the cations (crystallographic symmetry, 2) and anions (crystallographic symmetry, 222) are arranged alternately by N-H⋯O and O-H⋯N hydrogen bonds, forming layers parallel to the bc plane. These layers are further linked through O-H⋯N hydrogen bonds, generating a three-dimensional supra-molecular network.

Effects of replacement of trash fish with formulated diets on growth performance,body composition and fatty acid composition of Chinese mitten crab(Eriocheir sinensis)were investigated in this study.The culture tests were carried out at Chongming County,Shanghai,which lasted 240 days,from March to November.The survival and weight gain of each treatment were counted after breeding.Random sampling and then the hepatopancreas index(HSI),gonad index(GSI),meat percentage,body composition and fatty acid composition of each tissue of both male and female crab were determined.The result indicated that the formulated diets treatment had no significant influence on trash fish treatment in survival,weight gain,HSI,GSI and meat percentage(P0.05).The moisture content in hepatopancreas of female and male crab of trash fish treatment were significantly higher than the formulated diets treatment(P0.01),and the moisture content in meat of male crab of trash fish treatment was significantly higher than that of formulated diets treatment(P0.01).Total lipid in hepatopancreas and gonad of female and male crab of trash fish group were significantly lower than that of formulated diets(P0.05),and total lipid in meat of female crab of trash fish was significantly lower than that of formulated diets(P0.05).Crude protein in hepatopancreas of female and male crab of trash fish was significantly higher than that of formulated diets(P0.05),while crude protein in ovary of female crab of trash fish was significantly lower than that of formulated diets(P0.05).Free fatty acid(FAA)in hepatopancreas of female of formulated diets treatment was significantly higher than trash fish treatment(P0.05),and phospholipids(PL)content in hepatopancreas of female of trash fish treatment was significantly higher than formulated diets treatment(P0.05).Triglycerides(TG)in both ovary and muscle of female of formulated diets treatment were significantly higher than trash fish treatment(P0.05 or P0.01),while FAA and PL contents of female of trash fish treatment were significantly higher than formulated diets treatment in ovary and muscle(P0.05 or P0.01).Cholesterol(CHO)in muscle of female of trash fish treatment was significantly higher than formulated diets treatment(P0.01).There were no significantly differences in hepatopancreas of two treatments(P0.05).FAA and TG in testis of trash fish treatment were significantly higher than formulated diets treatment(P0.01),while PL in testis of trash fish treatment was significantly lower than formulated diets treatment(P0.05).CHO in muscle of male of formulated diets treatment was significantly lower than trash fish treatment(P0.01).Linolic acid(C18∶ 2n-6)in hepatopancreas and meat of male crab of trash fish were significantly lower than that of compound feed(P0.01 or P0.05),while ARA(C20∶ 4n-6)in meat of trash fish was significantly higher than that of compound feed(P0.05).Linolenic acid(C18∶ 3n-3),DHA(C22∶ 6n-3)and ARA in ovary of female crab of trash fish were significantly lower than those of compound feed(P0.01 or P0.05).The results obtained from the present study indicated that suitable compound feed replacement of trash fish had no significant influence on growth and development of crab,while body composition and fatty acid composition of crab changed with different feeds.

The reaction of [W(CN)(8)](3-) with Ln(3+) and pyrazine in acetonitrile yielded a series of isostructural compounds formulated as Ln(H(2)O)(4)(pyrazine)(0.5)W(CN)(8) (Ln = La(1), Ce(2), Pr(3), Nd(4), Sm(5), Eu(6), Gd(7)). The Ln(III) and W(V) centers in the structure are linked through cyanide groups to form two-dimensional (2D) layers, which are further pillared by pyrazine, generating 3D frameworks. The magnetic behavior for compounds 1-7 were driven by the lanthanide ions involved. The Ln(III) and W(V) ions in compounds 2 and 5 are ferromagnetically coupled with magnetic ordering occurring at 2.8 K, comparable with magnetic ordering with the critical temperature of 1.9 K for compound 4. In addition, the antiferromagnetic interactions were observed in compounds 3 and 7, while no significant magnetic couplings were found in compounds 1 and 6.

13 C NMR Chemical Shifts in Polypropylene and the Bi-Catalytic Propagation Mechanism in Polymerization