Effect of Sulfate Attack on the Expansion Behavior of Cement-Treated Aggregates.

The expansion induced by sulfate attack on cement-treated aggregates (SACA) is a well-known problem that can be solved. It causes obvious heaves in road bases and railway subgrades. In this paper, the effects of the sodium sulfate content, cement content, degree of compaction, sulfate types, attack types, aluminum ion supply, concentration of curing sulfate solution, and temperature on the expansion behavior induced by SACA were investigated over 60 days in the laboratory. Based on the Sobol sensitivity analysis method, the influence of the sensitivity of each factor on the expansion was quantitatively analyzed, and the dominant factor of expansion was proposed. Results show that sulfate content is the domain factor of expansion that is induced by SACA, and it presents a logarithmic function relationship with strain. The 0.5% sodium sulfate content is the minimum sulfate content which causes the expansion that is induced by SACA. When the sulfate content is less than 1%, the expansion induced by SACA is minor. When the sulfate content is between 1% and 3%, the expansion behavior is expressed in four stages as follows: rapid strain increase, followed by a short stagnation period, then a significant strain increase and, finally, constant strain. When the sulfate content is greater than 5%, there are two stages comprising the expansion behavior as follows: the rapid strain increases and constant strain occurs. Greater sulfate content, greater degree of compaction, and lower temperature have positive effects on the expansion induced by SACA. The cement content does not have a consistent effect on expansion behavior. Compared with a sodium sulfate attack, both the reaction rate and expansion of cement-treated aggregates that are attacked by gypsum are smaller, and the attack period is also longer. When the sulfate content is greater than 1%, the addition of kaolin promotes the progression of the expansion induced by SACA. A small amount of water is sufficient for the demand for the sulfate attack. When the sulfate content is at a certain level, the expansion induced by SACA that is under external attack is much smaller than the expansion that is under internal attack. This study is expected to serve as a reference for future research on the mechanics of SACA, and it attempts to provide theoretical support for amending expansions that are induced by SACA.

In vitro and vivo anti-tumor activity and mechanisms of the new cryptotanshinone derivative 11 against hepatocellular carcinoma.

Global burden of hepatocellular carcinoma (HCC) is increasing. Chemotherapy and immunotherapy are the prevailing options for therapy. Developing new therapeutic strategies for HCC patients is still highly desirable. Recent studies demonstrate that cryptotanshinone is capable of inhibiting tumor growth in HCC and induces antitumor immunity in vitro. In our previous research, we discovered a new cryptotanshinone derivative 11 as an effective immunoregulatory enzyme indoleamine 2, 3-dioxygenase 1 (IDO1) inhibitor. This study aims to evaluate its in vitro and in vivo antitumor activity against hepatocellular carcinoma. 11 displayed robust anti-proliferative activity against HCC cell lines and promoted apoptosis of HCC cell line through the mitochondrial-mediated apoptotic pathway. In H22 tumor-bearing mice models, 11 exhibited significant in vivo anti-tumor activity with different administration routes. And no obvious toxicity was observed. RNA-seq analysis demonstrated the differential expressed genes and alteration of key pathways associated with immune responses after administration of 11. Up-regulation of anti-tumor cytokines and down-regulation of cytokines that promote tumor growth were indicated and further validated. Our study demonstrates that 11 exhibits promising anti-tumor activity both in vitro and in vivo against hepatocellular carcinoma cancer. It is a lead compound for HCC immunotherapy and is worthy for further development.

Discovery and biological evaluation of a new type of dual inhibitors of indoleamine 2,3-dioxygenase 1 and tryptophan 2,3-dioxygenase from ethnomedicinal plant Dactylicapnos scandens.

The root of Dactylicapnos scandens (D.Don.) Hutch (Papaveraceae), one of the most famous ethno-medicinal plants from the Bai communities in P. R. China, is used to treat various inflammations and tumours. Bioassay-guided phytochemical research on D. scandens followed by semi-synthesis led to a series of undescribed tetrahydroisoquinoline alkaloids with dual inhibitory activities against indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO). The previously undescribed dark-green alkaloid dactycapnine A exhibited the best dual inhibitor effects among the identified compounds. Structure-activity relationship analysis revealed the importance of the base skeleton with a hyperconjugation system. The performed semi-synthesis further yielded bioactive dimeric and trimeric compounds with hyperconjugated systems. Performed STD NMR experiments disclosed direct interactions between dactycapnine A and IDO1/TDO. Inhibition kinetics indicated dactycapnine A as a mixed-type dual inhibitor. These findings provided a possible explanation for the anticancer properties of the ethno-medicinal plant species D. scandens.

The effect of different representations of pictures on the activation of gender stereotypes.

The purpose of this study is to explore whether there is N400 effect on the representation of gender stereotype in the different picture priming condition from the behavioral and ERP levels, and further explore whether there is hierarchical structure of upper category, secondary category, typical example and counter-example based on this. The results showed: (1) under the condition of picture priming, N400 effect would be induced when representing the conflict of gender stereotypes. (2) Category representation and example representation can activate different regions of the brain. When the priming stimulus was upper category (gender picture) and secondary category (occupational gender picture), N400 effect mainly appeared on the electrode of frontal region in left hemisphere.When the priming stimuli were typical example (typical example picture) and counter-example, the N400 effect mainly appeared on the electrodes in the frontal region of the right hemisphere.(3) the gender stereotype representation of picture activation has hierarchical structure, that is, N400 amplitude induced by upper category activation < secondary category activation < typical sample activation < counter-example activation. These findings suggest that the representation of gender stereotypes has a hierarchical structure at the picture level.

Hepatic epithelioid angiomyolipoma is scattered and unsuitable for surgery: a case report.

Hepatic epithelioid angiomyolipoma (HEAML) is a rare tumour of mesenchymal tissue with a malignant tendency. Occurring most frequently in women, the relative incidence in men and women, according to incomplete statistics, is approximately 1:5. In rare cases, disease occurrence and development is hidden. Lesions are generally discovered as chance findings by patients; abdominal pain is the first symptom, and imaging has no specificity in diagnosing the disease. Therefore, great difficulties exist in the diagnosis and treatment of HEAML. Here, the case of a 51-year-old female patient with a history of hepatitis B, and abdominal pain over 8 months as the initial symptom, is described. The patient was found to have multiple intrahepatic angiomyolipoma. Due to the small and scattered foci, complete resection was impossible, and because of her history of hepatitis B, conservative treatment was undertaken, with the patient undergoing regular follow-up. When hepatic cell carcinoma could not be excluded, the patient was treated with transcatheter arterial chemoembolization. No tumour neogenesis or metastasis was detected at the 1-year follow-up.

Design, synthesis and biological evaluation of a new class of Hsp90 inhibitors vibsanin C derivatives.

Hsp90, an ATP-dependent chaperone that is essential for a wide range of protein assembly and folding processes, has long been recognized as a potential target for cancer. Hsp90 has more recently been identified as having a significant pathogenic role in viral infection, neurodegenerative disease, and inflammation, therefore, the development of the agents to inhibit the chaperone could potentially treat such intractable diseases. Here, on the basis of primary structure-activity relationships and docking analysis, a series of novel vibsanin C analogues with an emphasis on the C18 position was first designed, synthesized and biologically evaluated. The most effective Hsp90 inhibitory activity among these analogues was demonstrated by 29 and 31, with IC50 values of 0.39 and 0.27 µM respectively. Direct interaction between Hsp90 and its inhibitors were further confirmed. Mechanism studies indicated that 29 promoted HL-60 cell apoptosis by mitochondrial-mediated apoptosis pathway. In addition, 29 suppressed tumor growth in the H22 tumor-bearing mice model and revealed low acute toxicity in mice (LD50 > 500 mg/kg), suggesting its potential for further investigations.

The Impact of Gratitude on Connection With Nature: The Mediating Role of Positive Emotions of Self-Transcendence.

Gratitude, as one of the positive emotions associated with self-transcendence, is also a moral and pro-social emotion with a pro-social nature. Therefore, in order to verify whether gratitude has the same effect as pro-social in promoting connection with nature, this study (N = 890) divided subjects into three groups (gratitude, recreation, and control) and used a questionnaire to explore the effects of gratitude on positive emotions of self-transcendence, connection with nature, and pro-environmental tendencies (willingness to participate in environmental protection, willingness to sacrifice for the environment). The results found that (1) positive emotions of self-transcendence partially mediated the effect of the gratitude condition on connection to nature, and (2) positive emotions of self-transcendence and connection to nature were fully and continuously mediated, suggesting that the gratitude condition had an indirect effect on both (a) willingness to participate in environmental protection and (b) willingness to sacrifice for the environment. These findings imply that we may need to pay more attention to the connection between gratitude and nature to promote a harmonious relationship between humans and nature.

Eleven undescribed alkaloids from the rhizomes of Sinomenium acutum and their IDO1 and TDO inhibitory activities.

Eleven previously undescribed alkaloids, named sinometumines A-K, along with three known alkaloids, were isolated from the rhizomes of Sinomenium acutum. The chemical structures of these unreported compounds were established using extensive spectroscopic methods (IR, UV, HRESIMS, and NMR), and their absolute configurations were determined by single crystal X-ray diffraction analyses and calculated electronic circular dichroism spectroscopy (ECD). Sinometumine D was the first aporphine-type derived alkaloid inner salt with a rearranged dibenzofuran ring backbone. Sinometumine E was a rare protoberberine-type alkaloid with a complex 6/6/6/6/6/6 hexacyclic skeleton. This was the first report of alkaloids with these two skeletons isolated from S. acutum. All isolates were evaluated for their inhibitory activities against indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO). Lysicamine possessed noteworthy inhibitory activities as an IDO1/TDO dual inhibitor with IC50 values of 6.22 ± 0.26 µM and 23.76 ± 2.93 µM, respectively, and liriodenine revealed moderate dual inhibition with IC50 values of 31.65 ± 4.44 µM and 15.64 ± 0.26 µM. The intermolecular interactions and binding modes between lysicamine and IDO1/TDO were elaborated by molecular docking studies.

Discovery and biological evaluation of tanshinone derivatives as potent dual inhibitors of indoleamine 2, 3-dioxygenase 1 and tryptophan 2, 3-dioxygenase.

Indoleamine 2, 3-dioxygenase 1 (IDO1) and tryptophan 2, 3-dioxygenase (TDO), catalyzing the first and rate-limiting step of tryptophan-kynurenine (Trp-Kyn) metabolism pathway, are the appealing targets for cancer immunotherapy. A few dual IDO1/TDO inhibitors are reported in literature. However, small-molecule IDO1 and TDO inhibitors are not yet available for clinical use. Here, we report synthetic analogues of the naturally occurring terpenoids tanshinone IIA and crytotanshinone, and their IDO1/TDO inhibitory activities using enzymatic and cellular assays. The most potent compound 30 was further characterized with respect to the direct interaction, inhibition kinetics, and different binding modes against IDO1 and TDO through surface plasmon resonance (SPR), enzyme kinetics, and spectroscopic analysis approaches, respectively. Preliminary mechanistic studies showed that 30 significantly promoted cell apoptosis through the potential mitochondria-mediated Bcl-2/Bax pathway. IDO1-overexpressing HeLa cells, mimicking cancer cells, were sensitive to 30 treatments. These results provide further insights for new clinical application of tanshinones, the main component of traditional herbal medicine.

Discovery of pseudolaric acid A as a new Hsp90 inhibitor uncovers its potential anticancer mechanism.

Pseudolaric acid A (PAA), one of the main bioactive ingredients in traditional medicine Pseudolarix cortex, exhibits remarkable anticancer activities. Yet its mechanism of action and molecular target have not been investigated and remain unclear. In this work, mechanistic study showed that PAA induced cell cycle arrest at G2/M phase and promoted cell death through caspase-8/caspase-3 pathway, demonstrating potent antiproliferation and anticancer activities. PAA was discovered to be a new Hsp90 inhibitor and multiple biophysical experiments confirmed that PAA directly bind to Hsp90. Active PAA-probe was designed, synthesized and biological evaluated. It was subsequently employed to verify the cellular interaction with Hsp90 in HeLa cells through photoaffinity labeling approach. Furthermore, NMR experiments showed that N-terminal domain of Hsp90 and essential groups in PAA are important for the protein-inhibitor recognition. Structure-activity relationship studies revealed the correlation between its Hsp90 inhibitory activity with anticancer activity. This work proposed a potential mechanism involved with the anticancer activity of PAA and will improve the appreciation of PAA as a potential cancer therapy candidate.

Identification and Characterization of ShSPI, a Kazal-Type Elastase Inhibitor from the Venom of Scolopendra Hainanum.

Elastase is a globular glycoprotein and belongs to the chymotrypsin family. It is involved in several inflammatory cascades on the basis of cleaving the important connective tissue protein elastin, and is strictly regulated to a balance by several endogenous inhibitors. When elastase and its inhibitors are out of balance, severe diseases will develop, especially those involved in the cardiopulmonary system. Much attention has been attracted in seeking innovative elastase inhibitors and various advancements have been taken on clinical trials of these inhibitors. Natural functional peptides from venomous animals have been shown to have anti-protease properties. Here, we identified a kazal-type serine protease inhibitor named ShSPI from the cDNA library of the venom glands of Scolopendra hainanum. ShSPI showed significant inhibitory effects on porcine pancreatic elastase and human neutrophils elastase with Ki values of 225.83 ± 20 nM and 12.61 ± 2 nM, respectively. Together, our results suggest that ShSPI may be an excellent candidate to develop a drug for cardiopulmonary diseases.

NCP activates chloroplast transcription by controlling phytochrome-dependent dual nuclear and plastidial switches.

Phytochromes initiate chloroplast biogenesis by activating genes encoding the photosynthetic apparatus, including photosynthesis-associated plastid-encoded genes (PhAPGs). PhAPGs are transcribed by a bacterial-type RNA polymerase (PEP), but how phytochromes in the nucleus activate chloroplast gene expression remains enigmatic. We report here a forward genetic screen in Arabidopsis that identified NUCLEAR CONTROL OF PEP ACTIVITY (NCP) as a necessary component of phytochrome signaling for PhAPG activation. NCP is dual-targeted to plastids and the nucleus. While nuclear NCP mediates the degradation of two repressors of chloroplast biogenesis, PIF1 and PIF3, NCP in plastids promotes the assembly of the PEP complex for PhAPG transcription. NCP and its paralog RCB are non-catalytic thioredoxin-like proteins that diverged in seed plants to adopt nonredundant functions in phytochrome signaling. These results support a model in which phytochromes control PhAPG expression through light-dependent double nuclear and plastidial switches that are linked by evolutionarily conserved and dual-localized regulatory proteins.

Diterpenoids and sesquiterpenoids from the stem bark of Metasequoia glyptostroboides.

A phytochemical study on the stem bark of Metasequoia glyptostroboides led to the isolation of sixty-one diterpenoids and sesquiterpenoids, including seventeen previously undescribed compounds, metaglyptins A-Q. Their structures were elucidated by extensive analysis of spectroscopic data (IR, UV, HRESIMS, and 1H, 13C and 2D NMR). The absolute configurations of metaglyptins I, J, and O were determined by the ECD data and single-crystal X-ray diffraction analysis. The undescribed compounds were evaluated for their cytotoxicity against HeLa, AGS, and MDA-MB-231 cancer cell lines. The results revealed that metaglyptin A exhibited moderate cytotoxicity against MDA-MB-231 cell line with IC50 value of 20.02 µM.

Sesquiterpenes from the Leaves of Magnolia delavayi Franch. and Their Cytotoxic Activities.

Thirteen sesquiterpenes including eight new ones, magnodelavins A-H (1-8), were obtained from the 95 % ethanolic extract of the leaves of Magnolia delavayi Franch. The structures of the new compounds were determined by exhaustive 1 H-, 13 C-, 2D-NMR, UV, IR, and HR-ESI-MS data, as well as X-ray crystallographic analysis. Compounds 9 and 10 showed potent cytotoxic activities against HL-60, A-549, SMMC-7721, MCF-7, and SW480 human cancer cell lines in vitro using MTS assay.

Isolation, Structural Assignment of Isoselagintamarlin A from Selaginella tamariscina and Its Biomimetic Synthesis.

Isoselagintamarlin A (1), a selaginellin analogue featured a rare benzofuran unit, was isolated from Selaginella tamariscina. Its complete structural assignment was established through a combination of high-field NMR technique and biomimetic synthesis. Notably, isoselagintamarlin A (1) was successfully synthesized via sequential oxidations and intramolecular cyclization.

Preparation and evaluation of fluorescent poly(p-phenyleneethylene) covalently coated microspheres with reactive sites for bioconjugation.

Fluorescent microspheres with reactive sites for interacting with biomolecules are greatly demanded in flow cytometry based suspension array. Aiming to develop a new method for preparing fluorescent microspheres, two poly(p-phenyleneethylene) (PPE) conjugated polymers (CPs) with pedant carboxylic groups were synthesized via Sonogashira coupling and followed with hydrolysis of ester groups; then the conjugated polymers were immobilized onto monodispersed amino-modified porous poly(glycidylmethacrylate) (APGMA) microspheres via coupling reaction between carboxylic and amino groups to give APGMA-CP fluorescent microspheres. The fluorescent microspheres were found to have good photo- and thermal stability as well as negligible influence from rigorous washing. The emission was uniform all across the inner and surface of the spheres. To evaluate the effectiveness of bioconjugation on the fluorescent microspheres, fluorescein isothiocyanate isomer I (FITC) labeled bovine serum albumin (BSA) (BSA-FITC) was chosen as the representative biomolecule to react with the fluorescent microspheres to give APGMA-CP-BSA-FITC. In the flow cytometry study, fluorescence compensation between the V500 and FITC detectors (receiving signals from fluorophores excited by 405 nm and 488 nm, respectively), to remove the interference between the emission of FITC and CPs, was realized using singly-stained microspheres. Finally, APGMA-CP-BSA-FITC microspheres were found to be double positive for CP and FITC with very high percentage (>95%), suggesting the bioconjugation is very effective. This study provides a facile method for simultaneous introduction of fluorescence and reactive sites onto the microspheres, which is very promising to be used as general strategy for fabricating fluorescence microspheres for application in high-throughput technology.

Preparation of Fluorescence-Encoded Microspheres Based on Hydrophobic Conjugated Polymer-Dye Combination and the Immunoassay.

Fluorescent microspheres are greatly demanded in many applications based on high-throughput suspension array technology. To realize the multiplexed assay, microspheres should be encoded to identify the interaction between analytes and spheres. This study advanced a strategy for preparing fluorescence-encoded microspheres, employing two hydrophobic fluorophores, poly(p-phenyleneethylene) (PPE), and Nile Red (NR), as well as the monodisperse amino-modified porous substrate polymeric spheres, poly(glycidyl methacrylate) microspheres (APGMA). Loading the fluorophores sequentially onto the substrate spheres via adsorption by immersing the spheres in the dipping solution of fluorophores resulted in the APGMA-PPE-NR spheres. By varying the concentration and combination of fluorophores in the solution, an array of 64-code APGMA-PPE-NR spheres was obtained and could be easily individually decoded via flow cytometry. A 2D dot plot from the flow cytometry of a set of mixed spheres with four different codes could also be differentiated, coincident with the overlaid plots of the spheres' corresponding codes but measured individually. These spheres were found to have good stability against washing, photobleaching, and thermal treatment. In addition, a sandwich immunoassay for the detection of goat IgG was performed, and the capability of the encoded spheres to be used in suspension array technology was demonstrated.

Layer-by-layer fabrication of fluorescent microspheres using micelles as a spacer: simultaneously realizing fluorescence enhancement and introduction of bioconjugation sites.

The combination of fluorescence properties and other functions can significantly enhance the multipurpose applications of functional materials. Herein, fluorescent microspheres with strong fluorescence and bioconjugation sites were prepared via the layer-by-layer (LBL) introduction of poly(p-phenylene vinylene) (PPV) with micelles as a spacer on the substrate spheres. At first, the diblock copolymer poly(acrylic acid)-block-polystyrene (PAA-b-PS) was synthesized and assembled into micelles (PSAm) with the carboxylic groups facing outward. Then, the negatively charged PSAm and positively charged PPV polymer precursor (pre-PPV) were alternately introduced into the substrate polystyrene-divinylbenzene microspheres with sulfonic groups on the surface (SPSDVB) followed by thermal elimination to obtain fluorescent SPSDVB-(PPV/PSAm)n microspheres by converting pre-PPV into PPV. The spheres were found to have stable and bright fluorescence with a very clear core-shell structure. The mechanism for fluorescence enhancement with PSAm as the spacer was studied, and the capability for bioconjugation was also demonstrated. This study provides a promising general strategy for the preparation of fluorescent microspheres combining strong emission with different functional groups to meet various applications.

Design, Synthesis, and Biological Activities of Vibsanin B Derivatives: A New Class of HSP90 C-Terminal Inhibitors.

Previously, vibsanin B (ViB) was found to preferentially target HSP90ß compared to HSP90α. In this study, multiple experiments, including pull-down assays of biotin-ViB with recombinant HSP90ß-NTD, MD, CTD, and full-length HSP90ß, molecular docking of ViB and its derivatives to the HSP90 CTD, and a inhibition assay of interaction of the HSP90ß CTD with GST-tagged cyclophilin 40 (Cyp40) by ViB derivatives, suggest that ViB can directly bind to the HSP90 C-terminus. On the basis of the docking predictions and primary structure-activity relationships (SARs), a series of ViB analogues devised with focus on the C18 position, along with compounds derivatized at the C4, C7, and C8 positions, were designed and chemically synthesized. Compound 12f (IC50 = 1.12 µM against SK-BR-3) exhibits great potency with drug-like properties. Overall, our findings demonstrate that compounds with the vibsanin B scaffold are a new class of HSP90 C-terminal inhibitors with considerable potential as anticancer agents.

Metabolomic signature associated with reproduction-regulated aging in Caenorhabditis elegans.

In Caenorhabditis elegans (C. elegans), ablation of germline stem cells (GSCs) leads to infertility, which extends lifespan. It has been reported that aging and reproduction are both inextricably associated with metabolism. However, few studies have investigated the roles of polar small molecules metabolism in regulating longevity by reproduction. In this work, we combined the nuclear magnetic resonance (NMR) and ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) to profile the water-soluble metabolome in C. elegans. Comparing the metabolic fingerprint between two physiological ages among different mutants, our results demonstrate that aging is characterized by metabolome remodeling and metabolic decline. In addition, by analyzing the metabolic profiles of long-lived germline-less glp-1 mutants, we discovered that glp-1 mutants regulate the levels of many age-variant metabolites to attenuate aging, including elevated concentrations of the pyrimidine and purine metabolism intermediates and decreased concentrations of the citric acid cycle intermediates. Interestingly, by analyzing the metabolome of daf-16;glp-1 double mutants, our results revealed that some metabolic exchange contributing to germline-mediated longevity was mediated by transcription factor FOXO/DAF-16, including pyrimidine metabolism and the TCA cycle. Based on a comprehensive metabolic analysis, we provide novel insight into the relationship between longevity and metabolism regulated by germline signals in C. elegans.