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Acute lung injury (ALI) is a severe lung respiratory failure characterized by high morbidity and mortality. Novel findings demonstrated the critical roles of long non‐coding RNA (lncRNA) in ALI. Here, we tried to investigate the roles and potential mechanism of lncRNA X‐inactive specific transcript (XIST) in ALI. Results illustrated that lncRNA XIST was up‐regulated in the lipopolysaccharide (LPS)‐induced ALI mice models and pulmonary endothelial cells. Biofunctional assays unveiled that knockdown of XIST repressed the inflammatory response and apoptosis in LPS‐induced endothelial cells. Mechanistically, XIST acted as the miR‐146a‐5p sponge to positively regulate STAT3. Moreover, STAT3 combined the promoter region of XIST to accelerate the transcription, constituting the positive feedback loop of XIST/miR‐146a‐5p/STAT3 in ALI. Collectively, these findings suggested that XIST knockdown attenuates the LPS‐induced ALI, providing a potential therapeutic target.

Rationale: Chemoresistance is a major obstacle in prostate cancer (PCa) treatment. We sought to understand the underlying mechanism of PCa chemoresistance and discover new treatments to overcome docetaxel resistance. Methods: We developed a novel phenotypic screening platform for the discovery of specific inhibitors of chemoresistant PCa cells. The mechanism of action of the lead compound was investigated using computational, molecular and cellular approaches. The in vivo toxicity and efficacy of the lead compound were evaluated in clinically-relevant animal models. Results: We identified LG1980 as a lead compound that demonstrates high selectivity and potency against chemoresistant PCa cells. Mechanistically, LG1980 binds embryonic ectoderm development (EED), disrupts the interaction between EED and enhancer of zeste homolog 2 (EZH2), thereby inducing the protein degradation of EZH2 and inhibiting the phosphorylation and activity of EZH2. Consequently, LG1980 targets a survival signaling cascade consisting of signal transducer and activator of transcription 3 (Stat3), S-phase kinase-associated protein 2 (SKP2), ATP binding cassette B 1 (ABCB1) and survivin. As a lead compound, LG1980 is well tolerated in mice and effectively suppresses the in vivo growth of chemoresistant PCa and synergistically enhances the efficacy of docetaxel in xenograft models. Conclusions: These results indicate that pharmacological inhibition of EED-EZH2 interaction is a novel strategy for the treatment of chemoresistant PCa. LG1980 and its analogues have the potential to be integrated into standard of care to improve clinical outcomes in PCa patients.

[Image: see text] There is substantial interest in the development of small molecules that inhibit the tight and highly challenging protein–protein interaction between the glycophosphatidylinositol (GPI)-anchored cell surface receptor uPAR and the serine protease uPA. While preparing derivatives of a fragment-like compound that previously emerged from a computational screen, we identified compound 5 (IPR-3242), which inhibited binding of uPA to uPAR with submicromolar IC(50)s. The high inhibition potency prompted us to carry out studies to rule out potential aggregation, lack of stability, reactivity, and nonspecific inhibition. We designed and prepared 16 derivatives to further explore the role of each substituent. Interestingly, the compounds only partially inhibited binding of a fluorescently labeled α-helical peptide that binds to uPAR at the uPAR·uPA interface. Collectively, the results suggest that the compounds bind to uPAR outside of the uPAR·uPA interface, trapping the receptor into a conformation that is not able to bind to uPA. Additional studies will have to be carried out to determine whether this unique inhibition mechanism can occur at the cell surface.

N6 -methyladenosine (m6 A) and long noncoding RNAs (lncRNAs) are both crucial regulators in non-small-cell lung cancer (NSCLC) tumorigenesis. However, the pathological roles of m6 A and lncRNAs in NSCLC progression are still limited and undefined. Here, lncRNA ABHD11-AS1 was upregulated in NSCLC tissue specimens and cells and the ectopic overexpression was closely correlated with unfavorable prognosis of NSCLC patients. Functionally, ABHD11-AS1 promoted the proliferation and Warburg effect of NSCLC. Mechanistically, m6 A profile was analyzed by methylated RNA immunoprecipitation sequencing (MeRIP-Seq). MeRIP-Seq presented that there was m6 A modification site in ABHD11-AS1. m6 A methyltransferase-like 3 (METTL3) installed the m6 A modification and enhanced ABHD11-AS1 transcript stability to increase its expression. In conclusion, our findings highlight the function and mechanism of METTL3-induced ABHD11-AS1 in NSCLC and inspire the understanding of m6 A and lncRNA in cancer biology.

Physicochemical properties of arsenic sulfide sludge (ASS) from copper smelter (ASS-I) and lead−zinc smelter (ASS-II) were examined by XRD, Raman spectroscopy, SEM−EDS, TG−DTA, XPS and chemical phase analysis method. The toxicity characteristic leaching procedure (TCLP), Chinese standard leaching tests (CSLT), three-stage sequential extraction procedure (BCR) and batch leaching experiments (BLE) were used to investigate the environmental stability. The ASSs from different smelters had obviously different physicochemical and environmental properties. The phase composition and micrograph analysis indicate that ASS-I mainly consists of super refined flocculent particles including amorphous arsenic sulfide adhered with amorphous sulfur and that ASS-II mainly consists of amorphous arsenic sulfide. The valence state of arsenic in both sludges is trivalent, but the valence composition of sulfur is quite different. The ASSs have thermal instability properties. The results of TCLP and CSLT indicate that the concentrations of As and Pd in the leaching solution exceed the standard limits. More than 5% and 90% of arsenic are in the form of acid soluble and oxidizable fractions, respectively, which explains the high arsenic leaching toxicity and environmental activity of ASS. This research provides comprehensive information for the disposal of ASS from copper and lead−zinc smelter.

The crash-worthiness design of civil transport aircraft fuel systems is significance to improve the safety of the aircraft in the case of a crash. CCAR25.993 (f) requires that “fuel feed line in the fuselage shall be assembled to allow reasonable deformation and tension without fuel leakage”. Fuel system fuselage fuel supply line with the appropriate hose configuration can take the advantage of the ductility of the material, and the guillotine test is accepted by worldwide examiners to validate the deformation and tensile capacity of the fuel hose to keep it from leaking fuel.

Purpose: Despite numerous therapeutic modalities, including chemotherapy and next-generation androgen deprivation therapy, metastatic castration-resistant prostate cancer (mCRPC) remains a dreadful evolution and still bears a poor prognosis for most patients who develop metastases to bones and other organs, which have no cure. It is urgent to identify new molecular targets and develop novel therapeutic agents against lethal mCRPC. Methods: We developed a novel small-molecule anticancer compound named GH501 via a “molecular hybridization” approach. The in vitro cytotoxicity of GH501 was evaluated in the NCI-60 human cancer cell panel and human mCRPC cell lines. Molecular targets of GH501 were investigated using in silico docking, biolayer interferometry, cellular thermal shift assay, and other molecular and cellular approaches. The in vivo anticancer efficacy of GH501 against mCRPC was evaluated in clinically-relevant xenograft models. Results: GH501 effectively inhibited the in vitro proliferation of NCI-60 human cancer cell lines and established mCRPC cell lines, including African American prostate cancer (PCa) cells, at nanomolar potency by inducing cell cycle arrest and apoptosis. Mechanistically, GH501 might bind S-phase kinase-associated protein 1 (Skp1) and disrupt the physical interaction between Skp1 and S-phase kinase-associated protein 2 (Skp2), thereby affecting multiple oncogenic signals implicated in mCRPC progression. RNA-Seq analyses indicated that GH501 treatment in C4-2 cells significantly inhibited E2F-, G2/M checkpoint, c-Myc- and β-catenin-regulated genes, androgen receptor (AR) transcription, androgen-responsive genes, and enhancer of zeste homolog 2 (EZH2)-activated genes. Proteomic studies identified 109 proteins upregulated and 154 proteins downregulated significantly by GH501 in CRW22Rv1 cells. The top physiological processes and signaling pathways affected by GH501 included cell cycle, autophagy, steroid biosynthesis, DNA replication, p53, AMP-activated protein kinase (AMPK), and mitogen-activated protein kinase (MAPK). As a lead compound, GH501 had excellent preclinical safety. In animal studies, GH501 monotherapy effectively inhibited the skeletal and subcutaneous growth of four mCRPC xenografts with heterogeneous genetic backgrounds. Conclusion: These results support that pharmacological interruption of Skp1-Skp2 interaction is a promising therapeutic strategy for mCRPC. To our knowledge, GH501 is the first synthetic Skp1 inhibitor with a unique chemical structure that can serve as the basis for lead optimization and development. Citation Format: Xin Li, Kenza Mamouni, Rui Zhao, Yifei Wu, Zhong-Ru Xie, Giuseppe Sautto, Degang Liu, Nathan Bowen, Alira Danaher, Lajos Gera, Daqing Wu. A novel Skp1 inhibitor has potent preclinical efficacy against metastatic castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 519.

The microstructural evolution and deformation behaviour of Fe-(13, 16, 18)Mn-8Al-0.8C (wt-%) low-density steels were investigated in the present work. During aging treatment, the increase in the vo...

The safe disposal of nuclear waste is a key factor restricting the sustainable use of nuclear energy. Exploring safe and reliable disposal methods for nuclear waste has become a research hotspot. In this paper, cullet-based glass (CBG) was chosen as a new immobilization agent to host the plutonium (Pu). The immobilization mechanism of Pu in the CBG was investigated by using cerium (Ce) as a surrogate for Pu, and the interaction was characterized by using XRD, XPS, FTIR and SEM-EDS analyses. The results indicate that there are two synergistic immobilization mechanisms by which Ce is hosted in the vitrified products. One mechanism is doping of the Ce into the crystal lattice of the glassy matrix to form Ce O Si bonds, which increases the proportions of non-bridging oxygen (NBO) bonds in the glass structure. The other mechanism is Ce co-existing in the glass structure gaps as individual crystals of CeO2. The synergistic immobilization makes Ce hard to release. The PCT results show that the normalized leach rate of Ce decreases with the Ce partitioning ratio in the CeO2 crystalline phase. These data show that CBG can be used as a good immobilization agent to vitrify the Pu presented in high-level radioactive wastes.

The hot deformation behavior of a Fe-11Mn-10Al-0.9C duplex low-density steel has been investigated, based on a series of isothermal compression tests at temperatures of 800-1100 °C and strain rates of 0.001-10 s−1. At relatively lower temperatures, with austenite decomposing, continuous dynamic recrystallization of ferrite and the formation of inter-granular κ-carbide were responsible for significant softening. At high deformation temperature where austenite was a dominant phase, dynamic recrystallization (DRX) is the restoration mechanism. Processing maps were developed at different plastic strains employing dynamic materials model and further verified through microstructural characterization. The optimal hot deformation condition at a large strain (0.7) was identified as deformation temperature of 950-1100 °C and strain rate of 0.01-1.0 s−1. In this domain, the original coarse grains could be replaced by the fine and uniform recrystallized grains, indicating that the high efficiency was dissipated by DRX. Meanwhile, two instable regions resulted from the formation of inter-granular κ-carbides and necklace structure should be avoided during hot processing.

Although cemented paste backfill (CPB) method has been proposed as a resource disposal technology for arsenic waste, the immobilization potential and immobilization mechanism of arsenic in CPB remain unclear. In this study, lead-zinc slag, gypsum, and sodium arsenate were used to simulate the disposal of arsenic waste in CPB. Toxicity characteristic leaching procedure (TCLP) and compressive strength tests were used to determine the immobilization potential of arsenic in CPB. The immobilization mechanisms of arsenic in CPB were studied by X-ray diffraction (XRD), scanning electronic microscopy-energy dispersive spectrometry (SEM-EDS), and Fourier transform infrared spectroscopy (FTIR). The high compressive strength and low leaching toxicity showed that CPB had better immobilization potential of arsenic. SEM and XRD analyses showed that the formation of As-ettringite is an important immobilization mechanism of arsenic in CPB. FTIR analysis showed that AsO 4 3 - substituted SeO 4 2 - inside the ettringite in the form of HAsO 4 2 - . In the hydration process from 0 to 3 days, physical encapsulation and Ca-As precipitates were the main immobilization mechanism of arsenic. In the hydration process from 3 to 28 days, the immobilization efficiency of As-ettringite on arsenic was significantly higher than that of physical encapsulation and Ca-As precipitation. This study demonstrated that CPB is suitable for the immobilization of arsenic waste.

We elucidate three distinguished microstructural features and their contribution to the overall properties and strengthening in a Fe–11Mn–10Al–1.25C alloy treated at various temperatures. At 1000 °C, the nano-scaled ordered κ-carbides in the austenitic matrix contributed to YS (1041 MPa) without scarifying ductility (∼30%). At 900 °C, the significantly refined triplex microstructure with GB κ-carbides caused similar YS but limited ductility (∼8%). At 800 °C, a jump of YS but almost no ductility resulted from the synergic effects of the hard ferrite and lamellar microstructure. The microstructure-dependent mechanical responses were further clarified by analyses of flow curves and fractographs.

The quenching temperatures below Ms are difficult to uniformly control during large-scale processing of quenched and partitioned (Q&P) steels, which results in significant variation in tensile properties for the entire coil. The present study is aimed at obtaining a stable elongation for a wide range of quenching temperatures in hot rolled Q&P steels through microstructural design. Instead of cold rolling and annealing processes, a novel process involving hot rolling and air cooling followed by cooling in furnace was applied to a newly designed 0.25C-3Mn-2Al (wt.%) steel. The results indicated that a stable amount of retained austenite (RA) ∼ 19–23% was obtained during air-cooling to finish temperatures in the range of ∼280–360 °C, resulting in no loss in elongation at low quenching temperatures. The RA that was promoted by the transfer of carbon from ferrite/bainite reached up to 1.346 μm, whereas the RA embedded in martensitic laths was ∼40 nm. The two types of RA provided continuous TRIP effect during tensile deformation and the ultra-fine martensite lath of ∼100 nm ensured tensile strength greater than 1091 MPa. Finally, a stable total elongation of ∼19.2–20.5% in combination with tensile strength of ∼1091–1196 MPa was obtained over a wide quenching temperature range of 80 °C, which broadened the processing window for the production of hot rolled Q&P steels. In addition, the isothermal transformation during the initial partitioning stage was the underlying reason to obtain stable amount of RA. The CCE (Constrained Carbon Equilibrium) model combined with isothermal transformation was used to quantitatively calculate the volume fraction of RA.

One of the primary mechanisms of tumor cell immune evasion is the loss of antigenicity, which arises due to lack of immunogenic tumor antigens as well as dysregulation of the antigen processing machinery. In a screen for small-molecule compounds from herbal medicine that potentiate T cell–mediated cytotoxicity, we identified atractylenolide I (ATT-I), which substantially promotes tumor antigen presentation of both human and mouse colorectal cancer (CRC) cells and thereby enhances the cytotoxic response of CD8(+) T cells. Cellular thermal shift assay (CETSA) with multiplexed quantitative mass spectrometry identified the proteasome 26S subunit non–ATPase 4 (PSMD4), an essential component of the immunoproteasome complex, as a primary target protein of ATT-I. Binding of ATT-I with PSMD4 augments the antigen-processing activity of immunoproteasome, leading to enhanced MHC-I–mediated antigen presentation on cancer cells. In syngeneic mouse CRC models and human patient–derived CRC organoid models, ATT-I treatment promotes the cytotoxicity of CD8(+) T cells and thus profoundly enhances the efficacy of immune checkpoint blockade therapy. Collectively, we show here that targeting the function of immunoproteasome with ATT-I promotes tumor antigen presentation and empowers T cell cytotoxicity, thus elevating the tumor response to immunotherapy.

The interactions between Fe2SiO4 and ZnO play an essential role in the recovery of zinc from copper slag. The dissolution and substitution mechanism of ZnO in fayalite were investigated by using TG-DSC, XRD, PPMS DynaCool, XPS, Mossbauer and SEM-EDS analyses and compared with MS calculation results. The results indicate that the dissolution and substitution are actually processes of the penetrating dissolution of Zn(II) ions that can be divided into three steps: 1) ZnO dissociates into Zn1-yO and Zn(II) ions; 2) Zn(II) penetrates the gap of the octahedron outer layer to substitute Fe(II) sites in the internal structure of SiOFe(II) (M2) to form (Fe2-x, Znx)SiO4; 3) Fe(II) is forced to migrate to the surface of (Fe2-x, Znx)SiO4 to form (Zn1-y, Fe(II)y)O. These findings can be derived the occurrence state and distribution of zinc in copper slag theoretically.

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A novel method to activate red mud was proposed in this study. Municipal solid waste incineration fly ash (MSWIFA) and red mud were utilized to prepare red mud-based geopolymer materials (RGM). The hydration characteristics of RGM were studied by X-ray diffraction, scanning electronic microscopy, and Fourier transform infrared spectroscopy. The long-term stability and physical properties of RGM were tested by freeze–thaw cycle, European Community Bureau reference (BCR) and unconfined compressive strength (UCS) tests. Results showed that mechanical activation can not only effectively activate red mud, but also effectively improve the reaction of MSWIFA and red mud. When 14% sodium silicate was added to the binder, the UCS reached 12.75 MPa at 28 days. In the RGM, aluminosilicate was effectively activated by mechanical activation and reacted with calcium ion to form complex hydration products. The activator reacts adequately with activated aluminum to form a high-strength geopolymer. The freeze–thaw cycles and BCR test results also showed that the RGM had long-term stability and the characteristics satisfied the requirements of MU10 fly ash bricks. This study demonstrated that RGM may be utilized in cement composites.

Lead smelting slag (LSS) has been identified as general industrial solid waste, which is produced from the pyrometallurgical treatment of the Shuikoushan process for primary lead production in China. The LSS-based geopolymer was synthesized after high-energy ball milling. The effect of unconfined compressive strength (UCS) on the synthesis parameters of the geopolymer was optimized. Under the best parameters of the geopolymer (modulus of water glass was 1&ndash, 1.5, dosage of water glass (W(SiO2+Na2O)) was 5% and water-to-binder ratio was 0.2), the UCS reached 76.09 MPa after curing for 28 days. The toxicity characteristic leaching procedure (TCLP) leaching concentration of Zn from LSS fell from 167.16 to 93.99 mg/L after alkali-activation, which was below the limit allowed. Meanwhile, C-S-H and the geopolymer of the hydration products were identified from the geopolymer. In addition, the behavior of iron was also discussed. Then, the hydration process characteristics of the LSS-based geopolymer were proposed. The obtained results showed that Ca2+ and Fe2+ occupied the site of the network as modifiers in the glass phase and then dissociated from the glass network after the water glass activation. At the same time, C-S-H, the geopolymer and Fe(OH)2 gel were produced, and then the Fe(OH)2 was easily oxidized to Fe(OH)3 under the air curing conditions. Consequently, the conclusion was drawn that LSS was an implementable raw material for geopolymer production.

This work aims at developing an energy-efficient process for production of high strength hot-rolled quenching and partitioning (Q&P) steel. A novel processing strategy involving quenching above martensite start temperature (Ms) in combination with dynamic carbon partitioning is first proposed for hot-rolled Q&P process. The alloy 0.25C-3Mn-2Al (wt%) was intentionally designed to low interface mobility during slow cooling in bainite range and thus controlled partial bainite transformation. Finally, multi-phases containing ferrite, martensite and nano-sized retained austenite were obtained and an improved mechanical property can be achieved with tensile strength ∼1096 MPa and uniform elongation ∼16%. This work breaks the Q&P constraint with quenching temperature below Ms and provides an easy-industrialized processing route.

A novel strategy involving thermo-mechanical controlled processing (TMCP) and quenching to obtain martensite (Q&P) or bainite (B&P) followed by dynamic carbon partitioning was applied to two low carbon steels. Effect of cooling path on the microstructural evolution was studied with particular focus on dynamic partitioning, and the impact fracture behavior was observed and discussed based on the duplex structures, especially the retained austenite (RA). It was found that majority of the carbides were present in Al contained steel subjected to B&P process, leading to low fraction of RA ~ 5.1%, while ~ 9.2 to 20.1% RA was obtained in Si contained steel subjected to Q&P and B&P process. The impact energy at 20 °C of B&P steels exceeded 100 J, which was not related to RA. However, the impact energy at 20 °C of steels subjected to Q&P process indicated a large difference with impact energy of ~ 43 J to 117.1J, which resulted from carbon content in martensite and the RA fraction. The steel quenched to 380 °C followed by furnace cooling contained 14.7% RA and 5.5% RA experienced TRIP effect with transformation product of twinned martensite, which resulted in excellent impact toughness of ~ 106.6 J. During impact process, the micro-voids preferentially formed at ferrite/hard phases interface and in ferrite. In particular, the micro-voids also formed in martensite with high carbon concentration and thus led to low impact toughness of ~ 43 J. The bainite lath, M/A (martensite-austenite) island and RA acted as barriers and thus increased the resistance to crack propagation. During low temperature impact, the blocky RA has low thermal stability and is partially transformed leading to approximately 40 J decrease at 0 °C, while the microstructure of martensite lath and film-like RA exhibits high impact energy ~104.4 J at 0 °C.

The aim of the present study was to investigate the novel mechanisms of forkhead box protein P3 (foxp3) in T regulatory (Treg) cells in lung cancer behavior. Treg cells were isolated from the peripheral blood of healthy volunteers and then co‑cultured with 95D cells. A plasmid overexpressing foxp3 was constructed and transfected into Treg cells and an MTS assay was performed to assess cell viability. Flow cytometry was performed to evaluate cell apoptosis and reverse transcription‑quantitative polymerase chain reaction was used to measure mRNA expression. A Transwell assay was used to assess cell invasion. Treg cells were successfully isolated from peripheral blood with purity of 94.26%. Foxp3 expression in Treg cells was significantly increased following co‑culture with 95D cells, while matrix metalloproteinase‑9 expression was upregulated in 95D cells co‑cultured with Treg cells. The apoptosis, invasion and migration abilities of 95D cells were suppressed by co‑culture with Treg cells, whereas the adhesive ability was enhanced. Foxp3 overexpression in Treg cells enhanced the viability and invasiveness of 95D cells, whereas cell adhesion and migration were decreased. The results of the present study demonstrate that the viability and invasiveness of 95D cells are enhanced by foxp3 overexpression in Treg cells, indicating that increased levels of foxp3 in the tumor microenvironment may promote tumor cell growth.

A new method in which Pb/Zn smelter waste containing arsenic and heavy metals (arsenic sludge), red mud and lime are utilized to prepare red mud-based cementitious material (RCM) is proposed in this study. XRD, SEM, FTIR and unconfined compressive strength (UCS) tests were employed to assess the physicochemical properties of RCM. In addition, ettringite and iron oxide-containing ettringite were used to study the hydration mechanism of RCM. The results show that the UCS of the RCM (red mud+arsenic sludge+lime) was higher than that of the binder (red mud+arsenic sludge). When the mass ratio of m (binder): m (lime) was 94:6 and then maintained 28days at ambient temperature, the UCS reached 12.05MPa. The red mud has potential cementitious characteristics, and the major source of those characteristics was the aluminium oxide. In the red mud-arsenic sludge-lime system, aluminium oxide was effectively activated by lime and gypsum to form complex hydration products. Some of the aluminium in ettringite was replaced by iron to form calcium sulfoferrite hydrate. The BCR and leaching toxicity results show that the leaching concentration was strongly dependent on the chemical speciation of arsenic and the hydration products. Therefore, the investigated red mud and arsenic sludge can be successfully utilized in cement composites to create a red mud-based cementitious material.

In this study, a novel ultra-high yield strength Fe-11Mn-10Al-1.25C low density steel was developed with aiming to fundamentally understand the formation of inter/intra-granular κ-carbides and its influence on the overall mechanical properties by varying cooling patterns, e.g. air cooling (AC), water quenching (WQ) and intensive quenching (IQ). The results show that the IQ microstructure is almost fully austenitic with very fine intra-granular κ-carbides of less than 13 nm, which is totally different from the chain-like ferrite and coarse inter-granular κ-carbides of 0.6–2.6 µm in both cases of AC and WQ. In contrast, the IQ sample exhibits similar high YS and UTS values (~ 1.1 GPa) to the others but significantly an enhanced ductility of ~ 29.3%, revealing an excellent balance of strength and ductility, i.e. the product of strength and ductility (PSE) can reach as high as 32.1 GPa%. The improved overall performance and continuously increasing strain hardening are dominated by planar glide, which is mainly attributed to the uniform distribution of nano-sized and shearable κ-carbides in the austenitic matrix. These results may provide theoretical supports for the κ-carbides-related alloy design and microstructural modification of ultra-high-strength medium Mn low density steels.

We have studied here the carbon partitioning during continuous cooling at different cooling rates using dilatometer. An interesting phase transition was observed involving multiple stages of transformation during dynamic partitioning and a mechanism was proposed to explain the observations. Two morphologies of nano-sized retained austenite were observed, film-like and block-type. It was proposed that the amount of retained austenite was stable in a certain range of cooling rate. When the cooling rate was between 0.05 °C/s and 1 °C/s, the carbon partitioning was adequate and ~ 11 to 14% retained austenite was obtained. With increase in cooling rate from 5 and 10 °C/s, carbon partitioning was not adequate, which resulted in decrease in film-like austenite. The austenite adjacent to ferrite had two different transformation products, M/A (martensite-austenite island) and twin martensite, based on the degree of carbon transfer from ferrite. However, macro-hardness test showed that cooling rate had little effect on hardness and the hardness was between 398 HV and 407 HV at cooling rate of ~ 0.05 to 10 ℃/s. Additionally, samples cooled at low cooling rate indicated continuous TRIP effect and excellent combination of high strength 1030 MPa and high elongation of ~ 25% was obtained in the plate cooled at 0.1 ℃/s. On the basis of results, a strategy was proposed to obtain high performance hot rolled Q&P steels. The study confirmed the viability of implementing quenching and partitioning process in the hot rolling production line.

Flotation waste of copper slag (FWCS), neutralization sludge (NS), and arsenic-containing gypsum sludge (GS), both of which are difficult to dispose of, are major solid wastes produced by the copper smelting. This study focused on the co-treatment of FWCS, NS, and GS for solidification/stabilization of arsenic and heavy metals with minimal cement clinker. Firstly, the preparation parameters of binder composed of FWCS, NS, and cement clinker were optimized to be FWCS dosage of 40%, NS dosage of 10%, cement clinker dosage of 50%, mill time of 1.5 h, and water-to-binder ratio of 0.25. On these conditions, the unconfined compressive strength (UCS) of the binder reached 43.24 MPa after hydration of 28 days. Then, the binder was used to solidify/stabilize the As-containing GS. When the mass ratio of binder-to-GS was 5:5, the UCS of matrix can reach 11.06 MPa after hydration of 28 days, meeting the required UCS level of MU10 brick in China. Moreover, arsenic and other heavy metals in FWCS, NS, and GS were effectively solidified or stabilized. The heavy metal concentrations in leachate were much lower than those in the limits of China standard leaching test (CSLT). Therefore, the matrices were potential to be used as bricks in some constructions. XRD analysis shows that the main hydration products of the matrix were portlandite and calcium silicate hydrate. These hydration products may play a significant role in the stabilization/solidification of arsenic and heavy metals.

The sintering behaviors among SiO2, FeS and Fe3O4 were detected to reveal the formation mechanism of Fe2SiO4. The results indicated that the formation mechanism is divided into five steps: (1) migration of O2− induced by S2− under a reducing atmosphere; (2) formation of Fe3O4−β ; (3) migration of Fe(II) into a ferrite cluster structure to gain oxygen and form Fe3−x O4; (4) Fe(II) invaded the silicon atomic position and released Si(IV); and (5) formation of the stable structure of Fe2SiO4 through chemical diffusion between cations of Fe(II) and Si(IV). These findings can provide theoretical support for controlling the process of the recovery of valuable metals in copper slag through the combined roasting modification–magnetic separation process.

In this paper, we study the interactive relationship between the agglomeration of urban elements and the evolution of eco-environmental pressure. We build an index system for evaluating the agglomeration of urban elements and eco-environmental pressure. Using the entropy method and response intensity model, we analyze how urban elements agglomeration influenced eco-environmental pressure in Changchun from 1990 to 2012, eliciting the changing features and influential factors. Ultimately, we conclude there is a significant interactive relationship between the agglomeration of urban elements and the evolution of eco-environmental pressure in Changchun. This is inferred from the degree of this agglomeration in Changchun having increased since 1990, with the degree of eco-environmental pressure first decreasing and then increasing. Alongside this, the impact of urban elements agglomeration on eco-environmental pressure has changed from negative to positive. The main reasons behind this shift are arguably the rapid growth of urban investment and ongoing urbanization.

Triple-negative breast cancers (TNBCs) lack the signature targets of other breast tumors, such as HER2, estrogen receptor, and progesterone receptor. These aggressive basal-like tumors are driven by a complex array of signaling pathways that are activated by multiple driver mutations. Here we report the discovery of 6 (KIN-281), a small molecule that inhibits multiple kinases including maternal leucine zipper kinase (MELK) and the non-receptor tyrosine kinase bone marrow X-linked (BMX) with single-digit micromolar IC(50)s. Several derivatives of 6 were synthesized to gain insight into the binding mode of the compound to the ATP binding pocket. Compound 6 was tested for its effect on anchorage-dependent and independent growth of MDA-MB-231 and MDA-MB-468 breast cancer cells. The effect of 6 on BMX prompted us to evaluate its effect on STAT3 phosphorylation and DNA binding. The compound’s inhibition of cell growth led to measurements of survivin, Bcl-X(L), p21(WAF1/CIP1), and cyclin A2 levels. Finally, LC3B-II levels were quantified following treatment of cells with 6 to determine whether the compound affected autophagy, a process that is known to be activated by STAT3. Compound 6 provides a starting point for the development of small molecules with polypharmacology that can suppress TNBC growth and metastasis.

Pyrimidine dimers are the most common DNA lesions generated under UV radiation. To reveal the molecular mechanisms behind their formation, it is of significance to reveal the roles of each pyrimidine residue. We thus replaced the 5'-pyrimidine residue with a photochemically inert xylene moiety (X). The electron-rich X can be readily oxidized but not reduced, defining the direction of interbase electron transfer (ET). Irradiation of the XpT dinucleotide under 254 nm UV light generates two major photoproducts: a pyrimidine (6-4) pyrimidone analog (6-4PP) and an analog of the so-called spore photoproduct (SP). Both products are formed by reaction at C4=O of the photo-excited 3'-thymidine (T), which indicates that excitation of a single "driver" residue is sufficient to trigger pyrimidine dimerization. Our quantum-chemical calculations demonstrated that photo-excited 3'-T accepts an electron from 5'-X. The resulting charge-separated radical pair lowers its energy upon formation of interbase covalent bonds, eventually yielding 6-4PP and SP.

Target-specific scoring methods are more commonly used to identify small-molecule inhibitors among compounds docked to a target of interest. Top candidates that emerge from these methods have rarely been tested for activity and specificity across a family of proteins. In this study we docked a chemical library into CaMKIIδ, a member of the Ca2+ /calmodulin (CaM)-dependent protein kinase (CaMK) family, and re-scored the resulting protein-compound structures using Support Vector Machine SPecific (SVMSP), a target-specific method that we developed previously. Among the 35 selected candidates, three hits were identified, such as quinazoline compound 1 (KIN-1; N4-[7-chloro-2-[(E)-styryl]quinazolin-4-yl]-N1,N1-diethylpentane-1,4-diamine), which was found to inhibit CaMKIIδ kinase activity at single-digit micromolar IC50 . Activity across the kinome was assessed by profiling analogues of 1, namely 6 (KIN-236; N4-[7-chloro-2-[(E)-2-(2-chloro-4,5-dimethoxyphenyl)vinyl]quinazolin-4-yl]-N1,N1-diethylpentane-1,4-diamine), and an analogue of hit compound 2 (KIN-15; 2-[4-[(E)-[(5-bromobenzofuran-2-carbonyl)hydrazono]methyl]-2-chloro-6-methoxyphenoxy]acetic acid), namely 14 (KIN-332; N-[(E)-[4-(2-anilino-2-oxoethoxy)-3-chlorophenyl]methyleneamino]benzofuran-2-carboxamide), against 337 kinases. Interestingly, for compound 6, CaMKIIδ and homologue CaMKIIγ were among the top ten targets. Among the top 25 targets of 6, IC50 values ranged from 5 to 22 μm. Compound 14 was found to be not specific toward CaMKII kinases, but it does inhibit two kinases with sub-micromolar IC50 values among the top 25. Derivatives of 1 were tested against several kinases including several members of the CaMK family. These data afforded a limited structure-activity relationship study. Molecular dynamics simulations with explicit solvent followed by end-point MM-GBSA free-energy calculations revealed strong engagement of specific residues within the ATP binding pocket, and also changes in the dynamics as a result of binding. This work suggests that target-specific scoring approaches such as SVMSP may hold promise for the identification of small-molecule kinase inhibitors that exhibit some level of specificity toward the target of interest across a large number of proteins.

Ral (Ras-like) GTPases are directly activated by oncogenic Ras GTPases. Mutant K-Ras (G12C) has enabled the development of covalent K-Ras inhibitors currently in clinical trials. However, Ral, and the overwhelming majority of mutant oncogenic K-Ras, are devoid of a druggable pocket and lack an accessible cysteine for the development of a covalent inhibitor. Here, we report that covalent bond formation by an aryl sulfonyl fluoride electrophile at a tyrosine residue (Tyr-82) inhibits guanine exchange factor Rgl2-mediated nucleotide exchange of Ral GTPase. A high-resolution 1.18-Å X-ray cocrystal structure shows that the compound binds to a well-defined binding site in RalA as a result of a switch II loop conformational change. The structure, along with additional high-resolution crystal structures of several analogs in complex with RalA, confirm the importance of key hydrogen bond anchors between compound sulfone oxygen atoms and Ral backbone nitrogen atoms. Our discovery of a pocket with features found on known druggable sites and covalent modification of a bystander tyrosine residue present in Ral and Ras GTPases provide a strategy that could lead to therapeutic agent targeting oncogenic Ras mutants that are devoid of a cysteine nucleophile.

When a civil aircraft is flying in high altitude and low temperature environment, once the fuel feed system freezes, the fuel pressure and flow of engine and APU will decrease, resulting in the loss of aircraft power and even the occurrence of flight accidents. In this paper, the icing test platform of aircraft fuel system is set up, the test configuration and measurement system design method are given. By carrying out icing test of a certain type of fuel system, the test results show the safety and rationality of the aircraft fuel system design and test rig design, so as to provide guidance and reference for the implementation of icing test of aircraft fuel system.

In the present study, the variations of microstructure and tensile properties were investigated as a function of aging time using a Fe–11Mn–10Al-1.2C medium-Mn lightweight steel. The 1000 °C-annealed specimen revealed an austenite matrix containing nano-sized particles of intra-granular (IG) κ-carbide and a small amount of α-ferrite. After aging at 550 °C for 3 min, pre-existing IG κ-carbide grew up rapidly and relatively coarse κ-carbide formed at the γ-austenite grain boundary (GB). With aging for 10 min, the C-depleted zones, close to the coarsened GB κ-carbide particles, were transformed to filmy grain boundary ferrite (GBF). When aging time increased to 30 min, the eutectoid reaction (γ → α + κ) occurred preferentially at the coarse particles of GB κ-carbide. The eutectoid reaction continued with increasing aging time up to 720 min, and finally the specimen had a eutectoid matrix (α+κ) with a few of α-ferrite. The annealed specimen possessed high strengths (yield strength (YS) of 1242 MPa and ultimate tensile strength (UTS) of 1314 GPa) with moderate elongation (El) of 22.2%. The YS value of aged specimens was improved to ~1.35 GPa by the growth of IG κ-carbide particles after aging for 3 min, and increased further up to ~1.54 GPa by the formation of eutectoid structure after aging for 720 min.

Non-ferrous metal smelting enterprises produce hundreds of thousands of tons of arsenic sulfide sludge (ASS) each year in China. Most of the ASS are stored at the companies without enough preventive measures. During the storage and natural drying process, arsenic sulfide is easily oxidized, thereby causing secondary pollution and increasing environmental risks. In this paper, experiments of simulated storage were used to study the release characteristics of heavy metals. During the simulated storage, the release concentrations of As, Pb, and Cd increased rapidly at first and then slowly. Although the total amount of arsenic released was the largest, the release ratio was in the order of Cd &gt, Pb &gt, As. The effects of different atmospheres and conditions on the release of arsenic and heavy metals were explored. The more the H2SO4 in the sludge, the higher the release concentration, and the addition of an appropriate amount of Ca(OH)2 is beneficial for reducing the release of heavy metals. Finally, SEM, XRD and TG-DTG techniques were carried out to confirm that the release of heavy metals was caused by the oxidation process resulting from the residual H2SO4 in the ASS and the air.

In the present work, the Fe-13Mn-8Al-(0.7, 1.2)C steels were subjected to different post-cold rolling annealing treatments in a temperature range of 800–1000 °C for 15 min to investigate the microstructural evolution and the mechanical properties. Both steels annealed at 800 °C consisted of fine austenite and ferrite grains along with intergranular κ-carbides formed by eutectoid reaction, which contributed to the high strength but deteriorated ductility. With annealing temperature increasing, the volume fraction of ferrite and intergranular κ-carbides progressively decreased. Meanwhile, the precipitation of intragranular κ′-carbides enhanced the yield strength, whereas coarse austenite was harmful to both strength and elongation. The increase in C content increased the volume fraction of intergranular κ-carbides and austenite as well as retarded the austenite recrystallization, which further increased strength and strain hardening rate but deteriorate ductility. The deformation mechanism in austenite was massive planar slip. The microbands were widely observed in both steels at an annealing temperature above 900 °C.

Extracellular calcium flow through neuronal voltage-gated Ca(V)2.2 calcium channels converts action potential-encoded information to the release of pronociceptive neurotransmitters in the dorsal horn of the spinal cord, culminating in excitation of the postsynaptic central nociceptive neurons. The Ca(V)2.2 channel is composed of a pore-forming α(1) subunit (Ca(V)α(1)) that is engaged in protein–protein interactions with auxiliary α(2)/δ and β subunits. The high-affinity Ca(V)2.2α(1)⋅Ca(V)β(3) protein–protein interaction is essential for proper trafficking of Ca(V)2.2 channels to the plasma membrane. Here, structure-based computational screening led to small molecules that disrupt the Ca(V)2.2α(1)⋅Ca(V)β(3) protein–protein interaction. The binding mode of these compounds reveals that three substituents closely mimic the side chains of hot-spot residues located on the α-helix of Ca(V)2.2α(1). Site-directed mutagenesis confirmed the critical nature of a salt-bridge interaction between the compounds and Ca(V)β(3) Arg-307. In cells, compounds decreased trafficking of Ca(V)2.2 channels to the plasma membrane and modulated the functions of the channel. In a rodent neuropathic pain model, the compounds suppressed pain responses. Small-molecule α-helical mimetics targeting ion channel protein–protein interactions may represent a strategy for developing nonopioid analgesia and for treatment of other neurological disorders associated with calcium-channel trafficking.

Extracellular calcium flow through neuronal voltage-gated Ca V 2.2 calcium channels converts action potential-encoded information to the release of pronociceptive neurotransmitters in the dorsal horn of the spinal cord, culminating in excitation of the postsynaptic central nociceptive neurons. The Ca V 2.2 channel is composed of a pore-forming α 1 subunit (Ca V α 1 ) that is engaged in protein–protein interactions with auxiliary α 2 /δ and β subunits. The high-affinity Ca V 2.2α 1 ⋅Ca V β 3 protein–protein interaction is essential for proper trafficking of Ca V 2.2 channels to the plasma membrane. Here, structure-based computational screening led to small molecules that disrupt the Ca V 2.2α 1 ⋅Ca V β 3 protein–protein interaction. The binding mode of these compounds reveals that three substituents closely mimic the side chains of hot-spot residues located on the α-helix of Ca V 2.2α 1 . Site-directed mutagenesis confirmed the critical nature of a salt-bridge interaction between the compounds and Ca V β 3 Arg-307. In cells, compounds decreased trafficking of Ca V 2.2 channels to the plasma membrane and modulated the functions of the channel. In a rodent neuropathic pain model, the compounds suppressed pain responses. Small-molecule α-helical mimetics targeting ion channel protein–protein interactions may represent a strategy for developing nonopioid analgesia and for treatment of other neurological disorders associated with calcium-channel trafficking.

In recent years, acid rain had a serious negative impact on the leaching behavior of industrial waste residue. Researches were mainly focused on the environmental hazards of heavy metal in the leachate, but ignored the effects of heavy metal speciation on the stability of waste residue in the subsequent stabilization process. In this study, the unstable calcium–arsenic compounds in the arsenic calcium residue were firstly removed by leaching process; subsequently, the crystallization agent was added to treat the remaining calcium–arsenic mixture. The results of the leaching process demonstrated that the decrease in particle size and pH value directly affected the increase in the cumulative leaching amount of arsenic, and the cumulative leaching ratio reached 1.55%. In addition, the concentration of arsenic decreased from 3583 to 49.1 mg L−1. After the crystallization process, the arsenic concentration was lower than the limit value of Identification Standards for Hazardous Wastes (GB 5085.3-2007). The SEM analysis showed the bulk structures, and XRD pattern confirmed that they were the stable compounds. Moreover, the result of XRD and SEM illustrated that acid concentration, chloride ions and sulfate ions were contributed to the transformation and growth of stable calcium arsenate compounds. Therefore, effective control of the acidity of acid rain, the type of anions in acid rain, and the particle size of residues would contribute to adjusting the arsenic speciation to be more stable. The leaching-crystallization process was of great significance to improve the stability of the arsenic-containing residue.

Bone is a common site of metastasis for breast, prostate, lung, kidney and other cancers. Bone metastases are incurable, and substantially reduce patient quality of life. To date, there exists no small-molecule therapeutic agent that can reduce tumor burden in bone. This is partly attributed to the lack of suitable in vitro assays that are good models of tumor growth in bone. Here, we take advantage of a novel ex vivo model of bone colonization to report a series of pyrrolopyrazolone small molecules that inhibit cancer cell invasion and ex vivo tumor growth in bone at single-digit micromolar concentration. We find that the compounds modulated the expression levels of genes associated with bone-forming osteoblasts, bone-destroying osteoclasts, cancer cell viability and metastasis. Our compounds provide chemical tools to uncover novel targets and pathways associated with bone metastasis, as well as for the development of compounds to prevent and reverse bone tumor growth in vivo.