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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 highresolution 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. [ABSTRACT FROM AUTHOR]

Highlights • The austenite-based, duplex and triplex structures were developed. • Different types of intra-granular and grain boundaries κ -carbides were observed. • The microstructure-dependent mechanical responses were analyzed. • This work can be used to tailor phase constituents of medium-Mn lightweight steels. Abstract 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The present work aims to reveal the influence of κ-carbides precipitated in grain interior (GI) and along grain boundaries (GBs) with various characteristics on the strain hardening behavior of Fe–11Mn-(7, 10)Al-(0.6, 0.9, 1.2)C steels. Because of the higher probability for moving dislocations meeting with κ-carbides and shearing them, the increase in the volume fraction of shearable nano κ-carbides is more favorable for the improvement of the yield strength (YS) but thus induces the lower strain hardening rate (SHR), especially at low strains. The SHR maintains almost constant values even gradually increases during straining as the enhanced κ-carbide precipitation is beneficial to the planar glide softening and thus promotes the slip bands refinement. EBSD and TEM analysis reveal that both the unshearable coarse and sub-micron κ-carbides formed along GBs and in GI hinder the dislocation movement, and the former results in the significant strain localization in α/κ interfaces, consequently bringing about high SHR but premature failure. It is hoped that these findings will help achieving better synergy of strength and ductility of lightweight steels by utilization of the unshearable sub-micron κ-carbide in addition to the shearable one and partial-recrystallization. [ABSTRACT FROM AUTHOR]

This paper aimed to study the effects of annealing temperature on the microstructures and yield strength (YS) in the Fe-11Mn-xAl-yC medium-Mn lightweight steels, and reveal the structure-strength relationships and strengthening mechanisms. As the annealing temperature decreased from 1100 °C to 850 °C, the YS of the IG κ-carbide-free Fe-11Mn-7Al-0.6C steel (0.6C) could be improved from 482 MPa to 630 MPa by grain size refinement strengthening. When the 0.6C steel was annealed below 800 °C, partial recrystallization occurred and brought about a great increase in the YS up to 1.1 GPa by the high dislocation density (8.2–10.9 × 1014 m−2). The increases in the contents of C and Al promoted the precipitation of both grain boundary (GB) and intra-granular (IG) κ-carbides. Thus, the 1000 °C-annealed Fe-11Mn-10Al-1.2C steel possessed an austenite matrix containing nano κ-carbide and a small amount of α-ferrite, and achieved ultrahigh YS of 1242 MPa by relying on the remarkable precipitation strengthening effect (679 MPa). This study provided a new insight into comprehensively understanding the relationships among alloy composition, thermomechanical process (TMP), microstructures and various strengthening mechanisms in the lightweight steels so as to improve the YS. [ABSTRACT FROM AUTHOR]

Substituted toluenyl groups are considered as close isosteres of the thymine residue. They can be recognized by DNA polymerases as if they were thymine. These toluene derivatives are generally inert toward radical additions, including the [2+2] photo-cycloadditions, due to the stable structure of the aromatic ring and are usually used as solvents for radical reactions. Surprisingly, after incorporating toluene into the dinucleotide framework, we found that the UV excited thymine residue readily dimerizes with the toluenyl moiety through a [2+2] photo-addition reaction. Furthermore, the reaction site on the toluenyl moiety is not the C5C6 bond, as commonly observed in cyclobutane pyrimidine dimers, but the C4C5 or C3C4 instead. Such a reaction pattern suggests that in the stacked structure, it is one of these bonds, not the C5C6, that is close to the thymine C5C6 bond. A similar structural feature is found in DNA duplex with a thymine replaced by a 2,4-difluorotoluene. Our results argue that although the substituted toluenyl moieties closely mimic the size and shape of the thymine residue, their more hydrophobic nature determines that they stack on DNA bases differently from the natural thymine residue and likely cause local conformational changes in duplex DNA. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The right half of (+)-pederin was synthesized through a convenient and efficient asymmetric synthesis in 14 steps with 8.3% overall yield. The key step was an iodine-induced heterocyclization to construct the pyran ring. The chiral centers were constructed separately via asymmetric allylation, substrate-controlled diastereoselective reactions, and Sharpless asymmetric dihydroxylation. [ABSTRACT FROM AUTHOR]

The dynamic recrystallization (DRX) and dynamic precipitation (DP) of grain boundary/intra-granular (GB/IG) κ-carbides in a novel medium-Mn lightweight steel are investigated by conducting compression tests over a wide range of temperatures (800–1100 °C) and strain rates (0.001–10 s−1). Two types of distinct flow behaviors have been observed: the flow curves show typical DRX features at high temperatures (≥ 950 °C), whereas the flow stress shows the significant softening after peak stress at low temperatures (≤ 900 °C), which is closely associated with the DP of GB/IG κ-carbides. According to the distinguished flow behaviors, two constitutive equations have been developed for the low and high temperature regimes, showing disparate hot deformation energy (Q) values (i.e. 600.58 kJ/mol and 355.51 kJ/mol). At low temperatures, the κ-carbides inhibit dislocation motion, and the pinning effect of fine GB κ-carbide particles retards the austenite grain boundary migration, which greatly improves the peak stress level and thus increases the energy barrier (i.e. Q). Furthermore, the volume fraction and grain size of GB κ-carbides increase with the decrease in strain rate, resulting in the consumption of stored deformation energy, which coupled with the continuous DRX (CDRX) in δ-ferrite are responsible for the significant softening. The DRX takes place more sufficiently with increasing temperature, and the deformation induced α-ferrite transformation (DIFT) and morphology evolution of δ-ferrite are observed at 950 °C and 1100 °C, respectively. [ABSTRACT FROM AUTHOR]

Urbanization is a complex process that covers a wide range of topics, of which population, industry and land urbanization are three important aspects. Jilin Province is an important agricultural province in China. The contradiction between population, industry and land urbanization is especially prominent here, and its coupling development is of great practical significance. In this paper, the coupling degree of population-industry-land urbanization in Jilin Province in 1990, 2000 and 2010 is measured by coupling mode. The spatial pattern of the coupling degree is analyzed by trend surface analysis and global and local spatial autocorrelation. The influence factors and their spatial differentiation are discussed using multiple linear regression (MLR) model and geographic weighted regression (GWR) model. The results show that: 1) the coupling degree of population-industry-land urbanization in Jilin Province is at a low level. Judging from the change of time scale, the urbanization of most research units is becoming more and more coordinated. From the comparison of spatial scales, there is significant spatial difference in the research units of different administrative levels. 2) Judging from the global change trend, the coupling degree of population-industry-land urbanization in the central region is higher than that in western and eastern regions. The coordination of urbanization in the central region is relatively good, and the distribution of the cold and hot spots is basically the same as that overall. 3) The spatial pattern of the coupling degree is related to the cold and hot spot distribution of the influence coefficient of urban population density and per capita urban construction land. The variation of the coupling degree spatial pattern is synchronous with the spatial change of the urban population density influence coefficient. 4) The degree of agglomeration of the urban population is the main factor promoting the coupling pattern of population-industry-land urbanization in Jilin Province, and the extent of its influence is gradually increasing. In addition, the level of city administrative, the efficiency of urban expansion and the capacity of market consumption also have an important influence on the coupling pattern. [ABSTRACT FROM AUTHOR]

The synthesis of heterocyclic amides containing pyrrole, pyrrolidinone, and piperidone fragments is described and these are tested together with a wide range of previously prepared analogous derivatives for their binding activity at the urokinase receptor. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

N6‐methyladenosine (m6A) and long noncoding RNAs (lncRNAs) are both crucial regulators in non‐small‐cell lung cancer (NSCLC) tumorigenesis. However, the pathological roles of m6A 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, m6A profile was analyzed by methylated RNA immunoprecipitation sequencing (MeRIP‐Seq). MeRIP‐Seq presented that there was m6A modification site in ABHD11‐AS1. m6A methyltransferase‐like 3 (METTL3) installed the m6A 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 m6A and lncRNA in cancer biology. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

• CBG was chosen to vitrify Pu directly by using Ce as a surrogate for Pu. • Two synergistic immobilization mechanism to make Ce difficult to release. • The formation of Ce-O-Si bonds increased the NBO proportion in the glass structure. • The 7-PCT results indicated that vitrification treatment of Ce by CBG is effective. 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 CeO 2. 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 CeO 2 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. [ABSTRACT FROM AUTHOR]

• Cemented paste backfill exhibited effective immobilization for arsenic waste. • AsO 4 3 - substituted SeO 4 2 - inside the ettringite in the form of HAsO 4 2 -. • The As-ettringite solid phase was formed as the primary retention phase for As (Ⅴ). 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. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • The occurrence state of zinc in the copper slag is obtained theoretically. • Zn(II) substitutes for the iron sites in the internal Si O Fe(II) (M2) bond to form Fe 2-x Zn x SiO 4. • Formation mechanism is actually an ion exchange process between Zn(II) and Fe(II). • The priority of the substituting for the iron site in the fayalite structure is proved by MS software calculation. Abstract The interactions between Fe 2 SiO 4 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 Zn 1-y O 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 Si O Fe(II) (M2) to form (Fe 2-x , Zn x)SiO 4 ; 3) Fe(II) is forced to migrate to the surface of (Fe 2-x , Zn x)SiO 4 to form (Zn 1-y , Fe(II) y)O. These findings can be derived the occurrence state and distribution of zinc in copper slag theoretically. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Red mud and MSWIFA are used for synthesis of RGM. • Aluminosilicate is effectively activated by mechanical activation. • The activator reacts adequately with activated aluminum. • RGM can be potentially used as a supplementary cementitious material. Abstract 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. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The Ras-like GTPases RalA and RalB are important drivers of tumour growth and metastasis. Chemicals that block Ral function would be valuable as research tools and for cancer therapeutics. Here we used protein structure analysis and virtual screening to identify drug-like molecules that bind to a site on the GDP-bound form of Ral. The compounds RBC6, RBC8 and RBC10 inhibited the binding of Ral to its effector RALBP1, as well as inhibiting Ral-mediated cell spreading of murine embryonic fibroblasts and anchorage-independent growth of human cancer cell lines. The binding of the RBC8 derivative BQU57 to RalB was confirmed by isothermal titration calorimetry, surface plasmon resonance and 1H-15N transverse relaxation-optimized spectroscopy (TROSY) NMR spectroscopy. RBC8 and BQU57 show selectivity for Ral relative to the GTPases Ras and RhoA and inhibit tumour xenograft growth to a similar extent to the depletion of Ral using RNA interference. Our results show the utility of structure-based discovery for the development of therapeutics for Ral-dependent cancers. [ABSTRACT FROM AUTHOR]

Arsenic sulfide sludge (ASS) generated during the treatment of strongly acidic wastewater with sulfide precipitation method has long been a problem for the nonferrous smelting enterprises. In this study, stabilization of ASS from a lead and zinc smelter by hydrothermal treatment was investigated. The ASS was characterized with high contents of arsenic (46.9%) and sulfur (32.6%), and leaching concentration of arsenic was determined to be 702.0 mg/L. The parameters of the hydrothermal treatment were studied in detail. It was found that the leaching concentrations of As, Pb and Cd, dehydration ratio, density and morphology of ASS changed dramatically during the hydrothermal treatment. Comprehensive consideration of these changes, the optimal conditions were determined to be temperature of 200 °C, reaction time of 4 h, liquid-to-solid (L/S) ratio of 1:1 and the initial pH of 2. Under the optimal conditions, the leaching concentration of As for the treated ASS decreased to <5 mg/L. The yellow muddy ASS changed into a big bulk with metallic luster. The density of the ASS increased from 1.20 g/cm3 to 2.29 g/cm3, the moisture content decreased from 62.59% to 6.50%, and the volume reduction ratio reached 91.67%. After the hydrothermal treatment, the speciation transformation of As, Pb and Cd occurred. Some of the As, Pb and Cd in ASS transformed into a more stable speciation after the hydrothermal treatment. As a result, the stabilization of As, Pb and Cd attributed to both of the microstructure transformation of ASS and the speciation transformation of As, Pb and Cd. • Hydrothermal treatment can achieve the stabilization of the arsenic sulfide sludge. • The optimum conditions were temperature of 200 °C, reaction time of 4 h, L/S ratio of 1:1 and initial pH of 2. • The leaching concentration of arsenic decreased from 702.0 mg/L to 0.67 mg/L. [ABSTRACT FROM AUTHOR]

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 > Pb > 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. [ABSTRACT FROM AUTHOR]