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Application of high performance concrete or self-compacting concrete is verycommon in prefabrication plants. For pre-tensioned concrete structures prestressing reinforcement may be prepared in the form of smooth or profiled steel wires or multi-wire strands. The transfer of the prestressing force onto pre-tensioned element takes place through the bond between concrete and steel. Proper recognition of bond phenomenon directly influences the safety and durability of structure. It is especially important for pre-tensioned concrete elements without the normal reinforcement, such as railway sleepers or hollow core floor slabs. The value of bond stress in pre-tensioned structures depends on the value of tendon's slippage and many material and technological aspects. Complex stress state in end zone of the element, caused by transferring the prestressing force to concrete, may result in different damages. In the elements without transverse reinforcement cracking of end zone can endanger its safety use. The paper presents also the calculations of the transmission length of prestressing force according to the latest regulations – Eurocode 2 and Model Code 2010. [ABSTRACT FROM AUTHOR]

The purpose of this work was to define the technical condition of the water tower building and an indication of the ways of repairing and strengthening the structure. The function of the building is to provide water under high pressure to water supply installation for a water railway distribution station. The structure was built in 1959. The building consists of four floors above the ground and the basement. The main masonry structure is made of brick casted on lime and cement mortar. Each story is separated by reinforced concrete ceilings constructed as two-way slabs supported by beams. A circumferential reinforced concrete water tank is situated on the top floor. The tank consists of two chambers with the total volume of 250 m 3 . Reinforced concrete stairs are located around the circumferential wall of the building and provide service and technological communication in the building. The roof is constructed with reinforced concrete panels. The scope of the study includes a technical condition assessment of masonry walls, reinforced concrete floors (slabs and beams), stairs, the tank and the dome. For this reason, experimental researches on structural elements were performed. Researches of structural concrete include destructive tests made on drilling trial elements and non-destructive tests, to qualify mechanical properties of the material. Supplementary tests concern the humidity measurements and concrete alkalinity examination. For detection of rebar in structural elements, scanning of the specimen surface was performed and the concrete cover was removed in several places. For brick walls the main attention was focused on moisture content measurements. Experimental investigations and on-site inspections made it possible to assess the level of consumption of individual elements and durability of the structure. On this basis, main guidelines for necessary repairs and strengthening of structural elements which endanger the safety of exploitation were proposed. [ABSTRACT FROM AUTHOR]

Highlights: [•] The repair kinetics of two common cyclic DNA adducts derived lipid peroxidation, Acr-dG and HNE-dG, in human colon cells was studied. [•] This study is the first to measure DNA repair rates by both DNA repair synthesis and LC–MS/MS methods. [•] Acr-dG, like HNE-dG, is repaired by NER pathway, but it is repaired at a much slower rate compared to HNE-dG. [•] HNE-dG can inhibit the repair of Acr-dG if both are present in the same DNA. [ • ] These results provide an explanation for the higher levels of Acr-dG than HNE-dG observed in vivo. [ABSTRACT FROM AUTHOR]

Summary: Background & aims: Isothiocyanates (ITCs) derived from cruciferous vegetables have been shown to be promising agents against cancer in human cell culture, animal models, and in epidemiological studies. Several epidemiological studies have demonstrated an inverse relationship between intake of dietary isothiocyanates and the risk of cancers, particularly lung, colon, and breast. More importantly, the protective effects of dietary ITCs appear to be influenced by glutathione S-transferase (GST) genotype; specifically, individuals with glutathione S-transferase theta 1 (GSTT1) and glutathione S-transferase Mu 1 (GSTM1) null are better protected than those with GSTT1 and M1 positive. Although the majority of studies, especially those conducted in populations exposed to ITC rich diets, demonstrated such effects, there are a few studies that showed opposite or no association. While evidence for the interactions of dietary ITCs with GST genes is relatively strong, the reasons for the differential effects remain unclear. In this study, we examined one possible mechanism: whether subjects with null genotypes excrete ITCs at a slower rate than those with positive genotypes after drinking watercress juice, a rich source of ITCs. Methods: A total of 48 subjects, 28 GSTT1 and M1 positive and 20 null genotypes were enrolled in the study. The rates of excretion were determined using five urine samples collected over a period of 24 h after drinking watercress juice. Results: No statistically significant differences in the rates of isothiocyanate excretion and the time of peak excretion were observed between the two tested groups having positive and null genotypes. Conclusions: GSTT1 and M1 genotypes are not likely to be involved in the rate of excretion of ITCs in watercress. The demonstrated differences in protection among subjects with the two genotypes are not likely due to differences in overall ITC excretion rates, however, excretion rates of ITCs other than PEITC need to be investigated. Other yet to be identified mechanism(s) may underlie the diet and gene interactions between dietary ITCs and GST genotypes in human cancer prevention. Further research is needed to evaluate the protective mechanisms of isothiocyanates against cancer. [Copyright &y& Elsevier]

Abstract: Novel 5-aza-ellipticine derivatives were synthesized and tested as antitumor agents. The new compounds were prepared more readily than the analogous ellipticine derivatives, which are known to be potent anti-tumor agents Although the novel 5-aza-ellipticine derivatives are not as biologically active as their corresponding ellipticine analogues, the new compounds represent a new, readily accessible class of heteroaromatic catalytic inhibitors of topoisomerase II and possible anti-tumor agents. [Copyright &y& Elsevier]

Individual oncogenic KRAS mutants confer distinct differences in biochemical properties and signaling for reasons that are not well understood. KRAS activity is closely coupled to protein dynamics and is regulated through two interconverting conformations: state 1 (inactive, effector binding deficient) and state 2 (active, effector binding enabled). Here, we use 31P NMR to delineate the differences in state 1 and state 2 populations present in WT and common KRAS oncogenic mutants (G12C, G12D, G12V, G13D, and Q61L) bound to its natural substrate GTP or a commonly used nonhydrolyzable analog GppNHp (guanosine-5'-[(β,γ)-imido] triphosphate). Our results show that GppNHp-bound proteins exhibit significant state 1 population, whereas GTP-bound KRAS is primarily (90% or more) in state 2 conformation. This observation suggests that the predominance of state 1 shown here and in other studies is related to GppNHp and is most likely nonexistent in cells. We characterize the impact of this differential conformational equilibrium of oncogenic KRAS on RAF1 kinase effector RAS-binding domain and intrinsic hydrolysis. Through a KRAS G12C drug discovery, we have identified a novel small-molecule inhibitor, BBO-8956, which is effective against both GDP- and GTP-bound KRAS G12C. We show that binding of this inhibitor significantly perturbs state 1-state 2 equilibrium and induces an inactive state 1 conformation in GTP-bound KRAS G12C. In the presence of BBO-8956, RAF1-RAS-binding domain is unable to induce a signaling competent state 2 conformation within the ternary complex, demonstrating the mechanism of action for this novel and active-conformation inhibitor. [ABSTRACT FROM AUTHOR]

Previous studies showed that 7-(1′,2′-dihydroxyheptyl)-substituted etheno DNA adducts are products of reactions with the epoxide of (E)-4-hydroxy-2-nonenal, an oxidation product of ω-6 polyunsaturated fatty acids (PUFAs). In this work, we report the detection of 7-(1′,2′-dihydroxyheptyl)-1,N6-ethenodeoxyadenosine (DHHedA) in rodent and human tissues by two independent methods: a 32P-postlabeling/HPLC method and an isotope dilution liquid chromatography-electrospray ionization-tandem mass spectrometry method, demonstrating for the first time that DHHedA is a background DNA lesion in vivo. We showed that DHHedA can be formed upon incubation of arachidonic acid with deoxyadenosine, supporting the notion that ω-6 PUFAs are the endogenous source of DHHedA formation. Because cyclic adducts are derived from the oxidation of PUFAs, we subsequently examined the effects of antioxidants, α-lipoic acid, Polyphenon E, and vitamin E, on the formation of DHHedA and γ-hydroxy-1,N2-propanodeoxyguanosine (γ-OHPdG), a widely studied acrolein-derived adduct arising from oxidized PUFAs, in the livers of Long Evans Cinnamon (LEC) rats. LEC rats are afflicted with elevated lipid peroxidation and prone to the development of hepatocellular carcinomas. The results showed that although the survival of LEC rats was increased significantly by α-lipoic acid, none of the antioxidants inhibited the formation of DHHedA, and only Polyphenon E decreased the formation of γ-OHPdG. In contrast, vitamin E caused a significant increase in the formation of both γ-OHPdG and DHHedA in the livers of LEC rats. [ABSTRACT FROM AUTHOR]

Our previous studies revealed that the nonapeptide fragment of HLA-DR molecule, located in the β chain 164–172 with the VPRSGEVYT sequence, suppresses the immune responses. The sequence is located on the exposed molecule loop, therefore it may be involved in the interactions with other proteins. We suggested that the loop may serve as a functional epitope on the HLA class II surface for intermolecular binding, and that possible mechanism of biological action of the synthesized peptides is associated with interfering of adhesion of HLA class II molecules to their coreceptors. It has been postulated that oligomerization of the coreceptors is required for stable binding to class II HLA. Based on the crystal dimeric structure of HLA-DR molecules, we designed, and synthesized molecules able to induce the putative coreceptors dimerization. The synthesized series of compounds consisted of two VPRSGEVYT sequences linked through their C-termini by spacers of different length: (VPRSGEVYTGn)2K-NH2 (n=4–6). The results demonstrate that the dimerization of the nonapeptide fragment of HLA-DR results in enhanced immunosuppressory properties. [Copyright &y& Elsevier]

The acrolein derived cyclic 1,N 2 -propanodeoxyguanosine adduct (Acr-dG), formed primarily from ω-3 polyunsaturated fatty acids such as docosahexaenoic acid (DHA) under oxidative conditions, while proven to be mutagenic, is potentially involved in DHA-induced apoptosis. The latter may contribute to the chemopreventive effects of DHA. Previous studies have shown that the levels of Acr-dG are correlated with apoptosis induction in HT29 cells treated with DHA. Because Acr-dG is shown to be repaired by the nucleotide excision repair (NER) pathway, to further investigate the role of Acr-dG in apoptosis, in this study, NER-deficient XPA and its isogenic NER-proficient XAN1 cells were treated with DHA. The Acr-dG levels and apoptosis were sharply increased in XPA cells, but not in XAN1 cells when treated with 125 μM of DHA. Because DHA can induce formation of various DNA damage, to specifically investigate the role of Acr-dG in apoptosis induction, we treated XPA knockdown HCT116 + ch3 cells with acrolein. The levels of both Acr-dG and apoptosis induction increased significantly in the XPA knockdown cells. These results clearly demonstrate that NER deficiency induces higher levels of Acr-dG in cells treated with DHA or acrolein and sensitizes cells to undergo apoptosis in a correlative manner. Collectively, these results support that Acr-dG, a ubiquitously formed mutagenic oxidative DNA adduct, plays a role in DHA-induced apoptosis and suggest that it could serve as a biomarker for the cancer preventive effects of DHA. [ABSTRACT FROM AUTHOR]

Abstract: Hemiasterlin (Hem) and dolastatin (Dol) are marine natural products which are cytotoxic for cancer cells. Hem, a tripeptide, and Dol, a hexapeptide, were conjugated with linkers (L) to the universal BB agonist DPhe-Gln-Trp-Ala-Val-βAla-His-Phe-Nle-NH2(BA1) and the effects of the Hem-BB and Dol-BB conjugates investigated on NCI-H1299 lung cancer cells. Hem-LA-BA1 and Hem-LB-BA1 inhibited specific (125I-Tyr4)BB binding to NCI-H1299 cells, which have BB2 receptors (R), with IC50 values of 15 and 25 nM, respectively. Addition of Hem-LA-BA1 and Hem-LB-BA1 to Fura-2 AM loaded cells containing BB2R, caused elevated cytosolic Ca2+. In a growth assay, Hem-LA-BA1 and Hem-LB-BA1 inhibited the proliferation of NCI-H1299 cells. Dol-succinamide (Dols)-LD-BA1 and Dols-LE-BA1 bound with high affinity to NCI-H1299 cells and elevated cytosolic Ca2+, but did not inhibit the proliferation of NCI-H1299 cells. Also, Hem-LA-BA1 inhibited 125I-DTyr-Gln-Trp-Ala-Val-βAla-His-Phe-Nle-NH2 (BA2) binding to Balb/3T3 cells transfected with BB1R or BB2R as well as with BRS-3 with IC50 values of 130, 8, and 540 nM, respectively. These results show that Hem-BB conjugates are cytotoxic for cancer cells containing BB2R. [Copyright &y& Elsevier]

The interactions of proteins with reactive oxygen species (ROS) may result in covalent modifications of amino acid residues in proteins, formation of protein–protein cross-linkages, and oxidation of the protein backbone resulting in protein fragmentation. In an attempt to elucidate the products of the metal-catalyzed oxidation of the human (H) and mouse (M) (1–10H), (1–10M), (1–16H) and (1–16M) fragments of β-amyloid peptide, the high performance liquid chromatography (HPLC) and matrix-assisted laser desorption/ionization mass spectrometry (MALDI-TOF MS) methods and Cu(II)/H2O2 as a model oxidizing system were employed. Peptide solution (0.50 mM) was incubated at 37 °C for 24 h with metal:peptide:H2O2 molar ratio 1:1:1 for the (1–16H), (1–16M) fragments, and 1:1:2 for the (1–10H), (1–10M) peptides in phosphate buffer, pH 7.4. Oxidation targets for all peptide studied are the histidine residues coordinated to the metal ions. For the (1–16H) peptide are likely His13 and/or His14, and for the (1–16M) fragment His6 and/or His14, which are converted to 2-oxo-His. Metal-binding residue, the aspartic acid (D1) undergoes the oxidative decarboxylation and deamination to pyruvate. The cleavages of the peptide bonds by either the diamide or α-amidation pathways were also observed. [Copyright &y& Elsevier]