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To target the pivotal BCR/ABL oncoprotein in chronic myeloid leukemia (CML) cells, tyrosine kinase inhibitors (TKIs) are utilized as landmark achievements in CML therapy. However, TKI resistance and intolerance remain principal obstacles in the treatment of CML patients. In recent years, drug repositioning provided alternative and promising perspectives apart from the classical cancer therapies, and promoted anthelmintic mebendazole (MBZ) as an effective anti-cancer drug in various cancers. Here, we investigated the role of MBZ in CML treatment including imatinib-resistant CML cells. Our results proved that MBZ inhibited the proliferation and induced apoptosis in CML cells. We found that MBZ effectively suppressed BCR/ABL kinase activity and MEK/ERK signaling pathway by reducing p-BCR/ABL and p-ERK levels with ABL1 targeting ability. Meanwhile, MBZ directly targeted the colchicine-binding site of β-tubulin protein, hampered microtubule polymerization and induced mitosis arrest and mitotic catastrophe. In addition, MBZ increased DNA damage levels and hampered the accumulation of ataxia-telangiectasia mutated and DNA-dependent protein kinase into the nucleus. This work discovered that anthelmintic MBZ exerts remarkable anticancer effects in both imatinib-sensitive and imatinib-resistant CML cells in vitro and revealed mechanisms underlying. From the perspective of drug repositioning and multi-target therapeutic strategy, this study provides a promising option for CML treatment, especially in TKI-resistant or intolerant individuals. [ABSTRACT FROM AUTHOR]

Objective: DNA damage response (DDR) deficiency has emerged as a prominent determinant of tumor immunogenicity. This study aimed to construct a DDR-related immune activation (DRIA) signature and evaluate the predictive accuracy of the DRIA signature for response to immune checkpoint inhibitor (ICI) therapy in gastrointestinal (GI) cancer. Methods: A DRIA signature was established based on two previously reported DNA damage immune response assays. Clinical and gene expression data from two published GI cancer cohorts were used to assess and validate the association between the DRIA score and response to ICI therapy. The predictive accuracy of the DRIA score was validated based on one ICI-treated melanoma and three pan-cancer published cohorts. Results: The DRIA signature includes three genes (CXCL10, IDO1, and IFI44L). In the discovery cancer cohort, DRIA-high patients with gastric cancer achieved a higher response rate to ICI therapy than DRIA-low patients (81.8% vs. 8.8%; P < 0.001), and the predictive accuracy of the DRIA score [area under the receiver operating characteristic curve (AUC) = 0.845] was superior to the predictive accuracy of PD-L1 expression, tumor mutational burden, microsatellite instability, and Epstein–Barr virus status. The validation cohort demonstrated that the DRIA score identified responders with microsatellite-stable colorectal and pancreatic adenocarcinoma who received dual PD-1 and CTLA-4 blockade with radiation therapy. Furthermore, the predictive performance of the DRIA score was shown to be robust through an extended validation in melanoma, urothelial cancer, and pan-cancer. Conclusions: The DRIA signature has superior and robust predictive accuracy for the efficacy of ICI therapy in GI cancer and pancancer, indicating that the DRIA signature may serve as a powerful biomarker for guiding ICI therapy decisions [ABSTRACT FROM AUTHOR]

Metal detoxification is essential for bacteria's survival in adverse environments and their pathogenesis in hosts. Understanding the underlying mechanisms is crucial for devising antibacterial treatments. In the Gram-negative bacterium Escherichia coli, membrane-bound sensor CusS and its response regulator CusR together regulate the transcription of the cus operon that plays important roles in cells' resistance to copper/silver, and they belong to the two-component systems (TCSs) that are ubiquitous across various organisms and regulate diverse cellular functions. In vitro protein reconstitution and associated biochemical/physical studies have provided significant insights into the functions and mechanisms of CusS-CusR and related TCSs. Such studies are challenging regarding multidomain membrane proteins like CusS and also lack the physiological environment, particularly the native spatial context of proteins inside a cell. Here, we use stroboscopic single-molecule imaging and tracking to probe the dynamic behaviors of both CusS and CusR in live cells, in combination with protein- or residue-specific genetic manipulations. We find that copper stress leads to a cellular protein concentration increase and a concurrent mobilization of CusS out of clustered states in the membrane. We show that the mobilized CusS has significant interactions with CusR for signal transduction and that CusS's affinity toward CusR switches on upon sensing copper at the interfacial metal-binding sites in CusS's periplasmic sensor domains, prior to ATP binding and autophosphorylation at CusS's cytoplasmic kinase domain(s). The observed CusS mobilization upon stimulation and its surprisingly early interaction with CusR likely ensure an efficient signal transduction by providing proper conformation and avoiding futile cross talks. [ABSTRACT FROM AUTHOR]

Dynamic characteristics of electroosmosis of a typical non-Newtonian liquid in a rectangular microchannel are investigated by using numerical simulations. The non-Newtonian behavior of liquids is assumed to obey the famous power-law model and then the mathematical model is solved numerically by using the finite element method. The results indicate that the non-Newtonian effect produces some noticeable dynamic responses in electroosmotic flow. Under a direct current (DC) driving electric field, it is found that the fluid responds more inertly to an external electric field and the steady-state velocity profile becomes more plug-like as the flow behavior index decreases. Under an alternating current (AC) driving electric field, the fluid is observed to experience more significant acceleration and the amplitude of oscillating velocity becomes larger as the fluid behavior index decreases. Furthermore, our investigation also shows that electroosmotic flow of power-law fluids under an AC/DC combined driving field is enhanced as compared with that under a pure DC electric field. These dynamic predictions are of practical use for the design of electroosmotically-driven microfluidic devices that analyze and process non-Newtonian fluids such as biofluids and polymeric solutions. [ABSTRACT FROM AUTHOR]

Corrosion of reinforced concrete structures has become a major problem worldwide, leading to very high repair costs. A dearth of studies has focused on the corrosion damage evolution of reinforced concrete. In this paper, the ultrasonic guided wave (UGW) technique is adopted to monitor the reinforced concrete corrosion damage evolution process. The properties of different guide wave modes were studied by steel rebar dispersion curves of UGWs through numerical calculation. The availability and validity of the UGW testing-reinforced concrete corrosion damage is proved by corrosion experiment. The experiment shows that the first wave peak value could describe the whole process of steel rebar corrosion. As the corrosion damage level increases, the relative variation for the first UGW peak value increases first and then decreases. [ABSTRACT FROM AUTHOR]

Human quiescin-sulfhydryl oxidase 1 isoform b (HsQSOX1b) is a highly efficient, multiple-domain enzyme that directly inserts disulfide bonds into client protein. However, previous studies have focused mainly on the catalytic activity of the whole protein rather than its domain structure. In this research, we dissected the structure and function of HsQSOX1b and explored its mechanism as a highly efficient sulfhydryl oxidase by analyzing the truncated variants. The results showed that the first HsQSOX1b thioredoxin domain was essential for thiol oxidase activity. The smallest active fragment (SAQ) was identified to consist of a helix-rich region (HRR) and an essential for respiration and viability/augmenter of liver regeneration (ERV/ALR) domain, which remained highly active to oxidize an artificial non-thiol substrate but not small molecular and protein thiols. Our study clearly demonstrated that SAQ is a highly efficient oxidative engine, which shows high efficiency in the de novo disulfide formation and oxygen reduction and that this more efficient oxidative engine is necessary for the highly efficient catalysis of QSOXs compared to Erv1 and Erv2. This study will help address the roles of different HsQSOX1b domains in de novo disulfide formation and encourage the engineering of more efficient QSOX variants for the in vitro folding of disulfide-containing proteins. [ABSTRACT FROM AUTHOR]

Chiroptical switches have found application in the detection of a multitude of different analytes with a high level of sensitivity and in asymmetric catalysis to offer switchable stereoselectivity. A wide range of scaffolds have been employed that respond to metals, small molecules, anions and other analytes. Not only have chiroptical systems been used to detect the presence of analytes, but also other properties such as oxidation state and other physical phenomena that influence helicity and conformation of molecules and materials. Moreover, the tunable responses of many such chiroptical switches enable them to be used in the controlled production of either enantiomer or diastereomer at will in many important organic reactions from a single chiral catalyst through selective use of a low-cost inducer: Co-catalysts (guests), metal ions, counter ions or anions, redox agents or electrochemical potential, solvents, mechanical forces, temperature or electromagnetic radiation. [ABSTRACT FROM AUTHOR]

Among all sulphhydryl oxidases involved in disulphide formation, quiescin-sulphhydryl oxidase (QSOX) is unique for its multidomain structure, protein thiol oxidation activity and highly efficient catalysis. In this study, site-directed mutagenesis and molecular modelling methods were integrated to investigate the structural and functional characteristics of QSOX, especially the importance of the three CXXC motifs. Site-directed mutagenesis suggested that the C449–C452 motif was essential for the activity of human QSOX 1b; the C70–C73 motif was fundamental in electron transfer from thiol-containing substrate including reduced proteins, DTT, GSH rather than the phosphine-based thiol reductant TCEP, to the C449–C452 motif; and the C509–C512 motif was not involved in electron transfer during disulphide formation. The different roles of the CXXC motifs indicated that there were discrepant electron transfer pathways for the oxidation of thiol-containing substrates and non-thiol disulphide reductants. Molecular modelling method was then used to draw a reasonable picture for the electron transfer process and to elucidate the mechanism of electron transfer when different substrates were oxidized, which will greatly enhance our understanding of the action mechanism of QSOX. [ABSTRACT FROM PUBLISHER]