Accurate forecast of cancer subtypes is rather important in the malignancy diagnosis. Disease etiology is sophisticated, which manifests in diverse omics levels. Therefore, the elaborate fusion of multiple-level omics is very helpful to the analysis of cancer subtypes. In this paper, multiple-level omics data based cancer subtypes prediction is treated as a multi-view subspace clustering problem, where integrating the complemental information among multiple omics data to build up a unified representation is a pivotal challenge. Due to the fact that the great inconsistency lies among diverse omics levels, which leads to an unsatisfactory integrative effect via traditional multi-view clustering. To address this issue, different data on omics levels is fused under the spectral embedding domain, since even the high-inconsistency data across all omics level still have a rather analogous spectral block structure. Owning to the fact that the spectral block structure across all omics levels satisfies the great consistency, the data across all omics levels would be melted into a common representation with slight information damage. Apart from that, to enhance the global structure of subspace across all omics levels, an innovative low-rank relaxation is established by resorting to the the logarithmic determinant function. Finally, experimental outcome exhibits that the raised approach achieves superior behavior than existing prediction schemes.
A low-cost and eco-friendly system based on a manganese-based complex cathode and zinc anode was demonstrated. The cathode is able to reversibly (de-)insert Zn2+ ions, providing a high capacity of 248 mA h g-1 at 0.1 A g-1. Ex situ TEM and XRD were utilized to determine the electrochemical mechanism of this high capacity cathode. Moreover, the contribution of pre-added Mn2+ in electrolyte to the capacity was revealed, and nearly 18.9% of the capacity is ascribed to the contribution of pre-added Mn2+. With the help of additive, this aqueous rechargeable battery shows outstanding electrochemical property. Its cycling performance is good with 6% capacity loss after 2000 cycles at 4.0 A g-1, highlighting it as a promising system for aqueous rechargeable battery applications.
Chemoproteomic profiling of cysteines has emerged as a powerful method for screening the proteome-wide targets of cysteine-reactive fragments, drugs and natural products. Herein, we report the development and an in-depth evaluation of a tetrafluoroalkyl benziodoxole as a cysteine-selective chemoproteomic probe. We show that this probe features numerous key improvements compared to the traditionally used cysteine-reactive probes, including a superior target occupancy, faster labeling kinetics, and broader proteomic coverage thus enabling profiling of cysteines directly in live cells. Further, the fluorine ‘signature’ of probe 7 constitutes an additional advantage resulting in a more confident adduct-amino acid site assignment in mass spectrometry-based identification workflows. We demonstrate the utility of our new probe for proteome-wide target profiling by identifying the cellular targets of (-)-myrocin G, an antiproliferative fungal natural product with a to-date unknown mechanism of action. We show that this natural product and its simplified analog target the X-ray repair cross-complementing protein 5 (XRCC5), an ATP-dependent DNA helicase that primes DNA repair machinery for non-homologous end joining (NHEJ) upon DNA double strand breaks, making them the first reported inhibitors of this biomedically highly important protein. We further demonstrate that myrocins disrupt the interaction of XRCC5 with DNA leading to sensitization of cancer cells to the chemotherapeutic agent etoposide as well as UV-light induced DNA damage. Altogether, our next generation cysteine-reactive probe enables broader and deeper profiling of the cysteinome rendering it a highly effective tool for elucidation of targets of electrophilic small molecules.
An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
Loading hyaluronidase (Hyal) in a nanocarrier is a potent strategy to degrade the tumor extracellular matrix for tumor deep penetration and enhanced tumor therapy. Herein, a pH-sensitive biomimicking nanosystem with high Hyal loading, effective tumor targeting, and controllable release is constructed. Specifically, cationic mesoporous silica nanoparticles (CMSNs) with large pores 13.52 nm in diameter were synthesized in a one-pot manner by adding N-[3-trimethoxysilylpropyl]-N,N,N-trimethylammonium to a reversed microemulsion reaction system. The Hyal loading rate was as high as 19.47% owing to matched pore size and the cationic surface charge. Subsequently, a pH-sensitive biomimetic hybrid membrane (pHH) composed of pH-sensitive liposome (pHL), red blood cell membrane, and pancreatic cancer cell membrane was camouflaged on the pHL-coated and doxorubicin/Hyal-loaded CMSNs (shortened as DHCM). The DHCM@pHL@pHH is stable at neutral pH while it releases the payloads smoothly in the tumor acidic microenvironment. Consequently, it can escape from macrophage clearance, be specifically taken up by pancreatic cancer cells, and efficiently accumulate at the tumor site. More importantly, it can penetrate deeply in pancreatic tumors with a tumor growth inhibition ratio of 80.46%. The nanosystem is biocompatible and has potential for clinical transformation, and the nanocarrier is promisingly applicable as a platform for encapsulation of various macromolecules for smart and tumor-targeted delivery.
The intake of certain nutrients, including ferric ion, is facilitated by the outer membrane-localized transporters. Due to ferric insolubility at physiological pH, Escherichia coli secretes a chelator, enterobactin, outside the cell and then transports back the enterobactin-ferric complex via an outer membrane receptor protein, FepA, whose activity is dependent on the proton motive force energy transduced by the TonB-ExbBD complex of the inner membrane. Consequently, ΔtonB mutant cells grow poorly on a medium low in iron. Prolonged incubation of ΔtonB cells on low-iron medium yields faster-growing colonies that acquired suppressor mutations in the yejM (pbgA) gene, which codes for a putative inner-to-outer membrane cardiolipin transporter. Further characterization of suppressors revealed that they display hypersusceptibility to vancomycin, a large hydrophilic antibiotic normally precluded from entering E. coli cells, and leak periplasmic proteins into the culture supernatant, indicating a compromised outer membrane permeability barrier. All phenotypes were reversed by supplying the wild-type copy of yejM on a plasmid, suggesting that yejM mutations are solely responsible for the observed phenotypes. The deletion of all known cardiolipin synthase genes (clsABC) did not produce the phenotypes similar to mutations in the yejM gene, suggesting that the absence of cardiolipin from the outer membrane per se is not responsible for increased outer membrane permeability. Elevated lysophosphatidylethanolamine levels and the synthetic growth phenotype without pldA indicated that defective lipid homeostasis in the yejM mutant compromises outer membrane lipid asymmetry and permeability barrier to allow enterobactin intake, and that YejM has additional roles other than transporting cardiolipin.IMPORTANCE The work presented here describes a positive genetic selection strategy for isolating mutations that destabilize the outer membrane permeability barrier of E. coli Given the importance of the outer membrane in restricting the entry of antibiotics, characterization of the genes and their products that affect outer membrane integrity will enhance the understanding of bacterial membranes and the development of strategies to bypass the outer membrane barrier for improved drug efficacy.
The nanostructured Er2O3 thin films implanted by Helium (He) were prepared by magnetron sputtering under different He partial pressure. The creep properties of the Er2O3 films under different temperatures ranging from ambient temperature to 450 °C were investigated systematically by nanoindentation measurements. The morphology and microstructure of the films were determined by a scanning electron microscope (SEM) and an X-ray diffractometer (XRD), respectively. The effects of He on the creep properties of the Er2O3 film were discussed by using a slope (dε˙/dσ) of the creep rate stress curve at the steady-state creep stage. The results show that the crystallinity of the films became weak with the He partial pressure. Furthermore, the implanting He has a strong impact on the creep resistance of the Er2O3 thin films.
As a vital micronutrient, zinc is integral to the structure, function, and signaling networks of diverse proteins. Dysregulated zinc levels, due to either excess intake or deficiency, are associated with a spectrum of health disorders. In this context, understanding zinc-regulated biological processes at the molecular level holds significant relevance to public health and clinical practice. Identifying and characterizing zinc-regulated proteins in their diverse proteoforms, however, remain a difficult task in advancing zinc biology. Herein, we address this challenge by developing a quantitative chemical proteomics platform that globally profiles the reactivities of proteinaceous cysteines upon cellular zinc depletion. Exploiting a protein-conjugated resin for the selective removal of Zn2+ from culture media, we identify an array of zinc-sensitive cysteines on proteins with diverse functions based on their increased reactivity upon zinc depletion. Notably, we find that zinc regulates the enzymatic activities, post-translational modifications, and subcellular distributions of selected target proteins such as peroxiredoxin 6 (PRDX6), platelet-activating factor acetylhydrolase IB subunit alpha1 (PAFAH1B3), and phosphoglycerate kinase (PGK1).
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