A hyper-branched sulfonated polyimide (
-PI) was synthesized successfully and composited with polyvinylidene fluoride (PVDF) to achieve ultra-high methanol-permeation resistive for direct methanol ...fuel cell application. The optimized
-PI-PVDF composite membrane exhibited methanol resistivity low to 1.80 × 10
cm²/s, two orders of magnitude lower than the value of the commercial Nafion 117 membrane (60 × 10
cm²/s). At the same time, the tensile strength of the composite membrane is 22 MPa, which is comparable to the value of the Nafion 117 membrane. Therefore, the composite membrane is promising for application in direct methanol fuel cell.
Lattice Strain Defects in a Ceria Nanolayer Ma, Liying; Doudin, Nassar; Surnev, Svetlozar ...
The journal of physical chemistry letters,
04/2016, Letnik:
7, Številka:
7
Journal Article
Recenzirano
Odprti dostop
An ultrathin two-dimensional CeO2 (ceria) phase on a Cu(110) surface has been fabricated and fully characterized by high-resolution scanning tunneling microscopy, photoelectron spectroscopy, and ...density functional theory. The atomic lattice structure of the ceria/Cu(110) system is revealed as a hexagonal CeO2(111)-type monolayer separated from the Cu(110) surface by a partly disordered Cu–O intercalated buffer layer. The epitaxial coupling of the two-dimensional ceria overlayer to the Cu(110)-O surface leads to a nanoscopic stripe pattern, which creates defect regions of quasi-periodic lattice distortions. The symmetry and lattice mismatch at the interface is clarified to be responsible for the topographic stripe geometry and the related anisotropic strain defect regions at the ceria surface. This ceria monolayer is in a fully oxidized and thermodynamically stable state.
Bromodomain containing protein 4 (BRD4), as an epigenetic reader, can specifically bind to the acetyl lysine residues of histones and has emerged as an attractive therapeutic target for various ...diseases, including cancer, cardiac remodeling and heart failure. Herein, we described the discovery of hit 5 bearing 4-phenylquinazoline skeleton through a high-throughput virtual screen using 2,003,400 compound library (enamine). Then, structure–activity relationship (SAR) study was performed and 47 new 4-phenylquinazoline derivatives toward BRD4 were further designed, synthesized and evaluated, using HTRF assay set up in our lab. Eventually, we identified compound C-34, which possessed better pharmacokinetic and physicochemical properties as well as lower cytotoxicity against NRCF and NRCM cells, compared to the positive control JQ1. Using computer-based molecular docking and cellular thermal shift assay, we further verified that C-34 could target BRD4 at molecular and cellular levels. Furthermore, treatment with C-34 effectively alleviated fibroblast activation in vitro and cardiac fibrosis in vivo, which was correlated with the decreased expression of BRD4 downstream target c-MYC as well as the depressed TGF-β1/Smad2/3 signaling pathway. Taken together, our findings indicate that novel BRD4 inhibitor C-34 tethering a 4-phenylquinazoline scaffold can serve as a lead compound for further development to treat fibrotic cardiovascular disease.
In current work, we performed high-throughput virtual screen and structure-based optimization targeting BRD4, leading to 47 new 4-phenylquinazoline derivatives with potent inhibitory activity toward BRD4. The representative compound C-34 shows favorable pharmacokinetic and physicochemical properties as well as low toxicity in vivo. Also, C-34 effectively reduced pathological cardiac fibrosis. Display omitted
Poly (ADP-ribose) polymerase 1 (PARP1) is highly expressed in small cell lung cancer (SCLC) and has emerged as an attractive target for treatment of SCLC. However, the clinical significance of PARP1 ...expression in SCLC remains elusive. In this study, we showed that high PARP1 expression was associated with better overall survival (OS), and was positively correlated with the expression of
paralogs in patients with SCLC. We demonstrated that
was transcriptionally regulated by
paralogs. Integrative analysis of multiple RNA-seq data sets indicated that DNA damage response (DDR) genes involved in the replication stress response (RSR) and homologous recombination (HR) repair pathways were highly enriched in
paralog-addicted SCLC cell models and in human SCLC specimens. Targeting the
paralog-PARP1 axis with concomitant BET and PARP inhibition resulted in synergistic effects in
paralog-activated SCLC. Our study identified a critical PARP1 regulatory pathway, and provided evidence for a rational combination treatment strategy for
paralog-activated SCLC.
•This study investigated the dynamics of HIV-1 diversity in participants on long-term antiretroviral therapy.•Approximately 65% of HIV mutations co-occurred in plasma HIV RNA and cellular DNA.•The ...number and frequency of intrahost single-nucleotide variations are more representative of intrahost HIV diversity.•The evolutionary rate was 0.02 mutations/day/kb in participants in whom treatment failed.
Human immunodeficiency virus (HIV) quasispecies diversity presents a large barrier to the eradication of HIV. The aim of this study was to investigate intrahost HIV quasispecies diversity and evolutionary patterns underpinning the mechanisms of viral pathogenesis during antiretroviral therapy (ART).
Forty-five participants with HIV-1 infection were enrolled in a follow-up cohort for >84 months in 2004, and received a lamivudine-based first-line ART regimen. Blood samples were collected every 6 months to measure viral load and CD4+ cell count. Ultra-deep sequencing and phylogenetic analysis were used to characterize the dynamics governing quasispecies diversity of HIV-1 circulating between plasma RNA and cellular DNA of participants with treatment failure (TF, n = 20) or virologic suppression (VS, n = 25).
Analysis of the distribution of intrahost single-nucleotide variations (iSNVs) and their mutated allele frequencies revealed that approximately 65% of the quasispecies co-occurred in plasma HIV RNA and cellular DNA either before or after ART. The number and frequency of iSNVs are more representative of intrahost HIV diversity, and have better generalizability than phylogenetic inference by measurement of phylogenetic associations. Furthermore, drug-resistance-associated mutations (DRAMs) accumulated to high levels, dramatically increasing the DRAM-to-total-mutation ratio for TF patients. Linear regression analysis revealed that emergent mutations accumulated faster in TF patients compared with VS patients, at a rate of 0.02 mutations/day/kb.
Based on iSNV analysis, the results demonstrate the dynamics of intrahost HIV quasispecies diversity in patients on ART, and provide a novel insight into the persistence of HIV and development of DRAMs.
The mitochondria act as the main producers of reactive oxygen species (ROS) within cells. Elevated levels of ROS can activate the mitochondrial apoptotic pathway, leading to cell apoptosis. In this ...study, we devised a molecular prodrug named CTT 2 P, demonstrating notable efficacy in facilitating mitochondrial apoptosis. To develop nanomedicine, we enveloped CTT 2 P within bovine serum albumin (BSA), resulting in the formulation known as CTT 2 P@B. The molecular prodrug CTT 2 P is achieved by covalently conjugating mitochondrial targeting triphenylphosphine (PPh 3 ), photosensitizer TPPOH 2 , ROS-sensitive thioketal (TK), and chemotherapeutic drug camptothecin (CPT). The prodrug, which is chemically bonded, prevents the escape of drugs while they circulate throughout the body, guaranteeing the coordinated dispersion of both medications inside the organism. Additionally, the concurrent integration of targeted photodynamic therapy and cascade chemotherapy synergistically enhances the therapeutic efficacy of pharmaceutical agents. Experimental results indicated that the covalently attached prodrug significantly mitigated CPT cytotoxicity under dark conditions. In contrast, TPPOH 2 , CTT 2 , CTT 2 P, and CTT 2 P@B nanoparticles exhibited increasing tumor cell-killing effects and suppressed tumor growth when exposed to light at 660 nm with an intensity of 280 mW cm −2 . Consequently, this laser-triggered, mitochondria-targeted, combined photodynamic therapy and chemotherapy nano drug delivery system, adept at efficiently promoting mitochondrial apoptosis, presents a promising and innovative approach to cancer treatment.
Bispecific killer cells engagers (BiKEs) which can bind to natural killer (NK) cells through the activating receptor CD16A and guide them to cells expressing the HIV-1 envelope glycoprotein (Env) are ...a promising new weapon for elimination of infected cells and eradication of the virus. Here we report the design, generation and characterization of BiKEs which consist of CD16A binding human antibody domains fused through a flexible linker to an engineered one-domain soluble human CD4. In presence of cells expressing HIV-1 envelope glycoproteins (Envs), these BiKEs activated specifically CD16A-expressing Jurkat T cells, degranulated NK cells, induced cytokine production and killed Env-expressing cells. They also effectively mediated killing of chronically and acutely HIV-1 infected T cells by human peripheral blood mononuclear cells. The presumed ability of these CD4-based BiKEs to bind all HIV-1 isolates, their small size and fully human origin, combined with high efficacy suggest their potential for HIV-1 eradication.
Exploring the characteristics of the HIV-1 envelope glycoprotein (
) gene in a natural HIV-1 infected individual, with broadly neutralizing activity, may provide insight into the generation of such ...broadly neutralizing antibodies and initiate the design of an appropriate immunogen. Recently, a chronically HIV-1 infected patient with broadly neutralization activity was identified and a VRC01-class neutralizing antibody DRVIA7 (A7) was isolated from the patient. In the present study, 155 full length HIV-1
gene fragments (including 68 functionally Env clones) were amplified longitudinally from the plasma of six time points spanning over 5 years in this donor. Viral features were analyzed by comparing Env clones of different time points, as well as 165 Chinese HIV-1 subtype B
sequences from HIV Sequence Database (Chinese B_database). Shorter V1 length, less potential glycan and a lower ratio of NXT: NXS in gp160 were observed in the first five time points compared to that from the last time points, as well that from the Chinese B_database. A sequence analysis and a neutralization assay of Env-pseudoviruses showed that the increasing diversity of
sequences in the patient was consistent with the appearance and maturation of A7 lineage antibodies. The potent neutralization activity and viruses that escaped from the neutralization of the concurrent autologous plasma, are consistent with higher residue variations at the antibody recognition sites. Almost all viruses from the plasmas were neutralization-resistant to VRC01 and A7 lineage antibodies. For a chronically HIV-1 infected individual over 10 years, we found that greater viral diversity, short V1 sequences and less potential N-linked glycosylation (PNGS) in V1, might be associated with the development of broadly neutralizing antibody responses.
Developing cheap and earth-abundant electrocatalysts with high activity and stability for oxygen reduction reactions (ORRs) is highly desired for the commercial implementation of fuel cells and ...metal-air batteries. Tremendous efforts have been made on doped-graphene catalysts. However, the progress of phosphorus-doped graphene (P-graphene) for ORRs has rarely been summarized until now. This review focuses on the recent development of P-graphene-based materials, including the various synthesis methods, ORR performance, and ORR mechanism. The applications of single phosphorus atom-doped graphene, phosphorus, nitrogen-codoped graphene (P, N-graphene), as well as phosphorus, multi-atoms codoped graphene (P, X-graphene) as catalysts, supporting materials, and coating materials for ORR are discussed thoroughly. Additionally, the current issues and perspectives for the development of P-graphene materials are proposed.
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