The efficient delivery of biopharmaceutical drugs such as proteins and peptides into the cytosol of target cells poses substantial challenges owing to their large size and susceptibility to degradation. Current protein delivery vehicles have limitations such as the need for protein modification, insufficient delivery of large-size proteins or small peptides, and loss of protein function after the delivery. Here, we adopted a rational approach to design a polymer with robust efficacy for intracellular protein and peptide delivery. The polymer is composed of a dendrimer scaffold, a hydrophobic membrane-disruptive region, and a multivalent protein binding surface. It allows efficient protein/peptide binding, endocytosis, and endosomal disruption and is capable of efficiently delivering various biomacromolecules including bovine serum albumin, R-phycoerythrin, p53, saporin, β-galactosidase, and peptides into the cytosol of living cells. Transduction of apoptotic proteins and peptides successfully induces apoptosis in cancer cells, suggesting that the activities of proteins and peptides are maintained during the delivery. This technology represents an efficient and useful tool for intracellular protein and peptide delivery and has broad applicability for basic research and clinical applications.
Hydrogels have exhibited remarkable benefits in drug delivery such as local delivery, days or even weeks of continuous drug release with improved bioavailability, and minimized adverse effects.Here we report a polydopamine (PDA) nanoparticle-knotted poly(ethylene glycol) (PEG) hydrogel for on-demand drug delivery and combined chemo-photothermal therapy. Anticancer drugs such as 7-ethyl-10-hydroxycamptothecin (SN38) loaded on PDA nanoparticles via π−π interaction in the gel exhibit minimal leakage at physiological conditions and could be released in an on-demand fashion upon near-infrared light exposure. The hydrogel shows excellent biocompatibility and does not induce any foreign-body reaction over a four-month implantation. The in vivo results demonstrate that the PDA nanoparticle-knotted PEG hydrogel loaded with SN38 could efficiently suppress tumor growth by a combined chemo-photothermal therapy. This smart hydrogel would benefit a series of local treatments for diverse diseases.
Android platform has dominated the markets of smart mobile devices in recent years. The number of Android applications (apps) has seen a massive surge. Unsurprisingly, Android platform has also become the primary target of attackers. The management of the explosively expansive app markets has thus become an important issue. On the one hand, it requires effectively detecting malicious applications (malapps) in order to keep the malapps out of the app market. On the other hand, it needs to automatically categorize a big number of benign apps so as to ease the management, such as correcting an app's category falsely designated by the app developer. In this work, we propose a framework to effectively and efficiently manage a big app market in terms of detecting malapps and categorizing benign apps. We extract 11 types of static features from each app to characterize the behaviors of the app, and employ the ensemble of multiple classifiers, namely, Support Vector Machine (SVM), K-Nearest Neighbor (K-NN), Naive Bayes (NB), Classification and Regression Tree (CART) and Random Forest (RF), to detect malapps and to categorize benign apps. An alarm will be triggered if an app is identified as malicious. Otherwise, the benign app will be identified as a specific category. We evaluate the framework on a large app set consisting of 107,327 benign apps as well as 8,701 malapps. The experimental results show that our method achieves the accuracy of 99.39% in the detection of malapps and achieves the best accuracy of 82.93% in the categorization of benign apps.
Here, we report the molecular self-assembly of hydroxidobridged {Ln 5 Ni 6 } ((Ln 3+ = Dy 3+ , Y 3+ ) metal clusters by the reaction of enantiopure chiral ligands, namely, (R/S)-(2-hydroxy-3-methoxybenzyl)serine), with Ni II and Ln III precursors. Single-crystal diffraction analysis reveals that these compounds are isostructural sandwich-like 3d−4f heterometallic clusters showing helical chirality. Direct current magnetic measurements on {Dy 5 Ni 6 } indicates ferromagnetic coupling between Dy III and Ni II centers, whereas those on {Y 5 Ni 6 } denote that the Ni II centers are antiferromagnetically coupled and/or magnetically anisotropic. Magnetochiral dichroism (MChD) measurements on {Dy 5 Ni 6 } and its comparison to that of {Y 5 Ni 6 } provide the first experimental observation of intense multimetal site MChD signals in the visible−near-infrared region. Moreover, the comparison of MChD with natural and magnetic circular dichroism spectra unambiguously demonstrate for the first time that the MChD signals associated with the Ni II d−d transitions are mostly driven by natural optical activity and those associated with the Dy III f−f transitions are driven by magnetic optical activity.
Cocrystallization of different metal nanoclusters facilitates the preparation of cluster-based nanomaterials with enhanced properties. Herein, two pairs of enantiomeric 3d-4f cocrystallization structures of clusters R/S-[Mn 10 Ln 6 ] and R/S-[Mn 6 Ln 2 ] (Ln = Dy for 1R and 1S, Y for 2R and 2S) have been reported. Compounds R/S-[Mn 10 Ln 6 ][Mn 6 Ln 2 ] exhibit a large optical activity and magneto-optic effect as verified by natural circular dichroism (NCD) and magnetic circular dichroism (MCD). In addition, alternating current (ac) magnetic measurements show that the chiral R/S-[Mn 10 Dy 6 ][Mn 6 Dy 2 ] cocrystallization structure displays slow magnetic relaxation with U eff = 25.1 K.
Cigarette smoke (CS) exposure increases the risk for acute respiratory distress syndrome in humans and promotes alveolar-capillary barrier permeability and acute lung injury in animal models. However, the underlying mechanisms are not well understood. Mitochondrial fusion and fission are essential for mitochondrial homeostasis in health and disease. In this study, we hypothesized that CS caused endothelial injury via an imbalance of mitochondrial fusion and fission and resultant mitochondrial oxidative stress and dysfunction. We noted that CS altered mitochondrial morphology by shortening mitochondrial networks and causing perinuclear accumulation of damaged mitochondria in primary rat lung microvascular endothelial cells. We also found that CS increased mitochondrial fission likely by decreasing Drp1-S637 and increasing FIS1, Drp1-S616 phosphorylation, mitochondrial translocation, and tetramerization and reduced mitochondrial fusion likely by decreasing Mfn2 in lung microvascular endothelial cells and mouse lungs. CS also caused aberrant mitophagy, increased mitochondrial oxidative stress, and reduced mitochondrial respiration. An inhibitor of mitochondrial fission and a mitochondria-specific antioxidant prevented CS-induced increased endothelial barrier dysfunction and apoptosis. Our data suggest that excessive mitochondrial fission and resultant oxidative stress are essential mediators of CS-induced endothelial injury and that inhibition of mitochondrial fission and mitochondria-specific antioxidants may be useful therapeutic strategies for CS-induced endothelial injury and associated pulmonary diseases.
Coronavirus disease 2019 (COVID-19) has gained prominence as a global pandemic. Studies have suggested that systemic alterations persist in a considerable proportion of COVID-19 patients after hospital discharge. We used proteomic and metabolomic approaches to analyze plasma samples obtained from 30 healthy subjects and 54 COVID-19 survivors 6 months after discharge from the hospital, including 30 non-severe and 24 severe patients. Through this analysis, we identified 1019 proteins and 1091 metabolites. The differentially expressed proteins and metabolites were then subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. Among the patients evaluated, 41% of COVID-19 survivors reported at least one clinical symptom and 26.5% showed lung imaging abnormalities at 6 months after discharge. Plasma proteomics and metabolomics analysis showed that COVID-19 survivors differed from healthy control subjects in terms of the extracellular matrix, immune response, and hemostasis pathways. COVID-19 survivors also exhibited abnormal lipid metabolism, disordered immune response, and changes in pulmonary fibrosis-related proteins. COVID-19 survivors show persistent proteomic and metabolomic abnormalities 6 months after discharge from the hospital. Hence, the recovery period for COVID-19 survivors may be longer.
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