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In cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) the vascular smooth muscle cells are destroyed and granular osmiophilic material is deposited followed by fibrosis of the arterial wall. To verify whether true stenosis of the fibrotic white matter arteries is a key pathogenic event in CADASIL, we analyzed the thickness of walls (expressed as sclerotic index) and luminal diameters of penetrating arterioles in both grey matter and white matter of four CADASIL patients due to the C475T (R133C) mutation in the Notch3 gene and in 9 age-matched controls. We also reconstructed 9 arterioles from 1000 serial sections in two CADASIL patients. The thickness of the arteriolar walls in both grey matter and white matter was significantly increased in the CADASIL patients compared with controls. Furthermore, in CADASIL patients the arteriolar walls were significantly thicker in the white matter than in the grey matter. The distribution curve of arteriolar internal diameters in CADASIL patients shifted towards smaller sizes. In serial sections, the marked increase in the thickness of the white matter penetrating arterioles or their branches did not occur until the internal diameters had decreased to about 20 to 30 pm and external diameters to about 100 to 130 microm. In conclusion, long penetrating arterioles and their branches supplying subcortical structures in CADASIL are stenosed and their walls are thickened. This conforms to the abundance of infarcts and primary ischemic damage in CADASIL patients' white matter.

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An original gadolinium-hybridized plasmonic gold nanocomposite is fabricated to provide an insightful and attractive strategy to overcome both the physiological and pathological barriers of tumor, and increase the transportation and permeability of imaging agents and drugs in tumor interior for achieving high-sensitive multimodal imaging and simultaneously improving the therapeutic efficacy of cancer.

When a nanomedicine is administrated into the human body, biomolecules in biological fluids, particularly proteins, form a layer on the surface of the nanoparticle known as a "personalized protein corona". An understanding of the formation and behavior of the personalized protein corona not only benefits the nanotherapy treatment efficacy but also can aid in disease diagnosis. Here we used Gd@ C 82 (OH) 22 nanoparticles, a nanomedicine effective against several types of cancer, as a model nanomedicine to investigate the natural protein fingerprint of the personalized protein corona formed in 10 human lung squamous cell carcinoma patients. Our analysis revealed a specific biomarker, complement component C1q, in lung cancer personalized protein coronas, abundantly bound to Gd@C 82 (OH) 22 NPs. This binding altered the secondary structure of C1q protein and led to the activation of an innate immune response, which could be exploited for cancer immune therapy. On the basis of this finding, we provide a new strategy for the development of precision nanomedicine derived from opsonization of a unique protein fingerprint within patients. This approach overcomes the common pitfall of protein corona formation and exploits the corona proteins to generate a precision nanomedicine and diagnostic tool.

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The nanoparticle (nano)−cell membrane interface is one of the most important interactions determining the fate of nanoparticles (NPs), which can stimulate a series of biological events, allowing theranostic and other biomedical applications. So far, there remains a lack of knowledge about the mechanisms governing the nanoparticle−cell membrane interface, especially the impact of ligand exchange, in which molecules on the nanosurface become replaced with components of the cell membrane, resulting in unique interfacial phenomena. Herein, we describe a family of gold nanoparticles (AuNPs) of the same core size (∼13 nm core), modified with 12 different kinds of surface ligands, and the effects of their exchangeable ligands on both nanoparticle−supported lipid bilayers (SLBs) and nanoparticle−natural cell membrane interfaces. The ligands are categorized according to their molecular weight, charge, and bonding modes (physisorption or chemisorption). Importantly, we found that, depending on the adsorption affinity and size of ligand molecules, physisorbed ligands on the surface of NPs can be exchanged with lipid molecules. At a ligand exchange-dominated interface, the AuNPs typically aggregated into an ordered monolayer in the lipid bilayers, subsequently affecting cell membrane integrity, NP uptake efficiency, and the NP endocytosis pathways. These findings advance our understanding of the underlying mechanisms of the biological effects of nanoparticles from a new point of view and will aid in the design of novel, safe, and effective nanomaterials for biomedicine.

Bone mesenchymal stem cells (BMSCs) have multiple potentials to differentiate into osteoblasts and adipocytes, and methods to enhance their osteogenic differentiation are gaining increasing attention. MicroRNAs are critical regulation factors during the process of the osteogenic induction in BMSCs, and mir-205 has been substantiated to be involved in the osteogenic process, but the underlying mechanisms remain unclear. The purpose of this article is to investigate the role of mir-205 in the osteogenic differentiation of BMSCs. We found that mir-205 expression was down-regulated in a time-dependent manner during BMSC osteo-induction. Inhibition of mir-205 enhanced osteogenic abilities by up-regulating bone sialoprotein (BSP) and osteopontin (OPN) protein levels and increasing alkaline phosphatase (ALP) activity and osteocalcin secretion. Furthermore, we found that mir-205 could regulate protein expression of special AT-rich sequence-binding protein 2 (SATB2) and runt-related transcription factor 2 (Runx2), and over-expression of SATB2 activated Runx2 and reversed the negative effects of mir-205 on osteoblastic differentiation. Furthermore, we examined the extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (p38 MAPK) pathways during osteogenic induction and our data indicates that mir-205 might exert negative functions on the osteogenic differentiation in BMSCs at least partly via altering phosphorylation of ERK and p38 MAPK. These results shed new light on the molecular mechanisms of microRNAs in governing differentiation of BMSCs.