Carbon dots (CDs) are a new class of photoluminescent (PL), biocompatible, environment-friendly, and low-cost carbon nanomaterials. Synthesis of highly efficient red-emitting carbon dots (R-CDs) on a gram scale is a great challenge at present, which heavily restricts the wide applications of CDs in the bioimaging field. Herein, R-CDs with a high quantum yield (QY) of 53% are produced on a gram scale by heating a formamide solution of citric acid and ethylenediamine. The as-prepared R-CDs have an average size of 4.1 nm and a nitrogen content of about 30%, with an excitation-independent emission at 627 nm. After detailed characterizations, such strong red fluorescence is ascribed to the contribution from the nitrogen- and oxygen-related surface states and the nitrogen-derived structures in the R-CD cores. Our R-CDs show good photostability and low cytotoxicity, and thus they are excellent red fluorescence probes for bioimaging both in vitro and in vivo.
Despite intense interest, the molecular mechanisms underlying the association of apoE4 with Alzheimer disease are not clear. Because the function (or dysfunction) of a protein is based on its structure, this review focuses on the effects of the structural differences among the isoforms on neurodegeneration. Understanding how apoE4 structure impacts neurodegeneration is likely to provide mechanistic insight as well as potential therapeutic approaches to blunt or reduce its effects.ApoE4 is the major genetic risk factor for AD 2 (1-3). ApoE is well known as a lipid transport protein in the plasma and central nervous system and plays a key role in the maintenance and repair of neurons (4 -6). Of the three common isoforms, apoE4 is associated with the greatest risk of AD and the lowest age of onset, apoE2 with the lowest risk and highest age of onset, and apoE3 with intermediate risk and age of onset. Several hypotheses have been proposed to explain this association (for review, see Ref. 7). Nevertheless, despite concerted efforts, the mechanism remains unknown.The variable effect of apoE isoforms in AD provides an opportunity to correlate their structural and biophysical differences with their respective impact. This approach is based on the principle that the structure and biophysical properties of a protein determine its normal function or (in the case of mutations) its dysfunction. In this review, we focus on the mechanistic insights gained from comparisons of the apoE isoforms. Because apoE may contribute to AD through both A-dependent and A-independent pathways (8), we will consider those pathways as they relate to structural correlations.
Common Structural Features of ApoE IsoformsThe three common apoE isoforms are coded at a single gene locus on chromosome 19; each contains 299 amino acids. ApoE has two structural domains, an N-terminal domain and a C-terminal domain, which fold independently ( Fig. 1) (9, 10). In the lipid-free state, the two domains are connected by a flexible "hinge region" (10). As shown by x-ray crystallography, the N-terminal domain forms an extended four-helix bundle (11). The region of apoE that interacts with members of the LDL receptor family is enriched in basic residues, is located in the N-terminal domain, and includes residues 136 -150 and Arg-172 ( Fig. 1) (12). The structure of the C-terminal domain is not known. It is modeled as a series of ␣-helices based on secondary structure prediction. This domain contains the major lipoprotein-binding elements of apoE, residues 244 -272 (13).
Structural and Biophysical Differences in ApoE IsoformsStructural Differences-The three isoforms are distinguished by arginyl/cysteinyl differences at positions 112 and 158: apoE2 contains cysteine at both positions, apoE3 contains cysteine at position 112 and arginine at position 158, and apoE4 contains arginine at both positions ( Fig. 1) (14). These differences exert profound effects on the structure and properties of the isoforms and thus hold the key to understanding their different effects...
SUMMARYThe three isoforms of apolipoprotein (apo) E are strongly associated with different risks for Alzheimer's disease: apoE4 > apoE3 > apoE2. Here, we show at physiological salt concentrations and pH that native tetramers of apoE form soluble aggregates in vitro that bind the amyloid dyes thioflavin T and Congo Red. However, unlike classic amyloid fibrils, the aggregates adopt an irregular protofilament-like morphology and are mostly -helical. The aggregates formed at substantially different rates (apoE4 > apoE3 > apoE2) and were significantly more toxic to cultured neuronal cells than the tetramer. Since the three isoforms have large differences in conformational stability that can influence aggregation and amyloid pathways, we tested the effects of mutations that increased or decreased stability. Decreasing the conformational stability of the amino-terminal domain of apoE increased aggregation rates and vice versa. Our findings provide a new perspective for an isoform-specific pathogenic role for apoE aggregation in which differences in the conformational stability of the amino-terminal domain mediate neurodegeneration.
Salinomycin is perhaps the first promising compound that was discovered through high throughput screening in cancer stem cells. This novel agent can selectively eliminate breast and other cancer stem cells, though the mechanism of action remains unclear. In this study, we found that salinomycin induced autophagy in human non-small cell lung cancer (NSCLC) cells. Furthermore, we demonstrated that salinomycin stimulated endoplasmic reticulum stress and mediated autophagy via the ATF4-DDIT3/CHOP-TRIB3-AKT1-MTOR axis. Moreover, we found that the autophagy induced by salinomycin played a prosurvival role in human NSCLC cells and attenuated the apoptotic cascade. We also showed that salinomycin triggered more apoptosis and less autophagy in A549 cells in which CDH1 expression was inhibited, suggesting that the inhibition of autophagy might represent a promising strategy to target cancer stem cells. In conclusion, these findings provide evidence that combination treatment with salinomycin and pharmacological autophagy inhibitors will be an effective therapeutic strategy for eliminating cancer cells as well as cancer stem cells.
Glutamatergic synapses are highly modifiable, suiting them for key roles in processes such as learning and memory. At crayfish glutamatergic neuromuscular junctions, hyperpolarization and cyclic nucleotide-activated (HCN) ion channels mediate hormonal modulation of glutamatergic synapses and a form activity-dependent long-term facilitation (LTF) of synaptic transmission. Here, we show that a new target for cAMP, exchange protein activated by cAMP (Epac) or cAMP-regulated guanine nucleotide exchange protein, is involved in the hormonal enhancement of synaptic transmission by serotonin. Induction of LTF "tags" synapses, rendering them responsive to cAMP in an HCN-independent manner. Epac also mediates the enhancement of tagged synapses. Thus, the cAMP-dependent enhancement of transmission is mediated by two separate pathways, neither of which involves protein kinase A.
A modified heat treatment process designated quenching–partitioning–tempering (Q–P–T) process is developed based on the quenching and partitioning process proposed by J.G. Speer et al. [Acta Mater.51, 2611 (2003)] and D.K. Matlock et al. [Mater. Sci. Forum426–432, 1089 (2003)]. A Fe–0.485C–1.195Mn–1.185Si–0.98Ni–0.21Nb steel after Q–P–T process satisfies the designed requirement of tensile strength over 2000 MPa and elongation over 10%. The microstructure characterization indicates that this ultrahigh-strength steel consists of nanomicrostructures including lath martensite, filmlike retained austenite, and dispersive Nb-containing carbides. The effect of tempering time on the mechanical properties is analyzed based on microstructures.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.