p53 protects against alcoholic fatty liver disease via ALDH2 inhibition.

The tumor suppressor p53 is critical for tumor suppression, but the regulatory role of p53 in alcohol-induced fatty liver remains unclear. Here, we show a role for p53 in regulating ethanol metabolism via acetaldehyde dehydrogenase 2 (ALDH2), a key enzyme responsible for the oxidization of alcohol. By repressing ethanol oxidization, p53 suppresses intracellular levels of acetyl-CoA and histone acetylation, leading to the inhibition of the stearoyl-CoA desaturase-1 (SCD1) gene expression. Mechanistically, p53 directly binds to ALDH2 and prevents the formation of its active tetramer and indirectly limits the production of pyruvate that promotes the activity of ALDH2. Notably, p53-deficient mice exhibit increased lipid accumulation, which can be reversed by ALDH2 depletion. Moreover, liver-specific knockdown of SCD1 alleviates ethanol-induced hepatic steatosis caused by p53 loss. By contrast, overexpression of SCD1 in liver promotes ethanol-induced fatty liver development in wild-type mice, while it has a mild effect on p53-/- or ALDH2-/- mice. Overall, our findings reveal a previously unrecognized function of p53 in alcohol-induced fatty liver and uncover pyruvate as a natural regulator of ALDH2.

U1 snRNP determines mRNA length and regulates isoform expression.

U1 snRNP (U1), in addition to its splicing role, protects pre-mRNAs from drastic premature termination by cleavage and polyadenylation (PCPA) at cryptic polyadenylation signals (PASs) in introns. Here, a high-throughput sequencing strategy of differentially expressed transcripts (HIDE-seq) mapped PCPA sites genome wide in divergent organisms. Surprisingly, whereas U1 depletion terminated most nascent gene transcripts within ~1 kb, moderate functional U1 level decreases, insufficient to inhibit splicing, dose-dependently shifted PCPA downstream and elicited mRNA 3' UTR shortening and proximal 3' exon switching characteristic of activated immune and neuronal cells, stem cells, and cancer. Activated neurons' signature mRNA shortening could be recapitulated by U1 decrease and antagonized by U1 overexpression. Importantly, we show that rapid and transient transcriptional upregulation inherent to neuronal activation physiology creates U1 shortage relative to pre-mRNAs. Additional experiments suggest cotranscriptional PCPA counteracted by U1 association with nascent transcripts, a process we term telescripting, ensuring transcriptome integrity and regulating mRNA length.

Cellular redox homeostasis maintained by malic enzyme 2 is essential for MYC-driven T cell lymphomagenesis.

T cell lymphomas (TCLs) are a group of rare and heterogeneous tumors. Although proto-oncogene MYC has an important role in driving T cell lymphomagenesis, whether MYC carries out this function remains poorly understood. Here, we show that malic enzyme 2 (ME2), one of the NADPH-producing enzymes associated with glutamine metabolism, is essential for MYC-driven T cell lymphomagenesis. We establish a CD4-Cre; Myc flox/+transgenic mouse mode, and approximately 90% of these mice develop TCL. Interestingly, knockout of Me2 in Myc transgenic mice almost completely suppresses T cell lymphomagenesis. Mechanistically, by transcriptionally up-regulating ME2, MYC maintains redox homeostasis, thereby increasing its tumorigenicity. Reciprocally, ME2 promotes MYC translation by stimulating mTORC1 activity through adjusting glutamine metabolism. Treatment with rapamycin, an inhibitor of mTORC1, blocks the development of TCL both in vitro and in vivo. Therefore, our findings identify an important role for ME2 in MYC-driven T cell lymphomagenesis and reveal that MYC-ME2 circuit may be an effective target for TCL therapy.

Inactivation of Malic Enzyme 1 in Endothelial Cells Alleviates Pulmonary Hypertension.

BACKGROUND: Pulmonary hypertension (PH) is a progressive cardiopulmonary disease with a high mortality rate. Although growing evidence has revealed the importance of dysregulated energetic metabolism in the pathogenesis of PH, the underlying cellular and molecular mechanisms are not fully understood. In this study, we focused on ME1 (malic enzyme 1), a key enzyme linking glycolysis to the tricarboxylic acid cycle. We aimed to determine the role and mechanistic action of ME1 in PH. METHODS: Global and endothelial-specific ME1 knockout mice were used to investigate the role of ME1 in hypoxia- and SU5416/hypoxia (SuHx)-induced PH. Small hairpin RNA and ME1 enzymatic inhibitor (ME1*) were used to study the mechanism of ME1 in pulmonary artery endothelial cells. Downstream key metabolic pathways and mediators of ME1 were identified by metabolomics analysis in vivo and ME1-mediated energetic alterations were examined by Seahorse metabolic analysis in vitro. The pharmacological effect of ME1* on PH treatment was evaluated in PH animal models induced by SuHx. RESULTS: We found that ME1 protein level and enzymatic activity were highly elevated in lung tissues of patients and mice with PH, primarily in vascular endothelial cells. Global knockout of ME1 protected mice from developing hypoxia- or SuHx-induced PH. Endothelial-specific ME1 deletion similarly attenuated pulmonary vascular remodeling and PH development in mice, suggesting a critical role of endothelial ME1 in PH. Mechanistic studies revealed that ME1 inhibition promoted downstream adenosine production and activated A2AR-mediated adenosine signaling, which leads to an increase in nitric oxide generation and a decrease in proinflammatory molecule expression in endothelial cells. ME1 inhibition activated adenosine production in an ATP-dependent manner through regulating malate-aspartate NADH (nicotinamide adenine dinucleotide plus hydrogen) shuttle and thereby balancing oxidative phosphorylation and glycolysis. Pharmacological inactivation of ME1 attenuated the progression of PH in both preventive and therapeutic settings by promoting adenosine production in vivo. CONCLUSIONS: Our findings indicate that ME1 upregulation in endothelial cells plays a causative role in PH development by negatively regulating adenosine production and subsequently dysregulating endothelial functions. Our findings also suggest that ME1 may represent as a novel pharmacological target for upregulating protective adenosine signaling in PH therapy.

Why is Superlubricity of Diamond-Like Carbon Rare at Nanoscale?

Hydrogenated diamond-like carbon (HDLC) is a promising solid lubricant for its superlubricity which can benefit various industrial applications. While HDLC exhibits notable friction reduction in macroscale tests in inert or reducing environmental conditions, ultralow friction is rarely observed at the nanoscale. This study investigates this rather peculiar dependence of HDLC superlubricity on the contact scale. To attain superlubricity, HDLC requires i) removal of ≈2 nm-thick air-oxidized surface layer and ii) shear-induced transformation of amorphous carbon to highly graphitic and hydrogenated structure. The nanoscale wear depth exceeds the typical thickness of the air-oxidized layer, ruling out the possibility of incomplete removal of the air-oxidized layer. Raman analysis of transfer films indicates that shear-induced graphitization readily occurs at shear stresses lower than or comparable to those in the nanoscale test. Thus, the same is expected to occur at the nanoscale test. However, the graphitic transfer films are not detected in ex-situ analyses after nanoscale friction tests, indicating that the graphitic transfer films are pushed out of the nanoscale contact area due to the instability of transfer films within a small contact area. Combining all these observations, this study concludes the retention of highly graphitic transfer films is crucial to achieving HDLC superlubricity.

Secondary cavitation bubble dynamics during laser-induced bubble formation in a small container.

We investigated secondary cavitation bubble dynamics during laser-induced bubble formation in a small container with a partially confined free surface and elastic thin walls. We employed high-speed photography to record the dynamics of sub-mm-sized laser-induced bubbles and small secondary bubble clouds. Simultaneous light scattering and acoustic measurements were used to detect the oscillation times of laser-induced bubbles. We observed that the appearance of secondary bubbles coincides with a prolonged collapse phase and with re-oscillations of the laser-induced bubble. We observed an asymmetric distribution of secondary bubbles with a preference for the upstream side of the focus, an absence of secondary bubbles in the immediate vicinity of the laser focus, and a migration of laser-induced bubble toward secondary bubbles at large pulse energies. We found that secondary bubbles are created through heating of impurities to form initial nanobubble nuclei, which are further expanded by rarefaction waves. The rarefaction waves originate from the vibration of the elastic thin walls, which are excited either directly by laser-induced bubble or by bubble-excited liquid-mass oscillations. The oscillation period of thin walls and liquid-mass were Twall = 116 µs and Tlm ≈ 160 µs, respectively. While the amplitude of the wall vibrations increases monotonically with the size of laser-induced bubbles, the amplitude of liquid-mass oscillation undulates with increasing bubble size. This can be attributed to a phase shift between the laser-induced bubble oscillation and the liquid-mass oscillator. Mutual interactions between the laser-induced bubble and secondary bubbles reveal a fast-changing pressure gradient in the liquid. Our study provides a better understanding of laser-induced bubble dynamics in a partially confined environment, which is of practical importance for microfluidics and intraluminal laser surgery.

Ars2 links the nuclear cap-binding complex to RNA interference and cell proliferation.

Here we identify a component of the nuclear RNA cap-binding complex (CBC), Ars2, that is important for miRNA biogenesis and critical for cell proliferation. Unlike other components of the CBC, Ars2 expression is linked to the proliferative state of the cell. Deletion of Ars2 is developmentally lethal, and deletion in adult mice led to bone marrow failure whereas parenchymal organs composed of nonproliferating cells were unaffected. Depletion of Ars2 or CBP80 from proliferating cells impaired miRNA-mediated repression and led to alterations in primary miRNA processing in the nucleus. Ars2 depletion also reduced the levels of several miRNAs, including miR-21, let-7, and miR-155, that are implicated in cellular transformation. These findings provide evidence for a role for Ars2 in RNA interference regulation during cell proliferation.

p53 transcriptionally regulates SQLE to repress cholesterol synthesis and tumor growth.

Cholesterol is essential for membrane biogenesis, cell proliferation, and differentiation. The role of cholesterol in cancer development and the regulation of cholesterol synthesis are still under active investigation. Here we show that under normal-sterol conditions, p53 directly represses the expression of SQLE, a rate-limiting and the first oxygenation enzyme in cholesterol synthesis, in a SREBP2-independent manner. Through transcriptional downregulation of SQLE, p53 represses cholesterol production in vivo and in vitro, leading to tumor growth suppression. Inhibition of SQLE using small interfering RNA (siRNA) or terbinafine (a SQLE inhibitor) reverses the increased cell proliferation caused by p53 deficiency. Conversely, SQLE overexpression or cholesterol addition promotes cell proliferation, particularly in p53 wild-type cells. More importantly, pharmacological inhibition or shRNA-mediated silencing of SQLE restricts nonalcoholic fatty liver disease (NAFLD)-induced liver tumorigenesis in p53 knockout mice. Therefore, our findings reveal a role for p53 in regulating SQLE and cholesterol biosynthesis, and further demonstrate that downregulation of SQLE is critical for p53-mediated tumor suppression.

SMN deficiency causes tissue-specific perturbations in the repertoire of snRNAs and widespread defects in splicing.

The survival of motor neurons (SMN) protein is essential for the biogenesis of small nuclear RNA (snRNA)-ribonucleoproteins (snRNPs), the major components of the pre-mRNA splicing machinery. Though it is ubiquitously expressed, SMN deficiency causes the motor neuron degenerative disease spinal muscular atrophy (SMA). We show here that SMN deficiency, similar to that which occurs in severe SMA, has unexpected cell type-specific effects on the repertoire of snRNAs and mRNAs. It alters the stoichiometry of snRNAs and causes widespread pre-mRNA splicing defects in numerous transcripts of diverse genes, preferentially those containing a large number of introns, in SMN-deficient mouse tissues. These findings reveal a key role for the SMN complex in RNA metabolism and in splicing regulation and indicate that SMA is a general splicing disease that is not restricted to motor neurons.

Improved Simulated-Daylight Photodynamic Therapy and Possible Mechanism of Ag-Modified TiO2 on Melanoma.

Simulated-daylight photodynamic therapy (SD-PDT) may be an efficacious strategy for treating melanoma because it can overcome the severe stinging pain, erythema, and edema experienced during conventional PDT. However, the poor daylight response of existing common photosensitizers leads to unsatisfactory anti-tumor therapeutic effects and limits the development of daylight PDT. Hence, in this study, we utilized Ag nanoparticles to adjust the daylight response of TiO2, acquire efficient photochemical activity, and then enhance the anti-tumor therapeutic effect of SD-PDT on melanoma. The synthesized Ag-doped TiO2 showed an optimal enhanced effect compared to Ag-core TiO2. Doping Ag into TiO2 produced a new shallow acceptor impurity level in the energy band structure, which expanded optical absorption in the range of 400-800 nm, and finally improved the photodamage effect of TiO2 under SD irradiation. Plasmonic near-field distributions were enhanced due to the high refractive index of TiO2 at the Ag-TiO2 interface, and then the amount of light captured by TiO2 was increased to induce the enhanced SD-PDT effect of Ag-core TiO2. Hence, Ag could effectively improve the photochemical activity and SD-PDT effect of TiO2 through the change in the energy band structure. Generally, Ag-doped TiO2 is a promising photosensitizer agent for treating melanoma via SD-PDT.

Nanoliposomes co-encapsulating Ce6 and SB3CT against the proliferation and metastasis of melanoma with the integration of photodynamic therapy and NKG2D-related immunotherapy on A375 cells.

Purpose. To overcome the insufficiency of conventional photodynamic therapy (PDT) for treating metastatic melanoma, the combination of smart nanoparticles and PDT with immunotherapy was used to achieve a higher efficiency by accumulating more photosensitizers in tumor areas and triggering stronger immune responses against tumors after PDT.Methods. In this study, we designed a nanoliposome co-encapsulation of chlorin E6 (Ce6) and SB-3CT to realize significant antitumoral proliferation and metastasis efficacy after laser irradiation in A375 cells. The morphology, size distribution, and loading efficiency of Ce6-SB3CT@Liposome (Lip-SC) were characterized. The reactive oxygen species (ROS) generation and cytotoxicity were evaluated in A375 cells, and the mechanisms of natural killer (NK) cell-mediated killing were assessed.Results. Lip-SC showed good stability and was well-dispersed with a diameter of approximately 140 nm in phosphate-buffered saline. The nanoliposomes could accumulate in tumor areas and induce apoptosis in cancer cells upon 660 nm light irradiation, which could trigger an immune response and induce the expression of NK group 2 member D (NKG2D) ligands. The subsequently released SB-3CT could further activate NK cells effectively and strengthen the immune system by inhibiting the shedding of soluble NKG2D ligands.Discussion. Taken together, the synergistic effects of SB-3CT on nanoliposomes for Ce6-mediated PDT were analyzed in detail to provide a new platform for future anti-melanoma treatment.

Classification and Segmentation of Hyperspectral Data of Hepatocellular Carcinoma Samples Using 1-D Convolutional Neural Network.

Pathological diagnosis plays an important role in the diagnosis and treatment of hepatocellular carcinoma (HCC). The traditional method of pathological diagnosis of most cancers requires freezing, slicing, hematoxylin and eosin staining, and manual analysis, limiting the speed of the diagnosis process. In this study, we designed a one-dimensional convolutional neural network to classify the hyperspectral data of HCC sample slices acquired by our hyperspectral imaging system. A weighted loss function was employed to promote the performance of the model. The proposed method allows us to accelerate the diagnosis process of identifying tumor tissues. Our deep learning model achieved good performance on our data set with sensitivity, specificity, and area under receiver operating characteristic curve of 0.871, 0.888, and 0.950, respectively. Meanwhile, our deep learning model outperformed the other machine learning methods assessed on our data set. The proposed method is a potential tool for the label-free and real-time pathologic diagnosis. © 2019 International Society for Advancement of Cytometry.

Study on the Correlation between Metabolism, Insulin Sensitivity and progressive weight loss change in Type-2 Diabetes.

OBJECTIVE: To observe the changes of lipid metabolism, blood glucose level and insulin sensitivity in patients with Type-2 diabetes after progressive weight loss of their body weight, so as to lay a theoretical foundation for diabetes treatment and education in the future. METHODS: One hundred obese patients with Type-2 diabetes (BMI ≥ 25 kg/m2) who visited the endocrinology department of our hospital from April 2017 to April 2018 were given diabetes health education, diabetic diet, exercise and other measures to control their weight. The changes of blood glucose, blood lipid, insulin level and insulin release test before weight loss (T1), and at the time points of weight loss reached 5% (T2), 10% (T3) and 15% (T4) were recorded respectively to understand the influence of progressive weight loss on relevant indexes of patients. RESULTS: With the decrease of body weight, the differences of TC, TG, LDL-C and HDL-C at different weight loss points were significant (p < 0.05), and the changes of fasting blood glucose in 5% and 10% weight loss were significant (p = 0.02). The 2h postprandial blood glucose showed the most significant difference when the weight loss reached 15% (p = 0.00). There was no statistical difference in the change of glycosylated hemoglobin among different weight loss points (p = 0.08). When the weight loss reached 10%, the blood insulin level was significantly lower than that before the weight loss, while the insulin level was not significantly changed when the weight loss reached 15%, but the peak of secretion was shifted forward. It is suggested that insulin sensitivity gradually increases with weight loss. CONCLUSION: Obese patients with Type-2 diabetes can benefit from weight loss, with abnormal blood glucose and lipid metabolism improved, insulin resistance relieved, and insulin sensitivity increased.

Multi-rate-equation modeling of the energy spectrum of laser-induced conduction band electrons in water.

We study the energy spectrum of laser-induced conduction band (CB) electrons in water by multi-rate equations (MRE) with different impact ionization schemes. Rethfeld's MRE model [Phys. Rev. Lett.92, 187401(2004)Phys. Rev.B 79, 155424(2009)], but the corresponding rate equations are computationally very expensive. We introduce a simplified splitting scheme and corresponding rate equations that still agree with energy conservation but enable the derivation of an asymptotic SRE. This approach is well suited for the calculation of energy spectra at long pulse durations and high irradiance, and for combination with spatiotemporal beam propagation/plasma formation models. Using the energy-conserving MREs, we present the time-evolution of CB electron density and energy spectrum during femtosecond breakdown as well as the irradiance dependence of free-electron density, energy spectrum, volumetric energy density, and plasma temperature. These data are relevant for understanding photodamage pathways in nonlinear microscopy, free-electron-mediated modifications of biomolecules in laser surgery, and laser processing of transparent dielectrics in general.

Dual sensing of glutathione and acidic pH values by using MnO2 nanosheets and 3-acetyl-7-hydroxy-2H-chromen-2-one as a fluorescent pH probe.

A multifunctional nanoprobe is described for dual sensing of acidic pH values and glutathione (GSH) by combining the pH-responsive fluorescent probe 3-acetyl-7-hydroxy-2H-chromen-2-one (AHC) and MnO2 nanosheets. The fluorescence of the MnO2/AHC composite is weak due to an inner filter effect. If, however, the MnO2 nanosheets are reductively decomposed by GSH, the blue fluorescence of the pH probe AHC (with excitation/emission maximum at 417/456 nm) will be restored. The MnO2 nanosheets also are decomposed by acidic pH values, and the fluorescence of AHC is decreased. According to absorbance and fluorescence signal changes, the pH and GSH induced responses can be easily distinguished. Thus, the nanoprobe can be used for logical analysis of acidic pH values and GSH. The nanoprobe works in the pH range from 4 to 7, and GSH can be determined in the concentration range from 0.5 to 200 µM. Graphical abstract Schematic presentation of a multifunctional nanoprobe for dual sensing of acidic pH values and glutathione by combining a pH-responsive fluorescent probe and MnO2 nanosheets. According to absorbance and fluorescence signal changes, the nanoprobe can be used for logical analysis.

Sensitive fluorometric determination of glutathione using fluorescent polymer dots and the dopamine-melanin nanosystem.

A bioinspired fluorometric method has been developed for the detection of glutathione (GSH) in biological fluids. It is based on the use of near-infrared fluorescent semiconducting polymer dots (P-dots) and of the dopamine (DA)-melanin nanosystem. The P-dots were prepared from poly(styrene-co-maleic anhydride), the semiconducting polymer poly[(9,9'-dioctyl-2,7-divinylenefluorenylene)-alt-2-methoxy-5-(2-ethyl-hexyloxy)-1,4-phenylene] and the fluorescent dye tetraphenylporphyrin. They have excitation/emission maxima at 458/656 nm, and this enables measurement to be performed with low autofluorescence and scattering background. DA can self-polymerize on the surface of the P-dots to yield a poly-DA coating. This coating, at weak alkaline pH values, causes the quenching of the fluorescence of the P-dots. However, the polymerization of DA is inhibited by GSH. Hence, quenching of fluorescence is prevented. This effect was used to design a fluorometric assay for GSH that has good selectivity and sensitivity. Under optimal conditions, the method has a linear response in the 0.2 to 20 µM GSH concentration range and a 60 nM detection limit. It was successfully applied to the determination of GSH in HepG2 cells and in spiked human serum. Graphical abstract Schematic representation of using a NIR fluorescent P-dots and dopamine (DA)-melanin nanohybrid as a probe for glutathione (GSH) detection. The P-dots were prepared from poly(styrene-co-maleic anhydride) (PSMA), the semiconducting polymer poly[(9,9'-dioctyl-2,7-divinylenefluorenylene)-alt-2-methoxy-5-(2-ethyl-hexyloxy)-1,4-phenylene] (PEPV) and the fluorescent dye tetraphenylporphyrin (TPP).The GSH can inhibit the dopamine self-polymerization and prevented the formation of PDA and fluorescence quenching of P-dots.

Experimental investigation on multiple breakdown in water induced by focused nanosecond laser.

Multiple breakdowns in liquids still remains obscure for its complex, non-equilibrium and transient dynamic process. We introduced three methods, namely, plasma imaging, light-scattering technique, and acoustic detection, to measure the multiple breakdown in water induced by focused nanosecond laser pulses simultaneously. Our results showed that linear dependence existed among the cavitation-bubble lifetime, the far-field peak pressure of the initial shock wave, and the corresponding plasma volume. Such a relationship can be used to evaluate the ideal size and energy of each bubble during multiple breakdown. The major bubble lifetime was hardly affected by the inevitable coalescence of cavitation bubbles, thereby confirming the availability of light-scattering technique on the estimation of bubble size during multiple breakdown. Whereas, the strength of collapse-shock-wave and the subsequent rebound of bubbles was strongly influenced, i.e., the occurrence of multiple breakdown suppressed the cavitation-bubble energy being converted into collapse-shock-wave energy but enhanced conversion into rebound-bubble energy. This study is a valuable contribution to research on the rapid mixing of microfluidics, damage control of microsurgery, and photoacoustic applications.

Conductometric immunoassay of alpha-fetoprotein in sera of liver cancer patients using bienzyme-functionalized nanometer-sized silica beads.

A conductometric immunoassay protocol was designed for the sensitive detection of a liver cancer biomarker, alpha-fetoprotein (AFP), in biological fluids by using enzyme-conjugated nanometer-sized enzyme-doped silica beads. Initially, urease molecules were doped into nanosilica particles by using the reverse micelle method. Thereafter, arginase-labeled anti-AFP antibodies were covalently conjugated onto the surface of the synthesized nanoparticles. The immunoreaction was carried out in a monoclonal anti-AFP capture antibody-coated microplate with a sandwich-type assay format by using bienzyme-functionalized silica nanobeads as the recognition elements. Upon l-arginine introduction, the substrate was cleaved into urea and l-ornithine on the basis of the arginase enzymatic reaction, and the as-produced urea was then decomposed into ammonia (NH4+) and bicarbonate (HCO3-) ions by the doped urease, thus causing the variation in the local conductivity of the detection solution on an interdigitated conductometric transducer. Under optimal conditions, the developed immunosensing system exhibited good conductometric responses toward target AFP within a dynamic linear range of 0.01-100 ng mL-1 at a relatively low detection limit of 4.8 pg mL-1 based on the 3sB criterion. Importantly, good reproducibility, high specificity and acceptable method accuracy were acquired for the analysis of human serum specimens in liver cancer patients.

Double NIR laser stimulation and enhancing the thermal sensitivity of Er3+/Tm3+/Nd3+ doped multilayer core-shell nanoparticles.

Non-contact thermal sensors are important devices to study cellular processes and monitor temperature in vivo. Herein, a novel highly sensitive nanothermometer based on NaYF4:Yb,Er@ NaYF4@NaYF4:Yb,Tm@ NaYF4:Nd (denoted as Er@Y@Tm@Nd) was prepared by a facile solvothermal method. When excited by the near-infrared (NIR) light of 808 and 980 nm, the as-prepared Er@Y@Tm@Nd nanoparticles could emit both blue and green light, respectively, since the lanthanide cations responsible for these emissions are gathered inside this nanostructure. The green and blue light intensity ratio exhibits obvious temperature dependence in the range of the physiological temperature. Additionally, the fluorescence intensity of Er3+ and Tm3+ are also greatly enhanced due to the multilayer structure that implies avoiding the Er3+ and Tm3+ energy cross-relaxation by introduction of a NaYF4 wall between them. The as-prepared core-shell-shell-shell structure with Er3+ and Tm3+ in different layers improves dozens of times of the thermal sensitivity based on the non-thermal coupling levels of the probe: the maximum values for the sensitivity are 2.95% K-1 (I Er-521/I Tm-450) and 6.30% K-1 (I Tm-474/I Er-541) when excited by 980 and 808 nm laser sources, respectively. These values are well above those previously reported (<0.7% K-1), indicating that the prepared nanostructures are temperature sensors with excellent thermal sensitivity and sensitive to NIR wavelength excitation that makes them highly preferred for thermal detection.

Exocytosis of gold nanoparticle and photosensitizer from cancer cells and their effects on photodynamic and photothermal processes.

We first illustrate the faster decrease of the photothermal (PT) effect with the delay time of laser treatment, in which the illumination of a 1064 nm laser effectively excites the localized surface plasmon (LSP) resonance of cell-up-taken gold nanoring (NRI) linked with a photosensitizer (PS), when compared with the photodynamic (PD) effect produced by the illumination of a 660 nm laser for effective PS excitation. The measurement results of the metal contents of Au NRI and PS based on inductively coupled plasma mass spectroscopy and the PS fluorescence intensity based on flow cytometry show that the linkage of NRI and PS is rapidly broken for releasing PS through the effect of glutathione in lysosome after cell uptake. Meanwhile, NRI escapes from a cell with a high rate such that the PT effect decays fast while the released PS can stay inside a cell longer for producing a prolonged PD effect. The effective delivery of PS through the linkage with Au NRI for cell uptake and the advantageous effect of LSP resonance at a PS absorption wavelength on the PD process are also demonstrated.