We have investigated a hybrid plasmonic-photonic mode in Si and Ge channel waveguides over the 1.55-8.0 ?m wavelength range. A 10-nm Cu ribbon was buried midway within a Si3N4 "photonic slot" centered in the semiconductor strip. For the TMo mode, propagation lengths L of several millimeters are predicted for a waveguide cross-section of about 0.7?/n x 0.7?/n which offers optical confinement mainly within the ~?2/400-area slot. The L increased strongly with ?. For 0.4?/n x 0.4?/n channels, we found multi-centimeter propagation, but there ~60% of the propagating energy had leaked out into the thick, all-around Si3N4 cladding.
Metals play a critical role in life processes, and metal-based drugs nowadays have been commonly used for therapeutic and diagnostic purposes. However, severe side-effects and acquired drug resistance are the major issues needing to be resolved prior to more effective metallodrugs being developed, which requires a full understanding of the underlying molecular mechanisms. Metallomic and metalloproteomic approaches have received growing attention and have been implemented in inorganic medicinal chemistry and chemical biology in the endeavor to expand our knowledge of the pharmacological profiles, potential targets and functional pathways of metallodrugs. This perspective summarizes some recent progress in using metallomic and metalloproteomic strategies to elucidate the mechanisms of action of representative anticancer and antimicrobial metal-based drugs and agents.
Falls are one of the major causes leading to injury of elderly people. Using wearable devices for fall detection has a high cost and may cause inconvenience to the daily lives of the elderly. In this paper, we present an automated fall detection approach that requires only a low-cost depth camera. Our approach combines two computer vision techniques-shape-based fall characterization and a learning-based classifier to distinguish falls from other daily actions. Given a fall video clip, we extract curvature scale space (CSS) features of human silhouettes at each frame and represent the action by a bag of CSS words (BoCSS). Then, we utilize the extreme learning machine (ELM) classifier to identify the BoCSS representation of a fall from those of other actions. In order to eliminate the sensitivity of ELM to its hyperparameters, we present a variable-length particle swarm optimization algorithm to optimize the number of hidden neurons, corresponding input weights, and biases of ELM. Using a low-cost Kinect depth camera, we build an action dataset that consists of six types of actions (falling, bending, sitting, squatting, walking, and lying) from ten subjects. Experimenting with the dataset shows that our approach can achieve up to 91.15% sensitivity, 77.14% specificity, and 86.83% accuracy. On a public dataset, our approach performs comparably to state-of-the-art fall detection methods that need multiple cameras.
Low cost and high conductivity make copper (Cu) nanowire (NW) electrodes an attractive material to construct flexible and stretchable electronic skins, displays, organic light-emitting diodes (OLEDs), solar cells, and electrochromic windows. However, the vulnerabilities that Cu NW electrodes have to oxidation, bending, and stretching still present great challenges. This work demonstrates a new Cu@Cu4Ni NW conductive elastomer composite with ultrahigh stability for the first time. Cu@Cu4Ni NWs, facilely synthesized through a one-pot method, have highly crystalline alloyed shells, clear and abrupt interfaces, lengths more than 50 ?m, and smooth surfaces. These virtues provide the NW-elastomer composites with a low resistance of 62.4 ohm/sq at 80% transparency, which is even better than the commercial ITO/PET flexible electrodes. In addition, the fluctuation amplitude of resistance is within 2 ohm/sq within 30 days, meaning that at ?R/R0 = 1, the actual lifetime is estimated to be more than 1200 days. Neither the conductivity nor the performances of OLED with elastomers as conductive circuits show evident degradation during 600 cycles of bending, stretching, and twisting tests. These high-performance and extremely stable NW elastomeric electrodes could endow great chances for transparent, flexible, stretchable, and wearable electronic and optoelectronic devices.
A 'turn-on' fluorescent probe based on aggregation-induced emission (AIE) has been developed. It exhibits excellent selectivity and sensitivity for monitoring angiotensin converting enzyme (ACE) activity both in solutions and in living cells as well as for screening ACE inhibitors in vitro.
This paper presents Group-sparse Nonnegative supervised Canonical Correlation Analysis (GNCCA), a novel methodology for identifying discriminative features from multiple feature views. Existing correlation-based methods do not guarantee positive correlations of the selected features and often need a pre-feature selection step to reduce redundant features on each feature view. The new GNCCA approach attempts to overcome these issues by incorporating (1) a nonnegativity constraint that guarantees positive correlations in the reduced representation and (2) a group-sparsity constraint that allows for simultaneous between- and within- view feature selection. In particular, GNCCA is designed to emphasize correlations between feature views and class labels such that the selected features guarantee better class separability. In this work, GNCCA was evaluated on three prostate cancer (CaP) prognosis tasks: (i) identifying 40 CaP patients with and without 5-year biochemical recurrence following radical prostatectomy by fusing quantitative features extracted from digitized pathology and proteomics, (ii) predicting in vivo prostate cancer grade for 16 CaP patients by fusing T2w and DCE MRI, and (iii) localizing CaP/benign regions on MR spectroscopy and MRI for 36 patients. For the three tasks, GNCCA identifies a feature subset comprising 2%, 1% and 22%, respectively, of the original extracted features. These selected features achieve improved or comparable results compared to using all features with the same Support Vector Machine (SVM) classifier. In addition, GNCCA consistently outperforms 5 state-of-the-art feature selection methods across all three datasets.
This paper presents a high-speed sample-and-hold circuit (SHC) for very fast signal analysis. Spatial sampling techniques are exploited with CMOS transmission lines in a 0.13 ?m standard CMOS process. The SHC includes on chip coplanar waveguides for signal and clock pulse transmission, a clock pulse generator, and three elementary samplers periodically (L = 7.2 mm) placed along the signal propagation line. The SHC samples at 13.3 Gs/s. The circuit occupies an area of 1660 ?m × 820 ?m and consumes ~6 mW at a supply voltage of 1.2 V. The obtained input bandwidth is ~11.5?GHz.
The interband ? plasmon of graphene has energy corresponding to the ultraviolet (UV) wave band, and hence is promising for UV nanophotonics and nanooptoelectronics. However, its special size effect and electric field-enhancement effect have not been well understood. Here, we have investigated the far-field optical extinction and near-field enhancement features of the interband ? plasmon in a graphene nanodisk using discrete dipole approximation and finite-difference time-domain methods. Very interestingly, it has been found that the in-plane (transverse mode) optical extinction peak of monolayer graphene firstly significantly red shifts with increasing diameter, but then tends to a saturation value when the diameter is above 20 nm, showing a strong small-size-sensitive effect. Furthermore, the transverse mode optical extinction peak obviously blue shifts with increasing thickness when the thickness is relatively small. Significantly, the corresponding local electric field enhancement factor produced by the plasmon, which can be found to be as large as several tens, firstly increases with the increase of the size and then reaches a maximum value at only several nanometers in size. Such an ultrasmall-size-sensitive plasmon in the UV region endows graphene dots with new promising potential uses in ultrasmall photo-electric devices and nanoantennas, and in UV enhancers.
In this work, we present a new methodology to facilitate prediction of recurrent prostate cancer (CaP) following radical prostatectomy (RP) via the integration of quantitative image features and protein expression extracted from the excised prostate. Creating a fused predictor from big data streams comprised of thousands of dimensions is challenged through at least two constraints. Firstly, the classifier must account for the 'curse of dimensionality' problem, which hinders classifier performance when the number of features is much larger than the number of patient studies. Secondly, the classifier must be able to balance the possible mismatch in the number of features for the different big data channels to avoid biasing the classifier towards channels with larger numbers of features. In this paper, we present a new data integration methodology, supervised Multiview Canonical Correlation Analysis (sMVCCA), which aims to integrate infinite views of high dimensional data to provide a more amenable data representation for classification of disease. We also explore a version of sMVCCA using Spearman's rank correlation which, unlike Pearson's correlation, can account for non-linear correlations and outliers. A cohort of 40 prostate cancer patients with pathological Gleason scores 6-8 were considered for this study. 21 of these men were found to have biochemical recurrence (BCR) following RP, while 19 did not. The sMVCCA classifier combined a total of 189 quantitative histomorphometric attributes describing glandular morphology, architecture, and orientation in addition to the expression levels of 650 proteins extracted from the site of the tumor for each of the patients. The fused histomorphometric and proteomic representation via sMVCCA combined with a random forest classifier was able to predict BCR with a mean area under the receiver operating characteristic curve (AUC) of 0.74 across all 400 classifications and a maximum AUC of 0.9286. We found sMVCCA to perform statistically significantly (p < 0:05) better than comparative state of the art data fusion strategies such as Principal Component Analysis (PCA), multi-view CCA (MVCCA), and supervised regularized CCA (SRCCA) for predicting BCR. Furthermore, Kaplan-Meier survival analysis demonstrated improved logrank p-values for the sMVCCA fused classifier as compared to histology or proteomic features alone.
We previously demonstrated that the growth of the poorly differentiated nasopharyngeal carcinoma cells (CNE-2Z) was more dependent on the activities of volume-activated chloride channels than that of the normal nasopharyngeal epithelial cells (NP69-SV40T). However, the activities and roles of such volume-activated chloride channels in highly differentiated nasopharyngeal carcinoma cells (CNE-1) are not clarified. In this study, it was found that a volume-activated chloride current and a regulatory volume decrease (RVD) were induced by 47% hypotonic challenges. The current density and the capacity of RVD in the highly differentiated CNE-1 cells were lower than those in the poorly differentiated CNE-2Z cells, and higher than those in the normal cells (NP69-SV40T). The chloride channel blockers, 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) and tamoxifen inhibited the current and RVD. Depletion of intracellular Cl(-) abolished the RVD. The chloride channel blockers reversibly inhibited cell proliferation in a concentration- and time-dependent manner, and arrested cells at the G0/G1 phases, but did not change cell viability. The sensitivity of the three cell lines to the chloride channel blockers was different, with the highest in poorly differentiated cells (CNE-2Z) and the lowest in the normal cells (NP69-SV40T). ClC-3 proteins were expressed in the three cells and distributed inside the cells as well as on the cell membrane. In conclusion, the highly differentiated nasopharyngeal carcinoma CNE-1 cells functionally expressed the volume-activated chloride channels, which may play important roles in controlling cell proliferation through modulating the cell cycle, and may be associated with cell differentiation. Chloride channels may be a potential target of anticancer therapy.
For all-solution-processed (ASP) devices, transparent conducting oxide (TCO) nanocrystal (NC) inks are anticipated as the next-generation electrodes to replace both those synthesized by sputtering techniques and those consisting of rare metals, but a universal and one-pot method to prepare these inks is still lacking. A universal one-pot strategy is now described; through simply heating a mixture of metal-organic precursors a wide range of TCO NC inks, which can be assembled into high-performance electrodes for use in ASP optoelectronics, were synthesized. This method can be used for various oxide NC inks with yields as high as 10 g. The formed NCs are of high crystallinity, uniform morphology, monodispersity, and high ink stability and feature effective doping. Therefore, the inks can be readily assembled into films with a surface roughness of 1.6 nm. Typically, a sheet resistance of 110 ??sq(-1) can be achieved with a transmittance of 88?%, which is the best performance for TCO NC ink-based electrodes described to date. These electrodes can thus drive a polymer light-emitting diode (PLED) with a luminance of 2200 cd?m(-2) at 100 mA?cm(-2) .
Simultaneous in vivo luminescence and X-ray bioimaging in a tissue or animal integrates the advantages of each single-modal imaging technology, and will find widespread application in biological and clinical fields. However, synergistic dual-modal bioimaging that utilizes a new generation of upconversion nanoprobes is still limited. In addition, investigations concentrated on in vivo biodistribution of these nanoprobes may contribute to diagnosis and treatment, but long-term in vivo tracking based on these nanoprobes is rarely reported. In this work, water-soluble NaLuF4: Yb/Er nanophosphors were prepared through modified one-pot simultaneous synthesis and surface modification method. Owing to the outstanding upconverting emissions and large X-ray absorption coefficient/K-edge value of Lu and doped Yb ions, the obtained nanoprobes were successfully used as luminescent nanoprobes and X-ray contrast agents for in vivo synergistic upconversion luminescence and X-ray bioimaging. The in vivo biodistribution of these nanoprobes were observed, and the results based on long-term tracking reveal that the as-prepared nanoprobes first aggregated in the lung of the mouse, transferred to the liver, and finally moved to the spleen.
Medulloblastoma, the most common malignant childhood brain tumor, exhibits distinct molecular subtypes and cellular origins. Genetic alterations driving medulloblastoma initiation and progression remain poorly understood. Herein, we identify GNAS, encoding the G protein G?s, as a potent tumor suppressor gene that, when expressed at low levels, defines a subset of aggressive Sonic hedgehog (SHH)-driven human medulloblastomas. Ablation of the single Gnas gene in anatomically distinct progenitors in mice is sufficient to induce Shh-associated medulloblastomas, which recapitulate their human counterparts. G?s is highly enriched at the primary cilium of granule neuron precursors and suppresses Shh signaling by regulating both the cAMP-dependent pathway and ciliary trafficking of Hedgehog pathway components. Elevation in levels of a G?s effector, cAMP, effectively inhibits tumor cell proliferation and progression in Gnas-ablated mice. Thus, our gain- and loss-of-function studies identify a previously unrecognized tumor suppressor function for G?s that can be found consistently across Shh-group medulloblastomas of disparate cellular and anatomical origins, highlighting G protein modulation as a potential therapeutic avenue.
Well unipolar resistive switching (RS) behaviors were observed from Ag/ZnO single-microwire/Ag memristors. The reset voltages were larger than the set voltages, and all of them were less than 1 V. The resistance ratios of high-resistance state (HRS) to low-resistance state (LRS) reached 10(3). The bistable RS behaviors were entirely reversible and steady within 100 cycles. It was found that the dominant conduction mechanisms in LRS and HRS were ohmic behavior and space-charge-limited current (SCLC), respectively.
Bacterial characteristics in corrosion products and their effect on the formation of dense corrosion scales on cast iron coupons were studied in drinking water, with sterile water acting as a reference. The corrosion process and corrosion scales were characterized by electrochemical and physico-chemical measurements. The results indicated that the corrosion was more rapidly inhibited and iron release was lower due to formation of more dense protective corrosion scales in drinking water than in sterile water. The microbial community and denitrifying functional genes were analyzed by pyrosequencing and quantitative polymerase chain reactions (qPCR), respectively. Principal component analysis (PCA) showed that the bacteria in corrosion products played an important role in the corrosion process in drinking water. Nitrate-reducing bacteria (NRB) Acidovorax and Hydrogenophaga enhanced iron corrosion before 6 days. After 20 days, the dominant bacteria became NRB Dechloromonas (40.08%) with the protective corrosion layer formation. The Dechloromonas exhibited the stronger corrosion inhibition by inducing the redox cycling of iron, to enhance the precipitation of iron oxides and formation of Fe3O4. Subsequently, other minor bacteria appeared in the corrosion scales, including iron-respiring bacteria and Rhizobium which captured iron by the produced siderophores, having a weaker corrosion-inhibition effect. Therefore, the microbially-driven redox cycling of iron with associated microbial capture of iron caused more compact corrosion scales formation and lower iron release.
Polyethylene glycol (PEG) modified BaLuF5:Gd/Yb/Er upconversion nanoparticles (UCNPs) were synthesized by a facile one-pot hydrothermal method for simultaneous synthesis and surface functionalization. The novel, excellently biocompatible and water-soluble bioprobes were used for simultaneous upconversion (UC) luminescence and X-ray bioimaging for the first time. The as-prepared BaLuF5:Gd/Yb/Er UCNPs possess a face-centered cubic structure with an average size of 23.7 ± 2.7 nm. Under 980 nm laser excitation, these UCNPs emitted intense UC luminescence via a two-photon process. In vitro bioimaging and localized luminescence spectra detected from HeLa cells and the background reveal that these UCNPs are ideal candidates for optical bioimaging in the absence of autofluorescence. Furthermore, the synergistic in vivo UC luminescence and X-ray bioimaging reveal that these PEG-modified BaLuF5:Gd/Yb/Er UCNPs can be successfully used as ideal dual-modal bioprobes. These results demonstrate that these PEG modified UCNPs are ideal multi-modal nanoprobes for bioimaging.
An enzymatic procedure based on a catalase biosensor for the detection of forchlorfenuron (CPPU) has been reported in this work. Catalase was immobilized on boron nitride (BN) sheets dispersed in chitosan by adsorption. The immobilized catalase exhibited direct electron transfer character and excellent electrocatalytic activity towards H2O2 reduction. After introducing CPPU into the H2O2 containing phosphate buffer solution, the catalase-catalyzed H2O2 reduction current decreased. By measuring the current decrease, CPPU can be determined in the range of 0.5-10.0 µM with the detection limit of 0.07 ?M. The non-competitive inhibition behavior of CPPU towards catalase was verified by the Lineweaver-Burk plots. Long stability character has been ascribed to this biosensor. Possible use of this biosensor in flow systems is illustrated. The proposed biosensor has been successfully applied to CPPU determination in fruits samples with satisfactory results.
The aim of the present study was to examine the role of the mitochondrial (mt) DNA common deletion (CD) 4977 (mtDNACD4977) in the hair shaft in patients with presbycusis. A total of 87 individuals with presbycusis and 95 normal?hearing controls were selected based on strict audiometric criteria. Nested polymerase chain reaction (PCR), sequencing and quantitative (q)PCR were used to examine the expression levels of mtDNACD4977 in the hair shaft in presbycusis. Nested PCR of the hair shaft demonstrated that 8/95 cases with normal hearing were found to be positive for mtDNACD4977, as compared with 59/87 cases in the presbycusis group. The mtDNACD4977 was positive in 22/43 cases with mild?to?moderate hearing loss, 25/31 cases with moderate?to?severe, severe hearing loss, and 12/13 cases with profound deafness. Statistically significant differences in mtDNACD4977 expression were identified among all of the groups (P<0.001). The sequencing and qPCR assays demonstrated a trend towards an increase in the mean CD level of mtDNACD4977 with a more severe hearing loss at 8 kHz (r=0.778, P<0.001) and all ranges of frequency (r=0.858, P<0.001). In conclusion, the present study demonstrates a correlation between mtDNACD4977 in the human hair shaft and the severity of hearing loss in presbycusis.
The first attempt of constructing pH responsive supramolecular prodrug micelles based on cucurbituril is reported. The obtained prodrug micelles are found to be able to inhibit proliferation of cancer cells. It is anticipated that this facile strategy may open a novel avenue for the development of multifunctional drug delivery systems.
As an important energy-saving technique, white-light-emitting diodes (W-LEDs) have been seeking for low-cost and environment-friendly substitutes for rare-earth-based expensive phosphors or Pd(2+) /Cd(2+) -based toxic quantum dots (QDs). In this work, precursors and chemical processes were elaborately designed to synthesize intercrossed carbon nanorings (IC-CNRs) with relatively pure hydroxy surface states for the first time, which enable them to overcome the aggregation-induced quenching (AIQ) effect, and to emit stable yellow-orange luminescence in both colloidal and solid states. As a direct benefit of such scarce solid luminescence from carbon nanomaterials, W-LEDs with color coordinate at (0.28, 0.27), which is close to pure white light (0.33, 0.33), were achieved through using these low-temperature-synthesized and toxic ion-free IC-CNRs as solid phosphors on blue LED chips. This work demonstrates that the design of surface states plays a crucial role in exploring new functions of fluorescent carbon nanomaterials.
Protein phosphatase magnesium-dependent 1 delta (PPM1D) is involved in several types of cancer. The current study examined the role of PPM1D expression in prostate cancer (PCa) tissues and in PCa cell lines. Expression of PPM1D was evaluated using immunohistochemistry in 234 PCa tissues after radical prostatectomy and 80 benign prostatic hyperplasia (BPH) tissues. The associations of PPM1D expression with clinicopathological parameters and survival were analyzed. In vitro, tumor cells were transfected with small interfering RNA targeting PPM1D (siPPM1D) or si-Scramble, and the cell proliferation, migration and invasion were determined. We found that PPM1D expression was significantly higher in PCa tissues than that in BPH tissues. PPM1D expression was positively correlated with Gleason score (p=0.022), T stage (p=0.015) and lymph node status (p=0.016). Kaplan-Meier curve analysis showed that patients with positive PPM1D expression had shorter biochemical recurrence-free survival and overall survival. Furthermore, multivariate analyses showed that PPM1D expression was an independent predictor of both biochemical recurrence-free (hazard ratio=3.437, 95% confidence interval=1.154-6.209, p=0.016) and overall survival (hazard ratio=5.026, 95% confidence interval=2.545-8.109, p=0.007). Knockdown of PPM1D inhibited the proliferation, migration and invasion capabilities of PC-3 and LNCaP cells. PPM1D expression may predict for both overall and biochemical recurrence-free survival in patients after radical prostatectomy for PCa. Elevated PPM1D expression plays a key role in progression of PCa.
Myelinogenesis is a complex process that involves substantial and dynamic changes in plasma membrane architecture and myelin interaction with axons. Highly ramified processes of oligodendrocytes in the central nervous system (CNS) make axonal contact and then extrapolate to wrap around axons and form multilayer compact myelin sheathes. Currently, the mechanisms governing myelin sheath assembly and axon selection by myelinating cells are not fully understood. Here, we generated a transgenic mouse line expressing the membrane-anchored green fluorescent protein (mEGFP) in myelinating cells, which allow live imaging of details of myelinogenesis and cellular behaviors in the nervous systems. mEGFP expression is driven by the promoter of 2'-3'-cyclic nucleotide 3'-phosphodiesterase (CNP) that is expressed in the myelinating cell lineage. Robust mEGFP signals appear in the membrane processes of oligodendrocytes in the CNS and Schwann cells in the peripheral nervous system (PNS), wherein mEGFP expression defines the inner layers of myelin sheaths and Schmidt-Lanterman incisures in adult sciatic nerves. In addition, mEGFP expression can be used to track the extent of remyelination after demyelinating injury in a toxin-induced demyelination animal model. Taken together, the membrane-anchored mEGFP expression in the new transgenic line would facilitate direct visualization of dynamic myelin membrane formation and assembly during development and process remodeling during remyelination after various demyelinating injuries.
Metallopolymer nanowalls were prepared through a simple wet-chemical process using reduced graphene oxides as heterogeneous nucleation aids, which also help to form conductive electron paths. The nanowalls grow vertically on graphene surface with 100-200 nm in widths and ?20 nm in thickness. The Fe-based metallopolymer nanowall-based electrode shows best performance as O2 cathode exhibiting high round-trip efficiencies and stable cycling performance among other transition metal containing metallopolymer counterparts. The electrode delivers discharge-charge capacities of 1000 mAh/g for 40 cycles and maintains round-trip efficiencies >78% at 50 mA/g. The 1(st)-cycle round-trip efficiencies are 79%, 72%, and 65% at current densities of 50, 200, and 400 mA/g, respectively. The NMR analysis of the Fe-based metallopolymer based electrode after 40 cycles reveals slow formation of the side products, CH3CO2Li and HCO2Li.
We present a simple and efficient approach for higher-order Berenger mode computation. We establish the physical mapping between radiation modes and complex Berenger modes, and theoretically prove that the higher-order substrate Berenger modes and cladding Berenger modes can converge to a cluster of complex modes with the same phase angle. This model can be explained by weighted optical path distance in both cladding and substrate, and can be implemented by adjusting parameters of perfectly matched layers. A germanium (Ge) photodetector is utilized to evaluate the merits of this method in terms of robustness, efficiency, and accuracy.
The organ donation system in China has far lagged behind international levels. Transformation of this situation began in July 2005. A complete organ donation system that ensures fairness, impartiality, transparency and respect for life has now been developed. This system is composed of regulations and policies, an organizational structure, operational guidelines, organ procurement organizations, registration of donors and recipients, and an organ allocation system. Since March 2010, pilot trials on donation after circulatory death (DCD) have been carried out. In four years, organ donation has started in 25 out of 32 provinces in the country. From 2010 to 2013, the ratio of DCD liver transplantation to total case numbers in China rose from 1.38% to 26.1%, as for kidney the ratio were 0.59% and 24.6%, respectively. The total number of DCD in China has accumulated to 1,564 cases and 4,243 organs were transplanted. In order to alleviate the further difficulties of donation, establishment of professional organ procurement organizations in transplant hospitals, legislation of brain death, and promulgation of legal guidelines on DCD will be the main targets of organ donation development in China. This article is protected by copyright. All rights reserved.
The primary cause(s) of neuronal death in most cases of neurodegenerative diseases, including Alzheimer's and Parkinson's disease, are still unknown. However, the association of certain etiological factors, e.g., oxidative stress, protein misfolding/aggregation, redox metal accumulation and various types of damage to the genome, to pathological changes in the affected brain region(s) have been consistently observed. While redox metal toxicity received major attention in the last decade, its potential as a therapeutic target is still at a cross-roads, mostly because of the lack of mechanistic understanding of metal dyshomeostasis in affected neurons. Furthermore, previous studies have established the role of metals in causing genome damage, both directly and via the generation of reactive oxygen species (ROS), but little was known about their impact on genome repair. Our recent studies demonstrated that excess levels of iron and copper observed in neurodegenerative disease-affected brain neurons could not only induce genome damage in neurons, but also affect their repair by oxidatively inhibiting NEIL DNA glycosylases, which initiate the repair of oxidized DNA bases. The inhibitory effect was reversed by a combination of metal chelators and reducing agents, which underscore the need for elucidating the molecular basis for the neuronal toxicity of metals in order to develop effective therapeutic approaches. In this review, we have focused on the oxidative genome damage repair pathway as a potential target for reducing pro-oxidant metal toxicity in neurological diseases.
The spindle assembly checkpoint (SAC), which blocks anaphase onset until all chromosomes have bi-oriented, is one of the key self-monitoring systems of the eukaryotic cell cycle for genome stability. The mitotic arrest-deficient protein 1 (Mad1), a critical component of the SAC, is hyperphosphorylated in mitosis. However, the kinases responsible for Mad1 phosphorylation and its functional significance are not fully understood. Here we report that Mad1 is phosphorylated on Serine 214 by the Ataxia-Telangiectasia Mutated (ATM) kinase, a critical DNA damage response protein also activated in mitosis and required for the SAC. We demonstrate that Mad1 Serine 214 phosphorylation promotes the formation of homodimerization of Mad1 and its heterodimerization with Mad2. Further we show that Mad1 Serine 214 phosphorylation contribute to activation of the SAC and the maintenance of chromosomal stability. Together, these findings reveal an important role of ATM-mediated Mad1 Serine 214 phosphorylation in mitosis.
The epithelial cell adhesion molecule (EpCAM) is overexpressed in the majority of human epithelial carcinomas, and its overexpression is associated with proliferation and neoplastic transformation. However, the precise molecular mechanism involved in EpCAM-related proliferation and metastasis in hypopharyngeal carcinoma is unknown. The aim of the present study was to identify the role of EpCAM in the metastasis and proliferation of hypopharyngeal carcinoma. An immunohistochemical staining assay indicated that EpCAM was overexpressed in primary hypopharyngeal carcinoma tissues, and that this overexpression correlated with the tumor size and lymph node metastasis. In the following treatment of the hypopharyngeal carcinoma FaDu cell line with EpCAM, the downregulation of EpCAM was found to significantly suppress cell metastasis and proliferation, as detected by Transwell, clone formation and MTT assays. Additionally, western blot analysis revealed that EpCAM downregulation increased the expression of the adhesion- and proliferation-related factors, E-cadherin, ?-catenin and ?-catenin, in the cytoskeleton, as well as ?-catenin expression in the nucleus. In conclusion, the present study indicated that EpCAM is a potential oncogene and contributes to the metastasis of hypopharyngeal carcinoma. The current study is the first to provide evidence for the potential value of targeting EpCAM in hypopharyngeal carcinoma therapy.
Gold nanorods (AuNRs), because of their strong absorption of near-infrared (NIR) light, are very suitable for in vivo photothermal therapy of cancer. However, appropriate surface modification must be performed on AuNRs before their in vivo application because of the high toxicity of their original stabilizer cetyltrimethylammonium bromide. Multidentate ligands have attracted a lot of attention for modification of inorganic nanoparticles (NPs) because of their high ligand affinity and multifunctionality, while the therapeutic effect of multidentate ligands modified NPs in vivo remains unexplored. Here, we modified AuNRs with a polythiol PEG-based copolymer. The multidentate PEG coated AuNRs (AuNR-PTPEGm950) showed good stabilities in high saline condition and wide pH range. And they had much stronger resistance to ligand competition of dithiothreitol (DTT) than AuNRs coated by monothiol-anchored PEG. The AuNR-PTPEGm950 had very low cytotoxicity and showed high efficacy for the ablation of cancer cells in vitro. Moreover, the AuNR-PTPEGm950 showed good stability in serum, and they had a long circulation time in blood that led to a high accumulation in tumors after intravenous injection. In vivo photothermal therapy showed that tumors were completely cured without reoccurrence by one-time irradiation of NIR laser after a single injection of these multidentate PEG modified AuNRs.
The heterostructure, a basic active unit applied in the device level, plays an important role in traditional inorganic optoelectronics. In the organic field, although the requirement for the heterostructure is crucial, achievement and understanding on the growth and functionality of organic heterostructure are still finite, especially for ordered crystalline organic multilayers with smooth interfaces. Here a series of highly ordered crystalline heterostructures with molecule-level smoothness were obtained from single layer to alternate multilayer with a phthalocyanine molecule and a perylene derivative. Well-defined epitaxy relationship and crystal alignment were evidenced from the atomic force microscopy (AFM), X-ray diffraction (XRD), and transmission electron microscope (TEM) results. The evolution of the films reveals that, for organic-organic alternate multilayer growth, along with the intrinsic properties of organic molecules such as the packing and preferred growth direction, the soft matter properties of organic films contribute to well-defined heteroepitaxy despite that the lattice mismatch between the two materials' bulk phases is large. Thin film phases of the first few layers benefit the grain coalescence and thus the formation of smooth films. Potential application is implied from the heterojunctions' good transport ability.
The classification of luminal breast cancer has been a popular topic regarding its heterogeneity with distinct biological features and clinical outcomes. This study aimed to assess the power of proliferative indices (Ki67 and histological grade) to determine various clinicopathological characteristics and survival in luminal disease. A total of 541 patients with stage I-III luminal breast cancer were enrolled. Subtypes were determined using proliferative indices and were compared with clinicopathological variables and short-term survival. The significance of various treatments was evaluated in a subgroup of pN0 (lymph node negative) patients. Histological grade, independent of other variables, was a better predictor in the ER/PR+, human epidermal growth factor receptor 2 (Her-2) subgroup (p = 0.011) and the pN0 subgroup (p = 0.044) compared with Ki67, which only showed significance in the ER/PR+, Her-2 subgroup (p = 0.008). Neither grade nor Ki67 was associated with outcomes in the luminal Her-2 class. In pN0 patients, various treatments did not show significance in short-term survival. Histological grade outperformed Ki67 as a determinant for the stratification of luminal class regarding short-term survival. Chemotherapy most likely did not provide additional benefit to pN0 patients with luminal breast cancer compared with endocrine therapy.
Multidrug resistance (MDR) is one of the most important obstacles affecting the efficacy of chemotherapy treatments for numerous types of cancer. In the present study, we have demonstrated the possible function of Twist1 in the chemosensitivity of head and neck squamous cell carcinoma (HNSCC) and have identified that its mechanism maybe associated with MDR1/P-gp regulation. To investigate this, the hypopharyngeal cancer cell line, FaDu, and its MDR cell line induced by taxol, FaDu/T, were employed. Stable transfectants targeted to Twist1 overexpression and Twist1 silencing based on FaDu were also conducted. Morphological observation, flow cytometry, reverse transcription-polymerase chain reaction (RT-PCR), western blotting and laser scanning confocal microscope detection were utilized to detect the associations between Twist1 and the chemosensitivity of FaDu cells. Our results demonstrated that Twist1 and MDR1/P-gp were upregulated in FaDu/T cells in a MDR dose-dependent manner. The anti-apoptotic capabilities of FaDu/T cells were enhanced during MDR progression, with apoptosis-related proteins (Bcl-2, Bax, activated caspase-3 and caspase-9) changing to resist apoptosis. Twist1 overexpression decreased the sensitivity of cells to taxol as revealed by a significant increase in MDR1/P-gp and IC50 (P<0.05). This overexpression also enhanced the resistance to apoptosis, with apoptotic proteins changing to resist cell death, and inhibited Ca2+ release induced by taxol (P<0.05). Detections in Twist1 silencing cells also confirmed this result. This study provided evidence that alterations of Twist1 expression modulates the chemosensitivity of FaDu cells to taxol. Therefore, Twist1 knockdown may be a promising treatment regimen for advanced hypopharyngeal carcinoma patients with MDR.
Two benzothienobenzothiophene (BTBT)-based conjugated oligomers, i.e., 2,2'-bibenzothieno[3,2-b]benzothiophene (1) and 5,5'-bis(benzothieno[3,2-b]benzothiophen-2-yl)-2,2'-bithiophene (2), were prepared and characterized. Both oligomers exhibit excellent thermal stability, with 5% weight-loss temperatures (T(L)) above 370 °C; no phase transition was observed before decomposition. The highest occupied molecular orbital (HOMO) levels of 1 and 2 are -5.3 and -4.9 eV, respectively, as measured by ultraviolet photoelectron spectroscopy. Thin-film X-ray diffraction and atomic force microscopy characterizations indicate that both oligomers form highly crystalline films with large domain sizes on octadecyltrimethoxysilane-modified substrates. Organic thin-film transistors with top-contact and bottom-gate geometry based on 1 and 2 exhibited mobilities up to 2.12 cm(2)/V·s for 1 and 1.39 cm(2)/V·s for 2 in an ambient atmosphere. 1-based devices exhibited great air and thermal stabilities, as evidenced by the slight performance degradation after 2 months of storage under ambient conditions and after thermal annealing at temperatures below 250 °C.
A novel amphiphilic ABA-type triblock copolymer poly(ethylene glycol)-b-poly(ethanedithiol-alt-nitrobenzyl)-b-poly(ethylene glycol) (PEG-b-PEDNB-b-PEG) is successfully prepared by sequential thiol-acrylate Michael addition polymerization in one pot. PEG-b-PEDNB-b-PEG is designed to have light-cleavable o-nitrobenzyl linkages and acid-labile ?-thiopropionate linkages positioned repeatedly in the main chain of the hydrophobic block. The light and pH dual degradation of PEG-b-PEDNB-b-PEG is traced by gel permeation chromatography (GPC). Such triblock copolymer can self-assemble into micelles, which can be used to encapsulate anticancer drug doxorubicin (DOX). Because of the different degradation chemistry of o-nitrobenzyl linkages and ?-thiopropionate linkages, DOX can be released from the micelles by two different manners, i.e., light-induced rapid burst release and pH-induced slow sustained release. Confocal laser scanning microscopy (CLSM) results indicated that DOX-loaded micelles exhibited faster drug release in A549 cells after UV irradiation. Furthermore, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) results show that the DOX-loaded micelles under UV light degradation exhibit better anticancer activity against A549 cells than that of the nonirradiated ones.
The molecular configuration, molecular weight distribution and thermal transition enthalpy (?H) of grass carp skin (GCS) collagens after heat treatment under different conditions were measured using circular dichroism, gel filtration chromatography and differential scanning calorimetry (DSC). The enzymatic stability of collagen was evaluated using different enzymes, while the ability to form fibrils in vitro was assessed by morphological observation of collagen fibrils and turbidity testing.
In this work, the amine-functionalized NaYbF4:Er nanoparticles were developed as dual-modal nanoprobes for synergistic upconversion (UC) luminescence and X-ray imaging in a single system by a simple one-step method of simultaneous synthesis and surface modification. The water-soluble NaYbF4:Er nanoparticles present excellent green and dominant red UC emissions. The in vitro cell imaging shows that the high-contrast green and intense red UC emissions can be observed from HeLa cells treated with these nanoparticles, indicating the successful labeling of HeLa cells. Moreover, the localized spectra measured from HeLa cells and background presented significant green and dominant red UC emissions with the absence of any autofluorescence, further verifying that these nanoparticles can be successfully used as ideal probes for optical UC bioimaging with high contrast and non-autofluorescence. In addition, the amine-functionalized NaYbF4:Er nanoparticles maintained low cell toxicity in HeLa cells evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. More importantly, these amine-functionalized NaYbF4:Er nanoparticles can also be used as X-ray imaging, owing to the large X-ray absorption efficiency of the Yb ion. The synergistic in vivo UC and X-ray imaging present significant UC luminescence and X-ray signals in the same region of a nude mouse, and the two signals are matched very well, which provides direct evidence for simultaneous UC luminescence and X-ray imaging in a single compound of lanthanide-doped material. Moreover, ex vivo UC imaging shows that these nanoparticles are first accumulated in the lung and gradually translocated from the lung into the liver. These results demonstrate that the amine-functionalized NaYbF4:Er nanoparticles presented here are very attractive nanoprobes for dual-modal UC luminescence and X-ray imaging with low cytotoxicity, autofluorescence free, and synergistic combination of the advantages of the two imaging modalities.
Clinical and animal studies implicate erythropoietin (EPO) and EPO receptor (EPOR) signaling in angiogenesis. In the eye, EPO is involved in both physiological and pathological angiogenesis in the retina. We hypothesized that EPOR signaling is important in pathological angiogenesis and tested this hypothesis using a rat model of oxygen-induced retinopathy that is representative of human retinopathy of prematurity. We first determined that EPOR expression and activation were increased and that activated EPOR was localized to retinal vascular endothelial cells (ECs) in retinas at postnatal day 18 (p18), when pathological angiogenesis in the form of intravitreal neovascularization occurred. In human retinal microvascular ECs, EPOR was up-regulated and activated by VEGF. Lentiviral-delivered shRNAs that knocked down Müller cell-expressed VEGF in the retinopathy of prematurity model also reduced phosphorylated EPOR (p-EPOR) and VEGFR2 (p-VEGFR2) in retinal ECs. In human retinal microvascular ECs, VEGFR2-activated EPOR caused an interaction between p-EPOR and p-VEGFR2; knockdown of EPOR by siRNA transfection reduced VEGF-induced EC proliferation in association with reduced p-VEGFR2 and p-STAT3; however, inhibition of VEGFR2 activation by siRNA transfection or semaxanib (SU5416) abolished VEGFA-induced proliferation of ECs and phosphorylation of VEGFR2, EPOR, and STAT3. Our results show that VEGFA-induced p-VEGFR2 activates EPOR and causes an interaction between p-EPOR and p-VEGFR2 to enhance VEGFA-induced EC proliferation by exacerbating STAT3 activation, leading to pathological angiogenesis.
In order to reverse the malignant characteristics of hypopharyngeal cancer, the proteasome inhibitor MG132 was introduced into FaDu/T cells and the mechanisms underlying its effects were investigated. The multi-drug resistance (MDR) sensitivities of FaDu/T and FaDu/T-MG132 cancer cells to several chemotherapeutics were investigated by a 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide (MTT) assay. Apoptosis was measured by staining cells with Annexin V and propidium iodide (PI) double staining. Reverse transcription-polymerase chain reaction and western blot analysis were conducted to detect mRNA and corresponding protein levels of the MDR- and apoptosis-related genes P-glycoprotein (P-gp), caspase-3, Bcl-2 and Bax. The nuclear protein of nuclear factor ?-light-chain-enhancer of activated B cells. (NF-?B) and p53 were also investigated via western blot analysis. Compared with FaDu/T cells, the drug resistance of FaDu/T + MG132 cells to cisplatin (DDP), 5-fluorouracil (5-FU), doxorubicin (Dox) and vincristine (VCR) decreased. With increased expression of caspase-3 and Bax and decreased expression of Bcl-2, the anti-apoptotic ability markedly decreased in FaDu/T + MG132 cells. P-gp and NF-?B significantly decreased; however, p53 increased in FaDu/T + MG132 cells. These results suggested that the proteasome inhibitor MG132 reversed the malignant characteristics of FaDu/T by enhancing apoptosis and inhibiting P-gp. MG132 was also able to inhibit the nuclear translocation of NF-?B and increase the expression of p53.
Nowadays, cancer is one of the most fatal threatens to human health. By utilizing the differences of cell environment between cancer cells and their normal counterparts as assembly-disassembly triggers, various smart drug nanocarriers have been designed to fight the cancer. Nevertheless, most of them are still not robust enough. One important reason is that they merely focus on a single stimulus. Thus, in order to achieve a better therapeutic effect, constructing multi responsive polymers is of great significance. However, most of multi responsive polymers used, up until now, are mainly based on block polymers synthesized via traditional polymerization methods, which are relatively time-consuming and laborious. Here in this article, a facile strategy preparing smart polymers with dual responsiveness (endosomal pH and over produced H2O2) was proposed and realized by orthogonal assembly of ?-CD-hydrazone-DOX and PEG-Fc. The obtained polymers were found to be able to spontaneously assemble into micelles in water, indicating their potential applications as drug nanocarriers. In vitro study revealed that the release of the encapsulated DOX was significantly enhanced by both H2O2 and low pH at 5.0. Furthermore, fluorescence microscopy and flow cytometry analysis showed that the assembled supramolecular prodrug micelles could be internalized into cancer cells. These properties suggested their promising application in cancer therapy.
Hpn-like (Hpnl) is a unique histidine- and glutamine-rich protein found only in Helicobacter pylori and plays a role on nickel homeostasis. We constructed the fluorescent sensor proteins CYHpnl and CYHpnl_1-48 (C-terminal glutamine-rich region truncated) using enhanced cyan and yellow fluorescent proteins (eCFP and eYFP) as the donor-acceptor pair to monitor the interactions of Hpnl with metal ions and to elucidate the role of conserved Glu-rich sequence in Hpnl by fluorescence resonance energy transfer (FRET). CYHpnl and CYHpnl_1-48 exhibited largest responses towards Ni(II) and Zn(II) over other metals studied and the binding of Bi(III) to CYHpnl was observed in the presence of an excess amount of Bi(III) ions (Kd=115±4.8?M). Moreover, both CYHpnl and CYHpnl_1-48 showed positive FRET responses towards the binding to Ni(II) and Zn(II) in Escherichia coli cells overexpressing CYHpnl and CYHpnl_1-48, whereas a decrease in FRET upon Bi(III)-binding in E. coli cells overexpressing the latter. Our study provides clear evidence on Hpnl binding to nickel in cells, and intracellular interaction of Hpnl with Bi(III) could disrupt the protein function, thus probably contributing to the efficacy of Bi(III) drugs against H. pylori.
A meaningful organic quantum well based on crystalline heteroepitaxy films is constructed. The quantum confinement effect is demonstrated by its reflections on optics and electrics: the blueshift of the optical characteristic peaks and the negative differential resistance at room temperature. The realization of an organic quantum well indicates the highly delocalized transport mechanism in well-defined organic crystalline systems and promises novel organic "quantum" optoelectronic devices.
In this paper, multi-functional hexagonal phase NaErF4:Yb nanorods were synthesized by a facile hydrothermal method. The upconversion luminescence (UCL) intensity and red to green ratio of the multi-functional NaErF4 nanorods can be improved by Yb(3+) doping. More importantly, owing to the decreased distance of Er and Yb, the significant enhancement of red UCL can be obtained, which is different to the usual green UCL of Yb/Er doped NaYF4 host. In addition, the intensity of UCL is strongest when the Yb(3+)-doped concentration reached 30%. The in vitro cell imaging and localized UCL spectra taken from HeLa cells revealed that these NaErF4: 30% Yb(3+) nanorods are ideal nanoprobes with absence of autofluorescence for optical bioimaging. Moreover, these nanorods possess large X-ray absorption ions (Er(3+) and doped Yb(3+)), and were successfully used as contrast agents for in vivo X-ray bioimaging for the first time. In addition to the excellent UCL and X-ray absorption properties, these nanorods present significant paramagnetic properties and can be used as T2-weighted magnetic resonance imaging (MRI) agents. Therefore, these enhanced red UCL NaErF4 nanocrystals with excellent paramagnetic properties and X-ray absorption properties can be used as promising multi-modal nanoprobes for optical bioimaging, MRI, computed X-ray tomography (CT), and may have potential applications in bioseparation.
The effect of UV/Cl2 disinfection on the biofilm and corrosion of cast iron pipes in drinking water distribution system were studied using annular reactors (ARs). Passivation occurred more rapidly in the AR with UV/Cl2 than in the one with Cl2 alone, decreasing iron release for higher corrosivity of water. Based on functional gene, pyrosequencing assays and principal component analysis, UV disinfection not only reduced the required initial chlorine dose, but also enhanced denitrifying functional bacteria advantage in the biofilm of corrosion scales. The nitrate-reducing bacteria (NRB) Dechloromonas exhibited the greatest corrosion inhibition by inducing the redox cycling of iron to enhance the precipitation of iron oxides and formation of Fe3O4 in the AR with UV/Cl2, while the rhizobia Bradyrhizobium and Rhizobium, and the NRB Sphingomonas, Brucella producing siderophores had weaker corrosion-inhibition effect by capturing iron in the AR with Cl2. These results indicated that the microbial redox cycling of iron was possibly responsible for higher corrosion inhibition and lower effect of water Larson-Skold Index (LI) changes on corrosion. This finding could be applied toward the control of water quality in drinking water distribution systems.
Speckle-type POZ protein (SPOP) is an adaptor of the cullin 3-based ubiquitin ligase responsible for the degradation of oncoproteins frequently overexpressed in many tumor cells. Altered expression and somatic mutations of SPOP have been observed in various tumor types with chromosomal aberrations, indicating a role of SPOP in maintaining genome stability, although a detailed mechanism remains unclear. Here, we show that SPOP is a component of the DNA damage response (DDR). SPOP is recruited to DNA double-strand break sites and it forms nuclear foci after DNA damage. SPOP foci colocalize with ?-H2AX foci and are predominantly dependent on the activity of the ataxia-telangiectasia mutated (ATM) kinase. Furthermore, SPOP interacts with ATM in response to DNA damage. Finally, we demonstrate that knocking down of SPOP resulted in an impaired DDR and a hypersensitivity to ionizing irradiation. Together, we highlight a critical role of SPOP in the DDR.
In this study, monodispersed and high-quality hexagonal phase LaF3 nanocrystals with different shapes and sizes were synthesized by a solvothermal method using oleic acid as the stabilizing agent. The as-prepared LaF3 nanocrystals were characterized by transmission electron microscopy (TEM), x-ray diffraction (XRD), and analysis of the upconversion spectra. The TEM results reveal that the samples present high uniformity and monodispersity and are self-assembled into a two-dimensional ordered array. Moreover, the shape, size and structure of the nanocrystals can be readily tuned by adjusting the NaF content. With increasing content of NaF, the shape of the LaF3 nanocrystals changed from particle to rod and the size gradually increased. More importantly, high NaF content favors the formation of one-dimensional nanorods. High Y b(3+) and Er(3+) content is beneficial to synthesizing the hexagonal phase of NaLaF4 nanocrystals. Furthermore, the TEM results show that the shape and size of the LaF3 nanocrystals can also be tuned by doping lanthanide ions, which provides a new route for size and shape control of nanocrystals. In addition, LaF3 nanocrystals co-doped with Y b(3+)/Tm(3+) present efficient near-infrared (NIR)-NIR upconversion luminescence. More importantly, the upconversion luminescent colors can be readily tuned from blue-white to blue by adjusting the excitation power. Therefore, it is expected that these LaF3 nanocrystals with well-controlled shape, size and NIR-NIR upconversion emission have potential applications in biomedical imaging fields.
Mammalian SPAG6 protein is localized to the axoneme central apparatus, and it is required for normal flagella and cilia motility. Recent studies demonstrated that the protein also regulates ciliogenesis and cilia polarity in the epithelial cells of brain ventricles and trachea. Motile cilia are also present in the epithelial cells of the middle ear and Eustachian tubes, where the ciliary system participates in the movement of serous fluid and mucus in the middle ear. Cilia defects are associated with otitis media (OM), presumably due to an inability to efficiently transport fluid, mucus and particles including microorganisms. We investigated the potential role of SPAG6 in the middle ear and Eustachian tubes by studying mice with a targeted mutation in the Spag6 gene. SPAG6 is expressed in the ciliated cells of middle ear epithelial cells. The orientation of the ciliary basal feet was random in the middle ear epithelial cells of Spag6-deficient mice, and there was an associated disrupted localization of the planar cell polarity (PCP) protein, FZD6. These features are associated with disordered cilia orientation, confirmed by scanning electron microscopy, which leads to uncoordinated cilia beating. The Spag6 mutant mice were also prone to develop OM. However, there were no significant differences in bacterial populations, epithelial goblet cell density, mucin expression and Eustachian tube angle between the mutant and wild-type mice, suggesting that OM was due to accumulation of fluid and mucus secondary to the ciliary dysfunction. Our studies demonstrate a role for Spag6 in the pathogenesis of OM in mice, possibly through its role in the regulation of cilia/basal body polarity through the PCP-dependent mechanisms in the middle ear and Eustachian tubes.
NADPH oxidase-generated reactive oxygen species (ROS) are implicated in angiogenesis. Isoforms of NADPH oxidase NOX1, NOX2, and NOX4 are reported to be expressed in endothelial cells (ECs). Of these, NOX1 and NOX2 have been reported to contribute to intravitreal neovascularization (IVNV) in oxygen-induced retinopathy (OIR) models. In this study, we tested the hypothesis that the isoform NOX4 in ECs contributed to vascular endothelial growth factor (VEGF)-induced angiogenesis and IVNV.
Nanofiber-based scaffolds may simultaneously provide immediate contact guidance for neural regeneration and act as a vehicle for therapeutic cell delivery to enhance axonal myelination. Additionally, nanofibers can serve as a neuron-free model to study myelination of oligodendrocytes. In this study, we fabricated nanofibers using a polycaprolactone and gelatin co-polymer. The ratio of the gelatin component in the fibers was confirmed by energy dispersive x-ray spectroscopy. The addition of gelatin to the polycaprolactone (PCL) for nanofiber fabrication decreased the contact angle of the electrospun fibers. We showed that both polycaprolactone nanofibers as well as polycaprolactone and gelatin co-polymer nanofibers can support oligodendrocyte precursor cell (OPC) growth and differentiation. OPCs maintained their phenotype and viability on nanofibers and were induced to differentiate into oligodendrocytes. The differentiated oligodendrocytes extend their processes along the nanofibers and ensheathed the nanofibers. Oligodendrocytes formed significantly more myelinated segments on the PCL and gelatin co-polymer nanofibers than those on PCL nanofibers alone.
Nanoscale morphology has been proved to be the key parameter deciding the exciton dissociation and charge transportation in bulk heterojunction (BHJ) solar cells. In this paper, we report a kind of small molecular organic photovoltaic cell (OPV) with a vertically ordered BHJ prepared by the weak epitaxial growth method. By this method, zinc phthalocyanine (ZnPc) can easily be formed into a highly ordered and continuous thin film and C60 is inclined to become dispersed crystalline grains in ZnPc film. Furthermore, we can control both the size and distribution density of C60 crystalline grains in ZnPc thin film without destroying the order of the ZnPc thin film. The OPVs with the vertically ordered BHJ show a high fill factor and a power conversion efficiency over 3% has been achieved.
Replacement of the lost myelin sheath is a therapeutic goal for treating demyelinating diseases of the central nervous system (CNS), such as multiple sclerosis (MS). The G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor (GPCR) GPR17, which is phylogenetically closely related to receptors of the "purinergic cluster," has emerged as a modulator of CNS myelination. However, whether GPR17-mediated signaling positively or negatively regulates this critical process is unresolved. We identified a small-molecule agonist, MDL29,951, that selectively activated GPR17 even in a complex environment of endogenous purinergic receptors in primary oligodendrocytes. MDL29,951-stimulated GPR17 engaged the entire set of intracellular adaptor proteins for GPCRs: G proteins of the G?(i), G?(s), and G?(q) subfamily, as well as ?-arrestins. This was visualized as alterations in the concentrations of cyclic adenosine monophosphate and inositol phosphate, increased Ca²? flux, phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), as well as multifeatured cell activation recorded with label-free dynamic mass redistribution and impedance biosensors. MDL29,951 inhibited the maturation of primary oligodendrocytes from heterozygous but not GPR17 knockout mice in culture, as well as in cerebellar slices from 4-day-old wild-type mice. Because GPCRs are attractive targets for therapeutic intervention, inhibiting GPR17 emerges as therapeutic strategy to relieve the oligodendrocyte maturation block and promote myelin repair in MS.
Activation of Rap1 GTPase can improve the integrity of the barrier of the retina pigment epithelium (RPE) and reduce choroidal neovascularization (CNV). Inhibition of NADPH oxidase activation also reduces CNV. We hypothesize that Rap1 inhibits NADPH oxidase-generated ROS and thereby reduces CNV formation. Using a murine model of laser-induced CNV, we determined that reduced Rap1 activity in RPE/choroid occurred with CNV formation and that activation of Rap1 by 2-O-Me-cAMP (8CPT)-reduced laser-induced CNV via inhibiting NADPH oxidase-generated ROS. In RPE, inhibition of Rap1 by Rap1 GTPase-activating protein (Rap1GAP) increased ROS generation, whereas activation of Rap1 by 8CPT reduced ROS by interfering with the assembly of NADPH oxidase membrane subunit p22phox with NOX4 or cytoplasmic subunit p47phox. Activation of NADPH oxidase with Rap1GAP reduced RPE barrier integrity via cadherin phosphorylation and facilitated choroidal EC migration across the RPE monolayer. Rap1GAP-induced ROS generation was inhibited by active Rap1a, but not Rap1b, and activation of Rap1a by 8CPT in Rap1b(-/-) mice reduced laser-induced CNV, in correlation with decreased ROS generation in RPE/choroid. These findings provide evidence that active Rap1 reduces CNV by interfering with the assembly of NADPH oxidase subunits and increasing the integrity of the RPE barrier.-Wang, H., Jiang, Y., Shi, D., Quilliam, L. A., Chrzanowska-Wodnicka, M., Wittchen, E. S., Li, D. Y., Hartnett, M. E. Activation of Rap1 inhibits NADPH oxidase-dependent ROS generation in retinal pigment epithelium and reduces choroidal neovascularization.
Epithelial-mesenchymal transition (EMT) is an important mechanism in cancer metastasis. Tumor necrosis factor ? (TNF?) can induce cancer invasion and metastasis associated with EMT. However, the underlying mechanisms are not entirely clear. Therefore, we investigated whether TNF? has an effect on EMT and invasion and metastasis in human hypopharyngeal cancer FaDu cells, and further explored the potential mechanisms. In the present study, we demonstrated that TNF? induced EMT in FaDu cells and promoted FaDu cell migration and invasion. TNF?-induced EMT was characterized by a change from well organized cell-cell adhesion and cell polarity to loss of cell-cell contacts, cell scattering and increased expression of vimentin and N-cadherin accompanied by a decrease in E-cadherin. Furthermore, we found that p65 translocated to the nucleus after TNF? stimulation and increased the nuclear expression of TWIST. We demonstrated that TNF? treatment also increased the expression of TWIST by activating the NF-?B signaling pathway. While p65 was inhibited by siRNA-65 or BAY11-7082 (inhibitor of NF-?B), TWIST expression was also decreased. Therefore, we conclude that TNF? induces EMT and promotes metastasis via NF-?B signaling pathway-mediated TWIST expression in hypopharyngeal cancer.
Worldwide, breast cancer is the most frequently diagnosed life-threatening cancer in women and is the leading cause of cancer-related mortality among women. It is extremely rare but highly lethal in men. The deubiquitinating enzyme USP39 plays important roles in mRNA processing, and our previous data showed that high levels of USP39 are selectively present in different types of human breast tumor cells. The potential of USP39 as a therapeutic target for breast cancer was investigated. The expression levels of USP39 protein in 23 breast cancer specimens were quantified using an immunohistochemical assay and were found to have high levels in human breast cancer tissues when compared to these levels in normal breast tissues. In the breast cancer cell line MCF-7, USP39 expression was knocked down by a lentiviral short hairpin RNA (shRNA) delivery system. The RNA interference (RNAi)-mediated downregulation of USP39 expression markedly reduced the proliferative and colony forming ability of MCF-7 cells. In addition, the inhibition of USP39 induced G0/G1-phase arrest and apoptosis of the cells. These results suggest that USP39 may act as an oncogenic factor in breast cancer and could be a potential molecular target for breast cancer gene therapy.
A novel quinazolinone compound containing quinazoline-fused moiety has been synthesized as fluorescence Off-On sensor QQ. The probe exhibited highly selective and sensitive recognition toward trivalent ferric ion (Fe(3+)) over other metal ions in HEPES buffer solution (10 mM, pH?=?7.0, DMF-H2O, 9:1, v/v). The significant quenching in the fluorescence spectral could be served as a selective fluorescence Off-On sensor. The titration study indicated the formation of 1:1 complex between QQ and Fe(3+).
Band-bending in organic semiconductors, occurring at metal/alkali-halide cathodes in organic-electronic devices, is experimentally revealed and electrostatically modeled. Metal-to-organic charge transfer through the insulator, rather than doping of the organic by alkali-metal ions, is identified as the origin of the observed band-bending, which is in contrast to the localized interface dipole occurring without the insulating buffer layer.
For the first time, pseudopolyrotaxane prodrug micelles with high drug content were prepared in water, which could be used for cancer therapy. It is anticipated that this facile strategy may open a novel avenue for the development of multifunctional drug delivery systems.
An effective and facile method for the synthesis of 2,2-di-substituted perhydrofuro[2,3-b]pyran (and furan) derivatives is described. The cyclization of 1,2-cyclopropanated sugars with olefins in the presence of BiCl3 is highly diastereoselective. 2,2-Di-substituted cyclization products were obtained in good to excellent yields.
Our previous study demonstrated that Toll-like receptor 4 (TLR4) could act as a co-receptor with annexin A2 (ANX2) mediating anti-?2-glycoprotein I/?2- glycoprotein I (anti-?2GPI/?2GPI) -induced tissue factor (TF) expression in human acute monocytic leukaemia cell line THP-1. In the current study, we further explored the roles of TLR4 and its adaptors, MD-2 and MyD88, as well as nuclear factor kappa B (NF-?B), in anti-?2GPI/?2GPI-induced the activation of THP-1 cells, especially on the expression of some proinflammatory molecules. The results showed that treatment of THP-1 cells with anti-?2GPI (10?g/ml)/?2GPI (100?g/ml) complex could increase IL-6 (interleukin-6), IL-8 (interleukin-8) as well as TNF-? (tumor necrosis factor alpha) expression (both mRNA and protein levels). These effects could be blocked by addition of TAK-242 (5?M), a blocker of signaling transduction mediated by the intracellular domain of TLR4, and also by NF-?B inhibitor PDTC (20?M). Overall, our results indicate that anti-?2GPI/?2GPI complex induced IL-6, IL-8 and TNF-? expression involving TLR4/MD-2/MyD88 and NF-?B signaling pathways and this might be associated with pathological mechanisms of antiphospholipid syndrome (APS).
HIV-infected individuals currently cannot be completely cured because existing antiviral therapy regimens do not address HIV provirus DNA, flanked by long terminal repeats (LTRs), already integrated into host genome. Here, we present a possible alternative therapeutic approach to specifically and directly mediate deletion of the integrated full-length HIV provirus from infected and latently infected human T cell genomes by using specially designed zinc-finger nucleases (ZFNs) to target a sequence within the LTR that is well conserved across all clades. We designed and screened one pair of ZFN to target the highly conserved HIV-1 5-LTR and 3-LTR DNA sequences, named ZFN-LTR. We found that ZFN-LTR can specifically target and cleave the full-length HIV-1 proviral DNA in several infected and latently infected cell types and also HIV-1 infected human primary cells in vitro. We observed that the frequency of excision was 45.9% in infected human cell lines after treatment with ZFN-LTR, without significant host-cell genotoxicity. Taken together, our data demonstrate that a single ZFN-LTR pair can specifically and effectively cleave integrated full-length HIV-1 proviral DNA and mediate antiretroviral activity in infected and latently infected cells, suggesting that this strategy could offer a novel approach to eradicate the HIV-1 virus from the infected host in the future.
A procedure for the determination of iodide, thiocyanate and perchlorate ions in environmental water by two-dimensional ion chromatography has been developed. At first the iodide, thiocyanate and perchlorate ions were separated from interfering ions by a column (IonPac AS16, 250 mm x 4 mm). The iodide ion, thiocyanate and perchlorate ions were then enriched with an enrichment column (MAC-200, 80 mm x 0.75 mm). In the 2nd-dimensional chromatography, iodide thiocyanate and perchlorate ions were separated and quantified by a capillary column (IonPac AS20 Capillary, 250 mm x 0.4 mm). The linear ranges were 0.05 -100 pg/L with correlation coefficients of 0. 999 9, and the detection limits were 0. 02 - 0.05 micro gg/L. The spiked recoveries of iodide, thiocyanate and perchlorate ions were in the range of 85.1% to 100.1%. The relative standard deviations of the recoveries were 1.7% to 4.9%.
Herpes simplex virus 1 (HSV-1) is regarded as an important underlying cause of Bells palsy, but the immunologic mechanism remains unknown. Here, we employed a mouse facial paralysis model to investigate the expressions of CD4(+) T lymphocytes and interleukin (IL)-2 and -4 in the left draining cervical lymph nodes (LCLN) and spleen, as well as the inhibitory effects of glucocorticoids (GCs).
The ?2-adrenergic receptors (?2-ARs), which mediate physiological responses to noradrenaline and adrenaline, are encoded by three different genes but all are coupled to the Gi/Go subfamily of G proteins. The present study investigated the localization of three subtypes, i.e., ?2a-, ?2b-, and ?2c-ARs, in cochlea and vestibular labyrinth in rat in the early postnatal period by immunohistochemistry. The results showed that ?2-ARs were widely distributed in regions, including the organ of Corti, spiral ganglion neurons, stria vascularis, crista ampullaris, Scarpas ganglion, utricle, and Reissners membrane. Furthermore, the cellular locations of ?2-ARs between different cell subtypes as well as receptor subtypes and different observed time points also had diversity. ?2a-AR mainly targeted to nuclei at postnatal ages (P)3. While at P(8), only ganglion neurons maintained this character whereas other cell types expressed ?2a-AR mainly in plasma membrane. The ?2b- and ?2c-ARs exhibited predominantly in plasma membrane. Compared with P(8), ?2c-AR was not present at stria vascularis at P(3). Overall, our observations indicated that there was region-specific regulation of ?2-ARs development in cochlea and vestibular labyrinth. In addition, the extensive expressions of ?2-ARs established a significant foundation for the exploration of the function of ?2-ARs in cochlea and vestibular labyrinth.
China has developed a new national program for deceased-organ donation to address the need for organ transplantation in the country. The program adheres to the World Health Organization (WHO) guiding principles, is compliant with the Declaration of Istanbul, and respects the cultural and social values of the Chinese people. The experience of pilot trials conducted between 2010 and 2012 was evaluated to generate a comprehensive design of a national program of organ donation and transplantation for implementation throughout China. The legal framework for this program was established from a series of legislative steps since 2007. Accountable national committees have been established to oversee activities of organ donation and transplantation across the nation. The Ministry of Health (MOH) has accredited 164 organ transplant hospitals in China, each of which has an organ procurement organization (OPO) to conduct organ donation and organ recovery. National protocols for deceased-organ donation in China include category I (organ donation after brain death), category II (organ donation after circulatory death), and category III (organ donation after brain death followed by circulatory death). The China Organ Transplant Response System (COTRS) has been developed to allocate organs equitably and transparently. Scientific registries have been established to evaluate the performance of transplant centers and OPOs. China is in the process of implementing a new national program for deceased-organ donation. The program includes a unique approach of organ donation, China category III, which will be promulgated throughout China and is intended to gain widespread acceptance of Chinese society.
Pseudogout, also known as calcium pyrophosphate dihydrate deposition disease (CPPD) with giant cell reparative granuloma (GCRG) of the temporal bone is a rare disease, which is very easy to misdiagnose. When two diseases occur simultaneously, the pathological tissue of diseases is closely associated, which complicates clinical representation and causes enormous difficulty in diagnosis and treatment. We report a case of CPPD of the temporomandibular joint accompanied by surrounding GCRG of temporal bone in a 62-year-old male.
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