Six tartrate-bridging rare-earth-substituted polytungstoarsenates [RE2(C4H4O6)(C4H2O6)(As W9O33)]2(18-) (Ho(III) (), Er(III) (), Tm(III) (), Yb(III) (), Lu(III) (), and Y(III) ()) have been synthesized under conventional solution conditions. They have been further characterized by elemental analyses, X-ray powder diffraction (XRPD), IR and UV-vis spectroscopy and single-crystal X-ray diffraction. Preliminary variable-temperature magnetic susceptibility measurements indicate that exhibit antiferromagnetic coupling.
We have previously reported that the removal of a 20-nucleotide sequence, termed the D-sequence, from both ends of the inverted terminal repeats (ITRs) in the adeno-associated virus serotype 2 (AAV2) genome, significantly impairs rescue, replication, and encapsidation of the viral genomes (J. Mol. Biol., 250: 573-580, 1995; J. Virol., 70: 1668-1677, 1996). Here we describe that substitution of only one D-sequence in either ITR restores each of these functions, but DNA strands of only single-polarity are encapsidated in mature progeny virions. Since most commonly used recombinant AAV vectors contain a single-stranded (ss) DNA, which is transcriptionally-inactive, efficient transgene expression from AAV vectors is dependent upon viral second-strand DNA synthesis. We have also identified a transcription-suppressor sequence in one of the D-sequences, which shares homology with the binding site for the cellular NF-?B-repressing factor (NRF). The removal of this D-sequence from, and substitution with a sequence containing putative binding sites for transcription factors in, ssAAV vectors significantly augments transgene expression both in human cell lines in vitro and in murine hepatocytes in vivo. The development of these genome-modified ssAAV vectors has implications not only in the basic biology of AAV, but also in the optimal use of these vectors in human gene therapy.
Current challenges for recombinant adeno-associated virus (rAAV) vector-based cancer treatment include the low-efficiency and the lack of specificity in vivo. rAAV serotype 3 (rAAV3) vectors have previously been shown to be ineffective in normal mouse tissues following systemic administration. In the present study, we report that rAAV3 vectors can efficiently target and transduce various human liver cancer cells in vivo. Elimination of specific surface-exposed serine and threonine residues on rAAV3 capsids results in further augmentation in the transduction efficiency of these vectors, without any change in the viral tropism and cellular receptor interactions. In addition, we have identified a potential chemotherapy drug, shikonin, as a multifunctional compound to inhibit liver tumor growth as well as to significantly enhance the efficacy of rAAV vector-based gene therapy in vivo. Furthermore, we also document that suppression of tumorigenesis in a human liver cancer xenograft model can be achieved through systemic administration of the optimized rAAV3 vectors carrying a therapeutic gene, and shikonin at a dose that does not lead to severe liver damage. Our research provides a novel means to achieve not only targeted delivery, but also the potential for gene therapy of human liver cancer.
To observe the effects of a novel all-trans retinoid acid (ATRA) derivative, N-(3-trifluoromethyl-phenyl)- retinamide (ATPR), on lung adenocarcinoma A549 cells and to explore the potential mechanism of ATPR inhibiting of A549 cell migration.
Objective To detect the expression of microRNA-143 (miR-143) in hepatocellular carcinoma and investigate whether transfection of miR-143 could influence the biological behaviors of hepatocellular carcinoma cells. Methods Hepatocellular carcinoma tissues and its corresponding adjacent normal tissues were obtained from patients undergoing radical surgical resection. Real-time quantitative PCR was utilized to detect the relative expression of miR-143 in hepatocellular carcinoma tissues and corresponding adjacent normal tissues. MiR-143 mimics and negative control oligonucleotides were synthesized and transfected into HepG-2 cells in vitro. Proliferation, apoptosis and invasion of the transfected cells were measured by MTT assay, flow cytometry (FCM) combined with annexin V-FITC/PI staining, and Transwell(TM) assay, respectively. The protein levels of Toll-like receptor 2 (TLR2), nuclear factor kappa B (NF-?B), matrix metalloproteinase 2 (MMP-2) and MMP-9 were detected by Western blotting. Results Expression of miR-143 was significantly lower in hepatocellular carcinoma tissues than in paired adjacent normal tissues. The level of miR-143 was significantly up-regulated after transfection of miR-143 mimics. And proliferation and invasion were significantly inhibited, but apoptosis was promoted after transfection. Expressions of TLR2, NF-?B, MMP-2 and MMP-9 were reduced by miR-143 mimics' transfection. Conclusion The miR-143 expression was low in hepatic carcinoma and its over-expression could down-regulate the expressions of TLR2, NF-?B, MMP-2 and MMP-9.
A novel Particle Tracking Velocimetry (PTV) algorithm based on Voronoi Diagram (VD) is proposed and briefed as VD-PTV. The robustness of VD-PTV for pulsatile flow is verified through a test that includes a widely used artificial flow and a classic reference algorithm. The proposed algorithm is then applied to visualize the flow in an artificial abdominal aortic aneurysm included in a pulsatile circulation system that simulates the aortic blood flow in human body. Results show that, large particles tend to gather at the upstream boundary because of the backflow eddies that follow the pulsation. This qualitative description, together with VD-PTV, has laid a foundation for future works that demand high-level quantification.
Generating an artificial blood flow in a circle system is an important step in hemodynamic research; thus, the influence of circle system components on the pulsatile flow wave forms should be investigated. In this study, a circle system was built, in which two solenoid valves were controlled by a timer to transform a constant flow into a pulsatile one, and two customized compliances with five different aeration volumes were set up upstream and downstream of the test chamber, achieving twenty-five different wave forms. Then, the influence of the compliance settings on the flow rate wave form was investigated. From the experimental data, it can be concluded that the absolute value of the maximum value and the minimum value of the wave forms increases along the aeration of the downstream compliance but decreases along the aeration of the upstream compliance. For the second maximum value and the offset between the maximum value and the minimum value, remarkable differences were obtained between runs with aeration of zero compliance and nonzero compliance. Finally, an emulational flow was achieved with the up- and downstream aeration volume equaling 360 mL and 180 mL, respectively, which fit the realistic wave form well.
Angiogenesis, the formation of new blood vessels from preexisting ones, is essential for development, wound healing, and tumor progression. The VEGF pathway plays irreplaceable roles during angiogenesis, but how other signals crosstalk with and modulate VEGF cascades is not clearly elucidated. Here, we identified that Gpr126, an endothelial cell enriched gene, plays an important role in angiogenesis by regulating endothelial cell proliferation, migration, and tube formation. Knockdown of Gpr126 in the mouse retina resulted in the inhibition of hypoxia-induced angiogenesis. Interference of Gpr126 expression in zebrafish embryos led to defects in intersegmental vessel formation. Finally, we identified that GPR126 regulated the expression of VEGFR2 by targeting STAT5 and GATA2 through the cAMP-PKA-CREB signaling pathway during angiogenesis. Our findings illustrate that GPR126 modulates both physiological and pathological angiogenesis through VEGF signaling, providing a potential target for the treatment of angiogenesis-related diseases.
Melatonin (MLT) is an endogenous indole compound with numerous biological activities that has been associated with atherosclerosis (AS). In the present study, rabbits were used as an AS model in order to investigate whether MLT affects endothelial cell permeability, myosin light chain kinase (MLCK) activity and MLCK expression via the mitogen?activated protein kinase (MAPK) pathway. Expression and activity of MLCK were measured using western blot analysis, quantitative polymerase chain reaction, immunohistochemistry and ??32P?adenosine triphosphate incorporation. Endothelial permeability was detected using rhodamine phalloidin fluorescence staining. The phosphorylation of extracellular regulated protein kinase (ERK), c?Jun N?terminal kinase (JNK) and p38 in endothelial cells were also analyzed using western blot analysis. Atheromatous plaques were formed in rabbits with a high cholesterol diet; however, following treatment with MLT, the number and areas of atheromatous plaques were significantly reduced. In addition, MLT treatment reversed the increase of MLCK activity and expression that occurred in rabbits with high cholesterol intake. Furthermore, levels of phosphorylated ERK, JNK and p38 decreased following MLT treatment. In conclusion, the results of the present study indicated that AS may be associated with increased MLCK expression and activity, which was reduced following treatment with MLT. The mechanism of action of MLT was thought to proceed via modulating MAPK pathway signal transduction; however, further studies are required in order to fully elucidate the exact regulatory mechanisms involved.
Transition metal dichalcogenide (TMDC) monolayers have recently emerged as an important class of two-dimensional semiconductors with potential for electronic and optoelectronic devices. Unlike semi-metallic graphene, layered TMDCs have a sizeable bandgap. More interestingly, when thinned down to a monolayer, TMDCs transform from indirect-bandgap to direct-bandgap semiconductors, exhibiting a number of intriguing optical phenomena such as valley-selective circular dichroism, doping-dependent charged excitons and strong photocurrent responses. However, the fundamental mechanism underlying such a strong light-matter interaction is still under intensive investigation. First-principles calculations have predicted a quasiparticle bandgap much larger than the measured optical gap, and an optical response dominated by excitonic effects. In particular, a recent study based on a GW plus Bethe-Salpeter equation (GW-BSE) approach, which employed many-body Green's-function methodology to address electron-electron and electron-hole interactions, theoretically predicted a diversity of strongly bound excitons. Here we report experimental evidence of a series of excitonic dark states in single-layer WS2 using two-photon excitation spectroscopy. In combination with GW-BSE theory, we prove that the excitons are of Wannier type, meaning that each exciton wavefunction extends over multiple unit cells, but with extraordinarily large binding energy (?0.7 electronvolts), leading to a quasiparticle bandgap of 2.7 electronvolts. These strongly bound exciton states are observed to be stable even at room temperature. We reveal an exciton series that deviates substantially from hydrogen models, with a novel energy dependence on the orbital angular momentum. These excitonic energy levels are experimentally found to be robust against environmental perturbations. The discovery of excitonic dark states and exceptionally large binding energy not only sheds light on the importance of many-electron effects in this two-dimensional gapped system, but also holds potential for the device application of TMDC monolayers and their heterostructures in computing, communication and bio-sensing.
In this paper, plasmonic photocatalyst Ag@AgCl nanotubes were prepared by a cost-efficient and template-based method and their photocatalytic properties were studied. In the synthesis, copper nanowires were first synthesized and Ag nanotubes were then obtained through the galvanic reaction between copper and Ag ions. The formation of Ag@AgCl nanotubes was finally achieved by in situ oxidation reaction upon the addition of FeCl3. The crystal structure of the product was characterized by X-ray powder diffraction. The morphology and composition of the composite were studied by scanning electron microscopy, transmission electron microscopy, and X-ray photoelectron spectroscopy measurements. All the structure characterizations showed that the tubulate product was produced by the synthetic processes. By using the obtained product as photocatalyst, the photodegradation of methyl orange (MO) was investigated under visible light. The experimental results showed that the as-prepared Ag@AgCl nanotubes exhibit excellent photocatalytic performance and high stability. Under visible light irradiation, more than 92.58% of the MO dye has been decomposed in 10 min on the product with a 1:1 ratio of Fe/Ag. On the basis of the proposed mechanism, the improved photocatalytic activities of the Ag@AgCl hybrids can be ascribed to the enhanced surface area for dye molecule adsorption, enhanced visible light absorbance, and the efficient charge separation of the hybrid nanostructures.
We recently found that HOTAIR (HOX antisense intergenic RNA) promotes development and induces radioresistance in cervical cancer. In the present study, we investigated the circulating HOTAIR expression and determined its relationships with the clinicopathological parameters in cervical cancer. The sera samples were obtained from 118 pathological diagnosed cervical cancer patients and 100 normal age-matched women. The expression of HOTAIR was measured by quantitative real time PCR. Patients' information were collected and analyzed by the SPSS 17.0 software. Compared with normal control, the expression of HOTAIR was significantly upregulated in the sera of cervical cancer patients (P?0.0001). In addition, elevated HOTAIR was associated with advanced tumor stages (P?0.0001), adenocarcinoma (P?0.0001), lymphatic vascular space invasion (P?=?0.0065), and lymphatic node metastasis (P?=?0.0259). In addition, our follow-up data showed that high HOTAIR was notably correlated with tumor recurrence (P?=?0.013) and short overall survival (P?=?0.009). Circulating HOTAIR was commonly upregulated and a potent prognostic marker in cervical cancer.
Two new copper(II) (2) and nickel(II) (3) complexes with a new coumarin derivative have been synthesized and structurally characterized. The DNA-binding activities of the two complexes have been investigated by spectrometric titrations, ethidium bromide displacement experiments, CD (circular dichroism) spectral analysis, and viscosity measurements. The results indicate that the two complexes, especially the complex 2, can strongly bind to calf-thymus DNA (CT--DNA). The intrinsic binding constants Kb of the complexes with CT-DNA are 2.99 × 10(5) and 0.61 × 10(5) for 2 and 3, respectively. Comparative cytotoxic activities of the two complexes are also determined by MTT assay. The results show that the drugs designed here have significant cytotoxic activity against the human hepatic (HepG2), human promyelocytic leukemia (HL60), and human prostate (PC3) cell lines. Cell apoptosis was detected by Annexin V/PI flow cytometry, and the results show that the two copper complexes can induce apoptosis of the three human tumor cells. In conclusions, the two complexes show considerable cytotoxic activity against the three human cancer and induce apoptosis of the threes.
Herbal medicines contain a large number of minor constituents, which could contribute to their therapeutic effects and provide valuable lead compounds for drug discovery. However, to explore minor constituents from complicated herbal extracts is usually laborious and time-consuming. In order to discover minor novel herbal constituents efficiently, we combined heart-cutting and comprehensive two-dimensional liquid chromatography (HC-2DLC) to remove major components from herbal extracts, and then characterized the minor ones by mass spectrometry. This strategy was employed to analyze Pueraria lobata and Pueraria thomsonii, the roots of which are used as the Chinese herbal medicine Ge-Gen. Five major compounds in Ge-Gen extract were removed by on-line heart-cutting, and the minor compounds were separated on an RP×RP 2DLC system (1D, Acquity CSH C18, 2.1×100mm, 1.7?m; 2D, Poroshell Phenyl-Hexyl, 3.0×50mm, 2.7?m). A synchronized gradient elution program was used to improve chromatographic resolution of the second dimension. By using this 2DLC system, a total of 271 and 254 peaks were separated in P. lobata and P. thomsonii within 35min, respectively. The practical and effective peak capacity was 1593 and 677, respectively, and the orthogonality was around 70%. Structures of 12 selected compounds were tentatively characterized by mass spectrometry, and 9 of them were discovered from Ge-Gen for the first time. Contents of these minor compounds in Ge-Gen were preliminarily determined to be 0.01-0.1% (w/w). The HC-2DLC/MS system is a powerful and convenient tool to explore minor novel chemical constituents from complex herbal extracts.
To observe the relationship between reduced pulmonary function and regulatory T cells (Tregs) and helper T cells (Th)1/Th2 drift in a rat model of adjuvant arthritis (AA), and to study the impact of Xinfeng capsule (XFC) on pulmonary function and investigate the mechanism of action.
The K121Q gene polymorphism of ectoenzyme nucleotide pyrophosphate phosphodiesterase 1(ENPP1) has been widely investigated, however, results have been somewhat conflicting. The aim of this meta-analysis was to establish a precise estimation of the association between ENPP1 gene polymorphisms and type 2 diabetes (T2D). A literature search in PubMed, Embase, Cochrane Library and China Biology Medicine (CBM) databases was conducted on publications published prior to November 21(st), 2013. The combined odds ratio (OR) with 95% confidence intervals (95%CI) was calculated to estimate the strength of the association using a random-effects/fixed-effects model. Statistical analyses were performed using the STATA 11.0 software. For the overall population, there was a significant association between ENPP1 gene polymorphisms and T2D when comparing the Q allele versus K allele (OR=1.29, 95%CI 1.16-1.44, p=0.000). Considering diverse ethnic groups, effect sizes were consistent for patients of Caucasian and Asian descent (OR=1.20, 95%CI=1.08-1.33 and OR=1.47, 95%CI=1.15-1.89, respectively); however, effect size was not consistent for those of African descent. Under other models of inheritance, significant associations were also observed. Sensitivity analyses did not leading to differing he results. In summary, the Q allele of the ENPP1 K121Q gene may contribute to the susceptibility for T2D in Caucasians and Asians.
A highly active Pt-Cu bimetallic catalyst for the electrocatalytic oxygen reduction reaction, with an average diameter of 2.9 nm and a Cu/Pt ratio of 0.30 for the bimetallic nanoparticles, was prepared by capturing Pt-Cu alloy nanoparticles on melem-modified carbon, followed by removing 90% of copper from the alloy NPs.
High-fat diet has been reported to be associated with cardiovascular diseases which is implicated in atherosclerosis. However, the underlying mechanisms remain unknown. MicroRNAs (miRNAs) are non-coding small RNAs that control gene expression at the post-transcriptional level. Dysregulated miRNAs have been shown to be involved in atherosclerosis.
We have previously reported that Zn(2+) infused into the coronary arteries of isolated rat hearts leads to the potent dephosphorylation of phospholamban (PLB) as well as a noticeable but less potent dephosphorylation of the ryanodine receptor 2. We hypothesized in the present study that a Zn(2+)-activated phosphatase is located in the vicinity of the sarcoplasmic reticulum (SR) where PLB and ryanodine receptor 2 reside. We report here the novel finding of tissue-nonspecific alkaline phosphatase (TNAP), a zinc-dependent enzyme, localized to the SR in the cardiac sarcomere of mouse myocardium. TNAP activity was enhanced by injection of Zn acetate into a tail vein before harvesting the heart and imaged using electron microscopy of electron dense deposits indicative of the hydrolysis of exogenous ?-glycerophosphate. TNAP activity was observed localized to the ends of the Z-line corresponding to SR and was qualitatively more visible in myocardium of males compared with females. Correspondingly, PLB phosphorylation status was potently reduced in myocardium of males injected with Zn acetate, whereas there was no apparent effect of Zn acetate injection on PLB phosphorylation in females. Surprisingly, Western blot analysis of TNAP content suggested a significantly lower TNAP content in males compared with females. These data suggest that TNAP plays a role in governing the phosphorylation status of calcium handling proteins in the SR. Furthermore, the content and activity of TNAP are differentially regulated between the sexes and thus may account for some sex differences in cardiopathologies associated with calcium handling.
To investigate the postoperative application of nasopharyngeal airway (NPA) in rhinogenous obstructive sleep apnea hypopnea syndrome (OSAHS) patients, so that to observe the parameters including vital signs of the patients and evaluatethe value of clinical application and reliability of NPA.
The SWI/SNF complex plays an important role in mouse embryonic stem cells (mESCs), but it remains to be determined whether this complex is required for the pluripotency of human ESCs (hESCs). Using RNAi, we demonstrated that depletion of BRG1, the catalytic subunit of the SWI/SNF complex, led to impaired self-renewing ability and dysregulated lineage specification of hESCs. A unique composition of the BRG1-SWI/SNF complex in hESCs was further defined by the presence of BRG1, BAF250A, BAF170, BAF155, BAF53A, and BAF47. Genome-wide expression analyses revealed that BRG1 participated in a broad range of biological processes in hESCs through pathways different from those in mESCs. In addition, chromatin immunoprecipitation sequencing (ChIP-seq) demonstrated that BRG1 played a repressive role in transcriptional regulation by modulating the acetylation levels of H3K27 at the enhancers of lineage-specific genes. Our data thus provide valuable insights into molecular mechanisms by which transcriptional repression affects the self-renewal and differentiation of hESCs.
We examined the magnesium dependence of five class II myosins, including fast skeletal muscle myosin, smooth muscle myosin, ?-cardiac myosin (CMIIB), Dictyostelium myosin II (DdMII), and nonmuscle myosin IIA, as well as myosin V. We found that the myosins examined are inhibited in a Mg(2+)-dependent manner (0.3-9.0 mm free Mg(2+)) in both ATPase and motility assays, under conditions in which the ionic strength was held constant. We found that the ADP release rate constant is reduced by Mg(2+) in myosin V, smooth muscle myosin, nonmuscle myosin IIA, CMIIB, and DdMII, although the ADP affinity is fairly insensitive to Mg(2+) in fast skeletal muscle myosin, CMIIB, and DdMII. Single tryptophan probes in the switch I (Trp-239) and switch II (Trp-501) region of DdMII demonstrate these conserved regions of the active site are sensitive to Mg(2+) coordination. Cardiac muscle fiber mechanic studies demonstrate cross-bridge attachment time is increased at higher Mg(2+) concentrations, demonstrating that the ADP release rate constant is slowed by Mg(2+) in the context of an activated muscle fiber. Direct measurements of phosphate release in myosin V demonstrate that Mg(2+) reduces actin affinity in the M·ADP·Pi state, although it does not change the rate of phosphate release. Therefore, the Mg(2+) inhibition of the actin-activated ATPase activity observed in class II myosins is likely the result of Mg(2+)-dependent alterations in actin binding. Overall, our results suggest that Mg(2+) reduces the ADP release rate constant and rate of attachment to actin in both high and low duty ratio myosins.
This study was aimed to explore the effect of realgar (As4S4) on growth inhibition and apoptosis induction of DLBCL cell line SU-DHL-4 and its mechanisms. The inhibitory effect of realgar on the cell growth were detected by MTT method. The morphological changes of SU-DHL-4 were observed by transmission electron microscopy (TEM). The apoptosis of SU-DHL-4 cells treated with realgar were detected by flow cytometry with Annexin V-FITC/PI double staining and DNA agarose gelelectrophoresis. The cell cycle was examined by flow cytometry with PI staining. The expressions of apoptosis-related proteins (BCL-2 , Caspase-3,BAX) were detected by Western blot. The results showed that the realgar at the concentration of 20, 40, 80 µmol/L all could inhibit the proliferation of SU-DHL-4 (P < 0.05), and in a certain time and concentration range, the inhibition rate was enhanced in a time and dose dependent manner(r = 0.982). Flow cytometric test results showed that realgar could induce SU-DHL-4 cell apoptosis after treating for 48 hours, and the apoptosis rate increased with the increasing of drug concentration (P < 0.05). After treating SU-DHL-4 cells with Realgar for 48 h, the cell cycle was blocked in the S phase (P < 0.05). TEM results revealed that when treated with realgar for 48 h, the typically apoptosis morphology-apoptotic bodies were observed in all drug-treated group, furthermore, some necrotic cells in the 80 µmol/L group were observed. After intervened by realgar for 48 h, the DNA Ladder pattern was seen according to agarose gelelectrophoresis. Western blot showed that the expression of Bcl-2 protein was down-regulated while the expressions of BAX and Caspase-3 protein were up-regulated when treating SU-DHL-4 cells with realgar for 48 h. It is concluded that realgar can inhibit cell growth and induce cell apoptosis, which may be related with up-regulation of Caspase-3 and BAX expression and down-regulation the of BCL-2 expression.
We tested whether cardiac myosin binding protein-C (cMyBP-C) affects myosin cross-bridge kinetics in the two cardiac myosin heavy chain (MyHC) isoforms. Mice lacking cMyBP-C (t/t) and transgenic controls [Formula: see text] were fed L-thyroxine (T4) to induce 90/10 % expression of ?/?-MyHC. Non-transgenic (NTG) and t/t mice were fed 6-n-propyl-2-thiouracil (PTU) to induce 100 % expression of ?-MyHC. Ca(2+)-activated, chemically-skinned myocardium underwent length perturbation analysis with varying [MgATP] to estimate the MgADP release rate [Formula: see text] and MgATP binding rate [Formula: see text]. Values for [Formula: see text] were not significantly different between [Formula: see text] (102.2 ± 7.0 s(-1)) and [Formula: see text] (91.3 ± 8.9 s(-1)), but [Formula: see text] was lower in [Formula: see text] (165.9 ± 12.5 mM(-1) s(-1)) compared to [Formula: see text] (298.6 ± 15.7 mM(-1) s(-1), P < 0.01). In myocardium expressing ?-MyHC, values for [Formula: see text] were higher in [Formula: see text] (24.8 ± 1.0 s(-1)) compared to [Formula: see text] (15.6 ± 1.3 s(-1), P < 0.01), and [Formula: see text] was not different. At saturating [MgATP], myosin detachment rate approximates [Formula: see text], and detachment rate decreased as sarcomere length (SL) was increased in both [Formula: see text] and [Formula: see text] with similar sensitivities to SL. In myocardium expressing ?-MyHC, detachment rate decreased more as SL increased in [Formula: see text] (21.5 ± 1.3 s(-1) at 2.2 ?m and 13.3 ± 0.9 s(-1) at 3.3 ?m) compared to [Formula: see text] (15.8 ± 0.3 s(-1) at 2.2 ?m and 10.9 ± 0.3 s(-1) at 3.3 ?m) as detected by repeated-measures ANOVA (P < 0.01). These findings suggest that cMyBP-C reduces MgADP release rate for ?-MyHC, but not for ?-MyHC, even as the number of cMyBP-C that overlap with the thin filament is reduced to zero. Therefore, cMyBP-C appears to affect ?-MyHC kinetics independent of its interaction with the thin filament.
By using water drop penetration time (WDPT) and molarity of ethanol droplet (MED) methods, the soil water repellence of undisturbed biological soil crusts (biocrusts) in five successional stages, from the hilly Loess Plateau region of China was tested. The five stages of biocrusts were light cyanobacterial crust, dark cyanobacterial crust, cyanobacterial with sparse moss crust, moss and tiny cyanobacteria patches crust and moss dominated crust. The results showed that 1) the soil water repellence was markedly increased both in the intensity and persistence since the formation of biocrusts. 2) The soil water repellence showed a decrease trend along with the successional stages of biocrusts. The soil water repellence of the biocrusts with the moss coverage above 20% was significantly lower than that of the cyanobacterial crusts. 3) The soil water repellence of the biocrusts was closely related to soil moisture and the dominant organism. The soil water repellence increased with the decrease of soil water content for the moss dominated biocrusts, while changed in a bimodal curve with the decrease of soil water content for the cyanobacterial biocrusts.
Soil surface roughness exerts profound influence on runoff and sediments yield from slopes. Biological soil crusts (BSCs) are ubiquitous living cover in the open spaces between plants in arid and semiarid ecosystems, which considerably impact the surface roughness. Aimed to determine the effect of biological crusts on the surface roughness and its influence factors, this study investigated the surface roughness of soil with BSCs at their different successional stages by using the chain method. Besides, the impacts of slope aspects, soil water content and freezing and thawing on surface roughness were also investigated. Then, the correlations between roughness and soil chemical and physical properties were evaluated. The results showed that soil surface roughness decreased at the initial successional stage of BSCs but increased along with BSCs' development in the region. Soil roughness tended to be stabile since BSCs developed ten years later. The roughness was reduced by 47.0% by the light cyanobacteria-dominated crust and 20.4% by the dark cyanobacteria-dominated crust (moss coverage < 20%), compared with the bare soil. Soil moisture significantly impacted surface roughness. The surface roughness of BSCs changed obviously with soil moisture in the early development, but only slightly in their later succession. Freezing-thawing also affected surface roughness with BSCs. Roughness was more susceptible to freezing-thawing in the early de- velopment of BSCs, with an increase of 29.7% compared with the bare soil. The surface roughness of late successional BSCs exhibited a slight change only after repeated freezing-thawing. The surface roughness of BSCs showed a statistically significant relationship with the coverage of moss (P < 0.1).
Modern high-throughput screening (HTS) is a well-established approach for hit finding in drug discovery that is routinely employed in the pharmaceutical industry to screen more than a million compounds within a few weeks. However, as the industry shifts to more disease-relevant but more complex phenotypic screens, the focus has moved to piloting smaller but smarter chemically/biologically diverse subsets followed by an expansion around hit compounds. One standard method for doing this is to train a machine-learning (ML) model with the chemical fingerprints of the tested subset of molecules and then select the next compounds based on the predictions of this model. An alternative approach would be to take advantage of the wealth of bioactivity information contained in older (full-deck) screens using so-called HTS fingerprints, where each element of the fingerprint corresponds to the outcome of a particular assay, as input to machine-learning algorithms. We constructed HTS fingerprints using two collections of data: 93 in-house assays and 95 publicly available assays from PubChem. For each source, an additional set of 51 and 46 assays, respectively, was collected for testing. Three different ML methods, random forest (RF), logistic regression (LR), and naïve Bayes (NB), were investigated for both the HTS fingerprint and a chemical fingerprint, Morgan2. RF was found to be best suited for learning from HTS fingerprints yielding area under the receiver operating characteristic curve (AUC) values >0.8 for 78% of the internal assays and enrichment factors at 5% (EF(5%)) >10 for 55% of the assays. The RF(HTS-fp) generally outperformed the LR trained with Morgan2, which was the best ML method for the chemical fingerprint, for the majority of assays. In addition, HTS fingerprints were found to retrieve more diverse chemotypes. Combining the two models through heterogeneous classifier fusion led to a similar or better performance than the best individual model for all assays. Further validation using a pair of in-house assays and data from a confirmatory screen--including a prospective set of around 2000 compounds selected based on our approach--confirmed the good performance. Thus, the combination of machine-learning with HTS fingerprints and chemical fingerprints utilizes information from both domains and presents a very promising approach for hit expansion, leading to more hits. The source code used with the public data is provided.
Inflammatory bowel disease (IBD), which can increase the risk of colorectal cancer (CRC), includes two primary subtypes, ulcerative colitis (UC) and Crohn's disease (CD). Although several individual genes involved in inflammation or cancer characterization have been identified, it is still difficult to elucidate functional relationship details between the molecules underlying pathogenesis at the system level. The global effect of miRNAs on genes or their involved functions is also poorly understood. We first integrated genome-wide gene expression profiles and biological pathway information to explore the underlying associations among UC, CD and CRC at the function and gene level. After identifying the pathways regulated by miRNAs, a global map of miRNA-mediated pathway crosstalk shared by the three diseases was further constructed to vertically explain the links of three level alterations. The three types of diseases have close associations with each other at the levels of function, gene and miRNA regulation. Several key biological pathways are involved in the three diseases, related to the immune system and inflammation, metabolism, or cell proliferation and apoptosis etc. Moreover, miRNAs exhibit dominant effects on multiple pathways. It is worth noting that UC shows relatively close associations with CD and CRC at the three levels. Finally, the miRNAs could mediate the crosstalk within or between pathways. For example, hsa-miR-125b, hsa-miR-335 and hsa-miR-155 mediated the crosstalk between three metabolic pathways. The crosstalk within the Toll-like receptor signaling pathway could be mediated by hsa-miR-124, hsa-miR-146a and hsa-mir-221/222. Our results make sense for the prevention and treatment of intestinal-related chronic inflammation or cancer.
The influences of storage time, pH, electrolytes and organic matters on the stability of two different suspensions of C60 nanoparticles were investigated. The results showed that the C60 nanoparticles prepared by solvent substitution (C60/son) were more stable than that prepared by prolonged stirring (C60/aq), and kept stable for a period of time. Higher pH enhanced the stability of C60 nanoparticles. The presence of electrolyte made a dramatic decrease in the surface zeta potential and an increase in the particle size. The aggregation process of C60 nanoparticles exhibited slow and rapid regions, which was found to be consistent with the classic Derjaguin-Landau-Verwey-Overbeek (DLVO) theory of colloidal stability. The critical coagulation concentration (CCC) values of C60/son, obtained from the intersection of the interpolated lines through the slow and fast regions, were estimated as 321 mmol x L(-1) NaCl, 316 mmol x L(-1) KCl, 9.6 mmol x L(-1) MgCl2 and 6.7 mmol x L(-1) CaCl2. The CCC values of C60/aq were estimated as 295 mmol x L(-1) NaCl, 278 mmol x L(-1) KCl, 7.8 mmol x L(-1) MgCl2 and 5.9 mmol x L(-1) CaCl2, which were much higher than their concentrations in natural waters. The presence of humic acid enhanced the stability of C60 nanoparticles, which was attributable to steric repulsion. Therefore, C60 nanoparticles will keep relatively stable in typical aquatic environments.
The objective of this study was to assess the clinical and histopathological relationship between pulmonary fibrosis and type 1 diabetes. We examined clinical pulmonary function parameters and transbronchial lung biopsies to assess associated histopathological changes in 12 type 1 diabetic patients presenting with dyspnea. Lung CT images pulmonary function tests from 12 diabetic patients without dyspnea and from 12 matched normal subjects served as controls. A similar histopathological analysis, including cytokine levels and pro-fibrotic markers, was performed on lung tissues in mice after the induction of experimental diabetes in an attempt to strengthen the link between diabetes and pulmonary fibrosis. Pulmonary function parameters (FVC, FEV1, TLC, and DLco/VA) were significantly reduced in diabetic patients with dyspnea and without dyspnea, compared to controls. Both patient groups also had increased lung CT scores and symptoms compared to normal controls, though the greatest increases were in the diabetic patients with dyspnea. Chronic hyperglycemia induced in mice led to histopathological changes in the lungs that were similar to those found in the human diabetic subjects and included alveoli compression by hyperplastic interstitium infiltrated with inflammatory cells and fibrotic in nature. Two inflammatory related genes, TNF-? and PAI-1, and two fibrosis-related genes, CTGF and fibronectin, demonstrated increased mRNA and protein expression in diabetic mouse lungs. In conclusion, there were significant clinical and histopathological correlations between pulmonary fibrosis and the presence of type 1 diabetes. Diabetes was clinically associated with pulmonary fibrosis and dysfunction in humans, and diabetes induction led to a similar pulmonary fibrosis in an experimental model. These clinical and non-clinical data suggest that diabetes is an independent risk factor for pulmonary fibrosis.
The aim of the present study was to explore the role of miR-126 in palmitate-induced HUVECs apoptosis and the possible mechanisms. Palmitate inhibited miR-126 expression in HUVECs, increased reactive oxygen species (ROS) production, and induced apoptosis as determined by up-regulation of caspase-3 activity and DNA fragmentation. Overexpression of miR-126 decreased ROS production, TNF-? expression, and apoptosis in palmitate-stimulated HUVECs. In contrast, miR-126 antagomir enhanced palmitate-induced ROS production, TNF-? expression, and apoptosis. The induction of miR-126 correlated with a reduction in TRAF7. We further showed that miR-126 targeted and inhibited TRAF7 expression through target sites located in the 3' untranslated region of TRAF7 mRNA. In concordance, miR-126 mimic reduced TRAF7 protein in HUVECs, whereas the inhibition of miR-126 increased it. This study demonstrates an anti-apoptotic role of miR-126 in HUVECs and identifies TRAF7 as a direct target of miR-126 in HUVECs.
To investigate whether endoplasmic reticulum (ER) stress participates in the induction of apoptosis in HepG2 cells exposed to high glucose and explore its probable mechanism. A series of experiments were performed following HepG2 cells treated with different concentrations of glucose for 48 h. The apoptosis was detected by means of Hoechst staining and flow cytometry. Caspase-3 activity assay was performed by measuring the pNA (p-nitroaniline) to indirectly reveal the catalytic activity of caspase-3. The expression levels of apoptosis-, ER stress-associated proteins and MAPKs were analyzed by western blot. To further characterize the molecular mechanisms, the effects of antioxidant alpha-lipoic acid (ALA) and specific inhibitors for JNK and p38 (SP600125 and SB203580, respectively) were examined by Hoechst staining, immunofluorescence, and western blot. After HepG2 cells were incubated with high glucose for 48 h, both Hoechst staining and flow cytometry analyses unveiled the apoptosis of HepG2 cells. Caspase-3 activity assay revealed that the activity of caspase-3 was enhanced. Western blot showed an enhancement of pro-caspase-9 degradation, a reduction of Bcl-2/Bax ratio, a decrease in GRP78 expression, and increases in CHOP and p47/phox levels. In addition, western blot analysis presented that phosphorylation of p38 and JNK was triggered and that the expression of ASK1 was elevated. In the case of the contributions of oxidative stress and the MAPK signaling pathways, all ALA, SP600125 and SB203580 were able to largely rescue high glucose-induced apoptosis. High glucose induced the apoptosis in HepG2 cells through the activation of ASK1-p38/JNK pathway mediated by ER stress and oxidative stress.
Oblique plane imaging, using remote focusing with a tilted mirror, enables direct two-dimensional (2D) imaging of any inclined plane of interest in three-dimensional (3D) specimens. It can image real-time dynamics of a living sample that changes rapidly or evolves its structure along arbitrary orientations. It also allows direct observations of any tilted target plane in an object of which orientational information is inaccessible during sample preparation. In this work, we study the optical resolution of this innovative wide-field imaging method. Using the vectorial diffraction theory, we formulate the vectorial point spread function (PSF) of direct oblique plane imaging. The anisotropic lateral resolving power caused by light clipping from the tilted mirror is theoretically analyzed for all oblique angles. We show that the 2D PSF in oblique plane imaging is conceptually different from the inclined 2D slice of the 3D PSF in conventional lateral imaging. Vectorial optical transfer function (OTF) of oblique plane imaging is also calculated by the fast Fourier transform (FFT) method to study effects of oblique angles on frequency responses.
Accurate prediction to the detonation performances of different kinds of energetic materials has attracted significant attention in the area of high energy density materials (HEDMs). A common approach for the estimation of CHNO explosives is the Kamlet-Jacobs (K-J) equation. However, with the development of energetic materials, the components of explosives are no longer restricted to CHNO elements. In this study, we have extended the K-J equation to the calculation of certain metal-containing explosives. A new empirical method, in which metal elements are assumed to form metallic oxides, has been developed on the basis of the largest exothermic principle. In this method, metal oxides can be deemed as inert solids that release heat other than gases. To evaluate the prediction accuracy of new method, a commercial program EXPLO5 has been employed for the calculation. The difference involved in the ways of treating products has been taken into account, and the detonation parameters from two methods were subject to close comparison. The results suggest that the mean absolute values (MAVs) of relative deviation for detonation velocity (D) and detonation pressure (P) are less than 5%. Overall, this new method has exhibited excellent accuracy and simplicity, affording an efficient way to estimate the performance of explosives without relying on sophisticated computer programs. Therefore, it will be helpful in designing and synthesizing new metallic energetic compounds.
In order to understand the potential health effect of radiation from Fukushima nuclear disaster, a group of people living in Japan during and after the accident were investigated 1 y after the accident. The venous blood samples were extracted in tune from 156 tested persons living in Tokyo and Niigata with average age of 42.4 ± 10.2 y old as well as 87 controls living in Beijing with similar age and sex proportion. Conventional chromosome culture and cytochalasin B micronucleus methods were applied. The unstable chromosome aberrations of 200 cells and micronuclei (MN) and micronuclei cells (MNC) of 1000 binucleated lymphocytes were analysed for each examined subject. The results showed that the frequencies ± SE (×100) of the dicentrics plus rings were 0.17 ± 0.024% and 0.13 ± 0.028% in the tested and control populations (p > 0.05), respectively. The frequencies of the extra acentrics were 0.21 ± 0.026% and 0.06 ± 0.018% in the tested and control groups (p < 0.01), respectively. The total chromosomal aberration frequencies of the tested and control groups were 0.40 ± 0.036% and 0.20 ± 0.034% (p < 0.01), respectively. The MN and MNC frequencies of the tested group were 29.25 ± 3.96 ‰ and 23.85 ± 4.23 ‰, and 25.30 ± 6.45 ‰ and 21.56 ± 3.99 ‰ for control group (p < 0.01). With the exception of dicentrics, there were significant differences (p < 0.01) between two groups in frequencies of chromosome aberration and MN. Generally, 1 y after the Fukushima nuclear accident, the dicentric frequencies had not increased in the 156 persons investigated in this study. The increase in chromatid aberrations, chromosomal acentrics and MN was induced but could not be directly linked to radiation exposures, as an excess of dicentric frequency is linked. However, the observed higher frequency of chromosomal alterations might be related to exposure to the low doses of ionising in this cohort. Consequently, it is recommended to assess the long-term health effects in this population.
Directing acoustic waves along curved paths is critical for applications such as ultrasound imaging, surgery and acoustic cloaking. Metamaterials can direct waves by spatially varying the material properties through which the wave propagates. However, this approach is not always feasible, particularly for acoustic applications. Here we demonstrate the generation of acoustic bottle beams in homogeneous space without using metamaterials. Instead, the sound energy flows through a three-dimensional curved shell in air leaving a close-to-zero pressure region in the middle, exhibiting the capability of circumventing obstacles. By designing the initial phase, we develop a general recipe for creating self-bending wave packets, which can set acoustic beams propagating along arbitrary prescribed convex trajectories. The measured acoustic pulling force experienced by a rigid ball placed inside such a beam confirms the pressure field of the bottle. The demonstrated acoustic bottle and self-bending beams have potential applications in medical ultrasound imaging, therapeutic ultrasound, as well as acoustic levitations and isolations.
The vertical distribution of aerosol optical properties of a typical floating-dust event on October 19, 2009 in Shanghai was analyzed by using Micro-pulse Lidar (MPL) and the CALIPSO satellite. The results showed that the floating-dust aerosol mainly existed below 2 km of height. The floating-dust aerosol backscatter coefficient ranged from 0 to 0.015 km(-1) x sr(-1), and the MPL extinction coefficient ranged from 0 to 0.32 km(-1). The MPL data showed that the aerosol extinction coefficient first increased and then decreased during the floating-dust event. At the same time, the aerosol layer was constantly lifting. The CALIPSO data showed that a large number of small particles were suspended in air at a height of below 2 km, while the big particles always stayed near the ground (0-0.5 km). At the height of 2-10 km, there was only few aerosols; in the range of 4-6 km, there was a mixture of particles with regular and irregular shapes. The vertical distribution of CALIPSO 532 nm total attenuated backscatter coefficient and MPL normalized relative backscatter signal was basically the same, but the extinction coefficient values gained by them were different. Observations by CALIPSO and MPL together could be more comprehensive and objective for monitoring floating-dust in Shanghai.
We previously reported frequent loss of microRNA?218 (miR?218) in human cervical cancer, which was associated with tumor progression and poor prognosis. In this study, we investigated whether restoration of the miR?218 level is a valid strategy for the treatment of cervical cancer. The expression of miR?218 in cervical cancer samples and cell lines was quantified by reverse transcription TaqMan quantitative (RT?q)PCR. Overexpression of miR?218 was achieved by both transient and stable transfection, using a miR?218 mimic and a miR?218?expressing plasmid, respectively. Alterations in cellular proliferation and cell?cycle progression were measured by the MTT assay and flow cytometry analysis. Nude mice bearing SiHa xenografts were used to investigate the functions of miR?218 and carboplatin on tumor growth and weight. The expression of cycle?related proteins was detected by western blotting and immunohistochemical staining. In vitro, miR?218 significantly inhibited cellular growth in all four cell lines tested (P=0.021 for CaSki, P=0.009 for HeLa, P=0.016 for SiHa, and P=0.029 for C33A). Overexpression of miR?218 induced G1 phase arrest and reduced expression of cyclin D1 and CDK4. In vivo, restoration of miR?218 notably inhibited tumor growth and decreased tumor weight. In primary cultured samples, tumors with high levels of miR?218 were more sensitive to carboplatin (R2=0.3319, P=0.0026); consistently, miR?218 overexpression suppressed tumor growth, induced cell?cycle arrest, and reduced the cyclin D1 level. Based on these and previous results, we conclude that restoration of the miR?218 level inhibits the growth of cervical cancer cells both in vitro and in vivo; furthermore, overexpression of miR?218 sensitizes cervical cancer cells to carboplatin. Our findings suggest a novel therapy for cervical cancer based on miR?218, especially in patients with reduced levels of miR?218.
Breast cancer is a highly heterogeneous disease that is characterized by genetic and epigenetic aberrations; however, our knowledge of epigenetic alterations of breast cancer subtypes remains limited. Here, we portrayed and compared the alterations of six types of histone modifications and DNA methylation between two breast cancer subtypes, luminal and basal. Widespread subtype-specific epigenetic alterations were observed in both subtypes, which preferentially occurred within CpG islands (CGIs) and promoter regions. Specifically, aberrant DNA methylation was mostly located inside CGIs in luminal subtype, whereas in basal subtype it was principally located within CGI shores. Moreover, different types and combinatorial patterns of epigenetic alterations were found to occupy at promoter regions between these two subtypes. And these epigenetic alterations regulated corresponding gene expression in a synergetic way in both subtypes. Functional enrichment analysis highlighted that epigenetically dysregulated genes were significantly involved in the hallmarks of cancers, most of which were subtype specific. Even genes involved in the same hallmarks associated biological processes were affected by various types of epi-modifications in different subtypes. Finally, we revealed distinct patterns of oncogenic pathways activation in different subtypes and provided novel insights into subtype specific therapeutic opportunities. In addition, genes in the key signaling pathways were able to discriminate between disease phenotypes, and subtype-specific progression associated genes were identified. This study presents the aberrant epigenetic patterns of breast cancer subtypes at a genome-wide level, which will be a highly valuable resource for investigations at understanding epigenetic regulation of breast cancer subtypes.
MDG-1, a water-soluble polysaccharide extracted from Ophiopogon japonicus, has potent hypoglycemic and weight control effects. We investigated the impact of MDG-1 on body weight, indirect calorimetry, body composition, plasma biochemical indices and obesity-related mitochondrial activity in diet-induced obese mice. Obese C57BL/6 mice induced by a high fat diet were given either vehicle or vehicle plus MDG-1 at 300 mg per body weight for 16-weeks. MDG-1 could evoked weight loss and reduce adipose tissue mass (by up to ? 50%) in the obese animals by increasing oxygen consumption and energy expenditure without inhibiting appetite or increasing physical activity. In addition, MDG-1 could ameliorate plasma lipid profiles, decrease leptin secretion, attenuate hepatic lipid accumulation and increased the expressions of genes related to lipid and energy metabolism in the liver. MDG-1 is a promising candidate drug to treat obesity-related metabolic diseases.
A complete set of new photolabile nucleoside phosphoramidites were synthesized, then site-specifically incorporated into sense or antisense strands of siRNA for phosphate caging. Single caging modification was made along siRNA strands and their photomodulation of gene silencing were examined by using the firefly luciferase reporter gene. Several key phosphate positions were then identified. Furthermore, multiple caging modifications at these key positions led to significantly enhanced photomodulation of gene silencing activity, suggesting a synergistic effect. The caging group on both the terminally phosphate-caged siRNA and the single-stranded caged RNA has comparatively high stability, whereas hydrolysis of the caged group from the internally caged siRNA was observed, irrespective of the presence of Mg(2+). Molecular dynamic simulations demonstrated that enhanced hydrolysis of the caging group on internally phosphate-caged siRNAs was due to easy fragmentation of the caging group upon formation of the pentavalent intermediate of the phosphotriester with attack by water. The caging group in the terminally phosphate-caged siRNA or single-stranded caged RNA prefers to form ?-? stacks with nearby nucleobases. In addition to providing explanations for previous observations, this study sheds further light on the design of caged oligonucleotides and indicates the direction of future development of nucleic acid drugs with phosphate modifications.
The chronic infection of hepatitis B virus (HBV) is closely related to the occurrence and development of hepatocellular carcinoma (HCC). Accumulated evidence has shown that HBV X protein (HBx protein) is a multifunctional regulator with a crucial role in hepatocarcinogenesis. However, information on the mechanism by which HBV induces HCC is lacking. This review focuses on the pathological functions of HBx in HBV-induced hepatocarcinogenesis. As a transactivator, HBx can modulate nuclear factor kappa-light-chain-enhancer of activated B cells (NF-?B) and transcription factor AP-2. Moreover, HBx can affect regulatory non-coding RNAs (ncRNAs) including microRNAs and long ncRNAs (lncRNAs), such as miRNA-205 and highly upregulated in liver cancer (HULC), respectively. HBx is also involved in epigenetic modification, including methylation and acetylation. HBx interacts with various signal-transduction pathways, such as protein kinase B/Akt, Wnt/?-catenin, signal transducer and activator of transcription, and NF-?B pathways. Moreover, HBx affects cellular fate by shifting the balance toward cell survival. HBx may lead to the loss of apoptotic functions or directly contributes to oncogenesis by achieving transforming functions, which induce hepatocarcinogenesis. Additionally, HBx can modulate apoptosis and immune response by direct or indirect interaction with host factors. We conclude that HBx hastens the development of hepatoma.
4-Amino-2-trifluoromethyl-phenyl retinate (ATPR) is a novel all-trans retinoic acid (ATRA) derivative which was reported to have a superior antitumor effect in breast cancer cells. However, little is known about its antitumor effects on human gastric cancer cells and the mechanisms have not been fully elucidated. The results of the present study suggest that in the human gastric carcinoma cell line BGC-823, ATPR plays a more effective role than ATRA at the same dose in inhibiting proliferation, migration and inducing differentiation after the same treatment time. Furthermore, we investigated the preliminary mechanism of ATPR's anti?migration effect. Immunofluorescence assay demonstrated that claudin-18 positioned from cytoplasm to cell surface following ATPR stimuli. Real-time quantitative RT-PCR and western blot analyses showed that ATPR had significant effects on downregulation of the phosphorylation level of myosin light chain II (MLC II) by suppressing myosin light chain kinase (MLCK) and Rho-associated coiled-coil containing kinase (ROCK), as well as its regulation in the protein expression of RAR? and RAR?. Moreover, ATPR increased the activity of myosin phosphatase by inhibiting ROCK. Consequently, ATPR showed more promising antitumor effects than ATRA in BGC-823 in vitro, and it may conduct its anti-migration effects by decreasing the phosphorylation level of MLC II, as well as by regulating MLCK and ROCK as downstream target genes.
Nucleophosmin 1 (NPM1) mutations have been identified in a substantial number of patients with acute myeloid leukemia (AML). Favorable outcomes in AML cases with NPM1 mutations have been previously reported. However, widely differing survival estimates have been indicated. Therefore, a meta-analysis of nine studies including a total of 4509 subjects was performed. The frequency of NPM1 mutations was found to be 6.45-56.08%. NPM1-mutation type (NPM1-mt) patients had >2-fold higher odds of achieving complete remission compared with NPM1-wild-type (NPM1-wt). The summary hazard ratio (HR) of NPM1-mt/NPM1-wt for disease-free survival (DFS) and OS was 0.67 and 0.63, respectively. In conclusion, these findings suggest that the NPM1 mutation has a favorable effect on the outcome for AML. The present meta-analysis was based on data abstracted from observational studies. However, the results obtained may justify the risk-adapted therapeutic strategies for AML according to the NPM1 status.
Triazophos (TAP) has been widely used in agriculture for controlling insect pests and is a known organophosphorus pesticide. Due to TAP characteristics, such as high chemical and photochemical stability, its potential toxicity to aquatic organisms has gained great interest. To explore the potential developmental toxicity of TAP, Gobiocypris rarus embryos and larvae were exposed to various concentrations of TAP (0.1-15 mg L(-1)) until 72 h. Results showed that values of 72 h LC50 and EC50 were 7.44 and 5.60 mg L(-1) for embryos, 2.52 and 1.37 mg L(-1) for larvae. Increased malformation, decreased heart rate and body length provide a gradual concentration-dependent pattern. Enzyme activities and mRNA levels were significantly changed even at low concentration (0.05 mg L(-1) for embryos and 0.01 mg L(-(1) for larvae). Overall, the present study points out that TAP is likely a risk to the early development of G. rarus. The information presented in this study will be helpful in better understanding the toxicity induced by TAP in fish embryos and larvae.
The optimal approach regarding breast cancer screening for Chinese women is unclear due to the relative low incidence rate. A risk assessment tool may be useful for selection of high-risk subsets of population for mammography screening in low-incidence and resource-limited developing country. The odd ratios for six main risk factors of breast cancer were pooled by review manager after a systematic research of literature. Health risk appraisal (HRA) model was developed to predict an individual's risk of developing breast cancer in the next 5 years from current age. The performance of this HRA model was assessed based on a first-round screening database. Estimated risk of breast cancer increased with age. Increases in the 5-year risk of developing breast cancer were found with the existence of any of included risk factors. When individuals who had risk above median risk (3.3?‰) were selected from the validation database, the sensitivity is 60.0 % and the specificity is 47.8 %. The unweighted area under the curve (AUC) was 0.64 (95 % CI?=?0.50-0.78). The risk-prediction model reported in this article is based on a combination of risk factors and shows good overall predictive power, but it is still weak at predicting which particular women will develop the disease. It would be very helpful for the improvement of a current model if more population-based prospective follow-up studies were used for the validation.
Background. Meniere's disease is characterized by refractory dizziness and hearing disturbance. We aimed to investigate the efficacy and tolerance of Diaoshi Jifa, a Chinese hand skill for treating dizziness in Meniere's disease. Methods. An open-labeled, randomized, controlled intervention trial was conducted. Twenty-seven patients diagnosed with Meniere's disease were randomly allocated to control group or experimental group. Both groups were assessed by DHI (dizziness handicap inventory (DHI)) questionnaire score before and within 24 hours of receiving treatment, respectively. Results. Twenty-six participants completed the study, and no adverse event was reported due to Diaoshi Jifa treatment. The difference in the DHI scores between baseline and posttreatment reached significant difference in both groups (63.88 ± 19.94 versus 10.25 ± 9.77 and 54.36 ± 17.97 versus 49.6 ± 20.50). Significant difference in DHI scores was observed between the two groups after treatment (10.25 ± 9.77 versus 49.6 ± 20.50). Further investigation of DHI subscales in the experimental group revealed significant improvement posttreatment in the physical domain, functional domain, and emotional domain. Although higher rate of improvement in the emotional domain compared to physical or functional domains was found, the difference was not statistically significant. Conclusions. Diaoshi Jifa might be a fast, effective, and well-tolerated method for alleviating dizziness in Meniere's disease.
Recent evidence indicated that endocan may be a potential cell marker and a new target for cancers including acute leukemia since the serum endocan level in patients with acute leukemia was associated with the status of the disease, i.e., endocan was higly expressed in untreated acute leukemia, but decreased after chemotherapy and increased again during bone marrow regeneration. The present study showed that there was high level expression of endocan in cytoplasm of bone marrow blasts of patients with acute myeloid leukemia or acute lymphoblastic leukemia. The expression level of endocan was significantly decreased when the patients underwent remission after chemotherapy and re-bounces back when the acute leukemia relapsed. No obvious change in expression of endocan was observed before and after chemotherapy if the patients showed no remission after chemotherapy. (N-(4-Hydroxyphenyl) retinamide), a potent anti-angiogenic agent, could not only down-regulate the expression of vascular epithelial growth factor, but also decrease endocan transcription and expression in NB4 cells, a human acute promyelocytic leukemia cell line. These observations suggest that endocan could act as a predictor for the severity and the prognosis of acute leukemia. The findings could be used as the basis for future targeted therapy directed against bone marrow angiogenesis in acute leukemia treatment.
Thermodynamically driven self-assembly offers a direct route to organize individual nanoscopic components into three-dimensional structures over a large scale. The most thermodynamically favourable configurations, however, may not be ideal for some applications. In plasmonics, for instance, nanophotonic constructs with non-trivial broken symmetries can display optical properties of interest, such as Fano resonance, but are usually not thermodynamically favoured. Here, we present a self-assembly route with a feedback mechanism for the bottom-up synthesis of a new class of symmetry-breaking optical metamaterials. We self-assemble plasmonic nanorod dimers with a longitudinal offset that determines the degree of symmetry breaking and its electromagnetic response. The clear difference in plasmonic resonance profiles of nanorod dimers in different configurations enables high spectra selectivity. On the basis of this plasmonic signature, our self-assembly route with feedback mechanism promotes the assembly of desired metamaterial structures through selective excitation and photothermal disassembly of unwanted assemblies in solution. In this fashion, our method can selectively reconfigure and homogenize the properties of the dimer, leading to highly monodispersed aqueous metamaterials with tailored symmetries and electromagnetic responses.
Voltage gated calcium channels (VGCC) are sensitive to oxidative stress, and their activation or inactivation can impact cell death. Although these channels have been extensively studied in expression systems, their role in the brain, particularly in the substantia nigra pars compacta (SNc), remain controversial. In this study, we assessed 6-hydroxydopamine (6-OHDA) induced transformation of firing pattern and functional changes of calcium channels in SNc dopaminergic neurons. Application of 6-OHDA (0.5-2mM) evoked a dose-dependent, desensitizing inward current and intracellular free calcium concentration ([Ca(2+)]i) rise. In voltage clamp, ?-conotoxin-sensitive Ca(2+) current modulation mediated by 6-OHDA reflected an altered sensitivity. Furthermore, we found that 6-OHDA modulated Ca(2+) currents through PKA pathway. These results provided evidence for the potential role of VGCCs and PKA involved in oxidative stress in degeneration of SNc neurons in Parkinson's disease (PD).
Graphene's unsurpassed specific surface area (up to 2630 m(2)/g) makes it be an ideal absorbent. To promote its use as a sorption coating in solid phase microextraction, an ultrafast method was established, able to coat a stable layer of graphene on a metal fiber in only 23s, with adjustable coating thickness between 10 and 40 µm by using sleeve barrels. The core idea includes: (1) use of semi-polymerized dimethylsiloxane as a sticky pre-liner to glue graphene and (2) rapid conversion from pre-liner to elastic polydimethylsiloxane (PDMS) to fix the glued graphene. Ultrafast conversion of the pre-liner to PDMS was achieved by direct heating of the metallic fibers. The method produced very stable and durable fibers, capable of being used for at least 120 extractions-desorption cycles and stored at room temperature for at least 20 months. Interestingly, the new method could always coat a layer of mossy graphene on the fibers to largely increase their extraction capacity. Their limit of detection reached 2 pg/L PAHs, being about 3 orders of magnitude better than that of the reported graphene-based fibers. They were applicable to the direct extraction of trace PAHs in beverages, with a linear regression range from 10 to 1000 pg/L, and recoveries of 88.9-105.3%. The relative standard deviations of peak area were 2.9-8.9% for the same fiber and 3.0-10.0% for different fibers. The method is also suitable for re-coating a used fiber and extendable to fast coating other solid sorbents on heat-resistant supports.
Neurotensin receptor 1 (NTR1) is a neurotensin (NT) receptor subtype with a high affinity for NT. NT and NTR1 signaling are involved in modulating the dopamine system. Individual variations in the dopamine system have been demonstrated to determine certain dimensions of personality, but no studies have thus far investigated the involvement of the NTR1 in the biological determination of personality. We therefore examined this link in a Chinese Han population.
The molecular mechanism that regulates epicardial development has yet to be understood. In this study, we explored the function of CDX1, a Caudal-related family member, in epicardial epithelial-to-mesenchymal transition (EMT) and in the migration and the differentiation of epicardium-derived progenitors into vascular smooth muscle cells. We detected a transient expression of CDX1 in murine embryonic hearts at 11.5 days post coitum (dpc). Using a doxycycline-inducible CDX1 mouse model, primary epicardium, and ex vivo heart culture, we further demonstrated that ectopic expression of CDX1 promoted epicardial EMT. In addition, a low-dose CDX1 induction led to enhanced migration and differentiation of epicardium-derived cells into ?-SMA+ vascular smooth muscles. In contrast, either continued high-level induction of CDX1 or CDX1 deficiency attenuated the ability of epicardium-derived cells to migrate and to mature into smooth muscles induced by TGF-?1. Further RNA-seq analyses showed that CDX1 induction altered the transcript levels of genes involved in neuronal development, angiogenesis, and cell adhesions required for EMT. Our data have revealed a previously undefined role of CDX1 during epicardial development, and suggest that transient expression of CDX1 promotes epicardial EMT, whereas subsequent down-regulation of CDX1 after 11.5 dpc in mice is necessary for further subepicardial invasion of EPDCs and contribution to coronary vascular endothelium or smooth muscle cells.
Melatonin, an indolamine produced and secreted predominately by the pineal gland, exhibits a variety of physiological functions, possesses antioxidant and antitumor properties. But, the mechanisms for the anti-cancer effects are unknown. The present study explored the effects of melatonin on the migration of human lung adenocarcinoma A549 cells and its mechanism.
Road traffic crashes in China kill in excess of 250,000 people annually, more than any other country in the world. They are the fourth leading cause of premature death in the country and are responsible for 2.4% of the burden of non-fatal health loss in the country. Interventions to curb speeding and drink driving are being implemented in the cities of Suzhou and Dalian since late 2010. We evaluated the ongoing effect of these activities through five roadside surveys, seven rounds of observational studies, and analysis of crash statistics in the two cities. We find that thus far, the prevalence of speeding has not reduced in either city with the notable exception of one site in Dalian, where the percentage of speeding vehicles declined from nearly 70% to below 10% after an interval-based speed enforcement system was installed. The broader deployment of such speed control technologies across China and other countries should be explored. Roadside alcohol testing suggests that prevalence of drink driving prevalence (i.e. BAC >20 mg%) declined from 6.4% to 0.5% in Suzhou and from 1.7% to 0.7% in Dalian during the monitored time period. However, the measured prevalence rates are very low and should be validated against estimates based on hospital studies. Roadside interviews suggest that the population of both cities is already highly sensitized to the risks associated with drink driving and speeding. Crash statistics from the two cities do not show appreciable declines in injuries and fatalities as yet. However, the possibility of substantial underreporting in crash statistics sourced from traffic police poses a severe threat to monitoring progress towards road safety in Suzhou, Dalian and across China. There is an urgent need for China to invest in a reliable road traffic injury surveillance system that can provide information for describing key risk factors, evaluating the impact of safety policies, and benchmarking achievements.
In this article, we report the change of optical properties for europium chelates on silver nanorods by near-field interactions. The silver rods were fabricated in a seed-growth method followed by depositing thin layers of silica on the surfaces. The europium chelates were physically absorbed in the silica layers on the silver rods. The silver rods were observed to exhibit two plasmon absorption bands from longitudinal and transverse directions, respectively, centered at 394 and 675 nm, close to absorption and emission bands from the Eu(III) chelates. As a result, the immobilized Eu(III) chelates on the silver rods should have strong interactions with the silver nanorods and lead to greatly improved optical properties. The Eu-Ag rod complexes were observed to have enhanced emission intensity up to 240-fold in comparison with the Eu(III) chelates in the metal-free silica templates. This enhancement is much larger than the value for the Eu(III) chelates on the gold rods or silver spheres indicating the presence of stronger interactions for the Eu(III) chelates with the silver rods. The interactions of Eu(III) chelates with the silver rods were also proven by extremely reduced lifetime. Moreover, the Eu-Ag rod complexes exhibited a polarized emission, which was also due to strong interactions of the Eu(III) chelates with the silver rods. All of these features may promise that the Eu(III)-Ag rod complexes have great potential for use as fluorescence imaging agents in biological assays.
Lignin nanotubes (LNTs) synthesized from the aromatic plant cell wall polymer lignin in a sacrificial alumina membrane template have as useful features their flexibility, ease of functionalization due to the availability of many functional groups, label-free detection by autofluorescence, and customizable optical properties. In this report we show that the physicochemical properties of LNTs can be varied over a wide range to match requirements for specific applications by using lignin with different subunit composition, a function of plant species and genotype, and by choosing the lignin isolation method (thioglycolic acid, phosphoric acid, sulfuric acid (Klason), sodium hydroxide lignin), which influences the size and reactivity of the lignin fragments. Cytotoxicity studies with human HeLa cells showed that concentrations of up to 90 mg/mL are tolerated, which is a 10-fold higher concentration than observed for single- or multiwalled carbon nanotubes (CNTs). Confocal microscopy imaging revealed that all LNT formulations enter HeLa cells without auxiliary agents and that LNTs made from NaOH-lignin penetrate the cell nucleus. We further show that DNA can adsorb to LNTs. Consequently, exposure of HeLa cells to LNTs coated with DNA encoding the green fluorescent protein (GFP) leads to transfection and expression of GFP. The highest transfection efficiency was obtained with LNTs made from NaOH-lignin due to a combination of high DNA binding capacity and DNA delivery directly into the nucleus. These combined features of LNTs make LNTs attractive as smart delivery vehicles of DNA without the cytotoxicity associated with CNTs or the immunogenicity of viral vectors.
Abstract Context: Protoporphyrin IX (PpIX), a well-known sensitizer that can enhance laser light or ultrasound induced cytotoxicity in photodynamic and sonodynamic therapy. However, PpIX alone could effectively cause anti-tumor effect and the underlying mechanisms are rarely been reported. Therefore, this study was to investigate the possible mechanism by which PpIX revealed anti-proliferative effect on murine leukemia L1210 cells. Materials and methods: The accumulation of PpIX in L1210 cells and normal peripheral blood mononuclear cells (PBMCs) was evaluated with flow cytometry. The subcellular localization of PpIX and apoptosis-inducing factor (AIF) translocation were determined by confocal microscope. The cell viability was examined by MTT assay. Annexin V-PE/7-AAD and DAPI staining were used to detect apoptotic cells. The mitochondrial membrane potential (MMP) changes were tested by rhodamine123 staining. DNA damage was measured by comet assay. Results: PpIX preferentially accumulated in L1210 cells compared to PBMCs and PpIX mainly located in the mitochondria of L1210 cells. PpIX at a concentration of 1?µg/ml or above exerted significant anti-tumor effect and the cell viability loss presented PpIX dose-dependent manner. Typical apoptotic features such as chromatin condensation were observed by DAPI staining. Annexin V-PE/7-AAD analysis showed 5?µg/ml PpIX could induce about 24% cell apoptosis, which was inhibited by cyclosporin A (CsA), an inhibitor of mitochondrial permeability transition pore. In addition, the PpIX caused MMP loss, AIF translocation to nucleus and serious DNA damage were also suppressed by CsA. Conclusion: The results indicate mitochondria-dependent apoptosis were involved in PpIX caused cell damage on L1210 cells.
Rheumatoid arthritis (RA), as a common systemic inflammatory autoimmune disease, affects approximately 1 in 100 individuals. Effective treatment for RA is not yet available because current research does not have a clear understanding of the etiology and pathogenesis of RA. Xinfeng Capsule, a patent Chinese herbal medicine, has been used in the treatment of RA in recent years. Despite its reported clinical efficacy, there are no large-sample, multicenter, randomized trials that support the use of Xinfeng Capsule for RA. Therefore, we designed a randomized, double-blind, multicenter, placebo-controlled trial to assess the efficacy and safety of Xinfeng Capsule in the treatment of RA.
A facile and scalable solution-based, spray pyrolysis synthesis technique was used to synthesize individual carbon nanospheres with specific surface area (SSA) up to 1106 m(2)/g using a novel metal-salt catalyzed reaction. The carbon nanosphere diameters were tunable from 10 nm to several micrometers by varying the precursor concentrations. Solid, hollow, and porous carbon nanospheres were achieved by simply varying the ratio of catalyst and carbon source without using any templates. These hollow carbon nanospheres showed adsorption of to 300 mg of dye per gram of carbon, which is more than 15 times higher than that observed for conventional carbon black particles. When evaluated as supercapacitor electrode materials, specific capacitances of up to 112 F/g at a current density of 0.1 A/g were observed, with no capacitance loss after 20?000 cycles.
We report giant suppression of photobleaching and a prolonged lifespan of single fluorescent molecules via the Purcell effect in plasmonic nanostructures. The plasmonic structures enhance the spontaneous emission of excited fluorescent molecules, reduce the probability of activating photochemical reactions that destroy the molecules, and hence suppress the bleaching. Experimentally, we observe up to a 1000-fold increase in the total number of photons that we can harvest from a single fluorescent molecule before it bleaches. This approach demonstrates the potential of using the Purcell effect to manipulate photochemical reactions at the subwavelength scale.
The growth patterns of different anatomic structures in the human body vary in terms of growth amount over time, growth rate and growth periods. The oral and pharyngeal structures, also known as vocal tract structures, are housed in the craniofacial complex where the cranium/brain follows a distinct neural growth pattern, and the face follows a distinct somatic or skeletal growth pattern. Thus, it is reasonable to expect the oral and pharyngeal structures to follow a combined or mixed growth pattern. Existing parametric growth models are limited in that they are mainly focused on modeling one particular type of growth pattern. In this paper, we propose a novel composite growth model using neural and somatic baseline curves to fit the combined growth pattern of select vocal tract structures. The method can also determine the overall percent contribution of each of the growth types.
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