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Objective: To investigate the effectiveness of SMI in evaluating hepatic IRI and detecting its therapy response. Methods: Thirty rats were randomly divided into sham (n = 12), IRI (n = 12), and andrographolide pretreatment (n = 6) groups. SMI, pathological, and biochemical examinations were conducted for the sham and IRI groups at 4 (n = 6) and 24 h (n = 6) after reperfusion, respectively. Two ultrasonologists measured the vascular index (VI). The interobserver agreement was evaluated using the intraclass correlation coefficient (ICC). The rat liver parameters, including Suzuki's score, alanine aminotransferase (ALT), and aspartate aminotransferase (AST), were obtained at different time steps in each group. For the andrographolide pretreatment group, data were obtained at 24 h after reperfusion to further verify the advantage of VI. Parameters were analyzed for correlations and compared between each group at 4 and 24 h. Results: The ICC between two ultrasonologists who measured the VI was 0.912 (95%CI: 0.889-0.940). Suzuki's score and VI were negatively correlated (r = -0.504, P = 0.012). Compared with the sham group, the IRI group showed a significant decrease in the VI at 4 and 24 h after reperfusion [(24.78 ± 3.23) versus (20.22 ± 2.55); (22.67 ± 1.36) versus (19.27 ± 2.23), P < 0.05)]. The VI in the andrographolide pretreatment group was higher than that in the IRI group [(21.90 ± 1.47) versus (19.27 ± 2.23), P < 0.05]. Conclusions: The VI on SMI can be used as a noninvasive and sensitive index to evaluate hepatic IRI and detect its therapeutic response. [ABSTRACT FROM AUTHOR]

Purpose: To determine the effect of diosmetin on young, non-alcoholic fatty liver disease (NAFLD) rats. Methods: Five groups of SD rats were used: control group, high-fat diet group, low-dose diosmetin group, medium-dose diosmetin group, and high-dose diosmetin group, each with 10 rats. After 3 months, interleukin 6 (IL-6), IL-1ß) and TNF-a) were assayed. Protein expressions of p-AMPKa, CPT-1 and PPAR-a, AMPKa, SREBP-1c and FAS were assayed. Results: In the high-fat diet group, the levels of p-AMPKa, CPT-1 and PPAR-a were lower than the corresponding control values, while p-AMPKa, CPT-1 and PPAR-a levels were dose-dependently higher in all diosmetin groups than in NAFLD group (p < 0.05). There were higher levels of SREBP-1c and FAS in the high-fat diet group than in control group, while SREBP-1c and FAS levels in all diosmetin groups were dose-dependently lower than the corresponding levels in NAFLD group. Serum IL-6, IL-1ß and TNF-a levels in NAFLD group were raised, relative to control values (p < 0.05). Conclusion: Diosmetin alleviates NAFLD lesions induced by high-fat diet, slows down liver cell apoptosis, and inhibits inflammation via activation of AMPK pathway. Thus, diosmetin has potentials for use in the repair of hepatic damage induced by high-fat diet. [ABSTRACT FROM AUTHOR]

Objective: We expected to demonstrate a practical framework for oral squamous cell carcinoma (OSCC) candidate biomarker analysis at the pathway level based on the attract method, so as to give great insights to reveal the pathological mechanism underlying this disease at its early stage.Methods: First, gene expression profile of OSCC was recruited and preprocessed. Then, Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis was conducted. Next, attract method, an approach that begins its analysis from the "foundation knowledge sets" to discriminate the cell-phenotypes by those well-annotated gene-sets, then expands the syn-expression groups via decomposing each significant pathway into correlated subsets and extends the analysis to the entire expression was applied to identify core pathways. Finally, gene ontology (GO) functional enrichment analysis was performed on each of the correlated set groups to discover any potentially shared biological themes.Results: A total of 226 pathways were obtained. Then, 39 core KEGG pathways was identified via attract. After removing the uninformative genes, a total of 1, 2, and 3 clusters were separately identified for the three discriminative pathways extracellular matrix (ECM)-receptor interaction, neuroactive ligand-receptor interaction, and cell adhesion molecules (CAMs) pathway based on the correlation coefficient < 0.85. GO functional enrichment analysis for the correlated partners groups indicated that there were 40, 11, 78 significant GO terms for ECM-receptor interaction, neuroactive ligand-receptor interaction, and CAMs pathway, respectively.Conclusions: We predict that pathways such as ECM-receptor interaction, neuroactive ligand-receptor interaction, and CAMs may play significant roles in OSCC and targeting these pathways may provide an effective avenue to combat the complicated illness. [ABSTRACT FROM AUTHOR]

An efficient palladium-catalyzed hydrocarbonylative C-N coupling of alkenes with amides has been developed. The reaction was performed via hydrocarbonylation of alkenes, followed by acyl metathesis with amides. Both intermolecular and intramolecular reactions proceed smoothly to give either branched or linear amides in high turnover number (3500) with NH4Cl or NMP·HCl as a proton source under the palladium catalysis. This reaction offers a catalytic convenient approach to deuterated amides when inexpensive NMP·DCl served as a deuterium source. [ABSTRACT FROM AUTHOR]

A new, facile, and efficient protocol for the synthesis of polysubstituted conjugated 1,3-dienes through Ni-catalyzed tandem dimerization/cross-coupling reaction of diarylacetylenes and arylboronic acids in the presence of a catalytic amount of B2pin2 has been developed. A series of arynes and arylboronic acids with different substituents participated well in this catalytic system, affording a variety of useful conjugated 1,3-dienes. [ABSTRACT FROM AUTHOR]

Background: The disparity between government health expenditures across regions is more severe in developing countries than it is in developed countries. The capitation subsidy method has been proven effective in developed countries in reducing this disparity, but it has not been tested in China, the world's largest developing country.Methods: The convergence method of neoclassical economics was adopted to test the convergence of China's regional government health expenditure. Data were obtained from Provinces, Prefectures and Counties Fiscal Statistical Yearbook (2003-2007) edited by the Chinese Ministry of Finance, and published by the Chinese Finance & Economics Publishing House.Results: The existence of σ-convergence and long-term and short-term β-convergence indicated the effectiveness of the capitation subsidy method in the New Rural Cooperative Medical Scheme on narrowing county government health expenditure disparities. The supply-side variables contributed the most to the county government health expenditure convergence, and factors contributing to convergence of county government health expenditures per capita were different in three regions.Conclusion: The narrowing disparity between county government health expenditures across regions supports the effectiveness of the capitation subsidy method adopted by China's New Rural Cooperative Scheme. However, subsidy policy still requires further improvement. [ABSTRACT FROM AUTHOR]

Background: Integrins are heterodimeric (α/β) membrane proteins that play fundamental roles in many biological processes, for example, cell adhesion and spreading, which are important for platelet function and hemostasis. The molecular mechanism that regulates integrin activation is not completely understood.Methods and Results: Here, we show that VPS33B, a member of the Sec1/Munc18 family, binds directly to the integrin β subunit. Overexpression of VPS33B in Chinese hamster ovary cells potentiated αIIbβ3 outside-in signaling but not inside-out signaling. Platelets, from megakaryocyte- and platelet-specific VPS33B conditional knockout mice, had normal morphology, yet their spreading on fibrinogen was impaired and they failed to support clot retraction. Platelet aggregation and ATP secretion in response to low-dose agonists were reduced in the VPS33B knockout mice. αIIbβ3-mediated endocytosis of fibrinogen was also defective. Tail bleeding times and times to occlusion in an FeCl3-induced thrombosis model were prolonged in the VPS33B knockout mice. Furthermore, VPS33B acted upstream of the RhoA-ROCK-MLC and Rac1-dependent pathways that lead to clot retraction and cell spreading, respectively.Conclusions: Our work demonstrates that vesicular trafficking complexes, containing VPS33B, are a novel class of modifiers of integrin function. Our data also provide insights into the molecular mechanism and treatment of arthrogryposis, renal dysfunction, and cholestasis syndrome. [ABSTRACT FROM AUTHOR]

Study Design. A retrospective clinical study. Objective. To investigate the lung volume (LV) change in patients with ankylosing spondylitis (AS) with thoracolumbar kyphosis after the pedicle subtraction osteotomy procedure. Summary of Background Data. Thoracolumbar kyphosis with respiratory impairment is the consequence of most untreated AS patients. Restrictive pulmonary function is prevalent in these patients. The ideal evidence for restrictive pulmonary function impairment is to investigate the LV. A computed tomography (CT)-based method can help to obtain accurate LV change during the osteotomy. Method. Twenty-eight patients with AS with thoracolumbar kyphosis were included. All of these patients underwent pedicle subtraction osteotomy to correct their sagittal deformity. Pre- and postoperative full-length radiographs and CT scans were reviewed. The sagittal correction of the spine was measured. CT scans were used to estimate the pre- and postoperative LV with software. The relationship between the sagittal correction and the LV change was investigated. All the patients were followed up for 2 years at least. Results. The pedicle subtraction osteotomy procedure was performed safely on each patient without serious complications. The average preoperative T1-S1 Cobb was 67.7° (42° ~ 88° ) and the postoperative was 7.6° (-11° ~ 21° ). T1-S1 Cobb change was 60.0° in average ( P < 0.05). The LV increased by 396 mL in average. Significant correlation was found between the percentage of LV change and T1-S1 Cobb change ( r = 0.7219, P < 0.05). The location we selected for pedicle subtraction osteotomy varied from T12 to L3. No relationship was found between the osteotomy location and the LV change. Conclusion. The pedicle subtraction osteotomy effectively corrected the sagittal deformity of patients with AS. LV increased significantly after the osteotomy. [ABSTRACT FROM AUTHOR]

A practical and efficient Rh(III)-catalyzed aerobic C -H activation has been developed for the facile synthesis of a broad range of indoles from simple anilines and alkynes. The protocol could be conducted under mild conditions and used environmentally friendly oxygen as the sole clear oxidant. [ABSTRACT FROM AUTHOR]

A novel and efficient Rh/O2 catalytic system has been developed and shown to catalyze highly efficient oxidative C—H activation/annulation reactions, producing a broad range of isoquinolinium salts with high turnover numbers (up to 740). Mechanistic studies provided strong evidence of facile oxidation of Rh(I) to Rh(III) by molecular oxygen facilitated by acid. [ABSTRACT FROM AUTHOR]

Background: ADP is an important physiological agonist that induces integrin activation and platelet aggregation through its receptors P2Y1 (Gαq -coupled) and P2Y12 (Gαi-coupled). P2Y12 plays a critical role in platelet activation and thrombosis. Adenosine-based P2Y12 antagonists, 2-methylthioadenosine 59-monophosphate triethylammonium salt hydrate (2MeSAMP) and Cangrelor (AR-C69931MX) have been widely used to demonstrate the role of P2Y12 in platelet function. Cangrelor is being evaluated in clinical trials of thrombotic diseases. However, a recent study reported that both 2MeSAMP and Cangrelor raise intra-platelet cAMP levels and inhibit platelet aggregation through a P2Y12-independent mechanism. Methodology/Principal Findings: The present work, using P2Y12 deficient mice, sought to clarify previous conflicting reports and to elucidate the mechanisms by which 2MeSAMP and Cangrelor inhibit platelet activation and thrombosis. 2MeSAMP and Cangrelor inhibited aggregation and ATP release of wild-type but not P2Y12 deficient platelets. 2MeSAMP and Cangrelor neither raised intracellular cAMP concentrations nor induced phosphorylation of vasodilator-stimulated phosphoprotein (VASP) in washed human or mouse platelets. Furthermore, unlike the activators (PGI2 and forskolin) of the cAMP pathway, 2MeSAMP and Cangrelor failed to inhibit Ca2+ mobilization, Akt phosphorylation, and Rap1b activation in P2Y12 deficient platelets. Importantly, while injection of Cangrelor inhibited thrombus formation in a FeCl3-induced thrombosis model in wild-type mice, it failed to affect thrombus formation in P2Y12 deficient mice. Conclusions: These data together demonstrate that 2MeSAMP and Cangrelor inhibit platelet function through the P2Y12- dependent mechanism both in vitro and in vivo. [ABSTRACT FROM AUTHOR]

The Src family kinases (SFKs) play essential roles in collagenand von Willebrand factor (VWF)-mediated platelet activation. However, the roles of SFKs in G protein-coupled receptor-mediated platelet activation and the molecular mechanisms whereby SFKs are activated by G protein-coupled receptor stimulation are not fully understood. Here we show that the thrombin receptor protease-activated receptor 4 agonist peptide AYPGKF elicited SFK phosphorylation in P2Y12 deficient platelets but stimulated minimal SFK phosphorylation in platelets lackingGq.We have previously shown that thrombin-induced SFK phosphorylation was inhibited by the calcium chelator 5,5'-dimethyl-bis- (o-aminophenoxy)ethane-N,N,Nα',N'-tetraacetic acid (dimethyl- BAPTA). The calcium ionophore A23187 induced SFK phosphorylation in both wild-type and Gq deficient platelets. Together, these results indicate that SFK phosphorylation in response to thrombin receptor stimulation is downstream from Gq/Ca2+ signaling. Moreover, A23187-induced thromboxane A2 synthesis, platelet aggregation, and secretion were inhibited by preincubation of platelets with a selective SFK inhibitor, PP2. AYPGKF-induced thromboxane A2 production in wild-type and P2Y12 deficient platelets was abolished by PP2, and AYPGKF-mediated P-selectin expression, integrin αIIbβ3 activation, and aggregation of P2Y12 deficient platelets were partially inhibited by the PKC inhibitor Ro-31-8220, PP2, dimethyl- BAPTA, or LY294002, but were abolished by Ro-31-8220 plus PP2, dimethyl-BAPTA, or LY294002. These data indicate that Ca2+/SFKs/PI3K andPKCrepresent two alternative signaling pathways mediating Gq-dependent platelet activation. [ABSTRACT FROM AUTHOR]

Accurate and rapid prediction of the coal and gas outburst is very significant for preventing accident and protecting environment, the paper presents a novel feature selection and outburst classifier framework which can identify effective candidate features and improve the classification accuracy. First, Apriori is applied for preliminarily extracting the association rules from sample data and attribute features in coal and outburst, and it can present the effective sample data and features for outburst prediction. Second, in order to reduce the redundancy of the strong association rules obtained from Apriori, Boruta is applied for selecting all highly relevant optimal features based on the obtained strong association rules. Third, Random Forest(RF) is used to assign different weights to different features in optimal candidate features considering the importance of different features to outburst, based on the above obtained high-quality sample data and optimal features, the parameters of KNN model optimized by Bayesian Optimization(BO) is used to predict the coal and gas outburst. The experimental results show that the proposed feature selection model Apriori-Boruta can obtain significant sample data, and the proposed RF-KNN optimized classifier model can achieve higher performance in terms of the number of optimal features and prediction accuracy compared with traditional prediction models. [ABSTRACT FROM AUTHOR]

We report on the fabrication of a novel type of ratiometric fluorescent polymeric probes for fluoride ions (F–) based on self-assembled micellar nanoparticles of P(MMA-co-NBDAE)-b-PF-b-P(MMA-co-NBDAE) coil–rod–coil triblock copolymer, where MMA, NBDAE, and PF are methyl methacrylate, 4-(2-acryloyloxyethylamino)-7-nitro-2,1,3-benzoxadiazole, and polyfluorene, respectively. Blue-emitting conjugated PF block and green-emitting NBDAE moieties with F–turn-off characteristics within the PMMA block serve as fluorescence resonance energy transfer (FRET) donors and switchable acceptors, respectively. For coil–rod–coil triblock copolymer in a good solvent such as THF, the blue emission of PF block dominates due to unimolecularly dissolved state associated with ineffective FRET process. The addition of F–ions only leads to ∼2.92-fold decrease of fluorescence intensity ratio, I515/I417, of characteristic NBDAE and PF emission bands. In acetone, the triblock copolymer spontaneously self-assembles into micelles possessing PF cores and NBDAE-labeled PMMA coronas. In the absence of F–ions, effective FRET processes between micellar cores and coronas occurs, resulting in prominently enhanced NBDAE emission. Upon addition of F–ions, the quenching of NBDAE emission bands leads to ∼8.75-fold decrease in the emission intensity ratio, I515/I417, which is also accompanied by naked eye-discernible fluorometric transition from cyan to blue emissions and colorimetric transition from green to yellowish. At a micellar concentration of 0.1 g/L in acetone at 25 °C, the detection limit of F–ions can be down to ∼4.78 μM (∼0.09 ppm). This work presents a new example of polymeric micelles-based optical F–probes and manifests that, upon proper structural design and optimization of spatial distribution of FRET donors and acceptors, self-assembled micelles of coil–rod–coil triblock copolymers serve as better ratiometric fluorescent F–ion sensors possessing visual detection capability, as compared to that of molecularly dissolved chains. [ABSTRACT FROM AUTHOR]

A simple copper-mediated cyanation of aryl halide with the combination of ammonium bicarbonate and N,N-dimethylformamide as a cyanide source is achieved, providing nitriles in moderate to good yields. This new approach represents an exceedingly practical and safe method for the synthesis of aryl nitriles. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) stimulates cGMP synthesis by activating its intracellular receptor, soluble guanylyl cyclase (sGC). It is a currently prevailing concept that No and cGMP inhibits platelet function. However, the data supporting the inhibitory role of NO/sGC/cGMP in platelets have been obtained either in vitro or using whole body gene deletion that affects vessel wall function. Here we have generated mice with sGC gene deleted only in megakaryocytes and platelets. Using the megakaryocyte- and platelet-specific sGC-deficient mice, we identify a stimulatory role of sGC in platelet activation and in thrombosis in vivo. Deletion of sGC in platelets abolished cGMP production induced by either NO donors or platelet agonists, caused a marked defect in aggregation and attenuated secretion in response to low doses of collagen or thrombin. Importantly, megakaryocyte- and platelet-specific sGC deficient mice showed prolonged tail-bleeding times and impaired FeCl3-induced carotid artery thrombosis in vivo. Interestingly, the inhibitory effect of the NO donor SNP on platelet activation was sGC-dependent only at micromolar concentrations, but sGC-independent at millimolar concentrations. Together, our data demonstrate important roles of sGC in stimulating platelet activation and in vivo thrombosis and hemostasis, and sGC-dependent and -independent inhibition of platelets by NO donors. [ABSTRACT FROM AUTHOR]

The Src family kinases (SFKs) have been proposed to play stimulatory and inhibitory roles in platelet activation. The mechanisms for these apparently contradictory roles are unclear. Here we show that SFK, mainly Lyn, is important in stimulating a common signaling pathway leading to secretion of platelet granules. Lyn knock-out or an isoform-nonselective SFK inhibitor, PP2, inhibited platelet secretion of both dense and α granules and the secretion-dependent platelet aggregation induced by thrombin, collagen, and thromboxane A2. The inhibitory effect of Lyn knock-out on platelet aggregation was reversed by supplementing granule content ADP, indicating that the primary role of Lyn is to stimulate granule secretion. Inhibitory effect of PP2 on platelet aggregation induced by thrombin and thromboxane A2 were also reversed by supplementing ADP. Furthermore, PP2 treatment or Lyn knock-out diminished agonist-induced Aktactivation and cyclic GMP production. The inhibitory effect of PP2 or Lyn knock-out on platelet response can be corrected by supplementing cyclic GMP. These data indicate that Lyn stimulates platelet secretion by activating the phosphoinositide 3-kinase-Akt-nitric oxide (NO)-cyclic GMP pathway and also provide an explanation why Lyn can both stimulate and inhibit platelet activation. [ABSTRACT FROM AUTHOR]

Cu(ii)/MCM-41, Cu(i)/MCM-41 and Cu(0)/MCM-41 materials were prepared with Cu[OCHMeCH2NMe2]2/MCM-41 as precursor under controlled conditions. The states of copper on the resulting samples were characterized by temperature programmed reduction (TPR), UV-Vis diffuse reflectance spectroscopy (UV-Vis DRS), X-ray photoelectron spectroscopy (XPS), photoluminescence spectroscopy (PL), infrared spectroscopy (FTIR) of NO and CO adsorption, X-ray diffraction (XRD), and N2adsorption. It was shown that pure Cu(ii)/MCM-41 can be acquired by calcining Cu[OCHMeCH2NMe2]2/MCM-41 in pure oxygen at 573 K. Pure Cu(i)/MCM-41 can be obtained by reducing the as-prepared Cu(ii)/MCM-41 in a CO/He atmosphere at 473 K, while pure Cu(0)/MCM-41 can be obtained viareduction of the Cu(ii)/MCM-41 in a CO/He atmosphere at 673 K. The Cu(ii)–O and Cu(i)–O species were showed to be highly dispersed on the surface of MCM-41 as isolated sites. The study provides an alternative method for the preparation of pure copper metal or copper oxide supported materials. [ABSTRACT FROM AUTHOR]

A well-defined ABC triblock copolymer, poly(2-(2-methoxyethoxy)ethyl methacrylate)-b-poly(2-(dimethylamino)ethyl methacrylate)-b-poly(2-(diethylamino)ethyl methacrylate) (PMEO2MA-b-PDMA-b-PDEA), was synthesized via sequential atom transfer radical polymerization using ethyl 2-bromoisobutyrate as the initiator. Reacting the triblock precursor with propargyl bromide in anhydrous tetrahydrofuran yielded PMEO2MA-b-P(DMA-co-QDMA)-b-PDEA triblock copolymer with “clickable” moieties, where QDMA was quaternized DMA residues. PMEO2MA-b-P(DMA-co-QDMA)-b-PDEA triblock copolymer exhibited “schizophrenic” micellization behavior in aqueous solution, forming three-layer onion-like PMEO2MA-core and PDEA-core micelles upon proper adjustment of the solution pH and temperature. For temperature-induced formation of PMEO2MA-core micelles at acidic pH, the critical micellization temperature can be tuned by incorporating oligo(ethylene glycol) methyl ether methacrylate (OEGMA; the mean degree of polymerization was 8−9) residues into the PMEO2MA block, shifting from 38 to 43 °C as the OEGMA contents varied in the range of 0−10 mol %. In both types of micelles, the inner shell layer consisted of the middle P(DMA-co-QDMA) segment. Subsequently, cross-linking with tetra(ethylene glycol) diazide via click chemistry in the presence of copper catalysts led to the facile preparation of two types of shell-cross-linked (SCL) micelles with “inverted” structures in purely aqueous solution. The cores and coronas of SCL micelles exhibited multiresponsive swelling/shrinking and collapse/aggregation behavior, respectively. To the best of our knowledge, this represents the first report of the fabrication of two types of SCL micelles with inverted structures from a single schizophrenic water-soluble triblock copolymer in purely aqueous solution. [ABSTRACT FROM AUTHOR]

The deposition of an organic copper precursor Cu[OCHMeCH 2NMe 2] 2on the surface of mesoporous silica MCM-41 dehydrated at 773 K was studied under high-vacuum conditions by infrared spectroscopy combined with elemental analysis, X-ray absorption spectroscopy (XAS), thermogravimetric analysis (TG), temperature-programmed decomposition (TPD), and X-ray photoelectron spectroscopy (XPS). It is revealed that the copper precursor is chemically adsorbed on the surface of MCM-41 to form a stable surface copper complex (SC1) coordinated with two framework oxygen atoms by ligand exchange at temperatures below 423 K. The surface copper complex is easily decomposed into Cu(I) and Cu(0) via a successive two-step pathway upon heating at temperatures beyond 423 K. IR and TPD results indicate that the first-step decomposition occurs at the temperature range from 423 to 523 K, where the surface complex SC1 loses one organic ligand and one methane molecule, leading to formation of a surface intermediate complex (SC2) with a Schiff base ligand. The second-step decomposition starts at 523 K, where the complex (SC2) is transformed to Cu(0) by losing the remanent organic ligand and undergoes a surface intermediate complex (SC3) to form Cu(I) oxide species by a consecutive loss of small molecules. The surface hydroxyl groups participate in the adsorption and reaction of the Cu precursor on the support MCM-41, which is a critical factor to controllable preparation of copper-containing MCM-41 catalysts. The mechanisms of thermolysis are suggested to be distinctly different from its MOCVD pathways reported in the literature. [ABSTRACT FROM AUTHOR]

An acid photocatalyst TiO2, modified with H2SO4, is prepared and used to decontaminate Chemical Warfare Agents (CWAs) simulants 2-CEES (2-chloroethyl ethyl sulfide) and DMMP (dimethyl methylphosphonate) in vapor phase. Compared with the unmodified pure TiO2 photocatalyst, the adsorption capacity on the sulfated photocatalyst increases by 50%, and the conversion for 2-CEES increases more than 20%. It is found that the durability for decontaminating DMMP is delayed by 200 min with the modified photocatalyst. The surface characteristics of the photocatalysts are analyzed by XPS and FT-IR. The results show that more Lewis and Brönsted acid sites, considered to be responsible for improving the reactivity performance of photocatalysts, are formed on the sulfated TiO2. [ABSTRACT FROM AUTHOR]

Thromboxane A[sub 2] (TX[sub A]2)-mediated platelet secretion and aggregation are important in thrombosis. Here, we present a novel finding that the stable TXA[sub 2] analogue, U46619, induces two waves of platelet secretion, each of which precedes a distinct wave of platelet aggregation. ADP released from platelets during the first wave of secretion played a major role in augmenting the first wave of platelet aggregation. The second wave of platelet secretion and aggregation required the first wave of both ADP secretion and aggregation and were blocked by either the integrin inhibitor RGDS or a P2Y12 receptor antagonist, indicating a requirement for both the integrin outside-in signal and ADP-activated Gi pathway. U46619 stimulated phosphoinositide 3-kinase (PI3K)-dependent phosphorylation of Akt, which was augmented by ADP but did not require integrin outside-in signaling. Platelets from PI3Kγ knock-out mice or PI3K inhibitor-treated platelets showed an impaired second wave of platelet secretion and aggregation. However, the second wave of platelet aggregation was restored by addition of exogenous ADP to PI3Kγ deficient or PI3K inhibitor-treated platelets. Thus, our data indicate that PI3K, together with the integrin outside-in signaling, play a central role in inducing the second wave of platelet secretion, which leads to the second wave of irreversible platelet aggregation. [ABSTRACT FROM AUTHOR]

Increased expression of extracellular matrix (ECM) proteins in circulating tumor cells (CTCs) suggests potential function of cancer cell-produced ECM in initiation of cancer cell colonization. Here, we showed that collagen and heat shock protein 47 (Hsp47), a chaperone facilitating collagen secretion and deposition, were highly expressed during the epithelial-mesenchymal transition (EMT) and in CTCs. Hsp47 expression induced mesenchymal phenotypes in mammary epithelial cells (MECs), enhanced platelet recruitment, and promoted lung retention and colonization of cancer cells. Platelet depletion in vivo abolished Hsp47-induced cancer cell retention in the lung, suggesting that Hsp47 promotes cancer cell colonization by enhancing cancer cell-platelet interaction. Using rescue experiments and functional blocking antibodies, we identified type I collagen as the key mediator of Hsp47-induced cancer cell-platelet interaction. We also found that Hsp47-dependent collagen deposition and platelet recruitment facilitated cancer cell clustering and extravasation in vitro. By analyzing DNA/RNA sequencing data generated from human breast cancer tissues, we showed that gene amplification and increased expression of Hsp47 were associated with cancer metastasis. These results suggest that targeting the Hsp47/collagen axis is a promising strategy to block cancer cell-platelet interaction and cancer colonization in secondary organs. [ABSTRACT FROM AUTHOR]

A Cu(OTf)2-mediated Chan-Lam reaction of carboxylic acids with arylboronic acids is described. It represents a facile and practical methodology to access phenolic esters in moderate to good yields. The procedure tolerates a series of functional groups, such as methoxycarbonyl, acetoxy, free phenolic hydroxyl, vinyl, nitro, trifluoromethyl, methoxyl, bromo, chloro, iodo, and acetyl groups. [ABSTRACT FROM AUTHOR]

Resveratrol is a polyphenolic compound, which has been revealed to induce apoptosis in numerous human cancer cells; however, the effects of resveratrol on the migration and invasion of human bladder cancer cells have not been reported. The present study aimed to evaluate the anti-metastatic potential of resveratrol against bladder cancer and its mechanism of action. The results indicated that resveratrol inhibits the adhesion, migration and invasion of bladder cancer cells in a dose-dependent manner. Resveratrol was shown to significantly inhibit the expression and secretion of matrix metalloproteinase (MMP)-2 and MMP-9 in bladder cancer cells. Furthermore, resveratrol suppressed the phosphorylation of c-Jun N-terminal kinase and extracellular signal-regulated protein kinase. In conclusion, the present study is the first, to the best of our knowledge, to demonstrate that resveratrol may be considered a novel anticancer agent for the treatment of bladder cancer via the inhibition of migration and invasion. [ABSTRACT FROM AUTHOR]

Background: Inflammation is currently recognized as one of the major causes of premature delivery. As a member of the interleukin-1ß (IL-1ß) family, interleukin-33 (IL-33) has been shown to be involved in normal pregnancy as well as a variety of pregnancy-related disorder. This study aims to investigate the potential function of IL-33 in uterine smooth muscle cells during labor. Methods: Myometrium samples from term pregnant (=37 weeks gestation) women were either frozen or cells were isolated and cultured. Immunohistochemistry and western blotting were used to assess the distribution of IL-33. Cultured cells were incubated with lipopolysaccharide (LPS) to mimic inflammation as well as in the presence of 4µ8C (IRE1 inhibitor III) to block endoplasmic reticulum (ER) stress and BAPTA-AM, a calcium chelator. Results: LPS reduced the expression of nuclear IL-33 in a time-limited manner and induced ER stress. However, knockdown of IL-33 increased LPS-induced calcium concentration, ER stress and phosphorylation of nuclear factor kappa-B (NF-κB), and P38 mitogen-activated protein kinase (P38 MAPK). In addition, siRNA IL-33 further stimulates LPS enhanced cyclooxygenase-2 (COX-2) expression via NF-κB and p38 pathways. IL-33 expression was decreased in the nucleus with the onset of labor. LPS-induced ER stress and increased expression of the labor-associated gene, COX-2, as well as IL-6 and IL-8 in cultured myometrial cells. IL-33 also increased COX-2 expression, but after it was knocked down, the stimulating effect of LPS on calcium was enhanced. 4µ8C also inhibited the expression of COX-2 markedly. The expression of calcium channels on the membrane and intracellular free calcium ion were both increased which was accompanied by phosphorylated NF-κB and p38. Conclusions: These data suggest that IL-33 may be involved in the initiation of labor by leading to stress of the ER via an influx of calcium ions in human uterine smooth muscle cells. [ABSTRACT FROM AUTHOR]

Effective patch management is critical to ensure the security of information systems that modern organizations count on today. Facing numerous patch releases from vendors, an information technology (IT) manager must weigh the costs of frequent patching against the security risks that can arise from delays in patch application. To this end, we develop a rigorous quantitative framework to analyze and compare several patching policies that are of practical interest. Our analyses of pure policies--policies that rely on a single metric such as elapsed time or patch severity level--show that certain policies are never optimal and no single policy may fit all information systems uniformly well. Depending on the context parameters, particularly the setup and business disruption costs for patching, either a time-based approach or an approach based on the cumulative severity level may be effective. To develop a more complete guideline for policy selection, we decipher hybrid policies that combine multiple metrics. Finally, we conduct extensive numerical experiments to verify the robustness of our analytical results. Overall, our paper establishes a comprehensive framework for analyzing various patching policies and furnishes useful insights for IT managers. [ABSTRACT FROM AUTHOR]

Background: China had 236 million internal migrants in 2012 and the majority of them migrated from rural to urban areas. The research based on medical and epidemical records found that the migrants had worse health than the urban residents, but the household and working place investigations reported better health status. The sick or unhealthy migrants are likely to return to their hometowns, which in turn may cause a report bias or over-estimation of the health status of rural-to-urban migrants in China. This paper explores the association of migration status and the physical and psychological health of Chinese internal migrants. Methods: Nationally representative household survey data from the China Labor-force Dynamics Survey 2012 (CLDS) were used to analyze the association between the migration status and the health status of internal migrants in China. Migration status of the respondents was measured by hukou status and migration experience and all respondents were divided into four groups: returned population, migrant population, urban residents, and rural residents. Health status of respondents was measured by self-reported physical and psychological health. Results: Migration experience was associated with the physical health of the returned population. The physical health of the returned population was worse than the migrant population and was distinguished by age and sex. The physical health status of migrant population was significantly better than rural residents, but not significantly better than urban residents. However, the association between migration status and psychological health was not statistically significant. Besides migration status, the socioeconomic status (SES) had a positive correlation with both physical and psychological health status, while occupational hazards exerted negative influence. Conclusion: The results indicate a tight association between migration experience and health status. The internal unhealthy migrants were more likely to return to their hometown and the migrant population might have limited health advantage. [ABSTRACT FROM AUTHOR]

IFN-γ-stimulated MHC class I (MHC-I) antigen presentation underlies the core of antitumor immunity. However, sustained IFN-γ signaling also enhances the programmed death ligand 1 (PD-L1) checkpoint pathway to dampen antitumor immunity. It remains unclear how these opposing effects of IFN-γ are regulated. Here, we report that loss of the histone dimethyltransferase WHSC1 impaired the antitumor effect of IFN-γ signaling by transcriptional downregulation of the MHC-I machinery without affecting PD-L1 expression in colorectal cancer (CRC) cells. Whsc1 loss promoted tumorigenesis via a non-cell-autonomous mechanism in an Apcmin/+ mouse model, CRC organoids, and xenografts. Mechanistically, we found that the IFN-γ/STAT1 signaling axis stimulated WHSC1 expression and, in turn, that WHSC1 directly interacted with NLRC5 to promote MHC-I gene expression, but not that of PD-L1. Concordantly, silencing Whsc1 diminished MHC-I levels, impaired antitumor immunity, and blunted the effect of immune checkpoint blockade. Patient cohort analysis revealed that WHSC1 expression positively correlated with enhanced MHC-I expression, tumor-infiltrating T cells, and favorable disease outcomes. Together, our findings establish a tumor-suppressive function of WHSC1 that relays IFN-γ signaling to promote antigen presentation on CRC cells and provide a rationale for boosting WHSC1 activity in immunotherapy. [ABSTRACT FROM AUTHOR]

he development of a highly selective and fast responsive fluorogenic biosensor for diverse analytes ranging from bioactive small molecules to specific antigens is highly desirable but remains a considerable challenge. We herein propose a new approach by integrating substrate-selective enzymatic reactions with fluorogens exhibiting aggregation-induced emission feature. Tyrosine-functionalized tetraphenylethene, TPE-Tyr, molecularly dissolves in aqueous media with negligible fluorescence emission; upon addition of horseradish peroxidase (HRP) and H2O2, effective cross-linking occurs due to HRP-catalyzed oxidative coupling of tyrosine moieties in TPE-Tyr. This leads to fluorescence emission turn-on and fast detection of H2O2 with high sensitivity and selectivity. As a validation of the new strategy’s generality, we further configure it into the biosensor design for glucose through cascade enzymatic reactions and for pathologically relevant antigens (e.g., human carcinoembryonic antigen) by combining with the ELISA kit. [ABSTRACT FROM AUTHOR]

In recent years, we have witnessed an unprecedented growth in the security software market. This market is now fiercely competitive with hundreds of nearly identical products; yet, the price is high and coverage low. Although recent research has examined such idiosyncrasies and found the existence of a negative network effect as a possible explanation, several important questions still remain: (1) What possibly discourages product differentiation in such a competitive market? (2) Why is versioning absent here? (3) How does the presence of free alternatives in this market impact its structure? We develop a comprehensive oligopoly model, with endogenous quality and versioning decisions, to address these issues. Our analyses reveal that, although the presence of numerous competitors leads to a greater need to differentiate, the network effect in this market works as a counterweight, incentivizing vendors to sacrifice differentiation in favor of collocating in the top end of the quality spectrum. We explain the reasons and implications of this important finding. We further show that this result is robust and applicable even when versioning by competing vendors or the presence of free software is taken into consideration. Furthermore, given that the presence of free software actually intensifies competitive pressure and heightens the need to differentiate, the role of the network effect in abating differentiation becomes even more discernible. [ABSTRACT FROM AUTHOR]

A simple route for the preparation of ZnS-reduced graphene oxide (RGO) composites via a one-pot hydrothermal synthesis is achieved. The chemical composition, morphology and structure of the ZnS-RGO samples were characterized by X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, X-ray photoelectron spectroscopy (XPS), thermogravimetric analysis (TGA), scanning electron microscopy (SEM), transmission electron microscopy (TEM), N2 adsorption-desorption specific surface area analysis (BET) and diffuse reflectance absorption (DRS). The results show that the ZnS nanoparticles were well dispersed on the RGO nanosheets which serve as the ZnS nanocrystal growth support and the morphology controller. It was found that the specific surface area of the ZnS-RGO composites increased with the incorporation of RGO. The ZnS-RGO composites were used as photocatalysts for the degradation of methylene blue (MB) under UV light irradiation. The results show the ZnS-RGO composites exhibited better photocatalytic activity and photodegradation kinetics compared with pure ZnS and commercial TiO2 (P25) which is attributed to the high specific surface area and the hindrance of electron-hole pair recombination of ZnS due to the RGO incorporation. Therefore, the RGO has a positive effect on the ZnS-RGO composite as a photocatalyst. [ABSTRACT FROM AUTHOR]

We report on a robust approach to the size-selective and template-free synthesis of asymmetrically functionalized ultrasmall (<4 nm) gold nanoparticles (AuNPs) stably anchored with a single amphiphilic triblock copolymer chain per NP. Directed NP self-assembly in aqueous solution can be facilely accomplished to afford organic/inorganic hybrid micelles, vesicles, rods, and large compound micelles by taking advantage of the rich microphase separation behavior of the as-synthesized AuNP hybrid amphiphilic triblock copolymers, PEO-AuNP-PS, which act as the polymer-metal-polymer analogue of conventional amphiphilic triblock copolymers. Factors affecting the size-selective fabrication and self-assembly characteristics and the time-dependent morphological evolution of NP assemblies were thoroughly explored. [ABSTRACT FROM AUTHOR]

Macrophages have long been recognized as a prominent component of tumors. Activated macrophages overexpress folate receptors and we used this phenomenon to image inflammatory reactions in colon dysplasia using a fluorescent folate probe (FFP). APCδ468 mice injected with FFP showed fluorescent adenomas (target-to-background ratio, adenoma vs. adjacent normal mucosa, of 2.46 ± 0.41), significantly higher (p < .001) than adenomas in animals injected with a non-folate-containing control probe. Fluorescence-activated cell-sorting analysis revealed a 3-fold higher content of Mac1-positive cells in colonic adenomas compared with normal adjacent mucosa (6.8% vs. 2.2%), and confirmed the source of FFP-positive cells to be primarily an F4/80-positive macrophage subpopulation. Taken together, these results indicate that FFP potentially can be used to image dysplastic intestinal adenomas in vivo. [ABSTRACT FROM AUTHOR]

In order to explore the noise reduction effect and application of different hearing protectors in different workplaces in a power station, so as to facilitate to select differently suitable hearing protectors to staff based on needs. This paper uses principal component analysis and evaluation according to the insertion loss test results of 112 kinds of hearing protectors. Combined with the field test results of 10 workplaces in a power station, it is found that 112 kinds of hearing protectors mostly are suitable in 7 working places. People need to select suitable hearing protectors specifically in other 3 places. At the same time, this paper can provide reference for the selection of hearing protection in other different working places. [ABSTRACT FROM AUTHOR]

Interleukin-8 (IL-8) possesses tumorigenic and proangiogenic properties, and is overexpressed in many human cancer types. However, only few studies have demonstrated the mechanisms of action of IL-8 regarding the ability to promote proliferation and to inhibit apoptosis in prostate cancer. Here, the aim of the present study was to investigate the effects of IL-8 on the prostate cancer cell line and determine possible mechanisms underlying its effect. In this study, IL-8 was shown to be significantly upregulated in prostate cancer compared with paired normal control tissues. The data showed that IL-8 exhibits direct oncogenicity, which significantly induced cell proliferation, invasion and attenuated apoptosis in prostate cancer cells via signal transducer and activator of transcription 3/protein kinase B/nuclear factor-κB signaling pathways. In conclusion, modulation of IL-8 expression or its associated signaling pathway may provide a novel working mechanism of IL-8 in prostate cancer, and a promising strategy for controlling the progression and metastasis of prostate cancer. [ABSTRACT FROM AUTHOR]

Ectopic activation of the canonical Hedgehog signaling pathway is involved in the development and progression of prostate cancer, which is one of the leading causes of cancer‑associated mortality in males worldwide. However, the role of the non‑canonical Hedgehog signaling pathway in prostate cancer remains generally unexplored. In the present study, it was identified that Gli (glioma‑associated oncogene)1 and Gli2 were highly expressed at the protein level in the androgen‑independent prostate cancer cell lines PC3 and DU145, but not in the androgen‑dependent cancer cell line LNCaP. Silencing of Gli1 using small interfering RNA markedly decreased PC3 cell viability and liquid colony formation in vitro. The Gli1/2‑specific inhibitor GANT61 markedly decreased cell viability by inducing cell apoptosis in PC3 and DU145 cells. GANT61 also alleviated liquid colony formation efficiency in PC3 and DU145 cells, suggesting that the activity of Gli1 is required for prostate cancer cell survival. To explore further the upstream signaling pathway involved in the regulation of Gli1 expression, it was identified that tumor necrosis factor α‑triggered mammalian target of rapamycin (mTOR)/p70 ribosomal protein S6 kinase 1 (S6K1) activation was required for Gli1 expression. Pharmacological and genetic inhibition of S6K1 activation markedly decreased Gli1 and its downstream target gene mRNA expression. In addition, the phosphoinositide 3‑kinase/mTOR inhibitor BEZ235 markedly decreased in vitro PC3 cell proliferation. The results of the present study indicate that the non‑canonical Hedgehog pathway (mTOR/S6K1/Gli1) contributes to the development and progression of prostate cancer and that Gli1 is a potential therapeutic target in the treatment of prostate cancer. [ABSTRACT FROM AUTHOR]

All‑trans‑retinoic acid (ATRA) can enhance iodine uptake capability of thyroid tumors, but the mechanisms remain poorly understood. The aim of the present study was to investigate the effects of ATRA on isotope susceptibility, proliferation and invasion of anaplastic thyroid carcinoma (ATC) and potential mechanisms. SW1736 cells were treated with 1 μmol/l ATRA or 1% ethanol for 5 days. A cell line stably expressing β‑catenin‑shRNA was established. An iodine uptake assay was performed using 125I. Proliferation and invasiveness were tested using MTT and Transwell assays, respectively. Western blotting was used to assess the expression of β‑catenin, glycogen synthase kinase‑3β (GSK‑3β), sodium/iodine symporter (NIS) and proteins involved in epithelial‑mesenchymal transition. Cells pretreated with ATRA were injected subcutaneously into SCID mice. Mice were intraperitoneally injected with 131I once on the first day of treatment, and tumor growth was then assessed. After 35 days of 131I treatment, ATRA‑pretreated tumor volume and weight were decreased compared with the 131I alone group (163.32±19.57 vs. 332.06±21.37 mm3; 0.35±0.14 vs. 0.67±0.23 g, both P<0.05). Similar results were observed in the β‑catenin shRNA‑pretreated tumors. ATRA also increased the uptake of iodine by SW1736 cells (P<0.01), and similar results were observed in β‑catenin shRNA cells. ATRA treatment decreased the cell proliferation and invasion compared with control cells (all P<0.05), similar to β‑catenin shRNA. ATRA treatment decreased the expression of phosphorylated (p‑)β‑catenin, p‑GSK‑3β, vimentin, and fibronectin, and increased the expression of NIS and E‑cadherin, compared with the control. ATRA increased the iodine uptake and inhibited the proliferation and invasion of SW1736 cells, involving β‑catenin phosphorylation. In conclusion, ATRA could be used to improve the isotope sensitivity of ATC. [ABSTRACT FROM AUTHOR]

The development of novel theranostic nanovectors is of particular interest in treating formidable diseases (e.g., cancers). Herein, we report a new tumor-targetable theranostic agent based on core crosslinked (CCL) micelles, possessing tumor targetable moieties and fluorescence and magnetic resonance (MR) dual imaging modalities. An azide-terminated diblock copolymer, N3-POEGMA-b-P(DPA-co-GMA), was synthesized via consecutive atom transfer radical polymerization (ATRP), where OEGMA, DPA, and GMA are oligo(ethylene glycol)methyl ether methacrylate, 2-(diisopropylamino)ethyl methacrylate, and glycidyl methacrylate, respectively. The resulting diblock copolymer was further functionalized with DOTA(Gd) (DOTA is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakisacetic acid) or benzaldehyde moieties via copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) chemistry, resulting in the formation of DOTA(Gd)-POEGMA-b-P(DPA-co-GMA) and benzaldehyde-POEGMA-b-P(DPA-co-GMA) copolymers. The resultant block copolymers co-assembled into mixed micelles at neutral pH in the presence of tetrakis[4-(2-mercaptoethoxy)phenyl]ethylene (TPE-4SH), which underwent spontaneous crosslinking reactions with GMA residues embedded within the micellar cores, simultaneously switching on TPE fluorescence due to the restriction of intramolecular rotation. Moreover, camptothecin (CPT) was encapsulated into the crosslinked cores at neutral pH, and tumor-targeting pH low insertion peptide (pHLIP, sequence: AEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTCG) moieties were attached to the coronas through the Schiff base chemistry, yielding a theranostic nanovector with fluorescence and MR dual imaging modalities and tumor-targeting capability. The nanovectors can be efficiently taken up by A549 cells, as monitored by TPE fluorescence. After internalization, intracellular acidic pH triggered the release of loaded CPT, killing cancer cells in a selective manner. On the other hand, the nanovectors labeled with DOTA(Gd) contrast agents exhibited increased relaxivity (r1 = 16.97 mM-1∙s-1) compared to alkynyl-DOTA(Gd) small molecule precursor (r1 = 3.16 mM-1∙s-1). Moreover, in vivo MRI (magnetic resonance imaging) measurements revealed CCL micelles with pHLIP peptides exhibiting better tumor accumulation and MR imaging performance as well. [ABSTRACT FROM AUTHOR]

Supramolecular vesicles, also referredto as polymersomes, self-assembledfrom amphiphilic polymers capable of synchronically loading with bothhydrophilic and hydrophobic payloads have shown promising potentialin drug delivery application. Herein, we report the fabrication ofpH-responsive polymersomes via supramolecular self-assembly of amphiphilicdiblock copolymers, poly(ethylene oxide)-b-poly(2-((((5-methyl-2-(2,4,6-trimethoxyphenyl)-1,3-dioxan-5-yl)methoxy)carbonyl)amino)ethylmethacrylate) (PEO-b-PTTAMA), which were synthesizedvia reversible addition–fragmentation chain transfer (RAFT)polymerization of a pH-responsive monomer (i.e., TTAMA) using a PEO-basedmacroRAFT agent. The resultant amphiphilic diblock copolymer thenself-assembled into vesicles consisting of hydrophilic PEO coronasand pH-responsive hydrophobic bilayers, as confirmed by TEM and DLSmeasurements. The polymersomes containing cyclic benzylidene acetalsin the hydrophobic bilayers were relatively stable under neutral pH,whereas they underwent hydrolysis with the liberation of hydrophobic2,4,6-trimethoxybenzaldehyde and the simultaneous generationof hydrophilic diol moieties upon exposure to acidic pH milieu, whichcould be monitored by UV/vis spectroscopy, SEM, and TEM observations.By loading hydrophobic model drug (Nile red) as well as hydrophilicchemotherapeutic drug (doxorubicin hydrochloride, DOX·HCl) intothe bilayer and aqueous interior of the polymersomes, the subsequentrelease of Nile red and DOX·HCl payloads was remarkably regulatedby the solution pH values, and a lower pH value led to a faster drugrelease profile. In vitroexperiment, observed bya confocal laser scanning microscope (CLSM), revealed that the pH-responsivepolymersomes were easily taken up by HeLa cells and were primarilylocated in the acidic organelles after internalization, where thepH-responsive cyclic acetal moieties were hydrolyzed and the embeddedpayloads were therefore released, allowing for on-demand release ofthe encapsulants mediated by intracellular pH. In addition to smallmolecule chemotherapeutic drugs, biomacromolecules (alkaline phosphatase,ALP) can also be encapsulated into the aqueous lumen of the polymersomes.Significantly, the pH-triggered degradation of polymersomes couldalso regulate the release of encapsulated ALP, as confirmed by ALP-activatedfluorogenic reaction. [ABSTRACT FROM AUTHOR]

Autophagy is important for maintaining cellular homeostasis, and thus its deficiency is implicated in a broad spectrum of human diseases. Its role in platelet function has only recently been examined. Our biochemical and imaging studies demonstrate that the core autophagy machinery exists in platelets, and that autophagy is constitutively active in resting platelets. Moreover, autophagy is induced upon platelet activation, as indicated by agonist-induced loss of the autophagy marker LC3II. Additional experiments, using inhibitors of platelet activation, proteases, and lysosomal acidification, as well as platelets from knock out mouse strains, show that agonist-induced LC3II loss is a consequence of platelet signaling cascades and requires proteases, acidic compartments, and membrane fusion. To assess the physiological role of platelet autophagy, we generated a mouse strain with a megakaryocyte- and platelet-specific deletion of Atg7, an enzyme required for LC3II production. Ex vivo analysis of platelets from these mice shows modest defects in aggregation and granule cargo packaging. Although these mice have normal platelet numbers and size distributions, they exhibit a robust bleeding diathesis in the tail-bleeding assay and a prolonged occlusion time in the FeCl3-induced carotid injury model. Our results demonstrate that autophagy occurs in platelets and is important for hemostasis and thrombosis. [ABSTRACT FROM AUTHOR]

Nonviral gene delivery vectors need to overcome both extracellular and intracellular obstacles before releasing plasmid DNA in the transcriptionally active form. However, serum and transport stability desired for cationic polymer/pDNA polyplexes contradicts with the eventual plasmid release requirement; chain lengths of cationic polymer vectors render additional compromise between cytotoxicity and transfection efficiency. Although the introduction of stimuli-triggered degradable cationic polymers can partially solve these issues, the quest for novel design criteria and elucidation of elementary cellular transport pathways are highly desirable. Herein we report a supramolecular approach to construct fluorogenic gene delivery vectors via self-assembly of intracellular milieu-reactive cationic amphiphiles. This new type of micellar nanocarriers can effectively bind pDNA to form polyplexes due to multivalent cationic segments at micellar coronas. Upon cellular uptake and endosomal escape, hydrophobic micellar cores are subjected to fluorogenic Michael addition reactions with highly hydrophilic cytoplasmic thiols, leading to micellar disintegration, pDNA release, and emission turn-on for image-guided delivery. [ABSTRACT FROM AUTHOR]

Magnetite (Fe3O4) polyhedral nanocrystals have been prepared successfully by a simple solvothermal reaction using a mixture of ethylene glycol (EG) and H2O as the solvent without the addition of any surfactants or templates. Based on SEM and TEM characterization, the products were determined to be 50-facet Fe3O4 nanocrystals, 200-300 nm in diameter, enclosed by {100}, {110}, {111}, and high-index {311} facets. The morphological evolution of 50-facet Fe3O4 polyhedra was studied carefully and in detail by adjusting the reaction parameters such as the reaction temperature, the reaction time, the amount of urea, and the volume ratio of EG to H2O in the solvent. The results indicated that an appropriate EG/H2O ratio in the solvent was crucial for the formation of the polyhedral nanocrystals and when the solvent was fixed, the size of the polyhedral nanocrystals could be tuned in a certain range by changing the amount of urea. A possible growth mechanism involving the aggregation and oriented attachment of Fe3O4 seed nanoparticles is proposed on the basis of time-dependent experiments. [ABSTRACT FROM AUTHOR]

Genome-wide association studies (GWAS) have linked genes encoding several soluble NSF attachment protein receptor (SNARE) regulators to cardiovascular disease risk factors. Because these regulatory proteins may directly affect platelet secretion, we used SNARE-containing complexes to affinity purify potential regulators from human platelet extracts. Syntaxin-binding protein 5 (STXBP5; also known as tomosyn-1) was identified by mass spectrometry, and its expression in isolated platelets was confirmed by RT-PCR analysis. Coimmunoprecipitation studies showed that STXBP5 interacts with core secretion machinery complexes, such as syntaxin-11/SNAP23 heterodimers, and fractionation studies suggested that STXBP5 also interacts with the platelet cytoskeleton. Platelets from Stxbp5 KO mice had normal expression of other key secretory components; however, stimulation-dependent secretion from each of the 3 granule types was markedly defective. Secretion defects in STXBP5-deicient platelets were confirmed via lumi-aggregometry and FACS analysis for P-selectin and LAMP-1 exposure. Interestingly, STXBP5-deicient platelets had altered granule cargo levels, despite having normal morphology and granule numbers. Consistent with secretion and cargo deficiencies, Stxbp5 KO mice showed dramatic bleeding in the tail transection model and defective hemostasis in the FeCl3-induced carotid injury model. Transplantation experiments indicated that these defects were due to loss of STXBP5 in BM-derived cells. Our data demonstrate that STXBP5 is required for normal arterial hemostasis, due to its contributions to platelet granule cargo packaging and secretion. [ABSTRACT FROM AUTHOR]

Cu2O/amorphous TiO2 core-shell nanocomposites with uniform cubic structure were prepared by a hydrolysis method and CuO/TiO2 core-shell nanocomposites were obtained by a post-calcination process. The structure and morphology of the products were characterized by powder X-ray diffraction, transmission electron microscopy, and scanning electron microscopy. The results showed that the cubic Cu2O/TiO2 core-shell nanocomposites were of 110-140nm in side length and the as-hydrolyzed TiO2 shell layer was amorphous. The products transformed to quasi-spheric CuO/TiO2 (anatase) nanocomposites after calcination. The visible-light photocatalytic properties of different products towards methyl orange (MO) were investigated. The results showed that the photocatalytic activity of the cubic Cu2O/amorphous TiO2 core-shell nanocomposites was higher than that of pure Cu2O nanocubes, pure TiO2 nanoparticles, and the spheric CuO/TiO2 core-shell nanocomposites. [ABSTRACT FROM AUTHOR]

Stimuli-triggered disassembly of block copolymer vesicles or polymersomes has been conventionally achieved via solubility switching of the bilayer-forming block, requiring cooperative changes of most of the repeating units. Herein we report an alternative approach by incorporating hydrophobic blocks exhibiting stimuli-triggered head-to-tail cascade depolymerization features. Amphiphilic block copolymers bearing this motif self-assemble into self-immolative polymersomes (SIPsomes). By modular design of terminal capping moieties, visible light, UV light, and reductive milieu can be utilized to actuate SIPsomes disintegration into water-soluble small molecules and hydrophilic blocks. The design of SIPsomes allows for triggered drug co-release and controllable access toward protons, oxygen, and enzymatic substrates. We also demonstrate programmed (OR-, AND-, and XOR-type logic) enzymatic reactions by integrating SIPsome encapsulation and trigger/capping moiety-selective cascade depolymerization events. [ABSTRACT FROM AUTHOR]

Solution self-assembly of block copolymers (BCPs) typically generates spheres, rods, and vesicles. The reproducible bottom-up fabrication of stable planar nanostructures remains elusive due to their tendency to bend into closed bilayers. This morphological vacancy renders the study of shape effects on BCP nanocarrier-cell interactions incomplete. Furthermore, the fabrication of single BCP assemblies with built-in drug delivery functions and geometry-optimized performance remains a major challenge. We demonstrate that PEG-b-PCPTM polyprodrug amphiphiles, where PEG is poly(ethylene glycol) and PCPTM is polymerized block of reduction-cleavable camptothecin (CPT) prodrug monomer, with >50 wt % CPT loading content can self-assemble into four types of uniform nanostructures including spheres, large compound vesicles, smooth disks, and unprecedented staggered lamellae with spiked periphery. Staggered lamellae outperform the other three nanostructure types, exhibiting extended blood circulation duration, the fastest cellular uptake, and unique internalization pathways. We also explore shape-modulated CPT release kinetics, nanostructure degradation, and in vitro cytotoxicities. The controlled hierarchical organization of polyprodrug amphiphiles and shape-tunable biological performance opens up new horizons for exploring next-generation BCP-based drug delivery systems with improved efficacy. [ABSTRACT FROM AUTHOR]

It is generally agreed that most colon cancers develop from adenomatous polyps, and it is this fact on which screening strategies are based. Although there is overwhelming evidence to link intrinsic genetic lesions with the formation of these preneoplastic lesions, recent data suggest that the tumor stromal environment also plays an essential role in this disease. In particular, it has been suggested that CD34+ immature myeloid precursor cells are required for tumor development and invasion. Here we have used mice conditional for the stabilization of β-catenin or defective for the adenomatous polyposis coli (APC) gene to reinvestigated the identity and importance of tumor-infiltrating hematopoietic cells in polyposis. We show that, from the onset, polyps are infiltrated with proinflammatory mast cells (MC) and their precursors. Depletion of MC either pharmacologically or through the generation of chimeric mice with genetic lesions in MC development leads to a profound remission of existing polyps. Our data suggest that MC are an essential hematopoietic component for preneoplastic polyp development and are a novel target for therapeutic intervention. [ABSTRACT FROM AUTHOR]