The activation and use of oxygen for the oxidation and functionalization of organic substrates are among the most important reactions in a chemist's toolbox. Nevertheless, despite the vast literature on catalytic oxidation, the phenomenon of autoxidation, an ever-present background reaction that occurs in virtually every oxidation process, is often neglected. In contrast, autoxidation can affect the selectivity to a desired product, to those dictated by pure free-radical chain pathways, thus affecting the activity of any catalyst used to carry out a reaction. This critical review compares catalytic oxidation routes by transition metals versus autoxidation, particularly focusing on the industrial context, where highly selective and "green" processes are needed. Furthermore, the application of useful tests to discriminate between different oxygen activation routes, especially in the area of hydrocarbon oxidation, with the aim of an enhanced catalyst design, is described and discussed. In fact, one of the major targets of selective oxidation is the use of molecular oxygen as the ultimate oxidant, combined with the development of catalysts capable of performing the catalytic cycle in a real energy and cost effective manner on a large scale. To achieve this goal, insights from metallo-proteins that could find application in some areas of industrial catalysis are presented, as well as considering the physicochemical principles that are fundamental to oxidation and autoxidation processes.
In this study, the psbA-trnH sequence as DNA barcode was used to evaluate the accuracy and stability for identification pteridophyte medicinal material Pyrrosiae Foliumas from adulterants. Genomic DNA from 106 samples were extracted successfully. The Kimura 2-Parameter (K2P) distances and ML tree were calculated using software MEGA 6.0. The intra-specific genetic distances of 3 original plants were lower than inter-specific genetic distances of adulterants. The ML tree indicated that Pyrrosiae Folium can be distinguished from its adulterants obviously. Therefore, the psbA-trnH sequence as a barcode of the pteridophyte, can accurately and stably distinguish Pyrrosiae Folium from its adulterants.
We analyzed the principle of the traditional local binary fitting operation, Gaussian kernel function weighted summation (GKFWS), to develop a novel level set model in this paper. In this model, the traditional GKFWS operation is replaced with the median filter operation in the second procedure of local fitting of the energy domain. Furthermore, we incorporated the edge stopping function of GAC model into it to introduce the edge information for segmentation. Experiments on synthetic and real images demonstrate that this model has promising performance in terms of computational cost, robustness to noises and segmentation of images with intensity inhomogeneity.
E-cadherin is a well-known mediator of cell-cell adherens junctions. However, many other functions of E-cadherin have been reported. Collectively, the available data suggest that E-cadherin may also act as a gene transcriptional regulator. Here, evidence supporting this claim is reviewed, and possible mechanisms of action are discussed. E-cadherin has been shown to modulate the activity of several notable cell signalling pathways, and given that most of these pathways in turn regulate gene expression, we proposed that E-cadherin may regulate gene transcription by affecting these pathways. Additionally, E-cadherin has been shown to accumulate in the nucleus where documentation of an E-cadherin fragment bound to DNA suggests that E-cadherin may directly regulate gene transcription. In summary, from the cell membrane to the nucleus, a role for E-cadherin in gene transcription may be emerging. Studies specifically focused on this potential role would allow for a more thorough understanding of this transmembrane glycoprotein in mediating intra- and intercellular activities.
A DTH8 / Ghd8 allele suppresses flowering by altering the expression patterns of the 'florigen' genes, but also negatively regulates chlorophyll biogenesis. Flowering time is a critical agronomic trait determining the growing season, regional adaptation and yield potential in rice (Oryza sativa L.). We characterized a mutant named early flowering 8 (ef8) selected from an ethyl methanesulfonate (EMS)-treated population of indica cultivar 93-11. It showed earlier flowering, less grains per main panicle and slightly darker green leaves than the wild-type 93-11 under natural long-day conditions, but was not significantly different from 93-11 under natural short-day conditions. We isolated the Early Flowering 8 (EF8) gene by map-based cloning. EF8 encodes a putative HAP3 subunit of the CCAAT-box-binding transcription factor, which is localized to the nucleus. EF8 was expressed in various tissues, especially in leaves, with a rhythmic expression pattern. Our data showed that EF8 delayed flowering time under long-day conditions by altering the rhythmic expression patterns of 'florigen' genes Hd3a and RFT1. We also found that EF8 negatively regulates the expression of chlorophyll biosynthetic genes to reduce the chlorophyll content. Our data indicate that EF8 plays an important role in rice photoperiodic flowering pathway as well as yield potential and chlorophyll biogenesis and will be an important target for rice breeding programs.
PML/RARA is the oncoprotein driving acute promyelocytic leukemia (APL). It suppresses genes expression by recruitment of a number of transcriptional repressors, resulting in differentiation block and malignant transformation of hematopoietic cells. Here, we found that mice primary hematopoietic progenitor cells (HPCs), transduced by DNA-binding-defective PML/RARA mutants, were deficient in colony formation. Further experiments showed that DNA-binding-defective PML/RARA mutants could not repress the transcription of retinoic acid regulated genes. Intriguingly, there were no significant differences of the micro-speckled intracellular distribution between the mutants and wild-type PML/RARA. Some retinoic acid target genes regulated by PML/RARA are involved in not only differentiation block but also hematopoietic cell self-renewal. Altogether, our data demonstrate that direct DNA-binding is essential for PML/RARA to immortalize hematopoietic cells, while disruption of PML-nuclear body does not seem to be a prerequisite for hematopoietic cell transformation.
Recent evidence has shown that an increase in CD4(+)CD25(+)FoxP3(+) regulatory T (Treg) cells may contribute to stroke-induced immunosuppression. However, the molecular mechanisms that underlie this increase in Treg cells remain unclear. Here, we used a transient middle cerebral artery occlusion model in mice and specific pathway inhibitors to demonstrate that stroke activates the sympathetic nervous system, which was abolished by 6-OHDA. The consequent activation of ?2-adrenergic receptor (AR) signaling increased prostaglandin E2 (PGE2) level in bone marrow. ?2-AR antagonist prevented the upregulation of PGE2. PGE2, which acts on prostaglandin E receptor subtype 4 (EP4), upregulated the expression of receptor activator for NF-?B ligand (RANKL) in CD4(+) T cells and mediated the increase in Treg cells in bone marrow. Treatment of MCAO mice with RANKL antagonist OPG inhibited the increase in percent of bone marrow Treg cells. PGE2 also elevated the expression of indoleamine 2,3 dioxygenase in CD11C(+) dendritic cells and promoted the development of functional Treg cells. The effect was neutralized by treatment with indomethacin. Concurrently, stroke reduced production of stromal cell-derived factor-1 (SDF-1) via ?3-AR signals in bone marrow but increased the expression of C-X-C chemokine receptor (CXCR) 4 in Treg and other bone marrow cells. Treatment of MCAO mice with ?3-AR antagonist SR-59230A reduced the percent of Treg cells in peripheral blood after stroke. The disruption of the CXCR4-SDF-1 axis may facilitate mobilization of Treg cells and other CXCR4(+) cells into peripheral blood. This mechanism could account for the increase in Treg cells, hematopoietic stem cells, and progenitor cells in peripheral blood after stroke. We conclude that cerebral ischemia can increase bone marrow CD4(+)CD25(+)FoxP3(+) regulatory T cells via signals from the sympathetic nervous system.
Silk-based porous scaffolds have been used extensively in tissue engineering because of their excellent biocompatibility, tunable biodegradability and robust mechanical properties. Although many silk-based scaffolds have been prepared through freeze-drying, a challenge remains to effectively control porous structures during this process. In the present study silk fibroin with different nanostructures were self-assembled in aqueous solution by repeated drying-dissolving process and then used to improve porous structure formation in lyophilization process. Viscosity, secondary structures and water interactions were also studied to exclude their influence on the formation and control of porous structures. Following nanofiber formation in aqueous solution, silk scaffolds with improved porous structure were directly formed after lyophilization and then stabilized with water or methanol annealing treatments. Compared to silk scaffolds derived from fresh solution, the nanofibrous scaffolds showed significantly better cell compatibility in vitro. Therefore, this nanoscale control of silk offers feasible way to regulate the matrix features including porous structure and nanostructure, which are important in regulating cell and tissue outcomes in tissue engineering and regeneration, and then achieve silk-based scaffolds with improved properties.
Interleukin 18 (IL-18), a member of the IL-1 family of cytokines, is an important regulator of innate and acquired immune responses. It signals through its ligand-binding primary receptor IL-18R? and accessory receptor IL-18R?. Here we report the crystal structure of IL-18 with the ectodomain of IL-18R?, which reveals the structural basis for their specific recognition. It confirms that surface charge complementarity determines the ligand-binding specificity of primary receptors in the IL-1 receptor family. We suggest that IL-18 signaling complex adopts an architecture similar to other agonistic cytokines and propose a general ligand-receptor assembly and activation model for the IL-1 family.
Deep brain stimulation (DBS) is the surgical procedure of choice for patients with advanced Parkinson disease (PD). The globus pallidus internus (GPi) and the subthalamic nucleus (STN) are commonly targeted by this procedure. The purpose of this meta-analysis was to compare the efficacy of DBS in each region.
High-performance photodetectors are critical for high-speed optical communication and environmental sensing, and flexible photodetectors can be used for a wide range of portable or wearable applications. Here we demonstrate the all-printable fabrication of polycrystalline nanowire-based high-performance photodetectors on flexible substrates. Systematic investigations have shown their ultra-high photoconductive gain, responsivity and detectivity up to 3.3 × 10(17) Jones. Further analysis shows that their high performance originates from the unique band-edge modulation along the nanowire axial direction, where the existence of Schottky barriers in series leads to highly suppressed dark current of the device and also gives rise to fast photoelectric response to low-intensity optical signal owing to barrier height modulation. The discovered rationale in this work can be utilized as guideline to design high-performance photodetectors with other nanomaterial systems. The developed fabrication scheme opens up possibility for future flexible and high-performance integrated optoelectronic sensor circuitry.
Objectives. To investigate the association of the polymorphisms in SPARC and NLRP2 with rheumatoid arthritis (RA) in a Chinese Han population. Methods. Four single nucleotide polymorphisms (SNPs) covering SPARC and three SNPs covering NLRP2 were investigated in 624 Chinese Han RA patients and 1920 healthy controls. Results. The A allele at SPARC rs3210714, SPARC rs11950384, NLRP2 rs2217659, and NLRP2 rs703468 were linked to reduced risk of RA (p = 0.0016, p = 0.0051, p < 0.0001, and p = 0.0033, respectively). Under the recessive model, the A/A genotype of rs3210714, rs11950384, rs2217659, and rs703468 were relevant with RA (p = 0.0071, p = 0.017, p < 0.0001 and p = 0.0066, respectively). Haplotype analysis identified the SPARC GGCG haplotype, AAAA haplotype were associated with the risk for RA (p < 0.0001 and p = 0.0015, respectively), while the risk of RA was lower for carriers of the GAAA haplotype (p < 0.0001), AACG haplotype (p < 0.0001), and the AGCG haplotype (p < 0.0001). The NLRP2 GG haplotype was a risk factor (p < 0.0001), while the GA haplotype and the AG haplotype were associated with lower risk of RA (p < 0.0001 and p = 0.0017, respectively). There was no significant difference between the RA patients and the controls in polymorphisms of rs7719521, rs1978707, and rs269913. Conclusion. This study indicates that polymorphisms in SPARC and NLRP2 are related to RA susceptibility in a Chinese Han population.
A high mobility of 109.0 cm(2) V(-1) s(-1) is obtained by thin-film transistors (TFTs) comprising a composite made by aligning SnO2 nanowires (NWs) in amorphous InGaZnO (a-IGZO) thin films. This composite TFT reaches an on-current density of 61.4 ?A ?m(-1) with a 10 ?m channel length. Its performance surpasses that of single-crystalline InGaZnO and is comparable with that of polycrystalline silicon.
Mammals must inflate their lungs and breathe within minutes of birth to survive. A key regulator of neonatal lung inflation is pulmonary surfactant, a lipoprotein complex which increases lung compliance by reducing alveolar surface tension (Morgan, 1971). Whether other developmental processes also alter lung mechanics in preparation for birth is unknown. We identify prenatal lymphatic function as an unexpected requirement for neonatal lung inflation and respiration. Mice lacking lymphatic vessels, due either to loss of the lymphangiogenic factor CCBE1 or VEGFR3 function, appear cyanotic and die shortly after birth due to failure of lung inflation. Failure of lung inflation is not due to reduced surfactant levels or altered development of the lung but is associated with an elevated wet/dry ratio consistent with edema. Embryonic studies reveal active lymphatic function in the late gestation lung, and significantly reduced total lung compliance in late gestation embryos that lack lymphatics. These findings reveal that lymphatic vascular function plays a previously unrecognized mechanical role in the developing lung that prepares it for inflation at birth. They explain respiratory failure in infants with congenital pulmonary lymphangiectasia, and suggest that inadequate late gestation lymphatic function may also contribute to respiratory failure in premature infants.
Endothelin-1 (ET-1)-induced cell damage is commonly involved in ischemia/hypoxia-associated diseases. PD155080 [sodium 2-benzo (1.3)dioxol-5-yl-3-benzyl-4-(4?metho-xyphenyl)-4-oxobut-2-enoate] is a selective endothelin A receptor (ETAR) antagonist that inhibits ET-1?induced cell damage. The aim of this study was to investigate the effects of PD155080 on hypoxia-induced rat brain microvascular endothelial cell (BMEC) injury. BMECs were isolated from the cerebral cortex of Wistar rats and cultured in an anoxia chamber, containing 95% N(2) and 5% CO(2) for 12 h. BMEC injury was assessed by determining cellular ultra-microstructural changes and cell viability by MTT assay, trypan blue (TB) staining and measuring the lactate dehydrogenase (LDH) levels. ET-1 mRNA expression was detected by in situ hybridization and reverse transcription PCR (RT-PCR); the ET-1 protein level was measured by radioimmunoassay. Following exposure to hypoxic conditions, the viability of the BMECs was markedly decreased and the ultrastructure of the BMECs was damaged, as demonstrated by chromatin margination, chromatin agglutination, plasma edema, the increased number of intracellular liposomes and vacuoles, mitochondrial swelling and the expansion of a rough surfaced endoplasmic reticulum. The levels of ET-1 and ET-1 mRNA expression in the BMECs were increased following exposure to hypoxic conditions. Of note, the administration of PD155080 greatly enhanced the viability of the BMECs and ameliorated hypoxia-induced cellular injury. PD155080 also inhibited hypoxia-induced ET-1 production by the BMECs. In conclusion, PD155080 exerts protective effects against hypoxia-induced BMEC injury.
Treatment of mammalian cells with chemotherapeutic drugs can result in perturbations of nucleotide pools. Monitoring these perturbations in cultured tumor cells from human sources is useful for assessment of the effect of drug therapy and a better understanding of the mechanism of action of these drugs. In this study, three classes of chemotherapeutic drugs with different mechanisms of action were used in the development of drug-treated cell models. The LC-based targeted metabolomics analysis of nucleotides in cells of the control group and the drug-treated group was carried out. Several data processing methods were combined for the identification of potential biomarkers associated with the action of drugs, including one-way analysis of variance, principal component analysis, and receiver operating characteristic curves. Intriguingly, tumor cells of both the control group and the drug-treated groups can be distinguished from each other, and several variables were recognized as potential biomarkers, such as ATP, GMP, and UDP for antimetabolite agents, ATP, GMP, and CTP for DNA-damaging agents, as well as GMP, ATP, UDP, and GDP for the mitotic spindle agents. Further validation of the potential biomarkers was performed using the receiver operating characteristic curve. Considering their corresponding area under the curve, which was larger than 0.9, it can be concluded that GMP and ATP are the best potential biomarkers for DNA-damaging drugs, as well as GMP, ATP, and UDP for the other two classes of drugs. This limited nucleotide approach cannot completely distinguish the mechanisms of the nine drugs, but it provides preliminary evidence for the role of pharmacometabolomics in the preclinical development of drugs at least.
A novel hollow fiber cell fishing procedure with high-performance liquid chromatography (HFCF-HPLC) was developed and used for rapid screening, fishing, and analysis of bioactive compounds from traditional Chinese medicines. Human breast cancer cell MCF7, mouse breast cancer cell MADB106, and gastric cancer cell SGC7901 were seeded on the internal surface of hollow fibers that were used to screen, fish, and analyze an antitumor-active protoberberine alkaloid group from Coptis chinensis decoction. The main variables that affect the HFCF-HPLC process were investigated and optimized. The surface properties of the hollow fiber-seeded cells, cell survival rate, non-specific binding between active centers in the hollow fiber and the target compounds, repeatability, reliability, and recovery of HFCF-HPLC were investigated in detail. Several active compounds structures that were screened from Coptis chinensis by using HFCF-HPLC were identified by comparing the retention time of the reference substances. The cell membrane and cell organelle were separated from MCF7 cells for a preliminary study of the target effect of active compounds on MCF7 cells. The living cell, cell membrane, and cell organelle fishing factors of the active compound, as the indexes of drug binding ability in HFCF-HPLC, were defined and discussed. In addition, tamoxifen as positive control substance and indomethacin as negative control substance were screened by using HFCF-HPLC to further verify the method's reliability. The results demonstrated that HFCF-HPLC is an effective, rapid, stable, and reliable method to screen and analyze bioactive compounds.
Alterations in the cerebral circulation time (CCT) are observed in several cerebrovascular diseases. We designed a new method of global CCT measurement using gray-scale contrast-enhanced ultrasound and studied healthy Chinese adults and patients with intracranial shunts. Eighty-one healthy volunteers and eight patients with intracranial shunt disease were enrolled. The contrast agent Sonovue was used. Perfusion in the carotid artery and internal jugular vein bilaterally was recorded. Start and peak filling CCTs were calculated and analyzed. Imaging of carotid vessels was uncomplicated in all patients. The bilateral start CCT was 6.23 ± 1.39 s in healthy patients. There were no significant differences within subgroups and contrast-dosage groups. In the patient group, the mean start CCT was 3.0 ± 0.56 s. There was a significant difference between the control and patient groups (p < 0.001). This new method using gray-scale contrast imaging can measure CCT and cerebral blood volume accurately. It can be used to visualize blood flow differences in real time and is less dependent on the training of the operator.
The increasing incidence of vulvovaginal candidiasis (VVC) and the emergence of fluconazole resistance are an indisputable fact. However, little information is available regarding the correlation between fluconazole resistance in vaginal Candida albicans and the expression of drug efflux pump genes. In this study, we investigated the species distribution, fluconazole susceptibility profiles and the mechanisms of fluconazole resistance in Candida strains. In total, 785 clinical Candida isolates were collected from patients with VVC. C. albicans was the most frequently isolated species(n = 529) followed by C. glabrata (n = 164) and C. krusei (n = 57). Of all Candida isolates, 4.7% were resistant to fluconazole. We randomly selected 18 fluconazole resistant isolates of C. albicans to evaluate the expression of CDR1, CDR2, MDR1 and FLU1 genes. Compared with fluconazole-susceptible C. albicans isolates, CDR1 gene expression displayed 3.16-fold relative increase, which was statistically significant. CDR2, MDR1 and FLU1 overexpression was observed in several fluconazole-resistant C. albicans isolates, but statistical significance was not achieved. These results demonstrate a high frequency of non-albicans species (32.6%); however, C. albicans is the most common Candida species implicated in vaginitis, and this strain displays considerable fluconazole resistance. Meanwhile, our study further indicates that fluconazole resistance in C. albicans may correlate with CDR1 gene overexpression.
In the present study, silk fibroin (SF) was used as a template to prepare nano-hydroxyapatite (nano-HA) via a biomineralization process. We observed that the content of SF affected both the morphology and water dispersibility of nano-HA particles. Scanning electron microscope (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), zetasizer, and Fourier transform infrared spectroscopy (FTIR) were used to examine nano-HA particle features including the surface morphology, aggregation performance, and crystallization. Rod-like nano-HA particles with desired water dispersibility were achieved when the ratio of SF/HA (calculated) was above 7:3. SEM, TEM, and zeta potential results revealed that nano-HA particles were enclosed by the SF which formed a negative charge layer preventing the aggregation of HA nanoparticles in aqueous solution. Moreover, the nano-HA particles were able to re-disperse in water without precipitation for two weeks at room temperature, 60°C, and 90°C. Our work suggested a facile and effective approach of designing water-dispersible nano-HA particles which may have wide potential application in tissue engineering especially bone regeneration.
Sofosbuvir, a hepatitis C virus (HCV) NS5B polymerase inhibitor, is a new direct-acting antiviral for chronic HCV infection. This systematic review and proportional meta-analysis examined the efficacy and safety of sofosbuvir-based therapy for chronic HCV infection in treatment-naïve and -experienced patients. Medline, Cochrane Database of Systematic Reviews, EMBASE and Web of Science databases were searched. Clinical trials examining sofosbuvir plus ribavirin (RBV) and pegylated interferon-? (peg-IFN) or sofosbuvir plus RBV among adults with chronic HCV infection were included. Data were extracted on virological responses including sustained virological response at post-treatment Week 12 (SVR12), relapse, treatment discontinuation due to an adverse event (AE), virological breakthrough during treatment, and AEs. One trial and 13 treatment arms/cohorts from seven studies met the criteria for analysis in treatment-naïve patients who were treated with sofosbuvir, RBV and peg-IFN; the SVR12 was 89% (95% CI 85-92%), relapse was 5% and the serious adverse event (SAE) rate was 4%. Six treatment arms/cohorts met the criteria for analysis in treatment-naïve patients who were treated with sofosbuvir and RBV; the SVR12 was 72% (95% CI 60-81%), relapse was 27% and the SAE rate was 3%. Three treatment arms/cohorts met the criteria for analysis in treatment-experienced patients who were treated with sofosbuvir and RBV; the SVR12 was 51% (95% CI 27-75%), relapse was 46% and the SAE rate was 4%. In conclusion, sofosbuvir-based treatment is effective and safe in treating chronic HCV infection, although the SVR12 of its combination with RBV, especially in treatment-experienced patients, requires improvement.
Fibulin-4, a member of the fibulin family of extracellular glycoproteins, is implicated in the progression of a number of types of cancer. However, the function of fibulin-4 in cervical cancer progression remains unexplored. Fibulin-4 mRNA and protein expression levels in normal cervical tissue, cervical intraepithelial neoplasia (CIN), cervical carcinoma, highly invasive subclones and low-invasive subclones were evaluated by real-time reverse transcriptase-polymerase chain reaction and immunohistochemistry. Serum fibulin-4 levels in patients with CIN and cervical carcinoma were measured by enzyme-linked immunosorbent assay. To assess the angiogenic properties of fibulin-4, vascular endothelial growth factor (VEGF) expression and tumor microvessel density (MVD) were analyzed in the cervical carcinoma cases by immunohistochemistry. Fibulin-4 expression was upregulated in the cervical carcinoma cases, and was positively correlated with MVD and VEGF expression. Fibulin-4 overexpression and high serum levels were significantly associated with advanced stage, low differentiation, lymph node metastasis, and poor prognosis in patients with cervical cancer. Fibulin-4 expression was also found to be overexpressed in highly invasive subclones when compared with the low-invasive subclones. Fibulin-4 is a newly identified glycoprotein that is overexpressed in cervical carcinoma. Fibulin-4 promotes angiogenesis and is associated with poor prognostic clinicopathologic features. This study demonstrated that fibulin-4 may serve as a new prognostic factor and as a potential therapeutic target for patients with cervical carcinoma.
By incorporating crystalline photosensitive nanowires (NWs), an amorphous InZnO (a-IZO) thin film is designed to be sensitive to the primary colors of light via a facile sol-gel approach. The mobility is also improved. The composite devices leverage the advantages of the transparency of a-IZO with the photosensitivity of CdS NWs.
Type 2 diabetes is one of the most common causes of cardiovascular disease as it causes arterial stiffness changes. The purpose of this study is to characterize, in vivo, carotid arterial structural and functional changes by applying radio frequency and X-strain ultrasound techniques.
Doping potassium ions in silver cyanide complexes leads to two heterometallic silver-potassium cyanide complexes, namely, [Me4N]2[KAg3(CN)6] (1) with a typical NaCl-type framework containing distinct ligand-unsupported argentophilic interactions, and [Ag3(H2O)3][K(CN)2]3 (2) with an unprecedented 3-D (4,4,6,6)-connected framework formed by unique [Ag3(H2O)3] clusters connecting concave-convex [K(CN)2] layers. The two complexes exhibit green luminescence, and the relationships between their structures and photoluminescence, as well as the regulating effect on the luminescence by doping of potassium ions are well investigated via density functional theory analysis.
Hydrogels have been widely used for 3-dimensional (3D) cell culture and tissue regeneration due to their tunable biochemical and physicochemical properties as well as their high water content, which resembles the aqueous microenvironment of the natural extracellular matrix. While many properties of natural hydrogel matrices are modifiable, their intrinsic isotropic structure limits the control over cellular organization, which is critical to restore tissue function. Here we report a generic approach to incorporate alignment topography inside the hydrogel matrix using a combination of electrical and mechanical stretching. Hydrogel fibres with uniaxial alignment were prepared from aqueous solutions of natural polymers such as alginate, fibrin, gelatin, and hyaluronic acid under ambient conditions. The unique internal alignment feature drastically enhances the mechanical properties of the hydrogel microfibres. Furthermore, the facile, organic solvent-free processing conditions are amenable to the incorporation of live cells within the hydrogel fibre or on the fibre surface; both approaches effectively induce cellular alignment. This work demonstrates a versatile and scalable strategy to create aligned hydrogel microfibres from various natural polymers.
The methyltransferase like 3 (METTL3)-containing methyltransferase complex catalyzes the N6-methyladenosine (m6A) formation, a novel epitranscriptomic marker; however, the nature of this complex remains largely unknown. Here we report two new components of the human m6A methyltransferase complex, Wilms' tumor 1-associating protein (WTAP) and methyltransferase like 14 (METTL14). WTAP interacts with METTL3 and METTL14, and is required for their localization into nuclear speckles enriched with pre-mRNA processing factors and for catalytic activity of the m6A methyltransferase in vivo. The majority of RNAs bound by WTAP and METTL3 in vivo represent mRNAs containing the consensus m6A motif. In the absence of WTAP, the RNA-binding capability of METTL3 is strongly reduced, suggesting that WTAP may function to regulate recruitment of the m6A methyltransferase complex to mRNA targets. Furthermore, transcriptomic analyses in combination with photoactivatable-ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) illustrate that WTAP and METTL3 regulate expression and alternative splicing of genes involved in transcription and RNA processing. Morpholino-mediated knockdown targeting WTAP and/or METTL3 in zebrafish embryos caused tissue differentiation defects and increased apoptosis. These findings provide strong evidence that WTAP may function as a regulatory subunit in the m6A methyltransferase complex and play a critical role in epitranscriptomic regulation of RNA metabolism.
To examine associations of matrix metalloproteinase-9 (MMP-9) and monocyte chemoattractant protein-1 (MCP-1) concentrations with the severity of carotid atherosclerosis, based on measurements of carotid plaque and intima-media thickness (IMT).
In Chinese traditional medicine, Agrimonia pilosa Ledeb (APL) exhibits great effect on treatment of type 2 diabetes mellitus (T2DM), however its mechanism is still unknown. Considering that T2DM are correlated with postprandial hyperglycemia and oxidative stress, we investigated the ?-glucosidase inhibitory activity and the antioxidant activity of flavonoid compound (FC) and triterpenoid compound (TC) from APL.
Gastroretentive drug delivery system is a promising option for the treatment of Helicobacter pylori infection, which can prolong gastric residence time and supply high drug concentration in the stomach. In the present study, a low density system of metronidazole-loaded porous Eudragit® RS microparticle with high drug loading capacity (>25%) was fabricated via electrospray method. The porous structure and size distribution of microparticles were affected by polymer concentration and flow rate of solution. FTIR and XRD analyses indicated that drug has been entrapped into the porous microparticles. In addition, sustained release profiles and slight cytotoxicity in vitro were detected. Gamma scintigraphy study in vivo demonstrated that ¹³¹I-labeled microparticles retained in stomach for over 8h, and about 65.50% radioactive counts were finally detected in the region of interest. The biodistribution study confirmed that hotspot of radioactivity was remaining in the stomach. Furthermore, metronidazole-loaded porous microparticles can eradicate H. pylori completely with lower dose and administration frequency of antibiotic compared with pure drug, which were also more helpful for the healing of mucosal damages. These results suggest that prepared porous microparticle has the potential to provide better treatment for H. pylori infection.
In this work, single-crystalline p-type Cd3P2 nanowires (NWs) were synthesized on a Cd sheet via a facile chemical vapor deposition method. Then field-effect transistors and high-performance photodetectors were fabricated based on these NWs. It was found that hole mobility of a pristine Cd3P2 NW is around 2.94 cm(2) V(-1) s(-1). Meanwhile, high responsivity and photoconductive gain were observed on these devices across a broad spectral range covering UV-visible to NIR with high stability and reproducibility. Furthermore, hybrid organic-inorganic n-type phenyl-C61-butyric acid methyl ester (PCBM) and p-type Cd3P2 NW heterojunction photodetectors were also fabricated, exhibiting much improved photocurrent and photoconductive gain, as compared to the device made of pristine Cd3P2 NWs. Intriguingly, the flexible hybrid photodetectors have been fabricated on plastic substrates and characterized under various bending conditions, demonstrating their excellent flexibility and robustness. The high performance and flexibility of the hybrid photodetectors are promising for further applications requiring large-area, high-sensitivity, and high-speed photodetectors with broad-spectrum photoresponse.
Carcinoid tumors of the middle ear are very rare. Here we describe a 37-year-old man with multiple recurrent carcinoid tumor of the right middle ear. The CT demonstrated the recurrent mass that filled the tympanum and mastoid with osteolytic invasion, and the tumor was removed by surgery. The pathological findings showed the tumor cells, without necrosis and mitotic activity, had round, oval, or slightly irregular nuclei and finely-dispersed chromatin, arranged in cords, nests, and glandular structures. They were strongly positive for synaptophysin and CD56, but were negative for S-100 and chromogranin A. Ki-67 proliferation activity was low (<2%). With a review of the literature, the clinical, pathological characteristics and treatment modalities of this rare tumor are discussed.
Small cell neuroendocrine carcinoma (NEC) that originates in the tonsil is extremely rare and carries a poor prognosis. Only a few cases of this tumor have been reported so far and the standard treatment protocol remains uncertain. Here we describe a 74-year-old woman presented with throat pain for about 2 months. Computed tomography (CT) scan revealed a 3.4×1.8 cm tumor with moderate enhancement in the left tonsil and a 1.3×1.0 cm neck mass in left level II. A biopsy of the tonsillar mass was performed and histologic examination revealed small round to oval tumor cells were arranged in cords or nests, containing hyperchromatic nuclei and scant cytoplasm. Mitotic figures were readily identified. Immunohistochemical staining showed that tumor cells were strongly positive for CD56, focally positive for PCK and negative for LCA. A diagnosis of primary small cell NEC of the left tonsil was obtained. The patient was treated by six cycles of cisplatin combined with etoposide and the masses showed initial complete response. But recurrence in the left neck was found 9 months after initial diagnosis and the patient refused any further treatment. With a review of the literature, the nomenclature, clinicopathological characteristics and treatment modalities of this rare tumor are discussed.
Process mining is automated acquisition of process models from event logs. Although many process mining techniques have been developed, most of them are based on control flow. Meanwhile, the existing role-oriented process mining methods focus on correctness and integrity of roles while ignoring role complexity of the process model, which directly impacts understandability and quality of the model. To address these problems, we propose a genetic programming approach to mine the simplified process model. Using a new metric of process complexity in terms of roles as the fitness function, we can find simpler process models. The new role complexity metric of process models is designed from role cohesion and coupling, and applied to discover roles in process models. Moreover, the higher fitness derived from role complexity metric also provides a guideline for redesigning process models. Finally, we conduct case study and experiments to show that the proposed method is more effective for streamlining the process by comparing with related studies.
Serum lens culinaris agglutinin-reactive fraction of ?-fetoprotein (AFP-L3%) has been widely used for HCC diagnosis and follow-up surveillance as tumor serologic marker. However, the prognostic value of high pre-treatment serum AFP-L3% in patients with hepatocellular carcinoma (HCC) remains controversial. We therefore conduct a meta-analysis to assess the relationship between high pre-treatment serum AFP-L3% and clinical outcome of HCC.
To demonstrate the clinical outcomes of maximal medical therapy(MMT) and functional endoscopic sinus surgery+ maximal medical therapy (FESS+MMT) for moderate to severe chronic rhinosinusitis without nasal polyps (CRSsNP) in China, to provide clinical evidence for treatment recommendation.
To select rabbiteye blueberry leaves from an appropriate harvest season to develop functional foods, this paper studied the bioactive secondary metabolites and the antioxidant capacity of rabbiteye blueberry leaves from May, September, and November. The results showed the leaves from May had the highest content of total flavonoids (114.21 mg/g) and the leaves from November had the highest content of total polyphenols and proanthocyanidins (425.24 and 243.29 mg/g, respectively). It was further found that blueberry leaves from different seasons have similar bioactive constituents, but their contents are obviously different by HPLC. The rabbiteye blueberry leaves from November had the highest antioxidant capacity, which was well correlated with their highest proanthocyanidin content. The results clarify that the blueberry leaves from different seasons have different contents of bioactive secondary metabolites and different antioxidant activities, which implied that leaves from November should be selected first for utilization in functional foods.
Quorum sensing (QS) is a signalling mechanism by which bacteria produce, release and then detect and respond to changes in their density and biosignals called autoinducers (AIs). There are multiple feedback loops in the QS system of Vibrio harveyi. However, how these feedback loops function to control signal processing remains unclear. In this study, the authors present a computational model for the switch-like regulation of signal transduction by small regulatory RNA-mediated QS based on intertwined network involving AIs, LuxO, LuxU, Qrr sRNAs and LuxR. In agreement with experimental observations, the model suggests that different feedbacks play critical roles in the switch-like regulation. The authors results reveal that V. harveyi uses multiple feedbacks to precisely control signal transduction.
We used blood as leaching medium, simulating clinical operation under maximum condition, to develop Liquid-phase extraction- High Performance Liquid Chromatography (HPLC) method for determination of plasticizer Di-(2-ethylhexyl)phthalate (DEHP) released from Disposable Extracorporeal Circulation Tube in order to lay the foundation of risk analysis of this product. The characteristic wavelength of DEHP in methanol was detected. Acetonitrile was added to the leaching blood in proportion and extracted DEHP from blood. The methodology for HPLC to quantify DEHP was established and the DEHP amount released from this disposable extracorporeal circulation tube was measured. The experiments showed good results as follows. The characteristic wavelength of DEHP was 272nm. The concentration of DEHP (5-250 microg/mL) kept good linear relationship with peak area (r=0.9999). Method sensitivity was 1 microg/mL. Precisions showed RSD<5%. The adding standard extraction Recovery Rates of 25, 100 and 250 microg DEHP standard were 61.91 +/- 3.32)%, (69.38 +/- 0.55)% and (68.47 +/- 1.15)%. The DEHP maximum amounts released from 3 sets of this disposable extracorporeal circulation tube were 204.14, 106.30 and 165.34 mg/set. Our Liquid-phase Extraction-HPLC method showed high accuracy and precision, and relatively stable recovery rate. Its operation was also convenient.
This study is designed to test the agreement in measuring left ventricular systolic function between transthoracic two-dimensional echocardiography (2DTTE) and "gold standard" of non-invasive cardiac imaging, magnetic resonance imaging (CMRI) and their impacts on the classification of patients according to the left ventricular ejection fraction (EF). 32 patients who were suspected with heart disease were evaluated by CMRI and 2DTTE examinations. End diastolic volume (EDV), end systolic volume (ESV), EF and left ventricular function category were then calculated and compared. There was no significant difference (P=0.504) for EDV, while ESV of CMRI was significantly higher than that of 2DTTE (P=0.049), and EF of CMRI was significantly lower than that of 2DTTE (P= 0.018). There was no significant difference (P=0.077) in left ventricular functional category. Bland-Altman analysis of LV volumetric data and EF measurements showed a good agreement between two methods. The 2DTTE over-estimated I (n=5) or II (n=1) degrees of functional classification when compared with the CMRI. Both CMRI and 2DTTE are of great clinical value in evaluating left ventricular systolic function, while CMR may be more beneficial to patients with abnormal LV functions.
At the molecular level, it is acknowledged that a TCM formula is often a complex system, which challenges researchers to fully understand its underlying pharmacological action. However, module detection technique developed from complex network provides new insight into systematic investigation of the mode of action of a TCM formula from the molecule perspective. We here proposed a computational approach integrating the module detection technique into a 2-class heterogeneous network (2-HN) which models the complex pharmacological system of a TCM formula. This approach takes three steps: construction of a 2-HN, identification of primary pharmacological units, and pathway analysis. We employed this approach to study Shu-feng-jie-du (SHU) formula, which aimed at discovering its molecular mechanism in defending against influenza infection. Actually, four primary pharmacological units were identified from the 2-HN for SHU formula and further analysis revealed numbers of biological pathways modulated by the four pharmacological units. 24 out of 40 enriched pathways that were ranked in top 10 corresponding to each of the four pharmacological units were found to be involved in the process of influenza infection. Therefore, this approach is capable of uncovering the mode of action underlying a TCM formula via module analysis.
Much greater surface-to-volume ratio of hierarchical nanostructures renders them with promising potential for high performance chemical sensing. In this work, crystalline nanocombs were synthesized via chemical vapor deposition and fabricated into resistive gas sensors. Particularly, NO2 sensing performance of these devices has been systematically characterized, showing higher sensitivity as compared to their nanobelt counterparts. Through device simulation, it was discovered that the teeth part of a nanocomb could serve as a "negative-potential gate" after accumulating electrons captured by surface adsorbed NO2 molecules. This self-gating effect eventually results in a greater reduction of nanocomb device channel conductance upon NO2 exposure, as compared to a nanobelt device, leading to a much higher NO2 detection sensitivity. This study not only sheds light on the mechanism of performance enhancement with hierarchical nanostructures, but also proposes a rational approach and a simulation platform to design nanostructure based chemical sensors with desirable performance.
We present here the application of graphene oxide (GO) and reduced graphene oxide (GOOH) sheet as novel stationary phases for open-tubular CEC (OTCEC) separation based on electrostatic assembly. The inner walls of a bare capillary column was first modified by ionic assembly of poly (diallyldimethylammonium chloride) (PDDA), and then negatively charged GO or GOOH was easily assembled on a positively charged interior walls of the capillary by electrostatic force. Scanning Electron Microscope images showed that GO and GOOH can still maintain sheet-layer-like structure when coated onto the capillary via electrostatic assembly. The chromatographic properties of the GO and GOOH coated columns were evaluated via OTCEC separations of various kinds of analytes, including three acid nitrophenol isomers, three basic nitroaniline isomers, and four neutral PAHs. Efficient separations of all the analytes were achieved with optimized buffer pH and organic additive. The reproducibility and stability of the GO or GOOH coated columns were investigated. Our results indicate the capability of application GO or GOOH sheet in OTCEC separation, which can be coated on the inner wall of fused-silica capillary via electrostatic assembly.
Interleukin (IL)-33 is an important member of the IL-1 family that has pleiotropic activities in innate and adaptive immune responses in host defense and disease. It signals through its ligand-binding primary receptor ST2 and IL-1 receptor accessory protein (IL-1RAcP), both of which are members of the IL-1 receptor family. To clarify the interaction of IL-33 with its receptors, we determined the crystal structure of IL-33 in complex with the ectodomain of ST2 at a resolution of 3.27 Å. Coupled with structure-based mutagenesis and binding assay, the structural results define the molecular mechanism by which ST2 specifically recognizes IL-33. Structural comparison with other ligand-receptor complexes in the IL-1 family indicates that surface-charge complementarity is critical in determining ligand-binding specificity of IL-1 primary receptors. Combined crystallography and small-angle X-ray-scattering studies reveal that ST2 possesses hinge flexibility between the D3 domain and D1D2 module, whereas IL-1RAcP exhibits a rigid conformation in the unbound state in solution. The molecular flexibility of ST2 provides structural insights into domain-level conformational change of IL-1 primary receptors upon ligand binding, and the rigidity of IL-1RAcP explains its inability to bind ligands directly. The solution architecture of IL-33-ST2-IL-1RAcP complex from small-angle X-ray-scattering analysis resembles IL-1?-IL-1RII-IL-1RAcP and IL-1?-IL-1RI-IL-1RAcP crystal structures. The collective results confer IL-33 structure-function relationships, supporting and extending a general model for ligand-receptor assembly and activation in the IL-1 family.
A kinesin-like protein regulates grain length and plant height by affecting expression levels of genes involved in GA synthesis and response in rice Grain shape, a complex agronomic trait, plays an important role in determining yield and quality in rice. In the present study, a mutant named short grain length (sgl) was identified among explants of tissue cultured japonica variety Kita-ake. It exhibited reduced plant height (about 72 % of WT) and short grain length (about 80 % of WT). The reduced length was due to decreased cell elongation. The Short Grain Length (SGL) gene was isolated via map-based cloning and identified to encode a kinesin-like protein. SGL was expressed in the whole plant, especially in the stem and panicles. SGL was shown to have transcriptional activity. In onion epidermal cells, SGL protein was found mainly in the nucleus. Real-time PCR analyses showed that expression levels of genes involved in gibberellin metabolic pathways were affected in the sgl mutant. These data suggested that SGL protein may be involved in regulating GA synthesis and response genes, that in turn, regulates grain length and plant height.
Nanofibers exist ubiquitously in natural extracellular matrix (ECM) of all kinds of human tissues forming hydrated interwoven network. Electrospinning nanotechnology has been proven to be a powerful technique to fabricate controllable nanofibers mimicking the natural ECM structures. Hyaluronic acid (HA), as a critical component of natural ECM, has been widely used in tissue engineering and regenerative medicine. In this study, pure HA nanofibers with average diameter of 33 +/- 5 nm, 59 +/- 12 nm, 79 +/- 12 nm and 113 +/- 19 nm were successfully prepared using different electrospinning parameters. The effect of the ambient relative humidity on HA electrospinnability was investigated for the first time in detail, which was proven to be one of the most important factors to control the morphology of HA nanofibers beside the solution properties. A critical value of humidity for a defined HA solution was observed, only below which HA nanofibers with similar diameters and morphologies could be successfully obtained. When the ambient relative humidity was higher than the critical value, the HA nanofibers started dissolving at the cross points and even fused together forming a spreading layer. Moreover, only a small amount of N, N-Dimethylformamide (DMF) was found to be required to promote the electrospinnability of HA solution by mixing with water as solvents. With the increase in the DMF content, the surface tension of the solution decreased significantly, which was thought to be benefit for the stable Taylor cone and fluid jet formation in electrospinning. At the same time, it should be noted that the conductivity of the solution also decreased with the increase of DMF content in the solution, which was believed to be responsible for the increasing diameters of HA nanofibers corresponding to higher DMF content. Controllable HA nanofibers with diameter below 100 nm have great promising for developing novel nanobiomaterials applied in tissue engineering and regenerative medicine.
This cross-sectional study aims to identify the potential risk factors of left ventricular hypertrophy (LVH) in hemodialysis (HD) patients. Echocardiography, anthropometric measurements and biochemical analyses were performed for 112 HD patients. In univariate analysis, body mass index, systolic blood pressure, diastolic blood pressure, glycosylated hemoglobin, glycated albumin, high sensitivity C-reactive protein (hs-CRP), cardiac troponin T (cTnT), amino-terminal pro-B-natriuretic peptide (NT-proBNP) and carotid artery intima-media thickness were positively correlated with left ventricular mass index (LVMI); pre-albumin, serum creatinine, left ventricular ejection fraction (LVEF) and fractional shortening were negatively correlated with LVMI. Linear regression analysis showed systolic blood pressure, NT-proBNP and LVEF were independently associated with LVMI. According to a binary logistic regression model, higher systolic blood pressure, NT-proBNP and hs-CRP levels showed independent correlation with LVH. Receiver operator characteristic curves analysis showed the associations between NT-proBNP and LVH more closely than hs-CRP and cTnT. The area under the curve for NT-proBNP, hs-CRP and cTnT was 0.762 (95% CI: 0.660-0.864, p?0.001), 0.734 (95% CI: 0.624-0.844, p?0.001) and 0.677 (95% CI: 0.563-0.790, p?=?0.004), respectively. These data support the main conclusions: hypertension, fluid overload and micro inflammation are associated with LVH in maintenance HD patients. It demonstrates traditional and nontraditional risk factors all play important roles in the development of LVH.
To observe the changes in the expressions of STAT3 and NF-KB in PC-3 cells after IL-6 stimulation and to verify the effects of the NF-KB inhibitor caffeic acid phenethyl ester (CAPE) on the expressions of p-STAT3 and IL-6 in the PC-3 prostate cancer cell line.
Strigolactones (SLs), a newly discovered class of carotenoid-derived phytohormones, are essential for developmental processes that shape plant architecture and interactions with parasitic weeds and symbiotic arbuscular mycorrhizal fungi. Despite the rapid progress in elucidating the SL biosynthetic pathway, the perception and signalling mechanisms of SL remain poorly understood. Here we show that DWARF 53 (D53) acts as a repressor of SL signalling and that SLs induce its degradation. We find that the rice (Oryza sativa) d53 mutant, which produces an exaggerated number of tillers compared to wild-type plants, is caused by a gain-of-function mutation and is insensitive to exogenous SL treatment. The D53 gene product shares predicted features with the class I Clp ATPase proteins and can form a complex with the ?/? hydrolase protein DWARF 14 (D14) and the F-box protein DWARF 3 (D3), two previously identified signalling components potentially responsible for SL perception. We demonstrate that, in a D14- and D3-dependent manner, SLs induce D53 degradation by the proteasome and abrogate its activity in promoting axillary bud outgrowth. Our combined genetic and biochemical data reveal that D53 acts as a repressor of the SL signalling pathway, whose hormone-induced degradation represents a key molecular link between SL perception and responses.
Traditional Chinese medicine (TCM) has shown significant efficacy in the treatment of cough variant asthma (CVA), a special type of asthma. However, there is shortage of explanations for relevant mechanism of treatment. As Zhengs differentiation is a critical concept in TCM, it is necessary to explain the mechanism of treatment of Zhengs. Based on TCM clinical cases, this study illustrated the mechanism of the treatment of three remarkably relevant Zhengs for CVA: "FengXieFanFei," "FeiQiShiXuan", and "QiDaoLuanJi." To achieve this goal, five steps were carried out: (1) determining feature Zhengs and corresponding key herbs of CVA by analyses of clinical cases; (2) finding out potential targets of the key herbs and clustering them based on their functional annotations; (3) constructing an ingredient-herb network and an ingredient network; (4) identifying modules of the ingredient network; (5) illustrating the mechanism of the treatment by further mining the latent biological implications within each module. The systematic study reveals that the treatment of "FengXieFanFei," "FeiQiShiXuan," and "QiDaoLuanJi" has effects on the regulation of multiple bioprocesses by herbs containing different ingredients with functions of steroid metabolism regulation, airway inflammation, and ion conduction and transportation. This network-based systematic study will be a good way to boost the scientific understanding of mechanism of the treatment of Zhengs.
GATA and Friend of GATA (FOG) form a transcriptional complex that plays a key role in cardiovascular development in both fish and mammals. In the present study we demonstrate that the basic helix-loop-helix transcription factor Atonal homolog 8 (Atoh8) is required for development of the heart in fish but not in mice. Genetic studies reveal that Atoh8 interacts specifically with Gata4 and Fog1 during development of the heart and swim bladder in the fish. Biochemical studies reveal that ATOH8, GATA4, and FOG2 associate in a single complex in vitro. In contrast to fish, ATOH8-deficient mice exhibit normal cardiac development and loss of ATOH8 does not alter cardiac development in Gata4(+/-) mice. This species difference in the role of ATOH8 is explained in part by LacZ and GFP reporter alleles that reveal restriction of Atoh8 expression to atrial but not ventricular myocardium in the mouse. Our findings identify ATOH8 as a novel regulator of GATA-FOG function that is required for cardiac development in the fish but not the mouse. Whether ATOH8 modulates GATA-FOG function at other sites or in more subtle ways in mammals is not yet known.
Highly aligned intrinsic and indium doped CdS nanopillar arrays were fabricated via a template assisted Solid Source Chemical Vapor Deposition method (SSCVD). The prepared nanopillar arrays were well aligned, dense and uniform in diameter and length. Their geometry can be well defined by the design of the templates. These unique properties make them promising candidates for future photonic and optoelectronic devices. The structure of the prepared nanopillars has been studied by high resolution transmission electron microscopy and their different growth orientation as compared to those grown in free space has been observed and interpreted by the template induced change of the liquid-solid interfacial energy and the surface tension at the edge of the circular interface. To investigate electrical property of CdS nanopillars, vertical nanopillar array devices and horizontal individual nanopillar field-effect transistors have been fabricated and characterized. The measurements showed that the location of the indium doping source significantly affected carrier concentration, conductivity and field-effect mobility of the prepared CdS nanopillars. Particularly, it was found that conductivity could be improved by 4 orders of magnitude and field-effect mobility could be enhanced up to 50 cm(2) V(-1) s(-1) via proper doping control. These results enable further applications of CdS nanopillars in nano-optoelectronic applications such as photodetection and photovoltaics in the future.
Indole-3-acetic acid (IAA), the natural auxin in plants, regulates many aspects of plant growth and development. Extensive analyses have elucidated the components of auxin biosynthesis, transport, and signaling, but the physiological roles and molecular mechanisms of auxin degradation remain elusive. Here, we demonstrate that the dioxygenase for auxin oxidation (DAO) gene, encoding a putative 2-oxoglutarate-dependent-Fe (II) dioxygenase, is essential for anther dehiscence, pollen fertility, and seed initiation in rice. Rice mutant lines lacking a functional DAO display increased levels of free IAA in anthers and ovaries. Furthermore, exogenous application of IAA or overexpression of the auxin biosynthesis gene OsYUCCA1 phenocopies the dao mutants. We show that recombinant DAO converts the active IAA into biologically inactive 2-oxoindole-3-acetic acid (OxIAA) in vitro. Collectively, these data support a key role of DAO in auxin catabolism and maintenance of auxin homeostasis central to plant reproductive development.
The spike glycoprotein (S) of recently identified Middle East respiratory syndrome coronavirus (MERS-CoV) targets the cellular receptor, dipeptidyl peptidase 4 (DPP4). Sequence comparison and modeling analysis have revealed a putative receptor-binding domain (RBD) on the viral spike, which mediates this interaction. We report the 3.0 Å-resolution crystal structure of MERS-CoV RBD bound to the extracellular domain of human DPP4. Our results show that MERS-CoV RBD consists of a core and a receptor-binding subdomain. The receptor-binding subdomain interacts with DPP4 ?-propeller but not its intrinsic hydrolase domain. MERS-CoV RBD and related SARS-CoV RBD share a high degree of structural similarity in their core subdomains, but are notably divergent in the receptor-binding subdomain. Mutagenesis studies have identified several key residues in the receptor-binding subdomain that are critical for viral binding to DPP4 and entry into the target cell. The atomic details at the interface between MERS-CoV RBD and DPP4 provide structural understanding of the virus and receptor interaction, which can guide development of therapeutics and vaccines against MERS-CoV infection.
The Drosophila defense against pathogens largely relies on the activation of two signaling pathways: immune deficiency (IMD) and Toll. The IMD pathway is triggered mainly by Gram-negative bacteria, whereas the Toll pathway responds predominantly to Gram-positive bacteria and fungi. The activation of these pathways leads to the rapid induction of numerous NF-?B-induced immune response genes, including antimicrobial peptide genes. The IMD pathway shows significant similarities with the TNF receptor pathway. Recent evidence indicates that the IMD pathway is also activated in response to various noninfectious stimuli (i.e., inflammatory-like reactions). To gain a better understanding of the molecular machinery underlying the pleiotropic functions of this pathway, we first performed a comprehensive proteomics analysis to identify the proteins interacting with the 11 canonical members of the pathway initially identified by genetic studies. We identified 369 interacting proteins (corresponding to 291 genes) in heat-killed Escherichia coli-stimulated Drosophila S2 cells, 92% of which have human orthologs. A comparative analysis of gene ontology from fly or human gene annotation databases points to four significant common categories: (i) the NuA4, nucleosome acetyltransferase of H4, histone acetyltransferase complex, (ii) the switching defective/sucrose nonfermenting-type chromatin remodeling complex, (iii) transcription coactivator activity, and (iv) translation factor activity. Here we demonstrate that sumoylation of the I?B kinase homolog immune response-deficient 5 plays an important role in the induction of antimicrobial peptide genes through a highly conserved sumoylation consensus site during bacterial challenge. Taken together, the proteomics data presented here provide a unique avenue for a comparative functional analysis of proteins involved in innate immune reactions in flies and mammals.
Drug loading capacity is an important property for an ideal drug delivery system. However, the drug loading capacity of prepared pH-sensitive polymeric nanoparticles is usually low. To overcome this drawback, the electrospray method was used to prepare Eudragit L 100-55 nanoparticles with high drug loading capacity in one step. Omeprazole was selected as the model drug. The maximum loading capacity of nanoparticles was 43.21% by changing the mass ratio of drug to polymer, and the entrapment efficiency was nearly 100%. The prepared nanoparticle showed spherical or ellipsoidal morphology and the average diameter was about 300 nm. The pH-sensitive nanoparticle displayed pH-dependent release in vitro. In addition, a slight cytotoxicity was detected in the cytotoxicity study. The results indicated that electrospray is an easy, rapid and efficient technique for the preparation of high-loading pH-sensitive polymeric nanoparticles, and the pH-sensitive nanoparticle is a promising carrier for oral drug delivery.
Low-temperature germination (LTG) is an important agronomic trait for direct seeding of rice in temperate regions of East Asia. To dissect the genetic control of LTG, we constructed a recombinant inbred line (RIL) population derived from a cross of japonica variety USSR5 and indica variety N22. Three putative QTL involved in LTG were detected and named qLTG-7, qLTG-9 and qLTG-12. They explained 9.5, 12.12 and 7.08 % of the phenotypic variation, respectively, and the alleles from USSR5 enhanced LTG. A set of advanced backcross lines selected for the presence of qLTG-9 (with the biggest contribution of the three QTL), by both linked markers and phenotype, was used to validate qLTG-9 in different generations, years and locations. A near-isogenic line in USSR5 background with a qLTG-9 insertion from N22 had retarded germination under low-temperature conditions. Finally, qLTG-9 was fine mapped between markers L9-25D and ID-1, to a 72.3-kb region in chromosome 9, which in the Nipponbare genome contains five predicted genes. This result provides a springboard for map-based cloning of qLTG-9 and is helpful in understanding the mechanism of seed germination under low-temperature conditions.
Glutaredoxins (Grxs) have been identified across taxa as important mediators in various physiological functions. A chloroplastic monothiol glutaredoxin, AtGRXS16 from Arabidopsis thaliana, comprises two distinct functional domains, an N-terminal domain (NTD) with GlyIleTyr-TyrIleGly (GIY-YIG) endonuclease motif and a C-terminal Grx module, to coordinate redox regulation and DNA cleavage in chloroplasts. Structural determination of AtGRXS16-NTD showed that it possesses a GIY-YIG endonuclease fold, but the critical residues for the nuclease activity are different from typical GIY-YIG endonucleases. AtGRXS16-NTD was able to cleave ?DNA and chloroplast genomic DNA, and the nuclease activity was significantly reduced in AtGRXS16. Functional analysis indicated that AtGRXS16-NTD could inhibit the ability of AtGRXS16 to suppress the sensitivity of yeast grx5 cells to oxidative stress; however, the C-terminal Grx domain itself and AtGRXS16 with a Cys123Ser mutation were active in these cells and able to functionally complement a Grx5 deficiency in yeast. Furthermore, the two functional domains were shown to be negatively regulated through the formation of an intramolecular disulfide bond. These findings unravel a manner of regulation for Grxs and provide insights into the mechanistic link between redox regulation and DNA metabolism in chloroplasts.
Transdiagnostic interventions present pragmatic benefits in treatment dissemination and training of mental health professionals when faced with emotional disorders such as anxiety and depression. Excessive worry is a common feature across emotional disorders and represents an ideal candidate target for transdiagnostic intervention. The current pilot trial examined the efficacy of a behavioural activation treatment for worry (BAW) in a community population. 49 individuals experiencing excessive worry were randomised to waitlist or BAW receiving an 8 week group based intervention. Results demonstrated that BAW was successful in reducing excessive worry, depressive symptoms, cognitive avoidance, Intolerance of Uncertainty and improving problem solving orientation. Twice as many individuals showed clinically significant reductions in excessive worry after treatment compared to the waitlist control. Despite limitations to sample size and power, this study presents promising support for BAW as a practical transdiagnostic treatment for worry.
In this study we transplanted bone marrow mononuclear cells (BM-MNCs) or microglia into rats that had undergone permanent cerebral ischemia and observed the distribution or morphology of transplanted cells in vivo. In addition, we compared the effects of BM-MNCs and microglia on infarct volume, brain water content, and functional outcome after permanent cerebral ischemia. BM-MNCs and microglia were obtained from femur and brain, respectively, of newborn rats. Adult rats were injected with vehicle or 3 million BM-MNCs or microglia via the tail vein 24h after permanent middle cerebral artery occlusion (pMCAO). The distribution or morphologic characteristics of transplanted BM-MNCs (double stained with BrdU/Cd34 or BrdU/CD45) and microglia (double stained with BrdU/Iba-1) were detected with immunofluorescent staining at 3 or 7 and 14 days after pMCAO. Functional deficits were assessed by the modified neurologic severity score at 1, 3, 7 and 14 days after pMCAO. Brain water content was assessed at 3 days, and infarct volume was determined at 14 days. We observed more BrdU/CD45 and BrdU/Iba-1 double-stained cells than BrdU/CD34 double-stained cells around the infarcted area. Some infused microglia showed the morphology of innate microglia at 7 days after pMCAO, and the number increased at 14 days. BM-MNC-treated rats showed significantly reduced infarct volume and brain water content compared to vehicle- and microglia-treated rats. In addition, BM-MNC treatment reduced neurologic deficit scores compared to those in the other groups. The results provide evidence that infusion of BM-MNCs, but not microglia, is neuroprotective after permanent cerebral ischemia.
A novel fluorescence quenching immunochromatographic sensor (ICS) was developed for detecting chromium (Cr(3+)) within 15 min utilizing the fluorescence quenching function of gold nanoparticles (Au-NPs). The sensor performed with a positive readout. When the low concentrations of Cr(3+) samples were applied, detection signals of the test line (T line) were quenched, whereas when higher concentration Cr(3+) samples (1.56 ng/mL) were applied, the detection signal of the T line appeared. The detection signal intensity of the T line increased with increasing concentrations of Cr(3+). The low detection limit of developed fluorescence quenching ICS was 1.56 ng/mL. The fluorescence quenching ICS has a linear range of detection of Cr(3+) comprising between 6.25 ng/mL to 800 ng/mL. The recoveries of the fluorescence quenching ICS to detect Cr(3+) in tap water ranged from 94.7% to 101.7%. This result indicated that the developed sensor gave higher sensitivity and reliable reproducibility. It could provide a general detection method for small analyte in water samples.
The treatment of interferon alfa (IFN-?) and ribavirin for chronic hepatitis C virus (HCV) infection achieves limited sustained virological response (SVR). We conducted a systematic review and meta-analysis to explore the efficacy of adding statins to IFN-? and ribavirin therapy for chronic hepatitis C. Studies with data pertinent to the effect of statins on chronic hepatitis C were reviewed, and randomized controlled trials (RCTs) evaluating the efficacy of the addition of statins to IFN-? and ribavirin were included in meta-analysis. The primary outcome measure was SVR. Secondary outcome measures were rapid virological response (RVR) and early virological response (EVR). The literature was systematically searched through October 2012. After screening of the 1724 non-duplicated entries, 54 potentially relevant studies were fully reviewed. Of those, 18 studies were relevant and 5 RCTs met the inclusion criteria for meta-analysis. In comparison with IFN-? and ribavirin therapy, the addition of statins significantly increased SVR (OR=2.02, 95% CI: 1.38-2.94), RVR (OR=3.51, 95% CI: 1.08-11.42) and EVR (OR=1.89, 95% CI: 1.20-2.98). The SVR increase remained significant for HCV genotype 1 (OR=2.11, 95% CI: 1.40-3.18). There were no significant increases in adverse events and withdrawals with the addition of statins. In conclusion, the addition of statins to IFN-? and ribavirin improves SVR, RVR, and EVR without additional adverse events and thus may be considered as adjuvant to IFN-? and ribavirin for chronic hepatitis C. Statins might also be used for HCV genotypes other than genotype 1, or in patients in whom the use of protease inhibitors is contraindicated or not indicated.
Propyl caffeate has the highest antioxidant capacity in the caffeate alkyl esters family, but industrial production of propyl caffeate is hindered by low yields using either the chemical or enzymatic catalysis method. To set up a high-yield process for obtaining propyl caffeate, a novel chemoenzymatic synthesis method using lipase-catalyzed transesterification of an intermediate methyl caffeate or ethyl caffeate and 1-propanol in ionic liquid was established. The maximum propyl caffeate yield of 98.5% was obtained using lipase-catalyzed transesterification under the following optimal conditions: Novozym 435 as a biocatalyst, [Bmim][CF3SO3] as a medium, a molar ratio of methyl caffeate to 1-propanol of 1:5, a mass ratio of methyl caffeate to lipase of 1:20, and a reaction temperature of 60°C. The two-step conversion of caffeic acid to propyl caffeate via methyl caffeate is an efficient way to prepare propyl caffeate with an overall yield of 82.7%.
Neuritic plaque is the pathological hallmark in Alzheimers disease (AD). Amyloid-? protein (A?), the central component of neuritic plaques, is generated from amyloid-? precursor protein (APP) by ?-site APP cleaving enzyme 1 (BACE1) and ?-secretase. ?-site APP cleaving enzyme 2 (BACE2), a homolog of BACE1, functions differently from BACE1 in APP processing. BACE1 is the ?-secretase essential for A? production, and BACE2, a ?-secretase, cleaves APP within the A? domain, preventing A? production. Elucidation of the mechanism underlying BACE2 degradation is important for defining its biological features and its potential role in Alzheimers disease drug development. In this report we first showed that the half-life of BACE2 is approximately 20 h. Lysosomal inhibition increased BACE2 protein levels whereas proteasomal inhibition had no effect on BACE2 protein expression. Furthermore, we identified that macroautophagy mediated BACE2 degradation. Finally, we showed that lysosomal inhibition increased BACE2 cleavage of APP. Taken together, our in vitro study showed that BACE2 is degraded through the macrophagy-lysosome pathway and that lysosomal inhibition affects BACE2 processing of APP. Modulation of BACE2 degradation via the lysosomal pathway could be a new target for AD drug development.
Hepatitis C virus (HCV) infection in Tupaia belangeri (Tupaia) represents an important model of HCV infection. Xanthohumol (XN), a major prenylated chalcone from hops, has various biological activities including hepatopreventive and anti-viral activities. In this study, Tupaias infected with HCV RNA positive serum were used to evaluate the effects of XN on liver damage, oxidative reaction, apoptosis and viral protein expression in liver tissues. The Tupaias inoculated with HCV positive serum had elevated serum aminotransferase levels and inflammation, especially hepatic steatosis, and HCV core protein expression in liver tissue. In the animals inoculated with HCV positive serum, XN significantly decreased aminotransferase levels, histological activity index, hepatic steatosis score and transforming growth factor ?1 expression in liver tissue compared with the animals without XN intervention. XN reduced HCV core protein expression in liver tissue compared with those without XN intervention but the difference was not significant. XN significantly decreased malondialdehyde, potentiated superoxide dismutase and glutathione peroxidase, reduced Bax expression, promoted Bcl-xL and inhibited caspase 3 activity in liver tissues compared with the animals without XN intervention. These results indicate that XN may effectively improve hepatic inflammation, steatosis and fibrosis induced by HCV in Tupaias primarily through inhibition of oxidative reaction and regulation of apoptosis and possible suppression of hepatic stellate cell activation. The anti-HCV potential of XN needs further investigation.
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