DNA vaccines are an appealing strategy for inducing cytotoxic T-lymphocyte and antibody responses against tumor cells as well as infectious agents. Dendritic cells (DCs) play a critical role in ...inducing immune responses, but their potential is not fully utilized in the DNA vaccine setting since they take up only a minor fraction of the injected DNA. Here we describe a novel DNA vaccination strategy based on the targeting of a modified tumor-associated antigen, the human papilloma virus (HPV) type 16 E7 protein, to DCs by a heat-shock protein (HSP) to enhance antigen presentation and immune responses. Specifically, a chimerical HPV-E7 and HSP70 fusion gene preceded with a leader sequence was constructed. When mice were immunized with this construct, the DNA is taken up by various types of cells, which then produce and secrete an HPV-E7-HSP70 fusion protein that is targeted to DCs by the HSP70 portion of the chimerical molecule for antigen presentation. In studies to test the efficacy of this strategy, we demonstrated that DNA vaccination with this secretory HPV-E7-HSP70 construct strongly enhanced an antigen-specific CD8+ T-cell response as well as a specific B-cell response in mice. Furthermore, this immunization approach not only protected mice against lethal challenge with an HPV E7-expressing tumor line (TC-1), but also showed a therapeutic effect against established tumors. The results of this study indicate that secretory HSPs can be broadly used to target tumor-associated antigens to DCs to enhance antigen-specific immune responses.
Tensile strain along the cR axis in epitaxial VO sub(2) films raises the temperature of the metal insulator transition and is expected to stabilize the intermediate monoclinic M2 phase. We employ ...surface-sensitive x-ray spectroscopy to distinguish from the TiO sub(2) substrate and identify the phases of VO sub(2) as a function of temperature in epitaxial VO sub(2)/TiO sub(2) thin films with well-defined biaxial strain. Although qualitatively similar to our Landau-Ginzburg theory predicted phase diagrams, the M2 phase is stabilized by nearly an order of magnitude more strain than expected for the measured temperature window. Our results reveal that the elongation of the c sub()Raxis is insufficient for describing the transition pathway of VO sub(2) epitaxial films and that a strain induced increase of electron correlation effects must be considered.
Stochastic sensing is an emerging analytical technique that relies upon single-molecule detection. Transmembrane pores, into which binding sites for analytes have been placed by genetic engineering, ...have been developed as stochastic sensing elements. Reversible occupation of an engineered binding site modulates the ionic current passing through a pore in a transmembrane potential and thereby provides both the concentration of an analyte and, through a characteristic signature, its identity. Here, we show that the concentrations of two or more divalent metal ions in solution can be determined simultaneously with a single sensor element. Further, the sensor element can be permanently calibrated without a detailed understanding of the kinetics of interaction of the metal ions with the engineered pore.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Molecular mechanisms of cell-cycle arrest caused by gambogic acid (GA), a natural product isolated from the gamboge resin of Garcinia hanburryi tree, have been investigated using BGC-823 human ...gastric carcinoma cells as a model. Based on our 3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyltetrazoliumbromide (MTT) assay and flow cytometric analysis, treatment of BGC-823 cells with growth suppressive concentrations of GA caused an irreversible arrest in the G2/M phase of the cell cycle. Western blot analysis demonstrated that GA-induced cell-cycle arrest in BGC-823 cells was associated with a significant decrease in CDC2/p34 synthesis, which led to the accumulation of phosphorylated-Tyr15 (inactive) form of CDC2/p34. Real-time PCR, western blot and kinase activity assays revealed that GA-induced reduction of CDC2/p34 expression was mediated through the inhibition of cyclin-dependent kinase (CDK)-activating kinase (CDK7/cyclin H) activity. In addition, GA-treated cells were shown to have a low level of CDK7 kinase-phosphorylated-Thr161 CDC2/p34 (active). Taken together, our results suggested that the inhibited proliferation of GA-treated BGC-823 cells was associated with the decreased production of CDK7 mRNA and protein, which in turn, resulted in the reduction of CDK7 kinase activity. The reduced CDK7 kinase activity is responsible for the inactivation of CDC2/p34 kinase and the irreversible G2/M phase cell-cycle arrest of human gastric carcinoma BGC-823 cells.
Summary
The two most commonly used airway management techniques during general anaesthesia are supraglottic airway devices and tracheal tubes. In older patients undergoing elective non‐cardiothoracic ...surgery under general anaesthesia with positive pressure ventilation, we hypothesised that a composite measure of in‐hospital postoperative pulmonary complications would be less frequent when a supraglottic airway device was used compared with a tracheal tube. We studied patients aged ≥ 70 years in 17 clinical centres. Patients were allocated randomly to airway management with a supraglottic airway device or a tracheal tube. Between August 2016 and April 2020, 2900 patients were studied, of whom 2751 were included in the primary analysis (1387 with supraglottic airway device and 1364 with a tracheal tube). Pre‐operatively, 2431 (88.4%) patients were estimated to have a postoperative pulmonary complication risk index of 1–2. Postoperative pulmonary complications, mostly coughing, occurred in 270 of 1387 patients (19.5%) allocated to a supraglottic airway device and 342 of 1364 patients (25.1%) assigned to a tracheal tube (absolute difference −5.6% (95%CI −8.7 to −2.5), risk ratio 0.78 (95%CI 0.67–0.89); p < 0.001). Among otherwise healthy older patients undergoing elective surgery under general anaesthesia with intra‐operative positive pressure ventilation of their lungs, there were fewer postoperative pulmonary complications when the airway was managed with a supraglottic airway device compared with a tracheal tube.
The detection of organic molecules is important in many areas, including
medicine, environmental monitoring and defence. Stochastic
sensing is an approach that relies on the observation of individual ...binding
events between analyte molecules and a single receptor. Engineered
transmembrane protein pores are promising sensor elements for stochastic detection, and in their simplest manifestation they produce a fluctuating
binary (‘on/off’) response in the transmembrane electrical current.
The frequency of occurrence of the fluctuations reveals the concentration
of the analyte, and its identity can be deduced from the characteristic magnitude
and/or duration of the fluctuations. Genetically engineered versions of the
bacterial pore-forming protein α-haemolysin have been used to identify
and quantify divalent metal ions in solution. But it is not
immediately obvious how versatile binding sites for organic ligands might
be obtained by engineering of the pore structure. Here we show that stochastic
sensing of organic molecules can be procured from α-haemolysin by equipping
the channel with an internal, non-covalently bound molecular ‘adapter’
which mediates channel blocking by the analyte. We use cyclodextrins as the
adapters because these fit comfortably inside the pore and present a hydrophobic
cavity suitable for binding a variety of organic analytes. Moreover, a single
sensing element of this sort can be used to analyse a mixture of organic molecules
with different binding characteristics. We envisage the use of other adapters,
so that the pore could be ‘programmed’ for a range of sensing
functions.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In this study, a numerical investigation of heat transfer deterioration (HTD) in supercritical water flowing through vertical tube is performed by using six low-Reynolds number turbulence models. All ...low-Reynolds models can be extended to reproduce the effect of buoyancy force on heat transfer and show the occurrence of localized HTD. However, most
k–
ε models seriously over-predict the deterioration and do not reproduce the subsequent recovery of heat transfer. The V2F and SST models perform better than other models in predicting the onset of deterioration due to strong buoyancy force. The SST model is able to quantitatively reproduce the two heat transfer deterioration phenomena with low mass flux which have been found in the present study.
A series of new anthrapyrazoles were derived from emodin by attaching various cationic alkyl amino side chains onto a pyrazole ring which had been incorporated into the anthraquinone chromophore. ...Compared with emodin, the derivatives had significantly higher DNA binding affinity based on interaction with calf thymus DNA, and much more potent cytotoxicity against different tumor cells. The derivatives with a mono-cationic alkyl side chain exhibited the highest DNA binding affinity and cytotoxicity.
Novel anthrapyrazole derivatives of emodin with various cationic alkyl amino side chains attached to a pyrazole ring incorporated into anthraquinone chromophore, showing improved cytotoxic and DNA binding activities.
Strong anisotropic compression with pressure on the remarkable non-linear optical material KBe2BO3F2 has been observed with the linear compression coefficient along the c axis found to be about 40 ...times larger than that along the a axis. An unusual non-monotonic pressure response was observed for the a lattice parameter. The derived bulk modulus of 31 ± 1 GPa indicates that KBe2BO3F2 is a very soft oxide material yet with stable structure up to 45 GPa. A combination of high-pressure synchrotron powder X-ray diffraction, high-pressure Raman spectroscopy, and Density Functional Theory calculations points to the mechanism for the unusual pressure response being due to the competition between the K-F bond length and K-F-K bond angle and the coupling between the stretching and twisting vibration modes.
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