Cisplatin induces tolerogenic dendritic cells in response to TLR agonists via the abundant production of IL-10, thereby promoting Th2-and Tr1-biased T-cell immunity

Although many advantageous roles of cisplatin (cis-diamminedichloroplatinum (II), CDDP) have been reported in cancer therapy, the immunomodulatory roles of cisplatin in the phenotypic and functional alterations of dendritic cells (DCs) are poorly understood. Here, we investigated the effect of cisplatin on the functionality of DCs and the changes in signaling pathways activated upon toll-like receptor (TLR) stimulation. Cisplatin-treated DCs down-regulated the expression of cell surface molecules (CD80, CD86, MHC class I and II) and up-regulated endocytic capacity in a dose-dependent manner. Upon stimulation with various TLR agonists, cisplatin-treated DCs showed markedly increased IL-10 production through activation of the p38 MAPK and NF-kappa B signaling pathways without altering the levels of TNF-alpha and IL-12p70, indicating the cisplatin-mediated induction of tolerogenic DCs. This effect was dependent on the production of IL-10 from DCs, as neither DCs isolated from IL-10(-/-) mice nor IL-10-neutralized DCs generated tolerogenic DCs. Interestingly, DCs that were co-treated with cisplatin and lipopolysaccharide (LPS) exhibited a decreased immunostimulatory capacity for inducing the proliferation of Th1- and Th17-type T cells; instead, these DCs contributed to Th2-type T cell immunity. Furthermore, in vitro and in vivo investigations revealed a unique T cell population, IL-10-producing CD3(+)CD4(+)LAG-3(+)CD49b(+)CD25(-)Foxp3(-) Tr1 cells, that was significantly increased without altering the Foxp3(+) regulatory T cell population. Taken together, our results suggest that cisplatin induces immune-suppressive tolerogenic DCs in TLR agonist-induced inflammatory conditions via abundant IL-10 production, thereby skewing Th cell differentiation towards Th2 and Tr1 cells. This relationship may provide cancer cells with an opportunity to evade the immune system.1123Ysciescopu

Deep Neural Networks - A Brief History

Introduction to deep neural networks and their history.Comment: 14 pages, 14 figure

Cisplatin induces tolerogenic dendritic cells in response to TLR agonists via the abundant production of IL-10, therby promoting Th2- and Tr1-biased T-cell immunity

Although many advantageous roles of cisplatin (cis-diamminedichloroplatinum (II), CDDP) have been reported in cancer therapy, the immunomodulatory roles of cisplatin in the phenotypic and functional alterations of dendritic cells (DCs) are poorly understood. Here, we investigated the effect of cisplatin on the functionality of DCs and the changes in signaling pathways activated upon toll-like receptor (TLR) stimulation. Cisplatin-treated DCs down-regulated the expression of cell surface molecules (CD80, CD86, MHC class I and II) and up-regulated endocytic capacity in a dose-dependent manner. Upon stimulation with various TLR agonists, cisplatintreated DCs showed markedly increased IL-10 production through activation of the p38 MAPK and NF-κB signaling pathways without altering the levels of TNF-α and IL- 12p70, indicating the cisplatin-mediated induction of tolerogenic DCs. This effect was dependent on the production of IL-10 from DCs, as neither DCs isolated from IL-10- /- mice nor IL-10-neutralized DCs generated tolerogenic DCs. Interestingly, DCs that were co-treated with cisplatin and lipopolysaccharide (LPS) exhibited a decreased immunostimulatory capacity for inducing the proliferation of Th1- and Th17-type T cells; instead, these DCs contributed to Th2-type T cell immunity. Furthermore, in vitro and in vivo investigations revealed a unique T cell population, IL-10-producing CD3+CD4+LAG-3+CD49b+CD25-Foxp3- Tr1 cells, that was significantly increased without altering the Foxp3+ regulatory T cell population. Taken together, our results suggest that cisplatin induces immune-suppressive tolerogenic DCs in TLR agonistinduced inflammatory conditions via abundant IL-10 production, thereby skewing Th cell differentiation towards Th2 and Tr1 cells. This relationship may provide cancer cells with an opportunity to evade the immune system.1231sciescopu

Effect of surfactant concentration variation on the thermoelectric properties of mesoporous ZnO

The electrical and thermal conductivities and the Seebeck coefficient of mesoporous ZnO thin films were investigated to determine the change of their thermoelectric properties by controlling surfactant concentration in the mesoporous ZnO films, because the thermoelectric properties of mesoporous ZnO films can be influenced by the porosity of the mesoporous structures, which is primarily determined by surfactant concentration in the films. Mesoporous ZnO thin films were successfully synthesized by using sol-gel and evaporation-induced self-assembly processes. Zinc acetate dihydrate and Brij-76 were used as the starting material and pore structure-forming template, respectively. The porosity of mesoporous ZnO thin films increased from 29% to 40% with increasing surfactant molar ratio. Porosity can be easily altered by controlling the molar ratio of surfactant/precursor. The electrical and thermal conductivity and Seebeck coefficients showed a close correlation with the porosity of the films, indicating that the thermoelectric properties of thin films can be changed by altering their porosity. Mesoporous ZnO thin films with the highest porosity had the best thermoelectric properties (the lowest thermal conductivity and the highest Seebeck coefficient) of the films examined. © 2013 Min-Hee Hong et al

Carbon and climate system coupling on timescales from the Precambrian to the Anthropocene

Author Posting. © Annual Reviews, 2007. This is the author's version of the work. It is posted here by permission of Annual Reviews for personal use, not for redistribution. The definitive version was published in Annual Review of Environment and Resources 32 (2007): 31-66, doi:10.1146/annurev.energy.32.041706.124700.The global carbon and climate systems are closely intertwined, with biogeochemical processes responding to and driving climate variations. Over a range of geological and historical time-scales, warmer climate conditions are associated with higher atmospheric levels of CO2, an important climate-modulating greenhouse gas. The atmospheric CO2-temperature relationship reflects two dynamics, the planet’s climate sensitivity to a perturbation in atmospheric CO2 and the stability of non-atmospheric carbon reservoirs to evolving climate. Both exhibit non-linear behavior, and coupled carbon-climate interactions have the potential to introduce both stabilizing and destabilizing feedback loops into the Earth System. Here we bring together evidence from a wide range of geological, observational, experimental and modeling studies on the dominant interactions between the carbon cycle and climate. The review is organized by time-scale, spanning interannual to centennial climate variability, Holocene millennial variations and Pleistocene glacial-interglacial cycles, and million year and longer variations over the Precambrian and Phanerozoic. Our focus is on characterizing and, where possible quantifying, the emergent behavior internal to the coupled carbon-climate system as well as the responses of the system to external forcing from tectonics, orbital dynamics, catastrophic events, and anthropogenic fossil fuel emissions. While there are many unresolved uncertainties and complexity in the carbon cycle, one emergent property is clear across time scales: while CO2 can increase in the atmosphere quickly, returning to lower levels through natural processes is much slower, so the consequences of the human perturbation will far outlive the emissions that caused them.S. Doney acknowledges support from the NSF Geosciences Carbon and Water program (NSF ATM-0628582) and the WHOI W. Van Alan Clark Sr. Chair. D. Schimel acknowledges support from the NSF Biocomplexity in the Environment program (NSF EAR-0321918)

High-efficiency photovoltaic cells with wide optical band gap polymers based on fluorinated phenylene-alkoxybenzothiadiazole

A series of semi-crystalline, wide band gap (WBG) photovoltaic polymers were synthesized with varying number and topology of fluorine substituents. To decrease intramolecular charge transfer and to modulate the resulting band gap of D-A type copolymers, electron-releasing alkoxy substituents were attached to electron-deficient benzothiadiazole (A) and electron-withdrawing fluorine atoms (0-4F) were substituted onto a 1,4-bis(thiophen-2-yl)benzene unit (D). Intra- and/or interchain noncovalent Coulombic interactions were also incorporated into the polymer backbone to promote planarity and crystalline intermolecular packing. The resulting optical band gap and the valence level were tuned to 1.93-2.15 eV and -5.37 to -5.67 eV, respectively, and strong interchain organization was observed by differential scanning calorimetry, high-resolution transmission electron microscopy and grazing incidence X-ray scattering measurements. The number of fluorine atoms and their position significantly influenced the photophysical, morphological and optoelectronic properties of bulk heterojunctions (BHJs) with these polymers. BHJ photovoltaic devices showed a high power conversion efficiency (PCE) of up to 9.8% with an open-circuit voltage of 0.94-1.03 V. To our knowledge, this PCE is one of the highest values for fullerene-based single BHJ devices with WBG polymers having a band gap of over 1.90 eV. A tandem solar cell was also demonstrated successfully to show a PCE of 10.3% by combining a diketopyrrolopyrrole-based low band gap polymer

Clinical application of a rapid microbiological test based on capillary zone electrophoresis to assess local skin infection

<p>Abstract</p> <p>Background</p> <p>The basic clinical problem associated with infection treatment is the fact that classic, commonly and routinely used isolation and identification methods are based on long-term processes of a phenotypic analysis of microorganisms. Consequently sometimes, especially in small centres, rapid implementation of antibacterial treatment becomes delayed.</p> <p>The work presents the initial results of rapid microbiological identification based on an original method of capillary zone electrophoresis (CZE). The study involved the analysis of 78 biological samples from post-operative wounds and trophic ulcers.</p> <p>Results</p> <p>The attempt was made to identify individual bacterial species based on characteristic features of electropherograms achieved. Finally, G(+) cocci type bacteria and different G(-) rods were identified with sensitivity of 88.1% and specificity of 100%.</p> <p>Conclusions</p> <p>Based on the clinical trials using an electrophoretic technique in the field of microbiological diagnostics of infected exudate from a post-operative wound it can be concluded that it is a rapid and relatively sensitive method for initial identification of infectious pathogens.</p

Single Gene Deletions of Orexin, Leptin, Neuropeptide Y, and Ghrelin Do Not Appreciably Alter Food Anticipatory Activity in Mice

Timing activity to match resource availability is a widely conserved ability in nature. Scheduled feeding of a limited amount of food induces increased activity prior to feeding time in animals as diverse as fish and rodents. Typically, food anticipatory activity (FAA) involves temporally restricting unlimited food access (RF) to several hours in the middle of the light cycle, which is a time of day when rodents are not normally active. We compared this model to calorie restriction (CR), giving the mice 60% of their normal daily calorie intake at the same time each day. Measurement of body temperature and home cage behaviors suggests that the RF and CR models are very similar but CR has the advantage of a clearly defined food intake and more stable mean body temperature. Using the CR model, we then attempted to verify the published result that orexin deletion diminishes food anticipatory activity (FAA) but observed little to no diminution in the response to CR and, surprisingly, that orexin KO mice are refractory to body weight loss on a CR diet. Next we tested the orexigenic neuropeptide Y (NPY) and ghrelin and the anorexigenic hormone, leptin, using mouse mutants. NPY deletion did not alter the behavior or physiological response to CR. Leptin deletion impaired FAA in terms of some activity measures, such as walking and rearing, but did not substantially diminish hanging behavior preceding feeding time, suggesting that leptin knockout mice do anticipate daily meal time but do not manifest the full spectrum of activities that typify FAA. Ghrelin knockout mice do not have impaired FAA on a CR diet. Collectively, these results suggest that the individual hormones and neuropepetides tested do not regulate FAA by acting individually but this does not rule out the possibility of their concerted action in mediating FAA

Lpg0393 of Legionella pneumophila is a guanine-nucleotide exchange factor for Rab5, Rab21 and Rab22

Legionella pneumophila, a human intracellular pathogen, encodes about 290 effector proteins that are translocated into host cells through a secretion machinery. Some of these proteins have been shown to manipulate or subvert cellular processes during infection, but functional roles of a majority of them remain unknown. Lpg0393 is a newly identified Legionella effector classified as a hypothetical protein. Through X-ray crystallographic analysis, we show that Lpg0393 contains a Vps9-like domain, which is structurally most similar to the catalytic core of human Rabex-5 that activates the endosomal Rab proteins Rab5, Rab21 and Rab22. Consistently, Lpg0393 exhibited a guanine-nucleotide exchange factor activity toward the endosomal Rabs. This work identifies the first example of a bacterial guanine-nucleotide exchange factor that is active towards the Rab5 sub-cluster members, implying that the activation of these Rab proteins might be advantageous for the intracellular survival of Legionella

Individual caspase-10 isoforms play distinct and opposing roles in the initiation of death receptor-mediated tumour cell apoptosis

The cysteine protease caspase-8 is an essential executioner of the death receptor (DR) apoptotic pathway. The physiological function of its homologue caspase-10 remains poorly understood, and the ability of caspase-10 to substitute for caspase-8 in the DR apoptotic pathway is still controversial. Here, we analysed the particular contribution of caspase-10 isoforms to DR-mediated apoptosis in neuroblastoma (NB) cells characterised by their resistance to DR signalling. Silencing of caspase-8 in tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)-sensitive NB cells resulted in complete resistance to TRAIL, which could be reverted by overexpression of caspase-10A or -10D. Overexpression experiments in various caspase-8-expressing tumour cells also demonstrated that caspase-10A and -10D isoforms strongly increased TRAIL and FasL sensitivity, whereas caspase-10B or -10G had no effect or were weakly anti-apoptotic. Further investigations revealed that the unique C-terminal end of caspase-10B was responsible for its degradation by the ubiquitin–proteasome pathway and for its lack of pro-apoptotic activity compared with caspase-10A and -10D. These data highlight in several tumour cell types, a differential pro- or anti-apoptotic role for the distinct caspase-10 isoforms in DR signalling, which may be relevant for fine tuning of apoptosis initiation