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991.
Olière S Douville R Sze A Belgnaoui SM Hiscott J 《Cytokine & growth factor reviews》2011,22(4):197-210
Infection with the Human T-cell Leukemia virus type I (HTLV-1) retrovirus results in a number of diverse pathologies, including the aggressive, fatal T-cell malignancy adult T-cell leukemia (ATL) and the chronic, progressive neurologic disorder termed HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Worldwide, it is estimated there are 15-20 million HTLV-1-infected individuals; although the majority of HTLV-1-infected individuals remain asymptomatic carriers (AC) during their lifetime, 2-5% of AC develops either ATL or HAM/TSP, but never both. Regardless of asymptomatic status or clinical outcome, HTLV-1 carriers are at high risk of opportunistic infection. The progression to pathological HTLV-1 disease is in part attributed to the failure of the innate and adaptive immune system to control virus spread. The innate immune response against retroviral infection requires recognition of viral pathogen-associated molecular patterns (PAMPs) through pattern-recognition receptors (PRR) dependent pathways, leading to the induction of host antiviral and inflammatory responses. Recent studies have begun to characterize the interplay between HTLV-1 infection and the innate immune response and have identified distinct gene expression profiles in patients with ATL or HAM/TSP--upregulation of growth regulatory pathways in ATL and constitutive activation of antiviral and inflammatory pathways in HAM/STP. In this review, we provide an overview of the replicative lifecycle of HTLV-1 and the distinct pathologies associated with HTLV-1 infection. We also explore the innate immune mechanisms that respond to HTLV-1 infection, the strategies used by HTLV-1 to subvert these defenses and their contribution to HTLV-1-associated diseases. 相似文献
992.
993.
Instrumental responses are hypothesized to be of two kinds: habitual and goal-directed, mediated by the sensorimotor and the associative cortico-basal ganglia circuits, respectively. The existence of the two heterogeneous associative learning mechanisms can be hypothesized to arise from the comparative advantages that they have at different stages of learning. In this paper, we assume that the goal-directed system is behaviourally flexible, but slow in choice selection. The habitual system, in contrast, is fast in responding, but inflexible in adapting its behavioural strategy to new conditions. Based on these assumptions and using the computational theory of reinforcement learning, we propose a normative model for arbitration between the two processes that makes an approximately optimal balance between search-time and accuracy in decision making. Behaviourally, the model can explain experimental evidence on behavioural sensitivity to outcome at the early stages of learning, but insensitivity at the later stages. It also explains that when two choices with equal incentive values are available concurrently, the behaviour remains outcome-sensitive, even after extensive training. Moreover, the model can explain choice reaction time variations during the course of learning, as well as the experimental observation that as the number of choices increases, the reaction time also increases. Neurobiologically, by assuming that phasic and tonic activities of midbrain dopamine neurons carry the reward prediction error and the average reward signals used by the model, respectively, the model predicts that whereas phasic dopamine indirectly affects behaviour through reinforcing stimulus-response associations, tonic dopamine can directly affect behaviour through manipulating the competition between the habitual and the goal-directed systems and thus, affect reaction time. 相似文献
994.
Kathleen A. Trychta Emily J. Heathward Agnieszka Sulima Susanne Bäck Mehdi Farokhnia Christopher T. Richie 《Biomarkers》2013,18(8):756-765
AbstractContext: Endoplasmic reticulum (ER) calcium depletion is associated with diverse diseases, including cardiac, hepatic, and neurologic diseases.Objective: The aim of the present study was to identify and characterize an endogenous protein that could be used to monitor ER calcium depletion comparably to a previously described exogenous reporter protein.Materials and methods: The use of a selective esterase-fluorescein diester pair allowed for carboxylesterase activity in extracellular fluid to be measured using a fluorescent readout. Cell culture media from three different cell lines, rat plasma, and human serum all possess quantifiable amounts of esterase activity.Results: Fluorescence produced by the interaction of carboxylesterases with a fluorescein diester substrate tracks with pharmacological and physiological inducers of ER calcium depletion. The fluorescence measured for in vitro and in vivo samples were consistent with ER calcium depletion being the trigger for increased esterase activity.Discussion: Decreased luminal ER calcium causes ER resident esterases to be released from the cell, and, when assessed concurrently with other disease biomarkers, these esterases may provide insight into the role of ER calcium homeostasis in human diseases.Conclusion: Our results indicate that carboxylesterases are putative markers of ER calcium dysfunction. 相似文献
995.
Mehdi Rajabi Elena Gorincioi Enzo Santaniello 《Nucleosides, nucleotides & nucleic acids》2013,32(6):474-481
Cytokinins and cytokinin nucleosides are purine derivatives with potential anticancer activity both in vitro and in vivo. N6-furfuryladenosine (kinetin riboside, KR) displays antiproliferative and apoptogenic activity against various human cancer cell lines and has recently been shown to suppress tumor growth in murine xenograft models of human leukemia and melanoma. In this study, we demonstrate that KR is able to inhibit the proliferation in HCT-15 human colon cancer cells in a dose-dependent manner with a concentration of 2.5 μM, which causes 50% inhibition of cell viability. The cell cycle analysis by flow cytometry showed that KR arrested cell cycle progression in the S Phase by blocking through G2/M and G0/G1 phase in HCT-15 colon cells. Moreover, suppression of clonogenic activity occurs after exposure to KR at a concentration of 2.5 μM for HCT-15. 相似文献
996.
Jean-Jacques Helesbeux Damien Peyronnet Mehdi Labaïed Philippe Grellier François Frappier Denis Seraphin 《Journal of enzyme inhibition and medicinal chemistry》2013,28(6):431-437
The synthesis of 1,2-dioxolane derivatives in two different acetophenone series, as simplified models of natural coumarins is described. 2-Acetyl-3-acetoxy-4-(3-hydroperoxy-3-methylbut-1-enyl)phenyl acetate and 2-acetyl-5-acetoxy-4-(3-hydroperoxy-3-methylbut-1-enyl) phenyl acetate synthons are used as precursors to these structures. In vitro antimalarial activity of the 1,2-dioxolane derivatives has been investigated. 相似文献
997.
Evidence that TNF-β (lymphotoxin α) can activate the inflammatory environment in human chondrocytes 总被引:1,自引:0,他引:1
Constanze Buhrmann Parviz Shayan Bharat B Aggarwal Mehdi Shakibaei 《Arthritis research & therapy》2013,15(6):R202
Introduction
Inflammatory cytokines play a key role in the pathogenesis of joint diseases such as rheumatoid arthritis (RA). Current therapies target mainly tumor necrosis factor α (TNF-α) as this has proven benefits. However, a large number of patients do not respond to or become resistant to anti-TNF-α therapy. While the role of TNF-α in RA is quite evident, the role of TNF-β, also called lymphotoxin-α (LT-α), is unclear. In this study we investigated whether TNF-β and its receptor play a role in chondrocytes in the inflammatory environment.Methods
An in vitro model of primary human chondrocytes was used to study TNF-β-mediated inflammatory signaling.Results
Cytokine-induced inflammation enhances TNF-β and TNF-β-receptor expression in primary human chondrocytes accompanied by the up-regulation of inflammatory (cyclooxygenase-2), matrix degrading (matrix metalloproteinase-9 and -13) and apoptotic (p53, cleaved caspase-3) signaling pathways, all known to be regulated by NF-κB. In contrast, anti-TNF-β, similar to the natural NF-κB inhibitor (curcumin, diferuloylmethane) or the knockdown of NF-κB by using antisense oligonucleotides (ASO), suppressed IL-1β-induced NF-κB activation and its translocation to the nucleus, and abolished the pro-inflammatory and apoptotic effects of IL-1β. This highlights, at least in part, the crucial role of NF-κB in TNF-β-induced-inflammation in cartilage, similar to that expected for TNF-α. Finally, the adhesiveness between TNF-β-expressing T-lymphocytes and the responding chondrocytes was significantly enhanced through a TNF-β-induced inflammatory microenvironment.Conclusions
These results suggest for the first time that TNF-β is involved in microenvironment inflammation in chondrocytes during RA parallel to TNF-α, resulting in the up-regulation of NF-κB signaling and activation of pro-inflammatory activity. 相似文献998.
The development of primordial germ cells (PGCs) involves several waves of epigenetic reprogramming. A major step is following specification and involves the transition from the stably suppressive histone modification H3K9me2 to the more flexible, still repressive H3K27me3, while PGCs are arrested in G2 phase of their cycle. The significance and underlying molecular mechanism of this transition were so far unknown. Here, we generated mutant mice for the Mad2l2 (Mad2B, Rev7) gene product, and found that they are infertile in both males and females. We demonstrated that Mad2l2 is essential for PGC, but not somatic development. PGCs were specified normally in Mad2l2−/− embryos, but became eliminated by apoptosis during the subsequent phase of epigenetic reprogramming. A majority of knockout PGCs failed to arrest in the G2 phase, and did not switch from a H3K9me2 to a H3K27me3 configuration. By the analysis of transfected fibroblasts we found that the interaction of Mad2l2 with the histone methyltransferases G9a and GLP lead to a downregulation of H3K9me2. The inhibitory binding of Mad2l2 to Cyclin dependent kinase 1 (Cdk1) could arrest the cell cycle in the G2 phase, and also allowed another histone methyltransferase, Ezh2, to upregulate H3K27me3. Together, these results demonstrate the potential of Mad2l2 in the regulation of both cell cycle and the epigenetic status. The function of Mad2l2 is essential in PGCs, and thus of high relevance for fertility. 相似文献
999.
Theoretical study on cooperative effects between X⋯N and X⋯Carbene halogen bonds (X = F,Cl,Br and I)
Mehdi D. Esrafili Fariba Mohammdain-Sabet Parvin Esmailpour 《Journal of molecular modeling》2013,19(11):4797-4804
Quantum chemical calculations are performed to study the interplay between halogen?nitrogen and halogen?carbene interactions in NCX?NCX?CH2 complexes, where X?=?F, Cl, Br and I. Molecular geometries and interaction energies of dyads and triads are investigated at the MP2/aug-cc-pVTZ level of theory. It is found that the X?N and X?Ccarbene interaction energies in the triads are larger than those in the dyads, indicating that both the halogen bonding interactions are enhanced. The estimated values of cooperative energy E coop are all negative with much larger E coop in absolute value for the systems including iodine. The nature of halogen bond interactions of the complexes is analyzed using parameters derived from the quantum theory atoms in molecules methodology and energy decomposition analysis. Figure
The structure of NCX?NCX?CH2 complexes (X?=?F, Cl, Br and I) 相似文献
1000.
Halogen-bonding, a noncovalent interaction between a halogen atom X in one molecule and a negative site in another, plays critical roles in fields as diverse as molecular biology, drug design and material engineering. In this work, we have examined the strength and origin of halogen bonds between carbene CH2 and XCCY molecules, where X?=?Cl, Br, I, and Y?=?H, F, COF, COOH, CF3, NO2, CN, NH2, CH3, OH. These calculations have been carried out using M06-2X, MP2 and CCSD(T) methods, through analyses of surface electrostatic potentials V S(r) and intermolecular interaction energies. Not surprisingly, the strength of the halogen bonds in the CH2···XCCY complexes depend on the polarizability of the halogen X and the electron-withdrawing power of the Y group. It is revealed that for a given carbene···X interaction, the electrostatic term is slightly larger (i.e., more negative) than the dispersion term. Comparing the data for the chlorine, bromine and iodine substituted CH2···XCCY systems, it can be seen that both the polarization and dispersion components of the interaction energy increase with increasing halogen size. One can see that increasing the size and positive nature of a halogen’s σ-hole markedly enhances the electrostatic contribution of the halogen-bonding interaction. Graphical abstract
Halogen bonding interactions between carbene and X-CC-Y molecules (X?=?Cl, Br, and I; Y?=?H, F, COF, COOH, CF3, NO2, CN, OH, NH2, CH3) 相似文献