Mapping the ATP-binding domain of DNA-dependent protein kinase (DNA-PK) with coumarin- and isocoumarin-derived inhibitors

Replacement of the core heterocycle of a defined series of chromen-4-one DNA-PK inhibitors by the isomeric chromen-2-one (coumarin) and isochromen-1-one (isocoumarin) scaffolds was investigated. Structure–activity relationships for DNA-PK inhibition were broadly consistent, albeit with a reduction of potency compared with the parent chromenone.     

The structural basis for high affinity binding of α1-acid glycoprotein to the potent antitumor compound UCN-01

The α1-acid glycoprotein (AGP) is an abundant blood plasma protein with important immunomodulatory functions coupled to endogenous and exogenous ligand-binding properties. Its affinity for many drug-like structures, however, means AGP can have a significant effect on the pharmokinetics and pharmacodynamics of numerous small molecule therapeutics. Staurosporine, and its hydroxylated forms UCN-01 and UCN-02, are kinase inhibitors that have been investigated at length as antitumour compounds. Despite their potency, these compounds display poor pharmokinetics due to binding to both AGP variants, AGP1 and AGP2. The recent renewed interest in UCN-01 as a cytostatic protective agent prompted us to solve the structure of the AGP2–UCN-01 complex by X-ray crystallography, revealing for the first time the precise binding mode of UCN-01. The solution NMR suggests AGP2 undergoes a significant conformational change upon ligand binding, but also that it uses a common set of sidechains with which it captures key groups of UCN-01 and other small molecule ligands. We anticipate that this structure and the supporting NMR data will facilitate rational redesign of small molecules that could evade AGP and therefore improve tissue distribution.     

Succès du repérage isotopique peropératoire dans l’éradication totale de l’ostéome ostéoïde persistant

The osteoid osteoma is a small benign, painful, bony tumour in which the treatment consists of a complete surgical ablation. The cases of recurrence often correspond to an incomplete surgical ablation. We report, in this work, the advantage of isotopic intraoperative marking for an accurate and complete excision of the pathological lesion in a young patient, during his surgical resumption after the short-term failure of the first intervention, which was accomplished without intraoperative location, and completed with a literature review.     

Photoluminescence in K3Ca2(SO4)3Cl‐doped Eu3+ phosphor

In this article we report Eu³⁺ luminescence in novel K₃Ca₂(SO₄)₃Cl phosphors prepared by wet chemical methods. The Eu³⁺ emission was observed at 594 nm and 615 nm, keeping the excitation wavelength constant at 396 nm nearer to light‐emitting diode excitation, Furthermore, phosphors were characterized by X‐ray diffraction for the confirmation of crystallinity. The variation of the photoluminescence intensity with impurity concentration has also been discussed. Thus, prominent emission in the red region makes prepared phosphors more applicable for white light‐emitting diodes. Copyright © 2013 John Wiley & Sons, Ltd.     

Lung epithelium injury biomarkers in workers exposed to sulphur dioxide in a non-ferrous smelter

Serum Clara cell protein (CC16) and surfactant-associated protein D (SP-D) were measured in 161 workers exposed to sulphur dioxide (SO₂) in a non-ferrous smelter. Seventy workers from a blanket manufacture served as referents. Exposure to SO₂ and tobacco smoking were associated with a decrease of CC16 and an increase of SP-D in serum. Tobacco smoking and exposure SO₂ interacted synergistically to decrease serum CC16 but not to increase serum SP-D. While further illustrating the potential of serum CC16 and SP-D, our study confirms that SO₂ can cause airways damage at exposure levels below current occupational exposure limits.     

Reduced tumour progression and angiogenesis in 1,2-dimethylhydrazine mice treated with NS-398 is associated with down-regulation of cyclooxygenase-2 and decreased beta-catenin nuclear localisation

Cyclooxygenase (COX)-2 is a key molecular target of colon cancer prevention. However, the mechanisms by which COX-2 inhibitors confer protective effects against tumour development are not completely understood. The aim of this study was to elucidate the effects of NS-398 in the 1,2-dimethylhydrazine (DMH) mouse model with respect to alteration in the expression of COX-2 and E-cadherin-catenin complex. Alterations in cell proliferation, apoptosis, and vascular density were investigated. NS-398 showed reduced COX-2 immunoreactivity in adenomas with a decrease in vascular density in non-dysplastic mucosa. Adenomas revealed increased E-cadherin and beta-catenin reactivity. NS-398 reduced the percentages of tumour cells with nuclear localisation of beta-catenin and cyclin D1. Bromodeoxyuridine (BrdUrd) index in adenomas was significantly higher in untreated animals. NS-398 resulted in significant increase in apoptosis in adenomas. Our results suggest a protective role of NS-398 on tumour development associated with reduced COX-2 expression, reduced vascular density and perturbation of beta-catenin signalling pathway.     

Involvement of source-sink relationship and hormonal control in the response of Medicago ciliaris - Sinorhizobium medicae symbiosis to salt stress

In order to explore the relationship between leaf hormonal status and source-sink relations in the response of symbiotic nitrogen fixation (SNF) to salt stress, three major phytohormones (cytokinins, abscisic acid and the ethylene precursor 1-aminocyclopropane-1-carboxylic acid), sucrose phosphate synthase activity in source leaves and sucrolytic activities in sink organs were analysed in two lines of Medicago ciliaris (salt-tolerant TNC 1.8 and salt-sensitive TNC 11.9). SNF (measured as nitrogenase activity and amount of N-fixed) was more affected by salt treatment in the TNC 11.9 than in TNC 1.8, and this could be explained by a decrease in nodule sucrolytic activities. SNF capacity was reflected in leaf biomass production and in the sink activity under salinity, as suggested by the higher salt-induced decrease in the young leaf sucrolytic activities in the sensitive line TNC 11.9, while they were not affected in the tolerant line TNC 1.8. As a consequence of maintaining sink activities in the actively growing organs, the key enzymatic activity for synthesis of sucrose (sucrose phosphate synthase) was also less affected in the mature leaves of the more tolerant genotype. Ours results showed also that the major hormone factor associated with the relative tolerance of TNC 1.8 was the stimulation of abscisic acid concentration in young leaves under salt treatment. This stimulation may control photosynthetic organ growth and also may contribute to a certain degree in the maintenance of coordinated sink-source relationships. Therefore, ABA may be an important component which conserves sucrose synthesis in source leaves.     

Lack of IL-6 during Coxsackievirus Infection Heightens the Early Immune Response Resulting in Increased Severity of Chronic Autoimmune Myocarditis

Background

Chronic myocarditis is often initiated by viral infection, the most common of which is coxsackievirus infection. The precise mechanism by which viral infection leads to chronic autoimmune pathology is poorly understood, however it is clear that the early immune response plays a critical role. Previous results have shown that the inflammatory cytokine interleukin (IL)-6 is integral to the development of experimental-induced autoimmune myocarditis. However, the function of IL-6 during viral-mediated autoimmunity has yet to be elucidated.

Methods and Results

To address the requirement of IL-6 during disease induction, IL-6 deficient mice were infected with coxsackievirus B3 (CB3). Following infection, mice lacking IL-6 developed increased chronic autoimmune disease pathology compared to wild type controls without a corresponding change in the level of viral replication in the heart. This increase in disease severity was accompanied by elevated levels of TNF-α, MCP-1, IL-10, activated T cells and cardiac infiltrating macrophage/monocytes. Injection of recombinant IL-6 early following infection in the IL-6 deficient mice was sufficient to lower the serum cytokines TNF-α and IL-10 as well as the serum chemokines MCP-1, MIP-1β, RANTES and MIG with a corresponding decrease in the chronic disease pathology strongly suggests an important regulatory role for IL-6 during the early response.

Conclusions

While IL-6 plays a pathogenic role in experimental-induced autoimmune disease, its function following viral-induced autoimmunity is not reprised. By regulating the early immune response and thereby controlling the severity of chronic disease, IL-6 directs the outcome of chronic autoimmune myocarditis.     

Enhancing collaborative detection of cyberbullying behavior in Twitter data

Cluster Computing - Cyberbullying is a menace in today’s socially networked world. It can have damaging physical and mental effects on the victims and hence, it needs to be tackled...