Neuroprotective Role of Selected Antioxidant Agents in Preventing Cisplatin-Induced Damage of Human Neurons In Vitro

Chemotherapy-induced peripheral neuropathy (CIPN) is a side effect of platinum-based chemotherapy and decreases the quality of life of cancer patients. We compared neuroprotective properties of several agents using an in vitro model of terminally differentiated human cells NT2-N derived from cell line NT2/D1. Sodium azide and an active metabolite of amifostine (WR1065) increase cell viability in simultaneous treatment with cisplatin. In addition, WR1065 protects the non-dividing neurons by decreasing cisplatin caused oxidative stress and apoptosis. Accumulation of Pt in cisplatin-treated cells was heterogeneous, but the frequency and concentration of Pt in cells were lowered in the presence of WR1065 as shown by X-ray fluorescence microscopy (XFM). Transition metals accumulation accompanied Pt increase in cells; this effect was equally diminished in the presence of WR1065. To analyze possible chemical modulation of Pt-DNA bonds, we examined the platinum L-III near edge spectrum by X-ray absorption spectroscopy. The spectrum found in cisplatin-DNA samples is altered differently by the addition of either WR1065 or sodium azide. Importantly, a similar change in Pt edge spectra was noted in cells treated with cisplatin and WR1065. Therefore, amifostine should be reconsidered as a candidate for treatments that reduce or prevent CIPN

Electronic structure of the substitutional vacancy in graphene: Density-functional and Green's function studies

We study the electronic structure of graphene with a single substitutional vacancy using a combination of the density-functional, tight-binding, and impurity Green's function approaches. Density functional studies are performed with the all-electron spin-polarized linear augmented plane wave (LAPW) method. The three $sp^2 \sigma$ dangling bonds adjacent to the vacancy introduce localized states (V$\sigma$) in the mid-gap region, which split due to the crystal field and a Jahn-Teller distortion, while the $p_z \pi$ states introduce a sharp resonance state (V$\pi$) in the band structure. For a planar structure, symmetry strictly forbids hybridization between the $\sigma$ and the $\pi$ states, so that these bands are clearly identifiable in the calculated band structure. As for the magnetic moment of the vacancy, the Hund's-rule coupling aligns the spins of the four localized V$\sigma_1 \uparrow \downarrow$, V$\sigma_2 \uparrow$, and the V$\pi \uparrow$ electrons resulting in a S=1 state, with a magnetic moment of $2 \mu_B$, which is reduced by about $0.3 \mu_B$ due to the anti-ferromagnetic spin-polarization of the $\pi$ band itinerant states in the vicinity of the vacancy. This results in the net magnetic moment of $1.7 \mu_B$. Using the Lippmann-Schwinger equation, we reproduce the well-known $\sim 1/r$ decay of the localized V$\pi$ wave function with distance and in addition find an interference term coming from the two Dirac points, previously unnoticed in the literature. The long-range nature of the V$\pi$ wave function is a unique feature of the graphene vacancy and we suggest that this may be one of the reasons for the widely varying relaxed structures and magnetic moments reported from the supercell band calculations in the literature.Comment: 24 pages, 15 figures. Accepted for publication in New Journal of Physic

(5,6:19,20-Dibenzo-1,4,11,14-tetra­oxa-8,17-diaza­cyclo­eicosane-κ4 N 8,O 11,O 14,N 17)dinitrato-κ4 O,O′-cadmium(II)

In the title compound, [Cd(NO3)2(C22H30N2O4)], the CdII atom is eight-coordinated by two amine N atoms and two O atoms from the 5,6:19,20-dibenzo-1,4,11,14-tetra­oxa-8,17-diaza­cyclo­eicosane ligand and four O atoms from two nitrate groups. The coordination geometry about Cd is antiprismatic. One nitro O atom is disordered equally over two positions

The iron KαK_\alpha lines as a tool for magnetic field estimations in non-flat accretion flows

Observations of AGNs and microquasars by ASCA, RXTE, Chandra and XMM-Newton indicate the existence of broad X-ray emission lines of ionized heavy elements in their spectra. Such spectral lines were discovered also in X-ray spectra of neutron stars and X-ray afterglows of GRBs. Recently, Zakharov et al. (MNRAS, 2003, 342, 1325) described a procedure to estimate an upper limit of the magnetic fields in regions from which X-ray photons are emitted. The authors simulated typical profiles of the iron $K_\alpha$ line in the presence of magnetic field and compared them with observational data in the framework of the widely accepted accretion disk model. Here we further consider typical Zeeman splitting in the framework of a model of non-flat accretion flows, which is a generalization of previous consideration into non-equatorial plane motion of particles emitting X-ray photons. Using perspective facilities of space borne instruments (e.g. Constellation-X mission) a better resolution of the blue peak structure of iron $K_\alpha$ line will allow to evaluate the magnetic fields with higher accuracy.Comment: 22 pages, 6 figure

Liver phospholipids fatty acids composition in response to different types of diets in rats of both sexes

Background: Dietary intake influence changes in fatty acids (FA) profiles in liver which plays a central role in fatty acid metabolism, triacylglycerol synthesis and energy homeostasis. We investigated the effects of 4-weeks treatment with milk-and fish-based diet, on plasma biochemical parameters and FA composition of liver phospholipids (PL) in rats of both sexes. Methods: Adult, 4 months old, Wistar rats of both sexes, were fed with different types of diets: standard, milk-based and fish-based, during 4 weeks. Analytical characterization of different foods was done. Biochemical parameters in plasma were determined. Fatty acid composition was analyzed by gas-chromatography. Statistical significance of FA levels was tested with two-way analysis of variance (ANOVA) using the sex of animals and treatment (type of diet) as factors on logarithmic or trigonometric transformed data. Results: Our results showed that both, milk-and fish-based diet, changed the composition and ratio of rat liver phospholipids FA, in gender-specific manner. Initially present sex differences appear to be dietary modulated. Although, applied diets changed the ratio of total saturated fatty acids (SFA), monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA), and effects were gender specific. Milk-based diet lowered SFA and elevated MUFA in males and increased PUFA in females vs. standard diet. The same diet decreased n-3, increased n-6 and n-6/n-3 ratio in males. Fish-based diet increased n-3, decreased n-6 and n-6/n-3 ratio vs. standard and milk-based diet in females. However, the ratio of individual FA in liver PL was also dietary-influenced, but with gender specific manner. While in females fish-based diet decreased AA (arachidonic acid) increased level of EPA (eicosapentaenoic acid), DPA (docosapentaenoic acid) and DHA (docosahexaenoic acid), the same diet elevated only DHA levels in males. Conclusion: Gender related variations in FA composition of rat liver PL were observed, and results have shown that those initial differences could be significantly modulated by the type of diet. Furthermore, the modulatory effects of milk-and fish-based diets on liver phospholipids FA profiles appeared to be sex-specific

Singular Fermi Liquids

An introductory survey of the theoretical ideas and calculations and the experimental results which depart from Landau Fermi-liquids is presented. Common themes and possible routes to the singularities leading to the breakdown of Landau Fermi liquids are categorized following an elementary discussion of the theory. Soluble examples of Singular Fermi liquids (often called Non-Fermi liquids) include models of impurities in metals with special symmetries and one-dimensional interacting fermions. A review of these is followed by a discussion of Singular Fermi liquids in a wide variety of experimental situations and theoretical models. These include the effects of low-energy collective fluctuations, gauge fields due either to symmetries in the hamiltonian or possible dynamically generated symmetries, fluctuations around quantum critical points, the normal state of high temperature superconductors and the two-dimensional metallic state. For the last three systems, the principal experimental results are summarized and the outstanding theoretical issues highlighted.Comment: 170 pages; submitted to Physics Reports; a single pdf file with high quality figures is available from http://www.lorentz.leidenuniv.nl/~saarloo

Personalised profiling to identify clinically relevant changes in tremor due to multiple sclerosis

Background: There is growing interest in sensor-based assessment of upper limb tremor in multiple sclerosis and other movement disorders. However, previously such assessments have not been found to offer any improvement over conventional clinical observation in identifying clinically relevant changes in an individual's tremor symptoms, due to poor test-retest repeatability. Method: We hypothesised that this barrier could be overcome by constructing a tremor change metric that is customised to each individual's tremor characteristics, such that random variability can be distinguished from clinically relevant changes in symptoms. In a cohort of 24 people with tremor due to multiple sclerosis, the newly proposed metrics were compared against conventional clinical and sensor-based metrics. Each metric was evaluated based on Spearman rank correlation with two reference metrics extracted from the Fahn-Tolosa-Marin Tremor Rating Scale: a task-based measure of functional disability (FTMTRS B) and the subject's self-assessment of the impact of tremor on their activities of daily living (FTMTRS C). Results: Unlike the conventional sensor-based and clinical metrics, the newly proposed ’change in scale’ metrics presented statistically significant correlations with changes in self-assessed impact of tremor (max R2>0.5,p< 0.05 after correction for false discovery rate control). They also outperformed all other metrics in terms of correlations with changes in task-based functional performance (R2=0.25 vs. R2=0.15 for conventional clinical observation, both p< 0.05).Conclusions: The proposed metrics achieve an elusive goal of sensor-based tremor assessment: improving on conventional visual observation in terms of sensitivity to change. Further refinement and evaluation of the proposed techniques is required, but our core findings imply that the main barrier to translational impact for this application can be overcome. Sensor-based tremor assessments may improve personalised treatment selection and the efficiency of clinical trials for new treatments by enabling greater standardisation and sensitivity to clinically relevant changes in symptoms

Specific Binding of the Pathogenic Prion Isoform: Development and Characterization of a Humanized Single-Chain Variable Antibody Fragment

Murine monoclonal antibody V5B2 which specifically recognizes the pathogenic form of the prion protein represents a potentially valuable tool in diagnostics or therapy of prion diseases. As murine antibodies elicit immune response in human, only modified forms can be used for therapeutic applications. We humanized a single-chain V5B2 antibody using variable domain resurfacing approach guided by computer modelling. Design based on sequence alignments and computer modelling resulted in a humanized version bearing 13 mutations compared to initial murine scFv. The humanized scFv was expressed in a dedicated bacterial system and purified by metal-affinity chromatography. Unaltered binding affinity to the original antigen was demonstrated by ELISA and maintained binding specificity was proved by Western blotting and immunohistochemistry. Since monoclonal antibodies against prion protein can antagonize prion propagation, humanized scFv specific for the pathogenic form of the prion protein might become a potential therapeutic reagent