Tryptophan pathway abnormalities in a murine model of hereditary glaucoma

Background: It has been shown that a possible pathogenetic mechanism of neurodegenera-tion in the mouse model of glaucoma (DBA/2J) may be an alteration of kynurenic acid (KYNA) in the retina. This study aimed to verify the hypothesis that alterations of tryptophan (TRP) metabolism in DBA/2J mice is not limited to the retina. Methods: Samples of the retinal tissue and serum were collected from DBA/2J mice (6 and 10 months old) and control C57Bl/6 mice of the same age. The concentration of TRP, KYNA, kynurenine (KYN), and 3-hydroxykynurenine (3OH-K) was measured by HPLC. The activity of indoleamine 2,3-dioxygenase (IDO) was also determined as a KYN/TRP ratio. Results: TRP, KYNA, L-KYN, and 3OH-K concentration were significantly lower in the retinas of DBA/2J mice than in C57Bl/6 mice. 3OH-K concentration was higher in older mice in both strains. Serum TRP, L-KYN, and KYNA concentrations were lower in DBA/2J than in age-matched controls. However, serum IDO activity did not differ significantly between compared groups and strains. Conclusions: Alterations of the TRP pathway seem not to be limited to the retina in the murine model of hereditary glaucoma

Tryptophan and Kynurenine Pathway Metabolites in Animal Models of Retinal and Optic Nerve Damage: Different Dynamics of Changes

Kynurenines, products of tryptophan (TRP) metabolism, display neurotoxic (e.g., 3-hydroxykynurenine; 3-HK), or neuroprotective (e.g., kynurenic acid; KYNA) properties. Imbalance between the enzymes constituting the kynurenine pathway (KP) plays a role in several disease, including neurodegeneration. In this study, we track changes in concentrations of tryptophan and its selected metabolites after damage to retinal ganglion cells and link this data with expression of KP enzymes. Brown-Norway rats were subjected to intravitreal N-methyl-D-aspartate (NMDA) injection or partial optic nerve crush (PONC). Retinas were collected 2 and 7 days after the completion of PONC or NMDA injection. Concentrations of TRP, kynurenine (KYN), and KYNA were determined by high performance liquid chromatography (HPLC). Data on gene expression in the rat retina were extracted from GEO, public microarray experiments database. Two days after NMDA injection concentration of TRP decreased, while KYN and KYNA increased. At day 7 compared to day 2 decrease of KYN, KYNA and further reduction of TRP concentration were observed, but on day 7 KYN concentration was still elevated when compared to controls. At day 2 and 7 after NMDA injection no statistically significant alterations of 3-HK were observed. TRP and 3-HK concentration was higher in PONC group than in controls. However, both KYN and KYNA were lower. At day seven concentration of TRP, 3-HK, and KYN was higher, whereas concentration of KYNA declined. In vivo experiments showed that retinal damage or optic nerve lesion affect TRP metabolism via KP. However, the pattern of changes in metabolite concentrations was different depending on the model. In particular, in PONC KYNA and KYN levels were decreased and 3-HK elevated. These observations correspond with data on expression of genes encoding KP enzymes assessed after optic nerve crush or transection. After intraorbital optic nerve crush downregulation of KyatI and KyatIII between 24 h and 3 days after procedure was observed. Kmo expression was transiently upregulated (12 h after the procedures). After intraorbital optic nerve transsection (IONT) Kmo expression was upregulated after 48 h and 7 days, KyatI and KyatIII were downregulated after 12, 48 h, 7 days and upregulated after 15 days. Collected data point to the conclusion that development of therapeutic strategies targeting the KP could be beneficial in diseases involving retinal neurodegeneration

Blood Levels of Macrophage Migration Inhibitory Factor after Successful Resuscitation from Cardiac Arrest

Introduction: Ischemia-reperfusion injury following cardiopulmonary resuscitation (CPR) is associated with a systemic inflammatory response, resulting in post-resuscitation disease. In the present study we investigated the response of the pleiotropic inflammatory cytokine macrophage migration inhibitory factor (MIF) to CPR in patients admitted to the hospital after out-of-hospital cardiac arrest (OHCA). To describe the magnitude of MIF release, we compared the blood levels from CPR patients with those obtained in healthy volunteers and with an aged- and gender-matched group of patient

New results on solar neutrino fluxes from 192 days of Borexino data

We report the direct measurement of the ^7Be solar neutrino signal rate performed with the Borexino detector at the Laboratori Nazionali del Gran Sasso. The interaction rate of the 0.862 MeV ^7Be neutrinos is 49+-3(stat)+-4(syst) counts/(day * 100ton). The hypothesis of no oscillation for ^7Be solar neutrinos is inconsistent with our measurement at the 4sigma level. Our result is the first direct measurement of the survival probability for solar nu_e in the transition region between matter-enhanced and vacuum-driven oscillations. The measurement improves the experimental determination of the flux of ^7Be, pp, and CNO solar nu_e, and the limit on the magnetic moment of neutrinos

New limits on nucleon decays into invisible channels with the BOREXINO Counting Test Facility

The results of background measurements with the second version of the BOREXINO Counting Test Facility (CTF-II), installed in the Gran Sasso Underground Laboratory, were used to obtain limits on the instability of nucleons, bounded in nuclei, for decays into invisible channels ($inv$): disappearance, decays to neutrinos, etc. The approach consisted of a search for decays of unstable nuclides resulting from $N$ and $NN$ decays of parents $^{12}$C, $^{13}$C and $^{16}$O nuclei in the liquid scintillator and the water shield of the CTF. Due to the extremely low background and the large mass (4.2 ton) of the CTF detector, the most stringent (or competitive) up-to-date experimental bounds have been established: $\tau(n \to inv) > 1.8 \cdot 10^{25}$ y, $\tau(p \to inv) > 1.1 \cdot 10^{26}$ y, $\tau(nn \to inv) > 4.9 \cdot 10^{25}$ y and $\tau(pp \to inv) > 5.0 \cdot 10^{25}$ y, all at 90% C.L.Comment: 22 pages, 3 figures,submitted to Phys.Lett.

The Borexino detector at the Laboratori Nazionali del Gran Sasso

Borexino, a large volume detector for low energy neutrino spectroscopy, is currently running underground at the Laboratori Nazionali del Gran Sasso, Italy. The main goal of the experiment is the real-time measurement of sub MeV solar neutrinos, and particularly of the mono energetic (862 keV) Be7 electron capture neutrinos, via neutrino-electron scattering in an ultra-pure liquid scintillator. This paper is mostly devoted to the description of the detector structure, the photomultipliers, the electronics, and the trigger and calibration systems. The real performance of the detector, which always meets, and sometimes exceeds, design expectations, is also shown. Some important aspects of the Borexino project, i.e. the fluid handling plants, the purification techniques and the filling procedures, are not covered in this paper and are, or will be, published elsewhere (see Introduction and Bibliography).Comment: 37 pages, 43 figures, to be submitted to NI

Pulse-Shape discrimination with the Counting Test Facility

Pulse shape discrimination (PSD) is one of the most distinctive features of liquid scintillators. Since the introduction of the scintillation techniques in the field of particle detection, many studies have been carried out to characterize intrinsic properties of the most common liquid scintillator mixtures in this respect. Several application methods and algorithms able to achieve optimum discrimination performances have been developed. However, the vast majority of these studies have been performed on samples of small dimensions. The Counting Test Facility, prototype of the solar neutrino experiment Borexino, as a 4 ton spherical scintillation detector immersed in 1000 tons of shielding water, represents a unique opportunity to extend the small-sample PSD studies to a large-volume setup. Specifically, in this work we consider two different liquid scintillation mixtures employed in CTF, illustrating for both the PSD characterization results obtained either with the processing of the scintillation waveform through the optimum Gatti's method, or via a more conventional approach based on the charge content of the scintillation tail. The outcomes of this study, while interesting per se, are also of paramount importance in view of the expected Borexino detector performances, where PSD will be an essential tool in the framework of the background rejection strategy needed to achieve the required sensitivity to the solar neutrino signals.Comment: 39 pages, 17 figures, submitted to Nucl. Instr. Meth.

New experimental limits on the Pauli forbidden transitions in 12^{12}C nuclei obtained with 485 days Borexino data

The Pauli exclusion principle (PEP) has been tested for nucleons ($n,p$) in $^{12}C$ with the Borexino detector.The approach consists of a search for $\gamma$, $n$, $p$ and $\beta^\pm$ emitted in a non-Paulian transition of 1$P_{3/2}$- shell nucleons to the filled 1$S_{1/2}$ shell in nuclei. Due to the extremely low background and the large mass (278 t) of the Borexino detector, the following most stringent up-to-date experimental bounds on PEP violating transitions of nucleons have been established: $\tau({^{12}\rm{C}}\to{^{12}\widetilde{\rm{C}}}+\gamma) \geq 5.0\cdot10^{31}$ y, $\tau({^{12}\rm{C}}\to{^{11}\widetilde{\rm{B}}}+ p) \geq 8.9\cdot10^{29}$ y, $\tau({^{12}\rm{C}}\to{^{11}\widetilde{\rm{C}}}+ n) \geq 3.4 \cdot 10^{30}$ y, $\tau({^{12}\rm{C}}\to{^{12}\widetilde{\rm{N}}}+ e^- + \widetilde{\nu_e}) \geq 3.1\cdot 10^{30}$ y and $\tau({^{12}\rm{C}}\to{^{12}\widetilde{\rm{B}}}+ e^+ + \nu_e) \geq 2.1 \cdot 10^{30}$ y, all at 90% C.L. The corresponding upper limits on the relative strengths for the searched non-Paulian electromagnetic, strong and weak transitions have been estimated: $\delta^2_{\gamma} \leq 2.2\cdot10^{-57}$, $\delta^2_{N} \leq 4.1\cdot10^{-60}$ and $\delta^2_{\beta} \leq 2.1\cdot10^{-35}$.Comment: 9 pages, 6 figure

Drug-Initiated Synthesis of Cladribine-Based Polymer Prodrug Nanoparticles: Biological Evaluation and Structure Activity Relationships

International audienceBy using two reversible deactivation radical polymerization techniques, either nitroxide-mediated polymerization or reversible addition-fragmentation chain transfer polymerization, the "drug-initiated" approach was applied to cladribine (CdA) as an anticancer drug to synthesize small libraries of well-defined and self-stabilized CdA-based polymer prodrug nanoparticles, differing from the nature and the molar mass of the grown polymer, and the nature of the linker between CdA and the polymer, thus allowing structure-cytotoxicity relationships to be determined. Their biological evaluation was investigated in vitro on L1210 cancer cells. The preparation of fluorescent CdA-based nanoparticles with excellent imaging ability was also reported by applying the "drug-initiated" approach to an aggregation-induced emission-active dye