Pharmacokinetic Characterization of the DDAH1 Inhibitors ZST316 and ZST152 in Mice Using a HPLC-MS/MS Method

The pharmacokinetic profile of ZST316 and ZST152, arginine analogues with inhibitory activity towards human dimethylarginine dimethylaminohydrolase-1 (DDAH1), was investigated in mice using a newly developed HPLC-MS/MS method. The method proved to be reproducible, precise, and accurate for the measurement of the compounds in plasma and urine. Four-week-old female FVB mice received a single dose of ZST316 and ZST152 by intravenous bolus (30 mg/Kg) and oral gavage (60 mg/Kg). ZST316 Cmax was 67.4 µg/mL (intravenous) and 1.02 µg/mL (oral), with a half-life of 6 h and bioavailability of 4.7%. ZST152 Cmax was 24.9 µg/mL (intravenous) and 1.65 µg/mL (oral), with a half-life of 1.2 h and bioavailability of 33.3%. Urinary excretion of ZST152 and ZST316 was 12.5%–22.2% and 2.3%–7.5%, respectively. At least eight urinary metabolites were identified. After chronic intraperitoneal treatment with the more potent DDAH1 inhibitor, ZST316 (30 mg/Kg/day for three weeks), the bioavailability was 59% and no accumulation was observed. Treatment was well tolerated with no changes in body weight vs. untreated animals and no clinical signs of toxicity or distress. The results of this study show that ZST316 has a favorable pharmacokinetic profile, following intraperitoneal administration, to investigate the effects of DDAH1 inhibition in mice.     

Superfluidity and quantum melting of p-H2 clusters

Structural and superfluid properties of p-H2 clusters of size up to N=40 molecules, are studied at low temperature (0.5 K相似文献   

Dysregulation of chemo-cytokine production in schizophrenic patients versus healthy controls

Background  

The exact cause of schizophrenia is not known, although several aetiological theories have been proposed for the disease, including developmental or neurodegenerative processes, neurotransmitter abnormalities, viral infection and immune dysfunction or autoimmune mechanisms. Growing evidence suggests that specific cytokines and chemokines play a role in signalling the brain to produce neurochemical, neuroendocrine, neuroimmune and behavioural changes. A relationship between inflammation and schizophrenia was supported by abnormal cytokines production, abnormal concentrations of cytokines and cytokine receptors in the blood and cerebrospinal fluid in schizophrenia. Since the neuropathology of schizophrenia has recently been reported to be closely associated with microglial activation we aimed to determined whether spontaneous or LPS-induced peripheral blood mononuclear cell chemokines and cytokines production is dysregulated in schizophrenic patients compared to healthy subjects. We enrolled 51 untreated first-episode schizophrenics (SC) and 40 healthy subjects (HC) and the levels of MCP-1, MIP-1α, IL-8, IL-18, IFN-γ and RANTES were determined by Elisa method in cell-free supernatants of PBMC cultures.     

Nonlocal elasticity in shape memory alloys modeled using peridynamics for solving dynamic problems

Nonlinear Dynamics - The work is primarily devoted to the peridynamic model elaborated for a solid body made of shape memory alloys (SMAs). The superelasticity effect is taken into consideration as...     

Study on Planar Whispering Gallery Dielectric Resonators. I. General Properties

Several basic properties of homogeneous planar Whispering Gallery dielectric resonators are investigated through a general approach. In particular the values for the minimum and maximum allowed radius, defined by irradiation and dielectric losses, respectively, are obtained in terms of the complex dielectric constant of the involved media. The same approach is employed in the analysis of the limit allowed frequencies of a fixed family of mode, leading to the definition of the ideal frequency band. The role of the transverse mode is then discussed, and the effective frequency band is introduced and determined both in simple disc and circular ring resonators. The extension of the effective band is limited at least by a factor 3, in terms of decades, in comparison to the extension of the ideal one; this limitation, due to the presence of transverse modes, can be overcome using suitable designed nonhomogeneous resonators, as discussed in a following companion paper.     

Characterisation of ancient Roman wall-painting fragments using non-destructive IBA and MA-XRF techniques

Scientific investigation is very important in studies addressing issues of archaeological and historical objects. Ion beam analysis (IBA) and macro X-ray fluorescence (MA-XRF) spectroscopy are remarkable tools to obtain information about elemental composition and imaging of historical artefacts with a non-invasive character. These investigation techniques were employed in the framework of a project aimed at supporting the characterization of materials and techniques related with the Roman wall painting. The archaeological excavations at Villa della Piscina in Rome have revealed a luxury building with a large pool (about 50 m long) and thermal baths and numerous fragments of plaster, coming from intentional demolitions referable to two distinct architectural contexts of the Villa during the imperial age, have been found. This work deals with studying the interesting wall pictorial apparatus of great cultural value of the heritage inherited from the Roman age in the area of the ancient city of Rome. The colour palette of the pigments investigated, in particular, by MA-XRF and particle-induced X-ray emission (PIXE) and has revealed Fe, Cu, Pb, Si and Hg as main elements. Traces of other constituents uncover the choice of the different colours chosen by the artists who had embellished the rooms of the Villa.     

Differentiability Properties of an Abstract Autonomous Composition Operator

The autonomous composition operator is the nonlinear map whichtakes a pair of functions into its composite function. The compositionoperator often appears in problems of nonlinear analysis andto analyse such problems it is often important to know whetherthe composition operator is continuous or differentiable. Afairly large number of papers in the literature have been devotedto the study of composition operators. For fullscale references,we refer the reader to the extensive monographs of Appell andZabrejko [1] and Runst and Sickel [8]. To exemplify a typicalsituation, we consider the semilinear Dirichlet boundary valueproblem where denotes a sufficiently regular bounded open subset ofR^N, and h₀ a map of R to R, and where u is the unknown of theproblem. We assume that we know that a certain function u₀ belongingto a certain function space X solves (1.1). Then if we wishto know whether by perturbing h₀ in a certain function space,say Y, the solutions u depend on h continuously, with differentiability,with analyticity or bifurcate, we could set G[h, u] u+h u,recast problem (1.1) into the abstract form G[h, u] (1.2) and study the solution set of equation (1.2) around the pair(h₀, u₀) by means of the implicit function theorem or by localbifurcation theorems in a Banach space setting.     

An assessment of the impact of construction work on fine particulate matter in the University of Jordan: A PIXE study

Aerosol sampling was carried out prior to and during an active construction work at the University of Jordan in Amman, Jordan. Elemental characterization for 60 PM_2.5 samples was performed by particle-induced X-ray emission (PIXE) technique at the LABEC laboratory of INFN in Florence, Italy. Twenty three elements (Na, Mg, Al, Si, P, S, Cl, K, Ca, Ti, V, Cr, Mn, Fe, Ni, Cu, Zn, Br, Rb, Sr, Zr, Ba, and Pb) were detected, and their concentrations were assessed during three sampling periods, namely, “No Construction,” “Pouring Concrete,” and “Bleaching.” The results showed higher concentrations of soil-related elements and lower concentrations of anthropogenic-related elements during construction periods compared with their concentrations before construction. Soil-related elements showed very low enrichment factor (EF) and high correlation coefficients during all sampling periods. Anthropogenic-related elements were very much enriched and correlated only during the first sampling period “No Construction.”