Selectivity of LG50643 for postjunctional muscarinic-receptor subtype in the guinea-pig trachea

The effects of (+/-)-LG50643, a new N-quaternary tropinic ester of phenylcyclohexene carboxylic acid, endowed with a potent antimuscarinic activity, have been investigated on muscarinic receptor-mediated responses of the guinea-pig trachea to electrical field stimulation. An isolated preparation which allows the simultaneous measurement of tritiated acetylcholine release (prejunctional effect) and smooth muscle contraction (postjunctional effect) was used. The guinea-pig epithelium-deprived trachea was stimulated with 500 pulses (20 Hz, 1 ms, 9 V for 5 s, 30 s apart) in the presence of indomethacin (1 microM). Three successive pre- and postjunctional responses were observed. The potencies (-logEC50) of (+/-)-LG50643 for pre- and postjunctional muscarinic receptors were determined and compared with those of selective muscarinic antagonists. In addition, the affinity values of (+/-)-LG50643 for muscarinic-receptor subtypes were determined in radioligand binding experiments in cerebral cortex, heart and salivary glands of rat as target tissues for M1, M2 and M3 receptors, respectively. The results obtained in both functional and binding assays indicate (+/-)-LG50643 is a potent and selective antagonist for the M3-receptor subtype.     

The Horace Method for Error-Correcting Codes

Here we apply the so-called Horace method for zero-dimensional schemes to error-correcting codes on complete intersections. In particular, we obtain sharper estimates on the minimum distance.     

Unsupervised tissue classification of brain MR images for voxel‐based morphometry analysis

In this article, a fully unsupervised method for brain tissue segmentation of T1‐weighted MRI 3D volumes is proposed. The method uses the Fuzzy C‐Means (FCM) clustering algorithm and a Fully Connected Cascade Neural Network (FCCNN) classifier. Traditional manual segmentation methods require neuro‐radiological expertise and significant time while semiautomatic methods depend on parameter's setup and trial‐and‐error methodologies that may lead to high intraoperator/interoperator variability. The proposed method selects the most useful MRI data according to FCM fuzziness values and trains the FCCNN to learn to classify brain’ tissues into White Matter, Gray Matter, and Cerebro‐Spinal Fluid in an unsupervised way. The method has been tested on the IBSR dataset, on the BrainWeb Phantom, on the BrainWeb SBD dataset, and on the real dataset “University of Palermo Policlinico Hospital” (UPPH), Italy. Sensitivity, Specificity, Dice and F‐Factor scores have been calculated on the IBSR and BrainWeb datasets segmented using the proposed method, the FCM algorithm, and two state‐of‐the‐art brain segmentation software packages (FSL and SPM) to prove the effectiveness of the proposed approach. A qualitative evaluation involving a group of five expert radiologists has been performed segmenting the real dataset using the proposed approach and the comparison algorithms. Finally, a usability analysis on the proposed method and reference methods has been carried out from the same group of expert radiologists. The achieved results show that the segmentations of the proposed method are comparable or better than the reference methods with a better usability and degree of acceptance.     

PLNoise: a package for exact numerical simulation of power-law noises

Many simulations of stochastic processes require colored noises: here I describe a small program library that generates samples with a tunable power-law spectral density: the algorithm can be modified to generate more general colored noises, and is exact for all time steps, even when they are unevenly spaced (as may often happen in the case of astronomical data, see e.g. [N.R. Lomb, Astrophys. Space Sci. 39 (1976) 447]. The method is exact in the sense that it reproduces a process that is theoretically guaranteed to produce a range-limited power-law spectrum 1/f1+β with −1<β?1. The algorithm has a well-behaved computational complexity, it produces a nearly perfect Gaussian noise, and its computational efficiency depends on the required degree of noise Gaussianity.

Program summary

Title of program: PLNoiseCatalogue identifier:ADXV_v1_0Program summary URL:http://cpc.cs.qub.ac.uk/summaries/ADXV_v1_0.htmlProgram obtainable from: CPC Program Library, Queen's University of Belfast, N. IrelandLicensing provisions: noneProgramming language used: ANSI CComputer: Any computer with an ANSI C compiler: the package has been tested with gcc version 3.2.3 on Red Hat Linux 3.2.3-52 and gcc version 4.0.0 and 4.0.1 on Apple Mac OS X-10.4Operating system: All operating systems capable of running an ANSI C compilerNo. of lines in distributed program, including test data, etc.:6238No. of bytes in distributed program, including test data, etc.:52 387Distribution format:tar.gzRAM: The code of the test program is very compact (about 50 Kbytes), but the program works with list management and allocates memory dynamically; in a typical run (like the one discussed in Section 4 in the long write-up) with average list length 2⋅¹⁰⁴, the RAM taken by the list is 200 Kbytes.External routines: The package needs external routines to generate uniform and exponential deviates. The implementation described here uses the random number generation library ranlib freely available from Netlib [B.W. Brown, J. Lovato, K. Russell, ranlib, available from Netlib, http://www.netlib.org/random/index.html, select the C version ranlib.c], but it has also been successfully tested with the random number routines in Numerical Recipes [W.H. Press, S.A. Teulkolsky, W.T. Vetterling, B.P. Flannery, Numerical Recipes in C: The Art of Scientific Computing, second ed., Cambridge Univ. Press, Cambridge, 1992, pp. 274-290]. Notice that ranlib requires a pair of routines from the linear algebra package LINPACK, and that the distribution of ranlib includes the C source of these routines, in case LINPACK is not installed on the target machine.Nature of problem: Exact generation of different types of Gaussian colored noise.Solution method: Random superposition of relaxation processes [E. Milotti, Phys. Rev. E 72 (2005) 056701].Unusual features: The algorithm is theoretically guaranteed to be exact, and unlike all other existing generators it can generate samples with uneven spacing.Additional comments: The program requires an initialization step; for some parameter sets this may become rather heavy.Running time: Running time varies widely with different input parameters, however in a test run like the one in Section 4 in this work, the generation routine took on average about 7 ms for each sample.     

Ultimate behavior of axially loaded RC wall-like columns confined with GFRP

The assessment of the effectiveness of the fiber reinforced polymer (FRP) confinement on rectangular reinforced concrete (RC) columns with high aspect ratio (wall-like) still represents an unresolved issue. The present paper aims at providing more experimental evidence about the behavior of such members confined with both uni-directional and quadri-directional glass FRP laminates. Particular attention is devoted to issues related to the premature failure of confining fibers experimentally observed in wall-like columns. Test results on nine axially loaded columns are herein presented; emphasis is also given to the analysis of FRP strain profiles along the sides of the cross-section. The analysis of test results highlights that glass FRP (GFRP) confinement could determine significant strength and ductility increases; the discussion of failure modes points out that the failure of GFRP confined wall-like columns is controlled by the shape of the cross-section and occurs at transverse strains in the jacket much lower than those ultimate of the fibers. Theoretical–experimental comparisons are performed using some available models for strength prediction of such members.     

Proteomics and Extracellular Vesicles as Novel Biomarker Sources in Peritoneal Dialysis in Children

Peritoneal dialysis (PD) represents the dialysis modality of choice for pediatric patients with end-stage kidney disease. Indeed, compared with hemodialysis (HD), it offers many advantages, including more flexibility, reduction of the risk of hospital-acquired infections, preservation of residual kidney function, and a better quality of life. However, despite these positive aspects, PD may be associated with several long-term complications that may impair both patient’s general health and PD adequacy. In this view, chronic inflammation, caused by different factors, has a detrimental impact on the structure and function of the peritoneal membrane, leading to sclerosis and consequent PD failure both in adults and children. Although several studies investigated the complex pathogenic pathways underlying peritoneal membrane alterations, these processes remain still to explore. Understanding these mechanisms may provide novel approaches to improve the clinical outcome of pediatric PD patients through the identification of subjects at high risk of complications and the implementation of personalized interventions. In this review, we discuss the main experimental and clinical experiences exploring the potentiality of the proteomic analysis of peritoneal fluids and extracellular vesicles as a source of novel biomarkers in pediatric peritoneal dialysis.     

On‐Chip Magnetic Platform for Single‐Particle Manipulation with Integrated Electrical Feedback

Methods for the manipulation of single magnetic particles have become very interesting, in particular for in vitro biological studies. Most of these studies require an external microscope to provide the operator with feedback for controlling the particle motion, thus preventing the use of magnetic particles in high‐throughput experiments. In this paper, a simple and compact system with integrated electrical feedback is presented, implementing in the very same device both the manipulation and detection of the transit of single particles. The proposed platform is based on zig‐zag shaped magnetic nanostructures, where transverse magnetic domain walls are pinned at the corners and attract magnetic particles in suspension. By applying suitable external magnetic fields, the domain walls move to the nearest corner, thus causing the step by step displacement of the particles along the nanostructure. The very same structure is also employed for detecting the bead transit. Indeed, the presence of the magnetic particle in suspension over the domain wall affects the depinning field required for its displacement. This characteristic field can be monitored through anisotropic magnetoresistance measurements, thus implementing an integrated electrical feedback of the bead transit. In particular, the individual manipulation and detection of single 1‐μm sized beads is demonstrated.     

The P2X7R-NLRP3 and AIM2 Inflammasome Platforms Mark the Complexity/Severity of Viral or Metabolic Liver Damage

P2X7R-NLRP3 and AIM2 inflammasomes activate caspase-1 and the release of cytokines involved in viral-related liver disease. Little is known about their role in non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steato-hepatitis (NASH). We characterized the role of inflammasomes in NAFLD, NASH, and HCV. Gene expression and subcellular localization of P2X7R/P2X4R-NLRP3 and AIM2 inflammasome components were examined in histopathological preparations of 46 patients with biopsy-proven viral and metabolic liver disease using real-time PCR and immunofluorescence. P2X7R, P2X4R, and Caspase-1 are two- to five-fold more expressed in patients with NAFLD/NASH associated with chronic HCV infection than those with metabolic damage only (p ≤ 0.01 for all comparisons). The AIM2 inflammasome is 4.4 times more expressed in patients with chronic HCV infection, regardless of coexistent metabolic abnormalities (p = 0.0006). IL-2, a cytokine playing a pivotal role during chronic HCV infection, showed a similar expression in HCV and NASH patients (p = 0.77) but was virtually absent in NAFLD. The P2X7R-NLRP3 complex prevailed in infiltrating macrophages, while AIM2 was localized in Kupffer cells. Caspase-1 expression correlated with elastography-based liver fibrosis (r = 0.35, p = 0.02), whereas P2X7R, P2X4R, NRLP3, Caspase-1, and IL-2 expression correlated with circulating markers of disease severity. P2X7R and P2X4R play a major role in liver inflammation accompanying chronic HCV infection, especially when combined with metabolic damage, while AIM2 is specifically expressed in chronic viral hepatitis. We describe for the first time the hepatic expression of IL-2 in NASH, so far considered a peculiarity of HCV-related liver damage.     

Integrating urban and port planning policies in a sustainable perspective: the case study of Naples historic harbour area

ABSTRACT

This paper explores the case of the historic harbour area of Naples, considered highly significant, due to its physical and cultural characteristics, with the aim of reflecting on the contemporary need for building renewed and synergic city–port relations in a sustainable perspective. Focusing on the physical and functional city–port integration, the study investigates Naples harbour planning policy between twentieth and twenty-first centuries in order to identify the limitations of older instruments and to exam the current proposal, finally suggesting perspectives for the future. The analysis highlights the fact that, in the port of Naples, with a landlord governance, the main obstacles to a more inclusive planning policy have been related to land use conflict between on one hand the public interest of the Port Authority and Municipality and the private interest of port operators on the other. In conclusion, the need for city–port plan integration is outlined as a central planning issue so as to combine the economic development of the harbour with social, cultural and ecological themes and to overcome the conflicts between the different actors involved in the complex planning process.     

Beneficial and Sexually Dimorphic Response to Combined HDAC Inhibitor Valproate and AMPK/SIRT1 Pathway Activator Resveratrol in the Treatment of ALS Mice

Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disorder. There is no cure and current treatments fail to slow the progression of the disease. Epigenetic modulation in the acetylation state of NF-kB RelA and the histone 3 (H3) protein, involved in the development of neurodegeneration, is a drugable target for the class-I histone deacetylases (HDAC) inhibitors, entinostat or valproate, and the AMP-activated kinase (AMPK)-sirtuin 1 pathway activator, resveratrol. In this study, we demonstrated that the combination of valproate and resveratrol can restore the normal acetylation state of RelA in the SOD1(G93A) murine model of ALS, in order to obtain the neuroprotective form of NF-kB. We also investigated the sexually dimorphic development of the disease, as well as the sex-sensibility to the treatment administered. We showed that the combined drugs, which rescued AMPK activation, RelA and the histone 3 acetylation state, reduced the motor deficit and the disease pathology associated with motor neuron loss and microglial reactivity, Brain-Derived Neurotrophic Factor (BDNF) and B-cell lymphoma-extra large (Bcl-xL) level decline. Specifically, vehicle-administered males showed earlier onset and slower progression of the disease when compared to females. The treatment, administered at 50 days of life, postponed the time of onset in the male by 22 days, but not in a significant way in females. Nevertheless, in females, the drugs significantly reduced symptom severity of the later phase of the disease and prolonged the mice’s survival. Only minor beneficial effects were produced in the latter stage in males. Overall, this study shows a beneficial and sexually dimorphic response to valproate and resveratrol treatment in ALS mice.