Pectic Galactan Polysaccharide-Based Gene Delivery System for Targeting Neuroinflammation

Treating neuroinflammation-related injuries and disorders through manipulation of neuroinflammation functions is being heralded as a new therapeutic strategy. In this study, a novel pectic galactan (PG) polysaccharide based gene therapy approach is developed for targeting reactive gliosis in neuroinflammation. Galectin-3 (Gal-3) is a cell protein with a high affinity to β-galactoside sugars and is highly expressed in reactive gliosis. Since PG carries galactans, it can target reactive gliosis via specific carbohydrate interaction between galactan and Gal-3 on the cell membrane, and therefore can be utilized as a carrier for delivering genes to these cells. The carrier is synthesized by modifying quaternary ammonium groups on the PG. The resulting quaternized PG (QPG) is found to form complexes with plasmid DNA with a mean diameter of 100 nm and have the characteristics required for targeted gene therapy. The complexes efficiently condense large amounts of plasmid per particle and successfully bind to Gal-3. The in vivo study shows that the complexes are biocompatible and safe for administration and can selectively transfect reactive glial cells of an induced cortical lesion. The results confirm that this PG-based delivery system is a promising platform for targeting Gal-3 overexpressing neuroinflammation cells for treating neuroinflammation-related injuries and neurodegenerative diseases.     

Multiplicative Operator Splittings in Nonlinear Diffusion: From Spatial Splitting to Multiple Timesteps

Operator splitting is a powerful concept used in many diversed fields of applied mathematics for the design of effective numerical schemes. Following the success of the additive operator splitting (AOS) in performing an efficient nonlinear diffusion filtering on digital images, we analyze the possibility of using multiplicative operator splittings to process images from different perspectives.We start by examining the potential of using fractional step methods to design a multiplicative operator splitting as an alternative to AOS schemes. By means of a Strang splitting, we attempt to use numerical schemes that are known to be more accurate in linear diffusion processes and apply them on images. Initially we implement the Crank-Nicolson and DuFort-Frankel schemes to diffuse noisy signals in one dimension and devise a simple extrapolation that enables the Crank-Nicolson to be used with high accuracy on these signals. We then combine the Crank-Nicolson in 1D with various multiplicative operator splittings to process images. Based on these ideas we obtain some interesting results. However, from the practical standpoint, due to the computational expenses associated with these schemes and the questionable benefits in applying them to perform nonlinear diffusion filtering when using long timesteps, we conclude that AOS schemes are simple and efficient compared to these alternatives.We then examine the potential utility of using multiple timestep methods combined with AOS schemes, as means to expedite the diffusion process. These methods were developed for molecular dynamics applications and are used efficiently in biomolecular simulations. The idea is to split the forces exerted on atoms into different classes according to their behavior in time, and assign longer timesteps to nonlocal, slowly-varying forces such as the Coulomb and van der Waals interactions, whereas the local forces like bond and angle are treated with smaller timesteps. Multiple timestep integrators can be derived from the Trotter factorization, a decomposition that bears a strong resemblance to a Strang splitting. Both formulations decompose the time propagator into trilateral products to construct multiplicative operator splittings which are second order in time, with the possibility of extending the factorization to higher order expansions. While a Strang splitting is a decomposition across spatial dimensions, where each dimension is subsequently treated with a fractional step, the multiple timestep method is a decomposition across scales. Thus, multiple timestep methods are a realization of the multiplicative operator splitting idea. For certain nonlinear diffusion coefficients with favorable properties, we show that a simple multiple timestep method can improve the diffusion process.     

Hartstoffschichten für das Pressen und Prägen von Gläsern bei hohen Temperaturen

Hard and wear resistant coatings for the moulding and embossing of glasses at elevated temperatures Hard and wear resistant coatings of Titanium Aluminium Nitride TiAlN were deposited on various substrates by the application of different reactive deposition processes: RF-magnetron-sputtering, ion beam-sputtering and by the energetic cluster impact (ECI) process. The deposition of the coatings was performed under variation of biasing conditions and of process parameters such as pressures and flow rates of the process gases argon and nitrogen as well as of energies of species hitting the substrate surfaces. The microstructure particularly the growth morphology of several films was investigated by pictures of film cross sections recorded by transmission electron microscopy. Residual intrinsic film stresses were analyzed by measuring deflections of substrates in an interference optical microscope before and after the deposition of the coatings. By heating coated substrates and in-situ observation of deflections at elevated temperatures dependencies of thermally induced stresses on temperatures and variations of intrinsic stresses due to changes within the films could be analyzed and related to microstructure and growth conditions. In the paper specific characteristics of the deposition processes occuring on the scale both of atoms and of clusters which may contain several thousand of atoms are described and related to microstructure, residual stress states and damaging conditions. Different contributions to residual film stresses are analyzed on the base of theoretical considerations taking into account deposition kinetics and thermomecanical properties. The significance of achieved film properties for application, i. e. for the coating of tools for the manufacturing of optical components by moulding and embossing of glasses is discussed.     

Directionality from anisotropic phonon production in solid state dark matter detection

We present results from computer simulations of the events immediately following the scattering of a dark matter particle off a nucleus in a crystal detector. Our simulations show that with NaF as the target, the recoil produces solitary waves that decay slowly, resulting in a narrow wake of phonons. The phonon wake allows a determination of direction of the nuclear recoil.     

Photochemical identification of transmembrane segment IVS6 as the binding region of semotiadil, a new modulator for the L-type voltage-dependent Ca2+ channel

To identify the binding domain of a new Ca2+ antagonist semotiadil on L-type Ca2+ channels from skeletal muscle, photolabeling was carried out by using an azidophenyl derivative of [3H]semotiadil. Photoincorporation was observed in several polypeptides of membrane triad preparations; the only specific photoincorporation was in the alpha1 subunit of the Ca2+ channel. After solubilization and purification, the photolabeled alpha1 subunit was subjected to proteolytic and CNBr cleavage followed by antibody mapping. Specific labeling was associated solely with the region of transmembrane segment S6 in repeat IV. Quantitative immunoprecipitation was found in the tryptic and the Lys-C/Glu-C fragments of 6.6 and 6.1 kDa, respectively. Further CNBr cleavage of the Lys-C digests produced two smaller fragments of 3.4 and 1.8 kDa that were included in the tryptic and Lys-C/Glu-C fragments. The smallest labeled fragments were: Tyr1350-Met1366 and Leu1367-Met1381 containing IVS6, a possible pore-forming region. The data suggest that semotiadil binds to a region that is overlapped with but not identical to those for phenylalkylamines, dihydropyridines and benzothiazepines. The present study also provides evidence that region IV represents an important component of a binding pocket for Ca2+ antagonists.     

Modulation of the allergic immune response in BALB/c mice by subcutaneous injection of high doses of the dominant T cell epitope from the major birch pollen allergen Bet v 1

Several in vitro and in vivo studies indicate that application of high doses of dominant T cell epitopes can induce a state of antigen-specific non-responsiveness (anergy). In the present study, we developed a murine model of an allergic immune response to Bet v 1, the major birch pollen allergen. Mice were sensitized by injection of rBet v 1 and the allergic state was proven by the presence of allergen-specific IgE and positive immediate-type skin tests to Bet v 1. In epitope mapping experiments, an immunodominant T cell epitope of Bet v 1 in BALB/c mice was identified by the use of overlapping peptides. This peptide (BV 139) was subsequently employed for treatment. Two tolerization protocols were used: in one approach, the peptide was administered to naive mice before immunization (group BV139-S), in the second, already sensitized mice were treated (S-BV139). The results demonstrated that administering high doses of the dominant T cell epitope of Bet v 1 profoundly diminished T cell proliferation to the peptide in the BV139-S group, and to the peptide as well as to the whole protein in the S-BV139 group. Skin test reactivity to Bet v 1 was reduced in the BV139-S group. However, no differences in terms of specific antibody production between treated and untreated mice could be observed. This study provides evidence that administration of dominant T cell epitopes can down-regulate the allergen-specific T cell response. Proceeding on the assumption that the T lymphocyte response to allergens is crucial for the induction and maintenance of the allergic disease, a modulation of the immune response to allergens by treatment with T cell epitope peptides could represent a promising concept for immunotherapy in the future.     

Is there a role for continuation phase cognitive therapy for depressed outpatients?

Two pilot studies evaluated the rate of relapse or recurrence (i.e., major depressive disorder) after cognitive therapy (CT). Two sequential cohorts included outpatients who responded to acute phase CT (A-CT) and who agreed to monthly, treatment-free follow-up. In Study 1, the Kaplan-Meier technique estimated relapse and recurrence rates of 40% at 6 months, 45% at 8 months, 50% at 12 months, 67% at 18 months, and 74% at 24 months. In Study 2, responders to A-CT received 8 months (10 sessions) of continuation phase CT (C-CT). In Study 2, relapse or recurrence was 20% at 6 and 8 months, 27% at 12 months, and 36% at 18 and 24 months after A-CT. An exploratory log-rank test showed that relapse or recurrence-free survival was greater in Study 2 than in Study 1. If replicated, this result suggests that C-CT can reduce depressive relapse or recurrence. Alternative explanations are presented. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Greedy hot-potato routing on the two-dimensional mesh

Summary We propose hot-potato (or, deflection) packet routing algorithms on the two-dimensional mesh. The algorithms are strongly greedy in the sense that they attempt to send packets in good directions whenever possible. Furthermore, the routing operations are simple and independent of the time that has elapsed. The first algorithm gives the best evacuation time known for delivering all the packets to their destinations. A batch ofk packets with maximal source-to-destination distanced _max is delivered in 2(k-1)+d _max. The second algorithm improves this bound tok+d _max when all packets are destined to the same node. This also implies a new bound for the multitarget case, which is the first to take into account the number of in-edges of a node. The third algorithm is designed for routing permutations with source-to-destination distance at most three, in which case the algorithm terminates in at most seven steps. We also show a lower bound of five steps for this problem. Ishai Ben-Aroya received the B.A. and M.Sc. in computer science from the Technion (Israel Institute of Technology). He is currently working with Microsoft Israel R&D group. His main interests include Routing Algorithms, Cryptography and Computer Security. Tamar Eilam received the B.A. degree in Computer Science from the Technion IIL in 1995, and is currently studying towards her M.A. degree. Assaf Schuster received his B.A., M.A. and Ph.D. degrees in Computer Science from the Hebrew University of Jerusalem (the last one in 1991). He is currently a lecturer at the Technion IIL. His main interests include Networks and Routing Algorithms, Parallel and Distributed Computation, Optical Computation and Communication, Dynamically Reconfiguring Networks, and Greedy Hot Potato Routing.This work was supported in part by the French-Israeli grant for cooperation in Computer Science, and by a grant from the Israeli Ministry of Science. An extended abstract appeared in proc. 2nd European Symposium on Algorithms, September 1994