Fighting the Huntington’s Disease with a G-Quadruplex-Forming Aptamer Specifically Binding to Mutant Huntingtin Protein: Biophysical Characterization,In Vitro and In Vivo Studies

A set of guanine-rich aptamers able to preferentially recognize full-length huntingtin with an expanded polyglutamine tract has been recently identified, showing high efficacy in modulating the functions of the mutated protein in a variety of cell experiments. We here report a detailed biophysical characterization of the best aptamer in the series, named MS3, proved to adopt a stable, parallel G-quadruplex structure and show high nuclease resistance in serum. Confocal microscopy experiments on HeLa and SH-SY5Y cells, as models of non-neuronal and neuronal cells, respectively, showed a rapid, dose-dependent uptake of fluorescein-labelled MS3, demonstrating its effective internalization, even in the absence of transfecting agents, with no general cytotoxicity. Then, using a well-established Drosophila melanogaster model for Huntington’s disease, which expresses the mutated form of human huntingtin, a significant improvement in the motor neuronal function in flies fed with MS3 was observed, proving the in vivo efficacy of this aptamer.     

Molecular dynamics simulations of polyphosphazenes: poly[bis(chloro)phosphazene][NPCl2] n

Suitable parameter sets for the CHARMm force field were derived for the structural units in polychlorophosphazene [P=N, P N, P Cl] using the Dinur Hagler energy second derivative procedure based on quantum mechanical SCI calculations using the 6–31G^* basis set. To validate the reliability of the parameter set, structural results obtained with CHARMm for the adopted model compounds (OP₂NCl₅ and OP₃N₂Cl₅) were compared with those derived fromab initio quantum mechanics using the 6–31G^* basis set. Application of molecular dynamics (MD) simulations in combinatioin with the available X-ray diffraction data provided structural and conformational information on the polymer. The calculation made using the periodic boundary conditions (PBC) agree well with the polychlorophosphazene ordered in a monoclinic unit cell (a=5.98,b=12.99,c=4.92 A; β=111.7). This model was stabilized mainly by the image atoms contribution to the electrostatic energy term and had aquasi-planar conformation of the backbone chain (glide symmetry). The MD calculations also provided evidence that the difference between single and double PN bonds is less marked than that measured experimentally. This result is, however, in agreement with more recent and accurate X-ray studies on poly(methylphosphazene). Validation of the polymer model provided a complete picture, otherwise experimentally inaccessible, of the internal fluctuations of the polymeric chains.     

Epidemiologic and demographic aspects of peritoneal dialysis in Mexico

The rationale for anti-tumour necrosis factor-alpha (anti-TNFalpha) therapy in rheumatoid arthritis (RA) is based on experiments on cultures of human rheumatoidjoint tissue, supported by experiments in animal models, all of which demonstrated that anti-TNFalpha antibody had profound effects on the disease activity. Clinical trials have substantiated this concept, and we have used the serum samples from the clinical trials, as well as biopsies to study the changes occurring during anti-TNFalpha therapy as clues to the pathogenesis of RA. The major effects of anti-TNFalpha therapy are in downregulating cytokine activity, and in reducing leucocyte trafficking to the joints.     

Surgery for esophageal achalasia. long-term results with three different techniques

BACKGROUND/AIMS: In surgery for achalasia, the length of the myotomy and the opportunity of associating an antireflux procedure are still debated. Prospective and comparative studies on different techniques are few. The aims of this work is to compare the long term results of three different techniques successively adopted by the same surgical group. MATERIALS AND METHODS: Between January 1955 and December 1991, 185 achalasic patients were submitted to myotomy by using in temporal sequence three different techniques. The first technique utilized (1955-1972) was a long esophagogastric abdominal myotomy (83 patients), secondly (1973-1978) a limited transthoracic myotomy (30 patients) and at last (1979-1991) a long esophagogastric abdominal myotomy associated to the Dor gastroplasty (72 patients). Since 1972, patients were prospectively followed up according to a protocol which included a clinical interview, x-rays, manometry and endoscopy at given dates. Post-operative esophagogastric transit and gastro-esophageal reflux were assessed to verify the therapeutical outcome. Results obtained with the three different techniques were analyzed and compared by using the actuarial Kaplan-Meier curves. RESULTS: The mean follow up was 193.3 months for the patient group that underwent abdominal myotomy (62/83 patients), 137.3 months for the thoracic myotomy group (30/30 patients) and 86.9 months for the abdominal myotomy plus Dor gastroplasty group (69/72 patients). Long-term results in the abdominal myotomy and in the thoracic myotomy groups were respectively poor in 51.6% and in 46.6% of patients. Major causes of failure were insufficient myotomy (6.5%), periesophageal scarring (9.6%) and reflux esophagitis (22.6%) for the abdominal myotomy group; insufficient myotomy (20%) and reflux esophagitis (23%) for the thoracic myotomy group. In the abdominal myotomy plus Dor gastroplasty group long-term results were excellent or good in 87% of patients and poor in 13%. Reflux esophagitis (10% of cases) was the principal cause of failure. CONCLUSIONS: The comparison of the actuarial curves shows a significantly better long term outcome for the abdominal myotomy plus Dor antireflux procedure than for the abdominal myotomy (p = 0.01) and for the thoracic myotomy (p = 0.002) techniques.     

Necessary and sufficient conditions for quadratic stability andstabilizability of uncertain linear time-varying systems

In this paper we consider linear time-varying systems subject to norm bounded, one block, structured uncertainties. First, given an unforced system, we find necessary and sufficient conditions for quadratic stability; then, considered a controlled system, we provide necessary and sufficient conditions for quadratic stabilizability both for the state and the output feedback case     

A scalable method for run-time loop parallelization

Current parallelizing compilers do a reasonable job of extracting parallelism from programs with regular, well behaved, statically analyzable access patterns. However, they cannot extract a significant fraction of the avaialable, parallelism if the program has a complex and/or statically insufficiently defined access pattern, e.g., simulation programs with irregular domains and/or dynamically changing interactions. Since such programs represent a large fraction of all applications, techniques are needed for extracting their inherent parallelism at run-time. In this paper we give a new run-time technique for finding an optimal parallel execution schedule for a partially parallel loop, i.e., a loop whose parallelization requires synchronization to ensure that the iterations are executed in the correct order. Given the original loop, the compiler generatesinspector code that performas run-time preprocessing of the loop's access pattern, andscheduler code that schedules (and executes) the loop interations. The inspector is fully parallel, uses no sychronization, and can be applied to any loop (from which an inspector can be extracted). In addition, it can implement at run-time the two most effective transformations for increasing the amount of parallelism in a loop:array privatization andreduction parallelization (elementwise). The ability to identify privatizable and reduction variables is very powerful since it eliminates the data dependences involving these variables and An abstract of this paper has been publsihed in Ref. 1. Research supported in part by Army contract #DABT63-92-C-0033. This work is not necessarily representative of the positions or policies of the Army of the Government. Research supported in part by Intel and NASA Graduate Fellowships. Research supported in part by an AT&T Bell Laboratoroies Graduate Fellowship and by the International Computer Science Institute, Berkeley, California.     

STEADY-STATE EXPANSION CHARACTERISTICS OF MONOSIZE SPHERES FLUIDISED BY LIQUIDS

Velocity-voidage experiments conducted on beds of truly monosized and spherical plastic particles fluidised by solutions of glycerol, enable the change of behaviour at high expansion conditions to be correlated with the unhindered particle Reynolds number.