Investigating synthetic oligonucleotide targeting of miR31 in Duchenne muscular dystrophy

Exon-skipping via synthetic antisense oligonucleotides represents one of the most promising potential therapies for Duchenne muscular dystrophy (DMD), yet this approach is highly sequence-specific and thus each oligonucleotide is of benefit to only a subset of patients. The discovery that dystrophin mRNA is subject to translational suppression by the microRNA miR31, and that miR31 is elevated in the muscle of DMD patients, raises the possibility that the same oligonucleotide chemistries employed for exon skipping could be directed toward relieving this translational block. This approach would act synergistically with exon skipping where possible, but by targeting the 3’UTR it would further be of benefit to the many DMD patients who express low levels of in-frame transcript. We here present investigations into the feasibility of combining exon skipping with several different strategies for miR31-modulation, using both in vitro models and the mdx mouse (the classical animal model of DMD), and monitoring effects on dystrophin at the transcriptional and translational level. We show that despite promising results from our cell culture model, our in vivo data failed to demonstrate similarly reproducible enhancement of dystrophin translation, suggesting that miR31-modulation may not be practical under current oligonucleotide approaches. Possible explanations for this disappointing outcome are discussed, along with suggestions for future investigations

Ocean gravity and geoid determination

Gravity anomalies have been recovered in the North Atlantic and the Indian Ocean regions. Comparisons of 63 2 deg x 2 deg mean free air gravity anomalies recovered in the North Atlantic area and 24 5 deg x 5 deg mean free air gravity anomalies in the Indian Ocean area with surface gravimetric measurements have shown agreement to + or - 8 mgals for both solutions. Geoids derived from the altimeter solutions are consistent with altimetric sea surface height data to within the precision of the data, about + or - 2 meters

Inclusion of unsteady aerodynamics in longitudinal parameter estimation from flight data

A simple vortex system, used to model unsteady aerodynamic effects into the rigid body longitudinal equations of motion of an aircraft, is described. The equations are used in the development of a parameter extraction algorithm. Use of the two parameter-estimation modes, one including and the other omitting unsteady aerodynamic modeling, is discussed as a means of estimating some acceleration derivatives. Computer generated data and flight data, used to demonstrate the use of the parameter-extraction algorithm are studied

Altered muscarinic and nicotinic receptor densities in cortical and subcortical brain regions in Parkinson's disease

Muscarinic and nicotinic cholinergic receptors and choline acetyltransferase activity were studied in postmortem brain tissue from patients with histopathologically confirmed Parkinson's disease and matched control subjects. Using washed membrane homogenates from the frontal cortex, hippocampus, caudate nucleus, and putamen, saturation analysis of specific receptor binding was performed for the total number of muscarinic receptors with [3H]quinuclidinyl benzilate, for muscarinic M1 receptors with [3H]pirenzepine, for muscarinic M2 receptors with [3H]oxotremorine-M, and for nicotinic receptors with (-)-[3H]nicotine. In comparison with control tissues, choline acetyl-transferase activity was reduced in the frontal cortex and hippocampus and unchanged in the caudate nucleus and putamen of parkinsonian patients. In Parkinson's disease the maximal binding site density for [3H]quinuclidinyl benzilate was increased in the frontal cortex and unaltered in the hippocampus, caudate nucleus, and putamen. Specific [3H]pirenzepine binding was increased in the frontal cortex, unaltered in the hippocampus, and decreased in the caudate nucleus and putamen. In parkinsonian patients Bmax values for specific [3H]oxotremorine-M binding were reduced in the cortex and unchanged in the hippocampus and striatum compared with controls. Maximal (-)-[3H]nicotine binding was reduced in both the cortex and hippocampus and unaltered in both the caudate nucleus and putamen. Alterations of the equilibrium dissociation constant were not observed for any ligand in any of the brain areas examined. The present results suggest that both the innominatocortical and the septohippocampal cholinergic systems degenerate in Parkinson's disease.(ABSTRACT TRUNCATED AT 250 WORDS

Temporal frequency of radio emissions for the April 25, 1984 flare

The National Geophysical Data Center archives data of the solar-terrestrial environment. The USAF Radio Solar Telescope Network (RSTN) data allow performance of time series analysis to determine temporal oscillations as low as three seconds. The X13/3B flare which erupted in region 4474 (S12E43) on the 24 to 25 of April 1984, was selected. The soft X-rays, 1 to 8 A, remained above X-levels for 50 minutes and the radio emissions measured at Learmonth Solar Observatory reached a maximum of 3.15 x 10 to the 5th power SFUs at 410 MHz at 0000UT. A power spectral analysis of the fixed frequency RSTN data from Learmonth shows possible quasi-periodic fluctuations in the range two to ten seconds. Repetition rates or quasi-periodicities, in the case of the power spectral analysis, generally showed the same trends as the average solar radio flux at 245 and 8800 MHz. The quasi-periodicities at 1415 MHz showed no such trends

A study of possible sea state information in the sample and hold gate statistics for the GEOS-3 satellite altimeter

The statistical variations in the sample gate outputs of the GEOS-3 satellite altimeter were studied for possible sea state information. After examination of a large number of statistical characteristics of the altimeter waveforms, it was found that the best sea predictor for H-1/3 in the range of 0 to 3 meters was the 75th percentile of sample and hold gate number 11