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Chemistry	50%

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Gentamicin-induced readthrough of stop codons in duchenne muscular dystrophy

ANNALS OF NEUROLOGY, Issue 6 2010
Vinod Malik PhD
Objective The objective of this study was to establish the feasibility of long-term gentamicin dosing to achieve stop codon readthrough and produce full-length dystrophin. Mutation suppression of stop codons, successfully achieved in the mdx mouse using gentamicin, represents an important evolving treatment strategy in Duchenne muscular dystrophy (DMD). Methods Two DMD cohorts received 14-day gentamicin (7.5mg/kg/day): Cohort 1 (n = 10) stop codon patients and Cohort 2 (n = 8) frameshift controls. Two additional stop codon DMD cohorts were gentamicin treated (7.5mg/kg) for 6 months: Cohort 3 (n = 12) dosed weekly and Cohort 4 (n = 4) dosed twice weekly. Pre- and post-treatment biopsies were assessed for dystrophin levels, as were clinical outcomes. Results In the 14-day study, serum creatine kinase (CK) dropped by 50%, which was not seen in frameshift DMD controls. After 6 months of gentamicin, dystrophin levels significantly increased (p = 0.027); the highest levels reached 13 to 15% of normal (1 in Cohort 3, and 2 in Cohort 4), accompanied by reduced serum CK favoring drug-induced readthrough of stop codons. This was supported by stabilization of strength and a slight increase in forced vital capacity. Pretreatment stable transcripts predicted an increase of dystrophin after gentamicin. Readthrough efficiency was not affected by the stop codon or its surrounding fourth nucleotide. In 1 subject, antigen-specific interferon-, enzyme-linked immunospot assay detected an immunogenic dystrophin epitope. Interpretation The results support efforts to achieve drug-induced mutation suppression of stop codons. The immunogenic epitope resulting from readthrough emphasizes the importance of monitoring T-cell immunity during clinical studies that suppress stop codons. Similar principles apply to other molecular strategies, including exon skipping and gene therapy. ANN NEUROL 2010;67:771,780 [source]

Phase and amplitude recovery and diffraction image generation method: structure of Sb/Au(110),,3,×,,3R54.7° from surface X-ray diffraction

ACTA CRYSTALLOGRAPHICA SECTION A, Issue 3 2007
R. Fung
The discovery that the phase problem of diffraction from non-periodic objects may be solved by oversampling the diffraction intensities in reciprocal space with respect to a Nyquist criterion has opened up new vistas for structure determination by diffraction methods. A similar principle may be applied to the problem of surface X-ray diffraction (SXRD), where, owing to the breaking of a crystal periodicity normal to its surface, diffraction data consist of a set of superstructure rods (SRs) due to scattering from the parts of the surface whose structure is different from that of the truncated bulk and of crystal truncation rods (CTRs), formed by interfering contributions from the surface and the bulk. A phase and amplitude recovery and diffraction image generation method (PARADIGM) is described that provides a prescription for finding the unmeasured amplitudes and phases of the surface contributions to the CTRs in addition to the phases of the SRs, directly from the diffraction data. The resulting `diffraction image' is the basis of a determination of the previously unknown multidomain structure of Sb/Au(110),,3,×,,3R54.7°. [source]

Vices and Virtues in Capacity Development by International NGOs

IDS BULLETIN, Issue 3 2010
Rick James
We know what works in capacity development: a succession of studies from official agencies, academics and NGO practitioners have all highlighted similar principles of good practice. But the evidence also suggests that there is a distressing dissonance between what international development agencies know about capacity development and what they implement. This article explores the reasons for this failure. It highlights constraints that arise from the changing aid context and from a lack of resources and skills. Ultimately, however, it concludes that capacity development is driven more by self-interest than by knowledge of what works. Until agencies' pride, greed and self-interest can be restrained, much capacity development will continue to be disappointing and ineffective. But if agencies combine existing professional knowledge with virtues of humility, patience and a genuine commitment to others, then capacity development becomes something that can bring transformation. [source]

Prediction of protein supply to ruminants from concentrates: comparison of the NRC-2001 model with the DVE/OEB system

JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE, Issue 4 2005
Peiqiang Yu
Abstract The objective of this study was to compare the DVE/OEB system (DVE = truly absorbed protein in the small intestine; OEB = degraded protein balance) and the NRC-2001 model in the prediction of supply of protein to dairy cows from 46 selected concentrates: malting-type barley (cv Harrington), feed-type barley (cv Valier), field tick beans (Vicia faba), white albus lupins (Lupinus albus), whole soybeans and horse beans (Vicia faba cv Alfred). The two barleys were processed by coarse (roller miller, 0.533 mm gap) and fine (hammer mill, 2 mm screen) processing. The field tick beans and white albus lupins were dry roasted at various conditions at the University of Melbourne. The soybeans and horse beans were pressure-toasted at 100, 118 and 136 °C for 3, 7, 15 and 30 min at Wageningen Feed Processing Centre. Comparisons were made in terms of (1) ruminally synthesized microbial protein, (2) truly absorbed protein in the small intestine and (3) degraded protein balance, based on 46 samples. The results showed that the predicted values from the DVE/OEB system and the NRC-2001 model had significant correlations. However, using the DVE/OEB system, the overall average microbial protein supply based on available energy was 10% lower and the truly absorbed protein in the small intestine was 8% lower than that predicted by the NRC-2001 model. A difference was also found in the prediction of the degraded protein balances, which was 16% higher than that estimated from the NRC-2001 model. These differences are due to factors used in calculations in the two models, although both are based on similar principles. This indicates that further refinement is needed for a modern protein evaluation and prediction system. Copyright © 2004 Society of Chemical Industry [source]