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Building a strong foundation
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A major impediment in the treatment of neurological diseases is the presence of the blood-brain barrier, which precludes the entry of therapeutic molecules from blood to brain. Here we show that a short peptide derived from rabies virus glycoprotein (RVG) enables the transvascular delivery of small interfering RNA (siRNA) to the brain. This 29-amino-acid peptide specifically binds to the acetylcholine receptor expressed by neuronal cells. To enable siRNA binding, a chimaeric peptide was synthesized by adding nonamer arginine residues at the carboxy terminus of RVG. This RVG-9R peptide was able to bind and transduce siRNA to neuronal cells in vitro, resulting in efficient gene silencing. After intravenous injection into mice, RVG-9R delivered siRNA to the neuronal cells, resulting in specific gene silencing within the brain. Furthermore, intravenous treatment with RVG-9R-bound antiviral siRNA afforded robust protection against fatal viral encephalitis in mice. Repeated administration of RVG-9R-bound siRNA did not induce inflammatory cytokines or anti-peptide antibodies. Thus, RVG-9R provides a safe and noninvasive approach for the delivery of siRNA and potentially other therapeutic molecules across the blood-brain barrier.
The impact factor is based on citations of papers published by a scientific journal. It has been published since 1961 by the Institute for Scientific Information. It may be regarded as an estimate of the citation rate of a journal's papers, and the higher its value, the higher the scientific esteem of the journal. Although the impact factor was originally meant for comparison of journals, it is also used for assessment of the quality of individual papers, scientists and departments. For the latter a scientific basis is lacking, as we will demonstrate in this contribution.
Citation of the various papers published in one and the same journal is highly skewed. Journals with a high impact factor obtain this high value by frequent citation of only a limited number of their papers and, on the other hand, journals with low impact factors publish many papers that remain uncited [1]. Thus, mere publication of a paper in a given journal cannot be regarded as a quality marker of that particular paper [2], it just means that the authors have ‘succeeded in surviving’ the review process of that journal. Seglen [3] has analyzed that 50% of the obtained citations are accumulated by only 15% of the contents of a journal. In addition, the most frequently cited 50% of the contents obtain almost all citations (90%). These numbers were based on an analysis of three biochemical journals ( Biochimica Biophysica Acta , Biochemical Journal and Journal of Biochemical Chemistry ) and have later been confirmed for two cardiovascular journals ( Circulation Research and Cardiovascular Research ) [4]. Both analyses applied to recently published papers [3,4]. It is not known whether these data vary over time and whether or not they depend on impact itself.
We have analyzed the original research papers of Cardiovascular Research published between 1992 and 2000 ( n = 1886). We have taken advantage from the fact that the impact factor of Cardiovascular Research increased from 1.47 in 1991 to 4.69 in 2002. This allowed us to relate the skewness of citations both to the time since publication and to impact. Thus, for year 1 (the calendar year of publication itself), we had nine sets of data (contents of 1992 as cited in 1992 through contents of 2000 as cited in 2000). For year 2 (the calendar year following the year of publication), we also had nine …
*Corresponding author. Tel.: +31-30-2538900; fax: +31-30-2539036. t.opthof{at}med.uu.nl