RNA-based translation activators for targeted gene upregulation.

Technologies capable of programmable translation activation offer strategies to develop therapeutics for diseases caused by insufficient gene expression. Here, we present "translation-activating RNAs" (taRNAs), a bifunctional RNA-based molecular technology that binds to a specific mRNA of interest and directly upregulates its translation. taRNAs are constructed from a variety of viral or mammalian RNA internal ribosome entry sites (IRESs) and upregulate translation for a suite of target mRNAs. We minimize the taRNA scaffold to 94 nucleotides, identify two translation initiation factor proteins responsible for taRNA activity, and validate the technology by amplifying SYNGAP1 expression, a haploinsufficiency disease target, in patient-derived cells. Finally, taRNAs are suitable for delivery as RNA molecules by lipid nanoparticles (LNPs) to cell lines, primary neurons, and mouse liver in vivo. taRNAs provide a general and compact nucleic acid-based technology to upregulate protein production from endogenous mRNAs, and may open up possibilities for therapeutic RNA research.

Ester modification at the 3' end of anti-microRNA oligonucleotides increases potency of microRNA inhibition.

MicroRNAs (miRNAs) are short noncoding RNAs that play a fundamental role in gene regulation. Deregulation of miRNA expression has a strong correlation with disease and antisense oligonucleotides that bind and inhibit miRNAs associated with disease have therapeutic potential. Current research on the chemical modification of anti-miRNA oligonucleotides (anti-miRs) is focused on alterations of the phosphodiester-ribose backbone to improve nuclease resistance and binding affinity to miRNA strands. Here we describe a structure-guided approach for modification of the 3'-end of anti-miRs by screening for modifications compatible with a nucleotide-binding pocket present on human Argonaute2 (hAgo2). We computationally screened a library of 190 triazole-modified nucleoside analogs for complementarity to the t1A-binding pocket of hAgo2. Seventeen top scoring triazoles were then incorporated into the 3' end of anti-miR21 and potency was evaluated for each in a cell-based assay for anti-miR activity. Four triazole-modified anti-miRs showed higher potency than anti-miR21 bearing a 3' adenosine. In particular, a triazole-modified nucleoside bearing an ester substituent imparted a nine-fold and five-fold increase in activity for both anti-miR21 and anti-miR122 at 300 and 5 nM, respectively. The ester group was shown to be critical as a similar carboxylic acid and amide were inactive. Furthermore, anti-miR 3' end modification with triazole-modified nucleoside analogs improved resistance to snake venom phosphodiesterase, a 3'-exonuclease. Thus, the modifications described here are good candidates for improvement of anti-miR activity.

The Path to U.S. Neurosurgical Residency for Foreign Medical Graduates: Trends from a Decade 2007-2017.

OBJECTIVE: The increasing competitiveness of the neurosurgical residency match has made it progressively difficult for foreign medical graduates (FMGs) to match in neurosurgery. We compared FMG to U.S. medical graduate (USMG) match rates in neurosurgery and identified factors associated with match outcomes for FMGs in neurosurgery. METHODS: Retrospective review of American Association of Neurological Surgeons membership data and Association of American Medical Colleges Charting the Outcomes match reports (2007-2017). RESULTS: Across 1857 neurosurgical residents (USMG: 91.1%, FMG: 8.9%), average FMG match rates were 24% (range, 15%-35%) versus 83% (range, 75%-94%; P < 0.001) for USMG. FMGs were more male (89.5% vs. 82.0%, P = 0.016), older (33.9 vs. 31.8 years, P = 0.008), and more likely to take research year(s) before matching (95.8% vs. 78.5%, P < 0.001). FMGs had greater publications (5 vs. 2, P < 0.001) and H-indices (3 vs. 1, P < 0.001). The number of matched USMGs increased by 3.3 annually, whereas that of matched FMGs remained unchanged (ß = 0.07). Compared with USMGs, FMGs were less likely to match to National Institutes of Health (NIH) Top 40 (32.7% vs. 47.5%, P < 0.001) and Doximity Top 20 (20.0% vs. 29.0%, P = 0.014) programs. FMGs with prior U.S. neurosurgery program affiliation were more likely to match at NIH and Doximity Top 20 programs (P < 0.05). For NIH programs, FMGs were older (35.3 vs. 32.0, P = 0.011), had higher H-indices (5 vs. 2, P < 0.001), publications (7 vs. 2, P < 0.001), and were more likely to take research year(s) (94.4% vs. 76.0%, P = 0.002) than USMGs. FMGs had similar patterns for matching into Doximity Top 20 programs. CONCLUSIONS: Although FMGs have lower match rates into U.S. neurosurgery residencies than USMGs, several demographic, professional, and academic factors could increase the chances of successful FMG neurosurgical match.