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This Week in PNAS: Aug 7, 2018

In the early, online version of the Proceedings of the National Academy of Sciences, a Massachusetts General Hospital- and Massachusetts Institute of Technology-led team describes a strategy for targeting recurrent mutations in the isocitrate dehydrogenase enzyme-coding genes IDH1 and IDH2 in lower-grade glioma central nervous system tumors. The researchers' precision intraoperative treatment approach — designed to apply IDH-mutant targeting metabolic drugs while avoiding more widespread systemic toxicity — relies on rapid multiplex genotyping diagnostic assay to find IDH1/2 mutations and a sustained release microparticle system to deliver metabolic drugs such as the nicotinamide phosphoribosyltransferase inhibitor GMX-1778 in a localized manner. Along with experiments to verify their IDH-mutant diagnostic approach, the authors showed that GMX-1778 is active against gliomas in vitro and in mouse disease models.

Endogenous retroviruses (ERVs) such as the koala retrovirus (KoRV) that attempt to infiltrate the koala genome appear to be inactivated with the help of ancient retroelements that recombine with them, according to researchers from Germany, Australia, and elsewhere. The researchers used long-read sequencing and available koala sequences to find structural variants in KoRV proviruses, detect recombinant KoRVs (recKoRVs) formed by interacting with an old koala retroelement, and characterize their positions in the koala host genome. "At least 15 additional different recombination events between KoRV and the older endogenous retroelement generated distinct recKoRVs with different geographic distributions," the authors report. "All of the identified recombinant viruses appear to have arisen independently and have highly disrupted [open reading frames], which suggests that recombination with existing degraded endogenous retroelements may be a means by which replication-competent ERVs that enter the germline are degraded." 

A team from China reports on results from a study that involved replacing a Bombyx mori silkworm gene with a gene from the spider species Nephila clavipes to prompt high levels of spider silk production by the silkworm. Rather than pursuing a transposon-based approach to engineer spider silk-producing silkworms, the researchers relied on transcription activator-like effector nuclease-mediated homology-directed repair to insert the spider gene MaSp1 in place of a silkworm FibH gene, altering silk fibers produced by the silkworm to give them more spider-like mechanical features.  "Our study provides a native promoter-driven, highly efficient system for expressing the heterologous spider silk gene instead of the transposon-based, random insertion of the spider gene into the silkworm genome," they write, noting that the method "provides a paradigm for the large-scale production of spider silk protein with genetically modified silkworms."