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<jats:title>RGM Proteins</jats:title> <jats:p> Members of the repulsive guidance molecule (RGM) family of proteins can be secreted or reside on the surface of cells where they bind to the cell surface receptor, neogenin. The RGM proteins are named for their role in axon guidance for developing neurons, but their function is also linked to a range of human diseases, including inflammation, multiple sclerosis, and cancer. <jats:bold> Bell <jats:italic>et al.</jats:italic> </jats:bold> (p. <jats:related-article xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" issue="6141" page="77" related-article-type="in-this-issue" vol="341" xlink:href="10.1126/science.1232322">77</jats:related-article> ) solved the crystal structures of the external portions of the RGMB protein with portions of neogenin. The structures revealed interactions of dimers of RGMB with neogenin in which ligand binding induced conformational changes that may initiate intracellular signaling from the receptor. RGM proteins contain a site of autocatalytic cleavage that affects secretion of the proteins, and some disease-associated mutations in RGM proteins were clustered at this site. </jats:p>

<jats:title>Spliceosome Helicase</jats:title> <jats:p> Introns are removed from eukaryotic premessenger RNA by the spliceosome. The spliceosome is assembled and disassembled during the course of each splicing reaction, and the RNA-protein remodeling involved is carried out by RNA helicases, whose activities must be closely regulated. <jats:bold> Mozaffari-Jovin <jats:italic>et al.</jats:italic> </jats:bold> (p. <jats:related-article xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" issue="6141" page="80" related-article-type="in-this-issue" vol="341" xlink:href="10.1126/science.1237515">80</jats:related-article> , published online 23 May) determined the crystal structure of the human Brr helicase in complex with the Jab1 domain of the Prp1 spliceosomal protein. The C-terminal tail of the Prp8 Jab1 domain inserts into the RNA-binding tunnel of Brr2, disrupting interaction of the RNA with the conserved helicase motifs inside tunnel. The temporal regulation of Brr2 RNA-binding and adenosine triphosphatase activity likely avoids premature disassembly of structures required during the splicing reaction. </jats:p>

<jats:title>Drug Targeting</jats:title> <jats:p> Drug efficacy depends on the extent of binding to a cellular target (often a protein) with adverse effects caused by excessive target binding or by off-target binding. Engagement of a target protein inside cells is influenced by the effective drug concentration and by factors that regulate the protein conformation, making it difficult to predict efficacy based on in vitro affinity studies. <jats:bold> Martinez Molina <jats:italic>et al.</jats:italic> </jats:bold> (p. <jats:related-article xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" issue="6141" page="84" related-article-type="in-this-issue" vol="341" xlink:href="10.1126/science.1233606">84</jats:related-article> ) took advantage of the shift in protein thermal stability caused by drug binding to directly monitor target protein-drug interactions in cells. The method was used to monitor drug target engagement in cancer cells and in mouse livers and kidneys. </jats:p>

<jats:title>Immunotherapy Packs a One-Two Punch</jats:title> <jats:p> Despite the immune system's best efforts, cancer always seems to be one step ahead. One example of this is that tumor cells express CD47 on their cell surface. CD47 acts as a “don't eat me” signal to phagocytic macrophages. A potential therapeutic strategy could thus be to block this signal. <jats:bold> Weiskopf <jats:italic>et al.</jats:italic> </jats:bold> (p. <jats:related-article xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" issue="6141" page="88" related-article-type="in-this-issue" vol="341" xlink:href="10.1126/science.1238856">88</jats:related-article> , published online 30 May; see the Perspective by <jats:related-article xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" issue="6141" page="41" related-article-type="in-this-issue" vol="341" xlink:href="10.1126/science.1241716"> <jats:bold>Kershaw and Smyth</jats:bold> </jats:related-article> ) created variants of the CD47 receptor, SIRPα, that could act as high-affinity antagonists of CD47. Although the antagonists blocked CD47 effectively in tumor-bearing mice, on their own they did not induce macrophages to phagocytose the tumor cells. When paired with a variety of therapeutic antitumor antibodies, however, the CD47 antagonists were very effective in treating several mouse tumor models. </jats:p>

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<jats:title>Cancer Hits a Nerve</jats:title> <jats:p> Solid tumors sculpt their microenvironment to maximize their growth and metastatic potential. This concept is illustrated most famously by tumor angiogenesis, a process whereby tumors induce the growth of new blood vessels to boost their supply of oxygen and blood-borne nutrients. <jats:bold> Magnon <jats:italic>et al.</jats:italic> </jats:bold> (p. <jats:related-article xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" related-article-type="in-this-issue" xlink:href="10.1126/science.1236361">10.1126/science.1236361</jats:related-article> ; see the Perspective by <jats:bold> <jats:related-article xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" issue="6142" page="134" related-article-type="in-this-issue" vol="341" xlink:href="10.1126/science.1241776">Isaacs</jats:related-article> </jats:bold> ) now highlight the important contribution made by another microenvironmental component—developing autonomic nerve fibers—to tumor growth and metastasis. In mouse models of prostate cancer, surgical or chemical destruction of sympathetic nerves prevented early-stage growth of tumors, whereas pharmacological inhibition of parasympathetic nerves inhibited tumor dissemination. In a small study of human prostate cancer specimens, the presence of a high density of nerve fibers in and around the tumor tissue was found to correlate with poor clinical outcome. These results raise the possibility that drugs targeting the autonomic nervous system may have therapeutic potential for prostate cancer. </jats:p>

<jats:title>Movers and Shakers</jats:title> <jats:p> We tend to view earthquakes as unpredictable phenomena caused by naturally shifting stresses in Earth's crust. In reality, however, a range of human activity can also induce earthquakes. <jats:bold>Ellsworth</jats:bold> (p. <jats:related-article xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" related-article-type="in-this-issue" xlink:href="10.1126/science.1225942">10.1126/science.1225942</jats:related-article> ) reviews the current understanding of the causes and mechanics of earthquakes caused by human activity and the means to decrease their associated risk. Notable examples include injection of wastewater into deep formations and emerging technologies related to oil and gas recovery, including hydraulic fracturing. In addition to directly causing increased local seismic activity, activities such as deep fluid injection may have other ramifications related to earthquake occurrence. <jats:bold> Van der Elst <jats:italic>et al.</jats:italic> </jats:bold> (p. <jats:related-article xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" issue="6142" page="164" related-article-type="in-this-issue" vol="341" xlink:href="10.1126/science.1238948">164</jats:related-article> ; see the news story by <jats:bold> <jats:related-article xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" issue="6142" page="126" related-article-type="in-this-issue" vol="341" xlink:href="10.1126/science.2013.341.6142.341_126">Kerr</jats:related-article> </jats:bold> ) demonstrate that in the midwestern United States, some areas with increased human-induced seismicity are also more prone to further earthquakes triggered by the seismic waves from large, remote earthquakes. Improved seismic monitoring and injection data near deep disposal sites will help to identify regions prone to remote triggering and, more broadly, suggest times when activities should, at least temporarily, be put on hold. </jats:p>