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Editors' Picks

        Genome engineering

        The bacterially derived CRISPR–Cas9 system has proven useful for genome editing in Drosophila, Caenorhabditis elegans, zebrafish, mouse, rat, and humans. Recently, Wu and colleagues successfully employed this system to correct a mutant gene in mice. In a mouse model of dominant cataract disorder caused by a defined mutation in the Crygc gene, the CRISPR–Cas9 system, which involves injection of the Cas9 mRNA and single-guide RNAs that target the mutant allele into zygotes, successfully and functionally corrected the heterozygous mutation via homologydirected repair. In several cases, however, nonhomologous end joining–based deletions or insertions were utilized in this process to functionally repair the gene. Importantly, only rare instances of off-target mutations were detected, and the pups were able to transmit the corrected allele to their progeny. Thus, the CRISPR–Cas9 system can be used to cure a genetic disease in mice, and these findings pave the way for exploration of use of this strategy for mutation correction in a human disease setting. (Cell Stem Cell 13:659–62, 2013) Selected by M. Amagai

        The dangers of light skin

        Low levels of melanin are correlated with the development of angiogenic ocular and skin diseases. Because intracellular pigment levels in retinal pigment epithelium cells are similar in all races, Adini and colleagues investigated the role of melanocytes in regulating angiogenesis in pigmented tissues in numerous wild-type and albino mouse models. These investigators found that melanocytes secrete fibromodulin, a previously unknown angiogenic factor that functions as a potent stimulator of endothelial cell growth, migration, sprouting, and capillary network formation. In addition, fibromodulin stimulated blood vessel formation and induced neovascularization in these mice. Mechanistically, fibromodulin was found to activate endothelial cells via transforming growth factor β-1, which ultimately initiates the SMAD pathway. These findings, which illuminate the mechanism of epidemiological correlation between fair skin and susceptibility to angiogenic disease, suggest that fibromodulin is a potential therapeutic target for treatment of pathological angiogenesis. (J Clin Invest 124:425–36, 2014) Selected by T. Schwarz

        UV promotes metastatic progression

        Although UV radiation is known to induce tumor-initiating genomic alterations in melanocytes, additional microenvironmental effects of UV radiation in melanoma pathogenesis are not well understood. Bald and colleagues recently demonstrated that repetitive UV exposure promoted metastatic progression in a mouse model in a manner that is independent of its tumor-initiating effects. Following repetitive irradiation of mice with established melanomas, the number of lung metastases, but not the incidence, multiplicity, or growth of the tumors, was increased. More specifically, UV irradiation promotes melanocyte perivascular expansion and metastatic dissemination via Toll-like receptor 4 (TLR4)/myeloid differentiation primary response gene 88 (MYD88)–driven neutrophilic inflammation, and this effect was directly initiated by high-mobility group box 1 (HMGB1) release from UV-damaged keratinocytes. These models offer new avenues for exploration of the mechanisms governing reciprocal melanoma–endothelial cell interactions and offer guidance for development of melanoma treatments that impair metastatic tumor progression via inhibition of neutrophilic inflammation driven by HMBG1 and/or the TLR4/MYDD88 signaling pathway. (Nature 507:109–13, 2014) Selected by T. Schwarz

        Ready, set, neutrophil

        Neutrophils are required for control and clearance of infection, including infection by the prevalent bacterial pathogen Staphylococcus aureus; however, the mechanisms of neutrophil homing from the bloodstream and subsequent interstitial migration after barrier breach are not well defined. Abtin and colleagues recently discovered that perivascular macrophages, which were previously not known to be involved in this process, produce chemoattractants that biochemically guide the neutrophils to the cutaneous interstitial space. Furthermore, these studies revealed that S. aureus directly hinders this neutrophil extravasation by destruction of the neutrophils via a pathway dependent on the primary pathogen- secreted cytotoxin α-hemolysin. Thus, S. aureus specifically targets these cells and diminishes the production of homing cytokines, extending the time before a successful immune response is mounted and allowing the bacteria time to proliferate. These findings indicate a critical role for nonendothelial blood vessel–associated cells in leukocyte extravasation and underscore the importance of the innate immune response in infection clearance. (Nat Immunol 15:45–;53, 2014) Selected by T. Schwarz

        Easy on the stomach

        No single etiology has been identified for the inflammatory bowel diseases (IBD) Crohn's disease and ulcerative colitis, but predisposing genetic and environmental factors have been implicated. Previous studies showed that antibiotics, nonsteroidal anti-inflammatory drugs, and hormone therapy are associated with an increased risk of IBD, and some cases of IBD following isotretinoin therapy have been reported. The vitamin A analog isotretinoin is widely prescribed to treat severe acne; therefore, whether such a risk is inherent in patients treated with isotretinoin is an important issue to address. In a large case–control study using the French National Health Insurance database of 7,593 cases of IBD and 30,372 controls, Racine and colleagues found no association between isotretinoin exposure and ulcerative colitis risk but identified an inverse association between isotretinoin exposure and Crohn's disease. These data support the safe use of isotretinoin for treatment of severe acne. (Am Gastroenterol 109:563–9, 2014) Selected by H. Williams