http://www.jci.org/just-published en-us 2012 The American Society for Clinical Investigation http://www.jci.org/icons/banner/rss_title.gif http://content.jci.org http://www.jci.org/articles/view/58832 lo). TIE2 expression was downregulated in angiogenic ECs, which abundantly expressed several integrins. ANG-2 bound to these integrins in TIE2^lo ECs, subsequently inducing, in a TIE2-independent manner, phosphorylation of the integrin adaptor protein FAK, resulting in RAC1 activation, migration, and sprouting angiogenesis. Correspondingly, in vivo ANG-2 blockade interfered with integrin signaling and inhibited FAK phosphorylation and sprouting angiogenesis of TIE2^lo ECs. These data establish a contextual model whereby differential TIE2 and integrin expression, binding, and activation control the role of ANG-2 in angiogenesis. The results of this study have immediate translational implications for the therapeutic exploitation of angiopoietin signaling. ]]> info:doi/10.1172/JCI58832 American Society for Clinical Investigation http://www.jci.org/articles/view/59735 + cells. In addition, the majority of GD2⁺ cells are also CD44^hiCD24^lo, the previously established CSC-associated cell surface phenotype. Gene expression analysis revealed that GD3 synthase (GD3S) is highly expressed in GD2⁺ as well as in CD44^hiCD24^lo cells and that interference with GD3S expression, either by shRNA or using a pharmacological inhibitor, reduced the CSC population and CSC-associated properties. GD3S knockdown completely abrogated tumor formation in vivo. Also, induction of epithelial-mesenchymal transition (EMT) in transformed human mammary epithelial cells (HMLER cells) dramatically increased GD2 as well as GD3S expression in these cells, suggesting a role of EMT in the origin of GD2⁺ breast CSCs. In summary, we identified GD2 as a new CSC-specific cell surface marker and GD3S as a potential therapeutic target for CSCs, with the possibility of improving survival and cure rates in patients with breast cancer. ]]> info:doi/10.1172/JCI59735 American Society for Clinical Investigation http://www.jci.org/articles/view/60006 Mkp1^–/– mice and found increased inflammatory gene induction in livers, increased circulating cytokines, cell death in intestinal epithelium, severe intestinal inflammation, hypothermia, and death. Mkp1^–/– mice had increased levels of phosphorylated JNK, which promotes apoptosis, in liver tissue. We further examined JNK-deficient mice for their response to TNF. Although Jnk1^–/– mice showed no change in sensitivity to TNF, Jnk2^–/– mice were significantly protected against TNF, identifying JNK2 as an essential player in inflammation induced by TNF. Furthermore, we found that loss of Jnk2 partially rescued the increased sensitivity of Mkp1^–/– and mutant GR mice to TNF. Our data show that GR dimerization inhibits JNK2 through MKP1 and protects from TNF-induced apoptosis and lethal inflammation. ]]> info:doi/10.1172/JCI60006 American Society for Clinical Investigation http://www.jci.org/articles/view/61019 Daf1^–/–) host BM and Daf1^–/– donor lymphocytes led to exacerbated GvHD outcome and resulted in splenic and organ-infiltrating T cell expansion. T cells deficient in C3a receptor (C3aR) and/or C5a receptor (C5aR) responded weakly in allogeneic hosts and exhibited limited ability to induce GvHD. Using a clinically relevant treatment strategy, we showed that pharmacological C5aR blockade reduced GvHD morbidity. Our data mechanistically link APC-derived complement to T cell–mediated GvHD and support complement inhibition as a therapeutic strategy for GvHD in humans. ]]> info:doi/10.1172/JCI61019 American Society for Clinical Investigation http://www.jci.org/articles/view/61319 Glo1) expression has previously been associated with anxiety in mice; however, its role in anxiety is controversial, and the underlying mechanism is unknown. Here, we demonstrate that GLO1 increases anxiety by reducing levels of methylglyoxal (MG), a GABA_A receptor agonist. Mice overexpressing Glo1 on a Tg bacterial artificial chromosome displayed increased anxiety-like behavior and reduced brain MG concentrations. Treatment with low doses of MG reduced anxiety-like behavior, while higher doses caused locomotor depression, ataxia, and hypothermia, which are characteristic effects of GABA_A receptor activation. Consistent with these data, we found that physiological concentrations of MG selectively activated GABA_A receptors in primary neurons. These data indicate that GLO1 increases anxiety by reducing levels of MG, thereby decreasing GABA_A receptor activation. More broadly, our findings potentially link metabolic state, neuronal inhibitory tone, and behavior. Finally, we demonstrated that pharmacological inhibition of GLO1 reduced anxiety, suggesting that GLO1 is a possible target for the treatment of anxiety disorders. ]]> info:doi/10.1172/JCI61319 American Society for Clinical Investigation http://www.jci.org/articles/view/61380 info:doi/10.1172/JCI61380 American Society for Clinical Investigation http://www.jci.org/articles/view/62644 Fgfr2^+/Y394C mice exhibited epidermal hyperplasia and premature closure of cranial sutures (craniosynostosis) due to abnormal cell proliferation and differentiation. We found ligand-independent phosphorylation of FGFR2 and activation of p38 signaling in mutant skin and calvarial tissues. Treating Fgfr2^+/Y394C mice with a p38 kinase inhibitor attenuated skin abnormalities by reversing cell proliferation and differentiation to near normal levels. This study reveals the pleiotropic effects of the FGFR2 Y394C mutation evidenced by cutis gyrata, acanthosis nigricans, and craniosynostosis and provides a useful model for investigating the molecular mechanisms of skin and skull development. The demonstration of a pathogenic role for p38 activation may lead to the development of therapeutic strategies for BSS and related conditions, such as acanthosis nigricans or craniosynostosis. ]]> info:doi/10.1172/JCI62644 American Society for Clinical Investigation