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TITLE: Aberrant nuclear localization of EBP50 promotes colorectalcarcinogenesis in xenotransplanted mice by modulating TCF-1 and -catenin interactions View this article at: articles/view/45661?key=1acc81fc56e1cb0c96bb Also in this issue IMMUNOLOGY Critical Function of MyD88 in Immune Tolerance Breakdown in MurineFoxp3 Deficiency The breakdown of peripheral tolerance upon Regulatory T (TR) celldeficiency due to mutations in Foxp3 precipitates a multi-systemautoimmune inflammatory disease. The role of the microbial signalsin disease pathogenesis was examined in Foxp3 mutant mice that hadconcurrent deficiencies in Toll-like receptor (TLR) pathways.Deficiency of the common TLR adaptor MyD88, but not more restricteddefects, dissociated the disease into a MyD88-dependent componentat the environmental boundaries in the skin, lungs and gut, and aMyD88-independent systemic lymphoproliferation. This effectinvolved the disruption of chemokine gradients that recruit Teffector and dendritic cells to target interface tissues. Thus akey role of TR cells is to maintain tolerance at host-microbialinterfaces by restraining tonic MyD88-dependent pro-inflammatorysignals. TITLE: MyD88 is critically involved in immune tolerance breakdownat environmental interfaces of Foxp3-deficient mice View this article at: articles/view/40591?key=047b407fa466953ed373 IMMUNOLOGY Mechanism of lipopolysaccharide-induced skin edema formation in themouse Prostaglandin E2 (PGE2) regulates many proinflammatory processes,including swelling and pain. Here we show that tissue residentdendritic cells (DCs) are the main source of PGE2 and the maincontrollers of tissue edema formation in a model of lipopolysaccharide (LPS)-inducedinflammation. Mechanistically, PGE2 production by DCs following LPSexposure is controlled by CD14/NFAT pathway, which regulates theexpression of the microsomal PGE synthase-1 (mPGES-1), a key enzymein the PGE2 biosynthesis. Therefore, tissue edema formation inducedby LPS is DCs- and CD14/NFAT-dependent. Moreover, by controllingthe transudate formation in the presence of LPS, DCs can regulatefree antigen arrival to draining lymph nodes. TITLE: CD14 and NFAT mediate lipopolysaccharide-induced skin edemaformation in mice View this article at: articles/view/60688?key=690bae7dd09d029af162 GASTROENTEROLOGY Anti-ceramide Antibody Prevents The Radiation GI Syndrome in Mice The Radiation Gastrointestinal (GI) Syndrome is a major lethaltoxicity that might occur after a radiation/nuclear incident. Thereare no prophylactic countermeasures against Radiation GI Syndromelethality for first responders, military personnel or remediationworkers entering a contaminated area. Pathophysiology of thissyndrome requires depletion of stem cell clonogens (SCCs) within the Crypts of Lieberk hn, necessary forpost-injury regeneration of gut epithelium. Recent evidenceindicates SCC reproductive death is not exclusively a result of DNAdamage, but is critically coupled to ceramide-induced endothelialcell apoptosis within the mucosal microvascular network. Here weshow that ceramide generated on the surface of endotheliumcoalesces to form ceramide-rich platforms that transmit anapoptotic signal. We report generation of 2A2 anti-ceramidemonoclonal Ab, a countermeasure that binds ceramide to preventplatform formation on the surface of irradiated endothelial cellsof the murine GI tract. Consequently, 2A2 protects againstendothelial apoptosis in the small intestinal lamina propria andfacilitates recovery of crypt SCCs, preventing death of mice fromthe GI Syndrome at high radiation doses, up to 17 Gy. As such, 2A2represents a prototype of a new class of anti-ceramide therapeuticsand an effective countermeasure against Radiation GI Syndromemortality. TITLE: Anti-ceramide Antibody Prevents The Radiation GI Syndrome inMice View this article at: articles/view/59920?key=1372fbfe9f90f79d09c5 DERMATOLOGY Revertant mosaicism in a human skin fragility disorder results fromslipped mispairing and mitotic recombination Spontaneous gene repair, also called revertant mosaicism, has beendocumented in several genetic disorders involving organs thatundergo self-regeneration, including the skin. Genetic reversionmay occur through different mechanisms, and in one individual themutation can be repaired in various ways. Here we describe adisseminated pattern of revertant mosaicism observed in sixpatients with Kindler syndrome (KS), a genodermatosis caused byloss of kindlin-1 and clinically characterized by patchy skinpigmentation and atrophy. All patients presented duplicationmutations (c.456dupA and c.676dupC) in the FERMT1 gene encodingkindlin-1, and slipped mispairing in direct nucleotide repeats wasidentified as the reversion mechanism in all investigated revertantskin spots. The sequence around the mutations demonstrated highpropensity to mutations, favoring both microinsertions and -deletions. Additionally, in some revertant patches mitoticrecombination generated areas with homozygous normal keratinocytes.Restoration of kindlin-1 expression led to clinically andstructurally normal skin. Since loss of kindlin-1 severely impairskeratinocyte proliferation, we predict that revertant cells have aselective advantage that allows their clonal expansion and,consequently, the improvement of the skin condition. TITLE: Revertant mosaicism in a human skin fragility disorderresults from slipped mispairing and mitotic recombination View this article at: articles/view/61976?key=3b0f274fc1938461dd73 HEPATOLOGY Hepatocyte-specific mutation of both NF- B RelA and STAT3abrogates the acute phase response in mice The acute phase response is an evolutionarily conserved reaction inwhich physiological stress triggers the liver to remodel the bloodproteome. It is stimulated by diverse cytokines that activateeither NF- B or STAT3, leading us to hypothesize that the acutephase response could be eliminated by interrupting bothtranscription factors selectively in hepatocytes. The combinedmutation of NF- B p65 (RelA) and STAT3 together, but neitheralone, abrogated all acute phase responses measured. This failureto respond was consistent across multiple different infectious,inflammatory, and noxious stimuli. Pneumococcal pneumonia altered the expression of 1100 transcripts in the liver, andthis outcome was 96% inhibited by the combined mutation of RelAand STAT3. This interruption of liver responses increased mortalityand exacerbated bacterial dissemination during pneumonia, possiblydue to an acute humoral enhancement of opsonophagocytosis that wasimpaired in hepatocyte-mutant mice. Thus, a critical role of theacute phase response is to compartmentalize local infection. Weconclude that RelA and STAT3 are essential for stress-inducedtranscriptional remodeling in the liver, and theirhepatocyte-specific mutation reveals functional roles of the acutephase response. TITLE: Hepatocyte-specific mutation of both NF- BRelA and STAT3 abrogates the acute phase response in mice View this article at: articles/view/59408?key=d1f1b014af15f850b079 Additional References Citations. 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