Receptor-interacting protein kinase 4 and interferon regulatory factor 6 function as a signaling axis to regulate keratinocyte differentiation

Receptor-interacting protein kinase 4 (RIPK4) and interferon regulatory factor 6 (IRF6) are critical regulators of keratinocyte differentiation, and their mutation causes the related developmental epidermal disorders Bartsocas-Papas syndrome and popliteal pterygium syndrome, respectively. However, the signaling pathways in which RIPK4 and IRF6 operate to regulate keratinocyte differentiation are poorly defined. Here we identify and mechanistically define a direct functional relationship between RIPK4 and IRF6. Gene promoter reporter and in vitro kinase assays, coimmunoprecipitation experiments, and confocal microscopy demonstrated that RIPK4 directly regulates IRF6 trans-activator activity and nuclear translocation. Gene knockdown and overexpression studies indicated that the RIPK4-IRF6 signaling axis controls the expression of key transcriptional regulators of keratinocyte differentiation, including Grainyhead-like 3 and OVO-like 1. Additionally, we demonstrate that the p.Ile121Asn missense mutation in RIPK4, which has been identified recently in Bartsocas-Papas syndrome, inhibits its kinase activity, thereby preventing RIPK4-mediated IRF6 activation and nuclear translocation. We show, through mutagenesis-based experiments, that Ser-413 and Ser-424 in IRF6 are important for its activation by RIPK4. RIPK4 is also important for the regulation of IRF6 expression by the protein kinase C pathway. Therefore, our findings not only provide important mechanistic insights into the regulation of keratinocyte differentiation by RIPK4 and IRF6, but they also suggest one mechanism by which mutations in RIPK4 may cause epidermal disorders (e.g. Bartsocas-Papas syndrome), namely by the impaired activation of IRF6 by RIPK4

Interferon regulatory factor 6 differentially regulates toll-like receptor 2-dependent chemokine gene expression in epithelial cells

Epidermal and mucosal epithelial cells are integral to host defense. They not only act as a physical barrier but also utilize pattern recognition receptors, such as the Toll-like receptors (TLRs), to detect and respond to pathogens. Members of the interferon regulatory factor (IRF) family of transcription factors are key components of TLR signaling as they impart specificity to downstream responses. Although IRF6 is a critical regulator of epithelial cell proliferation and differentiation, its role in TLR signaling has not previously been addressed. We show here that IRF6 is activated by IRAK1 as well as by MyD88 but not by TRIF or TBK1. Co-immunoprecipitation experiments further demonstrated that IRF6 can interact with IRAK1. Gene silencing in epithelial cells along with gene promoter reporter assays showed that IRAK1 mediates TLR2-inducible CCL5 gene expression at least in part by promoting IRF6 activation. Conversely, IRAK1 regulated CXCL8 gene expression independently of IRF6, thus identifying a molecular mechanism by which TLR2 signaling differentially regulates the expression of specific chemokines in epithelial cells. Bioinformatics analysis and mutagenesis-based experiments identified Ser-413 and Ser-424 as key regulatory sites in IRF6. Phosphomimetic mutation of these residues resulted in greatly enhanced IRF6 dimerization and trans-activator function. Collectively, our findings suggest that, in addition to its importance for epithelial barrier function, IRF6 also contributes to host defense by providing specificity to the regulation of inflammatory chemokine expression by TLR2 in epithelial cells

Graphic Interlude

This graphic interlude features a selection of pictures which can illustrate the topic of this issue: “Are you Game?”.Cet interlude iconographique comporte une sélection d’images illustrant à leur manière le thème de ce numéro: « Êtes-vous prêt(e) à jouer ? »

Dating the detachment fault system of the Ruby Mountains, Nevada: Significance for the kinematics of low‐angle normal faults

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94601/1/tect2138.pd

Does “Asymptomatic” Mean Without Symptoms for Those Living with HIV Infection?

Throughout the history of the HIV epidemic, HIV-positive patients with relatively high CD4 counts and no clinical features of opportunistic infections have been classified as ‘‘asymptomatic’’ by definition and treatment guidelines. This classification, however, does not take into consideration the array of symptoms that an HIV-positive person can experience long before progressing to AIDS. This short report describes two international multi-site studies conducted in 2003 - 2005 and 2005 - 2007. The results from the studies show that HIV-positive people may experience symptoms throughout the trajectory of their disease, regardless of CD4 count or classification. Providers should discuss symptoms and symptom management with their clients at all stages of the disease

Timing of detachment faulting in the Bullfrog Hills and Bare Mountain area, southwest Nevada: Inferences from 40Ar/39Ar, K-Ar, U-Pb and fission track thermochronology

Crustal extension in the Bullfrog Hills and Bare Mountain area of southwest Nevada is associated with movement along a regional detachment fault. Normal faulting in the upper plate and rapid cooling (denudation) of the lower plate were coeval with Miocene silicic volcanism and with west-northwest transport along the detachment fault. A west-northwest progression of tilting along upper plate normal faults is indicated by ages of the volcanic rocks in relation to angular unconformities. Near the breakaway, tilting in the upper plate occurred between 12.7 and 11.6 Ma, continued less strongly past 10.7 Ma, and was over by 8.2 Ma. Ten to 20 km west of the breakaway, tilting occurred between 10.7 and 10.33 Ma, continued less strongly after 10.33 Ma, and was over by 8.1 Ma. The cooling histories of the lower plate metamorphic rocks were determined by thermochronologic dating methods: K-Ar and Ar-40/(39)A on muscovite, biotite, and hornblende, Ar-40/(39)A on K-feldspar, U-Pb on apatite, zircon, and sphene, and fission track on apatite, zircon, and sphene. Lower plate rocks 10 km west of the breakaway cooled slowly from Early Cretaceous lower-amphibolite facies conditions through 350+/-50 degrees to 300+/-50 degrees C between 57 and 38 Ma, then cooled rapidly from 205+/-50 degrees to 120+/-5O degrees C between 12.6+/-1.6 and 11.1+/-1.9 Ma. Lower plate rocks 20 km west of the breakaway cooled slowly from Early Cretaceous upper-amphibolite facies conditions through 500+/-50 degrees C at 78-67 Ma, passed through 350+/-50 degrees to 300+/-50 degrees C between 16.3+/-0.4 and 10.5+/-0.3 Ma, then cooled rapidly from 285+/-50 degrees to 120+/-50 degrees C between 10.2 and 8.6 Ma. Upper plate tilting and rapid cooling (denudation) of the lower plate occurred simultaneously in the respective areas. The early slow-cooling part of the lower plate thermal histories was probably related to erosion at the Earth's surface, which stripped off about 9 km of material in 50 to 100 m.y. The results indicate an initial fault dip greater than or equal to 30 degrees and a 12 mm yr(-1) west-northwest migration of the locus of rapid tilting in the upper plate

Measurements of elliptic and triangular flow in high-multiplicity 3^{3}He++Au collisions at sNN=200\sqrt{s_{_{NN}}}=200 GeV

We present the first measurement of elliptic ($v_2$) and triangular ($v_3$) flow in high-multiplicity $^{3}$He$+$Au collisions at $\sqrt{s_{_{NN}}}=200$ GeV. Two-particle correlations, where the particles have a large separation in pseudorapidity, are compared in $^{3}$He$+$Au and in $p$$+$$p$ collisions and indicate that collective effects dominate the second and third Fourier components for the correlations observed in the $^{3}$He$+$Au system. The collective behavior is quantified in terms of elliptic $v_2$ and triangular $v_3$ anisotropy coefficients measured with respect to their corresponding event planes. The $v_2$ values are comparable to those previously measured in $d$$+$Au collisions at the same nucleon-nucleon center-of-mass energy. Comparison with various theoretical predictions are made, including to models where the hot spots created by the impact of the three $^{3}$He nucleons on the Au nucleus expand hydrodynamically to generate the triangular flow. The agreement of these models with data may indicate the formation of low-viscosity quark-gluon plasma even in these small collision systems.Comment: 630 authors, 9 pages, 4 figures, 2 tables. v2 is the version accepted for publication by Physical Review Letters. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (or will be) publicly available at http://www.phenix.bnl.gov/papers.htm

Characterization of Granulations of Calcium and Apatite in Serum as Pleomorphic Mineralo-Protein Complexes and as Precursors of Putative Nanobacteria

Calcium and apatite granulations are demonstrated here to form in both human and fetal bovine serum in response to the simple addition of either calcium or phosphate, or a combination of both. These granulations are shown to represent precipitating complexes of protein and hydroxyapatite (HAP) that display marked pleomorphism, appearing as round, laminated particles, spindles, and films. These same complexes can be found in normal untreated serum, albeit at much lower amounts, and appear to result from the progressive binding of serum proteins with apatite until reaching saturation, upon which the mineralo-protein complexes precipitate. Chemically and morphologically, these complexes are virtually identical to the so-called nanobacteria (NB) implicated in numerous diseases and considered unusual for their small size, pleomorphism, and the presence of HAP. Like NB, serum granulations can seed particles upon transfer to serum-free medium, and their main protein constituents include albumin, complement components 3 and 4A, fetuin-A, and apolipoproteins A1 and B100, as well as other calcium and apatite binding proteins found in the serum. However, these serum mineralo-protein complexes are formed from the direct chemical binding of inorganic and organic phases, bypassing the need for any biological processes, including the long cultivation in cell culture conditions deemed necessary for the demonstration of NB. Thus, these serum granulations may result from physiologically inherent processes that become amplified with calcium phosphate loading or when subjected to culturing in medium. They may be viewed as simple mineralo-protein complexes formed from the deployment of calcification-inhibitory pathways used by the body to cope with excess calcium phosphate so as to prevent unwarranted calcification. Rather than representing novel pathophysiological mechanisms or exotic lifeforms, these results indicate that the entities described earlier as NB most likely originate from calcium and apatite binding factors in the serum, presumably calcification inhibitors, that upon saturation, form seeds for HAP deposition and growth. These calcium granulations are similar to those found in organisms throughout nature and may represent the products of more general calcium regulation pathways involved in the control of calcium storage, retrieval, tissue deposition, and disposal