The lumen of the Golgi apparatus is regulated to be weakly acidic, which is critical for its functions. The Golgi pH regulator (GPHR) is an anion channel essential for normal acidification of the Golgi apparatus, and is therefore required for its functions. The Golgi apparatus has been thought to be the origin of lamellar granules in the skin. To study the functional role(s) of GPHR in the skin, we established keratinocyte-specific GPHR-knockout mice using the Cre-loxP system. These mutant mice exhibited hypopigmented skin, hair loss, and scaliness. Histological examination of GPHR-knockout mice showed ballooning of the basal cells and follicular dysplasia. In addition, inflammatory cells were seen in the dermis. The expression of trans-Golgi network 46, a marker for lamellar bodies, and kallikrein 7, a protein within lamellar bodies, is diminished in GPHR-knockout mouse skin. Examination by electron microscopy revealed that keratinocytes produced aberrant lamellar bodies. The transepidermal water loss of these knockout mice was increased compared with wild-type mice. Moreover, expression of cathelicidin-related antimicrobial peptide (CRAMP) in the skin was diminished. These results suggest that GPHR is essential for the homeostasis of the epidermis including the formation of lamellar bodies and for the barrier function.Journal of Investigative Dermatology advance online publication, 10 May 2012; doi:10.1038/jid.2012.100.

The yield of charged particles associated with high-p_{t} trigger particles (8<p_{t}<15  GeV/c) is measured with the ALICE detector in Pb-Pb collisions at sqrt[s_{NN}]=2.76  TeV relative to proton-proton collisions at the same energy. The conditional per-trigger yields are extracted from the narrow jetlike correlation peaks in azimuthal dihadron correlations. In the 5% most central collisions, we observe that the yield of associated charged particles with transverse momenta p_{t}>3  GeV/c on the away side drops to about 60% of that observed in pp collisions, while on the near side a moderate enhancement of 20%-30% is found.

The ALICE Collaboration has studied J/ψ production in pp collisions at sqrt[s]=7  TeV at the LHC through its muon pair decay. The polar and azimuthal angle distributions of the decay muons were measured, and results on the J/ψ polarization parameters λ_{θ} and λ_{ϕ} were obtained. The study was performed in the kinematic region 2.5<y<4, 2<p_{t}<8  GeV/c, in the helicity and Collins-Soper reference frames. In both frames, the polarization parameters are compatible with zero, within uncertainties.

Imiquimod (IMQ), a Toll-like receptor (TLR) 7/8 agonist, has been used to treat various skin neoplasms, including genital warts, actinic keratoses, and superficial basal cell carcinomas. Although IMQ has been recognized to activate both innate and adaptive immunity, the underlying mechanism(s) by which IMQ exerts its anti-tumor activity in vivo remains largely unknown. In this study, we took advantage of skin cancer-prone mice to characterize the effects of IMQ on ultraviolet irradiation (UV)-induced de novo carcinogenesis. Transgenic mice with keratinocytes expressing constitutively activated Stat3 (K5.Stat3C mice) developed squamous cell carcinomas (SCC in situ) as early as after 14 wk of UVB irradiation, while wild-type mice required much higher doses of UVB with more than 25 wk of UVB irradiation to produce SCC. Topical treatment of K5.Stat3C mice with IMQ attenuated UVB-induced epidermal dysplasia (SCC in situ). In addition, SCC growth due to increased total irradiation doses was significantly attenuated by IMQ treatment. Topical IMQ treatment induced T cell and plasmacytoid dendritic cell infiltrates at the tumor sites, where levels of IL-12/23p40, IL-12p35, IL-23p19, IL-17A, and IFN-γ mRNAs were up-regulated. Immunohistochemistry revealed T cell infiltrates consisting of T1, Th17, and CD8(+) T cells. We speculate that topical IMQ treatment attenuates the de novo growth of UVB-induced SCC through activation of Th17/Th1 cells and cytotoxic T lymphocytes. © 2012 Wiley Periodicals, Inc.

The epidermal growth factor receptor (EGFR) has an essential role in multiple signaling pathways, including cell proliferation and migration, through extracellular ligand binding and subsequent activation of its intracellular tyrosine kinase (TK) domain. The non-small cell lung cancer (NSCLC)-associated EGFR mutants, L858R and G719S, are constitutively active and oncogenic. They display sensitivity to TK inhibitors, including gefitinib and erlotinib. In contrast, the secondary mutation of the gatekeeper residue, T790M, reportedly confers inhibitor resistance on the oncogenic EGFR mutants. In this study, our biochemical analyses revealed that the introduction of the T790M mutation confers gefitinib resistance on the G719S mutant. The G719S/T790M double mutant has enhanced activity and retains high gefitinib-binding affinity. The T790M mutation increases the ATP affinity of the G719S mutant, explaining the acquired drug resistance of the double mutant. Structural analyses of the G719S/T790M double mutant, as well as the wild type and the G719S and L858R mutants, revealed that the T790M mutation stabilizes the hydrophobic spine of the active EGFR-TK conformation. The Met790 side chain of the G719S/T790M double mutant, in the apo form and gefitinib- and AMPPNP-bound forms, adopts different conformations that explain the accommodation of these ligands. In the L858R mutant structure, the active-site cleft is expanded by the repositioning of Phe723 within the P-loop. Notably, the introduction of the F723A mutation greatly enhanced the gefitinib sensitivity of the wild-type EGFR in vivo, supporting our hypothesis that the expansion of the active-site cleft results in enhanced gefitinib sensitivity. Taken together, our results provide a structural basis for the altered drug sensitivities caused by distinct NSCLC-associated EGFR mutations.Oncogene advance online publication 20 February 2012; doi:10.1038/onc.2012.21.

BACKGROUND Sacran is a newly discovered sulfated polysaccharide extracted from an algae, Aphanothece sacrum, grown in a river of the Kyushu region in Japan. OBJECTIVE To evaluate sacran's inhibitory effect in 2,4,6-trinitrochlorobenzene (TNCB)-induced allergic dermatitis in NC/Nga mice. METHODS Sacran was extracted by acid and alkaline treatment of A sacrum cyanobacterial biomaterials. To sensitize mice, 150 μL of 5% TNCB was applied epicutaneously on the abdomen of each mouse on day 1 and challenged with 15 μL of 1% TNCB applied on the ear skin of mice on day 8 and then every other day to induce skin lesions. Serum levels of inflammatory markers were measured and histopathologic examination of ear skin specimens performed. On the other hand, sacran's transepidermal water loss was evaluated in 11 volunteer women with dry skin. RESULTS Epicutaneous application of sacran in mice has significantly inhibited the development of allergic dermatitis skin lesions and reduced the number of scratching behavior episodes (P <.01). In addition, sacran efficiently inhibited IgE (P <.001), tumor necrosis factor α (P =.02), interleukin 4, interleukin 5, and interferon γ (P <.01; vs buffer in the TNCB group) production and eosinophilic infiltration in the chemical allergen-exposed ear skin. In addition, sacran-treated body regions of human volunteers with dry skin significantly reduced transepidermal water loss levels compared with exogenous hyaluronic acid (P <.01), which is known to improve skin moisture and exert skin barrier repair activity. CONCLUSIONS This study suggests that sacran exerts anti-inflammatory effects by improving skin barrier function and reducing T(H)2 cytokine production.

Extracorporeal membrane oxygenation (ECMO) has emerged as an effective mechanical support following cardiac surgery with respiratory and cardiac failure. However, there are no clear indications for ECMO use after pediatric cardiac surgery. We retrospectively reviewed medical records of 76 pediatric patients [mean age, 10.8 months (0-86); mean weight, 5.16 kg (1.16-16.5)] with congenital heart disease who received ECMO following cardiac surgery between January 1997 and October 2010. Forty-five patients were treated with an aggressive ECMO approach (aggressive ECMO group, April 2005-October 2010) and 31 with a delayed ECMO approach (delayed ECMO group, January 1997-March 2005). Demographics, diagnosis, operative variables, ECMO indication, and duration of survivors and non-survivors were compared. Thirty-four patients (75.5%) were successfully weaned from ECMO in the aggressive ECMO group and 26 (57.7%) were discharged. Conversely, eight patients (25.8%) were successfully weaned from ECMO in the delayed ECMO group and two (6.5%) were discharged. Forty-five patients with shunted single ventricle physiology (aggressive: 29 patients, delayed: 16 patients) received ECMO, but only 15 (33.3%) survived and were discharged. The survival rate of the aggressive ECMO group was significantly better when compared with the delayed ECMO group (p<0.01). Also, ECMO duration was significantly shorter among the aggressive ECMO group survivors (96.5 ± 62.9 h, p<0.01). Thus, the aggressive ECMO approach is a superior strategy compared to the delayed ECMO approach in pediatric cardiac patients. The aggressive ECMO approach improved our outcomes of neonatal and pediatric ECMO.

Flow coefficients v_{n} for n=2, 3, 4, characterizing the anisotropic collective flow in Au+Au collisions at sqrt[s_{NN}]=200  GeV, are measured relative to event planes Ψ_{n}, determined at large rapidity. We report v_{n} as a function of transverse momentum and collision centrality, and study the correlations among the event planes of different order n. The v_{n} are well described by hydrodynamic models which employ a Glauber Monte Carlo initial state geometry with fluctuations, providing additional constraining power on the interplay between initial conditions and the effects of viscosity as the system evolves. This new constraint can serve to improve the precision of the extracted shear viscosity to entropy density ratio η/s.