Epidermal ADAM17 maintains the skin barrier by regulating EGFR ligand-dependent terminal keratinocyte differentiation

ADAM17 (a disintegrin and metalloproteinase 17) is ubiquitously expressed and cleaves membrane proteins, such as epidermal growth factor receptor (EGFR) ligands, l-selectin, and TNF, from the cell surface, thus regulating responses to tissue injury and inflammation. However, little is currently known about its role in skin homeostasis. We show that mice lacking ADAM17 in keratinocytes (A17(ΔKC)) have a normal epidermal barrier and skin architecture at birth but develop pronounced defects in epidermal barrier integrity soon after birth and develop chronic dermatitis as adults. The dysregulated expression of epidermal differentiation proteins becomes evident 2 d after birth, followed by reduced transglutaminase (TGM) activity, transepidermal water loss, up-regulation of the proinflammatory cytokine IL-36α, and inflammatory immune cell infiltration. Activation of the EGFR was strongly reduced in A17(ΔKC) skin, and topical treatment of A17(ΔKC) mice with recombinant TGF-α significantly improved TGM activity and decreased skin inflammation. Finally, we show that mice lacking the EGFR in keratinocytes (Egfr(ΔKC)) closely resembled A17(ΔKC) mice. Collectively, these results identify a previously unappreciated critical role of the ADAM17–EGFR signaling axis in maintaining the homeostasis of the postnatal epidermal barrier and suggest that this pathway could represent a good target for treatment of epidermal barrier defects

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700

Processing and Properties of Metal-matrix Composites Reinforced With Continuous Fibers for the Control of Thermal-expansion, Creep Resistance and Fracture-toughness

Al-, Zn-, and Cu-based matrix composites reinforced with continuous fibres of carbon, SiC, Al2O3, or steel have been processed by squeeze casting or powder metallurgy. Interface reactions can be controlled by alloying additions in the matrix. Interface adhesion has been characterized from the distributions of fibre pull-out lengths on fracture surfaces. Thermal expansion curves reveal the magnitude of the stress transfer at interfaces. In the case of low melting point matrices, ductile steel fibres offer the best combination of fracture toughness and creep resistance

Formation and Structures of Hafnocene Complexes in MAO- and AlBui3/CPh3[B(C6F5)4]-Activated Systems

The formation of cationic species relevant to olefin polymerization based on (SBI)HfCl2, Me2C(C5H4)(Flu)HfCl2, Ph2C(C5H4)(Flu)HfCl2, and L'HfCl2 activated by MAO, AlMe3/CPh3[B(C6F5)4], and AlBui3/CPh3[B(C6F5)4] (SBI = rac-Me2Si(Ind)2; L' = C2H4(Flu)(5,6-C3H6-2-MeInd)) was studied by 1H, 13C, and 19F NMR spectroscopy. Thermally stable heterobinuclear intermediates of the type [LHf(µ-Me)2AlMe2]+[MeMAO]- and [LHf(µ-Me)2AlMe2]+[B(C6F5)4]- were identified when using MAO and AlMe3/CPh3[B(C6F5)4] as activators, respectively. The stability of these species explains the low productivity of hafnocene catalysts in the presence of AlMe3-containing activators, compared to zirconocenes. By contrast, in the ternary systems LHfCl2/AlBui3/CPh3[B(C6F5)4] hydride species were detected that must be responsible for the formation of the highly active sites in olefin polymerization. The ionic hydrido species differ significantly in stability. The formation of the mixed-alkyl complex L'Hf(Me)CH2SiMe3 proceeds with surprisingly high diastereoselectivity; the sterically more hindered isomer is produced preferentially. It reacts with CPh3[B(C6F5)4] to afford the ion pair [L'Hf-CH2SiMe3]+[B(C6F5)4]- as two diastereomers that exist in dynamic equilibrium. The rates of site epimerization of this ion pair indicate only small energy differences between the two isomers