Nonsteroidal anti‐inflammatory drugs interfere with the metabolism of arachidonic acid to proinflammatory prostaglandins and leukotrienes by targeting cyclooxygenases (COXs), 5‐lipoxygenase (LOX), or the 5‐LOX–activating protein (FLAP). These and related enzymes act in conjunction with marked crosstalk within a complex lipid mediator (LM) network where also specialized proresolving LMs (SPMs) are formed. Here, we present how prominent LM pathways can be differentially modulated in human proinflammatory M1 and proresolving M2 macrophage phenotypes that, upon exposure to Escherichia coli, produce either abundant prostaglandins and leukotrienes (M1) or SPMs (M2). Targeted liquid chromatography–tandem mass spectrometry–based metabololipidomics was applied to analyze and quantify the specific LM profiles. Besides expected on‐target actions, we found that: 1) COX or 15‐LOX‐1 inhibitors elevate inflammatory leukotriene levels, 2) FLAP and 5‐LOX inhibitors reduce leukotrienes in M1 but less so in M2 macrophages, 3) zileuton blocks resolution‐initiating SPM biosynthesis, whereas FLAP inhibition increases SPM levels, and 4) that the 15‐LOX‐1 inhibitor 3887 suppresses SPM formation in M2 macrophages. Conclusively, interference with discrete LM biosynthetic enzymes in different macrophage phenotypes considerably affects the LM metabolomes with potential consequences for inflammation‐resolution pharmacotherapy. Our data may allow better appraisal of the therapeutic potential of these drugs to intervene with inflammatory disorders.—Werner, M., Jordan, P. M., Romp, E., Czapka, A., Rao, Z., Kretzer, C., Koeberle, A., Garscha, U., Pace, S., Claesson, H.‐E., Serhan, C. N., Werz, O., Gerstmeier, J. Targeting biosynthetic networks of the proinflammatory and proresolving lipid metabolome. FASEB J. 33, 6140–6153 (2019). http://www.fasebj.org

Systemic vitamin E metabolites have been proposed as signaling molecules, but their physiological role is unknown. Here we show, by library screening of potential human vitamin E metabolites, that long-chain ω-carboxylates are potent allosteric inhibitors of 5-lipoxygenase, a key enzyme in the biosynthesis of chemoattractant and vasoactive leukotrienes. 13-((2R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)-2,6,10-trimethyltridecanoic acid (α-T-13′-COOH) can be synthesized from α-tocopherol in a human liver-on-chip, and is detected in human and mouse plasma at concentrations (8–49 nM) that inhibit 5-lipoxygenase in human leukocytes. α-T-13′-COOH accumulates in immune cells and inflamed murine exudates, selectively inhibits the biosynthesis of 5-lipoxygenase-derived lipid mediators in vitro and in vivo, and efficiently suppresses inflammation and bronchial hyper-reactivity in mouse models of peritonitis and asthma. Together, our data suggest that the immune regulatory and anti-inflammatory functions of α-tocopherol depend on its endogenous metabolite α-T-13′-COOH, potentially through inhibiting 5-lipoxygenase in immune cells.

Paper is the ideal substrate for the development of flexible and environmentally sustainable ubiquitous electronic systems, which, combined with two-dimensional materials, could be exploited in many Internet-of-Things applications, ranging from wearable electronics to smart packaging. Here we report high-performance MoS 2 field-effect transistors on paper fabricated with a "channel array" approach, combining the advantages of two large-area techniques: chemical vapor deposition and inkjet-printing. The first allows the pre-deposition of a pattern of MoS 2 ; the second, the printing of dielectric layers, contacts, and connections to complete transistors and circuits fabrication. Average I ON /I OFF of 8 × 10 3 (up to 5 × 10 4) and mobility of 5.5 cm 2 V −1 s −1 (up to 26 cm 2 V −1 s −1) are obtained. Fully functional integrated circuits of digital and analog building blocks, such as logic gates and current mirrors, are demonstrated, highlighting the potential of this approach for ubiquitous electronics on paper.

Highlights d S. aureus causes SPM formation in human M2 macrophages by a-hemolysin d a-hemolysin elicits SPM biosynthesis by activation of 15lipoxygenase-1 in M2 d Inhibition of ADAM10 or 15-lipoxygenase-1 knockdown reverts a-hemolysin actions d a-hemolysin elevates SPM levels in mouse peritoneum devoid of leukocyte influx

Out of the different structural phases of molybdenum ditelluride (MoTe 2 ), the distorted octahedral 1T′ possesses great interest for fundamental physics and is a promising candidate for the implementation of innovative devices such as topological transistors. Indeed, 1T′-MoTe 2 is a semimetal with superconductivity, which has been predicted to be a Weyl semimetal and a quantum spin Hall insulator in bulk and monolayer form, respectively. Large instability of monolayer 1T′-MoTe 2 in environmental conditions, however, has made its investigation extremely challenging so far. In this work, we demonstrate homogeneous growth of large single-crystal (up to 500 μm) monolayer 1T′-MoTe 2 via chemical vapor deposition (CVD) and its stabilization in air with a scalable encapsulation approach. The encapsulant is obtained by electrochemically delaminating CVD hexagonal boron nitride (hBN) from copper foil, and it is applied on the freshly grown 1T′-MoTe 2 via a top-down dry lamination step. The structural and electrical properties of encapsulated 1T′-MoTe 2 have been monitored over several months to assess the degree of degradation of the material. We find that when encapsulated with hBN, the lifetime of monolayer 1T′-MoTe 2 successfully increases from a few minutes to more than a month. Furthermore, the encapsulated monolayer can be subjected to transfer, device processing, and heating and cooling cycles without degradation of its properties. The potential of this scalable heterostack is confirmed by the observation of signatures of low-temperature phase transition in monolayer 1T′-MoTe 2 by both Raman spectroscopy and electrical measurements. The growth and encapsulation methods reported in this work can be employed for further fundamental studies of this enticing material as well as facilitate the technological development of monolayer 1T′-MoTe 2 .

The artificial stacking of atomically thin crystals suffers from intrinsic limitations in terms of control and reproducibility of the relative orientation of exfoliated flakes. This drawback is particularly severe when the properties of the system critically depends on the twist angle, as in the case of the dodecagonal quasicrystal formed by two graphene layers rotated by 30°. Here we show that large-area 30°-rotated bilayer graphene can be grown deterministically by chemical vapor deposition on Cu, eliminating the need of artificial assembly. The quasicrystals are easily transferred to arbitrary substrates and integrated in high-quality hBN-encapsulated heterostructures, which we process into dual-gated devices exhibiting carrier mobility up to 10 5 2 cm 2 /Vs. From low-temperature magnetotransport, we find that the graphene quasicrystals effectively behave as uncoupled graphene layers, showing 8-fold degenerate quantum Hall states: this result indicates that the Dirac cones replica detected by previous photo-emission experiments do not contribute to the electrical transport. KEYWORDS. twisted bilayer graphene, CVD, dodecagonal quasicrystals, quantum Hall effectTwisted bilayer graphene (TBG), a system made of two stacked single-layer graphene (SLG) with misaligned crystallographic orientation, is providing an incredibly rich platform for novel physical phenomena [1,2]. In the limit of small twist angle (<10°), the long-range moiré superpotential determines important modifications to the structural and electronic properties [3][4][5]. On the other hand, TBG falls in a weak coupling regime for large twisting, with the electronic properties resembling those of two SLG conducting in parallel [6,7]. However, relevant interlayer coupling seems to re-emerge in TBG with a twist angle of precisely 30 degrees, giving rise to multiple Dirac cones replica, as detected by angle-resolved photoemission spectroscopy (ARPES) in two recent experiments [8,9]. In this configuration, TBG forms an incommensurate structure with 12-fold rotational symmetry -although lacking of translational symmetry -known as dodecagonal quasicrystal (QC). In addition to the cones' multiplication, QC-TBG is predicted to host spiral Fermi surfaces resulting in novel quantum oscillations [10], van Hove singularities [11,12] and semi-localized electronic states following the dodecagonal tiling [11], which strongly motivates further experimental investigation, in particular low-temperature electrical transport in highmobility devices. However, the QC-TBG is extremely sensitive to small variation in the twist angle, which makes it highly challenging to realize with the common hBN-mediated "tear-and-13

Proinflammatory leukotrienes (LTs) are produced by 5-lipoxygenase (5-LO) aided by 5-LO-activating protein (FLAP). LT biosynthesis inhibitors are currently under clinical investigation as treatments for respiratory and cardiovascular diseases. Here, we have revealed a sex bias in the efficiency of clinically relevant LT biosynthesis inhibitors, showing that their effects are superior in females. We found that androgens cause these sex differences by impeding the LT-biosynthetic 5-LO/FLAP complex assembly. Lower doses of the FLAP inhibitor MK886 were required to reduce LTB4 levels in exudates of female versus male mice and rats. Following platelet-activating factor-induced shock, MK886 increased survival exclusively in female mice, and this effect was abolished by testosterone administration. FLAP inhibitors and the novel-type 5-LO inhibitors licofelone and sulindac sulfide exhibited higher potencies in human blood from females, and bioactive 5-LO/FLAP complexes were formed in female, but not male, human and murine leukocytes. Supplementation of female blood or leukocytes with 5α-dihydrotestosterone abolished the observed sex differences. Our data suggest that females may benefit from anti-LT therapy to a greater extent than males, prompting consideration of sex issues in LT modifier development

The anticarcinogenic and anti-inflammatory properties of curcumin have been extensively investigated, identifying prostaglandin E2 synthase (mPGES)-1 and 5-lipoxygenase (5-LO), key enzymes linking inflammation with cancer, as high affinity targets. A comparative structure-activity study revealed three modifications dissecting mPGES-1/5-LO inhibition, namely (i) truncation of the acidic, enolized dicarbonyl moiety and/or replacement by pyrazole, (ii) hydrogenation of the interaryl linker, and (iii) (dihydro)prenylation. The prenylated pyrazole analogue 11 selectively inhibited 5-LO, outperforming curcumin by a factor of up to 50, and impaired zymosan-induced mouse peritonitis along with reduced 5-LO product levels. Other pro-inflammatory targets of curcumin (i.e., mPGES-1, cyclooxygenases, 12/15-LOs, nuclear factor-κB, nuclear factor-erythroid 2-related factor-2, and signal transducer and activator of transcription 3) were hardly affected by 11. The strict structural requirements for mPGES-1 and 5-LO inhibition strongly suggest that specific interactions rather than redox or membrane effects underlie the inhibition of mPGES-1 and 5-LO by curcumin.