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Multidrug-resistant bacteria pose a major threat to effective antibiotics and alternatives to fight multidrug-resistant pathogens are needed. We synthetized molybdenum oxide (MoO3) nanoparticles (NP) and determined their antibacterial activity against 39 isolates: (i) eight Staphylococcus aureus, including representatives of methicillin-resistant S. aureus epidemic clones; (ii) six enterococci, including vancomycin-resistant isolates; and (iii) 25 Gram-negative isolates (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, Enterobacter cloacae), including extended spectrum beta-lactamases and carbapenemases producers. All isolates showed a MoO3 NP MIC of 700-800 mg l(-1). MoO3 NP produced a clear inhibition zone for S. aureus and all Gram-negative isolates at concentrations >= 25 mg ml(-1) and >= 50 mg ml(-1) for enterococci. When the NP solutions were adjusted to pH similar to 7, the biocidal activity was completely abolished. MoO3 NP create an acidic pH and show a universal antimicrobial activity against susceptible and resistant isolates belonging to the most relevant bacterial species responsible for hospital-acquired infections.

Approximately 75% of breast cancers are estrogen receptor alpha (ER alpha)-positive and are treatable with endocrine therapies, but often patients develop lethal resistant disease. Frequent mutations (10-40%) in the ligand-binding domain (LBD) codons in the gene encoding ER alpha (ESR1) have been identified, resulting in ligand-independent, constitutively active receptors. In addition, ESR1 chromosomal translocations can occur, resulting in fusion proteins that lack the LBD and are entirely unresponsive to all endocrine treatments. Thus, identifying coactivators that bind to these mutant ERa proteins may offer new therapeutic targets for endocrine-resistant cancer. To define coactivator candidate targets, a proteomics approach was performed profiling proteins recruited to the two most common ER alpha LBD mutants, Y537S and D538G, and an ESR1-YAP1 fusion protein. These mutants displayed enhanced coactivator interactions as compared to unliganded wild-type ER alpha. Inhibition of these coactivators decreased the ability of ESR1 mutants to activate transcription and promote breast cancer growth in vitro and in vivo. Thus, we have identified specific coactivators that may be useful as targets for endocrine-resistant breast cancers.

Spectacular progress has been made in the characterization of human hyper-IgE syndrome (HIES) over the last 50years. HIES is a primary immunodeficiency defined as an association of atopy in a context of very high serum IgE levels, characteristic bacterial and fungal diseases, low-level clinical and biological inflammation, and various non-hematopoietic developmental manifestations. Somewhat arbitrarily, three disorders were successively put forward as the underlying cause of HIES: autosomal dominant (AD) STAT3 deficiency, the only disorder corresponding to the original definition of HIES, and autosomal recessive (AR) DOCK8 and PGM3 deficiencies, in which atopy and high serum IgE levels occur in a context of manifestations not seen in patients with typical HIES. Indeed, these three disorders disrupt different molecular pathways, affect different cell types, and underlie different clinical phenotypes. Surprisingly, several other inherited inborn errors of immunity in which serum IgE levels are high, sometimes almost as high as those in HIES patients, are not considered to belong to the HIES group of diseases. Studies of HIES have been further complicated by the lack of a high serum IgE phenotype in all mouse models of the disease other than two Stat3 mutant strains. The study of infections in mutant mice has helped elucidate only some forms of HIES and infection. Mouse models of these conditions have also been used to study non-hematopoietic phenotypes for STAT3 deficiency, tissue-specific immunity for DOCK8 deficiency, and cell lineage maturation for PGM3 deficiency. We review here the history of the field of HIES since the first clinical description of this condition in 1966, together with the three disorders commonly referred to as HIES, focusing, in particular, on their mouse models. We propose the restriction of the term HIES to patients with an AD STAT3-deficiency phenotype, including the most recently described AR ZNF341 deficiency, thus excluding AR DOCK8 and PGM3 deficiencies from the definition of this disease.

The diffusivity of macromolecules in the cytoplasm of eukaryotic cells varies over orders of magnitude and dictates the kinetics of cellular processes. However, a general description that associates the Brownian or anomalous nature of intracellular diffusion to the architectural and biochemical properties of the cytoplasm has not been achieved. Here we measure the mobility of individual fluorescent nanoparticles in living mammalian cells to obtain a comprehensive analysis of cytoplasmic diffusion. We identify a correlation between tracer size, its biochemical nature and its mobility. Inert particles with size equal or below 50 nm behave as Brownian particles diffusing in a medium of low viscosity with negligible effects of molecular crowding. Increasing the strength of non-specific interactions of the nanoparticles within the cytoplasm gradually reduces their mobility and leads to subdiffusive behaviour. These experimental observations and the transition from Brownian to subdiffusive motion can be captured in a minimal phenomenological model.

Results are reported from a search for physics beyond the standard model in proton-proton collisions at a center-of-mass energy of root s=13TeV. The search uses a signature of a single lepton, large jet and bottom quark jet multiplicities, and high sum of large-radius jet masses, without any requirement on the missing transverse momentum in an event. The data sample corresponds to an integrated luminosity of 35.9 fb(-1) recorded by the CMS experiment at the LHC. No significant excess beyond the prediction from standard model processes is observed. The results are interpreted in terms of upper limits on the production cross section for R-parity violating supersymmetric extensions of the standard model using a benchmark model of gluino pair production, in which each gluino decays promptly via (g) over tilde -> tbs. Gluinos with a mass below 1610 GeV are excluded at 95% confidence level. (c) 2018 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (https://urldefense.proofpoint.com/v2/url?u=http-3A__creativecommons.org_licenses_by_4.0_&d=DwIDaQ&c=JeTkUgVztGMmhKYjxsy2rfoWYibK1YmxXez1G3oNStg&r=bWJiylK2oqB9vBxAFHE1PJcvSYL9TVkBaaVMsMDsLbs&m=VTpB_Xwivicryu99yNeoC2h8JMzHG23s6l8sMqCuZ4o&s=BNICcpZRv1cFogMPWOdQrUGkJAUcABVqQ0cOTBHqGcU&e=). Funded by SCOAP(3).

Piezo1 is a mechanosensitive (MS) ion channel with characteristic fast-inactivation kinetics. We found a slowly-inactivating MS current in mouse embryonic stem (mES) cells and characterized it throughout their differentiation into motor-neurons to investigate its components. MS currents were large and slowly-inactivating in the stem-cell stage, and became smaller and faster-inactivating throughout the differentiation. We found that Piezo1 is expressed in mES cells, and its knockout abolishes MS currents, indicating that the slowly-inactivating current in mES cells is carried by Piezo1. To further investigate its slow inactivation in these cells, we cloned Piezo1 cDNA from mES cells and found that it displays fast-inactivation kinetics in heterologous expression, indicating that sources of modulation other than the aminoacid sequence determine its slow kinetics in mES cells. Finally, we report that Piezo1 knockout ES cells showed a reduced rate of proliferation but no significant differences in other markers of pluripotency and differentiation.

Calcitonin gene-related peptide (CGRP) binds to the complex of the calcitonin receptor-like receptor (CLR) with receptor activity-modifying protein 1 (RAMP1). How CGRP interacts with the transmembrane domain (including the extracellular loops) of this family B receptor remains unclear. In this study, a photoaffinity cross-linker, p-azido L-phenylalanine (azF), was incorporated into CLR, chiefly in the second extracellular loop (ECL2) using genetic code expansion and unnatural amino acid mutagenesis. The method was optimized to ensure efficient photolysis of azF residues near the transmembrane bundle of the receptor. A CGRP analogue modified with fluorescein at position 15 was used for detection of ultraviolet-induced cross-linking. The methodology was verified by confirming the known contacts of CGRP to the extracellular domain of CLR. Within ECL2, the chief contacts were 1284 on the loop itself and L291, at the top of the fifth transmembrane helix (TM5). Minor contacts were noted along the lip of ECL2 between 5286 and L290 and also with M223 in TM3 and F349 in TM6. Full length molecular models of the bound receptor complex suggest that CGRP sits at the top of the TM bundle, with Thr(6) of the peptide making contacts with L291 and H295. 1284 is likely to contact Leu(12) and Ala(13) of CGRP, and Leu(16) of CGRP is at the ECL/extracellular domain boundary of CLR. The reduced potency, E-max, and affinity of [Leu(16)Ala]-human alpha CGRP are consistent with this model. Contacts between Thr(6) of CGRP and H295 may be particularly important for receptor activation.

Photosensitivity, or skin sensitivity to ultraviolet radiation (UVR), is a feature of lupus erythematosus and other autoimmune and dermatologic conditions, but the mechanistic underpinnings are poorly understood. We identify a Langerhans cell (LC)-keratinocyte axis that limits UVR-induced keratinocyte apoptosis and skin injury via keratinocyte epidermal growth factor receptor (EGFR) stimulation. We show that the absence of LCs in Langerin-diphtheria toxin subunit A (DTA) mice leads to photosensitivity and that, in vitro, mouse and human LCs can directly protect keratinocytes from UVR-induced apoptosis. LCs express EGFR ligands and a disintegrin and metalloprotease 17 (ADAM17), the metalloprotease that activates EGFR ligands. Deletion of ADAM17 from LCs leads to photosensitivity, and UVR induces LC ADAM17 activation and generation of soluble active EGFR ligands, suggesting that LCs protect by providing activated EGFR ligands to keratinocytes. Photosensitive systemic lupus erythematosus (SLE) models and human SLE skin show reduced epidermal EGFR phosphorylation and LC defects, and a topical EGFR ligand reduces photosensitivity. Together, our data establish a direct tissue-protective function for LCs, reveal a mechanistic basis for photosensitivity, and suggest EGFR stimulation as a treatment for photosensitivity in lupus erythematosus and potentially other autoimmune and dermatologic conditions.