Mott Insulators of Ultracold Fermionic Alkaline Earth Atoms: Underconstrained Magnetism and Chiral Spin Liquid

We study Mott insulators of fermionic alkaline earth atoms, described by Heisenberg spin models with enhanced SU(N) symmetry. In dramatic contrast to SU(2) magnetism, more than two spins are required to form a singlet. On the square lattice, the classical ground state is highly degenerate and magnetic order is thus unlikely. In a large-N limit, we find a chiral spin liquid ground state with topological order and Abelian fractional statistics. We discuss its experimental detection. Chiral spin liquids with non-Abelian anyons may also be realizable with alkaline earth atoms.Comment: 4 pages, 2 figures, 1 table. Minor changes from v2. Final published versio

Lung eosinophils elicited during allergic and acute aspergillosis express RORgammat and IL-23R but do not require IL-23 for IL-17 production

Exposure to the mold, Aspergillus, is ubiquitous and generally has no adverse consequences in immunocompetent persons. However, invasive and allergic aspergillosis can develop in immunocompromised and atopic individuals, respectively. Previously, we demonstrated that mouse lung eosinophils produce IL-17 in response to stimulation by live conidia and antigens of A. fumigatus. Here, we utilized murine models of allergic and acute pulmonary aspergillosis to determine the association of IL-23, IL-23R and RORgammat with eosinophil IL-17 expression. Following A. fumigatus stimulation, a population of lung eosinophils expressed RORgammat, the master transcription factor for IL-17 regulation. Eosinophil RORgammat expression was demonstrated by flow cytometry, confocal microscopy, western blotting and an mCherry reporter mouse. Both nuclear and cytoplasmic localization of RORgammat in eosinophils were observed, although the former predominated. A population of lung eosinophils also expressed IL-23R. While expression of IL-23R was positively correlated with expression of RORgammat, expression of RORgammat and IL-17 was similar when comparing lung eosinophils from A. fumigatus-challenged wild-type and IL-23p19-/- mice. Thus, in allergic and acute models of pulmonary aspergillosis, lung eosinophils express IL-17, RORgammat and IL-23R. However, IL-23 is dispensable for production of IL-17 and RORgammat

TEST-SYSTEM FOR ESTIMATION OF ACTIVITY OF GSK-3 INHIBITORS AS ANTIHYPOXANTS AND DIFFERENTIATION OF ENDOTHELIAL PROGENITORS IN VITRO

A model test-system was developed for validation in vitro of antihypoxic and endothelio-differentiating activity of newly created glycogen synthase kinase-3 inhibitors in comparison with the reference drug β4-thymosin

Critical role of IRF1 and BATF in forming chromatin landscape during type 1 regulatory cell differentiation

Type 1 regulatory T cells (Tr1 cells) are induced by interleukin-27 (IL-27) and have critical roles in the control of autoimmunity and resolution of inflammation. We found that the transcription factors IRF1 and BATF were induced early on after treatment with IL-27 and were required for the differentiation and function of Tr1 cells in vitro and in vivo. Epigenetic and transcriptional analyses revealed that both transcription factors influenced chromatin accessibility and expression of the genes required for Tr1 cell function. IRF1 and BATF deficiencies uniquely altered the chromatin landscape, suggesting that these factors serve a pioneering function during Tr1 cell differentiation.National Cancer Institute (U.S.) (Grant P30-CA14051

Selection of Clinically Relevant Protease Inhibitor-Resistant Viruses Using the Genotype 2a Hepatitis C Virus Infection System▿†

Treatment of patients infected with hepatitis C virus (HCV) with direct acting antivirals can lead to the emergence of drug-resistant variants that may pose a long-term threat to viral eradication. HCV replicons have been used to select resistance mutations; however, genotype 2a JFH-1-based viruses provide the opportunity to perform resistance selection in a bona fide infection system. In this study, we used a tissue culture-adapted J6/JFH-1 virus to select resistance to the NS3 protease inhibitors BILN-2061 and VX-950. Lunet-CD81 cells were infected with J6/JFH-1 virus and maintained in the presence of inhibitors until high-titer viral supernatant was produced. Viral supernatants were passaged over naive cells at escalating drug concentrations, and the resulting viruses were then characterized. Three NS3 resistance mutations were identified in BILN-2061-resistant viruses: A156G, D168A, and D168V. Interestingly, D168A, D168V, and A156T/V, but not A156G, were selected in parallel using a genotype 2a replicon. For VX-950, the T54A and A156S NS3 resistance mutations were identified in the virus selections, whereas only A156T/V emerged in genotype 2a replicon selections. Of note, VX-950 resistance mutations selected using the 2a virus (T54A and A156S) were also observed during VX-950 clinical studies in genotype 2 patients. We also performed viral fitness evaluations and determined that the mutations selected in the viral system did not confer marked reductions in virus production kinetics or peak titers. Overall, the HCV infection system is an efficient tool for drug resistance selections and has advantages for the rapid identification and characterization of clinically relevant resistance mutations

A Small-Molecule Inhibitor of Hepatitis C Virus Infectivity

One of the most challenging goals of hepatitis C virus (HCV) research is to develop well-tolerated regimens with high cure rates across a variety of patient populations. Such a regimen will likely require a combination of at least two distinct direct-acting antivirals (DAAs). Combining two or more DAAs with different resistance profiles increases the number of mutations required for viral breakthrough. Currently, most DAAs inhibit HCV replication. We recently reported that the combination of two distinct classes of HCV inhibitors, entry inhibitors and replication inhibitors, prolonged reductions in extracellular HCV in persistently infected cells. We therefore sought to identify new inhibitors targeting aspects of the HCV replication cycle other than RNA replication. We report here the discovery of the first small-molecule HCV infectivity inhibitor, GS-563253, also called HCV infectivity inhibitor 1 (HCV II-1). HCV II-1 is a substituted tetrahydroquinoline that selectively inhibits genotype 1 and 2 HCVs with low-nanomolar 50% effective concentrations. It was identified through a high-throughput screen and subsequent chemical optimization. HCV II-1 only permits the production and release of noninfectious HCV particles from cells. Moreover, infectious HCV is rapidly inactivated in its presence. HCV II-1 resistance mutations map to HCV E2. In addition, HCV-II prevents HCV endosomal fusion, suggesting that it either locks the viral envelope in its prefusion state or promotes a viral envelope conformation change incapable of fusion. Importantly, the discovery of HCV II-1 opens up a new class of HCV inhibitors that prolong viral suppression by HCV replication inhibitors in persistently infected cell cultures

A RORγt+ cell instructs gut microbiota-specific Treg cell differentiation

International audienc