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The microbiome modulates host immunity and aids the maintenance of tolerance in the gut, where microbial and food-derived antigens are abundant. Yet modern dietary factors and the excessive use of antibiotics have contributed to the rising incidence of food allergies, inflammatory bowel disease and other non-communicable chronic diseases associated with the depletion of beneficial taxa, including butyrate-producing Clostridia. Here we show that intragastrically delivered neutral and negatively charged polymeric micelles releasing butyrate in different regions of the intestinal tract restore barrier-protective responses in mouse models of colitis and of peanut allergy. Treatment with the butyrate-releasing micelles increased the abundance of butyrate-producing taxa in Clostridium cluster XIVa, protected mice from an anaphylactic reaction to a peanut challenge and reduced disease severity in a T-cell-transfer model of colitis. By restoring microbial and mucosal homoeostasis, butyrate-releasing micelles may function as an antigen-agnostic approach for the treatment of allergic and inflammatory diseases.

Hepatocytes compose up to 80% of the total liver and have been indicated as important players in the induction of immunologic tolerance in this organ. We show that hepatocytes possess the molecular machinery required for the cross-presentation of extracellular antigens. Using a derivative of the model antigen ovalbumin (OVA) covalently modified with a polymer containing multiple N-acetylgalactosamine residues (pGal-OVA) that enhance extracellular antigen uptake by mimicking the glycome of apoptotic debris, we show efficient hepatocyte-dependent induction of cross-tolerance of both adoptively transferred OT-I cells and endogenous OVA-specific CD8+ T lymphocytes, for example inducing tolerance to OVA-expressing skin transplants. Our study confirms that hepatocytes are capable of inducing peripheral tolerogenesis and provides proof of concept that they may be a valuable candidate for in vivo targeted tolerogenic treatments. [ABSTRACT FROM AUTHOR]

We explore the vapor-liquid phase behavior of binary mixtures of Lennard-Jones-type molecules where one component is supercritical, given the system temperature. We apply the self-consistency approach to the Ornstein–Zernike integral equations to obtain the correlation functions. The consistency checks include not only thermodynamic consistencies (pressure consistency and Gibbs–Duhem consistency), but also pointwise consistencies, such as the zero-separation theorems on the cavity functions. The consistencies are enforced via the bridge functions in the closure which contain adjustable parameters. The full solution requires the values of not only the monomer chemical potentials, but also the dimer chemical potentials present in the zero-separation theorems. These are evaluated by the direct chemical-potential formula [L. L. Lee, J. Chem. Phys. 97, 8606 (1992)] that does not require temperature nor density integration. In order to assess the integral equation accuracy, molecular-dynamics simulations are carried out alongside the states studied. The integral equation results compare well with simulation data. In phase calculations, it is important to have pressure consistency and valid chemical potentials, since the matching of phase boundaries requires the equality of the pressures and chemical potentials of both the liquid and vapor phases. The mixtures studied are methane-type and pentane-type molecules, both characterized by effective Lennard-Jones potentials. Calculations on one isotherm show that the integral equation approach yields valid answers as compared with the experimental data of Sage and Lacey. To study vapor-liquid phase behavior, it is necessary to use consistent theories; any inconsistencies, especially in pressure, will vitiate the phase boundary calculations. [ABSTRACT FROM AUTHOR]

A study of drug use locations in Hartford, CT, is designed to understand the environmental and social conditions within 'high risk sites' where drug users inject drugs or smoke crack, in order to develop AIDS prevention models that build upon the physical and social organization of these locations. The study assesses high-risk sites characterized on the basis of type of location or structure, presence and strength of gatekeepers, and presence and strength of HIV prevention opportunities and pressures. A combination of ethnographic, epidemiological, and social network methods are used to document the characteristics, social organization, natural history, and dynamics of these sites, the network relations of site users, and the various opportunities for, or barriers to, on-site social-level HIV prevention intervention. This paper provides an overview of the study and presents preliminary findings, including the degree to which drug injectors and crack smokers use specific types of sites in Hartford. The paper also discusses the ways these findings inform development of on-site, type-specific and peer-led or structural HIV-prevention interventions.

Biologics can improve bone formation, but may diffuse away from sites of therapeutic need. We developed a click-chemistry hydrogel that rapidly polymerizes in situ to control delivery of biologics during post-suturectomy resynostosis in 21-day-old male mice. Here, we used this model to determine the role of angiogenesis in post-suturectomy resynostosis and examine whether controlled release of angiogenesis inhibitors could delay bone regeneration. Hydrogels [DB-co-PEG/poly (TEGDMA)-co-(N3-TEGDMA)] were produced containing anti-angiogenic compounds [anti-VEGFA-antibody or hypoxia inducible factor 1α-inhibitor topotecan]. Bioactivity in vitro was assessed by tube length and branching points of endothelial cells in hydrogel-conditioned media. In vivo effects were examined 14 day post-suturectomy, based on the temporal analysis of angiogenic mRNAs during resynostosis following posterior frontal suture removal. MicroCT was used to quantify angiogenesis in contrast-agent-perfused blood vessels and bone defect size in defects receiving hydrogel, anti-VEGFA/hydrogel, or topotecan/hydrogel. Shorter endothelial tube length and less branching were seen in inhibitor-conditioned media (topotecan > AbVEGFA). In vivo, both compounds inhibited angiogenesis compared with hydrogel-only. Anti-VEGFA/hydrogel reduced resynostosis compared with empty defects, but topotecan/hydrogel blocked bone regeneration. We demonstrate that anti-angiogenic compounds can be incorporated into a spontaneously polymerizing hydrogel and remain active over 14 days in vitro and in vivo. Moreover, bone formation can be delayed by inhibiting neovascularization, suggesting possible use as a therapeutic to control resynostosis following suturectomies and potential applications in other conditions where rapid osteogenesis is not desired. © 2017 Wiley Periodicals Inc. J Biomed Mater Res Part A: 105A: 2742-2749, 2017. [ABSTRACT FROM AUTHOR]

Hepatocytes compose up to 80% of the total liver and have been indicated as important players in the induction of immunologic tolerance in this organ. We show that hepatocytes possess the molecular machinery required for the cross-presentation of extracellular antigens. Using a derivative of the model antigen ovalbumin (OVA) covalently modified with a polymer containing multiple N-acetylgalactosamine residues (pGal-OVA) that enhance extracellular antigen uptake by mimicking the glycome of apoptotic debris, we show efficient hepatocyte-dependent induction of cross-tolerance of both adoptively transferred OT-I cells and endogenous OVA-specific CD8 + T lymphocytes, for example inducing tolerance to OVA-expressing skin transplants. Our study confirms that hepatocytes are capable of inducing peripheral tolerogenesis and provides proof of concept that they may be a valuable candidate for in vivo targeted tolerogenic treatments., Competing Interests: The EPFL has filed for patent protection on the pGal-antigen delivery platform, and MD, DW, and JH are named as inventors on those patents. Anokion SA and Kanyos Bio, Inc., have licensed those patents, and JH and DW participate in equity in those companies. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Damo, Wilson, Watkins and Hubbell.)

Intra-articular delivery of therapeutics to modulate osteoarthritis (OA) is challenging. Delivery of interleukin-1 receptor antagonist (IL-1Ra), the natural protein inhibitor of IL-1, to modulate IL-1-based inflammation through gene therapy or bolus protein injections has emerged as a promising therapy for OA. However, these approaches suffer from rapid clearance and reduced potency over time. Nano/microparticles represent a promising strategy for overcoming the shortcomings of intra-articular drug delivery. However, these delivery vehicles are limited for delivery of protein therapeutics due to their hydrophobic character, low drug loading efficiency, and harsh chemical conditions during particle processing. We designed a new block copolymer that assembles into submicron-scale particles and provides for covalently tethering proteins to the particle surface for controlled intra-articular protein delivery. This block copolymer self-assembles into 300 nm-diameter particles with a protein tethering moiety for surface covalent conjugation of IL-1Ra protein. This copolymer particle system efficiently bound IL-1Ra and maintained protein bioactivity in vitro. Furthermore, particle-tethered IL-1Ra bound specifically to target synoviocyte cells via surface IL-1 receptors. Importantly, IL-1Ra nanoparticles inhibited IL-1-mediated signaling to equivalent levels as soluble IL-1Ra. Finally, the ability of nanoparticles to retain IL-1Ra in the rat stifle joint was evaluated by in vivo imaging over 14 days. IL-1Ra-tethered nanoparticles significantly increased the retention time of IL-1Ra in the rat stifle joint over 14 days with enhanced IL-1Ra half-life (3.01 days) compared to that of soluble IL-1Ra (0.96 days) and without inducing degenerative changes in cartilage structure or composition., (Copyright © 2012 Elsevier Ltd. All rights reserved.)