Macrophage-Specific Chemokines Induced via Innate Immunity by Amino Acid Copolymers and Their Role in EAE

The random amino acid copolymer poly(Y,E,A,K)n (Copaxone®) is widely used in multiple sclerosis treatment and a second generation copolymer poly(Y,F,A,K)n with enhanced efficacy in experimental autoimmune encephalomyelitis in mice has been described. A major mechanism through which copolymers function to ameliorate disease is the generation of immunosuppressive IL-10-secreting regulatory T cells entering the CNS. In addition, the antigen presenting cell to which these copolymers bind through MHC Class II proteins may have an important role. Here, both CCL22 (a Th2 cell chemoattractant) in large amounts and CXCL13 in much smaller amounts are shown to be secreted after administration of YFAK to mice and to a smaller extent by YEAK parallel to their serum concentrations. Moreover, bone marrow-derived macrophages secrete CCL22 in vitro in response to YFAK and to higher concentrations of YEAK. Strikingly, these chemokines are also secreted into serum of MHC Class II −/− mice, indicating that an innate immune receptor on these cells also has an important role. Thus, both the innate and the adaptive immune systems are involved in the mechanism of EAE amelioration by YFAK. The enhanced ability of YFAK to stimulate the innate immune system may account for its enhanced efficacy in EAE treatment

An extremely energetic supernova from a very massive star in a dense medium

The interaction of a supernova with a circumstellar medium (CSM) can dramatically increase the emitted luminosity by converting kinetic energy to thermal energy. In 'superluminous' supernovae (SLSNe) of Type IIn -- named for narrow hydrogen lines in their spectra -- the integrated emission can reach $\sim 10^{51}$ erg, attainable by thermalising most of the kinetic energy of a conventional SN. A few transients in the centres of active galaxies have shown similar spectra and even larger energies, but are difficult to distinguish from accretion onto the supermassive black hole. Here we present a new event, SN2016aps, offset from the centre of a low-mass galaxy, that radiated $\gtrsim 5 \times 10^{51}$ erg, necessitating a hyper-energetic supernova explosion. We find a total (SN ejecta $+$ CSM) mass likely exceeding 50-100 M$_\odot$, with energy $\gtrsim 10^{52}$ erg, consistent with some models of pair-instability supernovae (PISNe) or pulsational PISNe -- theoretically-predicted thermonuclear explosions from helium cores $>50$ M$_\odot$. Independent of the explosion mechanism, this event demonstrates the existence of extremely energetic stellar explosions, detectable at very high redshifts, and provides insight into dense CSM formation in the most massive stars.Comment: Published in Nature Astronomy, 13 April 202

An extremely energetic supernova from a very massive star in a dense medium

The interaction of a supernova with a circumstellar medium (CSM) can dramatically increase the emitted luminosity by converting kinetic energy to thermal energy. In ‘superluminous’ supernovae of type IIn—named for narrow hydrogen lines in their spectra—the integrated emission can reach ~10⁵¹ erg, attainable by thermalizing most of the kinetic energy of a conventional supernova. A few transients in the centres of active galaxies have shown similar spectra and even larger energies, but are difficult to distinguish from accretion onto the supermassive black hole. Here we present a new event, SN2016aps, offset from the centre of a low-mass galaxy, that radiated ≳5 × 10⁵¹ erg, necessitating a hyper-energetic supernova explosion. We find a total (supernova ejecta + CSM) mass likely exceeding 50−100 M_⊙, with energy ≳10⁵² erg, consistent with some models of pair-instability supernovae or pulsational pair-instability supernovae—theoretically predicted thermonuclear explosions from helium cores >50 M_⊙. Independent of the explosion mechanism, this event demonstrates the existence of extremely energetic stellar explosions, detectable at very high redshifts, and provides insight into dense CSM formation in the most massive stars

Crystal Structure of an HSA/FcRn Complex Reveals Recycling by Competitive Mimicry of HSA Ligands at a pH-Dependent Hydrophobic Interface

SummaryThe long circulating half-life of serum albumin, the most abundant protein in mammalian plasma, derives from pH-dependent endosomal salvage from degradation, mediated by the neonatal Fc receptor (FcRn). Using yeast display, we identified human serum albumin (HSA) variants with increased affinity for human FcRn at endosomal pH, enabling us to solve the crystal structure of a variant HSA/FcRn complex. We find an extensive, primarily hydrophobic interface stabilized by hydrogen-bonding networks involving protonated histidines internal to each protein. The interface features two key FcRn tryptophan side chains inserting into deep hydrophobic pockets on HSA that overlap albumin ligand binding sites. We find that fatty acids (FAs) compete with FcRn, revealing a clash between ligand binding and recycling, and that our high-affinity HSA variants have significantly increased circulating half-lives in mice and monkeys. These observations open the way for the creation of biotherapeutics with significantly improved pharmacokinetics