A secreted PD-L1 splice variant that covalently dimerizes and mediates immunosuppression

Targeting immune checkpoint pathways, such as programmed death ligand-1 (PD-L1, also known as CD274 or B7-H1) or its receptor programmed cell death-1 (PD-1) has shown improved survival for patients with numerous types of cancers, not limited to lung cancer, melanoma, renal cell carcinoma, and Hodgkin lymphoma. PD-L1 is a co-inhibitory molecule whose expression on the surface of tumor cells is associated with worse prognosis in many tumors. Here we describe a splice variant (secPD-L1) that does not splice into the transmembrane domain, but instead produces a secreted form of PD-L1 that has a unique 18 amino acid tail containing a cysteine that allows it to homodimerize and more effectively inhibit lymphocyte function than monomeric soluble PD-L1. We show that recombinant secPD-L1 can dimerize and inhibit T-cell proliferation and IFN-gamma production in vitro. The secPD-L1 variant is expressed by malignant cells in vitro that also express high levels of full-length PD-L1. Transcriptomic analysis of gene expression across The Cancer Genome Atlas found the strongest association of secPD-L1 with full-length PD-L1, but also with subsets of immunologic genes, such as in myeloid-derived suppressor cells. Moreover, the splice variant is also expressed in normal tissues and within normal peripheral blood cells it is preferentially expressed in activated myeloid cells. This is the first report of a form of secreted PD-L1 that homodimerizes and is functionally active. SecPD-L1 may function as a paracrine negative immune regulator within the tumor, since secPD-L1 does not require a cell-to-cell interaction to mediate its inhibitory effect

Two-pion Bose-Einstein correlations in central Pb-Pb collisions at sNN\sqrt{s_{\rm NN}} = 2.76 TeV

The first measurement of two-pion Bose-Einstein correlations in central Pb-Pb collisions at $\sqrt{s_{\rm NN}} = 2.76$ TeV at the Large Hadron Collider is presented. We observe a growing trend with energy now not only for the longitudinal and the outward but also for the sideward pion source radius. The pion homogeneity volume and the decoupling time are significantly larger than those measured at RHIC.Comment: 17 pages, 5 captioned figures, 1 table, authors from page 12, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/388

Suppression of charged particle production at large transverse momentum in central Pb-Pb collisions at sNN=2.76\sqrt{s_{\rm NN}} = 2.76 TeV

Inclusive transverse momentum spectra of primary charged particles in Pb-Pb collisions at $\sqrt{s_{_{\rm NN}}}$ = 2.76 TeV have been measured by the ALICE Collaboration at the LHC. The data are presented for central and peripheral collisions, corresponding to 0-5% and 70-80% of the hadronic Pb-Pb cross section. The measured charged particle spectra in $|\eta|<0.8$ and $0.3 < p_T < 20$ GeV/$c$ are compared to the expectation in pp collisions at the same $\sqrt{s_{\rm NN}}$, scaled by the number of underlying nucleon-nucleon collisions. The comparison is expressed in terms of the nuclear modification factor $R_{\rm AA}$. The result indicates only weak medium effects ($R_{\rm AA} \approx$ 0.7) in peripheral collisions. In central collisions, $R_{\rm AA}$ reaches a minimum of about 0.14 at $p_{\rm T}=6$-7GeV/$c$ and increases significantly at larger $p_{\rm T}$. The measured suppression of high-$p_{\rm T}$ particles is stronger than that observed at lower collision energies, indicating that a very dense medium is formed in central Pb-Pb collisions at the LHC.Comment: 15 pages, 5 captioned figures, 3 tables, authors from page 10, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/98

Strategies for improving the efficacy of a H6 subtype avian influenza DNA vaccine in chickens

A low-pathogenicity avian influenza H6N2 virus was used to investigate approaches to improve DNA vaccine efficacy. The viral hemagglutinin (HA) gene or its chicken biased HA gene, incorporating a Kozak sequence, was cloned into a pCAGGS vector to produce the pCAG-HAk and pCAG-optiHAk constructs. Following two intramuscular injections, the seroconversion rate in vaccinated chickens with 10, 100 or 300 μg pCAG-HAk were 87.5%, 75% and 75%, respectively. The profile of H6 hemagglutination inhibition (HI) antibodies induced by different doses of pCAG-HAk during the 8-week study period was similar. The HI titer rose significantly in the three different dose groups following the booster and reached a plateau 2-3. weeks post-booster. In a single dose vaccination group with 100 μg pCAG-HAk, a maximum seroconversion rate reached 53.3% at 5. weeks post-vaccination. The earliest time of seroconversion appeared two weeks after DNA immunization. Following two electroporation (EP) vaccinations with 100 μg pCAG-HAk, all birds seroconverted and the HI antibody titers were significantly higher than those using intramuscular immunization, suggesting that EP was more efficient than intramuscular delivery of the DNA vaccines. In comparison, chickens immunized with 10 or 100 μg pCAG-optiHAk showed 37.5% and 87.5% seroconversion rates, respectively, at 3. weeks following the booster. The pCAG-HAk was not significantly different from the pCAG-optiHAk in either the seroconversion rate or H6 HI titer, suggesting that the codon-optimized HA DNA vaccine did not achieve significantly better immunogenicity than the pCAG-HAk vaccine

Removal of soil biota alters soil feedback effects on plant growth and defense chemistry

We examined how the removal of soil biota affects plant–soil feedback (PSF) and defense chemistry of Jacobaea vulgaris, an outbreak plant species in Europe containing the defense compounds pyrrolizidine alkaloids (PAs). Macrofauna and mesofauna, as well as fungi and bacteria, were removed size selectively from unplanted soil or soil planted with J. vulgaris exposed or not to above‐ or belowground insect herbivores. Wet‐sieved fractions, using 1000‐, 20‐, 5‐ and 0.2‐μm mesh sizes, were added to sterilized soil and new plants were grown. Sieving treatments were verified by molecular analysis of the inocula. In the feedback phase, plant biomass was lowest in soils with 1000‐ and 20‐μm inocula, and soils conditioned with plants gave more negative feedback than without plants. Remarkably, part of this negative PSF effect remained present in the 0.2‐μm inoculum where no bacteria were present. PA concentration and composition of plants with 1000‐ or 20‐μm inocula differed from those with 5‐ or 0.2‐μm inocula, but only if soils had been conditioned by undamaged plants or plants damaged by aboveground herbivores. These effects correlated with leaf hyperspectral reflectance. We conclude that size‐selective removal of soil biota altered PSFs, but that these PSFs were also influenced by herbivory during the conditioning phase

Gaming Dynamic Parimutuel Markets

Abstract. We study the strategic behavior of risk-neutral non-myopic agents in Dynamic Parimutuel Markets (DPM). In a DPM, agents buy or sell shares of contracts, whose future payoff in a particular state depends on aggregated trades of all agents. A forward-looking agent hence takes into consideration of possible future trades of other agents when making its trading decision. In this paper, we analyze non-myopic strategies in a two-outcome DPM under a simple model of incomplete information and examine whether an agent will truthfully reveal its information in the market. Specifically, we first characterize a single agent’s optimal trading strategy given the payoff uncertainty. Then, we use a two-player game to examine whether an agent will truthfully reveal its information when it only participates in the market once. We prove that truthful betting is a Nash equilibrium of the two-stage game in our simple setting for uniform initial market probabilities. However, we show that there exists some initial market probabilities at which the first player has incentives to mislead the other agent in the two-stage game. Finally, we briefly discuss when an agent can participate more than once in the market whether it will truthfully reveal its information at its first play in a three-stage game. We find that in some occasions truthful betting is not a Nash equilibrium of the three-stage game even for uniform initial market probabilities.