CpG Oligodeoxynucleotides Enhance the Efficacy of Adoptive Cell Transfer Using Tumor Infiltrating Lymphocytes by Modifying the Th1 Polarization and Local Infiltration of Th17 Cells

Adoptive cell transfer immunotherapy using tumor infiltrating lymphocytes (TILs) was an important therapeutic strategy against tumors. But the efficacy remains limited and development of new strategies is urgent. Recent evidence suggested that CpG-ODNs might be a potent candidate for tumor immunotherapy. Here we firstly reported that CpG-ODNs could significantly enhance the antitumor efficacy of adoptively transferred TILs in vivo accompanied by enhanced activity capacity and proliferation of CD8+ T cells and CD8+ T cells, as well as a Th1 polarization immune response. Most importantly, we found that CpG-ODNs could significantly elevate the infiltration of Th17 cells in tumor mass, which contributed to anti-tumor efficacy of TILs in vivo. Our findings suggested that CpG ODNs could enhance the anti-tumor efficacy of adoptively transferred TILs through modifying Th1 polarization and local infiltration of Th17 cells, which might provide a clue for developing a new strategy for ACT based on TILs

Energy loss enhancement of very intense proton beams in dense matter due to the beam-density effect

Thoroughly understanding the transport and energy loss of intense ion beams in dense matter is essential for high-energy-density physics and inertial confinement fusion. Here, we report a stopping power experiment with a high-intensity laser-driven proton beam in cold, dense matter. The measured energy loss is one order of magnitude higher than the expectation of individual particle stopping models. We attribute this finding to the proximity of beam ions to each other, which is usually insignificant for relatively-low-current beams from classical accelerators. The ionization of the cold target by the intense ion beam is important for the stopping power calculation and has been considered using proper ionization cross section data. Final theoretical values agree well with the experimental results. Additionally, we extend the stopping power calculation for intense ion beams to plasma scenario based on Ohm's law. Both the proximity- and the Ohmic effect can enhance the energy loss of intense beams in dense matter, which are also summarized as the beam-density effect. This finding is useful for the stopping power estimation of intense beams and significant to fast ignition fusion driven by intense ion beams

High probability neurotransmitter release sites represent an energy efficient design

At most synapses, the probability of neurotransmitter release from an active zone (PAZ) is low, a design thought to confer many advantages. Yet, high PAZ can also be found at synapses. Speculating that high PAZ confers high energy efficiency, we examined energy efficiency at terminals of two Drosophila motor neurons (MNs) synapsing on the same muscle fiber, but with contrasting average PAZ. Through electrophysiological and ultrastructural measurements we calculated average PAZ for MNSNb/d-Is and MN6-Ib terminals (0.33±0.10 and 0.11±0.02 respectively). Using a miles-per-gallon analogy, we calculated efficiency as the number of glutamate molecules released for each ATP molecule that powers the release and recycling of glutamate and the removal of calcium (Ca2+) and sodium (Na+). Ca2+ and Na+ entry were calculated by microfluorimetry and morphological measurements respectively. Terminals with the highest PAZ release more glutamate but admit less Ca2+ and Na+, supporting the hypothesis that high PAZ confers greater energy efficiency than low PAZ (0.13±0.02 and 0.06±0.01 respectively). In an analytical treatment of parameters that influence efficiency we found that efficiency could be optimized in either terminal by increasing PAZ. Terminals with highest PAZ operate closest to this optimum but are less active and less able to sustain high release rates. Adopting an evolutionary biological perspective, we interpret the persistence of low PAZ release sites at more active terminals to be the result of selection pressures for sustainable neurotransmitter release dominating selection pressures for high energy efficiency

Geochemical reactions altering the mineralogical and multiscale pore characteristics of uranium-bearing reservoirs during CO2 + O2in situ leaching

CO2 + O2in situ leaching has been extensively applied in uranium recovery in sandstone-type uranium deposits of China. The geochemical processes impact and constrain the leaching reaction and leaching solution migration; thus, it is necessary to study the CO2 + O2–water–rock geochemical reaction process and its influence on the physical properties of uranium-bearing reservoirs. In this work, a CO2 + O2–water–rock geochemical reaction simulation experiment was carried out, and the mineralogical and multiscale pore characteristics of typical samples before and after this simulation experiment were compared by X-ray diffraction and high-pressure mercury intrusion porosimetry (HPMIP). The results show that the CO2 + O2–water–rock geochemical reaction has complicated effects on the mineral compositions due to the various reaction modes and types. After the CO2 + O2–water–rock geochemical reaction, the femic minerals decrease and the clay minerals in the coarse sandstone, medium sandstone, fine sandstone, and siltstone increase, while the femic minerals and clay minerals in sandy mudstone show a contrary changing trend. The CO2 + O2–water–rock geochemical reaction decreases the total pore volume of uranium-bearing reservoirs and then promotes pore transformation from small scale to large scale. The fractal dimensions of macropores are decreased, and the fractal dimensions of mesopores, transition pores, and micropores are increased. The effects of felsic mineral and carbonate dissolution, secondary mineral precipitate, clay mineral swelling, and mineral particle migration are simultaneously present in the CO2 + O2in situ leaching process, which exhibit the positive transformation and the negative transformation for the uranium-bearing reservoirs. The mineral dissolution may improve reservoir permeability to a certain degree, while the siltation effect will gradually reveal with the extension of CO2 + O2in situ leaching. This research will provide a deep understanding of the physical property response of uranium-bearing reservoirs during CO2 + O2in situ leaching and indicate the direction for the efficient recovery of uranium resources

Target density effects on charge tansfer of laser-accelerated carbon ions in dense plasma

We report on charge state measurements of laser-accelerated carbon ions in the energy range of several MeV penetrating a dense partially ionized plasma. The plasma was generated by irradiation of a foam target with laser-induced hohlraum radiation in the soft X-ray regime. We used the tri-cellulose acetate (C$_{9}$H$_{16}$O$_{8}$) foam of 2 mg/cm$^{-3}$ density, and $1$-mm interaction length as target material. This kind of plasma is advantageous for high-precision measurements, due to good uniformity and long lifetime compared to the ion pulse length and the interaction duration. The plasma parameters were diagnosed to be T$_{e}$=17 eV and n$_{e}$=4 $\times$ 10$^{20}$ cm$^{-3}$. The average charge states passing through the plasma were observed to be higher than those predicted by the commonly-used semiempirical formula. Through solving the rate equations, we attribute the enhancement to the target density effects which will increase the ionization rates on one hand and reduce the electron capture rates on the other hand. In previsous measurement with partially ionized plasma from gas discharge and z-pinch to laser direct irradiation, no target density effects were ever demonstrated. For the first time, we were able to experimentally prove that target density effects start to play a significant role in plasma near the critical density of Nd-Glass laser radiation. The finding is important for heavy ion beam driven high energy density physics and fast ignitions.Comment: 7 pages, 4 figures, 35 conference

BAFF Promotes Th17 Cells and Aggravates Experimental Autoimmune Encephalomyelitis

BAFF, in addition to promoting B cell survival and differentiation, may affect T cells. The objective of this study was to determine the effect of BAFF on Th17 cell generation and its ramifications for the Th17 cell-driven disease, EAE.Th17 cells were increased in BAFF-Tg B6 (B6.BTg) mice and decreased in B6.Baff(-/-) mice. Th17 cells in B6.Baff(-/-) mice bearing a BAFF Tg (B6.Baff(-/-).BTg mice) were identical to those in B6.BTg mice, indicating that membrane BAFF is dispensable for Th17 cell generation as long as soluble BAFF is plentiful. In T + non-T cell criss-cross co-cultures, Th17 cell generation was greatest in cultures containing B6.BTg T cells and lowest in cultures containing B6.Baff(-/-) T cells, regardless of the source of non-T cells. In cultures containing only T cells, Th17 cell generation followed an identical pattern. CD4(+) cell expression of CD126 (IL-6R α chain) was increased in B6.BTg mice and decreased in B6.Baff(-/-) mice, and activation of STAT3 following stimulation with IL-6 + TGF-β was also greatest in B6.BTg cells and lowest in B6.Baff(-/-) cells. EAE was clinically and pathologically most severe in B6.BTg mice and least severe in B6.Baff(-/-) mice and correlated with MOG(35-55) peptide-induced Th17 cell responses.Collectively, these findings document a contribution of BAFF to pathogenic Th17 cell responses and suggest that BAFF antagonism may be efficacious in Th17 cell-driven diseases

All-Trans Retinoic Acid Promotes TGF-β-Induced Tregs via Histone Modification but Not DNA Demethylation on Foxp3 Gene Locus

It has been documented all-trans retinoic acid (atRA) promotes the development of TGF-β-induced CD4(+)Foxp3(+) regulatory T cells (iTreg) that play a vital role in the prevention of autoimmune responses, however, molecular mechanisms involved remain elusive. Our objective, therefore, was to determine how atRA promotes the differentiation of iTregs.Addition of atRA to naïve CD4(+)CD25(-) cells stimulated with anti-CD3/CD28 antibodies in the presence of TGF-β not only increased Foxp3(+) iTreg differentiation, but maintained Foxp3 expression through apoptosis inhibition. atRA/TGF-β-treated CD4(+) cells developed complete anergy and displayed increased suppressive activity. Infusion of atRA/TGF-β-treated CD4(+) cells resulted in the greater effects on suppressing symptoms and protecting the survival of chronic GVHD mice with typical lupus-like syndromes than did CD4(+) cells treated with TGF-β alone. atRA did not significantly affect the phosphorylation levels of Smad2/3 and still promoted iTreg differentiation in CD4(+) cells isolated from Smad3 KO and Smad2 conditional KO mice. Conversely, atRA markedly increased ERK1/2 activation, and blockade of ERK1/2 signaling completely abolished the enhanced effects of atRA on Foxp3 expression. Moreover, atRA significantly increased histone methylation and acetylation within the promoter and conserved non-coding DNA sequence (CNS) elements at the Foxp3 gene locus and the recruitment of phosphor-RNA polymerase II, while DNA methylation in the CNS3 was not significantly altered.We have identified the cellular and molecular mechanism(s) by which atRA promotes the development and maintenance of iTregs. These results will help to enhance the quantity and quality of development of iTregs and may provide novel insights into clinical cell therapy for patients with autoimmune diseases and those needing organ transplantation