12 research outputs found
Nonflammable Dual-Salt Electrolytes for Graphite/LiNi<sub>0.8</sub>Co<sub>0.1</sub>Mn<sub>0.1</sub>O<sub>2</sub> Lithium-Ion Batteries: Li<sup>+</sup> Solvation Structure and Electrode/Eelectrolyte Interphase
Trimethyl phosphate (TMP) is the most promising safe
solvent for
lithium-ion battery (LIB) electrolyte because of the nonflammability,
oxidation stability, and low cost, but its application is hindered
by incompatibility with the graphite anode. Herein, nonflammable electrolytes
with ordinary concentration (1 mol L–1) are designed
for graphite/LiNi0.8Co0.1Mn0.1O2 (Gr/NCM811) LIBs with TMP/2,2,2-trifluoroethyl methyl carbonate
(FEMC) binary solvents. Stable cycling of the Li/Gr half cells with
high capacity is achieved via modulation of the Li+ solvation
structure. A dual-salt strategy of lithium hexafluorophosphate/lithium
difluoro(oxalato)borate is further used to realize the high performance
of the Gr/NCM811 full cells. More significantly, the functions and
relationship of Li+ solvation structure and electrode/electrolyte
interphase are elucidated. Li+ solvation structure and
interphase are respectively the thermodynamic and kinetic factors
for the side reactions of the electrolyte occurring at the electrode/electrolyte
interphase, which should be considered comprehensively in the design
of electrolytes for high-energy density LIBs
Identification of Novel Androgen Receptor Antagonists Using Structure- and Ligand-Based Methods
Androgen receptor (AR) plays a critical role in the development
and progression of prostate cancer (PCa). The AR hormone-binding site
(HBS) is intensively studied and represents the target area for current
antiandrogens including Bicalutamide and structurally related Enzalutamide.
As resistance to antiandrogens invariably emerges in advanced prostate
cancer, there exists a high medical need for the identification and
development of novel AR antagonists of different chemotypes. Given
the wealth of structural information on the AR in complex with a variety
of ligands, we have applied an integrated structure- and ligand-based
virtual screening methodology to identify novel AR antagonists. Virtual
hits generated by a consensus voting approach were experimentally
evaluated and resulted in the discovery of a number of structurally
diverse submicromolar antagonists of the AR. In particular, one identified
compound demonstrated anti-AR potency <i>in vitro</i> that
is comparable to the clinically used Bicalutamide. These results set
a ground for the development of novel classes of PCa drugs that are
structurally different from current AR antagonists
A Molybdenum Polysulfide <i>In-Situ</i> Generated from Ammonium Tetrathiomolybdate for High-Capacity and High-Power Rechargeable Magnesium Battery Cathodes
Rechargeable magnesium batteries (RMBs) are a promising
large-scale
energy-storage technology with low cost and high reliability. However,
developing high-performance cathode materials remains the most prominent
obstacle because of the insufficient magnesium-storage active sites
and unfavorable magnesium cation transport paths, as well as the strong
interaction between the cathode material and the bivalent magnesium
cation. Herein, ammonium tetrathiomolybdate is demonstrated to be
a high-performance RMB cathode material. Ammonium tetrathiomolybdate
exhibits a high capacity of 333 mAh g–1 at 50 mA
g–1 and a good rate performance of 129 mAh g–1 at 5.0 A g–1 (∼15 C). An
amorphous structure with plenty of efficient magnesium-storage active
sites and open magnesium transport paths is in situ formed during the first cycle via ammonium extraction. The covalent-like
bond between the molybdenum and sulfur delocalizes the negative charge,
weakening the interaction with the bivalent magnesium cation and accelerating
the kinetics. The covalent-like molybdenum–sulfur bond also
promotes the simultaneous redox of molybdenum and sulfur, leading
to a high specific capacity. The present work introduces a high-capacity
and high-power RMB cathode material, elucidates the origin of the
high performance, and provides insights for the design and optimization
of RMB cathode materials
Scaffold Tailoring by a Newly Detected Pictet–Spenglerase Activity of Strictosidine Synthase: From the Common Tryptoline Skeleton to the Rare Piperazino-indole Framework
The Pictet–Spenglerase strictosidine synthase
(STR1) has
been recognized as a key enzyme in the biosynthesis of some 2000 indole
alkaloids in plants, some with high therapeutic value. In this study,
a novel function of STR1 has been detected which allows for the first
time a simple enzymatic synthesis of the strictosidine analogue <b>3</b> harboring the piperazinoÂ[1,2-<i>a</i>]Âindole (PI)
scaffold and to switch from the common tryptoline (hydrogenated carboline)
to the rare PI skeleton. Insight into the reaction is provided by
X-ray crystal analysis and modeling of STR1 ligand complexes. STR1
presently provides exclusively access to <b>3</b> and can act
as a source to generate by chemoenzymatic approaches libraries of
this novel class of alkaloids which may have new biological activities.
Synthetic or natural monoterpenoid alkaloids with the PI core have
not been reported before
Flagellin and CpG ODN induce robust innate inflammatory infiltrates in the lung.
<p>(<b>A</b>), (<b>B</b>) Neutrophil accumulation in the airways one day after a single i.n. administration (d1) of OVA (O) or OVA plus flagellin (1 μg) (OFla) in wildtype, <i>Tlr5</i><sup><i>-/-</i></sup><i>Tlr11</i><sup><i>-/-</i></sup>, and <i>Nlrc4</i><sup><i>-/-</i></sup> mice (<b>A</b>) or in wildtype, <i>Tlr5</i><sup><i>-/-</i></sup><i>Tlr11</i><sup><i>-/-</i></sup> and <i>Tlr4</i><sup><i>-/-</i></sup> mice (<b>B</b>), as assessed by flow cytometry of the cells in the BAL fluid. (<b>C</b>) Cellular composition of the innate inflammatory infiltrate in the lung one day after the third i.n. sensitization (d3) with OVA, OVA plus flagellin (1 μg), or OVA plus CpG ODN (3 μg) (OCpG). Data in (<b>A</b>) contain 4 mice per group and are representative of two independent experiments, data in (<b>B</b>) contain 4 mice per group and are representative of two independent experiments, and data in (<b>C</b>) contain 3–4 mice per group and are representative of three independent experiments. Error bars indicate mean +SD. * P ≤ 0.05, ** P ≤ 0.01, *** P ≤ 0.001 using one-way anova with Bonferroni post-test. In (<b>A</b>) and (<b>B</b>), all groups of OVA-treated mice have statistically significant different values compared to OVA plus flagellin-treated wild-type mice (<b>A</b> and <b>B</b>), <i>Nlrc4</i><sup><i>-/-</i></sup> (<b>A</b>), and <i>Tlr4</i><sup><i>-/-</i></sup> mice (<b>B</b>) (*** P ≤ 0.001 for all comparisons; not indicated on the panel).</p
Migratory DCs require MyD88 signaling to respond normally to i.n. exposure to flagellin or CpG ODN.
<p>Expression of activation markers on migratory DCs in the lung-draining, mediastinal LNs of <i>Myd88</i><sup><i>fl/fl</i></sup> (<i>M</i><sup><i>F</i></sup>) and <i>Myd88</i><sup><i>fl/fl</i></sup> <i>CD11c-Cre</i> (<i>M</i><sup><i>F</i></sup> <i>CD11c-Cre</i>) mice one day after i.n. administration (d1) of OVA-AF647 or OVA-AF647 plus TLR ligand. (<b>A</b>) Migratory DCs were gated as CD11c<sup>+</sup>I-A<sup>b(hi)</sup>, then gated according to OVA-AF647 expression. (<b>B</b>) and (<b>C</b>) Comparison of different activation markers on migratory DCs between <i>M</i><sup><i>F</i></sup> and <i>M</i><sup><i>F</i></sup> <i>CD11c-Cre</i> mice treated i.n with OVA-AF647, OVA-AF647 plus flagellin (1 μg), or OVA-AF647 plus CpG (0.75 or 3 μg). (<b>B</b>) Representative histograms of different activation markers on migratory DCs that did take up OVA-AF647. (<b>C</b>) Level of expression (MFI) of activation markers on migratory DCs that did (OVA<sup>+</sup>) or did not (OVA<sup>-</sup>) take up fluorescent OVA. (<b>D</b>) and (<b>E</b>) Comparison of different activation markers on migratory DCs between <i>M</i><sup><i>F</i></sup> and <i>M</i><sup><i>F</i></sup> <i>CD11c-Cre</i> treated i.n with OVA-AF647 or OVA-AF647 plus CpG ODN (0.75 μg). (<b>D</b>) Representative histograms of different activation markers on migratory DCs that did take up OVA-AF647. (<b>E</b>) Level of expression (MFI) of activation markers on migratory DCs that did (OVA<sup>+</sup>) or did not (OVA<sup>-</sup>) take up fluorescent OVA. Data in (<b>B</b>) and (<b>C</b>) contain 3–4 mice per group and are representative of 3 independent experiments using OVA-AF647 and a fourth independent experiment using non-fluorescent OVA. Data in (<b>D</b>) and (<b>E</b>) contain 4–6 mice per group and are representative of two independent experiments. Negative control histograms (solid light gray) were from CD11c<sup>-</sup>I-A<sup>b-</sup> cells. Each circle represents an individual mouse. Error bars indicate mean +SD. * P ≤ 0.05, ** P ≤ 0.01, *** P ≤ 0.001 using one-way anova with Bonferroni post-test.</p
Multiple cytokines are likely involved in flagellin-induced T cell responses.
<p><i>Myd88</i><sup><i>fl/fl</i></sup> (<i>M</i><sup><i>F</i></sup>) and <i>Myd88</i><sup><i>fl/fl</i></sup> <i>CD11c-Cre</i> expressing the 4get/KN2 reporter were treated with anti-TSLP (IgG2a), anti-IL-33R (IgG1), and/or appropriate control antibodies (rat IgG2a, rat IgG1), one day before initial sensitization (i.p. 250 μg anti-TSLP, 160 μg anti-IL-33R, or corresponding amounts of appropriate isotype controls), and anti-IL-33R or rat IgG1 again on d2 (i.p. 160 μg). These mice were then administered i.n. OVA or OVA plus flagellin (1 μg) on d0, 1, and 2. On d6, expression of IL-4 (GFP<sup>+</sup>hCD2<sup>+</sup>) by CD4 T cells in the mediastinal LN was examined using the same gating strategy as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0167693#pone.0167693.g005" target="_blank">Fig 5</a>. (<b>A</b>) Numbers of CD4 T cells, (<b>B</b>) percentages and (<b>C</b>) numbers of GFP<sup>+</sup>IL-4<sup>+</sup>(hCD2<sup>+</sup>) CD4 T cells. Data are pooled from three independent experiments, one of which did not have the anti-TSLP and IL-33R treatment group, with combined totals of 7–11 mice per group. The comparisons between <i>M</i><sup><i>F</i></sup> mice treated i.n. with OVA or OVA plus flagellin, and <i>M</i><sup><i>F</i></sup> <i>CD11c-Cre</i> mice treated i.n. with OVA plus flagellin are representative of three additional independent experiments. Each circle represents one individual mouse. Error bars indicate mean +SD. * P ≤ 0.05, ** P ≤ 0.01, *** P ≤ 0.001 using one-way anova with Bonferroni post-test.</p
Flagellin induces rapid production of inflammatory cytokines by AMs, LECs, Ly6C<sup>hi</sup> monocytes, and CD103<sup>+</sup> cDCs.
<p>Inflammatory gene mRNA inductions and IL-33 protein in whole lung tissue (<b>A-E</b>), enriched lung cell populations (<b>E</b>), or sorted cell populations from the lung (<b>F</b>) after one i.n. administration of OVA, OVA plus flagellin (1 μg), or OVA plus CpG (3 μg). mRNA inductions were normalized to <i>Hprt</i>. (<b>A</b>) Inflammatory gene mRNA inductions in whole lung tissue 2h after i.n. administration. (<b>B</b>) IL-33 protein in whole lung homogenates at the indicated time points. (<b>C-F</b>) Inflammatory gene mRNA inductions were measured in whole lung tissue (<b>C</b>, <b>D</b>), in fractionated lung epithelial or hematopoietic-derived cell populations (<b>E</b>), or in sorted cell populations (<b>F</b>) 2h after i.n. administration of <i>Myd88</i><sup><i>fl/fl</i></sup> mice (<i>M</i><sup><i>F</i></sup>), <i>Myd88</i><sup><i>fl/fl</i></sup> <i>CD11c-Cre</i> (<i>M</i><sup><i>F</i></sup> <i>CD11c-Cre</i>) mice, or <i>Myd88</i><sup><i>fl/fl</i></sup> <i>LysM-Cre</i> (<i>M</i><sup><i>F</i></sup> <i>LysM-Cre</i>) mice. Data in (<b>A</b>) contain 5 mice per group and are representative of two independent experiments, data in (<b>B</b>) contain 3 mice per group and are representative of two independent experiments at each time point, data in (<b>C</b>) contain 3–5 mice per group and are representative of three independent experiments, data in (<b>D</b>) contain 3 mice per group and are representative of two independent experiments, data in (<b>E</b>) contain 3–4 mice per group and are representative of two independent experiments, and data in (<b>F</b>) are pooled from two independent experiments with combined totals of 6–7 mice per group; each circle represents the data from sorted cells obtained from 3–4 mice. Error bars indicate mean +SD. In (<b>A</b>), statistical differences (P ≤ 0.05) are indicated with the following symbols: O vs. OFla (†), and OFla vs. OCpG (00B6).* P ≤ 0.05, ** P ≤ 0.01, *** P ≤ 0.001 using one-way anova with Bonferroni post-test (<b>A</b>-<b>D</b>) or Student’s <i>t</i>-test within the same tissue/cell population (<b>E</b>).</p
Flagellin, but not CpG ODN, promotes development of IL-4-producing CD4 T cells in the draining LN.
<p>4get/KN2 reporter mice were administered OVA, OVA plus flagellin (1 μg), or OVA plus CpG (0.75 μg) i.n. on d0, 1 and 2. In addition, to block IL-12 action in some mice, mice were given anti-IL-12 p40 or control antibody (rat IgG2a) twice, one day before initial sensitization (700 μg i.p.) and again on d2 (300 μg i.p.). On d6, expression of IL-4 reporters (GFP<sup>+</sup>hCD2<sup>+</sup>) by CD4 T cells was examined in the mediastinal LN. (<b>A</b>) Gating strategy of CD4 T cells (CD4<sup>+</sup>), activated CD4 T cells (CD4<sup>+</sup>CD44<sup>hi</sup>B220<sup>-</sup>CD62L<sup>-</sup>), and T<sub>FH</sub> cells (CD4<sup>+</sup>CD44<sup>hi</sup>B220<sup>-</sup>CD62L<sup>-</sup>PD-1<sup>+</sup>CXCR5<sup>+</sup>). (<b>B</b>) Numbers of CD4 T cells, percentages and numbers of GFP<sup>+</sup>IL-4<sup>+</sup>(hCD2<sup>+</sup>) CD4 T cells. (<b>C</b>) Percentages and numbers of activated CD4 T cells, percentages and numbers of T<sub>FH</sub> cells, and percentages and numbers of GFP<sup>+</sup>IL-4<sup>+</sup>(hCD2<sup>+</sup>) T<sub>FH</sub>. Data are pooled from two independent experiments with combined totals of 8 mice per group. Each circle represents one individual mouse. Error bars indicate mean +SD. * P ≤ 0.05, ** P ≤ 0.01, *** P ≤ 0.001 using one-way anova with Bonferroni post-test.</p