Effect of the Cooling Rate on the Thermal Properties of a Polythiophene Thin Film

We present a systematic study of the thermal properties and electrical properties of poly­(3-hexylthiophene) (P3HT) thin films that were thermally treated and returned to room temperature at different cooling rates. The P3HT film that was slowly cooled after annealing near the P3HT melting point displayed significantly better properties than the P3HT film cooled rapidly, possibly because the thin film had a higher density of π-stacked ordered structures. The melt-crystallized P3HT films annealed above the P3HT melting point displayed thermal and electrical properties that varied significantly, depending on the cooling rate. The field-effect mobility in the slowly cooled P3HT film was high, 1.9 × 10^–3 cm²V^–1 s^–1, whereas the rapidly cooled P3HT film displayed a low field-effect mobility of 6.9 × 10^–5 cm² V^–1 s^–1 due to the reduced degree of crystallization. We concluded that the rate at which the P3HT film was cooled to room temperature as well as the temperature of the thermal annealing process was important for the molecular structure evolution and device performance. The molecular rearrangements in the P3HT films were observed during the thermal annealing process, providing critical insights into the dynamics of the structural evolution

Benchmarking the Effective Fragment Potential Dispersion Correction on the S22 Test Set

The usual modeling of dispersion interactions in density functional theory (DFT) is often limited by the use of empirically fitted parameters. In this study, the accuracies of the popular empirical dispersion corrections and the first-principles derived effective fragment potential (EFP) dispersion correction are compared by computing the DFT-D and HF-D equilibria interaction energies and intermolecular distances of the S22 test set dimers. Functionals based on the local density approximation (LDA) and generalized gradient approximation (GGA), as well as hybrid functionals, are compared for the DFT-D calculations using coupled cluster CCSD­(T) at the complete basis set (CBS) limit as the reference method. In general, the HF-D­(EFP) method provides accurate equilibrium dimerization energies and intermolecular distances for hydrogen-bonded systems compared to the CCSD­(T)/CBS reference data without using any empirical parameters. For dispersion-dominant and mixed systems, the structures and interaction energies obtained with the B3LYP-D­(EFP) method are similar to or better than those obtained with the other DFT-D and HF-D methods. Overall, the first-principles derived -D­(EFP) correction presents a robust alternative to the empirical -D corrections when used with the B3LYP functional for dispersion-dominant and mixed systems or with Hartree–Fock for hydrogen-bonded systems

Chitooligosaccharide Induces Mitochondrial Biogenesis and Increases Exercise Endurance through the Activation of Sirt1 and AMPK in Rats

<div><p>By catabolizing glucose and lipids, mitochondria produce ATPs to meet energy demands. When the number and activity of mitochondria are not sufficient, the human body becomes easily fatigued due to the lack of ATP, thus the control of the quantity and function of mitochondria is important to optimize energy balance. By increasing mitochondrial capacity? it may be possible to enhance energy metabolism and improve exercise endurance. Here, through the screening of various functional food ingredients, we found that chitooligosaccharide (COS) is an effective inducer of mitochondrial biogenesis. In rodents, COS increased the mitochondrial content in skeletal muscle and enhanced exercise endurance. In cultured myocytes, the expression of major regulators of mitochondrial biogenesis and key components of mitochondrial electron transfer chain was increased upon COS treatment. COS-mediated induction of mitochondrial biogenesis was achieved in part by the activation of silent information regulator two ortholog 1 (Sirt1) and AMP-activated protein kinase (AMPK). Taken together, our data suggest that COS could act as an exercise mimetic by inducing mitochondrial biogenesis and enhancing exercise endurance through the activation of Sirt1 and AMPK.</p> </div

Knockdown of Sirt1 or AMPK expression diminishes the mitochondriogenic effect of COS.

<p>C2C12 myotubes were transfected with scramble (sc), Sirt1, and AMPKα siRNA by using Lipofectamine™ 2000 reagent. After transfection, cells were treated with COS (100 µg/ml, and 500 µg/ml) for 12 h. Cells were rinsed with PBS and subjected for western blotting (<b>A</b>) or the measurement of mitochondrial density (n  = 3) (<b>B</b>). ** P<0.01 vs. sc/(-) (lane 1); *** P<0.001 vs. sc/(-) (lane 1); ## P<0.01 vs. sc/COS 100 (lane 2); ### P<0.001 vs. sc/COS 100 (lane 2); &&& P<0.001 vs. sc/COS 500 (lane 3). Relative expression level of PGC1, NDUFA9, and ATP5a is calculated in <b><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0040073#pone.0040073.s009" target="_blank">Figure S9G</a></b>.</p

COS activates Sirt1 and AMPK <i>in vivo</i>.

<p>COS-administered SD rats were sacrificed and proteins from skeletal muscle were subjected to the measurement of cellular NAD⁺/NADH ratio (n  = 6) (<b>A</b>) or western blotting (<b>B</b>). ** P<0.01 vs. vehicle. Densitometry of p-AMPK was shown in <b><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0040073#pone.0040073.s009" target="_blank">Figure S9H</a></b>.</p

COS increases mitochondrial content <i>in vivo</i>.

<p><b>A</b>. Electron microscopic image of skeletal muscle. White arrows indicate clusters of mitochondria. Bar  = 2 µM. <b>B.</b> Average time of exercise endurance (n  = 6). * P<0.05 vs. vehicle<b>. C</b>. Plasma lactate level before and after exercise (n  = 6). ** P<0.01 vs. pre-exercise vehicle (lane 1); ## P<0.01 vs. post-exercise vehicle (lane 2).</p

COS requires AMPK and Sirt1 to induce mitochondrial biogenesis.

<p>Differentiated C2C12 myocytes were pre-treated with nicotinamide (NAM, 1 mM) or Compound C (ComC; 10 µM) for 2 h prior to incubation with Res (11.4 µg/ml) or COS (500 µg/ml) for 12 h. Cells were rinsed with PBS and harvested for western blotting (<b>A</b>) or the measurement of mitochondrial density (n  = 3) (<b>B</b>). * P<0.05 vs. DMSO/(-) (lane 1); # P<0.05 vs. Res/(-) (lane 2); & P<0.05 vs. COS/(-) (lane 3). Relative protein expression level of PGC1, NDUFA9, and ATP5a is shown in <b><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0040073#pone.0040073.s009" target="_blank">Figure S9E</a></b>.</p

Biological parameters of COS-treated rats.

a<p>P  = 0.19 vs. vehicle; <b>^b</b> P  = 0.08 vs. vehicle; * P<0.05 vs. vehicle; ^*** P<0.001 vs. vehicle.</p

Discovery of 2‑((<i>R</i>)‑4-(2-Fluoro-4-(methylsulfonyl)phenyl)-2-methylpiperazin-1-yl)‑<i>N</i>‑((1<i>R</i>,2<i>s</i>,3<i>S</i>,5<i>S</i>,7<i>S</i>)‑5-hydroxyadamantan-2-yl)pyrimidine-4-carboxamide (SKI2852): A Highly Potent, Selective, and Orally Bioavailable Inhibitor of 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1)

A series of picolinamide- and pyrimidine-4-carboxamide-based inhibitors of 11β-hydroxysteroid dehydrogenase type 1 was synthesized and evaluated to optimize the lead compound <b>9</b>. The combination of the replacement of a pyridine ring of <b>9</b> with a pyrimidine ring and the introduction of an additional fluorine substituent at the 2-position of the phenyl ring resulted in the discovery of a potent, selective, and orally bioavailable inhibitor, <b>18a</b> (SKI2852), which demonstrated no CYP and PXR liabilities, excellent PK profiles across species, and highly potent and sustainable PD activity. Repeated oral administration of <b>18a</b> significantly reduced blood glucose and HbA1c levels and improved the lipid profiles in <i>ob</i>/<i>ob</i> mice. Moreover, the HbA1c-lowering effect of metformin was synergistically enhanced in combination with <b>18a</b>

Insights of a Lead Optimization Study and Biological Evaluation of Novel 4‑Hydroxytamoxifen Analogs as Estrogen-Related Receptor γ (ERRγ) Inverse Agonists

We evaluated the in vitro pharmacology as well as the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of chemical entities that not only were shown to be highly selective agonists for ERRγ but also exhibited enhanced pharmacokinetic profile compared with <b>3</b> (GSK5182). <b>6g</b> and <b>10b</b> had comparable potency to <b>3</b> and were far more selective for ERRγ over the ERRα, -β, and ERα. The in vivo pharmacokinetic profiles of <b>6g</b> and <b>10b</b> were further evaluated, as they possessed superior in vitro ADMET profiles compared to the other compounds. Additionally, we observed a significant increase of fully glycosylated NIS protein, key protein for radioiodine therapy in anaplastic thyroid cancer (ATC), in <b>6g</b>- or <b>10b</b>-treated CAL62 cells, which indicated that these compounds could be promising enhancers for restoring NIS protein function in ATC cells. Thus, <b>6g</b> and <b>10b</b> possess advantageous druglike properties and can be used to potentially treat various ERRγ-related disorders