Switchable Plasmonic–Dielectric Resonators with Metal–Insulator Transitions

Nanophotonic resonators offer the ability to design nanoscale optical elements and engineered materials with unconventional properties. Dielectric-based resonators intrinsically support a complete multipolar resonant response with low absorption, while metallic resonators provide extreme light confinement and enhanced photon–electron interactions. Here, we construct resonators out of a prototypical metal–insulator transition material, vanadium dioxide (VO₂), and demonstrate switching between dielectric and plasmonic resonances. We first characterize the temperature-dependent infrared optical constants of VO₂ single crystals and thin-films. We then fabricate VO₂ wire arrays and disk arrays. We show that wire resonators support dielectric resonances at low temperatures, a damped scattering response at intermediate temperatures, and plasmonic resonances at high temperatures. In disk resonators, however, upon heating, there is a pronounced enhancement of scattering at intermediate temperatures and a substantial narrowing of the phase transition. These findings may lead to the design of novel nanophotonic devices that incorporate thermally switchable plasmonic–dielectric behavior

Charge-Transfer-Induced Isomerization of DCNQI on Cu(100)

This article reports on the temperature-controlled irreversible transition between the two isomeric forms of the strong electron acceptor dicyano-<i>p</i>-quinonediimine (DCNQI) on the Cu(100) surface. A combination of experiment (time-resolved, variable-temperature scanning tunneling microscopy, STM) and theory (density functional theory, DFT) shows that the isomerization barrier is lower than in the gas phase or solution due to the fact that charge transfer from the substrate modifies the bond configuration of the molecule, aromatizing the quinoid ring of DCNQI and enabling a more free rotation of the cyano groups with respect to the molecular axis

Ancient Mycobacterium leprae genome reveals medieval English red squirrels as animal leprosy host

Leprosy, one of the oldest recorded diseases in human history, remains prevalent in Asia, Africa, and South America, with over 200,000 cases every year.1,2 Although ancient DNA (aDNA) approaches on the major causative agent, Mycobacterium leprae, have elucidated the disease’s evolutionary history,3,4,5 the role of animal hosts and interspecies transmission in the past remains unexplored. Research has uncovered relationships between medieval strains isolated from archaeological human remains and modern animal hosts such as the red squirrel in England.6,7 However, the time frame, distribution, and direction of transmissions remains unknown. Here, we studied 25 human and 12 squirrel samples from two archaeological sites in Winchester, a medieval English city well known for its leprosarium and connections to the fur trade. We reconstructed four medieval M. leprae genomes, including one from a red squirrel, at a 2.2-fold average coverage. Our analysis revealed a phylogenetic placement of all strains on branch 3 as well as a close relationship between the squirrel strain and one newly reconstructed medieval human strain. In particular, the medieval squirrel strain is more closely related to some medieval human strains from Winchester than to modern red squirrel strains from England, indicating a yet-undetected circulation of M. leprae in non-human hosts in the Middle Ages. Our study represents the first One Health approach for M. leprae in archaeology, which is centered around a medieval animal host strain, and highlights the future capability of such approaches to understand the disease’s zoonotic past and current potential.</p

Free Fatty Acid Receptor 1 (FFA1/GPR40) Agonists: Mesylpropoxy Appendage Lowers Lipophilicity and Improves ADME Properties

FFA1 (GPR40) is a new target for treatment of type 2 diabetes. We recently identified the potent FFA1 agonist TUG-469 (<b>5</b>). Inspired by the structurally related TAK-875, we explored the effects of a mesylpropoxy appendage on <b>5</b>. The appendage significantly lowers lipophilicity and improves metabolic stability while preserving potency, resulting in discovery of the potent FFA1 agonist <b>13</b>

Discovery of TUG-770: A Highly Potent Free Fatty Acid Receptor 1 (FFA1/GPR40) Agonist for Treatment of Type 2 Diabetes

Free fatty acid receptor 1 (FFA1 or GPR40) enhances glucose-stimulated insulin secretion from pancreatic β-cells and currently attracts high interest as a new target for the treatment of type 2 diabetes. We here report the discovery of a highly potent FFA1 agonist with favorable physicochemical and pharmacokinetic properties. The compound efficiently normalizes glucose tolerance in diet-induced obese mice, an effect that is fully sustained after 29 days of chronic dosing

Discovery of a Potent and Selective Free Fatty Acid Receptor 1 Agonist with Low Lipophilicity and High Oral Bioavailability

The free fatty acid receptor 1 (FFA1, also known as GPR40) mediates enhancement of glucose-stimulated insulin secretion and is emerging as a new target for the treatment of type 2 diabetes. Several FFA1 agonists are known, but the majority of these suffer from high lipophilicity. We have previously reported the FFA1 agonist <b>3</b> (TUG-424). We here describe the continued structure–activity exploration and optimization of this compound series, leading to the discovery of the more potent agonist <b>40</b>, a compound with low lipophilicity, excellent in vitro metabolic stability and permeability, complete oral bioavailability, and appreciable efficacy on glucose tolerance in mice

Time to the most recent common ancestor (tMRCAs) for the entire <i>M</i>. <i>leprae</i> tree and individual branches (HPD = Highest Posterior Density).

<p>Time to the most recent common ancestor (tMRCAs) for the entire <i>M</i>. <i>leprae</i> tree and individual branches (HPD = Highest Posterior Density).</p

Results of the genome-wide analysis for the samples with sufficient coverage.

<p>Results of the genome-wide analysis for the samples with sufficient coverage.</p

Worldwide distribution of the ancient and modern <i>M</i>. <i>leprae</i> strains analyzed in this study.

<p>Skulls represent strains from osteological specimens dated to the Medieval Period. Human silhouettes represent modern strains, sized to scale according to the number of samples, ranging from 1 (e.g. India) to 36 (South America) Animal silhouettes represent strains from the red squirrel, the nine-banded armadillo, and naturally infected nonhuman primates (a chimpanzee from Sierra Leone, a sooty mangabey from West Africa, and a cynomolgus macaque from The Philippines). Skulls outlined in black are the new <i>M</i>. <i>leprae</i> genomes reconstructed in this study, while skulls outlined in blue represent previously sequenced ancient genomes. Grey skulls are leprosy samples from this study that did not yield sufficient sequence for whole-genome analysis. The main <i>M</i>. <i>leprae</i> lineages, represented by branches (see <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1006997#ppat.1006997.g002" target="_blank">Fig 2</a>) are color-coded.</p

Phylogenetic analysis of ancient and modern <i>M</i>. <i>leprae</i> strains.

<p>(<b>A</b>) Maximum parsimony tree reconstructed from 3124 informative SNP positions. The tree is drawn to scale, with branch lengths representing number of substitutions. <i>M</i>. <i>lepromatosis</i> was used as outgroup. The novel strains from this study are labelled in red, and the previously published ancient strains are labelled in blue. Animal symbols indicate strains isolated from red squirrels, armadillos and non-human primates. The main branches are color-coded, and the SNP subtypes are marked with dotted vertical bars. Bootstrap values (500 replicates) are shown next to each node. (<b>B</b>) Bayesian phylogenetic tree based on 2371 SNP positions calculated with BEAST 1.8.1. Median divergence times in years B.C.E. and C.E. are shown on the main nodes (the 95% Highest Posterior Density ranges are given in square brackets). Tip labels for each sample show the name, the country of origin and the isolation date, or the radiocarbon dates. The novel strains from this study are labelled in red, and the previously published ancient strains are labelled in blue. Posterior probabilities for each node are shown in grey. The main branches are color-coded. The hypermutator strains 85054, Amami, S15, Br14-3, Br2016-15, Zensho-4, Zensho-5 and Zensho-9 (as described in [<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1006997#ppat.1006997.ref014" target="_blank">14</a>]) were excluded from this analysis.</p