Type I interferon is critical for the homeostasis and functional maturation of type 3 γδ T cells

Iridium­(III) cyclometalates (<b>1c</b> and <b>2c</b>) in which the two carborane units on the 4- or 5-positions of 2-phenylpyridine (ppy) ligands were tethered by an alkylene linker were prepared to investigate the effect of free rotation of <i>o</i>-carborane on phosphorescence efficiency. In comparison with the unlinked complex, tethering the <i>o</i>-carboranes to the 5-positions of ppy ligands (<b>2c</b>) enhanced phosphorescence efficiency by over 30-fold in polar medium (Φ_PL = 0.37 vs 0.011 in THF), while restricting the rotation of <i>o</i>-carborane at the 4-positions (<b>1c</b>) negatively affected the phosphorescence efficiency. The different effects of restricted rotation of <i>o</i>-carborane on phosphorescence efficiency were likely a result of the different variations of the carboranyl C–C bond distances in the excited state

New methods for the detection of cyanide based on displacement of the glutathione ligand of glutathionylcobalamin by cyanide

<p>Glutathionylcobalamin (GSCbl) is a vitamin B₁₂ derivative that contains glutathione as the upper axial ligand to cobalt via a Co–S bond. In the present study, we discovered that cyanide reacted with GSCbl, generating cyanocobalamin (CNCbl) and reduced glutathione (GSH) via dicyanocobalamin (diCNCbl) intermediate. This reaction was induced specifically by the nucleophilic attack of cyanide anion displacing the glutathione ligand of GSCbl. Based on the reaction of GSCbl with cyanide, we developed new methods for the detection of cyanide. The reaction intermediate, violet-coloured diCNCbl, could be applied for naked eye detection of cyanide and the detection limit was estimated to be as low as 520 μg L⁻¹ (20 μM) at pH = 10.0. The reaction product, CNCbl, could be applied for a spectrophotometric quantitative determination of cyanide with a detection limit of 26 μg L⁻¹ (1.0 μM) at pH = 9.0 and a linear range of 26–520 μg L⁻¹ (1.0–50 μM). In addition, the other reaction product, GSH, could be applied for a fluorometric quantitative determination of cyanide with a detection limit of 31 μg L⁻¹ (1.2 μM) at pH = 9.0 and a linear range of 31–520 μg L⁻¹ (1.2–20 μM). These new GSCbl-based methods are simple, highly specific and sensitive with great applicability for the detection of cyanide in biological and non-biological samples.</p

Exploring the Substrate Specificity of a Sugar Transporter with Biosensors and Cheminformatics

Sugars will eventually be exported transporters (SWEETs) are conserved sugar transporters that play crucial roles in plant physiology and biotechnology. The genomes of flowering plants typically encode about 20 SWEET paralogs that can be classified into four clades. Clades I, II, and IV have been reported to favor hexoses, while clade III SWEETs prefer sucrose. However, the molecular features of substrates required for recognition by members of this family have not been investigated in detail. Here, we show that SweetTrac1, a previously reported biosensor constructed from the Clade I Arabidopsis thaliana SWEET1, can provide insight into the structural requirements for substrate recognition. The biosensor translates substrate binding to the transporter into a change in fluorescence, and its application in a small-molecule screen combined with cheminformatics uncovered 12 new sugars and their derivatives capable of eliciting a response. Furthermore, we confirmed that the wild-type transporter mediates cellular uptake of three of these species, including the diabetes drugs 1-deoxynojirimycin and voglibose. Our results show that SWEETs can recognize different furanoses, pyranoses, and acyclic sugars, illustrating the potential of combining biosensors and computational techniques to uncover the basis of substrate specificity

Exploring the Substrate Specificity of a Sugar Transporter with Biosensors and Cheminformatics

Sugars will eventually be exported transporters (SWEETs) are conserved sugar transporters that play crucial roles in plant physiology and biotechnology. The genomes of flowering plants typically encode about 20 SWEET paralogs that can be classified into four clades. Clades I, II, and IV have been reported to favor hexoses, while clade III SWEETs prefer sucrose. However, the molecular features of substrates required for recognition by members of this family have not been investigated in detail. Here, we show that SweetTrac1, a previously reported biosensor constructed from the Clade I Arabidopsis thaliana SWEET1, can provide insight into the structural requirements for substrate recognition. The biosensor translates substrate binding to the transporter into a change in fluorescence, and its application in a small-molecule screen combined with cheminformatics uncovered 12 new sugars and their derivatives capable of eliciting a response. Furthermore, we confirmed that the wild-type transporter mediates cellular uptake of three of these species, including the diabetes drugs 1-deoxynojirimycin and voglibose. Our results show that SWEETs can recognize different furanoses, pyranoses, and acyclic sugars, illustrating the potential of combining biosensors and computational techniques to uncover the basis of substrate specificity

Deep Red Phosphorescence of Cyclometalated Iridium Complexes by <i>o</i>‑Carborane Substitution

Heteroleptic (C^∧N)₂Ir­(acac) (C^∧N = 5-MeCBbtp (<b>5a</b>); 4-BuCBbtp (<b>5b</b>); 5-BuCBbtp (<b>5c</b>); 5-(<i>R</i>)­CBbtp = 2-(2′-benzothienyl)-5-(2-<i>R</i>-<i>ortho</i>-carboran-1-yl)-pyridinato-C²,N, R = Me and <i>n</i>-Bu; 4-BuCBbtp = 2-(2′-benzothienyl)-4-(2-<i>n</i>-Bu-<i>ortho</i>-carboran-1-yl)-pyridinato-C²,N, acac = acetylacetonate) complexes supported by <i>o</i>-carborane substituted C^∧N-chelating ligand were prepared, and the crystal structures of <b>5a</b> and <b>5b</b> were determined by X-ray diffraction. While <b>5a</b> and <b>5c</b> exhibit a deep red phosphorescence band centered at 644 nm, which is substantially red-shifted compared to that of unsubstituted (btp)₂Ir­(acac) (<b>6</b>) (λ_em = 612 nm), <b>5b</b> is nonemissive in THF solution at room temperature. In contrast, all complexes are emissive at 77 K and in the solid state. Electrochemical and theoretical studies suggest that the carborane substitution leads to the lowering of both the HOMO and LUMO levels, but has higher impact on the LUMO stabilization than the HOMO, resulting in the reduction of the triplet excited state energy. In particular, the LUMO stabilization in the 4-substituted <b>5b</b> is more contributed by carborane than that in the 5-substituted <b>5a</b>. The solution-processed electroluminescent device incorporating <b>5a</b> as an emitter displayed deep red phosphorescence (CIE coordinate: 0.693, 0.290) with moderate performance (max η_EQE = 3.8%) whereas the device incorporating <b>5b</b> showed poor performance, as well as weak luminance

From in Silico Discovery to Intracellular Activity: Targeting JNK–Protein Interactions with Small Molecules

The JNK–JIP1 interaction represents an attractive target for the selective inhibition of JNK-mediated signaling. We report a virtual screening (VS) workflow, based on a combination of three-dimensional shape and electrostatic similarity, to discover novel scaffolds for the development of non-ATP competitive inhibitors of JNK targeting the JNK–JIP interaction. Of 352 (0.13%) compounds selected from the NCI Diversity Set, more than 22% registered as hits in a biochemical kinase assay. Several compounds discovered to inhibit JNK activity under standard kinase assay conditions also impeded JNK activity in HEK293 cells. These studies led to the discovery that the lignan (−)-zuonin A inhibits JNK–protein interactions with a selectivity of 100-fold over ERK2 and p38 MAPKα. These results demonstrate the utility of a virtual screening protocol to identify novel scaffolds for highly selective, cell-permeable inhibitors of JNK–protein interactions