To acquire sufficient mineral nutrients such as phosphate (Pi) from the soil, most plants engage in symbiosis with arbuscular mycorrhizal (AM) fungi. Attracted by plant-secreted strigolactones, the fungi colonize the roots and form highly-branched hyphal structures called arbuscules inside inner cortex cells. The host plant must control the different steps of this interaction to maintain its symbiotic nature. However, how plants sense the amount of Pi obtained from the fungus, and how this determines the arbuscule lifespan, are far from understood. Here, we show that Medicago truncatula SPX-domain containing proteins SPX1 and SPX3 regulate root Pi starvation responses, in part by interacting with PHOSPHATE RESPONSE REGULATOR2, as well as fungal colonization and arbuscule degradation. SPX1 and SPX3 are induced upon Pi starvation but become more restricted to arbuscule-containing cells upon the establishment of symbiosis. This induction in arbuscule-containing cells is associated with the presence of cis-regulatory AW-boxes and transcriptional regulation by the WRINKLED1-like transcription factor WRI5a. Under Pi-limiting conditions, SPX1 and SPX3 facilitate the expression of the strigolactone biosynthesis gene DWARF27, which could help explain the increased fungal branching in response to root exudates. Later, in arbuscule-containing cells, SPX1 and SPX3 redundantly control arbuscule degradation. Thus, SPX proteins play important roles as phosphate sensors to maintain a beneficial AM symbiosis.

• Arguably, symbiotic arbuscular mycorrhizal (AM) fungi have the broadest host range of all fungi, being able to intracellularly colonize root cells in the vast majority of all land plants. This raises the question how AM fungi effectively deal with the immune systems of such a widely diverse range of plants. •Here, we studied the role of a nuclear-localization signal containing effector from Rhizophagus irregularis, called Nuclear Localized Effector1 (RiNLE1), that is highly and specifically expressed in arbuscules. •We show that RiNLE1 is able to translocate to the host nucleus where it interacts with the plant core nucleosome protein Histone 2B (H2B). RiNLE1 is able to impair the mono-ubiquitination of H2B, which results in the suppression of defense-related gene expression and enhanced colonization levels. • This study highlights a novel mechanism by which AM fungi can effectively control plant epigenetic modifications through direct interaction with a core nucleosome component. Homologs of RiNLE1 are found in a range of fungi that establish intimate interactions with plants, suggesting that this type of effector may be more widely recruited to manipulate host defense responses.

RW, et al. Following cytochrome c release, autophagy is inhibited during chemotherapy-induced apoptosis by caspase 8-mediated cleavage of Beclin 1.

A single and simple ortho-sulfonyl benzonitrile template was developed to achieve remote C-H olefination of six different classes of N-heterocycles. We demonstrate that, by varying precatalysts and conditions, the same template can be applied to the remote C-H activation of six structurally distinct heterocyclic scaffolds, and the site-selectivity can be predicted based on distance and geometry. Furthermore, this new development shows that template-directed remote C-H activation is possible through macrocyclopalladation processes with smaller ring sizes.

The ferric uptake regulator (Fur) family of DNA-binding proteins represses and/or activates gene transcription via divalent metal ion-dependent signal sensing. The Borrelia burgdorferi Fur homologue, also known as Borrelia oxidative stress regulator (BosR), promotes spirochetal adaptation to the mammalian host by directly repressing the lipoproteins required for tick colonization and indirectly activating those required for establishing infection in the mammal. Here, we examined whether the DNA-binding activity of BosR was regulated by any of the four most prevalent transition metal ions in B. burgdorferi, Mn, Fe, Cu, and Zn. Our data indicated that in addition to a structural site occupied by Zn(II), BosR had two regulatory sites that could be occupied by Zn(II), Fe(II), or Cu(II) but not by Mn(II). While Fe(II) had no effect, Cu(II) and Zn(II) had a dose-dependent inhibitory effect on the BosR DNA-binding activity. Competition experiments indicated that Cu(II) had a higher affinity for BosR than Zn(II) or Fe(II). A BosR deficiency in B. burgdorferi resulted in a significant increase in the Cu level but no significant change in the levels of Mn, Fe, or Zn. These data suggest that Cu regulates BosR activity, and BosR in turn regulates Cu homeostasis in B. burgdorferi. While this regulatory paradigm is characteristic of the Fur family, BosR is the first one shown to be responsive to Cu(II), which may be an adaptation to the potentially high level of Cu present in the Lyme disease spirochete. IMPORTANCE Transition metal ions serve an essential role in the metabolism of all living organisms. Members of the ferric uptake regulator (Fur) family play critical roles in regulating the cellular homeostasis of transition metals in diverse bacteria, and their DNA-binding activity is often regulated by coordination of the cognate divalent metal ions. To date, regulators with metal ion specificity to Fe(II), Mn(II), Zn(II), and Ni(II) have all been described. In this study, we demonstrate that BosR, the sole Fur homologue in Borrelia burgdorferi, is responsive to Cu(II) and regulates Cu homeostasis in this bacterium, which may be an adaption to potentially Cu-rich milieu in the Lyme disease spirochete. This study has expanded the repertoire of the Fur family's metal ion specificity.

Recently, we have shown that harmine induces β-cell proliferation both in vitro and in vivo, mediated via the DYRK1A-NFAT pathway. We explore structure-activity relationships of the 7-position of harmine for both DYRK1A kinase inhibition and β-cell proliferation based on our related previous structure-activity relationship studies of harmine in the context of diabetes and β-cell specific targeting strategies. 33 harmine analogs of the 7-position substituent were synthesized and evaluated for biological activity. Two novel inhibitors were identified which showed DYRK1A inhibition and human β-cell proliferation capability. The DYRK1A inhibitor, compound 1-2b, induced β-cell proliferation half that of harmine at three times higher concentration. From these studies we can draw the inference that 7-position modification is limited for further harmine optimization focused on β-cell proliferation and cell-specific targeting approach for diabetes therapeutics.

Daidzein, an isoflavonoid with known prooxidative effects in heterogeneous lipid/water systems, changes to an antioxidant for 7-n-alkoxy derivatives of daidzein. For an alkyl length increasing from 4 to 8, 12, and 16 carbons, the oxidation potential decreases gradually from 1.09 V (vs NHE) for daidzein (D) to 0.94 V for D16 in tetrahydrofuran as determined by cyclic voltammetry at 25 °C. The prooxidative effects transform into antioxidative effects from D8 with a maximal effect for D12 for aqueous phase initiation of lipid oxidation in liposomes despite a gradual decrease in Trolox equivalent antioxidant capacity (TEAC) with increasing alkyl chain length. Quantum mechanical calculations using density functional theory (DFT) showed that the bond dissociation energy of the O-H bond of the 4'-phenol is constant along the homologue series in contrast to Δμ, the change in dipole moment upon hydrogen atom donation, which increases for increasing chain length. The frontier orbital energy gap goes through a maximum for D12. The change in the A-to-B dihedral angle upon hydrogen atom donation further shows a maximum for D12 of 6.45°. The importance of these microscopic properties for antioxidative activity was confirmed by a change in liposome fluorescence anisotropy using a fluorescent probe showing maximal penetration into the lipid bilayer for D12 along the homologue series.

Geometry optimizations at the HF/3-21G(*) and HF/6-31G* levels of ab initio theory have been carried out for various isomers of model disubstituted phosphoranes PH:>XY(X, Y=OH, CH3, NH2, and SH). Reasonable agreement was obtained between the optimized geometries and available crystal structure data for analogous compounds. The isomers were further characterized by frequency calculations. The MP2/6-31G*//6-31G* + ZPE energy data reveal that the interactions between the ligands are relatively small (0-4 kcal mol-') for the most stable conformations of the isomers. Hence, for these conformations the apicophilicities (based upon monosubstituted phosphoranes) are approximately additive. The less stable PHuXY conformations are in general transition states or higher-order saddle points, and their interligand interactions are larger in magnitude (up to 10 kcal mol-'); the results with these conformations suggest that apicophilicities may not be as additive for some highly substituted phosphoranes.