Transcriptomic Analysis of the Effect of Torin-2 on the Central Nervous System of Drosophila melanogaster.

Torin-2, a synthetic compound, is a highly selective inhibitor of both TORC1 and TORC2 (target of rapamycin) complexes as an alternative to the well-known immunosuppressor, geroprotector, and potential anti-cancer natural compound rapamycin. Torin-2 is effective at hundreds of times lower concentrations and prevents some negative side effects of rapamycin. Moreover, it inhibits the rapamycin-resistant TORC2 complex. In this work, we evaluated transcriptomic changes in D. melanogaster heads induced with lifetime diets containing Torin-2 and suggested possible neuroprotective mechanisms of Torin-2. The analysis included D. melanogaster of three ages (2, 4, and 6 weeks old), separately for males and females. Torin-2, taken at the lowest concentration being tested (0.5 µM per 1 L of nutrient paste), had a slight positive effect on the lifespan of D. melanogaster males (+4% on the average) and no positive effect on females. At the same time, RNA-Seq analysis revealed interesting and previously undiscussed effects of Torin-2, which differed between sexes as well as in flies of different ages. Among the cellular pathways mostly altered by Torin-2 at the gene expression level, we identified immune response, protein folding (heat shock proteins), histone modification, actin cytoskeleton organization, phototransduction and sexual behavior. Additionally, we revealed that Torin-2 predominantly reduced the expression of Srr gene responsible for the conversion of L-serine to D-serine and thus regulating activity of NMDA receptor. Via western blot analysis, we showed than in old males Torin-2 tends to increase the ratio of the active phosphorylated form of ERK, the lowest node of the MAPK cascade, which may play a significant role in neuroprotection. Thus, the complex effect of Torin-2 may be due to the interplay of the immune system, hormonal background, and metabolism. Our work is of interest for further research in the field of NMDA-mediated neurodegeneration.

De Novo Transcriptome Profiling of Brain Tissue from the Annual Killifish Nothobranchius guentheri.

Nothobranchius is a genus of small annual killifish found in Africa. Due to the relatively short lifespan, as well as easy breeding and care, Nothobranchius fish are becoming widely used as a vertebrate model system. Studying the genome and transcriptome of these fish is essential for advancing the field. In this study, we performed de novo transcriptome assembly of brain tissues from Nothobranchius guentheri using Trinity. Annotation of 104,271 potential genes (with transcripts longer than 500 bp) was carried out; for 24,967 genes (53,654 transcripts), in which at least one GO annotation was derived. We also analyzed the effect of a long-term food supplement with Torin 2, second-generation ATP-competitive inhibitor of mTOR, on the gene expression changes in brain tissue of adult N. guentheri. Overall, 1491 genes in females and 249 genes in males were differently expressed under Torin 2-supplemented diet. According to the Gene Set Enrichment Analysis (GSEA), the majority of identified genes were predominantly involved in the regulation of metabolic process, dendritic spine maintenance, circadian rhythms, retrotransposition, and immune response. Thus, we have provided the first transcriptome assembly and assessed the differential gene expression in response to exposure to Torin 2, which allow a better understanding of molecular changes in the brain tissues of adult fish in the mTOR pathway inhibition.

End-to-End Azido-Bridged Lanthanide Chain Complexes (Dy, Er, Gd, and Y) with a Pentadentate Schiff-Base [N3O2] Ligand: Synthesis, Structure, and Magnetism.

The syntheses, structure and magnetic properties are reported for five novel 1D polymeric azido-bridged lanthanide complexes with the general formula {[Ln(DAPMBH)(N3)C2H5OH]C2H5OH}n where H2DAPMBH = 2,6-diacetylpyridine bis(4-methoxybenzoylhydrazone)-a new pentadentate pyridine-base [N3O2] ligand and Ln = Dy (1), Y0.930Dy0.070 (2), Er (3), Y0.923Er0.077 (4), and Gd (5). X-ray diffraction analysis of 1-5 show that the central lanthanide atoms are eight-coordinated with the N5O3 donor set originating from the ligand DAPMBH, one coordinated ethanol molecule and two end-to-end type N3- bridges connecting the metal centers into infinite chain. The [LnN5O3] coordination polyhedron can be regarded as a distorted dodecahedron (D2d). AC magnetic measurements revealed that compounds 1-4 show field-induced single-molecule magnet behavior, with estimated energy barriers Ueff ≈ 47-17 K. The experimental study of magnetic properties was complemented by theoretical analysis based on crystal-field calculations. Direct current magnetic susceptibility studies revealed marginally weak intrachain exchange interaction between Ln3+ ions mediated by the end-to-end azide bridging groups (J ≈ -0.015 cm-1 for 5). Comparative analysis of static and dynamic magnetic properties of magnetically concentrated (1, 3) and diluted (2, 4) Dy and Er compounds showed that, despite fascinating 1D azido-bridged chain structure, compounds 1 and 3 are not single-chain magnets; their magnetic behavior is largely due to single-ion magnetic anisotropy of individual Ln3+ ions.

Heterometallic Palladium(II)-Indium(III) and -Gallium(III) Acetate-Bridged Complexes: Synthesis, Structure, and Catalytic Performance in Homogeneous Alkyne and Alkene Hydrogenation.

The reaction of Pd3(OOCMe)6 with indium(III) and gallium(III) acetates was studied to prepare new PdII-based heterometallic carboxylate complexes with group 13 metals. The heterometallic palladium(II)-indium(III) acetate-bridged complexes Pd(OOCMe)4In(OOCMe) (1) and Pd(OOCMe)4In(OOCMe)·MeCOOH (1a) were synthesized and structurally characterized with X-ray crystallography and extended X-ray absorption fine structure in the solid state and solution. A similar Pd-Ga heterometallic complex formed by the reaction of Pd3(OOCMe)6 with gallium(III) acetate in a dilute acetic acid solution, as evidenced by atmospheric pressure chemical ionization mass and UV-vis spectrometry, was unstable at higher concentrations and in the solid state. Complex 1 catalyzes the liquid-phase-selective phenylacetylene and styrene hydrogenation (1 atm of H2 at 20 °C) in acetic acid, ethyl acetate, and N, N-dimethylformamide solutions, while no Pd metal was formed until alkyne and alkene hydrogenation ceased.

On the Reaction of Carbonyl Diphosphonic Acid with Hydroxylamine and O-alkylhydroxylamines: Unexpected Degradation of P-C-P Bridge.

Derivatives of methylenediphosphonic acid possess wide spectra of biological activities and are used in enzymology as research tools as well as in practical medicine. Carbonyl diphosphonic acid is a promising starting building block for synthesis of functionally substituted methylenediphosphonates. Investigation of the interaction of carbonyl diphosphonic acid with hydroxylamine clearly demonstrates that it is impossible to isolate oxime within the pH range 2-12, while only cyanophosphonic and phosphoric acids are the products of the fast proceeding Beckmann-like fragmentation. In the case of O-alkylhydroxylamines, corresponding alcohols are found in the reaction mixtures in addition to cyanophosphonic and phosphoric acids. Therefore, two residues of phosphonic acid being attached to a carbonyl group provide new properties to this carbonyl group, making its oximes very unstable. This principally differs carbonyl diphosphonic acid from structurally related phosphonoglyoxalic acid and other α-ketophosphonates.

Hybrid photoactive fullerene derivative-ruboxyl nanostructures for photodynamic therapy.

Here we report the investigation of photophysical properties and photodynamic action of two novel water soluble hybrid molecular structures based on [60]fullerene dyads bearing covalently attached residues of anthracycline antibiotic "ruboxyl". Molecular structures of the designed compounds were confirmed by IR and UV-VIS absorption spectroscopy, electrospray mass spectrometry (compound 5), and (1)H and (13)C NMR spectroscopy. Dynamic light scattering, steady-state and kinetic fluorimetry and UV-VIS absorption spectroscopy techniques were used to study the behavior of the synthesized hybrid molecular structures in aqueous solutions. Photodynamic activity of the compounds was evaluated by monitoring the O2(-) generation under visible light irradiation using the NBT test. It has been shown that the anthracycline chromophore (ruboxyl moiety possesses no photodynamic activity) behaves as an efficient photosensitizer for the fullerene core operating via the energy and/or the electron transfer pathways. The presented approach opens up wide opportunities for the design of various fullerene-based donor-acceptor systems with enhanced photodynamic properties potentially suitable for biomedicinal applications.

Facile preparation of amine and amino acid adducts of [60]fullerene using chlorofullerene C60Cl6 as a precursor.

We report a general synthetic approach to the preparation of highly functionalized amine and amino acid derivatives of [60]fullerene starting from readily available chlorofullerene C(60)Cl(6). The synthesized water-soluble amino acid derivative of C(60) demonstrated pronounced antiviral activity, while the cationic amine-based compound showed strong antibacterial action in vitro.

Molecular and ionic complexes of pyrrolidinofullerene bearing chelating 3-pyridyl units.

Molecular and ionic complexes of cis-2',5'-di(pyridin-3-yl)pyrrolidino[3',4':1,9](C(60)-I(h))[5,6]fullerene DP3FP with chlorobenzene (C(6)H(5)Cl), manganese(II) tetraphenylporphyrin (Mn(II)TPP) and tetrakis(dimethylamino)ethylene (TDAE) have been obtained for the first time. X-ray single crystal structure determination for the crystalline DP3FP·C(6)H(5)Cl (1) solvate proved unambiguously its molecular structure with the cis-arrangement of chelating 3-pyridyl groups. It has been demonstrated that DP3FP easily forms self-assembled photoactive complexes with metallated porphyrins. For example, the formation of a 1 : 1 complex between DP3FP and zinc (II) tetraphenylporphyrin (Zn(II)TPP) in cyclohexane solution (2) was evidenced using absorption spectroscopy. A successful X-ray single crystal structure determination was performed for a self-assembled triad composed of a DP3FP molecule linked with two Mn(II)TPP molecules in {DP3FP·(Mn(II)TPP)(2)}·(C(6)H(4)Cl(2))(3) (3). A strong organic donor TDAE reduces DP3FP to the radical anion state thus forming an ionic complex (TDAE˙(+))·(DP3FP˙(-))·(C(6)H(4)Cl(2))(1.6) (4). Optical, electronic and magnetic properties of 4 were investigated in detail. The performed studies strongly suggest that pyrrolidinofullerene DP3FP can be used as a building block in the design of various organic materials with advanced optoelectronic and/or magnetic properties.

Synthesis and antiviral activity of highly water-soluble polycarboxylic derivatives of [70]fullerene.

We report here a facile preparation of highly water-soluble derivatives C(70)[p-C(6)H(4)(CH(2))(n)COOH](8) (n = 2, 3) starting from readily available chlorinated [70]fullerene precursors C(70)Cl(8) and C(70)Cl(10). The synthesized fullerene derivatives showed pronounced antiviral activity in vitro, particularly against human immunodeficiency virus (HIV) and influenza A virus (subtypes H1N1 and H3N2).