Integration of chromosome locations and functional aspects of enhancers and topologically associating domains in knowledge graphs enables versatile queries about gene regulation.

Knowledge about transcription factor binding and regulation, target genes, cis-regulatory modules and topologically associating domains is not only defined by functional associations like biological processes or diseases but also has a determinative genome location aspect. Here, we exploit these location and functional aspects together to develop new strategies to enable advanced data querying. Many databases have been developed to provide information about enhancers, but a schema that allows the standardized representation of data, securing interoperability between resources, has been lacking. In this work, we use knowledge graphs for the standardized representation of enhancers and topologically associating domains, together with data about their target genes, transcription factors, location on the human genome, and functional data about diseases and gene ontology annotations. We used this schema to integrate twenty-five enhancer datasets and two domain datasets, creating the most powerful integrative resource in this field to date. The knowledge graphs have been implemented using the Resource Description Framework and integrated within the open-access BioGateway knowledge network, generating a resource that contains an interoperable set of knowledge graphs (enhancers, TADs, genes, proteins, diseases, GO terms, and interactions between domains). We show how advanced queries, which combine functional and location restrictions, can be used to develop new hypotheses about functional aspects of gene expression regulation.

Unraveling the effect of aromaticity for the dynamics of excited states of single benzene fluorophores.

The photophysical properties of a series of recently synthesized single benzene fluorophores were investigated using ensemble density functional theory calculations. The energetic stability of the ground and excited state species were counterposed against the aromaticity index derived from local vibrational modes. It was found that the large Stokes shift of the fluorophores (up to ca. 5800 cm - 1 ) originates from the effect of electron donating and electron withdrawing substituents rather than π -delocalization and related (anti-)aromaticity. On the basis of nonadiabatic molecular dynamics simulations, the absence of fluorescence from one of the regioisomers was explained by the occurrence of easily accessible S 1 /S 0 conical intersections below the vertical excitation energy level. It is demonstrated in the manuscript that the analysis of local mode force constants and the related aromaticity index represent a useful tool for the characterization of π -delocalization effects in π -conjugated compounds.

Divergent synthesis of benzoxaphospholenes and phosphacoumarins via the reaction of 2-alkenylphenols with phosphorus(III/V) chlorides.

The divergent synthesis of benzo[e]-1,2-oxaphosphinines or benzo[d]-1,2-oxaphospholenes along with spirocyclic quasiphosphonium compounds based on 2-alkenylphenols and phosphorus(III/V) chlorides is presented. The reaction is condition-dependent and determined by the biphility of the phosphorus(III) derivative and the dual reactivity of 2-alkenylphenol. The procedures are applicable for obtaining benzo[e]-1,2-oxaphosphinines substituted at position 4 and disubstituted at positions 4 and 5 as well as 3,3-disubstituted benzo[d]-1,2-oxaphospholenes with good to high yields.

From a humorous post to a detailed quantum-chemical study: isocyanate synthesis revisited.

Isocyanates play an essential role in modern manufacturing processes, especially in polyurethane production. There are numerous synthesis strategies for isocyanates both under industrial and laboratory conditions, which do not prevent searching for alternative highly efficient synthetic protocols. Here, we report a detailed theoretical investigation of the mechanism of sulfur dioxide-catalyzed rearrangement of phenylnitrile oxide into phenyl isocyanate, which was first reported in 1977. The DLPNO-CCSD(T) method and up-to-date DFT protocols were used to perform a highly accurate quantum-chemical study of the rearrangement mechanism. An overview of various organic and inorganic catalysts has revealed other potential catalysts, such as sulfur trioxide and selenium dioxide. Furthermore, the present study elucidated how substituents in phenylnitrile oxide influence reaction kinetics. This study was performed by a self-organized collaboration of scientists initiated by a humorous post on the VK social network.

Degradation of high concentrations of commercial polylactide packaging on food waste composting in pilot-scale test.

The increasing use of synthetic biodegradable polymers, such as aliphatic polyesters, has led to a greater need to understand their behavior in an end-of-life scenario as food packaging materials. The aim of this work was to investigate the effect on composting of high to 10 wt% concentration of commercial polylactide packaging in food waste during a 98-day pilot-scale test. Members of the genera Bacillus, Geobacillus, Caldibacillus, Compostibacillus, Novibacillus, Planifilum and Aeribacillus accounted for 77 % of the bacterial community at the initial stage. Significant fragmentation of the polylactide packaging was observed after 14 days, and the appearance of low-molecular weight (approximately 5.4 kDa) hydrolytic degradation products led to an increase in biodiversity and a prolongation of the thermophilic stage by 12 days. The results obtained show the possibility of efficient disposal of food waste with high concentration of polylactide packaging under industrial composting conditions.

Biomimetic crimped/aligned microstructure to optimize the mechanics of fibrous hybrid materials for compliant vascular grafts.

The precise mechanical properties of many tissues are highly dependent on both the composition and arrangement of the nanofibrous extracellular matrix. It is well established that collagen nanofibers exhibit a crimped microstructure in several tissues such as blood vessel, tendon, and heart valve. This collagen fiber arrangement results in the classic non-linear 'J-shaped' stress strain curve characteristic of these tissues. Synthetic biomimetic fibrous materials with a crimped microstructure similar to natural collagen demonstrate similar mechanical properties to natural tissues. The following work describes a nanofabrication method based on electrospinning used to fabricate two component hybrid electrospun fibrous materials that mimic the microstructure and mechanical properties of vascular tissue. The properties of these samples can be precisely and predictably optimized by modifying fabrication parameters. Tubular grafts with biomimetic microstructure were constructed to demonstrate the potential of this fabrication method in vascular graft replacement applications. It was possible to closely match both the overall geometry and the compliance of specific blood vessels by optimizing graft microstructure.

Rational Design of Far-Red Archaerhodopsin-3-Based Fluorescent Genetically Encoded Voltage Indicators: from Elucidation of the Fluorescence Mechanism in Archers to Novel Red-Shifted Variants.

Genetically encoded voltage indicators (GEVIs) have found wide applications as molecular tools for visualization of changes in cell membrane potential. Among others, several classes of archaerhodopsin-3-based GEVIs have been developed and have proved themselves promising in various molecular imaging studies. To expand the application range for this type of GEVIs, new variants with absorption band maxima shifted toward the first biological window and enhanced fluorescence signal are required. Here, we integrate computational and experimental strategies to reveal structural factors that distinguish far-red bright archaerhodopsin-3-based GEVIs, Archers, obtained by directed evolution in a previous study (McIsaac et al., PNAS, 2014) and the wild-type archaerhodopsin-3 with an extremely dim fluorescence signal, aiming to use the obtained information in subsequent rational design. We found that the fluorescence can be enhanced by stabilization of a certain conformation of the protein, which, in turn, can be achieved by tuning the pK a value of two titratable residues. These findings were supported further by introducing mutations into wild-type archeorhodopsin-3 and detecting the enhancement of the fluorescence signal. Finally, we came up with a rational design and proposed previously unknown Archers variants with red-shifted absorption bands (λmax up to 640 nm) and potential-dependent bright fluorescence (quantum yield up to 0.97%).

Terpenes-Modified Lipid Nanosystems for Temozolomide, Improving Cytotoxicity against Glioblastoma Human Cancer Cells In Vitro.

Currently, increasing the efficiency of glioblastoma treatment is still an unsolved problem. In this study, a combination of promising approaches was proposed: (i) an application of nanotechnology approach to create a new terpene-modified lipid system (7% w/w), using soybean L-α-phosphatidylcholine, N-carbonyl-methoxypolyethylene glycol-2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine for delivery of the chemotherapy drug, temozolomide (TMZ, 1 mg/mL); (ii) use of TMZ associated with natural compounds-terpenes (1% w/w) abietic acid and Abies sibirica Ledeb. resin (A. sibirica). Different concentrations and combinations of terpene-lipid systems were employed to treat human cancer cell lines T 98G (glioblastoma), M-Hela (carcinoma of the cervix) and human liver cell lines (Chang liver). The terpene-lipid systems appeared to be unilamellar and of spherical shape under transmission electron microscopy (TEM). The creation of a TMZ-loaded terpene-lipid nanosystem was about 100 nm in diameter with a negative surface charge found by dynamic light scattering. The 74% encapsulation efficiency allowed the release time of TMZ to be prolonged. The modification by terpenes of TMZ-loaded lipid nanoparticles improved by four times the cytotoxicity against human cancer T 98G cells and decreased the cytotoxicity against human normal liver cells. Terpene-modified delivery lipid systems are of potential interest as a combination therapy.