Mammalian and Drosophila genomes are partitioned into topologically associating domains (TADs). Although this partitioning has been reported to be functionally relevant, it is unclear whether TADs ...represent true physical units located at the same genomic positions in each cell nucleus or emerge as an average of numerous alternative chromatin folding patterns in a cell population. Here, we use a single-nucleus Hi-C technique to construct high-resolution Hi-C maps in individual Drosophila genomes. These maps demonstrate chromatin compartmentalization at the megabase scale and partitioning of the genome into non-hierarchical TADs at the scale of 100 kb, which closely resembles the TAD profile in the bulk in situ Hi-C data. Over 40% of TAD boundaries are conserved between individual nuclei and possess a high level of active epigenetic marks. Polymer simulations demonstrate that chromatin folding is best described by the random walk model within TADs and is most suitably approximated by a crumpled globule build of Gaussian blobs at longer distances. We observe prominent cell-to-cell variability in the long-range contacts between either active genome loci or between Polycomb-bound regions, suggesting an important contribution of stochastic processes to the formation of the Drosophila 3D genome.
Alases, which are thermokarst depressions that are occupied by grasslands and lakes, are an important element of the Central Yakutian periglacial landscape. In recent decades, climatic changes in ...Central Yakutia have resulted in important changes in environmental conditions. We use different remote-sensing instruments (Landsat 8, TerraSAR-X, ENVISAT-RA2, and Jason-2) alongside in situ observations to investigate 1) the spatial distribution and water regime of alas lakes and their relationships with climatic and geomorphologic factors, 2) the relationship of the alas' grassland productivity with the water regime and 3) the potential of alas grasslands for local agriculture. During the 2002–2010 period, the lake water level rose by 1.3m on average, resulting in lake expansion throughout the region. Since 2011, the lake area decreased and the water level declined by 70cm on the middle terraces (low ground-ice content), while the wetting trend continued until 2016 at higher elevations. Small thermokarst lakes (<0.025km2), which indicate regions of young thermokarst, comprise up to 11% of the total lake area and experience high (30%) seasonal variations. In situ observations of the grassland dynamics show their synchronous cyclic variability with the lake extent and a general increasing trend for their productivity since 1985. Around 50% of these dynamics can be explained by the amount of pre-winter precipitation with a delay of two years. We explain this delay through the buffering effect of watershed soils. The cyclic variability of alas hydro-ecosystems strongly affects the local agriculture, which is based on horse and cattle breeding. We estimate that these alas grasslands can provide enough forage supply for local communities. However, the real alas yield is several times less than the theoretical value because of grassland degradation that is caused by recent thermokarst and waterlogging in the most productive phytocenosis.
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•The spatial distribution of alas lakes and grasslands is related to specific terrain cryogeomorphology.•Very small and young thermokarst lakes contribute up to 11% to the total lake area.•Lake extension started in 2006 continues only on fluvial terraces with high ground ice content.•Alas hydro-ecosystems follow the changes of pre-winter precipitation with 2years delay.•Thermokarst and waterlogging degradation of grassland reduce their potentially high forage supply capacity.
To clarify the role of mitochondrial electron transport chain (mtETC) in heavy-metal-induced neurotoxicity, we studied action of Cd2+, Hg2+, and Cu2+ on cell viability, intracellular reactive oxygen ...species formation, respiratory function, and mitochondrial membrane potential of rat cell line PC12. As found, the metals produced, although in a different way, dose- and time-dependent changes of all these parameters. Importantly, Cd2+ beginning from 10 muM and already at short incubation time (3 h) significantly inhibited the FCCP-uncoupled cell respiration; besides, practically the complete inhibition of the respiration was reached after 3 h incubation with 50 muM Hg2+ or 500 muM Cd2+, whereas even after 48 h exposure with 500 muM Cu2+, only a 50% inhibition of the respiration occurred. Against the Cd2+-induced cell injury, not only different antioxidants and mitochondrial permeability transition pore inhibitors were protective but also such mtETC effectors as FCCP and stigmatellin (complex III inhibitor). However, all mtETC effectors used did not protect against the Hg2+- or Cu2+-induced cell damage. Notably, stigmatellin was shown to be one of the strongest protectors against the Cd2+-induced cell damage, producing a 15–20% increase in the cell viability. The mechanisms of the mtETC involvement in the heavy-metal-induced mitochondrial membrane permeabilization and cell death are discussed.
Aeromonas spp. are gram-negative facultatively anaerobic bacilli recovered mainly from aquatic environments. Aeromonas spp. were reported to be associated with infections primarily in aquatic and to ...a lesser extent in terrestrial animals as well as in humans. Up-to-date little is known about aeromonads associated with wild animals, especially with rodents. This study reported the first isolation and characterization of two Aeromonas spp. from internal organs of apparently healthy wild rodents Apodemus uralensis and Apodemus flavicollis captured in the wild environment in the European part of Russia. Isolates were identified as A. hydrophila M-30 and A. encheleia M-2 using the multilocus sequence analysis (MLSA) approach. The isolation of the A. encheleia from rodents is the first described case. Both strains demonstrated beta-hemolytic activity towards human erythrocytes. Antimicrobial susceptibility testing showed that both Aeromonas strains were resistant and intermediate to carbapenems and piperacillin-tazobactam, which was caused by the expression of the genus-specific CphA carbapenemases. A. hydrophila M-30 also demonstrated trimethoprim resistant phenotype. This is usually caused by the carriage of the dfrA or dfrB genes in aeromonads which are frequently associated with integron class I. The latter however was absent in both isolates. Our results expand our understanding of possible aeromonad reservoirs and demonstrate the likelihood of the formation of natural foci of Aeromonas infection and a new link in the chain of the spread of antimicrobial resistance as well.
Herein, for the first time the complexation ability of a homological series of triphenylphosphonium surfactants (TPPB-
n
) toward DNA decamers has been explored. Formation of lipoplexes was confirmed ...by alternative techniques, including dynamic light scattering, indicating the occurrence of nanosized complexes (
ca.
100-150 nm), and monitoring the charge neutralization of nucleotide phosphate groups and the fluorescence quenching of dye-intercalator ethidium bromide. The complexation efficacy of TPPB-surfactants toward an oligonucleotide (ONu) is compared with that of reference cationic surfactants. Strong effects of the alkyl chain length and the structure of the head group on the surfactant/ONu interaction are revealed, which probably occur
via
different mechanisms, with electrostatic and hydrophobic forces or intercalation imbedding involved. Phosphonium surfactants are shown to be capable of disordering lipid bilayers, which is supported by a decrease in the temperature of the main phase transition,
T
m
. This effect enhances with an increase in the alkyl chain length, indicating the integration of TPPB-
n
with lipid membranes. This markedly differs from the behavior of typical cationic surfactant cetyltrimethylammonium bromide, which induces an increase in the
T
m
value. It was demonstrated that the cytotoxicity of TPPB-
n
in terms of the MTT-test on a human cell line 293T nonmonotonically changes within the homological series, with the highest cytotoxicity exhibited by the dodecyl and tetradecyl homologs.
Herein, for the first time the complexation ability of a homological series of triphenylphosphonium surfactants (TPPB-
n
) toward DNA decamers has been explored.
The paper discusses an application of the TOPEX/Poseidon (T/P) altimetry data to estimate the discharge of one of the largest Arctic rivers—the Ob' river. We first discuss the methodology to select ...and retrieve the altimeter water levels during the various phases of the hydrological regime. Then we establish the relationships between the satellite-derived water levels and the in situ river discharge measurements at the Salekhard gauging station near the Ob' estuary. The comparison of in situ and satellite-derived estimations of the Ob' discharge at Salekhard shows that the T/P data can successfully be used for hydrological studies of this river. We address the problems affecting the accuracy of the discharge estimations from altimeter measurements, identify potential solutions and suggest how satellite altimetry data may benefit hydrological studies of Arctic rivers.
Background Anemia associated with chronic kidney disease (CKD) often requires treatment with recombinant human erythropoietin (EPO). Hypoxia-inducible factor−prolyl hydroxylase inhibitors (PHIs) ...stimulate endogenous EPO synthesis and induce effective erythropoiesis by non-EPO effects. GSK1278863 is an orally administered small-molecule PHI. Study Design Multicenter, single-blind, randomized, placebo-controlled, parallel-group study. Setting & Participants Anemic non–dialysis-dependent patients with CKD stages 3-5 (CKD-3/4/5 group; n = 70) and anemic hemodialysis patients with CKD stage 5D (CKD-5D group; n = 37). Interventions Patients with CKD-3/4/5 received placebo or GSK1278863 (10, 25, 50, or 100 mg), and patients with CKD-5D received placebo or GSK1278863 (10 or 25 mg) once daily for 28 days. Outcomes & Measurements Primary pharmacokinetic and pharmacodynamic (increase and response rates in achieving the target hemoglobin Hb concentration, plasma EPO concentrations, reticulocyte count, and others) and safety and tolerability end points were obtained. Results Both CKD-3/4/5 and CKD-5D populations showed a dose-dependent increase in EPO concentrations and consequent increases in reticulocytes and Hb levels. Percentages of GSK1278863 participants with an Hb level increase > 1.0 g/dL (CKD-3/4/5) and >0.5 g/dL (CKD-5D) were 63% to 91% and 71% to 89%, respectively. Per-protocol–defined criteria, high rate of increase in Hb level, or high absolute Hb value was the main cause for withdrawal (CKD-3/4/5, 30%; CKD-5D, 22%). A dose-dependent decrease in hepcidin levels and increase in total and unsaturated iron binding were observed in all GSK1278863-treated patients. Limitations Sparse pharmacokinetic sampling may have limited covariate characterization. EPO concentrations at the last pharmacodynamic sample (5-6 hours) postdose may not represent peak concentrations, which occurred 8 to 10 hours postdose in previous studies. Patients were not stratified by diabetes status, potentially confounding vascular endothelial growth factor and glucose analyses. Conclusions GSK1278863 induced an effective EPO response and stimulated non-EPO mechanisms for erythropoiesis in anemic non–dialysis-dependent and dialysis-dependent patients with CKD.
The Ugi-click-strategy was employed for the synthesis of 12-28 membered 1,2,3-triazole derived macrocyclic peptidomimetics. The Ugi reaction with acid components bearing acetylenic fragments and ...azidoisocyanides provided the corresponding peptidomimetics in up to 97% isolated yield. The subsequent CuAAC click reaction with these bifunctional substrates containing both acetylene and azide groups was investigated to reveal the influence of the structure of Ugi products on the direction of the click-cyclization. It was demonstrated that this approach allows efficient synthesis of either monomeric (12- and 13-membered) or dimeric (24-, 26- and 28-membered) macrocycles prepared in up to 85% yield. The scope and limitations of this method are discussed.
Efficient synthesis of 12–28 membered 1,2,3‐triazole containing macrocyclic peptidomimetics having proline or pipecolic acid residue in the structure was elaborated using Ugi‐Click‐strategy. The ...corresponding linear peptidomimetics prepared via Ugi reaction were isolated in up to 86 % yield. Ring closure by CuAAC was investigated to reveal the influence of the structure of Ugi products on the course of the click‐macrocyclization. Possibility of the synthesis either monomeric (12‐ and 13‐membered) or dimeric (24‐, 26‐ and 28‐membered) macrocycles in up to 98 % yield by proposed approach was demonstrated.
Ugi‐Click strategy was implied for synthesis of pseudopeptides containing proline and pipecolic acid residues. Described approach allows to obtain monomeric and dimeric macrocycles depending on the rigidity of the structural fragments.
This review is focused on the synthesis of peptide macrocycles based on the intramolecular click reaction - 2+3-cycloaddition of alkynes and azides giving a 1,2,3-triazole moiety. The importance of ...this class of macrocyclic peptides and the general approach to the synthesis of these compounds are discussed. The review summarizes published data on these reactions proceeding in the presence of catalysts based on copper(I) and ruthenium(II) salts and thermal cyclization reactions that allow the synthesis of 1,4- and 1,5-disubstituted 1,2,3-triazoles. Special attention is given to the Ugi/click strategy for the synthesis of macrocyclic peptides. This approach is shown to be efficient for the preparation of various macrocycles. The bibliography includes 111 references.
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