New β‐diazopyrrole and β‐triazenylpyrrole derivatives were synthesized from isoxazoles and pyridinium salts in two and three steps, respectively. The apoptotic/necrotic difference for these compounds was estimated on THP‐1 cell line. The most effective of the panel is methyl 3‐diazo‐2‐(2,4‐dimethylphenyl)‐4‐phenyl‐3H‐pyrrole‐5‐carboxylate which demonstrated cytotoxic activity from the lowest concentration of 3.3 μM with a steep rise of the apoptotic effect and the largest apoptotic/necrotic difference within the range of 3.3 to 33 μM. Moreover, this diazopyrrole showed the highest sum total of apoptotic and necrotic AUCs within the same low range of concentrations. Methyl 2‐(4‐bromophenyl)‐3‐diazo‐4‐(3‐methoxyphenyl)‐3H‐pyrrole‐5‐carboxylate and methyl 5‐(4‐bromophenyl)‐3‐(3‐methoxyphenyl)‐4‐(piperidin‐1‐yl/morpholin‐4‐yldiazenyl)‐1H‐pyrrole‐2‐carboxylates were found to be quite promising compounds which deserve further cytophysiological and mechanistic research using different cell lines.
Cardiovascular disease associated with metabolic syndrome has a high prevalence, but the mechanistic basis of metabolic cardiomyopathy remains poorly understood. We characterised the cardiac transcriptome in a murine metabolic syndrome (MetS) model (LDLR−/−; ob/ob, DKO) relative to the healthy, control heart (C57BL/6, WT) and the transcriptional changes induced by ACE-inhibition in those hearts. RNA-Seq, differential gene expression and transcription factor analysis identified 288 genes differentially expressed between DKO and WT hearts implicating 72 pathways. Hallmarks of metabolic cardiomyopathy were increased activity in integrin-linked kinase signalling, Rho signalling, dendritic cell maturation, production of nitric oxide and reactive oxygen species in macrophages, atherosclerosis, LXR-RXR signalling, cardiac hypertrophy, and acute phase response pathways. ACE-inhibition had a limited effect on gene expression in WT (55 genes, 23 pathways), and a prominent effect in DKO hearts (1143 genes, 104 pathways). In DKO hearts, ACE-I appears to counteract some of the MetS-specific pathways, while also activating cardioprotective mechanisms. We conclude that MetS and control murine hearts have unique transcriptional profiles and exhibit a partially specific transcriptional response to ACE-inhibition.
Information flow between brain areas is difficult to estimate from EEG measurements due to the presence of noise as well as due to volume conduction. We here test the ability of popular measures of effective connectivity to detect an underlying neuronal interaction from simulated EEG data, as well as the ability of commonly used inverse source reconstruction techniques to improve the connectivity estimation. We find that volume conduction severely limits the neurophysiological interpretability of sensor-space connectivity analyses. Moreover, it may generally lead to conflicting results depending on the connectivity measure and statistical testing approach used. In particular, we note that the application of Granger-causal (GC) measures combined with standard significance testing leads to the detection of spurious connectivity regardless of whether the analysis is performed on sensor-space data or on sources estimated using three different established inverse methods. This empirical result follows from the definition of GC. The phase-slope index (PSI) does not suffer from this theoretical limitation and therefore performs well on our simulated data. We develop a theoretical framework to characterize artifacts of volume conduction, which may still be present even in reconstructed source time series as zero-lag correlations, and to distinguish their time-delayed brain interaction. Based on this theory we derive a procedure which suppresses the influence of volume conduction, but preserves effects related to time-lagged brain interaction in connectivity estimates. This is achieved by using time-reversed data as surrogates for statistical testing. We demonstrate that this robustification makes Granger-causal connectivity measures applicable to EEG data, achieving similar results as PSI. Integrating the insights of our study, we provide a guidance for measuring brain interaction from EEG data. Software for generating benchmark data is made available.
Recent advances enabled by the Hi-C technique have unraveled many principles of chromosomal folding that were subsequently linked to disease and gene regulation. In particular, Hi-C revealed that chromosomes of animals are organized into topologically associating domains (TADs), evolutionary conserved compact chromatin domains that influence gene expression. Mechanisms that underlie partitioning of the genome into TADs remain poorly understood. To explore principles of TAD folding in Drosophila melanogaster, we performed Hi-C and poly(A)(+) RNA-seq in four cell lines of various origins (S2, Kc167, DmBG3-c2, and OSC). Contrary to previous studies, we find that regions between TADs (i.e., the inter-TADs and TAD boundaries) in Drosophila are only weakly enriched with the insulator protein dCTCF, while another insulator protein Su(Hw) is preferentially present within TADs. However, Drosophila inter-TADs harbor active chromatin and constitutively transcribed (housekeeping) genes. Accordingly, we find that binding of insulator proteins dCTCF and Su(Hw) predicts TAD boundaries much worse than active chromatin marks do. Interestingly, inter TADs correspond to decompacted inter-bands of polytene chromosomes, whereas TADs mostly correspond to densely packed bands. Collectively, our results suggest that TADs are condensed chromatin domains depleted in active chromatin marks, separated by regions of active chromatin. We propose the mechanism of TAD self-assembly based on the ability of nucleosomes from inactive chromatin to aggregate, and lack of this ability in acetylated nucleosomal arrays. Finally, we test this hypothesis by polymer simulations and find that TAD partitioning may be explained by different modes of inter-nucleosomal interactions for active and inactive chromatin.
A major side effect of carbamazepine (CBZ), a drug used to treat neurological and neuropsychiatric disorders, is drowsiness, a state characterized by increased slow-wave oscillations with the emergence of sleep spindles in the electroencephalogram (EEG). We conducted cortical EEG and thalamic cellular recordings in freely moving or lightly anesthetized rats to explore the impact of CBZ within the intact corticothalamic (CT)–thalamocortical (TC) network, more specifically on CT 5–9-Hz and TC spindle (10–16-Hz) oscillations. Two to three successive 5–9-Hz waves were followed by a spindle in the cortical EEG. A single systemic injection of CBZ (20 mg/kg) induced a significant increase in the power of EEG 5–9-Hz oscillations and spindles. Intracellular recordings of glutamatergic TC neurons revealed 5–9-Hz depolarizing wave–hyperpolarizing wave sequences prolonged by robust, rhythmic spindle-frequency hyperpolarizing waves. This hybrid sequence occurred during a slow hyperpolarizing trough, and was at least 10 times more frequent under the CBZ condition than under the control condition. The hyperpolarizing waves reversed at approximately −70 mV, and became depolarizing when recorded with KCl-filled intracellular micropipettes, indicating that they were GABAA receptor-mediated potentials. In neurons of the GABAergic thalamic reticular nucleus, the principal source of TC GABAergic inputs, CBZ augmented both the number and the duration of sequences of rhythmic spindle-frequency bursts of action potentials. This indicates that these GABAergic neurons are responsible for the generation of at least the spindle-frequency hyperpolarizing waves in TC neurons. In conclusion, CBZ potentiates GABAA receptor-mediated TC spindle oscillations. Furthermore, we propose that CT 5–9-Hz waves can trigger TC spindles.
Nonalcoholic fatty liver disease (NAFLD) is the most common liver pathology. Here we propose tissue-cooperative, homeostatic model of NAFLD. During early stages of NAFLD the intrahepatic production of miR-122 falls, while the secretion of miRNA-containing exosomes by adipose increases. Bloodstream carries exosome to the liver, where their miRNA cargo is released to regulate their intrahepatic targets. When the deterioration of adipose catches up with the failing hepatic parenchyma, the external supply of liver-supporting miRNAs gradually tapers off, leading to the fibrotic decompensation of the liver and an increase in hepatic carcinogenesis. This model may explain paradoxical observations of the disease-associated decrease in intrahepatic production of certain miRNAs with an increase in their levels in serum. Infusions of miR-122 and, possibly, some other miRNAs may be efficient for preventing NAFLD-associated hepatocellular carcinoma. The best candidates for exosome-wrapped miRNA producer are adipose tissue-derived mesenchymal stem cells (MSCs), known for their capacity to shed large amounts of exosomes into the media. Notably, MSC-derived exosomes with no specific loading are already tested in patients with liver fibrosis. Carrier exosomes may be co-manufactured along with their cargo. Exosome-delivered miRNA cocktails may augment functioning of human organs suffering from a variety of chronic diseases.
The paper discusses the use of term ‘advocacy science’ which is communication of science which goes beyond simple reporting of scientific findings, using the case study of biotechnology. It argues that advocacy science should be used to distinguish the engagement of modern civil society organizations to interpret scientific knowledge for their lobbying. It illustrates how this new communicative process has changed political discourse in science and general perception of the role of science in contemporary society
In recent years, several assistive devices have been proposed to reconstruct arm and hand movements from electromyographic (EMG) activity. Although simple to implement and potentially useful to augment many functions, such myoelectric devices still need improvement before they become practical. Here we considered the problem of reconstruction of handwriting from multichannel EMG activity. Previously, linear regression methods (e.g., the Wiener filter) have been utilized for this purpose with some success. To improve reconstruction accuracy, we implemented the Kalman filter, which allows to fuse two information sources: the physical characteristics of handwriting and the activity of the leading hand muscles, registered by the EMG. Applying the Kalman filter, we were able to convert eight channels of EMG activity recorded from the forearm and the hand muscles into smooth reconstructions of handwritten traces. The filter operates in a causal manner and acts as a true predictor utilizing the EMGs from the past only, which makes the approach suitable for real-time operations. Our algorithm is appropriate for clinical neuroprosthetic applications and computer peripherals. Moreover, it is applicable to a broader class of tasks where predictive myoelectric control is needed.
The ecological modernisation of enterprises has led to significant levels of total emissions in the atmosphere. This is a very important and complex issue for the Republic of Armenia (RA). An agent-based model was developed to determine the best trade-offs for the ecological modernisation of enterprises. The aim is to solve the bi-objective optimisation problem, the objectives of which are the ‘Integrated Volume of Total Emissions’ and the ‘Integrated Index of Industrial Production’. The results indicate that it is possible to reduce the total emissions in the atmosphere by more than 20% for a ten-year period. This may be done by keeping up the positive dynamics of industrial production through choosing trade-offs in the frame of the ‘Pareto-optimal ecological modernisation’ scenario. The scenario was obtained with the help of the suggested genetic algorithm, modified for the problem of the binary control of transitions from initial non-ecological states of each enterprise, towards the target state of ecologically pure manufacturing.
Abstract The role of genes in the expression of aggression and masculinity traits in humans has been a focus of recent behavioral genetic studies. This is the first study on the variation in aggression, the digit ratio (the ratio between the second and the fourth digits, 2D:4D), the directional asymmetry in 2D:4D (DR-L) and polymorphisms of the AR, DRD4, and 5-HTTL genes in simple hunter-gatherers, namely the Hadza of Tanzania (142 adult men). The distribution of AR, DRD4E3, and 5-HTTLPR genotypes and allele frequencies in Hadza was compared to other African populations on which the data were available. Hadza and Ariaal differed significantly in the distributions of frequencies of AR alleles with different numbers of CAG repeats. Hadza population was similar to other African populations in the distribution of allelic frequencies of the DRD4E3 locus, and to Afro- Americans in the distribution of allelic types of the 5- HTTLPR locus. We found no influence of AR gene on the right hand 2D:4D ratio,DR-L, and any of aggression subscales of the Buss-Perry Aggression Questionnaire (AQ). Although, a weak positive correlation between CAG repeats and the left hand 2D:4Dwas found. The multiple regression analysis with digit ratios, DR-L and aggression subscales of AQ as dependent variables and the three gene candidates (AR, DRD4E3, and 5-HTTLPR) as independent variables revealed the following: men with lower number of CAG repeats had significantly lower left hand2D:4D ratio;men with highernumbers of 48-bp unit copies in exon 3 of a VNTR polymorphism in the DRD4 gene had significantly lower digit ratios on both hands; no effect of the 5-HTTLPR gene on either the digit ratio or aggressive behavior. These findings demonstrate the complexity of gene effects on digit ratios and aggression and call for simultaneous analysis of more candidate genes. It is noteworthy that these results were obtained for a human population that is still practicing foraging and has been subjected to a high selective pressure due to harsh environments and practically has no access to modern medical care. Hadza are highly egalitarian, and their culture does not favor persons with a dominant or aggressive behavior. It is still to be found to what extent the relationships observed in this study are similar to those in other human populations.
A general continual model of a medium composed of mechanically active cells is proposed. The medium is considered to be formed by three phases: cells, extracellular fluid, and an additional phase that is responsible for active interaction forces between cells and, for instance, may correspond to a system of protrusions that provide the development of active contractile forces. The deformation of the medium, which is identified with the deformation of the cell phase, consists of two components: elastic deformation of individual cells and cell rearrangements. The elastic deformation is associated with stresses in the cell phase. The spherical component of the stress tensor describes the nonlinear resistance of the cellular medium, which leads to the impossibility of its excessive compression. The constitutive equation for pressure in the cell phase is taken in the form of a nonlinear dependence on the volume cell density. The rearrangement of cells is considered as a flow controlled by stresses in the cell phase, active stresses, and fluid pressure. The tensor of active stresses is assumed to be spherical and nonlocally dependent on the cell density. Assuming that the process of biological tissue deformation is slow, we obtained a reduced model that neglects the elastic deformation of cells, compared to the inelastic deformation. A linear stability analysis of a spatially uniform steady-state solution was performed. The hydrostatic pressure of fluid is present among the parameters that are responsible for the loss of stability of the steady-state solution: an increase in it has a destabilizing effect owing to the action of the component of the interphase interaction force that is determined by the fluid pressure. The model we obtained can be used to describe the process of cavity formation in an initially homogeneous cell spheroid. The role of local and nonlocal mechanisms of active stress generation in the formation of cavity is investigated.
An age-structured bioeconomic model, which is completely continuous in age and time, is developed in order to compare with traditional discrete models. Both types have advantages and disadvantages. The continuous framework complements discrete models as it allows for deeper and more transparent analytical study and leads to analytical results that would be difficult to achieve within a discrete framework. To make the model realistic, a nonlinear recruitment function is introduced and steady state solutions and constant-effort optimal fishing are studied analytically. In addition, the framework has been used for numerical analysis. Simulations are used to investigate how optimal harvesting patterns vary with parameter values.
The spring-to-summer transition is of special importance in long range forecasting, as the general circulation transitions to a less energetic regime. This affects the Midwestern United States in a profound way, since agriculture is very sensitive to the variability of weather and climate. Beginning at the local scale, surface temperature observations are used from a representative station in the West Central Missouri Plains region in order to identify the shift from late spring to early summer. Using upper-air re-analyses as a supplement, the 500-mb height observations are examined to find a spring-to-summer transition date by tracking the location of a representative contour. Each of these is used to identify spring-to-summer transition date and then statistical analysis is performed on this long-term data set. Finally, teleconnections, specifically the influence of El Niño Southern Oscillation (ENSO) and Pacific Decadal Oscillation (PDO), and blocking are examined in order to quantify interannual variability. It was found that examining these criteria, developed in an earlier study that covered a much shorter time period, produced similar statistics to this 68-year study of spring-to-summer transitions. It was also found that the onset of La Niña was associated with hotter summers in the region, a result first found in the earlier study, but this association in much stronger here.
The article discusses the dramatic history of the Tsaritsyno Park and museum-reserve. By the mid-2000s it had become one of Moscow’s iconic places and a zone where urban public culture was shaped. The authors trace the history of this architectural ensemble and park in terms of their role in сity culture and analyse changes in the historical culture of contemporary post-Soviet Moscow. The Tsaritsyno Park and museum exemplify these changes. An unfinished country residence of Catherine II, with a Grand Palace that had stood as a ruin for over 200 years, it has been radically renewed by the Moscow city authorities in what came to be labelled ‘fantasy restoration.’ The palace was finished and now serves as the core of the museum, organised according to a controversial historical policy. Tsaritsyno as a whole became a cultural oddity featuring historical attractions for the public, effectively an ‘eighteenth-century theme park’.
The volume fraction of water related to myelin (fmy) is a promising MRI index for in vivo assessment of brain myelination, that can be derived from multi-component analysis of T1 and T2 relaxometry signals. However, existing quantification methods require rather long acquisition and/or post-processing times, making implementation difficult both in research studies on healthy unsedated children and in clinical examinations. The goal of this work was to propose a novel strategy for fmy quantification within acceptable acquisition andpost-processing times. Our approach is based on a 3-compartment model (myelin-related water, intra/extra-cellular water and unrestricted water), and uses calibrated values of inherent relaxation times (T1c and T2c) for each compartment c. Calibration was first performed on adult relaxometry datasets (N = 3) acquired with large numbers of inversion times (TI) and echo times (TE), using an original combination of a region contraction approach and a non-negative least-square (NNLS) algorithm. This strategy was compared with voxel-wise fitting, and showed robust estimation of T1c and T2c. The accuracy of fmy calculations depending on multiple factors was investigated using simulated data. In the testing stage, our strategy enabled fast fmy mapping, based on relaxometry datasets acquired with reduced TI and TE numbers (acquisition <6 min), and analyzed with NNLS algorithm (post-processing <5min). In adults (N = 13, mean age 22.4±1.6 years), fmy maps showed variability across white matter regions, in agreement with previous studies. In healthy infants (N = 18, aged 3 to 34 weeks), asynchronous changes in fmy values were demonstrated across bundles, confirming the well-known progression of myelination.
The fractal globule state is a popular model for describing chromatin packing in eukaryotic nuclei. Here we provide a scaling theory and dissipative particle dynamics computer simulation for the thermal motion of monomers in the fractal globule state. Simulations starting from different entanglement-free initial states show good convergence which provides evidence supporting the existence of a unique metastable fractal globule state. We show monomer motion in this state to be subdiffusive described by X2(t) ∼tαF with αF close to 0.4. This result is in good agreement with existing experimental data on the chromatin dynamics, which makes an additional argument in support of the fractal globule model of chromatin packing. © 2015 American Physical Society.
In practice, when tsunami approaches the coast and the time for decision making and issuing warning alert is limited, design formulas for fast estimation of tsunami runup characteristics are applied. Themost famous and themost used among them assume that incoming wave has a solitonic shape. However, the exact shape of the incoming wave is usually unknown. This is why it is important to know the error caused by the wave shape uncertainty. In this paper, we discuss how the uncertainty of the incoming wave shape influences its run-up characteristics in different bays. Two typical beach geometries: plane beach and U-shaped bay are considered.
Research on existing drugs often discovers novel mechanisms of their action and leads to the expansion of their therapeutic scope and subsequent remarketing. The Wnt signaling pathway is of the immediate therapeutic relevance, as it plays critical roles in cancer development and progression. However, drugs which disrupt this pathway are unavailable despite the high demand. Here we report an attempt to identify antagonists of the Wnt-FZD interaction among the library of the FDA-approved drugs. We performed an in silico screening which brought up several potential antagonists of the ligand-receptor interaction. 14 of these substances were tested using the TopFlash luciferase reporter assay and four of them identified as active and specific inhibitors of the Wnt3a-induced signaling. However, further analysis through GTP-binding and beta-catenin stabilization assays showed that the compounds do not target the Wnt-FZD pair, but inhibit the signaling at downstream levels. We further describe the previously unknown inhibitory activity of an anti-leprosy drug clofazimine in the Wnt pathway and provide data demonstrating its efficiency in suppressing growth of Wnt-dependent triple-negative breast cancer cells. These data provide a basis for further investigations of the efficiency of clofazimine in treatment of Wnt-dependent cancers. (C) 2013 Elsevier Inc. All rights reserved.
Previously published biographical accounts of Sir Boris Uvarov, K.C.M.G. F.R.S. (1886 [sic] — 1970) were based mostly on personal recollections by his friends and colleagues recorded for the first time in the 1970s or later. Archival research reveals the true date of his birth and allows some other key facts and dates of his early biography to be corrected.
In this paper a novel clustering algorithm is proposed as a version of the Seeded Region Growing (SRG) approach for the automatic recognition of coastal upwelling from Sea Surface Temperature (SST) images. The new algorithm, One Seed Expanding Cluster (SEC), takes advantage of the concept of approximate clustering due to Mirkin (1996, 2013) to derive a homogeneity criterion in the format of a product rather than the conventional difference between a pixel value and the mean of values over the region of interest. It involves a boundary-oriented pixel labeling so that the cluster growing is performed by expanding its boundary iteratively. The starting point is a cluster consisting of just one seed, the pixel with the cold est temperature. The baseline version of the SEC algorithm uses the Otsu’s thresholding method to fine-tune the homogeneity threshold. Unfortunately, this method does not always lead to a satisfactory solution. Therefore, we introduce a self-tuning version of the algorithm in which the homogeneity threshold parameter is abolished and the similarity threshold derived from the approximation criterion also serves as a homogeneity parameter.
Ribosomal protein S2 is an essential component of translation machinery, and its viable mutated variants conferring distinct phenotypes serve as a valuable tool in studying the role of S2 in translation regulation. One of a few available rpsB mutants, rpsB1, shows thermosensitivity and ensures enhanced expression of leaderless mRNAs. In this study, we identified the nature of the rpsB1 mutation. Sequencing of the rpsB1 allele revealed a G-to-A transition in the part of the rpsB gene which encodes a coiled-coil domain of S2. The resulting E132K substitution resides in a highly conserved site, TKKE, a so-called N-terminal capping box, at the beginning of the second alpha helix. The protruding coiled-coil domain of S2 is known to provide binding with 16S rRNA in the head of the 30S subunit and, in addition, to interact with a key mRNA binding protein, S1. Molecular dynamics simulations revealed a detrimental impact of the E132K mutation on the coiled-coil structure and thereby on the interactions between S2 and 16S rRNA, providing a clue for the thermosensitivity of the rpsB1 mutant. Using a strain producing a leaderless lacZ transcript from the chromosomal lac promoter, we demonstrated that not only the rpsB1 mutation generating S2/S1-deficient ribosomes but also the rpsA::IS10 mutation leading to partial deficiency in S1 alone increased translation efficiency of the leaderless mRNA by about 10-fold. Moderate overexpression of S1 relieved all these effects and, moreover, suppressed the thermosensitive phenotype of rpsB1, indicating the role of S1 as an extragenic suppressor of the E132K mutation.