Development of production technology for extruded starter compound feedsfor juvenile fish

The article presents the results of developing recipes for domestic extruded starter compound feeds for zander, tilapia and Clary catfish. Technological modes of their production, as well as physical-chemical, mechanical and technological indicators of the developed compound feeds are established. The developed compound feeds are well-loose grains of dark and light brown colors, with sizes from 0,2 to 2,0 mm. Indicators of water resistance were at least 2,5 hours, crumbling no more than 1,5 %, swelling of granules 10-15 minutes, volume mass below 1000 kg/m3. The data obtained show that the developed feed meets the regulatory requirements for starting fish feeds. The introduction of the developed technology for the production of starter compound feeds at domestic enterprises of the feed industry will reduce the dependence of industrial fish farms on the import of compound feeds and thereby increase the profitability of the industry

Discovery of host-directed modulators of virus infection by probing the SARS-CoV-2-host protein-protein interaction network

The ongoing coronavirus disease 2019 (COVID-19) pandemic has highlighted the need to better understand virus-host interactions. We developed a network-based method that expands the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-host protein interaction network and identifies host targets that modulate viral infection. To disrupt the SARS-CoV-2 interactome, we systematically probed for potent compounds that selectively target the identified host proteins with high expression in cells relevant to COVID-19. We experimentally tested seven chemical inhibitors of the identified host proteins for modulation of SARS-CoV-2 infection in human cells that express ACE2 and TMPRSS2. Inhibition of the epigenetic regulators bromodomain-containing protein 4 (BRD4) and histone deacetylase 2 (HDAC2), along with ubiquitin-specific peptidase (USP10), enhanced SARS-CoV-2 infection. Such proviral effect was observed upon treatment with compounds JQ1, vorinostat, romidepsin and spautin-1, when measured by cytopathic effect and validated by viral RNA assays, suggesting that the host proteins HDAC2, BRD4 and USP10 have antiviral functions. We observed marked differences in antiviral effects across cell lines, which may have consequences for identification of selective modulators of viral infection or potential antiviral therapeutics. While network-based approaches enable systematic identification of host targets and selective compounds that may modulate the SARS-CoV-2 interactome, further developments are warranted to increase their accuracy and cell-context specificity.Peer reviewe

A distinct first replication cycle of DNA introduced in mammalian cells

Many mutation events in microsatellite DNA sequences were traced to the first embryonic divisions. It was not known what makes the first replication cycles of embryonic DNA different from subsequent replication cycles. Here we demonstrate that an unusual replication mode is involved in the first cycle of replication of DNA introduced in mammalian cells. This alternative replication starts at random positions, and occurs before the chromatin is fully assembled. It is detected in various cell lines and primary cells. The presence of single-stranded regions increases the efficiency of this alternative replication mode. The alternative replication cannot progress through the A/T-rich FRA16B fragile site, while the regular replication mode is not affected by it. A/T-rich microsatellites are associated with the majority of chromosomal breakpoints in cancer. We suggest that the alternative replication mode may be initiated at the regions with immature chromatin structure in embryonic and cancer cells resulting in increased genomic instability. This work demonstrates, for the first time, differences in the replication progression during the first and subsequent replication cycles in mammalian cells

Synchronous Closing and Flow Analysis for Model Checking Timed Systems

Abstract. Formal methods, in particular model checking, are increas-ingly accepted as integral part of system development. With large soft-ware systems beyond the range of fully automatic verification, however, a combination of decomposition and abstraction techniques is needed. To model check components of a system, a standard approach is to close the component with an abstraction of its environment, as standard model checkers often do not handle open reactive systems directly. To make it useful in practice, the closing of the component should be automatic, both for data and for control abstraction. Specifically for model checking asynchronous open systems, external input queues should be removed, as they are a potential source of a combinatorial state explosion. In this paper we investigate a class of environmental processes for which the asynchronous communication scheme can safely be replaced by a synchronous one. Such a replacement is possible only if the environment is constructed under rather a severe restriction on the behavior, which can be partially softened via the use of a discrete-time semantics. We employ data-flow analysis to detect instances of variables and timers influenced by the data passing between the system and the environment

Treatment With Simvastatin and Rifaximin Restores the Plasma Metabolomic Profile in Patients With Decompensated Cirrhosis

Patients with decompensated cirrhosis, particularly those with acute-on-chronic liver failure (ACLF), show profound alterations in plasma metabolomics. The aim of this study was to investigate the effect of treatment with simvastatin and rifaximin on plasma metabolites of patients with decompensated cirrhosis, specifically on compounds characteristic of the ACLF plasma metabolomic profile. Two cohorts of patients were investigated. The first was a descriptive cohort of patients with decompensated cirrhosis (n = 42), with and without ACLF. The second was an intervention cohort from the LIVERHOPE-SAFETY randomized, double-blind, placebo-controlled trial treated with simvastatin 20 mg/day plus rifaximin 1,200 mg/day (n = 12) or matching placebo (n = 13) for 3 months. Plasma samples were analyzed using ultrahigh performance liquid chromatography–tandem mass spectroscopy for plasma metabolomics characterization. ACLF was characterized by intense proteolysis and lipid alterations, specifically in pathways associated with inflammation and mitochondrial dysfunction, such as the tryptophan–kynurenine and carnitine beta-oxidation pathways. An ACLF-specific signature was identified. Treatment with simvastatin and rifaximin was associated with changes in 161 of 985 metabolites in comparison to treatment with placebo. A remarkable reduction in levels of metabolites from the tryptophan–kynurenine and carnitine pathways was found. Notably, 18 of the 32 metabolites of the ACLF signature were affected by the treatment. Conclusion: Treatment with simvastatin and rifaximin modulates some of the pathways that appear to be key in ACLF development. This study unveils some of the mechanisms involved in the effects of treatment with simvastatin and rifaximin in decompensated cirrhosis and sets the stage for the use of metabolomics to investigate new targeted therapies in cirrhosis to prevent ACLF development

Combined in Silico, Ex Vivo, and in Vivo Assessment of L-17, a Thiadiazine Derivative with Putative Neuro-and Cardioprotective and Antidepressant Effects

Depression associated with poor general medical condition, such as post-stroke (PSD) or post-myocardial infarction (PMID) depression, is characterized by resistance to classical antidepres-sants. Special treatment strategies should thus be developed for these conditions. Our study aims to investigate the mechanism of action of 2-morpholino-5-phenyl-6H-1,3,4-thiadiazine, hydrobro-mide (L-17), a recently designed thiadiazine derivative with putative neuro-and cardioprotective and antidepressant-like effects, using combined in silico (for prediction of the molecular binding mechanisms), ex vivo (for assessment of the neural excitability using c-Fos immunocytochemistry), and in vivo (for direct examination of the neuronal excitability) methodological approaches. We found that the predicted binding affinities of L-17 to serotonin (5-HT) transporter (SERT) and 5-HT3 and 5-HT1A receptors are compatible with selective 5-HT serotonin reuptake inhibitors (SSRIs) and antagonists of 5-HT3 and 5-HT1A receptors, respectively. L-17 robustly increased c-Fos immunoreac-tivity in the amygdala and decreased it in the hippocampus. L-17 dose-dependently inhibited 5-HT neurons of the dorsal raphe nucleus; this inhibition was partially reversed by the 5-HT1A antagonist WAY100135. We suggest that L-17 is a potent 5-HT reuptake inhibitor and partial antagonist of 5-HT3 and 5-HT1A receptors; the effects of L-17 on amygdaloid and hippocampal excitability might be mediated via 5-HT, and putatively mediate the antidepressant-like effects of this drug. Since L-17 also possesses neuro-and cardioprotective properties, it can be beneficial in PSD and PMID. Combined in silico predictions with ex vivo neurochemical and in vivo electrophysiological assessments might be a useful strategy for early assessment of the efficacy and neural mechanism of action of novel CNS drugs. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.Funding: The work of the authors of this study was supported by the Slovak Research and Development Agency (contract APVV-19-0435), Scientific Grant Agency of the Ministry of Education of the Slovak Republic, the Slovak Academy of Sciences (grant VEGA 2/0046/18), and a Government Contract of the Russian Federation with the Institute of Immunology and Physiology (AAAA-A18-118020690020-1)

Reversible Integration of Microfluidic Devices with Microelectrode Arrays for Neurobiological Applications

The majority of current state-of-the-art microfluidic devices are fabricated via replica molding of the fluidic channels into PDMS elastomer and then permanently bonding it to a Pyrex surface using plasma oxidation. This method presents a number of problems associated with the bond strengths, versatility, applicability to alternative substrates, and practicality. Thus, the aim of this study was to investigate a more practical method of integrating microfluidics which is superior in terms of bond strengths, reversible, and applicable to a larger variety of substrates, including microfabricated devices. To achieve the above aims, a modular microfluidic system, capable of reversible microfluidic device integration, simultaneous surface patterning and multichannel fluidic perfusion, was built. To demonstrate the system’s potential, the ability to control the distribution of A549 cells inside a microfluidic channel was tested. Then, the system was integrated with a chemically patterned microelectrode array, and used it to culture primary, rat embryo spinal cord neurons in a dynamic fluidic environment. The results of this study showed that this system has the potential to be a cost effective and importantly, a practical means of integrating microfluidics. The system’s robustness and the ability to withstand extensive manual handling have the additional benefit of reducing the workload. It also has the potential to be easily integrated with alternative substrates such as stainless steel or gold without extensive chemical modifications. The results of this study are of significant relevance to research involving neurobiological applications, where primary cell cultures on microelectrode arrays require this type of flexible integrated solution

The MHD nature of ionospheric wave packets excited by the solar terminator

We obtained the first experimental evidence for the magnetohydrodynamic (MHD) nature of ionospheric medium-scale travelling wave packets (MSTWP). We used data on total electron content (TEC) measurements obtained at the dense Japanese network GPS/GEONET (1220 stations) in 2008-2009. We found that the diurnal, seasonal and spectral MSTWP characteristics are specified by the solar terminator (ST) dynamics. MSTWPs are the chains of narrow-band TEC oscillations with single packet's duration of about 1-2 hours and oscillation periods of 10-20 minutes. Their total duration is about 4--6 hours. The MSTWP spatial structure is characterized by a high degree of anisotropy and coherence at the distance of more than 10 wavelengths. The MSTWP direction of travelling is characterized by a high directivity regardless of seasons. Occurrence rate of daytime MSTWPs is high in winter and during equinoxes. Occurrence rate of nighttime MSTIDs has its peak in summer. These features are consistent with previous MS travelling ionosphere disturbance (TID) statistics obtained from 630-nm airglow imaging observations in Japan. In winter, MSTWPs in the northern hemisphere are observed 3-4 hours after the morning ST passage. In summer, MSTWPs are detected 1.5-2 hours before the evening ST occurrence at the point of observations, at the moment of the evening ST passage in the magneto-conjugate point. Both the high Q-factor of oscillatory system and synchronization of MSTWP occurrence with the solar terminator passage at the point of observations and in the magneto-conjugate area testify the MHD nature of ST-excited MSTWP generation. The obtained results are the first experimental evidence for the hypothesis of the ST-generated ion sound waves.Comment: 12 pages, 3 figure