Active Complex Research Articles

Mild to moderate post-COVID-19 alters markers of lymphocyte activation, exhaustion, and immunometabolic responses that can be partially associated by physical activity level- an observational sub-analysis fit- COVID study.

This study aimed to evaluate if physical activity is associated with systemic and cellular immunometabolic responses, in young adults after mild-to-moderate COVID-19 infection. Mild- to- moderate post-COVID-19 patients (70.50 ± 43.10 days of diagnosis; age: 29.4 (21.9- 34.9) years; BMI: 25.5 ± 4.3 kg m2 n = 20) and healthy age-matched controls (age: 29.3 (21.2 - 32.6) years; BMI: 25.4 ± 4.7 kg m2; n = 20) were evaluated. Physical activity levels (PAL), body composition, dietary habits, muscular and pulmonary function, mental health, sleep quality, metabolic parameters, immune phenotypic characterization, stimulated whole blood and PBMC culture (cytokine production), mRNA, and mitochondrial respiration in PBMCs were evaluated. The post-COVID-19 group exhibited lower levels of moderate to vigorous physical activity (MVPA) (p = 0.038); therefore, all study comparisons were performed with adjustment for MVPA. Post-COVID-19 impacted the pulmonary function (FEV1, FEV1%pred, FVC, and FVC %pred) compared with the control (p adjusted by MVPA (p adj) <0.05). Post-COVID-19 exhibited lower levels of serum IL-6 (p adj <0.01), whereas it showed higher serum IL-10, triglyceride, leptin, IgG, ACE activity, TNFRSF1A, and PGE2 (p adj <0.05) levels compared with controls. Post-COVID-19 presented a lower percentage of Treg cells (p adj = 0.03) and altered markers of lymphocyte activation and exhaustion (lower CD28 expression in CD8+ T cells (p adj = 0.014), whereas CD4+T cells showed higher PD1 expression (p adj = 0.037)) compared with the control group. Finally, post- COVID-19 presented an increased LPS-stimulated whole- blood IL-10 concentration (p adj <0.01). When exploring mitochondrial respiration and gene expression in PBMCs, we observed a higher LEAK state value (p adj <0.01), lower OXPHOS activity (complex I) (p adj = 0.04), and expression of the Rev-Erb-α clock mRNA after LPS stimulation in the post-COVID-19 patients than in the control (p adj <0.01). Mainly, PAL was associated with changes in IL-10, triglyceride, and leptin levels in the plasma of post-COVID-19 patients. PAL was also associated with modulation of the peripheral frequency of Treg cells and the expression of PD-1 in CD8+ T cells, although it abrogated the statistical effect in the analysis of TNF-α and IL-6 production by LPS- and PMA-stimulated PBMC of post-COVID-19 patients. Young adults after mild-to-moderate SARS-CoV-2 infection appeared to have lower physical activity levels, which can be associated with clinical and immunometabolic responses in a complex manner.

Structural Modeling of Cytokine-Receptor-JAK2 Signaling Complexes Using AlphaFold Multimer.

Homodimeric class 1 cytokine receptors include the erythropoietin (EPOR), thrombopoietin (TPOR), granulocyte colony-stimulating factor 3 (CSF3R), growth hormone (GHR), and prolactin receptors (PRLR). These cell-surface single-pass transmembrane (TM) glycoproteins regulate cell growth, proliferation, and differentiation and induce oncogenesis. An active TM signaling complex consists of a receptor homodimer, one or two ligands bound to the receptor extracellular domains, and two molecules of Janus Kinase 2 (JAK2) constitutively associated with the receptor intracellular domains. Although crystal structures of soluble extracellular domains with ligands have been obtained for all of the receptors except TPOR, little is known about the structure and dynamics of the complete TM complexes that activate the downstream JAK-STAT signaling pathway. Three-dimensional models of five human receptor complexes with cytokines and JAK2 were generated here by using AlphaFold Multimer. Given the large size of the complexes (from 3220 to 4074 residues), the modeling required a stepwise assembly from smaller parts, with selection and validation of the models through comparisons with published experimental data. The modeling of active and inactive complexes supports a general activation mechanism that involves ligand binding to a monomeric receptor followed by receptor dimerization and rotational movement of the receptor TM α-helices, causing proximity, dimerization, and activation of associated JAK2 subunits. The binding mode of two eltrombopag molecules to the TM α-helices of the active TPOR dimer was proposed. The models also help elucidate the molecular basis of oncogenic mutations that may involve a noncanonical activation route. Models equilibrated in explicit lipids of the plasma membrane are publicly available.

Nickel mixed ligand complexes against drug resistant bacteria: Synthesis, characterization, antibacterial activities and molecular docking studies

Five new nickel complexes of the type NiCl2L2 where (L is 4-picolylchloride (4PY), pyridin-4-ylmethyl 4-nitrobenzoate (L1), 4-(pyridine-4-ylmethoxy)aniline (L2), pyridin-4-ylmethyl 4-aminobenzoate (L3) and 4-((4-nitrophenoxy)methyl)pyridine (L4)) were synthesized, characterized, and evaluated for their ability to inhibit bacterial growth. Four of the complexes were synthesized using a green method of co-grinding using a pestle and mortar. All the complexes synthesized by the mechanochemical method were recovered at favorable yields between 70 and 78%, while Ni4PY was recovered at 47.1%. The thermal studies showed the different transformations of the complexes and their thermal stability through Differential Scanning Calorimetry (DSC), while Thermogravimetric analysis (TGA) showed the loss of different components of the complexes cementing their successful synthesis. FTIR data revealed all the significant functional groups originating from the ligands in the new complexes. The characterization results demonstrated the successful synthesis of these complexes. Electronic spectra and magnetic susceptibility studies showed all the complexes to be d8 tetrahedral, except NiL1 which showed a partial d8 octahedral geometry. To better understand the biological activities, molecular docking calculations against the PBP2a proteins from S. aureus, OmpK36 proteins from K. pneumoniae, and DHPS proteins were also carried out. According to the results, the active nickel complexes should have had better activity than the control drug AgSD, however their activity was decreased due to solubility issues.

Management of Perianal Fistulizing Crohn's Disease.

Perianal fistulizing Crohn's disease (CD) represents a severe phenotype of CD that is associated with significant morbidity and reduction in quality of life. Perianal fistulizing CD is caused by a complex interplay of genetic predisposition, immune dysregulation, gut dysbiosis, and various unknown physiological and mechanical factors. A multidisciplinary approach is hence required for optimal management . A detailed anatomical description and classification of perianal fistula, including comprehensive clinical, endoscopic, and radiological diagnostic workup, is an important prerequisite to treatment. For simple perianal fistulas, use of antibiotics and immunomodulators, with or without fistulotomy, are appropriate measures. The medical management of complex perianal fistula, on the other hand, requires adequate control of infection before initiation of therapy with immunomodulators. In active complex perianal fistula, anti-tumor necrosis factors remain the most accepted therapy, with concomitant use of antibiotics or immunomodulators enhancing the efficacy. For patients refractory to anti-tumor necrosis factors, treatment with anti-integrins, anti-interleukins, and small molecules is being evaluated. Mesenchymal stem cells, hyperbaric oxygen therapy, and exclusive enteral nutrition have also been investigated as adjunct therapies. Despite the expansion of the medical armamentarium, a large proportion of the patients require surgical interventions. In this review, we provide an up-to-date overview of the pathophysiology, clinical presentation, diagnosis, and medical management of perianal fistulizing CD. A brief overview of the surgical management of perianal fistulizing CD is also provided.

Identification of novel dithiocarbamate-copper complexes targeting p97/NPL4 pathway in cancer cells

Dithiocarbamates (DTCs) are simple organic compounds with many applications in industry and medicine. They are potent metal chelators forming complexes with various metal ions, including copper. Recently, bis(diethyldithiocarbamate)-copper complex (CuET) has been identified as a metabolic product of the anti-alcoholic drug Antabuse (disulfiram, DSF), standing behind DSF's reported anticancer activity. Mechanistically, CuET in cells causes aggregation of NPL4 protein, an essential cofactor of the p97 segregase, an integral part of the ubiquitin-proteasome system. The malfunction of p97/NPL4 caused by CuET leads to proteotoxic stress accompanied by heat shock and unfolded protein responses and cancer cell death. However, it is not known whether the NPL4 inhibition is unique for CuET or whether it is shared with other dithiocarbamate-copper complexes. Thus, we tested 20 DTCs-copper complexes in this work for their ability to target and aggregate NPL4 protein. Surprisingly, we have found that certain potency against NPL4 is relatively common for structurally different DTCs-copper complexes, as thirteen compounds scored in the cellular NPL4 aggregation assay. These compounds also shared typical cellular phenotypes reported previously for CuET, including the NPL4/p97 proteins immobilization, accumulation of polyubiquitinated proteins, the unfolded protein, and the heat shock responses. Moreover, the active complexes were also toxic to cancer cells (the most potent in the nanomolar range), and we have found a strong positive correlation between NPL4 aggregation and cytotoxicity, confirming NPL4 as a relevant target. These results show the widespread potency of DTCs-copper complexes to target NPL4 with subsequent induction of lethal proteotoxic stress in cancer cells with implications for drug development.

Ru-Based Organometallic Agents Bearing Phenyl Hydroxide: Synthesis and Antibacterial Mechanism Study against Staphylococcus aureus.

The development of antimicrobial agents with novel model of actions is a promising strategy to combat multiple resistant bacteria. Here, three ruthenium-based complexes, which acted as potential antimicrobial agents, were synthesized and characterized. Importantly, three complexes all showed strong bactericidal potency against Staphylococcus aureus. In particular, the most active one has a MIC of 6.25 μg/mL. Mechanistic studies indicated that ruthenium complex killed S. aureus by releasing ROS and damaging the integrity of bacterial cell membrane. In addition, the most active complex not only could inhibit the biofilm formation and hemolytic toxin secretion of S. aureus, but also serve as a potential antimicrobial adjuvant as well, which showed synergistic effects with eight traditional antibiotics. Finally, both G. mellonella larva infection model and mouse skin infection model all demonstrated that ruthenium complex also showed significant efficacy against S. aureus in vivo. In summary, our study suggested that ruthenium-based complexes bearing a phenyl hydroxide are promising antimicrobial agents for combating S. aureus.

Docking Complexes of Active Phytochemicals with VK-deficient Genes

Background:: Vitamin K (VK) deficiency occurs when the body does not have enough vitamin K to produce proteins that are essential for blood clotting and bone health. Vitamin K is a cofactor that plays a major role in various comorbidities. Over the years, efforts have been made to identify the interaction between natural compounds, such as K vitamers, that could play a sig-nificant role in regulation of the blood coagulation. We intended to obtain insights into the poten-tial therapeutic implications of phytochemicals for treating VK deficiency-related diseases by in-vestigating the interactions between phytochemicals and VK-deficient genes. Methods:: On active phytochemical docking complexes with VK-deficient genes, there is no spe-cific information available as of yet. In this computationally aided docking study, we were inter-ested in finding the pathogenic blood coagulation-related genes that are linked to VK deficiency. Based on literature reviews and databases, bioactive phytochemicals and other ligands were con-sidered. To provide precise predictions of ligand-protein interactions, docking parameters and scoring algorithms were thoroughly optimized. We have performed molecular docking studies and observed the way the complexes interact. Results:: Specific binding interactions between active phytochemicals and VK pathogenic muta-tions have been identified by the docking study. Hydrogen bonds, van der Waals interactions, and hydrophobic contacts, which are indications of high binding affinities, have been observed in the ligand-protein complexes. Few phytochemicals have demonstrated the ability to interact with the targets of VK-deficient genes, indicating their capacity to modify pathways relevant to VK defi-ciency. The results of the docking study have explained the three pathogenic genes, viz. VWF, F8, and CFTR, wherein VWF and F8 play important roles in blood coagulation and people with cyst-ic fibrosis, to have a deficiency in vitamin K. Thirty-five compounds from different plant and natural sources were screened through molecular docking, out of which two compounds have been considered as controls, including curcumin and warfarin (R-warfarin and S-warfarin), which are the most common anticoagulants readily available in the market. They act by inhibiting vita-min K epoxide reductase (VKOR), which is needed for the gamma-carboxylation of vitamin K-dependent factors. Conclusion:: A focus on other compounds, like theaflavin, ellagic acid, myricetin, and catechin was also made in this study as they show more binding affinity with the three pathogenic proteins. Based on the results, the complexes have been found to possess great potential and thus may be considered for further interaction studies. The potential for active phytochemicals to generate docking complexes with VK-deficient genes is highlighted in this computational analysis. Health disorders related to VK insufficiency may be significantly impacted by these interactions. To val-idate the expected interactions and determine the therapeutic potential of the identified phyto-chemicals, more experimental research, including in vitro and in vivo experiments, is needed.

Proteomics profiling of CD4+T-cell-derived exosomes from patients with rheumatoid arthritis.

Our study profiled the CD4+T-cell-derived exosomes from patients with rheumatoid arthritis (RA) using proteomics. Proteomic analysis of CD4+T-cell-derived exosomes was performed by tandem mass tags (TMT) combined with LC-MS/MS. We validated the most significantly upregulated and downregulated proteins using ELISA and WB. The proteomic results showed that there were 3 upregulated differentially expressed proteins and 31 downregulated differentially expressed proteins in the RA group. The results indicated that dihydropyrimidinase-related protein 3 (DPYSL3) was significantly upregulated in CD4+T-cell-derived exosomes, whereas proteasome activator complex subunit 1 (PSME1) was significantly downregulated in the RA group. Bioinformatics analysis showed that proteins were enriched in "positive regulation of gene expression", "antigen processing and presentation", "acute-phase response" and "PI3K-AKT signaling" pathways. ELISA verified that compared to the control group, the RA group showed significant upregulation of DPYSL3, and downregulation of PSME1 in CD4+T-cell-derived exosomes. The proteomic analysis results of CD4+T-cell-derived exosomes from patients with RA suggest that these differentially expressed proteins may be involved in RA pathogenesis. DPYSL3 and PSME1 may become useful biomarkers for RA.

The effects of environmental taxes, renewable energy consumption and environmental technology on the ecological footprint: Evidence from advanced panel data analysis

The world faces various challenges in terms of environmental sustainability. An increasing world population, the rigidity of traditional production and consumption patterns, the complexity of economic activities, globalization, and harmful emissions intensify environmental pressures. In this context, the evaluation of various environmental policy instruments is important to alleviate environmental pressures and, thus, combat climate change. This study aims to investigate the impact of environmental taxes, renewable energy consumption, and environmental technology on the ecological footprint in OECD countries by using data from 1994 to 2018 and modern panel data techniques. The results of the AMG estimator indicate that environmental taxation and renewable energy consumption play a role in reducing the ecological footprint; however, results imply that environmental technology does not have a statistically significant effect on the ecological footprint. In addition, we applied DCCE and CS-ARDL estimators to obtain robustness results and observed that the findings remained valid. Therefore, the results of the study suggest that regulations to increase the effectiveness of environmental taxes, renewable energy consumption, and environmental technology should be promoted to ensure environmental sustainability.

Found but Forgotten: On the Records, Misidentification, and Potential Rediscovery of the Rare Bromo Tengger Semeru Mountain Endemic Snake (Serpentes: Colubridae: &lt;i&gt;Tetralepis fruhstorferi&lt;/i&gt;)

Tetralepis fruhstorferi is a snake currently only known to be endemic to a single active volcano complex of Bromo Tengger Semeru National Park in East Java of Indonesia. Its taxonomic identity and natural history are poorly known, as the most recent collection was in 1978 and limited to only a few collection records. We investigated two recently published surveys that have misidentified this species. This may indicate that T. fruhstorferi is still present in its type locality and our future surveys would focus on finding this species to assess its taxonomy and population status.

ІСТОРІЯ ЕНЕРГЕТИКИ М. КИЄВА: 125 РОКІВ ЦЕНТРАЛЬНІЙ ЕЛЕКТРИЧНІЙ СТАНЦІЇ

The history of the construction and operation of the object of cultural heritage - the Kyiv Central Power Station (ЦЕС-1), the second alternating current station in pre-revolutionary Russia, is considered. The development and improvement of electrical and thermal equipment, changes in the fuel base during the difficult times of the First World War, the revolution and the establishment of Soviet power in Kyiv. The transfer of the station to the control of the Academy of Sciences of the Ukrainian SSR, the beginning of research on MHD energy generation, the construction of the second largest research facility in the USSR for this technology began a new - scientific stage in the life of CES-1 as a scientific and experimental base of the Institute of Electrodynamics of the Academy of Sciences of the Ukrainian SSR. For now, the work of the team of scientists and engineering personnel is focused on thermal engineering problems of energy already within the framework of a separate Institute - thermal energy technologies of the National Academy of Sciences of Ukraine. This living monument of the era of industrialization (end of the 19th - 20th centuries) has complex significance for Kyiv and Ukraine: as a legacy of the history of energy and as an active experimental and technological complex.

Electrochemically Modulated Separation of Olefin-Paraffin Gas Mixtures in Membrane Electrode Assemblies

Olefin-Paraffin separations are ubiquitous chemical processes used in purifying monomers for the manufacture of a large variety of polymers and chemical intermediates. Some of the highly demanded olefin-made products include polyethylene, ethylene oxide, vinyl acetate, polypropylene, acrylonitrile, propylene oxide, and acrylic acid. Olefin-paraffin mixtures are relatively difficult to separate because of the similarity in physical properties of each component. Currently, olefins are typically purified via cryogenic distillations, a highly energy-intensive process that liquifies the hydrocarbon gas mixture and re-vaporizes them repeatedly, requiring approximately 3.6 MJ per kg of olefin purified. Because of the large energy-intensive of the process, olefin separations are responsible for approximately 0.3% of the global energy consumption, to produce 200 and 130 million metric tons per year of ethylene and propylene respectively (2020).Alternative non-thermal olefin-paraffin separation methods have the potential to increase the efficiency of this separation, and thus increase its sustainability. In this presentation we will discuss an alternative separation method based on an electrochemically modulated swing absorption system. In this system, Nickel(II) maleonitriledithiolate, an electrochemically active organometallic complex, is dispersed in an ionogel and integrated in a membrane electrode assembly (MEA). The oxidation state of Nickel(II) maleonitriledithiolate can be electrochemically modulated based on potential. At its oxidized state [i.e., Ni (IV)], the complex has a strong affinity towards the olefin’s pi-bond, while at its reduced state [i.e., Ni (II)] the complex loses this affinity. Our results show that when exposed to propylene-propane gas mixtures, propylene was selectively captured by the organometallic species during oxidative phase, and then released or decoupled during reductive phase. Its paraffin counterpart, propane, behaved as spectator molecules throughout the whole process, demonstrating consistent olefin separation through this selective capture-and-release mechanism. I will discuss how varying the composition of the MEA exposed potential mass transport limitations that play an important role in the separation efficiency and throughput. Experiments conducted under varying potentials exhibited operational robustness of the MEA in gas separations if electric potentials are carefully tuned between 1-3V in the oxidative cycle, and at approximately -2V in the reductive cycle. This proof-of-concept demonstration represents an important step towards achieving high-performing electrochemically-modulated olefin-paraffin separations that can integrate renewable electricity sources directly and help decarbonize the chemical manufacturing industry. Figure 1

Protomer selectivity of type II RAF inhibitors within the RAS/RAF complex

RAF dimer inhibitors offer therapeutic potential in RAF- and RAS-driven cancers. The utility of such drugs is predicated on their capacity to occupy both RAF protomers in the RAS-RAF signaling complex. Here we describe a method to conditionally quantify drug-target occupancy at selected RAF protomers within an active RAS-RAF complex in cells. RAF target engagement can be measured in the presence or absence of any mutant KRAS allele, enabling the high-affinity state of RAF dimer inhibitors to be quantified in the cellular milieu. The intracellular protomer selectivity of clinical-stage type II RAF inhibitors revealed that ARAF protomer engagement, but not engagement of BRAF or CRAF, is commensurate with inhibition of MAPK signaling in various mutant RAS cell lines. Our results support a fundamental role for ARAF in mutant RAS signaling and reveal poor ARAF protomer vulnerability for a cohort of RAF inhibitors undergoing clinical evaluation.

Dynamic risk assessment of urban flood disasters based on functional area division—A case study in Shenzhen, China

The assessment of urban flood risk plays a vital role in disaster prevention and mitigation. This work aims to assess the dynamic risk of urban flood triggered by population movements through dividing urban functional zoning from the perspective of collective cognition. Firstly, the urban functional areas are identified using Points of Interest data and then the population movements mobile is detected based on functional areas using mobile signaling big data. Then, one-dimensional and two-dimensional hydrodynamic models are employed to simulate the 50-year flood scenario in Futian District, Shenzhen. Finally, a spatio-temporal dynamic assessment model for urban flood risk is constructed based on the extent of inundation, water depth, population density, and the disaster-bearing capacity of functional areas. The research findings are as follows: (1) Futian District's urban planning showcases harmonious integration of single-function and mixed-function areas. Utilizing the 50% perception standard efficiently identifies distinct functional types across diverse urban zones. The results are highly consistent with the actual situation. (2) During morning peak hours, the population exhibits a nuanced pattern of dispersal, concentration, and transition. Lunchtime witnesses multiple central clusters forming and gradually dispersing, while the evening peak witnesses population regrouping, covering broader geographical extents. Dynamic utilization of functional areas and mobile phone signaling data outperforms static population metrics, offering deeper insights into the complexities of human activity. (3) Between 12:00 and 13:00, lunchtime movements lead to a surge of 6 high-risk zones in the central area and 5 in the Meiling area. The dynamic flood risk assessment model, based on functional area delineation, effectively identifies disparities and fluctuations in flood risk across diverse functional areas during rainfall scenarios, ensuring heightened precision and accuracy in risk assessment.

Neuromuscular assessment of force development, postural, and gait performance under cognitive-motor dual-tasking in healthy older adults and early Parkinson's disease patients: Study protocol for a cross-sectional Mobile Brain/Body Imaging (MoBI) study

Background: Neuromuscular dysfunction is common in older adults and more pronounced in neurodegenerative diseases. In Parkinson's disease (PD), a complex set of factors often prevents the effective performance of activities of daily living that require intact and simultaneous performance of the motor and cognitive tasks. Methods: The cross-sectional study includes a multifactorial mixed-measure design. Between-subject factor grouping the sample will be Parkinson’s Disease (early PD vs. healthy). The within-subject factors will be the task complexity (single- vs. dual-task) in each motor activity, i.e., overground walking, semi-tandem stance, and isometric knee extension, and a walking condition (wide vs. narrow lane) will be implemented for the overground walking activity only. To study dual-task (DT) effects, in each motor activity participants will be given a secondary cognitive task, i.e., a visual discrimination task for the overground walking, an attention task for the semi-tandem, and mental arithmetic for the isometric extension. Analyses of DT effects and underlying neuronal correlates will focus on both gait and cognitive performance where applicable. Based on an a priori sample size calculation, a total N = 42 older adults (55-75 years) will be recruited. Disease-specific changes such as laterality in motor unit behavior and cortical control of movement will be studied with high-density surface electromyography and electroencephalography during static and dynamic motor activities, together with whole-body kinematics. Discussion: This study will be one of the first to holistically address early PD neurophysiological and neuromuscular patterns in an ecologically valid environment under cognitive-motor DT conditions of different complexities. The outcomes of the study aim to identify the biomarker for early PD either at the electrophysiological, muscular or kinematic level or in the communication between these systems. Clinical Trial Registration: ClinicalTrials.Gov, NCT05477654. This study was approved by the Medical Ethical Committee (106/2021).

Lis1 relieves cytoplasmic dynein-1 autoinhibition by acting as a molecular wedge

Cytoplasmic dynein-1 transports intracellular cargo towards microtubule minus ends. Dynein is autoinhibited and undergoes conformational changes to form an active complex that consists of one or two dynein dimers, the dynactin complex, and activating adapter(s). The Lissencephaly 1 gene, LIS1, is genetically linked to the dynein pathway from fungi to mammals and is mutated in people with the neurodevelopmental disease lissencephaly. Lis1 is required for active dynein complexes to form, but how it enables this is unclear. Here, we present a structure of two yeast dynein motor domains with two Lis1 dimers wedged in-between. The contact sites between dynein and Lis1 in this structure, termed ‘Chi,’ are required for Lis1’s regulation of dynein in Saccharomyces cerevisiae in vivo and the formation of active human dynein–dynactin–activating adapter complexes in vitro. We propose that this structure represents an intermediate in dynein’s activation pathway, revealing how Lis1 relieves dynein’s autoinhibited state.

The Role of the CuCl Active Complex in the Stereoselectivity of the Salt-Induced Peptide Formation Reaction: Insights from Density Functional Theory Calculations.

The salt-induced peptide formation (SIPF) reaction is a prebiotically plausible mechanism for the spontaneous polymerization of amino acids into peptides on early Earth. Experimental investigations of the SIPF reaction have found that in certain conditions, the l enantiomer is more reactive than the d enantiomer, indicating its potential role in the rise of biohomochirality. Previous work hypothesized that the distortion of the CuCl active complex toward a tetrahedral-like structure increases the central chirality on the Cu ion, which amplifies the inherent parity-violating energy differences between l- and d-amino acid enantiomers, leading to stereoselectivity. Computational evaluations of this theory have been limited to the protonated-neutral l + l forms of the CuCl active complex. Here, density functional theory methods were used to compare the energies and geometries of the homochiral (l + l and d + d) and heterochiral (l + d) CuCl-amino acid complexes for both the positive-neutral and neutral-neutral forms for alanine, valine, and proline. Significant energy differences were not observed between different chiral active complexes (i.e., d + d, l + l vs. l + d), and the distortions of active complexes between stereoselective systems and non-selective systems were not consistent, indicating that the geometry of the active complex is not the primary driver of the observed stereoselectivity of the SIPF reaction.

Potential suppression of multidrug-resistance-associated protein 1 by coumarin derivatives: an insight from molecular docking and MD simulation studies

Human MRP1 protein plays a vital role in cancer multidrug resistance. Coumarins show promising pharmacological properties. Virtual screening, ADMET, molecular docking and molecular dynamics (MD) simulations were utilized as pharmacoinformatic tools to identify potential MRP1 inhibitors among coumarin derivatives. Using in silico ADMET, 50 hits were further investigated for their selectivity toward the nucleotide-binding domains (NBDs) of MRP1 using molecular docking. Accordingly, coumarin, its symmetrical ketone derivative Lig. No. 4, and Reversan were candidates for focused docking study with the NBDs domains compared with ATP. The result indicates that Lig. No. 4, with the best binding score, interacts with NBDs via hydrogen bonds with residues: GLN713, LYS684, GLY683, CYS682 in NBD1, and GLY1432, GLY771, SER769 and GLN1374 in NBD2, which mostly overlap with ATP binding residues. Moreover, doxorubicin (Doxo) was docked to the transmembrane domains (TMDs) active site of MRP1. Doxo interaction with TMDs was subjected to MD simulation in the NBDs free and occupied with Lig. No. 4 states. The results showed that Doxo interacts more strongly with TMD residues in inward facing feature of TMDs helices. However, when Lig. No. 4 exists in NBDs, Doxo interactions are different, and TMD helices show more outward-facing conformation. This result may suggest a partial competitive inhibition mechanism for the Lig. No. 4 on MRP1 compared with ATP. So, it may inhibit active complex formation by interfering with ATP entrance to NBDs and locking MRP1 conformation in outward-facing mode. This study suggests a valuable coumarin derivative that can be further investigated for potent MRP1 inhibitors. Communicated by Ramaswamy H. Sarma

Fungal COP9 signalosome assembly requires connection of two trimeric intermediates for integration of intrinsic deneddylase

The conserved eight-subunit COP9 signalosome (CSN) is required for multicellular fungal development. The CSN deneddylase cooperates with the Cand1 exchange factor to control replacements of E3 ubiquitin cullin RING ligase receptors, providing specificity to eukaryotic protein degradation. Aspergillus nidulans CSN assembles through a heptameric pre-CSN, which is activated by integration of the catalytic CsnE deneddylase. Combined genetic and biochemical approaches provided the assembly choreography within a eukaryotic cell for native fungal CSN. Interactomes of functional GFP-Csn subunit fusions in pre-CSN deficient fungal strains were compared by affinity purifications and mass spectrometry. Two distinct heterotrimeric CSN subcomplexes were identified as pre-CSN assembly intermediates. CsnA-C-H and CsnD-F-G form independently of CsnB, which connects the heterotrimers to a heptamer and enables subsequent integration of CsnE to form the enzymatically active CSN complex. Surveillance mechanisms control accurate Csn subunit amounts and correct cellular localization for sequential assembly since deprivation of Csn subunits changes the abundance and location of remaining Csn subunits.

Эффективность использования региональных сырьевых ресурсов с целью повышения питательной ценности кормов

Purpose. Scientific and practical substantiation of the positive impact of the developed new feed additives on the metabolism of farm animals and poultry. Materials and Methods. The studies were carried out using traditional scientific methods of collecting information, processing primary material, generalization, and systematization. The analysis of biochemical, zootechnical, morphological, histological, organoleptic, functional and technological indicators was carried out in accordance with the generally accepted normative and technical documentation. Discussion. It has been proven that the use of natural sorbents and minerals (bentonites, diatomites, limestones, various fractions of bischofite), secondary raw materials and food production wastes (cake, meal, pomace) in the composition of feed for cattle makes it possible to reduce the technogenic load on the animal body (in 3-6 times), increase the level of conversion of feed nutrients (16-40%), improve metabolic processes, increase productivity (10-16%) and the level of profitability of the industry (7-14%). At the same time, animals of different breeds and directions of productivity differ in their ability to accumulate ecotoxicants. Inclusion in the diet of a vitamin-mineral complex containing betacarotene, vitamins E, C and selenium in a bioavailable form makes it possible to eliminate the stress factor that occurs during the parenteral administration of a commercial two-component analogue and achieve a more significant physiological effect on the body of lactating cows. The developed protein-mineral preparations containing bioavailable forms of iodine and selenium, feed additives based on lactulose in combination with honey extracts of highly valuable plant materials, biologically active complexes of lactulose and regional natural resources stimulate immune mechanisms, contribute to the formation of the functional properties of livestock products, which is especially important in the prevention of alimentary-dependent conditions in the population. Laying hens that consumed enriched feed used the nutrients of the diet more fully, as a result, more of them were excreted in egg products. So, protein with an egg was excreted more by 10.9-13.2%, fat – by 11.4-14.3%, calcium – by 2.3-2.7%, phosphorus – by 3.5-4.2%. In pig breeding, the results of the work performed have been tested and recommended for implementation in order to activate metabolic processes in the animal body, more complete protein digestion – by an average of 2.0%, an increase in the degree of nitrogen utilization – by an average of 6.0%, which leads to accumulation in the carcass of a higher protein content (on average by 19.2%). It has been established that the use of meat obtained from pigs grown with the use of feed antibiotics by rats leads to an increase in the functional activity of the liver, mainly due to the activation of protein metabolism, and the use of lard in the diet of rats causes an increase in the detoxification function of the liver, which leads to an increase in the activity of transaminases in the blood and tissue of the organ, a change in lipid metabolism and the appearance of fat-modified hepatocytes. The prospects for the use of regional entomoresources in feeding beef cattle are substantiated. As a result of studying the chemical composition and nutritional value of the extruded locust additive, its effect on the digestibility and use of dietary nutrients, the dynamics of morphological and biochemical blood parameters, the linear and weight gain of experimental calves, meat productivity, slaughter parameters of calves and the quality of raw meat, a economic efficiency of beef production, the expediency of further implementation of the development has been experimentally confirmed. Conclusion. Highly effective approaches have been developed to realize the genetic potential of regional breed resources by increasing the level of nutrient conversion of feed and diets.