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Carbonic anhydrase (CA) was among the first proteins whose X-ray crystal structure was solved to atomic resolution. CA proteins have essentially the same fold and similar active centers that differ in only several amino acids. Primary sulfonamides are well defined, strong and specific binders of CA. However, minor variations in chemical structure can significantly alter their binding properties. Over 1000 sulfonamides have been designed, synthesized and evaluated to understand the correlations between the structure and thermodynamics of their binding to the human CA isozyme family. Compound binding was determined by several binding assays: fluorescence-based thermal shift assay, stopped-flow enzyme activity inhibition assay, isothermal titration calorimetry and competition assay for enzyme expressed on cancer cell surfaces. All assays have advantages and limitations but are necessary for deeper characterization of these protein–ligand interactions. Here, the concept and importance of intrinsic binding thermodynamics is emphasized and the role of structure–thermodynamics correlations for the novel inhibitors of CA IX is discussed – an isozyme that is overexpressed in solid hypoxic tumors, and thus these inhibitors may serve as anticancer drugs. The abundant structural and thermodynamic data are assembled into the Protein–Ligand Binding Database to understand general protein–ligand recognition principles that could be used in drug discovery.

ABSTRACT Microbiomes are integral to ecological health and human well-being; however, their ecological and evolutionary drivers have not been systematically investigated, especially in urban park ecosystems. As microbes have different levels of tolerance to environmental changes and habitat preferences, they can be categorized into habitat generalists and specialists. Here, we explored the ecological and evolutionary characteristics of both prokaryotic and microeukaryotic habitat generalists and specialists from six urban parks across five habitat types, including moss, soil, tree hole, water, and sediment. Our results revealed that different ecological and evolutionary processes maintained and regulated microbial diversity in urban park ecosystems. Under ecological perspective, community assembly of microbial communities was mainly driven by stochastic processes; however, deterministic processes were higher for habitat specialists than generalists. Microbial interactions were highly dynamic among habitats, and habitat specialists played key roles as module hubs in intradomain networks. In aquatic interdomain networks, microeukaryotic habitat specialists and prokaryotic habitat specialists played crucial roles as module hubs and connectors, respectively. Furthermore, analyzing evolutionary characteristics, our results revealed that habitat specialists had a much higher diversification potential than generalists, while generalists showed shorter phylogenetic branch lengths as well as larger genomes than specialists. This study broadens our understanding of the ecological and evolutionary features of microbial habitat generalists and specialists in urban park ecosystems across multi-habitat.IMPORTANCEUrban parks, as an important urban greenspace, play essential roles in ecosystem services and are important hotspots for microbes. Microbial diversity is driven by different ecological and evolutionary processes, while little is currently known about the distinct roles of ecological and evolutionary features in shaping microbial diversity in urban park ecosystems. We explored the ecological and evolutionary characteristics of prokaryotic and microeukaryotic habitat generalists and specialists in urban park ecosystems based on a representative set of different habitats. We found that different ecological and evolutionary drivers jointly maintained and regulated microbial diversity in urban park microbiomes through analyzing the community assembly process, ecological roles in hierarchical interaction, and species diversification potential. These findings significantly advance our understanding regarding the mechanisms governing microbial diversity in urban park ecosystems.

During the preparation of high dilutions, repeated external vibration (shaking) is used. We hypothesized that it was the vibration treatment, and not the negligible content of the initial substance, that underlies the activity of highly diluted preparations. In order to test this, the vibration was separated from the dilution process. After vibrating two tubes together on a vortex mixer (one containing water and the other the initial substance) the electrical conductivity and radio frequency radiation intensity of water differed from the unvibrated control, and the ability to exert a modifying effect on the target solution appeared, as assessed using ELISA and terahertz spectroscopy, appeared. Thus, the properties of the neutral carrier (water) changed after non-contact exposure to the initial substance. We have named this process ‘crossing’ and its products ‘aqueous iterations of the initial substance’. Several aqueous iterations with different physical properties were obtained, some of which have a modifying effect and others cause various chemical (catalytic) and biological (antiviral) effects similar to those of the initial substance. This indicates that during crossing, substances enter into post-vibration supramolecular interactions. At the nanoscale level, aqueous iterations and the initial substance are structurally symmetrical, which allows us to assume that the preservation of the symmetry of substances subjected to vibration treatment is the basis of the post-vibration interaction phenomenon.

Abstract The supergroup Amoebozoa unites a wide diversity of amoeboid organisms and encompasses enigmatic lineages that have been recalcitrant to modern phylogenetics. Deep divergences, taxonomic placement of some key taxa and character evolution in the group largely remain poorly elucidated or controversial. We surveyed available Amoebozoa genomes and transcriptomes to mine conserved putative single copy genes, which were used to enrich gene sampling and generate the largest supermatrix in the group to date; encompassing 824 genes, including gene sequences not previously analyzed. We recovered a well-resolved and supported tree of Amoebozoa, revealing novel deep level relationships and resolving placement of enigmatic lineages congruent with morphological data. In our analysis the deepest branching group is Tubulinea. A recent proposed major clade Tevosa, uniting Evosea and Tubulinea, is not supported. Based on the new phylogenetic tree, paleoecological and paleontological data as well as data on the biology of presently living amoebozoans, we hypothesize that the evolution of Amoebozoa probably was driven by adaptive responses to a changing environment, where successful survival and predation resulted from a capacity to disrupt and graze on microbial mats-a dominant ecosystem of the mid-Proterozoic period of the Earth history.

The social cost of carbon (SCC) is estimated by integrated assessment models (IAMs) and is widely used by government agencies to value climate policy impacts. Although there is an ongoing debate about obtained numerical estimates and related uncertainties, little attention has been paid so far to the SCC calculation method itself. This work attempts to fill the gap by providing the theoretical background and economic interpretation of the SCC calculation approach implemented in the DICE (Dynamic Integrated Climate-Economy) IAM. Our analysis indicates that the present calculation method is unable to reflect the linkages between two key IAM components—complex interconnected systems—climate and economy, both influenced by emission abatement policies. Within the modeling framework of DICE, the presently estimated SCC valuates emissions, which are beyond policy control, against consumption of products, which cannot be produced by the economy. This makes the SCC irrelevant for application in climate-economic policies and, therefore, calls for a replacement by a more appropriate indicator. An apparent SCC alternative, which can be considered for policy formulation, is the direct output of the DICE model, the socially optimal marginal abatement cost (SMAC), which corresponds to technological possibilities at the optimal level of carbon emissions abatement. In policymaking, because of the revealed SCC deficiency, great attention needs to be paid to the use of estimates obtained earlier.

Modern teaching practice imposes special requirements on textbooks. The text should be concise, but at the same time extremely comprehensive - similar to the way encyclopedia texts were compiled in the "classical era". The authors show that such requirements are met by a modern philosophical problem of community, which may prove constructive for preparation of social philosophy textbooks. The aim of the article is to demonstrate the didactic and theoretical possibilities of the concept and problems of community in a textbook. A heterological approach is used to explore different concepts of community. A central feature of all concepts of community is the representation of the social without reliance on some central authority or transcendental denotation. Community in this logic is thought of not as a given, not as an idea or a representation, but as a state or a mode of existence. Community is being together. But 'being together' does not mean being as a common property. Being is only in sharing, only through which community is established. The material presented in a social philosophy textbook should meet the following criteria: 1. The notion of community captures a snapshot of sociality that opposes imitative, dogmatic, totalitarian and authoritarian cognitive models. 2. The practice of using the notion 'community' is closely linked to a number of key concepts in contemporary social philosophy, such as singularity, event, other, sociation, sharing, multiplicity, difference. 3. The use of material that in one way or another engages the notion of community allows us to better understand the paradigmatic methodological shift in contemporary social science from being as a supersubstantial ground to being as becoming. 4. Finally, the issue of a community in relation to social philosophy as a field of knowledge is universal and, to varying degrees of detail, can be used in almost all the topics of any relevant course.

The problem of lung damage originating from excessive inflammation and cytokine release during various types of infections remains relevant and stimulates the search for highly effective and safe drugs. The biological activity of the latter may be associated with the regulation of hyperactivation of certain immune cells and enzymes. Here, we propose the design and synthesis of amino derivatives of 4,6- and 5,7-diaryl substituted pyrimidines and [1,2,4]triazolo[1,5-a]pyrimidines as promising double-acting pharmacophores inhibiting IL-6 and NO. The anti-inflammatory activity of 14 target compounds was studied on isolated primary murine macrophages after LPS stimulation. Seven compounds were identified to inhibit the synthesis of nitric oxide and interleukin 6 at a concentration of 100 µM. The most active compounds are micromolar inhibitors of IL-6 secretion and NO synthesis, showing a minimal impact on innate immunity, unlike the reference drug dexamethasone, along with acceptable cytotoxicity. Evaluation in an animal model of acute lung injury proved the protective activity of compound 6e, which was supported by biochemical, cytological and morphological markers.

Multiple-Input Multiple Output (MIMO) is the key technology in most advanced wireless communication standarts like 3GPP Long Term Evolution (LTE) and IEEE 802.11n/ac/ad (Wi-Fi). The cost of MIMO improvements is increased computational complexity of the signal processing at both ends and, as a consequence, growing complexity of the hardware. We propose a new approach of implementation of traditional MMSE demodulator reducing computational complexity for massive MIMO systems.

Using of quantized channel state information on transmitter (CSIT) side for adaptive signal processing on base station (BS) side also called as precoding provides to reduce feedback channel bandwidth in comparison with full CSIT. There are many solutions for feedback channel quantization but the aim of this paper is to note the performance of grassmannian manifold for codebook design.

Quinazolines are a rich source of bioactive compounds. Previously, we showed NHE-1 inhibitory, anti-inflammatory, antiplatelet, intraocular pressure lowering, and antiglycating activity for a series of quinazoline-2,4(1H,3H)-diones and quinazoline-4(3H)-one guanidine derivatives. In the present work, novel N1,N3-bis-substituted quinazoline-2,4(1H,3H)-dione derivatives bearing two guanidine moieties were synthesized and pharmacologically profiled. The most potent NHE-1 inhibitor 3a also possesses antiplatelet and intraocular-pressure-reducing activity. Compound 4a inhibits NO synthesis and IL-6 secretion in murine macrophages without immunotoxicity and alleviates neutrophil infiltration, edema, and tissue lesions in a model of LPS-induced acute lung injury. Hence, we considered quinazoline derivative 4a as a potential agent for suppression of cytokine-mediated inflammatory response and acute lung injury.

The uranium sorption from productive solutions containing chloride ions using anion-exchange resins was investigated. The VPAE ion exchanger had the highest values of the sorption capacity, which for the experiment in the static mode was 13 kg U m-3, and for the experiment in the dynamic mode, it was equal to 36 kg U m-3. The use of VPAE anion exchanger will make it possible for uranium recovery from productive solutions with an increased content of chloride without sacrificing the productivity of the sorption plant. The process of saturated resins regeneration by various reagents was investigated. The use of ammonium nitrate solution with sulfuric acid ensured maximum value of uranium recovery from the saturated resin phase (76–97%).

Acute lung injury remains a challenging clinical condition, necessitating the development of novel, safe and efficient treatments. The prevention of macrophage M1-polarization is a viable venue to tackle excessive inflammation. We performed a phenotypic screening campaign to identify azolopyrimidine compounds that effectively inhibit LPS-induced NO synthesis and interleukin 6 (IL-6) secretion. We identified lead compound 9g that inhibits IL-6 secretion with IC50 of 3.72 µM without apparent cytotoxicity and with minimal suppression of macrophage phagocytosis in contrast to dexamethasone. In a mouse model of LPS-induced acute lung injury, 30 mg/kg i.p. 9g ameliorated anxiety-like behavior, inhibited IL-6 release, and limited neutrophil infiltration and pulmonary edema. A histological study confirmed the protective activity of 9g. Treatment with compound 9g prevented the migration of CD68+ macrophages and the incidence of hemorrhage. Hence, we have identified a promising pharmacological approach for the treatment of acute lung injury that may hold promise for the development of novel drugs against cytokine-mediated complications of bacterial and viral infections.

The formation of primordial black holes in the early universe in the Brans-Dicke scalar-tensor theory of gravity is investigated. Corrections to the threshold value of density perturbations are found. Above the threshold, the gravitational collapse occurs after the cosmological horizon crossing. The corrections depend in a certain way on the evolving scalar field. They affect the probability of primordial black holes formation, and can lead to their clustering at large scales if the scalar field is inhomogeneous. The formation of the clusters, in turn, increases the probability of black holes merge and the corresponding rate of gravitational wave bursts. The clusters can provide a significant contribution to the LIGO/Virgo gravitational wave events, if part of the observed events are associated with primordial black holes.

There is a discussion about common or various mechanisms of response inhibition and response switching. To understand these mechanisms, we used a modified Go/NoGo task with three stimulus categories. The subjects were instructed to press a button in response to frequent Go stimuli, press another button in response to rare Go stimuli and hold any motor response following the presentation of NoGo stimuli. The results showed a decrease in reaction time for frequent Go, following both categories of rare stimuli and the decrease was greater following rare Go. Also, the total number of errors did not differ between Go and NoGo, however, a greater bias of error rate towards frequent Go stimuli was found for rare Go compared to NoGo. Finally, positive correlations were found between the increase in reaction time for rare Go compared to frequent Go and the number of errors for both rare Go and rare NoGo. Together, these results indicate that both rare Go and NoGo stimuli required to inhibit the prepotent response, but rare Go in comparison to NoGo stimuli also evoked a conflict between prepotent and alternative responses, which is expressed in greater response bias toward frequent Go.

The structure-thermodynamics correlation analysis was performed for a series of fluorine- and chlorine-substituted benzenesulfonamide inhibitors binding to several human carbonic anhydrase (CA) isoforms. The total of 24 crystal structures of 16 inhibitors bound to isoforms CA I, CA II, CA XII, and CA XIII provided the structural information of selective recognition between a compound and CA isoform. The binding thermodynamics of all structures was determined by the analysis of binding-linked protonation events, yielding the intrinsic parameters, i.e., the enthalpy, entropy, and Gibbs energy of binding. Inhibitor binding was compared within structurally similar pairs that differ by para- or meta-substituents enabling to obtain the contributing energies of ligand fragments. The pairs were divided into two groups. First, similar binders—the pairs that keep the same orientation of the benzene ring exhibited classical hydrophobic effect, a less exothermic enthalpy and a more favorable entropy upon addition of the hydrophobic fragments. Second, dissimilar binders—the pairs of binders that demonstrated altered positions of the benzene rings exhibited the non-classical hydrophobic effect, a more favorable enthalpy and variable entropy contribution. A deeper understanding of the energies contributing to the protein-ligand recognition should lead toward the eventual goal of rational drug design where chemical structures of ligands could be designed based on the target protein structure.

The perspective of perceiving one’s action affects its speed and accuracy. In the present study, we investigated the change in accuracy and kinematics when subjects throw darts from the first-person perspective and the third-person perspective with varying angles of view. To model the third-person perspective, subjects were looking at themselves as well as the scene through the virtual reality head-mounted display (VR HMD). The scene was supplied by a video feed from the camera located to the up and 0, 20 and 40 degrees to the right behind the subjects. The 28 subjects wore a motion capture suit to register their right hand displacement, velocity and acceleration, as well as torso rotation during the dart throws. The results indicated that mean accuracy shifted in opposite direction with the changes of camera location in vertical axis and in congruent direction in horizontal axis. Kinematic data revealed a smaller angle of torso rotation to the left in all third-person perspective conditions before and during the throw. The amplitude, speed and acceleration in third-person condition were lower compared to the first-person view condition, before the peak velocity of the hand in the direction toward the target and after the peak velocity in lowering the hand. Moreover, the hand movement angle was smaller in the third-person perspective conditions with 20 and 40 angle of view, compared with the first-person perspective condition just preceding the time of peak velocity, and the difference between conditions predicted the changes in mean accuracy of the throws. Thus, the results of this study revealed that subject’s localization contributed to the transformation of the motor program.

A series of N-aryl-β-alanine derivatives and diazobenzenesulfonamides containing aliphatic rings were designed, synthesized, and their binding to carbonic anhydrases (CA) I, II, VI, VII, XII, and XIII was studied by the fluorescent thermal shift assay and isothermal titration calorimetry. The results showed that 4-substituted diazobenzenesulfonamides were more potent CA binders than N-aryl-β-alanine derivatives. Most of the N-aryl-β-alanine derivatives showed better affinity for CA II while diazobenzenesulfonamides possessed nanomolar affinities towards CA I isozyme. X-ray crystallographic structures showed the modes of binding of both compound groups.

Cereal-derived bioactive peptides with antimicrobial activity have been poorly explored compared to those from dicotyledonous plants. Furthermore, there are a few reports addressing the structural differences between antimicrobial peptides (AMPs) from cultivated and wild cereals, which may shed light on significant varieties in the range and level of their antimicrobial activity. We performed a primary structure analysis of some antimicrobial peptides from wild and cultivated cereals to find out the features that are associated with the much higher antimicrobial resistance characteristic of wild plants. In this review, we identified and analyzed the main parameters determining significant antifungal activity. They relate to a high variability level in the sequences of C-terminal fragments and a high content of hydrophobic amino acid residues in the biologically active defensins in wild cereals, in contrast to AMPs from cultivated forms that usually exhibit weak, if any, activity. We analyzed the similarity of various physicochemical parameters between thionins and defensins. The presence of a high divergence on a fixed part of any polypeptide that is close to defensins could be a determining factor. For all of the currently known hevein-like peptides of cereals, we can say that the determining factor in this regard is the structure of the chitin-binding domain, and in particular, amino acid residues that are not directly involved in intermolecular interaction with chitin. The analysis of amino acid sequences of alpha-hairpinins (hairpin-like peptides) demonstrated much higher antifungal activity and more specificity of the peptides from wild cereals compared with those from wheat and corn, which may be associated with the presence of a mini cluster of positively charged amino acid residues. In addition, at least one hydrophobic residue may be responsible for binding to the components of fungal cell membranes.

The early stage of drug discovery is often based on selecting the highest affinity lead compound. To this end the structural and energetic characterization of the binding reaction is important. The binding energetics can be resolved into enthalpic and entropic contributions to the binding Gibbs free energy. Most compound binding reactions are coupled to the absorption or release of protons by the protein or the compound. A distinction between the observed and intrinsic parameters of the binding energetics requires the dissection of the protonation/deprotonation processes. Since only the intrinsic parameters can be correlated with molecular structural perturbations associated with complex formation, it is these parameters that are required for rational drug design. Carbonic anhydrase (CA) isoforms are important therapeutic targets to treat a range of disorders including glaucoma, obesity, epilepsy, and cancer. For effective treatment isoform-specific inhibitors are needed. In this work we investigated the binding and protonation energetics of sixteen [(2-pyrimidinylthio)acetyl]benzenesulfonamide CA inhibitors using isothermal titration calorimetry and fluorescent thermal shift assay. The compounds were built by combining four sulfonamide headgroups with four tailgroups yielding 16 compounds. Their intrinsic binding thermodynamics showed the limitations of the functional group energetic additivity approach used in fragment-based drug design, especially at the level of enthalpies and entropies of binding. Combined with high resolution crystal structural data correlations were drawn between the chemical functional groups on selected inhibitors and intrinsic thermodynamic parameters of CA-inhibitor complex formation.