Efficient Expression in (LEXSY) of the Receptor-Binding Domain of the SARS-CoV-2 S-Protein and the Acetylcholine-Binding Protein from .

(LEXSY) system is an inexpensive and effective expression approach for various research and medical purposes. The stated advantages of this system are the possibility of obtaining the soluble product in the cytoplasm, a high probability of correct protein folding with a full range of post-translational modifications (including uniform glycosylation), and the possibility of expressing multi-subunit proteins. In this paper, a LEXSY expression system has been employed for obtaining the receptor binding domain (RBD) of the spike-protein of the SARS-CoV-2 virus and the homopentameric acetylcholine-binding protein (AChBP) from .

Radial structure of the constricted positive column: Modeling and experiment.

We present a detailed self-consistent model of a positive column in argon glow discharge at moderate pressures and currents. This model describes the discharge transition between diffuse and constricted states. The model includes an extensive set of plasma chemical reactions and equation for inhomogeneous gas heating.

[Analyzing A- and 0-rhythms of Conditioned Avoidance Reflex in the Rat Brain With Granger Causality].

It has been shown by the method of frequency decomposition of conditional Granger causality that under the execution of conditioned avoidance reflex θ-rhythm from the ventral hippocampus concurrently influences the ventral tegmental area and the series-connected basolateral amygdala and medial prefrontal cortex. Under the expectation of conditioned signal δ-rhythm from the prefrontal cortex influ- ences the ventral tegmental area and the amygdala.

[Δ-, θ-Modulation of the Ventral Tegmental Area Fast-Gamma Activity in the Course of Performance of Conditioned Avoidance Reflex in Rat].

The prestimulus expectation period of conditioned avoidance reflex features synchronized Δ-rhythm (1-4 Hz) in the medial prefrontal cortex and the ventral tegmental area (VTA), and synchronized θ-rhythm (6-8 Hz) in the above-mentioned structures and the hippocampus. According to "Granger causality" Δ- and θ-rhythms flow (are predictors) in the direction from the prefrontal cortex and the hippocampus to the VTA. Performance of conditioned avoidance reflex was marked by Δ-rhythm elimination simultaneously with generation of high-frequency (8-11 Hz) synchronized θ-rhythm.

[The Interaction of the Medial Prefrontal Cortex, Ventral Hippocampus and Basolateral Amygdala in the Course of Performance of Conditioned Avoidance Reflex].

The interaction (synchronization) of activity of the medial prefrontal cortex, hippocampus and basolateral amygdala have been studied in the course of performance of conditioned avoidance reflex. The pre-stimulus expectation period was characterized by low-frequency delta-activity (1-4 Hz) with the source (according to criteria of Granger causality) in the prefrontal cortex and also by synchronized theta-rhythm (6-8 Hz) in the hippocampus. The performance of conditioned avoidance reflex was characterized by generation of high-frequency synchronized theta-rhythm (8-11 Hz) simultaneously with delta-activity elimination.

[Long-term potentiation and oscillation synchrony in the-ventral hippocampal-prefrontal pathways].

The results of the present study show the augmentation of hippocampal-cortical coherence and phase synchronization in theta-frequency and wider (1-15 Hz) low frequency range, during the time-period of LTP of monosynaptic prefrontal cortex focal potentials. The augmentation was detectable only in that activity segments with low to near-zero hippocampal theta frequency power. No definite changes in amplitude correlation of theta-rhytm envelops has been established.

Drug-like density: a method of quantifying the "bindability" of a protein target based on a very large set of pockets and drug-like ligands from the Protein Data Bank.

One approach to estimating the "chemical tractability" of a candidate protein target where we know the atomic resolution structure is to examine the physical properties of potential binding sites. A number of other workers have addressed this issue. We characterize ~290,000 "pockets" from ~42,000 protein crystal structures in terms of a three parameter "pocket space": volume, buriedness, and hydrophobicity.

QSAR models for predicting the similarity in binding profiles for pairs of protein kinases and the variation of models between experimental data sets.

We propose a direct QSAR methodology to predict how similar the inhibitor-binding profiles of two protein kinases are likely to be, based on the properties of the residues surrounding the ATP-binding site. We produce a random forest model for each of five data sets (one in-house, four from the literature) where multiple compounds are tested on many kinases. Each model is self-consistent by cross-validation, and all models point to only a few residues in the active site controlling the binding profiles.

Spiroimidazolidinone NPC1L1 inhibitors. 1: Discovery by 3D-similarity-based virtual screening.

A series of spiroimidazolidinone NPC1L1 inhibitors was discovered by virtual screening of the Merck corporate sample repository using 3D-similarity-based screening. Selection of 330 compounds for testing in an in vitro NPC1L1 binding assay yielded six hits in six distinct chemical series. Follow-up 2D similarity searching yielded several sub- to low-micromolar leads; among these was spiroimidazolidinone 10, with an IC(50) of 2.

Approximation bounds for smooth functions in C(IRd) by neural and mixture networks.

We consider the approximation of smooth multivariate functions in C(IRd) by feedforward neural networks with a single hidden layer of nonlinear ridge functions. Under certain assumptions on the smoothness of the functions being approximated and on the activation functions in the neural network, we present upper bounds on the degree of approximation achieved over the domain IRd, thereby generalizing available results for compact domains. We extend the approximation results to the so-called mixture of expert architecture, which has received considerable attention in recent years, showing that the same type of approximation bound may be achieved.

On the optimality of neural-network approximation using incremental algorithms.

The problem of approximating functions by neural networks using incremental algorithms is studied. For functions belonging to a rather general class, characterized by certain smoothness properties with respect to the L2 norm, we compute upper bounds on the approximation error where error is measured by the Lq norm, 1< or =q< or =infinity. These results extend previous work, applicable in the case q=2, and provide an explicit algorithm to achieve the derived approximation error rate.

Comparison of topological, shape, and docking methods in virtual screening.

Virtual screening benchmarking studies were carried out on 11 targets to evaluate the performance of three commonly used approaches: 2D ligand similarity (Daylight, TOPOSIM), 3D ligand similarity (SQW, ROCS), and protein structure-based docking (FLOG, FRED, Glide). Active and decoy compound sets were assembled from both the MDDR and the Merck compound databases. Averaged over multiple targets, ligand-based methods outperformed docking algorithms.

Scoring of KDR kinase inhibitors: using interaction energy as a guide for ranking.

Within a congeneric series of ATP-competitive KDR kinase inhibitors, we determined that the IC(50) values, which span four orders of magnitude, correlated best with the calculated ligand-protein interaction energy using the Merck Molecular Force Field (MMFFs(94)). Using the ligand-protein interaction energy as a guide, we outline a workflow to rank order virtual KDR kinase inhibitors prior to synthesis. When structural information of the target is available, the ability to score molecules a priori can be used to rationally select reagents.

Dynamic control of allosteric antagonism of leukocyte function antigen-1 and intercellular adhesion molecule-1 interaction.

Leukocyte function associated antigen-1 (LFA-1) plays a critical role in T cell migration and has been recognized as a therapeutic target for immune disorders. Several classes of small molecule antagonists have been developed to block LFA-1 interaction with intercellular adhesion molecule-1 (ICAM-1). Recent structural studies show that the antagonists bind to an allosteric site in the I-domain of LFA-1.

The effects of systemic administration of selective antagonists of dopamine D1 and D2/D3 receptors on food-related and defensive (escape responses) conditioned paw-placing responses in cats.

Experiments were performed on cats to study the effects of systemic administration of antagonists of dopaminergic transmission on food-related and defensive (an escape response) operant conditioned reflexes acquired on the basis of the innate response of placing the forepaw on a support. Selective blockade of D1 receptors with SCH23390 (0.005-0.

Enhanced virtual screening by combined use of two docking methods: getting the most on a limited budget.

Flexible ligand docking is a routine part of a modern structure-based lead discovery process. As of today, there are quite a number of commercial docking programs that can be used to screen large databases (hundreds of thousands to millions of compounds). However, limiting factors such as the number of commercial software licenses needed to perform docking simultaneously on multiple processors ("software cost") and the relatively long time required per molecule to get good results ("quality-to-speed") should be taken into account when planning a large docking run.

The appearance of long-latency responses to a conditioned signal in the cortex is explained by strengthening of collateral connections between pyramidal neurons.

Experimental analysis and computer simulation of the neurophysiological processes underlying the "stable and local electrophysiological expression of conditioned reflexes" in the cerebral cortex, a phenomenon discovered in Asratyan's laboratory in the 1960s, showed that the long-latency components of cortical evoked potentials to a conditioned signal correspond to the late phases of the responses of motor cortex neurons, which are analogous to and probably generated by the same mechanism as long-latency epileptiform reactions of neurons in the epileptogenic cortex. Late long-latency components are generated via activation of NMDA receptors in the collateral connections between pyramidal neurons. The delay in the generation of responses depends on the initial activation of GABA(A) receptors and the slow kinetics of the current through NMDA channels.

Structural and functional modeling of human lysozyme reveals a unique nonapeptide, HL9, with anti-HIV activity.

We previously reported that lysozyme accounts for anti-HIV activity associated with the beta-core fraction of human chorionic gonadotropin [Lee-Huang, S., Huang, P. L.

Similarity to molecules in the training set is a good discriminator for prediction accuracy in QSAR.

How well can a QSAR model predict the activity of a molecule not in the training set used to create the model? A set of retrospective cross-validation experiments using 20 diverse in-house activity sets were done to find a good discriminator of prediction accuracy as measured by root-mean-square difference between observed and predicted activity. Among the measures we tested, two seem useful: the similarity of the molecule to be predicted to the nearest molecule in the training set and/or the number of neighbors in the training set, where neighbors are those more similar than a user-chosen cutoff. The molecules with the highest similarity and/or the most neighbors are the best-predicted.

[Long-latency responses to conditioned stimulus in the cat motor cortex can be generated through the enhancement of efficiency excitatory collaterals of pyramidal neuron].

The long-latency excitatory components are the characteristic feature of neuronal responses to conditional stimuli in the motor cortex of the cat. The data presented suggest that the neuronal machine that generates these reactions is that, generating long-latency epileptiform discharges in epileptogenic cortex. The long-latency component generation is based on NMDA-receptor activation in the recurrent excitatory collaterals of the cortical pyramidal neurons.

[Structure and expression of the F6.2 gene in Chironomus thummi and other Chironomus species].

A full-length copy of the F6.2 gene from the tissue-specific BRa locus of the Chironomus thummi chromosome IV was isolated and analyzed. The gene contains two exons (715 and 644 bp, respectively) and one 172-bp intron.

A computer model of neural processes observed in the cat motor cortex during performance of an operant movement.

This report describes a computer model of a "column" in the cat motor cortex. The model includes two layers of two-segment pyramidal neurons with two groups of inhibitory interneurons in each layer, which selectively control the somatic and dendritic segments of the pyramidal cells. In this model, neurons include active sodium, calcium, and several types of potassium currents.

NMDA-dependent and NMDA-independent neural processes in the bicucculline-disinhibited motor cortex of the cat during the acquisition and reproduction of a conditioned paw-on-support placing reflex.

Neuron activity was recorded in the motor area of the cat cortex during acquisition of an operant conditioned reflex consisting of placing the forepaw on a support in conditions of local disinhibition by spontaneous diffusion of the GABA(A) receptor blocker bicucculline from the recording micropipette. The conditioned signal was electrical stimulation of the parietal cortex with a train of 3-5 impulses. Addition of 2-amino-5-phosphopentanoic acid (APV), an NMDA glutamate receptor blocker, led to disappearance of the secondary excitatory components (in the poststimulus interval 30-120 msec) from neuronal responses in the disinhibited cortex both to the "indifferent" (before training) and the conditioned stimulation of the parietal cortex, while excitatory reactions associated with elevation and placing of the paw on the support showed no significant change in the presence of APV.