Aggrescan4D: structure-informed analysis of pH-dependent protein aggregation.

Protein aggregation is behind the genesis of incurable diseases and imposes constraints on drug discovery and the industrial production and formulation of proteins. Over the years, we have been advancing the Aggresscan3D (A3D) method, aiming to deepen our comprehension of protein aggregation and assist the engineering of protein solubility. Since its inception, A3D has become one of the most popular structure-based aggregation predictors because of its performance, modular functionalities, RESTful service for extensive screenings, and intuitive user interface.

A3D Model Organism Database (A3D-MODB): a database for proteome aggregation predictions in model organisms.

Protein aggregation has been associated with aging and different pathologies and represents a bottleneck in the industrial production of biotherapeutics. Numerous past studies performed in Escherichia coli and other model organisms have allowed to dissect the biophysical principles underlying this process. This knowledge fuelled the development of computational tools, such as Aggrescan 3D (A3D) to forecast and re-design protein aggregation.

A3DyDB: exploring structural aggregation propensities in the yeast proteome.

Background: The budding yeast Saccharomyces cerevisiae (S. cerevisiae) is a well-established model system for studying protein aggregation due to the conservation of essential cellular structures and pathways found across eukaryotes. However, limited structural knowledge of its proteome has prevented a deeper understanding of yeast functionalities, interactions, and aggregation.

A3D database: structure-based predictions of protein aggregation for the human proteome.

Summary: Protein aggregation is associated with many human disorders and constitutes a major bottleneck for producing therapeutic proteins. Our knowledge of the human protein structures repertoire has dramatically increased with the recent development of the AlphaFold (AF) deep-learning method. This structural information can be used to understand better protein aggregation properties and the rational design of protein solubility.

Protocols for Rational Design of Protein Solubility and Aggregation Properties Using Aggrescan3D Standalone.

Protein aggregation is a major hurdle in the development and manufacturing of protein-based therapeutics. Development of aggregation-resistant and stable protein variants can be guided by rational redesign using computational tools. Here, we describe the architecture and functionalities of the Aggrescan3D (A3D) standalone package for the rational design of protein solubility and aggregation properties based on three-dimensional protein structures.

A3D 2.0 Update for the Prediction and Optimization of Protein Solubility.

Protein aggregation propensity is a property imprinted in protein sequences and structures, being associated with the onset of human diseases and limiting the implementation of protein-based biotherapies. Computational approaches stand as cost-effective alternatives for reducing protein aggregation and increasing protein solubility. AGGRESCAN 3D (A3D) is a structure-based predictor of aggregation that takes into account the conformational context of a protein, aiming to identify aggregation-prone regions exposed in protein surfaces.

The Algorithm of a Game-Based System in the Relation between an Operator and a Technical Object in Management of E-Commerce Logistics Processes with the Use of Machine Learning.

Machine learning (ML) is applied in various logistic processes utilizing innovative techniques (e.g., the use of drones for automated delivery in e-commerce).

Aggrescan3D (A3D) 2.0: prediction and engineering of protein solubility.

Protein aggregation is a hallmark of a growing number of human disorders and constitutes a major bottleneck in the manufacturing of therapeutic proteins. Therefore, there is a strong need of in-silico methods that can anticipate the aggregative properties of protein variants linked to disease and assist the engineering of soluble protein-based drugs. A few years ago, we developed a method for structure-based prediction of aggregation properties that takes into account the dynamic fluctuations of proteins.

CABS-dock standalone: a toolbox for flexible protein-peptide docking.

Summary: CABS-dock standalone is a multiplatform Python package for protein-peptide docking with backbone flexibility. The main feature of the CABS-dock method is its ability to simulate significant backbone flexibility of the entire protein-peptide system in a reasonable computational time. In the default mode, the package runs a simulation of fully flexible peptide searching for a binding site on the surface of a flexible protein receptor.

Aggrescan3D standalone package for structure-based prediction of protein aggregation properties.

Summary: Aggrescan3D (A3D) standalone is a multiplatform Python package for structure-based prediction of protein aggregation properties and rational design of protein solubility. A3D allows the re-design of protein solubility by combining structural aggregation propensity and stability predictions, as demonstrated by a recent experimental study. It also enables predicting the impact of protein conformational fluctuations on the aggregation properties.

CABS-flex standalone: a simulation environment for fast modeling of protein flexibility.

Summary: CABS-flex standalone is a Python package for fast simulations of protein structure flexibility. The package combines simulations of protein dynamics using CABS coarse-grained protein model with the reconstruction of selected models to all-atom representation and analysis of modeling results. CABS-flex standalone is designed to allow for command-line access to the CABS computations and complete control over simulation process.

Combining Structural Aggregation Propensity and Stability Predictions To Redesign Protein Solubility.

The aggregation propensity of each particular protein seems to be shaped by evolution according to its natural abundance in the cell. The production and downstream processing of recombinant polypeptides implies attaining concentrations that are orders of magnitude above their natural levels, often resulting in their aggregation; a phenomenon that precludes the marketing of many globular proteins for biomedical or biotechnological applications. Therefore, there is a huge interest in methods aimed to increase the proteins solubility above their natural limits.

CABS-flex 2.0: a web server for fast simulations of flexibility of protein structures.

Classical simulations of protein flexibility remain computationally expensive, especially for large proteins. A few years ago, we developed a fast method for predicting protein structure fluctuations that uses a single protein model as the input. The method has been made available as the CABS-flex web server and applied in numerous studies of protein structure-function relationships.

The structure of adsorbed cyclic chains.

In order to determine the structure of polymer films formed of cyclic chains (rings) we developed and studied a simple coarse-grained model. Our main goal was to check how the percolation and jamming thresholds in such a system were related to the thresholds obtained for linear flexible chains system, i.e.

ATP and magnesium promote cotton short-form ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) activase hexamer formation at low micromolar concentrations.

We report a fluorescence correlation spectroscopy (FCS) study of the assembly pathway of the AAA+ protein ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) activase (Rca), a ring-forming ATPase responsible for activation of inhibited Rubisco complexes for biological carbon fixation. A thermodynamic characterization of simultaneously populated oligomeric states appears critical in understanding Rca structure and function. Using cotton β-Rca, we demonstrate that apparent diffusion coefficients vary as a function of concentration, nucleotide, and cation.

Protein oligomerization monitored by fluorescence fluctuation spectroscopy: self-assembly of rubisco activase.

A methodology is presented to characterize complex protein assembly pathways by fluorescence correlation spectroscopy. We have derived the total autocorrelation function describing the behavior of mixtures of labeled and unlabeled protein under equilibrium conditions. Our modeling approach allows us to quantitatively consider the relevance of any proposed intermediate form, and K(d) values can be estimated even when several oligomeric species coexist.

[The use of metabolic therapy in the treatment of ischemic heart disease in hemodynamically formed insignificant aortic stenosis with chronic heart failure].

Analysis of medical treatment was conducted with justified using of the metabolic component in a complex therapy of ischemic heart disease with chronic heart failure in hemodynamically formed insignificant aortic stenoses. The effect of metabolic correction is shown for pharmaceutical compounds Meldoniya in the form of Vasonat manufactured by "OlainFarm" (Latvia). Positive results of maintenance of systolic activity and prevention of diastolic dysfunction of myocardium were presented.

Atomic resolution x-ray structure of the substrate recognition domain of higher plant ribulose-bisphosphate carboxylase/oxygenase (Rubisco) activase.

The rapid release of tight-binding inhibitors from dead-end ribulose-bisphosphate carboxylase/oxygenase (Rubisco) complexes requires the activity of Rubisco activase, an AAA+ ATPase that utilizes chemo-mechanical energy to catalyze the reactivation of Rubisco. Activase is thought to play a central role in coordinating the rate of CO(2) fixation with the light reactions of photosynthesis. Here, we present a 1.

[Effect of metabolic therapy on the course of heart failure in patients after myocarditis complicated with systemic connecting tissue diseases].

In the course of observation over 40 patients after an old myocarditis against general systemic diseases of connective tissue who had been given a pharmacotherapy regarding main disease and a chronic heart failure, additionally Vazonat (campaign of "Olajnfarm", Latvia), preparation of the myocardial cytoprotection was prescribed in a therapeutic dose of 500 mg per day. Vazonat inclusion in basic therapy during 1 month was accompanied by improvement of a clinical condition of the patients, reduction of heart failure signs, and improvement of life quality.

[Efficacy of local application of kapsikam ointment in the complex therapy of osteoarthrosis].

The article presents the study of efficacy of local therapy with "Kapsikam" ointment in patients having predominantly their knee- and hip joints affected by osteoarthrosis. The main patients' complaints were sensation of knee- and hip joints pain aggravated by movement, joint stiffness and restriction of joint motions.

[The functional status of the sympathoadrenal system in hypertension patients being treated with captopril and dalargin].

The level of urinary excretion of catecholamines (CA) and their precursors was studied in 87 patients with stage I, II hypertensive disease (HD). Three groups were formed depending on the therapy option: group I comprised stage I HD patients in whom endonasal dalargin electrophoresis (EDE) was instituted, groups II and III were patients with stage II HD who were given a complex therapy with captopril plus EDE and monotherapy with captopril respectively. EDE led to a decline in the functional activity of the sympathoadrenal system (SAS) in stage I HD patients and potentiated a hypotensive effect of captopril resulting in diminution of excretion of norepinephrine.

Traumatic rupture of the aorta.

In a series of 28 patients with suspected ruptured thoracic aorta, only three were shown to have sustained such an injury. To minimise the number of negative examination, the importance of optimising the initial radiological examination of the chest is discussed along with the importance of visualisation of the descending aorta. The signs that lead to the suspicion of rupture of the aorta are numerous and non specific and indicate some change in the mediastinum which could be significant in the given clinical context.

[The optimization of the hypotensive therapy of hypertension patients taking into account the central hemodynamics and functional tests with obzidan and prazosin].

A study of 52 patients with hypertensive disease (grade II, age--from 30 to 50 years; men--32, women--24) using functional tests with physical loads revealed that pronounced hemodynamic changes were seen in patients with the hyperkinetic type of hemodynamics. Obsidan and prazosin reduced the degree of responses to physical loads, economy of energy expenses, increased tolerance to physical work. Association of pharmacological tests with functional physical loads in patients with hypertensive disease allows to realize selection of hypotensive drugs depending on the hemodynamic variant of the course of the pathological process and evaluate the adequacy of dosages for treatment courses.