The Hippo pathway as an antitumor target: time to focus on.

Introduction: The Hippo signaling governs the expression of genes critically important for cell proliferation and survival. The components of this pathway are considered antitumor drug targets. However, the design of Hippo inhibitors is a challenge given the complexity of the network and redundancy of its elements.

[Transgastric necrectomy for acute pancreatitis].

The review is devoted to transgastric necrectomy in the treatment of infected forms of acute pancreatitis. The authors discuss the indications for transgastric necrectomy and technical features of these interventions (direct endoscopic necrectomy, laparoscopic and open transgastric necrectomy). Numerous studies devoted to results of transgastric necrectomy indicate advisability of this procedure in carefully selected patients and interdisciplinary interaction of various specialists before and after surgery.

Light-induced spin-state switching in Fe(II) spin-crossover complexes with thiazole-based chelating ligands.

Homoleptic complexes [Fe(4bt)](ClO) (1), [Fe(2bt)](ClO) (2), and [Fe(3tpH)](ClO) (3) were obtained by a reaction between the Fe(II) precursor salt and the corresponding thiazole-based bidentate ligand (L = 4bt = 4,4'-bithiazole, 2bt = 2,2'-bithiazole, 3tpH = 3-(thiazol-2-yl)pyrazole). X-ray crystal structure determination revealed crystallization of solvent-free complex 1, a solvate 2·MeOH, and a co-crystal 3·2(3tpH). The crystal packing of all these complexes is dominated by one-dimensional interactions between the [Fe(L)] cations.

Phenotypic assessment of antiviral activity for spiro-annulated oxepanes and azepenes.

Evolutionary potential of viruses can result in outbreaks of well-known viruses and emergence of novel ones. Pharmacological methods of intervening the reproduction of various less popular, but not less important viruses are not available, as well as the spectrum of antiviral activity for most known compounds. In the framework of chemical biology paradigm, characterization of antiviral activity spectrum of new compounds allows to extend the antiviral chemical space and provides new important structure-activity relationships for data-driven drug discovery.

Effect of Combined Laser Thermal and Shock Wave Effects on the Mechanical and Tribological Properties of Steels.

Herein, we present the results of an experimental study on the mechanical properties of Fe-C alloys with different carbon contents (0.2, 0.45, and 0.

Assessing and Forecasting Fatigue Strength of Metals and Alloys under Cyclic Loads.

Within the scope of this research, patterns of changes in the fatigue life and limit of metals under cyclic stress were identified and the most informative parameters were determined as the basis for developing a method for the universal transformation of experimental data on the fatigue of metals and alloys for their subsequent generalization. Experimental data on metal fatigue, obtained by a large number of authors for a wide range of grades of steels and alloys, under the influence of various combinations of factors, were systematized. A generalized dependence of the recalculated parameters of fatigue life and limit was obtained, its characteristics were assessed, and a sensitivity analysis was performed, confirming the universal nature of the obtained dependence.

Laser Drilling in Alumina Ceramics Using a Combination of Laser Pulses in the Free-Running and Q-Switched Modes.

The possibility of using a two-pulse laser action consisting of a pulse of the free-running pulse followed by the Q-switched pulse in the processes of laser drilling in alumina ceramics is considered. A diagram of a laser machine for implementing the proposed processing method and the method for determining the energy required to form the through hole and the drilling time are presented. For thermal exposure, pulsed radiation of Nd:YAG of the laser operating in the free-running mode (pulse duration 0.

Conformal Noble Metal High-Entropy Alloy Nanofilms by Atomic Layer Deposition for an Enhanced Hydrogen Evolution Reaction.

The current synthesis methods of high-entropy alloy (HEA) thin-film coatings face huge challenges in facile preparation, precise thickness control, conformal integration, and affordability. These challenges are more specific and noteworthy for noble metal-based HEA thin films where the conventional sputtering methods encounter thickness control and high-cost issues (high-purity noble metal targets required). Herein, for the first time, we report a facile and controllable synthesis process of quinary HEA coatings consisting of noble metals (Rh, Ru, Pt, Pd, and Ir), by sequential atomic layer deposition (ALD) coupled with electrical Joule heating for post-alloying.

Stress promotes RNA G-quadruplex folding in human cells.

Guanine (G)-rich nucleic acids can fold into G-quadruplex (G4) structures under permissive conditions. Although many RNAs contain sequences that fold into RNA G4s (rG4s) in vitro, their folding and functions in vivo are not well understood. In this report, we showed that the folding of putative rG4s in human cells into rG4 structures is dynamically regulated under stress.

Investigation of the Technological Possibility of Manufacturing Volumetric Shaped Ductile Cast Iron Products in Open Dies.

Information about the technological possibility of stamping in open dies, round-shaped forgings made of ductile cast iron, is outlined herein. Cast iron's propensity for plastic deformation under complex loading conditions is analyzed from the standpoint of the morphology of graphite inclusions, depending on the degree and mechanical scheme of deformation. The research methodology included: the choice of a brand of cast iron with spherical graphite and the technological process of its deformation; mathematical modeling of the deformation process using the DEFORM-3D software package; stamping of an experimental batch of forgings; and microstructural studies of the forging material, together with the data of its stress-strain state and the direction of flow of the material.

PROTAC: targeted drug strategy. Principles and limitations.

The PROTAC () technology is a method of targeting intracellular proteins previously considered undruggable. This technology utilizes the ubiquitin-proteasome system in cells to specifically degrade target proteins, thereby offering significant advantages over conventional small-molecule inhibitors of the enzymatic function. Preclinical and preliminary clinical trials of PROTAC-based compounds (degraders) are presented.

Antiviral Activity and Crystal Structures of HIV-1 gp120 Antagonists.

As part of our effort to discover drugs that target HIV-1 entry, we report the antiviral activity and crystal structures of two novel inhibitors in a complex with a gp120 core. NBD-14204 showed similar antiviral activity against all the clinical isolates tested. The IC values were in the range of 0.

Comparative Pharmacokinetics of a Dual Inhibitor of HIV-1, NBD-14189, in Rats and Dogs with a Proof-of-Concept Evaluation of Antiviral Potency in SCID-hu Mouse Model.

We earlier reported substantial progress in designing gp120 antagonists. Notably, we discovered that NBD-14189 is not only the most active gp120 antagonist but also shows antiviral activity against HIV-1 Reverse Transcriptase (RT). We also confirmed its binding to HIV-1 RT by X-ray crystallography.

Design and Characterization of Novel Small Molecule Activators of Excitatory Amino Acid Transporter 2.

Excitotoxicity in the brain is a causal factor in several neurological and neurodegenerative disorders. Excitatory amino acid transporter 2 (EAAT2), an astrocytic glutamate transporter involved in the clearance of >80% of synaptic glutamate, is considered a therapeutically relevant target for excitotoxicity. We have previously designed GT951, an activator of EAAT2 with nanomolar efficacy but limited in vivo bioavailability.

Design and Synthesis of Fsp3-Enriched Spirocyclic-Based Biological Screening Compound Arrays via DOS Strategies and Their NNMT Inhibition Profiling.

Medicinal chemists are keen to explore tridimensional compounds, especially when it comes to small molecules. It has already been stressed that the majority of known drugs tend to be flat, whereas natural products tend to be more tridimensional and represent a good source of active compounds. 3D metrics have been implemented and computational descriptors are available to evaluate and prioritize compounds based on their 3D geometry.

Discovery of the 4-aminopiperidine-based compound EM127 for the site-specific covalent inhibition of SMYD3.

Recent findings support the hypothesis that inhibition of SMYD3 methyltransferase may be a therapeutic avenue for some of the deadliest cancer types. Herein, active site-selective covalent SMYD3 inhibitors were designed by introducing an appropriate reactive cysteine trap into reversible first-generation SMYD3 inhibitors. The 4-aminopiperidine derivative EM127 (11C) bearing a 2-chloroethanoyl group as reactive warhead showed selectivity for Cys186, located in the substrate/histone binding pocket.

In Situ Observation of Shear-Induced Jamming Front Propagation during Low-Velocity Impact in Polypropylene Glycol/Fumed Silica Shear Thickening Fluids.

Shear jamming, a relatively new type of phase transition from discontinuous shear thickening into a solid-like state driven by shear in dense suspensions, has been shown to originate from frictional interactions between particles. However, not all dense suspensions shear jam. Dense fumed silica colloidal systems have wide applications in the industry of smart materials from body armor to dynamic dampers due to extremely low bulk density and high colloid stability.

Targeting Virus-Induced Reprogrammed Cell Metabolism Glycolytic Inhibitors: An Effective Therapeutic Approach Against SARS-CoV-2.

Reprogrammed cell metabolism has been observed in a wide range of virally infected cells. Viruses do not have their metabolism; they rely on the cellular metabolism of the host to ensure the energy and macromolecules requirement for replication. Like other viruses, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) does not own its metabolism, but virus infected cells adopt aberrant cell metabolism.

In Vitro and In Vivo Pharmacological Characterization of a Novel TRPM8 Inhibitor Chemotype Identified by Small-Scale Preclinical Screening.

Transient receptor potential melastatin type 8 (TRPM8) is a target for the treatment of different physio-pathological processes. While TRPM8 antagonists are reported as potential drugs for pain, cancer, and inflammation, to date only a limited number of chemotypes have been investigated and thus a limited number of compounds have reached clinical trials. Hence there is high value in searching for new TRPM8 antagonistic to broaden clues to structure-activity relationships, improve pharmacological properties and explore underlying molecular mechanisms.

Discovery of Highly Potent Fusion Inhibitors with Potential Pan-Coronavirus Activity That Effectively Inhibit Major COVID-19 Variants of Concern (VOCs) in Pseudovirus-Based Assays.

We report the discovery of several highly potent small molecules with low-nM potency against severe acute respiratory syndrome coronavirus (SARS-CoV; lowest half-maximal inhibitory concentration (IC: 13 nM), SARS-CoV-2 (IC: 23 nM), and Middle East respiratory syndrome coronavirus (MERS-CoV; IC: 76 nM) in pseudovirus-based assays with excellent selectivity index (SI) values (>5000), demonstrating potential pan-coronavirus inhibitory activities. Some compounds showed 100% inhibition against the cytopathic effects (CPE; IC) of an authentic SARS-CoV-2 (US_WA-1/2020) variant at 1.25 µM.

Gompertz model in COVID-19 spreading simulation.

The paper reports on application of the Gompertz model to describe the growth dynamics of COVID-19 cases during the first wave of the pandemic in different countries. Modeling has been performed for 23 countries: Australia, Austria, Belgium, Brazil, Great Britain, Germany, Denmark, Ireland, Spain, Italy, Canada, China, the Netherlands, Norway, Serbia, Turkey, France, Czech Republic, Switzerland, South Korea, USA, Mexico, and Japan. The model parameters are determined by regression analysis based on official World Health Organization data available for these countries.

Design of gp120 HIV-1 entry inhibitors by scaffold hopping via isosteric replacements.

We present the development of alternative scaffolds and validation of their synthetic pathways as a tool for the exploration of new HIV gp120 inhibitors based on the recently discovered inhibitor of this class, NBD-14136. The new synthetic routes were based on isosteric replacements of the amine and acid precursors required for the synthesis of NBD-14136, guided by molecular modeling and chemical feasibility analysis. To ensure that these synthetic tools and new scaffolds had the potential for further exploration, we eventually tested few representative compounds from each newly designed scaffold against the gp120 inhibition assay and cell viability assays.