Combining Different Docking Engines and Consensus Strategies to Design and Validate Optimized Virtual Screening Protocols for the SARS-CoV-2 3CL Protease

The 3CL-Protease appears to be a very promising medicinal target to develop anti-SARS-CoV-2 agents. The availability of resolved structures allows structure-based computational approaches to be carried out even though the lack of known inhibitors prevents a proper validation of the performed simulations. The innovative idea of the study is to exploit known inhibitors of SARS-CoV 3CL-Pro as a training set to perform and validate multiple virtual screening campaigns. Docking simulations using four different programs (Fred, Glide, LiGen, and PLANTS) were performed investigating the role of both multiple binding modes (by binding space) and multiple isomers/states (by developing the corresponding isomeric space). The computed docking scores were used to develop consensus models, which allow an in-depth comparison of the resulting performances. On average, the reached performances revealed the different sensitivity to isomeric differences and multiple binding modes between the four docking engines. In detail, Glide and LiGen are the tools that best benefit from isomeric and binding space, respectively, while Fred is the most insensitive program. The obtained results emphasize the fruitful role of combining various docking tools to optimize the predictive performances. Taken together, the performed simulations allowed the rational development of highly performing virtual screening workflows, which could be further optimized by considering different 3CL-Pro structures and, more importantly, by including true SARS-CoV-2 3CL-Pro inhibitors (as learning set) when available.     

Simulations of ferrite-dielectric-wire composite negative index materials

We perform extensive finite difference time domain simulations of ferrite based negative index of refraction composites. A wire grid is employed to provide negative permittivity. The ferrite and wire grid interact to provide both negative and positive index of refraction transmission peaks in the vicinity of the ferrite resonance. Notwithstanding the extreme anisotropy in the index of refraction of the composite, negative refraction is seen at the composite air interface allowing the construction of a focusing concave lens with a magnetically tunable focal length.     

Interpretation of NMR Relaxation as a Tool for Characterising the Adsorption Strength of Liquids inside Porous Materials

Nuclear magnetic resonance (NMR) relaxation times are shown to provide a unique probe of adsorbate–adsorbent interactions in liquid‐saturated porous materials. A short theoretical analysis is presented, which shows that the ratio of the longitudinal to transverse relaxation times (T₁/T₂) is related to an adsorbate–adsorbent interaction energy, and we introduce a quantitative metric e_surf (based on the relaxation time ratio) characterising the strength of this surface interaction. We then consider the interaction of water with a range of oxide surfaces (TiO₂ anatase, TiO₂ rutile, γ‐Al₂O₃, SiO₂, θ‐Al₂O₃ and ZrO₂) and show that e_surf correlates with the strongest adsorption sites present, as determined by temperature programmed desorption (TPD). Thus we demonstrate that NMR relaxation measurements have a direct physical interpretation in terms of the characterisation of activation energy of desorption from the surface. Further, for a series of chemically similar solid materials, in this case a range of oxide materials, for which at least two calibration values are obtainable by TPD, the e_surf parameter yields a direct estimate of the maximum activation energy of desorption from the surface. The results suggest that T₁/T₂ measurements may become a useful addition to the methods available to characterise liquid‐phase adsorption in porous materials. The particular motivation for this work is to characterise adsorbate–surface interactions in liquid‐phase catalysis.     

From a Medicinal Mushroom Blend a Direct Anticancer Effect on Triple-Negative Breast Cancer: A Preclinical Study on Lung Metastases

Bioactive metabolites isolated from medicinal mushrooms (MM) used as supportive treatment in conventional oncology have recently gained interest. Acting as anticancer agents, they interfere with tumor cells and microenvironment (TME), disturbing cancer development/progression. Nonetheless, their action mechanisms still need to be elucidated. Recently, using a 4T1 triple-negative mouse BC model, we demonstrated that supplementation with Micotherapy U-Care, a MM blend, produced a striking reduction of lung metastases density/number, paralleled by decreased inflammation and oxidative stress both in TME and metastases, together with QoL amelioration. We hypothesized that these effects could be due to either a direct anticancer effect and/or to a secondary/indirect impact of Micotherapy U-Care on systemic inflammation/immunomodulation. To address this question, we presently focused on apoptosis/proliferation, investigating specific molecules, i.e., PARP1, p53, BAX, Bcl2, and PCNA, whose critical role in BC is well recognized. We revealed that Micotherapy U-Care is effective to influence balance between cell death and proliferation, which appeared strictly interconnected and inversely related (p53/Bax vs. Bcl2/PARP1/PCNA expression trends). MM blend displayed a direct effect, with different efficacy extent on cancer cells and TME, forcing tumor cells to apoptosis. Yet again, this study supports the potential of MM extracts, as adjuvant supplement in the TNBC management.     

Oxygenation of calixarene phenol rings

[structure: see text] The first examples of epoxy-p-quinol and diepoxy-p-quinol calixarene derivatives have been obtained by base-promoted direct addition of O(2)(oxygenation) to calixarene phenol rings. The regio- and stereochemistry of these derivatives was determined by 2D NMR studies, in conjunction with MM3 calculations, and X-ray crystallography. Both the oxygenation and the subsequent carbonyl reduction occur with a preferential attack to the less hindered exo face of the calixarene rings.     

Ancillary ligand effect on single-site styrene polymerization: isospecificity of group 4 metal bis(phenolate) catalysts

Styrene is polymerized isospecifically by group 4 metal complexes that contain a C2-symmetrically coordinated 1,4-dithiabutane-linked bis(phenolato) ligand activated by methylaluminoxane.     

Measurement of the resistivity of porous materials with an alternating air-flow method

Air-flow resistivity is a main parameter governing the acoustic behavior of porous materials for sound absorption. The international standard ISO 9053 specifies two different methods to measure the air-flow resistivity, namely a steady-state air-flow method and an alternating air-flow method. The latter is realized by the measurement of the sound pressure at 2 Hz in a small rigid volume closed partially by the test sample. This cavity is excited with a known volume-velocity sound source implemented often with a motor-driven piston oscillating with prescribed area and displacement magnitude. Measurements at 2 Hz require special instrumentation and care. The authors suggest an alternating air-flow method based on the ratio of sound pressures measured at frequencies higher than 2 Hz inside two cavities coupled through a conventional loudspeaker. The basic method showed that the imaginary part of the sound pressure ratio is useful for the evaluation of the air-flow resistance. Criteria are discussed about the choice of a frequency range suitable to perform simplified calculations with respect to the basic method. These criteria depend on the sample thickness, its nonacoustic parameters, and the measurement apparatus as well. The proposed measurement method was tested successfully with various types of acoustic materials.     

Path integral synthesis of lyapunov functionals for partial differential equations

A method is given for constructing Lyapunov Functionals for dynamical systems governed by partial differential equations. The functionals are obtained as path integrals in a suitably chosen state space of a generalized gradient operator, and the method may be viewed as an extension to infinite dimensional systems of the variable gradient technique. Some of the fundamental concepts underlying the formalism are reviewed, and examples of applications to some linear, non-linear and hybrid systems are given.     

Material electromagnetic fields and material forces

Electromagnetic fields address configurational forces in a natural way through an energy–stress tensor, which reduces to the Maxwell tensor in the simplest case. This tensor is related to physical forces and to the Cauchy traction in a continuum. Material forces, as opposed to physical forces, are of a different nature as they act upon a site of a continuum where the possible material inhomogeneity is located. A material energy–stress tensor, which is reminiscent of the Maxwell stress, is associated with these forces. Through appropriate balance laws, a material momentum is also associated with material forces. The material momentum is of particular interest in electromagnetic materials as it is intimately related to the pseudomomentum of light [Peierls in Highlights of Condensed Matter Physics, pp. 237–255 (1985) and in Surprises in Theoretical Physics, pp. 91–99 (1979); Thellung in Ann. Phys. 127, 289–301 (1980)]. The balance law for the material momentum can be derived either from the classical physical laws or independently of them. This derivation, which is based on the material electromagnetic potentials and the related gauge transformations, is discussed and commented on for an electromagnetic body.     

A preconditioning approach to the pagerank computation problem

Some spectral properties of the transition matrix of an oriented graph indicate the preconditioning of Euler-Richardson (ER) iterative scheme as a good way to compute efficiently the vertexrank vector associated with such graph. We choose the preconditioner from an algebra U of matrices, thereby obtaining an ER_U method, and we observe that ER_U can outperform ER in terms of rate of convergence. The proposed preconditioner can be updated at a very low cost whenever the graph changes, as is the case when it represents a generic set of information. The particular U utilized requires a surplus of operations per step and memory allocations, which make ER_U superior to ER for not too wide graphs. However, the observed high improvement in convergence rate obtained by preconditioning and the general theory developed, are a reason for investigating different choices of U, more efficient for huge graphs.