Since the first case of 2019 novel coronavirus disease (COVID-19) detected on Jan 30, 2020, in India, the number of cases rapidly increased to 3819 cases including 106 deaths as of 5 April 2020. Taking this into account, in the present work, we are studying a Bats-Hosts-Reservoir-People transmission fractional-order COVID-19 model for simulating the potential transmission with the thought of individual social response and control measures by the government. The real data available about infectious cases from $14^{th}$ March to $26^{th}$ March 2020 is analysed and accordingly various parameters of the model are estimated or fitted. The Picard successive approximation technique and Banach's fixed point theory have been used for verification of the existence and stability criteria of the model. Numerical computations are done utilizing the iterative Laplace transform method. In the end, we illustrate the obtained results graphically. The purpose of this study is to estimate the effectiveness of preventive measures, predicting future outbreaks and potential control strategies using the mathematical model.

The SARS-CoV-2 was confirmed to cause the regional outbreak of coronavirus disease 2019 (COVID-19) in Wuhan, China. The 3C-like protease (3CL^pro), an essential enzyme for viral replication, is a valid target to compacts SARS-CoV and MERS-CoV. In this research, an integrated library consisting of 1000 compounds from Asinex Focused Covalent (AFCL) library and 16 FDA-approved protease inhibitors were screened against SARS-CoV-2 3CL^pro. Top compounds with significant docking scores and making stable interactions with catalytic dyad residues were obtained. The screening results in identification of compound 621 from AFCL library as well as Paritaprevir and Simeprevir from FDA-approved protease inhibitors as potential inhibitors of SARS-CoV-2 3CL^pro. The mechanism and dynamic stability of binding between the identified compounds and SARS-CoV-2 3CL^pro were characterized using 50 nanoseconds (ns) molecular dynamic (MD) simulation approach. The identified compounds are potential inhibitors worthy of further development as SARS-CoV-2 3CLpro inhibitors/drugs. Importantly, the identified FDA-approved therapeutics could be ready for clinical trials to treat infected patients and help to curb the COVID-19.

In the study of relativistic jets one of the key open questions is their interaction with the environment on the microscopic level. Here, we study the initial evolution of both electron–proton (e^- - p⁺) and electron–positron (e^±) relativistic jets containing helical magnetic fields, focusing on their interaction with an ambient plasma. We have performed simulations of "global" jets containing helical magnetic fields in order to examine how helical magnetic fields affect kinetic instabilities such as the Weibel instability, the kinetic Kelvin-Helmholtz instability (kKHI) and the Mushroom instability (MI). In our initial simulation study these kinetic instabilities are suppressed and new types of instabilities can grow. In the e^- - p⁺ jet simulation recollimation-like instability occurs and jet electrons are strongly perturbed. In the e^± jet simulation a recollimation-like instability occurs at early times followed by a kinetic instability and the general structure is similar to a simulation without helical magnetic field. Simulations using much larger systems are required in order to thoroughly follow the evolution of global jets containing helical magnetic fields.

The emergence of SARS/MERS drug resistant COVID-19 with high transmission and mortality has recently been declared a deadly pandemic causing economic chaos and significant health problems. Like all coronaviruses, SARS-CoV-2 is a large virus that has many druggable components within its proteome. In this study, we focused on repurposing approved and investigational drugs by identifying potential drugs that are predicted to effectively inhibit critical enzymes within SARS-CoV-2. We shortlisted seven target proteins with enzymatic activities known to be essential at different stages of the virus life cycle. For virtual screening, the energy minimization of a crystal structure or modeled protein was carried out using Protein Preparation Wizard (Schrödinger LLC, 2020-1). Following active site selection based on data mining and COACH predictions, we performed a high-throughput virtual screen of drugs (n=5903) that are already approved by worldwide regulatory bodies including the FDA, using the ZINC database. Screening was performed against viral targets using three sequential docking modes (i.e. HTVS, SP and XP). Our in-silico virtual screening identified ~290 potential drugs based on the criteria of energy, docking parameters, ligand and binding site strain and score. Drugs specific to each target protein were further analyzed for binding free energy perturbation by molecular mechanics (prime MM-GBSA) and pruning the hits to the top 32 candidates. A top lead from each target group was further subjected to molecular dynamics simulation (MDS) using the Desmond module to validate the efficacy of the screening pipeline. All of the simulated hit-target complexes were predicted to strongly interact and with highly stable binding. Thus, we have identified a number of approved and investigational drugs with high likelihood of inhibiting a variety of key SARS-CoV-2 proteins. Follow-up studies will continue to identify inhibitors suitable for combination therapy based on drug-drug synergy to thwart resistance. In addition, the screening hits that we have identified provide excellent probes for understanding the binding properties of the active sites of all seven targets, further enabling us to derive consensus molecules through computer-aided drug design (CADD). While infections are expanding at a rampant pace, it must be recognized that resistance will grow commensurately through either genetic shift and/or genetic drift to all small molecule drugs identified. Vaccines should provide a more permanent solution through prevention, but resistivity is still a possible scenario. Nevertheless, a persistent multi-target drug development program is essential to curb this ongoing pandemic and to keep reemergence in check.

The dynamic behaviour of a machine tool (MT) directly influences the machining performances. The adoption of lightweight structures may reduce the effects of undesired vibrations and increasing the workpiece quality. This paper aims to present and compare a set of hybrid materials that may be excellent candidate to fabricate the MT moving parts. The selected materials have high dynamic characteristics and capacity to damp mechanical vibrations. In this way, starting by the kinematic model of a milling machine that highlights the main critical factors, this study paper evaluates a number of prototypes made of Al Foam sandwiches (AFS), Al Corrugated sandwiches (ACS) and materials reinforced by carbon fibres (CFRP). A set of prototypes has been fabricated, represented the Z-axis ram of a commercial milling machine. The static and dynamical properties have been evaluated by using both FE simulations and experimental tests. The obtained results show that the proposed structures may be a valid alternative to the conventional materials of MT moving parts, increasing machining performances. In particular, the AFS prototype highlighted a damping coefficient that is 20 times greater than a conventional ram (e.g. steel). The CFRP structure is able to satisfy the machining requirements with a reduced weight of 48.5%, while the ACS prototype showed a good trade-off between stiffness and damping.

We explore the possibility of using the external regions of galaxy clusters to measure their mass accretion rate (MAR). The main goal is to provide a method to observationally investigate the growth of structures on the nonlinear scales of galaxy clusters. We derive the MAR by using the mass profile beyond the splashback radius, evaluating the mass of a spherical shell and the time it takes to fall in. The infall velocity of the shell is extracted from N-body simulations. The average MAR returned by our prescription in the redshift range z=[0, 2] is within 20-40% of the average MAR derived from the merger trees of dark matter haloes in the reference N-body simulations. Our result suggests that the external regions of galaxy clusters can be used to measure the mean MAR of a sample of clusters.

Numerical models widely used for hydrocarbon phase behavior and compositional flow simulations are based on assumption of thermodynamic equilibrium. However, it is not uncommon for oil and gas-condensate reservoirs to exhibit essentially non-equilibrium phase behavior, e.g., in the processes of secondary recovery after pressure depletion below saturation pressure, or during gas injection, or for condensate evaporation at low pressures. In many cases the ability to match field data with equilibrium model depends on simulation scale. The only method to account for non-equilibrium phase behavior adopted by the majority of flow simulators is the option of limited rate of gas dissolution (condensate evaporation) in black oil models. For compositional simulations no practical yet thermodynamically consistent method has been presented so far except for some upscaling techniques in gas injection problems. Previously reported academic non-equilibrium formulations have a common drawback of doubling the number of flow equations and unknowns compared to the equilibrium formulation. In the paper a unified thermodynamically-consistent formulation for compositional flow simulations with non-equilibrium phase behavior model is presented. Same formulation and a special scale-up technique can be used for upscaling of an equilibrium or non-equilibrium model to a coarse-scale non-equilibrium model. A number of test cases for real oil and gas-condensate mixtures are given. Model implementation specifics in a flow simulator are discussed and illustrated with test simulations. A non-equilibrium constant volume depletion algorithm is presented to simulate condensate recovery at low pressures in gas-condensate reservoirs. Results of satisfactory model matching to field data are reported and discussed.

The anisotropy in the CMBR detected by the COBE satellite has sprouted the research and theories of the void that got created, after being washed away by a parallel universe after its collision. This details of the roadmap to the parallel universe, that are previously been entangled, but now, separated, with the concept of 2-time dimensions as a time curve of containing the closed curves embedded on the surface area, thereby time running backward in orientation in the parallel universe, along with the perspective of eternal inflation and divided subspaces giving birth to twin universes are provided here. This time curve being responsible for creating an exponentiality of time frames, growing in layers, giving us the perception of the confabulations being an indication of the previously connected worlds.

We reveal the significance of plasmonic nanoparticle’s (NP) shape and its surface morphology en route to an efficient self-assembled plasmonic nanoparticle cluster. A simplified model is simulated in the form of free-space dimer and trimer nanostructures (NPs in shape of sphere, cube, and disk). A ~ 200 % to ~ 125% raise in near field strength (gap mode enhancement) is observed for spherical NPs in comparison with cubical NPs (from 2 nm to 8 nm gap sizes). Full-width three-quarter maximum reveals better broad-spectral optical performance in a range of ~ 100 nm (dimer) and ~ 170 nm (trimer) from spherical NPs as compared to a cube (~ 60 nm for dimer and trimer). These excellent properties for sphere-based nanostructures are merited from its dipole mode characteristics.

Multi-step ahead streamflow forecasting is of practical interest for the operation of hydropower reservoirs. We provide generalized results on the error evolution in multi-step ahead forecasting by conducting several large-scale experiments based on simulations. We also present a multiple-case study using monthly time series of streamflow. Our findings suggest that some forecasting methods are more useful than others. However, the errors computed at each time step of a forecast horizon within a specific case study strongly depend on the case examined and can be either small or large, regardless of the forecasting method used and the time step of interest.

Fractional differential mathematical model unfolding the dynamics of the COVID-19 pandemic in India is presented and explored in this paper. The purpose of this study is to estimate the future outbreak of disease and potential control strategies using mathematical models in India as a whole country as well as in some of the states of the country. This model is calibrated based on reported cases of infections over the month of April 2020 in India. We have used iterative fractional complex transform method to find approximate solutions of the model having modified Riemann Liouville fractional differential operator. We have also carried out a comparative analysis between actual and estimated cumulative cases graphically, moreover, most sensitive parameters for basic reproduction number$(R_0)$ are computed and their effect on transmission dynamics of COVID-19 pandemic is investigated in detail.

As the energy efficiency demands for future buildings become increasingly stringent, preliminary assessments of energy consumption are mandatory. These are possible only through numerical simulations, whose reliability crucially depends on boundary conditions. We therefore investigate their role in numerical estimates for the usage of geothermal energy, performing annual simulations of transient heat transfer for a building employing a geothermal heat pump plant and energy piles. Starting from actual measurements, we solve the heat equations in 2D and 3D using COMSOL Multiphysics and IDA-ICE, and discover a negligible impact of the multiregional ground surface boundary conditions. Moreover, we verify that the thermal mass of the soil medium induces a small vertical temperature gradient on the piles surface. We also find a roughly constant temperature on each horizontal cross-section, with nearly identical values if the average temperature is integrated over the full plane or evaluated at one single point. Calculating the yearly heating need for an entire building we then show that the chosen upper boundary condition affects the energy balance dramatically. Using directly the pipes’ outlet temperature induces a 54% overestimation of the heat flux, while the exact ground surface temperature above the piles reduces the error to 0.03%.

The sensitivity of macroscopic mechanical and thermal properties of grey cast iron is computationally investigated for a variety of graphite microstructures over a wide temperature range. In order to represent common graphite microstructures according to DIN EN ISO 945-1, a synthetic approach is used to algorithmically generate simulation domains. The developed mechanical and thermal model is applied in a large simulation study. The study includes statistical volume elements of the graphite microstructures classes GG-15 and IA2 to IA5, with 10 v.-%, 11 v.-% and 12 v.-% graphite, respectively, for a temperature range from 20 °C to 750 °C. Homogenized macroscopic quantities such as the Young's moduli, Poisson's ratios, yield strengths and thermal conductivities are predicted for the different microstructure classes by applying simulation and data analysis tools of the research data infrastructure Kadi4Mat.

Transient analysis of gas flow in pipeline was studied. Finite Element Method based on ANSYS FLOTRAN was used to account for changes in pressure, temperature and flow rate. Compressibility factor function of temperature and pressure was considered. For non-isothermal transient results, the pressure and the flowrate gave wave propagation as a result of slow transients created by demand condition at the outlet end of custody transfer. Results obtained were in agreement with the demand restrictions at the outlet end of custody transfer indicating that the predictions are accurate and reliable. The results demonstrated that the Finite Element Method gave accurate prediction of pressure, temperature and flowrate in transient gas studies. For steady state non-isothermal model, results showed that the magnitude of the average pressure drop was higher when pressure was predicted with constant compressibility factor, but the same average pressure drop was reduced when the pressure was predicted with variable compressibility factor, z. Since compressibility factor is a function of temperature and pressure, the above findings signifies that in the case when gas temperature does not stabilize, the prediction of pressure with isothermal model and constant compressibility factor will lead to significant errors.

The effect of river fronts on oil slick transport has been demonstrated using high resolution forcing models and a fully fledged oil drift model, OpenOil. The model system is used to simulate the 2010 DeepWater Horizon oil spill. Metocean forcing data are taken from the GoM-HYCOM 1/50° ocean model with realistic river input and ECMWF global forecast products of wind and wave parameters with 1/8° resolution. The simulations are initialized from satellite observations of the surface oil patch. OpenOil includes most of the relevant processes, such as emulsification, evaporation, wave entrainment, stranding and droplet formation. The model takes account of the actual oil type and properties, using the ADIOS oil weathering database of NOAA. The effect of using a newly developed parameterization for oil droplet size distribution is studied and compared to a traditional algorithm. Although the algorithms provide different distributions for a single wave breaking event, it is found that the net difference after long simulations is negligible, indicating that the outcome is robust regarding the choice of parameterization. That indicates that the wave entrainment, vertical mixing and re-surfacing mechanisms that are part of OpenOil are more important for determining the final droplet size spectrum than the spectrum prescribed for individual wave breaking events. In both cases, the size of the droplets controls how much oil is present at the surface and hence are subject to wind and Stokes drift. The effect of removing river outflow in the ocean model is investigated in order to showcase effects of river induced fronts on oil spreading. A consistent effect on the amount and location of stranded oil is found, and considerable impact of river induced fronts is seen on the location of the surface oil patch. During a case with large river outflow (May 20-27, 2010), the total amount of stranded oil is reduced by about 50% in the simulation with no river input. The results compares well with satellite observations of the surface oil patch.

This study presents results of the sediment yield Watershed of Ribeirão do Pinhal, in the city of Limeira, São Paulo, conducted under three different scenarios of the land use: 1 – land use in 2008, 2 – with reforested protection areas, 3 – the increase sugarcane's areas over grassland and citrus areas. The Soil and Water Assessment Tool (SWAT) was used as a hydro-sedimentological modeling tool to simulate these scenarios. This watershed was divided into five sub-watersheds according to the prevalent use, and adjustments were made in soils database parameters and cultures that are in SWAT, to adapt it to the Brazilian reality. Was used climatological data of eight years (2007-2014) for this modeling. Different sediment yield could be noted in the different types of land use, sub-watersheds and scenarios. The uses that presented higher sediment yield, in ascending order, were: natural vegetation, sugarcane, citrus, annual crop e grassland. Sub-watershed number 2 had the highest sediment yield (~10Mg.ha^-1), while the sub-watershed 5, the lowest (5.51Mg.ha^-1). This remained in the three scenarios. Overall, scenario 2 had the lowest sediment yield (7.74Mg.ha^-1). Scenario 1 had 8.37 Mg.ha^-1 and scenario 3, 8.58Mg.ha^-1. SWAT was considered efficient to simulate the sediment yield by scenarios and by use, combining different thematic and tabular data when performing the necessary adjustments on their original database.

Histone Lysine Specific Demethylase 1 (LSD1) is overexpressed in many cancers and become a new target for anticancer drugs. In recent years, the small molecule inhibitors with various structures targeting LSD1 have been reported. Here we report the binding interaction modes of a series of thieno[3,2-b]pyrrole-5-carboxamides LSD1 inhibitors using molecular docking, three dimensional quantitative structure-activity relationship (3D-QSAR). Comparative molecular field analysis (CoMFA q²=0.783, r²=0.944, r²_pred=0.851) and Comparative molecular similarity indices analysis (CoMSIA q²=0.728, r²=0.982, r²_pred=0.814) were used to establish 3D-QSAR models, which had good verification and prediction capabilities. Based on the contour maps and the information of molecular docking, 8 novel small molecules were designed in silico, among which compounds D4, D5 and D8 with high predictive activity were subjected to further molecular dynamics simulations (MD), and their possible binding modes were explored. It was found that Asn535 plays a crucial role in stabilizing the inhibitors. Furthermore, the ADME and bioavailability prediction for D4, D5 and D8 were carried out. The results would provide valuable guidance for designing new reversible LSD1 inhibitors in the future.

This paper shows that by applying the Nyquist-Shannon sampling theorem, the spatial and temporal resolution of a simulation can be no more than half the resolution of the simulating reality. This has significant implications for not only the values of the observables in the simulation but also its physical laws. This progressive halving of nested simulations coupled with the minimum resolution compatible with the production of a simulation also sets a limit to the nestedness of a lineage of simulations (it is by no means infinite). The limit of nestedness is then used to calculate the probability that we are living in a simulation assuming a single base reality. This will be shown to be significantly lower than popular expectation. A Kardashev-like scale, with three variants, is also developed to gauge the technological advancement of a civilization in relation to the extent to which it can extract information from space and time.

Meta-aminobenzoic acid, an important model system in the study of polymorphism and crystallization of active pharmaceutical ingredients, exist in water in both the nonionic (mABA) and zwitterionic (mABA^±) forms. However, the constituent molecules of the polymorph that crystallizes from aqueous solutions are zwitterionic. This study reports atomistic simulations of the events surrounding the early stage of crystal nucleation of meta-aminobenzoic acid from aqueous solutions. Ab initio molecular dynamics was used to simulate the hydration of mABA± and mABA, and to quantify the interaction of these molecules with the surrounding water molecules. Density functional theory calculations were conducted to determine the low-lying energy conformers of meta-aminobenzoic acid dimers and compute the Gibbs free energies in water of nonionic, (mABA)₂, zwitterionic, (mABA^±)₂ and nonionic-zwitterionic, (mABA)(mABA^±), species. Classical molecular dynamics simulations of mixed mABA–mABA^± aqueous solutions were carried out to examine the aggregation of meta-aminobenzoic acid. According to these simulations the selective crystallization of the polymorph which constituent molecules are zwitterionic is driven by the formation of zwitterionic dimers in solution, which are thermodynamically more stable than (mABA)₂ and (mABA)(mABA^±) pairs. This work represents a paradigm of the role of molecular processes during the early stages of crystal nucleation in affecting polymorph selection during crystallization from solution.

Heavy metal contamination of drinking water is a public health concern that requires the development of more efficient bioremediation techniques. Absorption technologies, including biosorption, provide opportunities for improvements to increase the diversity of metal ions removed and overall binding capacity. Microorganisms are a key component in wastewater treatment plants and they naturally bind metal ions through surface macromolecules but with limited capacity. The long-term goal of this work is to engineer capsule polymerases to synthesize molecules with novel functionalities. In previously published work, we showed that the Neisseria meningitidis serogroup W (NmW) galactose-sialic acid (Gal—NeuNAc) heteropolysaccharide binds lead effectively, thereby demonstrating the potential for using this capsular polysaccharide in environmental decontamination applications. In this study, computational analysis of the NmW capsule polymerase galactosyltransferase (GT) domain was used to gain insight into how the enzyme could be modified to enable the synthesis N-acetylgalactosamine-sialic acid (GalNAc—NeuNAc) heteropolysaccharide. Various computational approaches, including molecular modeling with I-TASSER and molecular dynamics simulations (MD) with NAMD, were utilized to identify key amino acid residues in the substrate binding pocket of the GT domain that may be key to conferring UDP-GalNAc specificity. Through these combined strategies and using BshA, a UDP-GlcNAc transferase, as a structural template, several NmW active site residues were identified as mutational targets to accommodate the proposed N-acetyl group in UDP-GalNAc. Thus, a rational approach for potentially conferring new properties to bacterial capsular polysaccharides is demonstrated.

Background: Colorectal cancer is considered the third most fetal among all type of cancer. Spleen tyrosine kinase (SYK) is a non-receptor type tyrosine-protein that plays crucial role in signaling mediated via immune receptor. We adopted an onco-informatics analysis to evaluate the SYK expression and prognostic value of SYK in colorectal cancer, and identification of potential phytochemicals which may inhibit overexpression of SYK protein as well as minimized colorectal cancer. Materials & Methods: Differential expression of SYK gene was analyzed using the several transcriptomic databases including Oncomine, UALCAN, GENT2 and GEPIA2. The server, cBioPortal was used to analyze mutation and copy number alterations whereas GENT2, GEPIA, OncoLnc and PrognoScan were employed to examine the survival rate. A protein-protein interaction network of SYK and co-expressed genes of SYK was conducted via GeneMANIA. Considering SYK gene encoding protein as drug target, selected phytochemicals were assessed by molecular docking using PyRx 0.8 packages. YASARA molecular dynamics simulators were applied for the post validation of the molecular docking data. Results: We have observed significant overexpression of mRNA expression levels of SYK gene colorectal adenocarcinoma (COAD) samples compared with normal tissues. Significant methylation level and various genetic alterations are assembled in SYK gene which can lead to the development of colorectal cancer. As a result, lower level of SYK expression was related to the more chances of patients’ survival by which all the outcomes from the multiple bioinformatics platforms and web resources have demonstrated the significant evidences that the SYK kinsase can possess as a potential biomarker for the treatment of colorectal cancer. Here, aromatic phytochemicals namely, Kaempferol and Glabridin targeting SYK showed more stability compared to controls and may be useful for the treatment of colorectal cancer. Conclusion: Our study showed dysregulated expression of SYK in colorectal cancer and potentiality to act as a biomarker for the prognosis of CRC. Moreover, we have shown phytochemicals (Kaempferol and Glabridin) target SYK as potential treatment strategies and drug repositioning potentiality in colorectal cancer.

A new approach was presented in this study to simulate a stable atom along with subatomic particles in it. Subatomic particles in an atom are treated as conventional particles, exhibiting attraction and repulsion between them, giving a stable atom simulation. This new approach leads to developing new potentials for subatomic particles to simulate a stable atom. Subatomic particle dynamics (SPD) simulations were developed for within-atom simulations that give a stable atom structure for infinite time and provide many insights into electron trajectories and atom properties like energies and radius of the atom. The effect of protons and neutrons movement in the nucleus on electron trajectories was captured in SPD. Hydrogen and Carbon atom SPD were reported in this study. The Pilot-wave theory was implemented in this study to simulate the wave nature of subatomic particles in an atom. Electrons motion was guided by the interference pattern produced by the electron’s aether medium waves in SPD. SPD was implemented on molecules, resulting in a stable molecular structure giving insights into electron trajectories shared by multiple atoms.

In the current work, in continuation of our recent research [1] we synthesized and studied new chimeric compounds comprising the ribosome-targeting antibiotic chloramphenicol (CHL) and the membrane-penetrating cation triphenylphosphonium (TPP) connected by alkyl linkers of different lengths. Using various biochemical assays, we showed that these CAM-Cn-TPP compounds bind to the bacterial ribosome, inhibit protein synthesis in vitro and in vivo in a way similar to that of the parent CHL, and significantly decrease membrane potential. Similar to CAM-C4-TPP, the mode of action of CAM-C10-TPP and CAM-C14-TPP on bacterial ribosomes differ from that of CHL. By simulating the dynamics of complexes of CAM-Cn-TPP with bacterial ribosomes, we have proposed a possible explanation for the specificity of the action of these analogs on the translation process. CAM-C10-TPP and CAM-C14-TPP stronger inhibit the growth of the Gram-positive bacteria in comparison to the CHL and suppress some strains of CHL-resistant bacteria. Thus, we have shown that TPP derivatives of CHL are dual-acting compounds that target the ribosomes and the cellular membranes of bacteria. The TPP fragment of CAM-Cn-TPP compounds contributes to the inhibitory effect on bacteria. Moreover, since the mitochondria of eukaryotic cells have qualities similar to those of their prokaryotic ancestors, we demonstrate the possibility of targeting chemoresistant cancer cells with these compounds.

Eukaryotic cells contain membranes with various curvatures, from the near-plane plasma membrane to the highly curved membranes of organelles, vesicles, and membrane protrusions. These curvatures are generated and sustained by curvature-inducing proteins, peptides, and lipids, and describing these mechanisms is an important scientific challenge. In addition to that, some molecules can sense membrane curvature and a thereby be trafficked to specific locations. The description of curvature-sensing is another fundamental challenge. Curved lipid membranes and their interplay with membrane-associated proteins can be investigated with molecular dynamics (MD) simulations, given the right tools. Various methods for simulating curved membranes with MD are discussed here, including tools for setting up simulation of vesicles, and methods for sustaining membrane curvature. The latter are divided into methods that exploit scaffolding virtual beads, methods that use curvature-inducing molecules, and methods applying virtual forces. The variety of simulation tools allow the researcher to closely match the conditions of experimental studies of membrane curvatures.

Knowledge of the interaction between inorganic and organic phosphates with soil minerals is vital for improving the soil P fertility. To achieve an in-depth understanding we combined adsorption experiments and hybrid ab initio molecular dynamics simulations to analyze the adsorption of common phosphates, i.e. orthophosphate (OP), glycerolphosphate (GP) and inositolhexaphosphate (IHP), onto the 100 surface plane of goethite. Experimental adsorption data per mol P-molecule basis fitted to the Freundlich model show the adsorption strength increases in the order GP < OP < IHP, and IHP adsorption being saturated faster followed by GP and OP. Modeling results show that OP and GP form stable monodentate (M) and binuclear bidentate (B) motifs with B being more stable than M, whereas IHP forms stable M and 3M motifs. Interfacial water plays an important role through hydrogen bonds and proton transfers with OP/GP/IHP and goethite. It also controls the binding motifs of phosphates with goethite. Combining both experimental and modeling results, we propose that the B motif dominates for OP, whereas GP forms M and IHP forms a combination of M and 3M motifs. The joint approach plausibly explains why IHP is the predominant organically bound P form in soil. This study could be considered as a preliminary step for further studies for understanding the mechanisms of how microbes and plants overcome the strong IHP–mineral binding to implement the phosphate groups into their metabolism.

Remotely Piloted Aircraft Systems (RPAS) are increasingly becoming relevant actors flying through the airspace and will assume much more importance in the future perspective. In order to allow their safe integration with manned conventional traffic in non-segregated airspaces, in accordance with the overall Air Traffic Management (ATM) paradigm, specific enabling technologies are needed. As well known, among the enabling technologies identified as crucial for RPAS integration into the overall ATM system, the Detect and Avoid (DAA) technology is fundamental. In the meantime, to support extended surveillance, the universal introduction on-board of aircraft of cooperative Automatic Dependent Surveillance – Broadcast (ADS-B) is increasingly implemented, having the potential to allow coverage of the whole airspace also in remote areas not usually covered by conventional radar surveillance. In this paper, the experimental results are presented and discussed that have been obtained through the real-time validation, with hardware and human in the loop (RTS-HIL) simulations, of an automatic ADS-B based Separation Assurance and Collision Avoidance System aimed to support RPAS automatic operations as well as remote pilot decision making. In the paper, after an introductory outline of the Concept of Operations (ConOps) of the system and of its architectural organization, while also providing basic information about the main system functionalities, the description is reported of the tests that have been carried out and the obtained results are described and discussed, in order to emphasize the performances and limitations of the proposed system. In particular, not only the quantitative performances obtained are reported and commented but also the feedbacks received by the pilots in order to improve the system are described, for instance in terms of preferred typology of conflict resolution manoeuver elaborated by the system.

The application of instrumented indentation to assess material properties like Young’s modulus and micro-hardness has become a standard method. In recent developments, indentation experiments and simulations have been combined to inverse methods, from which further material parameters as yield strength, work hardening rate, and tensile strength can be determined. In this work, an inverse method is introduced by which material parameters for cyclic plasticity, i.e. kinematic hardening parameters, can be determined. To accomplish this, cyclic Vickers indentation experiments are combined with finite element simulations of the indentation with unknown material properties, which are then determined by inverse analysis. To validate the proposed method, these parameters are subsequently applied to predict the uniaxial stress-strain response of a material with success. The method has been validated successfully for a quenched and tempered martensitic steel and for technically pure copper, where an excellent agreement between measured and predicted cyclic stress-strain-curves has been achieved. Hence, the proposed inverse method based on cyclic nanoindentation, as a quasi-non-destructive method, could complement or even substitute the resource-intensive conventional fatigue testing in the future for some applications.

Here we propose a simple way in which one can considerably improve performance of the gas stripper setup at the GSI UNILAC. To do so, it will be enough to replace inside the main GSI stripper chamber the present nozzle and the short windowless storage gas cell (for pulsed gas-jet operation mode) by a simple conical diverging nozzle combined with a gas catcher tube placed on the axis of gas-jet at some distance downstream the nozzle exit. As a result, the background pressure in the main and differentially pumped adjacent vacuum chambers of the gas stripper at the GSI UNILAC will dramatically reduce, and it will make possible to achieve the required optimal thickness of gas targets. The pulsed gas stripper operation is simply realized by implementing a commercially available fast gas valve connected to the nozzle entrance. Moreover, the ion beam pulses repetition rate can be increased and it will allow for the considerably higher average intensity of the ion beams extracted from the GSI UNILAC. Performance of the proposed GSI UNILAC gas stripper modification we explored by means of detailed computer experiments, which give a realistic description of supersonic gas jets flowing out the nozzle into vacuum. Results of these computer experiments have presented and discussed.

Silicates are among the most abundant and important inorganic materials, not only in the Earth’s crust but also in the interstellar medium in the form of micro-/nano-particles or embedded in the matrices of comets, meteorites and other asteroidal bodies. Although the crystalline phases of silicates are indeed present in Nature, amorphous forms are also highly abundant. Here we report a theoretical investigation of the structural, dielectric and vibrational properties of the amorphous bulk for forsterite (Mg₂SiO₄) as a silicate test case by a combined approach of classical molecular dynamics (MD) simulations for structure evolution, and periodic quantum mechanical DFT calculations for electronic structure analysis. Using classical MD based on an empirical partial charge rigid ionic model within a melt-quenching scheme at different temperatures performed with the GULP 4.0 code amorphous bulk structures for Mg₂SiO₄ were generated using as initial guess the crystalline phase. This has been done for bulks with three different unit cell sizes adopting a super-cell approach; i.e., 1×1×2, 2×1×2 and 2×2×2. The radial distribution functions indicated a good degree of amorphisation of the structures. Periodic B3LYP-geometry optimizations performed with the CRYSTAL14 code on the generated amorphous systems were used to analyze their structure, to calculate their high frequency dielectric constants (ε_∞), and to simulate the IR, Raman and reflectance spectra, which were compared with the experimental and theoretical crystalline Mg₂SiO₄. The most significant changes of the physico-chemical properties of the amorphous systems compared to the crystalline ones are presented and discussed (e.g., larger deviations in the bond distances and angles, broadening of the IR bands, etc.), which are consistent with their disordered nature. It is also shown that by increasing the unit cell size the bulk structures present larger degree of amorphisation.

The classical Rotational Isomeric State (RIS) model, originally proposed by Flory, has been used to rationalize a wide range of physicochemical properties of neutral polymers. However, many weak polyelectrolytes of interest are able to regulate their charge depending on the conformational state of the bonds. Recently, it has been shown that the RIS model can be coupled with the Site Binding (SB) model, for which the ionizable sites can adopt two states: protonated or deprotonated. The resulting combined scheme, the SBRIS model, allows to analyse ionization and conformational equilibria on the same foot. In the present work this approach is extended to include pH-dependent electrostatic Long Range (LR) interactions, ubiquitous in weak polyelectrolytes at moderate and low ionic strengths. With this aim the original LR interactions are taken into account by defining effective Short Range (SR) and pH-dependent parameters, such as effective microscopic protonation constants and rotational bond energies. The new parameters are systematically calculated using variational methods. The machinery of statistical mechanics for SR interactions, including the powerful and fast transfer matrix methods, can then be applied. The resulting technique, to which we will refer as Local Effective Interaction Parameters (LEIP) method, is illustrated with a minimal model of a flexible linear polyelectrolyte containing only one type of rotating bonds. LEIP reproduces very well the pH dependence of the degree of protonation and bond probabilities obtained by semi-grand canonical Monte Carlo simulations, where LR interactions are taken explicitly into account. The reduction in the computational time in several orders of magnitude suggests that the LEIP technique could be useful in a range of areas involving linear weak polyelectrolytes, allowing direct fitting of the relevant physical parameters to the experimental quantities.

The objective of this study was to correlate the binding of drugs on a very popular nanoparticulate polymeric matrix; PLGA nanoparticles with their main constitutional, electronic and physico-chemical descriptors. Gaussian Processes (GPs) was the artificial intelligence machine learning method that was utilized to fulfil this task. The method could successfully model the results where optimum values of the investigated descriptors of the loaded drugs were deduced. A percentage bias of 12.68 % ± 2.1 was obtained in predicting the binding energies of a group of test drugs. As a conclusion, GPs could successfully model the drugs-PLGA interactions associated with a good predicting power. The GPs-predicted binding energies (ΔG) can easily be projected to the drugs loading as was previously proven. Adopting the “Pharmaceutics Informatics” approach can save the pharmaceutical industry and the drug delivery scientists a lot of exerted resources, efforts and time.

Molecular Dynamics (MD) simulations model motion of molecules in atomistic detail and aid in drug design. While simulations on large systems may require several days to complete, analysis of terabytes of data generated in the process could also be time consuming. Recent studies captured exciting and dramatic drug-receptor interactions under cell-like complex conditions. Such advances make simulations of biomolecular interactions more realistic, insightful, and informative and have potential to make drug design more realistic. However, currently available resources and techniques do not provide, in reasonable time, a comprehensive understanding of events seen in simulations. We demonstrate that big data approach results in significant speedups, and provides rapid insights into simulations performed. Advancing this improvement, we propose a scalable, self-tuning, and responsive framework based on Cloud-infrastructure to accomplish the best possible MD studies with given priorities and within available resources.

The description of protein disordered states is important for understanding protein folding mechanisms and their functions. In this short review, we briefly describe a simulation approach to modeling disordered protein interactions and unfolded states of globular proteins. It is based on the CABS coarse-grained protein model that uses a Monte Carlo (MC) sampling scheme and a knowledge-based statistical force field. We review several case studies showing that description of protein disordered states resulting from CABS simulations is consistent with experimental data. The case studies comprise investigations of protein-peptide binding and protein folding processes. The CABS model has been recently made available as the simulation engine of multiscale modeling tools enabling studies of protein-peptide docking and protein flexibility. Those tools offer customization of the modeling process, driving the conformational search using distance restraints, reconstruction of selected models to all-atom resolution and studies of large protein systems in a reasonable computational time. Therefore, CABS can be combined in integrative modeling pipelines incorporating experimental data and other modeling tools of various resolution.

Purification of biologically-derived therapeutics is a major cost contributor to the production of this rapidly growing class of pharmaceuticals. Monoclonal antibodies comprise a large percentage of these products therefore new antibody purification tools are needed. Small peptides, as opposed to traditional antibody affinity ligands such as Protein A, may have advantages in stability and production costs. Multiple heptapeptides that demonstrate Fc binding behavior that have been identified from a combinatorial peptide library using M13 Phage Display are presented herein. Seven unique peptide sequences of diverse hydrophobicity and charge were identified. All seven peptides showed strong binding to the four major human IgG isotypes, human IgM, as well as binding to canine, rat, and mouse IgG. These seven peptides were also shown to bind human IgG4 from DMEM cell culture media with 5% FCS and 5 g/L ovalbumin present. These peptides may be useful as surface ligands for antibody detection and purification purposes. Molecular docking and classical molecular dynamics (MD) simulations were conducted to elucidate the mechanisms and energetics for the binding of these peptides to the Fc region. The binding site was found to be located between the two glycan chains inside the Fc fragment. Both hydrogen bonding and hydrophobic interactions were found to be crucial for the binding interactions. Excellent agreement for the binding strength was obtained between experimental results and simulations.

Due to an increase of the monocrystalline PV systems installations, for a drive towards the sustainable smart cities in the hot arid developing country such as Pakistan, pose challenges of the performance and degradation issues. Monocrystalline PV module efficiencies are declining and damaging under the continuous exposure to higher surface day-time temperatures in the different parts of the country. A MATLAB simulations were performed based on the validated mathematical approach. This paper investigates the hot arid surface temperature impacts on the performance of PV modules during the summer and winter seasons in Pakistan. The investigations are performed examining the power generating efficiency of the PV system. This paper also investigates the influence of installations of PV-system in the North, South, East and West regions of Pakistan. It was examined that the northern areas of Pakistan are more suitable for maintaining the long-term durability of the PV system. Investigations are performed for the peak summer and peak winter days. During summer months, cooling strategies have to be implemented to overcome the heating effects whilst reducing degradation effect on installed PV-system.

Discrete, logic-based models are increasingly used to describe biological mechanisms. Initially introduced to study gene regulation, these models evolved to cover various molecular mechanisms, such as signalling, transcription factor cooperativity, and even metabolic processes. The abstract nature and amenability of discrete models to robust mathematical analyses make them appropriate for addressing a wide range of complex biological problems. Recent technological breakthroughs have generated a wealth of high throughput data. Novel, literature-based representations of biological processes and emerging algorithms offer new opportunities for model construction. Here, we review up-to-date efforts to address challenging biological questions by incorporating omic data into logic-based models, and discuss critical difficulties in constructing and analysing integrative, large-scale, logic-based models of biological mechanisms.

The present work is concerned with the study of the generalized Langevin equation and its link to the physical theories of statistical mechanics and scale relativity. It is demonstrated that the form of the coefficients of Langevin equation depend critically on the assumption of continuity of the reconstructed trajectory. This in turn demands for the fluctuations of the diffusion term to be discontinuous in time. This paper further investigates the connection between the scale-relativistic and stochastic mechanics approaches, respectively, with the study of the Burgers equation, which in this case appears as a stochastic geodesic equation. By further demanding time reversibility of the drift the Langevin equation can also describe equivalent quantum-mechanical systems in a path-wise manner. The resulting statistical description obeys the Fokker-Plank equation of the probability density of the differential system, which can be readily estimated from Monte Carlo simulations of the random paths. Based on the Fokker-Plank formalism a new derivation of the transient probability densities is presented. Finally, stochastic simulations are compared to the theoretical results.

ND1 subunit possesses the majority of the inhibitor binding domain of the human MRC-I. This is an attractive target for the search for new inhibitors that seek mitochondrial dysfunction. It is known, from in vitro experiments, some metabolites from Annona muricata called acetogenins have important biological activities such as anticancer, antiparasitic, and insecticide. Previous studies propose an inhibitory activity of bovine MRC-I by bis-THF acetogenins such as annocatacin B, however, there are few studies on its inhibitory effect on human MRC-I. In this work, we evaluate the molecular and energetic affinity of the annocatacin B molecule with the human ND1 subunit in order to elucidate its potential capacity to be a good inhibitor of this subunit. For this purpose, QM optimizations, MD simulations and MM/PBSA analysis were performed. As a control to compare our outcomes, the molecule rotenone, which is a known MRC-I inhibitor, was chosen. Our results show that annocatacin B has a greater affinity for the ND1 structure, its size and folding were probably the main characteristics that contributed to stabilize the molecular complex. Furthermore, the MM/PBSA calculations showed a 35% stronger BFE compared to the rotenone complex. Detailed analysis of the BFE shows that the aliphatic chains of annocatacin B play a key role in molecular coupling by distributing favorable interactions throughout the major part of the ND1 structure. These results are consistent with experimental studies that mention that acetogenins may be good inhibitors of MRC-I.

Based on a local causal model of the dynamics of curved discrete spacetime, a causal model of quantum field theory in curved discrete spacetime is described. At the elementary level, space(-time) is assumed to consists of interconnected space points. Each space point is connected to a small discrete set of neighbor space points. Density distribution of the space points and the lengths of the space point connections depend on the distance from the gravitational sources. This leads to curved spacetime in accordance with general relativity. Dynamics of spacetime (i.e., the emergence of space and the propagation of space changes) dynamically assigns "in-connections" and "out-connections" to the affected space points. Emergence and propagation of quantum fields (including particles) are mapped to the emergence and propagation of space changes by utilizing identical paths of in/out-connections. Compatibility with standard quantum field theory (QFT) requests the adjustment of the QFT techniques (e.g., Feynman diagrams, Feynman rules, creation/annihilation operators), which typically apply to three in/out connections, to n > 3 in/out connections. In addition, QFT computation in position space has to be adapted to a curved discrete space-time.

The Covid-19 pandemic has resulted in the closure of schools at every level, globally, forcing education to move online. Meeting the needs of students online for Science Lab classes, in particular, is a challenge since the physical labs are not available to the teachers or students. OLabs is a virtual Science Lab providing a complete learning environment of theory, experimental procedures, videos, animations, simulations, and assessments that capture real lab experiences with the relevant pedagogy. This study looks at the acquisition and behaviors of users, on the OLabs platform, during pre and Covid-19 times. Using Google Analytics, we observe that, during the pandemic time, users increasingly adopted OLabs as a new learning pedagogy for performing experiments as indicated by parameters like the number of users; the number of unique pages viewed per session; time spent on viewing content; bounce rate; and preference for content types such as theory, simulations, videos, and animations.

Heat emitters constitute the primary devices used in space heating and cover a fundamental role in the energy efficient use of buildings. In the search for an optimized design, heating devices should be compared with a benchmark emitter with maximum heat emission efficiency. However, such an ideal heater still needs to be defined. In this paper we perform an analysis of heat transfer in a European reference room, considering room side effects of thermal radiation and computing the induced operative temperature both analytically and numerically. By means of functional optimization, we analyse trends such as the variation of operative temperature with radiator panel dimensions, finding optimal configurations. In order to make our definitions as general as possible, we address panel radiators, convectors, underfloor (UFH) and ceiling heater. We obtain analytical formulas for the operative temperature induced by panel radiators and identify the 10-type as our ideal radiator, while the UFH provides the best performance overall. Regarding specifically UFH and ceiling heaters, we find optimal sizes that identify the according ideal emitters. The analytical method and quantitative results reported in this paper can be generalized and adopted in most studies concerning the efficiency of different heat emitter types in building enclosures.

Understanding the flow in urban environments is an increasingly relevant problem due to its significant impact on air quality and thermal effects in cities worldwide. In this review we provide an overview of efforts based on experiments and simulations to gain insight into this complex physical phenomenon. We highlight the relevance of coherent structures in urban flows, which are responsible for the pollutant-dispersion and thermal fields in the city. We also suggest a more widespread use of data-driven methods to characterize flow structures as a way to further understand the dynamics of urban flows, with the aim of tackling the important sustainability challenges associated to them.

The asymmetry in the dynamics of an electro-pneumatic actuating device consisting of an electro-pneumatic transducer and a single-action pneumatic actuator was unexpectedly found experimentally. This asymmetry manifests in response to large step excitations. The dynamic asymmetry effect is understood as a change in the shape of the response of an actuator depending on the direction of the actuators stem movement. The questions appears: How to explain this effect? Does this phenomenon reflect thermodynamic air processes? Is it connected with air-to-mechanical energy conversion? Together, six working hypotheses explaining this effect were formulated. The asymmetry was studied in detail using analytical and simulation modeling, as well as experimental research. In this respect, a nonlinear analytical model was developed, tuned, and later solved using simulations. The simulation model was verified based on the experiment data. In addition, the problem of the efficiency in the energy conversion of a single-action actuator was discussed and, in result, the maximum theoretical energy efficiency was determined. Subsequently, all six working hypotheses were verified. Finally, the hypothesis explaining asymmetry as an effect of the different thermodynamic air processes in both actuator’s stem travel directions was confirmed.

Molecular dynamics simulation is currently the theoretical technique eligible to simulate a wide range of systems from soft condensed matter to biological systems. However, of the excellent results that the technique has arrogated, this approach remains computationally expensive, but with the emergence of the new supercomputing technologies bases on graphics processing units graphical processing units-based systems GPUs, the perspective has changed. The GPUs allow performing large and complex simulations at a significantly reduced time. In this work, we present recent innovations in the acceleration of molecular dynamics in GPUs to simulate non-Hamiltonian systems. In particular, we show the performance of measure-preserving geometric integrator in the canonical ensemble, that is, at constant temperature. We provide a validation and performance evaluation of the code by calculating the thermodynamic properties of a Lennard-Jones fluid. Our results are in excellent agreement with reported data reported from literature, which were calculated with CPUs. The scope and limitations for performing simulations of high-throughput MD under rigorous statistical thermodynamics in the canonical ensemble are discussed and analyzed.

A ducted photovoltaic façade (DPV) unit Studied using experimental Prototype and simulated in a full scale Computational Fluid Dynamics CFD Model. The Study comes in two parts; This is Part I with the title detailed above and Part II titled ‘A Ducted Photovoltaic Façade Unit with Buoyancy Cooling: Part II CFD Simulation’.. The process adopted in the experimental study is replicated in the simulation Part. The aim was to optimize the duct width behind the solar cells to allow for maximum buoyancy-driven cooling for the cells during operation. Duct widths from 5 to 50 cm were tested in a Proto-type. A duct width of 45 cm had the maximum calculated heat removed from the duct; however, the lowest cell-operating temperature was reported for duct width of 50 cm. It was found that the DT between ducts' inlets and outlets range from 5.47 °C to 12.32 °C for duct widths of 5–50 cm, respectively. The ducted system enhanced module efficiency by 12.69% by reducing PV temperature by 27 °C from 100°C to 73 °C. The maximum calculated heat recovered from the ducted PV system is 422 W. This is 47.98% from the incident radiation in the test. Total summation of heat recovered and power enhanced by the ducted system is 61.67%.

A connection between the phenomenon of wafer bifurcation and that of spontaneous symmetry breaking (SSB) has been established. Indeed, by developing an analytical approximation of the elastic energy of a wafer coated with a thin layer (e.g. a metal), it is shown as the elastic potential energy, interpreted as a quantity contributing to the thermodynamic free energy, can be investigated within the framework of the Landau theory of the second order phase transitions. The elastic energy of a bifurcated wafer is a complex function of the stress and the curvatures in the two perpendicular directions. In this work, it is shown as a translation of the coordinate system of the curvatures allows to gain a potential which has a “Mexican hat” shape. This is a distinctive trait of the phenomenon of spontaneous symmetry breaking (SSB). Moreover, it is shown as the values of the coordinates at the minimum of the SSB potential agrees with those provided by the theory. Bifurcation is hence a phenomenon that can also be interpreted as a spontaneous symmetry breaking where the rotational symmetry of a disc shaped wafer is broken. It occurs because of a lowering of the wafer energy in the SSB broken symmetry configuration.

The analytical method for the calculation of the properties of a bolted connection established by the structural Eurocodes proposes the T-stub as a component for the characterization of the tension and compression zones in moment joints. In this article, a review of the state of the art on the T-stub component is developed, where the works developed since it was initially defined, and from the perspectives of formulation, experimentation and numerical simulation are summarized and discussed. Additionally, possible future lines of work are proposed.

Fires are complex multi-physics problems that span wide spatial scale ranges. Capturing this complexity in computationally affordable numerical simulations for process studies and “outer-loop” techniques (e.g., optimization and uncertainty quantification) is a fundamental challenge in reacting flow research. Further complications arise for propagating fires where a priori knowledge of the fire spread rate and direction is typically not available. In such cases, static mesh refinement at all possible fire locations is a computationally inefficient approach to bridging the wide range of spatial scales relevant to fire behavior. In the present study, we address this challenge by incorporating adaptive mesh refinement (AMR) in fireFoam, an OpenFOAM solver for simulations of complex fire phenomena involving pyrolyzing solid surfaces. The AMR functionality in the extended solver, called fireDyMFoam, is load balanced, models gas, solid, and liquid phases, and allows us to dynamically track regions of interest, thus avoiding inefficient over-resolution of areas far from a propagating flame. We demonstrate the AMR capability and computational efficiency for fire spread on vertical panels, showing that the AMR solver reproduces results obtained using much larger statically refined meshes, but at a substantially reduced computational cost. We then leverage the computational efficiency of the AMR solver to demonstrate an optimization framework for fire suppression based on the open-source Dakota toolkit.

FRAP technique have been used for decades to measure movements of molecules in 2D. Data obtained by FRAP experiments in cell plasma membranes are assumed to be described through means of two parameters, a diffusion coefficient D (as defined in a pure Brownian model) and a mobile fraction M. Nevertheless, it has also been shown that recoveries can be nicely fit using anomalous sub-diffusion. FRAP at variable radii has been developed using the Brownian diffusion model to access geometrical characteristics of the surrounding landscape of the molecule. Here we performed numerical simulations of continuous time random walk (CTRW) anomalous subdiffusion and interpreted them in the context of variable radii FRAP. These simulations were compared to experimental data obtained at variable radii on living cells using the PH domain of the membrane binding protein EFA6 (exchange factor for ARF6, a small G protein). This protein domain is an excellent candidate to explore the structure of the interface between cytosol and plasma membrane in cells. By direct comparison of our numerical simulations to the experiments, we show that this protein does not exhibit anomalous diffusion in BHK cells. The non Brownian PH-EFA6 dynamics observed here is more related to spatial heterogeneities such as cytoskeleton fences effects.

ORF6 is responsible for suppressing the immune response of cells infected by the SARS-CoV-2 virus. It is also the most toxic protein of SARS-CoV-2, and its actions are associated with the viral pathogenicity. Here we study in silico and in vitro the structure of the protein, its interaction with RAE1, and the mechanism of action behind its high toxicity. We show both computationally and experimentally that SARS-CoV-2 ORF6, embedded in the membranes of the endoplasmic reticulum, binds to RAE1 and sequesters it in the cytoplasm, thus depleting its availability in the nucleus and impairing nucleocytoplasmic mRNA transport. This negatively affects the cellular genome stability by compromising the cell cycle progression into the S-phase and by promoting the accumulation of RNA-DNA hybrids. Understanding the multiple ways in which ORF6 affects DNA replication may also have important implications for elucidating the pathogenesis of SARS-CoV-2 and developing therapeutic strategies to mitigate its deleterious effects on host cells.

The mean flow and turbulence statistics of the flow through a simplified urban environment, which is an active research area in order to improve the knowledge of turbulent flow in cities, is investigated. This is useful for civil engineering, pedestrian comfort and for health concerns caused by pollutant spreading. In this work, we provide analysis of the turbulence statistics obtained from well-resolved large-eddy simulations (LES). A detailed analysis of this database reveals the impact of the geometry of the urban array on the flow characteristics and provides for a good description of the turbulent features of the flow within a simplified urban environment. The most prominent features of this complex flow include coherent vortical structures such as the so-called arch vortex, the horseshoe vortex and the roof vortex. These structures of the flow have been identified by an analysis of the turbulence statistics. The influence of the geometry of the urban environment (and particularly the street width and the building height) on the overall flow behavior have also been studied. Finally, the well-resolved LES results were compared with the experimental database from Monnier et al. to discuss differences and similarities between the respective urban configurations.

In this paper, the columnar supramolecular aggregates of photosensitive star-shaped azobenzenes with benzene-1,3,5-tricarboxamide core and azobenzene arms are analysed theoretically applying a combination of computer simulation techniques. Without a light stimulus, the trans-stars build one-dimensional columns of stacked molecules during the first stage of the noncovalent association. These columnar aggregates represent the structural elements of more complex experimentally observed morphologies -- fibers, spheres, gels and others. Upon UV light exposure, the azobenzene arms isomerise from thermodynamically stable planar trans- to a metastable kinked cis-state influencing the aggregate morphology. Here, we determine the most favourable mutual orientations of the \textit{trans}-stars in the stack in terms of (i) the pi-pi distance between the cores lengthwise the aggregate, (ii) the star slipped displacements and (iii) the rotation promoting the helical twist and chirality of the aggregate by calculating the binding energy diagrams using density functional theory. The model predictions are further compared with available experimental data. The intermolecular forces responsible for the stability of the stacks made of trans-azobenzene stars in crystals are quantified using Hirshfeld surface analysis. Finally, to characterize the self-assembly mechanism of such stars in solution, we calculate the hydrogen bond lengths, the normalized dipole moment and the binding energies as the functions of the columnar length using molecular dynamics trajectories, and conclude about the cooperative nature of this process.

This paper presents the latest developments in microCT, both globally and locally, for supporting the additive manufacturing industry. There are a number of recently developed capabilities which are especially relevant to the non-destructive quality inspection of additive manufactured parts; and also for advanced process optimization. These new capabilities are all locally available but not yet utilized to their full potential, most likely due to a lack of knowledge of these capabilities. The aim of this paper is therefore to fill this gap and provide an overview of these latest capabilities, showcasing numerous local examples.

The tsscds method, recently developed in our group, discovers chemical reaction mechanisms with minimal human intervention. It employs accelerated molecular dynamics, spectral graph theory, statistical rate theory and stochastic simulations to uncover chemical reaction paths and to solve the kinetics at the experimental conditions. In the present review, its application to solve mechanistic/kinetics problems in different research areas will be presented. Examples will be given of reactions involved in photodissociation dynamics, mass spectrometry, combustion chemistry and organometallic catalysis. Some planned improvements will also be described.

We study in this paper the time evolution of stock markets using a statistical physics approach. We consider an ensemble of agents who sell or buy a good according to several factors acting on them: the majority of the neighbors, the market ambiance, the variation of the price and some specific measure applied at a given time. Each agent is represented by a spin having a number of discrete states q or continuous states, describing the tendency of the agent for buying or selling. The market ambiance is represented by a parameter T which plays the role of the temperature in physics: low T corresponds to a calm market, high T to a turbulent one. We show that there is a critical value of T, say T_c, where strong fluctuations between individual states lead to a disordered situation in which there is no majority: the numbers of sellers and buyers are equal, namely the market clearing. The specific measure, by the government or by economic organisms, is parameterized by $H$ applied on the market at the time t₁ and removed at the time t₂. We have used Monte Carlo simulations to study the time evolution of the price as functions of those parameters. In particular we show that the price strongly fluctuates near T_c and there exists a critical value H_c above which the boosting effect remains after H is removed. Our model replicates the stylized facts in finance (time-independent price variation), volatility clustering (time-dependent dynamics) and persistent effect of a temporary shock. The second party of the paper deals with the price variation using a time-dependent mean-field theory. By supposing that the sellers and the buyers belong to two distinct communities with their characteristics different in both intra-group and inter-group interactions, we find the price oscillation with time. Results are shown and discussed.

The combination of interstitial hyperthermia treatment (IHT) with high dose rate brachytherapy (HDR-BT) for prostate cancer treatment and has the potential to improve clinical outcome, since it highly enhances the efficiency of cell kill, especially when applied simultaneously. Therefore, we have developed the ThermoBrachy applicators. To effectively apply optimal targeted IHT, treatment planning is considered essential. However, treatment planning in IHT is rarely applied since it is regarded difficult to accurately calculate the deposited energy in the tissue in a short enough time for clinical practice. In this study, we investigated various time-efficient methods for fast computation of the electromagnetic (EM) energy deposition resulting from the ThermoBrachy applicators. Initially, we investigated the use of an electro-quasistatic solver. Next, we extended our investigation to the application of geometric simplifications. Furthermore, we investigated the validity of the superpositioning principle, which can enable adaptive treatment plan optimization without the need for continuous recomputation of the EM field. Finally, we evaluated the accuracy of the methods by comparing them to the golden standard Finite-Difference Time-Domain calculation method using gamma-index analysis. The simplifications considerably reduced the computation time needed, improving from >12 h to a few seconds. All investigated methods showed excellent agreement with the golden standard by showing a >99% passing rate with 1%/0.5 mm Dose Difference and Distance-to-Agreement criteria. These results allow the proposed electromagnetic simulation method to be used for fast and accurate adaptive treatment planning.

This paper describes a novel concept of producing energy efficient ”Maroon enriched natural gas “ and then Pink hydrogen” from any hydrocarbon base. The key idea is the extraction of hydrogen from water in addition to that from the hydrocarbon in an optimal fashion. This has the benefit of higher water vapor to CO2 exhaust ratio than conventional carbonaceous fuels when generating energy via combustion, a prudent step in achieving Netzero goals in a shorter time, and creating energy independence in most places.. The process of production makes concentrated CO₂ available for use and or sequestration. The process also maximizes use of renewable electricity in hydrogen generation, and maximizes use of existing infrastructure, with a minimum capital cost by energy recycle in the process. The process design applies sound thermodynamic principles which evolved during the nineteenth century, and mimics the geochemical processes going on in some of the natural 'colorless hydrogen'.

The Particle-In-Cell (PIC) method has been developed in order to investigate microscopic phenomena, and with the advances of computing power, newly developed codes have been used for several fields such as astrophysical, magnetospheric, and solar plasmas. PIC applications have grown extensively with large computing powers available on supercomputers such as Pleiades and Blue Waters in the US. For astrophysical plasma research PIC methods have been utilized for several topics such as reconnection, pulsar dynamics, non-relativistic shocks, relativistic shocks, relativistic jets, etc. PIC simulations of relativistic jets have been reviewed with the emphasis on the physics involved in the simulations. This review summarizes PIC simulations, starting with the Weibel instability in slab models of jets, and then focuses on global jet evolution in helical magnetic field geometry. In particular we address kinetic Kelvin-Helmholtz instabilities and mushroom instabilities.

Metal nanoparticles are used to modify/enhance the properties of a polymer matrix for a broad range of applications in bio-nanotechnology. Here, we study the properties of polymer/gold nanoparticle (NP) nanocomposites through atomistic molecular dynamics, MD, simulations. We probe the structural, conformational and dynamical properties of polymer chains at the vicinity of a gold (Au) NP and a functionalized (core/shell) Au NP, and compare them against the behavior of bulk PE. The bare Au NPs were constructed via a systematic methodology starting from ab-initio calculations and an atomistic Wulff construction algorithm resulting in the crystal shape with the minimum surface energy. For the functionalized NPs the interactions between gold atoms and chemically adsorbed functional groups change their shape. As a model polymer matrix we consider polyethylene of different molecular lengths, from the oligomer to unentangled Rouse like systems. By computing the different properties the concept of the interface, and the interphase as well, in polymer nanocomposites with metal NPs are critically examined. Results concerning polymer density profiles, bond order parameter, segmental and terminal dynamics show clearly that the size of the interface / interphase, depends on the actual property under study. In addition, the anchored polymeric chains change the behavior/properties, and especially the chain density profile and the dynamics, of the polymer chain at the vicinity of the Au NP.

We addressed the frequent occurrence of mixed-chain lipids in biological membranes and their impact on membrane structure by studying several chain-asymmetric phosphatidylcholines and the highly asymmetric milk sphingomyelin. Specifically, we report trans-membrane structures of the corresponding fluid lamellar phases using small-angle X-ray and neutron scattering, which were jointly analyzed in terms of a membrane composition-specific model, including a headgroup hydration shell. Focusing on terminal methyl groups at the bilayer center we found a linear relation between hydrocarbon chain length mismatch and the methyl-overlap for phosphatidylcholines, and a non-negligible impact of the glycerol backbone-tilting, letting the sn1-chain penetrate deeper into the opposing leaflet by half a CH2 group. That is, penetration-depth differences due to the ester-linked hydrocarbons at the glycerol backbone, reported previously for gel phase structures also extend to the physiological more relevant fluid phase, but are significantly reduced. Moreover, milk sphingomyelin was found to follow the same linear relationship suggesting a similar tilt of the sphingosine backbone. Complementary performed molecular dynamics simulations revealed that there is always a part of the lipid tails bending back, even if there is a high interdigitation with the opposing chains. This suggests that hydrocarbon chain interdigitation plays only a minor role in transbilayer coupling. For both cases of adaption to chain length mismatch, chain-asymmetry has a large impact on hydrocarbon chain ordering, inducing disorder in the longer of the two hydrocarbons.

3D facial surface imaging is a useful tool in dentistry and in terms of diagnostics and treatment planning. Between-groups PCA (bgPCA) is a method that has been used to analyse shapes in biological morphometrics, although various “pathologies” of bgPCA have recently been proposed. Monte Carlo (MC) simulated datasets were created here in order to explore “pathologies” of multilevel PCA (mPCA), where mPCA with two levels is equivalent to bgPCA. The first set of MC experiments involved 300 uncorrelated normally distributed variables, whereas the second set of MC experiments used correlated multivariate MC data describing 3D facial shape. We confirmed previous results of other researchers that indicated that bgPCA (and so also mPCA) can give a false impression of strong differences in component scores between groups when there is none in reality. These spurious differences in component scores via mPCA reduced strongly as the sample sizes per group were increased. Eigenvalues via mPCA were also found to be strongly effected by imbalances in sample sizes per group, although this problem was removed by using weighted forms of covariance matrices suggested by the maximum likelihood solution of the two-level model. However, this did not solve problems of spurious differences between groups in these simulations, which was driven by very small sample sizes in one group here. As a “rule of thumb” only, all of our experiments indicate that reasonable results are obtained when sample sizes per group in all groups are at least equal to the number of variables. Interestingly, the sum of all eigenvalues over both levels via mPCA scaled approximately linearly with the inverse of the sample size per group in all experiments. Finally, between-group variation was added explicitly to the MC data generation model in two experiments considered here. Results for the sum of all eigenvalues via mPCA predicted the asymptotic amount for the total amount of variance correctly in this case, whereas standard “single-level” PCA underestimated this quantity.

Under the oxidative stress condition, the small RNA (sRNA) Oxys that acts as essential post-transcriptional regulators of gene expression is produced and plays a regulatory function with the assistance of the RNA chaperone Hfq protein. Interestingly, experimental studies found that the N48A mutation of Hfq protein could enhance the binding affinity with OxyS while resulting in defection of gene regulation. But, how the Hfq protein interacts with sRNA Oxys and the origin of the stronger affinity of N48A mutation are both unclear. In this paper, molecular dynamics (MD) simulations were performed on the complex structure of Hfq and OxyS to explore their binding mechanism. The molecular mechanics generalized Born surface area (MM/GBSA) and interaction entropy (IE) method were combined to calculate the binding free energy between Hfq and OxyS sRNA, and the computational result is in excellent correlation with the experimental result. Per-residue decomposition of the binding free energy revealed that the enhanced binding ability of the N48A mutation mainly comes from the increased van der Waals interactions (vdW). This research explores the binding mechanism between Oxys and chaperone protein Hfq, and revealed the origin of the strong binding affinity of N48A mutation. The results provided important insights on the mechanism of gene expression regulation affected by protein mutations.

Bell type inequalities are proven using oversimplified probabilistic models and/or counterfactual definiteness (CFD). If setting-dependent variables describing measuring instruments are correctly introduced none of these inequalities may be proven. In spite of this a belief in a mysterious quantum nonlocality is not fading. Computer simulations of Bell tests allow studying different scenarios how the experimental data might have been created. They allow also to generate outcomes of various counterfactual experiments such as repeated or simultaneous measurements performed in different settings on the same ‘’ photon-pair” etc. They allow reinforcing or relaxing CFD- compliance and /or to study the impact of various “photon identification procedures” mimicking those used in real experiments. Using a specific setting- dependent identification procedure data samples consistent with quantum predictions may be generated. It reflects an active role of instruments during the measurement process. Each setting dependent data samples are consistent with specific setting –dependent probabilistic models which may not be deduced using non-contextual local realistic or stochastic hidden variables. In this paper we discuss the results of these simulations. Since the data samples are generated in a locally causal way, these simulations provide additional strong arguments for closing the door on quantum nonlocality

Based on a local causal model of the dynamics of curved discrete spacetime, a causal model of quantum field theory in curved discrete spacetime is described. At the elementary level, space(-time) is assumed to consists of interconnected space points. Each space point is connected to a small discrete set of neighbor space points. Density distribution of the space points and the lengths of the space point connections depend on the distance from the gravitational sources. This leads to curved spacetime in accordance with general relativity. Dynamics of spacetime (i.e., the emergence of space and the propagation of space changes) dynamically assigns "in-connections" and "out-connections" to the affected space points. Emergence and propagation of quantum fields (including particles) are mapped to the emergence and propagation of space changes by utilizing identical paths of in/out-connections. Compatibility with standard quantum field theory (QFT) requests the adjustment of the QFT techniques (e.g., Feynman diagrams, Feynman rules, creation/annihilation operators), which typically apply to three in/out connections, to n > 3 in/out connections. In addition, QFT computation in position space has to be adapted to a curved discrete space-time.

The non-symmetrical collapse of an empty cylindrical cavity is modelled using Smoothed Particle Hydrodynamics. The presence of a nearby surface produces an anisotropic pressure field generating a high velocity jet that hits the surface. The collapse follows a different dynamic based to the initial distance between the centre of the cavity and the surface. When the distance is greater than the cavity radius (detached cavity) the surface is hit by travelling shock waves. When the distance is less than the cavity radius (attached cavity) the surface is directly hit by the jet and later by other shock waves generated in the last stages of the of the collapse. The results show that the surface is hit by a stronger shock when distance between the centre of the cavity and the surface is zero while showing more complex double peaks behaviour for other distances.

Tsunami modeling and simulation has changed in the past few years more than it had in decades, especially so with respect to coastal inundation. Among other things, this change is supported by the approaching era of exa-scale computing, whether via GPU or more likely forms of hybrid computing whose presence is growing across the geosciences. For reasons identified across this review, exa-scale computing efforts will impact the on-shore, highly turbulent r\'egime to higher degree than the 2D shallow water equations used to model tsunami propagation in the open ocean. This short review describes the different approaches to tsunami modeling from generation to impact and underlines the limits of each model based on the flow r\'egime. Moreover, from the perspective of a future comprehensive multi-scale modeling infrastructure to simulate a full tsunami, we underline the current challenges associated with this approach and review the few efforts that are currently underway to achieve this goal. A table of existing tsunami software packages is provided along with an open Github repository to allow developers and model users to update the table with additional models as they are published and help with model discoverability.

Cardiac myosin-binding protein C (MyBPC) is a thick-filament associated regulatory protein in the sarcomere. It regulates the sensitive contractile system of the myocardium by acting as a mechanical tether, sensitizing the thin filament or modulating myosin motor activity. Mutations in the MYBPC3 gene are a frequent cause for the development of hypertrophic cardiomyopathy, the most frequent cardiac disorder. Recently, the monoallelic double mutation MYBPC3Δ25bp/D389V has been discovered as a subset of the common MYBPC3Δ25bp variant in South Asia. MYBPC3Δ25bp/D389V carriers exhibit hyperdynamic features, which are considered an early finding for the development of hypertrophic cardiomyopathy. Using correlation-guided molecular dynamics simulations sampling, we show that the D389V mutation shifts the conformational distribution of the C2 domain of MyBPC. We further applied biochemical approaches to probe the effects of the D389V mutation on structure, thermostability and protein-protein interactions of MyBPC C2. The melting temperature (Tm) of MyBPC C2 D389V is decreased by 4 to 7 °C compared to wild type while the interaction of the C0-C2 domains with myosin and actin remains unchanged. Additionally, we utilized steered molecular dynamics (SMD) simulations to investigate the altered unfolding pathway of MyBPC C2 D389V. Based on our data, we propose a pathomechanism for the development of HCM in MYBPC3Δ25bp and MYBPC3Δ25bp/D389V carriers.

The rational fabrication of low-dimensional materials with a well-defined topology and functions is an incredibly important aspect of nanotechnology. In particular, the on-surface synthesis (OSS) methods based on the bottom-up approach enable facile construction of sophisticated molecular architectures unattainable by traditional methods of wet chemistry. Among such supramolecular constructs especially interesting are surface-supported metal-organic networks (SMONs), composed of low-coordinated metal atoms and π-aromatic bridging linkers differing in size, shape and functionalization scheme. In this work, the lattice Monte Carlo (MC) simulation technique was used to extract the chemical information encoded in a family of Y-shaped positional isomers coadsorbed with trivalent metal atoms on a flat metallic surface with (111) geometry. For this purpose the investigated tritopic molecules/metal atoms were carefully mapped on a triangular lattice as interconnected/isolated segments with appropriatelly embedded anisotropic interactions. Depending on the intramolecular distribution of active centers (functional groups) within the simulated molecular bricks, we observed the metal-directed self-assembly of two-dimensional (2D) openwork patterns, aperiodic mosaics and metal-organic ladders. The obtained theoretical findings could be especially relevant for the scanning tunneling microscopy (STM) experimentalists interested in a surface-assisted construction of complex nanomaterials stabilized by directional coordination bonds.

Accurate treatment planning in radiotherapy essentially decreases secondary damage to healthy tissue surrounding the tumor. Due to plans to use a direct, highly collimated, narrow beam with high intensity to treat small area tumors, researchers have studied microbeam radiation therapy extensively. Using a synchrotron beam as the radiation source may help to limit secondary damage, but treatment planning using computerized simulations and dosimetry is still necessary to achieve optimal results. For this purpose, PDA-gel dosimeters were developed and their sensitivity around a 150 keV induced synchrotron X-ray radiation beam was examined via Monte Carlo simulations using the EGS5 code system. The microbeam development is now at the animal study stage. In this study, we simulate the irradiation of a rat's brain. The simulation results obtained spectra for two types of PDA-gel dosimeters that were compared with the spectrum obtained in a modelized brain tumor of a rat. Additionally, percentage depth dose curves were calculated for the brain tissue and the two gels. Correction equations for the dosimeters were obtained from the dose-difference plots. For further references, these equations can be used to calculate the actual dose in a brain tumor in a rat. The Monte Carlo simulations demonstrate that PDA-gel dosimeters can be used as a reference technique in planning treatment using synchrotron irradiations and in other medical treatment planning methods.

We prepared heterogeneous alumina-silicate glasses by consolidating nanoparticles using molecular dynamics simulations. Consolidated glasses from either low alumina content alumina-silicate glasses or high alumina content alumina-silicate glasses show significantly improved ductility around consolidation pressure of ~3 GPa. The introduced structural heterogeneities, namely over-coordinated network formers and their neighboring oxygen atoms, are identified as plasticity carriers due to their high rearrangement propensity. In addition, consolidated oxide glass from both 23.4Al₂O₃76.6SiO₂ and 73.1Al₂O₃26.9SiO₂ nanoparticles show improved flow strength (up to 1 GPa) due to the introduction of chemical heterogeneities. Last but not least, apparent hardening behavior appears upon cold work in consolidated glasses, with an increase of yield strength from ~3.3 GPa to ~6.4 GPa. This method is a big advancement toward ultra-strong and ultra-tough glasses by breaking the structure, composition and size limitations in traditional melt-quench process.

The extremely controversial conclusions about the function of human interferon-gamma (hIFNγ) C-terminus as well as the lack of a consistent model explaining its role in the receptor binding prompted us to scrutinize the interaction of hIFNγ with its extracellular receptor hIFNGR1 in different scenarios by means of molecular dynamics simulations. We find that the two molecules alone fail to form a stable complex but the presence of heparan-sulfate-like oligosaccharides largely facilitates the process by both demobilizing the highly flexible C-termini of the cytokine and assisting in the proper positioning of its globule between the receptor subunits. An antiproliferative-activity essay on cells depleted from surface sulfation confirms qualitatively the simulation-based multistage complex-formation model. Our results reveal the key role of HS and its proteoglycans in all processes involving hIFNγ signalling.

Chiroptical responses have been an essential tool over the last decades for chemical structural elucidation due to their exceptional sensitivity to geometry and intermolecular interactions. In recent times, there has been an increasing interest for the search of more efficient sensing by the rational design of tailored chiroptical systems. In this Review article, advances on chiroptical systems towards their implementation in sensing applications are summarized. Strategies to generate chiroptical responses are illustrated. Theoretical approaches to assist in the design of these systems are discussed. Development of efficient chiroptical reporters in different states of matter, essential for the implementation in sensing devises, is reviewed. In the last part, remarkable examples of chiroptical sensing applications are highlighted.

This study reports a general scenario for the out-of-equilibrium features of collapsing polymeric architectures. We use molecular dynamics simulations to characterize the coarsening kinetics, in bad solvent, for several macromolecular systems with an increasing degree of structural complexity. In particular, we focus on: flexible and semiflexible polymer chains, star polymers with 3 and 12 arms, and microgels with both ordered and disordered networks. Starting from a powerful analogy with critical phenomena, we construct a density field representation that removes fast fluctuations and provides a consistent characterization of the domain growth. Our results indicate that the coarsening kinetics presents a scaling behaviour that is independent of the solvent quality parameter, in analogy to time-temperature superposition principle. Interestingly, the domain growth in time follows a power-law behaviour that is approximately independent of the architecture for all the flexible systems; while it is steeper for the semiflexible chains. Nevertheless, the fractal nature of the dense regions emerging during the collapse exhibits the same scaling behaviour for all the macromolecules. This, suggests that the faster growing length scale in the semiflexible chains originates just from a faster mass diffusion along the chain contour, induced by the local stiffness. The decay of the dynamic correlations displays scaling behavior with the growing length scale of the system, which is a characteristic signature in coarsening phenomena.

Polyphenol ellagic acid (EA) possesses anti-oxidant, anti-inflammatory, anti-carcinogenic, anti-diabetic and cardio protection activities, remarking it an interesting multi-targeting profile. EA also controls the central nervous system (CNS) since it was proven to reduce the immobility time of mice in both the forced swimming and the tail-suspension tests, with an efficiency comparable to that of classic antidepressants. Interestingly, the anti-depressant-like effect was almost nulled by the concomitant administration of selective antagonists of the noradrenergic receptors, suggesting the involvement of these cellular targets in the central effects elicited by EA and its derivatives. By in silico and in vitro studies, we discuss how EA engages with human α2A-ARs and α2C-AR catalytic pockets, comparing EA behaviour with those ones of known agonist and antagonist. Structurally, the hydrophobic residues surrounding α2A-AR pocket confer specificity on the intermolecular interactions and hence lead to favourable binding of EA in the α2A-AR, with respect to α2C-AR. Moreover, EA seems to better accommodate within α2A-ARs into TM5 area, closely to S200 and S204 which play a crucial role for activation of aminergic GPCRs such as the α2-AR, highlighting its promising role as a partial agonist. Consistently, EA mimics clonidine in inhibiting noradrenaline exocytosis from hippocampal nerve endings in an yohimbine-sensitive fashion that confirms the engagement of naïve α2-ARs in the EA-mediated effect.

Thermal shape memory polymers (SMPs) find increasing applications in biology and medicine due to their promising potential for improved biocompatibility. In such applications, the inevitable penetration of small molecules from the ambient fluid into the polymer influences the shape recovery process and often leads to a reduction of the temperature, at which shape recovery takes place. We show here via molecular dynamics simulations that the size of additive molecules plays a key role for this process. While the effect of concentration on the recovery rate is monotonic in the investigated range, a non-monotonic dependence on the size of additive molecules emerges at temperatures close to the glass transition. This work thus identifies the additives’ size to be a qualitatively novel parameter for switching the recovery process in polymer-based shape memory materials.

Vernacular architecture constitutes a rich source of information and ancestral knowledge that can become a key resource for sustainable development through its passive design strategies, which effectively respond to local climatic and weather conditions using locally sourced materials for the construction of its supporting structure and enveloping elements, as well as spatial organization and the incorporation of a buffer area (patio) that optimize the use of renewable resources. This qualitative study analyzes a traditional housing typology with a central patio located in the Historic Center of Azogues city, Ecuador, to evaluate its interior thermal comfort through in-situ monitoring in the different building spaces. Using the open-source software Open Studio and EnergyPlus, a simulation model was built to assess the annual thermal performance of the house. Field records were used to verify the effectiveness of the strategies that respond to the climatic conditions of the area. The analysis carried out on the passive strategies used in the selected house with regard to natural ventilation, solar protection, and thermal insulation, which depend on various aspects of the building, such as its location, internal space arrangement, design of openings (doors and windows), among others. The thermal simulations reveal that the traditional house located in the Historic Center of Azogues city is well adapted to the local climate, although interior thermal comfort is not entirely satisfactory.

A quantitative analysis of X-ray emission from an electron cyclotron resonance (ECR) plasma was performed to probe the spatial properties of electrons having energy for effective ionisation. A series of measurements were taken by INFN-LNS and ATOMKI, capturing spatially and spectrally resolved X-ray maps as well as volumetric emissions from argon plasma. Comparing the former with model generated maps (involving space-resolved phenomenological electron energy distribution function and geometrical efficiency calculated using ray-tracing MC routine) furnished information on structural aspects of the plasma. Similarly, fitting a model composed of bremsstrahlung and fluorescence to the volumetric X-ray spectrum provided valuable insight into the density and temperature of confined and lost electrons. The latter can be fed back to existing electron kinetics models for simulating more relevant energies, consequently improving theoretical X-ray maps and establishing the method as an excellent indirect diagnostic tool for warm electrons, required for both fundamental and applied research in ECR plasmas.

Mesoscale imperfections, such as pores and voids, can strongly modify the properties and the mechanical response of materials under extreme conditions. Tracking the material response and microstructure evolution during void collapse is crucial for understanding its performance. In particular, imperfections in ablator materials, such as voids, can limit the efficiency of the fusion reaction and ultimately hinder ignition. To characterize how voids influence the response of materials during dynamic loading and seed hydrodynamic instabilities, we have developed a tailored fabrication procedure for designer targets with voids at specific locations. Our procedure uses SU-8 as a proxy for ablators materials and hollow silica microspheres as proxy for voids and pores. By using photolithography to design the targets’ geometry, we demonstrate precise and highly reproducible placement of a single void within the sample, which is key for a detailed understanding of its behavior under shock compression. This fabrication technique will benefit high-repetition rate experiments at x-ray and laser facilities. Insight from shock compression experiments will provide benchmarks for the next generation of microphysics modelling.

Multisource meteorological re-analyses are the most reliable forcing data for driving hydrological models to simulate streamflow. We aimed to assess the different hydrological responses through hydrological modeling in the upper Lancang-Mekong River Basin (LMRB) using the two gridded meteorological datasets, climate forecast system reanalysis (CFSR) and the China Meteorological Assimilation Driving Datasets for the SWAT model (CMADS). We selected the Pearson’s correlation coefficient (R), percent bias (PBIAS), and root mean square error (RMSE) indices to compare the six meteorological variables of the two datasets. The spatial distributions of the statistical indicators in the CFSR and CMADS, namely, the R, PBIAS, and RMSE values, were different. Furthermore, the soil and water assessment tool plus (SWAT+) model was used to do hydrological modeling based on CFSR and CMADS meteorological re-analyses in the upper LMRB. Different meteorological datasets resulted in significant differences of hydrological responses, which reflected by different sensitive parameters and their optimal value. These different calibrated optimal values of sensitive parameters further lead to the different simulated water balance components between CFSR- and CMADS-based SWAT+ model. These findings can help in a better understanding of the strengths and weaknesses of different meteorological re-analysis datasets and the roles on the hydrological modeling.

The natural product Salvinorin A (SalA) was the first nitrogen-lacking agonist discovered for the opioid receptors and exhibits high selectivity for the kappa opioid receptor (KOR) turning SalA into a promising analgesic to overcome the current opioid crisis. Since SalA’s suffers from poor pharmacokinetic properties, particularly the absence of gastrointestinal bioavailability, fast metabolic inactivation and subsequent short duration of action, the rational design of new tailored analogs with improved clinical usability is highly desired. Despite being known for decades, the binding mode of SalA within the KOR remains elusive as several conflicting binding modes of SalA were proposed hindering the rational design of new analgesics. In this study, we rationally determined the binding mode of SalA to the active state KOR by in silico experiments (docking, molecular dynamics simulations, dynophores) in the context of all available mutagenesis studies and structure-activity relationship (SAR) data. To the best of our knowledge this is the first comprehensive evaluation of SalA’s binding mode since the determination of the active state KOR crystal structure. SalA binds above the morphinan binding site with its furan pointing towards the intracellular core while the C2-acetoxy group is oriented towards the extracellular loop 2 (ECL2). SalA is solely stabilized within the binding pocket by hydrogen bonds (C210ECL2, Y3127.35, Y3137.36) and hydrophobic contacts (V1182.63, I1393.33, I2946.55, I3167.39). With the disruption of this interaction pattern or the establishment of additional interactions within the binding site we were able to rationalize the experimental data for selected analogs. We surmise the C2-substituent interactions as important for SalA and its analogs to be experimentally active, albeit moderate frequency within MD simulations of SalA. We further identified the non-conserved residues 2.63, 7.35, and 7.36 responsible for the KOR subtype selectivity of SalA. We are confident that the elucidation of the SalA binding mode will promote the understanding of KOR activation and the facilitate the development of novel analgesics that are urgently needed.

Motivated by the way animals react in nature, we introduce a fully-connected neural-network model, which incorporates the external pattern presented to the system as a fundamental tool of the recognition process. In this new scenario, in the absence of this external field, memories are not attractors inside basins of attraction, as in usual attractor neural networks, although basins may be created according to the external pattern, thus allowing storing a much larger number of memories. The key point consists in calibrating the influence of the external pattern such as to cancel the noise generated by those memories not correlated with the external pattern.We illustrate how this proposal works by including this new contribution in the standard Hopfield model, showing a significant increase in its recognition capacity (typically by a factor $10^{2}$). As an additional feature of this model, we show its ability to react promptly to changes in the external environment, a crucial attribute of living beings. This procedure can be applied to a wide variety of neural-network models to increase considerably their recognition and reaction capabilities.

Naltrexone (NTX) is a potent opioid antagonist with good blood-brain barrier permeability, targeting different endogenous opioid receptors, particularly the mu-opioid receptor (MOR). Therefore, it represents a promising candidate for drug development against drug addiction. However, the details of the molecular interactions of NTX and its derivatives with MOR are not fully understood, hindering ligand-based drug discovery. In the present study, taking advantage of the high-resolution X-ray crystal structure of the murine MOR (mMOR), we constructed a homology model of the human MOR (hMOR). A solvated phospholipid bilayer was built around the hMOR and submitted to microsecond (µs) molecular dynamics (MD) simulations to obtain an optimized hMOR model. NTX and its derivatives were docked into the optimized hMOR model and submitted to µs MD simulations in an aqueous membrane system. The MD simulation results were submitted to Molecular Mechanics Generalized-Born surface area (MMGBSA) binding free energy calculations and principal component analysis. Our results revealed that NTX and its derivatives showed differences in protein-ligand interactions; however, they shared contact with residues at TM2, TM3, H6, and TM7. The binding free energy and principal component analysis revealed the structural and energetic effects responsible for the higher potency of NTX compared to its derivatives.

Three body systems in which one of the bodies is ejected without escaping the binary system have previously been studied in various restricted forms. However, none of these studies dwells on the problem in a general setting. Thus, to study this phenomenon qualitatively, we try to expand this problem's scope to unequal mass systems and generalize them by considering various configurations of fixed initial points with precisely calculated initial velocities, some zero velocity models and some optimized models. We will see the use of terminology similar to the previous studies done in this domain but incorporate different analytical and evaluation methods.

The microstructure of oil pipeline steels is polycrystalline due to the presence of a complex grain boundary (GB) network in them. The performance of them when exposed to stresses in corrosive environments is largely dictated by the interplay between the hydrogen (H) diffusion, the dislocation slip, and their interactions with the GBs. However, the slip-GB interaction in the presence of H and the subsequent cracking along the GBs remains not fully understood up to date. It is challenging to simultaneously resolve the collective dislocation motions away from the GBs together with the H diffusion near the atomically structured GBs using single-scale techniques. To address this challenge, taking bcc iron as a model material, here we present a a concurrent atomistic-continuum (CAC) computational analysis of the interaction between dislocation slip and a H-charged GB. With the large number of dislocations-mediated plastic flow away from the GB together with the atomistic structure evolution at the GB being simultaneously retained, several main findings from our simulations are: (i) the large number of dislocation-mediated pileup-induced internal stress nearby the H-charged GB can be as high as 3GPa; (ii) the more dislocations accumulated nearby the GB, the slower H diffusion ahead of the slip-GB intersection; (iii) H atoms diffuse fast behind the pileup tip, get trapped within the GB, and diffuse slow ahead of the pileup tip; (iv) the local stresses nearby the pileup tip exhibits a strong heterogeneity along the dislocation line direction. This differs from the common wisdom in many existing 2D theories/models. The buildup of such a high local stress heterogeneity leads to inhomogeneous H diffusion within the GB plane. The CAC simulation-predicted local H diffusivity, Dpileup−tip, and local stresses, σ, nearby the GB are then correlated with each other and consolidated into a mechanics model by considering the dislocation pileup as an Eshelby inclusion. These findings will provide researchers with opportunities to: (a) characterize the coupled dynamics between plasticity, H diffusion, and crack initiation underlying the hydrogen-induced cracking (HIC); (b) develop mechanism-based constitutive rules to be used in diffusion-plasticity coupling models for understanding the interplay between mechanical and mass transport in materials at the continuum level; and (c) connect the atomistic deformation physics of polycrystalline materials with their overall performance in aqueous environments, which is currently difficult to achieve in laboratory experiments.

In this paper a new double-nozzle technique for in-gas-jet laser resonance ionization spectroscopy is proposed. The functionality of this new technique we explored by detailed gas dynamic and Monte Carlo atom-trajectory simulations, which results are presented and discussed. The results of similar computer simulations for JetRIS setup (as a typical representative of the conventional nowadays in-gas-jet technique) are presented and discussed as well. The direct comparison of calculation results for proposed new technique with the conventional one shows that the double-nozzle technique has many advantages compared with that one used in the JetRIS setup at GSI for future high-resolution laser spectroscopic study of heaviest elements. To fully implement the proposed new technique to all existing (or under construction) setups for in-gas-jet laser resonance ionization spectroscopy, it will be enough just replace the used their supersonic nozzle by the miniature double-nozzle device described in the paper.

The new coronavirus SARS-CoV-2 is the cause of the COVID-19 pandemic, which has created an incomparable global health problem. PLpro is a key protein involved in viral polyprotein processing and immune system evasion, making it a prime target for the development of antiviral drugs to combat COVID-19. The review begins by elucidating the functional and structural properties of SARS-CoV-2 PLpro, underscoring its significance in viral pathogenicity and replication. Employing homology modeling, a tertiary structure model of PLpro is constructed, laying the groundwork for subsequent investigations. To expedite the search for potential therapeutic candidates, the study harnesses computational methodologies. Molecular docking techniques are employed to explore binding sites for antiviral drugs within the catalytic region of PLpro. This computational approach not only aids in drug development but also provides crucial preliminary data before experimental research commences. The stability of drug-PLpro complexes is assessed through comprehensive all-atom molecular dynamics (MD) simulations, affording dynamic insights into drug-PLpro interactions. By evaluating binding energy estimates from MD simulations, stable drug-PLpro complexes with potential antiviral properties are identified. However, it is emphasized that experimental validation is imperative to confirm these computational findings, necessitating in vitro and in vivo tests to assess safety and efficacy. This pivotal stage bridges the computational realm with real-world clinical applications. The review emphasizes the imperative need for enhancements in the existing PLpro-targeting drugs currently on the market. Their actions are insufficient for clinical use and necessitate thorough characterization and improvement. The Supervised Molecular Dynamics (SuMD) simulation technique reveals critical information about drug unbinding pathways, shedding light on opportunities for refinement. In addition to optimizing existing drugs, the investigation of sub-structurally similar molecules emerges as a promising avenue for drug development. In conclusion, the review underscores the pivotal role of targeting SARS-CoV-2 PLpro in the ongoing battle against COVID-19. By integrating molecular dynamics simulations, structural modeling, and computational insights, a robust foundation is established for identifying promising antiviral drug candidates. The continual need for improvement in existing drugs and the exploration of novel compounds remain paramount in the global effort to combat COVID-19. The evolution and management of COVID-19 hinge on the symbiotic relationship between computational insights and experimental validation, illustrating the interdisciplinary synergy crucial to this endeavor.

In its prefusion state, the SARS-CoV-2 Spike protein (similarly to other class I viral fusion proteins) is metastable, which is considered to be an important feature for optimizing or regulating their functions. After the binding process of its S1 subunit (S1) with the ACE2, the Spike protein (S) suffers a dramatic conformational change where S1 splits from the S2 subunit, which then penetrates the membrane of the host cell, promoting the fusion of the viral and cell membranes. This results in the infection of the host cell. In a previous work, we showed -using large scale molecular dynamics simulations- that the application of external electric fields (EF) induces drastic changes and damage in the receptor-binding domain (RBD) of the wild type Spike protein, as well of the Alpha, Beta and Gamma variants, leaving a structure which cannot be recognized any more by ACE2. In this work, we first extend the study to the Delta and Omicron variants and confirm the high sensitivity and extreme vulnerability of S to moderate EF (as weak as 104 V m-1), but, more importantly, we also show that, in contrast, the postfusion state of the spike protein does not suffer structural damage even if electric field intensities four orders of magnitude higher are applied. These results provide a solid scientific basis to confirm the prefusion state metastability roots of the SARS-CoV-2 Spike protein susceptibility to be damaged by EF. After the virus docks to the ACE2 receptor, the stable and robust postfusion conformation develops, which exhibits a similar resistance to EF (damage threshold higher than 108 V m-1) like most globular proteins.

A series of cysteine-based perfluoroaromatic (hexafluorobenzene (I) and decafluorobiphenyl (II) were synthesized and established as a chemoselective and available core to simple or more complex systems since small molecules to biomolecules with interesting properties. As proof of concept of the potential application of perfluorinated derivatives as non-cleavable linkers, some antibody-perfluorinated conjugates were prepared via thiol, demonstrating that the bioconjugation process doesn’t affect to the macromolecular entity. Besides, some molecular properties of synthesized compounds are evaluated using a combination of spectroscopic characterization (FT-IR and 19F-NMR chemical shifts) and theoretical calculations. Moreover, molecular Docking was also developed to predict cysteine-based hexafluorobenzene and decafluorobiphenyl derivatives’ affinity against topoisomerase Il and cyclooxygenase 2 (COX-2). The results suggested that mainly cysteine-based decafluorobiphenyl derivatives could be potential topoisomerase II α and COX-2 inhibitors, becoming potential anticancer agents and candidates for anti-inflammatory treatment.

Thermal simulations are an important part in the design of electronic systems, especially as systems with high power density become common. In simulation-based design approaches, a considerable amount of time is spent by repeated simulations. In this work, we present a proof-of-concept study of the application of convolutional neural networks to accelerate those thermal simulations. The goal is not to replace standard simulation tools but to provide a method to quickly select promising samples for more detailed investigations. Based on a training set of randomly generated circuits with corresponding Finite Element solutions, the full 3D steady-state temperature field is estimated using a fully convolutional neural network. A custom network architecture is proposed which captures the long-range correlations present in heat conduction problems. We test the network on a separate dataset and find that the mean relative error is around 2 % and the typical evaluation time is 35 ms per sample ( 2 ms for evaluation, 33 ms for data transfer). The benefit of this neural-network-based approach is that, once training is completed, the network can be applied to any system within the design space spanned by the randomised training dataset (which includes different components, material properties, different positioning of components on a PCB, etc.).

Solid state sensors having timing capabilities are becoming an absolute need in particle tracking techniques of future experiments at colliders. In this sense, silicon sensors having 3D structure are becoming an interesting solution, due to their intrinsic speed and radiation resistance. A characteristics of such devices is the strict dependence of their performance on their geometric structure, which can be widely optimised by design, thus requiring suitable tools for an accurate modeling of their behaviour. This paper illustrates the development, performance and use of the TCoDe simulator, specifically dedicated to the fast simulation of carrier transportation phenomena in solid state sensors. Some examples of its effectiveness in the design and analysis of 3D sensors is also given.

The dynamic and surface manipulation of the M13 bacteriophage meeting application demands enable a pathway to design efficient applications with high selectivity and responsivity rate. Herein, we report the role of the M13 bacteriophage thin film layer deposited on an optical nanostructure involving gold nanoparticles/SiO2/Si and its influence on optical and geometrical properties. The thickness of the M13 phage layer was either controlled by varying the concentration or humidity exposure levels, and optical studies were conducted. We designed a standard and dynamic model based upon three-dimensional finite-difference time-domain (3D FDTD) simulations distinguishing the necessity of each model under variable conditions. As seen from the experiments, the origin of respective peak wavelength positions is addressed in detail with the help of simulations. The importance of the dynamic model was noted when humidity-based experiments were conducted. Inexpensive, multi-wavelength optical characteristics from a single structure, reproducibility, and reversible properties are significant advantages of involving M13 bacteriophage. We believe this work will provide fundamental insight into understanding and interpreting the geometrical and optical properties of the nanostructures involving M13 bacteriophage.

Pentagalloyl glucose (PGG) is currently being investigated as a non-surgical treatment for abdominal aortic aneurysms (AAA); however molecular mechanisms of action of PGG on the AAA matrix components and the intra-luminal thrombus (ILT) still need to be better understood. To assess these interactions, we utilized peptide fingerprinting and molecular docking simulations to predict the binding of PGG to vascular proteins in normal and aneurysmal aorta, including matrix metalloproteinases (MMPs), cytokines and fibrin. We performed PGG diffusion studies in pure fibrin gels and human ILT samples. PGG was predicted to bind with high affinity to most vascular proteins, the active sites of MMPs, and several cytokines known to be present in AAA. Finally, despite potential binding to fibrin, PGG was shown to diffuse readily through thrombus at physiologic pressures. In conclusion, PGG can bind to all the normal and aneurysmal aorta protein components with high affinity, potentially protecting the tissue from degradation and exerting anti-inflammatory activities. Diffusion studies showed that thrombus presence in AAA is not a barrier to endovascular treatment. Together, these results provide a deeper understanding of the clinical potential of PGG as a non-surgical treatment of AAA.

This study proposes a machine-learning-based framework for detecting mechanical damage in pipelines, utilizing physics-informed datasets collected from simulations for mechanical damage. The framework provides an effective workflow from dataset generation to damage detection and identification for three types of pipeline events: welds, clamps, and corrosion defects. While the study initially focused on optimizing the CNN structure using various advanced optimizers, it also investigated the impact of sensing systems on data classification and the effect of noise on classification performance. The study's analysis highlights the importance of selecting the appropriate sensing system for the specific application. The authors also found that the proposed framework is robust to experimentally relevant levels of noise, suggesting its applicability in real-world scenarios where noise is present. Overall, this study contributes to the development of a more reliable and effective method for detecting mechanical damage in pipelines. The proposed framework provides an effective workflow for damage detection and identification, and the findings on the impact of sensing systems and noise on classification performance add to its robustness and reliability.

Human behaviour was tipped as the mainstay in the control of further SARS-CoV-2 (COVID-19) spread especially after the lifting of restrictions by many countries. Countries in which restrictions were lifted soon after the first wave, had subsequent waves of the COVID-19 infections and it remains to be seen whether there will be more waves. In this paper, we formulate a deterministic model for COVID-19 incorporating dynamic non-pharmaceutical interventions, dubbed social dynamics. The model steady states are determined and their stability analysed. Numerical simulations are carried out to determine the pack of various parameters that influence the social dynamics. In South Africa, the first wave was the only wave in which the only interventions rested solely on human behavior. The model is thus fitted to COVID-19 data on the first wave in South Africa. The results presented in this paper have implications on the trajectory of the pandemic in the presence of changing social processes.

Integrating photovoltaic (PV) systems plays a pivotal role in the global shift toward renewable energy, offering significant environmental benefits. In many instances, utility companies pay for both energy and peak demand. PV systems can effectively reduce energy consumption during their operational periods, while, their contribution during peak hours, particularly in the early morning and late evening, is often limited. To address this issue, battery storage systems are utilized for storing energy during off-peak hours and releasing it during peak times. However, finding the optimal size of PV-battery systems remains a challenge. This study proposes a novel statistical model to optimize PV-battery system sizing for enhanced peak demand reduction. The model aims to flatten 95% of peak demand days up to a certain demand threshold, ensuring consistent energy supply and financial benefit for utility companies. A straightforward and effective search methodology is employed to determine the optimal system sizes. Additionally, the model effectiveness is rigorously tested through a modified Monte Carlo simulation coupled with time series clustering to generate various scenarios to assess performance under different conditions. The results indicate that the optimal PV-battery system successfully flattens 95% of daily peak demand up to 2000 kW, yielding a financial benefit of $812,648 over 20 years.

A major public health emergency has been created by the COVID-19 pandemic, which is brought on by the SARS-CoV-2 virus. Due to its crucial function in viral replication, the primary protease (Mpro) of the virus is a prime target for therapeutic research. In this study, we used molecular modeling and molecular dynamics simulations to examine the potential therapeutic uses of Mpro inhibitors for the treatment of COVID-19. Using induced fit docking and molecular dynamics simulations, we confirmed the top compounds after screening a library of compounds for their ability to bind to Mpro. Simulation interaction diagrams were used to investigate protein-ligand interactions, and MM-GBSA was used to determine binding energies. The Swiss ADME server was used to predict ADME properties. According to our findings, numerous substances are strong COVID-19 medication candidates since they have excellent ADME features and high binding affinities. This work serves as a foundation for additional experimental research and drug development initiatives aimed at Mpro.

Infectious diseases continue to be a significant threat to human health and civilization, and finding effective methods to combat them is crucial. In this research, we investigate the impact of awareness campaigns and optimal control techniques on infectious diseases without proper vaccines. Specifically, we develop an SIRS type mathematical model that incorporates awareness campaigns through media and treatment for disease transmission dynamics and control. The model displays two equilibria, a disease-free equilibrium and an endemic equilibrium, and exhibits Hopf bifurcation when the bifurcation parameter exceeds its critical value, causing a switch in the stability of the system. We also propose an optimal control problem that minimizes the cost of control measures while achieving a desired level of disease control. By applying the minimum principle to the optimal control problem, we obtain analytical and numerical results that show how the infection rate of the disease affects the stability of the system and how awareness campaigns and treatment can maintain system stability. This study highlights the importance of awareness campaigns in controlling infectious diseases and demonstrates the effectiveness of optimal control theory in achieving disease control with minimal cost.

1D spin crossover (SCO) solids which convert between the low-spin (LS) and the high-spin (HS) states are widely studied in the literature due to their diverse thermal and optical characters which allows obtaining many original behaviors, such as large thermal hysteresis, incomplete spin tran-sitions, as multi-step spin transitions with self-organized states. In the present work, we investigate the thermal behaviors of a system of two-elastically coupled 1D mononuclear chains, using the electro-elastic model, by including an elastic frustration in the nearest neighbors (nn) bond length distances of each chain. The chains are made of SCO sites that are coupled elastically through springs with their nn and next-nearest neighbors. The elastic inter-chain coupling includes diagonal springs, while the nn inter-chains distance is fixed to that of the high-spin state. The model is solved using MC simulations, performed on the spin states and the lattice distortions. When we only frustrate the first chain, we found a strong effect on the thermal-dependence of the HS fraction of the second chain, whose, by lowering its transition temperature which is also accompanied with the appearance of a significant residual HS fraction at low temperature. In the second step, we frustrate both chains by imposing different frustration rates and found that, for high frustration values, the thermal dependence of the total HS fraction exhibits three step and even four step spin transitions. The careful examination of the spin state structures in the plateau regions revealed the existence of special antiferro-elastic structure of type LSLS-HSHS-LSLS-HSHS along the first chain, and HSHS-LSLS-HSHS-LSLS along the second, also showing that the two chains seem to be antifer-ro-elastically coupled. This type of organization is interesting, because it anticipates the possible existence of periodic structures made of alternate 1D antiferro-like HS-LS strings coupled in the ferro-like fashion along the interchain direction in the 2D case.

Macromolecular assemblies, such as protein complexes, undergo continuous structural dynamics, including global reconfigurations critical for their function. Two fast analytical methods are widely used to study these global dynamics, namely elastic network model normal mode analysis and principal component analysis of ensembles of structures. These approaches have found wide use in various computational studies, driving the development of complex pipelines in several software packages. One common one has been conformational sampling through hybrid simulations incorporating all-atom molecular dynamics and global modes of motion. However, wide functionality is only available for experienced programmers with limited capabilities for other users. We have, therefore, integrated one popular and extensively developed software for such analyses, the ProDy Python application programming interface, into the Scipion workflow engine. This enables a wider range of users to access a complete range of macromolecular dynamics pipelines beyond the core functionalities available in its command-line applications and the normal mode wizard in VMD. The new protocols and pipelines can be further expanded and integrated into larger workflows together with other software packages for cryo-electron microscopy image analysis and molecular simulations. We present the resulting plugin, Scipion-EM-ProDy, in detail, highlighting the rich functionality made available by its development.

Hoechst 33342 (H33342) is a fluorescent probe that is commonly used to stain DNA of living cells. To do so, it needs to interact with and permeate through cell membranes. The pH of biological media may vary quite significantly and this influences H33342 ionization state, and may change its rate of permeation through biomembranes. In this work, we address the effect of pH in the association of H33342 with lipid bilayers using a combined experimental and computational approach. The partition of H33342 to 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipid membranes was experimentally quantified using fluorescence spectroscopy and isothermal titration calorimetry (ITC) measurements. Quantum chemical calculations were performed to select the most stable isomer of H33342 for the overall charges 0, +1, and +2, expected to predominate across the 5 < pH < 10 range. The interaction of these isomers with POPC bilayers was then studied by both unrestrained and umbrella sampling molecular dynamics simulations. While probe insertion occurs for all ionization states, with similar overall equilibrium location, orientation was found to depend on the probe charge, with the neutral form lying mostly parallel and the doubly charged displaying a significant tilt relative to the membrane plane. Both experimental results and computational free energy profiles indicate that the partition coefficient of H33342 displays a small variation over a wide pH range, not exceeding one order of magnitude. The enthalpy of interaction is negative and is larger at lower pH values. This suggests efficient hydrogen bonding between the probe and the lipid, namely for the protonated +2 form. The relatively high lipophilicity obtained for the charged species contrasts with the decrease in their general hydrophobicity as estimated from water and octanol partition. This highlights the distinction between lipophilicity and hydrophobicity, and the importance of considering association with lipid bilayers when predicting the affinity for biomembranes.