Monte Carlo (MC) simulations are the gold standard for describing various transport phenomena and have largely contributed to the understanding of these processes. However, while their implementation for classical transport governed by exponential step-length distributions is well-established, widely accepted approaches are still lacking for the more general class of anomalous transport phenomena. In this work, a set of rules for performing MC simulations in anomalous diffusion media is identified, which is also applicable in the case of finite-size geometries and/or heterogeneous inclusions. The results are presented in the context of radiative transfer, however their implications extend to all types of anomalous transport. The proposed set of rules exhibits full compatibility with the pathlength invariance property for random trajectories, and with the important radiometric concept of fluence. Additionally, it reveals the counter-intuitive possibility of introducing interfaces between independent subdomains with identical properties, which arise from the fact that non-exponential step-length distributions have a "memory" that can in principle be reset when traversing a boundary. These results have far-reaching consequences not just for the physical interpretation of the corrections required to handle these discontinuities, but also for their experimental verification, due to their expected effects on the observable pathlength distributions.

The Omicron wave was the largest wave of COVID-19 pandemic to date, more than doubling any other in terms of cases and hospitalizations in the United States. In this paper, we present a large-scale agent-based model of policy interventions that could have been implemented to mitigate the Omicron wave. Our model takes into account the behaviors of individuals and their interactions with one another within a nationally representative population, as well as the efficacy of various interventions such as social distancing, mask wearing, testing, tracing, and vaccination. We use the model to simulate the impact of different policy scenarios and evaluate their potential effectiveness in controlling the spread of the virus. Our results suggest the Omicron wave could have been substantially curtailed via a combination of interventions comparable in effectiveness to extreme and unpopular singular measures such as widespread closure of schools and workplaces, and highlight the importance of early and decisive action.

Chronic levels of inflammation lead to autoimmune diseases such as rheumatoid arthritis and atherosclerosis. A key molecular mediator responsible for the progression of these diseases is Chemokine C-C motif ligand 2 (CCL2), a homodimerized cytokine that dissociates into monomeric form and binds to the CCR2 receptor. CCL2, also known as monocyte chemoattractant protein-1 (MCP-1), attracts monocytes to migrate to areas of injury and mature into macrophages, leading to positive feedback inflammation with further release of proinflammatory molecules such as IL-1β and TNF-α. Sequestering CCL2 to prevent its binding to CCR2 may prevent this inflammatory activity. Prior work adapted an α-helical CCL2-binding peptide (WKNFQTI) from murine CCR2 through extracellular loop analysis. Here, higher-affinity peptide binders were computationally designed through homology modeling and energy calculations, yielding an 11-amino acid peptide with high binding affinity. In addition, Rosetta mutations improved binding affinity with blockage of the CCL2 dimerization site. Future work in analyzing binding kinetics and inflammation abrogation will confirm the accuracy of computational modeling techniques in rational design of CCL2 cytokine binders.

Our efforts as a society to combat the ongoing COVID-19 pandemic are continuously challenged by the emergence of new variants. These variants can be more infectious than existing strains and many of them are also more resistant to available vaccines. The appearance of these new variants cause new surges of infections, exacerbated by infrastructural difficulties, such as shortages of medical personnel or test kits. In this work, a high-resolution computational framework for modeling the simultaneous spread of two COVID-19 variants: a widely spread base variant and a new one, is established. The computational framework consists of a detailed database of a representative U.S. town and a high-resolution agent-based model that uses the Omicron variant as the base variant and offers flexibility in the incorporation of new variants. The results suggest that the spread of new variants can be contained with highly efficacious tests and mild loss of vaccine protection. However, the aggressiveness of the ongoing Omicron variant and the current waning vaccine immunity point to an endemic phase of COVID-19, in which multiple variants will coexist and residents continue to suffer from infections.

The receptor binding domain (RBD) of SARS-CoV-2 binds to human ACE2 leading to infection. In this study, the complexes that are formed by the attachment of the SARS-CoV-2 spike RBDs of the original strain, delta and omicron variants to the human ACE2 are investigated via density functional theory (DFT) simulations to obtain binding energies. The DFT computations are performed without fragmenting the interfaces to involve longer-range interactions for improved accuracy, which is one of the primary features of the approach used in this study. Basis set superposition error corrections and van der Waals dispersions are also included in the DFT simulations. The binding energies of the SARS-CoV-2 spike RBDs of the original strain, delta and omicron variants to the human ACE2 are computed as -4.76, -6.68, and -11.77 eV, respectively. These binding energy values indicate that the binding of the omicron variant to the ACE2 is much more favorable than the binding of the original strain and the delta variant, which constitute a molecular reason for the takeover of the omicron variant. The binding energies and the decomposition of these energies found in this study are expected to aid in the development of neutralizing agents.

The potential waning of the vaccination immunity to COVID-19 could pose threats to public health, as it is tenable that the timing of such waning would synchronize with the near-complete restoration of normalcy. Should also testing be relaxed, a resurgent COVID-19 wave in winter 2021/2022 might be witnessed. In response to this risk, an additional vaccine dose, the booster shot, is being administered worldwide. A projected study with an outlook of 6 months explores the interplay between the rate at which boosters are distributed and the extent to which testing practices are implemented, using a highly granular agent-based model tuned on a medium-sized US town. Theoretical projections indicate that the administration of boosters at the rate at which the vaccine is currently administered could yield a severe resurgence of the pandemic. Projections suggest that the peak levels of mid-spring 2021 in the vaccination rate may prevent such a scenario to occur, although exact agreement between observations and projections should not be expected due to the continuously evolving nature of the pandemic. This study highlights the importance of testing, especially to detect asymptomatic individuals in the near future, as the release of the booster reaches full speed.

The COVID-19 pandemic has caused a dramatic surge in demand for personal protective equipment (PPE) worldwide. Many countries have imposed export restrictions on PPE to ensure the sufficient domestic supply. The surging demand and export restrictions cause shortage contagions on the global PPE trade network. Here, an integrated network model is developed, which integrates a metapopulation model and a threshold model, to investigate the shortage contagion patterns. The metapopulation model captures disease contagion across countries. The threshold model captures the shortage contagion on the global PPE trade network. Due to the Pareto distribution in global exports, the shortage contagion pattern is mainly determined by the export restriction policies of the top exporters. Export restrictions exacerbate the shortages of PPE and cause the shortage contagion to transmit even faster than the disease contagion. To some extent, export restrictions can provide benefits for self-sufficient countries, at the sacrifice of immediate economic shocks at not-self-sufficient countries. With export restrictions, a large amount of PPE is hoarded instead of being distributed to where it is most needed, particularly at the early stage. Cooperation between countries plays an essential role in preventing global shortages of PPE regardless of the production level. Except for promoting global cooperation, governments and international organizations should take actions to reduce supply chain barriers and work together to increase global PPE production.

The COVID-19 pandemic has infected over 250 million people worldwide and killed more than 5 million as of November 2021. Many intervention strategies are utilized (e.g., masks, social distancing, vaccinations), but officials making decisions have a limited time to act. Computer simulations can aid them by predicting future disease outcomes, but they also require significant processing power or time. It is examined whether a machine learning model can be trained on a small subset of simulation runs to inexpensively predict future disease trajectories resembling the original simulation results. Using four previously published agent-based models (ABMs) for COVID-19, a decision tree regression for each ABM is built and its predictions are compared to the corresponding ABM. Accurate machine learning meta-models are generated from ABMs without strong interventions (e.g., vaccines, lockdowns) using small amounts of simulation data: the root-mean-square error (RMSE) with 25% of the data is close to the RMSE for the full dataset (0.15 vs 0.14 in one model; 0.07 vs 0.06 in another). However, meta-models for ABMs employing strong interventions require much more training data (at least 60%) to achieve a similar accuracy. In conclusion, machine learning meta-models can be used in some scenarios to assist in faster decision-making.

SARS-CoV-2 is what has caused the COVID-19 pandemic. Early viral infection is mediated by the SARS-CoV-2 homo-trimeric Spike (S) protein with its receptor binding domains (RBDs) in the receptor-accessible state. Molecular dynamics simulation on the S protein with a focus on the function of its -terminal domains (NTDs) is performed. The study reveals that the NTD acts as a "wedge" and plays a crucial regulatory role in the conformational changes of the S protein. The complete RBD structural transition is allowed only when the neighboring NTD that typically prohibits the RBD's movements as a wedge detaches and swings away. Based on this NTD "wedge" model, it is proposed that the NTD-RBD interface should be a potential drug target.

As COVID-19 vaccine is being rolled out in the US, public health authorities are gradually reopening the economy. To date, there is no consensus on a common approach among local authorities. Here, a high-resolution agent-based model is proposed to examine the interplay between the increased immunity afforded by the vaccine roll-out and the transmission risks associated with reopening efforts. The model faithfully reproduces the demographics, spatial layout, and mobility patterns of the town of New Rochelle, NY - representative of the urban fabric of the US. Model predictions warrant caution in the reopening under the current rate at which people are being vaccinated, whereby increasing access to social gatherings in leisure locations and households at a 1% daily rate can lead to a 28% increase in the fatality rate within the next three months. The vaccine roll-out plays a crucial role on the safety of reopening: doubling the current vaccination rate is predicted to be sufficient for safe, rapid reopening.

A recent work indicates that temporarily splitting larger populations into smaller groups can efficiently mitigate the spread of SARS-CoV-2 virus. The fact that, soon afterward, the two million people Slovenia was the first European country proclaiming the end of COVID-19 epidemic within national borders may be relevant from this perspective. Motivated by this evolution, in this paper the time dynamics of coronavirus cases in Slovenia is investigated with emphasis on how efficient various containment measures act to diminish the number of COVID-19 infections. Noteworthily, the present analysis does not rely on any speculative theoretical assumption; it is solely based on raw epidemiological data. Out of the results presented here, the most important one is perhaps the finding that, while imposing drastic curfews and travel restrictions reduce the infection rate κ by a factor of four with respect to the unrestricted state, they only improve the κ-value by ≈15% as compared to the much bearable state of social and economic life wherein wearing face masks and social distancing rules are enforced/followed. Significantly for behavioral and social science, our analysis may reveal an interesting self-protection instinct of the population, which became manifest even before the official lockdown enforcement.

The new COVID-19 pandemic has challenged policymakers on key issues. Most countries have adopted "lockdown" policies to reduce the spatial spread of COVID-19, but they have damaged the economic and moral fabric of society. Mathematical modeling in non-pharmaceutical intervention policy management has proven to be a major weapon in this fight due to the lack of an effective COVID-19 vaccine. A new hybrid model for COVID-19 dynamics using both an age-structured mathematical model based on the SIRD model and spatio-temporal model in silico is presented, analyzing the data of COVID-19 in Israel. Using the hybrid model, a method for estimating the reproduction number of an epidemic in real-time from the data of daily notification of cases is introduced. The results of the proposed model are confirmed by the Israeli Lockdown experience with a mean square error of 0.205 over 2 weeks. The use of mathematical models promises to reduce the uncertainty in the choice of "Lockdown" policies. The unique use of contact details from 2 classes (children and adults), the interaction of populations depending on the time of day, and several physical locations, allow a new look at the differential dynamics of the spread and control of infection.

All-atom simulations of various antibodies bound to the receptor-binding domain (RBD) of the spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are performed. Binding free energies calculated from umbrella sampling simulations show the strong binding between SARS-CoV-2 RBDs and antibodies, in agreement with recent experiments. Binding strengths of antibodies slightly differ, as further confirmed by calculating solvent accessible surface areas. Polar uncharged residues of RBD more predominantly bind to antibodies than do charged or hydrophobic residues of RBD. In particular, the binding between RBD and antibody is more significantly stabilized by multivalent hydrogen bonds of RBD residues (≈406th-505th) than by locally formed hydrogen bonds of only a few RBD residues (≈417th-487th or ≈487th-505th). Hydrogen-bond analyses reveal key residues of RBD for strong hydrogen-bond interactions between RBDs and antibodies, which help in the rational design of vaccine and drug molecules targeting the S protein of SARS-CoV-2.

Amid the ongoing COVID-19 pandemic, public health authorities and the general population are striving to achieve a balance between safety and normalcy. Ever changing conditions call for the development of theory and simulation tools to finely describe multiple strata of society while supporting the evaluation of "what-if" scenarios. Particularly important is to assess the effectiveness of potential testing approaches and vaccination strategies. Here, an agent-based modeling platform is proposed to simulate the spreading of COVID-19 in small towns and cities, with a single-individual resolution. The platform is validated on real data from New Rochelle, NY-one of the first outbreaks registered in the United States. Supported by expert knowledge and informed by reported data, the model incorporates detailed elements of the spreading within a statistically realistic population. Along with pertinent functionality such as testing, treatment, and vaccination options, the model accounts for the burden of other illnesses with symptoms similar to COVID-19. Unique to the model is the possibility to explore different testing approaches-in hospitals or drive-through facilities-and vaccination strategies that could prioritize vulnerable groups. Decision-making by public authorities could benefit from the model, for its fine-grain resolution, open-source nature, and wide range of features.

Since 2020, COVID-19 has wreaked havoc across the planet, taking the lives of more than one million people. The uncertainty and novelty of the current conditions call for the development of theory and simulation tools that can support effective policy-making. In article number 2000277, Agnieszka Truszkowska, Maurizio Porfiri, and co-workers report a high-resolution, agent-based modeling platform to simulate the spreading of COVID-19 in the city of New Rochelle, NY-one of the first outbreaks registered in the United States. Image by Anna Sawulska, Agnieszka Truszkowska, Beata Truszkowska, and Maurizio Porfiri.

The COVID-19 pandemic in a population modelled as a network wherein infection can propagate both via intra- and inter-group interactions is simulated. The results emphasize the importance of diminishing the inter-group infections in the effort of substantial flattening/delaying of the epi(demiologic) curve with concomitant mitigation of disastrous economy and social consequences. To exemplify, splitting a population into (say, 5 or 10) noninteracting groups while keeping intra-group interaction unchanged yields a stretched epidemiological curve having the maximum number of daily infections reduced and postponed in time by the same factor (5 or 10). More generally, the study suggests a practical approach to fight against SARS- CoV- 2 virus spread based on population splitting into groups and minimizing intermingling between them. This strategy can be pursued by large-scale infrastructure reorganization of activity at different levels in big logistic units (e.g., large productive networks, factories, enterprises, warehouses, schools, (seasonal) harvest work). Importantly, unlike total lockdown, the proposed approach prevents economic ruin and keeps social life at a more bearable level than distancing everyone from anyone. The declaration for the first time in Europe that COVID-19 epidemic ended in the two-million population Slovenia may be taken as support for the strategy proposed here.

The SARS-CoV-2 virus is currently causing a worldwide pandemic with dramatic societal consequences for the humankind. In the past decades, disease outbreaks due to such zoonotic pathogens have appeared with an accelerated rate, which calls for an urgent development of adaptive (smart) therapeutics. Here, a computational strategy is developed to adaptively evolve peptides that could selectively inhibit mutating S protein receptor binding domains (RBDs) of different SARS-CoV-2 viral strains from binding to their human host receptor, angiotensin-converting enzyme 2 (ACE2). Starting from suitable peptide templates, based on selected ACE2 segments (natural RBD binder), the templates are gradually modified by random mutations, while retaining those mutations that maximize their RBD-binding free energies. In this adaptive evolution, atomistic molecular dynamics simulations of the template-RBD complexes are iteratively perturbed by the peptide mutations, which are retained under favorable Monte Carlo decisions. The computational search will provide libraries of optimized therapeutics capable of reducing the SARS-CoV-2 infection on a global scale.

The beautiful interplay between light and matter can give rise to many striking physical phenomena, surface plasmon resonance (SPR) being one of them. Plasmonic immunosensors monitor refractive index changes that occur as a result of specific ligand-analyte or antibody-antigen interactions taking place on the sensor surface. The coronavirus disease (COVID-19) pandemic has jeopardized the entire world and has resulted in economic slowdown of most countries. In this work, a model of a sandwich plasmonic biosensor that utilizes gold nanorods (Au NRs) for the detection of COVID-19 SARS-CoV-2 spike protein is presented. Simulation results for different prismatic configurations for the basic Kretschmann layout are presented. It is found that a BK7 glass prism-based SPR sensor has an incremental sensitivity of 111.11 deg RIU. Additionally, using Comsol Multiphysics the electric field enhancement observed for various aspect ratios and layouts of Au NRs are discussed in depth.

The COVID-19 virus has been recently identified as a new species of virus that can cause severe infections such as pneumonia. The sudden outbreak of this disease is being considered a pandemic. Given all this, it is essential to develop smart biosensors that can detect pathogens with minimum time delay. Surface plasmon resonance (SPR) biosensors make use of refractive index (RI) changes as the sensing parameter. In this work, based on actual data taken from previous experimental works done on plasmonic detection of viruses, a detailed simulation of the SPR scheme that can be used to detect the COVID-19 virus is performed and the results are extrapolated from earlier schemes to predict some outcomes of this SPR model. The results indicate that the conventional Kretschmann configuration can have a limit of detection (LOD) of 2E-05 in terms of RI change and an average sensitivity of 122.4 degRIU at a wavelength of 780 nm.

A systematic and statistically robust protocol is applied for the evaluation of free energy calculations with and without replica-exchange. The protocol is based on ensemble averaging to generate accurate assessments of the uncertainties in the predictions. Comparison is made between FEP+ and TIES-free energy perturbation and thermodynamic integration with enhanced sampling-the latter with and without the so-called "enhanced sampling" based on replica-exchange protocols. Standard TIES performs best for a reference set of targets and compounds; no benefits accrue from replica-exchange methods. Evaluation of FEP+ and TIES with REST-replica-exchange with solute tempering-reveals a systematic and significant underestimation of free energy differences in FEP+, which becomes increasingly large for long duration simulations, is confirmed by extensive analysis of previous publications, and raises a number of questions pertaining to the accuracy of the predictions with the REST technique not hitherto discussed.

Over the past two decades, the use of fragment-based lead generation has become a common, mature approach to identify tractable starting points in chemical space for the drug discovery process. This approach naturally involves the study of the binding properties of highly heterogeneous ligands. Such datasets challenge computational techniques to provide comparable binding free energy estimates from different binding modes. The performance of a range of statistically robust ensemble-based binding free energy calculation protocols, called ESMACS (enhanced sampling of molecular dynamics with approximation of continuum solvent), is evaluated. Ligands designed to target two binding pockets in the lactate dehydogenase, a target protein, which vary in size, charge, and binding mode, are studied. When compared to experimental results, excellent statistical rankings are obtained across this highly diverse set of ligands. In addition, three approaches to account for entropic contributions are investigated: 1) normal mode analysis, 2) weighted solvent accessible surface area (WSAS), and 3) variational entropy. Normal mode analysis and WSAS correlate strongly with each other-although the latter is computationally far cheaper-but do not improve rankings. Variational entropy corrects exaggerated discrimination of ligands bound in different pockets but creates three outliers which reduce the quality of the overall ranking.