Continuous Time Graph Processes with Known ERGM Equilibria: Contextual Review, Extensions, and Synthesis.

Graph processes that unfold in continuous time are of obvious theoretical and practical interest. Particularly useful are those whose long-term behavior converges to a graph distribution of known form. Here, we review some of the conditions for such convergence, and provide examples of novel and/or known processes that do so. These include subfamilies of the well-known stochastic actor oriented models, as well as continuum extensions of temporal and separable temporal exponential family random graph models. We also comment on some related threads in the broader work on network dynamics, which provide additional context for the continuous time case. Graph processes that unfold in continuous time are natural models for social network dynamics: able to directly represent changes in structure as they unfold (rather than, e.g. as snapshots at discrete intervals), such models not only offer the promise of capturing dynamics at high temporal resolution, but are also easily mapped to empirical data without the need to preselect a level of granularity with respect to which the dynamics are defined. Although relatively few general frameworks of this type have been extensively studied, at least one (the stochastic actor-oriented models, or SAOMs) is arguably among the most successful and widely used families of models in the social sciences (see, e.g., Snijders (2001); Steglich et al. (2010); Burk et al. (2007); Sijtsema et al. (2010); de la Haye et al. (2011); Weerman (2011); Schaefer and Kreager (2020) among many others). Work using other continuous time graph processes has also found applications both within (Koskinen and Snijders, 2007; Koskinen et al., 2015; Stadtfeld et al., 2017; Hoffman et al., 2020) and beyond (Grazioli et al., 2019; Yu et al., 2020) the social sciences, suggesting the potential for further advances.

Spatially resolved detection of small molecules from press-dried plant tissue using MALDI imaging.

Premise: Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) is a chemical imaging method that can visualize spatial distributions of particular molecules. Plant tissue imaging has so far mostly used cryosectioning, which can be impractical for the preparation of large-area imaging samples, such as full flower petals. Imaging unsectioned plant tissue presents its own difficulties in extracting metabolites to the surface due to the waxy cuticle. Methods: We address this by using established delipidation techniques combined with a solvent vapor extraction prior to applying the matrix with many low-concentration sprays. Results: Using this procedure, we imaged tissue from three different plant species (two flowers and one carnivorous plant leaf). Material factorization analysis of the resulting data reveals a wide range of plant-specific small molecules with varying degrees of localization to specific portions of the tissue samples, while facilitating detection and removal of signal from background sources. Conclusions: This work demonstrates applicability of MALDI-MSI to press-dried plant samples without freezing or cryosectioning, setting the stage for spatially resolved molecule identification. Increased mass resolution and inclusion of tandem mass spectrometry are necessary next steps to allow more specific and reliable compound identification.

Premisa: Matrix­assisted laser desorption/ionization mass spectrometry imaging (MALDI­MSI) es un método de imagen química que puede visualizar distribuciones espaciales de moléculas particulares. Hasta ahora, las imágenes de tejido vegetal han utilizado principalmente la criosección, lo cual puede ser poco práctico para la preparación de muestras de imágenes con áreas grandes, tales como los pétalos completos de una flor. La obtención de imágenes de tejido vegetal no seccionado presenta sus propias dificultades durante la extracción de metabolitos a la superficie, debido a la cutícula cerosa de la planta. Métodos: Abordamos esto usando técnicas establecidas de deslipidación combinados con una extracción de vapor por solvente antes de aplicar por aspersión la matriz en bajas concentraciones. Resultados: Usando este procedimiento, obtuvimos imágenes de tejido de tres especies de plantas diferentes (dos flores y una hoja de planta carnívora). Análisis de factorización material de los datos obtenidos revelaron una amplia gama de pequeñas moléculas específicas en plantas con diversos grados de localización en porciones específicas de las muestras de tejido, al igual que facilitó la detección y remoción de las señales de fondo. Conclusión: Nuestro trabajo demuestra la aplicabilidad de MALDI­MSI hacía muestras de plantas secadas a presión sin congelación o criosección, creando el marco para la identificación de moléculas resueltas espacialmente. Aumento de la resolución de masas e inclusión de la espectrometría de masas en tándem son pasos necesarios para obtener identificación de compuestos más específica y confiable.

Comparative Modeling and Analysis of Extremophilic D-Ala-D-Ala Carboxypeptidases.

Understanding the molecular adaptations of organisms to extreme environments requires a comparative analysis of protein structure, function, and dynamics across species found in different environmental conditions. Computational studies can be particularly useful in this pursuit, allowing exploratory studies of large numbers of proteins under different thermal and chemical conditions that would be infeasible to carry out experimentally. Here, we perform such a study of the MEROPS family S11, S12, and S13 proteases from psychophilic, mesophilic, and thermophilic bacteria. Using a combination of protein structure prediction, atomistic molecular dynamics, and trajectory analysis, we examine both conserved features and trends across thermal groups. Our findings suggest a number of hypotheses for experimental investigation.

Network Hamiltonian Models for Unstructured Protein Aggregates, with Application to γD-Crystallin.

Network Hamiltonian models (NHMs) are a framework for topological coarse-graining of protein-protein interactions, in which each node corresponds to a protein, and edges are drawn between nodes representing proteins that are noncovalently bound. Here, this framework is applied to aggregates of γD-crystallin, a structural protein of the eye lens implicated in cataract disease. The NHMs in this study are generated from atomistic simulations of equilibrium distributions of wild-type and the cataract-causing variant W42R in solution, performed by Wong, E. K.; Prytkova, V.; Freites, J. A.; Butts, C. T.; Tobias, D. J. Molecular Mechanism of Aggregation of the Cataract-Related γD-Crystallin W42R Variant from Multiscale Atomistic Simulations. Biochemistry2019, 58 (35), 3691-3699. Network models are shown to successfully reproduce the aggregate size and structure observed in the atomistic simulation, and provide information about the transient protein-protein interactions therein. The system size is scaled from the original 375 monomers to a system of 10000 monomers, revealing a lowering of the upper tail of the aggregate size distribution of the W42R variant. Extrapolation to higher and lower concentrations is also performed. These results provide an example of the utility of NHMs for coarse-grained simulation of protein systems, as well as their ability to scale to large system sizes and high concentrations, reducing computational costs while retaining topological information about the system.

Mutation Effects on Structure and Dynamics: Adaptive Evolution of the SARS-CoV-2 Main Protease.

The main protease of SARS-CoV-2 (Mpro) plays a critical role in viral replication; although it is relatively conserved, Mpro has nevertheless evolved over the course of the COVID-19 pandemic. Here, we examine phenotypic changes in clinically observed variants of Mpro, relative to the originally reported wild-type enzyme. Using atomistic molecular dynamics simulations, we examine effects of mutation on protein structure and dynamics. In addition to basic structural properties such as variation in surface area and torsion angles, we use protein structure networks and active site networks to evaluate functionally relevant characters related to global cohesion and active site constraint. Substitution analysis shows a continuing trend toward more hydrophobic residues that are dependent on the location of the residue in primary, secondary, tertiary, and quaternary structures. Phylogenetic analysis provides additional evidence for the impact of selective pressure on mutation of Mpro. Overall, these analyses suggest evolutionary adaptation of Mpro toward more hydrophobicity and a less-constrained active site in response to the selective pressures of a novel host environment.

Privacy by Projection: Federated Population Density Estimation by Projecting on Random Features.

We consider the problem of population density estimation based on location data crowdsourced from mobile devices, using kernel density estimation (KDE). In a conventional, centralized setting, KDE requires mobile users to upload their location data to a server, thus raising privacy concerns. Here, we propose a Federated KDE framework for estimating the user population density, which not only keeps location data on the devices but also provides probabilistic privacy guarantees against a malicious server that tries to infer users' location. Our approach Federated random Fourier feature (RFF) KDE leverages a random feature representation of the KDE solution, in which each user's information is irreversibly projected onto a small number of spatially delocalized basis functions, making precise localization impossible while still allowing population density estimation. We evaluate our method on both synthetic and real-world datasets, and we show that it achieves a better utility (estimation performance)-vs-privacy (distance between inferred and true locations) tradeoff, compared to state-of-the-art baselines (e.g., GeoInd). We also vary the number of basis functions per user, to further improve the privacy-utility trade-off, and we provide analytical bounds on localization as a function of areal unit size and kernel bandwidth.

Highly scalable maximum likelihood and conjugate Bayesian inference for ERGMs on graph sets with equivalent vertices.

The exponential family random graph modeling (ERGM) framework provides a highly flexible approach for the statistical analysis of networks (i.e., graphs). As ERGMs with dyadic dependence involve normalizing factors that are extremely costly to compute, practical strategies for ERGMs inference generally employ a variety of approximations or other workarounds. Markov Chain Monte Carlo maximum likelihood (MCMC MLE) provides a powerful tool to approximate the maximum likelihood estimator (MLE) of ERGM parameters, and is generally feasible for typical models on single networks with as many as a few thousand nodes. MCMC-based algorithms for Bayesian analysis are more expensive, and high-quality answers are challenging to obtain on large graphs. For both strategies, extension to the pooled case-in which we observe multiple networks from a common generative process-adds further computational cost, with both time and memory scaling linearly in the number of graphs. This becomes prohibitive for large networks, or cases in which large numbers of graph observations are available. Here, we exploit some basic properties of the discrete exponential families to develop an approach for ERGM inference in the pooled case that (where applicable) allows an arbitrarily large number of graph observations to be fit at no additional computational cost beyond preprocessing the data itself. Moreover, a variant of our approach can also be used to perform Bayesian inference under conjugate priors, again with no additional computational cost in the estimation phase. The latter can be employed either for single graph observations, or for observations from graph sets. As we show, the conjugate prior is easily specified, and is well-suited to applications such as regularization. Simulation studies show that the pooled method leads to estimates with good frequentist properties, and posterior estimates under the conjugate prior are well-behaved. We demonstrate the usefulness of our approach with applications to pooled analysis of brain functional connectivity networks and to replicated x-ray crystal structures of hen egg-white lysozyme.

Geographical patterns of social cohesion drive disparities in early COVID infection hazard.

The uneven spread of COVID-19 has resulted in disparate experiences for marginalized populations in urban centers. Using computational models, we examine the effects of local cohesion on COVID-19 spread in social contact networks for the city of San Francisco, finding that more early COVID-19 infections occur in areas with strong local cohesion. This spatially correlated process tends to affect Black and Hispanic communities more than their non-Hispanic White counterparts. Local social cohesion thus acts as a potential source of hidden risk for COVID-19 infection.

Insight into Selecting Adolescents for Drinking Intervention Programs: a Simulation Based on Stochastic Actor-Oriented Models.

Adolescent drinking remains a prominent public health and socioeconomic issue in the USA with costly consequences. While numerous drinking intervention programs have been developed, there is little guidance whether certain strategies of participant recruitment are more effective than others. The current study aims at addressing this gap in the literature using a computer simulation approach, a more cost-effective method than employing actual interventions. We first estimate stochastic actor-oriented models for two schools from the National Longitudinal Study of Adolescent to Adult Health (Add Health). We then employ different strategies for selecting adolescents for the intervention (either based on their drinking levels or their positions in the school network) and simulate the estimated model forward in time to assess the aggregated level of drinking in the school at a later time point. The results suggest that selecting moderate or heavy drinkers for the intervention produces better results compared to selecting casual or light drinkers. The intervention results are improved further if network position information is taken into account, as selecting drinking adolescents with higher in-degree or higher eigenvector centrality values for intervention yields the best results. Results from this study help elucidate participant selection criteria and targeted network intervention strategies for drinking intervention programs in the USA.

The Moderating Role of Context: Relationships between Individual Behaviors and Social Networks.

A social context can be viewed as an entity or unit around which a group of individuals organize their activities and interactions. Social contexts take such diverse forms as families, dwelling places, neighborhoods, classrooms, schools, workplaces, voluntary organizations, and sociocultural events or milieus. Understanding social contexts is essential for the study of individual behaviors, social networks, and the relationships between the two. Contexts shape individual behaviors by providing an avenue for non-dyadic conformity and socialization processes. The co-participation within a context affects personal relationships by acting as a focus for tie formation. Where participation in particular contexts confers status, this effect may also lead to differences in popularity within interpersonal networks. Social contexts may further play a moderating role in within-network influence and selection processes, providing circumstances that either amplify or suppress these effects. In this paper we investigate the joint role of co-participation via social contexts and dyadic interaction in shaping and being shaped by individual behaviors with the context of a U.S. high school. Implications for future study of social contexts are suggested.

Neural Upscaling from Residue-Level Protein Structure Networks to Atomistic Structures.

Coarse-graining is a powerful tool for extending the reach of dynamic models of proteins and other biological macromolecules. Topological coarse-graining, in which biomolecules or sets thereof are represented via graph structures, is a particularly useful way of obtaining highly compressed representations of molecular structures, and simulations operating via such representations can achieve substantial computational savings. A drawback of coarse-graining, however, is the loss of atomistic detail-an effect that is especially acute for topological representations such as protein structure networks (PSNs). Here, we introduce an approach based on a combination of machine learning and physically-guided refinement for inferring atomic coordinates from PSNs. This "neural upscaling" procedure exploits the constraints implied by PSNs on possible configurations, as well as differences in the likelihood of observing different configurations with the same PSN. Using a 1 µs atomistic molecular dynamics trajectory of Aß1-40, we show that neural upscaling is able to effectively recapitulate detailed structural information for intrinsically disordered proteins, being particularly successful in recovering features such as transient secondary structure. These results suggest that scalable network-based models for protein structure and dynamics may be used in settings where atomistic detail is desired, with upscaling employed to impute atomic coordinates from PSNs.

Bayesian estimation of the hydroxyl radical diffusion coefficient at low temperature and high pressure from atomistic molecular dynamics.

The hydroxyl radical is the primary reactive oxygen species produced by the radiolysis of water and is a significant source of radiation damage to living organisms. Mobility of the hydroxyl radical at low temperatures and/or high pressures is hence a potentially important factor in determining the challenges facing psychrophilic and/or barophilic organisms in high-radiation environments (e.g., ice-interface or undersea environments in which radiative heating is a potential heat and energy source). Here, we estimate the diffusion coefficient for the hydroxyl radical in aqueous solution using a hierarchical Bayesian model based on atomistic molecular dynamics trajectories in TIP4P/2005 water over a range of temperatures and pressures.

Bayesian analysis of static light scattering data for globular proteins.

Static light scattering is a popular physical chemistry technique that enables calculation of physical attributes such as the radius of gyration and the second virial coefficient for a macromolecule (e.g., a polymer or a protein) in solution. The second virial coefficient is a physical quantity that characterizes the magnitude and sign of pairwise interactions between particles, and hence is related to aggregation propensity, a property of considerable scientific and practical interest. Estimating the second virial coefficient from experimental data is challenging due both to the degree of precision required and the complexity of the error structure involved. In contrast to conventional approaches based on heuristic ordinary least squares estimates, Bayesian inference for the second virial coefficient allows explicit modeling of error processes, incorporation of prior information, and the ability to directly test competing physical models. Here, we introduce a fully Bayesian model for static light scattering experiments on small-particle systems, with joint inference for concentration, index of refraction, oligomer size, and the second virial coefficient. We apply our proposed model to study the aggregation behavior of hen egg-white lysozyme and human γS-crystallin using in-house experimental data. Based on these observations, we also perform a simulation study on the primary drivers of uncertainty in this family of experiments, showing in particular the potential for improved monitoring and control of concentration to aid inference.

A cyclic peptide inhibitor of the SARS-CoV-2 main protease.

This paper presents the design and study of a first-in-class cyclic peptide inhibitor against the SARS-CoV-2 main protease (Mpro). The cyclic peptide inhibitor is designed to mimic the conformation of a substrate at a C-terminal autolytic cleavage site of Mpro. The cyclic peptide contains a [4-(2-aminoethyl)phenyl]-acetic acid (AEPA) linker that is designed to enforce a conformation that mimics a peptide substrate of Mpro. In vitro evaluation of the cyclic peptide inhibitor reveals that the inhibitor exhibits modest activity against Mpro and does not appear to be cleaved by the enzyme. Conformational searching predicts that the cyclic peptide inhibitor is fairly rigid, adopting a favorable conformation for binding to the active site of Mpro. Computational docking to the SARS-CoV-2 Mpro suggests that the cyclic peptide inhibitor can bind the active site of Mpro in the predicted manner. Molecular dynamics simulations provide further insights into how the cyclic peptide inhibitor may bind the active site of Mpro. Although the activity of the cyclic peptide inhibitor is modest, its design and study lays the groundwork for the development of additional cyclic peptide inhibitors against Mpro with improved activities.

Cutting Through the Noise: Predictors of Successful Online Message Retransmission in the First 8 Months of the COVID-19 Pandemic.

In this paper, we investigate how message construction, style, content, and the textual content of embedded images impacted message retransmission over the course of the first 8 months of the coronavirus disease 2019 (COVID-19) pandemic in the United States. We analyzed a census of public communications (n = 372,466) from 704 public health agencies, state and local emergency management agencies, and elected officials posted on Twitter between January 1 and August 31, 2020, measuring message retransmission via the number of retweets (ie, a message passed on by others), an important indicator of engagement and reach. To assess content, we extended a lexicon developed from the early months of the pandemic to identify key concepts within messages, employing it to analyze both the textual content of messages themselves as well as text included within embedded images (n = 233,877), which was extracted via optical character recognition. Finally, we modelled the message retransmission process using a negative binomial regression, which allowed us to quantify the extent to which particular message features amplify or suppress retransmission, net of controls related to timing and properties of the sending account. In addition to identifying other predictors of retransmission, we show that the impact of images is strongly driven by content, with textual information in messages and embedded images operating in similar ways. We offer potential recommendations for crafting and deploying social media messages that can "cut through the noise" of an infodemic.

A multi-contextual examination of non-school friendships and their impact on adolescent deviance and alcohol use.

Despite decades of research on adolescent friendships, little is known about adolescents who are more likely to form ties outside of school. We examine multiple social and ecological contexts including parents, the school, social networks, and the neighborhood to understand the origins and health significance of out of school ties using survey data from the National Longitudinal Study of Adolescent to Adult Health (N = 81,674). Findings indicate that out of school (more than in-school) friendships drive adolescent deviance and alcohol use, and youth with such friends tend to be involved in school activities and are central among their peer group. This suggests that intervention efforts aimed at reducing deviance and underage drinking may benefit from engaging youth with spanning social ties.

#Ebola: Emergency Risk Messages on Social Media.

Public health threats require effective communication. Evaluating effectiveness during a situation that requires emergency risk communication is difficult, however, because these events require an immediate response and collecting data may be secondary to more immediate needs. In this article, we draw on research analyzing the effectiveness of social media messages during times of imminent threat and research analyzing the emergency risk communication conceptual model in order to propose a method for evaluating emergency risk communication on social media. We demonstrate this method by evaluating 2,915 messages sent by local, state, and federal public health officials during the 2014 Ebola outbreak in the United States. The results provide empirical support for emergency risk communication and identify message strategies that have the potential to increase exposure to official communication on social media during future public health threats.

The First 60 Days: American Public Health Agencies' Social Media Strategies in the Emerging COVID-19 Pandemic.

In this paper, we capture, identify, and describe the patterns of longitudinal risk communication from public health communicating agencies on Twitter during the first 60 days of the response to the novel coronavirus disease 2019 (COVID-19) pandemic. We collected 138,546 tweets from 696 targeted accounts from February 1 to March 31, 2020, employing term frequency-inverse document frequency to identify keyword hashtags that were distinctive on each day. Our team conducted inductive content analysis to identify emergent themes that characterize shifts in public health risk communication efforts. As a result, we found 7 distinct periods of communication in the first 60 days of the pandemic, each characterized by a differing emphasis on communicating information, individual and collection action, sustaining motivation, and setting social norms. We found that longitudinal risk communication in response to the COVID-19 pandemic shifted as secondary threats arose, while continuing to promote pro-social activities to reduce impact on vulnerable populations. Identifying patterns of risk communication longitudinally allows public health communicators to observe changes in topics and priorities. Observations from the first 60 days of the COVID-19 pandemic prefigures ongoing messaging needs for this event and for future disease outbreaks.

Network Hamiltonian models reveal pathways to amyloid fibril formation.

Amyloid fibril formation is central to the etiology of a wide range of serious human diseases, such as Alzheimer's disease and prion diseases. Despite an ever growing collection of amyloid fibril structures found in the Protein Data Bank (PDB) and numerous clinical trials, therapeutic strategies remain elusive. One contributing factor to the lack of progress on this challenging problem is incomplete understanding of the mechanisms by which these locally ordered protein aggregates self-assemble in solution. Many current models of amyloid deposition diseases posit that the most toxic species are oligomers that form either along the pathway to forming fibrils or in competition with their formation, making it even more critical to understand the kinetics of fibrillization. A recently introduced topological model for aggregation based on network Hamiltonians is capable of recapitulating the entire process of amyloid fibril formation, beginning with thousands of free monomers and ending with kinetically accessible and thermodynamically stable amyloid fibril structures. The model can be parameterized to match the five topological classes encompassing all amyloid fibril structures so far discovered in the PDB. This paper introduces a set of network statistical and topological metrics for quantitative analysis and characterization of the fibrillization mechanisms predicted by the network Hamiltonian model. The results not only provide insight into different mechanisms leading to similar fibril structures, but also offer targets for future experimental exploration into the mechanisms by which fibrils form.

COVID-19: Retransmission of official communications in an emerging pandemic.

As the most visible face of health expertise to the general public, health agencies have played a central role in alerting the public to the emerging COVID-19 threat, providing guidance for protective action, motivating compliance with health directives, and combating misinformation. Social media platforms such as Twitter have been a critical tool in this process, providing a communication channel that allows both rapid dissemination of messages to the public at large and individual-level engagement. Message dissemination and amplification is a necessary precursor to reaching audiences, both online and off, as well as inspiring action. Therefore, it is valuable for organizational risk communication to identify strategies and practices that may lead to increased message passing among online users. In this research, we examine message features shown in prior disasters to increase or decrease message retransmission under imminent threat conditions to develop models of official risk communicators' messages shared online from February 1, 2020-April 30, 2020. We develop a lexicon of keywords associated with risk communication about the pandemic response, then use automated coding to identify message content and message structural features. We conduct chi-square analyses and negative binomial regression modeling to identify the strategies used by official risk communicators that respectively increase and decrease message retransmission. Findings show systematic changes in message strategies over time and identify key features that affect message passing, both positively and negatively. These results have the potential to aid in message design strategies as the pandemic continues, or in similar future events.