Uncertainty quantification and sensitivity analysis of COVID-19 exit strategies in an individual-based transmission model

Many countries are currently dealing with the COVID-19 epidemic and are searching for an exit strategy such that life in society can return to normal. To support this search, computational models are used to predict the spread of the virus and to assess the efficacy of policy measures before actual implementation. The model output has to be interpreted carefully though, as computational models are subject to uncertainties. These can stem from, e.g., limited knowledge about input parameters values or from the intrinsic stochastic nature of some computational models. They lead to uncertainties in the model predictions, raising the question what distribution of values the model produces for key indicators of the severity of the epidemic. Here we show how to tackle this question using techniques for uncertainty quantification and sensitivity analysis. We assess the uncertainties and sensitivities of four exit strategies implemented in an agent-based transmission model with geographical stratification. The exit strategies are termed Flattening the Curve, Contact Tracing, Intermittent Lockdown and Phased Opening. We consider two key indicators of the ability of exit strategies to avoid catastrophic health care overload: the maximum number of prevalent cases in intensive care (IC), and the total number of IC patient-days in excess of IC bed capacity. Our results show that uncertainties not directly related to the exit strategies are secondary, although they should still be considered in comprehensive analysis intended to inform policy makers. The sensitivity analysis discloses the crucial role of the intervention uptake by the population and of the capability to trace infected individuals. Finally, we explore the existence of a safe operating space. For Intermittent Lockdown we find only a small region in the model parameter space where the key indicators of the model stay within safe bounds, whereas this region is larger for the other exit strategies.     

Technical Critique of the Multimedia,Multipathway, Multireceptor Risk Assessment Model

The U.S. Environmental Protection Agency (USEPA) is developing the Multimedia, Multipathway, Multireceptor Risk Assessment (3MRA) model to evaluate potential human and ecological risks associated with the disposal of solid wastes designated as hazardous wastes in nonhazardous waste management units. USEPA intends to use the 3MRA model to determine national exit levels that will allow solid wastes that theoretically pose acceptable human and ecological risks to be safely managed in Subtitle D nonhazardous waste management units. We critically evaluated the 3MRA model to determine whether the methodology, interim modules, and input parameters are appropriate and scientifically defensible. Overall, our review of the 3MRA model indicates that it contains many conservative assumptions that may limit the validity of the model results and its use as a national model adequate for making regulatory decisions. Many of the assumptions and data inputs used to model the pathways involved in the transport of chemicals from a waste management unit are flawed. Other specific concerns include the lack of model validation, incompatibility of data between modules, and overestimation of potential human and ecological exposures. Before using the 3MRA model, we recommend that USEPA consider whether the 3MRA model is either an appropriate or accurate tool for evaluating the disposal of hazardous wastes nationwide.     

Morphology of the antennary gland exit duct in ecological and phylogenetic series of talitroid Amphipoda (Crustacea)

The form of the proximal segments of antenna two peduncle and of the antennary gland exit duct on peduncle article two has been examined in 16 species of amphipod crustaceans (including 14 species of Talitridae). Gammarus duebeni (Gammaridae), regarded as exemplifying the norm for aquatic amphipods, has a very distinctive fluted exit duct emanating from a pronounced gland cone. The talitroid Hyale nilssoni was regarded as a typical representative of the hyalid-like ancestors of the Talitridae. It also has a gland cone, but the exit duct of the antennary gland is a thin-walled, collapsible cone. The two proximal articles of antenna two peduncle are much reduced in Talitridae. Only the second may retain a degree of mobility. No gland cone remains. The structure of the urinary exit duct in seven species of simplidactylate landhoppers (Bousfield's Gp IVa) was very similar to the hyalid condition. Beachfleas (Gp II) have strengthened, often sculpted ducts. whilst sandhoppers (Gp III) have no protruding exit duct at all. Only one species of Gp IVb (cuspidactylate) landhopper ( Tasmanorchestia sp.) was investigated and it has an exit duct similar in form to that of the beachfleas (Gp II). Neorchestia plicibranchiata (a Gp IVa species), however, already known to be an anomalous species, has unusually elongate urinary ducts (for a Gp IVa species). These observations lend support to the notion that the landhoppers are a polyphyletic grouping and that the sandhoppers are a very isolated ecomorphological grouping within the family.     

Virtual patients and sensitivity analysis of the guyton model of blood pressure regulation: towards individualized models of whole-body physiology

Mathematical models that integrate multi-scale physiological data can offer insight into physiological and pathophysiological function, and may eventually assist in individualized predictive medicine. We present a methodology for performing systematic analyses of multi-parameter interactions in such complex, multi-scale models. Human physiology models are often based on or inspired by Arthur Guyton's whole-body circulatory regulation model. Despite the significance of this model, it has not been the subject of a systematic and comprehensive sensitivity study. Therefore, we use this model as a case study for our methodology. Our analysis of the Guyton model reveals how the multitude of model parameters combine to affect the model dynamics, and how interesting combinations of parameters may be identified. It also includes a "virtual population" from which "virtual individuals" can be chosen, on the basis of exhibiting conditions similar to those of a real-world patient. This lays the groundwork for using the Guyton model for in silico exploration of pathophysiological states and treatment strategies. The results presented here illustrate several potential uses for the entire dataset of sensitivity results and the "virtual individuals" that we have generated, which are included in the supplementary material. More generally, the presented methodology is applicable to modern, more complex multi-scale physiological models.     

容器形状和出口位置对台湾乳白蚁逃遁行为的影响(英文)

【目的】逃离危险对集群生活的动物来说是一项重要挑战。白蚁是真社会性昆虫,群体密度较大。因此,白蚁可能进化出了特殊的策略集体逃离危险情境。【方法】本研究比较了实验室条件下台湾乳白蚁Coptotermes formosanus工蚁在不同形状容器(没有出口的圆形和方形容器)的逃遁行为,并调查了在有出口的情况下,台湾乳白蚁工蚁从圆形容器边缘、方形容器直角处和方形容器直角边中间的撤离效 率。【结果】在没有出口的情况下,受惊的台湾乳白蚁立即移动到圆形或方形容器的边缘区域并沿着容器的壁移动。然而,在方形容器的直角处,逃遁的台湾乳白蚁工蚁形成明显的堵塞(直角附近的白蚁密度显著高于其他区域,而移动速度显著低于其他区域的白蚁)。当容器上有出口时,大部分台湾乳白蚁工蚁分散在容器边缘,因此在出口位置周围未发现明显的堵塞。有趣的是,台湾乳白蚁工蚁逃出有出口的圆形容器的时间与从出口在直角附近的方形容器的无显著差异,但其从出口在直角边中间的方形容器的逃出时间更长。【结论】研究结果表明容器形状与出口位置均对台湾乳白蚁工蚁的逃遁行为与撤离效率造成影响。此外,白蚁使用了特殊的策略来避免多见于其他群居动物(如人类、小鼠等)的“快即慢”效应。由于白蚁工蚁没有视觉,研究白蚁的逃遁策略可为人群如何高效撤离可视度较低的危险环境提供启示。     

Optimal population stabilization and control using the Leslie matrix model

We consider the problem of optimal stabilization and control of populations which follow the Leslie model dynamics, within state space and control systems theory and methodology. Various types of culling strategies are formulated and introduced into the Leslie model as control inputs, and their effect on global asymptotic stability is investigated. Our new approach provides answers to several unexplored problems. We show that in general it is possible to achieve a desired stable equilibrium population level, through the design of a class ofshifted-proportional stabilizing culling policies. Further, we formulate general non-linear constrained opitmization problems, for obtaining the cost-optimal policy among this generally infinite class of such stabilizing policies. The theoretical findings are illustrated through the solution of the problem over an infinite planning horizon for a numerical example. A comparative study of the costs and dynamic effects of various culling strategies also supports the mathematical results.     

Qualitative analysis of the all-cause black-white mortality crossover

To date, despite decades of investigations and the relative abundance of mortality data, our understanding of the phenomenon of ‘mortality crossover’ remains inadequate. We propose a methodology for transforming mortality data from the ‘age-domain’ to the ‘time-domain’. We then introduce a model of selection partially offset by mobility, to simulate the dynamics of vulnerability in a population cohort that is heterogeneous in health and death. Using our model of vulnerability simulating the dynamics of mortality in the time-domain, we compare the mortality experience of the Black and White populations of the United States, identify the significance of selection and mobility as potential factors producing the crossover phenomenon, and make diagnostic use of them.     

Thermal regime,predation danger and the early marine exit of sockeye salmon Oncorhynchus nerka

Marine exit timing of sockeye salmon Oncorhynchus nerka populations on the Haida Gwaii Archipelago, British Columbia, Canada, is described, with specific focus on Copper Creek. Marine exit in Copper Creek occurs > 130 days prior to spawning, one of the longest adult freshwater residence periods recorded for any O. nerka population. Copper Creek presents an easy upstream migration, with mild water temperatures (7 to 14° C), short distance (13·1 km) and low elevation gain (41 m) to the lake where fish hold prior to spawning. An energetic model estimates that <1% of the initial energy reserve is required for upstream migration, compared with 62% for lake holding and 38% for reproductive development. Historical records suggest that it is unlikely that water temperature in any of the O.nerka streams in Haida Gwaii has ever exceeded the presumed temperature threshold (19° C) for early marine exit. Although it is not impossible that the thermal tolerance of Copper Creek O.nerka is very low, the data presented here appear inconsistent with thermal avoidance as an explanation for the early marine exit timing in Copper Creek and in three other populations on the archipelago with early marine exit.     

A trans-membrane segment inside the ribosome exit tunnel triggers RAMP4 recruitment to the Sec61p translocase

Membrane protein integration occurs predominantly at the endoplasmic reticulum and is mediated by the translocon, which is formed by the Sec61p complex. The translocon binds to the ribosome at the polypeptide exit site such that integration occurs in a cotranslational manner. Ribosomal protein Rpl17 is positioned such that it contacts both the ribosome exit tunnel and the surface of the ribosome near the exit site, where it is intimately associated with the translocon. The presence of a trans-membrane (TM) segment inside the ribosomal exit tunnel leads to the recruitment of RAMP4 to the translocon at a site adjacent to Rpl17. This suggests a signaling function for Rpl17 such that it can recognize a TM segment inside the ribosome and triggers rearrangements of the translocon, priming it for subsequent TM segment integration.     

Prison Break: Pathogens' Strategies To Egress from Host Cells

Summary: A wide spectrum of pathogenic bacteria and protozoa has adapted to an intracellular life-style, which presents several advantages, including accessibility to host cell metabolites and protection from the host immune system. Intracellular pathogens have developed strategies to enter and exit their host cells while optimizing survival and replication, progression through the life cycle, and transmission. Over the last decades, research has focused primarily on entry, while the exit process has suffered from neglect. However, pathogen exit is of fundamental importance because of its intimate association with dissemination, transmission, and inflammation. Hence, to fully understand virulence mechanisms of intracellular pathogens at cellular and systemic levels, it is essential to consider exit mechanisms to be a key step in infection. Exit from the host cell was initially viewed as a passive process, driven mainly by physical stress as a consequence of the explosive replication of the pathogen. It is now recognized as a complex, strategic process termed “egress,” which is just as well orchestrated and temporally defined as entry into the host and relies on a dynamic interplay between host and pathogen factors. This review compares egress strategies of bacteria, pathogenic yeast, and kinetoplastid and apicomplexan parasites. Emphasis is given to recent advances in the biology of egress in mycobacteria and apicomplexans.     

Enabling methodology for the end functionalization of glycosaminoglycan oligosaccharides

The chemical functionalization of glycosaminoglycans is very challenging due to their structural heterogeneity and polyanionic character; but as an enabling technology it promises rich rewards in terms of the structural and biological data it will afford. This review surveys the known methods for the preparation of glycosaminoglycan oligosaccharides and conditions for the selective functionalization of both the reducing and non-reducing ends. The synthetic merits of each approach are discussed, together with the structural modification of the glycosaminoglycan oligosaccharide which they confer. Recent applications of this methodology are highlighted, including introduction of functional labels for gel mobility shift assays and NMR studies of glycosaminoglycan-protein complexes, and synthesis of immobilised glycosaminoglycan arrays.     

Optimal individualized dosing strategies: A pharmacologic approach to developing dynamic treatment regimens for continuous‐valued treatments

There have been considerable advances in the methodology for estimating dynamic treatment regimens, and for the design of sequential trials that can be used to collect unconfounded data to inform such regimens. However, relatively little attention has been paid to how such methodology could be used to advance understanding of optimal treatment strategies in a continuous dose setting, even though it is often the case that considerable patient heterogeneity in drug response along with a narrow therapeutic window may necessitate the tailoring of dosing over time. Such is the case with warfarin, a common oral anticoagulant. We propose novel, realistic simulation models based on pharmacokinetic‐pharmacodynamic properties of the drug that can be used to evaluate potentially optimal dosing strategies. Our results suggest that this methodology can lead to a dosing strategy that performs well both within and across populations with different pharmacokinetic characteristics, and may assist in the design of randomized trials by narrowing the list of potential dosing strategies to those which are most promising.     

Activation mobilizes the cholesterol in the late endosomes-lysosomes of Niemann Pick type C cells

A variety of intercalating amphipaths increase the chemical activity of plasma membrane cholesterol. To test whether intracellular cholesterol can be similarly activated, we examined NPC1 and NPC2 fibroblasts, since they accumulate large amounts of cholesterol in their late endosomes and lysosomes (LE/L). We gauged the mobility of intracellular sterol from its appearance at the surface of the intact cells, as determined by its susceptibility to cholesterol oxidase and its isotope exchange with extracellular 2-(hydroxypropyl)-β-cyclodextrin-cholesterol. The entire cytoplasmic cholesterol pool in these cells was mobile, exchanging with the plasma membrane with an apparent half-time of ～3-4 hours, ～4-5 times slower than that for wild type human fibroblasts (half-time ～0.75 hours). The mobility of the intracellular cholesterol was increased by the membrane-intercalating amphipaths chlorpromazine and 1-octanol. Chlorpromazine also promoted the net transfer of LE/L cholesterol to serum and cyclodextrin. Surprisingly, the mobility of LE/L cholesterol was greatly stimulated by treating intact NPC cells with glutaraldehyde or formaldehyde. Similar effects were seen with wild type fibroblasts in which the LE/L cholesterol pool had been expanded using U18666A. We also showed that the cholesterol in the intracellular membranes of fixed wild-type fibroblasts was mobile; it was rapidly oxidized by cholesterol oxidase and was rapidly replenished by exogenous sterol. We conclude that a) the cholesterol in NPC cells can exit the LE/L (and the extensive membranous inclusions therein) over a few hours; b) this mobility is stimulated by the activation of the cholesterol with intercalating amphipaths; c) intracellular cholesterol is even more mobile in fixed cells; and d) amphipaths that activate cholesterol might be useful in treating NPC disease.     

Severe hindrance of viral infection propagation in spatially extended hosts

The production of large progeny numbers affected by high mutation rates is a ubiquitous strategy of viruses, as it promotes quick adaptation and survival to changing environments. However, this situation often ushers in an arms race between the virus and the host cells. In this paper we investigate in depth a model for the dynamics of a phenotypically heterogeneous population of viruses whose propagation is limited to two-dimensional geometries, and where host cells are able to develop defenses against infection. Our analytical and numerical analyses are developed in close connection to directed percolation models. In fact, we show that making the space explicit in the model, which in turn amounts to reducing viral mobility and hindering the infective ability of the virus, connects our work with similar dynamical models that lie in the universality class of directed percolation. In addition, we use the fact that our model is a multicomponent generalization of the Domany-Kinzel probabilistic cellular automaton to employ several techniques developed in the past in that context, such as the two-site approximation to the extinction transition line. Our aim is to better understand propagation of viral infections with mobility restrictions, e.g., in crops or in plant leaves, in order to inspire new strategies for effective viral control.     

SHER: A Colored Petri Net Based Random Mobility Model for Wireless Communications

In wireless network research, simulation is the most imperative technique to investigate the network’s behavior and validation. Wireless networks typically consist of mobile hosts; therefore, the degree of validation is influenced by the underlying mobility model, and synthetic models are implemented in simulators because real life traces are not widely available. In wireless communications, mobility is an integral part while the key role of a mobility model is to mimic the real life traveling patterns to study. The performance of routing protocols and mobility management strategies e.g. paging, registration and handoff is highly dependent to the selected mobility model. In this paper, we devise and evaluate the Show Home and Exclusive Regions (SHER), a novel two-dimensional (2-D) Colored Petri net (CPN) based formal random mobility model, which exhibits sociological behavior of a user. The model captures hotspots where a user frequently visits and spends time. Our solution eliminates six key issues of the random mobility models, i.e., sudden stops, memoryless movements, border effect, temporal dependency of velocity, pause time dependency, and speed decay in a single model. The proposed model is able to predict the future location of a mobile user and ultimately improves the performance of wireless communication networks. The model follows a uniform nodal distribution and is a mini simulator, which exhibits interesting mobility patterns. The model is also helpful to those who are not familiar with the formal modeling, and users can extract meaningful information with a single mouse-click. It is noteworthy that capturing dynamic mobility patterns through CPN is the most challenging and virulent activity of the presented research. Statistical and reachability analysis techniques are presented to elucidate and validate the performance of our proposed mobility model. The state space methods allow us to algorithmically derive the system behavior and rectify the errors of our proposed model.     

Ion mobility-mass spectrometry analysis of large protein complexes

Here we describe a detailed protocol for both data collection and interpretation with respect to ion mobility-mass spectrometry analysis of large protein assemblies. Ion mobility is a technique that can separate gaseous ions based on their size and shape. Specifically, within this protocol, we cover general approaches to data interpretation, methods of predicting whether specific model structures for a given protein assembly can be separated by ion mobility, and generalized strategies for data normalization and modeling. The protocol also covers basic instrument settings and best practices for both observation and detection of large noncovalent protein complexes by ion mobility-mass spectrometry.     

Mobility strategies and the importance of community ties: former pulp and paper workers in Miramichi,New Brunswick

This article explores how global shifts in capital, production, the labor market, and its segmentation relate to mobility strategies and community ties in a specific local context. Mobility strategies or the refusal to be mobile are, at times, used in order to maintain households in communities that have seen their labor market constrict. Decisions about mobility are not purely about economic rationality. In the mobility strategies employed by former pulp and paper workers from Miramichi, New Brunswick, Canada, resistance to mobility is due to community and familial ties to place. Such local commitments may take precedence over, but are clearly impacted by, the ever-shifting tides of global capital.     

Analysis of the mitotic exit control system using locked levels of stable mitotic cyclin

Cyclin‐dependent kinase (Cdk) both promotes mitotic entry (spindle assembly and anaphase) and inhibits mitotic exit (spindle disassembly and cytokinesis), leading to an elegant quantitative hypothesis that a single cyclin oscillation can function as a ratchet to order these events. This ratchet is at the core of a published ODE model for the yeast cell cycle. However, the ratchet model requires appropriate cyclin dose–response thresholds. Here, we test the inhibition of mitotic exit in budding yeast using graded levels of stable mitotic cyclin (Clb2). In opposition to the ratchet model, stable levels of Clb2 introduced dose‐dependent delays, rather than hard thresholds, that varied by mitotic exit event. The ensuing cell cycle was highly abnormal, suggesting a novel reason for cyclin degradation. Cdc14 phosphatase antagonizes Clb2–Cdk, and Cdc14 is released from inhibitory nucleolar sequestration independently of stable Clb2. Thus, Cdc14/Clb2 balance may be the appropriate variable for mitotic regulation. Although our results are inconsistent with the aforementioned ODE model, revision of the model to allow Cdc14/Clb2 balance to control mitotic exit corrects these discrepancies, providing theoretical support for our conclusions.     

Cdc14 Early Anaphase Release,FEAR, Is Limited to the Nucleus and Dispensable for Efficient Mitotic Exit

Cdc14 phosphatase is a key regulator of exit from mitosis, acting primarily through antagonism of cyclin-dependent kinase, and is also thought to be important for meiosis. Cdc14 is released from its sequestration site in the nucleolus in two stages, first by the non-essential Cdc Fourteen Early Anaphase Release (FEAR) pathway and later by the essential Mitotic Exit Network (MEN), which drives efficient export of Cdc14 to the cytoplasm. We find that Cdc14 is confined to the nucleus during early mitotic anaphase release, and during its meiosis I release. Proteins whose degradation is directed by Cdc14 as a requirement for mitotic exit (e.g. the B-type cyclin, Clb2), remain stable during mitotic FEAR, a result consistent with Cdc14 being restricted to the nucleus and not participating directly in mitotic exit. Cdc14 released by the FEAR pathway has been proposed to have a wide variety of activities, all of which are thought to promote passage through anaphase. Proposed functions of FEAR include stabilization of anaphase spindles, resolution of the rDNA to allow its segregation, and priming of the MEN so that mitotic exit can occur promptly and efficiently. We tested the model for FEAR functions using the FEAR-deficient mutation net1-6cdk. Our cytological observations indicate that, contrary to the current model, FEAR is fully dispensable for timely progression through a series of anaphase landmarks and mitotic exit, although it is required for timely rDNA segregation. The net1-6cdk mutation suppresses temperature-sensitive mutations in MEN genes, suggesting that rather than activating mitotic exit, FEAR either inhibits the MEN or has no direct effect upon it. One interpretation of this result is that FEAR delays MEN activation to ensure that rDNA segregation occurs before mitotic exit. Our findings clarify the distinction between FEAR and MEN-dependent Cdc14 activities and will help guide emerging quantitative models of this cell cycle transition.