Is HIV short-sighted? Insights from a multistrain nested model

An important component of pathogen evolution at the population level is evolution within hosts. Unless evolution within hosts is very slow compared to the duration of infection, the composition of pathogen genotypes within a host is likely to change during the course of an infection, thus altering the composition of genotypes available for transmission as infection progresses. We develop a nested modeling approach that allows us to follow the evolution of pathogens at the epidemiological level by explicitly considering within-host evolutionary dynamics of multiple competing strains and the timing of transmission. We use the framework to investigate the impact of short-sighted within-host evolution on the evolution of virulence of human immunodeficiency virus (HIV), and find that the topology of the within-host adaptive landscape determines how virulence evolves at the epidemiological level. If viral reproduction rates increase significantly during the course of infection, the viral population will evolve a high level of virulence even though this will reduce the transmission potential of the virus. However, if reproduction rates increase more modestly, as data suggest, our model predicts that HIV virulence will be only marginally higher than the level that maximizes the transmission potential of the virus

Exact and approximate moment closures for non-Markovian network epidemics

Moment-closure techniques are commonly used to generate low-dimensional deterministic models to approximate the average dynamics of stochastic systems on networks. The quality of such closures is usually difficult to asses and the relationship between model assumptions and closure accuracy are often difficult, if not impossible, to quantify. Here we carefully examine some commonly used moment closures, in particular a new one based on the concept of maximum entropy, for approximating the spread of epidemics on networks by reconstructing the probability distributions over triplets based on those over pairs. We consider various models (SI, SIR, SEIR and Reed-Frost-type) under Markovian and non-Markovian assumption characterising the latent and infectious periods. We initially study two special networks, namely the open triplet and closed triangle, for which we can obtain analytical results. We then explore numerically the exactness of moment closures for a wide range of larger motifs, thus gaining understanding of the factors that introduce errors in the approximations, in particular the presence of a random duration of the infectious period and the presence of overlapping triangles in a network. We also derive a simpler and more intuitive proof than previously available concerning the known result that pair-based moment closure is exact for the Markovian SIR model on tree-like networks under pure initial conditions. We also extend such a result to all infectious models, Markovian and non-Markovian, in which susceptibles escape infection independently from each infected neighbour and for which infectives cannot regain susceptible status, provided the network is tree-like and initial conditions are pure. This works represent a valuable step in deepening understanding of the assumptions behind moment closure approximations and for putting them on a more rigorous mathematical footing.Comment: Main text (45 pages, 11 figures and 3 tables) + supplementary material (12 pages, 10 figures and 1 table). Accepted for publication in Journal of Theoretical Biology on 27th April 201

Real-time growth rate for general stochastic SIR epidemics on unclustered networks

Networks have become an important tool for infectious disease epidemiology. Most previous theoretical studies of transmission network models have either considered simple Markovian dynamics at the individual level, or have focused on the invasion threshold and final outcome of the epidemic. Here, we provide a general theory for early real-time behaviour of epidemics on large configuration model networks (i.e. static and locally unclustered), in particular focusing on the computation of the Malthusian parameter that describes the early exponential epidemic growth. Analytical, numerical and Monte-Carlo methods under a wide variety of Markovian and non-Markovian assumptions about the infectivity profile are presented. Numerous examples provide explicit quantification of the impact of the network structure on the temporal dynamics of the spread of infection and provide a benchmark for validating results of large scale simulations.Comment: 45 pages, 8 figures, submitted to Mathematical Biosciences on 29/11/2014; Version 2: resubmitted on 15/04/2015; accepted on 17/04/2015. Changes: better explanations in introduction; restructured section 3.3 (3.3.3 added); section 6.3.1 added; more precise terminology; typos correcte

Reproduction numbers for epidemic models with households and other social structures II: comparisons and implications for vaccination

In this paper we consider epidemic models of directly transmissible SIR (susceptible - infective - recovered) and SEIR (with an additional latent class) infections in fully-susceptible populations with a social structure, consisting either of households or of households and workplaces. We review most reproduction numbers defined in the literature for these models, including the basic reproduction number R0 introduced in the companion paper of this, for which we provide a simpler, more elegant derivation. Extending previous work, we provide a complete overview of the inequalities among these reproduction numbers and resolve some open questions. Special focus is put on the exponential-growth-associated reproduction number Rr, which is loosely defined as the estimate of R0 based on the observed exponential growth of an emerging epidemic obtained when the social structure is ignored. We show that for the vast majority of the models considered in the literature Rr >= R0 when R0 >=1 and Rr <= R0 when R0 <= 1. We show that, in contrast to models without social structure, vaccination of a fraction 1-1/R0 of the population, chosen uniformly at random, with a perfect vaccine is usually insufficient to prevent large epidemics. In addition, we provide significantly sharper bounds than the existing ones for bracketing the critical vaccination coverage between two analytically tractable quantities, which we illustrate by means of extensive numerical examples

Targets, tactics, and cooperation in the play fighting of two genera of old world monkeys (Mandrillus and Papio): Accounting for similarities and differences

Play fighting in many species involves partners competing to bite one another while avoiding being bitten. Species can differ in the body targets that are bitten and the tactics used to attack and defend those targets. However, even closely related species that attack and defend the same body target using the same tactics can differ markedly in how much the competitiveness of such interactions is mitigated by cooperation. A degree of cooperation is necessary to ensure that some turn-taking between the roles of attacker and defender occurs, as this is critical in preventing play fighting from escalating into serious fighting. In the present study, the dyadic play fighting of captive troops of 4 closely related species of Old World monkeys, 2 each from 2 genera of Papio and Mandrillus, was analyzed. All 4 species have a comparable social organization, are large bodied with considerable sexual dimorphism, and are mostly terrestrial. In all species, the target of biting is the same – the area encompassing the upper arm, shoulder, and side of the neck – and they have the same tactics of attack and defense. However, the Papio species exhibit more cooperation in their play than do the Mandrillus species, with the former using tactics that make biting easier to attain and that facilitate close bodily contact. It is possible that species differences in how rigidly dominance relationships are maintained are expressed in the play of juveniles by altering the balance between competition and cooperation

The Sword of Truth, Tribute Synthesizer Suite

This thesis is by graduate electronic composer Jay Pellis and provides an in depth discussion of composition techniques, music technology processes and notation examples for an original musical work based on Terry Goodkind\u27s epic fantasy The Sword of Truth. Various characters in the text are set to music similar to the leitmotif technique used by operatic and film composers such as Wagner and John Williams. Blind since birth, Jay Pellis used advanced computer software to create this work on a Windows PC. The thesis details the processes used to develop and perform his major work such as: musical computer techniques, sequencing software usage, keyboard synthesizers and an electronic wind controller. This electronic composition was performed live at his graduate recital and submitted as a major composition for a master\u27s degree in music technology/electronic composition. Jay Pellis in addition discusses the expressive freedom music technology provides to a visually impaired musician

Inspiration and mimesis in Plato\u27s criticism of poetry

Plato criticizes poetry in several of his dialogues, beginning with Apology, his first work, and ending with Laws, his last. In these dialogues, his criticism of poetry can be divided into two streams: poetry is criticized for either being divinely inspired, or because it is mimetic or imitative of reality. However, of the dialogues which criticize poetry in these ways, it is not until Laws that Plato mentions both inspiration and mimesis together, and then it is only in a few sentences. Furthermore, nowhere in the dialogues does Plato discuss their relationship. This situation has a parallel in the secondary literature. While much work has been done on inspiration or mimesis in Plato’s criticism of poetry, very little work exists which discusses the connection between them. This study examines Plato’s treatment - in the six relevant dialogues - of these two poetic elements, inspiration and mimesis, and shows that a relationship exists between them. Both can be seen to relate to two important Socratic-Platonic concerns: the care of the soul and the welfare of the state. These concerns represent a synthesis of Socratic moral philosophy with Platonic political beliefs. In the ‘inspiration’ dialogues, Ion, Apology, Meno, Phaedrus and Laws, poetic inspiration can affect the Socratic exhortation which considers the care of the individual soul. Further, as we are told in Apology, Crito and Gorgias, it is the good man, the virtuous man - the one who cares for his soul - who also cares for the welfare of the state. Therefore, in its effect on the individual soul, poetic inspiration can also indirectly affect the state. In the ‘mimesis’ dialogues, Republic and Laws, this same exhortation, on the care of the soul, is posed, but it is has now been rendered into a more Platonic form - as either the principle of specialization - the ‘one man, one job’ creed of Republic, which advances the harmony between the three elements of the soul, or as the concord between reason and emotion in Laws. While in Republic, mimesis can damage the tripartite soul\u27s delicate balance, in Laws, mimesis in poetry is used to promote the concord. Further, in both these dialogues, poetic mimesis can affect the welfare of the state. In Republic, Socrates notes that states arc but a product of the individuals of which they are composed Therefore, by affecting the harmony of the individual soul, mimesis can then undermine the harmony of the state, and an imperfect political system, such as a timarchy, an oligarchy, a democracy, or a tyranny, can result. However, in Laws, when it is harnessed by the philosophical lawgivers, mimesis can assist in the concord between the rulers and the ruled, thus serving the welfare of the state. Inspiration and mimesis can thus be seen to be related in their effect on the education of both the individual, in the care of the soul, and the state, in its welfare. Plato\u27s criticism of poetry, therefore, which is centred on these two features, addresses common Platonic concerns: in education, politics, ethics, epistemology and psychology

Dysfunctional play and dopamine physiology in the Fischer 344 rat

Juvenile Fischer 344 rats are known to be less playful than other inbred strains, although the neurobiological substrate(s) responsible for this phenotype is uncertain. In the present study, Fischer 344 rats were compared to the commonly used outbred Sprague-Dawley strain on several behavioral and physiological parameters in order to ascertain whether the lack of play may be related to compromised activity of brain dopamine (DA) systems. As expected, Fischer 344 rats were far less playful than Sprague-Dawley rats, with Fischer 344 rats less likely to initiate playful contacts with a playful partner and less likely to respond playfully to these contacts. We also found that Fischer 344 rats showed less of a startle response and greater pre-pulse inhibition (PPI), especially at higher prepulse intensities. The increase in PPI seen in the Fischer 344 rat could be due to reduced DA modulation of sensorimotor gating and neurochemical measures were consistent with Fischer 344 rats releasing less DA than Sprague-Dawley rats. Fast scan cyclic voltammetry (FSCV) revealed Fischer 344 rats had less evoked DA release in dorsal and ventral striatal brain slices and high-performance liquid chromatography revealed Fischer 344 rats to have less DA turnover in the striatum and prefrontal cortex. We also found DA-dependent forms of cortical plasticity were deficient in the striatum and prefrontal cortex of the Fischer 344 rat. Taken together, these data indicate that deficits in play and enhanced PPI of Fischer 344 rats may be due to reduced DA modulation of corticostriatal and mesolimbic/mesocortical circuits critical to the execution of these behaviors