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It is well established that sexual conflict can drive an endless coevolutionary chase between the sexes potentially leading to genetic divergence of isolated populations and allopatric speciation. We present a simple mathematical model that shows that sexual conflict over mating rate can result in two other general regimes. First, rather than ''running away'' from males, females can diversify genetically into separate groups, effectively ''trapping'' the males in the middle at a state characterized by reduced mating success. Female diversification brings coevolutionary chase to the end. Second, under certain conditions, males respond to female diversification by diversifying themselves. This response results in the formation of reproductively isolated clusters of genotypes that emerge sympatrically. Sexual conflict occurs when characteristics that enhance the fitness components of one sex reduce the fitness of the other sex. Numerous examples of sexual conflict resulting from the costs of mating, polyspermy, and sensory exploitation have been discussed in detail (1-11). For example, peptides contained in the seminal fluids of Drosophila melanogaster males increase female death rate (3), mating in bed bugs results in severe physical harm to females (9), and if more than one sperm fertilizes an egg, the egg usually dies (11). These detrimental effects of mating on female (or egg) fitness components can be reduced by females evolving resistance to male (or sperm) preand postmating manipulations (6). The potential for coevolution because of sexual conflict recently has been evaluated experimentally by using laboratory Drosophila populations (12-14), as well as by using comparative studies of insects (15, 16) and mathematical models (1,7,(17)(18)(19)(20). With respect to speciation, previous discussions have emphasized that sexual conflict drives an endless coevolutionary chase between the sexes and leads to the genetic divergence of isolated populations and allopatric speciation (6,7,11,21,22). This verbal reasoning has been supported recently by a mathematical model (17) demonstrating that coevolutionary chase between the sexes occurs under a range of conditions. That previous model used a standard Gaussian approximation for the distributions of male and female traits in the population. Here, in contrast, we make no a priori assumptions about the population distributions. By using a simple, explicit genetic model, we show that sexual conflict over mating rate can result in two other general regimes (which could not exist within the realm of the Gaussian approximation). First, rather than evolving away from males, females can diversify genetically and split into separate clusters, effectively ''trapping'' the males in the middle at a state characterized by low mating success. Second, under certain conditions, males themselves can split into separate groups that subsequently chase different female clusters. As a result, the population becomes subdivided into reproductively isolated groups that emerge sympatrically.

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Adaptive Dynamics is an approach to studying evolutionary change when fitness is density or frequency dependent. Modern papers identifying themselves as using this approach first appeared in the 1990s, and have greatly increased up to the present. However, because of the rather technical nature of many of the papers, the approach is not widely known or understood by evolutionary biologists. In this review we aim to remedy this situation by outlining the methodology and then examining its strengths and weaknesses. We carry this out by posing and answering 20 key questions on Adaptive Dynamics. We conclude that Adaptive Dynamics provides a set of useful approximations for studying various evolutionary questions. However, as with any approximate method, conclusions based on Adaptive Dynamics are valid only under some restrictions that we discuss.

Conventional cytotoxic cancer chemotherapy is often immunosuppressive and associated with drug resistance and tumor regrowth after a short period of tumor shrinkage or growth stasis. However, certain cytotoxic cancer chemotherapeutic drugs, including doxorubicin, mitoxantrone, and cyclophosphamide, can kill tumor cells by an immunogenic cell death pathway, which activates robust innate and adaptive anti-tumor immune responses and has the potential to greatly increase the efficacy of chemotherapy. Here, we review studies on chemotherapeutic drug-induced immunogenic cell death, focusing on how the choice of a conventional cytotoxic agent and its dose and schedule impact anti-tumor immune responses. We propose a strategy for effective immunogenic chemotherapy that employs a modified metronomic schedule for drug delivery, which we term medium-dose intermittent chemotherapy (MEDIC). Striking responses have been seen in preclinical cancer models using MEDIC, where an immunogenic cancer chemotherapeutic agent is administered intermittently and at an intermediate dose, designed to impart strong and repeated cytotoxic damage to tumors, and on a schedule compatible with activation of a sustained anti-tumor immune response, thereby maximizing anti-cancer activity. We also discuss strategies for combination chemo-immunotherapy, and we outline approaches to identify new immunogenic chemotherapeutic agents for drug development.

. In this work we consider the geometrical model of R. A. Fisher, in which individuals are characterized by a number of phenotypic characters under optimizing selection. Recent work on this model by H. A. Orr has demonstrated that as the number of characters increases, there is a significant reduction in the rate of adaptation. Orr has dubbed this a “cost of complexity.” Although there is little evidence as to whether such a cost applies in the natural world, we suggest that the prediction is surprising, at least naively. With this in mind, we examine the robustness of Orr's prediction by modifiying the model in various ways that might reduce or remove the cost. In particular, we explore the suggestion that modular pleiotropy, in which mutations affect only a subset of the traits, could play an important role. We conclude that although modifications of the model can mitigate the cost to a limited extent, Orr's finding is robust.

Sex differences in pituitary growth hormone (GH) secretion (pulsatile in males vs near continuous/persistent in females) impart sex-dependent expression to hundreds of genes in adult mouse liver. Signal transducer and activator of transcription (STAT) 5, a GH-activated transcription factor that is essential for liver sexual dimorphism, is dynamically activated in direct response to each male plasma GH pulse. However, the impact of GH-induced STAT5 pulses on liver chromatin accessibility and downstream transcriptional events is unknown. In this study, we investigated the impact of a single pulse of GH given to hypophysectomized mice on local liver chromatin accessibility (DNase hypersensitive site analysis), transcription rates (heterogeneous nuclear RNA analysis), and gene expression (quantitative polymerase chain reaction and RNA sequencing) determined 30, 90, or 240 minutes later. The STAT5-dependent but sex-independent early GH response genes Igf1 and Cish showed rapid, GH pulse-induced increases in chromatin accessibility and gene transcription, reversing the effects of hypophysectomy. Rapid increases in liver chromatin accessibility and transcriptional activity were also induced in hypophysectomized male mice for some (Ces2b, Ugt2b38) but not for other liver STAT5-dependent male-biased genes (Cyp7b1). Moreover, in pituitary-intact male mice, Igf1, Cish, Ces2b, and Ugt2b38 all showed remarkable cycles of chromatin opening and closing, as well as associated cycles of induced gene transcription, which closely followed each endogenous pulse of liver STAT5 activity. Thus, the endogenous rhythms of male plasma GH pulsation dynamically open and then close liver chromatin at discrete, localized regulatory sites in temporal association with transcriptional activation of Igf1, Cish, and a subset of STAT5-dependent male-biased genes.