Theoretical studies of diverse sexual patterns in marine animals.

Marine animals show diverse and flexible sexual systems. Here, we review several advancements of theoretical studies made in the last decade. (i) Sex change in coral fishes is often accompanied by a long break in reproductive activity. The delay can be shortened by retaining the inactive gonad for the opposite sex. (ii) Barnacles adopt diverse sexual patterns. The game model was analysed assuming that newly settled larvae choose either growth or immediate reproduction and large individuals adjust male-female investments. (iii) Some parasitic barnacles produce larvae with sexual size dimorphism and others produce larvae with the sex determined after settlement on hosts. (iv) In some fish and many reptiles, sex is determined by the temperature experienced as eggs. The dynamics of sex hormones were studied when the enzymatic reaction rates were followed by the Arrhenius equation. The FMF pattern (male at intermediates temperature; female both at high and low temperatures) required some reactions with enhanced temperature dependence at higher temperatures. The game model provides a useful framework for understanding diverse sexual patterns if we incorporate various constraints, such as unpredictability, cost of trait change and social situations. For further developments, we need to consider constraints imposed by physiological and molecular mechanisms.

[Long-Term Survival of an Adolescent and Young Adult Patient with Unresectable Advanced Gastric Cancer in Whom Multidisciplinary Treatment Was Effective].

We report the case of a long-term-surviving adolescent and young adult patient with unresectable advanced gastric cancer for whom multidisciplinary treatment was effective. A 29-year-old woman was referred to our hospital for further examination following a diagnosis of gastric cancer by a local physician. Esophagogastroduodenoscopy showed a deep ulcerated lesion in the lower third of the stomach, and analysis of biopsy specimens revealed an adenocarcinoma. Abdominal contrast- enhanced computed tomography showed gastric wall thickening in the lower third of the stomach. The patient underwent distal gastrectomy with lymph node dissection, including resection of localized peritoneal metastases, followed by Roux-en- Y reconstruction. The pathological diagnosis was serosa-invading poorly differentiated adenocarcinoma with 1 lymph node metastasis measuring 6.0×5.5 cm in the posterior wall of the lower third of the stomach and negative immunohistochemical staining for human epidermal growth factor receptor 2. The patient received postoperative chemotherapy with S-1 and oxaliplatin. She developed bilateral ovarian metastases measuring 13.0 cm and 7.8 cm after 17 months. The patient presented with severe lower abdominal pain and underwent an emergency bilateral ovarian metastasectomy, which revealed torsion of the right ovarian tumor, which had twisted twice on its pedicle, and a left ovarian mass. After the operation, 41 courses of ramucirumab with nab-paclitaxel were administered as a second-line treatment, and she received systemic drug treatment. Sixty months after the gastrectomy, the patient developed left hydronephrosis due to peritoneal metastases and was treated with nivolumab after ureteral stent replacement. No effective treatment was proposed in cancer multigene panel testing, and she died 66 months after the initial treatment because of disease progression. Comprehensive multidisciplinary treatment, including surgical and local therapy for peritoneal dissemination based on drug therapy for unresectable advanced gastric cancer, may result in long-term survival. Further research and accumulation of such cases would lead to the development of novel treatments.

Evolution of male nuptial gift and female remating: A quantitative genetic model.

In some species of separate sexes, males present a nuptial gift containing nutrition to their mate. Producing a large nuptial gift is a considerable cost to the male, but it may improve his siring success if the female reduces the likelihood to accept another male after receiving a large gift. The female may receive a direct benefit by accepting another male who provides an additional nuptial gift. Additionally, the female may receive an indirect fitness benefit via laying offspring sired by a male who is able to produce a large nuptial gift. We formalized the multivariate quantitative genetics model describing the coevolution of the size of nuptial gift produced by the male (x) and the female's propensity to engage in remating (y). We analyzed the model focusing two cases: [1] remating females receive no indirect fitness benefit, but enjoy direct benefit of nutrition; and [2] remating females receive no direct benefit, but enjoy an indirect fitness benefit due to a positive genetic correlation of x and y, which is possible if random mutations tend to make males produce small nuptial gifts. In both cases, the stable evolutionary equilibrium with neither nuptial gift nor remating (x-=y-=0) always exists. Another stable equilibrium may exist in which male produces nuptial gifts (x->0) and female engage in multiple mating (y->0). We discussed implications to the sexual conflict.

Optimal composition of chloride cells for osmoregulation in a randomly fluctuating environment.

Fish live in water with a different osmotic pressure from that in the body. Their gills have chloride cells that transport ions to maintain an appropriate level of osmotic pressure in the body. The direction of ion transport is different between seawater and freshwater. There are two types of chloride cells that specialize in unidirectional transport and generalist cells that can switch their function quickly in response to environmental salinity. In species that experience salinity changes throughout life (euryhaline species), individuals may replace some chloride cells with cells of different types upon a sudden change in environmental salinity. In this paper, we develop a dynamic optimization model for the chloride cell composition of an individual living in an environment with randomly fluctuating salinity. The optimal solution is to minimize the sum of the workload of chloride cells in coping with the difference in osmotic pressure, the maintenance cost, and the temporal cost due to environmental change. The optimal fraction of generalist chloride cells increases with the frequency of salinity changes and the time needed for new cells to be fully functional but decreases with excess maintenance cost.

Evolutionary game of life-cycle types in marine benthic invertebrates: Feeding larvae versus nonfeeding larvae versus direct development.

Many marine invertebrates have a benthic adult life with planktonic long feeding larval stages (planktotrophy). In other species, planktonic larvae do not eat, and after a rather short period, they settle and initiate their benthic stages (lecithotrophy). Still other species skip planktonic larval stages altogether, and adults produce benthic offspring (direct development). In this paper, we develop an evolutionary game among different life-cycle types and examine the conditions for each life-cycle type to win in a seasonal environment. The growth rate and mortality of benthic individuals are the same among all three life-cycle types, the local habitat (patches) for benthic individuals have a finite longevity, and adults may engage in a limited dispersal just before breeding. Planktotrophy evolves if the planktonic stages are more efficient in terms of biomass gain than benthic life. Otherwise, lecithotrophy or direct development should evolve. Among them, direct development is more advantageous than lecithotrophy if the cost of having planktonic larvae is large, the habitat for benthic individuals is stable, and adults engage in some dispersal.

Evolutionary game in an androdioecious population: Coupling of outcrossing and male production.

Androdioecy, the coexistence of hermaphrodites and males, is very rare in vertebrates but occurs in mangrove killifish living in ephemeral or unstable habitats. Hermaphrodites reproduce both by outcrossing with males and by selfing. Outbreeding is advantageous because of inbreeding depression, but it requires encounters with males. The advantages of a propensity for outcrossing among hermaphrodites and the production of males affect each other very strongly. To study the evolutionary coupling of these two aspects, we here analyze a simple evolutionary game for a population composed of three phenotypes: outcrossing-oriented hermaphrodites, selfing-oriented hermaphrodites, and males. Outcrossing-oriented hermaphrodites first attempt to search for males and perform outcrossing if they encounter males. If they fail to encounter males, they reproduce via selfing. Selfing-oriented hermaphrodites simply reproduce by selfing. The replicator dynamics may show bistability, in which both the androdioecious population (with outcrossing-oriented hermaphrodites and males) and the pure hermaphroditic population are locally stable. The model shows the fraction of males is either zero or relatively high (more than 25%), which is not consistent with the observed low fraction of males (less than 5%). To explain this discrepancy, we studied several models including immigration and enforced copulation. We concluded that the observed pattern can be most likely explained by a population dominated by selfing-oriented hermaphrodites receiving immigration of males.

Optimal control of root nodulation - Prediction of life history theory of a mutualistic system.

Legumes produce root nodules containing symbiotic rhizobial bacteria that convert atmospheric molecular nitrogen into ammonia or related nitrogenous compounds. The host plant supplies photosynthetic products to root nodules forming a mutualistic system. Legumes have physiological mechanisms for regulating nodule production with chemical signals produced in leaves, called the autoregulation of nodulation. In this paper, we discuss the optimal number of root nodules that maximizes the performance of the host plant. Here, we study two models. In the stationary plant model, the acquired photosynthetic products minus cost and loss are used for reproduction. In the growing plant model, the excess material is invested to produce leaves, roots, and root nodules, resulting in the exponential growth of the whole plant. The analysis shows that having root nodules is beneficial to the plant for a high leaf nitrogen content, faster plant growth rate, a short leaf longevity, a low root/shoot ratio, and low soil nutrient concentration. We discuss the long-distance control of nodulation-autoregulation and dependence on the environmental conditions of terrestrial plants considering these results.

Evolution of life cycle dimorphism: An example of sacoglossan sea slugs.

Many sea slugs of Sacoglossa (Mollusca: Heterobranchia) are sometimes called "solar-powered sea slugs" because they keep chloroplasts obtained from their food algae and receive photosynthetic products (termed kleptoplasty). Some species show life cycle dimorphism, in which a single species has some individuals with a complex life cycle (the mother produces planktotrophic larvae, which later settle in the adult habitat) and others with a simple life cycle (mothers produce benthic offspring by direct development or short-term nonfeeding larvae in which feeding planktonic stages are skipped). Life cycle dimorphism is not common among marine species. In this paper, we ask whether some aspects of the ecology of solar-powered sea slugs have promoted the evolution of life cycle dimorphism in them. We study the population dynamics of the two life-cycle types that differ in summer (one with planktonic life and the other with benthic life), but both have benthic life in other seasons. We obtain the conditions in which two types with different life cycles coexist stably or a single type generating offspring with different life cycles evolves. We conclude that the stable coexistence of two life cycles can evolve if benthic individuals in summer experience strongly density-dependent processes or if the between-year fluctuation of biomass growth in summer is very large. We discuss whether these results match the life cycles of solar-powered sea slugs with life cycle dimorphism.

Evaluation of Systemic Inflammatory Response and Nutritional Biomarkers as Predictive Factors in Patients with Recurrent Gastric Cancer.

BACKGROUND: The present study sought to evaluate host-related factors as predictors in patients receiving chemotherapy for recurrent advanced gastric cancer. METHODS: Sixty-three patients were enrolled in the study and received chemotherapy for recurrent gastric cancer at the Kochi Medical School from 2008 to 2015. Clinicopathological information and systemic inflammatory response data were obtained retrospectively to investigate associations between baseline cancer-related prognostic variables and survival outcomes. RESULTS: The median survival time was significantly higher for patients with a Glasgow prognostic score (GPS) of 0 compared to a GPS of 1 or 2 (18.2 vs. 7.1 months; p = 0.006), and for patients in the normal range for carbohydrate antigen-125 (CA125) compared to higher levels (17.9 vs. 4.1 months; p = 0.003). There was no significant influence on overall survival by age, gender, disease status, metastatic site, time to recurrence, carcinoembryonic antigen level, CA19-9 level, prognostic nutrition index, or neutrophil to lymphocyte ratio according to the results of the univariate log-rank tests. Multivariate survival analysis identified a GPS of 1 or 2 (hazard ratio, 3.520; 95% confidence interval, 1.343-9.227; p = 0.010) and a high CA125 level (hazard ratio, 3.135; 95% confidence interval, 1.276-7.697; p = 0.013) as significant independent predictors associated with a poorer prognosis in the studied group of cancer patients. CONCLUSIONS: A GPS of 1 or 2 and a high level of CA125 are independent predictors of a poorer prognosis in patients receiving chemotherapy for recurrent gastric cancer.

Bovine mastitis and optimal disease management: Dynamic programming analysis.

Wise decision-making for coping with infectious diseases is a key to the success of farming, agriculture, as well as public health. Mastitis of dairy cows causes large economic burden to dairy farmers. Here, we study the optimal operation for a dairy farmer to manage cows infected by mastitis. In the simple model, we considered cows with different number of breasts (quarters) infected by mastitis. In the detailed model, we considered additional complexities: a cow produces milk only after the first birth of a calf, old cows are culled, milking is not practiced for 10 weeks prior to expected calf-birth, and a newborn calf provides an economic benefit. By fitting the parameters to the Japanese dairy farming situation, the dynamic programming analysis reveals whether an infected cow should receive medical treatment depends on the number of breasts infected, age, and season. Cows should be culled if many breasts are infected, they are old, and it is not close to the next calf-birth. The optimal management policy depends critically on milk price, maintenance cost, and recovery rate from mastitis infection, but not on infection rate.

Why is bidirectional sex change rare?

Various species of fish living in coral reef communities show sequential hermaphroditism, or sex change. In a typical case, an individual first matures as a female, and later, when it becomes dominant in the mating group, it becomes a male (i.e., protogynous sex change). Many species show only unidirectional changes but some of coral reef fishes exhibit bidirectional sex changes, in which even a dominant male may revert to female when a socially more dominant competitor arrives. However, bidirectional sex change has rarely been observed in natural conditions, even among those species exhibiting it under experimental conditions. Here we explain the rarity of bidirectional sex change by studying dynamics of hormones controlling sex expression. We consider social status factor, SF, which is elevated when the individual becomes more dominant in the mating group. When the SF level is high, the dynamics would culminate with low estradiol expression and high testosterone expression, suggesting a male phenotype. In contrast, when SF level is low, the system converges to an equilibrium with high estradiol expression and low testosterone expression, suggesting a female phenotype. There is a parameter region in which the dynamics exhibit bistability. The model demonstrates hysteresis: as SF increases smoothly, the system undergoes a sudden transition in the levels of sex hormones. The model can explain why species show unidirectional sex change, in that an individual's switch to a new sex is irreversible, even if the individual's social situation returns to the original subdominant status.

Temperature-dependent sex determination, realized by hormonal dynamics with enzymatic reactions sensitive to ambient temperature.

Temperature-dependent sex determination (TSD) is adopted by many animal taxa, including reptiles and fishes. In some species, the eggs develop into females under a low hatching temperature, whereas they will develop into males under a high hatching temperature (called the FM-pattern). In other species, the eggs develop into males (or females) under a low (or high) hatching temperature (MF-pattern). Still, in other species, the eggs develop into females, males, or females, respectively, when under a low, intermediate, or high hatching temperature (FMF-pattern). In this paper, we study a mechanism for realizing TSD. Specifically, we explore a hypothesis that the temperature dependence of enzymatic reaction rates causes a clear switching of sex hormone levels with gradual change of temperature. Herein, we analyze a simple hormonal-dynamics with temperature-sensitive rates of enzymatic reactions included in the sex-determining gene-protein regulatory network. We first examined the cases in which the enzymatic reactions followed Arrhenius equation. The MF-pattern appeared when the rates of aromatase production and/or estradiol production depend more strongly on temperature than do the rates of their decay. By contrast, the FM-pattern appeared when the temperature dependence is stronger for the decay rates of aromatase and/or estradiol than their production rates. However, the FMF-pattern appeared only when some enzymatic reactions follow Berthelot-Hood equation, which exhibits a stronger temperature dependence under higher temperatures than Arrhenius equation. We discuss the possible mechanisms for TSD of FMF-pattern, including alternative splicing and post-translational modification.

Be a good loser: A theoretical model for subordinate decision-making on bi-directional sex change in haremic fishes.

Among animals living in groups with reproductive skew associated with a dominance hierarchy, subordinates may do best by using various alternative tactics. Sequential hermaphrodites or sex changers adopt a unique solution, that is, being the sex with weaker skew when they are small and subordinate, and changing sex when they become larger. In bi-directionally sex-changing fishes, although most are haremic and basically protogynous, subordinate males can change sex to being females. We study a mathematical model to examine when and why such reversed sex change is more adaptive than dispersal to take over another harem. We attempt to examine previously proposed hypotheses that the risk of dispersal and low density favor reversed sex change, and to specify an optimal decision-making strategy for subordinates. As a result, while the size-dependent conditional strategy in which smaller males tend to change sex is predicted, even large males are predicted to change sex under low density and/or high risk of dispersal, supporting both previous hypotheses. The importance of spatiotemporal variation of social and ecological conditions is also suggested. We discuss a unified framework to understand hermaphroditic and gonochoristic societies.

Time required for sex change in teleost fishes: Hormonal dynamics shaped by selection.

Bidirectional sex change is observed in many teleost fish. When social conditions change, the sex transition may take place over a period of several days to a few months. To understand temporal differences for sex change in either direction, I propose a simple mathematical model for the hormone-enzyme dynamics. Aromatase (P450arom) catalyses the synthesis of estradiol from testosterone. I assume that a change in social conditions for individuals affects the rates of production and degradation of P450arom. I then consider the evolution of parameters in the dynamics. Optimal parameter values are those that minimize total fitness cost, defined as the sum of fitness losses due to delay in being a functional male or female, and the cost of accelerated degradation of P450arom in changing from female to male sex. The model predicts that, in haremic species, sex change promotes a faster degradation of P450arom, resulting in a faster female-to-male transition than male-to-female transition. In contrast, in monogamous species, or with a small number of females, there is no benefit in a faster degradation of P450arom when changing to male, resulting in approximately equal timespans for sex change in either direction.

Phenotype adjustment promotes adaptive evolution in a game without conflict.

Organisms may adjust their phenotypes in response to social and physical environments. Such phenotypic plasticity is known to help or retard adaptive evolution. Here, we study the evolutionary outcomes of adaptive phenotypic plasticity in an evolutionary game involving two players who have no conflicts of interest. A possible example is the growth and sex allocation of a lifelong pair of shrimps entrapped in the body of a sponge. We consider random pair formation, the limitation of total resources for growth, and the needs of male investment to fertilize eggs laid by the partner. We compare the following three different evolutionary dynamics: (1) No adjustment: each individual develops a phenotype specified by its own genotype; (2) One-player adjustment: the phenotype of the first player is specified by its own genotype, and the second player chooses the phenotype that maximizes its own fitness; (3) Two-player adjustment: the first player exhibits an initial phenotype specified by its own genotype, the second player chooses a phenotype given that of the first player, and finally, the first player readjusts its phenotype given that of the second player. We demonstrate that both one-player and two-player adjustments evolve to achieve maximum fitness. In contrast, the dynamics without adjustment fails in some cases to evolve outcomes with the highest fitness. For an intermediate range of male cost, the evolution of no adjustment realizes two hermaphrodites with equal size, whereas the one-player and two-player adjustments realize a small male and a large female.

Evolution of sex determination and sexually dimorphic larval sizes in parasitic barnacles.

The parasitic (rhizocephalan) barnacles include species of which larval sex is determined by the mother (genetic sex determination, GSD), male larvae are larger than female larvae, and a female accepts only two dwarf males who sire all the eggs laid by her. In contrast, other species of parasitic barnacles exhibit monomorphic larvae that choose to become male or female depending on the condition of the host they settle (environmental sex determination, or ESD), and a female accepts numerous dwarf males. Here, we ask why these set of traits are observed together, by examining the evolution of sex determination and the larval size. ESD has an advantage over GSD because each larva has a higher chance of encountering a suitable host. On the other hand, GSD has two advantages over ESD: the larval size can be chosen differently between sexes, and their larvae can avoid spending time for sex determination on the host. We conclude that, in species whose female accepts only two males, the male larvae engage in intense contest competition for reproductive opportunities, and male's success-size relation is very different from female's. Then, larvae with predetermined sex (GSD) with sexually dimorphic larvae is more advantageous than ESD. In contrast, in species whose females accept many dwarf males, the competition among males is less intense, and producing larvae with undetermined sex should evolve. We also discuss the condition for females to evolve receptacles to limit the number of males she accepts.

Dwarf males, large hermaphrodites and females in marine species: a dynamic optimization model of sex allocation and growth.

In this study, we investigate the evolutionarily stable schedule of growth and sex allocation for marine benthic species that contain dwarf males. We consider a population in an ephemeral microhabitat that receives a constant supply of larvae. Small individuals can immediately reproduce as a dwarf male or remain immature and grow. Large individuals allocate reproductive resources between male and female functions. The fraction c of newly settled individuals who remain immature and the sex allocation of large individuals m are quantities to evolve. In the stationary ESS, if the relative reproductive success of dwarf males is greater than the survivorship of immature individuals until they reach a mature size, then the population is a mixture of females and dwarf males. If the opposite inequality holds, the population is dominated by hermaphrodites and lacks dwarf males. There is no case in which a mixture of hermaphrodites and dwarf males to be the ESS in the stationary solution. The ESS can be solved by dynamic programming when the strategies depend on the age of the microhabitat (c(t) and m(t)). Typically, the ESS schedule begins with a population composed only of hermaphrodites, which is replaced by a mixture of dwarf males and hermaphrodites and then by a mixture of dwarf males and pure females. The relative importance of these three phases depends on multiple parameters.

Small and poor females change sex: a theoretical and empirical study on protogynous sex change in a triggerfish under varying resource abundance.

Sex change is known from various fish species. In many polygynous species, the largest female usually changes sex to male when the dominant male disappeared, as predicted by the classical size-advantage model. However, in some fishes, the disappearance of male often induces sex change by a smaller female, instead of the largest one. The halfmoon triggerfish Sufflamen chrysopterum is one of such species. We conducted both field investigation and theoretical analysis to test the hypothesis that variation in female fecundity causes the sex change by less-fertile females, even if they are not the largest. We estimated the effect of body length and residual body width (an indicator of nutrition status) on clutch size based on field data. Sex-specific growth rates were also estimated from our investigation and a previous study. We incorporated these estimated value into an evolutionarily stable strategy model for status-dependent size at sex change. As a result, we predict that rich females change sex at a larger size than poor ones, since a rich fish can achieve high reproductive success as a female. In some situations, richer females no longer change sex (i.e. lifelong females), and poorer fish changes sex just after maturation (i.e. primary males). We also analyzed the effect of size-specific growth and mortality.

Sexual systems and dwarf males in barnacles: integrating life history and sex allocation theories.

Barnacles, which are sedentary marine crustaceans, have diverse sexual systems that include simultaneous hermaphroditism, androdioecy (coexistence of hermaphrodites and males) and dioecy (females and males). In dioecious and androdioecious species, the males are very small and are thus called dwarf males. These sexual systems are defined by two factors: sex allocation of non-dwarf individuals and the presence or absence of dwarf males. We constructed an ESS model treating sex allocation and life history simultaneously to explain sexual systems in barnacles. We analyzed the evolutionarily stable size-dependent resource allocation strategy to male reproductive function, female reproductive function and growth in non-dwarf barnacles, and the ESS proportion of dwarf males, under conditions of varying mortality and food availability. Sex allocation in non-dwarf individuals (hermaphrodites or females) is affected by mate availability and the proportion of dwarf males. When hermaphrodites appear, all hermaphrodites become protandric simultaneous hermaphrodites. Furthermore, high mortality and poor resource availability favor dwarf males because of their early maturation and weakened sperm competition. In conclusion, we showed that combining sex allocation and life history theories is a useful way to understand various sexual systems in barnacles and perhaps in other organisms as well.

Dwarf males and hermaphrodites can coexist in marine sedentary species if the opportunity to become a dwarf male is limited.

In many marine sedentary species, dwarf males coexist with large individuals who are either hermaphrodites or females. Simple models of the evolutionary game of sex allocation and life history choice predict that stable coexistence of dwarf males and hermaphrodites is rather difficult. In many of these models, however, newly settled larvae are assumed to choose freely between becoming a dwarf male or an immature fast growing individual. In this paper, we consider a new model in which the opportunity for a newly settled individual to become a dwarf male is limited, for example by the scarcity of large individuals near its settlement site. In the evolutionarily stable strategy, the stationary population is either (1) dominated by hermaphrodites, with dwarf males scarce or absent, if immature individuals are fast-growing, (2) a mixture of dwarf males and large females, if larval growth is slow and the opportunity to become dwarf males is high, (3) a mixture of dwarf males and hermaphrodites, if larval growth is slow and the opportunity to become dwarf males is limited. We also examine the case in which the opportunity to be a growing individual is spatially limited.