Systemic Scleroderma Induced by Nivolumab in Malignant Melanoma.

BACKGROUND: Immunotherapy using immune checkpoint inhibitors is not devoid of immune-related adverse events (irAEs) including rheumatological conditions. CASE REPORT: We report a rare case of a 47-year-old woman with metastatic melanoma who developed systemic scleroderma after initiating nivolumab. The patient displayed inflammatory arthralgias, morning stiffness, and classical cutaneous manifestations of the disease. Clinical evaluations also revealed carpal tunnel syndrome, cardiac involvement, and dyspnea. RNA-Polymerase III antibodies were positive. Nivolumab, an anti-PD-1 antibody, was considered as a potential trigger for this condition. CONCLUSION: To our knowledge, this is the first case of nivolumab-induced systemic scleroderma in the context of melanoma described in the literature that fulfills the classification criteria of the disease. This case underscores the need for increased awareness of immune-related adverse events in patients receiving immune checkpoint inhibitors, emphasizing timely intervention and further research.

Evolution of horn length and lifting strength in the Japanese rhinoceros beetle Trypoxylus dichotomus.

What limits the size of nature's most extreme structures? For weapons like beetle horns, one possibility is a tradeoff associated with mechanical levers: as the output arm of the lever system-the beetle horn-gets longer, it also gets weaker. This "paradox of the weakening combatant" could offset reproductive advantages of additional increases in weapon size. However, in contemporary populations of most heavily weaponed species, males with the longest weapons also tend to be the strongest, presumably because selection drove the evolution of compensatory changes to these lever systems that ameliorated the force reductions of increased weapon size. Therefore, we test for biomechanical limits by reconstructing the stages of weapon evolution, exploring whether initial increases in weapon length first led to reductions in weapon force generation that were later ameliorated through the evolution of mechanisms of mechanical compensation. We describe phylogeographic relationships among populations of a rhinoceros beetle and show that the "pitchfork" shaped head horn likely increased in length independently in the northern and southern radiations of beetles. Both increases in horn length were associated with dramatic reductions to horn lifting strength-compelling evidence for the paradox of the weakening combatant-and these initial reductions to horn strength were later ameliorated in some populations through reductions to horn length or through increases in head height (the input arm for the horn lever system). Our results reveal an exciting geographic mosaic of weapon size, weapon force, and mechanical compensation, shedding light on larger questions pertaining to the evolution of extreme structures.

The Arabidopsis SAC9 enzyme is enriched in a cortical population of early endosomes and restricts PI(4,5)P2 at the plasma membrane.

Membrane lipids, and especially phosphoinositides, are differentially enriched within the eukaryotic endomembrane system. This generates a landmark code by modulating the properties of each membrane. Phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] specifically accumulates at the plasma membrane in yeast, animal, and plant cells, where it regulates a wide range of cellular processes including endocytic trafficking. However, the functional consequences of mispatterning PI(4,5)P2 in plants are unknown. Here, we functionally characterized the putative phosphoinositide phosphatase SUPPRESSOR OF ACTIN9 (SAC9) in Arabidopsis thaliana (Arabidopsis). We found that SAC9 depletion led to the ectopic localization of PI(4,5)P2 on cortical intracellular compartments, which depends on PI4P and PI(4,5)P2 production at the plasma membrane. SAC9 localizes to a subpopulation of trans-Golgi Network/early endosomes that are enriched in a region close to the cell cortex and that are coated with clathrin. Furthermore, it interacts and colocalizes with Src Homology 3 Domain Protein 2 (SH3P2), a protein involved in endocytic trafficking. In the absence of SAC9, SH3P2 localization is altered and the clathrin-mediated endocytosis rate is reduced. Together, our results highlight the importance of restricting PI(4,5)P2 at the plasma membrane and illustrate that one of the consequences of PI(4,5)P2 misspatterning in plants is to impact the endocytic trafficking.

Multi-modal locomotor costs favor smaller males in a sexually dimorphic leaf-mimicking insect.

BACKGROUND: In most arthropods, adult females are larger than males, and male competition is a race to quickly locate and mate with scattered females (scramble competition polygyny). Variation in body size among males may confer advantages that depend on context. Smaller males may be favored due to more efficient locomotion leading to higher mobility during mate searching. Alternatively, larger males may benefit from increased speed and higher survivorship. While the relationship between male body size and mobility has been investigated in several systems, how different aspects of male body morphology specifically affect their locomotor performance in different contexts is often unclear. RESULTS: Using a combination of empirical measures of flight performance and modelling of body aerodynamics, we show that large body size impairs flight performance in male leaf insects (Phyllium philippinicum), a species where relatively small and skinny males fly through the canopy in search of large sedentary females. Smaller males were more agile in the air and ascended more rapidly during flight. Our models further predicted that variation in body shape would affect body lift and drag but suggested that flight costs may not explain the evolution of strong sexual dimorphism in body shape in this species. Finally, empirical measurements of substrate adhesion and subsequent modelling of landing impact forces suggested that smaller males had a lower risk of detaching from the substrates on which they walk and land. CONCLUSIONS: By showing that male body size impairs their flight and substrate adhesion performance, we provide support to the hypothesis that smaller scrambling males benefit from an increased locomotor performance and shed light on the evolution of sexual dimorphism in scramble competition mating systems.

Population differences in the strength of sexual selection match relative weapon size in the Japanese rhinoceros beetle, Trypoxylus dichotomus (Coleoptera: Scarabaeidae)†.

Exaggerated weapons of sexual selection often diverge more rapidly and dramatically than other body parts, suggesting that relevant agents of selection may be discernible in contemporary populations. We examined the ecology, reproductive behavior, and strength of sexual selection on horn length in five recently diverged rhinoceros beetle (Trypoxylus dichotomus) populations that differ in relative horn size. Males with longer horns were better at winning fights in all locations, but the link between winning fights and mating success differed such that selection favored large males with long horns at the two long-horned populations, but was relaxed or nonexistent at the populations with relatively shorter horns. Observations of local habitat conditions and breeding ecology point to shifts in the relative abundance of feeding territories as the most likely cause of population differences in selection on male weapon size in this species. Comparisons of ecological conditions and selection strength across populations offer critical first steps toward meaningfully linking mating system dynamics, selection patterns, and diversity in sexually selected traits.

Sexual dimorphism divergence between sister species is associated with a switch in habitat use and mating system in thorny devil stick insects.

The habitat and resource use of females critically affects their pattern of distribution and consequently their monoposibility by males and the mating system of a species. Shifts in habitat use are therefore likely to be associated with changes in mating system and sexual selection acting on males' phenotypes, consequently affecting patterns of sexual dimorphism. Although sexual dimorphism is often correlated with shifts in habitat use at the macroevolutionary scale, the underlying microevolutionary processes involved are typically unclear. Here, we used the New Guinean stick insect genus Eurycantha to investigate how changes in habitat use and mating system were associated with a change in sexual dimorphism seen specifically in the thorny devil stick insects (Eurycantha calcarata and Eurycantha horrida). Male thorny devils display sexually dimorphic and enlarged hindlegs endowed with a sharp spine. Sexual size dimorphism is also very reduced in these species relative to other phasmids. Using field observations, morphological measurements and radiotelemetry, we investigated changes in mating system associated with the reduction of sexual dimorphism and tested predictions from the hypothesis that sexual selection drove the evolution of this unusual male morphology. We found that thorny devils switched from solitary roosting in the canopy during the day to communal roosting inside cavities of a few host trees, shifting the distribution of females from scattered to clumped. Male thorny devils used their large hindlegs to fight with rivals for positions on the tree close to cavities containing females, and larger males were associated with cavities containing relatively more females. In contrast, the sister species, Eurycantha insularis, displays relatively small and unarmoured males (ancestral state). Adult female E. insularis were always scattered in the canopy, and this species displayed a scramble competition mating system typical of other phasmids, where mobility, rather than fighting ability, is probably critical to males' reproductive success. Overall, our study illustrates how a drastic change in sexual dimorphism can be associated with a switch from solitary to communal roosting and from a scramble competition to a defense-based polygyny mating system.

Cybernetic combatants support the importance of duels in the evolution of extreme weapons.

A current evolutionary hypothesis predicts that the most extreme forms of animal weaponry arise in systems where combatants fight each other one-to-one, in duels. It has also been suggested that arms races in human interstate conflicts are more likely to escalate in cases where there are only two opponents. However, directly testing whether duels matter for weapon investment is difficult in animals and impossible in interstate conflicts. Here, we test whether superior combatants experience a disproportionate advantage in duels, as compared with multi-combatant skirmishes, in a system analogous to both animal and military contests: the battles fought by artificial intelligence agents in a computer war game. We found that combatants with experimentally improved fighting power had a large advantage in duels, but that this advantage deteriorated as the complexity of the battlefield was increased by the addition of further combatants. This pattern remained under the two different forms of the advantage granted to our focal artificial intelligence (AI) combatants, and became reversed when we switched the roles to feature a weak focal AI among strong opponents. Our results suggest that one-on-one combat may trigger arms races in diverse systems. These results corroborate the outcomes of studies of both animal and interstate contests, and suggest that elements of animal contest theory may be widely applicable to arms races generally.

Muscle mass drives cost in sexually selected arthropod weapons.

Sexually selected weapons often function as honest signals of fighting ability. If poor-quality individuals produce high-quality weapons, then receivers should focus on other, more reliable signals. Cost is one way to maintain signal integrity. The costs of weapons tend to increase with relative weapon size, and thereby restrict large weapons to high-quality individuals who can produce and maintain them. Weapon cost, however, appears to be unpredictably variable both within and across taxa, and the mechanisms underlying this variation remain unclear. We suggest variation in weapon cost may result from variation in weapon composition-specifically, differences in the amount of muscle mass directly associated with the weapon. We test this idea by measuring the metabolic cost of sexually selected weapons in seven arthropod species and relating these measures to weapon muscle mass. We show that individuals with relatively large weapon muscles have disproportionately high resting metabolic rates and provide evidence that this trend is driven by weapon muscle mass. Overall, our results suggest that variation in weapon cost can be partially explained by variation in weapon morphology and that the integrity of weapon signals may be maintained by increased metabolic cost in species with relatively high weapon muscle mass.

Overcoming mechanical adversity in extreme hindleg weapons.

The size of sexually selected weapons and their performance in battle are both critical to reproductive success, yet these traits are often in opposition. Bigger weapons make better signals. However, due to the mechanical properties of weapons as lever systems, increases in size may inhibit other metrics of performance as different components of the weapon grow out of proportion with one another. Here, using direct force measurements, we investigated the relationship between weapon size and weapon force production in two hindleg weapon systems, frog-legged beetles (Sagra femorata) and leaf-footed cactus bugs (Narnia femorata), to test for performance tradeoffs associated with increased weapon size. In male frog-legged beetles, relative force production decreased as weapon size increased. Yet, absolute force production was maintained across weapon sizes. Surprisingly, mechanical advantage was constant across weapon sizes and large weaponed males had disproportionately large leg muscles. In male leaf-footed cactus bugs, on the other hand, there was no relationship between weapon size and force production, likely reflecting the importance of their hindlegs as signals rather than force-producing structures of male-male competition. Overall, our results suggest that when weapon force production is important for reproductive success, large weaponed animals may overcome mechanical challenges by maintaining proportional lever components and investing in (potentially costly) compensatory mechanisms.

The metabolic costs of fighting and host exploitation in a seed-drilling parasitic wasp.

Oviposition sites may be challenging and energetically costly to access for females in the presence of competitors contesting that resource. Additionally, oviposition sites may be difficult to reach, and penetrating a hard substrate can raise energy costs. In the seed-drilling parasitic wasp Eupelmus vuilleti, females actively fight with conspecific competitors over access to hosts. They are often observed laying eggs on already parasitized hosts (superparasitism) living inside cowpea seeds despite the resulting larval competition. Using flow-through respirometry, we quantified the metabolic costs of fighting and of drilling through the seed to access the host, to understand the wasp's fighting strategies and the occurrence of superparasitism. Agonistic interactions such as kicks or pushes generated very small instantaneous costs, but the females that won their contests had higher pre-contest metabolic rates, suggesting a potential long-term cost associated with dominance. We also found that drilling holes through the seed accounted for approximately 15% of a wasp's estimated daily energy budget, and that females can reduce these drilling costs by reusing existing holes. Because exploiting new seeds incurs both drilling costs and the risk of fights, it appears cost effective in some situations for females to avoid confrontations and lay eggs in existing holes, on already parasitized hosts. Our study helps explain the evolution of superparasitism in this system.

Crossing fitness valleys: empirical estimation of a fitness landscape associated with polymorphic mimicry.

Characterizing fitness landscapes associated with polymorphic adaptive traits enables investigation of mechanisms allowing transitions between fitness peaks. Here, we explore how natural selection can promote genetic mechanisms preventing heterozygous phenotypes from falling into non-adaptive valleys. Polymorphic mimicry is an ideal system to investigate such fitness landscapes, because the direction of selection acting on complex mimetic colour patterns can be predicted by the local mimetic community composition. Using more than 5000 artificial butterflies displaying colour patterns exhibited by the polymorphic Müllerian mimic Heliconius numata, we directly tested the role of wild predators in shaping fitness landscapes. We compared predation rates on mimetic phenotypes (homozygotes at the supergene controlling colour pattern), intermediate phenotypes (heterozygotes), exotic morphs (absent from the local community) and palatable cryptic phenotypes. Exotic morphs were significantly more attacked than local morphs, highlighting predators' discriminatory capacities. Overall, intermediates were attacked twice as much as local homozygotes, suggesting the existence of deep fitness valleys promoting strict dominance and reduced recombination between supergene alleles. By including information on predators' colour perception, we also showed that protection on intermediates strongly depends on their phenotypic similarity to homozygous phenotypes and that ridges exist between similar phenotypes, which may facilitate divergence in colour patterns.

Habituation in non-neural organisms: evidence from slime moulds.

Learning, defined as a change in behaviour evoked by experience, has hitherto been investigated almost exclusively in multicellular neural organisms. Evidence for learning in non-neural multicellular organisms is scant, and only a few unequivocal reports of learning have been described in single-celled organisms. Here we demonstrate habituation, an unmistakable form of learning, in the non-neural organism Physarum polycephalum In our experiment, using chemotaxis as the behavioural output and quinine or caffeine as the stimulus, we showed that P. polycephalum learnt to ignore quinine or caffeine when the stimuli were repeated, but responded again when the stimulus was withheld for a certain time. Our results meet the principle criteria that have been used to demonstrate habituation: responsiveness decline and spontaneous recovery. To distinguish habituation from sensory adaptation or motor fatigue, we also show stimulus specificity. Our results point to the diversity of organisms lacking neurons, which likely display a hitherto unrecognized capacity for learning, and suggest that slime moulds may be an ideal model system in which to investigate fundamental mechanisms underlying learning processes. Besides, documenting learning in non-neural organisms such as slime moulds is centrally important to a comprehensive, phylogenetic understanding of when and where in the tree of life the earliest manifestations of learning evolved.