Response to comment on 'A conserved strategy for inducing appendage regeneration in moon jellyfish, Drosophila, and mice'.

Previously we reported evidence that a regenerative response in the appendages of moon jellyfish, fruit flies, and mice can be promoted by nutrient modulation (Abrams et al., 2021). Sustar and Tuthill subsequently reported that they had not been able to reproduce the induced regenerative response in flies (Sustar and Tuthill, 2023). Here we discuss that differences in the amputation method, treatment concentrations, age of the animals, and stress management explain why they did not observe a regenerative response in flies. Typically, 30-50% of treated flies showed response in our assay.

A conserved strategy for inducing appendage regeneration in moon jellyfish, Drosophila, and mice.

Can limb regeneration be induced? Few have pursued this question, and an evolutionarily conserved strategy has yet to emerge. This study reports a strategy for inducing regenerative response in appendages, which works across three species that span the animal phylogeny. In Cnidaria, the frequency of appendage regeneration in the moon jellyfish Aurelia was increased by feeding with the amino acid L-leucine and the growth hormone insulin. In insects, the same strategy induced tibia regeneration in adult Drosophila. Finally, in mammals, L-leucine and sucrose administration induced digit regeneration in adult mice, including dramatically from mid-phalangeal amputation. The conserved effect of L-leucine and insulin/sugar suggests a key role for energetic parameters in regeneration induction. The simplicity by which nutrient supplementation can induce appendage regeneration provides a testable hypothesis across animals.

The ability of animals to replace damaged or lost tissue (or 'regenerate') is a sliding scale, with some animals able to regenerate whole limbs, while others can only scar. But why some animals can regenerate while others have more limited capabilities has puzzled the scientific community for many years. The likes of Charles Darwin and August Weismann suggested regeneration only evolves in a particular organ. In contrast, Thomas Morgan suggested that all animals are equipped with the tools to regenerate but differ in whether they are able to activate these processes. If the latter were true, it could be possible to 'switch on' regeneration. Animals that keep growing throughout their life and do not regulate their body temperatures are more likely to be able to regenerate. But what do growth and temperature regulation have in common? Both are highly energy-intensive, with temperature regulation potentially diverting energy from other processes. A question therefore presents itself: could limb regeneration be switched on by supplying animals with more energy, either in the form of nutrients like sugars or amino acids, or by giving them growth hormones such as insulin? Abrams, Tan, Li et al. tested this hypothesis by amputating the limbs of jellyfish, flies and mice, and then supplementing their diet with sucrose (a sugar), leucine (an amino acid) and/or insulin for eight weeks while they healed. Typically, jellyfish rearrange their remaining arms when one is lost, while fruit flies are not known to regenerate limbs. House mice are usually only able to regenerate the very tip of an amputated digit. But in Abrams, Tan, Li et al.'s experiments, leucine and insulin supplements stimulated limb regeneration in jellyfish and adult fruit flies, and leucine and sucrose supplements allowed mice to regenerate digits from below the second knuckle. Although regeneration was not observed in all animals, these results demonstrate that regeneration can be induced, and that it can be done relatively easily, by feeding animals extra sugar and amino acids. These findings highlight increasing the energy supplies of different animals by manipulating their diets while they are healing from an amputated limb can aid in regeneration. This could in the future pave the way for new therapeutic approaches to tissue and organ regeneration.

The Jellyfish Cassiopea Exhibits a Sleep-like State.

Do all animals sleep? Sleep has been observed in many vertebrates, and there is a growing body of evidence for sleep-like states in arthropods and nematodes [1-5]. Here we show that sleep is also present in Cnidaria [6-8], an earlier-branching metazoan lineage. Cnidaria and Ctenophora are the first metazoan phyla to evolve tissue-level organization and differentiated cell types, such as neurons and muscle [9-15]. In Cnidaria, neurons are organized into a non-centralized radially symmetric nerve net [11, 13, 15-17] that nevertheless shares fundamental properties with the vertebrate nervous system: action potentials, synaptic transmission, neuropeptides, and neurotransmitters [15-20]. It was reported that cnidarian soft corals [21] and box jellyfish [22, 23] exhibit periods of quiescence, a pre-requisite for sleep-like states, prompting us to ask whether sleep is present in Cnidaria. Within Cnidaria, the upside-down jellyfish Cassiopea spp. displays a quantifiable pulsing behavior, allowing us to perform long-term behavioral tracking. Monitoring of Cassiopea pulsing activity for consecutive days and nights revealed behavioral quiescence at night that is rapidly reversible, as well as a delayed response to stimulation in the quiescent state. When deprived of nighttime quiescence, Cassiopea exhibited decreased activity and reduced responsiveness to a sensory stimulus during the subsequent day, consistent with homeostatic regulation of the quiescent state. Together, these results indicate that Cassiopea has a sleep-like state, supporting the hypothesis that sleep arose early in the metazoan lineage, prior to the emergence of a centralized nervous system.

A Perspective - can copper complexes be developed as a novel class of therapeutics?

Although copper-ligand complexes appear to be promising as a new class of therapeutics, other than the family of copper(ii) coordination compounds referred to as casiopeínas these compounds have yet to reach the clinic for human use. The pharmaceutical challenges associated with developing copper-based therapeutics will be presented in this article along with a discussion of the potential for high-throughput chemistry, computer-aided drug design, and nanotechnology to address the development of this important class of drug candidates.

Gallium(iii) and iron(iii) complexes of quinolone antimicrobials.

Iron is an essential nutrient for many microbes. According to the "Trojan Horse Hypothesis", biological systems have difficulties distinguishing between Fe(3+) and Ga(3+), which constitutes the antimicrobial efficacy of the gallium(iii) ion. Nine novel tris(quinolono)gallium(iii) complexes and their corresponding iron(iii) analogs have been synthesized and fully characterized. Quinolone antimicrobial agents from three drug generations were used in this study: ciprofloxacin, enoxacin, fleroxacin, levofloxacin, lomefloxacin, nalidixic acid, norfloxacin, oxolinic acid, and pipemidic acid. The antimicrobial efficacy of the tris(quinolono)gallium(iii) complexes was studied against E. faecalis and S. aureus (both Gram-positive), as well as E. coli, K. pneumonia, and P. aeruginosa (all Gram-negative) in direct comparison to the tris(quinolono)iron(iii) complexes and the corresponding free quinolone ligands at various concentrations. For the tris(quinolono)gallium(iii) complexes, no combinational antimicrobial effects between Ga(3+) and the quinolone antimicrobial agents were observed.

Synthesis, characterization, and evaluation of the antimicrobial potential of copper(II) coordination complexes with quinolone and p-xylenyl-linked quinolone ligands.

The antimicrobial properties of copper have been known to mankind since the ancient times. In a coordination chemistry approach to develop novel antimicrobial agents, the quinolone antimicrobial agents ciprofloxacin (Hcipro) and pipemidic acid (Hpia), as well as dimers thereof (piperazinyl-linked with a p-xylenyl moiety) were complexed with copper(II). The synthesis and antimicrobial evaluation of bis(ciprofloxacino)copper(II) [Cu(cipro)2], bis(pipemido)copper(II) [Cu(pia)2], and the corresponding dimer complexes, [Cu2(ciproXcipro)2] and [Cu2(piaXpia)2], are reported. No combinational or synergistic effect between copper(II) and the respective quinolone ligands was observed in vitro.

Symmetrization in jellyfish: reorganization to regain function, and not lost parts.

We recently reported a previously unidentified strategy of self-repair in the moon jellyfish Aurelia aurita. Rather than regenerating lost parts, juvenile Aurelia reorganize remaining parts to regain essential body symmetry. This process that we called symmetrization is rapid and frequent, and is not driven by cell proliferation or cell death. Instead, the swimming machinery generates mechanical forces that drive symmetrization. We found evidence for symmetrization across three other species of jellyfish (Chrysaora pacifica, Mastigias sp., and Cotylorhiza tuberculata). We propose reorganization to regain function without recovery of initial morphology as a potentially broad class of self-repair strategy beyond radially symmetrical animals, and discuss the implications of this finding on the evolution of self-repair strategies in animals.

Self-repairing symmetry in jellyfish through mechanically driven reorganization.

What happens when an animal is injured and loses important structures? Some animals simply heal the wound, whereas others are able to regenerate lost parts. In this study, we report a previously unidentified strategy of self-repair, where moon jellyfish respond to injuries by reorganizing existing parts, and rebuilding essential body symmetry, without regenerating what is lost. Specifically, in response to arm amputation, the young jellyfish of Aurelia aurita rearrange their remaining arms, recenter their manubria, and rebuild their muscular networks, all completed within 12 hours to 4 days. We call this process symmetrization. We find that symmetrization is not driven by external cues, cell proliferation, cell death, and proceeded even when foreign arms were grafted on. Instead, we find that forces generated by the muscular network are essential. Inhibiting pulsation using muscle relaxants completely, and reversibly, blocked symmetrization. Furthermore, we observed that decreasing pulse frequency using muscle relaxants slowed symmetrization, whereas increasing pulse frequency by lowering the magnesium concentration in seawater accelerated symmetrization. A mathematical model that describes the compressive forces from the muscle contraction, within the context of the elastic response from the mesoglea and the ephyra geometry, can recapitulate the recovery of global symmetry. Thus, self-repair in Aurelia proceeds through the reorganization of existing parts, and is driven by forces generated by its own propulsion machinery. We find evidence for symmetrization across species of jellyfish (Chrysaora pacifica, Mastigias sp., and Cotylorhiza tuberculata).

Do high-status people really have fewer children? : Education, income, and fertility in the contemporary U.S.

Evolutionary discussions regarding the relationship between social status and fertility in the contemporary U.S. typically claim that the relationship is either negative or absent entirely. The published data on recent generations of Americans upon which such statements rest, however, are solid with respect to women but sparse and equivocal for men. In the current study, we investigate education and income in relation to age at first child, childlessness, and number of children for men and women in two samples-one of the general American population and one of graduates of an elite American university. We find that increased education is strongly associated with delayed childbearing in both sexes and is also moderately associated with decreased completed or near-completed fertility. Women in the general population with higher adult income have fewer children, but this relationship does not hold within all educational groups, including our sample with elite educations. Higher-income men, however, do not have fewer children in the general population and in fact have lower childlessness rates. Further, higher income in men is positively associated with fertility among our sample with elite educations as well as within the general population among those with college educations. Such findings undermine simple statements on the relationship between status and fertility.

Explanatory style change in supportive-expressive dynamic therapy.

Change in explanatory style (measured by the Attributional Style Questionnaire [ASQ]) has often been considered specific to cognitive therapy (CT). We used data from 59 patients who had received supportive-expressive (SE) dynamic therapy after meeting DSM-III-R criteria for a depressive spectrum disorder and who had completed the ASQ at intake and termination of treatment. We found that depressive symptoms decreased significantly and that explanatory style became more optimistic over the course of treatment. Furthermore, change in ASQ correlated with change in depression. There was some evidence suggesting that ASQ at termination predicted level of depression at follow-up.