Erp and Rev Adhesins of the Lyme Disease Spirochete's Ubiquitous cp32 Prophages Assist the Bacterium during Vertebrate Infection.

Almost all spirochetes in the genus Borrelia (sensu lato) naturally contain multiple variants of closely related prophages. In the Lyme disease borreliae, these prophages are maintained as circular episomes that are called circular plasmid 32 kb (cp32s). The cp32s of Lyme agents are particularly unique in that they encode two distinct families of lipoproteins, namely, Erp and Rev, that are expressed on the bacterial outer surface during infection of vertebrate hosts. All identified functions of those outer surface proteins involve interactions between the spirochetes and host molecules, as follows: Erp proteins bind plasmin(ogen), laminin, glycosaminoglycans, and/or components of complement and Rev proteins bind fibronectin. Thus, cp32 prophages provide their bacterial hosts with surface proteins that can enhance infection processes, thereby facilitating their own survival. Horizontal transfer via bacteriophage particles increases the spread of beneficial alleles and creates diversity among Erp and Rev proteins.

Activation of the Cap'n'collar C pathway (Nrf2 pathway in vertebrates) signaling in insulin pathway compromised Drosophila melanogaster flies ameliorates the diabetic state upon pro-oxidant conditions.

The insulin pathway is a crucial central system for metabolism and growth. The Nrf2 signaling pathway functions to counteract oxidative stress. Here we sought to study the consequences of an oxidative stress challenge to insulin compromised and control adult flies of different ages, varying the activation state of the Nrf2 pathway in flies, the Cap'n'collar C pathway. For this, we employed two different pro-oxidative conditions: 3 % hydrogen peroxide or 20 mM paraquat laced in the food. In both cases, wild type (control) flies die within a few days, yet there are significant differences between males and females, and also within flies of different ages (seven versus thirty days old flies). We repeated the same conditions with young (seven days old) flies that were heterozygous for a loss-of-function mutation in Keap1. There were no significant differences. We then tested two hypomorphic viable conditions of the insulin pathway (heteroallelic combination for the insulin receptor and the S6 Kinase), challenged in the same way: Whereas they also die in the pro-oxidant conditions, they fare significantly better when heterozygous for Keap1, in contrast to controls. We also monitored locomotion in all of these conditions, and, in general, found significant differences between flies without and with a mutant allele (heterozygous) for Keap1. Our results point to altered oxidative stress conditions in diabetic flies. These findings suggest that modest activation of the Cap'n'collar C pathway may be a treatment for diabetic symptoms.

Microbial ecology of vertebrate decomposition in terrestrial ecosystems.

Vertebrate decomposition results in an ephemeral disturbance of the surrounding environment. Microbial decomposers are recognized as key players in the breakdown of complex organic compounds, controlling carbon and nutrient fate in the ecosystem and potentially serving as indicators of time since death for forensic applications. As a result, there has been increasing attention on documenting the microbial communities associated with vertebrate decomposition, or the 'necrobiome'. These necrobiome studies differ in the vertebrate species, microhabitats (e.g. skin vs. soil), and geographic locations studied, but many are narrowly focused on the forensic application of microbial data, missing the larger opportunity to understand the ecology of these communities. To further our understanding of microbial dynamics during vertebrate decomposition and identify knowledge gaps, there is a need to assess the current works from an ecological systems perspective. In this review, we examine recent work pertaining to microbial community dynamics and succession during vertebrate (human and other mammals) decomposition in terrestrial ecosystems, through the lens of a microbial succession ecological framework. From this perspective, we describe three major microbial microhabitats (internal, external, and soil) in terms of their unique successional trajectories and identify three major knowledge gaps that remain to be addressed.

The Cynosure of CtBP: Evolution of a Bilaterian Transcriptional Corepressor.

Evolution of sequence-specific transcription factors clearly drives lineage-specific innovations, but less is known about how changes in the central transcriptional machinery may contribute to evolutionary transformations. In particular, transcriptional regulators are rich in intrinsically disordered regions that appear to be magnets for evolutionary innovation. The C-terminal Binding Protein (CtBP) is a transcriptional corepressor derived from an ancestral lineage of alpha hydroxyacid dehydrogenases; it is found in mammals and invertebrates, and features a core NAD-binding domain as well as an unstructured C-terminus (CTD) of unknown function. CtBP can act on promoters and enhancers to repress transcription through chromatin-linked mechanisms. Our comparative phylogenetic study shows that CtBP is a bilaterian innovation whose CTD of about 100 residues is present in almost all orthologs. CtBP CTDs contain conserved blocks of residues and retain a predicted disordered property, despite having variations in the primary sequence. Interestingly, the structure of the C-terminus has undergone radical transformation independently in certain lineages including flatworms and nematodes. Also contributing to CTD diversity is the production of myriad alternative RNA splicing products, including the production of "short" tailless forms of CtBP in Drosophila. Additional diversity stems from multiple gene duplications in vertebrates, where up to five CtBP orthologs have been observed. Vertebrate lineages show fewer major modifications in the unstructured CTD, possibly because gene regulatory constraints of the vertebrate body plan place specific constraints on this domain. Our study highlights the rich regulatory potential of this previously unstudied domain of a central transcriptional regulator.

Establishing allometric relationships between microsomal protein and cytochrome P450 content with body weight in vertebrate species.

Data from in vitro studies are routinely used to estimate in vivo hepatic clearance of chemicals and this information is needed to parameterise physiologically based kinetic models. Such clearance data can be obtained from laboratory experiments using liver microsomes, hepatocytes, precision-cut liver slices or recombinant enzymes. Irrespective of the selected test system, scaling factors are required to convert the in vitro measured intrinsic clearance to a whole liver intrinsic clearance. Scaling factors such as the hepatic microsomal protein per gram of liver and/or the amount of cytochrome P450 per hepatocyte provide a means to calculate the whole liver intrinsic clearance. Here, a database from the peer-reviewed literature has been developed and provides quantitative metrics on microsomal protein (MP) and cytochrome P450 contents in vertebrate orders namely amphibians, mammals, birds, fish and reptiles. This database allows to address allometric relationships between body weight and MP content, and body weight and cytochrome P450 content. A total of 85 and 74 vertebrate species were included to assess the relationships between log10 body weight versus log10 MP, and between log10 body weight and log10 cytochrome P450 content, respectively. The resulting slopes range from 0.76 to 1.45 in a range of vertebrate species. Such data-driven allometric relationships can be used to estimate the MP content necessary for in vitro to in vivo extrapolation of in vitro clearance data. Future work includes applications of these relationships for different vertebrate taxa using quantitative in vitro to in vivo extrapolation models coupled to physiologically based kinetic models using chemicals of relevance as case studies including pesticides, contaminants and feed additives.

Vertebrate OTOP1 is also an alkali-activated channel.

Although alkaline sensation is critical for survival, alkali-activated receptors are yet to be identified in vertebrates. Here, we showed that the OTOP1 channel can be directly activated by extracellular alkali. Notably, OTOP1 biphasically mediated proton influx and efflux with extracellular acid and base stimulation, respectively. Mutations of K221 and R554 at the S5-S6 and S11-S12 linkers significantly reduced alkali affinity without affecting acid activation, suggesting that different domains are responsible for acid- and alkali-activation of OTOP1. The selectivity for H+ was significantly higher in OTOP1 activated by alkali than that by acid, further suggesting that the two activations might be independent gating processes. Given that the alkali-activation of OTOP1 and the required key residues were conserved in the six representative vertebrates, we cautiously propose that OTOP1 participates in alkaline sensation in vertebrates. Thus, our study identified OTOP1 as an alkali-activated channel.

Comparative analysis of genome-scale, base-resolution DNA methylation profiles across 580 animal species.

Methylation of cytosines is a prototypic epigenetic modification of the DNA. It has been implicated in various regulatory mechanisms across the animal kingdom and particularly in vertebrates. We mapped DNA methylation in 580 animal species (535 vertebrates, 45 invertebrates), resulting in 2443 genome-scale DNA methylation profiles of multiple organs. Bioinformatic analysis of this large dataset quantified the association of DNA methylation with the underlying genomic DNA sequence throughout vertebrate evolution. We observed a broadly conserved link with two major transitions-once in the first vertebrates and again with the emergence of reptiles. Cross-species comparisons focusing on individual organs supported a deeply conserved association of DNA methylation with tissue type, and cross-mapping analysis of DNA methylation at gene promoters revealed evolutionary changes for orthologous genes. In summary, this study establishes a large resource of vertebrate and invertebrate DNA methylomes, it showcases the power of reference-free epigenome analysis in species for which no reference genomes are available, and it contributes an epigenetic perspective to the study of vertebrate evolution.

Tryptophan metabolism can modulate immunologic tolerance in primitive vertebrate lamprey via IDO-kynurenine-AHR pathway.

Tryptophan is mainly degraded through kynurenine pathway (KP) in vertebrates which is closely related to the nerve and depression, while the studies on immunity is still limited. This study aims to explore the functions of tryptophan in the innate immunity of primitive vertebrate lamprey. MTT (3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide) assay showed that tryptophan had no obvious effect on cell viability. Tryptophan was transported into leukocytes and degraded via the KP after tryptophan supplement. Tryptophan treatment (T1x and T2x) failed to alter the total antioxidant capacity regardless of stimulation and exposure time. Real-time quantitative PCR and western blotting results revealed that tryptophan was not only able to reduce the expression of pro-inflammatory factors Lj-TNF-α, Lj-IL1ß and Lj-NF-κB, but also to upregulate the expression of anti-inflammatory factor Lj-TGF-ß independent of stimulation and time. In addition, tryptophan can exert immune tolerance function by inhibiting TLR-MyD88 and promoting (Indoleamine 2, 3-Dioxygenase) IDO-kynurenine-AHR (aryl hydrocarbon receptor) pathways. This study provides a new understanding for tryptophan-kynurenine metabolism and mechanism of immune tolerance function in primitive vertebrate lamprey.

The origin and loss of interferon regulatory factor 10 (IRF10) in different lineages of vertebrates.

The vertebrate IFN regulatory factor (IRF) family consists of 11 members that exert distinct roles in a variety of biological processes, including antiviral defense, regulation of cell proliferation, differentiation and apoptosis. Of these, IRF10 is widely present in different vertebrate lineages, but appears to have been lost in primates and rodents. To understand the evolutionary occurrence of IRF10, we performed comparative analyses of currently available genomic data in a taxonomically diverse set of vertebrates, and found that IRF10 originated after the divergence of chondrichthyans from gnathostomes. Phylogenetically, vertebrate IRF10 is much more closely related to IRF4 than to IRF8 or IRF9, although these four IRFs may have a common ancestor. In addition, the loss of IRF10 in Euarchontoglires might be resulted from mutation accumulation, and the rate of mutations in rodents appears to be higher than in the primate lineage. In primates, the gene-disruptive mutations may have occurred at least prior to the separation of new world monkey and old world primates, roughly 40 million years ago. Overall, we propose a detailed evolutionary scenario for IRF10, which may help us understand the evolutionary mechanisms in the expansion and contraction of the IRF family.

Neuronal control of the vagina in vertebrates: A review.

BACKGROUND: At present, there is an increased interest in the vaginal microbiome. It is believed that microbes play equally important roles in the vagina, including the modulation of neuronal pathways, as in the gut. However, in man as well as in animals, the vagina is the least well-studied part of the female reproductive system. The vagina, a fibromuscular tract, having two main functions, i.e., childbirth and sexual intercourse, is mainly innervated by the pudendal nerve and the pelvic splanchnic nerves (the uterovaginal nerve plexus) containing sympathetic, parasympathetic and nociceptive nerve fibers. Innervation density in the vaginal wall undergoes significant remodeling due to hormonally mediated physiological activity. Knowledge about expression and function of neuropeptides and neurotransmitters in the vaginal fibers is incomplete or not established. Most research concerning the neuroregulation of the vagina and the function and expression of neuropeptides and neurotransmitters, is performed in several vertebrate species, including large farm animals, rodents, domestic fowl and lizards. METHODS: This review summarizes, on a bibliographic basis, the current knowledge on vaginal innervation and function of neuropeptides and neurotransmitters expressed in vaginal nerve fibers in several vertebrate species, including humans. The presence and role played by the local microbioma is also explored. CONCLUSION: A thorough knowledge of the vaginal innervation is necessary to unravel the putative communication of the vaginal microbiome and vaginal nerve fibers, but also to understand the effects of vaginal pathologies and of administered drugs on the neuroregulation of the vagina.

Evolution of the glomerulus in a marine environment and its implications for renal function in terrestrial vertebrates.

Nearly a century ago, Homer Smith proposed that the glomerulus evolved to meet the challenge of excretion of water in freshwater vertebrates. This hypothesis has been repeatedly restated in the nephrology and renal physiology literature, even though we now know that vertebrates evolved and diversified in marine (saltwater) environments. A more likely explanation is that the vertebrate glomerulus evolved from the meta-nephridium of marine invertebrates, with the driving force for ultrafiltration being facilitated by the apposition of the filtration barrier to the vasculature (in vertebrates) rather than the coelom (in invertebrates) and the development of a true heart and the more complex vertebrate vascular system. In turn, glomerular filtration aided individual regulation of divalent ions like magnesium, calcium, and sulfate compatible with the function of cardiac and skeletal muscle required for mobile predators. The metabolic cost, imposed by reabsorption of the small amounts of sodium required to drive secretion of these over-abundant divalent ions, was small. This innovation, developed in a salt-water environment, provided a preadaptation for life in freshwater, in which the glomerulus was co-opted to facilitate water excretion, albeit with the additional metabolic demand imposed by the need to reabsorb the majority of filtered sodium. The evolution of the glomerulus in saltwater also provided preadaptation for terrestrial life, where the imperative is conservation of both water and electrolytes. The historical contingencies of this scenario may explain why the mammalian kidney is so metabolically inefficient, with ∼80% of oxygen consumption being used to drive reabsorption of filtered sodium.

The evolutionary history and spectral tuning of vertebrate visual opsins.

Many animals depend on the sense of vision for survival. In eumetazoans, vision requires specialized, light-sensitive cells called photoreceptors. Light reaches the photoreceptors and triggers the excitation of light-detecting proteins called opsins. Here, we describe the story of visual opsin evolution from the ancestral bilaterian to the extant vertebrate lineages. We explain the mechanisms determining color vision of extant vertebrates, focusing on opsin gene losses, duplications, and the expression regulation of vertebrate opsins. We describe the sequence variation both within and between species that has tweaked the sensitivities of opsin proteins towards different wavelengths of light. We provide an extensive resource of wavelength sensitivities and mutations that have diverged light sensitivity in many vertebrate species and predict how these mutations were accumulated in each lineage based on parsimony. We suggest possible natural and sexual selection mechanisms underlying these spectral differences. Understanding how molecular changes allow for functional adaptation of animals to different environments is a major goal in the field, and therefore identifying mutations affecting vision and their relationship to photic selection pressures is imperative. The goal of this review is to provide a comprehensive overview of our current understanding of opsin evolution in vertebrates.

Gotta Go Slow: Two Evolutionarily Distinct Annelids Retain a Common Hedgehog Pathway Composition, Outlining Its Pan-Bilaterian Core.

Hedgehog signaling is one of the key regulators of morphogenesis, cell differentiation, and regeneration. While the Hh pathway is present in all bilaterians, it has mainly been studied in model animals such as Drosophila and vertebrates. Despite the conservatism of its core components, mechanisms of signal transduction and additional components vary in Ecdysozoa and Deuterostomia. Vertebrates have multiple copies of the pathway members, which complicates signaling implementation, whereas model ecdysozoans appear to have lost some components due to fast evolution rates. To shed light on the ancestral state of Hh signaling, models from the third clade, Spiralia, are needed. In our research, we analyzed the transcriptomes of two spiralian animals, errantial annelid Platynereis dumerilii (Nereididae) and sedentarian annelid Pygospio elegans (Spionidae). We found that both annelids express almost all Hh pathway components present in Drosophila and mouse. We performed a phylogenetic analysis of the core pathway components and built multiple sequence alignments of the additional key members. Our results imply that the Hh pathway compositions of both annelids share more similarities with vertebrates than with the fruit fly. Possessing an almost complete set of single-copy Hh pathway members, lophotrochozoan signaling composition may reflect the ancestral features of all three bilaterian branches.

Parallel evolution of amphioxus and vertebrate small-scale gene duplications.

BACKGROUND: Amphioxus are non-vertebrate chordates characterized by a slow morphological and molecular evolution. They share the basic chordate body-plan and genome organization with vertebrates but lack their 2R whole-genome duplications and their developmental complexity. For these reasons, amphioxus are frequently used as an outgroup to study vertebrate genome evolution and Evo-Devo. Aside from whole-genome duplications, genes continuously duplicate on a smaller scale. Small-scale duplicated genes can be found in both amphioxus and vertebrate genomes, while only the vertebrate genomes have duplicated genes product of their 2R whole-genome duplications. Here, we explore the history of small-scale gene duplications in the amphioxus lineage and compare it to small- and large-scale gene duplication history in vertebrates. RESULTS: We present a study of the European amphioxus (Branchiostoma lanceolatum) gene duplications thanks to a new, high-quality genome reference. We find that, despite its overall slow molecular evolution, the amphioxus lineage has had a history of small-scale duplications similar to the one observed in vertebrates. We find parallel gene duplication profiles between amphioxus and vertebrates and conserved functional constraints in gene duplication. Moreover, amphioxus gene duplicates show levels of expression and patterns of functional specialization similar to the ones observed in vertebrate duplicated genes. We also find strong conservation of gene synteny between two distant amphioxus species, B. lanceolatum and B. floridae, with two major chromosomal rearrangements. CONCLUSIONS: In contrast to their slower molecular and morphological evolution, amphioxus' small-scale gene duplication history resembles that of the vertebrate lineage both in quantitative and in functional terms.

Vertebrate Animal Models of RP59: Current Status and Future Prospects.

Retinitis pigmentosa-59 (RP59) is a rare, recessive form of RP, caused by mutations in the gene encoding DHDDS (dehydrodolichyl diphosphate synthase). DHDDS forms a heterotetrameric complex with Nogo-B receptor (NgBR; gene NUS1) to form a cis-prenyltransferase (CPT) enzyme complex, which is required for the synthesis of dolichol, which in turn is required for protein N-glycosylation as well as other glycosylation reactions in eukaryotic cells. Herein, we review the published phenotypic characteristics of RP59 models extant, with an emphasis on their ocular phenotypes, based primarily upon knock-in of known RP59-associated DHDDS mutations as well as cell type- and tissue-specific knockout of DHDDS alleles in mice. We also briefly review findings in RP59 patients with retinal disease and other patients with DHDDS mutations causing epilepsy and other neurologic disease. We discuss these findings in the context of addressing "knowledge gaps" in our current understanding of the underlying pathobiology mechanism of RP59, as well as their potential utility for developing therapeutic interventions to block the onset or to dampen the severity or progression of RP59.

TRPV4: Cell type-specific activation, regulation and function in the vertebrate eye.

The architecture of the vertebrate eye is optimized for efficient delivery and transduction of photons and processing of signaling cascades downstream from phototransduction. The cornea, lens, retina, vasculature, ciliary body, ciliary muscle, iris and sclera have specialized functions in ocular protection, transparency, accommodation, fluid regulation, metabolism and inflammatory signaling, which are required to enable function of the retina-light sensitive tissue in the posterior eye that transmits visual signals to relay centers in the midbrain. This process can be profoundly impacted by non-visual stimuli such as mechanical (tension, compression, shear), thermal, nociceptive, immune and chemical stimuli, which target these eye regions to induce pain and precipitate vision loss in glaucoma, diabetic retinopathy, retinal dystrophies, retinal detachment, cataract, corneal dysfunction, ocular trauma and dry eye disease. TRPV4, a polymodal nonselective cation channel, integrate non-visual inputs with homeostatic and signaling functions of the eye. The TRPV4 gene is expressed in most if not all ocular tissues, which vary widely with respect to the mechanisms of TRPV4 channel activation, modulation, oligomerization, and participation in protein- and lipid interactions. Under- and overactivation of TRPV4 may affect intraocular pressure, maintenance of blood-retina barriers, lens accommodation, neuronal function and neuroinflammation. Because TRPV4 dysregulation precipitates many pathologies across the anterior and posterior eye, the channel could be targeted to mitigate vision loss.

Cyclin B3 implements timely vertebrate oocyte arrest for fertilization.

To ensure successful offspring ploidy, vertebrate oocytes must halt the cell cycle in meiosis II until sperm entry. Emi2 is essential to keep oocytes arrested until fertilization. However, how this arrest is implemented exclusively in meiosis II and not prematurely in meiosis I has until now remained enigmatic. Using mouse and frog oocytes, we show here that cyclin B3, an understudied B-type cyclin, is essential to keep Emi2 levels low in meiosis I. Direct phosphorylation of Emi2 at an evolutionarily highly conserved site by Cdk1/cyclin B3 targets Emi2 for degradation. In contrast, Cdk1/cyclin B1 is inefficient in Emi2 phosphorylation, and this provides a molecular explanation for the requirement of different B-type cyclins for oocyte maturation. Cyclin B3 degradation at exit from meiosis I enables Emi2 accumulation and thus timely arrest in meiosis II. Our findings illuminate the evolutionarily conserved mechanisms that control oocyte arrest for fertilization at the correct cell-cycle stage, which is essential for embryo viability.

Ion regulation at gills precedes gas exchange and the origin of vertebrates.

Gas exchange and ion regulation at gills have key roles in the evolution of vertebrates1-4. Gills are hypothesized to have first acquired these important homeostatic functions from the skin in stem vertebrates, facilitating the evolution of larger, more-active modes of life2,3,5. However, this hypothesis lacks functional support in relevant taxa. Here we characterize the function of gills and skin in a vertebrate (lamprey ammocoete; Entosphenus tridentatus), a cephalochordate (amphioxus; Branchiostoma floridae) and a hemichordate (acorn worm; Saccoglossus kowalevskii) with the presumed burrowing, filter-feeding traits of vertebrate ancestors6-9. We provide functional support for a vertebrate origin of gas exchange at the gills with increasing body size and activity, as direct measurements in vivo reveal that gills are the dominant site of gas exchange only in ammocoetes, and only with increasing body size or challenges to oxygen supply and demand. Conversely, gills of all three taxa are implicated in ion regulation. Ammocoete gills are responsible for all ion flux at all body sizes, whereas molecular markers for ion regulation are higher in the gills than in the skin of amphioxus and acorn worms. This suggests that ion regulation at gills has an earlier origin than gas exchange that is unrelated to vertebrate size and activity-perhaps at the very inception of pharyngeal pores in stem deuterostomes.

The emerging significance of splicing in vertebrate development.

Splicing is a crucial regulatory node of gene expression that has been leveraged to expand the proteome from a limited number of genes. Indeed, the vast increase in intron number that accompanied vertebrate emergence might have aided the evolution of developmental and organismal complexity. Here, we review how animal models for core spliceosome components have provided insights into the role of splicing in vertebrate development, with a specific focus on neuronal, neural crest and skeletal development. To this end, we also discuss relevant spliceosomopathies, which are developmental disorders linked to mutations in spliceosome subunits. Finally, we discuss potential mechanisms that could underlie the tissue-specific phenotypes often observed upon spliceosome inhibition and identify gaps in our knowledge that, we hope, will inspire further research.

Evolutionary conservation of leptin effects on wound healing in vertebrates: Implications for veterinary medicine.

In mammals, the cytokine hormone leptin promotes wound healing by increasing inflammation, cellular recruitment, angiogenic regrowth, and re-epithelialization; however, it is not known whether leptin has conserved actions on wound healing in other vertebrates. Here, we tested the hypothesis that leptin promotes both the quality and speed of wound healing in the South African clawed frog, Xenopus laevis. First, fluorescent immunohistochemistry using a polyclonal antibody specific to Xenopus leptin showed that in juvenile dorsal skin, leptin protein is expressed in the dorsal epidermal layer, as well in blood vessel endothelial cells and sensory nerves that run along the base of the dermis. Injection of recombinant Xenopus leptin (rXleptin) stimulates phosphorylated STAT3 (pSTAT3), indicative of leptin-activated JAK/STAT signaling in the epidermis. Similar to mammals, leptin protein expression increases at the wound site after injury of the epidermis. We then cultured "punch-in-a-punch" full-thickness dorsal skin explants in three doses of rXleptin (0, 10, and 100 ng/ml) and showed that leptin treatment doubled the rate of wound closure after 48 h relative to skin punches cultured without leptin. Food restriction prior to wound explant culture reduced the amount of wound closure, but leptin injection prior to euthanasia rescued closure to similar control levels. Leptin treatment also significantly reduced bacterial infection of these epidermal punches by 48 h in culture. This study shows that leptin is likely an endogenous promoter of wound healing in amphibians. Leptin-based therapies have the potential to expedite healing and reduce the incidence of secondary infections without toxicity issues, the threat of antibiotic resistance, or environmental antibiotic contamination. The conservation of leptin's actions on wound healing also suggests that it may have similar veterinary applications for other exotic species.