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American bullfrog (Rana castesbeiana) saxiphilin (RcSxph) is a high-affinity "toxin sponge" protein thought to prevent intoxication by saxitoxin (STX), a lethal bis-guanidinium neurotoxin that causes paralytic shellfish poisoning (PSP) by blocking voltage-gated sodium channels (NaVs). How specific RcSxph interactions contribute to STX binding has not been defined and whether other organisms have similar proteins is unclear. Here, we use mutagenesis, ligand binding, and structural studies to define the energetic basis of Sxph:STX recognition. The resultant STX "recognition code" enabled engineering of RcSxph to improve its ability to rescue NaVs from STX and facilitated discovery of 10 new frog and toad Sxphs. Definition of the STX binding code and Sxph family expansion among diverse anurans separated by ∼140 My of evolution provides a molecular basis for understanding the roles of toxin sponge proteins in toxin resistance and for developing novel proteins to sense or neutralize STX and related PSP toxins.

BackgroundImpairment of bowel, urogenital and fertility-related function in patients treated for rectal cancer is common. While the rate of rectal cancer in the young (

Many poisonous organisms carry small-molecule toxins that alter voltage-gated sodium channel (NaV) function. Among these, batrachotoxin (BTX) from Pitohui poison birds and Phyllobates poison frogs stands out because of its lethality and unusual effects on NaV function. How these toxin-bearing organisms avoid autointoxication remains poorly understood. In poison frogs, a NaV DIVS6 pore-forming helix N-to-T mutation has been proposed as the BTX resistance mechanism. Here, we show that this variant is absent from Pitohui and poison frog NaVs, incurs a strong cost compromising channel function, and fails to produce BTX-resistant channels in poison frog NaVs. We also show that captivity-raised poison frogs are resistant to two NaV-directed toxins, BTX and saxitoxin (STX), even though they bear NaVs sensitive to both. Moreover, we demonstrate that the amphibian STX "toxin sponge" protein saxiphilin is able to protect and rescue NaVs from block by STX. Taken together, our data contradict the hypothesis that BTX autoresistance is rooted in the DIVS6 N→T mutation, challenge the idea that ion channel mutations are a primary driver of toxin resistance, and suggest the possibility that toxin sequestration mechanisms may be key for protecting poisonous species from the action of small-molecule toxins.

Intelligence quotient (IQ) is commonly measured in child development studies, while adaptive behavior is less frequently considered. Given its associations with functional outcomes in children with neurodevelopmental disabilities, adaptive behavior may be a useful outcome in general population samples, as well. This study aimed to compare social and environmental correlates of adaptive behavior vs. IQ in a sample of preschoolers exposed to the Flint water crisis (N = 184). Mother-child dyads were recruited from the community and administered a comprehensive battery to obtain information about child neurodevelopmental functioning, including direct assessment of IQ via the Wechsler Preschool and Primary Scale of Intelligence and assessment of parent-reported adaptive functioning via the Vineland Adaptive Behavior Scales. Multiple social environmental factors were explored as potential correlates of child outcomes (i.e., IQ and adaptive behavior), and robust correlates were identified using a data-driven approach [i.e., least absolute shrinkage and selection operator (LASSO) regression]. We then examined associations between the LASSO-selected predictors and IQ and adaptive behavior while controlling for child age, child sex, and maternal age. Children in this sample showed relative strength in adaptive behaviors, with scores in the adequate range, while average IQs fell in the low-average range. Adaptive behavior was significantly associated with maternal nurturance practices, while IQ was associated with the maternal education level. Implications for the use of adaptive behavior as an outcome measure in studies of children at an increased risk for neurodevelopmental problems are discussed.

Social monogamy, typically characterized by the formation of a pair bond, increased territorial defense, and often biparental care, has independently evolved multiple times in animals. Despite the independent evolutionary origins of monogamous mating systems, several homologous brain regions and neuropeptides and their receptors have been shown to play a conserved role in regulating social affiliation and parental care, but little is known about the neuromolecular mechanisms underlying monogamy on a genomic scale. Here, we compare neural transcriptomes of reproductive males in monogamous and nonmonogamous species pairs of Peromyscus mice, Microtus voles, parid songbirds, dendrobatid frogs, and Xenotilapia species of cichlid fishes. We find that, while evolutionary divergence time between species or clades did not explain gene expression similarity, characteristics of the mating system correlated with neural gene expression patterns, and neural gene expression varied concordantly across vertebrates when species transition to monogamy. Our study provides evidence of a universal transcriptomic mechanism underlying the evolution of monogamy in vertebrates.

Animals that wield toxins face self-intoxication. Poison frogs have a diverse arsenal of defensive alkaloids that target the nervous system. Among them is epibatidine, a nicotinic acetylcholine receptor (nAChR) agonist that is lethal at microgram doses. Epibatidine shares a highly conserved binding site with acetylcholine, making it difficult to evolve resistance yet maintain nAChR function. Electrophysiological assays of human and frog nAChR revealed that one amino acid replacement, which evolved three times in poison frogs, decreased epibatidine sensitivity but at a cost of acetylcholine sensitivity. However, receptor functionality was rescued by additional amino acid replacements that differed among poison frog lineages. Our results demonstrate how resistance to agonist toxins can evolve and that such genetic changes propel organisms toward an adaptive peak of chemical defense.

Genome size varies greatly across the tree of life and transposable elements are an important contributor to this variation. Among vertebrates, amphibians display the greatest variation in genome size, making them ideal models to explore the causes and consequences of genome size variation. However, high-quality genome assemblies for amphibians have, until recently, been rare. Here, we generate a high-quality genome assembly for the dyeing poison frog, Dendrobates tinctorius. We compare this assembly to publicly available frog genomes and find evidence for both large-scale conserved synteny and widespread rearrangements between frog lineages. Comparing conserved orthologs annotated in these genomes revealed a strong correlation between genome size and gene size. To explore the cause of gene-size variation, we quantified the location of transposable elements relative to gene features and find that the accumulation of transposable elements in introns has played an important role in the evolution of gene size in D. tinctorius , while estimates of insertion times suggest that many insertion events are recent and species-specific. Finally, we carry out population-scale mobile-element sequencing and show that the diversity and abundance of transposable elements in poison frog genomes can complicate genotyping from repetitive element sequence anchors. Our results show that transposable elements have clearly played an important role in the evolution of large genome size in D. tinctorius. Future studies are needed to fully understand the dynamics of transposable element evolution and to optimize primer or bait design for cost-effective population-level genotyping in species with large, repetitive genomes. [ABSTRACT FROM AUTHOR]

Aim: Some patients with inflammatory bowel disease (IBD) require subtotal colectomy (STC) with ileostomy. The recent literature reports a significant number of patients who do not undergo subsequent surgery and are resigned to living with a definitive stoma. The aim of this work was to analyse the rate of definitive stoma and the cumulative incidence of secondary reconstructive surgery after STC for IBD in a large national cohort study. Method: A national retrospective study (2013–2021) was conducted on prospectively collected data from the French Medical Information System Database (PMSI). All patients undergoing STC in France were included. The association between definitive stoma and potential risk factors was studied using univariate and multivariate analyses. Results: A total of 1860 patients were included (age 45 ± 9 years; median follow‐up 30 months). Of these, 77% (n = 1442) presented with ulcerative colitis. Mortality and morbidity at 90 days after STC were 5% (n = 100) and 47% (n = 868), respectively. Reconstructive surgery was identified in 1255 patients (67%) at a mean interval of 7 months from STC. Seveny‐four per cent (n = 932) underwent a completion proctectomy with ileal pouch anal anastomosis and 26% (n = 323) an ileorectal anastomosis. Six hundred and five (33%) patients with a definitive stoma had an abdominoperineal resection (n = 114; 19%) or did not have any further surgical procedure (n = 491; 81%). Independent risk factors for definitive stoma identified in multivariate analysis were older age, Crohn's disease, colorectal neoplasia, postoperative complication after STC, laparotomy and a low‐volume hospital. Conclusion: We found that 33% of patients undergoing STC with ileostomy for IBD had definitive stoma. Modifiable risk factors for definitive stoma were laparotomy and a low‐volume hospital. [ABSTRACT FROM AUTHOR]