Coevolutionary arms race versus host defense chase in a tropical herbivore-plant system.

Coevolutionary models suggest that herbivores drive diversification and community composition in plants. For herbivores, many questions remain regarding how plant defenses shape host choice and community structure. We addressed these questions using the tree genus Inga and its lepidopteran herbivores in the Amazon. We constructed phylogenies for both plants and insects and quantified host associations and plant defenses. We found that similarity in herbivore assemblages between Inga species was correlated with similarity in defenses. There was no correlation with phylogeny, a result consistent with our observations that the expression of defenses in Inga is independent of phylogeny. Furthermore, host defensive traits explained 40% of herbivore community similarity. Analyses at finer taxonomic scales showed that different lepidopteran clades select hosts based on different defenses, suggesting taxon-specific histories of herbivore-host plant interactions. Finally, we compared the phylogeny and defenses of Inga to phylogenies for the major lepidopteran clades. We found that closely related herbivores fed on Inga with similar defenses rather than on closely related plants. Together, these results suggest that plant defenses might be more evolutionarily labile than the herbivore traits related to host association. Hence, there is an apparent asymmetry in the evolutionary interactions between Inga and its herbivores. Although plants may evolve under selection by herbivores, we hypothesize that herbivores may not show coevolutionary adaptations, but instead "chase" hosts based on the herbivore's own traits at the time that they encounter a new host, a pattern more consistent with resource tracking than with the arms race model of coevolution.

Hospitalization Burden and Incidence of Krabbe Disease.

OBJECTIVE: The purpose of our study was to understand the healthcare burden and incidence of Krabbe disease (Krabbe). METHODS: Retrospective analysis of Krabbe patients identified October 1, 2015 through December 31, 2020, ages birth through age 3, evaluated in two national databases. We estimated point prevalence and incidence from year 2016 data. RESULTS: We identified 98 unique Krabbe patients with 736 visits including 260 were inpatient admissions. Total healthcare charges were $51.5 million dollars. We determined a point prevalence of 34 68 Krabbe patients in 2016 ages 0 3 years. This estimates a birth incidence of ~1 in 310,000 live births. Significance: Krabbe disease patients had over $51 million in health care charges and hundreds of hospitalizations. Estimated prevalence and birth incidence is similar to rates observed from newborn screening. Our findings show the tremendous health impacts of Krabbe disease, and provide guidance for efforts in screening and treatment planning.

National U.S. Patient and Transplant Data for Krabbe Disease.

Krabbe disease (KD) is a leukodystrophy caused by mutations in the galactosylceramidase gene. Presymptomatic hematopoietic stem cell transplantation (HSCT) is associated with improved outcomes, but most data are from single-center studies. Our objective was to characterize national patterns of HSCT for KD including whether there were disparities in HSCT utilization and outcomes. We conducted a retrospective study of KD patients ≤ age 18 years from November 1, 2015, through December 31, 2019, using the U.S. Children's Hospital Association's Pediatric Health Information System database. We evaluated outcomes for HSCT, intensive care unit days, and mortality, comparing age, sex, race/ethnicity, rural/urban location, and median household income. We identified 91 KD patients. HSCT, performed in 32% of patients, was associated with reduced mortality, 31 vs. 68% without HSCT (p < 0.003). Trends included the fact that more males than females had HSCT (39 vs. 23%); more Asian and White patients had HSCT compared to Black or Hispanic patients (75, 33, 25, and 17%, respectively); and patients from households with the lowest-income quartile (< $25,000) had more HSCT compared to higher-income quartiles (44 vs. 33, 30, and 0%). Overall, receiving HSCT was associated with reduced mortality. We noted trends in patient groups who received HSCT. Our findings suggest that disparities in receiving HSCT could affect outcomes for KD patients.

Novel four-disulfide insulin analog with high aggregation stability and potency.

Although insulin was first purified and used therapeutically almost a century ago, there is still a need to improve therapeutic efficacy and patient convenience. A key challenge is the requirement for refrigeration to avoid inactivation of insulin by aggregation/fibrillation. Here, in an effort to mitigate this problem, we introduced a 4th disulfide bond between a C-terminal extended insulin A chain and residues near the C-terminus of the B chain. Insulin activity was retained by an analog with an additional disulfide bond between residues A22 and B22, while other linkages tested resulted in much reduced potency. Furthermore, the A22-B22 analog maintains the native insulin tertiary structure as demonstrated by X-ray crystal structure determination. We further demonstrate that this four-disulfide analog has similar in vivo potency in mice compared to native insulin and demonstrates higher aggregation stability. In conclusion, we have discovered a novel four-disulfide insulin analog with high aggregation stability and potency.

A structurally minimized yet fully active insulin based on cone-snail venom insulin principles.

Human insulin and its current therapeutic analogs all show propensity, albeit varyingly, to self-associate into dimers and hexamers, which delays their onset of action and makes blood glucose management difficult for people with diabetes. Recently, we described a monomeric, insulin-like peptide in cone-snail venom with moderate human insulin-like bioactivity. Here, with insights from structural biology studies, we report the development of mini-Ins-a human des-octapeptide insulin analog-as a structurally minimal, full-potency insulin. Mini-Ins is monomeric and, despite the lack of the canonical B-chain C-terminal octapeptide, has similar receptor binding affinity to human insulin. Four mutations compensate for the lack of contacts normally made by the octapeptide. Mini-Ins also has similar in vitro insulin signaling and in vivo bioactivities to human insulin. The full bioactivity of mini-Ins demonstrates the dispensability of the PheB24-PheB25-TyrB26 aromatic triplet and opens a new direction for therapeutic insulin development.

Author Correction: A structurally minimized yet fully active insulin based on cone-snail venom insulin principles.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.