Small RNAs are key regulators in plant growth and development. One subclass, phased siRNAs (phasiRNAs) require a trigger microRNA for their biogenesis. In grasses, two pathways yield abundant phasiRNAs during anther development; miR2275 triggers one class, 24-nt phasiRNAs, coincident with meiosis, while a second class of 21-nt phasiRNAs are present in premeiotic anthers. Here we report that the 24-nt phasiRNA pathway is widely present in flowering plants, indicating that 24-nt reproductive phasiRNAs likely originated with the evolutionary emergence of anthers. Deep comparative genomic analyses demonstrated that this miR2275/24-nt phasiRNA pathway is widely present in eudicots plants, however, it is absent in legumes and in the model plant Arabidopsis, demonstrating a dynamic evolutionary history of this pathway. In Solanaceae species, 24-nt phasiRNAs were observed, but the miR2275 trigger is missing and some loci displaying 12-nt phasing. Both the miR2275-triggered and Solanaceae 24-nt phasiRNAs are enriched in meiotic stages, implicating these phasiRNAs in anther and/or pollen development, a spatiotemporal pattern consistent in all angiosperm lineages that deploy them.

This study aimed to investigate the pharmacokinetics (PK), safety, and tolerability of a single dose of ceftazidime-avibactam in pediatric patients. A phase I, multicenter, open-label PK study was conducted in pediatric patients hospitalized with an infection and receiving systemic antibiotic therapy. Patients were enrolled into four age cohorts (cohort 1, ≥12 to <18 years; cohort 2, ≥6 to <12 years; cohort 3, ≥2 to <6 years; cohort 4, ≥3 months to <2 years). Patients received a single 2-h intravenous infusion of ceftazidime-avibactam (cohort 1, 2,000 to 500 mg; cohort 2, 2,000 to 500 mg [≥40 kg] or 50 to 12.5 mg/kg [<40 kg]; cohorts 3 and 4, 50 to 12.5 mg/kg). Blood samples were collected to describe individual PK characteristics for ceftazidime and avibactam. Population PK modeling was used to describe characteristics of ceftazidime and avibactam PK across all age groups. Safety and tolerability were assessed. Thirty-two patients received study drug. Mean plasma concentration-time curves, geometric mean maximum concentration (Cmax), and area under the concentration-time curve from time zero to infinity (AUC0-∞) were similar across all cohorts for both drugs. Six patients (18.8%) reported an adverse event, all mild or moderate in intensity. No deaths or serious adverse events occurred. The single-dose PK of ceftazidime and avibactam were comparable between each of the 4 age cohorts investigated and were broadly similar to those previously observed in adults. No new safety concerns were identified. (This study has been registered at ClinicalTrials.gov under registration no. NCT01893346.).