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In germ cells, small non-coding PIWI-interacting RNAs (piRNAs) work to silence harmful transposons to maintain genomic stability and regulate gene expression to ensure fertility. However, these piRNAs must undergo a series of steps during biogenesis to be properly loaded onto PIWI proteins and reach the correct nucleotide length. This review is focused on what we are learning about a crucial step in this process, piRNA trimming, in which pre-piRNAs are shortened to final lengths of 21-35 nucleotides. Recently, the 3'-5' exonuclease trimmer has been identified in various models as PNLDC1/PARN-1. Mutations of the piRNA trimmers in vivo lead to increased transposon expression, elevated levels of untrimmed pre-piRNAs, decreased piRNA stability, and male infertility. Here, we will discuss the role of piRNA trimmers in piRNA biogenesis and function, describe consequences of piRNA trimmer mutations using mammalian models and human patients, and examine future avenues of piRNA trimming-related study for clinical advancements for male infertility.

Calcific aortic valve disease (CAVD) is a common cardiac defect, particularly in the aging population. While several risk factors, such as bi-leaflet valve structure and old age, have been identified in CAVD pathogenesis, molecular mechanisms resulting in this condition are still under active investigation. Bone morphogenetic protein signaling via the activin type I receptor (AcvRI) plays an important role during physiological and pathological processes involving calcification, e.g., bone formation and heterotopic ossification. In addition, AcvRI is required for normal cardiac valve development, yet its role in aortic valve disease, if any, is currently unknown. Here, we induced the expression of constitutively active AcvRI in developing mouse embryos in the endocardium and in cells at the valve leaflet–wall junction that are not of endocardium origin using the Nfac1Cre transgene. The mutant mice were born alive, but showed thickened aortic and pulmonary valve leaflets during the early postnatal period. Adult mutant mice developed aortic stenosis with high frequency, sclerotic aortic valves, and displayed Alcian Blue-positive hypertrophic chondrocyte-like cells at the leaflet–wall junction. Calcification was only seen with low penetrance. In addition, we observed that the expression levels of gene sets associated with inflammation-related cytokine signaling, smooth muscle cell contraction, and cGMP signaling were altered in the mutants when compared with those of the controls. This work shows that, in a mouse model, such continuous AcvRI activity in the Nfatc1Cre recombination domain results in pathological changes in the aortic valve structure and function.

To determine if the addition of alfentanil to propofol is more effective than propofol alone to provide adequate conditions for placement of a retrobulbar block prior to cataract surgery.Randomized, double-blinded study.Outpatients at a university hospital.40 adult ASA physical status I, II, and III outpatients scheduled for elective cataract surgery.Patients were randomly assigned to receive one of four drug combinations prior to the placement of a retrobulbar block: Group 1, propofol alone; Group 2, alfentanil 5 micrograms/kg plus propofol; Group 3, alfentanil 10 micrograms/kg plus propofol; Group 4, alfentanil 15 micrograms/kg plus propofol. All patients were preoxygenated by face mask for two minutes prior to drug administration. The quality of conditions for block placement were determined by: (1) assessing the amount of movement by the patients while the block needle was in place, (2) cooperativeness of the patients during the operation, (3) hemodynamic side effects, (4) incidence and severity of respiratory depression, (5) incidence of nausea and vomiting, (6) recall of placement of the block, and (7) time to discharge from the hospital.The addition of alfentanil to propofol for sedation prior to placement of the retrobulbar block resulted in a dose-dependent reduction in movement by the patients. However, the highest dose of alfentanil (15 micrograms/kg) resulted in the greatest frequency (40% of the patients in this group) of respiratory depression (SpO290%). All patients were cooperative during the operation and responsive to verbal command within 5 minutes of placement of the block. In addition, all of the patients denied being nauseated, having vomited, or recalling block placement in the recovery room or the next day.The combination of alfentanil and propofol may be used to sedate patients in order to limit movement and provide a cooperative, alert patient with stable hemodynamics and limited respiratory depression during placement of retrobulbar block prior to ophthalmic surgery. However, excessive dosage of these drugs may result in hazardous respiratory depression in this patient population.