Many acoustic problems involve acoustic wave radiation to the exterior field. A common approach in numerical simulations is to restrict the computational domain to a finite region with artificial boundaries. The so-called radiation or non-reflecting boundary conditions must be imposed at those artificial boundaries. Most existing non-reflecting boundary conditions are derived for computing disturbances propagating in a known uniform mean flow near the boundaries. In many applications such as the computation of jet noise or turbofan noise, the mean flow at an artificial boundary is non-uniform and unknown. The mean flow also needs to be computed in these cases. Incorrect computation of this mean flow at the boundary could directly affect the near field physics as well as the far field acoustics. In the present paper, a set of boundary conditions is proposed which focuses on computing the correct mean solution at an artificial boundary, while still maintaining the non-reflecting feature for the outgoing transient and acoustic waves.
Spastic paraplegia 50 (SPG50) is an ultrarare childhood-onset neurological disorder caused by biallelic loss-of-function variants in the AP4M1 gene. SPG50 is characterized by progressive spastic paraplegia, global developmental delay and subsequent intellectual disability, secondary microcephaly, and epilepsy. Preclinical studies evaluated an adeno-associated virus (AAV)/AP4M1 gene therapy for SPG50. In vitro studies demonstrated that transduction of patientderived fibroblasts with AAV2/AP4M1 resulted in phenotypic rescue. To evaluate efficacy in vivo, Ap4m1 knockout mice were intrathecally (IT) injected with 5E11, 2.5E11, or 1.25E11 vg doses of AAV9/AP4M1 at postnatal day p7-10 (pre-manifesting cohorts) or p90 (early manifesting cohorts). Age-and dose-dependent effects were observed, with early intervention and higher doses achieving the best therapeutic benefits. In parallel, three toxicology studies in wild-type mice, rats, and non-human primates (NHPs) demonstrated that AAV9/AP4M1 had an acceptable safety profile up to a target human dose of 1E15 vg. Of note, similar degrees of minimal to mild dorsal root ganglia (DRG) toxicity were observed in both rats and NHPs, supporting the use of rats to monitor DRG toxicity in future IT AAV studies. These preclinical results identify an acceptably safe and efficacious dose of IT-administered AAV9/AP4M1, supporting an investigational gene transfer clinical trial to treat SPG50.
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