Intracellular Delivery of Molecular Cargo Using Cell-Penetrating Peptides and the Combination Strategies

Cell-penetrating peptides (CPPs) can cross cellular membranes in a non-toxic fashion, improving the intracellular delivery of various molecular cargos such as nanoparticles, small molecules and plasmid DNA. Because CPPs provide a safe, efficient, and non-invasive mode of transport for various cargos into cells, they have been developed as vectors for the delivery of genetic and biologic products in recent years. Most common CPPs are positively charged peptides. While delivering negatively charged molecules (e.g., nucleic acids) to target cells, the internalization efficiency of CPPs is reduced and inhibited because the cationic charges on the CPPs are neutralized through the covering of CPPs by cargos on the structure. Even under these circumstances, the CPPs can still be non-covalently complexed with the negatively charged molecules. To address this issue, combination strategies of CPPs with other typical carriers provide a promising and novel delivery system. This review summarizes the latest research work in using CPPs combined with molecular cargos including liposomes, polymers, cationic peptides, nanoparticles, adeno-associated virus (AAV) and calcium for the delivery of genetic products, especially for small interfering RNA (siRNA). This combination strategy remedies the reduced internalization efficiency caused by neutralization.     

A Note on Diagnosing Multivariate Conditional Heteroscedasticity Models

In this paper we consider several tests for model misspecification after a multivariate conditional heteroscedasticity model has been fitted. We examine the performance of the recent test due to Ling and Li ( J. Time Ser. Anal. 18 (1997), 447–64), the Box–Pierce test and the residual-based F test using Monte Carlo methods. We find that there are situations in which the Ling–Li test has very weak power. The residual-based diagnostics demonstrate significant under-rejection under the null. In contrast, the Box–Pierce test based on the cross-products of the standardized residuals often provides a useful diagnostic that has reliable empirical size as well as good power against the alternatives considered.