Breaking in and Busting out: Cell-penetrating Peptides and the Endosomal Escape Problem

Cell-penetrating peptides (CPPs) have long held great promise for the manipulation of living cells for therapeutic and research purposes. They allow a wide array of biomolecules from large, oligomeric proteins to nucleic acids and small molecules to rapidly and efficiently traverse cytoplasmic membranes. With few exceptions, if a molecule can be associated with a CPP, it can be delivered into a cell. However, a growing realization in the field is that CPP-cargo fusions largely remain trapped in endosomes and are eventually targeted for degradation or recycling rather than released into the cytoplasm or trafficked to a desired subcellular destination. This ‘endosomal escape problem’ has confounded efforts to develop CPP-based delivery methods for drugs, enzymes, plasmids, etc. This review provides a brief history of CPP research and discusses current issues in the field with a primary focus on the endosomal escape problem, for which several promising potential solutions have been developed. Are we on the verge of developing technologies to deliver therapeutics such as siRNA, CRISPR/Cas complexes and others that are currently failing because of an inability to get into cells, or are we just chasing after another promising but unworkable technology? We make the case for optimism

Finite Volume Numerical Methods for Aeroheating Rate Calculations from Infrared Thermographic Data

The use of multi-dimensional finite volume heat conduction techniques for calculating aeroheating rates from measured global surface temperatures on hypersonic wind tunnel models was investigated. Both direct and inverse finite volume techniques were investigated and compared with the standard one-dimensional semi-infinite technique. Global transient surface temperatures were measured using an infrared thermographic technique on a 0.333-scale model of the Hyper-X forebody in the NASA Langley Research Center 20-Inch Mach 6 Air tunnel. In these tests the effectiveness of vortices generated via gas injection for initiating hypersonic transition on the Hyper-X forebody was investigated. An array of streamwise-orientated heating striations was generated and visualized downstream of the gas injection sites. In regions without significant spatial temperature gradients, one-dimensional techniques provided accurate aeroheating rates. In regions with sharp temperature gradients caused by striation patterns multi-dimensional heat transfer techniques were necessary to obtain more accurate heating rates. The use of the one-dimensional technique resulted in differences of 20% in the calculated heating rates compared to 2-D analysis because it did not account for lateral heat conduction in the model

Akirin Links Twist-Regulated Transcription with the Brahma Chromatin Remodeling Complex during Embryogenesis

The activities of developmentally critical transcription factors are regulated via interactions with cofactors. Such interactions influence transcription factor activity either directly through protein–protein interactions or indirectly by altering the local chromatin environment. Using a yeast double-interaction screen, we identified a highly conserved nuclear protein, Akirin, as a novel cofactor of the key Drosophila melanogaster mesoderm and muscle transcription factor Twist. We find that Akirin interacts genetically and physically with Twist to facilitate expression of some, but not all, Twist-regulated genes during embryonic myogenesis. akirin mutant embryos have muscle defects consistent with altered regulation of a subset of Twist-regulated genes. To regulate transcription, Akirin colocalizes and genetically interacts with subunits of the Brahma SWI/SNF-class chromatin remodeling complex. Our results suggest that, mechanistically, Akirin mediates a novel connection between Twist and a chromatin remodeling complex to facilitate changes in the chromatin environment, leading to the optimal expression of some Twist-regulated genes during Drosophila myogenesis. We propose that this Akirin-mediated link between transcription factors and the Brahma complex represents a novel paradigm for providing tissue and target specificity for transcription factor interactions with the chromatin remodeling machinery

Hypersonic Boundary-Layer Transition for X-33 Phase 2 Vehicle

A status review of the experimental and computational work performed to support the X-33 program in the area of hypersonic boundary-layer transition is presented. Global transition fronts are visualized using thermographic phosphor measurements. Results are used to derive transition correlations for "smooth body" and discrete roughness data and a computational tool is developed to predict transition onset for X-33 using these results. The X-33 thermal protection system appears to be conservatively designed for transition effects based on these studies. Additional study is needed to address concerns related to surface waviness. A discussion of future test plans is included

Numerical model for granular compaction under vertical tapping

A simple numerical model is used to simulate the effect of vertical taps on a packing of monodisperse hard spheres. Our results are in agreement with an experimantal work done in Chicago and with other previous models, especially concerning the dynamics of the compaction, the influence of the excitation strength on the compaction efficiency, and some ageing effects. The principal asset of the model is that it allows a local analysis of the packings. Vertical and transverse density profiles are used as well as size and volume distributions of the pores. An interesting result concerns the appearance of a vertical gradient in the density profiles during compaction. Furthermore, the volume distribution of the pores suggests that the smallest pores, ranging in size between a tetrahedral and an octahedral site, are not strongly affected by the tapping process, in contrast to the largest pores which are more sensitive to the compaction of the packing.Comment: 8 pages, 15 figures (eps), to be published in Phys. Rev. E. Some corrections have been made, especially in paragraph IV

Dilatancy transition in a granular model

We introduce a model of granular matter and use a stress ensemble to analyze shearing. Monte Carlo simulation shows the model to exhibit a second order phase transition, associated with the onset of dilatancy.Comment: Future versions can be obtained from: http://www.ma.utexas.edu/users/radin/papers/shear2.pd

Probing the outer edge of an accretion disk : a Her X-1 turn-on observed with RXTE

We present the analysis of Rossi X-ray Timing Explorer (RXTE) observations of the turn-on phase of a 35 day cycle of the X-ray binary Her X-1. During the early phases of the turn-on, the energy spectrum is composed of X-rays scattered into the line of sight plus heavily absorbed X-rays. The energy spectra in the 3–17 keV range can be described by a partial covering model, where one of the components is influenced by photoelectric absorption and Thomson scattering in cold material plus an iron emission line at 6.5 keV. In this paper we show the evolution of spectral parameters as well as the evolution of the pulse profile during the turn-on. We describe this evolution using Monte Carlo simulations which self-consistently describe the evolution of the X-ray pulse profile and of the energy spectrum