Pharmacokinetics, biodistribution and toxicology of novel cell-penetrating peptides.

Cell-penetrating peptides (CPPs) have been used in basic and preclinical research in the past 30 years to facilitate drug delivery into target cells. However, translation toward the clinic has not been successful so far. Here, we studied the pharmacokinetic (PK) and biodistribution profiles of Shuttle cell-penetrating peptides (S-CPP) in rodents, combined or not with an immunoglobulin G (IgG) cargo. We compared two enantiomers of S-CPP that contain both a protein transduction domain and an endosomal escape domain, with previously shown capacity for cytoplasmic delivery. The plasma concentration versus time curve of both radiolabelled S-CPPs required a two-compartment PK analytical model, which showed a fast distribution phase (t1/2α ranging from 1.25 to 3 min) followed by a slower elimination phase (t1/2ß ranging from 5 to 15 h) after intravenous injection. Cargo IgG combined to S-CPPs displayed longer elimination half-life, of up to 25 h. The fast decrease in plasma concentration of S-CPPs was associated with an accumulation in target organs assessed at 1 and 5 h post-injection, particularly in the liver. In addition, in situ cerebral perfusion (ISCP) of L-S-CPP yielded a brain uptake coefficient of 7.2 ± 1.1 µl g-1 s-1, consistent with penetration across the blood-brain barrier (BBB), without damaging its integrity in vivo. No sign of peripheral toxicity was detected either by examining hematologic and biochemical blood parameters, or by measuring cytokine levels in plasma. In conclusion, S-CPPs are promising non-toxic transport vectors for improved tissue distribution of drug cargos in vivo.

Rib Motions Don't Completely Hinge on Joint Design: Costal Joint Anatomy and Ventilatory Kinematics in a Teiid Lizard, Salvator merianae.

Rib rotations contribute to lung ventilation in most extant amniotes. These rotations are typically described as bucket-handle rotation about a dorsoventral axis, caliper rotation about a craniocaudal axis, and pump-handle rotation about a mediolateral axis. A synapomorphy for Lepidosauria is single-headed costovertebral articulations derived from the ancestral double-headed articulations of most amniotes. With a single articular surface, the costovertebral joints of squamates have the potential to rotate with three degrees-of-freedom (DOFs), but considerable variation exists in joint shape. We compared the costovertebral morphology of the Argentine black and white tegu, Salvator merianae, with the green iguana, Iguana iguana, and found that the costovertebral articulations of I. iguana were hemispherical, while those of S. merianae were dorsoventrally elongated and hemiellipsoidal. We predicted that the elongate joints in S. merianae would permit bucket-handle rotations while restricting caliper and pump-handle rotations, relative to the rounded joints of I. iguana. We used X-ray reconstruction of moving morphology to quantify rib rotations during breathing in S. merianae for comparison with prior work in I. iguana. Consistent with our hypothesis, we found less caliper motion in S. merianae than in I. iguana, but unexpectedly found similar pump-handle magnitudes in each species. The dorsoventrally elongate costovertebral morphology of S. merianae may provide passive rib support to reduce the conflict between locomotion and ventilation. Moreover, the observation of multiple DOFs during rib rotations in both species suggests that permissive costovertebral morphology may be more related to the biological roles of ribs outside of ventilation and help explain the evolution of this trait.

Natural character posing from a large motion database.

An interactive inverse kinematics approach robustly generates natural poses in a large human-reachable space. It employs adaptive kd clustering to select a representative frame set from a large motion database and employs sparse approximation to accelerate training and posing. Model training is required only once.