Data-based modeling of drug penetration relates human skin barrier function to the interplay of diffusivity and free-energy profiles

Based on experimental concentration depth profiles of the antiinflammatory drug dexamethasone in human skin, we model the time-dependent drug penetration by the 1D general diffusion equation that accounts for spatial variations in the diffusivity and free energy. For this, we numerically invert the diffusion equation and thereby obtain the diffusivity and the free-energy profiles of the drug as a function of skin depth without further model assumptions. As the only input, drug concentration profiles derived from X-ray microscopy at three consecutive times are used. For dexamethasone, skin barrier function is shown to rely on the combination of a substantially reduced drug diffusivity in the stratum corneum (the outermost epidermal layer), dominant at short times, and a pronounced free-energy barrier at the transition from the epidermis to the dermis underneath, which determines the drug distribution in the long-time limit. Our modeling approach, which is generally applicable to all kinds of barriers and diffusors, allows us to disentangle diffusivity from free-energetic effects. Thereby we can predict short-time drug penetration, where experimental measurements are not feasible, as well as long-time permeation, where ex vivo samples deteriorate, and thus span the entire timescales of biological barrier functioning

Mesoscopic models for DNA stretching under force: new results and comparison to experiments

Single molecule experiments on B-DNA stretching have revealed one or two structural transitions, when increasing the external force. They are characterized by a sudden increase of DNA contour length and a decrease of the bending rigidity. It has been proposed that the first transition, at forces of 60--80 pN, is a transition from B to S-DNA, viewed as a stretched duplex DNA, while the second one, at stronger forces, is a strand peeling resulting in single stranded DNAs (ssDNA), similar to thermal denaturation. But due to experimental conditions these two transitions can overlap, for instance for poly(dA-dT). We derive analytical formula using a coupled discrete worm like chain-Ising model. Our model takes into account bending rigidity, discreteness of the chain, linear and non-linear (for ssDNA) bond stretching. In the limit of zero force, this model simplifies into a coupled model already developed by us for studying thermal DNA melting, establishing a connexion with previous fitting parameter values for denaturation profiles. We find that: (i) ssDNA is fitted, using an analytical formula, over a nanoNewton range with only three free parameters, the contour length, the bending modulus and the monomer size; (ii) a surprisingly good fit on this force range is possible only by choosing a monomer size of 0.2 nm, almost 4 times smaller than the ssDNA nucleobase length; (iii) mesoscopic models are not able to fit B to ssDNA (or S to ss) transitions; (iv) an analytical formula for fitting B to S transitions is derived in the strong force approximation and for long DNAs, which is in excellent agreement with exact transfer matrix calculations; (v) this formula fits perfectly well poly(dG-dC) and $\lambda$-DNA force-extension curves with consistent parameter values; (vi) a coherent picture, where S to ssDNA transitions are much more sensitive to base-pair sequence than the B to S one, emerges.Comment: 14 pages, 9 figure

Survey of Beneficial Insects in Undisturbed Cattle Droppings on Oahu, Hawaii

Insects were collected from cattle droppings at 2 locations on Oahu, Hawaii; one on the wet east side (Kualoa) and one on the dry northwest side (Poamoho). From these areas, 7 species of Scarabaeidae were collected. The most numerous species were Onthophagus gazalla F., Onthophagus sagittarius (L.), and Aphodius lividus (Oliver). Four species of Hydrophilidae were collected of which Cercyon quisquilius (L.) was the most numerous. Of the predator beetles, 9 species of Staphylinidae [Oxytelus sp., Philonthus (probably longicornis Steph.), Philonthus rectangulus Shp., Philonthus discoideus Grav., Philonthus sp., Platystethus sp., Lithocharis sp., Eulissus sp., and Xantholininae gen. sp.] and 2 Histeridae [Pachylister caffer (Erich.) and Hister nomus Erich. J were collected; all low in numbers except the Oxytelus species. Dipterous larvae, in 6 families and other unidentified families, were collected. In general, beetles were more abundant at Poamoho than at Kualoa and dipterous larvae were more abundant at Kualoa

Susceptibilidade do besouro rola-bosta africano a reguladores de crescimento de insetos Susceptibility of African dung beetle to insect growth regulators

Verificou-se a ação dos reguladores de crescimento de insetos (IGR), diflubenzuron e methoprene, sobre o besouro rola-bosta africano, Digitonthophagus gazella (Fabricius), um inimigo natural da mosca-dos-chifres, Haematobia irritans irritans (Linnaeus). Casais de besouros foram colocados em baldes contendo terra úmida e alimentados com fezes bovinas contendo 1, 0,5 ou 0,2ppm de diflubenzuron e 0,2ppm de methoprene. Os insetos e sua prole foram recuperados com o auxílio de armadilhas pitfall. Diflubenzuron e methoprene não afetaram a sobrevivência dos adultos inicialmente expostos, mas interferiram na produção de descendentes. Diflubenzuron, nas concentrações de 1 e 0,5ppm, também afetou a duração do ciclo de vida dos besouros. Nenhum dos IGRs alterou a razão sexual dos descendentes obtidos. As concentrações testadas de diflubenzuron mostraram-se moderadamente nocivas ao besouro enquanto methoprene a 0,2ppm mostrou ser pouco nocivo, segundo os critérios da International Organization for Biological Control.<br>The effects of insect growth regulators (IGR), diflubenzuron and methoprene, on African dung beetle, Digitonthophagus gazella (Fabricius), a natural enemy of the horn fly, Haematobia irritans irritans (Linnaeus), was studied. Beetles were placed in buckets partially filled with humid soil and were fed bovine feces containing 1, 0.5, or 0.2ppm diflubenzuron and 0.2ppm methoprene. Insects and their progenies were recovered by pitfall traps. Diflubenzuron and methoprene did not affect the survival of the adults but reduced their progenies. Diflubenzuron 1 and 0.5ppm also affected the life cicle of the beetles. None of the IGR modified the gender ratio of the progenies. According to the IOBC criteria, diflubenzuron tested concentrations showed to be moderately harmful to the beetles, whereas methoprene 0.2ppm was slightly harmful