Numerical simulation of iontophoresis for in-silico prediction of transdermal drugs in the dermal layers using skin impedance values.

BACKGROUND AND OBJECTIVE: Transdermal delivery of a therapeutic drug is a non-invasive method of drug administration. For a controlled delivery of the maximum number of drugs, several external enhancement mechanisms are used in the domain of transdermal drug delivery (TDD). Iontophoresis is one of the processes which uses a weak electric current to increase drug delivery and electrically control its penetration into the body. This method is governed by the Nernst-Planck equation, which gives the total flux of administering drugs due to iontophoresis. In this work, an effort has been made to simulate iontophoresis to predict transdermal drugs in the dermal layers using electrical equivalent skin models. METHODS: As the executable route of drug administration is skin, the electrical impedance value of the dermal layers can be utilized in predicting the amount of iontophoretic drug flux by introducing impedance parameters of skin in the Nernst-Planck equation. Researchers have developed electrical equivalent models of skin that explain the skin's physiological stratification and biological properties. RESULTS: Numerical simulation of iontophoresis is performed using the human skin impedance values with these impedance models of skin to predict drug concentrations in the dermal layers. For the computation and analysis of drug delivery using simulations, boundary conditions were developed based on the descriptions of the electrical impedance models and the morphology of human skin. CONCLUSIONS: This proposed method establishes a clear relationship between TDD and skin impedance. It could be used in in-silico prediction before experimentation of any drugs on live animals or humans. The adopted methodology could be implemented in programming to develop software for real-time prediction of transdermal drugs in dermal layers using instantaneous skin impedance values. Further researchers can work upon this idea to include more natural constraints that identify complex biological features of the skin and physio-chemical properties of drugs.

Rates of protoplanetary accretion and differentiation set nitrogen budget of rocky planets.

The effect of protoplanetary differentiation on the fate of life-essential volatiles like nitrogen and carbon and its subsequent effect on the dynamics of planetary growth is unknown. Because the dissolution of nitrogen in magma oceans depends on its partial pressure and oxygen fugacity, it is an ideal proxy to track volatile re-distribution in protoplanets as a function of their sizes and growth zones. Using high pressure-temperature experiments in graphite-undersaturated conditions, here we show that the siderophile (iron-loving) character of nitrogen is an order of magnitude higher than previous estimates across a wide range of oxygen fugacity. The experimental data combined with metal-silicate-atmosphere fractionation models suggest that asteroid-sized protoplanets, and planetary embryos that grew from them, were nitrogen-depleted. However, protoplanets that grew to planetary embryo-size before undergoing differentiation had nitrogen-rich cores and nitrogen-poor silicate reservoirs. Bulk silicate reservoirs of large Earth-like planets attained nitrogen from the cores of latter type of planetary embryos. Therefore, to satisfy the volatile budgets of Earth-like planets during the main stage of their growth, the timescales of planetary embryo accretion had to be shorter than their differentiation timescales, i.e., Moon- to Mars-sized planetary embryos grew rapidly within ~1-2 Myrs of the Solar System's formation.

Estimation of skin impedance models with experimental data and a proposed model for human skin impedance.

The skin is a complex biological tissue whose impedance varies with frequency. The properties and structure of skin changes with the location on the body, age, geographical location and other factors. Considering these factors, skin impedance analysis is a sophisticated data analysis. However, despite all these variations, various researchers have always worked to develop an equivalent electrical model of the skin. The two most important categories of electrical models are RC-based model and CPE-based model which focus on the physiological stratification and biological properties of skin, respectively. In this work, experimental skin impedance data is acquired from ten sites on the body to find the fitting model. It is observed that a hybrid of fractional-order CPE-based model and higher-order RC layered-based model can provide the best fitting electrical model of skin. A new model is developed with this hybrid orders. Genetic algorithm is used for the extraction of parameter components. Least error of fitting has been observed for the proposed model as compared with the other models. This model can be used in correlating many skin problems and in the development of diagnostic tools. It will offer an additional supportive tool in-vitro to the medical specialist.

Various skin impedance models based on physiological stratification.

Transdermal drug delivery is a non-invasive method of drug administration. However, to achieve this, the drug has to pass through the complicated structure of the skin. The complex structure of skin can be modelled by an electrical equivalent circuit to calculate its impedance. In this work, the transfer function of three electrical models of the human skin (Montague, Tregear and Lykken Model) based on physiological stratification are analysed. Sensitivity analysis of these models is carried out to consider the extent to which changes in system parameters (different types of R and C as described by different models) affect the behaviour of the model. Techniques like normal of derivative and Hausdorff Distance is also used to study and understand the different curves. Comparison is also made with CPE based model. As Montague Model is the most widely used model, Tregear and Lykken Model are compared with it. It can be commented that out of the above observations Tregear Model at Level 3 can be used for establishing the electrical equivalent of human skin due to its simplicity. However, fractional ordered CPE models provide a good approximation. Future prospect lies in developing a model that characterize both biological properties and physiological stratification.

Great Oxidation and Lomagundi events linked by deep cycling and enhanced degassing of carbon.

For approximately the first 2 billion years of Earth history, atmospheric oxygen levels were extremely low. It wasn't until at least half a billion years after the evolution of oxygenic photosynthesis, perhaps as early as 3 billion years ago, that oxygen rose to appreciable levels during the Great Oxidation event. Shortly after, marine carbonates experienced a large positive spike in carbon isotope ratios known as the Lomagundi event. The mechanisms responsible for the Great Oxidation and Lomagundi events remain debated. Using a carbon-oxygen box model which tracks surface and interior C fluxes and reservoirs while also tracking C isotopes and atmospheric oxygen levels we demonstrate that about 2.5 billion years ago a tectonic transition resulting in increased volcanic CO2 emissions could have led to increased deposition of both carbonates and organic carbon via enhanced weathering and nutrient delivery to oceans. Increased burial of carbonates and organic carbon would have allowed accumulation of atmospheric oxygen while also increasing delivery of carbon to subduction zones. Coupled with preferential release of carbonates at arc volcanoes and deep recycling of organic C to ocean island volcanoes we find such a tectonic transition can simultaneously explain the Great Oxidation and Lomagundi events without any change in the fraction of carbon buried as organic carbon relative to carbonate, which is often invoked to explain carbon isotope excursions.

Delivery of carbon, nitrogen, and sulfur to the silicate Earth by a giant impact.

Earth's status as the only life-sustaining planet is a result of the timing and delivery mechanism of carbon (C), nitrogen (N), sulfur (S), and hydrogen (H). On the basis of their isotopic signatures, terrestrial volatiles are thought to have derived from carbonaceous chondrites, while the isotopic compositions of nonvolatile major and trace elements suggest that enstatite chondrite-like materials are the primary building blocks of Earth. However, the C/N ratio of the bulk silicate Earth (BSE) is superchondritic, which rules out volatile delivery by a chondritic late veneer. In addition, if delivered during the main phase of Earth's accretion, then, owing to the greater siderophile (metal loving) nature of C relative to N, core formation should have left behind a subchondritic C/N ratio in the BSE. Here, we present high pressure-temperature experiments to constrain the fate of mixed C-N-S volatiles during core-mantle segregation in the planetary embryo magma oceans and show that C becomes much less siderophile in N-bearing and S-rich alloys, while the siderophile character of N remains largely unaffected in the presence of S. Using the new data and inverse Monte Carlo simulations, we show that the impact of a Mars-sized planet, having minimal contributions from carbonaceous chondrite-like material and coinciding with the Moon-forming event, can be the source of major volatiles in the BSE.

The fate of nitrogen during core-mantle separation on Earth.

Nitrogen, the most dominant constituent of Earth's atmosphere, is critical for the habitability and existence of life on our planet. However, its distribution between Earth's major reservoirs, which must be largely influenced by the accretion and differentiation processes during its formative years, is poorly known. Sequestration into the metallic core, along with volatility related loss pre- and post-accretion, could be a critical process that can explain the depletion of nitrogen in the Bulk Silicate Earth (BSE) relative to the primitive chondrites. However, the relative effect of different thermodynamic parameters on the alloy-silicate partitioning behavior of nitrogen is still poorly known. Here we present equilibrium partitioning data of N between alloy and silicate melt ( D N alloy / silicate ) from 67 new high pressure (P = 1-6 GPa)-temperature (T = 1500-2200 °C) experiments under graphite saturated conditions at a wide range of oxygen fugacity (logfO2 ~ΔIW - 4.2 to - 0.8), mafic to ultramafic silicate melt compositions (NBO/T = 0.4 to 2.2), and varying chemical composition of the alloy melts (S and Si contents of 0-32.1 wt.% and 0-3.1 wt.%, respectively). Under relatively oxidizing conditions (~ΔIW - 2.2 to - 0.8) nitrogen acts as a siderophile element ( D N alloy / silicate between 1.1 and 52), where D N alloy / silicate decreases with decrease in fO2 and increase in T, and increases with increase in P and NBO/T. Under these conditions D N alloy / silicate remains largely unaffected between S-free conditions and up to ~17 wt.% S content in the alloy melt, and then drops off at > ~20 wt.% S content in the alloy melt. Under increasingly reduced conditions (< ~ ΔIW - 2.2), N becomes increasingly lithophile ( D N alloy / silicate between 0.003 and 0.5) with D N alloy / silicate decreasing with decrease in fO2 and increase in T. At these conditions fO2, along with Si content of the alloy under the most reduced conditions (< ~ΔIW - 3.0), is the controlling parameter with T playing a secondary role, while, P, NBO/T, and S content of the alloy have minimal effects. A multiple linear least-squares regression parametrization for D N alloy / silicate based on the results of this study and previous studies suggests, in agreement with the experimental data, that fO2 (represented by Si content of the alloy melt and FeO content of the silicate melt), followed by T, has the strongest control on D N alloy / silicate . Based on our modeling, to match the present-day BSE N content, impactors that brought N must have been moderately to highly oxidized. If N bearing impactors were reduced, and/or there was significant disequilibrium core formation, then the BSE would be too N-rich and another mechanism for N loss, such as atmospheric loss, would be required.

Carbon-dioxide-rich silicate melt in the Earth's upper mantle.

The onset of melting in the Earth's upper mantle influences the thermal evolution of the planet, fluxes of key volatiles to the exosphere, and geochemical and geophysical properties of the mantle. Although carbonatitic melt could be stable 250 km or less beneath mid-oceanic ridges, owing to the small fraction (∼0.03 wt%) its effects on the mantle properties are unclear. Geophysical measurements, however, suggest that melts of greater volume may be present at ∼200 km (refs 3-5) but large melt fractions are thought to be restricted to shallower depths. Here we present experiments on carbonated peridotites over 2-5 GPa that constrain the location and the slope of the onset of silicate melting in the mantle. We find that the pressure-temperature slope of carbonated silicate melting is steeper than the solidus of volatile-free peridotite and that silicate melting of dry peridotite + CO(2) beneath ridges commences at ∼180 km. Accounting for the effect of 50-200 p.p.m. H(2)O on freezing point depression, the onset of silicate melting for a sub-ridge mantle with ∼100 p.p.m. CO(2) becomes as deep as ∼220-300 km. We suggest that, on a global scale, carbonated silicate melt generation at a redox front ∼250-200 km deep, with destabilization of metal and majorite in the upwelling mantle, explains the oceanic low-velocity zone and the electrical conductivity structure of the mantle. In locally oxidized domains, deeper carbonated silicate melt may contribute to the seismic X-discontinuity. Furthermore, our results, along with the electrical conductivity of molten carbonated peridotite and that of the oceanic upper mantle, suggest that mantle at depth is CO(2)-rich but H(2)O-poor. Finally, carbonated silicate melts restrict the stability of carbonatite in the Earth's deep upper mantle, and the inventory of carbon, H(2)O and other highly incompatible elements at ridges becomes controlled by the flux of the former.

Copper systematics in arc magmas and implications for crust-mantle differentiation.

Arc magmas are important building blocks of the continental crust. Because many arc lavas are oxidized, continent formation is thought to be associated with oxidizing conditions. On the basis of copper's (Cu's) affinity for reduced sulfur phases, we tracked the redox state of arc magmas from mantle source to emplacement in the crust. Primary arc and mid-ocean ridge basalts have identical Cu contents, indicating that the redox states of primitive arc magmas are indistinguishable from that of mid-ocean ridge basalts. During magmatic differentiation, the Cu content of most arc magmas decreases markedly because of sulfide segregation. Because a similar depletion in Cu characterizes global continental crust, the formation of sulfide-bearing cumulates under reducing conditions may be a critical step in continent formation.

The redox state of arc mantle using Zn/Fe systematics.

Many arc lavas are more oxidized than mid-ocean-ridge basalts and subduction introduces oxidized components into the mantle. As a consequence, the sub-arc mantle wedge is widely believed to be oxidized. The Fe oxidation state of sub-arc mantle is, however, difficult to determine directly, and debate persists as to whether this oxidation is intrinsic to the mantle source. Here we show that Zn/Fe(T) (where Fe(T) = Fe(2+) + Fe(3+)) is redox-sensitive and retains a memory of the valence state of Fe in primary arc basalts and their mantle sources. During melting of mantle peridotite, Fe(2+) and Zn behave similarly, but because Fe(3+) is more incompatible than Fe(2+), melts generated in oxidized environments have low Zn/Fe(T). Primitive arc magmas have identical Zn/Fe(T) to mid-ocean-ridge basalts, suggesting that primary mantle melts in arcs and ridges have similar Fe oxidation states. The constancy of Zn/Fe(T) during early differentiation involving olivine requires that Fe(3+)/Fe(T) remains low in the magma. Only after progressive fractionation does Fe(3+)/Fe(T) increase and stabilize magnetite as a fractionating phase. These results suggest that subduction of oxidized crustal material may not significantly alter the redox state of the mantle wedge. Thus, the higher oxidation states of arc lavas must be in part a consequence of shallow-level differentiation processes, though such processes remain poorly understood.

Upside-down differentiation and generation of a 'primordial' lower mantle.

Except for the first 50-100 million years or so of the Earth's history, when most of the mantle may have been subjected to melting, the differentiation of Earth's silicate mantle has been controlled by solid-state convection. As the mantle upwells and decompresses across its solidus, it partially melts. These low-density melts rise to the surface and form the continental and oceanic crusts, driving the differentiation of the silicate part of the Earth. Because many trace elements, such as heat-producing U, Th and K, as well as the noble gases, preferentially partition into melts (here referred to as incompatible elements), melt extraction concentrates these elements into the crust (or atmosphere in the case of noble gases), where nearly half of the Earth's budget of these elements now resides. In contrast, the upper mantle, as sampled by mid-ocean ridge basalts, is highly depleted in incompatible elements, suggesting a complementary relationship with the crust. Mass balance arguments require that the other half of these incompatible elements be hidden in the Earth's interior. Hypotheses abound for the origin of this hidden reservoir. The most widely held view has been that this hidden reservoir represents primordial material never processed by melting or degassing. Here, we suggest that a necessary by-product of whole-mantle convection during the Earth's first billion years is deep and hot melting, resulting in the generation of dense liquids that crystallized and sank into the lower mantle. These sunken lithologies would have 'primordial' chemical signatures despite a non-primordial origin.

Investigation of in vitro iontophoresis facilitated transdermal delivery of glycine.

The research presented in this paper discusses the potential of iontophoresis facilitated transdermal delivery of glycine. Iontophoresis has been widely investigated as a noninvasive transdermal drug delivery system. Iontophoresis is the use of a low electric current to carry ionized as well as unionized drug molecules across tissues (like skin) in a noninvasive technique. In the present paper, a custom made low cost, battery powered, portable transdermal iontophoretic system has been investigated for the various parameters of transdermal iontophoretic drug delivery namely drug density in donor formulation, current density, current profile, presence of competitive ions and type of electrode material. In vitro release studies of glycine, as a drug, were done using a modified Franz type glass diffusion cell through excised mouse skin. Factors affecting the delivery of glycine (a non-essential amino acid used to treat schizophrenia, anxiety, insomnia, hypoglycemia etc.) by iontophoresis include concentration of glycine in donor solution, ionic strength of donor solution, density of applied current & its aspect ratio. The change in frequency and electrode type (Ag/AgCl & stainless steel) did not have any significant effect on glycine delivery. In conclusion it could be stated that it is possible to achieve appreciable control over the transdermal delivery of glycine by the low-cost portable iontophoretic drug delivery system developed.

Melting in the Earth's deep upper mantle caused by carbon dioxide.

The onset of partial melting beneath mid-ocean ridges governs the cycling of highly incompatible elements from the mantle to the crust, the flux of key volatiles (such as CO2, He and Ar) and the rheological properties of the upper mantle. Geophysical observations indicate that melting beneath ridges begins at depths approaching 300 km, but the cause of this melting has remained unclear. Here we determine the solidus of carbonated peridotite from 3 to 10 GPa and demonstrate that melting beneath ridges may occur at depths up to 330 km, producing 0.03-0.3% carbonatite liquid. We argue that these melts promote recrystallization and realignment of the mineral matrix, which may explain the geophysical observations. Extraction of incipient carbonatite melts from deep within the oceanic mantle produces an abundant source of metasomatic fluids and a vast mantle residue depleted in highly incompatible elements and fractionated in key parent-daughter elements. We infer that carbon, helium, argon and highly incompatible heat-producing elements (such as uranium, thorium and potassium) are efficiently scavenged from depths of approximately 200-330 km in the upper mantle.