Therapeutic and cytotoxic effects of the novel antipsoriasis codrug, naproxyl-dithranol, on HaCaT cells

A novel topical codrug, naproxyl–dithranol (Nap-DTH), in which dithranol and naproxen are linked via an ester in a 1:1 ratio to form a single chemical entity, was synthesized. The antiproliferative, anti-inflammatory and toxic effects of Nap-DTH were assessed, at the cellular level, using various in vitro methods. Cultured HaCaT keratinocytes were treated with Nap-DTH, and the cellular effects were compared with those of the parent compounds, individually and as a 1:1 mixture of naproxen:dithranol to mimic 1:1 in situ liberation from Nap-DTH. The results demonstrate that Nap-DTH did not modify proliferation and only exhibited slight toxic effects after 24 h at concentrations >21 μM. At a lower concentration (3.4 μM), Nap-DTH did not alter cell proliferation or inflammation, which suggests that the codrug is therapeutically inert. Relating to this, the 1:1 mixture of naproxen:dithranol exhibited the lowest toxic effect and the highest antiproliferative effect on HaCaT keratinocytes compared to dithranol at the same concentration. Moreover, the 1:1 mixture exhibited a reduced inflammatory effect compared to dithranol alone, as reflected by the upregulation of cyclooxygenase-2 by 45% and 136%, respectively. In spite of the 1:1 mixture showing a greater downregulation of Ki-67 and a 2-fold reduction of proliferating cell nuclear antigen (both cellular markers of proliferation) than dithranol, dithranol showed a much greater induction of cleaved caspase-3 protein expression (upregulated by 287%, compared to 85% for the 1:1 mixture). This suggests that when dithranol was administered with naproxen, inhibition of cell growth plays a more important role in the antiproliferation effects than the induction of apoptotic cell death. These results confirm that the codrug would lead to a better therapeutic profile and fewer adverse effects compared to its parent compounds.

Adding value to ecological risk assessment with population modeling

Current measures used to estimate the risks of toxic chemicals are not relevant to the goals of the environmental protection process, and thus ecological risk assessment (ERA) is not used as extensively as it should be as a basis for cost-effective management of environmental resources. Appropriate population models can provide a powerful basis for expressing ecological risks that better inform the environmental management process and thus that are more likely to be used by managers. Here we provide at least five reasons why population modeling should play an important role in bridging the gap between what we measure and what we want to protect. We then describe six actions needed for its implementation into management-relevant ERA.

Factors affecting regional SMEs progression to Digital Business Ecosystems

SMEs are widely recognized as an important driving force of economic growth, yet, their uptake of ICT is still very low. Tosupport SMEs ICT adoption and to foster regional development, in 2000, the Lisbon Strategy on the Information Society andKnowledge-based economy created a vision for 2010 towards the creation of the European Digital Business Ecosystems(DBE). This paper is positioned within that context and reports upon a project involving 6000 SMEs whose aim was tosupport ICT adoption and to encourage SME networks through the creation of a Regional Business Portal. The papere xplores factors affecting the regional SMEs participating in the DBE. An in-depth longitudinal case study approach was adopted and multiple sources of evidence were used. Many factors affecting SMEs progression to DBE were identified:including people and organization, environmental, diffusion networks, technological, regional and time factors

Wind-direction effects on urban-type flows

Practically all extant work on flows over obstacle arrays, whether laboratory experiments or numerical modelling, is for cases where the oncoming wind is normal to salient faces of the obstacles. In the field, however, this is rarely the case. Here, simulations of flows at various directions over arrays of cubes representing typical urban canopy regions are presented and discussed. The computations are of both direct numerical simulation and large-eddy simulation type. Attention is concentrated on the differences in the mean flow within the canopy region arising from the different wind directions and the consequent effects on global properties such as the total surface drag, which can change very significantly—by up to a factor of three in some circumstances. It is shown that for a given Reynolds number the typical viscous forces are generally a rather larger fraction of the pressure forces (principally the drag) for non-normal than for normal wind directions and that, dependent on the surface morphology, the average flow direction deep within the canopy can be largely independent of the oncoming wind direction. Even for regular arrays of regular obstacles, a wind direction not normal to the obstacle faces can in general generate a lateral lift force (in the direction normal to the oncoming flow). The results demonstrate this and it is shown how computations in a finite domain with the oncoming flow generated by an appropriate forcing term (e.g. a pressure gradient) then lead inevitably to an oncoming wind direction aloft that is not aligned with the forcing term vector.

Chemical characterisation and determination of sensory attributes of hydrolysates produced by enzymatic hydrolysis of whey proteins following a novel integrative process

The overall aim of this work was to characterize the major angiotensin converting enzyme (ACE) inhibitory peptides produced by enzymatic hydrolysis of whey proteins, through the application of a novel integrative process. This process consisted of the combination of adsorption and microfiltration within a stirred cell unit for the selective immobilization of β-lactoglobulin and casein derived peptides (CDP) from whey. The adsorbed proteins were hydrolyzed in-situ which resulted in the separation of peptide products from the substrate and fractionation of peptides. Two different hydrolysates were produced: (i) from CDP (IC50 =287μg/mL) and (ii) from β-lactoglobulin (IC50=128μg/mL). IC50 is the concentration of inhibitor needed to inhibit ACE by half. The well known antihypertensive peptide IPP and several novel peptides that have structural similarities with reported ACE inhibitory peptides were identified and characterized in both hydrolysates. Furthermore, the hydrolysates were assessed for bitterness. No significant difference was found between the control (milk with no hydrolysate) and hydrolysate samples at different concentrations (at, below and above the IC50).

Rhinocetin, a venom-derived integrin-specific antagonist inhibits collagen-induced platelet and endothelial cell functions

Snaclecs are small non-enzymatic proteins present in viper venoms reported to modulate haemostasis of victims through effects on platelets, vascular endothelial and smooth muscle cells. In this study, we have isolated and functionally characterised a snaclec which we named rhinocetin from the venom of West African gaboon viper, Bitis gabonica rhinoceros. Rhinocetin was shown to comprise α and β chains with the molecular masses of 13.5 and 13kDa respectively. Sequence and immunoblot analysis of rhinocetin confirmed this to be a novel snaclec. Rhinocetin inhibited collagen-stimulated activation of human platelets in dose dependent manner, but displayed no inhibitory effects on glycoprotein VI (collagen receptor) selective agonist, CRP-XL-, ADP- or thrombin-induced platelet activation. Rhinocetin antagonised the binding of monoclonal antibodies against the α2 subunit of integrin α2β1 to platelets and coimmunoprecipitation analysis confirmed integrin α2β1 as a target for this venom protein. Rhinocetin inhibited a range of collagen induced platelet functions such as fibrinogen binding, calcium mobilisation, granule secretion, aggregation and thrombus formation. It also inhibited integrin α2β1 dependent functions of human endothelial cells. Together, our data suggest rhinocetin to be a modulator of integrin α2β1 function and thus may provide valuable insights into the role of this integrin in physiological and pathophysiological scenarios including haemostasis, thrombosis and envenomation.

Turbulence dynamics near a turbulent/non-turbulent interface

The characteristics of the boundary layer separating a turbulence region from an irrotational (or non-turbulent) flow region are investigated using rapid distortion theory (RDT). The turbulence region is approximated as homogeneous and isotropic far away from the bounding turbulent/non-turbulent (T/NT) interface, which is assumed to remain approximately flat. Inviscid effects resulting from the continuity of the normal velocity and pressure at the interface, in addition to viscous effects resulting from the continuity of the tangential velocity and shear stress, are taken into account by considering a sudden insertion of the T/NT interface, in the absence of mean shear. Profiles of the velocity variances, turbulent kinetic energy (TKE), viscous dissipation rate (epsilon), turbulence length scales, and pressure statistics are derived, showing an excellent agreement with results from direct numerical simulations (DNS). Interestingly, the normalized inviscid flow statistics at the T/NT interface do not depend on the form of the assumed TKE spectrum. Outside the turbulent region, where the flow is irrotational (except inside a thin viscous boundary layer), epsilon decays as z^{-6}, where z is the distance from the T/NT interface. The mean pressure distribution is calculated using RDT, and exhibits a decrease towards the turbulence region due to the associated velocity fluctuations, consistent with the generation of a mean entrainment velocity. The vorticity variance and epsilon display large maxima at the T/NT interface due to the inviscid discontinuities of the tangential velocity variances existing there, and these maxima are quantitatively related to the thickness delta of the viscous boundary layer (VBL). For an equilibrium VBL, the RDT analysis suggests that delta ~ eta (where eta is the Kolmogorov microscale), which is consistent with the scaling law identified in a very recent DNS study for shear-free T/NT interfaces.

Entrepreneurial opportunities, implicit contracts and market making for complex consumer goods

This article extends the theory of entrepreneurial opportunity exploitation, outlining how under certain conditions, opportunity exploitation is dependent on market making innovations. Where adverse selection and moral hazard characterize markets, consumers are likely to withdraw regardless of product quality. In order to overcome consumer resistance, entrepreneurs must signal credible commitments. But because consumers purchase without fully specifying requirements, entrepreneurs' commitments take the partial form of implicit contracts, creating strong mutual commitments to repeated transactions. These commitments enable novel markets to function, but introduce additional costs. This article illustrates the theory with the historic case of Singer in sewing machines

The Natural History of Slapton Ley Nature Reserve XVIII: nitrogen and phosphorus losses from the catchment - an export coefficient modelling approach

Nitrogen and phosphorus losses from the catchment of Slapton Ley, a small coastal lake in SW England, were calculated using an adaptation of a model developed by Jorgensen (1980). A detailed survey of the catchment revealed that its land use is dominated by both permanent and temporary grassland (respectively 38 and 32% of its total area), and that the remainder is made up of the cultivation of cereals and field vegetables, and market gardening. Livestock numbers in the catchment constitute ca. 6600 head of cattle, 10,000 sheep, 590 pigs, 1700 poultry and 58 horses. The permanent human population of the area is ca. 2000, served by two small gravity-fed sewage treatment works (STWs). Inputs to, and losses from, farmland in the catchment were computed using Jorgensen’s model, and coefficients derived from the data of Cooke (1976), Gostick (1982), Rast and Lee (1983) and Vollenweider (1968). Allowing for outputs from STWs, the total annual external load of N and P upon Slapton Ley is 160 t (35 kg ha-1) a-1 N, and 4.8 t (1.05 kg ha-1) a-1 P. Accordingly to Vollenweider (1968, 1975), such loadings exceed OECD permissible level by a factor of ca. 50 in the case of N, and ca. 5 in that of P. In order to reduce nutrient loads, attention would need to be paid to both STW and agricultural sources.