Engineering a pharmacologically superior form of leptin for the treatment of obesity

Leptin plays a central role in the homeostasis of body weight through its regulatory effects on appetite and energy expenditure, yet in trials as a therapeutic agent for the treatment of obesity in humans it has been disappointing. The poor clinical efficacy of leptin results from its short circulating half-life, low potency and poor solubility, necessitating large and frequent doses to obtain even modest clinical benefit. Engineered Fc-leptin immunofusins, consisting of the Fc fragment of an immunoglobulin gamma chain followed by leptin, exhibit improved pharmacological properties with very consistent and potent biological activities. Furthermore, in extending the circulating half-life of the protein in vivo from a few minutes for leptin to many hours for Fc-leptin, these proteins have the potential to reduce drastically the dosage and frequency of administration required to obtain clinical benefit. The results of this study show that the engineered leptin immunofusins described here have significantly enhanced pharmacological properties in comparison with the recombinant leptin that was used in clinical trials. As such, they could represent an important step towards a therapeutically superior form of leptin if the disappointing performance of leptin in early clinical trials was due to its poor pharmacological properties rather than any conceptual weakness in the strategy of using leptin for the treatment of obesity and its related disorders.     

Comparative reactivities of coal asphaltenes during hydropyrolysis

Comparisons have been drawn in the relative reactivities of three coal asphaltenes during hydropyrolysis. All were derived from hydrogen donor-solvent extracts of bituminous coal, but had different hydrotreatment histories and different carbon contents (87.1, 91.9 and 90.8 wt% for asphaltenes 1, 2 and 3, respectively). The hydropyrolyses were carried out in the presence of CoO–MoO₃ catalyst and gaseous hydrogen at 8.7 MPa. For two of the asphaltenes (1 and 2) systematic comparisons were made for different reaction times at 425°C; for all three asphaltenes comparisons were made for l h of hydropyrolysis at 425°C. The general pattern of asphaltenes conversion indicated that more pentane-soluble product was produced from asphaltene isolated from straight coal extract (asphaltene 1). For the asphaltenes isolated from hydrotreated extracts, the extent of conversion to liquids was limited when the carbon content was high (asphaltene 2) although the pattern of conversion was similar in the other hydrotreated asphaltene (asphaltene 3). The aliphatic content of the liquid products formed was low, and the distribution of hydrogenated species in the highly aromatic liquid products indicated that complete hydrogenation of the polyaromatics produced in pyrolysis is difficult. Altogether the aliphatics made up ≈ 10 wt% of the asphaltene 1 hydropyrolysate. Aromatic hydrocarbons made up 90% of the liquid product. Phenanthrene, pyrene and anthracene were prominent, and the largest component in the mixture was phenanthrene which, together with other polyaromatics such as fluoroanthene, dominated the liquid product.     

Coupling granule properties and granulation rates in high-shear granulation

It is possible to link granulation rates to granule properties. The linkage is by multiple dimension population balance equations that, by means of simplifying assumptions, can be reduced to multiple one-dimensional (1-D) population balance equations (PBEs). Using simple physically based models, this paper demonstrates how multiple one-dimensional population balance equations can describe the results of high-shear granulation experiments of two different materials, calcium carbonate and lactose. Good agreement between experimental and simulated results was achieved enabling the granulation rates to be defined by two model parameters: the critical binder volume fraction and the aggregation rate constant. The modelling framework presented in this paper also provides a basis for the kinetic analysis of granulation experiments so that with further work, it is possible to determine the effect of process conditions and material properties on the model parameters.     

Autocatalytic reactions in the isothermal,continuous stirred tank reactor: Isolas and other forms of multistability

Autocatalytic reactions are often complicated, and analyses of their behaviour in open systems can seem too particular to permit useful generalisation. We study here the simplest of circumstances (uniform temperatures and concentrations in the isothermal CSTR) and the simplest of reaction schemes: (i) quadratic autocatalysis (A + B→2B); and (ii) cubic autocatalysis (A + 2B→3B). The catalyst B may be stable or have a finite lifetime (B→ inert products). Allowing for this finite lifetime adds another dimension to the interest.The phenomena encountered include multistability, hysteresis, critical extinctions, critical ignitions, and anomalous relaxation times (though infinite values do not arise). Patterns of stationary states as function of residence time can show isolas and mushrooms. All these aspects yield to simple algebraic analysis. The presence of the catalyst B in the inflow can make qualitative differences of a kind parallelled by an additional, non-catalytic reaction of the same stoichiometry (e.g. A→B). Invoking the reversibility of the reactions neither increases nor diminishes their variety, and thermodynamic considerations have little to do with the many different patterns of reactivity displayed.The local stability of the various stationary states has also been characterized. Quadratic autocatalysis shows limited variety (stable node, stable focus); cubic autocatalysis generates all the kinds of stationary state possible in a two-variable system. Again all the algebra is straightforward if not always simple. Sustained oscillatory behavior (limit cycles) also occur.All these remarks relate to isothermal systems, but there are the most striking parallels between isothermal autocatalysis and the exothermic, first-order reaction in the CSTR. Behaviour with an autocatalyst of complete stability corresponds to perfect heat insulation (adiabatic operation) in the non-isothermal, exothermic system.     

Effect of backwashing on activated carbon adsorption using plug flow pore surface diffusion model

A fixed bed is gradually exhausted from top to bottom without backwashing; however, backwashing can rearrange the concentration gradient in the bed. After backwashing, saturated particles which are located at the top of the bed are homogeneously distributed in the bed. The used model to predict adsorption and backwashing effect of organic component is the plug flow pore surface diffusion model (PFPSDM). A sensitivity analysis was performed to determine which parameters have the greatest impact on the model results for components which can represent various organics. In addition, the effects of backwashing were examined by rearranging concentration gradient. For single component sensitivity analysis, the molecular weight was an important parameter. The breakthrough of the smaller molecular weight component was impacted more by backwashing. The SPDFR showed a significant impact on the breakthrough pattern. When surface diffusion was the dominant mechanism, high SPDFR, the breakthrough profile was sharper than when pore diffusion was dominant, low SPDFR. The adsorbability was an important parameter in determining the breakthrough pattern. As expected, the strongly adsorbable component showed the later breakthrough. Backwashing yielded earlier breakthrough for all single components and multi-components examined.     

Pt-V2O5-WO3/TiO2 catalysts supported on SiC filter for NO reduction at low temperature

The catalytic filter, V₂O₅-WO₃-TiO₂ supported on a ceramic filter, is known as a promising material for treating particulates and NO _x simultaneously at optimum temperatures around 320°C. In order to improve its catalytic activity at low temperatures, the effect of Pt addition on the catalytic filter has been investigated. Catalytic filters, Pt-V₂O₅-WO₃-TiO₂/SiC, were prepared by co-impregnation of Pt, V, and W precursors on TiO₂ coated-SiC filter by vacuum aided-dip coating. The Pt-added catalytic filter shifted the optimum working temperature from 280–330°C (for the non Pt-impregnated filter) to 180–230°C, providing N _x slip concentration less than 20 ppm for the treatment of 700 ppm NO at a face velocity of 2 cm/s with the same value over the non Pt-added catalytic filters. The promotional effect following the addition of Pt is believed to result from electrical modification of the catalyst maintaining a high electron transfer state. Ammonia oxidation was also observed to be dominant above the optimal temperature for SCR.     

Mechanisms of antioxidant action: The effect of spin traps during the processing and photooxidation of PVC

It is demonstrated by the use of spin traps that during the early stages of thermal processing of PVC considerable concentrations (> 3 × 10^?6 mol g^?1) of free radicals are produced which are primarily responsible for the initial products (hydroperoxides, unsaturation, and hydrogen chloride) previously shown to be formed in the polymer. From a semiquantitative analysis of these products, it is estimated that more than 50% of the radicals are formed from hydroperoxides and the rest by mechanoscission of the polymer chain. The spin traps are effective processing stabilizers in combination with a tin maleate HC1 scavenger. One of them (2-methyl-2-nitroso propane, MNP) has also been shown to be a photoantioxidant.     

Studies on cocurrent gas-liquid flow in helically coiled tubes. II. Theory and experiments on turbulent mass transfer with and without chemical reaction

Pure carbon dioxide was absorbed into distilled water and sodium hydroxide solution, in cocurrent two phase annular flow in helically coiled tubes in order to measure physical and chemical mass transfer coefficients and interfacial areas. (k*_La) was correlated by the pressure drop in the test sections and interfacial areas were found to vary with the liquid phase energy dissipation. According to a new theory, (k*_L) has been shown to be a function of the root mean square vorticity near the interface. The root mean square vorticity has been related to the pressure drop, gas density, liquid flow rate and liquid velocity. The physical mass transfer coefficients theoretically predicted are in good agreement with experimental results.     

Olfactory aposematism

Visual and acoustic cues may serve as aposematic signals that warn predators of poisonous foods. Olfactory aposematism, the use of innocuous odors as warning signals for toxic foods, is another possible means of alerting an animal that a potential food item is unpalatable. Although it has been suggested that olfactory aposematism might be the principle mode of warning utilized by plants in their defense against herbivores, experimental evidence is lacking. This study demonstrates that the opossum,Didelphis virginiana, can utilize an innocuous volatile compound found naturally in a mushroom as a warning signal for a delayed illness caused by mushroom toxin. This supports the contention that characteristic odors of toxic plants may serve a warning function, protecting herbivores from being poisoned and plants from being consumed.     

Effect of nutrient seed coating on the emergence of wheat and oats

A series of experiments was conducted under controlled soil moisture and temperature conditions in a growth chamber to examine the effect of a range of nutrient seed coatings on the emergence to wheat (Triticum aestivum L. cv. Kite) and oats (Avena sativa L. cv. Blackbutt) sown in a coarse sandy loam soil. Final emergence of oats was not reduced by a coating containing 10 kg P ha^–1 (as monocalcium phosphate [MCP]) whereas the same coating reduced wheat emergence by 15%. The emergence of both wheat and oats was severely reduced by urea coatings (supplying 10 kg N ha^–1) to 33 and 13% respectively; this injury was lessened markedly by the inclusion of phenyl phosphorodiamidate (PPD) in the urea coatings at 1% (w/w) (emergence increased to 66 and 56% respectively).Low soil moisture (67% of field capacity [FC]) resulted in almost no emergence of wheat coated with urea (± bentonites of different pH). In soil at FC, the addition of bentonite of pH 5 (B5) to urea coatings permitted greater emergence (54%) than when bentonite of pH 9 (B9) was added (32%) which, in turn, permitted greater emergence than urea coating alone (10%). When PPD and bentonite (B5 or B9) were combined either singly or together with urea in seed coatings, PPD was more effective than either of the bentonites in reducing injury and masked the slight positive effect of B5.Coatings containing various combinations of N and P sources (at 3.6 and at 8 kg ha^–1 respectively) all reduced the emergence of wheat compared to raw seed (91% emergence). When applied alone, MCP was least damaging (74%); the combination of MCP with ammonium sulfate (AS) caused somewhat more injury (68%) whilst combination with calcium nitrate (CN) caused most injury (29%). In contrast, CN alone caused relatively little damage (73%) whilst AS alone was more damaging (50%). There was no significant regression found between percentage emergence and either the calculated partial salt index or the pH of the nutrient coatings. Further work is needed to examine the mechanisms of injury due to nutrient seed coatings so that safe but effective formulations can be developed.