The role of pinning and instability in a class of non-equilibrium growth models

We study the dynamics of a growing crystalline facet where the growth mechanism is controlled by the geometry of the local curvature. A continuum model, in (2+1) dimensions, is developed in analogy with the Kardar-Parisi-Zhang (KPZ) model is considered for the purpose. Following standard coarse graining procedures, it is shown that in the large time, long distance limit, the continuum model predicts a curvature independent KPZ phase, thereby suppressing all explicit effects of curvature and local pinning in the system, in the "perturbative" limit. A direct numerical integration of this growth equation, in 1+1 dimensions, supports this observation below a critical parametric range, above which generic instabilities, in the form of isolated pillared structures lead to deviations from standard scaling behaviour. Possibilities of controlling this instability by introducing statistically "irrelevant" (in the sense of renormalisation groups) higher ordered nonlinearities have also been discussed.

Growth of ultrananocrystalline diamond film by DC Arcjet plasma enhanced chemical vapor deposition

Self-standing diamond films were grown by DC Arcjet plasma enhanced chemical vapor deposition (CVD). The feed gasses were Ar/H 2/CH 4, in which the flow ratio of CH 4 to H 2 (FCH4/FH2) was varied from 5% to 20%. Two distinct morphologies were observed by scanning electron microscope (SEM), i.e. the pineapple-like morphology and the cauliflower-like morphology. It was found that the morphologies of the as-grown films are strongly dependent on the flow ratio of CH 4 to H 2 in the feed gasses. High resolution transmission electron microscope (HRTEM) survey results revealed that there were nanocrystalline grains within the pineapple-like films whilst there were ultrananocrystalline grains within cauliflower-like films. X-ray diffraction (XRD) results suggested that (110) crystalline plane was the dominant surface in the cauliflower-like films whilst (100) crystalline plane was the dominant surface in the pineapple-like films. Raman spectroscopy revealed that nanostructured carbon features could be observed in both types of films. Plasma diagnosis was carried out in order to understand the morphology dependent growth mechanism. It could be concluded that the film morphology was strongly influenced by the density of gas phases. The gradient of C2 radical was found to be different along the growth direction under the different growth conditions. © 2012 Elsevier B.V. All rights reserved.

Studies on the thermal decomposition behaviour, kinetics and electrical conductivity of the non-isothermal decomposition of pyridine mono carboxylic acids and some of their transition metal complexes

The thesis is divided into four chapters. They are: introduction, experimental, results and discussion about the free ligands and results and discussion about the complexes. The First Chapter, the introductory chapter, is a general introduction to the study of solid state reactions. The Second Chapter is devoted to the materials and experimental methods that have been used for carrying out tile experiments. TIle Third Chapter is concerned with the characterisations of free ligands (Picolinic acid, nicotinic acid, and isonicotinic acid) by using elemental analysis, IR spectra, X-ray diffraction, and mass spectra. Additionally, the thermal behaviour of free ligands in air has been studied by means of thermogravimetry (TG), derivative thermogravimetry (DTG), and differential scanning calorimetry (DSC) measurements. The behaviour of thermal decomposition of the three free ligands was not identical Finally, a computer program has been used for kinetic evaluation of non-isothermal differential scanning calorimetry data according to a composite and single heating rate methods in comparison with the methods due to Ozawa and Kissinger methods. The most probable reaction mechanism for the free ligands was the Avrami-Erofeev equation (A) that described the solid-state nucleation-growth mechanism. The activation parameters of the decomposition reaction for free ligands were calculated and the results of different methods of data analysis were compared and discussed. The Fourth Chapter, the final chapter, deals with the preparation of cobalt, nickel, and copper with mono-pyridine carboxylic acids in aqueous solution. The prepared complexes have been characterised by analyses, IR spectra, X-ray diffraction, magnetic moments, and electronic spectra. The stoichiometry of these compounds was ML2x(H20), (where M = metal ion, L = organic ligand and x = water molecule). The environments of cobalt, nickel, and copper nicotinates and the environments of cobalt and nickel picolinates were octahedral, whereas the environment of copper picolinate [Cu(PA)2] was tetragonal. However, the environments of cobalt, nickel, and copper isonicotinates were polymeric octahedral structures. The morphological changes that occurred throughout the decomposition were followed by SEM observation. TG, DTG, and DSC measurements have studied the thermal behaviour of the prepared complexes in air. During the degradation processes of the hydrated complexes, the crystallisation water molecules were lost in one or two steps. This was also followed by loss of organic ligands and the metal oxides remained. Comparison between the DTG temperatures of the first and second steps of the dehydration suggested that the water of crystallisation was more strongly bonded with anion in Ni(II) complexes than in the complexes of Co(II) and Cu(II). The intermediate products of decomposition were not identified. The most probable reaction mechanism for the prepared complexes was also Avrami-Erofeev equation (A) characteristic of solid-state nucleation-growth mechanism. The tempemture dependence of conductivity using direct current was determined for cobalt, nickel, Cl.nd copper isonicotinates. An activation energy (ΔΕ), the activation energy (ΔΕ ) were calculated.The ternperature and frequency dependence of conductivity, the frequency dependence of dielectric constant, and the dielectric loss for nickel isonicotinate were determined by using altemating current. The value of s paralneter and the value of'density of state [N(Ef)] were calculated. Keyword Thermal decomposition, kinetic, electrical conduclion, pyridine rnono~ carboxylic acid, cOlnplex, transition metal compJex.

Chemical studies of plasma etchants used in integrated circuit manufacture

Plasma or "dry" etching is an essential process for the production of modern microelectronic circuits. However, despite intensive research, many aspects of the etch process are not fully understood. The results of studies of the plasma etching of Si and Si02 in fluorine-containing discharges, and the complementary technique of plasma polymerisation are presented in this thesis. Optical emission spectroscopy with argon actinometry was used as the principle plasma diagnostic. Statistical experimental design was used to model and compare Si and Si02 etch rates in CF4 and SF6 discharges as a function of flow, pressure and power. Etch mechanisms m both systems, including the potential reduction of Si etch rates in CF4 due to fluorocarbon polymer formation, are discussed. Si etch rates in CF4 /SF6 mixtures were successfully accounted for by the models produced. Si etch rates in CF4/C2F6 and CHF3 as a function of the addition of oxygen-containing additives (02, N20 and CO2) are shown to be consistent with a simple competition between F, 0 and CFx species for Si surface sites. For the range of conditions studied, Si02 etch rates were not dependent on F-atom concentration, but the presence of fluorine was essential in order to achieve significant etch rates. The influence of a wide range of electrode materials on the etch rate of Si and Si02 in CF4 and CF4 /02 plasmas was studied. It was found that the Si etch rate in a CF4 plasma was considerably enhanced, relative to an anodised aluminium electrode, in the presence of soda glass or sodium or potassium "doped" quartz. The effect was even more pronounced in a CF4 /02 discharge. In the latter system lead and copper electrodes also enhanced the Si etch rate. These results could not be accounted for by a corresponding rise in atomic fluorine concentration. Three possible etch enhancement mechanisms are discussed. Fluorocarbon polymer deposition was studied, both because of its relevance to etch mechanisms and its intrinsic interest, as a function of fluorocarbon source gas (CF4, C2F6, C3F8 and CHF3), process time, RF power and percentage hydrogen addition. Gas phase concentrations of F, H and CF2 were measured by optical emission spectroscopy, and the resultant polymer structure determined by X-ray photoelectron spectroscopy and infrared spectroscopy. Thermal and electrical properties were measured also. Hydrogen additions are shown to have a dominant role in determining deposition rate and polymer composition. A qualitative description of the polymer growth mechanism is presented which accounts for both changes in growth rate and structure, and leads to an empirical deposition rate model.

Effect of methane concentration in hydrogen plasma on hydrogen impurity incorporation in thick large-grained polycrystalline diamond films

We investigate the impact of methane concentration in hydrogen plasma on the growth of large-grained polycrystalline diamond (PCD) films and its hydrogen impurity incorporation. The diamond samples were produced using high CH4 concentration in H2 plasma and high power up to 4350 W and high pressure (either 105 or 110 Torr) in a microwave plasma chemical vapor deposition (MPCVD) system. The thickness of the free-standing diamond films varies from 165 µm to 430 µm. Scanning electron microscopy (SEM), micro-Raman spectroscopy and Fourier-transform infrared (FTIR) spectroscopy were used to characterize the morphology, crystalline and optical quality of the diamond samples, and bonded hydrogen impurity in the diamond films, respectively. Under the conditions employed here, when methane concentration in the gas phase increases from 3.75% to 7.5%, the growth rate of the PCD films rises from around 3.0 µm/h up to 8.5 µm/h, and the optical active bonded hydrogen impurity content also increases more than one times, especially the two CVD diamond specific H related infrared absorption peaks at 2818 and 2828 cm−1 rise strongly; while the crystalline and optical quality of the MCD films decreases significantly, namely structural defects and non-diamond carbon phase content also increases a lot with increasing of methane concentration. Based on the results, the relationship between methane concentration and diamond growth rate and hydrogen impurity incorporation including the form of bonded infrared active hydrogen impurity in CVD diamonds was analyzed and discussed. The effect of substrate temperature on diamond growth was also briefly discussed. The experimental findings indicate that bonded hydrogen impurity in CVD diamond films mainly comes from methane rather than hydrogen in the gas source, and thus can provide experimental evidence for the theoretical study of the standard methyl species dominated growth mechanism of CVD diamonds grown with methane/hydrogen mixtures.

Impact of high microwave power on hydrogen impurity trapping in nanocrystalline diamond films grown with simultaneous nitrogen and oxygen addition into methane/hydrogen plasma

In this work, we study for the first time the influence of microwave power higher than 2.0 kW on bonded hydrogen impurity incorporation (form and content) in nanocrystalline diamond (NCD) films grown in a 5 kW MPCVD reactor. The NCD samples of different thickness ranging from 25 to 205 μm were obtained through a small amount of simultaneous nitrogen and oxygen addition into conventional about 4% methane in hydrogen reactants by keeping the other operating parameters in the same range as that typically used for the growth of large-grained polycrystalline diamond films. Specific hydrogen point defect in the NCD films is analyzed by using Fourier-transform infrared (FTIR) spectroscopy. When the other operating parameters are kept constant (mainly the input gases), with increasing of microwave power from 2.0 to 3.2 kW (the pressure was increased slightly in order to stabilize the plasma ball of the same size), which simultaneously resulting in the rise of substrate temperature more than 100 °C, the growth rate of the NCD films increases one order of magnitude from 0.3 to 3.0 μm/h, while the content of hydrogen impurity trapped in the NCD films during the growth process decreases with power. It has also been found that a new H related infrared absorption peak appears at 2834 cm-1 in the NCD films grown with a small amount of nitrogen and oxygen addition at power higher than 2.0 kW and increases with power higher than 3.0 kW. According to these new experimental results, the role of high microwave power on diamond growth and hydrogen impurity incorporation is discussed based on the standard growth mechanism of CVD diamonds using CH4/H2 gas mixtures. Our current experimental findings shed light into the incorporation mechanism of hydrogen impurity in NCD films grown with a small amount of nitrogen and oxygen addition into methane/hydrogen plasma.

Synthesis of magnetically separable and recyclable g‑C3N4−Fe3O4 hybrid nanocomposites with enhanced photocatalytic performance under visible-light irradiation

Herein we demonstrate a facile, reproducible, and template-free strategy to prepare g-C3N4–Fe3O4 nanocomposites by an in situ growth mechanism. The results indicate that monodisperse Fe3O4 nanoparticles with diameters as small as 8 nm are uniformly deposited on g-C3N4 sheets, and as a result, aggregation of the Fe3O4 nanoparticles is effectively prevented. The as-prepared g-C3N4–Fe3O4 nanocomposites exhibit significantly enhanced photocatalytic activity for the degradation of rhodamine B under visible-light irradiation. Interestingly, the g-C3N4–Fe3O4 nanocomposites showed good recyclability without loss of apparent photocatalytic activity even after six cycles, and more importantly, g-C3N4–Fe3O4 could be recovered magnetically. The high performance of the g-C3N4–Fe3O4 photocatalysts is due to a synergistic effect including the large surface-exposure area, high visible-light-absorption efficiency, and enhanced charge-separation properties. In addition, the superparamagnetic behavior of the as-prepared g-C3N4–Fe3O4 nanocomposites also makes them promising candidates for applications in the fields of lithium storage capacity and bionanotechnology.

Mechanism of attenuation of angiotensin-II-induced protein degradation by insulin-like growth factor-I (IGF-I)

Insulin-like growth factor-I (IGF-I) has been shown to attenuate protein degradation in murine myotubes induced by angiotensin II through downregulation of the ubiquitin-proteasome pathway, although the mechanism is not known. Angiotensin II is known to upregulate this pathway through a cellular signalling mechanism involving release of arachidonic acid, activation of protein kinase Cα (PKCα), degradation of inhibitor-κB (I-κB) and nuclear migration of nuclear factor-κB (NF-κB), and all of these events were attenuated by IGF-I (13.2 nM). Induction of the ubiquitin-proteasome pathway has been linked to activation of the RNA-activated protein kinase (PKR), since an inhibitor of PKR attenuated proteasome expression and activity in response to angiotensin II and prevented the decrease in the myofibrillar protein myosin. Angiotensin II induced phosphorylation of PKR and of the eukaryotic initiation factor-2 (eIF2) on the α-subunit, and this was attenuated by IGF-I, by induction of the expression of protein phosphatase 1, which dephosphorylates PKR. Release of arachidonic acid and activation of PKCα by angiotensin II were attenuated by an inhibitor of PKR and IGF-I, and the effect was reversed by Salubrinal (15 μM), an inhibitor of eIF2α dephosphorylation, as was activation of PKCα. In addition myotubes transfected with a dominant-negative PKR (PKRΔ6) showed no release of arachidonate in response to Ang II, and no activation of PKCα. These results suggest that phosphorylation of PKR by angiotensin II was responsible for the activation of the PLA2/PKC pathway leading to activation of NF-κB and that IGF-I attenuates protein degradation due to an inhibitory effect on activation of PKR. © 2007 Elsevier Inc. All rights reserved.

A nonantisense sequence-selective effect of a phosphorothioate oligodeoxynucleotide directed against the epidermal growth factor receptor in A431 cells

The overexpression of epidermal growth factor receptor (EGFr) has been implicated as a causative factor and a poor prognostic marker in a number of carcinomas. Therefore, strategies that down-regulate EGFr expression may be therapeutically useful. We designed antisense ODNs complementary to the initiation codon region of the EGFr mRNA and evaluated their efficacy in several tumor-derived cells, including the A431 cell line that express amplified levels of EGFr. A 15-mer phosphorothioate (PS) antisense ODN (erbB1AS15) induced a concentration-dependent reduction in proliferation that was accompanied by a change in the morphology of A431 cells into more tightly clustered and discrete colonies. A 15-mer sense (PS) control oligodeoxynucleotide (ODN) and a phosphodiester (PO) version of erbB1AS15 had little or no effect on cell number of morphology, and erbB1AS15 (PS) did not induce these effects in control cell lines expressing lower levels of EGFr. The effects of erbB1AS15 (PS) on A431 cells were not mediated by a true antisense mechanism in that there was no reduction in the level of EGFr mRNA or protein over a 24-hr period, as determined by Northern and Western blotting, respectively. However, autophosphorylation of the receptor was significantly reduced by erbB1AS15 (PS) and not by control ODNs. The results of further studies suggested that this effect was mediated by a direct, dose-dependent inhibition of the EGFr tyrosine kinase enzyme and was not due to impairment of either ligand-binding or receptor dimerization. These data suggest that erbB1AS15 (PS) can inhibit proliferation and alter the morphology of A431 cells by a sequence-selective, but nonantisense mechanism affecting receptor tyrosine kinase activity.

Receptor regulation of phosphoinositide 3-hydroxykinase in the NG115-401L-C3 neuronal cell line: stimulation by insulin-like growth factor-I

The activation of phosphoinositide 3-hydroxykinase (P13K) is currently believed to represent the critical regulatory event which leads to the production of a novel intracellular signal. We have examined the control of this pathway by a number of cell-surface receptors in NG115-401L-C3 neuronal cells. Insulin-like growth factor-I stimulated the accumulation of 3-phosphorylated inositol lipids in intact cells and the appearance of P13K in antiphosphotyrosine-antibody-directed immunoprecipitates prepared from lysed cells, suggesting that P13K had been activated by a mechanism involving a protein tyrosine kinase. In contrast, P13K in these cells was not regulated by a variety of G-protein-coupled receptors, nerve growth factor acting via a low affinity receptor, or receptors for transforming growth factor-beta and interleukin-1. The receptor-specificity of P13K activation in these cells places significant constraints on the possible physiological function(s) of this pathway.

Empirical analysis of human capital development and economic growth in Europe

Recent discussion of the knowledge-based economy draws increasingly attention to the role that the creation and management of knowledge plays in economic development. Development of human capital, the principal mechanism for knowledge creation and management, becomes a central issue for policy-makers and practitioners at the regional, as well as national, level. Facing competition both within and across nations, regional policy-makers view human capital development as a key to strengthening the positions of their economies in the global market. Against this background, the aim of this study is to go some way towards answering the question of whether, and how, investment in education and vocational training at regional level provides these territorial units with comparative advantages. The study reviews literature in economics and economic geography on economic growth (Chapter 2). In growth model literature, human capital has gained increased recognition as a key production factor along with physical capital and labour. Although leaving technical progress as an exogenous factor, neoclassical Solow-Swan models have improved their estimates through the inclusion of human capital. In contrast, endogenous growth models place investment in research at centre stage in accounting for technical progress. As a result, they often focus upon research workers, who embody high-order human capital, as a key variable in their framework. An issue of discussion is how human capital facilitates economic growth: is it the level of its stock or its accumulation that influences the rate of growth? In addition, these economic models are criticised in economic geography literature for their failure to consider spatial aspects of economic development, and particularly for their lack of attention to tacit knowledge and urban environments that facilitate the exchange of such knowledge. Our empirical analysis of European regions (Chapter 3) shows that investment by individuals in human capital formation has distinct patterns. Those regions with a higher level of investment in tertiary education tend to have a larger concentration of information and communication technology (ICT) sectors (including provision of ICT services and manufacture of ICT devices and equipment) and research functions. Not surprisingly, regions with major metropolitan areas where higher education institutions are located show a high enrolment rate for tertiary education, suggesting a possible link to the demand from high-order corporate functions located there. Furthermore, the rate of human capital development (at the level of vocational type of upper secondary education) appears to have significant association with the level of entrepreneurship in emerging industries such as ICT-related services and ICT manufacturing, whereas such association is not found with traditional manufacturing industries. In general, a high level of investment by individuals in tertiary education is found in those regions that accommodate high-tech industries and high-order corporate functions such as research and development (R&D). These functions are supported through the urban infrastructure and public science base, facilitating exchange of tacit knowledge. They also enjoy a low unemployment rate. However, the existing stock of human and physical capital in those regions with a high level of urban infrastructure does not lead to a high rate of economic growth. Our empirical analysis demonstrates that the rate of economic growth is determined by the accumulation of human and physical capital, not by level of their existing stocks. We found no significant effects of scale that would favour those regions with a larger stock of human capital. The primary policy implication of our study is that, in order to facilitate economic growth, education and training need to supply human capital at a faster pace than simply replenishing it as it disappears from the labour market. Given the significant impact of high-order human capital (such as business R&D staff in our case study) as well as the increasingly fast pace of technological change that makes human capital obsolete, a concerted effort needs to be made to facilitate its continuous development.

Mechanism of attenuation of skeletal muscle protein catabolism in cancer cachexia by eicosapentaenoic acid

Cancer cachexia is characterized by selective depletion of skeletal muscle protein reserves. Soleus muscles from mice bearing a cachexia-inducing tumor (MAC16) showed an increased protein degradation in vitro, as measured by tyrosine release, when compared with muscles from nontumor-bearing animals. After incubation under conditions that modify different proteolytic systems, lysosomal, calcium-dependent, and ATP-dependent proteolysis were found to contribute to the elevated protein catabolism. Treatment of mice bearing the MAC16 tumor with the polyunsaturated fatty acid, eicosapentaenoic acid (EPA), attenuated loss of body weight and significantly suppressed protein catabolism in soleus muscles through an inhibition of an ATP-dependent proteolytic pathway. The ATP-ubiquitin-dependent proteolytic pathway is considered to play a major role in muscle catabolism in cachexia, and functional proteasome activity, as determined by “chymotrypsin-like” enzyme activity, was significantly elevated in gastrocnemius muscle of mice bearing the MAC16 tumor as weight loss progressed. When animals bearing the MAC16 tumor were treated with EPA, functional proteasome activity was completely suppressed, together with attenuation of the expression of 20S proteasome a-subunits and the p42 regulator, whereas there was no effect on the expression of the ubiquitin-conjugating enzyme (E214k). These results suggest that EPA induces an attenuation of the up-regulation of proteasome expression in cachectic mice, and this was correlated with an increase in myosin expression, confirming retention of contractile proteins. EPA also inhibited growth of the MAC16 tumor in a dose-dependent manner, and this correlated with suppression of the expression of the 20S proteasome a-subunits in tumor cells, suggesting that this may be the mechanism of tumor growth inhibition. Thus EPA antagonizes loss of skeletal muscle proteins in cancer cachexia by down-regulation of proteasome expression, and this may also be the mechanism for inhibition of tumor growth.

The role of insulin and the insulin-like growth factors in the proliferation of the rat thymic lymphocyte

Concanavalin A, provoked a 35-fold increase in the rate of proliferation of rat thymocytes. Insulin (10-6M), and insulin-like growth factor I (10-10M) approximately doubled the rate of DNA synthesis. Both of these structurally related molecules acted through the type I insulin-like growth factor receptor. The sequential addition of Concanavalin A and insulin, promoted a much greater proliferative response than to either of the two agonists alone. Insulin also increased the uptake of glucose and amino acids by the cells. Glucose uptake was enhanced at insulin concentrations of 10-6M and 10-10M. Amino acid uptake was more strongly affected at the higher concentration. Insulin-like growth factor I (10-11M) also enhanced amino acid uptake. The effects of insulin on metabolism were mediated by both insulin and type I insulin-like growth factor receptors. These effects were greatly enhanced after a pre-treatment with Concanavalin A. Concanavalin A provided a primary mitogenic signal to the cells. Amongst the responses was an increased expression of insulin and/or type I insulin-like growth factor receptors. The consequent enhanced cellular sensitivity to these agonists, enabled them to facilitate the passage of the cells through the cell cycle by: i) providing a secondary mitogenic signal, and ii) promoting the uptake of raw materials and energy substrates. The initiation of DNA synthesis and passage through the cell cycle was thus punctuated by the sequential expression of various cell surface receptors. This regulated cellular sensitivity, enabling them to react in a precisely orchestrated fashion to hormones and other molecules in their environment. The intracellular mechanism of insulin action remains an enigma. Although the presence of extracellular calcium was essential for insulin stimulation of amino acid uptake and DNA synthesis, the cation did not subserve a direct mediator function. Insulin promoted an increase in intracellular pH, which was mediated by the Na+/H+ antiport. Other mechanisms were probably also involved in mediating the full cellular response to insulin.

Studies of the mechanism of antitumour activity of N-methylformamide

NMF induces the terminal differentiation or acquisition of more benign characteristics in certain malignant cells in vitro and has good antitumour activity against murine tumours in vivo. This study was concerned with a comparison of the mechanism of antitumour activity of NMF in vitro and in vivo against the murine TLX5 lymphoma, which is sensitive to NMF in vivo. TLX5 cells incubated continuously with NMF in vitro showed a concentration and time dependent decrease in cell growth rate, which was associated with an increase in membrane permeability, a decrease in cell size and at the higher NMF concentrations, cell death. Analysis of the cell cycle after incubation with NMF indicated an early G1 phase arrest. TLX5 cells were incubated with NMF and washed free of the drug. Analysis of clonogenicity and tumourigenicity showed that all viable cells retained their proliferative potential and malignancy. Therefore, TLX5 cells exposed to NMF in vitro are not terminally differentiated, but reside in a quiescent substate which was reversed on drug removal. The intracellular GSH levels of TLX5 cells was decreased in a concentration and time dependent fashion by NMF. GSH depletion of TLX5 cells was not however a prerequisite for growth arrest, unlike the reported data for human colon carcinoma cell lines. A single administration of NMF caused a dose dependent regression of the TLX5 lymphoma in tumour bearing mice. Cell death occurred by apoptosis and necrosis. The antitumour activity of NMF was dependent on formyl C-H bond fission, with the parent drug or metabolites reaching all parts of the tumour 4h after dosing. There was a non-dose dependent increase in the S phase population, which was due to an increase in DNA synthesis, 24h after administration of NMF. NMF administration caused a decrease in GSH levels of the TLX5 lymphoma, which did not correlate with the antitumour response. However, the GSH depleting agent, BSO, marginally increased the antitumour activity of NMF.

Role of the dsRNA-dependent protein kinase (PKR) in the attenuation of protein loss from muscle by insulin and insulin-like growth factor-I (IGF-I)

Proteolysis-inducing factor (PIF), a tumour-produced cachectic factor, induced a dose-dependent decrease in protein synthesis in murine myotubes, together with an increase in phosphorylation of eucaryotic initiation factor 2 (eIF2) on the alpha-subunit. Both insulin (1 nM) and insulin-like growth factor I (IGF-I) (13.2 nM) attenuated the depression of protein synthesis by PIF and the increased phosphorylation of eIF2alpha, by inhibiting the activation (autophosphorylation) of the dsRNA-dependent protein kinase (PKR) by induction of protein phosphatase 1. A low-molecular weight inhibitor of PKR also reversed the depression of protein synthesis by PIF to the same extent, as did insulin and IGF-I. Both insulin and IGF-I-stimulated protein synthesis in the presence of PIF, and this was attenuated by Salubrinal, an inhibitor of phospho eIF2alpha phosphatase, suggesting that at least part of this action was due to their ability to inhibit phosphorylation of eIF2alpha. Both insulin and IGF-I also attenuated the induction of protein degradation in myotubes induced by PIF, this effect was also attenuated by Salubrinal. These results suggest an alternative mechanism involving PKR to explain the effect of insulin and IGF-I on protein synthesis and degradation in skeletal muscle in the presence of catabolic factors.