K-ras is critical for modulating multiple c-kit-mediated cellular functions in wild-type and Nf1+/- mast cells

p21(ras) (Ras) proteins and GTPase-activating proteins (GAPs) tightly modulate extracellular growth factor signals and control multiple cellular functions. The specific function of each Ras isoform (H, N, and K) in regulating distinct effector pathways, and the role of each GAP in negatively modulating the activity of each Ras isoform in myeloid cells and, particularly, mast cells is incompletely understood. In this study, we use murine models of K-ras- and Nf1-deficient mice to examine the role of K-ras in modulating mast cell functions and to identify the role of neurofibromin as a GAP for K-ras in this lineage. We find that K-ras is required for c-kit-mediated mast cell proliferation, survival, migration, and degranulation in vitro and in vivo. Furthermore, the hyperactivation of these cellular functions in Nf1(+/-) mast cells is decreased in a K-ras gene dose-dependent fashion in cells containing mutations in both loci. These findings identify K-ras as a key effector in multiple mast cell functions and identify neurofibromin as a GAP for K-ras in mast cells.     

Deletion of Fifteen Open Reading Frames from Modified Vaccinia Virus Ankara Fails to Improve Immunogenicity

Modified vaccinia virus Ankara (MVA) is a highly attenuated strain of vaccinia virus, which has been used as a recombinant vaccine vector in many vaccine development programmes. The loss of many immunosuppressive and host-range genes resulted in a safe and immunogenic vaccine vector. However it still retains some immunomodulatory genes that may reduce MVA immunogenicity. Earlier reports demonstrated that the deletion of the A41L, B15R, C6L, or C12L open reading frames (ORFs) enhanced cellular immune responses in recombinant MVA (rMVA) by up to 2-fold. However, previously, we showed that deletion of the C12L, A44L, A46R, B7R, or B15R ORFs from rMVA, using MVA-BAC recombineering technology, did not enhance rMVA immunogenicity at either peak or memory cellular immune responses. Here, we extend our previous study to examine the effect of deleting clusters of genes on rMVA cellular immunogenicity. Two clusters of fifteen genes were deleted in one rMVA mutant that encodes either the 85A antigen of Mycobacterium tuberculosis or an immunodominant H2-K^d-restricted murine malaria epitope (pb9). The deletion mutants were tested in prime only or prime and boost vaccination regimens. The responses showed no improved peak or memory CD8⁺ T cell frequencies. Our results suggest that the reported small increases in MVA deletion mutants could not be replicated with different antigens, or epitopes. Therefore, the gene deletion strategy may not be taken as a generic approach for improving the immunogenicity of MVA-based vaccines, and should be carefully assessed for every individual recombinant antigen.     

Combinational therapeutics to combat cancer

Mono-therapeutics is rarely effective as a treatment option, which limits the survival of patients in advanced grade aggressive cancers. Combinational therapeutics (multiple drugs for multiple targets) to combat cancer is gaining momentum in recent years. Hence, it is of interest to document known data for combinational therapeutics in cancer treatment. An amalgamation of therapeutic agents enhances the efficacy and potency of the therapy. Combinational therapy can potentially target multiple pathways that are necessary for the cancer cells to proliferate, and/or target molecules, which may help cancer to become more aggressive and metastasize. In this review, we discuss combinational therapeutics, which include human γδ T cells in combinations with biologically active anti-cancer molecules, which synergistically may produce promising combinational therapeutics.     

Pertussis toxin reverses the inhibition of insulin secretion caused by [Arg8]vasopressin in rat pancreatic islets

When rat pancreatic islets were incubated with 10(-8) M arginine vasopressin in the presence of 15 mM glucose there was a pronounced inhibition of insulin release in comparison with controls. This inhibitory effect appeared to be specific for vasopressin since it was antagonised by vasopressin antibody. Moreover, pertussis toxin (100 ng/ml) reversed the inhibition of insulin release due to vasopressin, indicating the possible involvement of a guanyl-nucleotide regulatory protein in the inhibitory effect. Nevertheless, 10(-8) M vasopressin increased islet concentrations of cyclic AMP even under conditions where insulin release was decreased.     

Gulf societies and the image of unlimited good

Conclusion In conclusion, a number of theoretical points need to be made. The first relates to the question of the primacy of the economic infrastructure in determining the shape of social institutions and the direction of social change in society. We accept this theoretical position, but still one may ask, why then in the case of Kuwait is it the state which is now dominant in affecting sociocultural life? While appreciating the analytical value of the Marxist thesis which sees that it is the material economic base which in the final instance determines the evolution of society, at the same time we see that this does not mean that the material infrastructural base will also by necessity dominate society. For our purposes here Godelier's analytical distinction between what he terms infrastructural determination and superstructural domination is quite useful, and provides an adequate explanation as to why the state has come to be dominant in Gulf societies. Godelier argues that in both historical and contemporary comparative cases where superstructures (kinship, religion, the state, etc.) appeared to be dominant in society, such superstructures always functioned as a relation of production. For a social institution and/or an activity to play a dominant role in the functioning and evolution of society, it must necessarily, in addition to its own ostensible purpose and explicit functions, function directly and internally as a relation of production. Godelier's proposed hypothesis turns the analytical focus not so much on what the social relations or institutions are, but rather on what they do, or better, make people do. It is evident in the discussion above that the state structure in Kuwait, due to the peculiarities of the oil economy and other social factors, has come to play (in addition to its explicit political functions) a very important and again explicit economic role. The oil state controls not only the means of production and allocation of wealth, but simultaneously functions as a controller of the relations of production in society.The second point relates to an earlier reference made about George Foster's conceptualization of the image of limited good. Unlike the cognitive conceptual formulation made by Foster two decades ago about peasant society, our argument in this paper emphasizes that the image of the unlimited good is a derivative social and psychocultural phenomenon resulting from the impact of broader economic and historical transformations which have been taking place in recent years in the oil-rich Arab Gulf countries. The major shortcoming in Foster's analysis of the peasants' image of limited good is that he relies only on cognitive formulation and does not go beyond the limitations of derivative analysis.The third point ties in with our note on Foster's formulation. It emphasizes the fact that it is the broader impersonal socioeconomic conditions that in the final analysis produce certain images in a given society at a given time. These conditions also determine, but may not necessarily dominate, the forms and other cultural peculiarities these images may take. In fact, it has recently become noticeable that the image of the unlimited good has begun to shrink in people's minds, especially after the 1982–83 Al-Manakh stock market crash in Kuwait and the recent dramatic downfall in oil prices.Since we are using a Marxist socioeconomic perspective in our analysis one may ask whether there are no contradictions in this Kuwaiti image of the unlimited good. I believe that the absence of discussion on contradictions does not create an analytical gap. We have shown in the preceding discussion that the emergence of the oil welfare state with its tremendous capacities to dominate society as a result of its lavish wealthfarism and its role as a controller of wealth in society has enabled it to accomodate for the rising needs and expectations of a small society. In addition, the existence of other socioeconomic and political conditions and variables—such as smallness, expatriate labor force, national and ethnic loyalties still overshadowing real class loyalties, the short historical period for this social experiment of oil wealth, and so on — has helped in repressing the rise of contradictions along class lines.Moreover, a discourse which shows how it is possible for new socioeconomic conditions to arrest, at least for a given time period, the development of contradictions can competently follow a Marxist mode of analysis. I see, therefore, no analytical disjunction arising from the fact that a Marxist perspective has been used while at the same time we have tried to elucidate the nature of the forces and conditions which have brought about harmony epitomized by the image of the unlimited good. Such an elucidation has also aided us in seeing why it is satisfaction and acceptance of the economicopolitical system, and not contradictions, that have come to prevail in modern Kuwait.We also note at the end of our discussion how change in the larger impersonal socioeconomic conditions since 1984 has begun generating not only new perceptions away from the image of the umlimited good but also immature class contradictions and consciousness expressing themselves in mystified forms of envy of the super-rich or rivalry with expatriates.The last important fact is that perceptions, images and worldviews do not have a functional autonomy of their own. Images always need to be grounded.Dr. Sulayman N. Khalaf is Visiting Assistant Professor of Anthropology in the Department of Sociology and Social Work, the Faculty of Arts, United Arab Emirates University.

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Hatching of the Anostracan Branchiopod Chirocephalus diaphanus Prévost II. The role of embryonic movements

A study on the hatching mechanism in the egg of C. diaphanus was carried out. The complete escape of the nauplius from its three membranes takes place through two distinct stages, namely the breaking stage and the hatching stage. The former seems to be strictly an osmotic phenomenon, and the latter is more likely to be caused by mechanical means. A detailed study on the embryonic movements was carried out. The possible presence of a hatching movement was discussed. The presence of spiny projections aiding in the hatching process was also demonstrated.     

Delivery of Beneficial Microbes via Seed Coating for Medicinal and Aromatic Plant Production: A Critical Review

Journal of Plant Growth Regulation - Medicinal and aromatic plants (MAPs) producing a myriad of chemicals can be utilized in numerous sectors such as pharmaceutical products, feed and food...     

Studies on faecal streptococci in the river Tigris

Six hundred water samples collected from the river Tigris at Mosul City were investigated for faecal streptococci. Human faecal streptococci were predominant, and animal faecal streptococci were also detected. Eight species and varieties were identified, viz Streptococcus faecalis, atypical Streptococcus faecalis, Streptococcus bovis, Streptococcus equinus, Streptococcus faecalis var. liquefaciens, Streptococcus faecalis var. zymogenes, Streptococcus durans and Streptococcus faecium. The incidence of these species and varieties were 43.32%, 13.18%, 11.47%, 11.30%, 9.76%, 5.30%, 3.76% and 1.88%, respectively.     

Factorizing the role of a critical leucine residue in the binding of substrate to human 20α-hydroxysteroid dehydrogenase (AKR1C1): Molecular modeling and kinetic studies of the Leu308Val mutant enzyme

A comparison of the structures and kinetic properties of human 20α-hydroxysteroid dehydrogenase (AKR1C1) and its mutant enzymes (Leu308Val and Leu308Ala) indicates that Leu308 is a selectivity determinant for substrate binding. While the Leu308Val mutation improved the catalytic efficiency (k_cat/K_m) of AKR1C1 towards the two substrates 5α-pregnane-3α,20α-diol (PregA) and 5β-pregnan-3α-ol-20-one (PregB), the Leu308Ala mutation rendered the enzyme inactive. In the docked model of PregA the conformation of the steroid molecule was similar to that of 20α-hydroxyprogesterone in the crystal structure of the AKR1C1 complex where the steroid did not interact with the catalytic residues Tyr55 and His117. In the case of PregB the steroid interacted with the catalytic residue His117 and formed close contacts with Leu308, suggesting that the binding mechanism of 3α-hydroxysteroids in the active site of AKR1C1 is different from that of 20α-hydroxysteroids.     

Formulation of Controlled-Release Baclofen Matrix Tablets II: Influence of Some Hydrophobic Excipients on the Release Rate and In Vitro Evaluation

The aim of this study was to investigate the influence of polymer level and type of some hydrophobic polymers, including hydrogenated castor oil (HCO); Eudragit RS100 (E-RS100); Eudragit L100 (E-L100), and some fillers namely mannitol [soluble filler], Dibasic calcium phosphate dihydrate (Emcompress) and anhydrous dibasic calcium phosphate [insoluble fillers] on the release rate and mechanism of baclofen from matrix tablets prepared by a hot-melt granulation process (wax tablets) and wet granulation process (E-RS100 and E-L100 tablets). Statistically significant differences were found among the drug release profile from different classes of polymeric matrices. Higher polymeric content (40%) in the matrix decreased the release rate of drug because of increased tortuosity and decreased porosity. At lower polymeric level (20%), the rate and extent of drug release was elevated. HCO was found to cause the strongest retardation of drug. On the other hand, replacement of Emcompress or anhydrous dibasic calcium phosphate for mannitol significantly retarded the release rate of baclofen, except for E-L100 (pH-dependent polymer). Emcompress surface alkalinity and in-situ increase in pH of the matrix microenvironment enhanced the dissolution and erosion of these matrix tablets. The release kinetics was found to be governed by the type and content of the excipients (polymer or filler). The prepared tablets showed no significant change in drug release rate when stored at ambient room conditions for 6 months.