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PubMed2006

Antibody production with yeasts and filamentous fungi: on the road to large scale?

Yeasts and filamentous fungi have gained significant interest for the production of recombinant antibodies and antibody fragments. The opportunities and constraints of antibody (fragment) production in these hosts are highlighted as well as cell engineering strategies to overcome the constraints. Following aspects are addressed: folding, assembly and secretion of antibody related proteins, process optimization to improve productivity and quality, proteolysis, and, as a major point of interest, glycosylation.

Antibodies↗

PubMed2006

Structural studies of Bcl-xL/ligand complexes using 19F NMR.

Fluorine atoms are often incorporated into drug molecules as part of the lead optimization process in order to improve affinity or modify undesirable metabolic and pharmacokinetic profiles. From an NMR perspective, the abundance of fluorinated drug leads provides an exploitable niche for structural studies using 19F NMR in the drug discovery process. As 19F has no interfering background signal from biological sources, 19F NMR studies of fluorinated drugs bound to their protein receptors can yield easily interpretable and unambiguous structural constraints. 19F can also be selectively incorporated into proteins to obtain additional constraints for structural studies. Despite these advantages, 19F NMR has rarely been exploited for structural studies due to its broad lines in macromolecules and their ligand complexes, leading to weak signals in 1H/19F heteronuclear NOE experiments. Here we demonstrate several different experimental strategies that use 19F NMR to obtain ligand-protein structural constraints for ligands bound to the anti-apoptotic protein Bcl-xL, a drug target for anti-cancer therapy. These examples indicate the applicability of these methods to typical structural problems encountered in the drug development process.

Fluorine Compounds↗

PubMed2006

Information theory in living systems, methods, applications, and challenges.

Living systems are distinguished in nature by their ability to maintain stable, ordered states far from equilibrium. This is despite constant buffeting by thermodynamic forces that, if unopposed, will inevitably increase disorder. Cells maintain a steep transmembrane entropy gradient by continuous application of information that permits cellular components to carry out highly specific tasks that import energy and export entropy. Thus, the study of information storage, flow and utilization is critical for understanding first principles that govern the dynamics of life. Initial biological applications of information theory (IT) used Shannon's methods to measure the information content in strings of monomers such as genes, RNA, and proteins. Recent work has used bioinformatic and dynamical systems to provide remarkable insights into the topology and dynamics of intracellular information networks. Novel applications of Fisher-, Shannon-, and Kullback-Leibler informations are promoting increased understanding of the mechanisms by which genetic information is converted to work and order. Insights into evolution may be gained by analysis of the the fitness contributions from specific segments of genetic information as well as the optimization process in which the fitness are constrained by the substrate cost for its storage and utilization. Recent IT applications have recognized the possible role of nontraditional information storage structures including lipids and ion gradients as well as information transmission by molecular flux across cell membranes. Many fascinating challenges remain, including defining the intercellular information dynamics of multicellular organisms and the role of disordered information storage and flow in disease.

Computational Biology↗

PubMed1990

Three-dimensional determination of an oblique osteotomy in the hip by mathematical optimization fulfilling some anatomical demands.

The present paper describes a nonlinear optimization process to estimate the single cutting plane of an oblique osteotomy in the hip. This kind of osteotomy was introduced and practised by Charit (Research report 81, University of Witwaters brand, Johannesburg, 1981). We calculate the cutting plane in such a way that the postoperative coverage of the resulting two parts of the femur are as great as possible whereby some anatomical constraint conditions are fulfilled. Additionally a simplified preoperative planning is described by using a sphere lying on the femoral head and determined by a least-squares method.

Biomechanical Phenomena↗

PubMed1996

Characterization of the mechanical behavior of human knee ligaments: a numerical-experimental approach.

During knee-joint motions, the fiber bundles of the knee ligaments are nonuniformly loaded in a recruitment pattern, which depends on successive relative orientations of the insertion sites. These fiber bundles vary with respect to length, orientation and mechanical properties. As a result, the stiffness characteristics of the ligaments as a whole are variable during knee-joint motion. The purpose of the present study is to characterize this variable mechanical behavior. It is hypothesized that for this purpose it is essential to consider the ligaments mechanically as multi-bundle structures in which the variability in fiber bundle characteristics is accounted for, rather than as one-dimensional structures. To verify this hypothesis, bone-ligament-bone preparations of the ligaments were subjected to series of unidirectional subfailure tensile tests in which the relative insertion orientations were varied. For each individual test specimen, this series of tensile tests was simulated with a mathematical ligament model. Geometrically, this model consists of multiple line elements, of which the insertions and orientations are anatomically based. In a mathematical optimization process, the unknown stiffness and recruitment parameters of the line elements are identified by fitting the variable stiffness characteristics of the model to those of the test series. Thus, lumped parameters are obtained which describe the mechanical behavior of the ligament as a function of the relative insertion orientation. This method of identification was applied to all four knee ligaments. In all cases, a satisfactory fit between experimental results and computer simulation was obtained, although the residual errors were lower for the cruciate ligaments (1.0-2.4%) than for the collateral ligaments (3.7-8.1%). It was found that models with three or less line elements were very sensitive to geometrical parameters, whereas models with more than 7 line elements suffered from mathematical redundancy. Between 4 and 7 line elements little difference was found. It is concluded that the present ligament models can realistically simulate the variable tensile behavior of human knee ligaments. Hereby the hypothesis is verified that it is essential to consider the ligaments of the knee as multi-bundle structures in order to characterize fully their mechanical behavior.

Aged↗

PubMed1982

The spatial grain of the perifoveal visual field.

Measurements for normal human photopic vision in the fovea and in 2.5, 5 and 10 degree positions in the periphery reveal that hyperacuity thresholds rise faster with eccentricity than visual resolution thresholds. On the other hand, the retinal distances over which hyperacuity detection remains optimal show a much slower rise. At 10 degrees eccentricity, hyperacuity thresholds are 10 times higher visual resolution thresholds 4-5 times higher, and optimal processing distances for hyperacuity only 2-3 times larger than at the fovea. Psychophysical procedures do not, therefore, provide a single unambiguous measure for the changes of spatial grain across the visual field.

Differential Threshold↗

PubMed1994

Growth of and aflatoxin production by Aspergillus flavus in peanuts stored under modified atmosphere packaging (MAP) conditions.

The combined effects of water activity (aw), storage temperature, headspace oxygen and carbon dioxide concentrations on the growth of, and aflatoxin production by Aspergillus flavus on sterile peanuts were examined using a process optimization technique termed response surface methodology (RSM). Regression analysis of the data indicated that aw, storage temperature and initial headspace oxygen concentration were all significant factors (P < 0.001) affecting the growth of, and aflatoxin production by A. flavus. Extensive growth and aflatoxin production occurred during the first week of storage in most treatment combinations. Maximum growth occurred in peanuts with an aw of 0.97, a storage temperature of 25 degrees C and headspace oxygen of 10% (balance 60:40 carbon dioxide:nitrogen), after 21 days of storage while maximum aflatoxin production occurred at a lower aw of 0.94, after 21 days under similar storage/gaseous conditions. In several treatment combinations, where high levels of aflatoxin (> 20 ng/g) were initially detected, aflatoxin concentration decreased during storage to levels less than the current regulatory limit of 20 ng/g. This study has shown that A. flavus can grow and produce aflatoxin in carbon dioxide enriched atmospheres in the presence of oxygen. It also emphasizes the combined effect of several 'barriers' to inhibit and reduce aflatoxin in MAP products containing various levels of residual oxygen.

Aflatoxins↗

PubMed1996

Purification of biological molecules by continuous flow electrophoresis in the Second International Microgravity Laboratory.

The RAMSES instrument is a continuous-flow electrophoresis device that performs separation and purification of biological materials on a preparative scale. It was flown on board the shuttle Columbia during the Second International Microgravity Laboratory mission that took place from 8 to 23 July 1994. This project had a technological aim to qualify the design and the technologies used, and a more scientific one to improve understanding of the phenomena involved in this process. To reach these goals, experiments were performed in which different samples and a variety of operating conditions were used, some of which cannot be applied on earth. Useful purifications were obtained, allowing samples to be collected for further analysis on the ground. These results confirm the predictions of a numerical model that could be used for future process optimization and the samples were found to have retained their biological activity.

Albumins↗

PubMed1989

High-performance liquid chromatographic determination of metabolic products for fermentation control of mammalian cell culture: analysis of carbohydrates, organic acids and orthophosphate using refractive index and ultraviolet detectors.

A method for the determination of carbohydrate substrates and excreted metabolic end-products of cell culture supernatants using a strong cation-exchange column in the H+ form has been developed. Organic acids and carbohydrates can be determined in addition to orthophosphoric acid. Pyrrolidone carboxylic acid, resulting from chemical conversion of the amino acid glutamine during the incubation of fresh medium and during the fermentation process, can be determined. The chromatographic method allows the correction of glutamine uptake values for physiological studies. Measured values of pyrrolidone carboxylic acid in supernatants of human hybridoma cell line show that it cannot be consumed by the cells. This technique allows the separation of major metabolites used in process optimization. Peak homogeneity is proved by on-line monitoring of the effluent with an ultraviolet (214 nm) and a refractive index detector connected in series.

Acids↗

PubMedDate not supplied

Physiological oxygen tension is relevant to MHC-1 expression, spontaneous transformation, and interferon response of in vitro aging murine fibroblasts.

Working from the hypothesis that modest deviations from physiological oxygen tension will influence cell characteristics important for infections/immunity and tumor development, cells were studied at three oxygen tensions during in vitro aging. Primary mouse embryo fibroblasts were established and subsequently passaged at 3, 6, and 18 kPa oxygen tension (6 representing normal tissue tension and 18 being the conventionally tension at in vitro cultures). The growth rate was slightly higher at 6 than 3 and 18 kPa. All cultures eventually stopped growing and subsequently transformed to nonmalignant cells with unlimited growth capacity. Cells kept at 3 kPa reached the highest number of cell doublings before crisis. Stimulation with PolyI:C resulted in detectable interferon response only at the high oxygen tension, and after transformation none of the cultures responded with interferon production. Expression of the major histocompatibility complex H-2K was elevated above and below physiological oxygen tension, indicating regulatory processes optimizing MHC expression at about physiological oxygen tension.

Animals↗

PubMed1991

Enhanced chemiluminescence for the detection of membrane-bound nucleic acid sequences: advantages of the Amersham system.

A range of nonradioactive nucleic acid labeling and detection systems have been developed that enable the user to label probes directly with enzyme molecules or indirectly with hapten-derivatized nucleotides. Horseradish peroxidase is used for the direct labeling procedures due to the ease of chemical modification and the relative thermal and chemical stability of this enzyme. Horseradish peroxidase has also been conjugated to a high-specificity antifluorescein antibody for detection of hapten (fluorescein)-labeled hybrids. Enhanced chemiluminescence is a light-emitting process optimized for the detection of low levels of horseradish peroxidase on membrane supports. Results are obtained as hard copy images on x-ray film.

Base Composition↗

PubMed2004

Coconut oil cake--a potential raw material for the production of alpha-amylase.

Solid-state fermentation (SSF) was carried out using coconut oil cake (COC) as substrate for the production of alpha-amylase using a fungal culture of Aspergillus oryzae. Raw COC supported the growth of the culture, resulting in the production of 1372 U/gds alpha-amylase in 24 h. Process optimization using a single parameter mode showed enhanced enzyme titre, which was maximum (1827 U/gds) when SSF was carried out at 30 degrees C for 72 h using a substrate with 68% initial moisture. Supplementation with glucose and starch further enhanced enzyme titre, which was maximum (1911 U/gds) with 0.5% starch. However, maltose inhibited the enzyme production. Studies on the effect of addition of external organic and inorganic nitrogenous compounds further showed a positive impact on enzyme synthesis by the culture. Increase of 1.7-fold in the enzyme activity (3388 U/gds) was obtained when peptone at 1% concentration was added to the fermentation medium. The enzyme production was growth-related, the activity being the maximum when the fungal biomass was at its peak at 72 h. Use of COC as raw material for enzyme synthesis could be of great commercial significance. To the best of our knowledge this is the first report on alpha-amylase production using COC in SSF.

Aspergillus oryzae↗

PubMed2006

Oryza sativa L. husk as heavy metal adsorbent: optimization with lead as model solution.

The effects of initial concentration of lead, temperature, biomass loading and pH were investigated for an optimized condition of lead uptake from the aqueous solution. The optimization process was analyzed using Central Composite Face-Centered Experimental Design in Response Surface Methodology (RSM) by Design Expert Version 5.0.7 (StatEase, USA). The design was employed to derive a statistical model for the effect of parameters studied on the removal of lead ion from aqueous solution. The coefficient of determination, R2 was found to be 92.36%. The initial concentration of 50.0 mg/L, temperature of 60 degrees C, biomass loading of 0.2 g and pH of 5.0 had been found to be the optimum conditions for the maximum uptake of lead ions in 98.11% batch mode. Under the optimum conditions, the lead uptake was attained to be circa 8.60 mg/g.

Adsorption↗

PubMed2006

Solid-state fermentation for the production of Monascus pigments from jackfruit seed.

The aim of the present work was to investigate the feasibility of jackfruit seed powder as a substrate for the production of pigments by Monascus purpureus in solid-state fermentation (SSF). A pigment yield of 25ODUnits/g dry fermented substrate was achieved by employing jackfruit seed powder with optimized process parameters such as 50% initial moisture content, incubation temperature 30 degrees C, 9x10(4)spores/g dry substrate inoculum and an incubation period of seven days. The color of the pigments was stable over a wide range of pH, apparently due to the buffering nature of the substrate, which could be a significant point for its scope in food applications. To the best of our knowledge this is the first report on pigment production using jackfruit seed powder in solid-state fermentation (SSF).

Artocarpus↗

PubMed2006

Tannase production by Paecilomyces variotii.

Surface response methodology was applied to the optimization of the laboratory scale production of tannase using a lineage of Paecilomyces variotii. A preliminary study was conducted to evaluate the effects of variables, including temperature ( degrees C), residue (%) (coffee husk:wheat bran), tannic acid (%) and salt solutions (%) on the production of tannase during 3, 5 and 7 days of fermentation. Among these variables, temperature, residues and tannic acid had significant effects on tannase production. The variables were optimized using surface response methodology. The best conditions for tannase production were: temperature (29-34 degrees C); tannic acid (8.5-14%); % residue (coffee husk:wheat bran 50:50) and incubation time of 5 days. The supplementation of external nitrogen and carbon sources at 0.4%, 0.8% and 1.2% concentration on tannase production were studied in the optimized medium. Three different nitrogen sources included yeast extract, ammonia nitrate and sodium nitrate along with carbon source (starch) were studied. Only ammonia nitrate showed a significant effect on tannase production. After the optimization process, the tannase activity increased 8.6-fold.

Carbon↗

PubMed2004

In silico prediction of central nervous system activity of compounds. Identification of potential pharmacophores by the TOPS-MODE approach.

The central nervous system (CNS) activity has been investigated by using a topological substructural molecular approach (TOPS-MODE). A discriminant analysis to classify CNS and non-CNS drugs was developed on a data set (302 compounds) of great structural variability where more than 81% (247/302) were well classified. Randic's orthogonalization procedures was carried out to allow the interpretation of the model and to avoid the collinearity among descriptors. The discriminant model was assessed by a leave-n-out (when n varies from 2 to 20) cross-validation procedure (79.94% of correct classification), an external prediction set composed by 78 CNS/non-CNS drugs (80.77% of correct classification) and a 5-fold full cross-validation (removing 78 compounds in each cycle, 80.00% of good classification). With this methodology was demonstrated that the hydrophobicity increase the CNS activity, while the dipole moment and the polar surface area decrease it; evidencing the capacity of the TOPS-MODE descriptors to estimate CNS activity for new drug candidates. The structural contributions to the CNS activity for two compounds are presented on the basis of fragment contributions. The model has also been able to identify potential structural pharmacophore, showing its possibilities in the lead generation and optimization processes.

Central Nervous System↗

PubMed2005

Pyridazines part 41: synthesis, antiplatelet activity and SAR of 2,4,6-substituted 5-(3-oxo-3-phenylprop-1-en-1-yl)- or 5-(3-phenylprop-2-enoyl)pyridazin-3(2H)-ones.

As part of the optimization process of the lead compound I a focussed library of diversely substituted pyridazin-3(2H)-ones containing a 3-oxo-3-phenylprop-1-en-1-yl or 3-phenylprop-2-enoyl fragment at position 5 has been obtained and evaluated as antiplatelet agents. The structural modification at positions 2, 6 and 4 of the heterocyclic moiety allowed us to obtain preliminary information on the structure-activity relationship in this family.

Molecular Structure↗

PubMed2006

The discovery and optimization of pyrimidinone-containing MCH R1 antagonists.

Optimization of a series of constrained melanin-concentrating hormone receptor 1 (MCH R1) antagonists has provided compounds with potent and selective MCH R1 activity. Details of the optimization process are provided and the use of one of the compounds in an animal model of diet-induced obesity is presented.

Animals↗