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Introduction. Over the centuries, bio-sourced compounds isolated from plants, insects and microorganisms have been a potent source of drugs for the treatment of human diseases. Literature. Bio-sourced extracts offer a wide diversity of compounds with a large number of potentially beneficial effects in humans. Serendipity has frequently played a key role in the discovery of new medicines. The canonical discovery of penicillin required both chance and a prepared mind to understand and exploit its potential for the treatment of human infections. Nowadays, most anti-cancer drugs currently in clinical use were at least partly discovered by a "fortunate happenstance". Conclusions. In this review, we recapitulate the story of one of these compounds, 2-propylpentanoic acid, derived from the Valeriana officinalis flowering plant and its path to validation as a cancer treatment.

The production of fungal metabolites and conidia at an industrial scale requires an adequate yield at relatively low cost. To this end, many factors are examined and the design of the bioreactor to be used for the selected product takes a predominant place in the analysis. One approach to addressing the issue is to integrate the scaling-up procedure according to the biological characteristics of the microorganism considered, i.e. in our case filamentous fungi. Indeed, the scaling-up procedure is considered as one of the major bottlenecks in fermentation technology, mainly due to the near impossibility of reproducing the ideal conditions obtained in small reactors designed for research purposes when transposing them to a much larger production scale. The present review seeks to make the point regarding the bioreactor design and its implementation for cultivation of filamentous fungi and the production of fungal metabolites according to different developmental stages of fungi of industrial interest. Solid-state (semi-solid), submerged, fermentation and biofilm reactors are analyzed. The different bioreactor designs used for these three processes are also described at the technological level.

Overview of current knowledge on management of hydrocarbon pollution in mangroves. Mangrove forests are vital in terms of biomass production and maintenance of the natural balance in coastal areas in the tropics. However, mangroves are subject to pollution from human activities. Oil pollution is one of the causes leading to the decline of mangroves, which represent only 1% of the area of all the world's tropical forests. Several techniques are available for the remediation of oil contaminated areas. Biodegradation appears to be the best suited to mangrove ecosystems. However this technique remains confined to the laboratory. Field tests in situ need to be conducted in order to evaluate the results obtained in the laboratory.

Bioreactor scale-up and design on the basis of physiologically relevant parameters: application to the production of lipase by Yarrowia lipolytica. Bioreactor scale-up often poses a serious issue during the industrial development of a bioprocess considering the numerous physical and biological phenomena occurring in the reacting volume. The basic principles of scale-up coming from the traditional chemical and process engineering approaches will be first reviewed and will be then compared to a new one involving recent development at the level of microbial strain manipulation. This "physiological" approach of scale-up involves directly a biological component of the system (by comparison with the traditional approach for scaling-up involving physical parameters indirectly linked to the physiological phenomena occurring in the bioreactor), i.e. the synthesis of a reporter fluorescent protein when microbial cells are exposed to stress. It will be shown how this principle can be used for a better understanding of the relationship between bioreactor hydrodynamics and microbial stress.

The impact of the fluctuations in dissolved oxygen tension (DOT) on the lipase production by Yarrowia lipolytica has been investigated in a scale-down reactor (SDR). This bioreactor comprises a 20 l agitated vessel with an automatic valve controlling the opening and closure of the air flow line. This kind of scale-down apparatus is used in order to generate DOT gradients encountered in large-scale, while maintaining the other environmental conditions constant. The impact of DOT fluctuations has been estimated at three levels of the lipase synthesis machinery: lipase gene expression, lipase translation, lipase excretion to the extracellular medium. Among these levels, the performance of lipase production under oscillating DOT was significantly affected at the lipase gene expression level.

Understanding and modeling the complex interactions between biological reaction and hydrodynamics are a key problem when dealing with bioprocesses. It is fundamental to be able to accurately predict the hydrodynamics behavior of bioreactors of different size and its interaction with the biological reaction. CFD can provide detailed modeling about hydrodynamics and mixing. However, it is computationally intensive, especially when reactions are taken into account. Another way to predict hydrodynamics is the use of "Compartment" or "Multi-zone" models which are much less demanding in computation time than CFD. However, compartments and fluxes between them are often defined by considering global quantities not representative of the flow. To overcome the limitations of these two methods, a solution is to combine compartment modeling and CFD simulations. Therefore, the aim of this study is to develop a methodology in order to propose a compartment model based on CFD simulations of a bioreactor. The flow rate between two compartments can be easily computed from the velocity fields obtained by CFD. The difficulty lies in the definition of the zones in such a way they can be considered as perfectly mixed. The creation of the model compartments from CFD cells can be achieved manually or automatically. The manual zoning consists in aggregating CFD cells according to the user's wish. The automatic zoning defines compartments as regions within which the value of one or several properties are uniform with respect to a given tolerance. Both manual and automatic zoning methods have been developed and compared by simulating the mixing of an inert scalar. For the automatic zoning, several algorithms and different flow properties have been tested as criteria for the compartment creation.

Trehalose is a reserve carbohydrate produced by Saccharomyces cerevisiae under stress conditions and used as a cryoprotectant during freeze drying. So the cellular content of trehalose is an important parameter to control in industrial context. Scale-down reactors have been used to produce Saccharomyces cerevisiae. These reactors permit to mimic the hydrodynamic conditions experienced by cells during large scale production. Three types of scale-down reactors have been tested, differing by the geometry of the non-mixed part and the recirculation flow rate. The results show that cells cultivated in scale-down reactors produced less trehalose compared to the reference reactor. These results are completed by the study of the expression of the TPS2 promoter coupled with a green fluorescent protein (GFP). TPS2 is a gene coding for a subunit of the enzymatic complex responsible of trehalose synthesis. This strain was produced in mini-bioreactors which are shake flasks equipped with a dissolved oxygen probe. This approach allows using trehalose, or related enzymes, as a cellular marker of the stress encountered by yeast in industrial process.

Heterogeneities caused by deficient mixing in large-scale bioreactors have been identified and described in literature. These heterogeneities affect physiological changes of microorganisms through its passage in different zones of concentrations. Consequently the differences in terms of productivities, qualities and/or yields of products of interest have been observed during scaling-up from laboratory to larger scales. For this reason, large-scale process improvement depends on the understanding of dynamic interactions between microbial responses and physical phenomena inside bioreactors. The dynamic responses of microorganisms are used as a tool for gaining insight into the fundamentals of microbial changes under a mixing-well controlled environment. Our research group has not only applied scale-down methodology to study the microbial responses at molecular, microscopic and macroscopic levels of observation, but also has used innovative strains and process engineering tools to evaluate fast dynamic responses of microorganism at time scales from seconds to minutes. This presentation focuses on the application of rational strategies in order to characterize distributed relaxation times of microorganisms which are considered to be constant at all fermentation scales. Experiments were conducted with reporter bioluminescent strains of Escherichia coli in which the luxCDABE operon was fused to promoters responding to different selected environmental stresses (dissolved oxygen, pH, temperature and substrate, etc.). Such strains allow real-time recording of the expression of genes involved in stress responses. Kinetic analyses of biomass, extracellular metabolites, inlet/exhaust gas, were carried out in order to determine mass balances and biological kinetic parameters. We will present our approach and the results concerning continuous culture of E. coli DPD2417 (nirB::luxCDABE) to monitor the microbial responses to oxygen limitation.

Mangrove ecosystems are areas prone to various types of pollution, especially hydrocarbons. These hydrocarbons mostly stem from human activities such as spills coming from offshore oil operations, runoff from surrounding urban areas or atmospheric deposition. This pollution causes the decline of mangroves, which results in an imbalance in the functioning of this particular ecosystem with damages to the microbiota. Biodegradation allows to restore these ecosystems. This biodegradation can only be effective in specific environmental conditions. The presence of nutrients, which stimulate bacterial growth and promote biodegradation, is a key parameter to be considered. During this experiment, we achieved biodegradation tests to assess the effect of nitrogen and phosphorus on the process. The results showed that the biodegradation rates were strongly bound to the presence of nutrients. The degradation rates depended on the medium. The treatment that reached the best rate of degradation of diesel after 10 days was the one using 20% of a nutrient solution (MSM) containing nitrogen and phosphorus. This treatment led to a maximal degradation of 84.7% ± 4.7% obtained in the flasks containing 20% of a nutrient solution (MSM) containing nitrogen and phosphorus. [ABSTRACT FROM AUTHOR]

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