Lactate Control Enhances Growth Advantage in Fed-batch Cultures of Metabolically Engineered CHO Cells with Reduced Novel Growth-inhibitory Compound Formation

CHO cells have been recently shown to produce amino acid catabolism derived byproducts, which accumulate in fed-batch cultures to growth-inhibitory levels. Residual amino acid limitation or genetic engineering strategies have been successfully employed to suppress production of these novel growth inhibitory metabolic byproducts. However, the growth advantage attained due to suppression of these metabolic byproducts in fed-batch cultures is more pronounced when lactate accumulation is also controlled. BCAT1 knock-out (KO) CHO cells, which produce negligible levels of the metabolic byproducts isovalerate, isobutyrate and 2-methylbutyrate, grow to significantly higher peak cell densities in fed-batch cultures with lactate control (HiPDOG) as compared to cultures without lactate control. Henceforth, strategies involving novel metabolic byproduct control should preferably include lactate control to more easily assess the enhanced cell growth and productivities attainable.

Well-Defined Construction of Functional Macromolecular Architectures Based on Polymerization of Amino Acid Urethanes

Polypeptide synthesis was accomplished using the urethane derivatives of amino acids as monomers, which can be easily prepared, purified, and stored at ambient temperature without the requirement for special precautions. The urethanes of amino acids are readily synthesized by the N-carbamoylation of onium salts of amino acids using diphenyl carbonate (DPC). The prepared urethanes are then efficiently cyclized to produce amino acid N-carboxyanhydrides (NCAs). Thereafter, in the presence of primary amines, the ring-opening polymerization (ROP) of NCAs is initiated using the amines, to yield polypeptides with controlled molecular weights. The polypeptides have propagating chains bearing reactive amino groups and initiating chain ends endowed with functional moieties that originate from the amines. Aiming to benefit from these interesting characteristics of the polypeptide synthesis using the urethanes of amino acids, various macromolecular architectures containing polypeptide components have been constructed and applied as biofunctional materials in highly efficient antifouling coatings against proteins and cells, as biosensors for specific molecules, and in targeted drug delivery.

Current theories on the pathophysiology of equine laminitis – the link between the gut and foot

Equine laminitis is a painful debilitating condition that seems to be a product of domestication of horses associated with the practice of feeding carbohydrate rich pasture in excess of requirements, particularly in ponies. We have been working on the hypothesis that caecal bacteria, when presented with carbohydrate in large quantities tend to ferment this. Fermentation by gram positive bacteria is associated with a fall in pH of the caecal liquor. As a means of providing themselves with increased intracellular buffering capacity, these bacteria produce amino acid decarboxylase enzymes which convert amino acids present in the caecal fluid into primary amines which can act as intracellular buffers. The reason we thought this might be the case was that foods formed by bacterial fermentation processes (e.g. cheese and wines) have a high content of amines. Primary amines derived from some amino acids have vasoactive properties. In the 1960s it was recognised that human patients taking drugs that inhibit the metabolism of amines (monoamine oxidase inhibitors) could suffer from severe hypertensive crises if they ate cheese or drank red wines with high tyramine content. This so called ‘cheese effect’ is the result of the indirect sympathomimetic effect of tyramine which displaces norepinephrine from sympathetic nerve endings leading to a rise in blood pressure. Monoamine oxidase enzymes present in the epithelial cells lining the gut wall and in liver cells normally protect individuals from suffering these hypertensive crises. We wondered whether amines released from the gut in response to ingestion of excessive amounts of carbohydrate might lead to a similar reaction in ponies whereby dietary amines caused vasoconstriction of the digital vasculature, leading to the prodromal phases of laminitis.

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