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Plants are the sources of major food, feed, and fiber products that are used globally. This past year has seen advances in our understanding of the enzymes that modify wall architecture, the cloning of the first cellulose synthase gene, and revisions to the lignin biosynthetic pathway. These discoveries have facilitated the development of new strategies to alter cell wall properties in transgenic plants.
Alteplase (t-PA), a recombinant analogue of human tissue plasminogen activator, became the first genetically engineered thrombolytic approved by the Food and Drug Administration in 1987 for acute myocardial infarction (AMI). In addition to AMI, alteplase is currently approved for the treatment of acute ischemic stroke and pulmonary embolism, and we anticipate approval for catheter clearance in late 2001 in a 2-mg vial configuration. With the withdrawal of human neonatal kidney cell-derived urokinase, alteplase has become an alternative agent in peripheral vascular applications. Because few interventionalists had prior experience with the handling and dosage of alteplase, the Advisory Panel to the Society of Cardiovascular and Interventional Radiology established practice guidelines for use in noncoronary applications. Emerging clinical experience with contemporary dosing regimens shows a safety and efficacy profile similar to urokinase but with significantly reduced drug costs. Tenecteplase (TNK) is a genetically modified version of alteplase. TNK is the only plasminogen activator available that has shown a significantly enhanced safety profile versus alteplase in AMI. Approved for a 5-second, single-bolus injection in AMI, TNK possesses a longer half-life, increased resistance to plasminogen activator inhibitor, and improved fibrin specificity compared with alteplase. Because of its enhanced safety profile, TNK may be a desirable agent for peripheral vascular applications. Initial clinical studies with TNK in acute arterial and venous disease are ongoing. This article outlines the Advisory Panel guidelines for using alteplase and highlights features of tenecteplase.
In order to understand variations in thresholds to chemical carcinogens, it is important to appreciate, besides the genetic determinants, those many environmental factors which are at play, at all times, modifying the thresholds for chemical carcinogenesis. An understanding of the mechanisms of action of these factors may make it possible to tackle the difficult problem of determining human threshold levels.
Molecular links between miRNA: target modules regulating downstream genes for crop maturation/yield are poorly understood. Here, we report that elevated miR169d expression and concomitant reduced NF-YA2 (Nuclear Factor-Y subunit-A) target levels positively regulate vegetative growth and yield in Arabidopsis along with a shorter life cycle. In agreement, increased NF-YA2 levels in (1) NF-YA2-OE (overexpression) lines, (2) miR169d-target-mimicry lines (in which miR169d is chelated), and (3) miR169d-non-cleavable NF-YA2 resistant target lines show the opposite phenotype. Further, we find increased auxin levels in MIR169d-OE and nf-ya2 mutant lines, supporting the enrichment of 'auxin terms' in MIR169-OE transcriptome data. We show that ARGOS (auxin-regulated gene involved in organ size) is upregulated in MIR169d-OE due to reduced NF-YA2 repressor levels and that NF-YA2 directly binds the ARGOS promoter. Genetic screens of this module show that neither overexpressing miR169d in an argos mutant background nor the nf-ya2:argos double mutants rescue the argos mutant phenotype, suggesting a parallel pathway of ARGOS regulation via the MIR169:NF-YA2 node, independent of auxin. To assess the translational potential of this module in a crop, we show that Sly-MIR169-OE lines in tomato, having reduced target Sly-NF-YA10 levels, also regulate Sly-ARGOS resulting in early flowering, larger sized fruits, more fruit fresh weight, higher fruit set, early fruiting, and better shelf life than wild-type plants. In contrast, Sly-STTM169 plants inhibited for Sly-miR169 action and having increased levels of Sly-NF-YA10 have a longer life cycle with reduced biomass, decreased fruit set, and an overall reduction in yield. Thus, our findings show a conserved MIR169:NF-YA:ARGOS module which can be applied to crops for addressing future food demands.
First we remind general considerations concerning biodiversity on earth and particularly the loss of genetic biodiversity that seems irreversible whether its origin is directly or indirectly linked to human activities. Urgent and considerable efforts must be made from now on to cataloge, understand, preserve, and enhance the value of biodiversity while ensuring food safety and human and animal health. Ambitious integrated and multifield research programs must be implemented in order to understand the causes and anticipate the consequences of loss of biodiversity. Such losses are a serious threat to sustainable development and to the quality of life of future generations. They have an influence on the natural balance of global biodiversity in particularly in reducing the capability of species to adapt rapidly by genetic mutations to survive in modified ecosystems. Usually, the natural immune systems of mammals (both human and animal), are highly polymorphic and able to adapt rapidly to new situations. We more specifically discuss the fact that if the genetic diversity of the affected populations is low the invading microorganisms, will suddenly expand and create epidemic outbreaks with risks of pandemic. So biodiversity appears to function as an important barrier (buffer), especially against disease-causing organisms, which can function in different ways. Finally, we discuss the importance of preserving biodiversity mainly in the wildlife ecosystems as an integrated and sustainable approach among others in order to prevent and control the emergence or reemergence of diseases in animals and humans (zoonosis). Although plants are also part of this paradigm, they fall outside our field of study.
Plant genetic engineering has the potential to both introduce new allergenic proteins into foods and remove established allergens. A number of allergenic plant proteins have been characterized, showing that many are related to proteins which have potentially valuable properties for use in nutritional enhancement, food processing and crop protection. It is therefore important to monitor the allergenic potential of proteins used for plant genetic engineering and major biotechnology companies have established systems for this. Current technology allows gene expression to be down-regulated using antisense or co-suppression and future developments may allow targeted gene mutation or gene replacement. However, the application of this technology may be limited at least in the short term by the presence of multiple allergens and their contribution to food processing or other properties. Furthermore, the long-term stability of these systems needs to be established as reversion could have serious consequences.
Amid the explosion of fundamental knowledge generated from transgenic animal models, a small group of scientists has been producing transgenic livestock with goals of improving animal production efficiency and generating new products. The ability to modify mammary-specific genes provides an opportunity to pursue several distinctly different avenues of research. The objective of the emerging gene "pharming" industry is to produce pharmaceuticals for treating human diseases. It is argued that mammary glands are an ideal site for producing complex bioactive proteins that can be cost effectively harvested and purified. Consequently, during the past decade, approximately a dozen companies have been created to capture the US market for pharmaceuticals produced from transgenic bioreactors estimated at $3 billion annually. Several products produced in this way are now in human clinical trials. Another research direction, which has been widely discussed but has received less attention in the laboratory, is genetic engineering of the bovine mammary gland to alter the composition of milk destined for human consumption. Proposals include increasing or altering endogenous proteins, decreasing fat, and altering milk composition to resemble that of human milk. Initial studies using transgenic mice to investigate the feasibility of enhancing manufacturing properties of milk have been encouraging. The potential profitability of gene "pharming" seems clear, as do the benefits of transgenic cows producing milk that has been optimized for food products. To take full advantage of enhanced milk, it may be desirable to restructure the method by which dairy producers are compensated. However, the cost of producing functional transgenic cattle will remain a severe limitation to realizing the potential of transgenic cattle until inefficiencies of transgenic technology are overcome. These inefficiencies include low rates of gene integration, poor embryo survival, and unpredictable transgene behavior.
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Dietary recommendations evolved from instructions directed at prevention of starvation diseases to the level of intake of essential nutrients that are adequate to meet the known nutrient needs of practically all healthy persons. Vitamin requirements have been modified various times over the years and there are still differences in recommended intakes in different countries. A debate on optimal vitamin intake is ongoing, based on the concepts of deficiency, sufficiency and hypothetical identification of a range within which a further biological advantage can be expected. In establishing appropriate criteria for food and nutrient intakes, additional studies are warranted on the physiological interactions between nutrients and non-nutrients and on many other factors such as genetic determinants and lifestyle which could interfere with disease prevention.
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The engineering of industrially important genetically modified organisms by the integration of heterologous genes into the chromosome is often the method of choice for several reasons concerned with long-term stability, homogeneous population distribution, and the enabling of selection without the addition of antibiotics. However, integration may disrupt endogenous gene expression, giving rise to increased levels of toxic metabolic byproducts or activating otherwise silent genes. The position of integration of a foreign gene in the chromosome can also influence its expression levels, and this effect will be of relevance in terms of optimizing protein production parameters. In this study, we determine how the random integration of a foreign reporter gene might affect expression levels and assess the use of proteome analysis to investigate possible effects on synthesis of endogenous proteins in two important food-relevant microorganisms, Saccharomyces cerevisiae and Lactococcus lactis. Eleven L. lactis integrants carrying the gusA gene were analyzed, and expression levels were found to vary by a factor of threefold in contrast to expression levels of lacZ in 18 S. cerevisiae integrants, which showed a 14-fold variation. Of relevance to industry is whether any changes in expression levels might occur as a consequence of storage of the modified strains. Here it is also shown that the above differences in expression levels were not significantly affected by storage of frozen cultures over a period of several months. Analysis of the protein composition of the yeast and lactococcal integrant strains by separation on one-dimensional (1D) and 2D gels showed no significant variations in position beyond those observed in control samples.
Intracerebroventricular (i.c.v.) injection of tachykinins (TKs) inhibits ethanol intake and angiotensin II-induced water intake; the effects are apparently mediated by NK-3 and NK-1 receptors, respectively. The present study evaluated the effect of the TK PG-KII, a novel kassinin-like peptide isolated from the skin of the Australian frog Pseudophryne güntheri, in these in vivo tests for central activity. PG-KII, given by i.c.v. injection, potently inhibited alcohol intake in genetically selected alcohol-preferring rats, being about 3 times more potent than the selective NK-3 receptor agonist NH2-SENK. The dose of 100 ng/rat, that markedly inhibited ethanol intake, did not inhibit food intake and prandial drinking in food deprived rats, providing evidence that the effect of PG-KII on ethanol intake is behaviorally selective. The effect on ethanol intake was inhibited by i.c.v. injection of the NK-3 receptor antagonist R820, but was not modified by the NK-1 receptor antagonist SR 140333. PG-KII inhibited drinking induced by angiotensin II only at doses of 300 or 1000 ng/rat, being about 5 times less potent than the selective NK-1 receptor agonist [Sar9, Met(O2)11] substance P. These doses of PG-KII produced also marked increase in competing behaviors, such as grooming and locomotion. The dose of 1000 ng/rat evoked a general inhibition of the ingestive behavior, reducing also food intake. The i.c.v. injection of the NK-1 receptor antagonist SR 140,333 only slightly inhibited the effect of PG-KII on angiotensin II-induced drinking, while it markedly reduced that of [Sar9, Met(O2)11] substance P. These findings, in accordance with those of previous studies, indicate that PG-KII is endowed with marked activity at central NK-3 receptors, and low activity at NK-1 receptors.
AIMS: Recent studies have shown that Hypericum perforatum extracts (HPE) inhibit ethanol intake in alcohol-preferring rats, but their mechanism of action is still unknown. HPE have been shown to bind at gamma-aminobutyric acid (GABA)(A) and GABA(B) receptors, to inhibit GABA reuptake, to evoke GABA release from synaptosomes and to exert an anxiolytic effect that is blocked by the benzodiazepine antagonist flumazenil. Since GABA-ergic mechanisms are known to influence ethanol intake, the present study was aimed at investigating whether they might mediate the effect of a CO2 Hypericum extract (HPCO2) on ethanol intake in genetically selected Marchigian Sardinian alcohol-preferring (msP) rats. METHODS: The GABA(A) receptor antagonist bicuculline and the GABA(B) receptor antagonists CGP-36742 and phaclofen were tested versus the effect of HPCO2 on ethanol intake. RESULTS: The results of the present study confirm that HPCO2, given by intragastric injection, markedly reduces ethanol intake in msP rats and its effect is behaviourally selective, since the same doses which inhibited ethanol intake did not modify the simultaneous intake of food or water. The GABA(A) receptor antagonist bicuculline, given by intraperitoneal (i.p.) injection at a dose of 2 mg/kg, which effectively antagonizes the effects of GABA(A) receptor agonists, did not modify the effect of HPCO2, 15 or 125 mg/kg. The GABA(B) receptor antagonists CGP-36742, given by i.p. injection at a dose of 100 mg/kg, and phaclofen, given by intracerebroventricular injection at a dose of 25 micro g/rat, did not modify the inhibitory effect on alcohol intake induced by HPCO2, 15 or 125 mg/kg. The same doses of the two GABA(B) receptor antagonists induced a pronounced reduction of the effect of the GABA(B) receptor agonist bacoflen, given by i.p. injection at a dose of 5 mg/kg. CONCLUSIONS: These findings suggest that the inhibitory effects of HPE on ethanol intake are not mediated by GABA agonist actions.
Research into bovine spongiform encephalopathy (BSE) commenced immediately following its discovery in November 1986. Formal epidemiological studies commenced in June 1987 and were part of a large research programme set up mainly at the Central Veterinary Laboratory Weybridge and the Institute for Animal Health, AFRC/MRC Neuropathogenesis Unit in Edinburgh. This programme also covered the clinicopathology of BSE, transmission studies and molecular chemistry. Research results have shown that BSE is a member of the group of diseases known as the sub-acute spongiform encephalopathies caused by unconventional transmissible agents and which includes scrapie of sheep, from which BSE was probably derived, and Creutzfeldt Jakob disease (CJD) of man. The agent causing BSE closely resembles strains of the scrapie agent but is not identical. Spongiform encephalopathy has developed in sheep, goats, pigs, cattle, marmosets and mice but not hamsters following experimental inoculation of brain material from confirmed clinical cases of BSE. BSE agent has been detected by mouse bio-assay in brain from cows from several sources confirmed to have BSE. Infectivity has not been detected in spleen, buffy coat, semen, muscles, placenta and bone marrow (all following parenteral inoculation) nor in milk/mammary gland, spleen, placenta and a variety of lymph nodes following substantial oral exposure. This latter route successfully transmitted disease to mice with brain/cerebrospinal fluid. The introduction of modified rendering systems, which did not employ hydrocarbon solvent extraction, were probably responsible for an increase in exposure of cattle from 1981-1988 sufficient to cause the disease. Experiments are in progress to investigate the effectiveness of different rendering systems used in the European Community and of chemical and physical de-activating procedures for destroying BSE and scrapie infectivity. A clear genetic influence on disease susceptibility has been suggested but is not yet proven. The Agricultural and Food Research Council have set up a large Biology of Spongiform Encephalopathies Research Programme to address some of the more fundamental unknowns of this group of diseases but it is too early to report results. As with scrapie, no epidemiological relationship has been demonstrated between BSE and the human diseases through the monitoring programme that has been established by the Department of Health to detect such an occurrence. BSE research results so far show that controls to protect animal and human health and based initially on scrapie research findings, are sound.(ABSTRACT TRUNCATED AT 400 WORDS)
Widespread interest in the possibility that selected foods might promote health has resulted in the coining of the term functional food, although agreement about what is and what is not a functional food is lacking. Public interest in functional foods is increasing because of higher health care costs; the passage of federal legislation affecting many food categories, including the expanded category of dietary supplements; and recent scientific discoveries linking dietary habits with the development of many diseases, including coronary heart disease and some cancers. A variety of foods have been proposed as providing health benefits by altering one or more physiologic processes. Biomarkers are needed to assess the ability of functional foods or their bioactive components to modify disease and to evaluate the ability of these foods to promote health, growth, and well-being. Evidence suggests that several biomarkers may be useful for distinguishing between diseased and nondiseased states and even for predicting future susceptibility to disease. A variety of biomarkers will probably be needed to develop a profile for an individual that reflects the impact of diet on performance and health. Another area of interest is the interaction of nutrients and their association with genetics. These interactions may account for the inconsistent interrelations observed between specific dietary constituents and the incidence of disease. Greater understanding of how diet influences a person's genetic potential, overall performance, and susceptibility to disease can have enormous implications for society. As new discoveries are made in this area, consumers will need access to this information so that they can make informed decisions.
Lysozyme is a key antimicrobial component of human milk that has several health-promoting functions including the development of a healthy intestinal tract. However, levels of lysozyme in the milk of dairy animals are negligible. We have generated transgenic dairy goats that express human lysozyme (HLZ) in their milk in an attempt to deliver the benefits of human milk in a continual fashion. To test the feasibility of this transgenic approach to achieve a biological impact at the level of the intestine, feeding trials were conducted in two animal models. Pasteurized milk from HLZ transgenic animals was fed to both kid goats (ruminant model) and young pigs (human model), and the numbers of total coliforms and Escherichia coli present in the small intestine were determined. Data from this proof-of-principle study demonstrate that milk from transgenic animals was capable of modulating the bacterial population of the gut in both animal models. Pigs that consumed pasteurized milk from HLZ transgenic goats had fewer numbers of coliforms and E. coli in their intestine than did those receiving milk from non-transgenic control animals. The opposite effect was seen in goats. Milk from these transgenic animals not only represent one of the first transgenic food products with the potential of benefiting human health, but are also a unique model to study the development and role of intestinal microflora on health, well-being and resistance to disease.
We have engineered two new versions of the doxycycline (dox) inducible system for use in Drosophila. In the first system, we have used the ubiquitously expressed Drosophila actin5C promoter to express the Tet-Off transactivator (tTA) in all tissue. Induction of a luciferase target transgene begins 6 h after placing the flies on dox-free food. Feeding drug-free food to mothers results in universal target gene expression in their embryos. Larvae raised on regular food also show robust expression of a target reporter gene. In the second version, we have used the Gal4-UAS system to spatially limit expression of the transactivator. Dox withdrawal results in temporally- and spatially-restricted, inducible expression of luciferase in the adult head and embryo. Both the actin5C and Gal4-UAS versions produce more than 100-fold induction of luciferase in the adult, with virtually no leaky expression in the presence of drug. Reporter gene expression is also undetectable in larvae or embryos from mothers fed dox-containing food. Such tight control may be due to the incorporation of Drosophila insulator elements (SCS and SCS') into the transgenic vectors. These systems offer a practical, effective alternative to currently available expression systems in the Drosophila research community.
Oral administration of disease-specific autoantigens can prevent or delay the onset of autoimmune disease symptoms. We have generated transgenic potato plants that synthesize human insulin, a major insulin-dependent diabetes mellitus autoantigen, at levels up to 0.05% of total soluble protein. To direct delivery of plant-synthesized insulin to the gut-associated lymphoid tissues, insulin was linked to the C-terminus of the cholera toxin B subunit (CTB). Transgenic potato tubers produced 0.1% of total soluble protein as the pentameric CTB-insulin fusion, which retained GM1-ganglioside binding affinity and native antigenicity of both CTB and insulin. Nonobese diabetic mice fed transformed potato tuber tissues containing microgram amounts of the CTB-insulin fusion protein showed a substantial reduction in pancreatic islet inflammation (insulitis), and a delay in the progression of clinical diabetes. Feeding transgenic potato tissues producing insulin or CTB protein alone did not provide a significant reduction in insulitis or diabetic symptoms. The experimental results indicate that food plants are feasible production and delivery systems for immunotolerization against this T cell-mediated autoimmune disease.