Genetic manipulation of antitumor-agent biosynthesis to produce novel drugs

Current methods of obtaining novel drugs may be complemented in the near future by the genetic engineering of antitumor-agent biosynthesis in microorganisms. Biosynthetic gene clusters from several antitumor pathways in actinomycetes are presently being characterized and expressed in order to generate novel drugs. Several novel hydroxylated and glycosylated antitumor-drug derivatives have been produced that show a relaxed substrate specificity for secondary-metabolic enzymes, which opens up the possibility of generating novel drugs by genetic manipulation.     

A piece in the puzzle: an ion channel candidate gene for schizophrenia

Mutations in ion channels have been found to cause a variety of mendelian genetic diseases, and polyglutamine repeat expansion is a newly recognized pathogenic mechanism that causes several rare, genetic, late-onset neurological syndromes. Polymorphic polyglutamine tracts are present in a recently described human, calcium-activated potassium channel, KCNN3 (also known as hKCa3), and alleles of this gene that contain longer repeats have been associated with schizophrenia. The physiological function of the channel is consistent with an etiological role in this disease; drugs designed to target this channel might therefore provide novel psychotherapeutics.     

Interleukin-13 inhibits cytokine secretion by blood monocytes from patients with IgA nephropathy

The study of hypertrophic cardiomyopathy has been at the vanguard of molecular genetic investigation into inherited diseases of the cardiovascular system for the greater part of the last decade. These studies have shown it to be a disease of sarcomeric contractile proteins and have highlighted its genetic heterogeneity. There are now seven known genetic loci and six disease genes associated with the condition. The biology of the mutant polypeptides has been studied in vitro, and animal models are being developed. Increased understanding gained from these studies has clarified features of the condition at the clinical level and has had an impact on management of patients. It is hoped that this work will lead to the development of novel therapies for both hypertrophic cardiomyopathy and acquired forms of left ventricular hypertrophy.     

Congenital heart defects and 22q11 deletions: which genes count?

Hemizygous deletions on the long arm of chromosome 22 (del22q11) are a relatively common cause of congenital heart disease. For some specific heart defects such as interrupted aortic arch type B and tetralogy of Fallot with absent pulmonary valve, del22q11 is probably the most frequent genetic cause. Although extensive gene searches have been successful in discovering many novel genes in the deleted segment, standard positional cloning has so far failed to demonstrate a role for any of these genes in the disease. We show how the use of experimental animal models is beginning to provide an insight into the developmental role of some of these genes, while novel genome manipulation technologies promise to dissect the genetic aspects of this complex syndrome.     

Minor histocompatibility antigens

The existence of transplantation antigens, in addition to those encoded by genes in the MHC, has been known for over half a century. The molecular identification of these additional minor histocompatibility (H) antigens lagged behind that of their MHC counterparts, largely because minor H antigens are recognised by T cells and not by antibodies. In the past year, however, new minor H antigens have been identified at both the genetic and protein level and include Uty, a second novel gene encoding a male-specific epitope in mice, a novel autosomal gene encoding each of the H-13 alleles of mice, and a second male-specific epitope encoded by the SMCY gene.     

A novel immune genetic algorithm based on quasi secondary response

Combining the advantages of a genetic algorithm and an artificial immune system,a novel genetic algorithm named immune genetic algorithm based on quasi secondary response(IGA-QSR) is proposed. IGA-QSR employs a database to simulate the standard secondary response and the quasi secondary response. Elitist strategy,automatic extinction,clonal propagation,diversity guarantee,and selection based on comprehensive fitness are also used in the process of IGA-QSR.Theoretical analysis,numerical examples of three benchmark mathematical optimization problems and a traveling salesman problem all demonstrate that IGA-QSR is more effective not only on convergence speed but also on convergence probability than a simple genetic algorithm with the elitist strategy (SGA-ES). Besides,IGA-QSR allows the designers to stop and restart the optimization process freely without losing the best results that have already been obtained.These properties make IGA-QSR be a feasible,effective and robust search algorithm for complex engineering problems.     

Pantoprazole 20 mg is effective for relief of symptoms and healing of lesions in mild reflux oesophagitis

The primary immunodeficiencies are congenital disorders that affect the function of the immune system. The result is an inadequate immune response to microorganisms, self-antigens, and tumor cells, which leads to increased susceptibility to infections, autoimmunity, or malignant disease. A substantial advance has been made in the understanding of the exact molecular mechanisms leading to primary immunodeficiencies; however, for some types, a specific genetic defect has not yet been determined. The life expectancy of patients with primary immunodeficiencies has increased considerably because of bone marrow transplantation and replacement therapies. Gene therapy has already been used for a particular type of immunodeficiency and is a promising alternative for the future management of many other types of primary immunodeficiencies. A better understanding of the genetic defects that lead to primary immunodeficiencies would result in the development of novel therapeutic strategies.     

Facing death in the fly: genetic analysis of apoptosis in Drosophila

Apoptosis, a gene-directed form of cell death, occurs normally during development and plays a major role in many diseases, including cancer and neurodegenerative disorders. Molecular genetic studies in Drosophila have revealed the existence of three novel apoptotic activators, reaper, head involution defective and grim. Additionally, Drosophila homologs of evolutionarily conserved IAPs (inhibitor of apoptosis proteins) and CED-3/ICE-like proteases have been identified and characterized. Through the combined use of genetic, molecular, biochemical and cell biological techniques in Drosophila it should now be possible to elucidate the precise mechanism by which apoptosis occurs, and how the death program is activated in response to many distinct death-inducing signals.     

Molecular and pharmacological analysis of cyclic nucleotide-gated channel function in the central nervous system

Most functional studies of cyclic nucleotide-gated (CNG) channels have been confined to photoreceptors and olfactory epithelium, in which CNG channels are abundant and easy to study. The widespread distribution of CNG channels in tissues throughout the body has only recently been recognized and the functions of this channel family in many of these tissues remain largely unknown. The molecular biological and pharmacological properties of the CNG channel family are summarized in order to put in context studies aimed at probing CNG channel functions in these tissues using pharmacological and genetic methods. Compounds have now been identified that are useful in distinguishing CNG channel activated pathways from cAMP/cGMP dependent-protein kinases or other pathways. The ways in which these interact with CNG channels are understood and this knowledge is leading to the identification of more potent and more specific CNG channel subtype-specific agonists or antagonists. Recent molecular and genetic analyses have identified novel roles of CNG channels in neuronal development and plasticity in both invertebrates and vertebrates. Targeting CNG channels via specific drugs and genetic manipulation (such as knockout mice) will permit better understanding of the role of CNG channels in both basic and higher orders of brain function.     

Application of the genetic algorithm to estimate the parameters related to the kinetics of the reduction of the iron ore,coal mixture

A novel methodology has been developed to calculate the kinetic parameters associated with reduction of ore-coal composite mixtures and to describe the time course of reduction of hematite to iron. The empirical parameters, namely, the three sets of activation energies and frequency factors, have been estimated by employing an evolutionary optimization tool, the genetic algorithm (GA). The model prediction matches well with the experimental literature data. The estimated activation energies are higher than the corresponding intrinsic values, indicating the role of heat transfer in the process.     

Efficient Hybrid Genetic Algorithm for Resource Leveling via Activity Splitting

Resource leveling problem is an attractive field of research in project management. Traditionally, a basic assumption of this problem is that network activities could not be split. However, in real-world projects, some activities can be interrupted and resumed in different time intervals but activity splitting involves some cost. The main contribution of this paper lies in developing a practical algorithm for resource leveling in large-scale projects. A novel hybrid genetic algorithm is proposed to tackle multiple resource-leveling problems allowing activity splitting. The proposed genetic algorithm is equipped with a novel local search heuristic and a repair mechanism. To evaluate the performance of the algorithm, we have generated and solved a new set of network instances containing up to 5,000 activities with multiple resources. For small instances, we have extended and solved an existing mixed integer programming model to provide a basis for comparison. Computational results demonstrate that, for large networks, the proposed algorithm improves the leveling criterion at least by 76% over the early schedule solutions. A case study on a tunnel construction project has also been examined.     

pBECKS. A flexible series of binary vectors for Agrobacterium-mediated plant transformation

A series of binary T-DNA vectors (pBECKS) has been created for use in the Agrobacterium-mediated genetic transformation of plants. The pBECKS series has corrected the undesirable features of the popular pBIN19 vector; the deleterious mutation within the coding sequence of nptII has been amended and the cloning sites are now adjacent to the right border repeat in order to reduce the possibility of producing truncated sequences of novel genes within transformants. One set of vectors incorporates various combinations of the marker genes gusA, C1/Lc, nptII, hph, and bar, for pursuit of early and stable transformation events. A set of constructs which contain deleted T-DNA borders in various combinations and display predictably altered efficacies for gene transfer has also been created. A modular set of vectors has been designed to facilitate the insertion and transfer of novel gene sequences by providing a nptII-linked plant expression cassette or lacZ-multiple cloning site. A range of antibiotic resistance genes has been incorporated into the non-T-DNA part of the vectors in order to facilitate their selection across the range of Agrobacterium virulence strains.     

Pipe Index Vector: A Method to Improve Genetic-Algorithm-Based Pipe Optimization

This paper proposes a methodology for the optimal design of water distribution systems based on genetic algorithms. The objective of the optimization is to minimize the capital cost, subject to ensuring adequate pressures at all nodes during peak demands. The proposed method is novel in that it involves the use of a pipe index vector to control the genetic algorithm search. The pipe index vector is a measure of the relative importance of pipes in a network in terms of their impact on the hydraulic performance of the network. By using the pipe index vector it is possible to exclude regions of the search space where impractical and infeasible solutions exist. By reducing the search space it is possible to generate feasible solutions more quickly and hence process much healthier populations than would be the case in a standard genetic algorithm. This results in optimal solutions being found in a fewer number of generations resulting in a substantial saving in terms of computational time. The method has been tested on several networks, including networks used for benchmark testing least cost design algorithms, and has been shown to be efficient and robust.     

Deletions in HOXD13 segregate with an identical, novel foot malformation in two unrelated families

Synpolydactyly (SPD) is a dominantly inherited congenital limb malformation consisting of 3/4 syndactyly in the hands and 4/5 syndactyly in the feet, with digit duplication in the syndactylous web. The condition recently has been found to result from different-sized expansions of an amino-terminal polyalanine tract in HOXD13. We report a novel type of mutation in HOXD13, associated in some cases with features of classic SPD and in all cases with a novel foot phenotype. In two unrelated families, each with a different intragenic deletion in HOXD13, all mutation carriers have a rudimentary extra digit between the first and second metatarsals and often between the fourth and fifth metatarsals as well. This phenotype has not been reported in any mice with genetic modifications of the HoxD gene cluster. The two different deletions affect the first exon and the homeobox, respectively, in each case producing frameshifts followed by a long stretch of novel sequence and a premature stop codon. Although the affected genes may encode proteins that exert a dominant negative or novel effect, they are most likely to act as null alleles. Either possibility has interesting implications for the role of HOXD13 in human autopod development.     

Stroke in young adults: progress and opportunities

The epidemiology of stroke in young adults has been a relatively neglected area of study considering its relative prevalence in clinical practice; the relationship of oral contraceptive use, pregnancy, and migraine to stock risk; and the importance of prognosis when stroke occurs at a young age. In addition, stroke in your adult scan be used as a model system for understanding stroke incidence trends, the excess stroke risk experienced by African-American, and novel risk factors for stroke, including the genetic basis for stroke risk.     

Behavioral and neuroendocrine reactivity to stress in the WKHA/WKY inbred rat strains: a multifactorial and genetic analysis

Genetic factors have been shown to influence the nature and the intensity of the stress responses. In order to understand better the genetic mechanisms involved, we have studied the behavioral and neuroendocrine responses to novel environments in the WKHA/WKY inbred strains and we have investigated the genetic relationships between these traits in a segregating F2 intercross. The animals were submitted to behavioral tests known to provide both indices of activity and fear (activity cages, open field and elevated plus-maze). The plasma levels of prolactin, ACTH, corticosterone, glucose and renin activity were determined after a 10-min exposure to novelty. Our results showed that WKHA rats, compared to WKYs, were more active in a familiar as well as in novel environments. They exhibited also less anxiety-related behaviors and lower neuroendocrine responses. A principal component analysis performed on the behavioral F2 results defined three independent factors: general activity, anxiety and defecation, none of them being correlated with the neuroendocrine measures. Thus this study suggests that these different responses to stress are independent components that may have distinct molecular bases.     

A phenotype-based screen for embryonic lethal mutations in the mouse

The genetic pathways that control development of the early mammalian embryo have remained poorly understood, in part because the systematic mutant screens that have been so successful in the identification of genes and pathways that direct embryonic development in Drosophila, Caenorhabditis elegans, and zebrafish have not been applied to mammalian embryogenesis. Here we demonstrate that chemical mutagenesis with ethylnitrosourea can be combined with the resources of mouse genomics to identify new genes that are essential for mammalian embryogenesis. A pilot screen for abnormal morphological phenotypes of midgestation embryos identified five mutant lines; the phenotypes of four of the lines are caused by recessive traits that map to single regions of the genome. Three mutant lines display defects in neural tube closure: one is caused by an allele of the open brain (opb) locus, one defines a previously unknown locus, and one has a complex genetic basis. Two mutations produce novel early phenotypes and map to regions of the genome not previously implicated in embryonic patterning.     

Increased incidence of Guillain-Barré syndrome postpartum

In addition to classic vascular insults such as inflammation, trauma, malignancy, and surgery, a number of hereditary coagulation defects predispose patients to a wide array of thrombotic complications. A novel genetic defect in factor V allowing for resistance to its cleavage by activated protein C has recently been implicated in a significant number of cases of familial thrombophilia. A brief case report and review of the literature is presented to familiarize surgeons to this important and quite frequent cause of hypercoagulability.     

Variations in hemostasis and fibrinolysis during the treatment of acute myocardial infarct (AMI) with tissue-type plasminogen activator (TTPA). A study of 17 cases

The inherited disease Lesch-Nyhan syndrome, which is caused by a deficiency of the enzyme hypoxanthine phosphoribosyltransferase (HPRT), is characterized by behavioural alterations, including self-injurious behaviour and mental retardation. Although HPRT-deficient mice have been generated using the embryonic stem cell system, no spontaneous behavioural abnormalities had been reported. We examined whether mice were more tolerant of HPRT deficiency because they were more reliant on adenine phosphoribosyltransferase (APRT) than HPRT for their purine salvage. The administration of an APRT inhibitor to HPRT-deficient mice induced persistent self-injurious behaviour. This combined genetic and biochemical model will facilitate the study of Lesch-Nyhan syndrome and the evaluation of novel therapies.