Enzymes and receptors in the leukotriene cascade

Leukotrienes are a family of paracrine hormones derived from the oxidative metabolism of arachidonic acid. These lipid mediators are recognized as important signal molecules in a variety of inflammatory and allergic conditions affecting the skin, joints, gastrointestinal and respiratory systems, in particular asthma. Such conditions are typified by local pain, tissue edema, hyperemia and functional losses. In the tissues, immunocompetent cells accumulate at the site of injury which contribute to tissue damage and perpetuation of the disease process. Leukotrienes can elicit most, if not all, of these signs and symptoms. Thus, leukotriene B₄ is one of the most powerful chemotactic agents known to date and participates in the recruitment of leukocytes. The cysteinyl leukotrienes, on the other hand, contract smooth muscles, particularly in the peripheral airways and microcirculation. Recently, drugs which block the formation and action of leukotrienes have been introduced as novel antiasthmatic medications. This chapter reviews the biochemistry, molecular biology and cell biology of the key enzymes and cognate receptors in the leukotriene cascade.     

Axonal transport of neurofilaments in normal and disease states

Neurofilaments are among the most abundant organelles in neurones. They are synthesised in cell bodies and then transported into and through axons by a process termed 'slow axonal transport' at a rate that is distinct from that driven by conventional fast motors. Several recent studies have now demonstrated that this slow rate of transport is actually the consequence of conventional fast rates of movement that are interrupted by extended pausing. At any one time, most neurofilaments are thus stationary. Accumulations of neurofilaments are a pathological feature of several human neurodegenerative diseases suggesting that neurofilament transport is disrupted in disease states. Here, we review recent advances in our understanding of neurofilament transport in both normal and disease states. Increasing evidence suggests that phosphorylation of neurofilaments is a mechanism for regulating their transport properties, possibly by promoting their detachment from the motor(s). In some neurodegenerative diseases, signal transduction mechanisms involving neurofilament kinases and phosphatases may be perturbed leading to disruption of transport. Received 11 July 2001; received after revision 30 August 2001; accepted 31 August 2001     

Testing testimony: toxicology and the law of evidence in early nineteenth-century England

Examines how, when confronted with a case of possible criminal poisoning, early-19th-century English toxicologists sought to generate and to represent their evidence in the courtroom. Contends that in both these activities, toxicologists were inextricably engaged in a complex communicative exercise. On the one hand, they distanced themselves from the instabilities of language, styling themselves as testifiers to fact alone. At the same time, they saw themselves as deeply implicated in the difficulties of forging a coherent signifying system out of a disparate collection of signs that in themselves bore no intrinsic meaning. The article suggests first, why criminal poisoning featured so prominently in the burgeoning legal literature on evidence, which provided the framework for expert testimony in English courts; next, that the scientific evidence offered by toxicologists in poisoning cases can be usefully understood as a form of (unstable) language; and finally, that this recourse to signs informed the toxicologist's encounter with another type of courtroom expert - the legal advocate - who was equally (though differently) interested in manipulating signs in order to construct (and deconstruct) legally sanctioned proof.     

Magnetic shape-memory effects in a crystal

Magnetic fields affect the motion of electrons and the orientation of spins in solids, but are thought to have little impact on crystal structure, particularly in compounds with low magnetic susceptibility, such as antiferromagnets. Here we describe an unexpected magnetic effect on crystal shape, in which the direction of the crystal's axes are swapped and the shape changes when a magnetic field is applied; this in turn induces curious memory effects in resistivity and magnetic susceptibility. Ironically, this phenomenon occurs in one of the most well-studied two-dimensional antiferromagnets, La(2-x)Sr(x)CuO(4).     

Cdc25b phosphatase is required for resumption of meiosis during oocyte maturation

In a wide variety of animal species, oocyte maturation is arrested temporarily at prophase of meiosis I (ref. 1). Resumption of meiosis requires activation of cyclin-dependent kinase-1 (CDK1, p34cdc2), one component of maturation-promoting factor (MPF). The dual specificity phosphatases Cdc25a, Cdc25b and Cdc25c are activators of cyclin-dependent kinases; consequently, they are postulated to regulate cell-cycle progression in meiosis and mitosis as well as the DNA-damage response. We generated Cdc25b-deficient (Cdc25b-/-) mice and found that they are viable. As compared with wildtype cells, fibroblasts from Cdc25b-/- mice grew vigorously in culture and arrested normally in response to DNA damage. Female Cdc25b-/- mice were sterile, and Cdc25b-/- oocytes remained arrested at prophase with low MPF activity. Microinjection of wildtype Cdc25b mRNA into Cdc25b-/- oocytes caused activation of MPF and resumption of meiosis. Thus, Cdc25b-/- female mice are sterile because of permanent meiotic arrest resulting from the inability to activate MPF. Cdc25b is therefore essential for meiotic resumption in female mice. Mice lacking Cdc25b provide the first genetic model for studying the mechanisms regulating prophase arrest in vertebrates.     

Immunotherapy against antigenic tumors: a game with a lot of players

Our understanding of how immune responses are generated and regulated drives the design of possible immunotherapies for cancer patients. For that reason, we first describe briefly the actual immunological theories and their common perspectives about cancer vaccine development. Second, we describe cancer vaccines that are able to induce tumor-specific immune responses in cancer patients. However, these responses are not always followed by tumor rejection. At the end of the review, we discuss two possible reasons that might explain this dichotomy of cancer immunology. First, the immune response generated, although detectable, may not be quantitatively sufficient to reject the tumor. Second, the tumor microenvironment may modulate tumor cell susceptibility to the systemic immune response induced by the immunization. Finally, we discuss what, in our opinion, might be the best way to improve cancer vaccine strategies and how the relationship between the tumor and its surroundings might be studied in more details. Received 21 June 2001; received after revision 15 August 2001; accepted 15 August 2001     

The functions of mucosal T cells in containing the indigenous commensal flora of the intestine

There is an immense load of non-pathogenic commensal bacteria in the distal small intestine and the colon of mammals. The physical barrier that prevents penetration (translocation) of these organisms into the body is a simple epithelium comprised of the single enterocyte/colonocyte cell layer with its overlying mucus. In this review, we discuss the roles of intestinal T cells in initiating and regulating innate and adaptive mucosal immune responses of the mucosal immune system that avoid or limit penetration of the commensal intestinal bacteria. Received 9 August 2002; accepted 9 September 2002 RID="*" ID="*"Corresponding author.     

Mutant deoxynucleotide carrier is associated with congenital microcephaly

The disorder Amish microcephaly (MCPHA) is characterized by severe congenital microcephaly, elevated levels of alpha-ketoglutarate in the urine and premature death. The disorder is inherited in an autosomal recessive pattern and has been observed only in Old Order Amish families whose ancestors lived in Lancaster County, Pennsylvania. Here we show, by using a genealogy database and automated pedigree software, that 23 nuclear families affected with MCPHA are connected to a single ancestral couple. Through a whole-genome scan, fine mapping and haplotype analysis, we localized the gene affected in MCPHA to a region of 3 cM, or 2 Mb, on chromosome 17q25. We constructed a map of contiguous genomic clones spanning this region. One of the genes in this region, SLC25A19, which encodes a nuclear mitochondrial deoxynucleotide carrier (DNC), contains a substitution that segregates with the disease in affected individuals and alters an amino acid that is highly conserved in similar proteins. Functional analysis shows that the mutant DNC protein lacks the normal transport activity, implying that failed deoxynucleotide transport across the inner mitochondrial membrane causes MCPHA. Our data indicate that mitochondrial deoxynucleotide transport may be essential for prenatal brain growth.