Thymic regeneration: teaching an old immune system new tricks

Recent studies in mice and humans show that the importance of the thymus extends well beyond the initial seeding of the peripheral T-cell pool. Although peripheral homeostasis can maintain T-cell numbers, the thymus is the major, if not the exclusive, source of new T-cell specificities. With age, thymus atrophy dramatically reduces the export of new T cells and predisposes an individual to impaired T-cell function, reduced T-cell immunity, and increased autoimmunity. Thymus atrophy is also the primary obstacle to restoration of the T-cell pool in the aftermath of HIV treatment or lymphoablative therapies. Here, we review thymus T-cell production, with particular attention to the factors that influence thymocyte export, and examine the impact that recent thymic emigrants have on the peripheral pool. In the future, thymic regeneration might become a feasible and potentially powerful approach to rejuvenating a depleted peripheral T-cell pool.     

New roles for old proteins in adult CNS axonal regeneration

The past year has yielded many insights and a few surprises in the field of axonal regeneration. The identification of oligodendrocyte-myelin glycoprotein as an inhibitor of axonal growth, and the discovery that the three major myelin-associated inhibitors of CNS regeneration share the same functional receptor, has launched a new wave of studies that aim to identify the signaling components of these inhibitory pathways. These findings also offer new avenues of research directed toward blocking possible therapeutic targets that inhibit regeneration and toward encouraging axonal regeneration in the CNS after injury.     

CNS regeneration: a morphogen's tale

Tissue regeneration will soon become an avenue for repair of damaged or diseased tissues as stem cell niches have been found in almost every organ of the vertebrate body including the CNS. In addition, different animals display an array of regenerative capabilities that are currently being researched to dissect the molecular mechanisms involved. This review concentrates on the different ways in which CNS tissues such as brain, spinal cord and retina can regenerate or display neurogenic potential and how these abilities are modulated by morphogens.     

The molecular basis of amphibian limb regeneration: integrating the old with the new

Is regeneration close to revealing its secrets? Rapid advances in technology and genomic information, coupled with several useful models to dissect regeneration, suggest that we soon may be in a position to encourage regeneration and enhanced repair processes in humans.     

Evolution of bioengineering at UCSD: opening new vistas

Before this, the field of bioengineering refers to biomedical engineering of prosthetic devices in physiology. In addition to exciting applications of engineering principles, UCSD Department of Bioengineering began to extend the notion of engineering models of physiological systems to physiological processes. This led to a conceptual shift in the discipline and contributed to the areas of tissue and physiological process engineering. In 1988, Dr. Shu Chien and Richard Skalak joined UCSD to begin research and education on cellular and molecular bioengineering, especially, mechanobiology. Dr. Fung and Dr. Skalak initiated the new field of tissue engineering. These two decades of evolution of bioengineering and its growth across the country was spearheaded by the Whitaker Foundation, whose leitmotif was the building of bioand biomedical engineering across the country. We have garnered other accomplishments in the following fields: regenerative medicine; bioinspired artificial extracellular matrices; flexible bioelectronics and tatoos; cells show how to synchronize biological clocks; and systems medicine.     

Reeler: new tales on an old mutant mouse

Neurological mouse mutants provide an opportunity to dissect the complex mechanisms that underlie vertebrate brain development. Advances in genetic technologies have permitted the identification of genes disrupted in many mutants, allowing a molecular interpretation of the phenotypes. For several decades, the spontaneous mutant mouse reeler has been used as a model for the analysis of the development of laminated brain structures. In this ataxic mutant, the migration of many neurons is aberrant, resulting in disrupted cellular organization. Recently, reelin, the gene disrupted in the reeler mouse, has been identified. reelin encodes a novel extracellular molecule that controls neural cell positioning through mechanisms that are not yet completely understood. Analysis of the expression pattern and the properties of the reelin gene product (Reelin) suggests models for its function during brain development. Furthermore, the recent identification of genes that may function in the Reelin signaling pathway advances our knowledge of the molecular basis of neuronal migration. BioEssays 20 :235–244, 1998.© 1998 John Wiley & Sons, Inc.     

Manganese phytotoxicity: new light on an old problem

Background Manganese (Mn) is an essential micronutrient that is phytotoxic under certain edaphic and climatic conditions. Multiple edaphic factors regulate Mn redox status and therefore its phytoavailability, and multiple environmental factors including light intensity and temperature interact with Mn phytotoxicity. The complexity of these interactions coupled with substantial genetic variation in Mn tolerance have hampered the recognition of Mn toxcity as an important stress in many natural and agricultural systems.Scope Conflicting theories have been advanced regarding the mechanism of Mn phytotoxicity and tolerance. One line of evidence suggests that Mn toxicity ocurs in the leaf apoplast, while another suggests that toxicity occurs by disruption of photosynthetic electron flow in chloroplasts. These conflicting results may at least in part be attributed to the light regimes employed, with studies conducted under light intensities approximating natural sunlight showing evidence of photo-oxidative stress as a mechanism of toxicity. Excessive Mn competes with the transport and metabolism of other cationic metals, causing a range of induced nutrient deficiencies. Compartmentation, exclusion and detoxification mechanisms may all be involved in tolerance to excess Mn. The strong effects of light, temperature, precipitation and other climate variables on Mn phytoavailability and phytotoxicity suggest that global climate change is likely to exacerbate Mn toxicity in the future, which has largely escaped scientific attention.Conclusions Given that Mn is terrestrially ubiquitous, it is imperative that the heightened risk of Mn toxicity to both managed and natural plant ecosystems be factored into evaluation of the potential impacts of global climate change on vegetation. Large inter- and intraspecific genetic variation in tolerance to Mn toxicity suggests that increased Mn toxicity in natural ecosystems may drive changes in community composition, but that in agroecosystems crops may be developed with greater Mn tolerance. These topics deserve greater research attention.     

Regulation of ABC transporters at the blood-brain barrier: new targets for CNS therapy

Worldwide, more than one billion people are affected by CNS disorders. Despite the huge demand for treatments, existing drugs have limited or no efficacy for some neurological diseases, including brain cancer and certain epilepsies. Furthermore, no effective therapies are available at all for some common disorders of the central nervous system (CNS) such as Alzheimer's disease. ATP-binding cassette (ABC) transporters at the blood-brain barrier (BBB) have become increasingly important in the treatment and pathogenesis of CNS disorders. Here we highlight a novel strategy--targeting signaling pathways that control ABC transporters at the BBB--to protect the brain, improve brain drug delivery, and reduce CNS pathology.     

Nitric oxide regulates axonal regeneration in an insect embryonic CNS

In higher vertebrates, the central nervous system (CNS) is unable to regenerate after injury, at least partially because of growth-inhibiting factors. Invertebrates lack many of these negative regulators, allowing us to study the positive factors in isolation. One possible molecular player in neuronal regeneration is the nitric oxide (NO)-cyclic guanosine-monophosphate (cGMP) transduction pathway which is known to regulate axonal growth and neural migration. Here, we present an experimental model in which we study the effect of NO on CNS regeneration in flat-fillet locust embryo preparations in culture after crushing the connectives between abdominal ganglia. Using whole-mount immunofluorescence, we examine the morphology of identified serotonergic neurons, which send a total of four axons through these connectives. After injury, these axons grow out again and reach the neighboring ganglion within 4 days in culture. We quantify the number of regenerating axons within this period and test the effect of drugs that interfere with NO action. Application of exogenous NO or cGMP promotes axonal regeneration, whereas scavenging NO or inhibition of soluble guanylyl cyclase delays regeneration, an effect that can be rescued by application of external cGMP. NO-induced cGMP immunostaining confirms the serotonergic neurons as direct targets for NO. Putative sources of NO are resolved using the NADPH-diaphorase technique. We conclude that NO/cGMP promotes outgrowth of regenerating axons in an insect embryo, and that such embryo-culture systems are useful tools for studying CNS regeneration.     

The temperature optima of enzymes: a new perspective on an old phenomenon

Careful analysis of the dependence of enzyme activity on assay temperature has revealed that some enzymes might have real temperature optima in which the decrease in catalytic rate at temperatures above the optimum is not primarily a result of irreversible thermal inactivation. The 'equilibrium model' has been formulated to describe genuine temperature optima, and to suggest a simple experimental method by which to distinguish these cases from those in which enzyme instability is the major determinant of temperature optima.     

The role of extracellular matrix in CNS regeneration

Chondroitin sulfate proteoglycans are the principal inhibitory component of glial scars, which form after damage to the adult central nervous system and act as a barrier to regenerating axons. Recent findings have furthered our understanding of the mechanisms that result in a failure of regeneration after spinal cord injury and suggest that a multipartite approach will be required to facilitate long-distance regeneration and functional recovery.     

The archaellum: an old motility structure with a new name

Motility structures, called flagella, have been described in all three domains of life: Bacteria, Archaea and Eukarya. These structures are well studied in both Bacteria and Eukarya. However, already in eukaryotes there exists some confusion as to whether these structures should actually be called cilia. With increased studies conducted on organisms of the third domain of life, the Archaea, it has become clear that the archaeal flagellum only functionally appears similar to the bacterial flagellum, whereas it structurally resembles a bacterial type IV pilus. To resolve confusion due to unclear nomenclature, we propose renaming the archaeal flagellum as the 'archaellum'. This will make clear that the archaellum and the bacterial flagellum are two distinct structures that happen to both be used to enable microorganisms to swim.