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1061. Prospects for new restorative and neuroprotective treatments in Parkinson's disease.
The degeneration of forebrain dopamine systems in Parkinson's disease has been an effective target for pharmaceutical research over the past four decades. However, although dopamine replacement may alleviate the symptoms of the disease, it does not halt the underlying neuronal degeneration. The past decade has seen major advances in identifying discrete genetic and molecular causes of parkinsonism and mapping the events involved in nigral cell death. This new understanding of the pathogenesis of the disease now offers novel prospects for therapy based on targeted neuroprotection of vulnerable neurons and effective strategies for their replacement.
1062. Translating cell biology into therapeutic advances in Alzheimer's disease.
Studies of the molecular basis of Alzheimer's disease exemplify the increasingly blurred distinction between basic and applied biomedical research. The four genes so far implicated in familial Alzheimer's disease have each been shown to elevate brain levels of the self-aggregating amyloid-beta protein, leading gradually to profound neuronal and glial alteration, synaptic loss and dementia. Progress in understanding this cascade has helped to identify specific therapeutic targets and provides a model for elucidating other neurodegenerative disorders.
1063. Emerging insights into the genesis of epilepsy.
Epilepsies are a diverse collection of brain disorders that affect 1-2% of the population. Current therapies are unsatisfactory as they provide only symptomatic relief, are effective in only a subset of affected individuals, and are often accompanied by persistent toxic effects. It is hoped that insight into the cellular and molecular mechanisms of epileptogenesis will lead to new therapies, prevention, or even a cure. Emerging insights point to alterations of synaptic function and intrinsic properties of neurons as common mechanisms underlying the hyperexcitability in diverse forms of epilepsy.
1064. The changing landscape of ischaemic brain injury mechanisms.
Thrombolysis has become established as an acute treatment for human stroke. But despite multiple clinical trials, neuroprotective strategies have yet to be proved effective in humans. Here we discuss intrinsic tissue mechanisms of ischaemic brain injury, and present a perspective that broadening of therapeutic targeting beyond excitotoxicity and neuronal calcium overload will be desirable for developing the most effective neuroprotective therapies.
1065. New order from neurological disorders.
The neurological diseases described in this review supplement impact across a wide spectrum of the population. Here, their similarities and differences are highlighted, and common themes of the interactions between basic and clinical sciences for their understanding and treatment are explored.
1066. Marine viruses and their biogeochemical and ecological effects.
Viruses are the most common biological agents in the sea, typically numbering ten billion per litre. They probably infect all organisms, can undergo rapid decay and replenishment, and influence many biogeochemical and ecological processes, including nutrient cycling, system respiration, particle size-distributions and sinking rates, bacterial and algal biodiversity and species distributions, algal bloom control, dimethyl sulphide formation and genetic transfer. Newly developed fluorescence and molecular techniques leave the field poised to make significant advances towards evaluating and quantifying such effects.
1067. Genetic instabilities in human cancers.
Whether and how human tumours are genetically unstable has been debated for decades. There is now evidence that most cancers may indeed be genetically unstable, but that the instability exists at two distinct levels. In a small subset of tumours, the instability is observed at the nucleotide level and results in base substitutions or deletions or insertions of a few nucleotides. In most other cancers, the instability is observed at the chromosome level, resulting in losses and gains of whole chromosomes or large portions thereof. Recognition and comparison of these instabilities are leading to new insights into tumour pathogenesis.
1068. Leptin and the regulation of body weight in mammals.
The assimilation, storage and use of energy from nutrients constitute a homeostatic system that is essential for life. In vertebrates, the ability to store sufficient quantities of energy-dense triglyceride in adipose tissue allows survival during the frequent periods of food deprivation encountered during evolution. However, the presence of excess adipose tissue can be maladaptive. A complex physiological system has evolved to regulate fuel stores and energy balance at an optimum level. Leptin, a hormone secreted by adipose tissue, and its receptor are integral components of this system. Leptin also signals nutritional status to several other physiological systems and modulates their function. Here we review the role of leptin in the control of body weight and its relevance to the pathogenesis of obesity.
1069. Allosteric effects of DNA on transcriptional regulators.
Selective gene transcription is mediated in part by regulatory proteins that bind to DNA response elements. These regulatory proteins receive global information from signal-transduction events. But transcriptional regulators may also be modified in an allosteric manner by response elements themselves to generate the pattern of regulation that is appropriate to an individual gene.
1070. Human gene therapy.
Although gene therapy as a treatment for disease holds great promise, progress in developing effective clinical protocols has been slow. The problem lies in the development of safe and efficient gene-delivery systems. This review will evaluate the problems and the potential solutions in this new field of medicine.
1071. Cell therapy.
Cell therapy has emerged as a strategy for the treatment of many human diseases. Because no single cell or universal donor is likely to be useful for all diseases, it is the source and the desired function of the cell that will dictate which cell type is most useful for each disease. Concerns related to immunological compatibility, ability to multiply cells in vitro before transplantation and general issues of quality control and safety are now being addressed by the convergence of disciplines interested in the potential for cell therapy.
1072. Drug delivery and targeting.
When a pharmaceutical agent is encapsulated within, or attached to, a polymer or lipid, drug safety and efficacy can be greatly improved and new therapies are possible. This has provided the impetus for active study of the design of degradable materials, intelligent delivery systems and approaches for delivery through different portals in the body.
1073. Asymmetric cell division.
With the recent identification of intrinsic cell-fate determinants for asymmetric cell division in several systems, biologists have begun to gain insight into the cellular mechanisms by which these determinants are preferentially segregated into one of the two daughter cells during mitosis so that the daughter cells acquire different fates.
1074. Chemokines and leukocyte traffic.
Over the past ten years, numerous chemokines have been identified as attractants of different types of blood leukocytes to sites of infection and inflammation. They are produced locally in the tissues and act on leukocytes through selective receptors. Chemokines are now known to also function as regulatory molecules in leukocyte maturation, traffic and homing of lymphocytes, and the development of lymphoid tissues.
1075. Dendritic cells and the control of immunity.
B and T lymphocytes are the mediators of immunity, but their function is under the control of dendritic cells. Dendritic cells in the periphery capture and process antigens, express lymphocyte co-stimulatory molecules, migrate to lymphoid organs and secrete cytokines to initiate immune responses. They not only activate lymphocytes, they also tolerize T cells to antigens that are innate to the body (self-antigens), thereby minimizing autoimmune reactions. Once a neglected cell type, dendritic cells can now be readily obtained in sufficient quantities to allow molecular and cell biological analysis. With knowledge comes the realization that these cells are a powerful tool for manipulating the immune system.
1076. TGF-beta signalling from cell membrane to nucleus through SMAD proteins.
The recent identification of the SMAD family of signal transducer proteins has unravelled the mechanisms by which transforming growth factor-beta (TGF-beta) signals from the cell membrane to the nucleus. Pathway-restricted SMADs are phosphorylated by specific cell-surface receptors that have serine/threonine kinase activity, then they oligomerize with the common mediator Smad4 and translocate to the nucleus where they direct transcription to effect the cell's response to TGF-beta. Inhibitory SMADs have been identified that block the activation of these pathway-restricted SMADs.
1077. Histone acetylation in chromatin structure and transcription.
'The amino termini of histones extend from the nucleosomal core and are modified by acetyltransferases and deacetylases during the cell cycle. These acetylation patterns may direct histone assembly and help regulate the unfolding and activity of genes.
1078. Regulation of transcription by proteins that control the cell cycle.
In eukaryotes, progression of a cell through the cell cycle is partly controlled at the level of transcriptional regulation. Yeast and mammalian cells use similar mechanisms to achieve this regulation. Although gaps still remain, progress has been made recently in connecting the links between the cell's cycle and its transcriptional machinery.
1079. Fossils, genes and the evolution of animal limbs.
The morphological and functional evolution of appendages has played a crucial role in the adaptive radiation of tetrapods, arthropods and winged insects. The origin and diversification of fins, wings and other structures, long a focus of palaeontology, can now be approached through developmental genetics. Modifications of appendage number and architecture in each phylum are correlated with regulatory changes in specific patterning genes. Although their respective evolutionary histories are unique, vertebrate, insect and other animal appendages are organized by a similar genetic regulatory system that may have been established in a common ancestor.
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