New approaches to disease mapping in admixed populations

Admixed populations such as African Americans and Hispanic Americans are often medically underserved and bear a disproportionately high burden of disease. Owing to the diversity of their genomes, these populations have both advantages and disadvantages for genetic studies of complex phenotypes. Advances in statistical methodologies that can infer genetic contributions from ancestral populations may yield new insights into the aetiology of disease and may contribute to the applicability of genomic medicine to these admixed population groups.     

New approaches to the therapy of demyelinating disease.

The pace of research on the pathogenesis and treatment of multiple sclerosis, the principal human demyelinating disease of the central nervous system, has intensified in the past 3 years, due in part, to the application of advances in molecular and cellular immunology. Many lessons that have been learned in an animal model of central nervous system demyelinating disease, experimental allergic encephalomyelitis, also apply to multiple sclerosis and certain successful approaches for the treatment of this disease are now being attempted in humans.     

Seeing in the dark: molecular approaches to the study of bat populations

Whilst the use of molecular genetic techniques is widespread in the fields of population and evolutionary biology, their application within the mammalian order Chiroptera neither reflects the species richness nor the ecological and behavioural diversity of the order. This is despite the fact that the Chiroptera are problematic to study using more direct observational techniques. Here, we standardize and synthesise the current data, assess the contribution of molecular research to the study of bat species and highlight the importance of its continued and expanded use. At an inter-population level, molecular studies have demonstrated a great diversity of population genetic structure within the order. Among populations of migratory species, genetic structure appears universally low, and hence seasonal movement is likely to be the prevailing influence. However, for sedentary species an array of factors including dispersal ability, extrinsic barriers to gene flow and historical events may determine the extent of genetic partitioning among populations. Intrinsic factors such as wing morphology or roost requirements may also influence population genetic structure in sedentary bat species, a proposal which requires further research. Molecular studies have also made important contributions towards an understanding of social organisation in bats. Evidence indicates that in many polygynous species male mating success does not translate directly into reproductive success, perhaps as a result of multiple mating by females. Estimates of relatedness within and genetic structure among colonies are, in general, very low; a finding which has important implications regarding theories concerning the formation and persistence of bat social groups. Molecular studies have provided new and important insights into the ecology of bats, and have opened up exciting and previously unexplored avenues of research. The data from these studies suggest not only a predictive framework for future studies, but also the use of genetic data in the management and conservation of bat species.     

New approaches to the study of developing wood

Two recent papers illustrate contrasting approaches to studying gene expression during development of the xylem, the tissue that transports water and solutes around higher plants. The two methods used, studying single cells differentiating in vitro and collecting samples from across the region around the cambium of poplar trees, have both revealed genes that have altered expression during xylem development.     

Reverse-genetic approaches to the study of Borna disease virus

Borna disease virus (BDV) is an enveloped virus that has a non-segmented, negative-strand RNA genome with the characteristic organization of the mononegaviruses. However, based on its unique genetic and biological features, BDV is considered to be the prototypic member of a new mononegavirus family, the Bornaviridae. BDV causes central nervous system (CNS) disease in a wide variety of mammals. This article discusses the recently developed reverse-genetics systems for BDV, and the implications for the elucidation of the molecular mechanisms underlying BDV-host interactions, including the basis of BDV persistence in the CNS and its associated diseases.     

International study on Artemia. LIV. Morphological study of Artemia with emphasis to Old World strains. II. Parthenogenetic populations

Eleven morphometric and one meristic character in 15 parthenogeneticArtemia populations have been studied by using discriminant andcluster analysis as well as scanning electron microscopy.Discriminant analysis revealed five main groups of morphologicalpatterns: (i) the coastal Chinese populations together with apopulation from Kazakhstan, (ii) the inland Chinese salt lakepopulations, (iii) the Greek populations, (iv) one African populationfrom Namibia and (v) a Chinese population from Xuyu (Jiangsuprovince). Cluster analysis was not always in agreement withdiscriminant analysis and these results are discussed.     

New approaches to the synthesis of antiviral nucleosides.

There is a pressing, worldwide need for new antiviral agents. The chemical synthesis of novel nucleosides for chemotherapeutic screening usually involves multistage processes which can be time consuming. The application of enzymatic methods for the synthesis and modification of antiviral nucleosides shows great promise because of the simplicity and high specificity of enzymatic reactions.     

International study on Artemia. LIII. Morphological study of Artemia with emphasis to Old World strains. I. Bisexual populations

A detailed morphological and allometrical study was performed withadult males and females of eleven bisexual populations of brineshrimp Artemia. Multivariate procedures, discriminant andcluster analysis, allowed to separate and group together populationswhich exhibit great genetic similarities. The eleven populationsstudied form four distinct groups: the A. franciscana group,the A. tunisiana group, the A. urmiana group and abroader group which includes Eastern Old World populations. Scanningelectron microscopy revealed differences in the male genital organsof an A. tunisiana population by lacking a medial protuberancein the base of the penes while the pattern of the ectodermal ridgesof the brood pouch of A. urmiana markedly differed from theother populations studied.     

Mitochondrial genome size variation in New World and Old World populations of Drosophila melanogaster

Drosophila melanogaster originated in Africa, spread to Europe and Asia, and is believed to have colonized the New World in the past few hundred years. Levels of genetic variation are typically reduced in New World populations, consistent with a founder event following range expansion out of Africa and the Old World. We describe the patterns of mtDNA length variation within and among several populations of Drosophila melanogaster from the Old and New World. MtDNA length variation is due to insertion and deletion of tandem repeats in the control region (D-loop) of D. melanogaster mitochondrial genome. The distinct mutational dynamics of this system provide an opportunity to compare the patterns of variation in this marker to those of other markers with different mutational pressures and linkage relationships. The data show significantly more length variation in African and Asian samples than in New World samples. New World samples also show more pronounced skew of the length distribution. Our results are distinct from an earlier study that showed significantly higher levels of length variation and heteroplasmy. The level of heteroplasmy is highly correlated with the number of years that samples have been maintained in laboratory culture, suggesting that relaxed selection in small populations permits the accumulation of mtDNA length variation and heteroplasmy. Together, the data indicate that mtDNA length variants retain a signature of founder events and selection, and suggest that further investigation into the mutation-selection dynamics of the D-loop region of mtDNA would provide a distinct and informative marker for analysis of the recent history of populations.     

Characterization of ancestral and derived Y-chromosome haplotypes of New World native populations.

We analyze the allelic polymorphisms in seven Y-specific microsatellite loci and a Y-specific alphoid system with 27 variants (alphah I-XXVII), in a total of 89 Y chromosomes carrying the DYS199T allele and belonging to populations representing Amerindian and Na-Dene linguistic groups. Since there are no indications of recurrence for the DYS199C-->T transition, it is assumed that all DYS199T haplotypes derive from a single individual in whom the C-->T mutation occurred for the first time. We identified both the ancestral founder haplotype, 0A, of the DYS199T lineage and seven derived haplogroups diverging from the ancestral one by one to seven mutational steps. The 0A haplotype (5.7% of Native American chromosomes) had the following constitution: DYS199T, alphah II, DYS19/13, DYS389a/10, DYS389b/27, DYS390/24, DYS391/10, DYS392/14, and DYS393/13 (microsatellite alleles are indicated as number of repeats). We analyzed the Y-specific microsatellite mutation rate in 1,743 father-son transmissions, and we pooled our data with data in the literature, to obtain an average mutation rate of.0012. We estimated that the 0A haplotype has an average age of 22,770 years (minimum 13,500 years, maximum 58,700 years). Since the DYS199T allele is found with high frequency in Native American chromosomes, we propose that 0A is one of the most prevalent founder paternal lineages of New World aborigines.     

New approaches to study the development of morphine tolerance and dependence

Morphine is now believed not to cause tolerance and dependence when it is appropriately used in clinic. However, in terminal cancer pain, patients' analgesic tolerance to morphine is developed due to the use of high doses of morphine for complete blockade of pain. At higher doses, morphine has more opportunity to show serious side effects, which worsens quality of life (QOL), and leads to the use of potent analgesic adjuvants to reduce the morphine dosage. Here we attempt to summarize recent studies of the molecular basis of morphine tolerance and dependence, and to discuss whether these mechanisms could provide new molecular targets as analgesic adjuvants. They include protein kinase C inhibitor, opioid agonist with low RAVE value, and antagonists of antiopioid receptors (GluRepsilon1 or nociceptin/OFQ receptor). In addition, we demonstrate new approaches to find further candidates of such molecular targets. These approaches include the visualization of neuronal networks in the downstream of opioid neurons by use of the WGA transgene technique and the single cell dissection technique to get new genes involved in plasticity during morphine tolerance and dependence.     

Molecular genetic approaches to understanding disease.

Molecular genetics has greatly increased the understanding of diseases in which there is a single gene defect such as cystic fibrosis. Discovering the gene responsible and its function not only helps determine the pathogenesis of the disease but also offers a possible treatment-gene therapy. Polygenic disorders such as diabetes may soon yield their secrets to the same approach. Animal models of genetic diseases are proving useful research tools, and transgenesis has made xenografting possible. Furthermore, antisense technology allows specific inhibition of undesirably overexpressed genes such as those driving unwanted vascular cell proliferation and restenosis after angioplasty. The completion of the human genome project should make the search for "disease" gene much quicker and will increase still further the importance of these gene based approaches toward diseases.     

5. New approaches to the management of flail chest.

Although continuous positive-pressure ventilation (internal pneumatic fixation) was a great advance in the treatment of flail chest and is now the standard treatment of this condition, early and late complications related to tracheostomy and long-term ventilation are associated with this method. These complications can be avoided by use of three recently adopted techniques--expectant therapy, intermittent mandatory ventilation with positive end-expiratory pressure, and early surgical stabilization of fractures. All patients should continue to be treated in intensive care units so that impending respiratory failure can be identified and treated. These newer forms of therapy not only have the advantages of avoiding complications inherent in tracheostomy and prolonged ventilation, but also decrease the length of hospital stay and expense of treatment.     

New molecular approaches to tissue analysis.

The completion of the Human Genome Project will produce new opportunities for analysis of genes and their products in human tissue. The emergence of new technologies will enable investigators to directly examine human tissues for gene deletion, transposition, and amplification. In addition, we will be able to assess the complete gene expression of a tissue by examining the mRNA species using microarray chips. The emerging technologies of laser capture microdissection and RNA amplification enables these procedures to be carried out on groups of a few hundred cells, which will facilitate the examination of heterogeneous lesions. Finally, the application of tissue arrays and the capability of obtaining protein sequences in samples of only a few femtomoles of protein using desorption mass spectroscopy will revolutionize the analysis of protein expression.