The myotubularin family: from genetic disease to phosphoinositide metabolism

The myotubularin-related genes define a large family of eukaryotic proteins, most of them initially characterized by the presence of a ten-amino acid consensus sequence related to the active sites of tyrosine phosphatases, dual-specificity protein phosphatases and the lipid phosphatase PTEN. Myotubularin (hMTM1), the founder member, is mutated in myotubular myopathy, and a close homolog (hMTMR2) was recently found mutated in a recessive form of Charcot-Marie-Tooth neuropathy. Although myotubularin was thought to be a dual-specificity protein phosphatase, recent results indicate that it is primarily a lipid phosphatase, acting on phosphatidylinositol 3-monophosphate, and might be involved in the regulation of phosphatidylinositol 3-kinase (PI 3-kinase) pathway and membrane trafficking.     

The interpretations of fox possession: Illness as metaphor

Although fox possession is a rare phenomenon in contemporary Japan, it is a matter of concern in psychiatry and in folk healing. The case study presented here deals with the social process of role transformation, from client to shaman, as a way of self healing. The discussion then assumes that fox possession renders multiple interpretations and argues that it is, in fact, a metaphorical representation in much the same way that biomedical interpretation is. The argument also proposes that an etiological (causal) understanding of fox possession is less productive than a metaphorical one.     

Supportive family relationships and adolescent health in the socio-cultural context of Iran: a qualitative study

Parents have a critical role in adolescent health. The association of adolescents'' perceptions of family relationships with adolescent health was investigated using a sample of 67 female adolescents who participated in eight focus group discussions, utilising a purposeful sampling method. All tape-recorded data were fully transcribed and content analysis was performed. Three themes were identified, namely emotional support, responsible parents and well-informed parents. With regard to some of the challenges in Iranian adolescents'' relationships with their parents, it is necessary to educate parents to be alert to their role in adolescent health.     

The relationship between the concepts of genetic diversity and differentiation

Summary Diversity as a measure of individual variation within a population is widely agreed to reflect the number of different types in the population, taking into account their frequencies. In contrast, differentiation measures variation between two or more populations, demes or subpopulations. As such, it is based on the relative frequencies of types within these subpopulations and, ideally, measures the average distance of subpopulations from their respective lumped remainders. This concept of subpopulation differentiation can be applied consistently to a single population by regarding each individual as a deme (subpopulation) of its own, and it results in a measure of population differentiation _T which depends on the relative frequencies of the types and the population size. _T corresponds to several indices of variation frequently applied in population genetics and ecology, and it verifies these indices as measures of differentiation rather than diversity. For any particular frequency distribution of types, the diversity is then shown to be the size of a hypothetical population in which each type is represented exactly once, i. e. for which _T =1. Hence, the diversity of a population is its differentiation effective number of types. This uniquely specifies the link between the two concepts. Moreover, again corresponds to known measures of diversity applied in population genetics and ecology. While population differentiation can always be estimated from samples, the diversity of a population, particularly if it is large, may not be. In such cases, it is recommended that population differentiation is estimated and the corresponding sample diversity merely computed. Finally, a solution to the problem of measuring multi-locus diversities is provided.     

The granulin gene family: from cancer to dementia

The growth factor progranulin (PGRN) regulates cell division, survival, and migration. PGRN is an extracellular glycoprotein bearing multiple copies of the cysteine‐rich granulin motif. With PGRN family members in plants and slime mold, it represents one of the most ancient of the extracellular regulatory proteins still extant in modern animals. PRGN has multiple biological roles. It contributes to the regulation of early embryogenesis, to adult tissue repair and inflammation. Elevated PGRN levels often occur in cancers, and PGRN immunotherapy inhibits the growth of hepatic cancer xenografts in mice. Recent studies have demonstrated roles for PGRN in neurobiology. An autosomal dominant mutation in GRN, the gene for PGRN, leads to neuronal atrophy in the frontal and temporal lobes, resulting in the disease frontotemporal lobar dementia. In this review we will discuss current knowledge of the multifaceted biology of PGRN.     

The GDNF family: from neurotrophic factors to oncogenesis

The structure and in vivo functions of the glial cell-derived neurotrophic factor (GDNF) family ligands (GFLs) and their high-affinity receptors are considered. These proteins play an important role in the development of the nervous system, morphogenesis of the kidneys, and in regulation of spermatogenesis. Tyrosine kinase Ret is a receptor component common for all GFLs. Its role in multiple endocrine neoplasia type 2 (MEN2) is discussed.     

Robust and stable feature selection by integrating ranking methods and wrapper technique in genetic data classification

High dimensional data increase the dimension of space and consequently the computational complexity and result in lower generalization. From these types of classification problems microarray data classification can be mentioned. Microarrays contain genetic and biological data which can be used to diagnose diseases including various types of cancers and tumors. Having intractable dimensions, dimension reduction process is necessary on these data. The main goal of this paper is to provide a method for dimension reduction and classification of genetic data sets. The proposed approach includes different stages. In the first stage, several feature ranking methods are fused for enhancing the robustness and stability of feature selection process. Wrapper method is combined with the proposed hybrid ranking method to embed the interaction between genes. Afterwards, the classification process is applied using support vector machine. Before feeding the data to the SVM classifier the problem of imbalance classes of data in the training phase should be overcame. The experimental results of the proposed approach on five microarray databases show that the robustness metric of the feature selection process is in the interval of [0.70, 0.88]. Also the classification accuracy is in the range of [91%, 96%].     

Animal cognition: concepts from apes to bees

New research shows that honeybees can classify arrangements of two visual patterns according to their spatial configuration. Can bees learn relational concepts of 'above' and 'below'? And are the underlying psychological processes comparable in humans and other primates facing similar tasks?     

Avian navigation: from historical to modern concepts

Studies on avian navigation began at the end of the 19th century with testing various hypotheses, followed by large-scale displacement experiments to assess the capacity of the birds' navigational abilities. In the 1950s, the first theoretical concepts were published. Kramer proposed his ‘Map-and-Compass’ model, assuming that birds establish the direction to a distant goal with the help of an external reference, a compass. The model describes homing as a two-step process, with the first step determining the direction to the goal as a compass course and the second step locating this course with the help of a compass. This model was widely accepted when numerous experiments with clock-shifted pigeons demonstrated the use of the sun compass, and thus a general involvement of compass orientation, in homing. The ‘map’ step is assumed to use local site-specific information, which led to the idea of a ‘grid map’ based on environmental gradients. Kramer's model still forms the basis of our present concept on avian homing, yet route integration with the help of an external reference provides an alternative strategy to determine the home course, and the magnetic compass is a second compass mechanism available to birds. These mechanisms are interrelated by ontogenetic learning processes. A two-step process, with the first step providing the compass course and the second step locating this course with the help of a compass, appears to be a common feature of avian navigation tasks, yet the origin of the compass courses differs between tasks according to their nature, with courses acquired by experience for flights within the home range, courses based on navigational processes for returning home, and courses derived from genetically coded information in first-time migrants. Compass orientation thus forms the backbone of the avian navigational system. Copyright 2003 The Association for the Study of Animal Behaviour. Published by Elsevier Science Ltd. All rights reserved.      

The Toll-like receptors: analysis by forward genetic methods

Many genes, and conceivably most genes, are constitutively expressed yet have conditional functions. Their products are utilized only under special circumstances, and enforce homeostatic regulation. Mutations do not disclose the function of such genes unless the proper conditions are applied. The genes that encode the Toll-like receptors (TLRs) fall into this category. The TLRs represent the principal sensors of infection in mammals. Absent infection, mammals have little need for the TLRs; they are essential only when microbes gain access to the interior milieu of the host. The function of the TLRs in mammals was first disclosed by a spontaneous mutation in a locus called Lps, when it was shown by positional cloning to be identical to Tlr4. Random germline mutagenesis has since permitted an estimate of the total number of proteins required for TLR signaling to the level of tumor necrosis factor (TNF) synthesis and activity, and has also shown that these sensors are extremely broad in their ability to detect microbes. Ultimately, the TLRs are responsible for most infection-related phenomena, both good and bad. These include the development of fever, shock, and tissue injury, but also the activation of innate and adaptive effector mechanisms that lead to the elimination of microbes.     

Snf2 family ATPases and DExx box helicases: differences and unifying concepts from high-resolution crystal structures

Proteins with sequence similarity to the yeast Snf2 protein form a large family of ATPases that act to alter the structure of a diverse range of DNA–protein structures including chromatin. Snf2 family enzymes are related in sequence to DExx box helicases, yet they do not possess helicase activity. Recent biochemical and structural studies suggest that the mechanism by which these enzymes act involves ATP-dependent translocation on DNA. Crystal structures suggest that these enzymes travel along the minor groove, a process that can generate the torque or energy in remodelling processes. We review the recent structural and biochemical findings which suggest a common mechanistic basis underlies the action of many of both Snf2 family and DExx box helicases.     

Comparative chemical anatomy of the brain: concepts and methods

The study of neuropeptides represents an appropriate playground for comparative and evolutionary research. Comparative analysis can give insight into the conservative pattern of intercellular transmission molecules, possibly bound both to some evolutionary antiquity and to cellular constraints. In the same time it can teach us how modulation has occurred at molecular, cellular, multicellular levels in order to give the species-specific functional organization. Using some examples from vertebrate central neurons system (CNS) immunocytochemical analyses, the results so far obtained suggest the rise of a new comparative chemical neuroanatomy. The rationale of "what" and "why" we are comparing is, however, needed in order to understand constancy, heterogeneity or else trends toward complexity in the distribution of neuropeptides.     

The individualistic and community-unit concepts as falsifiable hypotheses

This study reformulates the community-unit and individualistic concepts of plant communities as hypotheses concerning the distribution of species' boundaries along a gradient. These hypotheses are tested by an analysis of deviance on data derived from a direct-gradient analysis of a freshwater marsh plant community in Breckenridge, Quebec, Canada. Boundaries are clustered at certain intervals along the gradient (p<0.001), contradicting the individualistic hypothesis. Upper boundaries are not consistently clustered at the same intervals as lower boundaries (p<0.001), contradicting the community-unit hypothesis. Thus, neither of the two usual models of community structure explain the patterns found in Breckenridge Marsh, suggesting that the historical dichotomy is too limited. Hypotheses of pattern should be tested using inferential statistics. Hypotheses of mechanism should be tested by experimentation. The way out of the community-unit vs. individualistic community debate is to deny the dichotomy and to consider multiple working hypotheses of community structure.Nomenclature as in Gleason & Cronquist (1963), Manual of vascular plants of notheastern United States and adjacent Canada, Boston, unless otherwise indicated except for the the grasses which are from Dore & McNeill (1980), Grasses of Ontario, Quebec.The statistical advice of Dr L. Lefkovitch is gratefully acknowledged. We also thank Mme. Claire Gauthier for the use of her property, C. Kettle for assistance with data collection as well as Robin Day and Dr P. Catling for assistance with identification of species. This research was supported by a National Sciences and Engineering Research Council of Canada operating grant.     

Protein localization as a principal feature of the etiology and comorbidity of genetic diseases

Proteins targeting the same subcellular localization tend to participate in mutual protein–protein interactions (PPIs) and are often functionally associated. Here, we investigated the relationship between disease‐associated proteins and their subcellular localizations, based on the assumption that protein pairs associated with phenotypically similar diseases are more likely to be connected via subcellular localization. The spatial constraints from subcellular localization significantly strengthened the disease associations of the proteins connected by subcellular localizations. In particular, certain disease types were more prevalent in specific subcellular localizations. We analyzed the enrichment of disease phenotypes within subcellular localizations, and found that there exists a significant correlation between disease classes and subcellular localizations. Furthermore, we found that two diseases displayed high comorbidity when disease‐associated proteins were connected via subcellular localization. We newly explained 7584 disease pairs by using the context of protein subcellular localization, which had not been identified using shared genes or PPIs only. Our result establishes a direct correlation between protein subcellular localization and disease association, and helps to understand the mechanism of human disease progression.