Current Genomics (v.10, #2)
Living without Oxygen: Anoxia-Responsive Gene Expression and Regulation by Kevin Larade, Kenneth Storey (76-85).
Many species of marine mollusks demonstrate exceptional capacities for long term survival without oxygen. Analysis of gene expression under anoxic conditions, including the subsequent translational responses, allows examination of the functional mechanisms that support and regulate natural anaerobiosis and permit noninjurious transitions between aerobic and anoxic states. Identification of stress-specific gene expression can provide important insights into the metabolic adaptations that are needed for anoxia tolerance, with potential applications to anoxia-intolerant systems. Various methods are available to do this, including high throughput microarray screening and construction and screening of cDNA libraries. Anoxia-responsive genes have been identified in mollusks; some have known functions in other organisms but were not previously linked with anoxia survival. In other cases, completely novel anoxia-responsive genes have been discovered, some that show known motifs or domains that hint at function. Selected genes are expressed at different times over an anoxia-recovery time course with their transcription and translation being actively regulated to ensure protein expression at the optimal time. An examination of transcript status over the course of anoxia exposure and subsequent aerobic recovery identifies genes, and the proteins that they encode, that enhance cell survival under oxygen-limited conditions. Analysis of data generated from non-mainstream model systems allows for insight into the response by cells to anoxia stress.
High-Throughput Omics Technologies: Potential Tools for the Investigation of Influences of EMF on Biological Systems by M. Blankenburg, L. Haberland, H.-D. Elvers, C. Tannert, B. Jandrig (86-92).
The mode of action of a huge amount of agents on biological systems is still unknown. One example where more questions than answers exist is covered by the term electromagnetic fields (EMF). Use of wireless communication, e.g. mobile phones, has been escalated in the last few years. Due to this fact, a lot of discussions dealt with health consequences of EMF emitted by these devices and led to an increased investigation of their effects to biological systems, mainly by using traditional methods. Omics technologies have the advantage to contain methods for investigations on DNA-, RNA- and protein level as well as changes in the metabolism. This literature survey is an overview of the available scientific publications regarding biological and health effects of EMF and the application of new high-throughput technologies. The aim of the study was to analyse the amount and the distribution of these technologies and to evaluate their relevance to the risk analysis of EMF. At present, only transcriptomics is able to analyse almost all of the specific molecules. In comparison to ionising radiation, fewer articles dealt with health effects of EMF. Interestingly, most of the EMF articles came from European institutions. Although omics techniques allow exact and simultaneous examinations of thousands of genes, proteins and metabolites in high-throughput technologies, it will be an absolute prerequisite to use standardised protocols and to independently validate the results for comparability and eventually for sound standing statements concerning possible effects of agents like EMF on biological systems.
Current Screens Based on the AlphaScreen™ Technology for Deciphering Cell Signalling Pathways by Said Taouji, Sophie Dahan, Roger Bosse, Eric Chevet (93-101).
Global deciphering of signal transduction pathways represents a new challenge of the post-genomic era. However, for the majority of these signaling pathways the role(s), the function(s) and the interaction(s) of the signaling intermediates remain to be characterized in an integrated fashion. The global molecular study of cell signaling pathways and networks consequently requires sensitive, robust technologies which may allow in addition multi-parallel and highthroughput applications. The Alphascreenand#8482; technology, relying on a bead-based homogenous approach, constitutes a valuable tool to detect and quantify a wide range of signaling events such as enzymatic activities or biomolecular interactions. In this article, we exhaustively review the literature and report the broad spectrum of Alphascreenand#8482;-based applications in the study of signal transduction pathways.
Translational Science: Epistemology and the Investigative Process by Edward Dougherty (102-109).
The term and#x201C;translational scienceand#x201D; has recently become very popular with its usage appearing to be almost exclusively related to medicine, in particular, the and#x201C;translationand#x201D; of biological knowledge into medical practice. Taking the perspective that translational science is somehow different than science and that sound science is grounded in an epistemology developed over millennia, it seems imperative that the meaning of translational science be carefully examined, especially how the scientific epistemology manifests itself in translational science. This paper examines epistemological issues relating mainly to modeling in translational science, with a focus on optimal operator synthesis. It goes on to discuss the implications of epistemology on the nature of collaborations conducive to the translational investigative process. The philosophical concepts are illustrated by considering intervention in gene regulatory networks.
Type 2 Diabetes Mellitus: New Genetic Insights will Lead to New Therapeutics by M. Wolfs, M. Hofker, C. Wijmenga, T. van Haeften (110-118).
Type 2 diabetes is a disorder of dysregulated glucose homeostasis. Normal glucose homeostasis is a complex process involving several interacting mechanisms, such as insulin secretion, insulin sensitivity, glucose production, and glucose uptake. The dysregulation of one or more of these mechanisms due to environmental and/or genetic factors, can lead to a defective glucose homeostasis. Hyperglycemia is managed by augmenting insulin secretion and/or interaction with hepatic glucose production, as well as by decreasing dietary caloric intake and raising glucose metabolism through exercise. Although these interventions can delay disease progression and correct blood glucose levels, they are not able to cure the disease or stop its progression entirely. Better management of type 2 diabetes is sorely needed. Advances in genotyping techniques and the availability of large patient cohorts have made it possible to identify common genetic variants associated with type 2 diabetes through genome-wide association studies (GWAS). So far, genetic variants on 19 loci have been identified. Most of these loci contain or lie close to genes that were not previously linked to diabetes and they may thus harbor targets for new drugs. It is also hoped that further genetic studies will pave the way for predictive genetic screening. The newly discovered type 2 diabetes genes can be classified based on their presumed molecular function, and we discuss the relation between these gene classes and current treatments. We go on to consider whether the new genes provide opportunities for developing alternative drug therapies.
Obstructive Sleep Apnea Syndrome: From Phenotype to Genetic Basis by M. Casale, M. Pappacena, V. Rinaldi, F. Bressi, P. Baptista, F. Salvinelli (119-126).
Obstructive sleep apnea syndrome (OSAS) is a complex chronic clinical syndrome, characterized by snoring, periodic apnea, hypoxemia during sleep, and daytime hypersomnolence. It affects 4-5and#x25; of the general population. Racial studies and chromosomal mapping, familial studies and twin studies have provided evidence for the possible link between the OSAS and genetic factors and also most of the risk factors involved in the pathogenesis of OSAS are largely genetically determined. A percentage of 35-40and#x25; of its variance can be attributed to genetic factors. It is likely that genetic factors associated with craniofacial structure, body fat distribution and neural control of the upper airway muscles interact to produce the OSAS phenotype. Although the role of specific genes that influence the development of OSAS has not yet been identified, current researches, especially in animal model, suggest that several genetic systems may be important. In this chapter, we will first define the OSAS phenotype, the pathogenesis and the risk factors involved in the OSAS that may be inherited, then, we will review the current progress in the genetics of OSAS and suggest a few future perspectives in the development of therapeutic agents for this complex disease entity.
Endometrial Cancer as a Familial Tumor: Pathology and Molecular Carcinogenesis (Review) by Kouji Banno, Megumi Yanokura, Yusuke Kobayashi, Makiko Kawaguchi, Hiroyuki Nomura, Akira Hirasawa, Nobuyuki Susumu, Daisuke Aoki (127-132).
Some cases of endometrial cancer are associated with a familial tumor and are referred to as hereditary nonpolyposis colorectal cancer (HNPCC or Lynch syndrome). Such tumors are thought to be induced by germline mutation of the DNA mismatch repair (MMR) gene, but many aspects of the pathology of familial endometrial cancer are unclear and no effective screening method has been established. However, the pathology of endometrial cancer with familial tumor has been progressively clarified in recent studies. At present, about 0.5and#x25; of all cases of endometrial cancers meet the clinical diagnostic criteria for HNPCC. A recent analysis of the three MMR genes (hMLH1, hMSH2 and hMSH6) revealed germline mutations in 18 of 120 cases (15.0and#x25;) of endometrial cancer with familial accumulation of cancer or double cancer, with a frameshift mutation of the hMSH6 gene being the most common. Many cases with mutation did not meet the current clinical diagnostic criteria for HNPCC, indicating that familial endometrial cancer is often not diagnosed as HNPCC. The results suggest that the hMSH6 gene mutation may be important in carcinogenesis in endometrial cancer and germline mutations of the MMR gene may be more prevalent in cases associated with familial accumulation of cancer. An international large-scale muticenter study is required to obtain further information about the pathology of endometrial cancer as a familial tumor.
The Arrestin Fold: Variations on a Theme by Laurence Aubry, Dorian Guetta, Gerard Klein (133-142).
Endocytosis of ligand-activated plasma membrane receptors has been shown to contribute to the regulation of their downstream signaling. and#946;-arrestins interact with the phosphorylated tail of activated receptors and act as scaffolds for the recruitment of adaptor proteins and clathrin, that constitute the machinery used for receptor endocytosis. Visual- and and#946;-arrestins have a two-lobe, immunoglobulin-like, and#946;-strand sandwich structure. The recent resolution of the crystal structure of VPS26, one of the retromer subunits, unexpectedly evidences an arrestin fold in this protein, which is otherwise unrelated to arrestins. From a functional point of view, VPS26 is involved in the retrograde transport of the mannose 6-P receptor from the endosomes to the trans-Golgi network. In addition to the group of genuine arrestins and Vps26, mammalian cells harbor a vast repertoire of proteins that are related to arrestins on the basis of their PFAM Nter and Cter arrestin- domains, which are named Arrestin Domain- Containing proteins (ADCs). The biological role of ADC proteins is still poorly understood. The three subfamilies have been merged into an arrestin-related protein clan. This paper provides an overall analysis of arrestin clan proteins. The structures and functions of members of the subfamilies are reviewed in mammals and model organisms such as Drosophila, Caenorhabditis, Saccharomyces and Dictyostelium.