The molecular epidemiology of parasites

Summary The explosion of new techniques, made available by the rapid advance in molecular biology, has provided a battery of novel approaches and technology which can be applied to more practical issues such as the epidemiology of parasites. In this review, we discuss the ways in which this new field of molecular epidemiology has contributed to and corroborated our existing knowledge of parasite epidemiology. Similar epidemiological questions can be asked about many different types of parasites and, using detailed examples such as the African trypanosomes and theLeishmania parasites, we discuss the techniques and the methodologies that have been or could be employed to solve many of these epidemiological problems.     

Cellular and molecular mechanisms of alcohol-induced osteopenia

Alcoholic beverages are widely consumed, resulting in a staggering economic cost in different social and cultural settings. Types of alcohol consumption vary from light occasional to heavy, binge drinking, and chronic alcohol abuse at all ages. In general, heavy alcohol consumption is widely recognized as a major epidemiological risk factor for chronic diseases and is detrimental to many organs and tissues, including bones. Indeed, recent findings demonstrate that alcohol has a dose-dependent toxic effect in promoting imbalanced bone remodeling. This imbalance eventually results in osteopenia, an established risk factor for osteoporosis. Decreased bone mass and strength are major hallmarks of osteopenia, which is predominantly attributed not only to inhibition of bone synthesis but also to increased bone resorption through direct and indirect pathways. In this review, we present knowledge to elucidate the epidemiology, potential pathogenesis, and major molecular mechanisms and cellular effects that underlie alcoholism-induced bone loss in osteopenia. Novel therapeutic targets for correcting alcohol-induced osteopenia are also reviewed, such as modulation of proinflammatory cytokines and Wnt and mTOR signaling and the application of new drugs.     

Progress in molecular parasitology

Substantial progress has been made in the last ten years in understanding the structural and functional organization of parasitic protozoa and helminths and the complex physiological relationships that exist between these organisms and their hosts. By employing the new powerful techniques of biochemistry, molecular biology and immunology the genomic organization in parasites, the molecular basis of parasite's variation in surface antigens and the biosynthesis, processing, transport and membrane anchoring of these and other surface proteins were extensively investigated. Significant advances have also been made in our knowledge of the specific and often peculiar strategies of intermediary metabolism, cell compartmentation, the role of oxygen for parasites and the mechanisms of antiparasitic drug action. Further major fields of interest are currently the complex processes which enables parasites to evade the host's immune defense system and other mechanisms which have resulted in the specific adaptations which enabled parasites to survive within their host environments. Various approaches in molecular and biochemical parasitology and in immunoparasitology have been proven to be of high potential for serodiagnosis, immunoprophylaxis and drug design.     

Toxin bioportides: exploring toxin biological activity and multifunctionality

Toxins have been shown to have many biological functions and to constitute a rich source of drugs and biotechnological tools. We focus on toxins that not only have a specific activity, but also contain residues responsible for transmembrane penetration, which can be considered bioportides—a class of cell-penetrating peptides that are also intrinsically bioactive. Bioportides are potential tools in pharmacology and biotechnology as they help deliver substances and nanoparticles to intracellular targets. Bioportides characterized so far are peptides derived from human proteins, such as cytochrome c (CYCS), calcitonin receptor (camptide), and endothelial nitric oxide synthase (nosangiotide). However, toxins are usually disregarded as potential bioportides. In this review, we discuss the inclusion of some toxins and molecules derived thereof as a new class of bioportides based on structure activity relationship, minimization, and biological activity studies. The comparative analysis of the amino acid residue composition of toxin-derived bioportides and their short molecular variants is an innovative analytical strategy which allows us to understand natural toxin multifunctionality in vivo and plan novel pharmacological and biotechnological products. Furthermore, we discuss how many bioportide toxins have a rigid structure with amphiphilic properties important for both cell penetration and bioactivity.     

Progress in molecular parasitology

Summary Substantial progress has been made in the last ten years in understanding the structural and functional organization of parasitic protozoa and helminths and the complex physiological relationships that exist between these organisms and their hosts. By employing the new powerful techniques of biochemistry, molecular biology and immunology the genomic organization in parasites, the molecular basis of parasite's variation in surface antigens and the biosynthesis, processing, transport and membrane anchoring of these and other surface proteins were extensively investigated. Significant advances have also been made in our knowledge of the specific and often peculiar strategies of intermediary metabolism, cell compartmentation, the role of oxygen for parasites and the mechanisms of antiparasitic drug action. Further major fields of interest are currently the complex processes which enables parasites to evade the host's immune defense system and other mechanisms which have resulted in the specific adaptations which enabled parasites to survive within their host environments. Various approaches in molecular and biochemical parasitology and in immunoparasitology have been proven to be of high potential for serodiagnosis, immunoprophylaxis and drug design.This paper is based on a review presented at a workshop on Molecular Parasitology, organized by the Swiss Society of Tropical Medecine and Parasitology at the University of Neuchâtel, March 1985.     

Targeting NADPH oxidases for the treatment of cancer and inflammation

NADPH oxidases are a family of oxidases that utilize molecular oxygen to generate hydrogen peroxide and superoxide, thus indicating physiological functions of these highly reactive and short-lived species. The regulation of these NADPH oxidases (nox) enzymes is complex, with many members of this family exhibiting complexity in terms of subunit composition, cellular location, and tissue-specific expression. While the complexity of the nox family (Nox1-5, Duox1, 2) is daunting, the complexity also allows for targeting of NADPH oxidases in disease states. In this review, we discuss which inflammatory and malignant disorders can be targeted by nox inhibitors, as well as clinical experience in the use of such inhibitors.     

Molecular diagnosis of parasites

Summary New developments in molecular biology have generated exciting possibilities for improved diagnosis of parasitic diseases. Through gene clonign and expression and peptide synthesis, defined parasite antigens can be produced in vitro for use in serodiagnosis, while nuclear hybridization techniques offer a vastly improved approach to identification of parasites in the tissue specimens of infected hosts as a means of diagnosis. Furthermore, the advent of the polymerase chain reaction technique has made it possible to increase the sensitivity of nuclear hybridization techniques, through amplification of target DNA sequences of the parasites in test material, by in situ synthesis of these sequences prior to hybridization with the diagnostic probe. Finally, through the use of monoclonal antibody technology, it is possible to design highly specific and sensitive serological assays, as well as assays for parasite antigen detection in tissue fluids and in the excreta of infected hosts, as a means of diagnosis.     

Molecular diagnosis of parasites

New developments in molecular biology have generated exciting possibilities for improved diagnosis of parasitic diseases. Through gene cloning and expression and peptide synthesis, defined parasite antigens can be produced in vitro for use in serodiagnosis, while nuclear hybridization techniques offer a vastly improved approach to identification of parasites in the tissue specimens of infected hosts as a means of diagnosis. Furthermore, the advent of the polymerase chain reaction technique has made it possible to increase the sensitivity of nuclear hybridization techniques, through amplification of target DNA sequences of the parasites in test material, by in situ synthesis of these sequences prior to hybridization with the diagnostic probe. Finally, through the use of monoclonal antibody technology, it is possible to design highly specific and sensitive serological assays, as well as assays for parasite antigen detection in tissue fluids and in the excreta of infected hosts, as a means of diagnosis.     

Self-organised criticality—what it is and what it isn’t

The last decade and a half has seen an ardent development of self-organised criticality (SOC), a new approach to complex systems, which has become important in many domains of natural as well as social science, such as geology, biology, astronomy, and economics, to mention just a few. This has led many to adopt a generalist stance towards SOC, which is now repeatedly claimed to be a universal theory of complex behaviour. The aim of this paper is twofold. First, I provide a brief and non-technical introduction to SOC. Second, I critically discuss the various bold claims that have been made in connection with it. Throughout, I will adopt a rather sober attitude and argue that some people have been too readily carried away by fancy contentions. My overall conclusion will be that none of these bold claims can be maintained. Nevertheless, stripped of exaggerated expectations and daring assertions, many SOC models are interesting vehicles for promising scientific research.     

Single cell biology beyond the era of antibodies: relevance,challenges, and promises in biomedical research

Research of the past two decades has proved the relevance of single cell biology in basic research and translational medicine. Successful detection and isolation of specific subsets is the key to understand their functional heterogeneity. Antibodies are conventionally used for this purpose, but their relevance in certain contexts is limited. In this review, we discuss some of these contexts, posing bottle neck for different fields of biology including biomedical research. With the advancement of chemistry, several methods have been introduced to overcome these problems. Even though microfluidics and microraft array are newer techniques exploited for single cell biology, fluorescence-activated cell sorting (FACS) remains the gold standard technique for isolation of cells for many biomedical applications, like stem cell therapy. Here, we present a comprehensive and comparative account of some of the probes that are useful in FACS. Further, we illustrate how these techniques could be applied in biomedical research. It is postulated that intracellular molecular markers like nucleostemin (GNL3), alkaline phosphatase (ALPL) and HIRA can be used for improving the outcome of cardiac as well as bone regeneration. Another field that could utilize intracellular markers is diagnostics, and we propose the use of specific peptide nucleic acid probes (PNPs) against certain miRNAs for cancer surgical margin prediction. The newer techniques for single cell biology, based on intracellular molecules, will immensely enhance the repertoire of possible markers for the isolation of cell types useful in biomedical research.     

Prevention or acceleration of type 1 diabetes by viruses

Type 1 diabetes is an autoimmune disease characterized by the destruction of insulin-producing pancreatic β-cells. Even though extensive scientific research has yielded important insights into the immune mechanisms involved in pancreatic β-cell destruction, little is known about the events that trigger the autoimmune process. Recent epidemiological and experimental data suggest that environmental factors are involved in this process. In this review, we discuss the role of viruses as an environmental factor on the development of type 1 diabetes, and the immune mechanisms by which they can trigger or protect against this pathology.     

Common Molecular Mechanisms of Mammary Gland Development and Breast Cancer

Evidence is accumulating that breast cancer is not one disease but many separate diseases. DNA microarray-based gene expression profiling has demonstrated subtypes with distinct phenotypic features and clinical responses. Prominent among the new subtypes is 'basal-like' breast cancer, one of the 'intrinsic' subtypes defined by negativity for the estrogen, progesterone, and HER2/neu receptors and positivity for cytokeratins-5/6. Focusing on basal-like breast cancer, we discuss how molecular technologies provide new chemotherapy targets, optimising treatment whilst sparing patients from unnecessary toxicity. Clinical trials are needed that incorporate long-term follow-up of patients with well-characterised tumour markers. Whilst the absence of an obvious dominant oncogene driving basal-like breast cancer and the lack of specific therapeutic agents are serious stumbling blocks, this review will highlight several promising therapeutic candidates currently under evaluation. Thus, new molecular technologies should provide a fundamental foundation for better understanding breast and other cancers which may be exploited to save lives. (Part of a Multi-author Review).     

Oxidative damage to RNA: mechanisms, consequences, and diseases

Overproduction of free radicals can damage cellular components resulting in progressive physiological dysfunction, which has been implicated in many human diseases. Oxidative damage to RNA received little attention until the past decade. Recent studies indicate that RNA, such as messenger RNA and ribosomal RNA, is very vulnerable to oxidative damage. RNA oxidation is not a consequence of dying cells but an early event involved in pathogenesis. Oxidative modification to RNA results in disturbance of the translational process and impairment of protein synthesis, which can cause cell deterioration or even cell death. In this review, we discuss the mechanisms of oxidative damage to RNA and the possible biological consequences of damaged RNA. Furthermore, we review recent evidence suggesting that oxidative damage to RNA may contribute to progression of many human diseases.     

Hearing molecules: contributions from genetic deafness

Considerable progress has been made over the past decade identifying many genes associated with deafness. With the identification of these hereditary deafness genes and the proteins they encode, molecular elements of basic hearing mechanisms emerge. As functional studies of these molecular elements become available, we can put together the pieces of the puzzle and begin to reach an understanding of the molecular mechanisms of hearing. The goal of this review is to discuss studies over the past decade that address the function of the proteins implicated in genetic deafness and to place them in the context of basic molecular mechanisms in hearing. The first part of this review highlights structural and functional features of the cochlea and auditory nerve. This background will provide a context for the second part, which addresses the molecular mechanisms underlying cochlear function as elucidated by genetic causes of deafness. Received 20 September 2006; received after revision 24 October 2006; accepted 5 December 2006     

Leptin signaling and circuits in puberty and fertility

Leptin is an adipocyte-derived hormone involved in a myriad of physiological process, including the control of energy balance and several neuroendocrine axes. Leptin-deficient mice and humans are obese, diabetic, and display a series of neuroendocrine and autonomic abnormalities. These individuals are infertile due to a lack of appropriate pubertal development and inadequate synthesis and secretion of gonadotropins and gonadal steroids. Leptin receptors are expressed in many organs and tissues, including those related to the control of reproductive physiology (e.g., the hypothalamus, pituitary gland, and gonads). In the last decade, it has become clear that leptin receptors located in the brain are major players in most leptin actions, including reproduction. Moreover, the recent development of molecular techniques for brain mapping and the use of genetically modified mouse models have generated crucial new findings for understanding leptin physiology and the metabolic influences on reproductive health. In the present review, we will highlight the new advances in the field, discuss the apparent contradictions, and underline the relevance of this complex physiological system to human health. We will focus our review on the hypothalamic circuitry and potential signaling pathways relevant to leptin’s effects in reproductive control, which have been identified with the use of cutting-edge technologies of molecular mapping and conditional knockouts.     

Mechanisms of cellular invasion by intracellular parasites

Numerous disease-causing parasites must invade host cells in order to prosper. Collectively, such pathogens are responsible for a staggering amount of human sickness and death throughout the world. Leishmaniasis, Chagas disease, toxoplasmosis, and malaria are neglected diseases and therefore are linked to socio-economical and geographical factors, affecting well-over half the world’s population. Such obligate intracellular parasites have co-evolved with humans to establish a complexity of specific molecular parasite–host cell interactions, forming the basis of the parasite’s cellular tropism. They make use of such interactions to invade host cells as a means to migrate through various tissues, to evade the host immune system, and to undergo intracellular replication. These cellular migration and invasion events are absolutely essential for the completion of the lifecycles of these parasites and lead to their for disease pathogenesis. This review is an overview of the molecular mechanisms of protozoan parasite invasion of host cells and discussion of therapeutic strategies, which could be developed by targeting these invasion pathways. Specifically, we focus on four species of protozoan parasites Leishmania, Trypanosoma cruzi, Plasmodium, and Toxoplasma, which are responsible for significant morbidity and mortality.     

Mechanisms of sperm-egg interactions emerging from gene-manipulated animals

Untangling the molecular nature of sperm-egg interactions is fundamental if we are to understand fertilization. These phenomena have been studied for many years using biochemical approaches such as antibodies and ligands that interact with sperm or with eggs and their vestments. However, when homologous genetic recombination techniques were applied, most of the phenotypic factors of the gene-manipulated animals believed “essential” for fertilization were found to be dispensable. Of course, all biological systems contain redundancies and compensatory mechanisms, but as a whole the old model of fertilization clearly requires significant modification. In this review, we use the results of gene manipulation experiments in animals to propose the basis for a new vision. Received 26 January 2007; received after revision 7 March 2007; accepted 17 April 2007