Prophages and bacterial genomics: what have we learned so far?

Bacterial genome nucleotide sequences are being completed at a rapid and increasing rate. Integrated virus genomes (prophages) are common in such genomes. Fifty-one of the 82 such genomes published to date carry prophages, and these contain 230 recognizable putative prophages. Prophages can constitute as much as 10-20% of a bacterium's genome and are major contributors to differences between individuals within species. Many of these prophages appear to be defective and are in a state of mutational decay. Prophages, including defective ones, can contribute important biological properties to their bacterial hosts. Therefore, if we are to comprehend bacterial genomes fully, it is essential that we are able to recognize accurately and understand their prophages from nucleotide sequence analysis. Analysis of the evolution of prophages can shed light on the evolution of both bacteriophages and their hosts. Comparison of the Rac prophages in the sequenced genomes of three Escherichia coli strains and the Pnm prophages in two Neisseria meningitidis strains suggests that some prophages can lie in residence for very long times, perhaps millions of years, and that recombination events have occurred between related prophages that reside at different locations in a bacterium's genome. In addition, many genes in defective prophages remain functional, so a significant portion of the temperate bacteriophage gene pool resides in prophages.     

Therapy-related myeloid neoplasms - what have we learned so far?

Therapy-related myeloid neoplasms are neoplastic processes arising as a result of chemotherapy, radiation therapy, or a combination of these modalities given for a primary condition. The disease biology varies based on the etiology and treatment modalities patients receive for their primary condition. Topoisomerase Ⅱ inhibitor therapy results in balanced translocations. Alkylating agents, characteristically, give rise to more complex karyotypes and mutations in p53. Other etiologies include radiation therapy, high-dose chemotherapy with autologous stem cell transplantation and telomere dysfunction. Poor-risk cytogenetic abnormalities are more prevalent than they are in de novo leukemias and the prognosis of these patients is uniformly dismal. Outcome varies according to cytogenetic risk group. Treatment recommendations should be based on performance status and karyotype. An in-depth understanding of risk factors that lead to the development of therapyrelated myeloid neoplasms would help developing riskadapted treatment protocols and monitoring patients after treatment for the primary condition, translating into reduced incidence, early detection and timely treatment.     

Fanconi's anemia: what have we learned from the genes so far?

Fanconi's anemia (FA) is a rare genetic disorder affecting children at an early age; patients suffer from progressive bone marrow failure and, in many cases, from congenital malformations. As cells from FA patients have an increased sensitivity to DNA-crosslinking agents, FA has been included among the group of DNA repair disorders. However, identification of a specific DNA repair defect in FA has not been firmly established. None the less, this cellular phenotype has allowed the classification of FA patients into eight complementation groups defining eight possible FA genes. Two of these genes have now been cloned and, although they have raised more questions than they have answered, are facilitating the identification of cellular processes implicated in the pathophysiology of FA, and the design of new therapies.     

Invertebrate models of lysosomal storage disease: what have we learned so far?

The lysosomal storage diseases (LSDs) collectively account for death in 1 in 8,000 children. Although some forms are treatable, they are essentially incurable and usually are lethal in the first decade of life. The most intractable forms of LSD are those with neuronal involvement. In an effort to identify the pathological signaling driving pathology in the LSDs, invertebrate models have been developed. In this review, we outline our current understanding of LSDs and recent findings using invertebrate models. We outline strategies and pitfalls for the development of such models. Available models of LSD in Drosophila and Caenorhabditis elegans are uncovering roles for LSD-related proteins with previously unknown function using both gain-of-function and loss-of-function strategies. These models of LSD in Drosophila and C. elegans have identified potential pathogenic signaling cascades that are proving critical to our understanding of these lethal diseases.     

Ten years muscle-bone hypothesis: what have we learned so far?--almost a festschrift--

The importance of mechanical stimuli for bone is widely appreciated. Mechanostat theory proposes a negative feedback system to explain the adaptation of bone by homeostatic control of peak strains. However, no assumption is made as to which forces cause these strains. Biomechanical analyses suggest that the largest forces emerge from muscle contractions, rather than from body weight per se. Hence, the idea of a 'muscle-bone' unit emerged ten years ago, proposing that bones adapt to muscle strength. This muscle-bone hypothesis is well able to account for the accrual of bone mass and strength during childhood, and also to explain why certain types of exercise are able to prevent bone loss during immobilization. However, the hypothesis fails to explain why exercise becomes rather ineffective to increase bone strength after puberty. It is here proposed that joint size as a 'third agent' might solve the conundrum. More specifically, the assumptions are made that the peak forces determine joint size until the end of puberty, and that motor control limits joint reaction forces to critical limits during adulthood in order to prevent joint damage. Providing evidence in favour or against these conjectures will improve our understanding of the musculoskeletal system.     

Proteomic analysis of red blood cells and the potential for the clinic: what have we learned so far?

Introduction: Red blood cells (RBC) are the most abundant host cells in the human body. Mature erythrocytes are devoid of nuclei and organelles and have always been regarded as circulating ‘bags of hemoglobin’. The advent of proteomics has challenged this assumption, revealing unanticipated complexity and novel roles for RBCs not just in gas transport, but also in systemic metabolic homeostasis in health and disease.

Areas covered: In this review we will summarize the main advancements in the field of discovery mode and redox/quantitative proteomics with respect to RBC biology. We thus focus on translational/clinical applications, such as transfusion medicine, hematology (e.g. hemoglobinopathies) and personalized medicine. Synergy of omics technologies – especially proteomics and metabolomics – are highlighted as a hallmark of clinical metabolomics applications for the foreseeable future.

Expert commentary: The introduction of advanced proteomics technologies, especially quantitative and redox proteomics, and the integration of proteomics data with omics information gathered through orthogonal technologies (especially metabolomics) promise to revolutionize many biomedical areas, from hematology and transfusion medicine to personalized medicine and clinical biochemistry.     

Systems biology of the secretory pathway: What have we learned so far?

Several RNAi screens were performed in search for regulators of the secretory pathway. These screens were performed in different organisms and cell lines and relied on different readouts. Therefore, they have only little overlap among their hits, leading to the question of what we have learned from this approach so far and how these screens contributed towards an integrative understanding of the endomembrane system. The aim of this review is to revisit these screens and discuss their strengths and weaknesses as well as potential reasons for their failure to overlap with each other. As with secretory trafficking, RNAi screens were also performed on other cellular processes such as cell migration and autophagy, both of which were shown to be intimately linked to secretion. Another aim of this review is to compare the outcome of the RNAi screens on secretion, autophagy and cell migration and ask whether the functional genomic approaches have uncovered potential mechanistic insights into the links between these processes.     

Cerebral cortex expansion and folding: what have we learned?

One of the most prominent features of the human brain is the fabulous size of the cerebral cortex and its intricate folding. Cortical folding takes place during embryonic development and is important to optimize the functional organization and wiring of the brain, as well as to allow fitting a large cortex in a limited cranial volume. Pathological alterations in size or folding of the human cortex lead to severe intellectual disability and intractable epilepsy. Hence, cortical expansion and folding are viewed as key processes in mammalian brain development and evolution, ultimately leading to increased intellectual performance and, eventually, to the emergence of human cognition. Here, we provide an overview and discuss some of the most significant advances in our understanding of cortical expansion and folding over the last decades. These include discoveries in multiple and diverse disciplines, from cellular and molecular mechanisms regulating cortical development and neurogenesis, genetic mechanisms defining the patterns of cortical folds, the biomechanics of cortical growth and buckling, lessons from human disease, and how genetic evolution steered cortical size and folding during mammalian evolution .     

Statin pharmacogenomics: what have we learned, and what remains unanswered?

PURPOSE OF REVIEW: Statins are widely prescribed and are established as first-line therapy for the primary and secondary prevention of coronary heart disease. Response to treatment varies considerably from person to person; however, inherited traits (genetic variability) may play a central role in this inter-individual variation. The purpose of this review is to summarize recent progress in the research for exploring genetic determinants of clinical efficacy and safety of statin therapy. RECENT FINDINGS: In addition to 41 previous studies of 19 genes, the results of 17 pharmacogenomic studies investigating the relationship between common genetic variants and response to statin therapy in terms of lipid responses, clinical outcomes, and adverse events have been reported since January 2004 - 15 candidate genes related to pharmacodynamics and three to pharmacokinetics of statins. These reported data suggest that genetic variations influencing intestinal cholesterol absorption, cholesterol production, and lipoprotein catabolism may all play a role in modulating responsiveness, as well as genes involved in drug metabolism of statins. They also suggest that combined analysis of multiple variants in several genes, all of which have possible functional relations, is more likely to give significant results, especially when being performed with a larger number of participants. SUMMARY: Pharmacogenomic studies of statin therapy will provide a better picture as to who is most likely and least likely to benefit from treatment, which results in more individualized management of coronary artery disease.     

Marine phage genomics: what have we learned?

Marine phages are the most abundant and diverse form of life on the planet, and their genomes have been described as the largest untapped reservoir of genomic information. To date, however, the complete genome sequences of only 17 marine phage are known. Nevertheless, these genomes have revealed some interesting features, including the presence of photosynthetic genes in cyanophage and common patterns of genomic organization. Intriguing findings are also being made from studies of the uncultivated marine viral community genome ('metavirome'). The greatest challenge in interpreting the biology of these phages, and for making comparisons with their terrestrial counterparts, is the high proportion of unidentifiable open reading frames (approximately 60%). Future studies are likely to focus on sequencing more marine phage genomes from disparate hosts and diverse environments and on further basic studies of the biology of existing marine phages.     

Microplastics and freshwater microalgae: what do we know so far?

The constant entry of microplastics in several environmental matrices has been of great concern to the scientific community and to society in general, mainly due to the mysteries that surround the implications of this pollutant in the environment. Freshwater ecosystems are resources especially susceptible to variations in environmental quality, and the lack of data on the impacts caused by plastic fragments exacerbates the vulnerability of this environment. Considering the results of other studies, which demonstrate the increasing entry of polymeric fragments in the aquatic environment can lead to algae growth inhibition, an investigation was carried out to determine the current state of research on the interaction between microplastics and freshwater microalgae. In total, 20 scientific articles were analyzed. Different species were subjected to toxicological tests under controlled conditions in the laboratory with small microplastics (size range between 0.1 and 1000 µm), primary and secondary microplastics of different types of polymer. Four toxicity class of indicators were chosen to assess the microalgae response to exposure to microplastic in the selected studies: growth inhibition; photosynthetic activity; pigment analysis; and enzymatic activity and oxidative stress. In this review, a critical analysis is made on the effects of the shape, size, concentration, and duration of exposure to microplastics and research gaps are identified to guide future research priorities in this area of study.

     

Advances in cellular technology in the hematology field: What have we learned so far?

Despite the advances in the hematology field, blood transfusion-related iatrogenesis is still a major issue to be considered during such procedures due to blood antigenic incompatibility. This places pluripotent stem cells as a possible ally in the production of more suitable blood products. The present review article aims to provide a comprehensive summary of the state-of-theart concerning the differentiation of both embryonic stem cells and induced pluripotent stem cells to hematopoietic cell lines. Here, we review the most recently published protocols to achieve the production of blood cells for future application in hemotherapy, cancer therapy and basic research.     

Genetics of rheumatoid arthritis: what have we learned?

Rheumatoid arthritis (RA) is a chronic autoimmune disease affecting 0.5–1% of the population worldwide. The disease has a heterogeneous character, including clinical subsets of anti-citrullinated protein antibody (ACPA)-positive and APCA-negative disease. Although the pathogenesis of RA is poorly understood, progress has been made in identifying genetic factors that contribute to the disease. The most important genetic risk factor for RA is found in the human leukocyte antigen (HLA) locus. In particular, the HLA molecules carrying the amino acid sequence QKRAA, QRRAA, or RRRAA at positions 70–74 of the DRβ1 chain are associated with the disease. The HLA molecules carrying these “shared epitope” sequences only predispose for ACPA-positive disease. More than two decades after the discovery of HLA-DRB1 as a genetic risk factor, the second genetic risk factor for RA was identified in 2003. The introduction of new techniques, such as methods to perform genome-wide association has led to the identification of more than 20 additional genetic risk factors within the last 4 years, with most of these factors being located near genes implicated in immunological pathways. These findings underscore the role of the immune system in RA pathogenesis and may provide valuable insight into the specific pathways that cause RA.     

Clamp techniques in paediatrics: what have we learned?

The marked increase in conditions associated with insulin resistance in youth, including obesity, polycystic ovary syndrome, type 2 diabetes mellitus etc., has prompted the need to assess insulin sensitivity in this age group. Even though insulin resistance plays an important role in disorders of glucose metabolism and other pathological conditions, both insulin sensitivity and insulin secretion should be determined for a comprehensive evaluation of glucose homeostasis disorders. Insulin sensitivity and secretion are intricately coupled with a delicate feedback mechanism governing their relationship. This article will delineate our paediatric experience with the clamp technique, the hyperinsulinaemic-euglycaemic clamp in assessing in vivo insulin sensitivity, and the hyperglycaemic clamp in assessing insulin secretion.     

The first decade of microbial genomics: what have we learned and where are we going next?

A report on the International Conference on Microbial Genomics, Halifax, Canada, 13-16 April 2005.     

The diversification of Heliconius butterflies: what have we learned in 150 years?

Research into Heliconius butterflies has made a significant contribution to evolutionary biology. Here, we review our understanding of the diversification of these butterflies, covering recent advances and a vast foundation of earlier work. Whereas no single group of organisms can be sufficient for understanding life's diversity, after years of intensive study, research into Heliconius has addressed a wide variety of evolutionary questions. We first discuss evidence for widespread gene flow between Heliconius species and what this reveals about the nature of species. We then address the evolution and diversity of warning patterns, both as the target of selection and with respect to their underlying genetic basis. The identification of major genes involved in mimetic shifts, and homology at these loci between distantly related taxa, has revealed a surprising predictability in the genetic basis of evolution. In the final sections, we consider the evolution of warning patterns, and Heliconius diversity more generally, within a broader context of ecological and sexual selection. We consider how different traits and modes of selection can interact and influence the evolution of reproductive isolation.     

Testing methods in species distribution modelling using virtual species: what have we learnt and what are we missing?

Species distribution models (SDMs) have become one of the major predictive tools in ecology. However, multiple methodological choices are required during the modelling process, some of which may have a large impact on forecasting results. In this context, virtual species, i.e. the use of simulations involving a fictitious species for which we have perfect knowledge of its occurrence–environment relationships and other relevant characteristics, have become increasingly popular to test SDMs. This approach provides for a simple virtual ecologist framework under which to test model properties, as well as the effects of the different methodological choices, and allows teasing out the effects of targeted factors with great certainty. This simplification is therefore very useful in setting up modelling standards and best practice principles. As a result, numerous virtual species studies have been published over the last decade. The topics covered include differences in performance between statistical models, effects of sample size, choice of threshold values, methods to generate pseudo‐absences for presence‐only data, among many others. These simulations have therefore already made a great contribution to setting best modelling practices in SDMs. Recent software developments have greatly facilitated the simulation of virtual species, with at least three different packages published to that effect. However, the simulation procedure has not been homogeneous, which introduces some subtleties in the interpretation of results, as well as differences across simulation packages. Here we 1) review the main contributions of the virtual species approach in the SDM literature; 2) compare the major virtual species simulation approaches and software packages; and 3) propose a set of recommendations for best simulation practices in future virtual species studies in the context of SDMs.