Immunology of fungal infections: lessons learned from animal models

The continuing AIDS epidemic coupled with increased usage of immunosuppressive drugs to prevent organ rejection or treat autoimmune diseases has resulted in an increase in individuals at risk for acquiring fungal diseases. These concerns highlight the need to elucidate mechanisms of inducing protective immune responses against fungal pathogens. Consequently, several experimental models of human mycoses have been developed to study these diseases. The availability of transgenic animal models allows for in-depth analysis of specific components, receptors, and signaling pathways that elicit protection against fungal diseases. This review focuses on recent advances in our understanding of immune responses to fungal infections gained using animal models.     

Cancer,aging and immunotherapy: lessons learned from animal models

Aging of the immune system is associated with a dramatic reduction in responsiveness as well as functional dysregulation. This deterioration of immune function with advancing age is associated with an increased incidence of cancer. Although there is a plethora of reports evaluating the effect of immunotherapy in stimulating antitumor immune responses, the majority of these studies do not pay attention to the effect aging has on the immune system. Studies from our group and others indicate that immunotherapies could be effective in the young, are not necessarily effective in the old. To optimally stimulate an antitumor immune response in the old, it is necessary to (1) identify and understand the intrinsic defects of the old immune system and (2) use relevant models that closely reflect those of cancer patients, where self-tolerance and aging are present simultaneously. The present review summarizes some defects found in the old immune system affecting the activation of antitumor immune responses, the strategies used to activate stronger antitumor immune response in the old and the use of a tolerant animal tumor model to target a self-tumor antigen for the optimization of immunotherapeutic interventions in the old.     

Exploring molecular genetics of bladder cancer: lessons learned from mouse models

Urothelial cell carcinoma (UCC) of the bladder is one of the most common malignancies worldwide, causing considerable morbidity and mortality. It is unusual among the epithelial carcinomas because tumorigenesis can occur by two distinct pathways: low-grade, recurring papillary tumours usually contain oncogenic mutations in FGFR3 or HRAS, whereas high-grade, muscle-invasive tumours with metastatic potential generally have defects in the pathways controlled by the tumour suppressors p53 and retinoblastoma (RB). Over the past 20 years, a plethora of genetically engineered mouse (GEM) models of UCC have been developed, containing deletions or mutations of key tumour suppressor genes or oncogenes. In this review, we provide an up-to-date summary of these GEM models, analyse their flaws and weaknesses, discuss how they have advanced our understanding of UCC at the molecular level, and comment on their translational potential. We also highlight recent studies supporting a role for dysregulated Wnt signalling in UCC and the development of mouse models that recapitulate this dysregulation.     

The phylogeny of the Trypanosomatidae: the molecular and morphological approaches

The results of comparative analysis of two phylogenetic trees of the trypanosomatids based on morphological and molecular characters are discussed. The morphological dendrogram was based on 33 ultrastructural characters, 6 light microscope characteristics and 8 biological characters. Molecular UPGMA dendrogram depicting differences (Dice distance) between examined trypanosomatids is based on the universally primed PCR polymorphisms. The general topology of both dendrograms are similar, with the Trypanosoma at the base. The genus Wallaceina appears to be monophyletic. In a contrary, the genera Leptomonas, Crithidia and Herpetomonas look like artificial groups according to both methods used. The cyst-forming homoxenous trypanosomatids from insects represent a monophyletic clade, which seems to be a separate genus. Two species of within genus Wallaceina are arranged as a separate subgenus.     

Testing the new animal phylogeny: a phylum level molecular analysis of the animal kingdom

The new animal phylogeny inferred from ribosomal genes some years ago has prompted a number of radical rearrangements of the traditional, morphology based metazoan tree. The two main bilaterian clades, Deuterostomia and Protostomia, find strong support, but the protostomes consist of two sister groups, Ecdysozoa and Lophotrochozoa, not seen in morphology based trees. Although widely accepted, not all recent molecular phylogenetic analyses have supported the tripartite structure of the new animal phylogeny. Furthermore, even if the small ribosomal subunit (SSU) based phylogeny is correct, there is a frustrating lack of resolution of relationships between the phyla that make up the three clades of this tree. To address this issue, we have assembled a dataset including a large number of aligned sequence positions as well as a broad sampling of metazoan phyla. Our dataset consists of sequence data from ribosomal and mitochondrial genes combined with new data from protein coding genes (5139 amino acid and 3524 nucleotide positions in total) from 37 representative taxa sampled across the Metazoa. Our data show strong support for the basic structure of the new animal phylogeny as well as for the Mandibulata including Myriapoda. We also provide some resolution within the Lophotrochozoa, where we confirm support for a monophyletic clade of Echiura, Sipuncula and Annelida and surprising evidence of a close relationship between Brachiopoda and Nemertea.     

Cellular and molecular pathogenesis of systemic lupus erythematosus: lessons from animal models

Systemic lupus erythematosus (SLE) is a complex disease characterized by the appearance of autoantibodies against nuclear antigens and the involvement of multiple organ systems, including the kidneys. The precise immunological events that trigger the onset of clinical manifestations of SLE are not yet well understood. However, research using various mouse strains of spontaneous and inducible lupus in the last two decades has provided insights into the role of the immune system in the pathogenesis of this disease. According to our present understanding, the immunological defects resulting in the development of SLE can be categorized into two phases: (a) systemic autoimmunity resulting in increased serum antinuclear and antiglomerular autoantibodies and (b) immunological events that occur within the target organ and result in end organ damage. Aberrations in the innate as well as adaptive arms of the immune system both play an important role in the genesis and progression of lupus. Here, we will review the present understanding - as garnered from studying mouse models - about the roles of various immune cells in lupus pathogenesis.     

How to establish a lasting relationship with your host: lessons learned from Mycobacterium spp

Mycobacterium spp. enjoy an intracellular lifestyle that is fatal to most microorganisms. Bacilli persist and multiply within mononuclear phagocytes in the face of defences ranging from toxic oxygen and nitrogen radicals, acidic proteases and bactericidal peptides. Uptake of Mycobacterium by phagocytes results in the de novo formation of a phagosome, which is manipulated by the pathogen to accommodate its needs for intracellular survival and replication. The present review describes the intracellular compartment occupied by Mycobacterium spp. and presents current ideas on how mycobacteria may establish this niche, placing special emphasis on the involvement of mycobacterial cell wall lipids.     

150 years beyond Darwin's Origin of species: finding new approaches to reconstruct early animal phylogeny

The conference ‘Celebrating Darwin: From the Origin of Species to Deep Metazoan Phylogeny’ was held at the Humboldt University in Berlin, from 3 to 6 March 2009. Specialists from the fields of bioinformatics, molecular biology, developmental biology, comparative morphology and paleontology joined forces to present and discuss novel approaches in reconstructing the still unresolved early branching patterns of the metazoan tree of life.     

A molecular view of primate phylogeny and important systematic and evolutionary questions

Phylogenetic analysis of extensive nucleotide sequence data from primate beta-globin gene clusters elucidates the systematics and evolution of the order Primates and reveals that rates of accumulation of mutations vary by as much as a factor of seven among different primate lineages. The picture of primate phylogeny from DNA sequences clarifies many ambiguities of the morphological picture. In the molecular picture, dwarf and brown lemurs group together into superfamily Lemuroidea, Lemuroidea and Lorisoidea into suborder Strepsirhini, and Tarsius and Anthropoidea into suborder Haplorhini. The molecular picture also provides both significant evidence for a human-chimpanzee clade that narrowly excludes gorilla and overwhelming evidence for the gorilla-chimpanzee-human clade within Hominoidea. Rates of DNA sequence evolution appear to have been fastest in the early primates ancestral to Anthropoidea and next fastest on the lorisoid branch. Rates were slowest over the past 25 Myr of hominoid descent, suggesting that mechanisms lowering the mutation rate evolved in correlation with lengthened life spans.     

New approaches to a better understanding of nematode phylogeny: molecular and developmental studies*

Recent studies making use of ribosomal DNA sequences have led to a wealth of new information that can be used to construct phylogenetic trees and compare them with those derived from more traditional approaches. Here, some examples are presented where the molecular data have stimulated alternative views. To determine whether differences in developmental processes can be used as markers for intraphyletic relationships, comparative studies of nematode embryogenesis have been performed. These results indicate that considerable deviations from the standard pattern found in the model system Caenorhabditis elegans exist which appear to be characteristic for certain subgroups within the taxon Nematoda.     

Iron and protein biofortification of cassava: lessons learned

Over two hundred and fifty million Africans rely on the starchy root crop cassava (Manihot esculenta) as their primary source of calories. Cassava roots, however, have the lowest protein:energy ratio of all the world's major staple crops. Furthermore, a typical cassava-based diet provides less than 10-20% of the required amounts of iron, zinc, vitamin A and vitamin E. The BioCassava Plus program employed modern biotechnologies to improve the health of Africans through development and delivery of novel cassava germplasm with increased nutrient levels. Here we describe the development of molecular strategies and their outcomes to meet minimum daily allowances for protein and iron in cassava based diets. We demonstrate that cyanogens play a central role in cassava nitrogen metabolism and that strategies employed to increase root protein levels result in reduced cyanogen levels in roots. We also demonstrate that enhancing root iron uptake has an impact on the expression of genes that regulate iron homeostasis in multiple tissues. These observations demonstrate the complex metabolic interactions involved in enhancing targeted nutrient levels in plants and identify potential new strategies for further enhancing nutrient levels in cassava.     

How Bayes tests of molecular phylogenies compare with frequentist approaches

MOTIVATION: The desire to compare molecular phylogenies has stimulated the design of numerous tests. Most of these tests are formulated in a frequentist framework, and it is not known how they compare with Bayes procedures. I propose here two new Bayes tests that either compare pairs of trees (Bayes hypothesis test, BHT), or test each tree against an average of the trees included in the analysis (Bayes significance test, BST). RESULTS: The algorithm, based on a standard Metropolis-Hastings sampler, integrates nuisance parameters out and estimates the probability of the data under each topology. These quantities are used to estimate Bayes factors for composite vs. composite hypotheses. Based on two data sets, the BHT and BST are shown to construct similar confidence sets to the bootstrap and the Shimodaira Hasegawa test, respectively. This suggests that the known difference among previous tests is mainly due to the null hypothesis considered.     

Evaluation of biomedical text-mining systems: lessons learned from information retrieval

Biomedical text-mining systems have great promise for improving the efficiency and productivity of biomedical researchers. However, such systems are still not in routine use. One impediment to their development is the lack of systematic and rigorous evaluation, comparable to the approaches developed for information retrieval systems. The developers of text-mining systems need to improve both test collections for system-oriented evaluation and undertake user-oriented evaluations to determine the most effective use of their systems for their intended audience.