Why, so far, have epidemics always eventually petered out? Quasispecies theory suggests a (testable!) answer.

In this paper, it is argued that the fact that, so far, even the worst and most far-reaching epidemics-from the Plague of Athens in 430 BC and the Plague of Justinian in 541/542 AD to the Hong Kong Flu from 1968/69-always finally petered out can be explained using Manfred Eigen's quasispecies concept: Indeed, as the infectious agents, while duplicating themselves in the infected organisms, mutate all the time, these infected organisms carry along quite a multitude of mutational variants or-in Manfred Eigen's terms-a whole quasispecies of infectious agents implying that, within that quasispecies, those variants that differ from the wild type may actually serve as some kind of vaccination program when infecting some previously uninfected persons. In this context, some data regarding various recent epidemics will also be illustrated, using Daniel Huson's SplitsTree software tool.

MiR-34a modulates ErbB2 in breast cancer.

Breast cancer is the second highest cause of carcinoma-related death caused by distant metastasis in women. Estrogen receptor (ER), human epidermal growth factor receptor 2, (HER2) and progesterone receptor (PR) are three classified makers of breast cancer, which are defined as ER+, HER2+, and the most serious ER-PR-HER2- (triple-negative). It is well known that ErbB2 (V-Erb-B2 avian erythroblastic leukemia viral oncogene homolog 2) plays an important part in breast cancer. However, the molecular mechanisms underlying ErbB2 action needs to be well studied. In this report, we discovered that the decreased expression levels of miR-34a were inversely correlated with the increased ErbB2 levels in breast cancer. A luciferase reporter assay was done to understand the potential correlation between ErbB2 and miR-34a. Over-expression of miR-34a reduces ErbB2 expression and suppresses breast cancer cell invasion and growth in vitro. What's more, reduced expression of ErbB2 inhibits breast Cancer cell proliferation and re-expression of ErbB2 reversed miR-34a-dependent tumor suppression. Meanwhile, miR-34a levels were correlated inversely with breast cancer malignancy. Our study demonstrates that miR-34a, like ErbB2, might be a diagnostic target in breast cancer.

'Lassoing' a phylogenetic tree I: basic properties, shellings, and covers.

A classical result, fundamental to evolutionary biology, states that an edge-weighted tree T with leaf set X, positive edge weights, and no vertices of degree 2 can be uniquely reconstructed from the leaf-to-leaf distances between any two elements of X. In biology, X corresponds to a set of taxa (e.g. extant species), the tree T describes their phylogenetic relationships, the edges correspond to earlier species evolving for a time until splitting in two or more species by some speciation/bifurcation event, and their length corresponds to the genetic change accumulating over that time in such a species. In this paper, we investigate which subsets of [Formula: see text] suffice to determine ('lasso') the tree T from the leaf-to-leaf distances induced by that tree. The question is particularly topical since reliable estimates of genetic distance-even (if not in particular) by modern mass-sequencing methods-are, in general, available only for certain combinations of taxa.

Species, clusters and the 'Tree of life': a graph-theoretic perspective.

A hierarchical structure describing the inter-relationships of species has long been a fundamental concept in systematic biology, from Linnean classification through to the more recent quest for a 'Tree of Life'. In this paper we use an approach based on discrete mathematics to address a basic question: could one delineate this hierarchical structure in nature purely by reference to the 'genealogy' of present-day individuals, which describes how they are related with one another by ancestry through a continuous line of descent? We describe several mathematically precise ways by which one can naturally define collections of subsets of present day individuals so that these subsets are nested (and so form a tree) based purely on the directed graph that describes the ancestry of these individuals. We also explore the relationship between these and related clustering constructions.

Self-assembly in aqueous solution of wheel-shaped Mo154 oxide clusters into vesicles.

Surfactants and membrane lipids readily assemble into complex structures such as micelles, liposomes or hollow vesicles owing to their amphiphilic character-the fact that part of their structure is attracted to polar environments while another part is attracted to non-polar environments. The self-assembly of complex structures also occurs in polyoxometallate chemistry, as exemplified by the molybdenum blue solutions known for centuries. But while the presence of nanometre-sized metal oxide aggregates in these solutions has long been recognized, unravelling the composition and formation process of these aggregates proved difficult. Recent work has indicated that discrete, wheel-shaped mixed-valence polyoxomolybdate clusters of the type [Mo154] (refs 2-4) assemble into well-defined nanometre-sized aggregates, including spherical structures. Here we report light-scattering data and transmission electron microscopy images of hollow spherical structures with an average, almost monodisperse radius of about 45 nm and composed of approximately 1,165 [Mo154] wheel-shaped clusters. The clusters appear to lie flat and homogeneously distributed on the vesicle surface. Unlike conventional lipid vesicles, the structures we observe are not stabilized by hydrophobic interactions. Instead, we believe the polyoxomolybdate-based vesicles form owing to a subtle interplay between short-range van der Waals attraction and long-range electrostatic repulsion, with important further stabilization arising from hydrogen bonding involving water molecules encapsulated between the wheel-shaped clusters and in the vesicles' interior.

Analyzing proteome topology and function by automated multidimensional fluorescence microscopy.

Temporal and spatial regulation of proteins contributes to function. We describe a multidimensional microscopic robot technology for high-throughput protein colocalization studies that runs cycles of fluorescence tagging, imaging and bleaching in situ. This technology combines three advances: a fluorescence technique capable of mapping hundreds of different proteins in one tissue section or cell sample; a method selecting the most prominent combinatorial molecular patterns by representing the data as binary vectors; and a system for imaging the distribution of these protein clusters in a so-called toponome map. By analyzing many cell and tissue types, we show that this approach reveals rules of hierarchical protein network organization, in which the frequency distribution of different protein clusters obeys Zipf's law, and state-specific lead proteins appear to control protein network topology and function. The technology may facilitate the development of diagnostics and targeted therapies.

miR-195 inhibits tumor growth and angiogenesis through modulating IRS1 in breast cancer.

Angiogenesis has been found as an attractive target for drug therapy as it is necessary for tumor growth. Accumulating evidences show that microRNAs (miRNAs), which are a group of highly conserved, single-stranded, short non-coding RNAs, play important roles through directly targeting angiogenic factors and protein kinases. The purpose of this study is to investigate the role of miR-195 in breast cancer development and angiogenesis through targeting IRS1. We show that miR-195 is inversely related with Insulin receptor substrate 1 (IRS1) in both breast cancer cells and breast cancer tissues. Induction of miR-195 could suppress IRS1 protein expression through binding to its 3'UTR regions either by transfection with miR-195 oligo or by infection with lentivirus encoding miR-195 gene. Moreover, re-expression of IRS1 reverses miR-195-mediated repression of tumor cell growth and miR-195 inhibits tumor angiogenesis through suppressing IRS1-VEGF axis. These data suggest that miR-195 mimics are potential therapeutic agents for breast cancer diagnose.

Constructing splits graphs.

Phylogenetic trees correspond one-to-one to compatible systems of splits and so splits play an important role in theoretical and computational aspects of phylogeny. Whereas any tree reconstruction method can be thought of as producing a compatible system of splits, an increasing number of phylogenetic algorithms are available that compute split systems that are not necessarily compatible and, thus, cannot always be represented by a tree. Such methods include the split decomposition, Neighbor-Net, consensus networks, and the Z-closure method. A more general split system of this kind can be represented graphically by a so-called splits graph, which generalizes the concept of a phylogenetic tree. This paper addresses the problem of computing a splits graph for a given set of splits. We have implemented all presented algorithms in a new program called SplitsTree4.

Fermat's principle of least time predicts refraction of ant trails at substrate borders.

Fermat's principle of least time states that light rays passing through different media follow the fastest (and not the most direct) path between two points, leading to refraction at medium borders. Humans intuitively employ this rule, e.g., when a lifeguard has to infer the fastest way to traverse both beach and water to reach a swimmer in need. Here, we tested whether foraging ants also follow Fermat's principle when forced to travel on two surfaces that differentially affected the ants' walking speed. Workers of the little fire ant, Wasmannia auropunctata, established "refracted" pheromone trails to a food source. These trails deviated from the most direct path, but were not different to paths predicted by Fermat's principle. Our results demonstrate a new aspect of decentralized optimization and underline the versatility of the simple yet robust rules governing the self-organization of group-living animals.

MiR-145 inhibits tumor angiogenesis and growth by N-RAS and VEGF.

MiR-145 is known as a tumor suppressor in numerous human cancers. However, its role in tumor angiogenesis remains poorly defined. In this study, we found that miR-145 was significantly downregulated in breast cancer tissues by using 106 cases of normal and cancer tissues as well as in breast cancer cells. MiR-145 exhibited inhibitory role in tumor angiogenesis, cell growth and invasion and tumor growth through the post-transcriptional regulation of the novel targets N-RAS and VEGF-A. In addition, we provide evidence that the expression levels of miR-145 correlate inversely with malignancy stages of breast tumors, although there is no association between miR-145 levels and hormone receptor levels in breast cancer. Taken together, these results demonstrate that miR-145 plays important inhibitory role in breast cancer malignancy by targeting N-RAS and VEGF-A, which may be potential therapeutic and diagnostic targets.

Analysis of MiR-195 and MiR-497 expression, regulation and role in breast cancer.

PURPOSE: To investigate expression, regulation, potential role and targets of miR-195 and miR-497 in breast cancer. EXPERIMENTAL DESIGN: The expression patterns of miR-195 and miR-497 were initially examined in breast cancer tissues and cell lines by Northern blotting and quantitative real-time PCR. Combined bisulfite restriction analysis and bisulfite sequencing were carried out to study the DNA methylation status of miR-195 and miR-497 genes. Breast cancer cells stably expressing miR-195 and miR-497 were established to study their role and targets. Finally, normal, fibroadenoma and breast cancer tissues were employed to analyze the correlation between miR-195/497 levels and malignant stages of breast tumor tissues. RESULTS: MiR-195 and miR-497 were significantly downregulated in breast cancer. The methylation state of CpG islands upstream of the miR-195/497 gene was found to be responsible for the downregulation of both miRNAs. Forced expression of miR-195 or miR-497 suppressed breast cancer cell proliferation and invasion. Raf-1 and Ccnd1 were identified as novel direct targets of miR-195 and miR-497. miR-195/497 expression levels in clinical specimens were found to be correlated inversely with malignancy of breast cancer. CONCLUSIONS: Our data imply that both miR-195 and miR-497 play important inhibitory roles in breast cancer malignancy and may be the potential therapeutic and diagnostic targets.

Efficient tools for comparative substring analysis.

This paper introduces an efficient implementation of approaches to alignment-free comparative genome analysis and genome-based phylogeny relying on substring composition. Distances derived from substring statistics have been proposed recently as a meaningful alternative to distances derived from sequence alignment. In particular, procaryote phylogenies based on comparative 5- and 6-mer analysis of whole proteomes have successfully been worked out. The present implementation extends the computation of composition-based distances so as to involve allk-mers for anyk up to any preset m aximum length K (including K=infinity). Remarkably, although there may be Theta(L(2)) distinct strings that occur in a given sequence of length L (and Theta(KL) of length k< or =K), it is shown that composition-based distances as well as many other details of interest in comparative genome analysis can be computed in O(L) time and space (with a constant that is independent of the size of K, that is, the same constant works for all K). A typical run with 2 sequences of altogether 1.5 million characters computes their composition-based distance in about 2s, a performance to be contrasted with the several hours needed, even when restricting attention to substrings of length at most 6, by the direct method in use. This paper.

Towards prediction and prioritization of disease genes by the modularity of human phenome-genome assembled network.

Empirical clinical studies on the human interactome and phenome not only illustrates prevalent phenotypic overlap and genetic overlap between diseases, but also reveals a modular organization of the genetic landscape of human disease, providing new opportunities to reduce the complexity in dissecting the phenotype-genotype association. We here introduce a network-module based method towards phenotype-genotype association inference and disease gene identification. This approach incorporates protein-protein interaction network, phenotype similarity network and known phenotype-genotype associations into an assembled network. We then decomposes the resulted network into modules (or communities) wherein we identified and prioritized the disease genes from the candidates within the loci associated with the query disease using a linear regression model and concordance score. For the known phenotype-gene associations in the OMIM database, we used the leave-one-out validation to evaluate the feasibility of our method, and successfully ranked known disease genes at top 1 in 887 out of 1807 cases. Moreover, applying this approach on 850 OMIM loci characterized by an unknown molecular basis, we propose high-probability candidates for 81 genetic diseases.

An information theoretic thresholding method for detecting protein colocalizations in stacks of fluorescence images.

In this note, we present a new method that allows us to determine threshold values for separating presence and absence of proteins in a stack of fluorescence images describing a spatial distribution of proteins across a biological object (like a slice of nervous tissue, a sample of blood cells, etc.). We apply this method to stacks of fluorescence images and find that the resulting threshold values are almost identical with threshold values found using completely independent methods based on technological and biological aspects of the images in question.

Stability of multiple alignments and phylogenetic trees: an analysis of ABC-transporter proteins family.

BACKGROUND: Sequence-based phylogeny reconstruction is a fundamental task in Bioinformatics. Practically all methods for phylogeny reconstruction are based on multiple alignments. The quality and stability of the underlying alignments is therefore crucial for phylogenetic analysis. RESULTS: In this short report, we investigate alignments and alignment-based phylogenies constructed for a set of 22 ABC transporters using CLUSTAL W and DIALIGN. Comparing the 22 "one-out phylogenies" one can obtain for this sequence set, some intrinsic phylogenetic instability is observed - even if attention is restricted to branches with high bootstrapping frequencies, the so-called safe branches. We show that this instability is caused by the fact that both, CLUSTAL W as well as DIALIGN, apparently get "confused" by sequence repeats in some of the ABC-transporter. To deal with such problems, two new DIALIGN options are introduced that prove helpful in our context, the "exclude-fragment" (or "xfr") and the "self-comparison" (or "sc") option. CONCLUSION: "One-out strategies", known to be a useful tool for testing the stability of all sorts of data-analysis procedures, can successfully be used also in testing alignment stability. In case instabilities are observed, the sequences under consideration should be carefully checked for putative causes. In case one suspects sequence repeats to be the cause, the new "sc" option can be used to detect such repeats, and the "xfr" option can help to resolve the resulting problems.

Noisy: identification of problematic columns in multiple sequence alignments.

MOTIVATION: Sequence-based methods for phylogenetic reconstruction from (nucleic acid) sequence data are notoriously plagued by two effects: homoplasies and alignment errors. Large evolutionary distances imply a large number of homoplastic sites. As most protein-coding genes show dramatic variations in substitution rates that are not uncorrelated across the sequence, this often leads to a patchwork pattern of (i) phylogenetically informative and (ii) effectively randomized regions. In highly variable regions, furthermore, alignment errors accumulate resulting in sometimes misleading signals in phylogenetic reconstruction. RESULTS: We present here a method that, based on assessing the distribution of character states along a cyclic ordering of the taxa, allows the identification of phylogenetically uninformative homoplastic sites in a multiple sequence alignment. Removal of these sites appears to improve the performance of phylogenetic reconstruction algorithms as measured by various indices of "tree quality". In particular, we obtain more stable trees due to the exclusion of phylogenetically incompatible sites that most likely represent strongly randomized characters. SOFTWARE: The computer program noisy implements this approach. It can be employed to improving phylogenetic reconstruction capability with quite a considerable success rate whenever (1) the average bootstrap support obtained from the original alignment is low, and (2) there are sufficiently many taxa in the data set - at least, say, 12 to 15 taxa. The software can be obtained under the GNU Public License from http://www.bioinf.uni-leipzig.de/Software/noisy/.

QNet: an agglomerative method for the construction of phylogenetic networks from weighted quartets.

We present QNet, a method for constructing split networks from weighted quartet trees. QNet can be viewed as a quartet analogue of the distance-based Neighbor-Net (NNet) method for network construction. Just as NNet, QNet works by agglomeratively computing a collection of circular weighted splits of the taxa set which is subsequently represented by a planar split network. To illustrate the applicability of QNet, we apply it to a previously published Salmonella data set. We conclude that QNet can provide a useful alternative to NNet if distance data are not available or a character-based approach is preferred. Moreover, it can be used as an aid for determining when a quartet-based tree-building method may or may not be appropriate for a given data set. QNet is freely available for download.