Successive Weighting and Polymorphic Terminals—A Warning to PAUP Users

The naïve user of PAUP 3.1.1 (and earlier versions) is warned about a shortcoming in the program's successive weighting facility. With matrices containing multistate terminals, PAUP, under the "polymorphism" interpretation, will assign higher weight to characters with more within-terminal steps, other things being equal, i.e. to characters with the largest amount of homoplasy. The shortcoming has been corrected in PAUP* version 4.0.     

A Unified Conformational Selection and Induced Fit Approach to Protein-Peptide Docking

Protein-peptide interactions are vital for the cell. They mediate, inhibit or serve as structural components in nearly 40% of all macromolecular interactions, and are often associated with diseases, making them interesting leads for protein drug design. In recent years, large-scale technologies have enabled exhaustive studies on the peptide recognition preferences for a number of peptide-binding domain families. Yet, the paucity of data regarding their molecular binding mechanisms together with their inherent flexibility makes the structural prediction of protein-peptide interactions very challenging. This leaves flexible docking as one of the few amenable computational techniques to model these complexes. We present here an ensemble, flexible protein-peptide docking protocol that combines conformational selection and induced fit mechanisms. Starting from an ensemble of three peptide conformations (extended, a-helix, polyproline-II), flexible docking with HADDOCK generates 79.4% of high quality models for bound/unbound and 69.4% for unbound/unbound docking when tested against the largest protein-peptide complexes benchmark dataset available to date. Conformational selection at the rigid-body docking stage successfully recovers the most relevant conformation for a given protein-peptide complex and the subsequent flexible refinement further improves the interface by up to 4.5 Å interface RMSD. Cluster-based scoring of the models results in a selection of near-native solutions in the top three for ∼75% of the successfully predicted cases. This unified conformational selection and induced fit approach to protein-peptide docking should open the route to the modeling of challenging systems such as disorder-order transitions taking place upon binding, significantly expanding the applicability limit of biomolecular interaction modeling by docking.     

Forum. Stratigraphic Fit to Phylogenies: A Proposed Solution

Three measures intended to assess the fit of stratigraphic age to the fossil record have been suggested previously: the Spearman Rank Correlation (SRC), the Stratigraphic Consistency Index (SCI) and the Relative Completeness Index (RCI). The original formulation of SRC is intractable to all but pectinate trees and the corrective pruning procedure that circumvents this precludes whole-tree estimates of fit. SCI, though it has been claimed otherwise, is strongly biased by tree shape, particularly as one adds more information. RCI is a measure of the amount of gap in the fossil record but has awkward consequences for evolutionary biology when it is maximized. A new approach, the Manhattan Stratigraphic Measure, uses the Manhattan distance between stratigraphic ages to determine fit to a tree. It is not biased by tree shape, it is sensitive to the magnitude of age discrepancy and there is an obvious significance test.     

Seven Steps to Stellate Cells

Hepatic stellate cells are liver-resident cells of star-like morphology and are located in the space of Disse between liver sinusoidal endothelial cells and hepatocytes^1,2. Stellate cells are derived from bone marrow precursors and store up to 80% of the total body vitamin A^{1, 2}. Upon activation, stellate cells differentiate into myofibroblasts to produce extracellular matrix, thus contributing to liver fibrosis³. Based on their ability to contract, myofibroblastic stellate cells can regulate the vascular tone associated with portal hypertension⁴. Recently, we demonstrated that hepatic stellate cells are potent antigen presenting cells and can activate NKT cells as well as conventional T lymphocytes⁵. Here we present a method for the efficient preparation of hepatic stellate cells from mouse liver. Due to their perisinusoidal localization, the isolation of hepatic stellate cells is a multi-step process. In order to render stellate cells accessible to isolation from the space of Disse, mouse livers are perfused in situ with the digestive enzymes Pronase E and Collagenase P. Following perfusion, the liver tissue is subjected to additional enzymatic treatment with Pronase E and Collagenase P in vitro. Subsequently, the method takes advantage of the massive amount of vitamin A-storing lipid droplets in hepatic stellate cells. This feature allows the separation of stellate cells from other hepatic cell types by centrifugation on an 8% Nycodenz gradient. The protocol described here yields a highly pure and homogenous population of stellate cells. Purity of preparations can be assessed by staining for the marker molecule glial fibrillary acidic protein (GFAP), prior to analysis by fluorescence microscopy or flow cytometry. Further, light microscopy reveals the unique appearance of star-shaped hepatic stellate cells that harbor high amounts of lipid droplets. Taken together, we present a detailed protocol for the efficient isolation of hepatic stellate cells, including representative images of their morphological appearance and GFAP expression that help to define the stellate cell entity.Download video file.^{(41M, mov)}     

A Multisclae Probabilisitc Framework to Model Early Steps in Tumor Metastasis

Tumor metastasis is the leading cause of nearly all cancer related deaths. While several experimental and computational studies have addressed individual stages of the complex metastasis process, a comprehensive systems-biology model that links various stages of metastasis has not been put forth as of yet. In this paper we discuss the formulation and application of such a model that utilizes basic principles of cell biology, physics and mechanics to study the migratory patterns of tumor cells as they move from the parent tumor site to the connective tissue via the basement membrane. The model is first of its kind in capturing the essential early features of metastasis in a single simulation and shows good agreement with recent experimental studies.     

A Bayesian Chi‐Squared Goodness‐of‐Fit Test for Censored Data Models

Summary We propose a Bayesian chi‐squared model diagnostic for analysis of data subject to censoring. The test statistic has the form of Pearson's chi‐squared test statistic and is easy to calculate from standard output of Markov chain Monte Carlo algorithms. The key innovation of this diagnostic is that it is based only on observed failure times. Because it does not rely on the imputation of failure times for observations that have been censored, we show that under heavy censoring it can have higher power for detecting model departures than a comparable test based on the complete data. In a simulation study, we show that tests based on this diagnostic exhibit comparable power and better nominal Type I error rates than a commonly used alternative test proposed by Akritas (1988, Journal of the American Statistical Association 83, 222–230). An important advantage of the proposed diagnostic is that it can be applied to a broad class of censored data models, including generalized linear models and other models with nonidentically distributed and nonadditive error structures. We illustrate the proposed model diagnostic for testing the adequacy of two parametric survival models for Space Shuttle main engine failures.     

Steps to a Semiotics of Being

The following points, which represent a path to a semiotics of being, are pertinent to various sub-fields at the conjunction of semiotics of nature (biosemiotics, ecosemiotics, zoosemiotics) and semiotics of culture—semioethics and existential semiotics included. 1) Semiotics of being entails inquiry at all levels of biological organization, albeit, wherever there are individuals, with emphasis on the living qua individuals (integrated biological individualism). 2) An Umwelt is the public aspect (cf. the Innenwelt, the private aspect) of a phenomenal/experienced world that is organism-specific (rather than species-specific) and ultimately refers to an existential realm. 3) Existential universals at work on Earth include seeking out the edible, dwelling in a medium, holding a phenomenal world (possibly an Umwelt) and being endowed with life, and consequently being mortal. 4) Human Umwelten include speechless Umwelten, spoken Umwelten and alphabetic Umwelten. 5) An Uexküllian phenomenology—stating that semiotic states represent the general class to which all mental/cognitive states belong—can draw on the works of the phenomenologists David Abram and Ted Toadvine (The notion of semiotic states is treated in Tønnessen 2009a: 62–63. For an introduction to eco-phenomenology, see Brown and Toadvine (eds.) 2003). 6) A task for such a phenomenology is to portray the natural history of the phenomenal world. 7) An imperative task in our contemporary world of faltering biological diversity is that of Umwelt mapping, i.e. a mapping of ontological niches. 8) The ecological crisis is an ontological crisis with historical roots in humankind’s domestication of animals and plants, which can be taken as archetypical for our attempted planet-scale taming of the wild. 9) The process of globalization is expressed by correlated trends of depletion of semiotic diversity and semiotic diversification. 10) Semiotic economy is a field which task it is to map the human ontological niche insofar as its semiotic relations are of an economic nature. All ten points will be commented (explicitly or implicitly) in due time.     

Steps to a sustainable Northern Australia

Summary Northern Australia's globally significant savannas and rivers face major threats, from cattle to weeds to land clearing to climate change. In the face of imperatives and pressures such as reducing carbon emissions, nature conservation, alleviating Indigenous disadvantage, the resources boom and global food security, how should development be managed to protect its globally significant ecosystems? Nine planks in a ‘Sustainable Northern Australia’ agenda are proposed: (i) enhance investment in mitigating pervasive landscape threats; (ii) strengthen support for Indigenous Caring for Country activities and incorporation of Traditional Ecological Knowledge into land management; (iii) align and strengthen invasive species control and management; (iv) facilitate new economic development pathways focused on sustainability; (v) build climate resilience by maintaining and enhancing landscape‐scale connectivity; (vi) protect free‐flowing rivers from dams and major water resource development; (vii) establish and effectively manage a large interconnected network of protected areas; (viii) develop cooperative governance arrangements; and (ix) enhance knowledge generation and research and monitoring capacity.