Log-linear models for mutations in the HIV genome

We discuss a general application of categorical data analysis to mutations along the HIV genome. We consider a multidimensional table for several positions at the same time. Due to the complexity of the multidimensional table, we may collapse it by pooling some categories. However, the association between the remaining variables may not be the same as before collapsing. We discuss the collapsibility of tables and the change in the meaning of parameters after collapsing categories. We also address this problem with a log-linear model. We present a parameterization with the consensus output as the reference cell as is appropriate to explain genomic mutations in HIV. We also consider five null hypotheses and some classical methods to address them. We illustrate methods for six positions along the HIV genome, through consideration of all triples of positions

Tumor Suppressor Function of Syk in Human MCF10A In Vitro and Normal Mouse Mammary Epithelium In Vivo

The normal function of Syk in epithelium of the developing or adult breast is not known, however, Syk suppresses tumor growth, invasion, and metastasis in breast cancer cells. Here, we demonstrate that in the mouse mammary gland, loss of one Syk allele profoundly increases proliferation and ductal branching and invasion of epithelial cells through the mammary fat pad during puberty. Mammary carcinomas develop by one year. Syk also suppresses proliferation and invasion in vitro. siRNA or shRNA knockdown of Syk in MCF10A breast epithelial cells dramatically increased proliferation, anchorage independent growth, cellular motility, and invasion, with formation of functional, extracellular matrix-degrading invadopodia. Morphological and gene microarray analysis following Syk knockdown revealed a loss of luminal and differentiated epithelial features with epithelial to mesenchymal transition and a gain in invadopodial cell surface markers CD44, CD49F, and MMP14. These results support the role of Syk in limiting proliferation and invasion of epithelial cells during normal morphogenesis, and emphasize the critical role of Syk as a tumor suppressor for breast cancer. The question of breast cancer risk following systemic anti-Syk therapy is raised since only partial loss of Syk was sufficient to induce mammary carcinomas

Analysis of human immunodeficiency virus type 1 nef gene sequences present in vivo.

The nef genes of the human immunodeficiency viruses type 1 and 2 (HIV-1 and HIV-2) and the related simian immunodeficiency viruses (SIVs) encode a protein (Nef) whose role in virus replication and cytopathicity remains uncertain. As an attempt to elucidate the function of nef, we characterized the nucleotide and corresponding protein sequences of naturally occurring nef genes obtained from several HIV-1-infected individuals. A consensus Nef sequence was derived and used to identify several features that were highly conserved among the Nef sequences. These features included a nearly invariant myristylation signal, regions of sequence polymorphism and variable duplication, a region with an acidic charge, a (Pxx)4 repeat sequence, and a potential protein kinase C phosphorylation site. Clustering of premature stop codons at position 124 was noted in 6 of the 54 Nef sequences. Further analysis revealed four stretches of residues that were highly conserved not only among the patient-derived HIV-1 Nef sequences, but also among the Nef sequences of HIV-2 and the SIVs, suggesting that Nef proteins expressed by these retroviruses are functionally equivalent. The "Nef-defining" sequences were used to evaluate the sequence alignments of known proteins reported to share sequence similarity with Nef sequences and to conduct additional computer-based searches for similar protein sequences. A gene encoding the consensus Nef sequence was also generated. This gene encodes a full-length Nef protein that should be a valuable tool in further studies of Nef function

Detecting failure of climate predictions

The practical consequences of climate change challenge society to formulate responses that are more suited to achieving long-term objectives, even if those responses have to be made in the face of uncertainty. Such a decision-analytic focus uses the products of climate science as probabilistic predictions about the effects of management policies. Here we present methods to detect when climate predictions are failing to capture the system dynamics. For a single model, we measure goodness of fit based on the empirical distribution function, and define failure when the distribution of observed values significantly diverges from the modelled distribution. For a set of models, the same statistic can be used to provide relative weights for the individual models, and we define failure when there is no linear weighting of the ensemble models that produces a satisfactory match to the observations. Early detection of failure of a set of predictions is important for improving model predictions and the decisions based on them. We show that these methods would have detected a range shift in northern pintail 20 years before it was actually discovered, and are increasingly giving more weight to those climate models that forecast a September ice-free Arctic by 2055

Analyzing 2D gel images using a two-component empirical bayes model

<p>Abstract</p> <p>Background</p> <p>Two-dimensional polyacrylomide gel electrophoresis (2D gel, 2D PAGE, 2-DE) is a powerful tool for analyzing the proteome of a organism. Differential analysis of 2D gel images aims at finding proteins that change under different conditions, which leads to large-scale hypothesis testing as in microarray data analysis. Two-component empirical Bayes (EB) models have been widely discussed for large-scale hypothesis testing and applied in the context of genomic data. They have not been implemented for the differential analysis of 2D gel data. In the literature, the mixture and null densities of the test statistics are estimated separately. The estimation of the mixture density does not take into account assumptions about the null density. Thus, there is no guarantee that the estimated null component will be no greater than the mixture density as it should be.</p> <p>Results</p> <p>We present an implementation of a two-component EB model for the analysis of 2D gel images. In contrast to the published estimation method, we propose to estimate the mixture and null densities simultaneously using a constrained estimation approach, which relies on an iteratively re-weighted least-squares algorithm. The assumption about the null density is naturally taken into account in the estimation of the mixture density. This strategy is illustrated using a set of 2D gel images from a factorial experiment. The proposed approach is validated using a set of simulated gels.</p> <p>Conclusions</p> <p>The two-component EB model is a very useful for large-scale hypothesis testing. In proteomic analysis, the theoretical null density is often not appropriate. We demonstrate how to implement a two-component EB model for analyzing a set of 2D gel images. We show that it is necessary to estimate the mixture density and empirical null component simultaneously. The proposed constrained estimation method always yields valid estimates and more stable results. The proposed estimation approach proposed can be applied to other contexts where large-scale hypothesis testing occurs.</p

Re-evaluating the Quoit Brooch Style: Economic and Cultural Transformations in the 5th Century ad, with an Updated Catalogue of Known Quoit Brooch Style Artefacts

Quoit Brooch Style material, produced from the early 5th century onwards, has previously been considered mostly from a stylistic point of view, leaving much scope for further investigation. In addition, the known corpus of material has been much expanded through newly excavated and metal-detected finds. In this article, I bring together the known extant material for the first time, and document important evidence relating to contextual dating, gender associations, manufacture (including new compositional analysis of c 75 objects), repair, and reuse. The article questions previous interpretations of Quoit Brooch Style material relating to Germanic mercenaries and/or post-Romano-British political entities. It interprets the earliest material as part of wider trends elsewhere, in Britain and in Continental northwestern Europe, for the production of material imitating late Roman symbols of power. It presents new evidence for connectivity with Continental Europe via the western Channel route in the 5th century. A detailed investigation of individual artefacts shows that many Quoit Brooch Style objects were reused, sometimes being subjected to extensive repair and modification. This provides new insights into the 5th century metal economy, for instance, acute problems in the availability of new metal objects in southeastern Britain in the middle years of the 5th century. Compositional analysis contributes further to our understanding of metal supply in the 5th century and relationships with the post-Roman West. Insights are provided into wider cultural transformations in the 5th century and the gradual loss of value that occurred for Roman-style objects

4-Thiocellooligosaccharides : their synthesis and use as ligand for the separation of cellobiohydrolases of Trichoderma reesei by affinity chromatography

International audienc

Analysis of human immunodeficiency virus type 1 nef gene sequences present in vivo.

The nef genes of the human immunodeficiency viruses type 1 and 2 (HIV-1 and HIV-2) and the related simian immunodeficiency viruses (SIVs) encode a protein (Nef) whose role in virus replication and cytopathicity remains uncertain. As an attempt to elucidate the function of nef, we characterized the nucleotide and corresponding protein sequences of naturally occurring nef genes obtained from several HIV-1-infected individuals. A consensus Nef sequence was derived and used to identify several features that were highly conserved among the Nef sequences. These features included a nearly invariant myristylation signal, regions of sequence polymorphism and variable duplication, a region with an acidic charge, a (Pxx)4 repeat sequence, and a potential protein kinase C phosphorylation site. Clustering of premature stop codons at position 124 was noted in 6 of the 54 Nef sequences. Further analysis revealed four stretches of residues that were highly conserved not only among the patient-derived HIV-1 Nef sequences, but also among the Nef sequences of HIV-2 and the SIVs, suggesting that Nef proteins expressed by these retroviruses are functionally equivalent. The "Nef-defining" sequences were used to evaluate the sequence alignments of known proteins reported to share sequence similarity with Nef sequences and to conduct additional computer-based searches for similar protein sequences. A gene encoding the consensus Nef sequence was also generated. This gene encodes a full-length Nef protein that should be a valuable tool in further studies of Nef function