Hic-5, an adaptor-like nuclear receptor coactivator

In recent years, numerous nuclear receptor-interacting proteins have been identified that influence nuclear transcription through their direct modification of chromatin. Along with coactivators that possess histone acetyltransferase (HAT) or methyltransferase activity, other coactivators that lack recognizable chromatin-modifying activity have been discovered whose mechanism of action is largely unknown. The presence of multiple protein-protein interaction motifs within mechanistically undefined coactivators suggests that they function as adaptor molecules, either recruiting or stabilizing promoter-specific protein complexes. This perspective will focus on a family of nuclear receptor coactivators (i.e., group III LIM domain proteins related to paxillin) that appear to provide a scaffold to stabilize receptor interactions with chromatin-modifying coregulators

MyD88-dependent interplay between myeloid and endothelial cells in the initiation and progression of obesity-associated inflammatory diseases.

Low-grade systemic inflammation is often associated with metabolic syndrome, which plays a critical role in the development of the obesity-associated inflammatory diseases, including insulin resistance and atherosclerosis. Here, we investigate how Toll-like receptor-MyD88 signaling in myeloid and endothelial cells coordinately participates in the initiation and progression of high fat diet-induced systemic inflammation and metabolic inflammatory diseases. MyD88 deficiency in myeloid cells inhibits macrophage recruitment to adipose tissue and their switch to an M1-like phenotype. This is accompanied by substantially reduced diet-induced systemic inflammation, insulin resistance, and atherosclerosis. MyD88 deficiency in endothelial cells results in a moderate reduction in diet-induced adipose macrophage infiltration and M1 polarization, selective insulin sensitivity in adipose tissue, and amelioration of spontaneous atherosclerosis. Both in vivo and ex vivo studies suggest that MyD88-dependent GM-CSF production from the endothelial cells might play a critical role in the initiation of obesity-associated inflammation and development of atherosclerosis by priming the monocytes in the adipose and arterial tissues to differentiate into M1-like inflammatory macrophages. Collectively, these results implicate a critical MyD88-dependent interplay between myeloid and endothelial cells in the initiation and progression of obesity-associated inflammatory diseases

Antigen-Engaged B Cells Undergo Chemotaxis toward the T Zone and Form Motile Conjugates with Helper T Cells

Interactions between B and T cells are essential for most antibody responses, but the dynamics of these interactions are poorly understood. By two-photon microscopy of intact lymph nodes, we show that upon exposure to antigen, B cells migrate with directional preference toward the B-zone–T-zone boundary in a CCR7-dependent manner, through a region that exhibits a CCR7-ligand gradient. Initially the B cells show reduced motility, but after 1 d, motility is increased to approximately 9 μm/min. Antigen-engaged B cells pair with antigen-specific helper T cells for 10 to more than 60 min, whereas non-antigen-specific interactions last less than 10 min. B cell–T cell conjugates are highly dynamic and migrate extensively, being led by B cells. B cells occasionally contact more than one T cell, whereas T cells are strictly monogamous in their interactions. These findings provide evidence of lymphocyte chemotaxis in vivo, and they begin to define the spatiotemporal cellular dynamics associated with T cell–dependent antibody responses

A Novel Biclustering Approach to Association Rule Mining for Predicting HIV-1–Human Protein Interactions

Identification of potential viral-host protein interactions is a vital and useful approach towards development of new drugs targeting those interactions. In recent days, computational tools are being utilized for predicting viral-host interactions. Recently a database containing records of experimentally validated interactions between a set of HIV-1 proteins and a set of human proteins has been published. The problem of predicting new interactions based on this database is usually posed as a classification problem. However, posing the problem as a classification one suffers from the lack of biologically validated negative interactions. Therefore it will be beneficial to use the existing database for predicting new viral-host interactions without the need of negative samples. Motivated by this, in this article, the HIV-1–human protein interaction database has been analyzed using association rule mining. The main objective is to identify a set of association rules both among the HIV-1 proteins and among the human proteins, and use these rules for predicting new interactions. In this regard, a novel association rule mining technique based on biclustering has been proposed for discovering frequent closed itemsets followed by the association rules from the adjacency matrix of the HIV-1–human interaction network. Novel HIV-1–human interactions have been predicted based on the discovered association rules and tested for biological significance. For validation of the predicted new interactions, gene ontology-based and pathway-based studies have been performed. These studies show that the human proteins which are predicted to interact with a particular viral protein share many common biological activities. Moreover, literature survey has been used for validation purpose to identify some predicted interactions that are already validated experimentally but not present in the database. Comparison with other prediction methods is also discussed

Evolution of response dynamics underlying bacterial chemotaxis

© 2011 Soyer and Goldstein; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background: The ability to predict the function and structure of complex molecular mechanisms underlying cellular behaviour is one of the main aims of systems biology. To achieve it, we need to understand the evolutionary routes leading to a specific response dynamics that can underlie a given function and how biophysical and environmental factors affect which route is taken. Here, we apply such an evolutionary approach to the bacterial chemotaxis pathway, which is documented to display considerable complexity and diversity.Results: We construct evolutionarily accessible response dynamics starting from a linear response to absolute levels of attractant, to those observed in current-day Escherichia coli. We explicitly consider bacterial movement as a two-state process composed of non-instantaneous tumbling and swimming modes. We find that a linear response to attractant results in significant chemotaxis when sensitivity to attractant is low and when time spent tumbling is large. More importantly, such linear response is optimal in a regime where signalling has low sensitivity. As sensitivity increases, an adaptive response as seen in Escherichia coli becomes optimal and leads to 'perfect' chemotaxis with a low tumbling time. We find that as tumbling time decreases and sensitivity increases, there exist a parameter regime where the chemotaxis performance of the linear and adaptive responses overlap, suggesting that evolution of chemotaxis responses might provide an example for the principle of functional change in structural continuity.Conclusions: Our findings explain several results from diverse bacteria and lead to testable predictions regarding chemotaxis responses evolved in bacteria living under different biophysical constraints and with specific motility machinery. Further, they shed light on the potential evolutionary paths for the evolution of complex behaviours from simpler ones in incremental fashion

Use of prasugrel vs clopidogrel and outcomes in patients with acute coronary syndrome undergoing percutaneous coronary intervention in contemporary clinical practice: Results from the PROMETHEUS study.

BACKGROUND AND OBJECTIVES: We sought to determine the frequency of use and association between prasugrel and outcomes in acute coronary syndrome patients undergoing percutaneous coronary intervention (PCI) in clinical practice. METHODS: PROMETHEUS was a multicenter observational registry of acute coronary syndrome patients undergoing PCI from 8 centers in the United States that maintained a prospective PCI registry for patient outcomes. The primary end points were major adverse cardiovascular events at 90days, a composite of all-cause death, nonfatal myocardial infarction, stroke, or unplanned revascularization. Major bleeding was defined as any bleeding requiring hospitalization or blood transfusion. Hazard ratios (HRs) were generated using multivariable Cox regression and stratified by the propensity to treat with prasugrel. RESULTS: Of 19,914 patients (mean age 64.4years, 32% female), 4,058 received prasugrel (20%) and 15,856 received clopidogrel (80%). Prasugrel-treated patients were younger with fewer comorbid risk factors compared with their counterparts receiving clopidogrel. At 90days, there was a significant association between prasugrel use and lower major adverse cardiovascular event (5.7% vs 9.6%, HR 0.58, 95% CI 0.50-0.67, P<.0001) and bleeding (1.9% vs 2.9%, HR 0.65, 95% CI 0.51-0.83, P<.001). After propensity stratification, associations were attenuated and no longer significant for either outcome. Results remained consistent using different approaches to adjusting for potential confounders. CONCLUSIONS: In contemporary clinical practice, patients receiving prasugrel tend to have a lower-risk profile compared with those receiving clopidogrel. The lower ischemic and bleeding events associated with prasugrel use were no longer evident after accounting for these baseline differences