The rockefeller university

The Mediator is an evolutionarily conserved, multiprotein complex that is a key regulator of protein-coding genes. In metazoan cells, multiple pathways that are responsible for homeostasis, cell growth and differentiation converge on the Mediator through transcriptional activators and repressors that target one or more of the almost 30 subunits of this complex. Besides interacting directly with RNA polymerase II, Mediator has multiple functions and can interact with and coordinate the action of numerous other co-activators and co-repressors, including those acting at the level of chromatin. These interactions ultimately allow the Mediator to deliver outputs that range from maximal activation of genes to modulation of basal transcription to long-term epigenetic silencing.

High-fructose corn syrup (HFCS) accounts for as much as 40% of caloric sweeteners used in the United States Some studies have shown that short-term access to HFCS can cause increased body weight but the findings are mixed The current study examined both short and long-term effects of HFCS on body weight body fat and circulating triglycerides In Experiment 1 male Sprague-Dawley rats were maintained or short term (8 weeks) on (1) 12 h/day of 8% HFCS (2) 12 h/day 10% sucrose (3) 24 h/day HFCS all with ad libitum rodent chow or (4) ad libitum chow alone Rats with 12-h access to HFCS gained significantly more body weight than animals given equal access to 10% sucrose even though they consumed the same number of total calories but fewer calories from HFCS than sucrose In Experiment 2 the long-term effects of HFCS on body weight and obesogenic parameters as well as gender differences were explored Over the course of 6 or 7 months both male and female rats with access to HFCS gained significantly more body weight than control groups This increase in body weight with HFCS was accompanied by an increase in adipose fat notably in the abdominal region and elevated circulating triglyceride levels Translated to humans these results suggest that excessive consumption of HFCS may contribute to the incidence of obesity (C) 2010 Elsevier Inc All rights reserved

Heme oxygenase-1 (HO-1) and its catabolic by-products have potent anti-inflammatory activity in many models of disease. It is not known, however, if HO-1 also plays a role in the homeostatic control of T cell activation and proliferation. We demonstrate here that the HO-1 inhibitor tin mesoporphyrin (SnMP) induces activation, proliferation, and maturation of naive CD4(+) and CD8(+) T cells via interactions with CD14(+) monocytes in vitro. This response is dependent upon interactions of T cells with MHC class I and II on the surface of CD14(+) monocytes. Furthermore, CD4(+)CD25(+)FoxP3(+) regulatory T cells were able to suppress this proliferation, even though their suppressive activity was itself impaired by SnMP. Given the magnitude of the Ag-independent T cell response induced by SnMP, we speculate that HO-1 plays an important role in dampening nonspecific T cell activation. Based on these findings, we propose a potential role for HO-1 in the control of naive T cell homeostatic proliferation. The Journal of Immunology, 2010, 185: 5279-5288.

ADP-ribosylation is an important post-translational modification involved in processes including cellular replication, DNA repair, and cell death. Despite these roles, the functions of ADP-ribosylation, in particular mono-ADP-ribosylation, remain poorly understood. The development of a technique to generate large amounts of site-specific, ADP-ribosylated peptides would provide a useful tool for deconvoluting the biochemical roles of ADP-ribosylation. Here we demonstrate that synthetic histone H2B tail peptides, incorporating aminooxy or N-methyl aminooxy functionalized amino acids, can be site-specifically conjugated to ADP-ribose. These peptides are recognized as substrates by the ADP-ribosylation biochemical machinery (PARP1), can interact with the ADP-ribose binding proteins macroH2A1.1 and PARP9, and demonstrate superior enzymatic and chemical stability when compared to ester-linked ADP-ribose. In addition, the incorporation of benzophenone photo-cross-linkers into these peptides is demonstrated to provide a means to probe for and enrich ADP-ribose binding proteins.

We present a search for the lightest supersymmetric partner of the top quark in proton-antiproton collisions at a center-of-mass energy root s = 1: 96 TeV. This search was conducted within the framework of the R parity conserving minimal supersymmetric extension of the standard model, assuming the stop decays dominantly to a lepton, a sneutrino, and a bottom quark. We searched for events with two oppositely-charged leptons, at least one jet, and missing transverse energy in a data sample corresponding to an integrated luminosity of 1 fb(-1) collected by the Collider Detector at Fermilab experiment. No significant evidence of a stop quark signal was found. Exclusion limits at 95% confidence level in the stop quark versus sneutrino mass plane are set. Stop quark masses up to 180 GeV/c(2) are excluded for sneutrino masses around 45 GeV/c(2), and sneutrino masses up to 116 GeV/c(2) are excluded for stop quark masses around 150 GeV/c(2).

Experience-dependent brain plasticity typically declines after an early critical period during which circuits are established. Loss of plasticity with closure of the critical period limits improvement of function in adulthood, but the mechanisms that change the brain's plasticity remain poorly understood. Here, we identified an increase in expression of Lynx1 protein in mice that prevented plasticity in the primary visual cortex late in life. Removal of this molecular brake enhanced nicotinic acetylcholine receptor signaling. Lynx1 expression thus maintains stability of mature cortical networks in the presence of cholinergic innervation. The results suggest that modulating the balance between excitatory and inhibitory circuits reactivates visual plasticity and may present a therapeutic target.

To achieve high compaction, most genomic DNA in eukaryotes is incorporated into nucleosomes; however, regulatory factors and transcriptional machinery must gain access to chromatin to extract genetic information. This conflict is partially resolved by a particular arrangement of nucleosome locations on the genome. Across all eukaryotic species, promoters and other regulatory sequences are more nucleosome-depleted, whereas transcribed regions tend to be occupied with well-positioned, high-density nucleosomal arrays. This nucleosome positioning pattern, as well as its dynamic regulation, facilitates the access of transcription factors to their target sites and plays a crucial role in determining the transcription level, cell-to-cell variation and activation or repression dynamics.

Cellular Fc gamma receptors are essential for IgG-dependent effector functions in vivo. There is convincing evidence that selective activating Fc gamma receptors are responsible for the activity of individual IgG subclasses. Thus, IgG1 activity is absent in Fc gamma RIII-deficient mice, and several studies suggest that the activity of the most potent IgG subclasses, IgG2a and IgG2b, might be dependent on either individual or a combination of activating Fc gamma Rs. To study the role of individual activating Fc gamma Rs for IgG subclass activity, we generated an Fc gamma RIV-deficient mouse and showed that a variety of IgG2a- and IgG2b- dependent effector functions are impaired in the absence of this activating Fc gamma receptor in models of autoimmunity and antibody-dependent cellular cytotoxicity.

mAbs directed against immunologic molecules have emerged as a new class of drugs for treating patients with various immunologic conditions. However, mAb-based treatments may confer a predisposition to various infections. The authors argue that infections in individuals treated with mAbs directed against molecules of the immune system may display some similarities to those in patients with primary immunodeficiency of the corresponding mAb target. A comprehensive dissection of the tremendously diverse human primary immunodeficiencies and the careful description of their clinical features in different populations living in diverse environments thus represents an original, neglected, but promising approach to assessing the potential risk of infection associated with therapeutic mAbs, or with any therapeutic compound inhibiting a specific immunologic molecule. (J Allergy Clin Immunol 2010; 126:910-7.)

Regulatory networks in cells may comprise a variety of types of molecular interactions. The most basic are pairwise interactions, in which one species controls the behaviour of another (e.g. a transcription factor activates or represses a gene). Higher-order interactions, while more subtle, may be important for determining the function of networks. Here, the authors systematically expand a simple master equation model for a gene to derive an approach for robustly assessing the cooperativity (effective copy number) with which a transcription factor acts. The essential idea is that moments of a joint distribution of protein copy numbers determine the Hill coefficient of a cis-regulatory input function without non-linear fitting. The authors show that this method prescribes a definition of cooperativity that is meaningful even in highly complex situations in which the regulation does not conform to a simple Hill function. To illustrate the utility of the method, the authors measure the cooperativity of the transcription factor CI in simulations of phage-lambda and show how the cooperativity accurately reflects the behaviour of the system. The authors numerically assess the effects of deviations from ideality, as well as possible sources of error. The relationship to other definitions of cooperativity and issues for experimentally realising the procedure are discussed.