The rockefeller university

Recent genome-wide association studies have identified a genetic locus at human chromosome 8q24 as having minor alleles associated with lower levels of plasma triglyceride (TG) and LDL cholesterol (LDL-C), higher levels of HDL-C, as well as decreased risk for myocardial infarction. This locus contains only one annotated gene, tribbles homolog 1 (TRIB1), which has not previously been implicated in lipoprotein metabolism. Here we demonstrate a role for Trib1 as a regulator of lipoprotein metabolism in mice. Hepatic-specific overexpression of Trib1 reduced levels of plasma TG and cholesterol by reducing VLDL production; conversely, Trib1-knockout mice showed elevated levels of plasma TG and cholesterol due to increased VLDL production. Hepatic Trib1 expression was inversely associated with the expression of key lipogenic genes and measures of lipogenesis. Thus, we provide functional evidence for what we believe to be a novel gene regulating hepatic lipogenesis and VLDL production in mice that influences plasma lipids and risk for myocardial infarction in humans.

The platelet integrin alpha(IIb)beta(3) is essential for hemostasis and thrombosis through its binding of adhesive plasma proteins. We have determined crystal structures of the alpha(IIb)beta(3) headpiece in the absence of ligand and after soaking in RUC-1, a novel small molecule antagonist. In the absence of ligand, the alpha(IIb)beta(3) headpiece is in a closed conformation, distinct from the open conformation visualized in presence of Arg-Gly-Asp (RGD) antagonists. In contrast to RGD antagonists, RUC-1 binds only to the alpha(IIb) subunit. Molecular dynamics revealed nearly identical binding. Two species-specific residues, alpha(IIb) Y190 and alpha(IIb) D232, in the RUC-1 binding site were confirmed as important by mutagenesis. In sharp contrast to RGD-based antagonists, RUC-1 did not induce alpha(IIb)beta(3) to adopt an open conformation, as determined by gel filtration and dynamic light scattering. These studies provide insights into the factors that regulate integrin headpiece opening, and demonstrate the molecular basis for a novel mechanism of integrin antagonism. (Blood. 2010;116(23):5050-5059)

We present a measurement of the WW + WZ production cross section observed in a final state consisting of an identified electron or muon, two jets, and missing transverse energy. The measurement is carried out in a data sample corresponding to up to 4.6 fb(-1) of integrated luminosity at root s = 1.96 TeV collected by the CDF II detector. Matrix element calculations are used to separate the diboson signal from the large backgrounds. The WW + WZ cross section is measured to be 17.4 +/- 3.3 pb in agreement with standard model predictions. A fit to the dijet invariant mass spectrum yields a compatible cross section measurement.

Mitotically active, growth-arrested cells and proliferatively senescent cultures of human fetal lung fibroblasts (WI-38) were exposed to six different oxygen tensions for various lengths of time and then analyzed to determine the responses of their antioxidant defense system. Glutathione (GSH) concentration increased as a function of ambient oxygen tension in early passage cultures; the effect was larger in exponentially growing cultures than in those in a state of contact-inhibited growth arrest, but was absent in senescent cells. Conversely, the activity of glutathione disulfide reductase was greater in growth-arrested cultures than in mitotically active cells irrespective of oxygen tension. Glucose-6-phosphate dehydrogenase was lowest in log-phase cells exposed to different oxygen tensions for 24 h and in senescent cells. Both hypoxia and hyperoxia depressed selenium-dependent glutathione peroxidase activity in early passage cultures, while the activity of the enzyme progressively declined with increasing oxygen in senescent cells. The GSH S-transferase activity was unresponsive to changes in ambient oxygen tension in either young or senescent cultures. Manganese-containing superoxide dismutase (MnSOD) activity was unaffected by oxygen tension, but was elevated in young confluent cultures as compared with cultures in log-phase growth. MnSOD activity was significantly higher in senescent cultures than in early passage cultures and was also responsive to increased oxygen tension in senescent cultures. Copper-zinc-containing superoxide dismutases activity was not affected by oxygen tension or the passage of time, but it declined in senescent cultures.

The cell cycle oscillator, based on a core negative feedback loop and modified extensively by positive feedback, cycles with a frequency that is regulated by environmental and developmental programs to encompass a wide range of cell cycle times. We discuss how positive feedback allows frequency tuning, how size and morphogenetic checkpoints regulate oscillator frequency, and how extrinsic oscillators such as the circadian clock gate cell cycle frequency. The master cell cycle regulatory oscillator in turn controls the frequency of peripheral oscillators controlling essential events. A recently proposed phase-locking model accounts for this coupling.

Inappropriate recollections and responses in stressful conditions are hallmarks of post-traumatic stress disorder and other anxiety and mood disorders, but how stress contributes to the disorders is unclear. Here we show that stress itself reactivates memories even if the memory is unrelated to the stressful experience. Forced-swim stress one day after learning enhanced memory recall. One-day post-learning amnestic treatments were ineffective unless administered soon after the swim, indicating that a stressful experience itself can reactivate unrelated consolidated memories. The swim also triggered inter-hemispheric transfer of a lateralized memory, confirming stress reactivates stable memories. These novel effects of stress on memory required the hippocampus although the memories themselves did not, indicating hippocampus-dependent modulation of extrahippocampal memories. These findings that a stressful experience itself can activate memory suggest the novel hypothesis that traumatic stress reactivates pre-trauma memories, linking them to memory for the trauma and pathological facilitation of post-traumatic recall.

Multifunctional molecules bearing different dyes, such as donor-acceptor systems, synthesized by covalent chemistry have provided a wealth of information on the fundamental nature of electron and energy transfer in organic systems and there is a growing literature on the materials properties of dyes on surfaces. However, in the vast majority of cases the synthetic costs of producing these covalently bound systems prohibit them from deployment in commercially viable devices. Thus, to achieve both the needed multifunctionality and to bring the synthetic costs in line with potential commercialization, supramolecular approaches to the formation of photonic materials can be exploited. This perspective focuses on porphyrinoids as exemplary dyes, but the concepts and design principles extend to other chromophores.

Interaction of pathogens with cells of the immune system results in activation of inflammatory gene expression. This response, although vital for immune defence, is frequently deleterious to the host due to the exaggerated production of inflammatory proteins. The scope of inflammatory responses reflects the activation state of signalling proteins upstream of inflammatory genes as well as signal-induced assembly of nuclear chromatin complexes that support mRNA expression(1-4). Recognition of post-translationally modified histones by nuclear proteins that initiate mRNA transcription and support mRNA elongation is a critical step in the regulation of gene expression(5-10). Here we present a novel pharmacological approach that targets inflammatory gene expression by interfering with the recognition of acetylated histones by the bromodomain and extra terminal domain (BET) family of proteins. We describe a synthetic compound (I-BET) that by 'mimicking' acetylated histones disrupts chromatin complexes responsible for the expression of key inflammatory genes in activated macrophages, and confers protection against lipopolysaccharide-induced endotoxic shock and bacteria-induced sepsis. Our findings suggest that synthetic compounds specifically targeting proteins that recognize post-translationally modified histones can serve as a new generation of immunomodulatory drugs.

The G protein-coupled receptor (GPCR), chemokine CXC-type receptor 4 (CXCR4), and its ligand, CXCL12, mediate the retention of polymorphonuclear neutrophils (PMNs) and hematopoietic stem and progenitor cells (HSPCs) in the bone marrow. Agents that disrupt CXCL12-mediated chemoattraction of CXCR4-expressing cells mobilize PMNs and HSPCs into the peripheral circulation and are therapeutically useful for HSPC collection before autologous bone marrow transplantation (ABMT). Our aim was to develop unique CXCR4-targeted therapeutics using lipopeptide GPCR modulators called pepducins. A pepducin is a synthetic molecule composed of a peptide derived from the amino acid sequence of one of the intracellular (IC) loops of a target GPCR coupled to a lipid tether. We prepared and screened a small CXCR4-targeted pepducin library and identified several pepducins with in vitro agonist activity, including ATI-2341, whose peptide sequence derives from the first IC loop. ATI-2341 induced CXCR4-and G protein-dependent signaling, receptor internalization, and chemotaxis in CXCR4-expressing cells. It also induced dose-dependent peritoneal recruitment of PMNs when administered i.p. to mice. However, when administered systemically by i.v. bolus, ATI-2341 acted as a functional antagonist and dose-dependently mediated release of PMNs from the bone marrow of both mice and cynomolgus monkeys. ATI-2341-mediated release of granulocyte/macrophage progenitor cells from the bone marrow was confirmed by colony-forming assays. We conclude that ATI-2341 is a potent and efficacious mobilizer of bone marrow PMNs and HSPCs and could represent a previously undescribed therapeutic approach for the recruitment of HSPCs before ABMT.

Drug addiction remains a substantial health issue with limited treatment options currently available. Despite considerable advances in the understanding of human genetic architecture, the genetic underpinning of complex disorders remains elusive. On the basis of our current understanding of neurobiology, numerous candidate genes have been implicated in the etiology and response to treatment for different addictions. Genome-wide association (GWA) studies have also identified novel targets. However, replication of these studies is often lacking, and this complicates interpretation. The situation is expected to improve as issues such as phenotypic characterization, the apparent "missing heritability," the identification of functional variants, and possible gene-environment (G x E) interactions are addressed. In addition, there is growing evidence that genetic information can be useful in refining the choice of addiction treatment. As genetic testing becomes more common in the practice of medicine, a variety of ethical and practical challenges, some of which are unique to drug addiction, will also need to be considered.