The rockefeller university

Current approaches for the treatment of psoriasis with anti-cytokine therapies involve the blockade of TNE-alpha, or the p40 sub-unit of IL-12 and IL-23. However, the field is currently evolving to test more selective antagonists, such as anti-IL-23p19, IL-17 and other inflammatory cytokines. Here we discuss our current understanding of dendritic cell and T cell subsets that are relevant in psoriasis, and the pharmacologic strategies that temper their activity in this disease. (C) 2011 Elsevier Inc. All rights reserved.

The economy of space and materials and the continuously increasing demand for advanced functionalities for diverse technologies requires the development of new synthetic methods. Many nanomaterials have enhanced photophysical and photochemical properties in solutions and/or on surfaces, while others have enhanced chemical properties, compared to the atomic, molecular, or bulk phases. Nanomaterials have a wide range of applications in catalysis, sensors, photonic devices, drug delivery, and as therapeutics for treatment of a variety of diseases. Inorganic nanoparticles are widely studied, but the formation of organic nanomaterials via supramolecular chemistry is more recent, and porphyrinoids are at the forefront of this research because of their optical, chemical, and structural properties. The formation of nanoscaled materials via self-assembly and/or self-organization of molecular subunits is an attractive approach because of reduced energy requirements, simpler molecular subunits, and the material can be adaptive to environmental changes. The presence of biocompatible groups such as peptides, carbohydrates, polyglycols and mixtures of these on the periphery of the porphyrin macrocycle may make nanoparticles suitable for therapeutics. This perspective focuses on responsive, non-crystalline porphyrinoid nanomaterials that are less than about 100 nm in all dimensions and used for catalytic or therapeutic applications.

Antiinflammatory drugs achieve their therapeutic actions at least in part by regulation of cytokine formation. A "cytokine hypothesis" of depression is supported by the observation that depressed individuals have elevated plasma levels of certain cytokines compared with healthy controls. Here we investigated a possible interaction between antidepressant agents and antiinflammatory agents on antidepressant-induced behaviors and on p11, a biochemical marker of depressive-like states and antidepressant responses. We found that widely used antiinflammatory drugs antagonize both biochemical and behavioral responses to selective serotonin reuptake inhibitors (SSRIs). In contrast to the levels detected in serum, we found that frontal cortical levels of certain cytokines (e. g., TNF alpha and IFN gamma) were increased by serotonergic antidepressants and that these effects were inhibited by antiinflammatory agents. The antagonistic effect of antiinflammatory agents on antidepressant-induced behaviors was confirmed by analysis of a dataset from a large-scale real-world human study, "sequenced treatment alternatives to relieve depression" (STAR*D), underscoring the clinical significance of our findings. Our data indicate that clinicians should carefully balance the therapeutic benefits of antiinflammatory agents versus the potentially negative consequences of antagonizing the therapeutic efficacy of antidepressant agents in patients suffering from depression.

Cognitive functions that require the prefrontal cortex are highly sensitive to aging in humans, nonhuman primates, and rodents, although the neurobiological correlates of this vulnerability remain largely unknown. It has been proposed that dendritic spines represent the primary site of structural plasticity in the adult brain, and recent data have supported the hypothesis that aging is associated with alterations of dendritic spine morphology and plasticity in prefrontal cortex. However, no study to date has directly examined whether aging alters the capacity for experience-dependent spine plasticity in aging prefrontal neurons. To address this possibility, we used young, middle-aged, and aged rats in a behavioral stress paradigm known to produce spine remodeling in prefrontal cortical neurons. In young rats, stress resulted in dendritic spine loss and altered patterns of spine morphology; in contrast, spines from middle-aged and aged animals were remarkably stable and did not show evidence of remodeling. The loss of stress-induced spine plasticity observed in aging rats occurred alongside robust age-related reductions in spine density and shifts in remaining spine morphology. Together, the data presented here provide the first evidence that experience-dependent spine plasticity is altered by aging in prefrontal cortex, and support a model in which dendritic spines become progressively less plastic in the aging brain.

Hadronic event shapes have been measured in proton-proton collisions at root s = 7 TeV, with a data sample collected with the CMS detector at the LHC. The sample corresponds to an integrated luminosity of 3.2 pb(-1). Event-shape distributions, corrected for detector response, are compared with five models of QCD multijet production. (C) 2011 CERN. Published by Elsevier B.V. All rights reserved.

The dynamic modification of nuclear and cytoplasmic proteins by the monosaccharide N-acetyl-glucosamine (GlcNAc) continues to emerge as an important regulator of many biological processes. Herein we describe the development of an alkynyl-modified GlcNAc analog (GlcNAlk) as a new chemical reporter of O-GlcNAc modification in living cells. This strategy is based on metabolic incorporation of reactive functionality into the GlcNAc biosynthetic pathway. When combined with the Cu(I)-catalyzed [3 + 2] azide-alkyne cycloaddition, this chemical reporter allowed for the robust in-gel fluorescent visualization of O-GlcNAc and affinity enrichment and identification of O-GlcNAc-modified proteins. Using in-gel fluorescence detection, we characterized the metabolic fates of GlcNAlk and the previously reported azido analog, GlcNAz. We confirmed previous results that GlcNAz can be metabolically interconverted to GalNAz, whereas GlcNAlk does not, thereby yielding a more specific metabolic reporter of O-GlcNAc modification. We also used GlcNAlk, in combination with a biotin affinity tag, to identify 374 proteins, 279 of which were not previously reported, and we subsequently confirmed the enrichment of three previously uncharacterized proteins. Finally we confirmed the O-GlcNAc modification of the ubiquitin ligase NEDD4-1, the first reported glycosylation of this protein.

Elucidating physiological and pathogenic functions of protein methyltransferases (PMTs) relies on knowing their substrate profiles. S-adenosyl-L-methionine (SAM) is the sole methyl-donor cofactor of PMTs. Recently, SAM analogues have emerged as novel small-molecule tools to efficiently label PMT substrates. Here we reported the development of a clickable SAM analogue cofactor, 4-propargyloxy-but-2-enyl SAM, and its implementation to label substrates of human protein arginine methyltransferase 1 (PRMT1). In the system, the SAM analogue cofactor, coupled with matched PRMT1 mutants rather than native PRMT1, was shown to label PRMT1 substrates. The transferable 4-propargyloxy-but-2-enyl moiety of the SAM analogue further allowed corresponding modified substrates to be characterized through a subsequent click chemical ligation with an azido-based probe. The SAM analogue, in combination with a rational protein-engineering approach, thus shows potential to label and identify PMT targets in the context of a complex cellular mixture.

We report measurements of direct CP-violating asymmetries in charmless decays of neutral bottom hadrons to pairs of charged hadrons with the upgraded Collider Detector at the Fermilab Tevatron. Using a data sample corresponding to 1 fb(-1) of integrated luminosity, we obtain the first measurements of direct CP violation in bottom strange mesons, A(CP)(B-s(0) -> K- pi(+)) = +0.39 + 0.15(stat) +/- 0.08(syst), and bottom baryons, A(CP)(Lambda(0)(b) -> p pi(-)) = 0.03 +/- 0.17(stat) +/- 0.05(syst) and A(CP)(Lambda(0)(b) -> pK(-)) = +0.37 +/- 0.17(stat) +/- 0.03dsyst_. In addition, we measure CP violation in B-0 -> K+ pi(-) decays with 3.5 sigma significance, A(CP)(B-0 -> K+ pi(-)) = -0.086 +/- 0.023(stat) +/- 0.009(syst), in agreement with the current world average. Measurements of branching fractions of B-s(0) -> K+K- and B-0 -> pi(+)pi- decays are also updated.

Centrioles are self-reproducing organelles that form the core structure of centrosomes or microtubule-organizing centers (MTOCs). However, whether duplication and MTOC organization reflect innate activities of centrioles or activities acquired conditionally is unclear. In this paper, we show that newly formed full-length centrioles had no inherent capacity to duplicate or to organize pericentriolar material (PCM) but acquired both after mitosis through a Plk1-dependent modification that occurred in early mitosis. Modified centrioles initiated PCM recruitment in G1 and segregated equally in mitosis through association with spindle poles. Conversely, unmodified centrioles segregated randomly unless passively tethered to modified centrioles. Strikingly, duplication occurred only in centrioles that were both modified and disengaged, whereas unmodified centrioles, engaged or not, were "infertile," indicating that engagement specifically blocks modified centrioles from reduplication. These two requirements, centriole modification and disengagement, fully exclude unlimited duplication in one cell cycle. We thus uncovered a Plk1-dependent mechanism whereby duplication and segregation are coupled to maintain centriole homeostasis.

Background: DNA-based vaccines have been safe but weakly immunogenic in humans to date. Methods and Findings: We sought to determine the safety, tolerability, and immunogenicity of ADVAX, a multigenic HIV-1 DNA vaccine candidate, injected intramuscularly by in vivo electroporation (EP) in a Phase-1, double-blind, randomized placebo-controlled trial in healthy volunteers. Eight volunteers each received 0.2 mg, 1 mg, or 4 mg ADVAX or saline placebo via EP, or 4 mg ADVAX via standard intramuscular injection at weeks 0 and 8. A third vaccination was administered to eleven volunteers at week 36. EP was safe, well-tolerated and considered acceptable for a prophylactic vaccine. EP delivery of ADVAX increased the magnitude of HIV-1-specific cell mediated immunity by up to 70-fold over IM injection, as measured by gamma interferon ELISpot. The number of antigens to which the response was detected improved with EP and increasing dosage. Intracellular cytokine staining analysis of ELISpot responders revealed both CD4+ and CD8+ T cell responses, with co-secretion of multiple cytokines. Conclusions: This is the first demonstration in healthy volunteers that EP is safe, tolerable, and effective in improving the magnitude, breadth and durability of cellular immune responses to a DNA vaccine candidate.