The rockefeller university

Psoriasis vulgaris is a chronic inflammatory skin disease that results from the complex interplay between keratinocytes, dendritic cells, and T cells. Keratinocytes trigger innate and adaptive immune responses. Dermal myeloid dendritic cells regulate T cell activation and production of cytokines and chemokines that amplify inflammation. Most of the psoriatic T cells discretely produce interferon-gamma, interleukin (IL)-17, and IL-22. The initiation phase of psoriasis involves Toll-like receptors, antimicrobial peptide LL37, and plasmacytoid dendritic cells. Keratinocytes are the main cutaneous cell type expressing IL-17 receptors and hence the immune circuit is amplified by keratinocytes upregulating mRNAs for a range of inflammatory products.

Background: Drug addiction is influenced by genetic factors. Aim: To determine if genetic variants in the serotonergic and adrenergic pathways are associated with heroin and/or cocaine addiction. Subjects & methods: The study examined 140 polymorphisms in 19 genes in 1855 subjects with predominantly European or African ancestries. Results: A total of 38 polymorphisms (13 genes) showed nominal associations, including novel associations in S100A10 (p11) and SLC18A2 (VMAT2). The association of HTR3B SNP rs11606194 with heroin addiction in the European ancestry subgroup remained significant after correction for multiple testing (p(corrected) = 0.04). Conclusion: The study strengthens our previous findings of association of polymorphisms in HTR3A, HTR3B and ADRA1A. The study suggests partial overlap in genetic susceptibility between populations of different ancestry and between heroin and cocaine addiction.

Abuse and addiction to prescription opioids such as oxycodone (a short-acting Mu opioid receptor (MOP-r) agonist) in adolescence is a pressing public health issue. We have previously shown differences in oxycodone self-administration behaviors between adolescent and adult C57BL/6J mice and expression of striatal neurotransmitter receptor genes, in areas involved in reward. In this study, we aimed to determine whether oxycodone self-administration differentially affects genes regulating synaptic plasticity in the hippocampus of adolescent compared to adult mice, since the hippocampus may be involved in learning aspects associated with chronic drug self administration. Hippocampus was isolated for mRNA analysis from mice that had self administered oxycodone (0.25 mg/kg/infusion) 2 h/day for 14 consecutive days or from yoked saline controls. Gene expression was analyzed with real-time polymerase chain reaction (PCR) using a commercially available "synaptic plasticity'' PCR array containing 84 genes. We found that adolescent and adult control mice significantly differed in the expression of several genes in the absence of oxycodone exposure, including those coding for mitogenactivated protein kinase, calcium/calmodulin-dependent protein kinase II gamma subunit, glutamate receptor, ionotropic AMPA2 and metabotropic 5. Chronic oxycodone self administration increased proviral integration site 1 (Pim1) and thymoma viral proto-oncogene 1 mRNA levels compared to controls in both age groups. Both Pim1 and cadherin 2 mRNAs showed a significant combined effect of Drug Condition and Age x Drug Condition. Furthermore, the mRNA levels of both cadherin 2 and cAMP response element modulators showed an experiment-wise significant difference between oxycodone and saline control in adult but not in adolescent mice. Overall, this study demonstrates for the first time that chronic oxycodone self-administration differentially alters synaptic plasticity gene expression in the hippocampus of adolescent and adult mice. (C) 2014 Published by Elsevier Ltd. on behalf of IBRO.

Differential cross sections for the production of Z bosons or off-shell photons gamma* in association with jets are measured in proton-antiproton collisions at center-of-mass energy root s = 1.96 TeV using the full data set collected with the Collider Detector at Fermilab in Tevatron run II and corresponding to 9.6 fb(-1) of integrated luminosity. Results include first measurements at CDF of differential cross sections in events with a Z/gamma* boson and three or more jets, the inclusive cross section for production of Z/gamma* and four or more jets, and cross sections as functions of various angular observables in lower jet-multiplicity final states. Measured cross sections are compared to several theoretical predictions.

Arc is a unique immediate early gene whose expression is induced as synapses are being modified during learning. The uniqueness comes from the fact that newly synthesized Arc mRNA is rapidly transported throughout dendrites where it localizes near synapses that were recently activated. Here, we summarize aspects of Arc mRNA translation in dendrites in vivo, focusing especially on features of its expression that are paradoxical or that donot fit in with current models of how Arc protein operates. Findings from in vivo studies that donot quite fit include: (1) Following induction of LIP in vivo, Arc mRNA and protein localize near active synapses, but are also distributed throughout dendrites. In contrast, Arc mRNA localizes selectively near active synapses when stimulation is continued as Arc mRNA is transported into dendrites; (2) Strong induction of Arc expression as a result of a seizure does not lead to a rundown of synaptic efficacy in vivo as would be predicted by the hypothesis that high levels of Arc cause glutamate receptor endocytosis and LTD. (3) Arc protein is synthesized in the perinuclear cytoplasm rapidly after transcriptional activation, indicating that at least a pool of Arc mRNA is not translationally repressed to allow for dendritic delivery; (4) Increases in Arc mRNA in dendrites are not paralleled by increases in levels of exon junction complex (EJC) proteins. These results of studies of mRNA trafficking in neurons in vivo provide a new perspective on the possible roles of Arc in activity-dependent synaptic modifications.

As the central organ of stress and adaptation to stressors, the brain plays a pivotal role in behavioral and physiological responses that may lead to successful adaptation or to pathophysiology and mental and physical disease. In this context, resilience can be defined as "achieving a positive outcome in the face of adversity". Underlying this deceptively simple statement are several questions; first, to what extent is this ability limited to those environments that have shaped the individual or can it be more flexible; second, when in the life course does the brain develop capacity for flexibility for adapting positively to new challenges; and third, can such flexibility be instated in individuals where early life experiences have limited that capacity? Brain architecture continues to show plasticity throughout adult life and studies of gene expression and epigenetic regulation reveal a dynamic and ever-changing brain. The goal is to recognize those biological changes that underlie flexible adaptability, and to recognize gene pathways, epigenetic factors and structural changes that indicate lack of resilience leading to negative outcomes, particularly when the individual is challenged by new circumstances. Early life experiences determine individual differences in such capabilities via epigenetic pathways and laying down of brain architecture that determine the later capacity for flexible adaptation or the lack thereof. Reactivation of such plasticity in individuals lacking such resilience is a new challenge for research and practical application. Finally, sex differences in the plasticity of the brain are often overlooked and must be more fully investigated.

After a brief discussion and evaluation of Fisher's additive polygenic inheritance model, a few other approaches to polygenic inheritance are discussed, notably the polygenic threshold model. A literature review of applications of such models in human genetics is presented, and a simple approach, based on a finite polygenic model, is developed in detail. The fit of the model to recurrence risks in schizophrenia is discussed. (C) 2016 S. Karger AG, Basel

Colorectal cancer primarily metastasizes to the liver and globally kills over 600,000 people annually. By functionally screening 661 microRNAs (miRNAs) in parallel during liver colonization, we have identified miR-551a and miR-483 as robust endogenous suppressors of liver colonization and metastasis. These miRNAs convergently target creatine kinase, brain-type (CKB), which phosphorylates the metabolite creatine, to generate phosphocreatine. CKB is released into the extracellular space by metastatic cells encountering hepatic hypoxia and catalyzes production of phosphocreatine, which is imported through the SLC6A8 transporter and used to generate ATP-fueling metastatic survival. Combinatorial therapeutic viral delivery of miR-551a and miR-483-5p through single-dose adeno-associated viral (AAV) delivery significantly suppressed colon cancer metastasis, as did CKB inhibition with a small-molecule inhibitor. Importantly, human liver metastases express higher CKB and SLC6A8 levels and reduced miR-551a/miR-483 levels relative to primary tumors. We identify the extracellular space as an important compartment for malignant energetic catalysis and therapeutic targeting.

Antibodies developed during HIV-1 infection lose efficacy as the viral spike mutates. We postulated that anti-HIV-1 antibodies primarily bind monovalently because HIV's low spike density impedes bivalent binding through inter-spike crosslinking, and the spike structure prohibits bivalent binding through intra-spike crosslinking. Monovalent binding reduces avidity and potency, thus expanding the range of mutations permitting antibody evasion. To test this idea, we engineered antibody-based molecules capable of bivalent binding through intra-spike crosslinking. We used DNA as a "molecular ruler'' to measure intra-epitope distances on virion-bound spikes and construct intra-spike crosslinking molecules. Optimal bivalent reagents exhibited up to 2.5 orders of magnitude increased potency (>100-fold average increases across virus panels) and identified conformational states of virion-bound spikes. The demonstration that intra-spike crosslinking lowers the concentration of antibodies required for neutralization supports the hypothesis that low spike densities facilitate antibody evasion and the use of molecules capable of intra-spike crosslinking for therapy or passive protection.