The rockefeller university

Objective: Infliximab is a human/mouse chimeric anti-tumour necrosis factor (TNF)-alpha antibody that is effective in the management of psoriasis. Anti-TNF treatments may reactivate latent tuberculosis infection (LTBI); therefore, screening for LTBI is mandatory before starting any anti-TNF-alpha therapy. The aim of this study is to evaluate the usefulness of the QuantiFERON (R)-TB Gold (QFT-G) test in psoriatic patients under treatment with infliximab. Research design and methods: A retrospective study had been performed on patients affected by psoriasis who had been treated with infliximab from 2003 to 2012 at a single centre. Main outcomes measures: QFT-G was tested by a standard TB enzyme-linked immunosorbent assay, based on detection of interferon-gamma release from sensitized leucocytes exposed to the synthetic Mycobacterium tuberculosis antigens at baseline and every 6 months until the end of treatment. Results: A total of 140 patients were included. At baseline, 7 QFT-G tests were positive and 133 tests were negative. Of the 133 patients, 11 (8%) who were negative at baseline became QFT-G test positive during treatment. Of those 11 patients, 5 had a reversion during treatment. Of the 133 patients, 122 (92%) who were negative at baseline remained negative. Conclusions: It was found that the development of positive QFT-G tests, observed in 8% treated with infliximab, was not associated with pulmonary or extra-pulmonary tuberculosis.

Background: IL-17 is the defining cytokine of the Th17, Tc17, and gamma delta T cell populations that plays a critical role in mediating inflammation and autoimmunity. Psoriasis vulgaris is an inflammatory skin disease mediated by Th1 and Th17 cytokines with relevant contributions of IFN-gamma, TNF-alpha, and IL-17. Despite the pivotal role IL-17 plays in psoriasis, and in contrast to the other key mediators involved in the psoriasis cytokine cascade that are capable of inducing broad effects on keratinocytes, IL-17 was demonstrated to regulate the expression of a limited number of genes in monolayer keratinocytes cultured in vitro. Methodology/Principal Findings: Given the clinical efficacy of anti-IL-17 agents is associated with an impressive reduction in a large set of inflammatory genes, we sought a full-thickness skin model that more closely resemble in vivo epidermal architecture. Using a reconstructed human epidermis (RHE), IL-17 was able to upregulate 419 gene probes and downregulate 216 gene probes. As possible explanation for the increased gene induction in the RHE model is that C/CAAT-enhancer-binding proteins (C/EBP) -beta, the transcription factor regulating IL-17-responsive genes, is expressed preferentially in differentiated keratinocytes. Conclusions/Significance: The genes identified in IL-17-treated RHE are likely relevant to the IL-17 effects in psoriasis, since ixekizumab (anti-IL-17A agent) strongly suppressed the "RHE" genes in psoriasis patients treated in vivo with this IL-17 antagonist.

The blood-brain barrier (BBB) is a dynamic structure that maintains the homeostasis of the brain and thus proper neurological functions. BBB compromise has been found in many pathological conditions, including neuroinflammation. Monocyte chemoattractant protein-1 (MCP1), a chemokine that is transiently and significantly up-regulated during inflammation, is able to disrupt the integrity of BBB and modulate the progression of various diseases, including excitotoxic injury and hemorrhage. In this review, we first introduce the biochemistry and biology of MCP1, and then summarize the effects of MCP1 on BBB integrity as well as individual BBB components.

Hepatitis C virus (HCV) infection can result in viral chronicity or clearance. Although host genetics and particularly genetic variation in the interferon lambda (IFNL) locus are associated with spontaneous HCV clearance and treatment success, the mechanisms guiding these clinical outcomes remain unknown. Using a laser capture microdissection-driven unbiased systems virology approach, we isolated and transcriptionally profiled HCV-infected and adjacent primary human hepatocytes (PHHs) approaching single-cell resolution. An innate antiviral immune signature dominated the transcriptional response but differed in magnitude and diversity between HCV-infected and adjacent cells. Molecular signatures associated with more effective antiviral control were determined by comparing donors with high and low infection frequencies. Cells from donors with clinically unfavorable IFNL genotypes were infected at a greater frequency and exhibited dampened antiviral and cell death responses. These data suggest that early virus-host interactions, particularly host genetics and induction of innate immunity, critically determine the outcome of HCV infection.

In the first phase of this research, we conducted, audio-recorded, and transcribed seven focus groups with more than 50 English- or Spanish-speaking women of childbearing age. Qualitative analysis revealed the following themes: (1) expectation that participation would involve relationships based on trust that is built over time and impacted by cultural factors; (2) perceived characteristics of research staff that would help facilitate the development of trusting relationships; (3) perceptions about the location of the visits that may affect trust; (4) perceptions of a research study and trust for the institution conducting the study may affect trust; (5) connecting the study to larger communities, including faith communities, could affect trust and willingness to participate. In the second phase of this research, we conducted, recorded, transcribed, and analyzed interviews with leaders from diverse faith communities to explore the potential for research partnerships between researchers and faith communities. In addition to confirming themes identified in focus groups, faith leaders described an openness to research partnerships between the university and faith communities and considerations for the formation of these partnerships. Faith leaders noted the importance of finding common ground with researchers, establishing and maintaining trusting relationships, and committing to open, bidirectional communication.

The nematode Caenorhabditis elegans can use olfaction to discriminate among different kinds of bacteria, its major food source. We asked how natural genetic variation contributes to choice behavior, focusing on differences in olfactory preference behavior between two wild-type C. elegans strains. The laboratory strain N2 strongly prefers the odor of Serratia marcescens, a soil bacterium that is pathogenic to C. elegans, to the odor of Escherichia coli, a commonly used laboratory food source. The divergent Hawaiian strain CB4856 has a weaker attraction to Serratia than the N2 strain, and this behavioral difference has a complex genetic basis. At least three quantitative trait loci (QTLs) from the CB4856 Hawaii strain (HW) with large effect sizes lead to reduced Serratia preference when introgressed into an N2 genetic background. These loci interact and have epistatic interactions with at least two antagonistic QTLs from HW that increase Serratia preference. The complex genetic architecture of this C. elegans trait is reminiscent of the architecture of mammalian metabolic and behavioral traits.

Posttraumatic stress disorder (PTSD) co-occurs highly with substance use disorders (SUDs), yet the neurobiological basis for this comorbid relationship remains unclear. PTSD and SUDs result in similar pathological states including impulsive behavior, reward deficiency, and heightened stress sensitivity. Hence, PTSD and SUD may depend on overlapping dysfunctional neurocircuitry. Here we provide a short overview of the relationship between comorbid PTSD and SUD, as well as the potential role of select neurotransmitter systems that may underlie enhanced vulnerability to drug abuse in the context of PTSD. (C) 2013 Elsevier Inc. All rights reserved.

A collection of alpha IIb beta 3 integrin receptor antagonists possessing a unique MIDAS metal ion displacement mechanism of action is presented. Insight into these agents' structure- activity relationships, binding modality, and pharmacokinetic and pharmacodynamic profiles highlight the potential of these small molecule ion displacement ligands as attractive candidates for clinical development. Published by Elsevier Ltd.

In social species, the phenotype and fitness of an individual depend in part on the genotype of its social partners. However, how these indirect genetic effects affect genotype fitness in competitive situations is poorly understood in animal societies. We therefore studied phenotypic plasticity and fitness of two clones of the ant Cerapachys biroi in monoclonal and chimeric colonies. Here we show that, while clone B has lower fitness in isolation, surprisingly, it consistently outcompetes clone A in chimeras. The reason is that, in chimeras, clone B produces more individuals specializing in reproduction rather than cooperative tasks, behaving like a facultative social parasite. A cross-fostering experiment shows that the proportion of these individuals depends on intergenomic epistasis between larvae and nursing adults, explaining the flexible allocation strategy of clone B. Our results suggest that intergenomic epistasis can be the proximate mechanism for social parasitism in ants, revealing striking analogies between social insects and social microbes.

We motivate a measurement of various ratios of W and Z cross sections at the Large Hadron Collider (LHC) at large values of the boson transverse momentum (p(T) greater than or similar to M-W,M-Z). We study the dependence of predictions for these cross-section ratios on the multiplicity of associated jets, the boson p(T) and the LHC centre-of-mass energy. We present the flavour decomposition of the initial-state partons and an evaluation of the theoretical uncertainties. We show that the W+/W- ratio is sensitive to the up-quark to down-quark ratio of parton distribution functions (PDFs), while other theoretical uncertainties are negligible, meaning that a precise measurement of the W+/W- ratio at large boson p(T) values could constrain the PDFs at larger momentum fractions x than the usual inclusive W charge asymmetry. The W+/-/Z ratio is insensitive to PDFs and most other theoretical uncertainties, other than possibly electroweak corrections, and a precise measurement will therefore be useful in validating theoretical predictions needed in data-driven methods, such as using W (-> l nu)+ jets events to estimate the Z (-> nu(nu) over bar)+ jets background in searches for new physics at the LHC. The differential W and Z cross sections themselves, d sigma/dp(T), have the potential to constrain the gluon distribution, provided that theoretical uncertainties from higher-order QCD and electroweak corrections are brought under control, such as by inclusion of anticipated next-to-next-to-leading order QCD corrections.