The rockefeller university

DCs are critical for initiating immunity. The current paradigm in vaccine biology is that DCs migrating from peripheral tissue and classical lymphoid-resident DCs (cDCs) cooperate in the draining LNs to initiate priming and proliferation of T cells. Here, we observe subcutaneous immunity is Fms-like tyrosine kinase 3 ligand (Flt3L) dependent. Flt3L is rapidly secreted after immunization; Flt3 deletion reduces T cell responses by 50%. Flt3L enhances global T cell and humoral immunity as well as both the numbers and antigen capture capacity of migratory DCs (migDCs) and LN-resident cDCs. Surprisingly, however, we find immunity is controlled by cDCs and actively tempered in vivo by migDCs. Deletion of Langerin(+) DC or blockade of DC migration improves immunity. Consistent with an immune-regulatory role, transcriptomic analyses reveals different skin migDC subsets in both mouse and human cluster together, and share immune-suppressing gene expression and regulatory pathways. These data reveal that protective immunity to protein vaccines is controlled by Flt3L-dependent, LN-resident cDCs.

Over the past two decades, disability activists, ethicists, and genetic counselors have examined the moral complexities inherent in prenatal genetic counseling and considered whether and in what ways genetic counseling may negatively affect individuals in the disability community. Many have expressed concerns about defining disability in the context of prenatal decision-making, as the definition presented may influence prenatal choices. In the past few years, publications have begun to explore the responsibility of counselors in presenting a balanced view of disability and have questioned the preparedness of counselors for this duty. Currently, the Accreditation Council for Genetic Counseling (ACGC) only minimally includes disability training in their competencies for genetic counselors, and in their accreditation requirements for training programs. In an attempt to describe current practice, this article details two studies that assess disability training in ABGC-accredited genetic counseling programs. Results from these studies demonstrate that experience with disability is not required by the majority of programs prior to matriculation. Though most program directors agree on the importance of including disability training in the curriculum, there is wide variability in the amount and types of training students receive. Hours dedicated to disability exposure among programs ranged from 10 to 600 hours. Eighty-five percent of program directors surveyed agree that skills for addressing disability should be added to the core competencies. Establishing a set of disability competencies would help to ensure that all graduates have the skills necessary to provide patients with an accurate understanding of disability that facilitates informed decision-making. (C) 2014 Wiley Periodicals, Inc.

Environmental Surveyor of Natural Product Diversity (eSNaPD) is a web-based bioinformatics and data aggregation platform that aids in the discovery of gene clusters encoding both novel natural products and new congeners of medicinally relevant natural products using (meta) genomic sequence data. Using PCR-generated sequence tags, the eSNaPD data-analysis pipeline profiles biosynthetic diversity hidden within (meta) genomes by comparing sequence tags to a reference data set of characterized gene clusters. Sample mapping, molecule discovery, library mapping, and new clade visualization modules facilitate the interrogation of large (meta) genomic sequence data sets for diverse downstream analyses, including, but not limited to, the identification of environments rich in untapped biosynthetic diversity, targeted molecule discovery efforts, and chemical ecology studies. eSNaPD is designed to generate a global atlas of biosynthetic diversity that can facilitate a systematic, sequence-based interrogation of nature's biosynthetic potential.

To identify physiological targets of drugs and bioactive small molecules, we developed an approach, named DrugTargetSeqR, which combines high-throughput sequencing, computational mutation discovery and clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9-based genome editing. We applied this approach to ispinesib and YM155, drugs that have undergone clinical trials as anticancer agents, and uncovered mechanisms of action and identified genetic and epigenetic mechanisms likely to cause drug resistance in human cancer cells.

Ethnopharmacological relevance: Antrodia cinnamomea - a medicinal fungus that is indigenous to Taiwan - has been used as a health tonic by aboriginal tribes and the Asian population. Recent studies indicate that Antrodia cinnamomea extracts exhibit hepato-protective, anti-hypertensive, anti-oxidative, anti-inflammatory, immuno-modulatory, and anti-cancer effects on cultured cells and laboratory animals. This study aims to explore the anti-inflammatory activity of an Antrodia cinnamomea ethanol extract (ACEE) and elucidate its underlying mechanisms of action using lipopolysaccharide (LPS)-primed, ATP-stimulated human THP-1 macrophages. Materials and methods: The effects of ACEE on cell viability were studied using the MTT assay. The expressions of genes, proteins, and pro-inflammatory cytokines were measured by quantitative real-time RT-PCR, Western blotting and ELISA, respectively. The ACEE was further investigated for its effects on reactive oxygen species (ROS) production using ROS detection kit. Results: Our results showed that ACEE significantly inhibits ATP-induced secretion of interleukin-1 beta (IL-1 beta), interleukin-18 (IL-18) and tumor necrosis factor-alpha (TNF-alpha) by LPS-primed macrophages. ACEE also suppresses the transcription and activation of caspase-1, which is responsible for the cleavage and activation of IL-1 beta and IL-18. Of note, ACEE not only reduces expression of the inflammasome component NLRP3 and the purinergic receptor P2X(7)R but also inhibits ATP-induced ROS production and caspase-1 activation. Furthermore, the anti-inflammatory properties of ACEE correlate with reduced activation of the MAPK and NF-kappa B pathways. Conclusion: The results of the present study indicate that Antrodia cinnamomea suppresses the secretion of IL-1 beta and IL-18 associated with inhibition of the NLRP3 inflammasome in macrophages. These findings suggest that ACEE may have therapeutic potential for the treatment of inflammatory diseases. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

Aim This study investigates how founder size may affect local genetic diversity and spatial genetic structure of the invasive American eastern grey squirrel (Sciurus carolinensis) in European areas. It also examines whether dispersal propensity and invasion rate may be related to founder size, genetic diversity and structure. Location Piedmont, Italy; Northern Ireland, Northumberland and East Anglia, UK. Methods Across the invaded range in Europe, 315 squirrels from 14 locations, grouped in four areas, were sampled and examined at 12 highly polymorphic microsatellite loci. We estimated both genetic variation and population structure using AMOVA, Mantel tests and Bayesian analysis. We also estimated migration rates and range expansion rates. Results Genetic diversity varied in accordance with numbers of founders across populations. For instance, the Italian population had the smallest founder size and lowest genetic variability, whereas Northumberland had high values for both. Significant levels of genetic differentiation were observed in all the examined regions. Gene flow, migration and population range expansion rate were also higher in England and Ireland than in Italy. Main conclusions Populations descending from human-mediated releases of few individuals were more genetically depauperate and more differentiated than populations established from a greater number of founders. Propagule pressure is therefore a significant factor in squirrel invasions. There is a trend whereby larger founder sizes were associated with greater genetic diversity, more dispersal, less local genetic differentiation and faster range expansion rate in squirrels. These findings have important management implications for controlling spread rate of squirrels and other invasive species: good practice should prioritize preventing further releases and the merging of genetically distinct populations as these events can augment genetic diversity.

A search for physics beyond the standard model in events with at least three leptons is presented. The data sample, corresponding to an integrated luminosity of 19.5 fb(-1) of proton-proton collisions with center-of-mass energy root s = 8 TeV, was collected by the CMS experiment at the LHC during 2012. The data are divided into exclusive categories based on the number of leptons and their flavor, the presence or absence of an opposite-sign, same-flavor lepton pair (OSSF), the invariant mass of the OSSF pair, the presence or absence of a tagged bottom-quark jet, the number of identified hadronically decaying tau leptons, and the magnitude of the missing transverse energy and of the scalar sum of jet transverse momenta. The numbers of observed events are found to be consistent with the expected numbers from standard model processes, and limits are placed on new-physics scenarios that yield multilepton final states. In particular, scenarios that predict Higgs boson production in the context of supersymmetric decay chains are examined. We also place a 95% confidence level upper limit of 1.3% on the branching fraction for the decay of a top quark to a charm quark and a Higgs boson (t -> cH), which translates to a bound on the left-and right-handed top-charm flavor-violating Higgs Yukawa couplings, lambda(H)(tc) and lambda(H)(ct), respectively, of root vertical bar lambda(H)(tc)vertical bar(2)+ vertical bar lambda(H)(tc)vertical bar(2) < 0.21.

Immunological memory has been regarded as a unique feature of the adaptive immune response mediated in an antigen-specific manner by T and B lymphocytes. However, natural killer (NK) cells and gamma delta T cells, which traditionally are classified as innate immune cells, have been shown in recent studies to have hallmark features of memory cells. Invariant NKT cell (iNKT cell)-mediated antitumor effects indicate that iNKT cells are activated in vivo by vaccination with iNKT cell ligand-loaded CD1d(+) cells, but not by vaccination with unbound NKT cell ligand. In such models, it previously was thought that the numbers of IFN-gamma-producing cells in the spleen returned to the basal level around 1 wk after the vaccination. In the current study, we demonstrate the surprising presence of effector memory-like iNKT cells in the lung. We found long-term antitumor activity in the lungs of mice was enhanced after vaccination with iNKT cell ligand-loaded dendritic cells. Further analyses showed that the KLRG1(+) (Killer cell lectin-like receptor subfamily G, member 1-positive) iNKT cells coexpressing CD49d and granzyme A persisted for several months and displayed a potent secondary response to cognate antigen. Finally, analyses of CDR3 beta by RNA deep sequencing demonstrated that some particular KLRG1(+) iNKT-cell clones accumulated, suggesting the selection of certain T-cell receptor repertoires by an antigen. The current findings identifying effector memory-like KLRG1(+) iNKT cells in the lung could result in a paradigm shift regarding the basis of newly developed extrathymic iNKT cells and could contribute to the future development of antitumor immunotherapy by uniquely energizing iNKT cells.