The rockefeller university

The CoPanFlu-France cohort of households was set up in 2009 to study the risk factors for infection by the pandemic influenza virus (H1N1pdm) in the French general population. The authors developed an integrative data-driven approach to identify individual, collective and environmental factors associated with the post-seasonal serological H1N1pdm geometric mean titer, and derived a nested case-control analysis to identify risk factors for infection during the first season. This analysis included 1377 subjects (601 households). The GMT for the general population was 47.1 (95% confidence interval (CI): 45.1, 49.2). According to a multivariable analysis, pandemic vaccination, seasonal vaccination in 2009, recent history of influenza-like illness, asthma, chronic obstructive pulmonary disease, social contacts at school and use of public transports by the local population were associated with a higher GMT, whereas history of smoking was associated with a lower GMT. Additionall!

Mammalian Quaking (QKI) and its Caenorhabditis elegans homolog, GLD-1 (defective in germ line development), are evolutionarily conserved RNA-binding proteins, which post-transcriptionally regulate target genes essential for developmental processes and myelination. We present X-ray structures of the STAR (signal transduction and activation of RNA) domain, composed of Qua1, K homology (KH), and Qua2 motifs of QKI and GLD-1 bound to high-affinity in vivo RNA targets containing YUAAY RNA recognition elements (RREs). The KH and Qua2 motifs of the STAR domain synergize to specifically interact with bases and sugar-phosphate backbones of the bound RRE. Qua1-mediated homodimerization generates a scaffold that enables concurrent recognition of two RREs, thereby plausibly targeting tandem RREs present in many QKI-targeted transcripts. Structure-guided mutations reduced QKI RNA-binding affinity in vitro and in vivo, and expression of QKI mutants in human embryonic kidney cells (HEK2!

Finding the first time a fluctuating quantity reaches a given boundary is a deceptively simple-looking problem of vast practical importance in physics, biology, chemistry, neuroscience, economics, and industrial engineering. Problems in which the bound to be traversed is itself a fluctuating function of time include widely studied problems in neural coding, such as neuronal integrators with irregular inputs and internal noise. We show that the probability p(t) that a Gauss-Markov process will first exceed the boundary at time t suffers a phase transition as a function of the roughness of the boundary, as measured by its Holder exponent H. The critical value occurs when the roughness of the boundary equals the roughness of the process, so for diffusive processes the critical value is H-c = 1/2. For smoother boundaries, H > 1/2, the probability density is a continuous function of time. For rougher boundaries, H < 1/2, the probability is concentrated on a Cantor-like set of !

An adenoviral vector enhances and modifies immune responses by targeting antigen to DCs.Replication-defective adenoviral vectors have emerged as promising vaccine candidates for diseases relying on strong CD8 T-cell responses for protection. In this study, we modified a non-replicative adenoviral vector to selectively deliver, in situ, an encoded ovalbumin (OVA) model antigen to dendritic cells (DCs). Efficient uptake and presentation of OVA was achieved through fusion of the antigen to a single-chain antibody directed against DEC205, an endocytic receptor expressed on DCs. The immunogenicity of the vaccine was thereby enhanced as demonstrated by elevated antibody levels and increased T-cell responses after low-dose vaccination with 10(7) viral particles compared with a non-targeted control. Nevertheless, after immunization with higher doses of the targeted vaccine, the capacity of vaccine-induced CD8 T cells to produce the cytokine IL-2 was diminished and the CD8 T-cell !

Background Adaptation is key to survival. An organism must adapt to environmental challenges in order to be able to thrive in the environment in which they find themselves. Resilience can be thought of as a measure of the ability of an organism to adapt, and to withstand challenges to its stability. In higher animals, the brain is a key player in this process of adaptation and resilience, and through a process known as allostasis can obtain stability through change; protecting homeostasis in the face of stressors in the environment. Mediators of allostasis, such as glucocorticoids, can cause changes in the structure and function of neural circuits, clearly impacting behavior. How developmental stage interacts with stress and leads to long-lasting changes is a key question addressed in this review. Scope and Methods We discuss the concept of allostasis, its role in resilience, the neural and physiological systems mediating these responses, the modulatory role of developmen!

Apoptosis has been implicated in sperm chromatin damage; it is unclear whether apoptosis occurs through cytoplasmic or mitochondrial pathways. Sperm has minimal volume of cytoplasm but prominent mitochondria. Propidium iodide (PI), annexin V (AV), DiIC(1)(5) and proprietary fluorochrome (PF-1) were used to investigate apoptosis activation in human sperm using multichannel flow cytometry. There was a time-dependent increase in staining of spermatozoa with both AV and PF-1 and decrease in mitochondrial staining with DiIC(1)(5). These results strongly suggest that the drop in mitochondrial potential precedes changes in membrane phospholipids, and thus suggest apoptotic activation through mitochondrial pathway in human spermatozoa. (C) 2012, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

Inhibition of Sonic hedgehog (Shh) signaling is of great clinical interest. Here we exploit Hedgehog acyltransferase (Hhat)-mediated Shh palmitoylation, a modification critical for Shh signaling, as a new target for Shh pathway inhibition. A target-oriented high-throughput screen was used to identify small-molecule inhibitors of Hhat. In cells, these Hhat inhibitors specifically block Shh palmitoylation and inhibit autocrine and paracrine Shh signaling.

Targeted delivery of antigens to dendritic cells (DCs) is a promising vaccination strategy. However, to ensure immunity, the approach depends on coadministration of an adjuvant. Here we ask whether targeting of both adjuvant and antigen to DCs is sufficient to induce immunity. Using a protein ligation method, we develop a general approach for linking the immune stimulant, poly dA:dT (pdA:dT), to a monoclonal antibody (mAb) specific for DEC205 (DEC). We show that DEC-specific mAbs deliver pdA:dT to DCs for the efficient production of type I interferon in human monocyte-derived DCs and in mice. Notably, adaptive T-cell immunity is elicited when mAbs specific for DEC-pdA:dT are used as the activation stimuli and are administered together with a DC-targeted antigen. Collectively, our studies indicate that DCs can integrate innate and adaptive immunity in vivo and suggest that dual delivery of antigen and adjuvant to DCs might be an efficient approach to vaccine development.

Here we report a modified peptide reagent useful for the rapid, native elution of protein complexes containing a Protein-A-tagged component. We tested this reagent for the elution of tagged endogenous protein complexes from yeast (Nup53p/Nup170p dimer; Nup1p/Kap95p/Kap60p trimer; pentameric GINS complex) and bacteria (RNAPII holoenzyme). The majority of the affinity-isolated material is released within 15 minutes under mild conditions, and the elution reagent itself is readily depleted from the elution mixture by simple spin column gel filtration. This reagent is ideal for eluting protein complexes after Protein A / IgG affinity isolation when protease cleavage is not possible or not desirable and facile depletion of the elution reagent is needed.