The rockefeller university

A fundamental property of cells of the innate immune system is their ability to elicit a transcriptional response to a microbial stimulus or danger signal with a high degree of cell type and stimulus specificity. The selective response activates effector pathways to control the insult and plays a central role in regulating adaptive immunity through the differential regulation of cytokine genes. Selectivity is dictated by signaling pathways and their transcription factor targets. However, a growing body of evidence supports models in which different subsets of genes exhibit distinct chromatin features that play active roles in shaping the response. Chromatin also participates in innate memory mechanisms that can promote tolerance to a stimulus or prime cells for a more robust response. These findings have generated interest in the capacity to modulate chromatin regulators with small-molecule compounds for the treatment of diseases associated with innate or adaptive immunity.

According to the literature, intense pulsed light (IPL) represents a versatile tool in the treatment of some dermatological conditions (i.e., pigmentation disorders, hair removal, and acne), due to its wide range of wavelengths. The authors herein report on 58 unconventional but effective uses of IPL in several cutaneous diseases, such as rosacea (10 cases), port-wine stain (PWS) (10 cases), disseminated porokeratosis (10 cases), pilonidal cyst (3 cases), seborrheic keratosis (10 cases), hypertrophic scar (5 cases) and keloid scar (5 cases), Becker's nevus (2 cases), hidradenitis suppurativa (2 cases), and sarcoidosis (1 case). Our results should suggest that IPL could represent a valid therapeutic support and option by providing excellent outcomes and low side effects, even though it should be underlined that the use and the effectiveness of IPL are strongly related to the operator's experience (acquired by attempting at least one specific course on the use of IPL and one-year experience in a specialized centre). Moreover, the daily use of these devices will surely increase clinical experience and provide new information, thus enhancing long-termresults and improving IPL effectiveness.

Background: The stability and propagation of hepatitis C virus (HCV) is dependent on a functional interaction between the HCV genome and liver-expressed microRNA-122 (miR-122). Miravirsen is a locked nucleic acid-modified DNA phosphorothioate antisense oligonucleotide that sequesters mature miR-122 in a highly stable heteroduplex, thereby inhibiting its function. Methods: In this phase 2a study at seven international sites, we evaluated the safety and efficacy of miravirsen in 36 patients with chronic HCV genotype 1 infection. The patients were randomly assigned to receive five weekly subcutaneous injections of miravirsen at doses of 3 mg, 5 mg, or 7 mg per kilogram of body weight or placebo over a 29-day period. They were followed until 18 weeks after randomization. Results: Miravirsen resulted in a dose-dependent reduction in HCV RNA levels that endured beyond the end of active therapy. In the miravirsen groups, the mean maximum reduction in HCV RNA level (log10 IU per milliliter) from baseline was 1.2 (P = 0.01) for patients receiving 3 mg per kilogram, 2.9 (P = 0.003) for those receiving 5 mg per kilogram, and 3.0 (P = 0.002) for those receiving 7 mg per kilogram, as compared with a reduction of 0.4 in the placebo group. During 14 weeks of follow-up after treatment, HCV RNA was not detected in one patient in the 5-mg group and in four patients in the 7-mg group. We observed no dose-limiting adverse events and no escape mutations in the miR-122 binding sites of the HCV genome. Conclusions: The use of miravirsen in patients with chronic HCV genotype 1 infection showed prolonged dose-dependent reductions in HCV RNA levels without evidence of viral resistance. (Funded by Santaris Pharma; ClinicalTrials.gov number, NCT01200420.) (C) 2013 European Association for the Study of the Liver. Published by Elsevier B. V. All rights reserved.

Aquatic organisms have to deal with different hydrodynamic regimes, depending on their size and speed during locomotion. The pea crab swims by beating the third and fourth pereiopod on opposite sides as pairs. Using particle tracking velocimetry and high-speed video recording, we quantify the kinematics and vortices in the wake of the pea crab. Where the proximal parts of the pereiopods beat in antiphase, their distal parts show an overlapping beat period. By using four instead of two limbs for propulsion, an uninterrupted forward movement is established, reducing the influence of the acceleration reaction. Before body speed is maximal, force generation of the pereiopods seems most active when passing an orthogonal position with the body.

Mutagenesis drives natural selection. In the lab, mutations allow gene function to be deciphered. C. elegans is highly amendable to functional genetics because of its short generation time, ease of use, and wealth of available gene-alteration techniques. Here we provide an overview of historical and contemporary methods for mutagenesis in C. elegans, and discuss principles and strategies for forward (genome-wide mutagenesis) and reverse (target-selected and gene-specific mutagenesis) genetic studies in this animal.

Mechanisms controlling release of brain-derived neurotrophic factor (BDNF) in the mesolimbic dopamine reward pathway remain unknown. We report that phasic optogenetic activation of this pathway increases BDNF amounts in the nucleus accumbens (NAc) of socially stressed mice but not of stress-naive mice. This stress gating of BDNF signaling is mediated by corticotrophin-releasing factor (CRF) acting in the NAc. These results unravel a stress context-detecting function of the brain's mesolimbic circuit.

New insights in the study of virus and host biology in the context of viral infection are made possible by the development of model systems that faithfully recapitulate the in vivo viral life cycle. Standard tissue culture models lack critical emergent properties driven by cellular organization and in vivo-like function, whereas animal models suffer from limited susceptibility to relevant human viruses and make it difficult to perform detailed molecular manipulation and analysis. Tissue engineering techniques may enable virologists to create infection models that combine the facile manipulation and readouts of tissue culture with the virus-relevant complexity of animal models. Here, we review the state of the art in tissue engineering and describe how tissue engineering techniques may alleviate some common shortcomings of existing models of viral infection, with a particular emphasis on hepatotropic viruses. We then discuss possible future applications of tissue engineering to virology, including current challenges and potential solutions.

A general approach is presented for the extraction of a classifier of disease risk that is latent in large scale disease/control databases. Novel features are the following: (1) a data reorganization into a regularized standard form that emphasizes individual alleles instead of the single nucleotide polymorphism (Snp) allele pair to which they belong; (2) from this a procedure that significantly enhances the discovery of high value genomic loci; (3) an investigative analysis based on the hypothesis that disease represents a very small signal (small signal-to-noise) that is latent in the data. The resulting analyses applied to the FUSION T2D database leads to the polling of thousands of genomic loci to classify disease. This large genomic kernel of loci is shared by non-diabetics at nearly the same high level; but a small well defined separation exists and it is speculated that this might be due to unconventional disease mechanisms. Another analysis demonstrates that the FUSION database size limits its disease predictability, and only one third of the resulting classifier loci are estimated to relate to T2D. The remainder is associated with hidden features that might contrast the disease and control populations and that more data would eliminate.

Tumor necrosis factor a (TNF) is a proinflammatory cytokine with established roles in host defense and immune system organogenesis. We studied TNF function and found a previously unidentified physiological function that extends its effect beyond the host into the developing offspring. A partial or complete maternal TNF deficit, specifically in hematopoietic cells, resulted in reduced milk levels of the chemokines IP-10, MCP-1, MCP-3, MCP-5 and MIP-1 beta, which in turn augmented offspring postnatal hippocampal proliferation, leading to improved adult spatial memory in mice. These effects were reproduced by the postpartum administration of a clinically used anti-TNF agent. Chemokines, fed to suckling pups of TNF-deficient mothers, restored both postnatal proliferation and spatial memory to normal levels. Our results identify a TNF-dependent `lactrocrine pathway that programs offspring hippocampal development and memory. The level of ambient TNF is known to be downregulated by physical activity, exercise and adaptive stress. We propose that the maternal TNF milk chemokine pathway evolved to promote offspring adaptation to post-weaning environmental challenges and competition.

The Cytotoxin associated gene A (CagA) protein of Helicobacter pylori is associated with increased virulence and risk of cancer. Recent proteomic studies have demonstrated an association of CagA with the human tumor suppressor Apoptosis-stimulating Protein of p53-2 (ASPP2). We present here a genetic, biochemical, and structural analysis of CagA with ASPP2. Domain delineation of the 120-kDa CagA protein revealed a stable N-terminal subdomain that was used in a yeast two-hybrid screen that identified the proline-rich domain of ASPP2 as a host cellular target. Biochemical experiments confirm this interaction. The cocrystal structure to 2.0-angstrom resolution of this N-terminal subdomain of CagA with a 7-kDa proline-rich sequence of ASPP2 reveals that this domain of CagA forms a highly specialized three-helix bundle, with large insertions in the loops connecting the helices. These insertions come together to form a deep binding cleft for a highly conserved 20-aa peptide of ASPP2. ASPP2 forms an extended helix in this groove of CagA, burying more than 1,000 angstrom(2) of surface area. This interaction is disrupted in vitro and in vivo by structure-based, loss-of-contact point mutations of key residues in either CagA or ASPP2. Disruption of CagA and ASPP2 binding alters the function of ASPP2 and leads to the decreased survival of H. pylori-infected cells.