The de Rham homotopy theory and differential graded category

This paper is a generalization of arXiv:0810.0808. We develop the de Rham homotopy theory of not necessarily nilpotent spaces, using closed dg-categories and equivariant dg-algebras. We see these two algebraic objects correspond in a certain way. We prove an equivalence between the homotopy category of schematic homotopy types and a homotopy category of closed dg-categories. We give a description of homotopy invariants of spaces in terms of minimal models. The minimal model in this context behaves much like the Sullivan's minimal model. We also provide some examples. We prove an equivalence between fiberwise rationalizations and closed dg-categories with subsidiary data.Comment: 47 pages. final version. The final publication is available at http://www.springerlink.co

Superheated Microdrops as Cold Dark Matter Detectors

It is shown that under realistic background considerations, an improvement in Cold Dark Matter sensitivity of several orders of magnitude is expected from a detector based on superheated liquid droplets. Such devices are totally insensitive to minimum ionizing radiation while responsive to nuclear recoils of energies ~ few keV. They operate on the same principle as the bubble chamber, but offer unattended, continuous, and safe operation at room temperature and atmospheric pressure.Comment: 15 pgs, 4 figures include

Homogeneous Bubble Nucleation driven by local hot spots: a Molecular Dynamics Study

We report a Molecular Dynamics study of homogenous bubble nucleation in a Lennard-Jones fluid. The rate of bubble nucleation is estimated using forward-flux sampling (FFS). We find that cavitation starts with compact bubbles rather than with ramified structures as had been suggested by Shen and Debenedetti (J. Chem. Phys. 111:3581, 1999). Our estimate of the bubble-nucleation rate is higher than predicted on the basis of Classical Nucleation Theory (CNT). Our simulations show that local temperature fluctuations correlate strongly with subsequent bubble formation - this mechanism is not taken into account in CNT

To respond or not to respond - a personal perspective of intestinal tolerance

For many years, the intestine was one of the poor relations of the immunology world, being a realm inhabited mostly by specialists and those interested in unusual phenomena. However, this has changed dramatically in recent years with the realization of how important the microbiota is in shaping immune function throughout the body, and almost every major immunology institution now includes the intestine as an area of interest. One of the most important aspects of the intestinal immune system is how it discriminates carefully between harmless and harmful antigens, in particular, its ability to generate active tolerance to materials such as commensal bacteria and food proteins. This phenomenon has been recognized for more than 100 years, and it is essential for preventing inflammatory disease in the intestine, but its basis remains enigmatic. Here, I discuss the progress that has been made in understanding oral tolerance during my 40 years in the field and highlight the topics that will be the focus of future research

Knockdown of MBP-1 in Human Foreskin Fibroblasts Induces p53-p21 Dependent Senescence

MBP-1 acts as a general transcriptional repressor. Overexpression of MBP-1 induces cell death in a number of cancer cells and regresses tumor growth. However, the function of endogenous MBP-1 in normal cell growth regulation remains unknown. To unravel the role of endogenous MBP-1, we knocked down MBP-1 expression in primary human foreskin fibroblasts (HFF) by RNA interference. Knockdown of MBP-1 in HFF (HFF-MBPsi-4) resulted in an induction of premature senescence, displayed flattened cell morphology, and increased senescence-associated beta-galactosidase activity. FACS analysis of HFF-MBPsi-4 revealed accumulation of a high number of cells in the G1-phase. A significant upregulation of cyclin D1 and reduction of cyclin A was detected in HFF-MBPsi-4 as compared to control HFF. Senescent fibroblasts exhibited enhanced expression of phosphorylated and acetylated p53, and cyclin-dependent kinase inhibitor, p21. Further analysis suggested that promyolocytic leukemia protein (PML) bodies are dramatically increased in HFF-MBPsi-4. Together, these results demonstrated that knockdown of endogenous MBP-1 is involved in cellular senescence of HFF through p53-p21 pathway

Acetylation Regulates WRN Catalytic Activities and Affects Base Excision DNA Repair

Background: The Werner protein (WRN), defective in the premature aging disorder Werner syndrome, participates in a number of DNA metabolic processes, and we have been interested in the possible regulation of its function in DNA repair by post-translational modifications. Acetylation mediated by histone acetyltransferases is of key interest because of its potential importance in aging, DNA repair and transcription. Methodology/Principal Findings: Here, we have investigated the p300 acetylation mediated changes on the function of WRN in base excision DNA repair (BER). We show that acetylation of WRN increases in cells treated with methyl methanesulfonate (MMS), suggesting that acetylation of WRN may play a role in response to DNA damage. This hypothesis is consistent with our findings that acetylation of WRN stimulates its catalytic activities in vitro and in vivo, and that acetylated WRN enhances pol b-mediated strand displacement DNA synthesis more than unacetylated WRN. Furthermore, we show that cellular exposure to the histone deacetylase inhibitor sodium butyrate stimulates long patch BER in wild type cells but not in WRN depleted cells, suggesting that acetylated WRN participates significantly in this process. Conclusion/Significance: Collectively, these results provide the first evidence for a specific role of p300 mediated WRN acetylation in regulating its function during BER

Small Cationic DDA:TDB Liposomes as Protein Vaccine Adjuvants Obviate the Need for TLR Agonists in Inducing Cellular and Humoral Responses

Most subunit vaccines require adjuvants in order to induce protective immune responses to the targeted pathogen. However, many of the potent immunogenic adjuvants display unacceptable local or systemic reactogenicity. Liposomes are spherical vesicles consisting of single (unilamellar) or multiple (multilamellar) phospholipid bi-layers. The lipid membranes are interleaved with an aqueous buffer, which can be utilised to deliver hydrophilic vaccine components, such as protein antigens or ligands for immune receptors. Liposomes, in particular cationic DDA:TDB vesicles, have been shown in animal models to induce strong humoral responses to the associated antigen without increased reactogenicity, and are currently being tested in Phase I human clinical trials. We explored several modifications of DDA:TDB liposomes - including size, antigen association and addition of TLR agonists – to assess their immunogenic capacity as vaccine adjuvants, using Ovalbumin (OVA) protein as a model protein vaccine. Following triple homologous immunisation, small unilamellar vesicles (SUVs) with no TLR agonists showed a significantly higher capacity for inducing spleen CD8 IFNγ responses against OVA in comparison with the larger multilamellar vesicles (MLVs). Antigen-specific antibody reponses were also higher with SUVs. Addition of the TLR3 and TLR9 agonists significantly increased the adjuvanting capacity of MLVs and OVA-encapsulating dehydration-rehydration vesicles (DRVs), but not of SUVs. Our findings lend further support to the use of liposomes as protein vaccine adjuvants. Importantly, the ability of DDA:TDB SUVs to induce potent CD8 T cell responses without the need for adding immunostimulators would avoid the potential safety risks associated with the clinical use of TLR agonists in vaccines adjuvanted with liposomes

Phagocytosis of Enterovirus-Infected Pancreatic β-Cells Triggers Innate Immune Responses in Human Dendritic Cells

Contains fulltext : 89763.pdf (publisher's version ) (Closed access)OBJECTIVE: Type 1 diabetes is a chronic endocrine disorder in which enteroviruses, such as coxsackie B viruses and echoviruses, are possible environmental factors that can trigger or accelerate disease. The development or acceleration of type 1 diabetes depends on the balance between autoreactive effector T-cells and regulatory T-cells. This balance is particularly influenced by dendritic cells (DCs). The goal of this study was to investigate the interaction between enterovirus-infected human pancreatic islets and human DCs. RESEARCH DESIGN AND METHODS: In vitro phagocytosis of human or porcine primary islets or Min6 mouse insuloma cells by DCs was investigated by flow cytometry and confocal analysis. Subsequent innate DC responses were monitored by quantitative PCR and Western blotting of interferon-stimulated genes (ISGs). RESULTS: In this study, we show that both mock- and coxsackievirus B3 (CVB3)-infected human and porcine pancreatic islets were efficiently phagocytosed by human monocyte-derived DCs. Phagocytosis of CVB3-infected, but not mock-infected, human and porcine islets resulted in induction of ISGs in DCs, including the retinoic acid-inducible gene (RIG)-I-like helicases (RLHs), RIG-I, and melanoma differentiation-associated gene 5 (Mda5). Studies with murine Min6 insuloma cells, which were also efficiently phagocytosed, revealed that increased ISG expression in DCs upon encountering CVB-infected cells resulted in an antiviral state that protected DCs from subsequent enterovirus infection. The observed innate antiviral responses depended on RNA within the phagocytosed cells, required endosomal acidification, and were type I interferon dependent. CONCLUSIONS: Human DCs can phagocytose enterovirus-infected pancreatic cells and subsequently induce innate antiviral responses, such as induction of RLHs. These responses may have important consequences for immune homeostasis in vivo and may play a role in the etiology of type 1 diabetes.1 mei 201