Dextran Sodium Sulfate (DSS) Induces Colitis in Mice by Forming Nano-Lipocomplexes with Medium-Chain-Length Fatty Acids in the Colon

Inflammatory bowel diseases (IBDs), primarily ulcerative colitis and Crohn's disease, are inflammatory disorders caused by multiple factors. Research on IBD has often used the dextran sodium sulfate (DSS)-induced colitis mouse model. DSS induces in vivo but not in vitro intestinal inflammation. In addition, no DSS-associated molecule (free glucose, sodium sulfate solution, free dextran) induces in vitro or in vivo intestinal inflammation. We find that DSS but not dextran associated molecules established linkages with medium-chain-length fatty acids (MCFAs), such as dodecanoate, that are present in the colonic lumen. DSS complexed to MCFAs forms nanometer-sized vesicles ∼200 nm in diameter that can fuse with colonocyte membranes. The arrival of nanometer-sized DSS/MCFA vesicles in the cytoplasm may activate intestinal inflammatory signaling pathways. We also show that the inflammatory activity of DSS is mediated by the dextran moieties. The deleterious effect of DSS is localized principally in the distal colon, therefore it will be important to chemically modify DSS to develop materials beneficial to the colon without affecting colon-targeting specificity

Microbiota Modulate Host Gene Expression via MicroRNAs

Microbiota are known to modulate host gene expression, yet the underlying molecular mechanisms remain elusive. MicroRNAs (miRNAs) are importantly implicated in many cellular functions by post-transcriptionally regulating gene expression via binding to the 3′-untranslated regions (3′-UTRs) of the target mRNAs. However, a role for miRNAs in microbiota-host interactions remains unknown. Here we investigated if miRNAs are involved in microbiota-mediated regulation of host gene expression. Germ-free mice were colonized with the microbiota from pathogen-free mice. Comparative profiling of miRNA expression using miRNA arrays revealed one and eight miRNAs that were differently expressed in the ileum and the colon, respectively, of colonized mice relative to germ-free mice. A computational approach was then employed to predict genes that were potentially targeted by the dysregulated miRNAs during colonization. Overlapping the miRNA potential targets with the microbiota-induced dysregulated genes detected by a DNA microarray performed in parallel revealed several host genes that were regulated by miRNAs in response to colonization. Among them, Abcc3 was identified as a highly potential miRNA target during colonization. Using the murine macrophage RAW 264.7 cell line, we demonstrated that mmu-miR-665, which was dysregulated during colonization, down-regulated Abcc3 expression by directly targeting the Abcc3 3′-UTR. In conclusion, our study demonstrates that microbiota modulate host microRNA expression, which could in turn regulate host gene expression

NaxD is a deacetylase required for lipid A modification and Francisella pathogenesis

Modification of specific Gram-negative bacterial cell envelope components, such as capsule, O-antigen and lipid A, are often essential for the successful establishment of infection. Francisella species express lipid A molecules with unique characteristics involved in circumventing host defences, which significantly contribute to their virulence. In this study, we show that NaxD, a member of the highly conserved YdjC superfamily, is a deacetylase required for an important modification of the outer membrane component lipid A in Francisella. Mass spectrometry analysis revealed that NaxD is essential for the modification of a lipid A phosphate with galactosamine in Francisella novicida, a model organism for the study of highly virulent Francisella tularensis. Significantly, enzymatic assays confirmed that this protein is necessary for deacetylation of its substrate. In addition, NaxD was involved in resistance to the antimicrobial peptide polymyxin B and critical for replication in macrophages and in vivo virulence. Importantly, this protein is also required for lipid A modification in F. tularensis as well as Bordetella bronchiseptica. Since NaxD homologues are conserved among many Gram-negative pathogens, this work has broad implications for our understanding of host subversion mechanisms of other virulent bacteria

Synthetic Nanoparticles for Vaccines and Immunotherapy

The immune system plays a critical role in our health. No other component of human physiology plays a decisive role in as diverse an array of maladies, from deadly diseases with which we are all familiar to equally terrible esoteric conditions: HIV, malaria, pneumococcal and influenza infections; cancer; atherosclerosis; autoimmune diseases such as lupus, diabetes, and multiple sclerosis. The importance of understanding the function of the immune system and learning how to modulate immunity to protect against or treat disease thus cannot be overstated. Fortunately, we are entering an exciting era where the science of immunology is defining pathways for the rational manipulation of the immune system at the cellular and molecular level, and this understanding is leading to dramatic advances in the clinic that are transforming the future of medicine.1,2 These initial advances are being made primarily through biologic drugs– recombinant proteins (especially antibodies) or patient-derived cell therapies– but exciting data from preclinical studies suggest that a marriage of approaches based in biotechnology with the materials science and chemistry of nanomaterials, especially nanoparticles, could enable more effective and safer immune engineering strategies. This review will examine these nanoparticle-based strategies to immune modulation in detail, and discuss the promise and outstanding challenges facing the field of immune engineering from a chemical biology/materials engineering perspectiveNational Institutes of Health (U.S.) (Grants AI111860, CA174795, CA172164, AI091693, and AI095109)United States. Department of Defense (W911NF-13-D-0001 and Awards W911NF-07-D-0004

Protective effects of N-acetylcysteine on acetic acid-induced colitis in a porcine model

BACKGROUND: Ulcerative colitis is a chronic inflammatory disease and involves multiple etiological factors. Acetic acid (AA)-induced colitis is a reproducible and simple model, sharing many characteristics with human colitis. N-acetylcysteine (NAC) has been widely used as an antioxidant in vivo and in vitro. NAC can affect several signaling pathways involving in apoptosis, angiogenesis, cell growth and arrest, redox-regulated gene expression, and inflammatory response. Therefore, NAC may not only protect against the direct injurious effects of oxidants, but also beneficially alter inflammatory events in colitis. This study was conducted to investigate whether NAC could alleviate the AA-induced colitis in a porcine model. METHODS: Weaned piglets were used to investigate the effects of NAC on AA-induced colitis. Severity of colitis was evaluated by colon histomorphology measurements, histopathology scores, tissue myeloperoxidase activity, as well as concentrations of malondialdehyde and pro-inflammatory mediators in the plasma and colon. The protective role of NAC was assessed by measurements of antioxidant status, growth modulator, cell apoptosis, and tight junction proteins. Abundances of caspase-3 and claudin-1 proteins in colonic mucosae were determined by the Western blot method. Epidermal growth factor receptor, amphiregulin, tumor necrosis factor-alpha (TNF-α), and toll-like receptor 4 (TLR4) mRNA levels in colonic mucosae were quantified using the real-time fluorescent quantitative PCR. RESULTS: Compared with the control group, AA treatment increased (P < 0.05) the histopathology scores, intraepithelial lymphocyte (IEL) numbers and density in the colon, myeloperoxidase activity, the concentrations of malondialdehyde and pro-inflammatory mediators in the plasma and colon, while reducing (P < 0.05) goblet cell numbers and the protein/DNA ratio in the colonic mucosa. These adverse effects of AA were partially ameliorated (P < 0.05) by dietary supplementation with NAC. In addition, NAC prevented the AA-induced increase in caspase-3 protein, while stimulating claudin-1 protein expression in the colonic mucosa. Moreover, NAC enhanced mRNA levels for epidermal growth factor and amphiregulin in the colonic mucosa. CONCLUSION: Dietary supplementation with NAC can alleviate AA-induced colitis in a porcine model through regulating anti-oxidative responses, cell apoptosis, and EGF gene expression

Emigration as popular culture: the case of Morocco

This article explores the symbolic dimensions of emigration by enquiring into the relationship between emigration as a social phenomenon in Morocco, and Moroccan popular culture. The article critiques the discourses of unity and reconciliation inherent in analyses of Moroccan popular culture and contends that the popular in Moroccan popular culture is a pseudo-popular that speaks for the voices of the centre. This article concentrates on three taken-for-granted, non-institutionalized, popular cultural spaces in Moroccan popular culture: popular jokes, the Derb and the queue outside western embassies, and argues that emigration in Morocco is not an isolated social phenomenon, but a pervasive part of the make-up of its popular culture. (Reprinted by permission of Sage Publications Ltd from Sabry, Tarik (2005) Emigration as popular culture: the case of Morocco. © 2005 SAGE Publications

Edge and fog computing for IoT: A survey on current research activities &amp; future directions

The Internet of Things (IoT) allows communication between devices, things, and any digital assets that send and receive data over a network without requiring interaction with a human. The main characteristic of IoT is the enormous quantity of data created by end-user's devices that needs to be processed in a short time in the cloud. The current cloud-computing concept is not efficient to analyze very large data in a very short time and satisfy the users’ requirements. Analyzing the enormous quantity of data by the cloud will take a lot of time, which affects the quality of service (QoS) and negatively influences the IoT applications and the overall network performance. To overcome such challenges, a new architecture called edge computing — that allows to decentralize the process of data from the cloud to the network edge has been proposed to solve the problems occurred by using the cloud computing approach. Furthermore, edge computing supports IoT applications that require a short response time and consequently enhances the consumption of energy, resource utilization, etc. Motivated by the extensive research efforts in the edge computing and IoT applications, in this paper, we present a comprehensive review of edge and fog computing research in the IoT. We investigate the role of cloud, fog, and edge computing in the IoT environment. Subsequently, we cover in detail, different IoT use cases with edge and fog computing, the task scheduling in edge computing, the merger of software-defined networks (SDN) and network function virtualization (NFV) with edge computing, security and privacy efforts. Furthermore, the Blockchain in edge computing. Finally, we identify open research challenges and highlight future research directions

DSS induces colitis.

<p>(A) Mouse body weight changes during DSS treatment compared to that of control animals (drinking water). C57BL/6 mice were exposed to 3% (w/v) DSS in the drinking water for the indicated numbers of days. Body weight changes are shown as means±SEMs. * P<0.05, ** P<0.01. (B) Hematoxylin-stained colonic sections of mice treated with DSS; the mice were sacrificed on day 8. (C) Associated histological scores. *** P<0.001. (D) Macroscopic inflammation was assessed using a mouse colonoscope. Photographs were obtained on the day of sacrifice and (E) an endoscopic score was calculated. *** P<0.001. (F) KC mRNA expression was measured in test and control animals. *** P<0.001. (G) Determination of MPO enzymatic activity as an index of neutrophil infiltration into injured tissue. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0032084#s3" target="_blank">Results</a> are expressed as MPO –fold increases compared to those of control mice and represent means±SEMs of three independent determinations. *** P<0.01.</p