A Novel Scaffold-Based Hybrid Multicellular Model for Pancreatic Ductal Adenocarcinoma-Toward a Better Mimicry of the in vivo Tumor Microenvironment

With a very low survival rate, pancreatic ductal adenocarcinoma (PDAC) is a deadly disease. This has been primarily attributed to (i) its late diagnosis and (ii) its high resistance to current treatment methods. The latter specifically requires the development of robust, realistic in vitro models of PDAC, capable of accurately mimicking the in vivo tumor niche. Advancements in the field of tissue engineering (TE) have helped the development of such models for PDAC. Herein, we report for the first time a novel hybrid, polyurethane (PU) scaffold-based, long-term, multicellular (tri-culture) model of pancreatic cancer involving cancer cells, endothelial cells, and stellate cells. Recognizing the importance of ECM proteins for optimal growth of different cell types, the model consists of two different zones/compartments: an inner tumor compartment consisting of cancer cells [fibronectin (FN)-coated] and a surrounding stromal compartment consisting of stellate and endothelial cells [collagen I (COL)-coated]. Our developed novel hybrid, tri-culture model supports the proliferation of all different cell types for 35 days (5 weeks), which is the longest reported timeframe in vitro. Furthermore, the hybrid model showed extensive COL production by the cells, mimicking desmoplasia, one of PDAC's hallmark features. Fibril alignment of the stellate cells was observed, which attested to their activated state. All three cell types expressed various cell-specific markers within the scaffolds, throughout the culture period and showed cellular migration between the two zones of the hybrid scaffold. Our novel model has great potential as a low-cost tool for in vitro studies of PDAC, as well as for treatment screening

A dandelion-encoded evolutionary algorithm for the delay-constrained capacitated minimum spanning tree problem

This paper proposes an evolutionary algorithm with Dandelion-encoding to tackle the Delay-Constrained Capacitated Minimum Spanning Tree (DC-CMST) problem. This problem has been recently proposed, and consists of finding several broadcast trees from a source node, jointly considering traffic and delay constraints in trees. A version of the problem in which the source node is also included in the optimization process is considered as well in the paper. The Dandelion code used in the proposed evolutionary algorithm has been recently proposed as an effective way of encoding trees in evolutionary algorithms. Good properties of locality has been reported on this encoding, which makes it very effective to solve problems in which the solutions can be expressed in form of trees. In the paper we describe the main characteristics of the algorithm, the implementation of the Dandelion-encoding to tackled the DC-CMST problem and a modification needed to include the source node in the optimization. In the experimental section of this article we compare the results obtained by our evolutionary with that of a recently proposed heuristic for the DC-CMST. the Least Cost (LC) algorithm. We show that our Dandelion-encoded evolutionary algorithm is able to obtain better results that the LC in all the instances tackled. (C) 2008 Elsevier B.V. All rights reserved

Canadian national surveys on pandemic influenza preparations: pre-pandemic and peri-pandemic findings

BACKGROUND: Prior to the 2009 H1N1 Influenza pandemic, public health authorities in Canada and elsewhere prepared for the future outbreak, partly guided by an ethical framework developed within the Canadian Program of Research on Ethics in a Pandemic (CanPREP). We developed a telephone-based survey based on that framework, which was delivered across Canada in late 2008. In June, 2009, the WHO declared pandemic Phase 6 status and from the subsequent October (2009) until May 2010, the CanPREP team fielded a second (revised) survey, collecting another 1,000 opinions from Canadians during a period of pre-pandemic anticipation and peri-pandemic experience. METHODS: Surveys were administered by telephone with random sampling achieved via random digit dialing. Eligible participants were adults, 18 years or older, with per province stratification approximating provincial percentages of national population. Descriptive results were tabulated and logistic regression analyses used to assess whether demographic factors were significantly associated with outcomes, and to identify divergences (between the pre-pandemic and intra-pandemic surveys). RESULTS: N = 1,029 interviews were completed from 1,986 households, yielding a gross response rate of 52% (AAPOR Standard Definition 3). Over 90% of subjects indicated the most important goal of pandemic influenza preparations was saving lives, with 41% indicating that saving lives solely in Canada was the highest priority and 50% indicating saving lives globally was the highest priority. About 90% of respondents supported the obligation of health care workers to report to work and face influenza pandemic risks excepting those with serious health conditions which that increased risks. Strong majorities favoured stocking adequate protective antiviral dosages for all Canadians (92%) and, if effective, influenza vaccinations (95%). Over 70% agreed Canada should provide international assistance to poorer countries for pandemic preparation, even if resources for Canadians were reduced. CONCLUSIONS: Results suggest Canadians trust public health officials to make difficult decisions, providing emphasis is maintained on reciprocity and respect for individual rights. Canadians also support international obligations to help poorer countries and associated efforts to save lives outside the country, even if intra-national efforts are reduced

Complexity of coordinated beamforming and scheduling for OFDMA based heterogeneous networks

Coordination is foreseen to be an important component of future mobile radio networks. It is especially relevant in heterogeneous networks, where high power base stations produce strong interference to an underlying layer of low power base stations. This work investigates in detail the achievable performance gains for one coordination technique—coordinated beamforming. It reveals the main factors that influence the throughput of the mobile stations. These findings are combined with an analysis of the computational complexity. As a result, a heuristic algorithm is presented that achieves results close to an exhaustive search with significantly less calculations. Detailed simulation analysis is presented on a realistic network layout

Anaerobic Carbon Monoxide Dehydrogenase Diversity in the Homoacetogenic Hindgut Microbial Communities of Lower Termites and the Wood Roach

Anaerobic carbon monoxide dehydrogenase (CODH) is a key enzyme in the Wood-Ljungdahl (acetyl-CoA) pathway for acetogenesis performed by homoacetogenic bacteria. Acetate generated by gut bacteria via the acetyl-CoA pathway provides considerable nutrition to wood-feeding dictyopteran insects making CODH important to the obligate mutualism occurring between termites and their hindgut microbiota. To investigate CODH diversity in insect gut communities, we developed the first degenerate primers designed to amplify cooS genes, which encode the catalytic (β) subunit of anaerobic CODH enzyme complexes. These primers target over 68 million combinations of potential forward and reverse cooS primer-binding sequences. We used the primers to identify cooS genes in bacterial isolates from the hindgut of a phylogenetically lower termite and to sample cooS diversity present in a variety of insect hindgut microbial communities including those of three phylogenetically-lower termites, Zootermopsis nevadensis, Reticulitermes hesperus, and Incisitermes minor, a wood-feeding cockroach, Cryptocercus punctulatus, and an omnivorous cockroach, Periplaneta americana. In total, we sequenced and analyzed 151 different cooS genes. These genes encode proteins that group within one of three highly divergent CODH phylogenetic clades. Each insect gut community contained CODH variants from all three of these clades. The patterns of CODH diversity in these communities likely reflect differences in enzyme or physiological function, and suggest that a diversity of microbial species participate in homoacetogenesis in these communities

Simple Metals at High Pressure

In this lecture we review high-pressure phase transition sequences exhibited by simple elements, looking at the examples of the main group I, II, IV, V, and VI elements. General trends are established by analyzing the changes in coordination number on compression. Experimentally found phase transitions and crystal structures are discussed with a brief description of the present theoretical picture.Comment: 22 pages, 4 figures, lecture notes for the lecture given at the Erice course on High-Pressure Crystallography in June 2009, Sicily, Ital

ApoB siRNA-induced Liver Steatosis is Resistant to Clearance by the Loss of Fatty Acid Transport Protein 5 (Fatp5)

The association between hypercholesterolemia and elevated serum apolipoprotein B (APOB) has generated interest in APOB as a therapeutic target for patients at risk of developing cardiovascular disease. In the clinic, mipomersen, an antisense oligonucleotide (ASO) APOB inhibitor, was associated with a trend toward increased hepatic triglycerides, and liver steatosis remains a concern. We found that siRNA-mediated knockdown of ApoB led to elevated hepatic triglycerides and liver steatosis in mice engineered to exhibit a human-like lipid profile. Many genes required for fatty acid synthesis were reduced, suggesting that the observed elevation in hepatic triglycerides is maintained by the cell through fatty acid uptake as opposed to fatty acid synthesis. Fatty acid transport protein 5 (Fatp5/Slc27a5) is required for long chain fatty acid (LCFA) uptake and bile acid reconjugation by the liver. Fatp5 knockout mice exhibited lower levels of hepatic triglycerides due to decreased fatty acid uptake, and shRNA-mediated knockdown of Fatp5 protected mice from diet-induced liver steatosis. Here, we evaluated if siRNA-mediated knockdown of Fatp5 was sufficient to alleviate ApoB knockdown-induced steatosis. We determined that, although Fatp5 siRNA treatment was sufficient to increase the proportion of unconjugated bile acids 100-fold, consistent with FATP5's role in bile acid reconjugation, Fatp5 knockdown failed to influence the degree, zonal distribution, or composition of the hepatic triglycerides that accumulated following ApoB siRNA treatment

Evolution and Dynamics of Regulatory Architectures Controlling Polymyxin B Resistance in Enteric Bacteria

Complex genetic networks consist of structural modules that determine the levels and timing of a cellular response. While the functional properties of the regulatory architectures that make up these modules have been extensively studied, the evolutionary history of regulatory architectures has remained largely unexplored. Here, we investigate the transition between direct and indirect regulatory pathways governing inducible resistance to the antibiotic polymyxin B in enteric bacteria. We identify a novel regulatory architecture—designated feedforward connector loop—that relies on a regulatory protein that connects signal transduction systems post-translationally, allowing one system to respond to a signal activating another system. The feedforward connector loop is characterized by rapid activation, slow deactivation, and elevated mRNA expression levels in comparison with the direct regulation circuit. Our results suggest that, both functionally and evolutionarily, the feedforward connector loop is the transitional stage between direct transcriptional control and indirect regulation

IFNAR1-Signalling Obstructs ICOS-mediated Humoral Immunity during Non-lethal Blood-Stage Plasmodium Infection

Funding: This work was funded by a Career Development Fellowship (1028634) and a project grant (GRNT1028641) awarded to AHa by the Australian National Health & Medical Research Council (NHMRC). IS was supported by The University of Queensland Centennial and IPRS Scholarships. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD