Assessing the influence of connected and automated mobility on the liveability of cities

In this work we are concerned with how the introduction of connected and automated mobility (CAM) will influence liveability in cities. We engaged with city and transport planners from both Europe and the U.S. and adopted a system dynamics approach to capturing the discussions and exploring potential outcomes. There are two aims in doing this: (1) to identify the concerns of city planners and how they differ from the traditional focus of transport researchers; but also (2) to develop a causal loop diagram (CLD) that can both explore the potential systemic effects of CAM and help to communicate those effects and the underlying mental models. Addressing these aims can inform policy design related to both CAM specifically and urban mobility more generally. In a change from previous related studies, we allowed the participants to establish their concept of liveability in cities and did not define a specific CAM scenario. This broad scope was critical in capturing the high-level view of what really matters to city stakeholders. We have established that a focus on a more holistic understanding of interactions related to sustainability is required rather than on specific transport modes or technology. A key insight that emerged was that quality of life (QoL) was the dominant concern of city planners, regardless of how it is achieved. The specifics of new services or technologies (such as CAM) are secondary concerns - which are important only insofar as they support the higher goal of improving QoL. As a result, we have produced a high level CLD that can be used as a starter for any future research in the area of CAM and liveability in cities and which may resonate better than previous CAM models have with city planners and policy makers—those who will ultimately play a key role in recommending and then implementing changes affecting QoL

The blind monks and the elephant : contrasting narratives of financial crisis

Three persuasive narratives of the US subprime crisis are explored with reference both to theory and to emergency acts of public policy undertaken. First the role of pecuniary externalities that amplify any shocks to the quality of risk-assets held by Investment Banks and others. Second is adverse selection in marketing these assets; and third the role of financial panic in making investment-banking disaster-prone. How relevant these differing perspectives proved is attested by the nature of state support and by subsequent findings in courts of law. As Chair of the US Federal Reserve, Janet Yellen argued that vulnerabilities within the US financial system in the mid-2000s were “numerous and familiar from past financial panics”. That the varied threats to stability featuring in these narratives should be complements and not substitutes is of more than technical interest: it helps to explain why the US financial system was so exposed to radical failure

Microbial Patterns Signaling via Toll-Like Receptors 2 and 5 Contribute to Epithelial Repair, Growth and Survival

Epithelial cells (ECs) continuously interact with microorganisms and detect their presence via different pattern-recognition receptors (PRRs) including Toll-like receptors (TLRs). Ligation of epithelial TLRs by pathogens is usually associated with the induction of pro-inflammatory mediators and antimicrobial factors. In this study, using human airway ECs as a model, we found that detection of microbial patterns via epithelial TLRs directly regulates tissue homeostasis. Staphylococcus aureus (S. aureus) and microbial patterns signaling via TLR2 and TLR5 induce a set of non-immune epithelial responses including cell migration, wound repair, proliferation, and survival of primary and cancerous ECs. Using small interfering RNA (siRNA) gene targeting, receptor-tyrosine kinase microarray and inhibition studies, we determined that TLR and the epidermal growth factor receptor (EGFR) mediate the stimulating effect of microbial patterns on epithelial repair. Microbial patterns signaling via Toll-like receptors 2 and 5 contribute to epithelial repair, growth and survival. This effect is independent of hematopoietic and other cells as well as inflammatory cytokines suggesting that epithelia are able to regulate their integrity in an autonomous non-inflammatory manner by sensing microbes directly via TLRs

Study of TLR3, TLR4 and TLR9 in breast carcinomas and their association with metastasis

<p>Abstract</p> <p>Background</p> <p>Toll-like receptors (TLRs) have garnered an extraordinary amount of interest in cancer research due to their role in tumor progression. By activating the production of several biological factors, TLRs induce type I interferons and other cytokines, which drive an inflammatory response and activate the adaptive immune system. The aim of this study was to investigate the expression and clinical relevance of TLR3, 4 and 9 in breast cancer.</p> <p>Methods</p> <p>The expression levels of TLR3, TLR4 and TLR9 were analyzed on tumors from 74 patients with breast cancer. The analysis was performed by immunohistochemistry.</p> <p>Results</p> <p>Samples of carcinomas with recurrence exhibited a significant increase in the mRNA levels of TLR3, TLR4 and TLR9. Tumors showed high expression of TLRs expression levels by cancer cells, especially TLR4 and 9. Nevertheless, a significant percentage of tumors also showed TLR4 expression by mononuclear inflammatory cells (21.6%) and TLR9 expression by fibroblast-like cells (57.5%). Tumors with high TLR3 expression by tumor cell or with high TLR4 expression by mononuclear inflammatory cells were significantly associated with higher probability of metastasis. However, tumours with high TLR9 expression by fibroblast-like cells were associated with low probability of metastasis.</p> <p>Conclusions</p> <p>The expression levels of TLR3, TLR4 and TLR9 have clinical interest as indicators of tumor aggressiveness in breast cancer. TLRs may represent therapeutic targets in breast cancer.</p

Tissue Microenvironments Define and Get Reinforced by Macrophage Phenotypes in Homeostasis or during Inflammation, Repair and Fibrosis

Current macrophage phenotype classifications are based on distinct in vitro culture conditions that do not adequately mirror complex tissue environments. In vivo monocyte progenitors populate all tissues for immune surveillance which supports the maintenance of homeostasis as well as regaining homeostasis after injury. Here we propose to classify macrophage phenotypes according to prototypical tissue environments, e.g. as they occur during homeostasis as well as during the different phases of (dermal) wound healing. In tissue necrosis and/or infection, damage- and/or pathogen-associated molecular patterns induce proinflammatory macrophages by Toll-like receptors or inflammasomes. Such classically activated macrophages contribute to further tissue inflammation and damage. Apoptotic cells and antiinflammatory cytokines dominate in postinflammatory tissues which induce macrophages to produce more antiinflammatory mediators. Similarly, tumor-associated macrophages also confer immunosuppression in tumor stroma. Insufficient parenchymal healing despite abundant growth factors pushes macrophages to gain a profibrotic phenotype and promote fibrocyte recruitment which both enforce tissue scarring. Ischemic scars are largely devoid of cytokines and growth factors so that fibrolytic macrophages that predominantly secrete proteases digest the excess extracellular matrix. Together, macrophages stabilize their surrounding tissue microenvironments by adapting different phenotypes as feed-forward mechanisms to maintain tissue homeostasis or regain it following injury. Furthermore, macrophage heterogeneity in healthy or injured tissues mirrors spatial and temporal differences in microenvironments during the various stages of tissue injury and repair. Copyright (C) 2012 S. Karger AG, Base

Improving Appropriate Use of Antifungal Medications: The Role of an Over-the-Counter Vaginal pH Self-Test Device

Objectives: To determine whether patients can understand and use the vaginal pH device in the diagnosis of vaginitis. To compare whether vaginal pH readings determined by patients and healthcare providers are similar. To determine whether vaginalpHcan reduce inappropriate over-the-counter (OTC) antifungal medication use and improve the correct diagnosis of vaginitis. Methods: One hundred and fifty-one women indicated their belief about the cause of their vaginal infection, read the instructions of the vaginal pH device package insert, used the device and interpreted the findings. The patient interpretations were compared with results obtained by healthcare providers, blinded to patient findings. Results: Over 96% of patients stated that they could easily read the instructions, use the vaginal pH device and interpret the readings. They obtained the same readings as healthcare professionals (Kappa = 0.9). Restricting the use of OTC antifungal medications to those individuals with vaginitis symptoms and vaginal pH ≤ 4.5 significantly reduced inappropriate use by approximately 50%, Fisher's exact test,p-value = 0.018. Conversely, seeking healthcare provider assessment with vaginal pH > 4.5, leads to correct diagnosis of vaginitis. Conclusions: The vaginal pH device can be used as an OTC diagnostic tool by consumers when a vaginal infection is suspected. Vaginal pH readings would direct patients whether to purchase an antifungal medication or seek professional diagnosis from a healthcare provider. Understanding and use of this vaginal pH device could reduce inappropriate use of OTC antifungal medications by approximately 50% and improve the correct diagnosis of vaginitis

Modulation of epithelial immunity by mucosal fluid

Mucosal epithelial cells, including those at the ocular surface, resist infection by most microbes in vivo but can be susceptible to microbial virulence in vitro. While fluids bathing mucosal surfaces (e.g. tears) contain antimicrobials, potentially pathogenic microbes often thrive in these fluids, suggesting that additional mechanisms mediate epithelial resistance in vivo. Here, tear fluid acted directly upon epithelial cells to enhance their resistance to bacterial invasion and cytotoxicity. Resistance correlated with tear fluid-magnified activation of NFκB and AP-1 transcription factors in epithelial cells in response to bacterial antigens, suggesting priming of innate defense pathways. Further analysis revealed differential regulation of potential epithelial cell defense genes by tears. siRNA knockdown confirmed involvement of at least two factors, RNase7 and ST-2, for which tears increased mRNA levels, in protection against bacterial invasion. Thus, the role of mucosal fluids in defense can include modulation of epithelial immunity, in addition to direct effects on microbes

Site and Strain-Specific Variation in Gut Microbiota Profiles and Metabolism in Experimental Mice

The gastrointestinal tract microbiota (GTM) of mammals is a complex microbial consortium, the composition and activities of which influences mucosal development, immunity, nutrition and drug metabolism. It remains unclear whether the composition of the dominant GTM is conserved within animals of the same strain and whether stable GTMs are selected for by host-specific factors or dictated by environmental variables.The GTM composition of six highly inbred, genetically distinct strains of mouse (C3H, C57, GFEC, CD1, CBA nu/nu and SCID) was profiled using eubacterial -specific PCR-DGGE and quantitative PCR of feces. Animals exhibited strain-specific fecal eubacterial profiles that were highly stable (c. >95% concordance over 26 months for C57). Analyses of mice that had been relocated before and after maturity indicated marked, reproducible changes in fecal consortia and that occurred only in young animals. Implantation of a female BDF1 mouse with genetically distinct (C57 and Agoutie) embryos produced highly similar GTM profiles (c. 95% concordance) between mother and offspring, regardless of offspring strain, which was also reflected in urinary metabolite profiles. Marked institution-specific GTM profiles were apparent in C3H mice raised in two different research institutions.Strain-specific data were suggestive of genetic determination of the composition and activities of intestinal symbiotic consortia. However, relocation studies and uterine implantation demonstrated the dominance of environmental influences on the GTM. This was manifested in large variations between isogenic adult mice reared in different research institutions

O-Antigen Delays Lipopolysaccharide Recognition and Impairs Antibacterial Host Defense in Murine Intestinal Epithelial Cells

Although Toll-like receptor (TLR) 4 signals from the cell surface of myeloid cells, it is restricted to an intracellular compartment and requires ligand internalization in intestinal epithelial cells (IECs). Yet, the functional consequence of cell-type specific receptor localization and uptake-dependent lipopolysaccharide (LPS) recognition is unknown. Here, we demonstrate a strikingly delayed activation of IECs but not macrophages by wildtype Salmonella enterica subsp. enterica sv. (S.) Typhimurium as compared to isogenic O-antigen deficient mutants. Delayed epithelial activation is associated with impaired LPS internalization and retarded TLR4-mediated immune recognition. The O-antigen-mediated evasion from early epithelial innate immune activation significantly enhances intraepithelial bacterial survival in vitro and in vivo following oral challenge. These data identify O-antigen expression as an innate immune evasion mechanism during apical intestinal epithelial invasion and illustrate the importance of early innate immune recognition for efficient host defense against invading Salmonella