Intramacrophage survival of uropathogenic Escherichia coli : differences between diverse clinical isolates and between mouse and human macrophages

Uropathogenic E. coli (UPEC) are the primary cause of urinary tract infections. Recent studies have demonstrated that UPEC can invade and replicate within epithelial cells, suggesting that this bacterial pathogen may occupy an intracellular niche within the host. Given that many intracellular pathogens target macrophages, we assessed the interactions between UPEC and macrophages. Colonization of the mouse bladder by UPEC strain CFT073 resulted in increased expression of myeloid-restricted genes, consistent with the recruitment of inflammatory macrophages to the site of infection. In in vitro assays, CFT073 was able to survive within primary mouse bone marrow-derived macrophages (BMM) up to 24 h post-infection. Three additional well-characterized clinical UPEC isolates associated with distinct UTI symptomatologies displayed variable long-term survival within BMM. UPEC strains UTI89 and VR50, originally isolated from patients with cystitis and asymptomatic bacteriuria respectively, showed elevated bacterial loads in BMM at 24 h post-infection as compared to CFT073 and the asymptomatic bacteriuria strain 83972. These differences did not correlate with differential effects on macrophage survival or initial uptake of bacteria. E. coli UTI89 localized to a Lamp1+ vesicular compartment within BMM. In contrast to survival within mouse BMM, intracellular bacterial loads of VR50 were low in both human monocyte-derived macrophages (HMDM) and in human T24 bladder epithelial cells. Collectively, these data suggest that some UPEC isolates may subvert macrophage anti-microbial pathways, and that host species differences may impact on intracellular UPEC survival.

Interactions of ingested food, beverage, and tobacco components involving human cytochrome P4501A2, 2A6, 2E1, and 3A4 enzymes

Human cytochrome P450 (P450) enzymes are involved in the oxidation of natural products found in foods, beverages, and tobacco products and their catalytic activities can also be modulated by components of the materials. The microsomal activation of aflatoxin B1 to the exo-3,9-epoxide is stimulated by flavone and 7,8-benzoflavone, and attenuated by the flavonoid naringenin, a major component of grapefruit. P4502E1 has been demonstrated to play a potentially major role in the activation of a number of very low-molecular weight cancer suspects, including ethyl carbamate (urethan), which is present in alcoholic beverages and particularly stone brandies. The enzyme (P4502E1) is also known to be inducible by ethanol. Tobacco contains a large number of potential carcinogens. In human liver microsomes a significant role for P4501A2 can be demonstrated in the activation of cigarette smoke condensate. Some of the genotoxicity may be due to arylamines. P4501A2 is also inhibited by components of crude cigarette smoke condensate. The tobacco-specific nitrosamines are activated by a number of P450 enzymes. Of those known to be present in human liver, P4501A2, 2A6, and 2E1 can activate these nitrosamines to genotoxic products.

The rise of englightened shareholder primacy and its impact on US corporate self-regulation

Enlightened shareholder primacy (“ESP”) is a new approach in the corporate governance (“CG”) framework. The emergence of this approach is important owing to its role in answering a vital question: is the company really a private organisation to be seen only through the economic prism of contract? Or is it public and about a wider group of interests and underwritten by communitarian concern about social responsibility? Apart from answering this question, ESP explains the changes in corporate directors’ roles and self-regulation strategies of companies.

The co-transcriptome of uropathogenic Escherichia coli-infected mouse macrophages reveals new insights into host-pathogen interactions

Urinary tract infections (UTI) are among the most common infections in humans. Uropathogenic Escherichia coli (UPEC) can invade and replicate within bladder epithelial cells, and some UPEC strains can also survive within macrophages. To understand the UPEC transcriptional program associated with intramacrophage survival, we performed host–pathogen co-transcriptome analyses using RNA sequencing. Mouse bone marrow-derived macrophages (BMMs) were challenged over a 24 h time course with two UPEC reference strains that possess contrasting intramacrophage phenotypes: UTI89, which survives in BMMs, and 83972, which is killed by BMMs. Neither of these strains caused significant BMM cell death at the low multiplicity of infection that was used in this study. We developed an effective computational framework that simultaneously separated, annotated, and quantified the mammalian and bacterial transcriptomes. BMMs responded to the two UPEC strains with a broadly similar gene expression program. In contrast, the transcriptional responses of the UPEC strains diverged markedly from each other. We identified UTI89 genes upregulated at 24 h post-infection, and hypothesized that some may contribute to intramacrophage survival. Indeed, we showed that deletion of one such gene (pspA) significantly reduced UTI89 survival within BMMs. Our study provides a technological framework for simultaneously capturing global changes at the transcriptional level in co-cultures, and has generated new insights into the mechanisms that UPEC use to persist within the intramacrophage environment.

Why I will celebrate NAIDOC Week next year

The Guardian recently published an article by Nakkiah Lui, a Gamillaroi and Torres Strait Islander woman and writer, titled “Why this year’s NAIDOC week will be my last”. In response, Dr Chelsea Bond, an Aboriginal (Munanjahli) and South Sea Islander Australian and a senior lecturer with the Aboriginal and Torres Strait Islander Studies Unit at the University of Queensland, explains why she will continue to celebrate NAIDOC Week – as an act of agency.

Stories have the power to save us: A neurological framework for the imperative to tell stories

The evolutionary advantage of humans is in our unique ability to process stories – we have highly evolved ‘narrative organs.’ Through storytelling, vicarious knowledge, even guarded knowledge, is used to help our species to survive. We learn, regardless of whether the story being told is ‘truth’ or ‘fiction.’ This article discusses how humans place themselves in stories, as both observer and participant, to create a ‘neural balance’ or sweet spot that allows them to be immersed in a story without being entirely threatened by it – and how this involvement in story is the formation of empathy – an empathy that is integral to forging a future humanity. It is through empathy, we argue, that stories have the power to save us.

Re/membering Pedagogical Spaces

Educational spaces across the world largely continue to be designed with little variance from the traditional industrial classroom model, and pedagogies seem stuck somewhere between the Sage-on-the-Stage, lecture-dominated paradigm, and the Guide-on-the-Side, in which the instructor acts primarily as an aide watching, encouraging, and monitoring students working on projects individually or in groups. Rather than “reinventing the wheel,” the authors argue for an academic environment based on the British coffee house or French café of the 18th and 19th centuries. Not only should this 21st-century classroom offer an innovative melding of space and technology but also introduce a new pedagogical model. The Meddler-in-the-Middle model repositions the teacher and students as co-facilitators in the creation and use of knowledge in an environment where bodies move seamlessly in and out of collegial collaborations filled with free-to-fail open debate.

Smell and taste dysfunction following minor stroke: A case report

Smell (olfactory) and taste (gustatory) are key senses in the regulation of nourishment and individual safety. Olfactory and gustatory dysfunctions have been infrequently reported together in patients following stroke (Landis et al., 2006; Leopold et al., 2006). This case report details two patients who experienced smell and taste dysfunction following minor stroke events. Symptoms reported included hyposmia (diminished sense of smell) and anosmia (complete loss of smell), and dysgeusia (distorted taste). Patients' sense of smell and taste were assessed in an ambulatory care stroke prevention clinic eight months following their strokes. Patient A presented with minor stroke due to a lesion in the anterior circulation, patient B with a lesion in the posterior circulation. Both patients reported intense olfactory and gustatory dysfunction immediately following their strokes. Examination revealed a general inability to detect subtle odours and the ability to identify only 'sweet' tastes for both patients. In addition, both patients reported heavily salting or sweetening their food to mask the distorted and unpleasant taste, which also impacted comorbid conditions such as hypertension and diabetes. Patients and their spouses reported a decrease in their appreciation of family-related activities due to the patients' olfactory and gustatory dysfunction. Patients reported weight loss, lack of energy and strength, likely due to poor nutrition. Olfactory and gustatory dysfunctions are potentially deleterious outcomes following minor stroke and should be assessed by health care professionals prior to patient discharge. Assistance may be required to promote the health and well-being of patients and their carers if smell and taste are impacted by the stroke event.

Patents for humanity

This article evaluates two policy initiatives by the United States Government to address access to essential medicines -- Priority Review vouchers and “Patents for Humanity." Such proposals are aimed at speeding up the regulatory review of inventions with humanitarian uses and applications by the United States Food and Drug Administration, and the United States Patent and Trademark Office. It is argued that such measures fall short of international standards and norms established by the World Intellectual Property Organization Development Agenda 2007; the World Trade Organization’s Doha Declaration on the TRIPS Agreement and Public Health 2001 and the WTO General Council Decision of August 30, 2003; and the World Health Organization’s declarations on intellectual property and public health. This article concludes that there is a need for broader patent law reform in the United States to address matters of patent law and public health. Moreover, there is a need to experiment with other, more promising alternative models of research and development -- such as medical innovation prizes, a Health Impact Fund, the Medicines Patent Pool, and Open Source Drug Discovery.

A creature of statute: Copyright law and legal formalism

This article argues that copyright law is not just a creature of statute, but it is also a social and imaginative contruct. It evaluates a number of critiques of legal formalism. Part 1 examines whether the positive rules and principles of copyright law are the product of historical contingency and political expediency. Part 2 considers the social operation of copyright law in terms of its material effects and cultural significance. Part 3 investigates the future of copyright law, in light of the politics of globalisation and the impact of new information technologies.

The nutritional profile of baby and toddler food products sold in Australian supermarkets

Background/Aims To examine the nutritional profile of baby and toddler foods sold in Australia. Methods Nutrient information for baby and toddler foods available at Australian supermarkets was collected between August and December 2013. Levels of declared energy, total fat, saturated fat, total sugar, sodium and estimated added sugar were examined, as well as the presence of additional micronutrients on the label. The Health Star Rating (HSR) system was used to determine nutritional quality. The range of products on offer was also examined by product type and by the age category for which the product was marketed. Results Of the 309 products included, 29 % were fortified. On a per 100 g basis, these 309 products provided a mean (±SD) of 476 ± 486 kJ, 1.6 ± 2.4 g total fat, 10.7 ± 12.2 g total sugar, 2.7 ± 7.4 g added sugar, and 33.5 ± 66.5 mg sodium. Fruit-based products or products with fruit listed as an ingredient (58 %) were the predominant product type. On the nutrition label, 42 % displayed at least one additional micronutrient while 37 % did not display saturated fat. The most common HSR was four stars (45 %) and 6? months was the most commonly identified targeted age group (36 %). Conclusions The majority of baby and toddler foods sold in Australian supermarkets are ready-made fruit-based products aimed at children under 12 months of age. Baby and toddler foods are overlooked in public policy discussions pertaining to population nutrient intake but their relatively high sugar content deriving from fruits requires close attention to ensure these foods do not replace other more nutrient dense foods, given children have an innate preference for sweet tastes.

Strain- and host species-specific inflammasome activation, IL-1β release, and cell death in macrophages infected with uropathogenic Escherichia coli

Uropathogenic Escherichia coli (UPEC) is the main etiological agent of urinary tract infections (UTIs). Little is known about interactions between UPEC and the inflammasome, a key innate immune pathway. Here we show that UPEC strains CFT073 and UTI89 trigger inflammasome activation and lytic cell death in human macrophages. Several other UPEC strains, including two multidrug-resistant ST131 isolates, did not kill macrophages. In mouse macrophages, UTI89 triggered cell death only at a high multiplicity of infection, and CFT073-mediated inflammasome responses were completely NLRP3-dependent. Surprisingly, CFT073- and UTI89-mediated responses only partially depended on NLRP3 in human macrophages. In these cells, NLRP3 was required for interleukin-1β (IL-1β) maturation, but contributed only marginally to cell death. Similarly, caspase-1 inhibition did not block cell death in human macrophages. In keeping with such differences, the pore-forming toxin α-hemolysin mediated a substantial proportion of CFT073-triggered IL-1β secretion in mouse but not human macrophages. There was also a more substantial α-hemolysin-independent cell death response in human vs. mouse macrophages. Thus, in mouse macrophages, CFT073-triggered inflammasome responses are completely NLRP3-dependent, and largely α-hemolysin-dependent. In contrast, UPEC activates an NLRP3-independent cell death pathway and an α-hemolysin-independent IL-1β secretion pathway in human macrophages. This has important implications for understanding UTI in humans.

Evaluation of protein bait laced with various insecticides on the Queensland fruit fly (Diptera: Tephritidae): Attraction, feeding, mortality and bait persistence

The use of malathion in fruit fly protein bait sprays has raised serious concerns due to its adverse effects on non-target organisms. This has necessitated the evaluation of novel reduced-risk compounds. This study evaluated the effects of spinosad, fipronil, malathion and chlorpyrifos mixed with fruit fly protein bait (Mauri Pinnacle protein®) on attraction, feeding and mortality of the Queensland fruit fly, Bactrocera tryoni (Froggatt). The effects of outdoor weathering of these mixtures on fly mortality were also determined. In field-cage experiment, protein-starved flies showed the same level of attraction to baits containing spinosad, fipronil, malathion, chlorpyrifos and protein alone used as control. Female protein-starved flies were deterred from feeding on baits containing malathion and chlorpyrifos compared to baits containing spinosad, fipronil and protein alone. Baits containing malathion and chlorpyrifos caused higher fly mortality and rapid fly knock down than spinosad and fipronil. However, spinosad acted slowly and caused an increase in fly mortality over time, causing up to 90% fly mortality after 72-h. Baits containing malathion and chlorpyrifos, applied on citrus leaves and weathered outdoors, had longer residual effectiveness in killing flies than spinosad and fipronil. Residual effectiveness of the spinosad bait mixture waned significantly after 3 days of outdoor weathering. Results suggest that spinosad and fipronil can be potential alternatives for malathion in protein bait sprays.

Mauve: How one man invented the colour that changed the world

In an essay, "The Books of Last Things", Delia Falconer discusses the emergence of a new genre in publishing - microhistories. She cites a number of recent titles in non-fiction and fiction - Longitude, Cod, Tulips, Pushkin's Button, Nathaniel's Nutmeg, Zarafa, The Surgeon of Crowthorne, The Potato, The Perfect Storm. Delia Falconer observes of this tradition: "One has the sense, reading these books, of a surprising weight, of pleasant shock. In part, it is because we are looking at things which are generally present around us, but modestly out of sight and mind - historical nitty gritty like cod, potatoes, longitudinal clocks - which the authors have thrust suddenly, like a Biblical visitation of frogs or locusts, in our face. Things like spice and buttons and clocks are generally seen to enable history on the large scale, but are not often viewed as its worthy subjects. And by the same grand logic of history, more unusual phenomena like cabinets of curiosities or glass-making or farm lore or sailors' knots are simply odd blips on its radar screen, interesting footnotes. These new books, microhistories, reverse the usual order of history, which argues from the general to the particular, in order to prove its inevitable progress. They start from the footnotes. But by reversing the process, and walking through the back door of history, you don't necessarily end up at the front of the same house." Delia Falconer speculates about the reasons for the popularity of microhistories. She concludes: "I would like to think that reading them is not simply an exercise in nostalgia, but a challenge to the present". In Mauve, Simon Garfield provides a new way of thinking and writing about the history of intellectual property. Instead of providing a grand historical narrative of intellectual property, he tells the story of a particular invention, and its exploitation. Simon Garfield relates how English chemist William Perkin accidentally discovered a way to mass-produce colour mauve in a factory. Working on a treatment for malaria in his London home laboratory, Perkin failed to produce artificial quinine. Instead he created a dark oily sludge that turned silk a beautiful light purple. The colour was unique and became the most desirable shade in the fashion houses of Paris and London. ... The book Mauve will have a number of contemporary resonances for intellectual property lawyers and academics. Simon Garfield emphasizes the difficulties inherent in commercialising an invention and managing intellectual property. He investigates the uneasy collaboration between industry and science. Simon Garfield suggests that complaints about the efficacy of patent offices are perennial. He also highlights the problems faced by courts and law-makers in accommodating new technologies within the logic of patent law. In his elegant microhistory of the colour mauve, Simon Garfield confirms the conclusion of Brad Sherman and Lionel Bently that many aspects of modern intellectual property law can only be understood through an understanding of the past: "The image of intellectual property law that developed during the 19th century and the narrative of identity which this engendered played and continue to play an important role in the way we think about and understand intellectual property law".

International copyright law: A book review

n his 1994 book, Copyright's Highway, Paul Goldstein made the telling prophecy: The celestial jukebox may also portend more revolutional changes in international copyright markets. As the celestial jukebox disseminates information and entertainment over the air and without regard for national boundaries, the importance of the nation-state as a traditional guarantor of copyright may be replaced by international institutions such as the newly established World Trade Organization. In retrospect, it was an accurate prediction. The celestial jukebox has shown little respect for national boundaries. In particular, ephemeral file-sharing programs such as Napster, Freenet and Filetopia have posed difficulties for copyright law. International treaties have taken on larger significance and international institutions such as the World Intellectual Property Organization and World Trade Organization have assumed a greater role in regulating international copyright markets.