The tales of two organic cation transporters, OCT-1 and OCT-2, in Caenorhabditis elegans

Solute carrier transporters, previously thought to perform roles in the transport of ions and various nutrients are now assigned broader functions. These transporters have recently been shown to permit entry of therapeutic drugs into cells. There is growing interest to understand the broad spectrum of drugs and chemical compounds that are recognized by these transporters such that specific ligands can be used as therapeutics to target definite physiological pathways. To facilitate this investigation, simpler and cost effective model systems are needed, one of such is the live whole model animal Caenorhabditis elegans (C. elegans) that offers a multitude of advantages. In general, studies with C. elegans are feasible due to the simplicity of the readouts that include lifespan, brood size, germ cell death, and visualization by epifluorescent microscopy, which can be set up in any laboratory. In C. elegans, two solute carrier transporters, the organic cation transporters OCT-1 and its paralogue OCT-2 have been partially characterized. OCT-1 mutants display a significantly reduced lifespan and brood size, as well as exhibiting an increased susceptibility towards oxidative stress and a subset of DNA damaging agents. These multiple phenotypes are directly linked to OCT-1 depletion causing upregulation of OCT-2, as RNAi-mediated downregulation of OCT-2 rescues the oct-1 mutant phenotypes. Thus, in C. elegans OCT-1 exerts control onto OCT-2, and this latter transporter plays a predominant role in the uptake of various ligands. We first showed that OCT-2 can efficiently mediate uptake of the widely used anticancer drug doxorubicin into the animals, but prevented uptake upon its downregulation. Additional ligands of OCT-2 including cisplatin and camptothecin were revealed by ligand-docking prediction studies. These analyses generated docking scores indicating that OCT-2 can make robust contact with a number of therapeutics and anticancer drugs, as well as chemical compounds that possess the ability to target specific physiological pathways. Several of the compounds displaying high docking scores with OCT-2 were validated and indeed found to be substrates that OCT-2 transported into the animals. This review provides an insight how the transporters OCT-1 and OCT-2 of a simple model organism C. elegans can be exploited to report on the cytotoxicities and genotoxicities of therapeutic agents, as well as trace amounts of undocumented toxic compounds with neoplastic potentials that are present in the environment

LEGITIMATING USER PARTICIPATION IN MATURE ORGANISATIONS- EXPLORING SOCIAL MEDIA ADOPTION IN A FINANCIAL SERVICES ORGANIZATION

In this paper, we explore strategies that institutional entrepreneurs use to legitimate entreprise social media in a context where ESM interest vary across and within organisational units. Using an in-depth case study of a financial firm we contribute to IS-legitimation research in several ways. First, we outline an institutional logics template that future IS-legitimation research can use to conceptualise organisational and technological values, in order to effectively assess legitimacy gaps. Second, we address calls by Flynn and Du(2011) for studies of IS legitimation in pluralistic contexts by proposing that when ESM interest vary across and within organisational units legitimation seekers may successfully gain and sustain participation by applying pragmatic selection, conformation and advertising legitimation strategies, .Finally, we advance a professional ESM design that can be used to gain participation for ESM before network effects are generated

General Geometry Computed Tomography Reconstruction

The discovery of Carbon Nanotubes and their ability to produce X-rays can usher in a new era in Computed Tomography (CT) technology. These devices will be lightweight, flexible and portable. The proposed device, currently under development, is envisioned as a flexible band of tiny X-ray emitters and detectors. The device is wrapped around an appendage and a CT image is obtained. However, current CT reconstruction algorithms can only be used if the geometry of the CT device is regular (usually circular). We present an efficient and accurate reconstruction technique that is unconstrained by the geometry of the CT device. Indeed the geometry can be both regular and highly irregular. To evaluate the feasibility of reconstructing a CT image from such a device, a simulated test bed was built to generate simulated CT ray sums of an image. This data was then used in our reconstruction method. We take this output data and grid it according to what we would expect from a parallel-beam CT scanner. The Filtered Back Projection can then be used to perform reconstruction. We have also included data inaccuracies as is expected in "real world" situations. Observations of reconstructions, as well as quantitative results, suggest that this simple method is efficient and accurate

Full vehicle simulation and exploration of a range extended electric vehicle battery pack and thermal management system in diurnal operating environments

A full vehicle model is created in Autonomie to represent a production extended range electric vehicle (EREV), specifically including the high voltage battery pack which is validated in dynamic operation against experimental data. Vehicle data is utilized as comparative input to a thermal equivalent circuit model developed analytically which aims to capture and understand the heat propagation from the cells through the entire pack, to and from the environment. The inclusion of production hardware and the liquid battery thermal management system components into the physical model considers detail geometric properties to calculate thermal resistances of components (conduction, convection and radiation) along with their associated thermal capacitances. Analog equivalent circuit simulations using PSPICE are compared to experimental results in order to validate internal temperature nodes and the heat rate through various elements with heat flux sensors; all used to refine the model. The solar data, diurnal temperature and terrain are included in the simulations to model the effects of gradient, convection and road radiation on the battery pack; both stationary and through drive cycles. The thermal equivalent circuit accurately quantifies the heat flow dynamics of the battery. Convection and radiation sources primarily influenced the baseplate and underbody shield components whereas cell heat propagation was closely linked to cell retention frame hardware details. The distribution of cooling indicated close to 90% was directed to the cell while the remaining 10% went to the surrounding hardware. Modeling a quiescent background cooling showed the ability to reduce the diurnal temperature effects on the battery pack at the 50 watt level. The addition of insulation in key areas delineated the ability to reduce initial cell temperatures for all drive cycles, while a miniscule amount added between the cell and retention frame interface showed increased cooling capacity directed towards the cells nearing 100%. The models developed incorporated many elements which were neglected or highly simplified in all previous works and the methodology developed highlights an ability to generate accurate dynamic results with little computational power. This is a prerequisite to enable predictive controls and accurate onboard system diagnostics to extend the pack???s operational life

Cellular Responses to Anthracyclines Identify Ku70, a DNA Repair Factor that Changes Compartment and Remains Stable in Leukemic Cells

Anthracyclines such as doxorubicin and daunorubicin are anticancer drugs that act by damaging the DNA and used for treating a variety of cancers including adult acute myeloid leukemia.  To date, nearly 50 % of acute myeloid leukemia patients show resistance to anthracyclines although the cause is not known.  We first investigate if there is a relationship between the expression level of 23 DNA repair genes in three leukemic cell lines (KG-1, HL-60 and Mono-Mac1) and cellular responses to anthracyclines.  We observed that the DNA repair genes were all downregulated in these cell lines following exposure to doxorubicin.  Further analysis revealed that the general downregulation of the genes was linked to a substantial decrease in the recovery of total RNA raising the possibility that assessment of total RNA, and not specific gene or set of genes, can be used as a simple indicator of cellular responses to anthracyclines.  Furthermore, examination of total protein extracts derived from these cell lines revealed for the first time that Ku70 is a key protein that remained stable, while the majority of proteins were loss, upon anthracycline treatment.  Importantly, Ku70 redistributes from the cytoplasm to the nucleoli in a time-dependent manner in response to anthracycline exposure.  We propose that Ku70 redistribution might play a vital role in predicting cellular response to anthracycline and promoting cell death

The internal diffusion of new digital innovations : a case of enterprise social networking adoption

Despite a growing interest in processes of diffusion within organisations and some understanding of the social processes of creating and enacting external and internal IT innovations, little empirical research has studied potentially relevant intra-organisational diffusion dynamics underlying the movement of innovations adopted at an organisational level, into the front-line practices of organisational subunits. Furthermore, we know even less about the diffusion processes of non-transactional digital innovations, such as enterprise social networking (ESN). ESNs embedded “ideology of openness” and its nontransactional nature particularly create social tensions that largely run against the grain of organisational rationality and efficiency, pervade key organisational processes and lead to wide variations in how organisational actors interpret and appropriate ESN features within organisations. The goal of this research is to theorize about the institutional mechanisms and processes by which these highly flexible digital innovations become misaligned, aligned and diffused at the micro-level of everyday work, as well as the enabling and precipitating dynamics that condition and trigger these mechanisms. This theorization involved a longitudinal exploration of how different communities of actors in a globally distributed technology services firm appropriated an ESN platform over a four year period, and how managerial intervention shaped appropriation outcomes. These dynamics can be understood through a rhetorical legitimation lens as a process where organisational actors with competing interests use strategic communications, to legitimate and enable the generation of collective meanings around distinctly different IT features and practices. Findings indicate that the core internal diffusion process was intra-organisational theorizing around ESN. Intra-organisational theorizing was an on-going process of elaborating and refining the organisational level theorization for ESN to suit front- line employees in their immediate contexts. In this way, it gradually helped to standardize and scale the ESNs features and functions as it was appropriated by different communities of actors (infusion). In each infusion, intra-organisational theorizing unfolded in three cumulative and relatively sequential phases of legitimation: (1) rationale framing (2) value advertising, and (3) motivating engagement, which were instrumental for respectively managing political, technical and cultural institutional misalignments, and promoting intra-group meaning making. On the other hand, negotiation and inter-group meaning-making was enabled by strategically grafting on other intra-organisational theorizations, and co-opting people, ESN functions, and practices from other infusions. Further, these legitimation processes unfolded as a sequence of primarily pragmatic pathos and logos appeals. In particular, early and on-going logos appeals helped to de-legitimate established, competing technologies, and directly enabled legitimation and collective meaning-making around ESN

The production and detoxification of a potent cytotoxin, nitric oxide, by pathogenic enteric bacteria

The nitrogen cycle is based on several redox reactions that are mainly accomplished by prokaryotic organisms, some archaea and a few eukaryotes, which use these reactions for assimilatory, dissimilatory or respiratory purposes. One group is the Enterobacteriaceae family of Gammaproteobacteria, which have their natural habitats in soil, marine environments or the intestines of humans and other warm-blooded animals. Some of the genera are pathogenic and usually associated with intestinal infections. Our body possesses several physical and chemical defence mechanisms to prevent pathogenic enteric bacteria from invading the gastrointestinal tract. One response of the innate immune system is to activate macrophages, which produce the potent cytotoxin nitric oxide (NO). However, some pathogens have evolved the ability to detoxify NO to less toxic compounds, such as the neuropharmacological agent and greenhouse gas nitrous oxide (N2O), which enables them to overcome the host's attack. The same mechanisms may be used by bacteria producing NO endogenously as a by-product of anaerobic nitrate respiration. In the present review, we provide a brief introduction into the NO detoxification mechanisms of two members of the Enterobacteriaceae family: Escherichia coli and Salmonella enterica serovar Typhimurium. These are discussed as comparative non-pathogenic and pathogenic model systems in order to investigate the importance of detoxifying NO and producing N2O for the pathogenicity of enteric bacteria

Requirement for Abasic Endonuclease Gene Homologues in Arabidopsis Seed Development

Arabidopsis thaliana has three genes, Ape1L, Ape2, and Arp, that show homology to abasic (apurinic/apyrimidinic) endonuclease genes of bacterial, yeast, or animal cells. In bacteria, yeast, and animals, abasic endonucleases function in base excision repair of oxidized and other modified DNA bases. Here we report that plants with knock-out mutations in any one of Ape1L, Ape2, or Arp show no apparent differences from wild type in growth rate, growth habit, and fertility. However, coincident knock-out mutations in Ape1L and Ape2 are lethal and lead to abortion of developing embryos. Mutations of Arp are not deleterious, even in combination with one of the other two mutations. The results are consistent with the interpretation that the process of base excision repair, involving at least one intact copy of Ape1L or Ape2, is required in the process of embryogenesis

Suboptimal clinical response to ciprofloxacin in patients with enteric fever due to Salmonella spp. with reduced fluoroquinolone susceptibility: a case series

BACKGROUND: Salmonella spp. with reduced susceptibility to fluoroquinolones have higher than usual MICs to these agents but are still considered "susceptible" by NCCLS criteria. Delayed treatment response to fluoroquinolones has been noted, especially in cases of enteric fever due to such strains. We reviewed the ciprofloxacin susceptibility and clinical outcome of our recent enteric fever cases. METHODS: Salmonella enterica Serotype Typhi (S. Typhi) and Serotype Paratyphi (S. Paratyphi) blood culture isolates (1998–2002) were tested against nalidixic acid by disk diffusion (DD) and agar dilution (AD) and to ciprofloxacin by AD using NCCLS methods and interpretive criteria. Reduced fluoroquinolone susceptibility was defined as a ciprofloxacin MIC of 0.125–1.0 mg/L. The clinical records of patients treated with ciprofloxacin for isolates with reduced fluoroquinolone susceptibility were reviewed. RESULTS: Seven of 21 (33%) S. Typhi and S. Paratyphi isolates had reduced susceptibility to fluoroquinolones (MIC range 0.125–0.5 mg/L). All 7 were nalidixic acid resistant by DD (no zone) and by AD (MIC 128- >512 mg/L). The other 14 isolates were nalidixic acid susceptible and fully susceptible to ciprofloxacin (MIC range 0.015–0.03 mg/L). Five of the 7 cases were treated initially with oral ciprofloxacin. One patient remained febrile on IV ciprofloxacin until cefotaxime was added, with fever recurrence when cefotaxime was discontinued. Two continued on oral or IV ciprofloxacin alone but had prolonged fevers of 9–10 days duration, one was switched to IV beta-lactam therapy after remaining febrile for 3 days on oral/IV ciprofloxacin and one was treated successfully with oral ciprofloxacin. Four of the 5 required hospitalization. CONCLUSIONS: Our cases provide further evidence that reduced fluoroquinolone susceptibility of S. Typhi and S. Paratyphi is clinically significant. Laboratories should test extra-intestinal Salmonella spp. for reduced fluoroquinolone susceptibility