Functional characterization of a Na+-dependent dicarboxylate transporter from Vibrio cholerae

The SLC13 transporter family, whose members play key physiological roles in the regulation of fatty acid synthesis, adiposity, insulin resistance, and other processes, catalyzes the transport of Krebs cycle intermediates and sulfate across the plasma membrane of mammalian cells. SLC13 transporters are part of the divalent anion:Na(+) symporter (DASS) family that includes several well-characterized bacterial members. Despite sharing significant sequence similarity, the functional characteristics of DASS family members differ with regard to their substrate and coupling ion dependence. The publication of a high resolution structure of dimer VcINDY, a bacterial DASS family member, provides crucial structural insight into this transporter family. However, marrying this structural insight to the current functional understanding of this family also demands a comprehensive analysis of the transporter's functional properties. To this end, we purified VcINDY, reconstituted it into liposomes, and determined its basic functional characteristics. Our data demonstrate that VcINDY is a high affinity, Na(+)-dependent transporter with a preference for C4- and C5-dicarboxylates. Transport of the model substrate, succinate, is highly pH dependent, consistent with VcINDY strongly preferring the substrate's dianionic form. VcINDY transport is electrogenic with succinate coupled to the transport of three or more Na(+) ions. In contrast to succinate, citrate, bound in the VcINDY crystal structure (in an inward-facing conformation), seems to interact only weakly with the transporter in vitro. These transport properties together provide a functional framework for future experimental and computational examinations of the VcINDY transport mechanism

IKKα negatively regulates ASC-dependent inflammasome activation.

The inflammasomes are multiprotein complexes that activate caspase-1 in response to infections and stress, resulting in the secretion of pro-inflammatory cytokines. Here we report that IκB kinase α (IKKα) is a critical negative regulator of apoptosis-associated specklike protein containing a C-terminal caspase-activation-andrecruitment (CARD) domain (ASC)-dependent inflammasomes. IKKα controls the inflammasome at the level of the adaptor ASC, which interacts with IKKα in the nucleus of resting macrophages in an IKKα kinase-dependent manner. Loss of IKKα kinase activity results in inflammasome hyperactivation. Mechanistically, the downstream nuclear effector IKK-related kinase (IKKi) facilitates translocation of ASC from the nucleus to the perinuclear area during inflammasome activation. ASC remains under the control of IKKα in the perinuclear area following translocation of the ASC/IKKα complex. Signal 2 of NLRP3 activation leads to inhibition of IKKα kinase activity through the recruitment of PP2A, allowing ASC to participate in NLRP3 inflammasome assembly. Taken together, these findings reveal a IKKi-IKKα-ASC axis that serves as a common regulatory mechanism for ASC-dependent inflammasomes

Secondary user relations in emerging mobile computing environments

Mobile technologies are enabling access to information in diverse environ.ments, and are exposing a wider group of individuals to said technology. Therefore, this paper proposes that a wider view of user relations than is usually considered in information systems research is required. Specifically, we examine the potential effects of emerging mobile technologies on end-­‐user relations with a focus on the ‘secondary user’, those who are not intended to interact directly with the technology but are intended consumers of the technology’s output. For illustration, we draw on a study of a U.K. regional Fire and Rescue Service and deconstruct mobile technology use at Fire Service incidents. Our findings provide insights, which suggest that, because of the nature of mobile technologies and their context of use, secondary user relations in such emerging mobile environments are important and need further exploration

Energy gap in superconducting fullerides: optical and tunneling studies

Tunneling and optical transmission studies have been performed on superconducting samples of Rb3C60. At temperatures much below the superconducting transition temperature Tc the energy gap is 2 Delta=5.2 +- 0.2meV, corresponding to 2 Delta/kB Tc = 4.2. The low temperature density of states, and the temperature dependence of the optical conductivity resembles the BCS behavior, although there is an enhanced ``normal state" contribution. The results indicate that this fulleride material is an s-wave superconductor, but the superconductivity cannot be described in the weak coupling limit.Comment: RevTex file with four .EPS figures. Prints to four pages. Also available at http://buckminster.physics.sunysb.edu/papers/pubrece.htm

Working through whiteness, race and (anti) racism in physical education teacher education

Background: The persistent gaps between a largely white profession and ethnically diverse school populations have brought renewed calls to support teachers' critical engagement with race. Programmes examining the effects of racism have had limited impact on practice, with student teachers responding with either denial, guilt or fear; they also contribute to a deficit view of racialised students in relation to an accepted white ‘norm’, and position white teachers ‘outside’ of race. Recent calls argue for a shift in focus towards an examination of the workings of the dominant culture through a critical engagement with whiteness, positioning white teachers within the processes of racialisation. Teacher educators' roles are central, and yet, while we routinely expect student teachers to reflect critically on issues of social justice, we have been less willing to engage in such work ourselves. This is particularly the case within physical education teacher education (PETE), an overwhelmingly white, embodied space, and where race and racism as professional issues are largely invisible. Purpose: This paper examines the operation of whiteness within PETE through a critical reflection on the three co-authors' careers and experiences working for social justice. The research questions were twofold: How are race, (anti) racism and whiteness constructed through everyday experiences of families, schooling and teacher education? How can collective biography be used to excavate discourses of race, racism and whiteness as the first step towards challenging them? In beginning the process of reflecting on what it means for us ‘to do own work’ in relation to (anti) racism, we examine some of the tensions and challenges for teacher educators in PE attempting to work to dismantle whiteness. Methodology: As co-authors, we engaged in collective biography work – a process in which we reflected upon, wrote about and shared our embodied experiences and memories about race, racism and whiteness as educators working for social justice. Using a critical whiteness lens, these narratives were examined for what they reveal about the collective practices and discourses about whiteness and (anti)racism within PETE. Results: The narratives reveal the ways in which whiteness operates within PETE through processes of naturalisation, ex-denomination and universalisation. We have been educated, and now work within, teacher education contexts where professional discourse about race at best focuses on understanding the racialised ‘other’, and at worse is invisible. By drawing on a ‘racialised other’, deficit discourse in our pedagogy, and by ignoring race in own research on inequalities in PETE, we have failed to disrupt universalised discourses of ‘white-as-norm’, or addressed our own privileged racialised positioning. Reflecting critically on our biographies and careers has been the first step in recognising how whiteness works in order that we can begin to work to disrupt it. Conclusion: The study highlights some of the challenges of addressing (anti)racism within PETE and argues that a focus on whiteness might offer a productive starting point. White teacher educators must critically examine their own role within these processes if they are to expect student teachers to engage seriously in doing the same

Extracellular superoxide dismutase (SOD3) regulates oxidative stress at the vitreoretinal interface

Oxidative stress is a pathogenic feature in vitreoretinal disease. However, the ability of the inner retina to manage metabolic waste and oxidative stress is unknown. Proteomic analysis of antioxidants in the human vitreous, the extracellular matrix opposing the inner retina, identified superoxide dismutase-3 (SOD3) that localized to a unique matrix structure in the vitreous base and cortex. To determine the role of SOD3, Sod3-/- mice underwent histological and clinical phenotyping. Although the eyes were structurally normal, at the vitreoretinal interface Sod3-/- mice demonstrated higher levels of 3-nitrotyrosine, a key marker of oxidative stress. Pattern electroretinography also showed physiological signaling abnormalities within the inner retina. Vitreous biopsies and epiretinal membranes collected from patients with diabetic vitreoretinopathy (DVR) and a mouse model of DVR showed significantly higher levels of nitrates and/or 3-nitrotyrosine oxidative stress biomarkers suggestive of SOD3 dysfunction. This study analyzes the molecular pathways that regulate oxidative stress in human vitreous substructures. The absence or dysregulation of the SOD3 antioxidant at the vitreous base and cortex results in increased oxidative stress and tissue damage to the inner retina, which may underlie DVR pathogenesis and other vitreoretinal diseases

Impact of generic alendronate cost on the cost-effectiveness of osteoporosis screening and treatment

Introduction: Since alendronate became available in generic form in the Unites States in 2008, its price has been decreasing. The objective of this study was to investigate the impact of alendronate cost on the cost-effectiveness of osteoporosis screening and treatment in postmenopausal women. Methods: Microsimulation cost-effectiveness model of osteoporosis screening and treatment for U.S. women age 65 and older. We assumed screening initiation at age 65 with central dual-energy x-ray absorptiometry (DXA), and alendronate treatment for individuals with osteoporosis; with a comparator of "no screening" and treatment only after fracture occurrence. We evaluated annual alendronate costs of $20 through$800; outcome measures included fractures; nursing home admission; medication adverse events; death; costs; quality-adjusted life-years (QALYs); and incremental cost-effectiveness ratios (ICERs) in 2010 U.S. dollars per QALY gained. A lifetime time horizon was used, and direct costs were included. Base-case and sensitivity analyses were performed. Results: Base-case analysis results showed that at annual alendronate costs of $200 or less, osteoporosis screening followed by treatment was cost-saving, resulting in lower total costs than no screening as well as more QALYs (10.6 additional quality-adjusted life-days). When assuming alendronate costs of$400 through $800, screening and treatment resulted in greater lifetime costs than no screening but was highly cost-effective, with ICERs ranging from$714 per QALY gained through $13,902 per QALY gained. Probabilistic sensitivity analyses revealed that the cost-effectiveness of osteoporosis screening followed by alendronate treatment was robust to joint input parameter estimate variation at a willingness-to-pay threshold of$50,000/QALY at all alendronate costs evaluated. Conclusions: Osteoporosis screening followed by alendronate treatment is effective and highly cost-effective for postmenopausal women across a range of alendronate costs, and may be cost-saving at annual alendronate costs of $200 or less. © 2012 Nayak et al

Lignin biomarkers as tracers of mercury sources in lakes water column

This study presents the role of specific terrigenous organic compounds as important vectors of mercury (Hg) transported from watersheds to lakes of the Canadian boreal forest. In order to differentiate the autochthonous from the allochthonous organic matter (OM), lignin derived biomarker signatures [Lambda, S/V, C/V, P/(V ? S), 3,5-Bd/V and (Ad/Al)v] were used. Since lignin is exclusively produced by terrigenous plants, this approach can give a non equivocal picture of the watershed inputs to the lakes. Moreover, it allows a characterization of the source of OM and its state of degradation. The water column of six lakes from the Canadian Shield was sampled monthly between June and September 2005. Lake total dissolved Hg concentrations and Lambda were positively correlated, meaning that Hg and ligneous inputs are linked (dissolved OM r2 = 0.62, p\0.0001; particulate OM r2 = 0.76, p\0.0001). Ratios of P/(V ? S) and 3,5-Bd/V from both dissolved OM and particulate OM of the water column suggest an inverse relationship between the progressive state of pedogenesis and maturation of the OM in soil before entering the lake, and the Hg concentrations in the water column. No relation was found between Hg levels in the lakes and the watershed flora composition—angiosperm versus gymnosperm or woody versus non-woody compounds. This study has significant implications for watershed management of ecosystems since limiting fresh terrestrial OM inputs should reduce Hg inputs to the aquatic systems. This is particularly the case for largescale land-use impacts, such as deforestation, agriculture and urbanization, associated to large quantities of soil OM being transferred to aquatic systems

Knee Arthroplasty: Disabilities in Comparison to the General Population and to Hip Arthroplasty Using a French National Longitudinal Survey

International audienceBACKGROUND: Knee arthroplasty is increasing exponentially due to the aging of the population and to the broadening of indications. We aimed to compare physical disability and its evolution over two years in people with knee arthroplasty to that in the general population. A secondary objective was to compare the level of disabilities of people with knee to people with hip arthroplasty. METHODOLOGY/PRINCIPAL FINDINGS: 16,945 people representative of the French population were selected in 1999 from the French census and interviewed about their level of disability. This sample included 815 people with lower limb arthroplasty. In 2001, 608 of them were re-interviewed, among whom 134 had knee arthroplasty. Among the other participants re-interviewed, we identified 68 who had undergone knee arthroplasty and 145 hip arthroplasty within the last two years (recent arthroplasty). People with knee arthroplasty reported significantly greater difficulties than the general population with bending forward (odds ratio [OR] = 4.7; 95% confidence interval [CI]: 1.7, 12.6), walking more than 500 meters (OR = 6.0; 95% CI: 1.5, 24.7) and carrying 5 kg kilograms for 10 meters (OR = 4.6; 95% CI: 1.3, 16.4). However, the two years evolution in disability was similar to that in the general population for most activities. The level of mobility was similar between people with recent knee arthroplasty and those with recent hip arthroplasty. Nevertheless, people with recent knee arthroplasty reported a lower level of disability than the other group for washing and bending forward (OR = 0.3; 95% CI: 0.1, 0.6 and OR = 0.4; 95% CI: 0.1, 0.9, respectively). CONCLUSIONS/SIGNIFICANCE: People with knee arthroplasty reported a higher risk of disability than the general population for common activities of daily living but a similar evolution. There was no relevant difference between recent knee and hip arthroplasties for mobility