Type 1 ryanodine receptor in cardiac mitochondria: Transducer of excitation–metabolism coupling

AbstractMitochondria in a variety of cell types respond to physiological Ca2+ oscillations in the cytosol dynamically with Ca2+ uptakes. In heart cells, mitochondrial Ca2+ uptakes occur by a ruthenium red-sensitive Ca2+ uniporter (CaUP), a rapid mode of Ca2+ uptake (RaM) and a ryanodine receptor (RyR) localized in the inner mitochondrial membrane (IMM). Three subtypes of RyRs have been described and cloned, however, the subtype identity of the mitochondrial ryanodine receptor (mRyR) is unknown. Using subtype specific antibodies, we characterized the mRyR in the IMM from rat heart as RyR1. These results are substantiated by the absence of RyR protein in heart mitochondria from RyR1 knockout mice. The bell-shape Ca2+-dependent [3H]ryanodine binding curve and its modulation by caffeine and adenylylmethylenediphosphonate (AMPPCP) give further evidence that mRyR functions pharmacologically like RyR1. Ryanodine prevents mitochondrial Ca2+ uptake induced by raising extramitochondrial Ca2+ to 10 μM. Similarly, ryanodine inhibits oxidative phosphorylation stimulated by 10 μM extramitochondrial Ca2+. In summary, our results show that the mRyR in cardiac muscle has similar biochemical and pharmacological properties to the RyR1 in the sarcoplasmic reticulum (SR) of skeletal muscle. These results could also suggest an efficient mechanism by which mitochondria sequesters Ca2+ via mRyR during excitation–contraction coupling to stimulate oxidative phosphorylation for ATP production to meet metabolic demands. Thus, the mRyR functions as a transducer for excitation–metabolism coupling

Validation of Urban NO2NO_2 Concentrations and Their Diurnal and Seasonal Variations Observed from the SCIAMACHY and OMI Sensors Using In Situ Surface Measurements in Israeli Cities

We compare a full-year (2006) record of surface air $NO_2$ concentrations measured in Israeli cities to coinciding retrievals of tropospheric $NO_2$ columns from satellite sensors (SCIAMACHY aboard ENVISAT and OMI aboard Aura). This provides a large statistical data set for validation of $NO_2$ satellite measurements in urban air, where validation is difficult yet crucial for using these measurements to infer $NO_x$ emissions by inverse modeling. Assuming that $NO_2$ is well-mixed throughout the boundary layer (BL), and using observed average seasonal boundary layer heights, near-surface $NO_2$ concentrations are converted into BL $NO_2$ columns. The agreement between OMI and (13:45) BL $NO_2$ columns (slope=0.93, n=542), and the comparable results at 10:00 h for SCIAMACHY, allow a validation of the seasonal, weekly, and diurnal cycles in satellite-derived $NO_2$. OMI and BL $NO_2$ columns show consistent seasonal cycles (winter $NO_2$ 1.6–2.7× higher than summer). BL and coinciding OMI columns both show a strong weekly cycle with 45–50% smaller $NO_2$ columns on Saturday relative to the weekday mean, reflecting the reduced weekend activity, and validating the weekly cycle observed from space. The diurnal difference between SCIAMACHY (10:00) and OMI (13:45) $NO_2$ is maximum in summer when SCIAMACHY is up to 40% higher than OMI, and minimum in winter when OMI slightly exceeds SCIAMACHY. A similar seasonal variation in the diurnal difference is found in the source region of Cairo. The surface measurements in Israel cities confirm this seasonal variation in the diurnal cycle. Using simulations from a global 3-D chemical transport model (GEOS-Chem), we show that this seasonal cycle can be explained by a much stronger photochemical loss of $NO_2$ in summer than in winter.Engineering and Applied Science

Use of Serum MicroRNAs as Biomarker for Hepatobiliary Diseases in Dogs

Copyrigh

From High to Low Temperature The Revival of Sodium Beta Alumina for Sodium Solid State Batteries

Sodium based batteries are promising post lithium ion technologies because sodium offers a specific capacity of 1166 amp; 8197;mAh amp; 8201;g amp; 8722;1 and a potential of amp; 8722;2.71 amp; 8197;V vs. the standard hydrogen electrode. The solid electrolyte sodium beta alumina shows a unique combination of properties because it exhibits high ionic conductivity, as well as mechanical stability and chemical stability against sodium. Pairing a sodium negative electrode and sodium beta alumina with Na ion type positive electrodes, therefore, results in a promising solid state cell concept. This review highlights the opportunities and challenges of using sodium beta alumina in batteries operating from medium to low temperatures 200 amp; 8201; C 20 amp; 8201; C . Firstly, the recent progress in sodium beta alumina fabrication and doping methods are summarized. We discuss strategies for modifying the interfaces between sodium beta alumina and both the positive and negative electrodes. Secondly, recent achievements in designing full cells with sodium beta alumina are summarized and compared. The review concludes with an outlook on future research directions. Overall, this review shows the promising prospects of using sodium beta alumina for the development of solid state batterie

Expression of parathyroid hormone-related protein during immortalization of human peripheral blood mononuclear cells by HTLV-1: Implications for transformation

<p>Abstract</p> <p>Background</p> <p>Adult T-cell leukemia/lymphoma (ATLL) is initiated by infection with human T-lymphotropic virus type-1 (HTLV-1); however, additional host factors are also required for T-cell transformation and development of ATLL. The HTLV-1 Tax protein plays an important role in the transformation of T-cells although the exact mechanisms remain unclear. Parathyroid hormone-related protein (PTHrP) plays an important role in the pathogenesis of humoral hypercalcemia of malignancy (HHM) that occurs in the majority of ATLL patients. However, PTHrP is also up-regulated in HTLV-1-carriers and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients without hypercalcemia, indicating that PTHrP is expressed before transformation of T-cells. The expression of PTHrP and the PTH/PTHrP receptor during immortalization or transformation of lymphocytes by HTLV-1 has not been investigated.</p> <p>Results</p> <p>We report that PTHrP was up-regulated during immortalization of lymphocytes from peripheral blood mononuclear cells by HTLV-1 infection in long-term co-culture assays. There was preferential utilization of the PTHrP-P2 promoter in the immortalized cells compared to the HTLV-1-transformed MT-2 cells. PTHrP expression did not correlate temporally with expression of HTLV-1 tax. HTLV-1 infection up-regulated the PTHrP receptor (PTH1R) in lymphocytes indicating a potential autocrine role for PTHrP. Furthermore, co-transfection of HTLV-1 expression plasmids and PTHrP P2/P3-promoter luciferase reporter plasmids demonstrated that HTLV-1 up-regulated PTHrP expression only mildly, indicating that other cellular factors and/or events are required for the very high PTHrP expression observed in ATLL cells. We also report that macrophage inflammatory protein-1α (MIP-1α), a cellular gene known to play an important role in the pathogenesis of HHM in ATLL patients, was highly expressed during early HTLV-1 infection indicating that, unlike PTHrP, its expression was enhanced due to activation of lymphocytes by HTLV-1 infection.</p> <p>Conclusion</p> <p>These data demonstrate that PTHrP and its receptor are up-regulated specifically during immortalization of T-lymphocytes by HTLV-1 infection and may facilitate the transformation process.</p

Middle East respiratory syndrome coronavirus (MERS-CoV) infections in two returning travellers in the Netherlands, May 2014

Two patients, returning to the Netherlands from pilgrimage in Medina and Mecca, Kingdom of Saudi Arabia, were diagnosed with Middle East respiratory syndrome coronavirus (MERS-CoV) infection in May 2014. The source and mode of transmission have not yet been determined. Hospital-acquired infection and community-acquired infection are both possible

High STEAP1 expression is associated with improved outcome of Ewing's sarcoma patients

Background Ewing's sarcoma (ES) is the second most common bone or soft-tissue sarcoma in childhood and adolescence and features a high propensity to metastasize. The six-transmembrane epithelial antigen of the prostate 1 (STEAP1) is a membrane-bound mesenchymal stem cell marker highly expressed in ES. Here, we investigated the role of STEAP1 as an immunohistological marker for outcome prediction in patients with ES. Patients and methods Membranous STEAP1 immunoreactivity was analyzed using immunohistochemistry in 114 primary pre-chemotherapy ES of patients diagnosed from 1983 to 2010 and compared with clinical parameters and patient outcome. Median follow-up was 3.85 years (range 0.43-17.51). Results A total of 62.3% of the ES samples displayed detectable STEAP1 expression with predominant localization of the protein at the plasma membrane. High membranous STEAP1 immunoreactivity was found in 53.5%, which correlated with better overall survival (P=0.021). Accordingly, no or low membranous STEAP1 expression was identified as an independent risk factor in multivariate analysis (hazard ratio 2.65, P=0.036). Conclusion High membranous STEAP1 expression predicts improved outcome and may help to define a specific subgroup of ES patients, who might benefit from adapted therapy regimen

Middle East respiratory syndrome coronavirus (MERS-CoV) infections in two returning travellers in the Netherlands, May 2014

Two patients, returning to the Netherlands from pilgrimage in Medina and Mecca, Kingdom of Saudi Arabia, were diagnosed with Middle East respiratory syndrome coronavirus (MERS-CoV) infection in May 2014. The source and mode of transmission have not yet been determined. Hospital-acquired infection and community-acquired infection are both possible

Reconfiguring tissue banking consent through enrichment of a restricted debate

Tissue banks are thought to be an essential resource for medical research in the post-genomic age. Collections of tissue, usually removed in the course of diagnostic or therapeutic procedures, enable laboratory-based epidemiological studies to be carried out, linking abnormalities in the tissue to disease aetiology, prognosis and treatment responsiveness. There are, however, a number of technical, regulatory and ethical concerns that challenge those wishing to engage in tissue banking research. It is becoming increasingly apparent that tissue banking research is not without risk of harms, even though there is no direct physical risk to donors. This is because, in order to be most useful, banked specimens need to be linked to personal information about tissue donors and this poses the risk of inadvertent disclosure of personal─ particularly genetic─ information to those who might exploit such information (eg. insurance companies and employers). Furthermore, the long-term storage of specimens, and the impossibility of predicting all potential types of research programs for which they might be useful, raises the possibility that future projects will be carried out that are unacceptable to some (past) tissue donors. The ethical principles of autonomy and respect for persons demand that research subjects be informed of such risks and of the nature of the research, and that they participate willingly. On the other hand, there is a desire for science to progress unhindered by stringent consent requirements. For these reasons, a debate has emerged in the academic (bioethical and biomedical) literature and in the legal (law reform) sphere over what would constitute adequate consent. Despite an extensive discourse, it is still unclear whether it is permissible to carry out research on archival tissue that was originally taken for diagnostic purposes and whether project-specific (as opposed to open-ended) consent is required for research on tissue collected today. This lack of clarity is of concern to researchers, ethics committees and research subjects, all of whom recognise the importance of tissue banking research, yet fear that current consent procedures may be ethically or legally inadequate. Thus it is important that the consent dilemma be resolved as quickly and definitively as possible. Ongoing controversy and regulatory ambiguity are appropriate when morally contentious issues are at stake, and their existence does not, on its own, signal any flaws in the discourse process. There are, however, two reasons to suspect that the current 'consent to tissue banking' debate, as portrayed in the academic literature and law reform documentation, is problematic. Firstly, the debate appears to be mired in an intractable conflict between those who want to maximise personal autonomy through stringent consent requirements, and those who want the scientific endeavour to progress in a manner that is unconstrained by what are viewed as arduous consent procedures. Secondly, the possible practical options (consent models) being generated by the debate are all limited because they are underpinned by a restricted notion of consent as an individualistic, legalistic and static activity, without consideration of any alternative conceptualisations of consent. Through a thematic analysis of the current 'consent to tissue banking' debate in the academic and law reform literature (Section 3), this thesis shows that debate is essentially occurring between those who see individual autonomy (and stringent consent) as being of primary importance, and those who see unimpeded, market-driven scientific progress as the more important social good, which should not be impeded by unnecessarily stringent consent. Thematic analysis also confirms the existence of the two problems described above, and a failure of those engaged in the debate to reflect on, and challenge, the value-level assumptions underpinning their arguments and those of their opponents. It is argued that this lack of reflection accounts for the two problems: • Firstly, it precludes recognition of the cause of─ and, therefore, ways of resolving─ the intractable conflict at the centre of the debate. Value-level reflection shows that this is a result of the logical and moral conflict within western liberalism, between two modernist goods: individual freedom and scientific progress. • Secondly, it precludes the generation of varied conceptions of consent. Value-level reflection shows that the current range of consent models is restricted to procedures which are individualistic, abstract, static and legalistic, since they are underpinned by western liberal notions of autonomy and scientific progress. This recognition paves the way to consideration of alternative notions of autonomy, scientific progress and, therefore, consent, such as those derived from communitarian and feminist systems of values. A conceptually enriched model of tissue banking consent is then developed (Section 4). This model incorporates dominant (liberal) conceptions of autonomy and scientific progress as well as alternative notions of autonomy and scientific progress espoused by communitarian and feminist systems of values. It is argued that this conceptually-enriched model provides a practical solution to the two problems associated with the standard 'consent to tissue banking' debate. In relation to the philosophically intractable conflict─ or what is termed the 'modernist dilemma'─ between those privileging autonomy and those privileging scientific progress, it shows how the two apparently conflicting 'modernist' goods can both be accommodated at a practical level, thus making the 'consent to tissue banking' debate more tractable and fruitful. In relation to the restricted range of consent models being generated by the current debate, it provides new insights into the ways in which consent might be obtained such that a broader range of community values can be accommodated. More specifically, it stimulates the construction of a model that 1) involves communities, as opposed to merely individuals, in all stages of the scientific process; 2) is flexible and able to adapt consent procedures to specific contexts, rather than predefining procedures in abstract terms; and 3) is transactional and relational rather than static and legalistic. This outcome has interesting philosophical as well as practical implications. It shows that despite apparently unresolved, and possibly irresolvable, normative-level conflicts between the two modernist elements of western liberalism (autonomy and scientific progress), and between liberal, feminist and communitarian systems of values, a multi-perspectival, inclusive, model-building approach provides a practical solution that circumvents these normative-level conflicts