19 research outputs found
An orally bioavailable antipoxvirus compound (ST-246) inhibits extracellular virus formation and protects mice from lethal orthopoxvirus challenge
No full textST-246 is a low-molecular-weight compound (molecular weight=376), that is potent (concentration that inhibited virus replication by 50%=0.010 micro M), selective (concentration of compound that inhibited cell viability by 50%=>40 micro M), and active against multiple orthopoxviruses, including vaccinia, monkeypox, camelpox, cowpox, ectromelia (mousepox), and variola viruses. Cowpox virus variants selected in cell culture for resistance to ST-246 were found to have a single amino acid change in the V061 gene. Reengineering this change back into the wild-type cowpox virus genome conferred resistance to ST-246, suggesting that V061 is the target of ST-246 antiviral activity. The cowpox virus V061 gene is homologous to vaccinia virus F13L, which encodes a major envelope protein (p37) required for production of extracellular virus. In cell culture, ST-246 inhibited plaque formation and virus-induced cytopathic effects. In single-cycle growth assays, ST-246 reduced extracellular virus formation by 10 fold relative to untreated controls, while having little effect on the production of intracellular virus. In vivo oral administration of ST-246 protected BALB/c mice from lethal infection, following intranasal inoculation with 10x 50% lethal dose (LD50) of vaccinia virus strain IHD-J. ST-246-treated mice that survived infection acquired protective immunity and were resistant to subsequent challenge with a lethal dose (10x LD50) of vaccinia virus. Orally administered ST-246 also protected A/NCr mice from lethal infection, following intranasal inoculation with 40 000x LD50 of ectromelia virus. Infectious virus titers at day 8 postinfection in liver, spleen, and lung from ST-246-treated animals were below the limits of detection (<10 PFU/ml). In contrast, mean virus titers in liver, spleen, and lung tissues from placebo-treated mice were 6.2x107, 5.2x107, and 1.8x105 PFU/ml, respectively. Finally, oral administration of ST-246 inhibited vaccinia virus-induced tail lesions in Naval Medical Research Institute mice inoculated via the tail vein. Taken together, these results validate F13L as an antiviral target and demonstrate that an inhibitor of extracellular virus formation can protect mice from orthopoxvirus-induced disease..Source type: Electronic(1
The impact of heat waves on mortality.
No full textBACKGROUND: Heat waves have been linked with an increase in mortality, but the associated risk has been only partly characterized. METHODS: We examined this association by decomposing the risk for temperature into a "main effect" due to independent effects of daily high temperatures, and an "added" effect due to sustained duration of heat during waves, using data from 108 communities in the United States during 1987-2000. We adopted different definitions of heat-wave days on the basis of combinations of temperature thresholds and days of duration. The main effect was estimated through distributed lag nonlinear functions of temperature, which account for nonlinear delayed effects and short-time harvesting. We defined the main effect as the relative risk between the median city-specific temperature during heat-wave days and the 75th percentile of the year-round distribution. The added effect was defined first using a simple indicator, and then a function of consecutive heat-wave days. City-specific main and added effects were pooled through univariate and multivariate meta-analytic techniques. RESULTS: The added wave effect was small (0.2%-2.8% excess relative risk, depending on wave definition) compared with the main effect (4.9%-8.0%), and was apparent only after 4 consecutive heat-wave days. CONCLUSIONS: Most of the excess risk with heat waves in the United States can be simply summarized as the independent effects of individual days' temperatures. A smaller added effect arises in heat waves lasting more than 4 days
Experimental and theoretical analysis of vacuum circuit breaker prestrike effect on a transformer
No full textThe work presented in this paper deals with the investigation of circuit breaker prestrike effect that occurs during energizing a distribution transformer. An experimental test setup that consists of a supply transformer, a vacuum circuit breaker (VCB), a cable and a test transformer is built, and the prestrikes in the VCB are recorded. The test transformer is a prototype distribution transformer, with installed measuring points along transformer windings in each phase. Voltage oscillations are measured along the windings and transformer terminals. The transformer is modeled by lumped parameters extracted from telegrapher's equations in discrete form. Voltage oscillations during switching-in operations are recorded and calculated with and without a cable installed between the VCB and the transformer. Computed voltages show good agreement with the measured voltages. Described method can be used by transformer manufacturers to estimate voltage wave forms during switching or lightning, to provide useful information for insulation coordination studies, and to investigate resonance effects in transformer windings.Electrical Sustainable EnergyElectrical Engineering, Mathematics and Computer Scienc
Conceptual Metaphors, Geography, Literature, and the Implications on the In-place or Out-of-place of People and Actions
No full textThere are three primary aims of this study: first, to investigate how geographical locations, countries of origins, building typologies, and vehicles/machines are presented as source domains frequently activated in metaphorical linguistic expressions to
point to entangled socio-economical, environmental, and political issues within Douglas Coupland's narratives. Second, to discuss the ways in which the author juggles what is coherent/incoherent with a mainstream spatialization or orientational metaphor; third, to ascertain if, beyond the author’s interest in “his geographical and historical surroundings” (McGill, 2000) and beyond his need to portray a subcultural logic of priorities, geographical metaphors allow Coupland to borrow labels of origin, both global and localised ones, and reshape them as a way of thinking that is socio-political and post-colonial in scope, questioning what is proper or inappropriate and for whom. A collection of evidence from different novels will be provided and analysed to demonstrate the expanded conceptual phenomenon Coupland generates from geographical metaphors “as a way of thinking and acting with geographical and political implications” (Cresswell, 1997)
Novel carbocyclic nucleoside analogs suppress glomerular mesangial cells proliferation and matrix protein accumulation through ROS-dependent mechanism in the diabetic milieu
No full textThe synthesis of a series of novel 3,4-cis- and 3,4-trans-substituted carbocyclic nucleoside analogs from protected uracil and thymine is described. The key reaction in the followed synthetic protocols utilized the Mitsunobu reaction to couple 3,4-substituted cyclopentanols to 3N-benzoyl uracil or 3N-benzoyl thymine. These molecules were evaluated with regard to their ability to treat diabetic nephropathy. Our results show that two analogs significantly reduced high-glucose induced glomerular mesangial cells proliferation and matrix protein accumulation in vitro and, more interestingly, exhibited an anti-oxidative effect suggesting that the activity may be mediated through ROS-dependent mechanism.Abboud H E, 1997, Kidney Int Suppl, V60, pS3; Al-Khalil N., 2006, THESIS AM U BEIRUT; Awazu M, 1999, J AM SOC NEPHROL, V10, P738; Balzarini J, 2000, PHARMACOL THERAPEUT, V87, P175, DOI 10.1016-S0163-7258(00)00050-4; BAYNES JW, 1991, DIABETES, V40, P405, DOI 10.2337-diabetes.40.4.405; BILOUS RW, 1989, DIABETES, V38, P1142, DOI 10.2337-diabetes.38.9.1142; Bouhadir KH, 2012, MOLECULES, V17, P1, DOI 10.3390-molecules17010001; Crimmins MT, 1998, TETRAHEDRON, V54, P9229, DOI 10.1016-S0040-4020(98)00320-2; DECLERCQ E, 1984, ANTIVIR RES, V4, P119, DOI 10.1016-0166-3542(84)90012-3; Eid AA, 2009, DIABETES, V58, P1201, DOI 10.2337-db08-1536; Eid AA, 2010, J BIOL CHEM, V285, P37503, DOI 10.1074-jbc.M110.136796; Farah M., 2007, THESIS AM U BEIRUT; HA HJ, 1994, FREE RADICAL BIO MED, V16, P271, DOI 10.1016-0891-5849(94)90152-X; Hinokio Y, 1999, DIABETOLOGIA, V42, P995, DOI 10.1007-s001250051258; ISONO K, 1991, PHARMACOL THERAPEUT, V52, P269, DOI 10.1016-0163-7258(91)90028-K; JENNY TF, 1991, TETRAHEDRON LETT, V32, P7029, DOI 10.1016-0040-4039(91)85031-Y; Koya D, 2003, J AM SOC NEPHROL, V14, P250; Kuroki T, 2003, J AM SOC NEPHROL, V14, P216; Lee H. B., 2003, J AM SOC NEPHROL, V14, P241; Ludek OR, 2003, NUCLEOS NUCLEOT NUCL, V22, P683, DOI 10.1081-NCN-120022700; MATTHEWS DP, 1993, BIOORG MED CHEM LETT, V3, P165, DOI 10.1016-S0960-894X(01)80869-6; Onozato ML, 2002, KIDNEY INT, V61, P186, DOI 10.1046-j.1523-1755.2002.00123.x; Phillips Aled O, 2003, Curr Diab Rep, V3, P491, DOI 10.1007-s11892-003-0013-1; Sano T, 1998, DIABETOLOGIA, V41, P1355, DOI 10.1007-s001250051076; Schnackenberg CG, 2002, CURR OPIN PHARMACOL, V2, P121, DOI 10.1016-S1471-4892(02)00133-9; SHANNON WM, 1980, PHARMACOL THERAPEUT, V11, P263, DOI 10.1016-0163-7258(80)90034-0; Shatila RS, 2006, TETRAHEDRON LETT, V47, P1767, DOI 10.1016-j.tetlet.2006.01.035; Tsai JY, 2003, J ORG CHEM, V68, P1235, DOI 10.1021-jo026379k; Wolf Gunter, 2003, Curr Diab Rep, V3, P485, DOI 10.1007-s11892-003-0012-2; Wolf G, 1999, KIDNEY INT, V56, P393, DOI 10.1046-j.1523-1755.1999.00590.x; YOUNG BA, 1995, KIDNEY INT, V47, P935, DOI 10.1038-ki.1995.139; Zhou JL, 1999, SYNTHETIC COMMUN, V29, P3003, DOI 10.1080-00397919908086475; Zhou JL, 1997, TETRAHEDRON LETT, V38, P4037, DOI 10.1016-S0040-4039(97)00867-8; ZIYADEH FN, 1993, AM J KIDNEY DIS, V22, P736; Ziyadeh FN, 2000, P NATL ACAD SCI USA, V97, P8015, DOI 10.1073-pnas.12005509723
The tale of TILs in breast cancer: A report from The International Immuno-Oncology Biomarker Working Group
No full textThe advent of immune-checkpoint inhibitors (ICI) in modern oncology has significantly improved survival in several cancer settings. A subgroup of women with breast cancer (BC) has immunogenic infiltration of lymphocytes with expression of programmed death-ligand 1 (PD-L1). These patients may potentially benefit from ICI targeting the programmed death 1 (PD-1)/PD-L1 signaling axis. The use of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarkers has been under intense examination. Emerging data suggest that TILs are associated with response to both cytotoxic treatments and immunotherapy, particularly for patients with triple-negative BC. In this review from The International Immuno-Oncology Biomarker Working Group, we discuss (a) the biological understanding of TILs, (b) their analytical and clinical validity and efforts toward the clinical utility in BC, and (c) the current status of PD-L1 and TIL testing across different continents, including experiences from low-to-middle-income countries, incorporating also the view of a patient advocate. This information will help set the stage for future approaches to optimize the understanding and clinical utilization of TIL analysis in patients with BC. (Group author: Int Immuno-Oncology Biomarker
The Efficiency of a Group-Specific Mandated Benefit Revisited: The Effect of Infertility Mandates
No full textThis paper examines the labor market effects of state health insurance mandates that increase the cost of employing a demographically identifiable group. State mandates requiring that health insurance plans cover infertility treatment raise the relative cost of insuring older women of child-bearing age. Empirically, wages in this group are unaffected, but their total labor input decreases. Workers do not value infertility mandates at cost, and so will not take wage cuts in exchange, leading employers to decrease their demand for this affected and identifiable group. Differences in the empirical effects of mandates found in the literature are explained by a model including variations in the elasticity of demand, moral hazard, ability to identify a group, and adverse selection.labor supply, infertility, health insurance, health insurance mandates
Interpersonal and affective dimensions of psychopathic traits in adolescents : development and validation of a self-report instrument
No full textWe report the development and psychometric evaluations of a self-report instrument designed to screen for psychopathic traits among mainstream community adolescents. Tests of item functioning were initially conducted with 26 adolescents. In a second study the new instrument was administered to 150 high school adolescents, 73 of who had school records of suspension for antisocial behavior. Exploratory factor analysis yielded a 4-factor structure (Impulsivity α = .73, Self-Centredness α = .70, Callous-Unemotional α = .69, and Manipulativeness α = .83). In a third study involving 328 high school adolescents, 130 with records of suspension for antisocial behaviour, competing measurement models were evaluated using confirmatory factor analysis. The superiority of a first-order model represented by four correlated factors that was invariant across gender and age was confirmed. The findings provide researchers and clinicians with a psychometrically strong, self-report instrument and a greater understanding of psychopathic traits in mainstream adolescents
Forecasting the demand for privatized transport - What economic regulators should know, and why
No full textForecasting has long been a challenge, and will remain so for the foreseeable future. But the analytical instruments and data processing capabilities available through the latest technology, and software, should allow much better forecasting than transport ministries, or regulatory agencies typically observe. Privatization brings new needs for demand forecasting. More attention is paid to risk under privatization, than when investments are publicly financed. And regulators must be able to judge traffic studies done by operators, and to learn what strategic behavior influenced these studies. Many governments, and regulators avoid good demand, modeling out of lack of conviction that theory, and models can do better than the"old hands"of the sector. This is dangerous when privatization changes the nature of business. For projects amounting to investments of 100,000-200,000 is not a reason to reject a reasonable modeling effort. And some private forecasting firms are willing to sell guarantees, or insurance with their forecasts, to cover significant gaps between forecasts, and reality.Markets and Market Access,Environmental Economics&Policies,Economic Theory&Research,Decentralization,Banks&Banking Reform,Markets and Market Access,Economic Theory&Research,Banks&Banking Reform,Access to Markets,Environmental Economics&Policies
Samuel Beckett and the Writers of Port-Royal
No full textIt has been observed that ‘the literary influences on Beckett have been far more important than has been acknowledged, and more important indeed, than the philosophical influences’ (Smith 2002: 3). The truth of this statement is evidenced by the description that scholars have given of Samuel Beckett’s relationship to seventeenth century French classicism. To date, critical interest has been limited for the most part to the figure of the philosopher René Descartes on the (fragile) grounds that Beckett was exclusively concerned with the Cartesian imperative of clarity and order, the fundamental dualism between body and mind, and Nominalism.
Together with the assumption that Beckett’s vision was essentially Cartesian, his literary filiation with Pascal was suggested by critics, but only in terms of Beckett’s formal approach to the theatre. In his short article on En attendant Godot in 1953, the playwright Jean Anouilh was among the first reviewers to suggest that Beckett’s drama synthesizes the encounter between ‘classicism’ and a ‘modern’ form of art. It is well known that Beckett retained a lifelong admiration for Pascal – indeed, Pascal was one of his ‘old chestnuts’ (Knowlson 1997: 653). Little attention has been paid, however, to the originality of Pascal’s thought, the specific nature of his prose, and the impact these might have had upon Beckett’s mature work, especially the trilogy and the subsequent short prose. Yet, in the literary and philosophical context of post-war France, Beckett’s filiation with Pascal, their corresponding preoccupations, were evident to his contemporaries, who identified Pascal as an underlying presence in his works
