Approaches to Global Citizenship

James Tully, University of Virginia, describes two different yet overlapping modes of global citizenship which he calls liberal and democratic global citizenship. More information ... Respondent: Louis-Philippe Hodgson, York University, Dept. of Philosoph

Approaches to Global Citizenship

James Tully, University of Virginia, describes two different yet overlapping modes of global citizenship which he calls liberal and democratic global citizenship. More information ... Respondent: Louis-Philippe Hodgson, York University, Dept. of Philosoph

Evaluating the environmental dimension of material efficiency strategies relating to the circular economy.

Material efficiency is a key element of new thinking to address the challenges of reducing impacts on the environment and of resource scarcity, whilst at the same time meeting service and functionality demands on materials. Directly related to material efficiency is the concept of the Circular Economy, which is based on the principle of optimising the utility embodied in materials and products through the life-cycle. Although materials such as steel, on account of high recycling rates at end-of-life, are amongst the most ‘circular’ of manufactured materials, significant opportunities for greater material efficiency exist, which are yet to be widely implemented. Life Cycle Assessment (LCA) is commonly used to assess the environmental benefits of recovering and recycling materials through the manufacturing supply chain and at end-of-life. Using an example taken from renewable energy generation, this paper explores the correlation between product circularity and the environmental case for strategies designed to improve material efficiency. An LCA-based methodology for accounting for the recovery and reuse of materials from the supply chain and at end-of-life is used as the basis for calculating the carbon footprint benefits of five material efficiency scenarios. The results are compared with a number of proposed material circularity indicators. Two conclusions from this exercise are that (i) LCA methodologies based around end-of-life approaches are well placed for quantifying the environmental benefits of material efficiency and circular economy strategies and (ii) when applying indicators relating to the circularity of materials these should also be supported by LCA-based studies.N/

The synthesis, conformation and hydrolytic stability of an N,S-bridging thiophosphoramidate analogue of thymidylyl-3 ',5 '-thymidine

A 3 ’ - N ,5 ’ - S -bridging thiophosphoramidate analogue of thymidylyl-3 ’ ,5 ’ -thymidine was synthesised underaqueous conditions.1H NMR conformational measurements show that the 3 ’ - N -substituted deoxyribosering is biased towards the ‘ north ’ , RNA-like conformation. Rate constants for hydrolysis of the analoguewere measured at 90 °C in the pH range 1.3 – 10.9. The pH-log k obs pro fi le displays a pH-independentregion between approximately pH 7 and 10 ( t 1/2 ∼ 13 days). Under acidic conditions, k obs displays a fi rstorder dependence on [H 3 O+]</p

A RhoC Biosensor Reveals Differences in the Activation Kinetics of RhoA and RhoC in Migrating Cells

RhoA and RhoC GTPases share 92% amino acid sequence identity, yet play different roles in regulating cell motility and morphology. To understand these differences, we developed and validated a biosensor of RhoC activation (RhoC FLARE). This was used together with a RhoA biosensor to compare the spatio-temporal dynamics of RhoA and RhoC activity during cell protrusion/retraction and macropinocytosis. Both GTPases were activated similarly at the cell edge, but in regions more distal from the edge RhoC showed higher activation during protrusion. The two isoforms differed markedly in the kinetics of activation. RhoC was activated concomitantly with RhoA at the cell edge, but distally, RhoC activation preceded RhoA activation, occurring before edge protrusion. During macropinocytosis, differences were observed during vesicle closure and in the area surrounding vesicle formation

Optogenetic regulation of endogenous proteins

Techniques of protein regulation, such as conditional gene expression, RNA interference, knock-in and knock-out, lack sufficient spatiotemporal accuracy, while optogenetic tools suffer from non-physiological response due to overexpression artifacts. Here we present a near-infrared light-activatable optogenetic system, which combines the specificity and orthogonality of intrabodies with the spatiotemporal precision of optogenetics. We engineer optically-controlled intrabodies to regulate genomically expressed protein targets and validate the possibility to further multiplex protein regulation via dual-wavelength optogenetic control. We apply this system to regulate cytoskeletal and enzymatic functions of two non-tagged endogenous proteins, actin and RAS GTPase, involved in complex functional networks sensitive to perturbations. The optogenetically-enhanced intrabodies allow fast and reversible regulation of both proteins, as well as simultaneous monitoring of RAS signaling with visible-light biosensors, enabling all-optical approach. Growing number of intrabodies should make their incorporation into optogenetic tools the versatile technology to regulate endogenous targets. Optogenetic approaches to control protein-protein interactions usually require overexpression of the target proteins. Here the authors integrate intrabodies into near-infrared- and blue-light activatable optogenetic tools to control endogenous proteins in mammalian cells.Peer reviewe

Variant histology, IgD and CD30 expression in low‐risk pediatric nodular lymphocyte predominant Hodgkin lymphoma: A report from the Children’s Oncology Group

BackgroundHistologic prognostic factors have been described for nodular lymphocyte predominant Hodgkin lymphoma (NLPHL). This study examines histologic and immunophenotypic variants in a clinical trial for pediatric NLPHL.ProcedureOne hundred sixty‐eight cases of localized NLPHL were examined for histologic variants, CD30 and immunoglobulin D (IgD) expression, and outcome. Histologic types were scored categorically as 0 = 0, 1 ≤ 25%, and 2 > 25% of the sample.ResultsFifty‐eight (35.1%) cases showed only typical nodular with or without serpiginous histology (types A and B). The remainder showed mixtures of histologies. The numbers of patients with score 2 are 85 (50.6%) type A, 21 (12.5%) type B, 46 (27.4%) with extranodular large B cells (type C), 3 with T‐cell‐rich nodular pattern (type D), 55 (32.7%) with diffuse T‐cell‐rich (type E) pattern, and 2 (1.2%) with diffuse B‐cell pattern (type F). Higher level of types C (P = 0.048) and D (P = 0.033) resulted in lower event‐free survival (EFS). Cytoplasmic IgD was found in 65 of 130 tested (50%), did not significantly associate with EFS but positively correlated with types C and E histology (P < 0.0001) and negatively correlated with types A (P = 0.0003) and B (P = 0.006). Seventeen (10%) expressed CD30, with no adverse effect.ConclusionsVariant histology is common in pediatric NLPHL, especially types C and E, which are associated with IgD expression. Type C variant histology and possibly type D are associated with decreased EFS, but neither IgD nor CD30 are adverse features. Variant histology may warrant increased surveillance, but did not affect overall survival.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139999/1/pbc26753_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139999/2/pbc26753.pd

A Biosensor of S100A4 Metastasis Factor Activation: Inhibitor Screening and Cellular Activation Dynamics †

S100A4, a member of the S100 family of Ca2+-binding proteins, displays elevated expression in malignant human tumors compared with benign tumors, and increased expression correlates strongly with poor patient survival. S100A4 has a direct role in metastatic progression, likely due to the modulation of actomyosin cytoskeletal dynamics, which results in increased cellular motility. We developed a fluorescent biosensor (Mero-S100A4) that reports on the Ca2+-bound, activated form of S100A4. Direct attachment of a novel solvatochromatic reporter dye to S100A4 results in a sensor that, upon activation, undergoes a 3-fold enhancement in fluorescence, thus providing a sensitive assay for use in vitro and in vivo. In cells, localized activation of S100A4 at the cell periphery is observed during random migration and following stimulation with lysophosphatidic acid, a known activator of cell motility and proliferation. Additionally, a screen against a library of FDA-approved drugs with the biosensor identified an array of phenothiazines as inhibitors of myosin-II associated S100A4 function. These data demonstrate the utility of the new biosensor both for drug discovery and for probing the cellular dynamics controlled by the S100A4 metastasis factor

The Durban World Congress Ethics Round Table Conference Report: II. Withholding or withdrawing of treatment in elderly patients admitted to the intensive care unit

Introduction: Life-sustaining treatment (LST) limitation for elderly patients is highly controversial. In that context, it is useful to evaluate the attitudes to LST in the elderly among experienced intensive care unit (ICU) physicians with different backgrounds and cultures. Methods: A panel of 22 international ICU physicians from 13 countries responded to a questionnaire related to withholding (WH) and withdrawing (WD) LST in elderly patients using a semi-Likert scale. Results: Most experts disagree or strongly disagree (77%) that age should be used as the sole criterion for WH or WD LST, and almost all disagree (91%) that there should be a specific age for such decision making. However, the vast majority (91%) acknowledge that age should be an important consideration in conjunction with other factors. Disagreement for consideration of prioritizing the young over the old in normal ICU operations was reported in 68%, whereas in an emergency triage situation, disagreement dropped to 18%. Conclusions: There is a consensus among ICU physicians that age cannot be the sole criterion on which health care decisions should be made. In that perspective, it is important to provide data showing that outcome differences between elderly and nonelderly patients are partly related to decisions to forgo LSTs

Direct multiplex imaging and optogenetics of Rho GTPases enabled by near-infrared FRET

Direct visualization and light control of several cellular processes is a challenge, owing to the spectral overlap of available genetically encoded probes. Here we report the most red-shifted monomeric near-infrared (NIR) fluorescent protein, miRFP720, and the fully NIR Forster resonance energy transfer (FRET) pair miRFP670-miRFP720, which together enabled design of biosensors compatible with CFP-YFP imaging and blue-green optogenetic tools. We developed a NIR biosensor for Rac1 GTPase and demonstrated its use in multiplexed imaging and light control of Rho GTPase signaling pathways. Specifically, we combined the Rac1 biosensor with CFP-YFP FRET biosensors for RhoA and for Rac1-GDI binding, and concurrently used the LOV-TRAP tool for upstream Rac1 activation. We directly observed and quantified antagonism between RhoA and Rac1 dependent on the RhoA-downstream effector ROCK; showed that Rac1 activity and GDI binding closely depend on the spatiotemporal coordination between these two molecules; and simultaneously observed Rac1 activity during optogenetic manipulation of Rac1.Peer reviewe