A Balancing Act: Reading \u27Amoris Laetitia\u27

Five religious scholars provide commentary on Amoris Laetitia (The Joy of Love), Pope Francis\u27s 2016 apostolic exhortation on love in the family

Critical Thinking Activities and the Enhancement of Ethical Awareness: An application of a ‘Rhetoric of Disruption’ to the undergraduate general education classroom

This article explores how critical thinking activities and assignments can function to enhance students’ ethical awareness and sense of civic responsibility. Employing Levinas’s Othercentered theory of ethics, Burke’s notion of ‘the paradox of substance’, and Murray’s concept of ‘a rhetoric of disruption’, this article explores the nature of critical thinking activities designed to have students question their (often taken-for-granted) moral assumptions and interrogate their (often unexamined) moral identities. This article argues that such critical thinking activities can trigger a metacognitive destabilization of subjectivity, understood as a dialectical prerequisite (along with exposure to otherness) for increased ethical awareness. This theoretical model is illustrated through a discussion of three sample classroom activities designed to destabilize moral assumptions and identity, thereby clearing the way for a heightened acknowledgment of otherness. In so doing, this article provides an alternative (and dialectically inverted) strategy for addressing one of the central goals of many General Education curricula: the development of ethical awareness and civic responsibility. Rather than introducing students to alternative perspectives and divergent cultures with the expectation that heightened moral awareness will follow, this article suggests classroom activities and course assignments aimed at disrupting moral subjectivity and creating an opening in which otherness can be more fully acknowledged and the diversity of our world more fully appreciated

MDR1 causes resistance to the antitumour drug miltefosine

Miltefosine (hexadecylphosphocholine) is used for topical treatment of breast cancers. It has been shown previously that a high percentage of breast carcinomas express MDR1 or MRP. We investigated the sensitivity of MDR1 -expressing cells to treatment with miltefosine. We show that cells overexpressing MDR1 (NCI/ADR-RES, KB-8-5, KB-C1, CCRF/VCR1000, CCRF/ADR5000) were less sensitive to miltefosine treatment when compared to the sensitive parental cell lines. HeLa cells transfected with MDR1 exhibited resistance to the compound, indicating that expression of this gene is sufficient to reduce the sensitivity to miltefosine. The resistance of MDR1 -expressing cells to miltefosine was less pronounced than that to adriamycin or vinblastine. Expression of MDR2 did not correlate with the resistance to miltefosine. As shown by a fluorescence quenching assay using MIANS-labelled P-glycoprotein (PGP), miltefosine bound to PGP with a K d of approximately 7 μM and inhibited PGP-ATPase activity with an IC 50 of approximately 35 μM. Verapamil was not able to reverse the resistance to miltefosine. Concentrations of miltefosine up to approximately 60 μM stimulated, whereas higher concentrations inhibited the transport of [3H]-colchicine with an IC 50 of approximately 297 μM. Binding studies indicated that miltefosine seems to interact with the transmembrane domain and not the cytosolic nucleotide-binding domain of PGP. These data indicate that expression of MDR1 may reduce the response to miltefosine in patients and that this compound interacts with PGP in a manner different from a number of other substrates. © 2001 Cancer Research Campaign www.bjcancer.co

Proton Motive Force-Dependent Hoechst 33342 Transport by the ABC Transporter LmrA of Lactococcus lactis

The fluorescent compound Hoechst 33342 is a substrate for many multidrug resistance (MDR) transporters and is widely used to characterize their transport activity. We have constructed mutants of the adenosine triphosphate (ATP) binding cassette (ABC)-type MDR transporter LmrA of Lactococcus lactis that are defective in ATP hydrolysis. These mutants and wild-type LmrA exhibited an atypical behavior in the Hoechst 33342 transport assay. In membrane vesicles, Hoechst 33342 transport was shown to be independent of the ATPase activity of LmrA, and it was not inhibited by orthovanadate but sensitive to uncouplers that collapse the proton gradient and to N,N'-dicyclohexylcarbodiimide, an inhibitor of the F0F1-ATPase. In contrast, transport of Hoechst 33342 by the homologous, heterodimeric MDR transporter LmrCD showed a normal ATP dependence and was insensitive to uncouplers of the proton gradient. With intact cells, expression of LmrA resulted in an increased rate of Hoechst 33342 influx while LmrCD caused a decrease in the rate of Hoechst 33342 influx. Cellular toxicity assays using a triple knockout strain, i.e., L. lactis ΔlmrA ΔlmrCD, demonstrate that expression of LmrCD protects cells against the growth inhibitory effects of Hoechst 33342, while in the presence of LmrA, cells are more susceptible to Hoechst 33342. Our data demonstrate that the LmrA-mediated Hoechst 33342 transport in membrane vesicles is influenced by the transmembrane pH gradient due to a pH-dependent partitioning of Hoechst 33342 into the membrane.

P-glycoprotein-mediated resistance to chemotherapy in cancer cells: using recombinant cytosolic domains to establish structure-function relationships

Estão abertas as inscrições para o concurso Jovens Criadores 2008, iniciativa conjunta do Instituto Português da Juventude e do Clube Português de Artes e Ideias e destinada a dar a conhecer artistas em início de carreira (até aos 30 anos), de nacionalidade portuguesa ou residentes no país.As áreas a concurso são Artes Plásticas, Banda Desenhada, Ilustração, Ciber Arte, Fotografia, Vídeo, Dança, Música, Design de Equipamento, Design Gráfico, Joalharia, Moda e Literatura.Inscrições até 12 de M..

P-glycoprotein-mediated resistance to chemotherapy in cancer cells: using recombinant cytosolic domains to establish structure-function relationships

Resistance to chemotherapy in cancer cells is mainly mediated by overexpression of P-glycoprotein (Pgp), a plasma membrane ATP-binding cassette (ABC) transporter which extrudes cytotoxic drugs at the expense of ATP hydrolysis. Pgp consists of two homologous halves each containing a transmembrane domain and a cytosolic nucleotide-binding domain (NBD) which contains two consensus Walker motifs, A and B, involved in ATP binding and hydrolysis. The protein also contains an S signature characteristic of ABC transporters. The molecular mechanism of Pgp-mediated drug transport is not known. Since the transporter has an extraordinarily broad substrate specificity, its cellular function has been described as a "hydrophobic vacuum cleaner". The limited knowledge about the mechanism of Pgp, partly due to the lack of a high-resolution structure, is well reflected in the failure to efficiently inhibit its activity in cancer cells and thus to reverse multidrug resistance (MDR). In contrast to the difficulties encountered when studying the full-length Pgp, the recombinant NBDs can be obtained in large amounts as soluble proteins. The biochemical and biophysical characterization of recombinant NBDs is shown here to provide a suitable alternative route to establish structure-function relationships. NBDs were shown to bind ATP and analogues as well as potent modulators of MDR, such as hydrophobic steroids, at a region close to the ATP site. Interestingly, flavonoids also bind to NBDs with high affinity. Their binding site partly overlaps both the ATP-binding site and the steroid-interacting region. Therefore flavonoids constitute a new promising class of bifunctional modulators of Pgp