The drug efflux protein, P-glycoprotein, additionally protects drug-resistant tumor cells from multiple forms of caspase-dependent apoptosis

Multidrug resistance mediated by the drug efflux protein, P-glycoprotein (P-gp), is one mechanism that tumor cells use to escape death induced by chemotherapeutic agents. However, the mechanism by which P-gp confers resistance to a large variety of structurally diverse molecules has remained elusive. In this study, classical multidrug resistant human CEM and K562 tumor cell lines expressing high levels of P-gp were less sensitive to multiple forms of caspase-dependent cell death, including that mediated by cytotoxic drugs and ligation of Fas. The DNA fragmentation and membrane damage inflicted by these stimuli were defined as caspase dependent by various soluble peptide fluoromethylketone caspase inhibitors. Inhibition of P-gp function by the anti-P-gp mAb MRK-16 or verapamil could reverse resistance to these forms of cell death. Inhibition of P-gp function also enhanced drug or Fas-mediated activation of caspase-3 in drug-resistant CEM cells. By contrast, caspase-independent cell death events in the same cells, including those mediated by pore-forming proteins or intact NK cells, were not affected by P-gp expression. These observations suggest that, in addition to effluxing drugs, P-gp may play a specific role in regulating some caspase-dependent apoptotic pathways.

Folding and activity of circularly permuted forms of a polytopic membrane protein

The transmembrane subunit of the Glc transporter (IICBGlc), which mediates uptake and concomitant phosphorylation of glucose, spans the membrane eight times. Variants of IICBGlc with the native N and C termini joined and new N and C termini in the periplasmic and cytoplasmic surface loops were expressed in Escherichia coli. In vivo transport/in vitro phosphotransferase activities of the circularly permuted variants with the termini in the periplasmic loops 1 to 4 were 35/58, 32/37, 0/3, and 0/0% of wild type, respectively. The activities of the variants with the termini in the cytoplasmic loops 1 to 3 were 0/25, 0/4 and 24/70, respectively. Fusion of alkaline phosphatase to the periplasmic C termini stabilized membrane integration and increased uptake and/or phosphorylation activities. These results suggest that internal signal anchor and stop transfer sequences can function as N-terminal signal sequences in a circularly permuted α-helical bundle protein and that the orientation of transmembrane segments is determined by the amino acid sequence and not by the sequential appearance during translation. Of the four IICBGlc variants with new termini in periplasmic loops, only the one with the discontinuity in loop 4 is inactive. The sequences of loop 4 and of the adjacent TM7 and TM8 are conserved in all phosphoenolpyruvate-dependent carbohydrate:phosphotransferase system transporters of the glucose family.

Genetic control of resistance to experimental infection with virulent Mycobacterium tuberculosis

Over 2 billion people are estimated to be infected with virulent Mycobacterium tuberculosis, yet fewer than 10% progress to clinical tuberculosis within their lifetime. Twin studies and variations in the outcome of tuberculosis infection after exposure to similar environmental risks suggest genetic heterogeneity among individuals in their susceptibility to disease. In a mouse model of tuberculosis, we have established that resistance and susceptibility to virulent M. tuberculosis is a complex genetic trait. A new locus with a major effect on tuberculosis susceptibility, designated sst1 (susceptibility to tuberculosis 1), was mapped to a 9-centimorgan (cM) interval on mouse chromosome 1. It is located 10–19 cM distal to a previously identified gene, Nramp1, that controls the innate resistance of mice to the attenuated bacillus Calmette–Guérin vaccine strain. The phenotypic expression of the newly identified locus is distinct from that of Nramp1 in that sst1 controls progression of tuberculosis infection in a lung-specific manner. Mice segregating at the sst1 locus exhibit marked differences in the growth rates of virulent tubercle bacilli in the lungs. Lung lesions in congenic sst1-susceptible mice are characterized by extensive necrosis and unrestricted extracellular multiplication of virulent mycobacteria, whereas sst1-resistant mice develop interstitial granulomas and effectively control multiplication of the bacilli. The resistant allele of sst1, although powerful in controlling infection, is not sufficient to confer full protection against virulent M. tuberculosis, indicating that other genes located outside of the sst1 locus are likely also to be important for controlling tuberculosis infection.

Acridones: a chemically new group of protonophores.

Although the interaction of proton-conducting ionophores (protonophores) with photosynthetic electron transport has been extensively studied during the past decade, the mode of action of protonophores remained uncertain. For a better understanding of the molecular mechanism of the action of protonophores, the introduction of chemically new types of molecules will be required. In this work, we demonstrate that acridones (9-azaanthracene-10-ones) completely fulfill this requirement. At low concentrations of acridones, the thermoluminescence bands at +20 degrees C and +10 degrees C were strongly inhibited, while normal electron transport activity was retained. This indicates that the concentrations of S2 and S3 states involved in the generation of these bands are reduced. At higher concentrations, an increased activity of electron transport was observed, which is attributed to the typical uncoupler effect of protonophores. Indeed, acridones accelerate the decay of the electrochromic absorbance change at 515 nm and also inhibit the generation of the transmembrane proton gradient, measured as an absorbance transient of neutral red. Variable fluorescence induction was quenched even at low concentrations of acridones but was restored by either a long-term illumination or high light intensity. Acridones, similarly to other protonophores, promoted the autooxidation of the high-potential form of cytochrome b559 and partially converted it to lower potential forms. These results suggest that acridones, acting as typical protonophores, uncouple electron transport, accelerate the deactivation of the S2 and S3 states on the donor side, and facilitate the oxidation of cytochrome b559 on the acceptor side of photosystem II.

Identification of the local productive systems in Spain: a new approach

Paper submitted to the 44th European Congress of the European Regional Science Association, Porto, 25-29 August 2004.

Cultural Politics of Resilience in Kingston, Jamaica

Recently, resilience has become a catchall solution for some of the world’s most pressing ecological, economic and social problems. This dissertation analyzes the cultural politics of resilience in Kingston, Jamaica by examining them through their purported universal principles of adaptation and flexibility. On the one hand, mainstream development regimes conceptualize resilience as a necessary and positive attribute of economies, societies and cultures if we are to survive any number of disasters or disturbances. Therefore, in Jamaican cultural and development policy resilience is championed as both a means and an end of development. On the other hand, critics of resilience see the new rollout of resilience projects as deepening neoliberalism, capitalism and new forms of governmentality because resilience projects provide the terrain for new forms of securitization and surveillance practices. These scholars argue that resilience often forecloses the possibilities to resist that which threatens us. However, rather than dismissing resilience as solely a sign of domination and governmentality, this dissertation argues that resilience must be understood as much more ambiguous and complex, rather than within binaries such as subversion vs. neoliberal and resistance vs. resilience. Overly simplistic dualities of this nature have been the dominant approach in the scholarship thus far. This dissertation provides a close analysis of resilience in both multilateral and Jamaican government policy documents, while exploring the historical and contemporary production of resilience in the lives of marginalized populations. Through three sites within Kingston, Jamaica—namely dancehall and street dances, WMW-Jamaica and the activist platform SO((U))L HQ—this dissertation demonstrates that “resilience” is best understood as an ambiguous site of power negotiations, social reproduction and survival in Jamaica today. It is often precisely this ambiguous power of ordinary resilience that is capitalized on and exploited to the detriment of vulnerable groups. At once demonstrating creative negotiation and reproduction of colonial capitalist social relations within the realms of NGO, activist work and cultural production, this dissertation demonstrates the complexity of resilience. Ultimately, this dissertation draws attention to the importance of studying spaces of cultural production in order to understand the power and limits of contemporary policy discourses and political economy. 

The larger forms of musical composition; an exhaustive explanation of the variations, rondos, and sonata designs, for the general student of musical analysis, and for the special student of structural composition,

"A sequel to the Homophonic forms and Applied counterpoint."--Pref.

Counterpoint applied in the invention, fugue, canon and other polyphonic forms; an exhaustive treatise on the structural and formal details of the polyphonic or contrapuntal forms of music, for the use of general and special students of music,

At head of title: Thirteenth issue.

The homophonic forms of musical composition, an exhaustive treatise on the structure and development of musical forms ...

Mode of access: Internet.

Evenings at the microscope : or, Researches among the minuter organs and forms of animal life /

Originally published in London, 1859.

The American debater : being a plain exposition of the principles and practice of public debate, wherein will be found an account of the qualifications necessary to a good deliberative orator, as also the mode of acquiring them, the rules of order observed in deliberative assemblies, debates in full and in outline, on various interesting topics, numerous questions for discussion, forms of a constitution for literary clubs or debating societies, etc., etc. /

Publishers include Moore, Wilstach, Keys & Co., Cincinnati.

Invitation to contractors and forms of contract, bond andcontractor's proposal for construction of a part of the ... Rapid transit railroad ... Form finaly adopted by the Commission ...

Some numbers have special subtitles, as follows: no. 5, sect. 8/11, "proposal for installation of cable feed pipes..." no. 16/18/36/37 [combined] "proposal for construction of signal towers..." no. 18 (180th street and 239th street yards)" proposal for furnishing and erecting structural steel for inspection sheds..." no. 19/22, sect. 2. "proposal for erection of structural steel..." no. 49, sect. 1/2, "proposal for construction of concrete track floors and platforms ..." no. 49, sect. 3, "proposal for the supply of structural steel ..."

Invitation to contractors, information for contractors and forms of contract, bond and contractor's proposal for construction of station finish for a part of the ... rapid transit railroad ... Form finally adopted by the Commission ...

No. 36/37 & 50, sect. 1-3. Queensboro subway.--No. 39, sect. 2. Broadway - Fourth avenue (New Utrecht avenue) - No. 43, 4/38, see no. 4/38, 43.--No. 48, sect. 1-2. Seventh avenue - Lexington avenue.--No. 50. Queensboro subway (Hunters Point avenue station

Invitation to contractors, information for contractors and forms of contract, bond and contractor's proposal for the supply of ... [materials] for use in the construction of rapid transit railroads.

On covers: Contract for the supply of ... [materials] Order [s] ...

The voice of the church one : under all the successive forms of Christianity... /

Mode of access: Internet.