P-glycoproteins encoded by mdr 1b in murine gravid uterus and multidrug resistant tumor cell lines are differentially glycosylated

AbstractThere are 3 members of the multidrug-resitance gene family expressed in mouse. Only one of these, mdr lb, and its gene product P-glycoprotein are induced to high levels in the mouse endometrium during pregnancy. It is shown here that P-glycoprotein in the gravid uterus is significantly larger (Mr 155000) compared to P-glycoprotein encoded by mdr lb in a murine multidrug-resistant cell line (Mr 140000). However, both species co-migrate after enzymatic removal of N-linked sugars (Mr 125000). These results demonstrate that differential glycosylation of the mdr lb gene product contributes to molecular heterogeneity found in P-glycoprotein from normal and multidrug-resistant cells

High-rise apartments and urban mental health—Historical and contemporary views

High-rise apartment buildings have long been associated with the poor mental health of their residents. The aims of this paper are to examine whether this connection is necessarily so, by reviewing the evidence relating to the relationships between high-rise living and social wellbeing, occupant’s stress levels, and the influence they have on mental health. From selected literature, psychological stress and poor mental health outcomes of the populations that live in high-rise apartments are indeed apparent, and this is particularly so for apartments in poor neighbourhoods. Yet many apartments in developed cities are in affluent areas (particularly those with views of green/blue space), where residences on higher floors are more expensive. Either way, high-rise living and mental health outcomes are a social justice issue. Our review allows us to propose two models relating to high-rise living relevant today, based on these difference

Selective potentiation of paclitaxel (taxol)-induced cell death by mitogen-activated protein kinase kinase inhibition in human cancer cell lines

ABSTRACT Activation of the mitogen-activated protein kinase (MAPK) pathway in HeLa and Chinese hamster ovary cells after treatment with paclitaxel (Taxol) and other microtubule interacting agents has been investigated. Using a trans-reporting system, the phosphorylation of the nuclear transcription factors Elk-1 and c-jun was measured. Concentration-and time-dependent activation of the Elk-1 pathway, mediated primarily by the extracellular signal-regulated kinase (ERK) component of the MAPK family, was observed. Inactive drug analogs and other cytotoxic compounds that do not target microtubules failed to induce similar levels of activation, thereby indicating that an interaction between these drugs and the microtubule is essential for the activation of MAPKs. Evaluation of the endogenous levels of MAPK expression revealed cell-dependent expression of the ERK, c-jun N-terminal kinase, and p38 pathways. In the case of HeLa cells, time-dependent activation of ERK coincided with increased poly(ADP-ribose) polymerase (PARP) cleavage, phosphatidylserine externalization, and increased accumulation of cells in G 2 M. In both cell lines, inhibition of ERK activity potentiated paclitaxel-induced PARP cleavage and phosphatidylserine externalization, suggesting that ERK activity coincided with, but did not mediate, the cytotoxic effects of paclitaxel. We evaluated the nature of the interaction between paclitaxel and the MAPK kinase inhibitor U0126 in three cell lines, on the basis of a potential chemotherapeutic advantage of paclitaxel plus ERK inhibition. Our data confirmed additivity in those cells lines that undergo paclitaxel-induced ERK activation, and antagonism in cells with low ERK activity, suggesting that in tumors with high ERK activity, there may be an application for this strategy in therapy

Helicobacter hepaticus infection in mice: models for understanding lower bowel inflammation and cancer

Pioneering work in the 1990s first linked a novel microaerobic bacterium, Helicobacter hepaticus, with chronic active hepatitis and inflammatory bowel disease in several murine models. Targeted H. hepaticus infection experiments subsequently demonstrated its ability to induce colitis, colorectal cancer, and extraintestinal diseases in a number of mouse strains with defects in immune function and/or regulation. H. hepaticus is now widely utilized as a model system to dissect how intestinal microbiota interact with the host to produce both inflammatory and tolerogenic responses. This model has been used to make important advances in understanding factors that regulate both acquired and innate immune response within the intestine. Further, it has been an effective tool to help define the function of regulatory T cells, including their ability to directly inhibit the innate inflammatory response to gut microbiota. The complete genomic sequence of H. hepaticus has advanced the identification of several virulence factors and aided in the elucidation of H. hepaticus pathogenesis. Delineating targets of H. hepaticus virulence factors could facilitate novel approaches to treating microbially induced lower bowel inflammatory diseases.National Institutes of Health (U.S.) (grant R01-DK052413)National Institutes of Health (U.S.) (grant P01-CA026731)National Institutes of Health (U.S.) (grant R01-CA067529)National Institutes of Health (U.S.) (grant P30-ES02109)National Institutes of Health (U.S.) (grant R01-A1052267)National Institutes of Health (U.S.) (grantR01-CA108854

Upregulation of caveolin-1 and caveolae organelles in Taxol-resistant A549 cells

AbstractCaveolin is a principal component of caveolae membranes. It has been demonstrated that the interaction of the caveolin scaffolding domain with signaling molecules can functionally inhibit the activity of these molecules. Taxol is an antitumor agent that suppresses microtubule dynamics and binds to microtubules thereby stabilizing them against depolymerization. The drug also has been implicated in the induction of apoptosis through activation of components in signal transduction cascades. Here we have investigated the role of caveolin in the development of drug resistance by examining the expression of caveolins in low- and high-level drug-resistant cell lines. Caveolin-1, but not caveolin-2, was upregulated in highly multidrug resistant SKVLB1 cells that express high levels of P-glycoprotein, and in low-level Taxol-resistant A549 cell lines that express low amounts of P-glycoprotein. Two drug-resistant A549 cell lines (one 9-fold resistant to Taxol and the other 1.5-fold resistant to epothilone B), both of which express no P-glycoprotein, demonstrate a significant increase in the expression of caveolin-1. These results indicate that in low-level epothilone B- or Taxol-resistant A549 cells, increased caveolin-1 expression occurs independently of P-glycoprotein expression. Electron microscopic studies clearly demonstrate the upregulation of caveolae organelles in Taxol-resistant A549 cells. Upregulation of caveolin-1 expression in drug-sensitive A549 cells was observed acutely beginning 48 h after incubation with 10 nM Taxol. Thus, caveolin-1 may play a role in the development of Taxol resistance in A549 cells

Evidence for linear extrachromosomal elements mediating gene amplification in the multidrug-resistant J774.2 murine cell line

Previous studies from our laboratory have demonstrated specific cytogenetic alterations accompanying development of colchicine resistance in the J774.2 murine cell line and in two sublines (J7.Cl-30 and J7.Cl-100) [1]. Although gene amplification is not observed in the parental J774.2 cell line, a ~35-fold amplification of the gene for p-glycoprotein (mdr) was noted in the J7.Cl-30 subline (770-fold CLCR) and a ~70-fold amplification in the J7.Cl-100 subline (2500-fold CLCR). In this study, we analyzed the localization and organization of the mdr gene. In the colchicine-resistant (CLCR) J7.Cl-30 subline, the p-glycoprotein domain was observed to reside on differently sized extrachromosomal elements. Our results indicate not only circular extrachromosomal elements but also linear extrachromosomal elements. By means of pulsed-field gel electrophoresis (PFGE), the sizes of the extrachromosomal elements were shown to be >2,500 kilobasepairs (kb), 800 kb, and 400 kb. In contrast, the J7.Cl-100 subline was characterized by the presence of homogeneously staining regions (HSRs). We have noted that with increasing colchicine resistance the extrachromosomal elements are replaced by HSRs. Our findings of linear elements that appear to be precursors of HSRs may offer a new way to interpret different theories of extrachromosomal gene amplification. The J7.Cl-30 cell line presents a unique system to analyze further the formation and structure of extrachromosomal elements.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30158/1/0000541.pd

Advanced EFL learners' beliefs about language learning and teaching: a comparison between grammar, pronunciation, and vocabulary

This paper reports on the results of a study exploring learners’ beliefs on the learning and teaching of English grammar, pronunciation and vocabulary at tertiary level. While the importance of learners’ beliefs on the acquisition process is generally recognized, few studies have focussed on and compared learners’ views on different components of the language system. A questionnaire containing semantic scale and Likert scale items probing learners’ views on grammar, pronunciation and vocabulary was designed and completed by 117 native speakers of Dutch in Flanders, who were studying English at university. The analysis of the responses revealed that (i) vocabulary was considered to be different from grammar and pronunciation, both in the extent to which an incorrect use could lead to communication breakdown and with respect to the learners’ language learning strategies, (ii) learners believed in the feasibility of achieving a native-like proficiency in all three components, and (iii) in-class grammar, pronunciation and vocabulary exercises were considered to be useful, even at tertiary level. The results are discussed in light of pedagogical approaches to language teaching

Discrimination Task Reveals Differences in Neural Bases of Tinnitus and Hearing Impairment

We investigated auditory perception and cognitive processing in individuals with chronic tinnitus or hearing loss using functional magnetic resonance imaging (fMRI). Our participants belonged to one of three groups: bilateral hearing loss and tinnitus (TIN), bilateral hearing loss without tinnitus (HL), and normal hearing without tinnitus (NH). We employed pure tones and frequency-modulated sweeps as stimuli in two tasks: passive listening and active discrimination. All subjects had normal hearing through 2 kHz and all stimuli were low-pass filtered at 2 kHz so that all participants could hear them equally well. Performance was similar among all three groups for the discrimination task. In all participants, a distributed set of brain regions including the primary and non-primary auditory cortices showed greater response for both tasks compared to rest. Comparing the groups directly, we found decreased activation in the parietal and frontal lobes in the participants with tinnitus compared to the HL group and decreased response in the frontal lobes relative to the NH group. Additionally, the HL subjects exhibited increased response in the anterior cingulate relative to the NH group. Our results suggest that a differential engagement of a putative auditory attention and short-term memory network, comprising regions in the frontal, parietal and temporal cortices and the anterior cingulate, may represent a key difference in the neural bases of chronic tinnitus accompanied by hearing loss relative to hearing loss alone