Transcription factors that mediate epithelial-mesenchymal transition lead to multidrug resistance by upregulating ABC transporters

Development of multidrug resistance (MDR) is a major deterrent in the effective treatment of metastatic cancers by chemotherapy. Even though MDR and cancer invasiveness have been correlated, the molecular basis of this link remains obscure. We show here that treatment with chemotherapeutic drugs increases the expression of several ATP binding cassette transporters (ABC transporters) associated with MDR, as well as epithelial-mesenchymal transition (EMT) markers, selectively in invasive breast cancer cells, but not in immortalized or non-invasive cells. Interestingly, the mere induction of an EMT in immortalized and non-invasive cell lines increased their expression of ABC transporters, migration, invasion, and drug resistance. Conversely, reversal of EMT in invasive cells by downregulating EMT-inducing transcription factors reduced their expression of ABC transporters, invasion, and rendered them more chemosensitive. Mechanistically, we demonstrate that the promoters of ABC transporters carry several binding sites for EMT-inducing transcription factors, and overexpression of Twist, Snail, and FOXC2 increases the promoter activity of ABC transporters. Furthermore, chromatin immunoprecipitation studies revealed that Twist binds directly to the E-box elements of ABC transporters. Thus, our study identifies EMT inducers as novel regulators of ABC transporters, thereby providing molecular insights into the long-standing association between invasiveness and MDR. Targeting EMT transcription factors could hence serve as novel strategies to curb both metastasis and the associated drug resistance. Cell Death and Disease (2011) 2, e179; doi:10.1038/cddis.2011.61; published online 7 July 2011

Hyper-activation of the TCP4 transcription factor in Arabidopsis thaliana accelerates multiple aspects of plant maturation

Plant organs are initiated as primordial outgrowths, and require controlled cell division and differentiation to achieve their final size and shape. Superimposed on this is another developmental program that orchestrates the switch from vegetative to reproductive to senescence stages in the life cycle. These require sequential function of heterochronic regulators. Little is known regarding the coordination between organ and organismal growth in plants. The TCP gene family encodes transcription factors that control diverse developmental traits, and a subgroup of class II TCP genes regulate leaf morphogenesis. Absence of these genes results in large, crinkly leaves due to excess division, mainly at margins. It has been suggested that these class II TCPs modulate the spatio-temporal control of differentiation in a growing leaf, rather than regulating cell proliferation per se. However, the link between class II TCP action and cell growth has not been established. As loss-of-function mutants of individual TCP genes in Arabidopsis are not very informative due to gene redundancy, we generated a transgenic line that expressed a hyper-activated form of TCP4 in its endogenous expression domain. This resulted in premature onset of maturation and decreased cell proliferation, leading to much smaller leaves, with cup-shaped lamina in extreme cases. Further, the transgenic line initiated leaves faster than wild-type and underwent precocious reproductive maturation due to a shortened adult vegetative phase. Early senescence and severe fertility defects were also observed. Thus, hyper-activation of TCP4 revealed its role in determining the timing of crucial developmental events, both at the organ and organism level.

Factors associated with 2009 pandemic influenza A (H1N1) vaccination acceptance among university students from India during the post-pandemic phase

Background: There was a low adherence to influenza A (H1N1) vaccination program among university students and health care workers during the pandemic influenza in many parts of the world. Vaccination of high risk individuals is one of the recommendations of World Health Organization during the post-pandemic period. It is not documented about the student's knowledge, attitude and willingness to accept H1N1 vaccination during the post-pandemic period. We aimed to analyze the student's knowledge, attitude and willingness to accept H1N1 vaccination during the post-pandemic period in India. Methods: Vaccine against H1N1 was made available to the students of Vellore Institute of Technology, India from September 2010. The data are based on a cross-sectional study conducted during October 2010 to January 2011 using a self-administered questionnaire with a representative sample of the student population (N = 802). Results: Of the 802 respondents, only 102/802 (12.7%) had been vaccinated and 105/802 (13%) planned to do so in the future, while 595/802 (74%) would probably or definitely not get vaccinated in the future. The highest coverage was among the female (65/102, 63.7%) and non-compliance was higher among men in the group (384/595; 64.5%) (p < 0.0001). The representation of students from school of Bio-sciences and Bio-technology among vaccinees is significantly higher than that of other schools. Majority of the study population from the three groups perceived vaccine against H1N1 as the effective preventive measure when compared to other preventive measures. 250/595 (42%) of the responders argued of not being in the risk group. The risk perception was significantly higher among female (p < 0.0001). With in the study group, 453/802 (56.4%) said that they got the information, mostly from media. Conclusions: Our study shows that the vaccination coverage among university students remains very low in the post-pandemic period and doubts about the safety and effectiveness of the vaccine are key elements in their rejection. Our results indicate a need to provide accessible information about the vaccine safety by scientific authorities and fill gaps and confusions in this regard.

Reliability-based load and resistance factors for soil-nail walls

Existing soil nailing design methodologies are essentially based on limit equilibrium principles that together with a lumped factor of safety or a set of partial factors on the material parameters and loads account for uncertainties in design input parameter values. Recent trends in the development of design procedures for earth retaining structures are towards load and resistance factor design (LRFD). In the present study, a methodology for the use of LRFD in the context of soil-nail walls is proposed and a procedure to determine reliability-based load and resistance factors is illustrated for important strength limit states with reference to a 10 m high soil-nail wall. The need for separate partial factors for each limit state is highlighted, and the proposed factors are compared with those existing in the literature.

Rule-based modelling of iron homeostasis in tuberculosis

To establish itself within the host system, Mycobacterium tuberculosis (Mtb) has formulated various means of attacking the host system. One such crucial strategy is the exploitation of the iron resources of the host system. Obtaining and maintaining the required concentration of iron becomes a matter of contest between the host and the pathogen, both trying to achieve this through complex molecular networks. The extent of complexity makes it important to obtain a systems perspective of the interplay between the host and the pathogen with respect to iron homeostasis. We have reconstructed a systems model comprising 92 components and 85 protein-protein or protein-metabolite interactions, which have been captured as a set of 194 rules. Apart from the interactions, these rules also account for protein synthesis and decay, RBC circulation and bacterial production and death rates. We have used a rule-based modelling approach, Kappa, to simulate the system separately under infection and non-infection conditions. Various perturbations including knock-outs and dual perturbation were also carried out to monitor the behavioral change of important proteins and metabolites. From this, key components as well as the required controlling factors in the model that are critical for maintaining iron homeostasis were identified. The model is able to re-establish the importance of iron-dependent regulator (ideR) in Mtb and transferrin (Tf) in the host. Perturbations, where iron storage is increased, appear to enhance nutritional immunity and the analysis indicates how they can be harmful for the host. Instead, decreasing the rate of iron uptake by Tf may prove to be helpful. Simulation and perturbation studies help in identifying Tf as a possible drug target. Regulating the mycobactin (myB) concentration was also identified as a possible strategy to control bacterial growth. The simulations thus provide significant insight into iron homeostasis and also for identifying possible drug targets for tuberculosis.

Thermal Weight Functions and Stress Intensity Factors for Bonded Dissimilar Media Using Body Analogy

In this study, an analytical method is presented for the computation of thermal weight functions in two dimensional bi-material elastic bodies containing a crack at the interface and subjected to thermal loads using body analogy method. The thermal weight functions are derived for two problems of infinite bonded dissimilar media, one with a semi-infinite crack and the other with a finite crack along the interface. The derived thermal weight functions are shown to reduce to the already known expressions of thermal weight functions available in the literature for the respective homogeneous elastic body. Using these thermal weight functions, the stress intensity factors are computed for the above interface crack problems when subjected to an instantaneous heat source.

A derivation of thermodynamic quantities of liquid alloys from their structure factors

A method of deriving the thermodynamic properties of mixing in liquid alloys Delta G, Delta S and Delta H, from low-Q scattering data has been presented. As an example, the method has been demonstrated with liquid Na-Ga alloys for which both thermodynamic and diffraction data have recently been obtained by the authors.