Wolbachia-mediated resistance to dengue virus infection and death at the cellular level

Dengue is currently the most important arthropod-borne viral disease of humans. Recent work has shown dengue virus displays limited replication in its primary vector, the mosquito Aedes aegypti, when the insect harbors the endosymbiotic bacterium Wolbachia pipientis. Wolbachia-mediated inhibition of virus replication may lead to novel methods of arboviral control, yet the functional and cellular mechanisms that underpin it are unknown.

Overcoming organisational resistance to sustainability innovations in Australian universities

Sustainability is becoming a guiding paradigm to industries, businesses and our societies. Higher education institutions have the potential to take an active part in creating a sustainable future, due to their moral responsibility, social obligation, and their own needs to adapt to new circumstances. By either signing declarations or making public statements, many universities in Australia have expressed their desires to become role models for enhancing sustainability. However, universities in general have been slow to implement sustainability innovations, sometimes even lagging behind private sectors. Accordingly, there is pressing need to promote innovations on campus in order to drive universities’ sustainability goals. Existing seminal literature tend to focus on technological issues. There has been very little research examining the fundamental problems from an organizational perspective. To address the deficiency, the authors designed and carried out 24 semi-structured interviews to investigate the general organizational environment of Australian universities and to identify organizational resistance to sustainability innovations. Based on the data analysis, a set of strategies to reduce or overcome organizational resistance are explored and developed. The expected outcome of this research is to develop a genetic framework to facilitate supportive decision making for promoting sustainability innovations on campus, as a vital step towards achieving sustainability in universities on a practical level.

The N550K/H mutations in FGFR2 confer differential resistance to PD173074, dovitinib and ponatinib ATP-competitive inhibitors

We sought to identify fibroblast growth factor receptor 2 (FGFR2) kinase domain mutations that confer resistance to the pan-FGFR inhibitor, dovitinib, and explore the mechanism of action of the drug-resistant mutations. We cultured BaF3 cells overexpressing FGFR2 in high concentrations of dovitinib and identified fourteen dovitinib-resistant mutations, including the N550K mutation observed in 25% of FGFR2mutant endometrial cancers (EC). Structural and biochemical in vitro kinase analyses, together with BaF3 proliferation assays, showed that the resistance mutations elevate the intrinsic kinase activity of FGFR2. BaF3 lines were used to assess the ability of each mutation to confer cross-resistance to PD173074 and ponatinib. Unlike PD173074, ponatinib effectively inhibited all the dovitinib-resistant FGFR2 mutants except the V565I gatekeeper mutation, suggesting ponatinib but not dovitinib targets the active conformation of FGFR2 kinase. EC cell lines expressing wild-type FGFR2 were relatively resistant to all inhibitors. Whereas EC cell lines expressing mutated FGFR2 showed differential sensitivity. Within the FGFR2mutant cell lines, 3/7 showed marked resistance to PD173074 and relative resistance to dovitinib and ponatinib. This suggests that alternative mechanisms distinct from kinase domain mutations are responsible for intrinsic resistance in these three EC lines. Finally, overexpression of FGFR2N550K in JHUEM-2 cells (FGFR2C383R) conferred resistance (~5 fold) to PD173074, providing independent data that FGFR2N550K can be associated with drug resistance. Biochemical in vitro kinase analyses also shows ponatinib is more effective than dovitinib at inhibiting FGFR2N550K. We propose tumors harboring mutationally activated FGFRs should be treated with FGFR inhibitors that specifically bind the active kinase.

The role of epigenetics in resistance to cisplatin chemotherapy in lung cancer

Non-small cell lung cancer (NSCLC) is the most common cause of cancer related death in the world. Cisplatin and carboplatin are the most commonly used cytotoxic chemotherapeutic agents to treat the disease. These agents, usually combined with drugs such as gemcitabine or pemetrexed, induce objective tumor responses in only 20-30% of patients. Aberrant epigenetic regulation of gene expression is a frequent event in NSCLC. In this article we review the emerging evidence that epigenetics and the cellular machinery involved with this type of regulation may be key elements in the development of cisplatin resistance in NSCLC. © 2011 by the authors; licensee MDPI, Basel, Switzerland.

The Yd2 resistance to barley yellow dwarf virus is effective in barley plants but not in their leaf protoplasts

The Yd2 gene for “resistance” to barley yellow dwarf virus (BYDV) has been widely used in barley (Hordeum vulgare). We have tested Australian isolates of BYDV of varying severity against barley genotypes with and without the Yd2 gene and report here a positive relationship between symptoms and virus levels determined by ELISA. Cultivar Shannon is the result of backcrossing the resistant line CI 3208 to cultivar Proctor, a susceptible line. It appears to be intermediate in reaction to BYDV between Proctor and CI 3208, although it carries the major gene, Yd2. Unlike the whole plant studies, no significant differences were observed with regard to the ability of protoplasts derived from these various genotypes to support BYDV replication. It is therefore demonstrated for the first time that the Yd2 gene is not among the small number of resistance genes which are effective against virus replication in isolated protoplasts.

Resistance to exercise-induced weight loss : compensatory behavioral adaptations

In many interventions that are based on an exercise program intended to induce weight loss, the mean weight loss observed is modest and sometimes far less than what the individual expected. The individual responses are also widely variable, with some individuals losing a substantial amount of weight, others maintaining weight, and a few actually gaining weight. The media have focused on the subpopulation that loses little weight, contributing to a public perception that exercise has limited utility to cause weight loss. The purpose of the symposium was to present recent, novel data that help explain how compensatory behaviors contribute to a wide discrepancy in exercise-induced weight loss. The presentations provide evidence that some individuals adopt compensatory behaviors, that is, increased energy intake and/or reduced activity, that offset the exercise energy expenditure and limit weight loss. The challenge for both scientists and clinicians is to develop effective tools to identify which individuals are susceptible to such behaviors and to develop strategies to minimize their effect.

Targeting nuclear factor-kappa B to overcome resistance to chemotherapy

Intrinsic or acquired resistance to chemotherapeutic agents is a common phenomenon and a major challenge in the treatment of cancer patients. Chemoresistance is defined by a complex network of factors including multi-drug resistance proteins, reduced cellular uptake of the drug, enhanced DNA repair, intracellular drug inactivation, and evasion of apoptosis. Pre-clinical models have demonstrated that many chemotherapy drugs, such as platinum-based agents, antracyclines, and taxanes, promote the activation of the NF-κB pathway. NF-κB is a key transcription factor, playing a role in the development and progression of cancer and chemoresistance through the activation of a multitude of mediators including anti-apoptotic genes. Consequently, NF-κB has emerged as a promising anti-cancer target. Here, we describe the role of NF-κB in cancer and in the development of resistance, particularly cisplatin. Additionally, the potential benefits and disadvantages of targeting NF-κB signaling by pharmacological intervention will be addressed.

Dispositional resistance to change : measurement equivalence and the link to personal values across 17 nations

The concept of dispositional resistance to change has been introduced in a series of exploratory and confirmatory analyses through which the validity of the Resistance to Change (RTC) Scale has been established (S. Oreg, 2003). However, the vast majority of participants with whom the scale was validated were from the United States. The purpose of the present work was to examine the meaningfulness of the construct and the validity of the scale across nations. Measurement equivalence analyses of data from 17 countries, representing 13 languages and 4 continents, confirmed the cross-national validity of the scale. Equivalent patterns of relationships between personal values and RTC across samples extend the nomological net of the construct and provide further evidence that dispositional resistance to change holds equivalent meanings across nations.

Trait and behavioural motor control is associated with resistance to overconsumption

While overall obesity rates are rising, a minority of individuals appear to resist overconsumption and remain lean in spite of an ‘obesogenic’ environment. Studying the factors hypothesised to underpin behaviours associated with resistance to overconsumption may inform weight management strategies in an adverse environment. Trait (BIS-11) and behavioural (response inhibition, GoStop) self control were assessed in the laboratory. Snack food consumption was measured covertly via a sham taste test. Lack of motor control was positively correlated (r = .32, p <. 05) and successful response inhibition was negatively correlated (r = −.35, p <. 05) with snack food intake. Low motor control was also associated with further food intake when satiated (r = .39, p < .01). These relationships were independent of self-reported palatability and perceived reward value of the food. Motor control may be an important factor implicated in ‘mindless’ eating in an environment abundant in palatable, energy-dense snack foods.

Measurement equivalence of the dispositional resistance to change scale

Intended to bridge the gap between the latest methodological developments and cross-cultural research, this interdisciplinary resource presents the latest strategies for analyzing cross-cultural data. Techniques are demonstrated through the use of applications that employ cross national data sets such as the latest European Social Survey. With an emphasis on the generalized latent variable approach, internationally?prominent researchers from a variety of fields explain how the methods work, how to apply them, and how they relate to other methods presented in the book. Syntax and graphical and verbal explanations of the techniques are included. [from publisher's website]

The biology of breast tumor progression : acquisition of hormone independence and resistance to cytotoxic drugs

Many breast tumors appear to follow a predictable clinical pattern, being initially responsive to endocrine therapy and to cytotoxic chemotherapy but ultimately exhibiting a phenotype resistant to both modalities. Using the MCF-7 human breast cancer cell line as an example of an 'early' phenotype (estrogen and progesterone receptor positive, steroid responsive, low metastatic potential), we have isolated and characterized a series of hormone-independent but hormone-responsive variants (MIII and MCF7/LCC1). However, these variants remain responsive to both antiestrogens and cytotoxic drugs (methotrexate and colchicine). MIII and MCF7/LCCl cells appear to mimic some of the critical aspects of the early progression to a more aggressive phenotype. An examination of the phenotype of these cells suggests that some hormone-independent breast cancer cells are derived from hormone-dependent parental cells. The development of a hormone-independent phenotype can arise independently of acquisition of a cytotoxic drug resistant phenotype.

Deamplification of pfmdr1-Containing Amplicon on Chromosome 5 in Plasmodium falciparum Is Associated with Reduced Resistance to Artelinic Acid In Vitro

Amplification of the Plasmodium falciparum multidrug resistance 1 gene (pfmdr1) has been implicated in multidrug resistance, including in vitro resistance to artelinic acid (AL). The stability and fitness of having multiple copies of pfmdr1 are important factors due to their potential effects on the resistance phenotype of parasites. These factors were investigated by using an AL-resistant line of P. falciparum (W2AL80) and clones originating from W2AL80. A rapid reduction in pfmdr1 copy number (CN) was observed in the uncloned W2AL80 line; 63% of this population reverted to a CN of <3 without exposure to the drug. Deamplification of the pfmdr1 amplicon was then determined in three clones, each initially containing three copies of pfmdr1. Interestingly, two outcomes were observed during 3 months without drug pressure. In one clone, parasites with fewer than 3 copies of pfmdr1 emerged rapidly. In two other clones, the reversion was significantly delayed. In all subclones, the reduction in pfmdr1 CN involved the deamplification of the entire amplicon (19 genes). Importantly, deamplification of the pfmdr1 amplicon resulted in partial reversal of resistance to AL and increased susceptibility to mefloquine. These results demonstrate that multiple copies of the pfmdr1-containing amplicon in AL-resistant parasites are unstable when drug pressure is withdrawn and have practical implications for the maintenance and spread of parasites resistant to artemisinin derivatives.

B-lactamase-mediated resistance to antimicrobials : the relationship between genotype and phenotype

This thesis examined the ability to predict the emergence of bacteria resistant to antibiotics using genetic markers in the bacteria. Bacteria containing the genetic markers were able to become resistant to antibiotics, whereas bacteria that did not have the genetic markers remained susceptible. Existing techniques can identify the presence of resistance by looking at the characteristics of the bacteria during growth. However, having the ability to predict antibiotic resistance before it emerges could improve the preservation of currently available antibiotics and minimise treatment failure.

Resistance to amoebic gill disease (AGD) is characterised by the transcriptional dysregulation of immune and cell cycle pathways

Amoebic gill disease (AGD) is a parasite-mediated proliferative gill disease capable of affecting a range of teleost hosts. While a moderate heritability for AGD resistance in Atlantic salmon has been reported previously, the mechanisms by which individuals resist the proliferative effects remain poorly understood. To gain more knowledge of this commercially important trait, we compared gill transcriptomes of two groups of Atlantic salmon, one designated putatively resistant, and one designated putatively susceptible to AGD. Utilising a 17k Atlantic salmon cDNA microarray we identified 196 transcripts that were differentially expressed between the two groups. Expression of 11 transcripts were further examined with real-time quantitative RT-PCR (qPCR) in the AGD-resistant and AGD-susceptible animals, as well as non-infected naïve fish. Gene expression determined by qPCR was in strong agreement with the microarray analysis. A large number of differentially expressed genes were involved in immune and cell cycle responses. Resistant individuals displayed significantly higher expression of genes involved in adaptive immunity and negative regulation of the cell cycle. In contrast, AGD-susceptible individuals showed higher expression of acute phase proteins and positive regulators of the cell cycle. Combined with the gill histopathology, our results suggest AGD resistance is acquired rather than innately present, and that this resistance is for the most part associated with the dysregulation of immune and cell cycle pathways. © 2008 Elsevier Ltd. All rights reserved.

Inducible resistance to maize streak virus

Maize streak virus (MSV), which causes maize streak disease (MSD), is the major viral pathogenic constraint on maize production in Africa. Type member of the Mastrevirus genus in the family Geminiviridae, MSV has a 2.7 kb, single-stranded circular DNA genome encoding a coat protein, movement protein, and the two replication-associated proteins Rep and RepA. While we have previously developed MSV-resistant transgenic maize lines constitutively expressing ‘‘dominant negative mutant’’ versions of the MSV Rep, the only transgenes we could use were those that caused no developmental defects during the regeneration of plants in tissue culture. A better transgene expression system would be an inducible one, where resistance-conferring transgenes are expressed only in MSV-infected cells. However, most known inducible transgene expression systems are hampered by background or ‘‘leaky’’ expression in the absence of the inducer. Here we describe an adaptation of the recently developed INPACT system to express MSV-derived resistance genes in cell culture. Split gene cassette constructs (SGCs) were developed containing three different transgenes in combination with three different promoter sequences. In each SGC, the transgene was split such that it would be translatable only in the presence of an infecting MSV’s replication associated protein. We used a quantitative real-time PCR assay to show that one of these SGCs (pSPLITrepIII-Rb-Ubi) inducibly inhibits MSV replication as efficiently as does a constitutively expressed transgene that has previously proven effective in protecting transgenic maize from MSV. In addition, in our cell-culture based assay pSPLITrepIII-Rb-Ubi inhibited replication of diverse MSV strains, and even, albeit to a lesser extent, of a different mastrevirus species. The application of this new technology to MSV resistance in maize could allow a better, more acceptable product.