A FimH inhibitor prevents acute bladder infection and treats chronic cystitis caused by multidrug-resistant uropathogenic Escherichia coli ST131

Background. Escherichia coli O25b:H4-ST131 represents a predominant clone of multidrug-resistant uropathogens currently circulating worldwide in hospitals and the community. Urinary tract infections (UTIs) caused by E. coli ST131 are typically associated with limited treatment options and are often recurrent. Methods. Using established mouse models of acute and chronic UTI, we mapped the pathogenic trajectory of the reference E. coli ST131 UTI isolate, strain EC958. Results. We demonstrated that E. coli EC958 can invade bladder epithelial cells and form intracellular bacterial communities early during acute UTI. Moreover, E. coli EC958 persisted in the bladder and established chronic UTI. Prophylactic antibiotic administration failed to prevent E. coli EC958–mediated UTI. However, 1 oral dose of a small-molecular-weight compound that inhibits FimH, the type 1 fimbriae adhesin, significantly reduced bacterial colonization of the bladder and prevented acute UTI. Treatment of chronically infected mice with the same FimH inhibitor lowered their bladder bacterial burden by >1000-fold. Conclusions. In this study, we provide novel insight into the pathogenic mechanisms used by the globally disseminated E. coli ST131 clone during acute and chronic UTI and establish the potential of FimH inhibitors as an alternative treatment against multidrug-resistant E. coli.

Insights into a multidrug resistant Escherichia coli pathogen of the globally disseminated ST131 lineage : genome analysis and virulence mechanisms

Escherichia coli strains causing urinary tract infection (UTI) are increasingly recognized as belonging to specific clones. E. coli clone O25b:H4-ST131 has recently emerged globally as a leading multi-drug resistant pathogen causing urinary tract and bloodstream infections in hospitals and the community. While most molecular studies to date examine the mechanisms conferring multi-drug resistance in E. coli ST131, relatively little is known about their virulence potential. Here we examined E. coli ST131 clinical isolates from two geographically diverse collections, one representing the major pathogenic lineages causing UTI across the United Kingdom and a second representing UTI isolates from patients presenting at two large hospitals in Australia. We determined a draft genome sequence for one representative isolate, E. coli EC958, which produced CTX-M-15 extended-spectrum β-lactamase, CMY-23 type AmpC cephalosporinase and was resistant to ciprofloxacin. Comparative genome analysis indicated that EC958 encodes virulence genes commonly associated with uropathogenic E. coli (UPEC). The genome sequence of EC958 revealed a transposon insertion in the fimB gene encoding the activator of type 1 fimbriae, an important UPEC bladder colonization factor. We identified the same fimB transposon insertion in 59% of the ST131 UK isolates, as well as 71% of ST131 isolates from Australia, suggesting this mutation is common among E. coli ST131 strains. Insertional inactivation of fimB resulted in a phenotype resembling a slower off-to-on switching for type 1 fimbriae. Type 1 fimbriae expression could still be induced in fimB-null isolates; this correlated strongly with adherence to and invasion of human bladder cells and bladder colonisation in a mouse UTI model. We conclude that E. coli ST131 is a geographically widespread, antibiotic resistant clone that has the capacity to produce numerous virulence factors associated with UTI.

“Well, hang on, they’re actually much better than that!” : disrupting dominant discourses of deficit about English language learners in senior high school English

This paper explores how four English teachers position their English language learners for critical literacy within senior high school curriculum in Queensland, Australia. Such learners are often positioned, even by their teachers, within a broader “deficit discourse” that claims they are inherently lacking the requisite knowledge and skills to engage with intransigent school curricula. As such, English language learners’ identity formation is often constrained by deficit views that can ultimately see limited kinds of literacy teaching offered to them. Using Fairclough’s (2003) critical discourse analysis method, analysis of 16 interviews with the teachers was conducted as part of a larger, critical instrumental case study in two state high schools during 2010. Five competing discourses were identified: deficit as lack; deficit as need; learner “difference” as a resource; conceptual capacity for critical literacy; and linguistic, cultural and conceptual difficulty with critical literacy. While a deficit view is present, counter-hegemonic discourses also exist in their talk. The combination of discourses challenges monolithic deficit views of English language learners, and opens up generative discursive territory to position English language learners in ways other than “problematic”. This has important implications for how teachers view and teach English language learners and their capacity for critical literacy work in senior high school classrooms.

Conceptualisation and enactment of critical literacy for senior high school EAL learners in Queensland, Australia : commitments, constraints and contradictions

This case study examined four teachers' understandings and teaching of Critical Literacy with senior English as an Additional Language (EAL) learners in two Queensland high schools. Despite continuous, rapid curriculum change in Australia and efforts to diminish Critical Literacy, the four teachers continued to feature it successfully in their teaching with often marginalised learners. They used critical literacy to provide access to and critique dominant language codes, and to draw on learners' diverse experiences. To a lesser extent, the teachers created opportunities for redesigning dominant texts. Implications are important for policy production and interpretation, school planning and teacher professional development.

Editorial - Assessment of EAL/D learners : the validity of teachers' professional judgements

Assessment is a recurring theme in this issue of TESOL in Context. It is the focus of a themed section; addressed in some of the award-winning thesis research we feature; and one of several topics in an article on EFL teacher preparation in an Australian university. In the first section of the issue we are pleased to publish précis of the theses produced by the joint winners of the Penny McKay Memorial Award for Best Thesis in Language Education. Penny was a major figure in the development of EAL/D education in Australia (see Dooley & Moore, 2009). Her work is remembered and continued through an Award established by the Australian Council of TESOL Associations (ACTA) and the Applied Linguistics Association of Australia (ALAA). The award recognises doctoral research which makes an outstanding contribution to second/additional language education in Australian schools (http://www.tesol.org.au/About-ACTA/PENNY-MCKAY-MEMORIAL-FUND)...

Establishing statistical foundations early : data modeling with young learners

This paper addresses research from a three-year longitudinal study that engaged children in data modeling experiences from the beginning school year through to third year (6-8 years). A data modeling approach to statistical development differs in several ways from what is typically done in early classroom experiences with data. In particular, data modeling immerses children in problems that evolve from their own questions and reasoning, with core statistical foundations established early. These foundations include a focus on posing and refining statistical questions within and across contexts, structuring and representing data, making informal inferences, and developing conceptual, representational, and metarepresentational competence. Examples are presented of how young learners developed and sustained informal inferential reasoning and metarepresentational competence across the study to become “sophisticated statisticians”.

Therapeutic options for metastatic castration resistant prostate cancer : has the situation improved?

Limited treatment options for Castration Resistant Prostate Cancer (CRPC) still remain a major challenge. Despite therapeutic advances, most patients with malignant PCa have a poor prognosis. Since the year 2000, we have rapidly expanded our understanding of the molecular mechanisms underlying CRPC and this has led to an unprecedented number of new drug approvals within a short span of time. Recently, four new agents namely Abiraterone Acetate, Enzalutamide, Cabazitaxel, and Radium-223 have been shown to be effective in the post-chemotherapy setting in CRPC. The continued dependency of CRPC on androgen synthesis has seen the development of a number of new anti-androgen therapies, with abiraterone acetate and Enzalutamide being the most promising discoveries. Immunotherapeutic approaches have also found their niche in PCa with Sipuleucel-T shown to be effective in minimally asymptomatic CRPC. Research focussed on bone-targeting therapies has witnessed the arrival of promising new drugs with Denosumab and Radium-223 displaying improved survival of patients with CRPC. This review briefly discusses the findings and limitations from ongoing and completed clinical trials of novel treatments and regimens. In addition, potential mechanisms of therapy resistance and future challenges are discussed.

A conjugative plasmid carrying the carbapenem resistance gene blaOXA-23 in AbaR4 in an extensively resistant GC1 Acinetobacter baumannii isolate

OBJECTIVES: To locate the acquired bla(OXA-23) carbapenem resistance gene in an Australian A. baumannii global clone 1 (GC1) isolate. METHODS: The genome of the extensively antibiotic-resistant GC1 isolate A85 harbouring bla(OXA-23) in Tn2006 was sequenced using Illumina HiSeq, and the reads were used to generate a de novo assembly. PCR was used to assemble relevant contigs. Sequences were compared with ones in GenBank. Conjugation experiments were conducted. RESULTS: The sporadic GC1 isolate A85, recovered in 2003, was extensively resistant, exhibiting resistance to imipenem, meropenem and ticarcillin/clavulanate, to cephalosporins and fluoroquinolones and to the older antibiotics gentamicin, kanamycin and neomycin, sulfamethoxazole, trimethoprim and tetracycline. Genes for resistance to older antibiotics are in the chromosome, in an AbaR3 resistance island. A second copy of the ampC gene in Tn6168 confers cephalosporin resistance and the gyrA and parC genes have mutations leading to fluoroquinolone resistance. An 86 335 bp repAci6 plasmid, pA85-3, carrying bla(OXA-23) in Tn2006 in AbaR4, was shown to transfer imipenem, meropenem and ticarcillin/clavulanate resistance into a susceptible recipient. A85 also contains two small cryptic plasmids of 2.7 and 8.7 kb. A85 is sequence type ST126 (Oxford scheme) and carries a novel KL15 capsule locus and the OCL3 outer core locus. CONCLUSIONS: A85 represents a new GC1 lineage identified by the novel capsule locus but retains AbaR3 carrying genes for resistance to older antibiotics. Resistance to imipenem, meropenem and ticarcillin/clavulanate has been introduced into A85 by pA85-3, a repAci6 conjugative plasmid carrying Tn2006 in AbaR4.

Genome Sequence of Acinetobacter baumannii Strain A1, an Early Example of Antibiotic-Resistant Global Clone 1

Acinetobacter baumannii isolate A1 was recovered in the United Kingdom in 1982 and belongs to global clone 1 (GC1). Here, we present its complete 3.91-Mbp genome sequence, generated via a combination of short-read sequencing (Illumina), long-read sequencing (PacBio), and manual finishing.

Drug accumulation into single drug-sensitive and drug-resistant prostate cancer cells conducted on the single cell bioanalyzer

Multidrug resistance (MDR) occurs in prostate cancer, and this happens when the cancer cells resist chemotherapeutic drugs by pumping them out of the cells. MDR inhibitors such as cyclosporin A (CsA) can stop the pumping and enhance the drugs accumulated in the cells. The cellular drug accumulation is monitored using a microfluidic chip mounted on a single cell bioanalyzer. This equipment has been developed to measure accumulation of drugs such as doxorubicin (DOX) and fluorescently labeled paclitaxel (PTX) in single prostate cancer cells. The inhibition of drug efflux on the same prostate cell was examined in drug-sensitive and drug-resistant cells. Accumulation of these drug molecules was not found in the MDR cells, PC-3 RX-DT2R cells. Enhanced drug accumulation was observed only after treating the MDR cell in the presence of 5 μM of CsA as the MDR inhibitor. We envision this monitoring of the accumulation of fluorescent molecules (drug or fluorescent molecules), if conducted on single patient cancer cells, can provide information for clinical monitoring of patients undergoing chemotherapy in the future.

Overcoming acculturation: Physical education recruits' experiences of an alternative pedagogical approach to games teaching

Background Physical education teacher education (PETE) programmes have been identified as a critical platform to encourage the exploration of alternative teaching approaches by pre-service teachers. However, the socio-cultural constraint of acculturation or past physical education and sporting experiences results in the maintenance of the status quo of a teacher-driven, reproductive paradigm. Previous studies have reported successfully overcoming the powerful influence of acculturation, resulting in a change in PETE students’ custodial teaching beliefs and receptiveness to alternative teaching approaches. However, to date, limited information has been reported about how PETE students’ acculturation shaped their receptiveness to an alternative teaching approach. This is particularly the case for PETE recruits identified in the literature as most resistant to change. Purpose To explore the features and experiences of an alternative games teaching approach that appealed to PETE recruits’ identified as most resistant to change, requiring a specific sample of PETE recruits with strong, custodial, traditional physical education teaching beliefs, and whom are high achieving sporting products of this traditional culture. The alternative teaching approach explored in this study is the constraints-led approach (CLA), which is similar operationally to TGfU, but distinguished by a neurobiological theoretical framework (nonlinear pedagogy) that informs learning design. Participants and Setting A purposive sample of 10 Australian PETE students was recruited for the study. All participants initially had strong, custodial, traditional physical education teaching beliefs, and were successful sporting products of this teaching approach. After experiencing the CLA as learners during a games unit, participants demonstrated receptiveness to the alternative pedagogy. Data Collection and Analysis Semi-structured interviews and written reflections were sources of data collection. Each participant was interviewed separately, once prior to participation in the games unit to explore their positive physical education experiences, and then again after participation to explore the specific games unit learning experiences that influenced their receptiveness to the alternative pedagogy. Participants completed written reflections about their personal experiences after selected practical sessions. Data were qualitatively analysed using grounded theory. Findings: Thorough examination of the data resulted in establishment of two prominent themes related to the appeal of the CLA for the participants: (i) psychomotor (effective in developing skill), and (ii), inclusivity (included students of varying skill level). The efficacy of the CLA in skill development was clearly an important mediator of receptiveness for highly successful products of a traditional culture. This significant finding could be explained by three key factors: the acculturation of the participants, the motor learning theory underpinning the alternative pedagogy and the unit learning design and delivery. The inclusive nature of the CLA provided a solution to the problem of exclusion, which also made the approach attractive to participants. Conclusion PETE educators could consider these findings when introducing an alternative pedagogy aimed at challenging PETE recruits’ custodial, traditional teaching beliefs. To mediate receptiveness, it is important that the learning theory underpinning the alternative approach is operationalised in a research-informed pedagogical learning design that facilitates students’ perceptions of the effectiveness of the approach through experiencing and or observing it working.

3D cultures of prostate cancer cells cultured in a novel high-throughput culture platform are more resistant to chemotherapeutics compared to cells cultured in monolayer

Despite monolayer cultures being widely used for cancer drug development and testing, 2D cultures tend to be hypersensitive to chemotherapy and are relatively poor predictors of whether a drug will provide clinical benefit. Whilst generally more complicated, three dimensional (3D) culture systems often better recapitulate true cancer architecture and provide a more accurate drug response. As a step towards making 3D cancer cultures more accessible, we have developed a microwell platform and surface modification protocol to enable high throughput manufacture of 3D cancer aggregates. Herein we use this novel system to characterize prostate cancer cell microaggregates, including growth kinetics and drug sensitivity. Our results indicate that prostate cancer cells are viable in this system, however some non-cancerous prostate cell lines are not. This system allows us to consistently control for the presence or absence of an apoptotic core in the 3D cancer microaggregates. Similar to tumor tissues, the 3D microaggregates display poor polarity. Critically the response of 3D microaggregates to the chemotherapeutic drug, docetaxel, is more consistent with in vivo results than the equivalent 2D controls. Cumulatively, our results demonstrate that these prostate cancer microaggregates better recapitulate the morphology of prostate tumors compared to 2D and can be used for high-throughput drug testing.

Using academagogy to meet the needs of millennial learners: A comparative case study

Higher education institutions across the world are experiencing a new generation of students, known as millennial learners. They are more technologically literate and digitally connected than previous generations of learners. To meet the teaching and learning needs of these learners, we must offer more deliberate and meaningful learning experiences and opportunities, where students can see the connections between new material and their own experiences and real world applications – an academagogic approach. This study compares the implementation of academagogy for two different groups of millennial learners – one a traditional face-to-face undergraduate Engineering unit, and the other a mixed-mode (online and face-to-face) undergraduate Design unit. The units are discussed in terms of their student evaluation results, both qualitative and quantitative, and in terms of their academic outcomes for students. Conclusions are drawn about the applicability of academagogy as a heuristic for improving teaching and learning across disciplines, as well as its strengths and limitations in terms of student results.

Learning English pragmatics in China: An investigation into Chinese EFL learners’ perceptions of pragmatics

This paper reports the findings of a study investigating Chinese English language learners’ perceptions of pragmatics in the EFL learning context in China. A total of 237 Chinese EFL first-year university students participated in the study. A questionnaire and focus group interviews were used to collect data about learners’ pragmatics insights during their English language acquisition process. The findings of the study have provided empirical evidence for English educators and practitioners in China, indicating that there have been substantive changes in Chinese university students’ perceptions of English pragmatics. Except for organizational knowledge, they have a strong desire to acquire English pragmatic knowledge in their English language learning process, and would like to be pragmatically competent language users. This inquiry emphasizes the necessity to introduce pragmatics use and practice, which can effectively facilitate Chinese English learners to achieve pragmatic competence in communication.

The role of DNA repair pathways in cisplatin resistant lung cancer

Platinum chemotherapeutic agents such as cisplatin are currently used in the treatment of various malignancies such as lung cancer. However, their efficacy is significantly hindered by the development of resistance during treatment. While a number of factors have been reported that contribute to the onset of this resistance phenotype, alterations in the DNA repair capacity of damaged cells is now recognised as an important factor in mediating this phenomenon. The mode of action of cisplatin has been linked to its ability to crosslink purine bases on the DNA, thereby interfering with DNA repair mechanisms and inducing DNA damage. Following DNA damage, cells respond by activating a DNA-damage response that either leads to repair of the lesion by the cell thereby promoting resistance to the drug, or cell death via activation of the apoptotic response. Therefore, DNA repair is a vital target to improving cancer therapy and reduce the resistance of tumour cells to DNA damaging agents currently used in the treatment of cancer patients. To date, despite the numerous findings that differential expression of components of the various DNA repair pathways correlate with response to cisplatin, translation of such findings in the clinical setting are still warranted. The identification of alterations in specific proteins and pathways that contribute to these unique DNA repair pathways in cisplatin resistant cancer cells may potentially lead to a renewed interest in the development of rational novel therapies for cisplatin resistant cancers, in particular, lung cancer.