Microtubulin binding sites as target for developing anticancer agents

Microtubules (MTs) play important and diverse roles in eukaryotic cells. Their function and biophysical properties have made α−and β−tubulin, the main components of MTs, the subject of intense study. Interfering with normal MT dynamics, for example, by the addition of tubulin ligands, can cause the cell great distress and affect MT stability and functions, including mitosis, cell motion and intracellular organelle transport. It has been shown in the literature that tubulin is an important target molecule for developing anticancer drugs. Tubulin binding molecules have generated considerable interest after the successful introduction of the taxanes into clinical oncology and the widespread use of the vinca alkaloids vincristine and vinblastine. These compounds inhibit cell mitosis by binding to the protein tubulin in the mitotic spindle and preventing polymerization into the MTs. This mode of action is also shared with other natural agents eg colchicine and podophyllotoxin. However various tubulin isotypes have shown resistance to taxanes and other MT agents. Therefore, there is a strong need to design and develop new natural analogs as antimitotic agents to interact with tubulin at sites different from those of vinca alkaloids and taxanes. This minireview provides SAR on several classes of antimitotic agents reported in the literature. The structures and data given are essential to the scientists who are involved in drug design and development in the field of anticancer drugs.

In the Solanaceae, a hierarchy of bHLHs confer distinct target specificity to the anthocyanin regulatory complex

The anthocyanin biosynthetic pathway is regulated by a transcription factor complex consisting of an R2R3 MYB, a bHLH, and a WD40. Although R2R3 MYBs belonging to the anthocyanin-activating class have been identified in many plants, and their role well elucidated, the subgroups of bHLH implicated in anthocyanin regulation seem to be more complex. It is not clear whether these potential bHLH partners are biologically interchangeable with redundant functions, or even if heterodimers are involved. In this study, AcMYB110, an R2R3 MYB isolated from kiwifruit (Actinidia sp.) showing a strong activation of the anthocyanin pathway in tobacco (Nicotiana tabacum) was used to examine the function of interacting endogenous bHLH partners. Constitutive expression of AcMYB110 in tobacco leaves revealed different roles for two bHLHs, NtAN1 and NtJAF13. A hierarchical mechanism is shown to control the regulation of transcription factors and consequently of the anthocyanin biosynthetic pathway. Here, a model is proposed for the regulation of the anthocyanin pathway in Solanaceous plants in which AN1 is directly involved in the activation of the biosynthetic genes, whereas JAF13 is involved in the regulation of AN1 transcription.

Sneak peek: Dance audience relationships during open rehearsals

Over the past decade there has been a surge of interest in behind-the-scenes events from mainstream dance companies and audiences alike. Online videos, open classes, open rehearsals, and backstage tours all provide insights for audiences about daily life in a dance company and how dance work is made. This article focuses on the use of open rehearsals in studio sites and investigates audience experience and relationship with dancers during these events. Applying Clare Dyson’s (2010) scales of audience engagement, I analyse two open rehearsal models that I observed as an audience participant in 2013: Friends Open Days with English National Ballet (London), and Inner Workings with Chunky Move (Melbourne). Through this analysis, open rehearsals emerge as an experience with elements reminiscent of both the traditional presentation paradigm and non-traditional presentation models. Elements such as close audience-dancer proximity, authenticity, and experiences in liminal sites, such as staircases and green rooms, present the possibility of new audience-dancer relationship within the mainstream dance company context.

Audience as performer: The changing role of theatre audiences in the twenty-first century

'Actors always talk about what the audience does. I don’t understand, we are just sitting here.' Audience as Performer proposes that in the theatre, there are two troupes of performers: the actors and the audience. Although academics have scrutinised how audiences respond, make meaning and co-create while watching a performance, little research has considered the behaviour of the theatre audience as a performance in and of itself. This insightful book describes how an audience performs through its myriad gestural, vocal and paralingual actions, and considers the following questions: •If the audience are performers, who are their audiences? •How have audiences’ roles changed throughout history? •How do talkbacks and technology influence the audience’s role as critics? •What influence does the audience have on the creation of community in theatre? •How can the audience function as both consumer and co-creator? Drawing from over 140 interviews with audience members, actors and ushers in the UK, USA and Australia, Heim reveals the lived experience of audience members at the theatrical event. It is a fresh reading of mainstream audiences’ activities, bringing their voices to the fore and exploring their emerging new roles in the theatre of the Twenty-First Century.

Room-temperature tilted-target sputtering deposition of highly transparent and low sheet resistance Al doped ZnO electrodes

Target-tilted room temperature sputtering of aluminium doped zinc oxide (AZO) provides transparent conducting electrodes with sheet resistances of <10 Ω □-1 and average transmittance in the visible region of up to 84%. The properties of the AZO electrode are found to be strongly dependent on the target-tilting angle and film thickness. The AZO electrodes showed comparable performance to commercial indium tin oxide (ITO) electrodes in organic photovoltaic (OPV) devices. OPV devices containing a bulk heterojunction active layer comprised of poly(3-n-hexylthiophene) (P3HT):phenyl-C61-butyric acid methyl ester (PCBM) and an AZO transparent conducting electrode had a power conversion efficiency (PCE) of up to 2.5% with those containing ITO giving a PCE of 2.6%. These results demonstrate that AZO films are a good alternative to ITO for transparent conducting electrodes.

Audience response systems can facilitate communal course feedback

Background At Queensland University of Technology (QUT), the Bachelor of Radiation Therapy course evaluation has previously suffered from low online survey participation rates. A communal instantaneous feedback event using an audience response system (ARS) was evaluated as a potential solution to this problem. The aims of the project were to determine the extent to which this feedback event could be facilitated by ARS technology and to evaluate the impact the technology made on student satisfaction and engagement. Methods Students were invited to a timetabled session to provide feedback on individual study units and the course overall. They provided quantitative Likert-style responses to prompts for each unit and the course using an ARS as well as anonymous typed qualitative comments. Data collection was performed live so students were able to view collective class responses. This prompted further discussion and enabled a prospective action plan to be developed. To inform future ARS use, students were asked for their opinions on the feedback method. Results Despite technological difficulties, student evaluation indicated that all responders enjoyed the session and the opportunity to view the combined responses. All students felt that useful feedback was generated and that this method should be used in the future. The student attendance and response rates were high, and it was clear that the session had led to the development of some insightful qualitative feedback comments. Conclusions: An ARS contributed well to the collection of course feedback in a communal and interactive environment. Students found it enjoyable to use, and it helped to stimulate useful qualitative comments

Social Media Audience Metrics as a New Form of TV Audience Measurement

Digital media have contributed to significant disruptions in the business of audience measurement. Television broadcasters have long relied on simple and authoritative measures of who is watching what. The demand for ratings data, as a common currency in transactions involving advertising and program content, will likely remain, but accompanying measurements of audience engagement with media content would also be of value. Today's media environment increasingly includes social media and second-screen use, providing a data trail that affords an opportunity to measure engagement. If the limitations of using social media to indicate audience engagement can be overcome, social media use may allow for quantitative and qualitative measures of engagement. Raw social media data must be contextualized, and it is suggested that tools used by sports analysts be incorporated to do so. Inspired by baseball's Sabremetrics, the authors propose Telemetrics in an attempt to separate actual performance from contextual factors. Telemetrics facilitates measuring audience activity in a manner controlling for factors such as time slot, network, and so forth. It potentially allows both descriptive and predictive measures of engagement.

Target acquired: Progress and promise of targeted therapeutics in the treatment of prostate cancer

Cancer is fundamentally a genomic disease caused by mutations or rearrangements in the DNA or epigenetic machinery of a patient. An emerging field in cancer treatment targets key aberrations arising from the mutational landscape of an individual patient’s disease rather than employing a cancer-wide cytotoxic therapy approach. In prostate cancer in particular, where there is an observed variation in response to standard treatments between patients with disease of a similar pathological stage and grade, mutationdirected treatment may grow to be a viable tool for clinicians to tailor more effective treatments. This review will describe a number of mutations across multiple forms of cancer that have been successfully antagonised by targeted therapeutics including their identification, the development of targeted compounds to combat them and the development of resistance to these therapies. This review will continue to examine these same mutations in the treatment and management of prostate cancer; the prevalence of targetable mutations in prostate cancer, recent clinical trials of targeted-agents and the potential or limitations for their use.

Crowdfunding and independent screen content production in Australia: A direct economic relationship between producer and audience

This thesis examines the significance of crowdfunding for Australian filmmakers and provides an empirical basis to current claims about the role of crowdfunding in the film production and policy sectors. It has found that crowdfunding is a small but growing source of supplementary finance which is opening up new possibilities for Australian independent screen content producers. This project also highlights the discussion within Australian film policy circles that is opening the way for crowdfunding to potentially become a larger and more formalised component of current and emerging policy initiatives.

Evaluation of polymorphisms in predicted target sites for micro RNAs differentially expressed in endometriosis

Previous microarray analyses identified 22 microRNAs (miRNAs) differentially expressed in paired ectopic and eutopic endometrium of women with and without endometriosis. To investigate further the role of these miRNAs in women with endometriosis, we conducted an association study aiming to explore the relationship between endometriosis risk and single-nucleotide polymorphisms (SNPs) in miRNA target sites for these differentially expressed miRNAs. A panel of 102 SNPs in the predicted miRNA binding sites were evaluated for an endometriosis association study and an ingenuity pathway analysis was performed. Fourteen rare variants were identified in this study. We found SNP rs14647 in the Wolf-Hirschhorn syndrome candidate gene1 (WHSC1) 3'UTR (untranslated region) was associated with endometriosis-related infertility presenting an odds ratio of 12.2 (95% confidence interval = 2.4-60.7, P = 9.03 x 10(-5)). SNP haplotype AGG in the solute carrier family 22, member 23 (SLC22A23) 3'UTR was associated with endometriosis-related infertility and more severe disease. With the individual genotyping data, ingenuity pathways analysis identified the tumour necrosis factor and cyclin-dependant kinase inhibitor as major factors in the molecular pathways. Significant associations between WHSC1 alleles and endometriosis-related infertility and SLC22A23 haplotypes and the disease severe stage were identified. These findings may help focus future research on subphenotypes of this disease. Replication studies in independent large sample sets to confirm and characterize the involvement of the gene variation in the pathogenesis of endometriosis are needed.

Uncertainty based online planning for UAV target finding in cluttered and GPS-denied environments

There are some scenarios in which Unmmaned Aerial Vehicle (UAV) navigation becomes a challenge due to the occlusion of GPS systems signal, the presence of obstacles and constraints in the space in which a UAV operates. An additional challenge is presented when a target whose location is unknown must be found within a confined space. In this paper we present a UAV navigation and target finding mission, modelled as a Partially Observable Markov Decision Process (POMDP) using a state-of-the-art online solver in a real scenario using a low cost commercial multi rotor UAV and a modular system architecture running under the Robotic Operative System (ROS). Using POMDP has several advantages to conventional approaches as they take into account uncertainties in sensor information. We present a framework for testing the mission with simulation tests and real flight tests in which we model the system dynamics and motion and perception uncertainties. The system uses a quad-copter aircraft with an board downwards looking camera without the need of GPS systems while avoiding obstacles within a confined area. Results indicate that the system has 100% success rate in simulation and 80% rate during flight test for finding targets located at different locations.

Identification of a novel FGFRL1 MicroRNA target site polymorphism for bone mineral density in meta-analyses of genome-wide association studies

MicroRNAs (miRNAs) are critical post-transcriptional regulators. Based on a previous genome-wide association (GWA) scan, we conducted a polymorphism in microRNAs' Target Sites (poly-miRTS)-centric multistage meta-analysis for lumbar spine (LS)-, total hip (HIP)-, and femoral neck (FN)-bone mineral density (BMD). In stage I, 41,102 poly-miRTSs were meta-analyzed in 7 cohorts with a genome-wide significance (GWS) α=0.05/41,102=1.22×10-6. By applying α=5×10-5 (suggestive significance), 11 poly-miRTSs were selected, with FGFRL1 rs4647940 and PRR5 rs3213550 as top signals for FN-BMD (P-value=7.67×10-6 and 1.58×10-5) in gender-combined sample. In stage II in silico replication (two cohorts), FGFRL1 rs4647940 was the only signal marginally replicated for FN-BMD (P-value=5.08×10-3) at α=0.10/11=9.09×10-3. PRR5 rs3213550 was also selected based on biological significance. In stage III de novo genotyping replication (two cohorts), FGFRL1 rs4647940 was the only signal significantly replicated for FN-BMD (P-value=7.55×10-6) at α=0.05/2=0.025 in gender-combined sample. Aggregating three stages, FGFRL1 rs4647940 was the single stage I-discovered and stages II- and III-replicated signal attaining GWS for FN-BMD (P-value=8.87×10-12). Dual-luciferase reporter assays demonstrated that FGFRL1 3' untranslated region harboring rs4647940 appears to be hsa-miR-140-5p's target site. In a zebrafish microinjection experiment, dre-miR-140-5p is shown to exert a dramatic impact on craniofacial skeleton formation. Taken together, we provided functional evidence for a novel FGFRL1 poly-miRTS rs4647940 in a previously known 4p16.3 locus, and experimental and clinical genetics studies have shown both FGFRL1 and hsa-miR-140-5p are important for bone formation. © The Author 2015. Published by Oxford University Press. All rights reserved.

How cancer doctors use personalized medicine to target variations unique to each tumour

The Children’s Cancer Institute in Sydney recently launched an ambitious program. From early next year, scientists will analyse the unique cancer cells of 12 children diagnosed with the most aggressive forms of the disease to find the best treatment for each child. By 2020, they aim to have these individualised treatment options available to all children diagnosed with cancers that have a less than 30% survival rate. This way of tailoring treatment to each person is known as personalised medicine, and advances in DNA sequencing have paved the way for a new era in cancer management.

Theatre, networked performance, and notions of ‘democratised’ spectatorship

The potential to cultivate new relationships with spectators has long been cited as a primary motivator for those using digital technologies to construct networked or telematics performances or para-performance encounters in which performers and spectators come together in virtual – or at least virtually augmented – spaces and places. Today, with Web 2.0 technologies such as social media platforms becoming increasingly ubiquitous, and increasingly easy to use, more and more theatre makers are developing digitally mediated relationships with spectators. Sometimes for the purpose of an aesthetic encounter, sometimes for critical encounter, or sometimes as part of an audience politicisation, development or engagement agenda. Sometimes because this is genuinely an interest, and sometimes because spectators or funding bodies expect at least some engagement via Facebook, Twitter or Instagram. In this paper, I examine peculiarities and paradoxes emerging in some of these efforts to engage spectators via networked performance or para-performance encounters. I use examples ranging from theatre, to performance art, to political activism – from ‘cyberformaces’ on Helen Varley Jamieson’s Upstage Avatar Performance Platform, to Wafaa Bilal’s Domestic Tension installation where spectators around the world could use a webcam in a chat room to target him with paintballs while he was in residence in a living room set up in a gallery for a week, as a comment on use of drone technology in war, to Liz Crow’s Bedding Out where she invited people to physically and virtually join her in her bedroom to discuss the impact of an anti-disabled austerity politics emerging in her country, to Dislife’s use of holograms of disabled people popping up in disabled parking spaces when able bodied drivers attempted to pull into them, amongst others. I note the frequency with which these performance practices deploy discourses of democratisation, participation, power and agency to argue that these technologies assist in positioning spectators as co-creators actively engaged in the evolution of a performance (and, in politicised pieces that point to racism, sexism, or ableism, pushing spectators to reflect on their agency in that dramatic or daily-cum-dramatic performance of prejudice). I investigate how a range of issues – from the scenographic challenges in deploying networked technologies for both participant and bystander audiences others have already noted, to the siloisation of aesthetic, critical and audience activation activities on networked technologies, to conventionalised dramaturgies of response informed by power, politics and impression management that play out in online as much as offline performances, to the high personal, social and professional stakes involved in participating in a form where spectators responses are almost always documented, recorded and re-represented to secondary and tertiary sets of spectators via the circulation into new networks social media platforms so readily facilitate – complicate discourses of democratic co-creativity associated with networked performance and para-performance activities.