The fatty acid synthase inhibitor triclosan : repurposing an anti-microbial agent for targeting prostate cancer

Inhibition of FASN has emerged as a promising therapeutic target in cancer, and numerous inhibitors have been investigated. However, severe pharmacological limitations have challenged their clinical testing. The synthetic FASN inhibitor triclosan, which was initially developed as a topical antibacterial agent, is merely affected by these pharmacological limitations. Yet, little is known about its mechanism in inhibiting the growth of cancer cells. Here we compared the cellular and molecular effects of triclosan in a panel of eight malignant and non-malignant prostate cell lines to the well-known FASN inhibitors C75 and orlistat, which target different partial catalytic activities of FASN. Triclosan displayed a superior cytotoxic profile with a several-fold lower IC50 than C75 or orlistat. Structure-function analysis revealed that alcohol functionality of the parent phenol is critical for inhibitory action. Rescue experiments confirmed that end product starvation was a major cause of cytotoxicity. Importantly, triclosan, C75 and orlistat induced distinct changes to morphology, cell cycle, lipid content and the expression of key enzymes of lipid metabolism, demonstrating that inhibition of different partial catalytic activities of FASN activates different metabolic pathways. These finding combined with its well-documented pharmacological safety profile make triclosan a promising drug candidate for the treatment of prostate cancer.

The nature of errors made by drivers [Austroads Publication no: AP-R378-11]

It is important that we understand the factors and conditions that shape driver behaviour – those conditions within the road transport system that contribute to driver error and the situations where driver non-compliance to road regulations is likely. This report presents the findings derived from a program of research investigating the nature of errors made by drivers, involving a literature review and an on-road study. The review indicates that, despite significant investigation, the role of different error types in road traffic crashes remains unclear, as does the role of the wider road transport system failures in driver error causation.

The whole world shook : shifts in ethnic, national and heroic identities in children's fiction about 9/11

Like many other cataclysmic events September 11, a day now popularly believed to have 'changed the world', has become a topic taken up by children's writers. This thesis, titled The Whole World Shook: Ethnic, National and Heroic Identities in Children's Fiction About 9/11, examines how cultural identities are constructed within fictional texts for young people written about the attacks on the Twin Towers. It identifies three significant identity categories encoded in 9/11 books for children: ethnic identities, national identities, and heroic identities. The thesis argues that the identities formed within the selected children's texts are in flux, privileging performances of identities that are contingent on post-9/11 politics. This study is located within the field of children's literature criticism, which supports the understanding that children's books, like all texts, play a role in the production of identities. Children's literature is highly significant both in its pedagogical intent (to instruct and induct children into cultural practices and beliefs) and in its obscurity (in making the complex simple enough for children, and from sometimes intentionally shying away from difficult things). This literary criticism informed the study that the texts, if they were to be written at all, would be complex, varied and most likely as ambiguous and contradictory as the responses to the attacks on New York themselves. The theoretical framework for this thesis draws on a range of critical theories including literary theory, cultural studies, studies of performativity and postmodernism. This critical framework informs the approach by providing ways for: (i) understanding how political and ideological work is performed in children's literature; (ii) interrogating the constructed nature of cultural identities; (iii) developing a nuanced methodology for carrying out a close textual analysis. The textual analysis examines a representative sample of children's texts about 9/11, including picture books, young adult fiction, and a selection of DC Comics. Each chapter focuses on a different though related identity category. Chapter Four examines the performance of ethnic identities and race politics within a sample of picture books and young adult fiction; Chapter Five analyses the construction of collective, national identities in another set of texts; and Chapter Six does analytic work on a third set of texts, demonstrating the strategic performance of particular kinds of heroic identities. I argue that performances of cultural identities constructed in these texts draw on familiar versions of identities as well as contribute to new ones. These textual constructions can be seen as offering some certainties in increasingly uncertain times. The study finds, in its sample of books a co-mingling of xenophobia and tolerance; a binaried competition between good and evil and global harmony and national insularity; and a lauding of both the commonplace hero and the super-human. Being a recent corpus of texts about 9/11, these texts provide information on the kinds of 'selves' that appear to be privileged in the West since 2001. The thesis concludes that the shifting identities evident in texts that are being produced for children about 9/11 offer implicit and explicit accounts of what constitute good citizenship, loyalty to nation and community, and desirable attributes in a Western post-9/11 context. This thesis makes an original contribution to the field of children's literature by providing a focussed and sustained analysis of how texts for children about 9/11 contribute to formations of identity in these complex times of cultural unease and global unrest.

The O-specific polysaccharide structure and biosynthetic gene cluster of Yersinia pseudotuberculosis serotype O:11

In the Yersinia pseudotuberculosis serotyping scheme, 21 serotypes are present originating from about 30 different O-factors distributed within the species. With regard to the chemical structures of lipopolysaccharides (LPSs) and the genetic basis of their biosynthesis, a number, but not all, of Y. pseudotuberculosis strains representing different serotypes have been investigated. In order to present an overall picture of the relationship between genetics and structures, we have been working on the genetics and structures of various Y. pseudotuberculosis O-specific polysaccharides (OPSs). Here, we present a structural and genetic analysis of the Y. pseudotuberculosis serotype O:11 OPS. Our results showed that this OPS structure has the same backbone as that of Y. pseudotuberculosis O:1b, but with a 6d-l-Altf side-branch instead of Parf. The 3′ end of the gene cluster is the same as that for O:1b and has the genes for synthesis of the backbone and for processing the completed repeat unit. The 5′ end has genes for synthesis of 6d-l-Altf and its transfer to the repeating unit backbone. The pathway for the synthesis of the 6d-l-Altf appears to be different from that for 6d-l-Altp in Y. enterocolitica O:3. The chemical structure of the O:11 repeating unit is [Figure]

Coming of Age in 9/11 Fiction: Bildungsroman and Loss of Innocence

Directly after the horrific events of September 11, 2001, many Americans were saying the same thing: the world has changed forever. They were overwhelmed with a sense that “the party was over.” It was clear that America had lost its innocence; it now had to “grow up.” Much of the fiction produced since 9/11 and with 9/11 at its core provides evidence of the larger cultural belief that September 11 was a turning point (much like adolescence) from which there is no turning back. In this chapter, I examine how three post-9/11 novels—Lorrie Moore’s A Gate at the Stairs, Joyce Maynard’s The Usual Rules, and John Updike’s Terrorist—position readers to understand September 11 as a moment that changed how young Americans come of age.

Brain network efficiency and topology depend on the fiber tracking method: 11 tractography algorithms compared in 536 subjects

As connectivity analyses become more popular, claims are often made about how the brain's anatomical networks depend on age, sex, or disease. It is unclear how results depend on tractography methods used to compute fiber networks. We applied 11 tractography methods to high angular resolution diffusion images of the brain (4-Tesla 105-gradient HARDI) from 536 healthy young adults. We parcellated 70 cortical regions, yielding 70×70 connectivity matrices, encoding fiber density. We computed popular graph theory metrics, including network efficiency, and characteristic path lengths. Both metrics were robust to the number of spherical harmonics used to model diffusion (4th-8th order). Age effects were detected only for networks computed with the probabilistic Hough transform method, which excludes smaller fibers. Sex and total brain volume affected networks measured with deterministic, tensor-based fiber tracking but not with the Hough method. Each tractography method includes different fibers, which affects inferences made about the reconstructed networks.

Provisioning a 3.3 MW PhotoVoltaic generation system onto a distribution authority’s 11 kV rural feeder

This paper describes part of an engineering study that was undertaken to demonstrate that a multi-megawatt Photovoltaic (PV) generation system could be connected to a rural 11 kV feeder without creating power quality issues for other consumers. The paper concentrates solely on the voltage regulation aspect of the study as this was the most innovative part of the study. The study was carried out using the time-domain software package, PSCAD/EMTDC. The software model included real time data input of actual measured load and scaled PV generation data, along with real-time substation voltage regulator and PV inverter reactive power control. The outputs from the model plot real-time voltage, current and power variations throughout the daily load and PV generation variations. Other aspects of the study not described in the paper include the analysis of harmonics, voltage flicker, power factor, voltage unbalance and system losses.

Budesonide and Formoterol Reduce Early Innate Anti-Viral Immune Responses In Vitro

Asthma is a chronic inflammatory airways disease in which respiratory viral infections frequently trigger exacerbations. Current treatment of asthma with combinations of inhaled corticosteroids and long acting beta2 agonists improves asthma control and reduces exacerbations but what impact this might have on innate anti-viral immunity is unclear. We investigated the in vitro effects of asthma drugs on innate anti-viral immunity. Peripheral blood mononuclear cells (PBMC) from healthy and asthmatic donors were cultured for 24 hours with the Toll-like receptor 7 agonist, imiquimod, or rhinovirus 16 (RV16) in the presence of budesonide and/or formoterol. Production of proinflammatory cytokines and expression of anti-viral intracellular signalling molecules were measured by ELISA and RT-PCR respectively. In PBMC from healthy donors, budesonide alone inhibited IP-10 and IL-6 production induced by imiquimod in a concentration-dependent manner and the degree of inhibition was amplified when budesonide and formoterol were used in combination. Formoterol alone had little effect on these parameters, except at high concentrations (10−6 M) when IL-6 production increased. In RV16 stimulated PBMC, the combination of budesonide and formoterol inhibited IFNα and IP-10 production in asthmatic as well as healthy donors. Combination of budesonide and formoterol also inhibited RV16-stimulated expression of the type I IFN induced genes myxovirus protein A and 2′, 5′ oligoadenylate synthetise. Notably, RV16 stimulated lower levels of type Myxovirus A and oligoadenylate synthase in PBMC of asthmatics than control donors. These in vitro studies demonstrate that combinations of drugs commonly used in asthma therapy inhibit both early pro-inflammatory cytokines and key aspects of the type I IFN pathway. These findings suggest that budesonide and formoterol curtail excessive inflammation induced by rhinovirus infections in patients with asthma, but whether this inhibits viral clearance in vivo remains to be determined.

Genome-wide association analysis identifies 11 risk variants associated with the asthma with hay fever phenotype

Background To date, no genome-wide association study (GWAS) has considered the combined phenotype of asthma with hay fever. Previous analyses of family data from the Tasmanian Longitudinal Health Study provide evidence that this phenotype has a stronger genetic cause than asthma without hay fever. Objective We sought to perform a GWAS of asthma with hay fever to identify variants associated with having both diseases. Methods We performed a meta-analysis of GWASs comparing persons with both physician-diagnosed asthma and hay fever (n = 6,685) with persons with neither disease (n = 14,091). Results At genome-wide significance, we identified 11 independent variants associated with the risk of having asthma with hay fever, including 2 associations reaching this level of significance with allergic disease for the first time: ZBTB10 (rs7009110; odds ratio [OR], 1.14; P = 4 × 10−9) and CLEC16A (rs62026376; OR, 1.17; P = 1 × 10−8). The rs62026376:C allele associated with increased asthma with hay fever risk has been found to be associated also with decreased expression of the nearby DEXI gene in monocytes. The 11 variants were associated with the risk of asthma and hay fever separately, but the estimated associations with the individual phenotypes were weaker than with the combined asthma with hay fever phenotype. A variant near LRRC32 was a stronger risk factor for hay fever than for asthma, whereas the reverse was observed for variants in/near GSDMA and TSLP. Single nucleotide polymorphisms with suggestive evidence for association with asthma with hay fever risk included rs41295115 near IL2RA (OR, 1.28; P = 5 × 10−7) and rs76043829 in TNS1 (OR, 1.23; P = 2 × 10−6). Conclusion By focusing on the combined phenotype of asthma with hay fever, variants associated with the risk of allergic disease can be identified with greater efficiency.

Effect of an estrogen receptor-α intron 4 polymorphism on fat mass in 11-year-old children

Context: in the ESR1 gene encoding estrogen receptor (ER)-α may be associated with fat mass in adults. Objectives: The objective of the study was to establish whether ESR1 polymorphisms influence fat mass in childhood. Design: This was a cross-sectional analysis after genotyping of rs9340799, rs2234693, and rs7757956 ESR1 polymorphisms. Setting: The Avon Longitudinal Study of Parents and Children (ALSPAC) was a population-based prospective study. Participants: Participants included 3097 11-yr-old children with results for ESR1 genotyping, puberty measures, and dual-energy x-ray absorptiometry results. Outcomes: Relationships between ESR1 polymorphisms and indices of body composition were measured. Results: The rs7757956 polymorphism was associated with fat mass (P = 0.002). Total body fat mass (adjusted for height) was reduced by 6% in children with TA/AA genotypes, and risk of being overweight (≥85th centile of fat mass) was decreased by 20%. This genetic effect appeared to interact with puberty in girls (P = 0.05 for interaction): in those with the TT genotype, total body fat mass (adjusted for height) was 18% higher in Tanner stages 3-5 vs. stages 1-2; the equivalent difference was 7% in those with TA/AA genotypes. Furthermore, the risk of being overweight was 36% lower in girls with TA/AA genotypes in Tanner stages 3-5, but no reduction was seen in those in stages 1-2. Neither rs9340799 nor rs2234693 polymorphisms were associated with body composition measures. Conclusions: Fat mass in 11-yr-old children was related to the rs7757956 ESR1 polymorphism. This association was strongest in girls in more advanced puberty, in whom the risk of being overweight was reduced by 36% in those with the TA/AA genotype.

Prolonged hyperinsulinemia affects metabolic signal transduction markers in a tissue specific manner

Insulin dysregulation is common in horses although the mechanisms of metabolic dysfunction are poorly understood. We hypothesized that insulin signaling in striated (cardiac and skeletal) muscle and lamellae may be mediated through different receptors as a result of receptor content, and that transcriptional regulation of downstream signal transduction and glucose transport may also differ between tissues sites during hyperinsulinemia. Archived samples from horses treated with a prolonged insulin infusion or a balanced electrolyte solution were used. All treated horses developed marked hyperinsulinemia and clinical laminitis. Protein expression was compared across tissues for the insulin receptor and insulin-like growth factor 1 receptor (IGF-1R) by immunoblotting. Gene expression of metabolic insulin-signaling markers (insulin receptor substrate 1, Akt2, and glycogen synthase kinase 3 beta [GSK-3β]) and glucose transport (basal glucose transporter 1 and insulin-sensitive glucose transporter 4) was evaluated using real-time reverse transcription polymerase chain reaction. Lamellar tissue contained significantly more IGF-1R protein than skeletal muscle, indicating the potential significance of IGF-1R signaling for this tissue. Gene expression of the selected markers of insulin signaling and glucose transport in skeletal muscle and lamellar tissues was unaffected by prolonged hyperinsulinemia. In contrast, the significant upregulation of Akt2, GSK-3β, GLUT1, and GLUT4 gene expression in cardiac tissue suggested that the prolonged hyperinsulinemia induced an increase in insulin sensitivity and a transcriptional activation of glucose transport. Responses to insulin are tissue-specific, and extrapolation of data across tissue sites is inappropriate.

Correlación entre la personalidad y los factores de la Teoría del Comportamiento Planeado (TCP) en adolescentes escolarizados de 11-19 años del Caribe Colombiano

The increasing rate of pregnancies in teenagers and the high incident of the infections of sexual transmission (HIV/ AIDS, for example), these are health related issues (and especially the sexual and reproductive health), which have received great attention on the part of investigators and of the public opinion in general. Recently, there has been evidenced that teenagers carry out very easily risk sexual behaviors, and those who have not presented the above mentioned behaviors also show high levels of intention to carry out them. There is the hypothesis that besides cognitive variables such as attitudes, subjective norms, perceived behavioral control and intention, the personality of the young persons is an aspect that plays an important paper in their sexual and reproductive health. Significant correlations were found between the variales of the TPB and the personality traits; the results suggest that the direction of these correlations is associated with the specific type of behavior or situation that is assessed. Keywords: personality, theory of planned behavior, adolescents, reproductive sexuality.

A deadline-constrained 802.11 MAC Protocol with QoS differentiation for soft real-time control

As one of the most widely used wireless network technologies, IEEE 802.11 wireless local area networks (WLANs) have found a dramatically increasing number of applications in soft real-time networked control systems (NCSs). To fulfill the real-time requirements in such NCSs, most of the bandwidth of the wireless networks need to be allocated to high-priority data for periodic measurements and control with deadline requirements. However, existing QoS-enabled 802.11 medium access control (MAC) protocols do not consider the deadline requirements explicitly, leading to unpredictable deadline performance of NCS networks. Consequentially, the soft real-time requirements of the periodic traffic may not be satisfied, particularly under congested network conditions. This paper makes two main contributions to address this problem in wireless NCSs. Firstly, a deadline-constrained MAC protocol with QoS differentiation is presented for IEEE 802.11 soft real-time NCSs. It handles periodic traffic by developing two specific mechanisms: a contention-sensitive backoff mechanism, and an intra-traffic-class QoS differentiation mechanism. Secondly, a theoretical model is established to describe the deadline-constrained MAC protocol and evaluate its performance of throughput, delay and packet-loss ratio in wireless NCSs. Numerical studies are conducted to validate the accuracy of the theoretical model and to demonstrate the effectiveness of the new MAC protocol.