Studies on the reverse antibiotic natural products, the nybomycins

Antimicrobial resistance (AMR) is likely to be one of the greatest challenges faced by humanity and if nothing changes it is projected to kill one person every 5 seconds by 2050. Despite this, there are few new therapeutic options in development and so there is a need for new solutions to be identified. One new strategy is the reverse antibiotic approach originally published by Akamatsu and co-workers. Here treatment with the first antibiotic leads to resistance so a new antibiotic is needed. Resistance to the second antibiotic can only be achieved by a back-mutation thus re-sensitising the bacteria to the first antibiotic. The bacteria will be trapped in an ‘evolutionary loop’ where it will always be sensitive to either the first or second antibiotic. Work outlined in this thesis will look to investigate and develop one of the key series of antibiotics in the reverse antibiotic approach, the Nybomycin family of natural products. A new robust and scalable synthetic route that facilitated the synthesis of the best literature compound DNM-2, as well as novel analogues to probe the SAR, is reported. The whole cell inhibition of these compounds is reported as well as selected analogue’s enzymatic inhibition of the key biological targets. The ability of the series to inhibit Gram-negative bacteria was also explored and led to the discovery that the series is a substrate for efflux via the AcrAB/TolC efflux channel. However, the compounds are active in E. coli if TolC or AcrB is removed. After initial profiling, aqueous solubility was found to be the major hurdle in the development of the series. This was addressed using medicinal chemistry techniques as well as computational chemistry to aid in the design of novel analogues. This led to the discovery of 6DNM-2-L1A, the most potent and soluble analogue tested to date.Open Acces

Damping and Mass Sensitivity of Laterally Vibrating Resonant Microcantilevers in Viscous Liquid Media

The effect of liquid viscosity and density on the characteristics of laterally excited microcantilevers is investigated and compared to transversely excited microcantilevers. When immersed into a viscous liquid medium such as water from air, the resonant frequency of laterally (in-plane) vibrating microcantilevers is shown to decrease by only 5-10% as compared to ~50% reduction for transversely (out-of-plane) vibrating microcantilevers. Furthermore, as the viscosity of the medium increases the resonant frequency of a laterally vibrating beam is shown to decrease at a slower rate than that of a transversely vibrating beam. The decreased viscous damping also leads to increases in the quality factor of the system by a factor of 4-5 compared to beams vibrating transversely. The mass sensitivities of laterally vibrating beams are also theoretically predicted to be roughly two orders of magnitude larger in water for some cantilever geometries. The increase in the quality factor and mass sensitivity indicate that operating in the in-plane flexural mode (lateral vibration) will decrease the limit of detection compared to operating in the more common out-of-plane flexural mode (transverse vibration). These improvements in device characteristics indicate that microcantilevers excited laterally are more suited for operating in media of high viscosities

Phonetic lessons from automatic phonemic transcription: preliminary reflections on Na (Sino-Tibetan) and Tsuut’ina (Dene) data

International audienceAutomatic phonemic transcription tools now reach high levels of accuracy on a single speaker with relatively small amounts of training data: on the order of 100 to 250 minutes of transcribed speech. Beyond its practical usefulness for language documentation, use of automatic transcription also yields some insights for phoneticians. The present report illustrates this by going into qualitative error analysis on two test cases, Yongning Na (Sino-Tibetan) and Tsuut’ina (Dene). Among other benefits, error analysis allows for a renewed exploration of phonetic detail: examining the output of phonemic transcription software compared with spectrographic and aural evidence. From a methodological point of view, the present report is intended as a case study in Computational Language Documentation: an interdisciplinary approach that associates fieldworkers (“diversity linguists”) and computer scientists with phoneticians/phonologists

The international consequences of the EU referendum — LSE Ideas Podcast

Brexit – Britain at the Crossroads: European Consequences, Geopolitical Risks? LSE IDEAS Strategic Breakfast Series, is a private discussion event held at LSE IDEAS exclusively for executive MSc International Strategy and Diplomacy Alumni with leading practitioners and academics. This strategic breakfast assessed the international consequences of the forthcoming referendum on the United Kingdom’s membership in the European Union

Improved detection and monitoring of fungicide resistance in Blumeria graminis f. sp. hordei with high-throughput genotype quantification by digital PCR

The increased occurrence of triazole fungicide resistant strains of Blumeria graminis f. sp. hordei (Bgh) is an economic concern for the barley industry in Australia and elsewhere. High levels of resistance to triazoles in the field are caused by two separate point mutations in the Cyp51 gene, Y136F and S509T. Early detection of these mutations arising in pathogen field populations is important as this allows time for changes in fungicide practices to be adopted, thus mitigating potential yield losses due to fungicide failure and preventing the resistance from becoming dominant. A digital PCR (dPCR) assay has been developed for the detection and quantification of the Y136F and S509T mutations in the Bgh Cyp51 gene. Mutation levels were quantifiable as low as 0.2% in genomic DNA extractions and field samples. This assay was applied to the high throughput screening of Bgh field and bait trial samples from barley growing regions across Australia in the 2015 and 2016 growing seasons and identified the S509T mutation for the first time in the Eastern states of Australia. This is the first report on the use of digital PCR technology for fungicide resistance detection and monitoring in agriculture. Here we describe the potential application of dPCR for the screening of fungicide resistance mutations in a network of specifically designed bait trials. The combination of these two tools constitute an early warning system for the development of fungicide resistance that allows for the timely adjustment of management practices

Resonant Microcantilevers Vibrating Laterally in Viscous Liquid Media

The characteristics of microcantilevers vibrating in the in-plane flexural mode (also known as lateral vibration) in viscous liquid media are investigated. A numerical model was utilized to determine a correction to Stokes\u27 solution for an infinite plate to obtain an analytical expression for the hydrodynamic forces acting on a laterally vibrating microcantilever as a function of both Reynolds number and aspect ratio (thickness over width). The results allowed for the resonant frequency and quality factor to be investigated as a function of both beam geometry and medium properties. Trends in these characteristics can be used to optimize device geometry and maximize the frequency stability. As the thickness of a microcantilever is increased, both its stiffness and the medium\u27s viscous damping increase. This will lead to an optimum quality factor in terms of the thickness. The characteristics of laterally and transversely vibrating microcantilevers with similar geometries are also compared. It is found that the resonant frequency and quality factor are higher for laterally vibrating microcantilevers (at least by a factor of 2 to 3 or higher for the Q-factor depending on the geometry) compared to those of similar beams under transverse (or out-of-plane) vibration. The improvement in sensitivity (due to the increase in frequency) and in the quality factor (thus a reduced frequency noise) are expected to yield much lower limits of detection in liquid-phase chemical sensing applications

The Development of a Spanish Language Version of the Worn Out Scale of the General Well-Being Questionnaire (GWBQ)

The paper describes the development of a short Spanish-language version of the General Well-Being Questionnaire (GWBQ; Cox & Gotts, 1987), based on the 12 items of its Worn Out scale. Research has shown the English-version Worn Out scale to be sensitive to aspects of the design and management of work. This study aimed to test its crosscultural consistency in a Spanish-language workplace context. The data were collected from a sample of 229 workers in Valencia (Spain). Confirmatory Factor Analyses showed the factorial validity, reliability, and concurrent validity of the new Spanish version to be adequate. The sensitivity of the new measure to safety behavior and the reporting of accidents was also assessed and shown to be good. The new questionnaire extends the usefulness of the parent questionnaire to occupational health psychology research in the Spanish language by offering a short assessment tool appropriate for workplace [email protected]

The Development of a Spanish Language Version of the Worn Out Scale of the General Well-Being Questionnaire (GWBQ)

The paper describes the development of a short Spanish-language version of the General Well-Being Questionnaire (GWBQ; Cox & Gotts, 1987), based on the 12 items of its Worn Out scale. Research has shown the English-version Worn Out scale to be sensitive to aspects of the design and management of work. This study aimed to test its crosscultural consistency in a Spanish-language workplace context. The data were collected from a sample of 229 workers in Valencia (Spain). Confirmatory Factor Analyses showed the factorial validity, reliability, and concurrent validity of the new Spanish version to be adequate. The sensitivity of the new measure to safety behavior and the reporting of accidents was also assessed and shown to be good. The new questionnaire extends the usefulness of the parent questionnaire to occupational health psychology research in the Spanish language by offering a short assessment tool appropriate for workplace studies.El artículo describe el desarrollo de la versión corta en español del General Well-Being Questionnaire (GWBQ; Cox & Gotts, 1987; en español el “Cuestionario de Bienestar General”), basada en los 12 ítems de su subescala de “Agotamiento”. La investigación ha mostrado que la versión en inglés de la escala de Agotamiento es sensible a ciertos aspectos del diseño y gestión del trabajo. El propósito de este estudio fue comprobar la consistencia transcultural en un contexto de trabajo de habla española. Los datos se recogieron de una muestra de 229 trabajadores en Valencia (España). Análisis factoriales confirmatorios demostraron la adecuación de la validez factorial, la fiabilidad, y la validez concurrente de la nueva versión española. También se evaluó la sensibilidad de la nueva medida hacia la conducta de seguridad y distintas medidas de siniestralidad, comprobando asimismo su adecuación. El cuestionario nuevo amplía la utilidad del cuestionario original al frecerse como herramienta para los investigadores en psicología de la salud cupacional en lengua española, ofreciendo un nstrumento corto de evaluación apropiado para el lugar de trabajo

Combination Schemes for Turning Point Predictions

We propose new forecast combination schemes for predicting turning points of business cycles. The combination schemes deal with the forecasting performance of a given set of models and possibly providing better turning point predictions. We consider turning point predictions generated by autoregressive (AR) and Markov-Switching AR models, which are commonly used for business cycle analysis. In order to account for parameter uncertainty we consider a Bayesian approach to both estimation and prediction and compare, in terms of statistical accuracy, the individual models and the combined turning point predictions for the United States and Euro area business cycles