Total synthesis of dehaloperophoramidine using a highly diastereoselective Hosomi-Sakurai reaction

The authors would like to acknowledge EPSRC for PhD funding through the Doctoral Training Schemes.The synthesis of dehaloperophoramidine, a non-halogenated derivative of the marine natural product perophoramidine, is reported. The key steps included a [3,3]-Claisen rearrangement and an epoxide opening/allylsilylation (modified Hosomi-Sakurai) reaction to install the contiguous all-carbon quaternary stereocentres with the required relative stereochemistry. The first five steps were carried out on seventy gram scale without the need for chromatography. Resolution of the [3,3]-Claisen product gave samples of the highly enantiomerically-enriched ketones which are flexible starting points for the synthesis of a number of complex ring structures. A regio- and diastereo-selective iodocyclisation was then used to differentiate between two allyl groups enabling the synthesis of the target molecule by two different routes. A detailed comparison of the trifluoroacetic acid salt of the synthetic dehaloperophoramidine with authentic material was carried out including a key doping experiment. Biological testing showed that (±)-dehaloperophoramidine was cytotoxic to HCT116, HT29 and LoVo colorectal carcinoma cells with comparable activity to that reported for the halogenated perophoramidine. This demonstrated for the first time that the halogens are not essential for the biological activity of this alkaloid class.Publisher PDFPeer reviewe

An integrated computational-experimental approach reveals Yersinia pestis genes essential across a narrow or a broad range of environmental conditions

Background The World Health Organization has categorized plague as a re-emerging disease and the potential for Yersinia pestis to also be used as a bioweapon makes the identification of new drug targets against this pathogen a priority. Environmental temperature is a key signal which regulates virulence of the bacterium. The bacterium normally grows outside the human host at 28 °C. Therefore, understanding the mechanisms that the bacterium used to adapt to a mammalian host at 37 °C is central to the development of vaccines or drugs for the prevention or treatment of human disease. Results Using a library of over 1 million Y. pestis CO92 random mutants and transposon-directed insertion site sequencing, we identified 530 essential genes when the bacteria were cultured at 28 °C. When the library of mutants was subsequently cultured at 37 °C we identified 19 genes that were essential at 37 °C but not at 28 °C, including genes which encode proteins that play a role in enabling functioning of the type III secretion and in DNA replication and maintenance. Using genome-scale metabolic network reconstruction we showed that growth conditions profoundly influence the physiology of the bacterium, and by combining computational and experimental approaches we were able to identify 54 genes that are essential under a broad range of conditions. Conclusions Using an integrated computational-experimental approach we identify genes which are required for growth at 37 °C and under a broad range of environments may be the best targets for the development of new interventions to prevent or treat plague in humans

Genome Resequencing of Laboratory Stocks of Burkholderia pseudomallei K96243.

We have resequenced the genomes of four Burkholderia pseudomallei K96243 laboratory cultures and compared them to the reported genome sequence that was published in 2004. Compared with the reference genome, these laboratory cultures harbored up to 42 single-nucleotide variants and up to 11 indels, including a 31.7-kb deletion in one culture

A Combined Subaru/VLT/MMT 1--5 Micron Study of Planets Orbiting HR 8799: Implications for Atmospheric Properties, Masses, and Formation

We present new 1--1.25 micron (z and J band) Subaru/IRCS and 2 micron (K band) VLT/NaCo data for HR 8799 and a rereduction of the 3--5 micron MMT/Clio data first presented by Hinz et al. (2010). Our VLT/NaCo data yields a detection of a fourth planet at a projected separation of ~ 15 AU -- "HR 8799e". We also report new, albeit weak detections of HR 8799b at 1.03 microns and 3.3 microns. Empirical comparisons to field brown dwarfs show that at least HR 8799b and HR8799c, and possibly HR 8799d, have near-to-mid IR colors/magnitudes significantly discrepant from the L/T dwarf sequence. Standard cloud deck atmosphere models appropriate for brown dwarfs provide only (marginally) statistically meaningful fits to HR 8799b and c for unphysically small radii. Models with thicker cloud layers not present in brown dwarfs reproduce the planets' SEDs far more accurately and without the need for rescaling the planets' radii. Our preliminary modeling suggests that HR 8799b has log(g) = 4--4.5, Teff = 900K, while HR 8799c, d, and (by inference) e have log(g) = 4--4.5, Teff = 1000--1200K. Combining results from planet evolution models and new dynamical stability limits implies that the masses of HR 8799b, c, d, and e are 6--7 Mj, 7--10 Mj, 7--10 Mj and 7--10 Mj. 'Patchy" cloud prescriptions may provide even better fits to the data and may lower the estimated surface gravities and masses. Finally, contrary to some recent claims, forming the HR 8799 planets by core accretion is still plausible, although such systems are likely rare.Comment: 27 pages, 15 figures, Accepted for publication in The Astrophysical Journa

Stretching the IR theoretical spectrum on Irish neutrality: a critical social constructivist framework

In a 2006 International Political Science Review article, entitled "Choosing to Go It Alone: Irish Neutrality in Theoretical and Comparative Perspective," Neal G. Jesse argues that Irish neutrality is best understood through a neoliberal rather than a neorealist international relations theory framework. This article posits an alternative "critical social constructivist" framework for understanding Irish neutrality. The first part of the article considers the differences between neoliberalism and social constructivism and argues why critical social constructivism's emphasis on beliefs, identity, and the agency of the public in foreign policy are key factors explaining Irish neutrality today. Using public opinion data, the second part of the article tests whether national identity, independence, ethnocentrism, attitudes to Northern Ireland, and efficacy are factors driving public support for Irish neutrality. The results show that public attitudes to Irish neutrality are structured along the dimensions of independence and identity, indicating empirical support for a critical social constructivist framework of understanding of Irish neutrality

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

STE-QUEST - Test of the Universality of Free Fall Using Cold Atom Interferometry

In this paper, we report about the results of the phase A mission study of the atom interferometer instrument covering the description of the main payload elements, the atomic source concept, and the systematic error sources

Paediatric acute hepatitis of unknown aetiology : a national investigation and adenoviraemia case-control study in the UK

Funding Information: This work was undertaken as part of a national enhanced incident by UK public health agencies. We thank the parents and guardians of the children who gave up their valuable time to speak to the public health investigation teams; without their support we could not have been able to undertake a thorough investigation. We are grateful to the many paediatricians and liver specialists who reported cases to us and responded to follow-up with further information. We also thank Ezra Linley and Simon Tonge of the UK Health Security Agency Seroepidemiology Unit for rapidly providing serum samples for testing. We would like to thank the Incident Management Teams of the UK nations, members of the incident cells, epidemiology, laboratory, and local Health Protection Teams who supported the investigations, in particular: Katy Sinka, Mike Gent, Suzanna Howes, Eileen Gallagher, Selene Corsini, Eleanor Clarke, Rajani Raghu, Kelsey Mowat, Iain Hayden, Matt Hibbert, Skye Firminger, Catriona Angel, Donna Haskins, Kay Ratcliffe, Hannah Emmett, Alex Elliot, Helen Hughes, Sarah Deeny, Sarah Garner, Sarah Gerver, Flora Stevens, Paula Blomquist, Gabriel Gurmail Kauffman, Kristine Cooper, Hannah Taylor, Giovanni Leonardi, Michelle Dickinson and Michelle Watson from England; Kimberly Marsh, Michael Lockhart, David Yirrell, Sandra Currie, Kate Templeton, Samantha Shepherd, Roisin Ure, Jim McMenamin, Rachel Tayler, Louisa Pollock, Antonia Ho, Chris Cunningham and Hayley Peacock from Scotland; and Katie Binley and Meg Wallace from Northern Ireland.Peer reviewe

Design of a dual species atom interferometer for space

Atom interferometers have a multitude of proposed applications in space including precise measurements of the Earth's gravitational field, in navigation & ranging, and in fundamental physics such as tests of the weak equivalence principle (WEP) and gravitational wave detection. While atom interferometers are realized routinely in ground-based laboratories, current efforts aim at the development of a space compatible design optimized with respect to dimensions, weight, power consumption, mechanical robustness and radiation hardness. In this paper, we present a design of a high-sensitivity differential dual species $^{85}$Rb/$^{87}$Rb atom interferometer for space, including physics package, laser system, electronics and software. The physics package comprises the atom source consisting of dispensers and a 2D magneto-optical trap (MOT), the science chamber with a 3D-MOT, a magnetic trap based on an atom chip and an optical dipole trap (ODT) used for Bose-Einstein condensate (BEC) creation and interferometry, the detection unit, the vacuum system for $10^{-11}$ mbar ultra-high vacuum generation, and the high-suppression factor magnetic shielding as well as the thermal control system. The laser system is based on a hybrid approach using fiber-based telecom components and high-power laser diode technology and includes all laser sources for 2D-MOT, 3D-MOT, ODT, interferometry and detection. Manipulation and switching of the laser beams is carried out on an optical bench using Zerodur bonding technology. The instrument consists of 9 units with an overall mass of 221 kg, an average power consumption of 608 W (819 W peak), and a volume of 470 liters which would well fit on a satellite to be launched with a Soyuz rocket, as system studies have shown.Comment: 30 pages, 23 figures, accepted for publication in Experimental Astronom

The SHED-IT community trial study protocol: a randomised controlled trial of weight loss programs for overweight and obese men

<p>Abstract</p> <p>Background</p> <p>Obesity is a major cause of preventable death in Australia with prevalence increasing at an alarming rate. Of particular concern is that approximately 68% of men are overweight/obese, yet are notoriously difficult to engage in weight loss programs, despite being more susceptible than women to adverse weight-related outcomes. There is a need to develop and evaluate obesity treatment programs that target and appeal to men. The primary aim of this study is to evaluate the efficacy of two relatively low intensity weight loss programs developed specifically for men.</p> <p>Methods and Design</p> <p>The study design is an assessor blinded, parallel-group randomised controlled trial that recruited 159 overweight and obese men in Newcastle, Australia. Inclusion criteria included: BMI 25-40 (kg/m²); no participation in other weight loss programs during the study; pass a health-screening questionnaire and pre-exercise risk assessment; available for assessment sessions; access to a computer with e-mail and Internet facilities; and own a mobile phone. Men were recruited to the SHED-IT (Self-Help, Exercise and Diet using Internet Technology) study via the media and emails sent to male dominated workplaces. Men were stratified by BMI category (overweight, obese class I, obese class II) and randomised to one of three groups: (1) SHED-IT <it>Resources </it>- provision of materials (DVD, handbooks, pedometer, tape measure) with embedded behaviour change strategies to support weight loss; (2) SHED-IT <it>Online </it>- same materials as SHED-IT <it>Resources </it>plus access to and instruction on how to use the study website; (3) Wait-list Control. The intervention programs are three months long with outcome measures taken by assessors blinded to group allocation at baseline, and 3- and 6-months post baseline. Outcome measures include: weight (primary outcome), % body fat, waist circumference, blood pressure, resting heart rate, objectively measured physical activity, self-reported dietary intake, sedentary behaviour, physical activity and dietary cognitions, sleepiness, quality of life, and perceived sexual health. Generalised linear mixed models will be used to assess all outcomes for the impact of group (<it>Resources</it>, <it>Online</it>, and <it>Control</it>), time (treated as categorical with levels baseline, 3-months and 6-months) and the group-by-time interaction. These three terms will form the base model. 'Intention-to-treat' analysis will include all randomised participants.</p> <p>Discussion</p> <p>Our study will compare evidence-based and theoretically driven, low cost and easily disseminated strategies specifically targeting weight loss in men. The SHED-IT community trial will provide evidence to inform development and dissemination of sustainable strategies to reduce obesity in men.</p> <p>Trial Registration</p> <p>Australian New Zealand Clinical Trials Registry (ACTRN12610000699066)</p