Inverse Compton Scattering as the Source of Diffuse EUV Emission in the Coma Cluster of Galaxies

We have examined the hypothesis that the majority of the diffuse EUV flux in the Coma cluster is due to inverse Compton scattering of low energy cosmic ray electrons (0.16 < epsilon < 0.31 GeV) against the 3K black-body background. We present data on the two-dimensional spatial distribution of the EUV flux and show that these data provide strong support for a non-thermal origin for the EUV flux. However, we show that this emission cannot be produced by an extrapolation to lower energies of the observed synchrotron radio emitting electrons and an additional component of low energy cosmic ray electrons is required.Comment: 11 pages, 5 figure

Host genetic and environmental factors shape the human gut resistome

BACKGROUND: Understanding and controlling the spread of antimicrobial resistance is one of the greatest challenges of modern medicine. To this end many efforts focus on characterising the human resistome or the set of antibiotic resistance determinants within the microbiome of an individual. Aside from antibiotic use, other host environmental and genetic factors that may shape the resistome remain relatively underexplored. METHODS: Using gut metagenome data from 250 TwinsUK female twins, we quantified known antibiotic resistance genes to estimate gut microbiome antibiotic resistance potential for 41 types of antibiotics and resistance mechanisms. Using heritability modelling, we assessed the influence of host genetic and environmental factors on the gut resistome. We then explored links between gut resistome, host health and specific environmental exposures using linear mixed effect models adjusted for age, BMI, alpha diversity and family structure. RESULTS: We considered gut microbiome antibiotic resistance to 21 classes of antibiotics, for which resistance genes were detected in over 90% of our population sample. Using twin modelling, we estimated that on average about 25% of resistome variability could be attributed to host genetic influences. Greatest heritability estimates were observed for resistance potential to acriflavine (70%), dalfopristin (51%), clindamycin (48%), aminocoumarin (48%) and the total score summing across all antibiotic resistance genes (38%). As expected, the majority of resistome variability was attributed to host environmental factors specific to an individual. We compared antibiotic resistance profiles to multiple environmental exposures, lifestyle and health factors. The strongest associations were observed with alcohol and vegetable consumption, followed by high cholesterol medication and antibiotic usage. Overall, inter-individual variation in host environment showed modest associations with antibiotic resistance profiles, and host health status had relatively minor signals. CONCLUSION: Our results identify host genetic and environmental influences on the human gut resistome. The findings improve our knowledge of human factors that influence the spread of antibiotic resistance genes and may contribute towards helping to attenuate it

Diverse modes of binding in structures of Leishmania major N-myristoyltransferase with selective inhibitors

The leishmaniases are a spectrum of global diseases of poverty associated with immune dysfunction and are the cause of high morbidity. Despite the long history of these diseases, no effective vaccine is available and the currently used drugs are variously compromised by moderate efficacy, complex side effects and the emergence of resistance. It is therefore widely accepted that new therapies are needed. N-Myristoyltransferase (NMT) has been validated pre-clinically as a target for the treatment of fungal and parasitic infections. In a previously reported high-throughput screening program, a number of hit compounds with activity against NMT from Leishmania donovani have been identified. Here, high-resolution crystal structures of representative compounds from four hit series in ternary complexes with myristoyl-CoA and NMT from the closely related L. major are reported. The structures reveal that the inhibitors associate with the peptide-binding groove at a site adjacent to the bound myristoyl-CoA and the catalytic -carboxylate of Leu421. Each inhibitor makes extensive apolar contacts as well as a small number of polar contacts with the protein. Remarkably, the compounds exploit different features of the peptide-binding groove and collectively occupy a substantial volume of this pocket, suggesting that there is potential for the design of chimaeric inhibitors with significantly enhanced binding. Despite the high conservation of the active sites of the parasite and human NMTs, the inhibitors act selectively over the host enzyme. The role of conformational flexibility in the side chain of Tyr217 in conferring selectivity is discussed

Gaps in detailed knowledge of human papillomavirus (HPV) and the HPV vaccine among medical students in Scotland

&lt;p&gt;Background: A vaccination programme targeted against human papillomavirus (HPV) types16 and 18 was introduced in the UK in 2008, with the aim of decreasing incidence of cervical disease. Vaccine roll out to 12–13 year old girls with a catch-up programme for girls aged up to 17 years and 364 days was accompanied by a very comprehensive public health information (PHI) campaign which described the role of HPV in the development of cervical cancer.&lt;/p&gt; &lt;p&gt;Methods: A brief questionnaire, designed to assess acquisition of knowledge of HPV infection and its association to cervical cancer, was administered to two different cohorts of male and female 1st year medical students (school leavers: 83% in age range 17–20) at a UK university. The study was timed so that the first survey in 2008 immediately followed a summer's intensive PHI campaign and very shortly after vaccine roll-out (150 students). The second survey was exactly one year later over which time there was a sustained PHI campaign (213 students).&lt;/p&gt; &lt;p&gt;Results: We addressed three research questions: knowledge about three specific details of HPV infection that could be acquired from PHI, whether length of the PHI campaign and/or vaccination of females had any bearing on HPV knowledge, and knowledge differences between men and women regarding HPV. No female student in the 2008 cohort had completed the three-dose vaccine schedule compared to 58.4% of female students in 2009. Overall, participants’ knowledge regarding the sexually transmitted nature of HPV and its association with cervical cancer was high in both year groups. However, in both years, less than 50% of students correctly identified that HPV causes over 90% of cases of cervical cancer. Males gave fewer correct answers for these two details in 2009. In 2008 only around 50% of students recognised that the current vaccine protects against a limited subset of cervical cancer-causing HPV sub-types, although there was a significant increase in correct response among female students in the 2009 cohort compared to the 2008 cohort.&lt;/p&gt; &lt;p&gt;onclusions: This study highlights a lack of understanding regarding the extent of protection against cervical cancer conferred by the HPV vaccine, even among an educated population in the UK who could have a vested interest in acquiring such knowledge. The intensive PHI campaign accompanying the first year of HPV vaccination seemed to have little effect on knowledge over time. This is one of the first studies to assess detailed knowledge of HPV in both males and females. There is scope for continued improvements to PHI regarding the link between HPV infection and cervical cancer.&lt;/p&gt

The Physics of Cluster Mergers

Clusters of galaxies generally form by the gravitational merger of smaller clusters and groups. Major cluster mergers are the most energetic events in the Universe since the Big Bang. Some of the basic physical properties of mergers will be discussed, with an emphasis on simple analytic arguments rather than numerical simulations. Semi-analytic estimates of merger rates are reviewed, and a simple treatment of the kinematics of binary mergers is given. Mergers drive shocks into the intracluster medium, and these shocks heat the gas and should also accelerate nonthermal relativistic particles. X-ray observations of shocks can be used to determine the geometry and kinematics of the merger. Many clusters contain cooling flow cores; the hydrodynamical interactions of these cores with the hotter, less dense gas during mergers are discussed. As a result of particle acceleration in shocks, clusters of galaxies should contain very large populations of relativistic electrons and ions. Electrons with Lorentz factors gamma~300 (energies E = gamma m_e c^2 ~ 150 MeV) are expected to be particularly common. Observations and models for the radio, extreme ultraviolet, hard X-ray, and gamma-ray emission from nonthermal particles accelerated in these mergers are described.Comment: 38 pages with 9 embedded Postscript figures. To appear in Merging Processes in Clusters of Galaxies, edited by L. Feretti, I. M. Gioia, and G. Giovannini (Dordrecht: Kluwer), in press (2001

Selective Inhibitors of Protozoan Protein N-myristoyltransferases as Starting Points for Tropical Disease Medicinal Chemistry Programs

Inhibition of N-myristoyltransferase has been validated pre-clinically as a target for the treatment of fungal and trypanosome infections, using species-specific inhibitors. In order to identify inhibitors of protozoan NMTs, we chose to screen a diverse subset of the Pfizer corporate collection against Plasmodium falciparum and Leishmania donovani NMTs. Primary screening hits against either enzyme were tested for selectivity over both human NMT isoforms (Hs1 and Hs2) and for broad-spectrum anti-protozoan activity against the NMT from Trypanosoma brucei. Analysis of the screening results has shown that structure-activity relationships (SAR) for Leishmania NMT are divergent from all other NMTs tested, a finding not predicted by sequence similarity calculations, resulting in the identification of four novel series of Leishmania-selective NMT inhibitors. We found a strong overlap between the SARs for Plasmodium NMT and both human NMTs, suggesting that achieving an appropriate selectivity profile will be more challenging. However, we did discover two novel series with selectivity for Plasmodium NMT over the other NMT orthologues in this study, and an additional two structurally distinct series with selectivity over Leishmania NMT. We believe that release of results from this study into the public domain will accelerate the discovery of NMT inhibitors to treat malaria and leishmaniasis. Our screening initiative is another example of how a tripartite partnership involving pharmaceutical industries, academic institutions and governmental/non-governmental organisations such as Medical Research Council and Wellcome Trust can stimulate research for neglected diseases

Drones y el orden legal internacional. Tecnología, estrategia y largas cadenas de acción

The main thesis of this article is that the increasing recourse to the use of unmanned aerial systems in asymmetric warfare and the beginning routinization of U.S. drone operations represent part of an evolutionary change in the spatial ordering of global politics -- Using a heuristic framework based on actor-network theory, it is argued that practices of panoptic observation and selective airstrikes, being in need of legal justification, contribute to a reterritorialization of asymmetric conflicts -- Under a new normative spatial regime, a legal condition of state immaturity is constructed, which establishes a zone of conditional sovereignty subject to transnational aerial policing -- At the same time, this process is neither a deterministic result of the new technology nor a deliberate effect of policies to which drones are merely neutral instruments -- Rather, military technology and political decisions both form part of a long chain of action which has evolved under the specific circumstances of recent military interventionsEste artículo propone que la creciente utilización de sistemas aéreos no tripulados y la rutinización de sus operaciones en guerras asimétricas representan parte de un cambio evolutivo en el ordenamiento espacial de la política global -- Utilizando un marco heurístico basado en la teoría del actor-red, se argumenta que las prácticas de observación panóptica y ataques aéreos selectivos, carentes aún de justificación legal, contribuyen a una reterritorialización de los conflictos asimétricos -- En virtud de un nuevo régimen normativo espacial, se construye una condición legal de inmadurez estatal que facilita el establecimiento de una zona de soberanía condicionada, sometida a la vigilancia aérea transnacional -- Al mismo tiempo, esté proceso no es resultado predeterminado de la nueva tecnología, ni efecto deliberado de decisiones políticas para las que los drones son solo instrumentos neutros -- Antes que ello, la tecnología militar y las decisiones políticas forman parte importante de una larga cadena de acción que se ha desarrollado en las circunstancias específicas de intervenciones militares más reciente