A drug repurposing screen for whipworms informed by comparative genomics.

Hundreds of millions of people worldwide are infected with the whipworm Trichuris trichiura. Novel treatments are urgently needed as current drugs, such as albendazole, have relatively low efficacy. We have investigated whether drugs approved for other human diseases could be repurposed as novel anti-whipworm drugs. In a previous comparative genomics analysis, we identified 409 drugs approved for human use that we predicted to target parasitic worm proteins. Here we tested these ex vivo by assessing motility of adult worms of Trichuris muris, the murine whipworm, an established model for human whipworm research. We identified 14 compounds with EC50 values of ≤50 μM against T. muris ex vivo, and selected nine for testing in vivo. However, the best worm burden reduction seen in mice was just 19%. The high number of ex vivo hits against T. muris shows that we were successful at predicting parasite proteins that could be targeted by approved drugs. In contrast, the low efficacy of these compounds in mice suggest challenges due to their chemical properties (e.g. lipophilicity, polarity, molecular weight) and pharmacokinetics (e.g. absorption, distribution, metabolism, and excretion) that may (i) promote absorption by the host gastrointestinal tract, thereby reducing availability to the worms embedded in the large intestine, and/or (ii) restrict drug uptake by the worms. This indicates that identifying structural analogues that have reduced absorption by the host, and increased uptake by worms, may be necessary for successful drug development against whipworms

Polymer-Layered Silicate Nanocomposites for Cryotank Applications

Previous composite cryotank designs have relied on the use of conventional composite materials to reduce microcracking and permeability. However, revolutionary advances in nanotechnology derived materials may enable the production of ultra-lightweight cryotanks with significantly enhanced durability and damage tolerance, as well as reduced propellant permeability. Layered silicate nanocomposites are especially attractive in cryogenic storage tanks based on results that have been reported for epoxy nanocomposite systems. These materials often exhibit an order of magnitude reduction in gas permeability when compared to the base resin. In addition, polymer-silicate nanocomposites have been shown to yield improved dimensional stability, strength, and toughness. The enhancement in material performance of these systems occurs without property trade-offs which are often observed in conventionally filled polymer composites. Research efforts at NASA Glenn Research Center have led to the development of epoxy-clay nanocomposites with 70% lower hydrogen permeability than the base epoxy resin. Filament wound carbon fiber reinforced tanks made with this nanocomposite had a five-fold lower helium leak rate than the corresponding tanks made without clay. The pronounced reduction observed with the tank may be due to flow induced alignment of the clay layers during processing. Additionally, the nanocomposites showed CTE reductions of up to 30%, as well as a 100% increase in toughness

Ten questions on the soundscapes of the built environment

Soundscape research represents a paradigm shift from noise control policies towards a new multidisciplinary approach as it involves not only physical measurements but also the cooperation of humanity and social sciences to account for the diversity of soundscapes across countries and cultures, with more focus on how people actually experience the acoustic environments; and it considers environmental sounds as a ‘resource’ rather than a ‘waste’. The ten questions presented in this paper range from the very basic definitions underlying the emerging soundscape ‘science’, to more applied topics about how to use soundscape as a design approach for the planning and management of the built environments. Although significant research activity has been conducted so far, there is still a need to systematically provide the underpinning science and practical guidance in soundscaping. Thus, the last question aims to identify the most crucial gaps in soundscape research and set the agenda for future advancements in the field

A multisample study of longitudinal changes in brain network architecture in 4-13-year-old children

Pathways through Adolescenc

Antiretroviral therapy and the prevalence and incidence of diabetes [2] (multiple letters)

In the study by Brown et al,1 the authors did not mention several limitations that might have an important impact on the interpretation of the results. First, the study only included men, who were mostly white (approximately 86%). Therefore, the results cannot be extrapolated to women and other ethnic groups. Second, the family history of diabetes was not ascertained in the study participants, and this could have confounded the magnitude of differences in prevalence and incidence of diabetes between the 2 study groups. Third, the reported prevalence and incidence rates of diabetes were likely to be overestimated because the diagnosis of diabetes was not confirmed by a repeated measurement of fasting plasma glucose

RHESSI Results -- Time For a Rethink?

Hard X-rays and gamma-rays are the most direct signatures of energetic electrons and ions in the sun's atmosphere which is optically thin at these energies and their radiation involves no coherent processes. Being collisional they are complementary to gyro-radiation in probing atmospheric density as opposed to magnetic field and the electrons are primarily 10--100 keV in energy, complementing the (>100 keV) electrons likely responsible for microwave bursts. The pioneering results of the Ramaty High Energy Solar Spectroscopic Imager (RHESSI) are raising the first new major questions concerning solar energetic particles in many years. Some highlights of these results are discussed -- primarily around RHESSI topics on which the authors have had direct research involvement -- particularly when they are raising the need for re-thinking of entrenched ideas. Results and issues are broadly divided into discoveries in the spatial, temporal and spectral domains, with the main emphasis on flare hard X-rays/fast electrons but touching also on gamma-rays/ions, non-flare emissions, and the relationship to radio bursts.Comment: Proceedings CESRA Workshop 2004: "The High Energy Solar Corona: Waves, Eruptions, Particles", Lecture Notes in Physics, 2006 (accepted

Evolution and Flare Activity of Delta-Sunspots in Cycle 23

The emergence and magnetic evolution of solar active regions (ARs) of beta-gamma-delta type, which are known to be highly flare-productive, were studied with the SOHO/MDI data in Cycle 23. We selected 31 ARs that can be observed from their birth phase, as unbiased samples for our study. From the analysis of the magnetic topology (twist and writhe), we obtained the following results. i) Emerging beta-gamma-delta ARs can be classified into three topological types as "quasi-beta", "writhed" and "top-to-top". ii) Among them, the "writhed" and "top-to-top" types tend to show high flare activity. iii) As the signs of twist and writhe agree with each other in most cases of the "writhed" type (12 cases out of 13), we propose a magnetic model in which the emerging flux regions in a beta-gamma-delta AR are not separated but united as a single structure below the solar surface. iv) Almost all the "writhed"-type ARs have downward knotted structures in the mid portion of the magnetic flux tube. This, we believe, is the essential property of beta-gamma-delta ARs. v) The flare activity of beta-gamma-delta ARs is highly correlated not only with the sunspot area but also with the magnetic complexity. vi) We suggest that there is a possible scaling-law between the flare index and the maximum umbral area

Multiple Interactions and the Structure of Beam Remnants

Recent experimental data have established some of the basic features of multiple interactions in hadron-hadron collisions. The emphasis is therefore now shifting, to one of exploring more detailed aspects. Starting from a brief review of the current situation, a next-generation model is developed, wherein a detailed account is given of correlated flavour, colour, longitudinal and transverse momentum distributions, encompassing both the partons initiating perturbative interactions and the partons left in the beam remnants. Some of the main features are illustrated for the Tevatron and the LHC.Comment: 69pp, 33 figure

Tight Lower Bound for Linear Sketches of Moments

The problem of estimating frequency moments of a data stream has attracted a lot of attention since the onset of streaming algorithms [AMS99]. While the space complexity for approximately computing the $p^{\rm th}$ moment, for $p\in(0,2]$ has been settled [KNW10], for $p>2$ the exact complexity remains open. For $p>2$ the current best algorithm uses $O(n^{1-2/p}\log n)$ words of space [AKO11,BO10], whereas the lower bound is of $\Omega(n^{1-2/p})$ [BJKS04]. In this paper, we show a tight lower bound of $\Omega(n^{1-2/p}\log n)$ words for the class of algorithms based on linear sketches, which store only a sketch $Ax$ of input vector $x$ and some (possibly randomized) matrix $A$. We note that all known algorithms for this problem are linear sketches.Comment: In Proceedings of the 40th International Colloquium on Automata, Languages and Programming (ICALP), Riga, Latvia, July 201

Gravitational Lensing at Millimeter Wavelengths

With today's millimeter and submillimeter instruments observers use gravitational lensing mostly as a tool to boost the sensitivity when observing distant objects. This is evident through the dominance of gravitationally lensed objects among those detected in CO rotational lines at z>1. It is also evident in the use of lensing magnification by galaxy clusters in order to reach faint submm/mm continuum sources. There are, however, a few cases where millimeter lines have been directly involved in understanding lensing configurations. Future mm/submm instruments, such as the ALMA interferometer, will have both the sensitivity and the angular resolution to allow detailed observations of gravitational lenses. The almost constant sensitivity to dust emission over the redshift range z=1-10 means that the likelihood for strong lensing of dust continuum sources is much higher than for optically selected sources. A large number of new strong lenses are therefore likely to be discovered with ALMA, allowing a direct assessment of cosmological parameters through lens statistics. Combined with an angular resolution <0.1", ALMA will also be efficient for probing the gravitational potential of galaxy clusters, where we will be able to study both the sources and the lenses themselves, free of obscuration and extinction corrections, derive rotation curves for the lenses, their orientation and, thus, greatly constrain lens models.Comment: 69 pages, Review on quasar lensing. Part of a LNP Topical Volume on "Dark matter and gravitational lensing", eds. F. Courbin, D. Minniti. To be published by Springer-Verlag 2002. Paper with full resolution figures can be found at ftp://oden.oso.chalmers.se/pub/tommy/mmviews.ps.g