Discovery of pyrazolopyrimidines that selectively inhibit CSF-1R kinase by iterative design, synthesis and screening against glioblastoma cells

We are grateful to Medical Research Scotland (PHD-1046-2016) for funding and a joint Cancer Research UK (A28596) and The Brain Tumour Charity award (GN-000676) to N. O. C. T. V. thanks EU Horizon 2020 research and innovation programme under the Marie Skls PHD-1046-2016Medical Research Scotland A28596Cancer Research UK GN-000676Brain Tumour Charity award 749299European Union (EU)MS

Population coverage of artemisinin-based combination treatment in children younger than 5 years with fever and Plasmodium falciparum infection in Africa, 2003–2015: a modelling study using data from national surveys

Background Artemisinin-based combination therapies (ACTs) are the most effective treatment for uncomplicated Plasmodium falciparum malaria infection. A commonly used indicator for monitoring and assessing progress in coverage of malaria treatment is the proportion of children younger than 5 years with reported fever in the previous 14 days who have received an ACT. We propose an improved indicator that incorporates parasite infection status (as assessed by a rapid diagnostic test [RDT]), which is available in recent household surveys. In this study we estimated the annual proportion of children younger than 5 years with fever and a positive RDT in Africa who received an ACT in 2003–15. Methods Our modelling study used cross-sectional data on treatment for fever and RDT status for children younger than 5 years compiled from all nationally available representative household surveys (the Malaria Indicator Surveys, Demographic and Health Surveys, and Multiple Indicator Cluster Surveys) across sub-Saharan Africa between 2003 and 2015. Estimates for the proportion of children younger than 5 years with a fever within the previous 14 days and P falciparum infection assessed by RDT who received an ACT were incorporated in a generalised additive mixed model, including data on ACT distributions, to estimate coverage across all countries and time periods. We did random effects meta-analyses to examine individual, household, and community effects associated with ACT coverage. Findings We obtained data on 201 704 children younger than 5 years from 103 surveys (22 MIS, 61 DHS, and 20 MICS) across 33 countries. RDT results were available for 40 of these surveys including 40 261 (20%) children, and we predicted RDT status for the remaining 161 443 (80%) children. Our results showed that ACT coverage in children younger than 5 years with a fever and P falciparum infection increased across sub-Saharan Africa in 2003–15, but even in 2015, only 19·7% (95% CI 15·6–24·8) of children younger than 5 years with a fever and P falciparum infection received an ACT. In meta-analyses, children younger than 5 years were more likely to receive an ACT for fever and P falciparum infection if they lived in an urban area (vs rural area; odds ratio [OR] 1·18, 95% CI 1·06–1·31), had household wealth above the national median (vs wealth below the median; OR 1·26, 1·16–1·39), had a caregiver with any education (vs no education; OR 1·31, 1·22–1·41), had a household insecticide-treated net (ITN; vs no ITN; OR 1·21, 1·13–1·29), were older than 2 years (vs ≤2 years; OR 1·09, 1·01–1·17), or lived in an area with a higher mean P falciparum prevalence in children aged 2–10 years (OR 1·12, 1·02–1·23). In the subgroup of children for whom treatment was sought, those who sought treatment in the public sector were more likely to receive an ACT (vs the private sector; OR 3·18, 2·67–3·78). Interpretation Despite progress during the 2003–15 malaria programme, ACT treatment for children with malaria remains unacceptably low. More work is needed at the country level to understand how health-care access, service delivery, and ACT supply might be improved to ensure appropriate treatment for all children with malaria

Follow-up observations at 16 and 33 GHz of extragalactic sources from WMAP 3-year data: I - Spectral properties

We present follow-up observations of 97 point sources from the Wilkinson Microwave Anisotropy Probe (WMAP) 3-year data, contained within the New Extragalactic WMAP Point Source (NEWPS) catalogue between declinations of -4 and +60 degrees; the sources form a flux-density-limited sample complete to 1.1 Jy (approximately 5 sigma) at 33 GHz. Our observations were made at 16 GHz using the Arcminute Microkelvin Imager (AMI) and at 33 GHz with the Very Small Array (VSA). 94 of the sources have reliable, simultaneous -- typically a few minutes apart -- observations with both telescopes. The spectra between 13.9 and 33.75 GHz are very different from those of bright sources at low frequency: 44 per cent have rising spectra (alpha < 0.0), where flux density is proportional to frequency^-alpha, and 93 per cent have spectra with alpha < 0.5; the median spectral index is 0.04. For the brighter sources, the agreement between VSA and WMAP 33-GHz flux densities averaged over sources is very good. However, for the fainter sources, the VSA tends to measure lower values for the flux densities than WMAP. We suggest that the main cause of this effect is Eddington bias arising from variability.Comment: 12 pages, 13 figures, submitted to MNRA

Hybrid modeling of biological networks: mixing temporal and qualitative biological properties

<p>Abstract</p> <p>Background</p> <p>Modeling a dynamical biological system is often a difficult task since the a <it>priori </it>unknown parameters of such models are not always directly given by the experiments. Despite the lack of experimental quantitative knowledge, one can see a dynamical biological system as (i) the combined evolution tendencies (increase or decrease) of the biological compound concentrations, and: (ii) the temporal features, such as delays between two concentration peaks (i.e. the times when one of the components completes an increase (resp. decrease) phase and starts a decrease (resp. increase) phase).</p> <p>Results</p> <p>We propose herein a new hybrid modeling framework that follows such biological assumptions. This hybrid approach deals with both a qualitative structure of the system and a quantitative structure. From a theoretical viewpoint, temporal specifications are expressed as equality or inequality constraints between delay parameters, while the qualitative specifications are expressed as an ordered pattern of the concentrations peaks of the components. Using this new hybrid framework, the temporal specifications of a biological system can be obtained from incomplete experimental data. The model may be processed by a hybrid model-checker (e.g. Phaver) which is able to give some new constraints on the delay parameters (e.g. the delay for a given transition is exactly 5 hours after the later peak of a gene product concentration). Furthermore, by using a constraint solver on the previous results, it becomes possible to get the set of parameters settings which are consistent with given specifications. Such a modeling approach is particularly accurate for modeling oscillatory biological behaviors like those observed in the Drosophila circadian cycles. The achieved results concerning the parameters of this oscillatory system formally confirm the several previous studies made by numerical simulations. Moreover, our analysis makes it possible to propose an automatic investigation of the respective impact of per and tim on the circadian cycle.</p> <p>Conclusions</p> <p>A new hybrid technique for an automatic formal analysis of biological systems is developed with a special emphasis on their oscillatory behaviors. It allows the use of incomplete and empirical biological data.</p

Non-locality and Communication Complexity

Quantum information processing is the emerging field that defines and realizes computing devices that make use of quantum mechanical principles, like the superposition principle, entanglement, and interference. In this review we study the information counterpart of computing. The abstract form of the distributed computing setting is called communication complexity. It studies the amount of information, in terms of bits or in our case qubits, that two spatially separated computing devices need to exchange in order to perform some computational task. Surprisingly, quantum mechanics can be used to obtain dramatic advantages for such tasks. We review the area of quantum communication complexity, and show how it connects the foundational physics questions regarding non-locality with those of communication complexity studied in theoretical computer science. The first examples exhibiting the advantage of the use of qubits in distributed information-processing tasks were based on non-locality tests. However, by now the field has produced strong and interesting quantum protocols and algorithms of its own that demonstrate that entanglement, although it cannot be used to replace communication, can be used to reduce the communication exponentially. In turn, these new advances yield a new outlook on the foundations of physics, and could even yield new proposals for experiments that test the foundations of physics.Comment: Survey paper, 63 pages LaTeX. A reformatted version will appear in Reviews of Modern Physic

Spectroscopy of luminous z>7 galaxy candidates and sources of contamination in z>7 galaxy searches

We present three bright z+ dropout candidates selected from deep Near-Infrared (NIR) imaging of the COSMOS 2 square degree field. All three objects match the 0.8-8um colors of other published z>7 candidates but are three magnitudes brighter, facilitating further study. Deep spectroscopy of two of the candidates covering 0.64-1.02um with Keck-DEIMOS and all three covering 0.94-1.10um and 1.52-1.80um with Keck-NIRSPEC detects weak spectral features tentatively identified as Ly-alpha at z=6.95 and z=7.69 in two of the objects. The third object is placed at z~1.6 based on a 24um and weak optical detection. A comparison with the spectral energy distributions of known z<7 galaxies, including objects with strong spectral lines, large extinction, and large systematic uncertainties in the photometry yields no objects with similar colors. However, the lambda>1um properties of all three objects can be matched to optically detected sources with photometric redshifts at z~1.8, so the non-detection in the i+ and z+ bands are the primary factors which favors a z>7 solution. If any of these objects are at z~7 the bright end of the luminosity function is significantly higher at z>7 than suggested by previous studies, but consistent within the statistical uncertainty and the dark matter halo distribution. If these objects are at low redshift, the Lyman-Break selection must be contaminated by a previously unknown population of low redshift objects with very strong breaks in their broad band spectral energy distributions and blue NIR colors. The implications of this result on luminosity function evolution at high redshift is discussed. We show that the primary limitation of z>7 galaxy searches with broad filters is the depth of the available optical data.Comment: 15 Pages, 15 figures, accepted to Ap

A Bitter Pill: The Primordial Lithium Problem Worsens

The lithium problem arises from the significant discrepancy between the primordial 7Li abundance as predicted by BBN theory and the WMAP baryon density, and the pre-Galactic lithium abundance inferred from observations of metal-poor (Population II) stars. This problem has loomed for the past decade, with a persistent discrepancy of a factor of 2--3 in 7Li/H. Recent developments have sharpened all aspects of the Li problem. Namely: (1) BBN theory predictions have sharpened due to new nuclear data, particularly the uncertainty on 3He(alpha,gamma)7Be, has reduced to 7.4%, and with a central value shift of ~ +0.04 keV barn. (2) The WMAP 5-year data now yields a cosmic baryon density with an uncertainty reduced to 2.7%. (3) Observations of metal-poor stars have tested for systematic effects, and have reaped new lithium isotopic data. With these, we now find that the BBN+WMAP predicts 7Li/H = (5.24+0.71-0.67) 10^{-10}. The Li problem remains and indeed is exacerbated; the discrepancy is now a factor 2.4--4.3 or 4.2sigma (from globular cluster stars) to 5.3sigma (from halo field stars). Possible resolutions to the lithium problem are briefly reviewed, and key nuclear, particle, and astronomical measurements highlighted.Comment: 21 pages, 4 figures. Comments welcom

Genetic modification for disease resistance: a position paper

This Position Paper was prepared by members of the Task Force on Global Food Security of the International Society for Plant Pathology. An objective approach is proposed to the assessment of the potential of genetic modification (GM) to reduce the impact of crop diseases. The addition of GM to the plant breeder’s conventional toolbox facilitates gene-by-gene introduction into breeding programmes of well defined characters, while also allowing access to genes from a greatly extended range of organisms. The current status of GM crops is outlined. GM could make an additional contribution to food security but its potential has been controversial, sometimes because of fixed views that GM is unnatural and risky. These have no factual basis: GM technology, where adopted, is widely regulated and no evidence has been reported of adverse consequences for human health. The potential benefits of GM could be particularly valuable for the developing world but there are numerous constraints. These include cost, inadequate seed supply systems, reluctance to adopt unfamiliar technology, concern about markets, inadequacy of local regulatory systems, mismatch between research and growers’ needs, and limited technical resources. The lower cost of new gene-editing methods should open the practice of GM beyond multinational corporations. As yet there are few examples of utilization of GM-based resistance to plant diseases. Two cases, papaya ringspot virus and banana xanthomonas wilt, are outlined. In the developing world there are many more potential cases whose progress is prevented by the absence of adequate biosafety regulation. It is concluded that there is untapped potential for using GM to introduce disease resistance. An objective approach to mobilizing this potential is recommended, to address the severe impact of plant disease on food security