Oropharyngeal botryomycosis in a geriatric mare

Botryomycosis is an uncommon chronic bacterial infection that can have cutaneous and visceral involvement. This report describes an 18‐year‐old mixed‐breed mare presented with dysphagia, dyspnoea and an upper respiratory noise that developed secondary to oropharyngeal botryomycosis. Histological examination of the mass showed a granulomatous formation with Splendore–Hoeppli phenomenon surrounding Gram‐positive bacteria. This report describes the clinical signs, approach and management of an oropharyngeal Staphylococcus aureus granuloma in a geriatric mare.info:eu-repo/semantics/acceptedVersio

Maximizing resource usage in multifold molecular dynamics with rCUDA

[EN] The full-understanding of the dynamics of molecular systems at the atomic scale is of great relevance in the fields of chemistry, physics, materials science, and drug discovery just to name a few. Molecular dynamics (MD) is a widely used computer tool for simulating the dynamical behavior of molecules. However, the computational horsepower required by MD simulations is too high to obtain conclusive results in real-world scenarios. This is mainly motivated by two factors: (1) the long execution time required by each MD simulation (usually in the nanoseconds and microseconds scale, and beyond) and (2) the large number of simulations required in drug discovery to study the interactions between a large library of compounds and a given protein target. To deal with the former, graphics processing units (GPUs) have come up into the scene. The latter has been traditionally approached by launching large amounts of simulations in computing clusters that may contain several GPUs on each node. However, GPUs are targeted as a single node that only runs one MD instance at a time, which translates into low GPU occupancy ratios and therefore low throughput. In this work, we propose a strategy to increase the overall throughput of MD simulations by increasing the GPU occupancy through virtualized GPUs. We use the remote CUDA (rCUDA) middleware as a tool to decouple GPUs from CPUs, and thus enabling multi-tenancy of the virtual GPUs. As a working test in the drug discovery field, we studied the binding process of a novel flavonol to DNA with the GROningen MAchine for Chemical Simulations (GROMACS) MD package. Our results show that the use of rCUDA provides with a 1.21x speed-up factor compared to the CUDA counterpart version while requiring a similar power budget.The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was jointly supported by the Fundación Séneca (Agencia Regional de Ciencia y Tecnología, Región de Murcia) under grants (20524/PDC/18, 20813/PI/ 18, and 20988/PI/18) and by the Spanish MEC and Eur-opean Commission FEDER under grants TIN2015-66972-C5-3-R, TIN2016-78799-P, and CTQ2017-87974-R (AEI/FEDER, UE). Researchers from the Universitat Politècnica de València are supported by the Generalitat Valenciana under grant PROMETEO/2017/077.Prades, J.; Imbernon, B.; Reaño González, C.; Peña-García, J.; Cerón-Carrasco, JP.; Silla Jiménez, F.; Pérez-Sánchez, H. (2020). Maximizing resource usage in multifold molecular dynamics with rCUDA. 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Pharmacology and preclinical validation of a novel anticancer compound targeting PEPCK-M

Background: Phosphoenolpyruvate carboxykinase (PEPCK) catalyzes the decarboxylation of oxaloacetate to phosphoenolpyruvate. The mitochondrial isozyme, PEPCK-M is highly expressed in cancer cells, where it plays a role in nutrient stress response. To date, pharmacological strategies to target this pathway have not been pursued. Methods: A compound embodying a 3-alkyl-1,8-dibenzylxanthine nucleus (iPEPCK-2), was synthesized and successfully probed in silico on a PEPCK-M structural model. Potency and target engagement in vitro and in vivo were evaluated by kinetic and cellular thermal shift assays (CETSA). The compound and its target were validated in tumor growth models in vitro and in murine xenografts. Results: Cross-inhibitory capacity and increased potency as compared to 3-MPA were confirmed in vitro and in vivo. Treatment with iPEPCK-2 inhibited cell growth and survival, especially in poor-nutrient environment, consistent with an impact on colony formation in soft agar. Finally, daily administration of the PEPCK-M inhibitor successfully inhibited tumor growth in two murine xenograft models as compared to vehicle, without weight loss, or any sign of apparent toxicity. Conclusion: We conclude that iPEPCK-2 is a compelling anticancer drug targeting PEPCK-M, a hallmark gene product involved in metabolic adaptations of the tumor

The social value of a QALY : raising the bar or barring the raise?

Background: Since the inception of the National Institute for Health and Clinical Excellence (NICE) in England, there have been questions about the empirical basis for the cost-per-QALY threshold used by NICE and whether QALYs gained by different beneficiaries of health care should be weighted equally. The Social Value of a QALY (SVQ) project, reported in this paper, was commissioned to address these two questions. The results of SVQ were released during a time of considerable debate about the NICE threshold, and authors with differing perspectives have drawn on the SVQ results to support their cases. As these discussions continue, and given the selective use of results by those involved, it is important, therefore, not only to present a summary overview of SVQ, but also for those who conducted the research to contribute to the debate as to its implications for NICE. Discussion: The issue of the threshold was addressed in two ways: first, by combining, via a set of models, the current UK Value of a Prevented Fatality (used in transport policy) with data on fatality age, life expectancy and age-related quality of life; and, second, via a survey designed to test the feasibility of combining respondents’ answers to willingness to pay and health state utility questions to arrive at values of a QALY. Modelling resulted in values of £10,000-£70,000 per QALY. Via survey research, most methods of aggregating the data resulted in values of a QALY of £18,000-£40,000, although others resulted in implausibly high values. An additional survey, addressing the issue of weighting QALYs, used two methods, one indicating that QALYs should not be weighted and the other that greater weight could be given to QALYs gained by some groups. Summary: Although we conducted only a feasibility study and a modelling exercise, neither present compelling evidence for moving the NICE threshold up or down. Some preliminary evidence would indicate it could be moved up for some types of QALY and down for others. While many members of the public appear to be open to the possibility of using somewhat different QALY weights for different groups of beneficiaries, we do not yet have any secure evidence base for introducing such a system

Analysis of Fragmentation of Rock Blocks from Real-Scale Tests

Real-scale fragmentation tests provide high quality data in order to study the fragmentation pattern of rock blocks. In the tests carried out, the initial rock mass, in terms of both volume and shape, was reconstructed by means of 3D photogrammetry. The fragments size distribution of the bocks tested was measured by hand using a tape. The drop tests were performed in four different sites, releasing a total of 124 blocks and measuring 2907 fragments. The obtained fragment size distributions may be well fitted using power laws. The survival rate (Sr), which is the proportion of remaining block shows a wide range of values. Observing the fragment distribution, two parameters are needed to characterize the fragmentation: the number of fragments produced and Sr. The intensity of the fragmentation is expressed by the exponent of the fitted power laws. Although the results are highly variable and show a stochastic behavior of the fragmentation, we have identified different patterns that reflect some local test conditions