Drug Discovery Using Chemical Systems Biology: Weak Inhibition of Multiple Kinases May Contribute to the Anti-Cancer Effect of Nelfinavir

Nelfinavir is a potent HIV-protease inhibitor with pleiotropic effects in cancer cells. Experimental studies connect its anti-cancer effects to the suppression of the Akt signaling pathway, but the actual molecular targets remain unknown. Using a structural proteome-wide off-target pipeline, which integrates molecular dynamics simulation and MM/GBSA free energy calculations with ligand binding site comparison and biological network analysis, we identified putative human off-targets of Nelfinavir and analyzed the impact on the associated biological processes. Our results suggest that Nelfinavir is able to inhibit multiple members of the protein kinase-like superfamily, which are involved in the regulation of cellular processes vital for carcinogenesis and metastasis. The computational predictions are supported by kinase activity assays and are consistent with existing experimental and clinical evidence. This finding provides a molecular basis to explain the broad-spectrum anti-cancer effect of Nelfinavir and presents opportunities to optimize the drug as a targeted polypharmacology agent

Treatment of canine atopic dermatitis: 2015 updated guidelines from the International Committee on Allergic Diseases of Animals (ICADA)

Background: In 2010, the International Task Force on Canine Atopic Dermatitis (now International Committee on Allergic Diseases of Animals, ICADA) published the first consensus guidelines for the treatment of atopic dermatitis (AD) in dogs. This is the first 5-year minor update of this document. Results: The treatment of acute flares of AD should involve the search for, and then elimination of, the cause of the flares, bathing with mild shampoos, and controlling pruritus and skin lesions with interventions that include topical and/or oral glucocorticoids or oclacitinib. For chronic canine AD, the first steps in management are the identification and avoidance of flare factors, as well as ensuring that there is adequate skin and coat hygiene and care;this might include more frequent bathing and possibly increasing essential fatty acid intake. The medications currently most effective in reducing chronic pruritus and skin lesions are topical and oral glucocorticoids, oral ciclosporin, oral oclacitinib, and, where available, injectable recombinant interferons. Allergen-specific immunotherapy and proactive intermittent topical glucocorticoid applications are the only interventions likely to prevent or delay the recurrence of flares of AD. Conclusions: This first 5-year minor update of the international consensus guidelines for treatment of AD in dogs further establishes that the treatment of this disease is multifaceted, and that interventions should be combined for a proven (or likely) optimal benefit. Importantly, treatment plans are likely to vary between dogs and, for the same dog, between times when the disease is at different stages

Rupture Directivity in 3D Inferred From Acoustic Emissions Events in a Mine-Scale Hydraulic Fracturing Experiment

This research has been funded by the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement N degrees 754446 and UGR Research and Knowledge Transfer Found -Athenea3i; and by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) -Projektnummer (407141557). SC and PN received funding from the EU project PostMinQuake, RFCS (899192). AZ was supported by funding received from the European Union's Horizon 2020 research and innovation programme, Grant Agreement No. 691728 (Destress).The in situ experiment at Äspö Hard Rock Laboratory (HRL) was supported by the GFZ German Research Center for Geosciences (75%), the KIT Karlsruhe Institute of Technology (15%) and the Nova Center for University Studies, Research and Development Oskarshamn (10%). An additional in-kind contribution of the Swedish Nuclear Fuel and Waste Management Co. (SKB) for using Äspö HRL as test site for geothermal research is greatly acknowledged.Rupture directivity, implying a predominant earthquake rupture propagation direction, is typically inferred upon the identification of 2D azimuthal patterns of seismic observations for weak to large earthquakes using surface-monitoring networks. However, the recent increase of 3D monitoring networks deployed in the shallow subsurface and underground laboratories toward the monitoring of microseismicity allows to extend the directivity analysis to 3D modeling, beyond the usual range of magnitudes. The high-quality full waveforms recorded for the largest, decimeter-scale acoustic emission (AE) events during a meter-scale hydraulic fracturing experiment in granites at similar to 410 m depth allow us to resolve the apparent durations observed at each AE sensor to analyze 3D-directivity effects. Unilateral and (asymmetric) bilateral ruptures are then characterized by the introduction of a parameter kappa, representing the angle between the directivity vector and the station vector. While the cloud of AE activity indicates the planes of the hydrofractures, the resolved directivity vectors show off-plane orientations, indicating that rupture planes of microfractures on a scale of centimeters have different geometries. Our results reveal a general alignment of the rupture directivity with the orientation of the minimum horizontal stress, implying that not only the slip direction but also the fracture growth produced by the fluid injections is controlled by the local stress conditions.European Commission 754446 691728UGR Research and Knowledge Transfer Found -Athenea3iGerman Research Foundation (DFG) 407141557EU project PostMinQuake, RFCS 89919

Kinship intensity and the use of mental states in moral judgment across societies

Decades of research conducted in Western, Educated, Industrialized, Rich, & Democratic (WEIRD) societies have led many scholars to conclude that the use of mental states in moral judgment is a human cognitive universal, perhaps an adaptive strategy for selecting optimal social partners from a large pool of candidates. However, recent work from a more diverse array of societies suggests there may be important variation in how much people rely on mental states, with people in some societies judging accidental harms just as harshly as intentional ones. To explain this variation, we develop and test a novel cultural evolutionary theory proposing that the intensity of kin-based institutions will favor less attention to mental states when judging moral violations. First, to better illuminate the historical distribution of the use of intentions in moral judgment, we code and analyze anthropological observations from the Human Area Relations Files. This analysis shows that notions of strict liability—wherein the role for mental states is reduced—were common across diverse societies around the globe. Then, by expanding an existing vignette-based experimental dataset containing observations from 321 people in a diverse sample of 10 societies, we show that the intensity of a society's kin-based institutions can explain a substantial portion of the population-level variation in people's reliance on intentions in three different kinds of moral judgments. Together, these lines of evidence suggest that people's use of mental states has coevolved culturally to fit their local kin-based institutions. We suggest that although reliance on mental states has likely been a feature of moral judgment in human communities over historical and evolutionary time, the relational fluidity and weak kin ties of today's WEIRD societies position these populations' psychology at the extreme end of the global and historical spectrum

Kinship intensity and the use of mental states in moral judgment across societies

Decades of research conducted in Western, Educated, Industrialized, Rich, & Democratic (WEIRD) societies have led many scholars to conclude that the use of mental states in moral judgment is a human cognitive universal, perhaps an adaptive strategy for selecting optimal social partners from a large pool of candidates. However, recent work from a more diverse array of societies suggests there may be important variation in how much people rely on mental states, with people in some societies judging accidental harms just as harshly as intentional ones. To explain this variation, we develop and test a novel cultural evolutionary theory proposing that the intensity of kin-based institutions will favor less attention to mental states when judging moral violations. First, to better illuminate the historical distribution of the use of intentions in moral judgment, we code and analyze anthropological observations from the Human Area Relations Files. This analysis shows that notions of strict liability—wherein the role for mental states is reduced—were common across diverse societies around the globe. Then, by expanding an existing vignette-based experimental dataset containing observations from 321 people in a diverse sample of 10 societies, we show that the intensity of a society's kin-based institutions can explain a substantial portion of the population-level variation in people's reliance on intentions in three different kinds of moral judgments. Together, these lines of evidence suggest that people's use of mental states has coevolved culturally to fit their local kin-based institutions. We suggest that although reliance on mental states has likely been a feature of moral judgment in human communities over historical and evolutionary time, the relational fluidity and weak kin ties of today's WEIRD societies position these populations' psychology at the extreme end of the global and historical spectrum

Buccal micronucleus cytome assay

The Buccal Micronucleus Cytome (BMCyt) assay is a minimally invasive method for studying DNA damage, chromosomal instability, cell death and the regenerative potential of human buccal mucosal tissue. This method is increasingly used in molecular epidemiological studies for investigating the impact of nutrition, lifestyle factors, genotoxin exposure and genotype on DNA damage, chromosome malsegregation and cell death. The biomarkers measured in this assay have been associated with increased risk of accelerated ageing, cancer and neurodegenerative diseases. This protocol describes one of the current established methods for buccal cell collection using a small-headed toothbrush, the generation of a single-cell suspension, slide preparation using cytocentrifugation, fixation and staining using Feulgen and Light Green for both bright field and fluorescence microscopic analysis. The scoring criteria for micronuclei and other nuclear anomalies are also described in detail. The protocol in its current form takes approximately 4 h to complete from the time of buccal cell collection to the generation of stained slides for microscopic analysis.Philip Thomas, Nina Holland, Claudia Bolognesi, Micheline Kirsch-Volders, Stefano Bonassi, Errol Zeiger, Siegfried Knasmueller & Michael Fenec