In this study a combination of computer tools for coupling and virtual screening is detailed, in 108 active molecules and 3620 decoys to find stabilizers for G quadruplex. To have more precise results, combinations of coupling programs with fifteen energy scoring functions were applied. The validation and evaluation of the metrics was done with the CompScore genetic algorithm. The results showed an increase in BEDROC and EF of 50% compared to other strategies, as well as reflecting early recognition of active (...) molecules. From these results it is possible to work with the molecules that showed a good early recognition and evaluate their effect as G4 stabilizers. This ensures more efficient and accurate results in the preclinical stage for the development of anticancer drugs. Keywords: Enrichment metrics; telomere; G quadruplex ; CompScore. References [1]M. Porru, P. Zizza, M. Franceschin, C. Leonetti and A. Biroccio. «EMICORON: A multi-targeting G4 ligand with a promising preclinical profile» 2017. Biochimica et Biophysica Acta - General Subjects, 1861, 1362–1370. [Online]. Available: https://doi.org/10.1007/s00294-018-0836-6. [2]K. Tomita. «How long does telomerase extend telomeres? Regulation of telomerase release and telomere length homeostasis». Current Genetics, 64, 1177–1181. 2018. [Online]. Available: https://doi.org/10.1016/j.bbagen. 2016.11.010. [3]M. Jafri, S. Ansari, M. Alqahtani and J. Shay. «Roles of telomeres and telomerase in cancer, and advances in telomerase-targeted therapies. Genome Medicine., 2016. [Online]. Available: https://doi.org/10.3390/ijms19020482. [4]J. Huppert and S. Balasubramanian. «G-quadruplexes in promoters throughout the human genome». 35, 406–413. 2007. [Online]. Available: https://doi.org/10.1016/j.bbapap.2017.06.012. [5]S. Joy, Vijayakumar, S. Choi and H. Sunhye. «Role of computer-aided drug design in modern drug discovery». Archives of Pharmacal Research. 2015. [Online]. Available: https://doi.org/10.1007/s12272-015-0640-5. [6]S. Asamitsu, S. Obata, Z. Yu, T. Bando and H. Sugiyama. «Recent Progress of Targeted G-Quadruplex-Preferred Ligands Toward Cancer Therapy». Molecules, 24, 429. 2019. [En línea]. Available: https://doi.org/10.3390/molecules24030429. [7]R. Monsen and J. Trent. «Biochimie G-quadruplex virtual drug screening : A review». Biochimie, 152, 134–148. 2018. [Online]. Available: https://doi.org/10.1039/c9cc06748e. [8]J. Beauvarlet, P. Bensadoun, E. Darbo, G. Labrunie, E. Richard, I. Draskovic and M. Djavaheri-mergny. «Modulation of the ATM / autophagy pathway by a G-quadruplex ligand tips the balance between senescence and apoptosis in cancer cells». 1–18. 2019. [Online]. Available: https://doi.org/10.1093/nar/gkz095. [9].Z. Crees, J. Girard, Z. Rios, G. Botting, K. Harrington and C. Shearrow. « Oligonucleotides and G-quadruplex stabilizers: targeting telomeres and telomerase in cancer therapy».2014. [Online]. Available: https://doi.org/10.2174/1381612820666140630100702. [10].M. Meier, A. Moya-torres, N. Krahn, M. Mcdougall, L. Orriss, E. Mcrae and T. Patel. «Structure and hydrodynamics of a DNA Gquadruplex with a cytosine bulge»., 1–13. 2018. [Online]. Available: https://doi.org/10.1093/nar/gky307. (shrink)

Commentary and supercommentary, with text, on Īśvarapratyabhijñā, classical verse work, expounding the Trika philosophy in Kashmir Sivaism, by Utpala, fl. 900-950.

Climate engineering with stratospheric sulfate aerosol injections (SSAI) has the potential to reduce risks of injustice related to anthropogenic emissions of greenhouse gases. Relying on evidence from modeling studies, this paper makes the case that SSAI could have the potential to reduce many of the key physical risks of climate change identified by the Intergovernmental Panel on Climate Change. Such risks carry potential injustice because they are often imposed on low-emitters who do not benefit from climate change. Because SSAI has (...) the potential to reduce those risks, it thereby has the potential to reduce the injustice associated with anthropogenic emissions. While acknowledging important caveats, including uncertainty in modeling studies and the potential for SSAI to carry its own risks of injustice, the paper argues that there is a strong case for continued research into SSAI, especially if attention is paid to how it might be used to reduce emissions-driven injustice. (shrink)

In this paper Popper formulates and discusses a new aspect of the theory of mind. This theory is partly based on his earlier developed interactionistic theory. It takes as its point of departure the observation that mind and physical forces have several properties in common, at least the following six: both are located, unextended, incorporeal, capable of acting on bodies, dependent upon body, capable of being influenced by bodies. Other properties such as intensity and extension in time may be added. (...) It is argued that a fuller understanding of the nature of forces is essential for the analysis of the mind-brain problem. The relative autonomy and indeterministic nature of mind is stressed. Indeterminism is treated in relation to a theorem of Hadamard. The computer theory of mind and the Turing test are criticized. Finally the evolution of mind is discussed. (shrink)

OBJECTIVES: To study the resources available and resources needed for ethics teaching to medical students in UK medical schools as required by the new GMC core curriculum. DESIGN: A structured questionnaire was piloted and then circulated to deans of medical schools. SETTING: All UK medical schools. RESULTS: Eighteen out of 28 schools completed the questionnaire, the remainder either indicating that their arrangements were "under review" (4) or not responding (6). Among those responding: 1) library resources, including video and information technology (...) were found to be fairly well developed; 2) many schools had a good supply of handouts and sample cases for teaching; 3) most had a written syllabus, and 4) two-thirds examined in the subject. However, many schools indicated that there was an urgent need for: 1) full-time teachers (most ethics teaching is still by part-time and voluntary staff); funding for books and journals, and 3) additional teaching materials (including further case vignettes, handouts and sample exam questions). CONCLUSIONS: There has been a considerable overall improvement in resources for medical ethics teaching since the time of the last national survey (The Pond Report). However, provision varies widely from medical school to medical school. The particular needs identified were for full-time teachers, library resources and teaching materials. Wider use of existing organisations concerned with medical ethics could help to meet these needs. (shrink)

This collection examines prevalent assumptions in moral reasoning which are often accepted uncritically in medical ethics. It introduces a range of perspectives from philosophy and medicine on the nature of moral reasoning and relates these to illustrative problems, such as New Reproductive Technologies, the treatment of sick children, the assessment of quality of life, genetics, involuntary psychiatric treatment and abortion. In each case, the contributors address the nature and worth of the moral theories involved in discussions of the relevant issues, (...) and focus on the types of reasoning which are employed. 'Medical ethics is in danger of becoming a subject kept afloat by a series of platitudes about respect for persons or the importance of autonomy. This book is a bold and imaginative attempt to break away from such rhetoric into genuine informative dialogue between philosophers and doctors, with no search after consensus.' Mary Warnock. (shrink)

A recursive notation system of a strong segment of ordinals was developped by Jäger [3]. An unessential modified versionT(J) of this notation system was described in [4]. In the following, the well-ordering ofT(J) is proved in a formal system of second order arithmetic with the axiom schema ofΠ 2 1 -comprehension. It follows, that the proof theoretical ordinal ofΠ 2 1 -analysis is greater than the order type ofT(J).

Open peer commentary on the article “Learning about Urban Sustainability with Digital Stories: Promoting Collaborative Creativity from a Constructionist Perspective” by Maria Daskolia, Chronis Kynigos & Katerina Makri. Upshot: Daskolia, Kynigos and Makri’s article offers us a view into potential applications of constructionist learning theory to help students conceive of and collaborate on solutions to today’s complex problems. This work in many ways parallels the efforts of those investigating systems thinking and highlights the importance of digital production in that process. (...) While many efforts rely on simulations and models, the authors place centrally the role of digital production in understanding complexity. This, in turn, calls our attention to the affordances and limitations of our current tools for facilitating learning and collaboration, and ultimately to the need for new tools. (shrink)

Level statistics and nodal point distribution in a rectangular semiconductor quantum dot are studied for different degrees of spin-orbit coupling. The chaotic features occurring from the spin-orbit coupling have no classical counterpart. Using experimental values for GaSb/InAs/GaSb semiconductor quantum wells we find that level repulsion can lead to the semi-Poisson distribution for nearest level separations. Nodal lines and nodal points are also investigated. Comparison is made with nodal point distributions for fully chaotic states.