102,005 research outputs found
Customizing the therapeutic response of signaling networks to promote antitumor responses by drug combinations
No full textThis work was supported by grants from Breakthrough Breast Cancer and Scottish Funding Council (SRDG), and personal support to Alexey Goltsov from Scottish Informatics and Computer Science Alliance (SICSA) and to James Bown from The Northwood Trust.Drug resistance, de novo and acquired, pervades cellular signaling networks (SNs) from one signaling motif to another as a result of cancer progression and/or drug intervention. This resistance is one of the key determinants of efficacy in targeted anti-cancer drug therapy. Although poorly understood, drug resistance is already being addressed in combination therapy by selecting drug targets where SN sensitivity increases due to combination components or as a result of de novo or acquired mutations. Additionally, successive drug combinations have shown low resistance potential. To promote a rational, systematic development of combination therapies, it is necessary to establish the underlying mechanisms that drive the advantages of combination therapies, and design methods to determine drug targets for combination regimens. Based on a joint systems analysis of cellular SN response and its sensitivity to drug action and oncogenic mutations, we describe an in silico method to analyze the targets of drug combinations. Our method explores mechanisms of sensitizing the SN through a combination of two drugs targeting vertical signaling pathways. We propose a paradigm of SN response customization by one drug to both maximize the effect of another drug in combination and promote a robust therapeutic response against oncogenic mutations. The method was applied to customize the response of the ErbB/PI3K/PTEN/AKT pathway by combination of drugs targeting HER2 receptors and proteins in the down-stream pathway. The results of a computational experiment showed that the modification of the SN response from hyperbolic to smooth sigmoid response by manipulation of two drugs in combination leads to greater robustness in therapeutic response against oncogenic mutations determining cancer heterogeneity. The application of this method in drug combination co-development suggests a combined evaluation of inhibition effects together with the capability of drug combinations to suppress resistance mechanisms before they become clinically manifest.Peer reviewe
Bibliographie Hilarion G. Petzold 1958 – 2009 mit Anhang als Einführung
No full textDieses Archiv enthält die Gesamtbibliographie der Werke des Autors nebst einiger Texte „Über H. G. Petzold“ im Schlussteil der Bibliographie sowie einen Anhang mit einer Einführung in die Architektur des Werkes in seinem wissenslogischen Aufbau als Ausarbeitung seines „Tree of Science Modells“ (2007).This archive contains the complete bibliography of the author and some texts about H. G. Petzold, moreover an epilogue with an introduction to the architecture of the works in its epistemological structure and composition and as an elaborations of Petzold’s „Tree of Science Modell (2007).https://www.fpi-publikation.de/polyloge/01-2009-petzold-h-g-gesamtbibliographie-h-g-petzold-1958-2009-updating-november2009/peerReviewedpublishedVersio
Dispelling the Myths Behind First-author Citation Counts
No full textWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
Recommended from our members
3346: Samuel G. Freedman, author, 2013
No full textPhotograph of author Samuel G. Freedman, at NT Daily Slash meeting in the Mayborn School of Journalism at UNT
RFLP discordance in a PKU family due to a deletion in the PAH gene
No full text: We have previously reported preliminary data on a PKU family showing a discordant segregation of Pvu II (b) alleles at the PAH locus. A combination of several restriction enzymes and probe C2.6 (Intron 2) as well as STR typing were used to dissect the molecular structure of the PAH gene around exon 3. In this family, the results of this analysis and a re-examination of the physical map of the 5'-end of the gene provided strong evidence for the occurrence of a deletion removing exon 3. The "Sicilian" (approximately 2.5 kb) and "Yemenite Jew" (6.7 kb) deletions, the latter one also deleting exon 3, are different in terms of both the 5'-end breakpoint and apparent length. This study, besides adding a new member to the long and increasing list of nearly 200 PAH gene mutations, also proposes to undertake a careful evaluation of RFLP discordances incidentally detected at the PAH locus
The Right to Strike under the United States Constitution: Theory, Practice, and Possible Implications for Canada
No full textAnswering critics of the Canadian Supreme Court's judgment in B.C. Health, the author argues that the Court laid the foundation for a principled and durable doctrine protecting constitutional labour rights, one that goes directly to the heart of the matter — the inequality of workers’ power in the employment relation. In the author’s view, two paths could lead from B.C. Health to the recognition of Charter protec- tion for a right to strike: one that treats the right as an accessory to col- lective bargaining, and one that upholds the right directly on the basis of the Charter values of equality and participation. The author supports the latter approach, contending that constitutional rights should be defined in relation to fundamental values, in a way that is not contingent on time-bound or fact-sensitive assessments about the role of strikes within a particular collective bargaining regime. Although a Charter right to strike may involve the courts in difficult choices about when to defer to legislative policy decisions, and courts may lack the institutional capac- ity to deal effectively with labour law issues, the author points out that judges can look to ILO standards for expert guidance. Noting that the U.S. experience in this area might be of considerable use to Canadians, the author concludes by providing an overview of American case law concerning a constitutional right to strike.Peer reviewe
G-Rank: Unsupervised Continuous Learn-to-Rank for Edge Devices in a P2P Network
No full textRanking algorithms in traditional search engines are powered by enormous training data sets that are meticulously engineered and curated by a centralized entity. Decentralized peer-to-peer (p2p) networks such as torrenting applications and Web3 protocols deliberately eschew centralized databases and computational architectures when designing services and features. As such, robust search-and-rank algorithms designed for such domains must be engineered specifically for decentralized networks, and must be lightweight enough to operate on consumer-grade personal devices such as a smartphone or laptop computer. We introduce G-Rank, an unsupervised ranking algorithm designed exclusively for decentralized networks. We demonstrate that accurate, relevant ranking results can be achieved in fully decentralized networks without any centralized data aggregation, feature engineering, or model training. Furthermore, we show that such results are obtainable with minimal data preprocessing and computational overhead, and can still return highly relevant results even when a user’s device is disconnected from the network. G-Rank is highly modular in design, is not limited to categorical data, and can be implemented in a variety of domains with minimal modification. The results herein show that unsupervised ranking models designed for decentralized p2p networks are not only viable, but worthy of further research.https://github.com/awrgold/G-RankComputer Scienc
Author inscription in The Chinese slave-girl: a story of woman's life in China
No full textThis edition includes a gift inscription by author Rev. J.A. Davis, "To Rev. A. G. Russell with the warmest regards of the author J.A. Davis."Davis, John Agnell, 1839-1897
Wissenschaftliche Bibliographie Hilarion G. Petzold 1958 – 2014 mit Anhang von 2007 als Einführung
No full textDieses Archiv enthält die Gesamtbiliograpie der Werke des Autors bis Dez. 2013 nebst einiger Texte „Über H. G. Petzold“ und einen Anhang mit einer Einführung in die Struktur des Werkes in seinem wissenslogischen Aufbau als Ausarbeitung seines „Tree of Science Modells“ (2007).This archive contains the complete bibliography of the author up to Dec. 2013 and some texts about H. G. Petzold, moreover an appendix with an introduction to the structure of the work in its epistemological structure and composition as an elaborations of Petzold’s „Tree of Science Modell (2007).https://www.fpi-publikation.de/polyloge/01-2014-petzold-h-g-2014-wissenschaftliche-gesamtbibliographie-1958-2014/peerReviewedpublishedVersio
- …
