Hedgehog proteins are of pivotal importance for development and maintenance of tissue patterns in adult organisms. Despite the role of Hedgehogs in differentiation and tumorigenesis, signal transduction of Hedgehog remains a relatively uncharted area of signalling biochemistry. For proper Hedgehog distribution into tissues, two highly unusual covalent modifications are necessary, palmitoylation of a secreted protein and the attachment of a cholesterol group, making Hedgehog the only established sterolated protein in nature. Hedgehog exerts its function via two membrane‐bound receptors, Patched and (...) Smoothened; presumably, Patched transports a cholesterol derivate out of cells which inhibits Smoothened. Binding of Hedgehog to Patched impedes this proposed pump function and thus Inhibition of Smoothened, which leads to expression of genetic Hedgehog targets via relief of transcriptional repression. These atypical features make Hedgehog physiology unique in biology and may explain why this field has attracted such significant attention. BioEssays 26:387–394, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Titles and abstracts for the Pitt-London Workshop in the Philosophy of Biology and Neuroscience: September 2001.

The rise of the platform economy in the past two decades (and neoliberal capitalist expansion and crises more in general), have on the whole negatively affected working conditions, leading to growing concerns about the “human side” of organizations. To address these concerns, the purpose of this paper is to apply Axel Honneth’s recognition theory and method of normative reconstruction to working conditions in the platform economy. The paper concludes that the ways in which platform organizations function constitutes a normative paradox, (...) promising flexibility and autonomy while at the same time creating working conditions that undercut these promises. The paper ends with a critical discussion of Honneth’s approach, possible supplementing ideas and further lines of future research. (shrink)

This paper examines the implications of the General Agreement on Trade in Services (GATS), the World Trade Organization’s agreement governing trade in health-related services, for health policy and healthcare reform in the United States. The paper describes the nature and scope of US obligations under the GATS, the ways in which the trade agreement intersects with domestic health policy, and the institutional factors that mediate trade-offs between health and trade policy. The analysis suggests that the GATS provisions on market access, (...) national treatment and domestic regulation, which are designed to eliminate ‘regulatory barriers’ to global trade in health services, limit the range of options that state and federal regulators and legislative bodies can employ to regulate the health sector and implement healthcare reforms. As such, the paper identifies the broader social and ethical implications of free trade policy. (shrink)

Structural equation model trees are data-driven tools for finding variables that predict group differences in SEM parameters. SEM trees build upon the decision tree paradigm by growing tree structures that divide a data set recursively into homogeneous subsets. In past research, SEM trees have been estimated predominantly with the R package semtree. The original algorithm in the semtree package selects split variables among covariates by calculating a likelihood ratio for each possible split of each covariate. Obtaining these likelihood ratios is (...) computationally demanding. As a remedy, we propose to guide the construction of SEM trees by a family of score-based tests that have recently been popularized in psychometrics. These score-based tests monitor fluctuations in case-wise derivatives of the likelihood function to detect parameter differences between groups. Compared to the likelihood-ratio approach, score-based tests are computationally efficient because they do not require refitting the model for every possible split. In this paper, we introduce score-guided SEM trees, implement them in semtree, and evaluate their performance by means of a Monte Carlo simulation. (shrink)

A Correction to this paper has been published: 10.1007/s40926-021-00173-1.

Przekład i opracowanie naukowe - Rafał Michalski, Jarosław Rolewski, redakcja naukowa przekładu - Stanisław Czerniak, rozdział 7, 8 i 10 przełożyła - Elżbieta Paczkowska-Łagowska Arnold Gehlen (1904–1976), wybitny niemiecki filozof i socjolog, współtwórca antropologii filozoficznej. Autor licznych prac podejmujących zagadnienia antropologiczne w kontekście współczesnych przemian społeczno-kulturowych. W swojej twórczości rozwijał oryginalną filozofię techniki, psychologię społeczną, teorię instytucji oraz antropologiczną estetykę. Prezentowane polskiemu czytelnikowi ostatnie dzieło filozofa Moralność i hipertrofia moralności zawiera koncepcję pluralizmu etycznego oraz antropologiczną teorię genezy norm moralnych. (...) Gehlen opiera swoje wywody na rozbudowanych socjologiczno-historycznych analizach, które uwzględniają kulturową zmienność wyróżnionych przez niego etosów, a jednocześnie wskazuje na inwariantny charakter popędowych źródeł moralności. W swojej rozprawie antropolog przeprowadza również krytyczną diagnozę stanu współczesnej kultury i życia politycznego. W zglobalizowanej, przemysłowej kulturze opanowanej przez „superstruktury” (zintegrowane systemy techniki, gospodarki i nauki) dominuje według niego zuniwersalizowany etos eudajmonistycznego humanitaryzmu, marginalizujący pozostałe imperatywy, a zwłaszcza nakaz ochrony państwa. W rezultacie tego rodzaju hipertrofii moralności zanika biologicznie ugruntowana metaetyczna równowaga równorzędnych systemów wartości, narażając na szwank, o czym świadczą skutki uboczne nadmiernej subiektywizacji, antropologiczne zdrowie ludzkiego gatunku. Po opublikowaniu Moralności i hipertrofii moralności Gehlen zaczął uchodzić za nieprzejednanego krytyka lewicowych intelektualistów i wywarł znaczący wpływ na niemiecki neokonserwatyzm. (shrink)

The ease with which genotyping technologies generate tremendous amounts of data on research participants has been well chronicled, a feat that continues to become both faster and cheaper to perform. In parallel to these advances come additional ethical considerations and debates, one of which centers on providing individual research results and incidental findings back to research participants taking part in genetic research efforts. In 2006 the Industry Pharmacogenomics Working Group offered some ‘Points-to-Consider’ on this topic within the context of the (...) drug development process from those who are affiliated to pharmaceutical companies. Today many of these points remain applicable to the discussion but will be expanded upon in this updated viewpoint from the I-PWG. The exploratory nature of pharmacogenomic work in the pharmaceutical industry is discussed to provide context for why these results typically are not best suited for return. Operational challenges unique to this industry which cause barriers to returning this information are also explained. (shrink)

Husserl beruft sich immer wieder programmatisch auf Platon als den Gründervater der europäischen Philosophie, arbeitet jedoch die Bezüge der Phänomenologie zum Platonismus nie auf - obwohl er die "historische Rückbesinnung" auf die Urstiftung seines Denkens als wesentlichen Bestandteil der "Selbstbesinnung auf ein Selbstverständnis dessen hin, worauf man eigentlich hinaus will, als der man ist, als historisches Wesen" charakterisiert. Die vorliegende Arbeit will diese Reflexion leisten. Ihr Gegenstand ist mithin die Transformation Platonischer Gedanken in Husserls Phänomenologie. Dabei werden sechs Problemgebiete thematisiert: (...) A) Philosophie als Wissenschaft, B) Philosophie als Ethik, C) Philosophie als Polemik, D) Philosophie und das Ende der Lebenswelt, E) Philosophie und das Eigenrecht des Eidetischen, F) Philosophie und das Absolute. Den Abschnitten folgen jeweils kritische Erwägungen zu den Spannungen, die vor dem Platonischen Hintergrund innerhalb der Phänomenologie sichtbar werden. Die Arbeit zeigt, dass die Phänomenologie tatsächlich als eine eigenwillige Endstiftung des Platonismus betrachtet werden kann, wodurch sich eine neue Perspektive auf ihre programmatische und systematische Grundkonfiguration ergibt. (shrink)

For the safe and economical construction of embankment dams, the mechanical behaviour of the rockfill materials used in the dam’s shell must be analyzed. The characterization of rockfill materials with specified shear strength is difficult and expensive due to the presence of particles greater than 500 mm in diameter. This work investigates the feasibility of using an extreme gradient boosting computing paradigm to estimate the shear strength of rockfill materials. To train and validate the proposed XGBoost model, a total of (...) 165 databases obtained from the literature are chosen. The XGBoost model was compared against support vector machine, adaptive boosting, random forest, and K-nearest neighbor models described in the literature. XGBoost beats SVM, RF, AdaBoost, and KNN models in terms of performance evaluation metrics such as coefficient of determination, Nash–Sutcliffe coefficient, and error in the root mean square ratio to the standard deviation of the measured data. The results demonstrated that the XGBoost model has the highest prediction performance with, followed by the SVM model with, RF, the AdaBoost model with and the KNN model with. A sensitivity analysis has been conducted to ascertain the impact of each investigated input parameter. This study demonstrates that the established XGBoost model for estimating the shear strength of rockfill materials is reliable. (shrink)

Fascinating illustrations contribute to this illuminating and award-winning account of how and why philosophy emerged and make it a must-read for any inquisitive thinker unsatisfied with prevailing assumptions on this timely and highly relevant subject._ By taking the reader back to the Greek colonies of Southern Italy more than 500 years B.C., the author, with unparalleled insight, tells the story of the Pythagorean quest for otherwordly konwledge -- a tale of cultism, political conspiracies, and bloody uprisings that eventually culminate in (...) tragic failure. The emerging hero is Parmenides, who introduces for the first time a technique for testing the truth of a statement that was not based on physical evidence or mortal sense-perception, but instead relied exclusively on the faculty we humans share with the gods: the ability to reason. "Figures from Anaximander to Zeno, the ruins where they lived and thought, and the paradoxes and thought-experiments they proposed are depicted among the [many] well-chosen color illustrations. The results read like an introductory textbook, but one that has been lovingly written, lavishly laid-out and crisply printed-- making it engaging enough to draw in readers to whom it has not been assigned." - _ Publishers Weekly___ "_To Think Like God_ is a highly ambitious book... Hermann's approach deserves to be taken seriously as an alternative to standard interpretations." - _ Richard D. McKirahan, Jr., Edwin Clarence Norton Professor of Classics and Professor of Philosophy, Pomona College___ "Arnold Hermann brings fresh life into the specialists' debates... a blow of wind that dissipates much fog." - _ Walter Burkert, Professor Emeritus of Classical Philology, University of Zurich___ ARNOLD HERMANN_ is pursuing independent research on the origins of philosophy and methods of thinking. He specialices on subjects connected with Parmenides and Plato's _Parmenides._. (shrink)

Le « je pense, donc je suis » doit être interprété comme la vérification d’une hypothèse, c’est-à-dire comme une intuition qui porte sur un existant et qui est explicitée au moyen d’un syllogisme hypothétique. L’activité du sujet pensant dépend aussi bien du pouvoir déductif que du pouvoir appréciatif de la raison. La recherche métaphysique a pour tâche de découvrir les conditions dernières de l’existence et de l’activité du sujet pensant et de son rapport avec ce qui se pose devant lui (...) comme un « donné ». (shrink)

The main purpose of this paper is to define and study a particular variety of Montague-Scott neighborhood semantics for modal propositional logic. We call this variety the first-order neighborhood semantics because it consists of the neighborhood frames whose neighborhood operations are, in a certain sense, first-order definable. The paper consists of two parts. In Part I we begin by presenting a family of modal systems. We recall the Montague-Scott semantics and apply it to some of our systems that have hitherto (...) be uncharacterized. Then, we define the notion of a first-order indefinite semantics, along with the more specific notion of a first-order uniform semantics, the latter containing as special cases the possible world semantics of Kripke. In Part II we prove consistency and completeness for a broad range of the systems considered, with respect to the first-order indefinite semantics, and for a selected list of systems, with respect to the first-order uniform semantics. The completeness proofs are algebraic in character and make essential use of the finite model property. A by-product of our investigations is a result relating provability in S-systems and provability in T-systems, which generalizes a known theorem relating provability in the systems S 2° and C 2. (shrink)

In this paper we prove three theorems about the theory of Borel sets in models of ZF without any form of the axiom of choice. We prove that if \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${B\subseteq 2^\omega}$$\end{document} is a Gδσ-set then either B is countable or B contains a perfect subset. Second, we prove that if 2ω is the countable union of countable sets, then there exists an Fσδ set \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} (...) \setlength{\oddsidemargin}{-69pt} \begin{document}$${C\subseteq 2^\omega}$$\end{document} such that C is uncountable but contains no perfect subset. Finally, we construct a model of ZF in which we have an infinite Dedekind finite \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${D\subseteq 2^\omega}$$\end{document} which is Fσδ. (shrink)

Rockburst phenomenon is the primary cause of many fatalities and accidents during deep underground projects constructions. As a result, its prediction at the early design stages plays a significant role in improving safety. The article describes a newly developed model to predict rockburst intensity grade using Adaptive Boosting classifier. A database including 165 rockburst case histories was collected from across the world to achieve a comprehensive representation, in which four key influencing factors such as maximum tangential stress of the excavation (...) boundary, uniaxial compressive strength of rock, tensile rock strength, and elastic energy index were selected as the input variables, and the rockburst intensity grade was selected as the output. The output of the AdaBoost model is evaluated using statistical parameters including accuracy and Cohen's kappa index. The applications for the aforementioned approach for predicting the rockburst intensity grade are compared and discussed. Finally, two real-world applications are used to verify the proposed AdaBoost model. It is found that the prediction results are consistent with the actual conditions of the subsequent construction. (shrink)