α-Synuclein Expression Selectively Affects Tumorigenesis in Mice Modeling Parkinson's Disease

Alpha Synuclein (α-Syn) is a protein implicated in mechanisms of neuronal degeneration in Parkinson's disease (PD). α-Syn is primarily a neuronal protein, however, its expression is found in various tumors including ovarian, colorectal and melanoma tumors. It has been hypothesized that neurodegeneration may share common mechanisms with oncogenesis. We tested whether α-Syn expression affects tumorigenesis of three types of tumors. Specifically, B16 melanoma, E0771 mammary gland adenocarcinoma and D122 Lewis lung carcinoma. For this aim, we utilized transgenic mice expression the human A53T α-Syn form. We found that the in vivo growth of B16 and E0771 but not D122 was enhanced in the A53T α-Syn mice. The effect on tumorigenesis was not detected in age-matched APP/PS1 mice, modeling Alzheimer's disease (AD), suggesting a specific effect for α-Syn- dependent neurodegeneration. Importantly, transgenic α-Syn expression was detected within the three tumor types. We further show uptake of exogenously added, purified α-Syn, by the cultured tumor cells. In accord, with the affected tumorigenesis in the young A53T α-Syn mice, over- expression of α-Syn in cultured B16 and E0771 cells enhanced proliferation, however, had no effect on the proliferation of D122 cells. Based on these results, we suggest that certain forms of α-Syn may selectively accelerate cellular mechanisms leading to cancer

Negative feedback regulation of the ERK1/2 MAPK pathway

The extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase (MAPK) signalling pathway regulates many cellular functions, including proliferation, differentiation, and transformation. To reliably convert external stimuli into specific cellular responses and to adapt to environmental circumstances, the pathway must be integrated into the overall signalling activity of the cell. Multiple mechanisms have evolved to perform this role. In this review, we will focus on negative feedback mechanisms and examine how they shape ERK1/2 MAPK signalling. We will first discuss the extensive number of negative feedback loops targeting the different components of the ERK1/2 MAPK cascade, specifically the direct posttranslational modification of pathway components by downstream protein kinases and the induction of de novo gene synthesis of specific pathway inhibitors. We will then evaluate how negative feedback modulates the spatiotemporal signalling dynamics of the ERK1/2 pathway regarding signalling amplitude and duration as well as subcellular localisation. Aberrant ERK1/2 activation results in deregulated proliferation and malignant transformation in model systems and is commonly observed in human tumours. Inhibition of the ERK1/2 pathway thus represents an attractive target for the treatment of malignant tumours with increased ERK1/2 activity. We will, therefore, discuss the effect of ERK1/2 MAPK feedback regulation on cancer treatment and how it contributes to reduced clinical efficacy of therapeutic agents and the development of drug resistance

The republic of science and its citizens: what role may humanities play within the popperian framework?

This essay aims at underlining Ian Jarvie’s specific contribution to the study of some of Karl Popper’s ideas in The Poverty of Historicism. It will also show how he goes further than Popper. Jarvie acknowledges the difficulty of writing about Popper’s view of the differences between the natural and the social sciences because Popper never addresses the critique of anti-naturalistic doctrines. He offers instead a critique of methodological essentialism and an apology of a certain nominalism. Popper shares these two ideas with Friedrich A. Hayek; however, Popper minimizes Hayek’s subjectivism of the social sciences. Looking through Hayek’s subjectivism, this chapter argues that the difference in method is greater than it seems, and that something akin to a Republic of Letters should be built alongside the Republic of Science, without ignoring the inherent faults in these republics that Jarvie underlines.Universidad de Navarrainfo:eu-repo/semantics/publishedVersio

Sociopolitical Engineering

This paper first addresses the historical lexicon of socila (or sociopolitical) enginneering. I then illsutrates the actual cases of Fascist Italy; Turkish Nationalism; National Socialist Germany and Soviet Communism; Eastern European Communism; and post-Cold War changes

The history and ideas of critical rationalism: the philosophy of Karl Popper and its implications for OR

Critical rationalism is the philosophy developed by Karl Popper during the middle of the 20th century. Popper's approach is based on the naturalistic idea that society has developed through a process of solving problems using trial and error. The natural and social sciences have been born out of such problem solving and progressed by subjecting potential theories to vigorous testing and criticism. Falsified theories are rejected. Popper calls for a society which is conducive to such problem solving, a society which permits bold theorizing followed by unfettered criticism, a society in which there is a genuine possibility of change in the light of criticism: an open society. Popper's ideas provide a doorway for accessing philosophical ideas and debates relevant to OR. For some such as Boothroyd it has proved inspirational, for others such as Ulrich it has provided a critical point of departure