Age-related macular degeneration (AMD) is a chronic and progressive degenerative disease of the retina, which culminates in blindness and affects mainly the elderly population. AMD pathogenesis and pathophysiology are incredibly complex due to the structural and cellular complexity of the retina, and the variety of risk factors and molecular mechanisms that contribute to disease onset and progression. AMD is driven by a combination of genetic predisposition, natural ageing changes and lifestyle factors, such as smoking or nutritional intake. The mechanism by which these risk factors interact and converge towards AMD are not fully understood and therefore drug discovery is challenging, where no therapeutic attempt has been fully effective thus far. Genetic and molecular studies have identified the complement system as an important player in AMD. Indeed, many of the genetic risk variants cluster in genes of the alternative pathway of the complement system and complement activation products are elevated in AMD patients. Nevertheless, attempts in treating AMD via complement regulators have not yet been successful, suggesting a level of complexity that could not be predicted only from a genetic point of view. In this review, we will explore the role of complement system in AMD development and in the main molecular and cellular features of AMD, including complement activation itself, inflammation, ECM stability, energy metabolism and oxidative stress.
Taking a cue from remarks Thomas Kuhn makes in 1990 about the historical turn in philosophy of science, I examine the history of history and philosophy of science within parts of the British philosophical context in the 1950s and early 1960s. During this time, ordinary language philosophy's influence was at its peak. I argue that the ordinary language philosophers' methodological recommendation to analyze actual linguistic practice influences several prominent criticisms of the deductive-nomological model of scientific explanation and that these criticisms relate to the historical turn in philosophy of science. To show these connections, I primarily examine the work of Stephen Toulmin, who taught at Oxford from 1949 to 1954, and Michael Scriven, who completed a dissertation on explanation under Gilbert Ryle and R.B. Braithwaite in 1956. I also consider Mary Hesse's appeal to an ordinary language-influenced account of meaning in her account of the role of models and analogies in scientific reasoning, and W.H. Watson's Wittgensteinian philosophy of science, an early influence on Toulmin. I think there are two upshots to my historical sketch. First, it fills out details of the move away from logical positivism to more historical- and practice-focused philosophies of science. Second, questions about linguistic meaning and the proper targets and aims of philosophical analysis are part and parcel of the historical turn, as well as its reception. Looking at the philosophical background during which so-called linguistic philosophers also had a hand in bringing these questions to prominence helps us understand why. 相似文献
Effects of macromolecular crowding on structural and functional properties of ordered proteins, their folding, interactability, and aggregation are well documented. Much less is known about how macromolecular crowding might affect structural and functional behaviour of intrinsically disordered proteins (IDPs) or intrinsically disordered protein regions (IDPRs). To fill this gap, this review represents a systematic analysis of the available literature data on the behaviour of IDPs/IDPRs in crowded environment. Although it was hypothesized that, due to the excluded-volume effects present in crowded environments, IDPs/IDPRs would invariantly fold in the presence of high concentrations of crowding agents or in the crowded cellular environment, accumulated data indicate that, based on their response to the presence of crowders, IDPs/IDPRs can be grouped into three major categories, foldable, non-foldable, and unfoldable. This is because natural cellular environment is not simply characterized by the presence of high concentration of “inert” macromolecules, but represents an active milieu, components of which are engaged in direct physical interactions and soft interactions with target proteins. Some of these interactions with cellular components can cause (local) unfolding of query proteins. In other words, since crowding can cause both folding and unfolding of an IDP or its regions, the outputs of the placing of a query protein to the crowded environment would depend on the balance between these two processes. As a result, and because of the spatio-temporal heterogeneity in structural organization of IDPs, macromolecular crowding can differently affect structures of different IDPs. Recent studies indicate that some IDPs are able to undergo liquid–liquid-phase transitions leading to the formation of various proteinaceous membrane-less organelles (PMLOs). Although interiors of such PMLOs are self-crowded, being characterized by locally increased concentrations of phase-separating IDPs, these IDPs are minimally foldable or even non-foldable at all (at least within the physiologically safe time-frame of normal PMLO existence). 相似文献
