scholarly journals Mentors And The Butterfly Effect: Triggers For Discovering Signalling by Proteinases via Proteinase-Activated Receptors (PARs) And More

2012 ◽  
Vol 35 (6) ◽  
pp. 378
Author(s):  
Morley D Hollenberg

The essential role of proteinases as regulatory digestive enzymes, recognized since the late 1800s, has been underscored by the discovery that more than 2% of the genome codes for proteinases and their inhibitors. Further, by the early 1970s it was appreciated that in addition to their digestive actions, proteinases can affect cell function: (1) by the generation or degradation of peptide hormones and (2) by the direct regulation of signalling by receptors like the one for insulin. It was the discovery in the 1990s of the novel G-protein-coupled ‘proteinase-activated receptor’ (PAR) family that has caused a paradigm shift in the understanding of the way that proteinases can regulate cell signalling. This overview provides a perspective for the discovery of the PARs and my laboratory’s role in (1) understanding the molecular pharmacology of these fascinating receptors and (2) identifying the potential pathophysiological roles that the PAR family can play in inflammatory disease. In this context, the overview also portrays the essential impact that seemingly minor comments/insights provided by my lifelong mentors have had on kindling my intense interest in proteinase-mediated signalling. The ‘butterfly effect’ of those comments has led to an unexpectedly large impact on my own research directions. Hopefully my own ‘butterfly comments’ will also be heard by my trainees and other colleagues with whom I am currently working and will promote future discoveries that will be directly relevant to the treatment of inflammatory disease.

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Michele Bonus ◽  
Dieter Häussinger ◽  
Holger Gohlke

Abstract Liver cell hydration (cell volume) is dynamic and can change within minutes under the influence of hormones, nutrients, and oxidative stress. Such volume changes were identified as a novel and important modulator of cell function. It provides an early example for the interaction between a physical parameter (cell volume) on the one hand and metabolism, transport, and gene expression on the other. Such events involve mechanotransduction (osmosensing) which triggers signaling cascades towards liver function (osmosignaling). This article reviews our own work on this topic with emphasis on the role of β1 integrins as (osmo-)mechanosensors in the liver, but also on their role in bile acid signaling.


2018 ◽  
Vol 12 (2) ◽  
pp. 260-278
Author(s):  
Christoph Demmerling

Abstract The following article argues that fictional texts can be distinguished from non-fictional texts in a prototypical way, even if the concept of the fictional cannot be defined in classical terms. In order to be able to characterize fictional texts, semantic, pragmatic, and reader-conditioned factors have to be taken into account. With reference to Frege, Searle, and Gabriel, the article recalls some proposals for how we might define fictional speech. Underscored in particular is the role of reception for the classification of a text as fictional. I make the case, from a philosophical perspective, for the view that fictional texts represent worlds that do not exist even though these worlds obviously can, and de facto do, contain many elements that are familiar to us from our world. I call these worlds reading worlds and explain the relationship between reading worlds and the life world of readers. This will help support the argument that the encounter with fictional literature can invoke real feelings and that such feelings are by no means irrational, as some defenders of the paradox of fiction would like us to believe. It is the exemplary character of fictional texts that enables us to make connections between the reading worlds and the life world. First and foremost, the article discusses the question of what it is that readers’ feelings are in fact related to. The widespread view that these feelings are primarily related to the characters or events represented in a text proves too simple and needs to be amended. Whoever is sad because of the fate of a fictive character imagines how he or she would fare if in a similar situation. He or she would feel sad as it relates to his or her own situation. And it is this feeling on behalf of one’s self that is the presupposition of sympathy for a fictive character. While reading, the feelings related to fictive characters and content are intertwined with the feelings related to one’s own personal concerns. The feelings one has on his or her own behalf belong to the feelings related to fictive characters; the former are the presupposition of the latter. If we look at the matter in this way, a new perspective opens up on the paradox of fiction. Generally speaking, the discussion surrounding the paradox of fiction is really about readers’ feelings as they relate to fictive persons or content. The question is then how it is possible to have them, since fictive persons and situations do not exist. If, however, the emotional relation to fictive characters and situations is conceived of as mediated by the feelings one has on one’s own behalf, the paradox loses its confusing effect since the imputation of existence no longer plays a central role. Instead, the conjecture that the events in a fictional story could have happened in one’s own life is important. The reader imagines that a story had or could have happened to him or herself. Readers are therefore often moved by a fictive event because they relate what happened in a story to themselves. They have understood the literary event as something that is humanly relevant in a general sense, and they see it as exemplary for human life as such. This is the decisive factor which gives rise to a connection between fiction and reality. The emotional relation to fictive characters happens on the basis of emotions that we would have for our own sake were we confronted with an occurrence like the one being narrated. What happens to the characters in a fictional text could also happen to readers. This is enough to stimulate corresponding feelings. We neither have to assume the existence of fictive characters nor do we have to suspend our knowledge about the fictive character of events or take part in a game of make-believe. But we do have to be able to regard the events in a fictional text as exemplary for human life. The representation of an occurrence in a novel exhibits a number of commonalities with the representation of something that could happen in the future. Consciousness of the future would seem to be a presupposition for developing feelings for something that is only represented. This requires the power of imagination. One has to be able to imagine what is happening to the characters involved in the occurrence being narrated in a fictional text, ›empathize‹ with them, and ultimately one has to be able to imagine that he or she could also be entangled in the same event and what it would be like. Without the use of these skills, it would remain a mystery how reading a fictional text can lead to feelings and how fictive occurrences can be related to reality. The fate of Anna Karenina can move us, we can sympathize with her, because reading the novel confronts us with possibilities that could affect our own lives. The imagination of such possibilities stimulates feelings that are related to us and to our lives. On that basis, we can participate in the fate of fictive characters without having to imagine that they really exist.


Author(s):  
Giovanni Camurati ◽  
Aurélien Francillon ◽  
François-Xavier Standaert

Recently, some wireless devices have been found vulnerable to a novel class of side-channel attacks, called Screaming Channels. These leaks might appear if the sensitive leaks from the processor are unintentionally broadcast by a radio transmitter placed on the same chip. Previous work focuses on identifying the root causes, and on mounting an attack at a distance considerably larger than the one achievable with conventional electromagnetic side channels, which was demonstrated in the low-noise environment of an anechoic chamber. However, a detailed understanding of the leak, attacks that take full advantage of the novel vector, and security evaluations in more practical scenarios are still missing. In this paper, we conduct a thorough experimental analysis of the peculiar properties of Screaming Channels. For example, we learn about the coexistence of intended and unintended data, the role of distance and other parameters on the strength of the leak, the distortion of the leakmodel, and the portability of the profiles. With such insights, we build better attacks. We profile a device connected via cable with 10000·500 traces. Then, 5 months later, we attack a different instance at 15m in an office environment. We recover the AES-128 key with 5000·1000 traces and key enumeration up to 223. Leveraging spatial diversity, we mount some attacks in the presence of obstacles. As a first example of application to a real system, we show a proof-of-concept attack against the authentication method of Google Eddystone beacons. On the one side, this work lowers the bar for more realistic attacks, highlighting the importance of the novel attack vector. On the other side, it provides a broader security evaluation of the leaks, helping the defender and radio designers to evaluate risk, and the need of countermeasures.


Endocrinology ◽  
2011 ◽  
Vol 152 (10) ◽  
pp. 3706-3716 ◽  
Author(s):  
Isabel R. Orriss ◽  
Ning Wang ◽  
Geoffrey Burnstock ◽  
Timothy R. Arnett ◽  
Alison Gartland ◽  
...  

Accumulating evidence indicates that extracellular nucleotides, signaling through P2 receptors, play a significant role in bone remodeling. Osteoclasts (the bone-resorbing cell) and osteoblasts (the bone-forming cell) display expression of the G protein-coupled P2Y6 receptor, but the role of this receptor in modulating cell function is unclear. Here, we demonstrate that extracellular UDP, acting via P2Y6 receptors, stimulates the formation of osteoclasts from precursor cells, while also enhancing the resorptive activity of mature osteoclasts. Furthermore, osteoclasts derived from P2Y6 receptor-deficient (P2Y6R−/−) animals displayed defective function in vitro. Using dual energy x-ray absorptiometry scanning and microcomputed tomographic analysis we showed that P2Y6R−/− mice have increased bone mineral content, cortical bone volume, and cortical thickness in the long bones and spine, whereas trabecular bone parameters were unaffected. Histomorphometric analysis showed the perimeter of the bone occupied by osteoclasts on the endocortical and trabecular surfaces was decreased in P2Y6R−/− mice. Taken together these results show the P2Y6 receptor may play an important role in the regulation of bone cell function in vivo.


2020 ◽  
Vol 9 (2) ◽  
pp. R14-R27 ◽  
Author(s):  
Giovanni Tulipano

A variety of endocrine and metabolic signals regulate pituitary cell function acting through the hypothalamus-pituitary neuroendocrine axes or directly at the pituitary level. The underlying intracellular transduction mechanisms in pituitary cells are still debated. AMP-activated protein kinase (AMPK) functions as a cellular sensor of low energy stores in all mammalian cells and promotes adaptive changes in response to calorie restriction. It is also regarded as a target for therapy of proliferative disorders. Various hormones and drugs can promote tissue-specific activation or inhibition of AMPK by enhancing or inhibiting AMPK phosphorylation, respectively. This review explores the preclinical studies published in the last decade that investigate the role of AMP-activated protein kinase in the intracellular transduction pathways downstream of endocrine and metabolic signals or drugs affecting pituitary cell function, and its role as a target for drug therapy of pituitary proliferative disorders. The effects of the hypoglycemic agent metformin, which is an indirect AMPK activator, are discussed. The multiple effects of metformin on cell metabolism and cell signalling and ultimately on cell function may be either dependent or independent of AMPK. The in vitro effects of metformin may also help highlighting differences in metabolic requirements between pituitary adenomatous cells and normal cells.


2020 ◽  
Vol 25 (3) ◽  
pp. 61-66
Author(s):  
Konstantin A. Ozherelyev
Keyword(s):  
New Age ◽  

The paper analyzes the key philosophical contexts and subtexts of M. Shelley’s most famous work “Frankenstein”. According to the author of the article, the philosophical layer of this Gothic novel consists of ideas and maxims that directly inherit the concepts of the worldview platforms of Plato, J.-J. Russo, G. W. F. Hegel, K. F. Volney, W. Godwin, M. Wollstonecraft, as well as the philosophy of the New Age and romanticism. An assumption is made, on the one hand, about the proximity of some worldview attitudes of these philosophers and the author of “Frankenstein” and, on the other hand, about the deliberate introduction of philosophical passages into the fabric of the novel, which play the role of retardation elements.


2020 ◽  
pp. 002198941990052
Author(s):  
Asha Jeffers

David Chariandy’s lauded 2007 debut novel Soucouyant explores the way that immigrants transmit lessons, beliefs, and ways of being to their children both intentionally and unintentionally, and the ways that these transmissions can contradict one another. This article argues that while much of the critical writing about Soucouyant has foregrounded the relationship between the unnamed narrator and his dementia-suffering mother, the text is just as concerned with exploring intragenerational relationships as it is with intergenerational ones. Indeed, the text demonstrates the interweaving of both intergenerational and intragenerational relationships in a unique and compelling way. The lessons that get passed on between the generations shape the lives and interactions of second generation subjects between themselves. In particular, the relationship between the narrator and Meera, the mysterious woman who has moved in with and is taking care of his mother when he returns to her home after deserting her for several years, poses the question of how these two second generation subjects of differing class backgrounds might reconcile themselves with both their parents’ Caribbean pasts, their own Canadian presents, and uncertain futures. The novel’s subtitle, “a novel of forgetting,” signals the central role of memory and forgetting play in the novel. The immigrant parents’ desire and attempts to forget the past are not wholly successful and their second generation children are forced to first remember before they can move forward without being haunted by the traumas, silences, and anxieties of their parents. The complex racial and class politics of Trinidad and Canada lead to the narrator and Meera receiving very different legacies from their parents. However, their eventual coming together, in all its difficulty, suggests that there is hope for second generation subjects who wish to choose a different path than the one set for them by either their parents or the nation-state.


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