Teleological Role Research Articles

The Mineralocorticoid Receptor in the Vasculature: Friend or Foe?

Originally described as the renal aldosterone receptor that regulates sodium homeostasis, it is now clear that mineralocorticoid receptors (MRs) are widely expressed, including in vascular endothelial and smooth muscle cells. Ample data demonstrate that endothelial and smooth muscle cell MRs contribute to cardiovascular disease in response to risk factors (aging, obesity, hypertension, atherosclerosis) by inducing vasoconstriction, vascular remodeling, inflammation, and oxidative stress. Extrapolating from its role in disease, evidence supports beneficial roles of vascular MRs in the context of hypotension by promoting inflammation, wound healing, and vasoconstriction to enhance survival from bleeding or sepsis. Advances in understanding how vascular MRs become activated are also reviewed, describing transcriptional, ligand-dependent, and ligand-independent mechanisms. By synthesizing evidence describing how vascular MRs convert cardiovascular risk factors into disease (the vascular MR as a foe), we postulate that the teleological role of the MR is to coordinate responses to hypotension (the MR as a friend).

Chrysippus’ Theory of Cosmic Pneuma: Some Remarks in Light of Medical and Biological Doctrines on Respiration, Digestion and Pulse

Abstract The aim of this paper is to explore how the cosmic soul works and how it accomplishes its providential and demiurgic tasks in Chrysippus’ system. Drawing on (i) the analogy Chrysippus establishes between the individuum and the cosmos and (ii) biological and medical theories of respiration, digestion, and pulse, I will show that the movements of Chrysippus’ cosmic soul reproduce the processes of digestion, pulse, and respiration at a cosmic level. My claim is that Chrysippus, in addition to adopting Praxagoras’ notion that inhaled air nourishes pneuma—well established in the scholarship—appropriated Aristotle’s complex mechanism of respiration and digestion based on the teleological role of cold air, crucial for preserving vital heat. So understood, Chrysippus’ application of biological notions to cosmology allows him to endow the active principle with effective causation throughout the cosmos.

Teleological role of L-2-hydroxyglutarate dehydrogenase in the kidney.

ABSTRACTL-2-hydroxyglutarate (L-2HG) is an oncometabolite found elevated in renal tumors. However, this molecule might have physiological roles that extend beyond its association with cancer, as L-2HG levels are elevated in response to hypoxia and during Drosophila larval development. L-2HG is known to be metabolized by L-2HG dehydrogenase (L2HGDH), and loss of L2HGDH leads to elevated L-2HG levels. Despite L2HGDH being highly expressed in the kidney, its role in renal metabolism has not been explored. Here, we report our findings utilizing a novel CRISPR/Cas9 murine knockout model, with a specific focus on the role of L2HGDH in the kidney. Histologically, L2hgdh knockout kidneys have no demonstrable histologic abnormalities. However, GC-MS metabolomics demonstrates significantly reduced levels of the TCA cycle intermediate succinate in multiple tissues. Isotope labeling studies with [U-13C] glucose demonstrate that restoration of L2HGDH in renal cancer cells (which lowers L-2HG) leads to enhanced incorporation of label into TCA cycle intermediates. Subsequent biochemical studies demonstrate that L-2HG can inhibit the TCA cycle enzyme α-ketoglutarate dehydrogenase. Bioinformatic analysis of mRNA expression data from renal tumors demonstrates that L2HGDH is co-expressed with genes encoding TCA cycle enzymes as well as the gene encoding the transcription factor PGC-1α, which is known to regulate mitochondrial metabolism. Restoration of PGC-1α in renal tumor cells results in increased L2HGDH expression with a concomitant reduction in L-2HG levels. Collectively, our analyses provide new insight into the physiological role of L2HGDH as well as mechanisms that promote L-2HG accumulation in disease states.

La belleza circular: Una aproximación a la estética de la sustentabilidad para el Capitaloceno

La estética no es independiente de la época en la que se ubica ni de la ideología a la que apoya o contesta; por el contrario puede convertirse en un vector de gran importancia facilitador de cambios de cosmovisión, según hemos podido comprobar en las revoluciones sociopolíticas del siglo pasado. A diferencia de la estética de la posmodernidad, con su condición epidérmica y escasamente crítica, los tiempos de la crisis ecológica del Capitaloceno y de la necesaria transición a sociedades más sustentables reclaman una creatividad y una estética muy distinta (Albelda, Parreño y Marrero, 2018). El presente artículo defiende la necesidad de recuperar el papel identitario y teleológico que en el pasado han jugado el arte y la estética. En este contexto, identificaremos los aspectos fundacionales de una estética circular, y su indisoluble unión con la ética ecológica de la que parte. Asimismo, argumentaremos sobre la amplitud del concepto de lo circular que, trascendiendo los aspectos más conocidos vinculados al reciclaje de materiales, adquiere una importante función moral vinculado al antropocentrismo débil, expresando la aceptación de la fugacidad individual, e incluso de la cultura y de la especie, desde una perspectiva holística (Spier, 2011). Aesthetics are not independent of the time in which they are located, nor of the ideology they support or answer; on the contrary, they can become a very important vector that facilitates changes in the worldview, as we have seen in the sociopolitical revolutions of the last century. Unlike the aesthetics of postmodernity, with their epidermic and scarcely critical condition, the times of the ecological crisis of the Capitalocene and of the transition to more sustainable societies demand a very different creativity and aesthetics (Albelda, Parreño y Marrero, 2018). This article defends the need to recover the identity and teleological role that art and aesthetics have played in the past. In this context, we will identify the foundational aspects of a circular aesthetic, and the indissoluble union with the ecological ethics from which it departs. Likewise, we will argue about the amplitude of the concept of circularity that, transcending the most known aspects linked to the recycling of materials, acquires an important moral function linked to the weak anthropocentrism, expressing the acceptance of individual fugacity, and even of culture and species, from a holistic perspective (Spier, 2011).

Living Without a Pulse: The Vascular Implications of Continuous-Flow Left Ventricular Assist Devices.

Pulsatility seems to have a teleological role because evolutionary hierarchy favors higher ordered animals with more complex, multichamber circulatory systems that generate higher pulse pressure compared with lower ordered animals. Yet despite years of such natural selection, the modern generation of continuous-flow left ventricular assist devices (CF-LVADs) that have been increasingly used for the last decade have created a unique physiology characterized by a nonpulsatile, nonlaminar blood flow profile with the absence of the usual large elastic artery Windkessel effect during diastole. Although outcomes and durability have improved with CF-LVADs, patients supported with CF-LVADs have a high rate of complications that were not as frequently observed with older pulsatile devices, including gastrointestinal bleeding from arteriovenous malformations, pump thrombosis, and stroke. Given the apparent fundamental biological role of the pulse, the purpose of this review is to describe the normal physiology of ventricular-arterial coupling from pulsatile flow, the effects of heart failure on this physiology and the vasculature, and to examine the effects of nonpulsatile blood flow on the vascular system and potential role in complications seen with CF-LVAD therapy. Understanding these concomitant vascular changes with CF-LVADs may be a key step in improving patient outcomes as modulation of pulsatility and flow characteristics may serve as a novel, yet simple, therapy for reducing complications.

Joel Barlow's Miltonic Epic and Western Directional Poetics

Joel Barlow's Miltonic Epic and Western Directional Poetics Edward Simon Joel Barlow's epic poem The Columbiad (1807) remains a curiosity of American literature.1 It has been unfairly maligned as derivative and jingoistic, and largely relegated to the dustbin of literary history along with various other early American works.2 No one could argue for the epic's aesthetic superiority over a text like John Milton's Paradise Lost. Yet, I would maintain that The Columbiad cleverly appropriates political, theological, and aesthetic themes from the earlier poem and refashions them in a specifically "American" manner. It does this with a heavy reliance on the classical trope of translatio studii et imperii. By emphasizing a certain geographic western orientation, the text takes part in a literary trope that I call "western directional poetics."3 That Milton had a central role in early American literature and politics has been widely commented on in scholarship.4 Barlow explicitly returned to Milton's literary sources to make a teleological argument on behalf of America's providential role in world history. Throughout The Columbiad Barlow cannily developed his own secular political theology from the Nonconformist Protestant thought of Milton. The Columbiad is an important Miltonic expression of a particular strain of American radical republicanism and American [End Page 87] exceptionality. Barlow's debt to Milton is evident in part in the descriptions of paradise that appear in The Columbiad. What is even more important, the influence of Milton on Barlow is also seen in the narrative relationship between the characters of Columbus and Hesper, who are functionally equivalent to Adam and the archangel Michael in Paradise Lost. Finally, I argue that the relationship between Columbus and Hesper takes part in the previously mentioned textual phenomenon of "directional poetics," which is something that I claim is implicit in Milton and explicit in Barlow. "Directional poetics" is the tendency of certain texts to endow a particular cardinal direction with a transcendent significance. The significance of any particular direction depends on how it is being deployed in a given text and, more broadly, across a tradition. North, south, east, and west can all signify different concepts across different texts; directional poetics offers a critical vocabulary to conceptualize more precisely the central place that directional spatiality has in literature. The west is often associated in Anglo-American literature with concepts such as manifest destiny, imperialism, progress, and even apocalypse. This "western" discourse is often assumed to originate in nineteenth century American literature, but I argue that the discourse goes back to the earliest era of New World colonialism.5 It is this early "western directional poetic" to which Milton alludes and which Barlow in his appropriation of Milton makes explicit in The Columbiad. In short, directional poetics is written throughout the text of The Columbiad, drawing from similar but more subtle evocations in Paradise Lost. The Columbiad provides an important perspective on early American radical politics, the relationship of early American literary culture to its cultural antecedents, and the appropriation of Milton to a particularly American vision during the revolutionary and early republican periods, when the United States attempted to exert itself as a particular polity whose destiny was in the greater Western Hemisphere. Christopher Kendrick writes, "Barlow's description of the American landscape at the beginning of his epic conducts in context a searching engagement with Milton's poem," [End Page 88] and in this engagement Barlow offered one vision of American political theology.6 My essay demonstrates that Barlow's literary innovation was to marshal Milton's narrative tropes in the service of an argument about the United States' teleological role based on its western directionality. In doing so, Barlow subverts Milton's distinction between the prelapsarian and postlapsarian worlds to present a paradisal America, and thus to make a nationalist, political, commercial, and religious argument about the arrival of a new world order in the form of the United States of America. Barlow's claim about American exceptionality in The Columbiad hence functions as a type of "Paradise Found." What was precisely evocative about Paradise Lost to Barlow was Milton's "Americanness," a quality I will explore at greater length below. Barlow's Columbiad...

Phytoestrogens modulate hepcidin expression by Nrf2: Implications for dietary control of iron absorption

Hepcidin is a liver-derived antimicrobial peptide that regulates iron absorption and is also an integral part of the acute phase response. In a previous report, we found evidence that this peptide could also be induced by toxic heavy metals and xenobiotics, thus broadening its teleological role as a defensin. However it remained unclear how its sensing of disparate biotic and abiotic stressors might be integrated at the transcriptional level. We hypothesized that its function in cytoprotection may be regulated by NFE2-related factor 2 (Nrf2), the master transcriptional controller of cellular stress defenses. In this report, we show that hepcidin regulation is inextricably linked to the acute stress response through Nrf2 signaling. Nrf2 regulates hepcidin expression from a prototypical antioxidant response element in its promoter, and by synergizing with other basic leucine-zipper transcription factors. We also show that polyphenolic small molecules or phytoestrogens commonly found in fruits and vegetables including the red wine constituent resveratrol can induce hepcidin expression in vitro and post-prandially, with concomitant reductions in circulating iron levels and transferrin saturation by one such polyphenol quercetin. Furthermore, these molecules derepress hepcidin promoter activity when its transcription by Nrf2 is repressed by Keap1. Taken together, the data show that hepcidin is a prototypical antioxidant response or cytoprotective gene within the Nrf2 transcriptional circuitry. The ability of phytoestrogens to modulate hepcidin expression in vivo suggests a novel mechanism by which diet may impact iron homeostasis.

DPP4 in cardiometabolic disease: recent insights from the laboratory and clinical trials of DPP4 inhibition.

The discovery of incretin-based medications represents a major therapeutic advance in the pharmacological management of type 2 diabetes mellitus (T2DM), as these agents avoid hypoglycemia, weight gain, and simplify the management of T2DM. Dipeptidyl peptidase-4 (CD26, DPP4) inhibitors are the most widely used incretin-based therapy for the treatment of T2DM globally. DPP4 inhibitors are modestly effective in reducing HbA1c (glycated hemoglobin) (≈0.5%) and while these agents were synthesized with the understanding of the role that DPP4 plays in prolonging the half-life of incretins such as glucagon-like peptide-1 and gastric inhibitory peptide, it is now recognized that incretins are only one of many targets of DPP4. The widespread expression of DPP4 on blood vessels, myocardium, and myeloid cells and the nonenzymatic function of CD26 as a signaling and binding protein, across a wide range of species, suggest a teleological role in cardiovascular regulation and inflammation. Indeed, DPP4 is upregulated in proinflammatory states including obesity, T2DM, and atherosclerosis. Consistent with this maladaptive role, the effects of DPP4 inhibition seem to exert a protective role in cardiovascular disease at least in preclinical animal models. Although 2 large clinical trials suggest a neutral effect on cardiovascular end points, current limitations of performing trials in T2DM over a limited time horizon on top of maximal medical therapy must be acknowledged before rendering judgment on the cardiovascular efficacy of these agents. This review will critically review the science of DPP4 and the effects of DPP4 inhibitors on the cardiovascular system.

Reply

We appreciate and welcome the comments from Drs Tharion and Subramani on our paper (Sin et al. 2010), which we summarize as follows: (1) ventilatory equivalents of carbon dioxide ( ) and oxygen ( ) are imperfect measures of pulmonary gas exchange efficiency; and therefore (2) our study does not allow conclusions to be drawn regarding the role of respiratory sinus arrhythmia (RSA) in pulmonary gas exchange optimization. At first glance it may seem that our measurement choice compromises our study conclusions. Closer examination of our stated hypothesis, however, shows that the conclusions are in fact well justified. To date, evidence in favour of Hayano's hypothesis that ‘RSA improves pulmonary gas exchange efficiency by matching alveolar ventilation and capillary perfusion throughout respiratory cycle…by suppressing unnecessary heartbeats during expiration and ineffective ventilation during waning phases of perfusion’ is largely based on animal experiments (Hayano & Yasuma, 2003). In an attempt to establish the relevance of this hypothesis in humans, Giardino et al. (2003) showed that and were significantly reduced during slow breathing and attributed this ‘pulmonary gas exchange’ improvement to the concomitant rise in RSA amplitude. We were sceptical of this interpretation given we had already shown that physiological levels of RSA do not give rise to significant heartbeat redistribution (Tzeng et al. 2009). Consequently, the study was conducted to test our hypothesis that a previously described association between RSA amplitude, and is unrelated to the presence of RSA itself; the study was not an attempt to re-examine Hayano's hypothesis, which we had already shown to be physiologically improbable (Tzeng et al. 2009). Although ventilatory equivalents have been previously applied as indices of pulmonary gas exchange efficiency (e.g. Giardino et al. 2003), we are in full agreement with Drs Tharion and Subramani that they are not gold standard and never alluded to this being the case. Nevertheless, as discussed in the Viewpoint article that accompanied our work, ‘opinions based upon faulty logic can have a long duration, unless being meticulously challenged’ (Buchheit, 2010). Knowing that the fundamental premise of Hayano's hypothesis is not met, we simply took one further step to demonstrate unequivocally the faulty logic that underpins current evidence. Thus, for the benefit of the general readership, we reiterate again that the use of ventilatory equivalents, whatever they reflect, does not compromise our position that the concurrent rise in RSA and reduction in and during slow breathing cannot be taken as evidence that RSA optimizes human pulmonary gas exchange efficiency. The commentary from Drs Tharion and Subramani further reinforces our core message that a teleological role of human RSA, if it has one, remains to be determined.

The hunt for the epiallele

Understanding the origin of phenotypic variation remains one of the principle challenges of contemporary biology. Recent genome-wide association studies have identified association between common genetic variants and complex phenotype; however, the minimal effect sizes observed in such studies highlight the potential for other causal factors to be involved in phenotypic variation. The epigenetic state of an organism (or 'epigenome') incorporates a landscape of complex and plastic molecular events that may underlie the 'missing link' that integrates genotype with phenotype. The nature of these processes has been the subject of intense scientific study over the recent years, and characterisation of epigenetic variation, in the form of 'epialleles', is providing fascinating insight into how the genome functions within a range of developmental processes, environments, and in states of health and disease. This review will discuss how and when mammalian epialleles may be generated and their interaction with genetic and environmental factors. We will outline how an epiallele has a variable relationship with phenotype, and how new technologies may be used for their detection and to facilitate an understanding of their contribution to phenotype. Finally, we will consider epialleles in population variation and their teleological role in evolution. variation and their teleological role in evolution.

Dialética nos Contraditórios Judicial e Arbitral: a Arte do Direito e Sua Regulação

ABSTRACT: The objective of this article is to analyze the problems arisen by the contradictory in the ambient of the positivist law, in which dialectic - and, therefore, the intersubjectivity and dialogic rhetoric between the protagonists of the conflict - is underestimate and substituted by the artificial manicheaist by the alienating operators, under the selection of the authorities who had the jurisdictio­nal power. The author propose a recapitulation of the law, taking to account its aspect of art, efficient to reverse the logic of the judicial contradictory and, also, the arbitral, once the law have to be as support of the legal dialogic, doing its systematical and teleological role, and not like a law itself, as a system. A new contradictory, which is evaluative and collaborative, will make a bridge between mediate act, in its continued intersubjectivity and dialogic, and the law, in its systematic order, to give birth to the justice, as a legitimate force and socially efficient. The author support that the society belonging to the knowledge's era demand a legal culture, in which the regulate dialogical art consti­tutes the rule of law, with an ethic and pedagogic function, to give celerity and social effectiveness for the self and hetero compositions.

Endings Lost and Found in the Poema de Fernán González

Inspired by the lost ending of the Poema de Fernán González and the question of its content, this paper argues that an ideology of judgement and salvation is evoked in the introductory stanzas of the poem which inheres in the body of the work, and may have reached completion in the lost conclusion. Attention is paid to the early description of the conversion of the poet's Spanish ancestors from estrangement from Christ to an acceptance of his law. The legalistic theme which underpins this narrative invites the theme of judgement into the heart of the poem, where it parallels the theological process of justification. The description of ancestral conversion also outlines stages of salvation, thus asserting the meaningful, teleological role of time in the poem and situating the career of the hero within an eschatological framework which attaches special importance to the attainment of moral, not just material, worth. I argue that in conflating legal and temporal discourses the poem represents the hero within a model of divine sonship, according to which he would have represented, conclusively, the cumulation of the lost moral and territorial worth of the Visigoths, but also the prospect of the eternal heritage to come.

Electrophysiology of the electrocardiographic changes of atrial fibrillation

The history of atrial fibrillation is described in terms of its electrocardiographic delineation, characteristics and clinical associations. The variant configurations are described and their relationship to rhythm duration and cardioversion success. The inter-relationship of fibrillation with flutter and their diagnostic differences are reviewed. The electrophysiologic basis of atrial remodeling is exemplified, together with its relationship to failure of rate adaptation of the atrial refractory period. Electric countershock causes an acute abbreviation of the atrial refractory period as does the induction of hyperthyroidism in the experimental animal. Current theories of the mechanism of fibrillation and the issue of originating pulmonary venous foci are reviewed. The lack of protection from ventricular fibrillation that exists with preexcitation via an accessory pathway is discussed in terms of the teleological role of orthograde downstream refractory periods.

Metabolic and vascular support for the role of myoglobin in humans: a multiparametric NMR study

In human muscle the role of myoglobin (Mb) and its relationship to factors such as muscle perfusion and metabolic capacity are not well understood. We utilized nuclear magnetic resonance (NMR) to simultaneously study the Mb concentration ([Mb]), perfusion, and metabolic characteristics in calf muscles of athletes trained long term for either sprint or endurance running after plantar flexion exercise and cuff ischemia. The acquisitions for (1)H assessment of Mb desaturation and concentration, arterial spin labeling measurement of muscle perfusion, and (31)P spectroscopy to monitor high-energy phosphate metabolites were interleaved in a 4-T magnet. The endurance-trained runners had a significantly elevated [Mb] (0.28 +/- 0.06 vs. 0.20 +/- 0.03 mmol/kg). The time constant of creatine rephosphorylation (tauPCr), an indicator of oxidative capacity, was both shorter in the endurance-trained group (34 +/- 6 vs. 64 +/- 20 s) and negatively correlated with [Mb] across all subjects (r = 0.58). The time to reach maximal perfusion after cuff release was also both shorter in the endurance-trained group (306 +/- 74 vs. 560 +/- 240 s) and negatively correlated with [Mb] (r = 0.56). Finally, Mb reoxygenation rate tended to be higher in the endurance-trained group and was positively correlated with tauPCr (r = 0.75). In summary, these NMR data reveal that [Mb] is increased in human muscle with a high oxidative capacity and a highly responsive vasculature, and the rate at which Mb resaturates is well correlated with the rephosphorylation rate of Cr, each of which support a teleological role for Mb in O(2) transport within highly oxidative human skeletal muscle.

(Re)‐telling stories: Narrative theory and the practice of client counselling

The field of narrative studies is currently influencing methodology in many areas of research and learning in the arts and social sciences historiography, psychology, philosophy, theology, therapy and education amongst others. Researchers in these domains have used narrative theory to help them examine how narratives concerning professionals are constructed, and what this tells us of the professionals themselves, their view of their profession, their place within it, and their relations with clients. Most of these studies emphasise the teleological role that narrative inquiry can play in providing individuals with the opportunities to achieve new understandings about the nature and process of practice and the communities within such practice is enacted. This article describes the application of aspects of narrative theory to legal education. It describes the use to which narrative criticism was put in a third level module on clinical legal skills at Glasgow Caledonian University. Some key concepts in narrative theory were used in class discussion of videotaped client counselling interviews between solicitors and clients. The narrative concepts were also reinforced in other areas of the module dealing with negotiation and writing skills. Through the discussion of the videotapes and reflective practice using recipes, students came to a deeper appreciation of the experience of one important aspect of legal practice. [T]he study of narrative, like the study of other significant human creations, has taken a quantum leap in the modern era. No longer the province of literary specialists who borrow their terms from psychology and linguistics, the study of narrative has become an invaluable source of insight for all the branches of human and natural science’. Why is there such a rush to storytelling? Why has narrative become such an important and recurring theme in legal scholarship these days? It is with this question that the editor Kim Lane Scheppele opened the Foreword to a special issue in 1989 of the Michigan Law Review on the place of narrative in legal discourse. Throughout the eighties and especially in America there was a steady growth in the number of articles and books concerned with law and narrative; and in the nineties there has been no slackening of interest: narrative and especially narrative theory remains a recurring interest for lawyers. There are two clear strands to the research. First, the law and literature movement has used narrative theory to analyse the relations between literature and law, and to critique the place of law in society. Second, those involved in ‘critical lawyering’, clinical skills, and the ethnography of legal discourse have employed narrative theory teleologically in order to open up new

Opioid modulation of appetite

The discovery of opiate receptors and endogenous opioid peptides within the central nervous system has resulted in a number of speculations concerning the physiological significance of these peptides. In the present article, we review the evidence suggesting a primary role for some of the opioid peptides as regulators of ingestive behavior. In particular, we elaborate a hypothesis in which we suggest that in some species opioid peptides may play a role as a tonic inducer of ingestive behaviors, held in check by a variety of neuropeptides and monoamines. This review explores in detail the role of the opioid peptides as major mediators of the reward system and as a link between reward and feeding behaviors. Finally, a teleological role for opioid peptides in species preservation, which may explain the discrepancies in the role of the opioid peptides in feeding behavior in different species is proposed. It is suggested that the feeding profile of the animal provides important clues as to whether or not the animal has an opiate-sensitive feeding system. We stress that interactions with ingested nutrients and the milieu interieur provide an important means by which animals modulate the opiate-entrained feeding drives.