Journal articles on the topic 'Roll forward peripheral'
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1
Andersen, George J., and Brian P. Dyre. "Induced Roll Vection from Stimulation of the Central Visual Field." Proceedings of the Human Factors Society Annual Meeting 31, no. 2 (September 1987): 263–65. http://dx.doi.org/10.1177/154193128703100228.
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An important consideration for some types of flight simulation is that sufficient visual information be provided for a perception of self-motion. A general conclusion of earlier research is that peripheral stimulation (outside a 30 deg. diameter area of the central visual field) is necessary for perceived self-motion to occur. More recently Andersen and Braunstein (1985) demonstrated that induced self-motion could occur when visual information simulating forward motion of the observer was presented to a limited area of the central visual field. In the present study, the perception of induced roll vection (rotation about the line of sight) from visual stimulation of the central visual field was examined. Subjects viewed computer generated displays that simulated observer motion relative to a volume of randomly positioned points. Two variables were examined: 1) the presence or absence of a simulated forward motion, and 2) the presence of a 15 deg. or 30 deg. sinusoidal roll motion. It was found that: 1) induced roll vection occurred with stimulation restricted to a 10 deg. diameter area of the central visual field; 2) greater postural instability occurred for displays with a 30 deg. roll as compared to a 15 deg. roll; and 3) significantly greater postural instability occurred along the X-axis (left/right) as compared to the Y-axis (front/back). The implications of this research for flight simulation will be discussed.
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Rangel, Maria L., Lidiane Souza, Erika C. Rodrigues, José M. Oliveira, Michelle F. Miranda, Antonio Galves, and Claudia D. Vargas. "Predicting Upcoming Events Occurring in the Space Surrounding the Hand." Neural Plasticity 2021 (February 20, 2021): 1–10. http://dx.doi.org/10.1155/2021/6649135.
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Predicting upcoming sensorimotor events means creating forward estimates of the body and the surrounding world. This ability is a fundamental aspect of skilled motor behavior and requires an accurate and constantly updated representation of the body and the environment. To test whether these prediction mechanisms could be affected by a peripheral injury, we employed an action observation and electroencephalogram (EEG) paradigm to assess the occurrence of prediction markers in anticipation of observed sensorimotor events in healthy and brachial plexus injury (BPI) participants. Nine healthy subjects and six BPI patients watched a series of video clips showing an actor’s hand and a colored ball in an egocentric perspective. The color of the ball indicated whether the hand would grasp it (hand movement), or the ball would roll toward the hand and touch it (ball movement), or no event would occur (no movement). In healthy participants, we expected to find distinct electroencephalographic activation patterns (EEG signatures) specific to the prediction of the occurrence of each of these situations. Cluster analysis from EEG signals recorded from electrodes placed over the sensorimotor cortex of control participants showed that predicting either an upcoming hand movement or the occurrence of a tactile event yielded specific neural signatures. In BPI participants, the EEG signals from the sensorimotor cortex contralateral to the dominant hand in the hand movement condition were different compared to the other conditions. Furthermore, there were no differences between ball movement and no movement conditions in the sensorimotor cortex contralateral to the dominant hand, suggesting that BPI blurred specifically the ability to predict upcoming tactile events for the dominant hand. These results highlight the role of the sensorimotor cortex in creating estimates of both actions and tactile interactions in the space around the body and suggest plastic effects on prediction coding following peripheral sensorimotor loss.
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Tanaka, E., T. Ho, and M. W. Kirschner. "The role of microtubule dynamics in growth cone motility and axonal growth." Journal of Cell Biology 128, no. 1 (January 1, 1995): 139–55. http://dx.doi.org/10.1083/jcb.128.1.139.
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The growth cone contains dynamic and relatively stable microtubule populations, whose function in motility and axonal growth is uncharacterized. We have used vinblastine at low doses to inhibit microtubule dynamics without appreciable depolymerization to probe the role of these dynamics in growth cone behavior. At doses of vinblastine that interfere only with dynamics, the forward and persistent movement of the growth cone is inhibited and the growth cone wanders without appreciable forward translocation; it quickly resumes forward growth after the vinblastine is washed out. Direct visualization of fluorescently tagged microtubules in these neurons shows that in the absence of dynamic microtubules, the remaining mass of polymer does not invade the peripheral lamella and does not undergo the usual cycle of bundling and splaying and the growth cone stops forward movement. These experiments argue for a role for dynamic microtubules in allowing microtubule rearrangements in the growth cone. These rearrangements seem to be necessary for microtubule bundling, the subsequent coalescence of the cortex around the bundle to form new axon, and forward translocation of the growth cone.
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Grabstein, K. H., T. J. Waldschmidt, F. D. Finkelman, B. W. Hess, A. R. Alpert, N. E. Boiani, A. E. Namen, and P. J. Morrissey. "Inhibition of murine B and T lymphopoiesis in vivo by an anti-interleukin 7 monoclonal antibody." Journal of Experimental Medicine 178, no. 1 (July 1, 1993): 257–64. http://dx.doi.org/10.1084/jem.178.1.257.
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The effects of interleukin 7 (IL-7) on the growth and differentiation of murine B cell progenitors has been well characterized using in vitro culture methods. We have investigated the role of IL-7 in vivo using a monoclonal antibody that neutralizes IL-7. We find that treatment of mice with this antibody completely inhibits the development of B cell progenitors from the pro-B cell stage forward. We also provide evidence that all peripheral B cells, including those of the B-1 and conventional lineages, are derived from IL-7-dependent precursors. The results are consistent with the rapid turnover of B cell progenitors in the marrow, but a slow turnover of mature B cells in the periphery. In addition to effects on B cell development, anti-IL-7 treatment substantially reduced thymus cellularity, affecting all major thymic subpopulations.
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Biscetti, Federico, Elisabetta Nardella, Andrea Leonardo Cecchini, Raffaele Landolfi, and Andrea Flex. "The Role of the Microbiota in the Diabetic Peripheral Artery Disease." Mediators of Inflammation 2019 (May 8, 2019): 1–16. http://dx.doi.org/10.1155/2019/4128682.
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Vascular complications of diabetes mellitus represent a major public health problem. Although many steps forward have been made to define the causes and to find the best possible therapies, the problem remains crucial. In recent years, more and more evidences have defined a link between microbiota and the initiation, promotion, and evolution of atherosclerotic disease, even in the diabetic scenario. There is an urgency to develop the knowledge of modern medicine about the link between gut microbiota and its host’s metabolic pathways, and it would be useful to understand and justify the interindividual diversity of clinical disease presentation of diabetic vascular complication even if an optimization of pharmacological treatment has been made or in the case of young patients where hypertension, dyslipidemia, and diabetes are not able to justify a very quick progress of atherosclerotic process. The aim of the present review is to gather all the best available evidence in this regard and to define a new role of the microbiota in this field, from biomarker to possible therapeutic target.
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Sarkar, Abhijit, Hananeh Alambeigi, Anthony McDonald, Gustav Markkula, and Jeff Hickman. "Role of Peripheral Vision in Brake Reaction Time During Safety Critical Events." Proceedings of the Human Factors and Ergonomics Society Annual Meeting 65, no. 1 (September 2021): 695–99. http://dx.doi.org/10.1177/1071181321651219.
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The criticality of a rear end event depends on the brake reaction time (BRT) of the driver. Therefore, distracted driving poses greater threat in such events. Evidence accumulation model (EAM) that uses looming of the lead vehicle as main stimuli has shown significant success in estimating drivers’ BR Ts. It is often argued that drivers collect evidence for braking through peripheral vision, especially during off-road glances, and transition to forward. In this work, we have modeled evidence accumulation as a function of gaze eccentricity for off-road glances while approaching safety critical events. The model is tested with real world crash and near crash event data from SHRP2 naturalistic study. Our model shows that linear relation between gaze eccentricity and evidence accumulation rate during off road glances helps to improve EAM estimation in predicting BRT. We have also shown that brake-light onset does not influence EAM in presence of active looming.
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Ohmi, M. "Vection with Real-World Stimuli." Perception 25, no. 1_suppl (August 1996): 112. http://dx.doi.org/10.1068/v96p0114.
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Psychophysical studies have revealed that retinal and depth periphery play a dominant role in activating vection, or visually induced sensation of self-motion. But since abstract stimuli such as random-dot patterns and vertical stripes have been used in these studies, the results are not always applicable for designing more realistic visual displays in real-world applications. Indeed, it has been shown that for human orientation, a real-world display is more effective than an abstract one (Howard and Childerson, 1994 Perception23 753 – 762). We investigated how vection was controlled by the peripheral part of a stimulus consisting of a real-world display. Stereoscopic and nonstereoscopic video clips were taken through a windshield while driving on (i) a straight, (ii) a gradually curved, and (iii) a sharply curved road at slow and fast speeds. Vection was measured with these stimuli which were presented on a 63 deg wide and 38 deg high video projection monitor. The results showed that although the stereoscopic display generally activated more forward and sideways vection than the nonstereoscopic one, the difference was barely statistically significant. When only the central 18 deg diameter of the display was presented, similar vection was activated as with a full field display. When the central 40 deg diameter of the display was occluded, vection did not change significantly, though observers found difficulty in assessing the direction of self-motion. It is concluded that retinal and depth periphery of real-world stimuli do not play a significant role in activating vection.
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Dellas, Harris, and George S. Tavlas. "The Dog that Did Not Bark: The Curious Case of Lloyd Mints, Milton Friedman, and the Emergence of Monetarism." History of Political Economy 53, no. 4 (June 23, 2021): 633–72. http://dx.doi.org/10.1215/00182702-9308897.
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Evidence about Lloyd Mints’s role in the development of monetary economics at the University of Chicago has proven elusive, with the result that Mints has long been considered a peripheral figure at Chicago. We provide evidence showing that the standard assessment of Mints’s standing in Chicago monetary economics—and in American monetary economics more broadly—is deficient. In light of (1) the originality and the breadth of his monetary contributions, (2) the cross-fertilization of his thinking with that of Milton Friedman, and (3) the way Mints’s original contributions helped shape part of Friedman’s framework and were pushed forward by Friedman, we argue that, far from being a peripheral figure in the development of Chicago monetary economics, Mints played a more substantial role than has been previously thought in the emerging Chicago monetary economics of the late 1940s and early 1950s.
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Curtis, Stephanie L., Andrew Zambanini, Jamil Mayet, Simon A. McG Thom, Rodney Foale, Kim H. Parker, and Alun D. Hughes. "Reduced systolic wave generation and increased peripheral wave reflection in chronic heart failure." American Journal of Physiology-Heart and Circulatory Physiology 293, no. 1 (July 2007): H557—H562. http://dx.doi.org/10.1152/ajpheart.01095.2006.
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In human heart failure the role of wave generation by the ventricle and wave reflection by the vasculature is contentious. The aim of this study was to compare wave generation and reflection in normal subjects with patients with stable compensated heart failure. Twenty-nine normal subjects and 67 patients with heart failure (New York Heart Association class II or III) were studied by noninvasive techniques applied to the common carotid artery. Data were analyzed by wave intensity analysis to determine the nature and direction of waves during the cardiac cycle. The energy carried by an early systolic forward compression wave (S wave) generated by the left ventricle and responsible for acceleration of flow in systole was significantly reduced in subjects with heart failure ( P < 0.001), and the timing of the peak of this wave was delayed. In contrast, reflection of this wave was increased in subjects with heart failure ( P < 0.001), but the timing of reflections with respect to the S wave was unchanged. The energy of an expansion wave generated by the heart in protodiastole was unaffected by heart failure. The carotid artery wave speed and the augmentation index did not significantly differ between subjects with heart failure compared with normal individuals. The ability of the left ventricle to generate a forward compression wave is markedly impaired in heart failure. Increased wave reflection serves to maintain systolic blood pressure but also places an additional load on cardiac function in heart failure.
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Endale, Mehari, H. Ibrahim Aksoylar, and Kasper Hoebe. "Central Role of Gimap5 in Maintaining Peripheral Tolerance and T Cell Homeostasis in the Gut." Mediators of Inflammation 2015 (2015): 1–11. http://dx.doi.org/10.1155/2015/436017.
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Inflammatory bowel disease (IBD) including Crohn’s disease and ulcerative colitis is often precipitated by an abnormal immune response to microbiota due to host genetic aberrancies. Recent studies highlight the importance of the host genome and microflora interactions in the pathogenesis of mucosal inflammation including IBD. Specifically, genome-wide (GWAS) and also next-generation sequencing (NGS)—including whole exome or genome sequencing—have uncovered a large number of susceptibility loci that predispose to autoimmune diseases and/or the two phenotypes of IBD. In addition, the generation of “IBD-prone” animal models using both reverse and forward genetic approaches has not only helped confirm the identification of susceptibility loci but also shed critical insight into the underlying molecular and cellular pathways that drive colitis development. In this review, we summarize recent findings derived from studies involving a novel early-onset model of colitis as it develops in GTPase of immunity-associated protein 5- (Gimap5-) deficient mice. In humans,GIMAP5has been associated with autoimmune diseases although its function is poorly defined. Here, we discuss how defects in Gimap5 function impair immunological tolerance and lymphocyte survival and ultimately drive the development of CD4+T cell-mediated early-onset colitis.
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Lindberg, Ylva. "The Power of the Periphery: Circulation of Cross-Cultured Languaging Through the Importation of Francophone Comics in the Nation-State of Sweden, 1900–2020." Bandung 9, no. 1-2 (February 24, 2022): 223–47. http://dx.doi.org/10.1163/21983534-09010009.
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Abstract The objective with this study is to shed light upon how international exchanges on the comic art market contribute to democratization processes and renegotiation of hegemonies in the literary field worldwide. The focus is on how the variation in imported comics from a central language, in this case French, to the peripheral space of Sweden, can be observed during the time-period 1900–2020, as well as on which diversity importation of comics has been allowed over time. Theoretically anchored in sociological perspectives in literary studies highly influenced by Casanova’s ([1999]2004) seminal work, this contribution challenges established approaches in the field that depart from central cultural spaces in the world. Instead, this analysis highlights how the periphery gains agency on the international market and challenges relations of domination through translation practices. One hypothesis put forward consists of the idea that Francophone author-illustrators from the global South would be identifiable in the data in 1990’s, as is the case in the literary field. However, in the comics field this change emerges later, and does not appear distinctively until 2005. The change is paired with a promotion of Francophone female author-illustrators in Swedish translations, equally from the global South and the global North. The results also highlight that Sweden positions the Francophone space as hyper-central within the comics field. The specific practices adopted in the importation point to how a periphery creates agency to define a medium and a genre locally and play a role in international cultural exchanges.
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Purcell, I. M., and A. A. Perachio. "Three-Dimensional Analysis of Vestibular Efferent Neurons Innervating Semicircular Canals of the Gerbil." Journal of Neurophysiology 78, no. 6 (December 1, 1997): 3234–48. http://dx.doi.org/10.1152/jn.1997.78.6.3234.
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Purcell, I. M. and A. A. Perachio. Three-dimensional analysis of vestibular efferent neurons innervating semicircular canals of the gerbil. J. Neurophysiol. 78: 3234–3248, 1997. Anterograde labeling techniques were used to examine peripheral innervation patterns of vestibular efferent neurons in the crista ampullares of the gerbil. Vestibular efferent neurons were labeled by extracellular injections of biocytin or biotinylated dextran amine into the contralateral or ipsilateral dorsal subgroup of efferent cell bodies (group e) located dorsolateral to the facial nerve genu. Anterogradely labeled efferent terminal field varicosities consist mainly of boutons en passant with fewer of the terminal type. The bouton swellings are located predominately in apposition to the basolateral borders of the afferent calyces and type II hair cells, but several boutons were identified close to the hair cell apical border on both types. Three-dimensional reconstruction and morphological analysis of the terminal fields from these cells located in the sensory neuroepithelium of the anterior, horizontal, and posterior cristae were performed. We show that efferent neurons densely innervate each end organ in widespread terminal fields. Subepithelial bifurcations of parent axons were minimal, with extensive collateralization occurring after the axons penetrated the basement membrane of the neuroepithelium. Axonal branching ranged between the 6th and 27th orders and terminal field collecting area far exceeds that of the peripheral terminals of primary afferent neurons. The terminal fields of the efferent neurons display three morphologically heterogeneous types: central, peripheral, and planum. All cell types possess terminal fields displaying a high degree of anisotropy with orientations typically parallel to or within ±45° of the longitudinal axis if the crista. Terminal fields of the central and planum zones predominately project medially toward the transverse axis from the more laterally located penetration of the basement membrane by the parent axon. Peripheral zone terminal fields extend predominately toward the planum semilunatum. The innervation areas of efferent terminal fields display a trend from smallest to largest for the central, peripheral, and planum types, respectively. Neurons that innervate the central zone of the crista do not extend into the peripheral or planum regions. Conversely, those neurons with terminal fields in the peripheral or planum regions do not innervate the central zone of the sensory neuroepithelium. The central zone of the crista is innervated preferentially by efferent neurons with cell bodies located in the ipsilateral group e. The peripheral and planum zones of the crista are innervated preferentially by efferent neurons with cell bodies located in the contralateral group e. A model incorporating our anatomic observations is presented describing an ipsilateral closed-loop feedback between ipsilateral efferent neurons and the periphery and an open-loop feed-forward innervation from contralateral efferent neurons. A possible role for the vestibular efferent neurons in the modulation of semicircular canal afferent response dynamics is proposed.
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Eigler, Friederike. "Moving Forward: New Perspectives on German-Polish Relations in Contemporary Europe." German Politics and Society 31, no. 4 (December 1, 2013): 1–15. http://dx.doi.org/10.3167/gps.2013.310401.
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Since the end of the Cold War and the reconfiguration of the map ofEurope, scholars across the disciplines have looked anew at the geopoliticaland geocultural dimensions of East Central Europe. Although geographicallyat the periphery of Eastern Europe, Germany and its changing discourseson the East have also become a subject of this reassessment inrecent years. Within this larger context, this special issue explores thefraught history of German-Polish border regions with a special focus oncontemporary literature and film.1 The contributions examine the representationof border regions in recent Polish and German literature (IreneSywenky, Claudia Winkler), filmic accounts of historical German and Polishlegacies within contemporary European contexts (Randall Halle, MeghanO’Dea), and the role of collective memory in contemporary German-Polishrelations (Karl Cordell). Bringing together scholars of Polish and Germanliterature and film, as well as political science, some of the contributionsalso ponder the advantages of regional and transnational approaches toissues that used to be discussed primarily within national parameters.
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Shields, Stuart. "The EBRD, fail forward neoliberalism and the construction of the European periphery." Economic and Labour Relations Review 31, no. 2 (April 29, 2020): 230–48. http://dx.doi.org/10.1177/1035304620916652.
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The European Bank for Reconstruction and Development is an institution, a set of programmes and policies designed to mark a number of important reforms not just in the post-Soviet space but in the wider European political economy. It is committed to developing a competitive business environment, foreign investment and private sector activity in the post-communist space. The European Bank for Reconstruction and Development is considered to be a key inter-state mechanism enabling member states to negotiate post-communist reforms. The paper reorients analysis of the European Bank for Reconstruction and Development, claiming that existing framings of the role of the EBRD ignore its tangible neoliberalising pressures. It argues that the EBRD works to fundamentally restructure states in the post-communist space in three ways: (1) the configuration of an ‘appropriately’ neoliberal economic space, (2) the construction of subaltern subjectivities in the regional space, and (3) the persistent dominance of expert knowledge and policy practice external to the state. This restructuring is intended to further neoliberalism in the economic space of the region. By uncoupling the European Bank for Reconstruction and Development from a state centric analysis, the paper reveals how the technical aspects of the European Bank for Reconstruction and Development activities configure particular neoliberal rationalities and competencies not as a putative superstate, but as a key site for the ever-deeper encroachment of neoliberalisation in peripheral European states. JEL Codes: P390, F550
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White, Morris F. "IRS proteins and the common path to diabetes." American Journal of Physiology-Endocrinology and Metabolism 283, no. 3 (September 1, 2002): E413—E422. http://dx.doi.org/10.1152/ajpendo.00514.2001.
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Although a full understanding of insulin/insulin-like growth factor (IGF) action is evolving, the discovery of insulin receptor substrate (IRS) proteins and their role to link cell surface receptors to the intracellular signaling cascades provided an important step forward. Moreover, Insulin/IGF receptors use common signaling pathways to accomplish many tasks, the IRS proteins add a unique layer of specificity and control. Importantly, the IRS-2 branch of the insulin/IGF-signaling pathway is a common element in peripheral insulin response and pancreatic β-cell growth and function. Failure of IRS-2 signaling might explain the eventual loss of compensatory hyperinsulinemia during prolonged periods of peripheral insulin resistance. Moreover, short-term inhibition of IRS protein functions by serine phosphorylation, or sustained inhibition by ubiquitin-targeted proteosome-mediated degradation suggests a common molecular mechanism for insulin resistance during acute injury or infection, or the sensitivity of β-cells to autoimmune destruction. The broad role of IRS-1 and IRS-2 in cell growth and survival reveals a common regulatory pathway linking development, somatic growth, fertility, neuronal proliferation, and aging to the core mechanisms used by vertebrates for nutrient sensing.
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Conner, James R., Irina I. Smirnova, and Alexander Poltorak. "Forward genetic analysis of Toll-like receptor responses in wild-derived mice reveals a novel antiinflammatory role for IRAK1BP1." Journal of Experimental Medicine 205, no. 2 (February 11, 2008): 305–14. http://dx.doi.org/10.1084/jem.20071499.
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Although inflammatory cytokines produced by activation of Toll-like receptors (TLRs) are essential for early host defense against infection, they also mediate a vast array of pathologies, including autoimmune disease, hypersensitivity reactions, and sepsis. Thus, numerous regulatory mechanisms exist in parallel with proinflammatory pathways to prevent excessive release of these potent effector molecules. We report elucidation of a novel regulatory function for interleukin receptor–associated kinase (IRAK)-1 binding protein 1 (IRAK1BP1, also known as SIMPL) through quantitative trait locus mapping of the TLR response in wild-derived mouse strains. This gene emerged as a negative regulator of TLR2-mediated interleukin (IL)-6 production in MOLF/Ei mice, which expressed IRAK1BP1 mRNA in an allele-specific manner when crossed with the C57BL/6J strain. Human peripheral blood mononuclear cells and primary macrophages from two other wild-derived mouse strains also induced IRAK1BP1 mRNA by 4 hours after stimulation with agonists of various TLRs. Examination of its effects on IL-6 and other cytokines demonstrated that IRAK1BP1 regulates transcription of a specific subset of TLR-responsive genes, producing an overall antiinflammatory profile. Our results reveal that IRAK1BP1 is a critical factor in preventing dangerous overproduction of proinflammatory cytokines by the innate immune system and in influencing the specificity of TLR responses. Furthermore, these results show that the genetic diversity of wild-derived mouse strains makes them a valuable model of important human gene functions that have been lost in some laboratory-inbred strains.
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Ueda, Hiroshi. "LPA receptor signaling as a therapeutic target for radical treatment of neuropathic pain and fibromyalgia." Pain Management 10, no. 1 (January 2020): 43–53. http://dx.doi.org/10.2217/pmt-2019-0036.
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Since the first discovery that the bioactive lipid, lysophosphatidic acid (LPA) and LPA1 receptor signaling play a role in the initiation of neuropathic pain (NeuP), accumulated reports have supported the original findings and extended the study toward possible therapeutic applications. The present review describes beneficial roles of LPA receptor signaling in a variety of chronic pain, such as peripheral NeuP induced by nerve injury, chemotherapy and diabetes, central NeuP induced by cerebral ischemia with hemorrhage and spinal cord injury, and fibromyalgia-like wide spread pain induced by repeated cold, psychological and muscular acidic stress. Emerging mechanistic findings are the feed-forward amplification of LPA production through LPA1, LPA3 and microglia and the evidence for maintenance of chronic pain by LPA receptor signaling.
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Chellappa, Rani C., Rani Palanisamy, and Karthikeyan Swaminathan. "RAGE Isoforms, its Ligands and their Role in Pathophysiology of Alzheimer’s Disease." Current Alzheimer Research 17, no. 14 (March 5, 2021): 1262–79. http://dx.doi.org/10.2174/1567205018666210218164246.
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Receptor for Advanced Glycation End product (RAGE) plays a crucial role in a variety of physiological and pathological processes due to its ability to bind a broad repertory of ligands. There are also multiple forms of RAGE that exist; some work on promoting feed-forward pathways while others perform inhibitory actions. This review focuses on the RAGE isoforms expression, its intracellular pathways activation via RAGE- ligand interaction, and its importance in the physiological and pathological process of the brain. Many studies have suggested that RAGE induces the pathophysiological changes in Alzheimer’s disease (AD) by being an intermediator of inflammation and inducer of oxidative stress. The critical roles played by RAGE in AD include its involvement in amyloid-beta (Aβ) production, clearance, synaptic impairment, and neuronal circuit dysfunction. RAGE-Aβ interaction also mediates the bi-directional crosstalk between peripheral and central systems. This interaction underlies a potential molecular pathway that disrupts the material structure and physiology of the brain. This review highlights the structure-function relation for RAGEAβ interaction and the role of RAGE as a potential target in the development of treatments for AD.
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Bidaye, Salil S., Till Bockemühl, and Ansgar Büschges. "Six-legged walking in insects: how CPGs, peripheral feedback, and descending signals generate coordinated and adaptive motor rhythms." Journal of Neurophysiology 119, no. 2 (February 1, 2018): 459–75. http://dx.doi.org/10.1152/jn.00658.2017.
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Walking is a rhythmic locomotor behavior of legged animals, and its underlying mechanisms have been the subject of neurobiological research for more than 100 years. In this article, we review relevant historical aspects and contemporary studies in this field of research with a particular focus on the role of central pattern generating networks (CPGs) and their contribution to the generation of six-legged walking in insects. Aspects of importance are the generation of single-leg stepping, the generation of interleg coordination, and how descending signals influence walking. We first review how CPGs interact with sensory signals from the leg in the generation of leg stepping. Next, we summarize how these interactions are modified in the generation of motor flexibility for forward and backward walking, curve walking, and speed changes. We then review the present state of knowledge with regard to the role of CPGs in intersegmental coordination and how CPGs might be involved in mediating descending influences from the brain for the initiation, maintenance, modification, and cessation of the motor output for walking. Throughout, we aim to specifically address gaps in knowledge, and we describe potential future avenues and approaches, conceptual and methodological, with the latter emphasizing in particular options arising from the advent of neurogenetic approaches to this field of research and its combination with traditional approaches.
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Kashkin, E., and Daria Mordashova. "Polysemy and grammaticalization of verbs of throwing: evidence from Hill Mari." Acta Linguistica Petropolitana XVI, no. 1 (August 2020): 494–520. http://dx.doi.org/10.30842/alp2306573716115.
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The paper deals with verbs of throwing in Hill Mari (Finno-Ugric). The data were collected in fieldwork mainly by elicitation, as well as by analyzing the corpus of transcribed oral narratives. First of all, two dominant lexemes of this semantic field are taken into account. These lexemes display clear differences in their Aktionsart properties. The differences between the lexemes with regard to a number of parameters previously proposed in typology are investigated, their relevance is evaluated. New parameters for their opposition are put forward. In addition, the article discusses the peripheral verbs of adjacent semantic fields (destruction and distribution in space). The correlations between more general distributive semantics of the peripheral lexemes and their semantic content in the contexts of throwing are considered. Special attention is paid to the grammaticalization of dominant verbs of throwing in complex verb constructions and to the analysis of their distributional constraints. Both the similarities between the constructions (participant with a semantic role of Patient, semantics of destruction) and the diff erences between them (constraints on plurality) are studied. Data on complex verb constructions are also discussed in the light of the cross-linguistic variation in the semantic shifts typical of the domain under consideration
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Ryan, Marnie A., Ellen Xing, David Schleimer, Kalpana Nattamai, Deidre Daria, Wei Liu, Michael Jansen, et al. "Pharmacological Inhibition of EGFR Signaling Enhances G-CSF Induced Hematopoietic Stem Cell Mobilization." Blood 112, no. 11 (November 16, 2008): 2337. http://dx.doi.org/10.1182/blood.v112.11.2337.2337.
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Abstract Mobilization of hematopoietic stem and progenitor cells (HSPCs) from bone marrow into peripheral blood by the cytokine G-CSF has become the preferred source of HSPCs for clinical stem cell transplants. However, up to 10% of donors fail to mobilize sufficient numbers of stem cells impeding autologous transplants or significantly delaying transplant recovery time. Consequently, novel regimens are warranted to increase the number of stem cells in peripheral blood upon mobilization. Using a forward genetic approach in the mouse, we map the epidermal growth factor receptor (EGFR) to a genetic region on murine chromosome 11 modifying G-CSF-mediated HSPC mobilization. Expression levels of EGFR in HSPCs were inversely correlated with HSPC mobilization, implying a negative role for EGFR signaling in mobilization. Genetic reduction of EGFR activity (waved2 mice) or treatment with the EGFR inhibitor erlotinib increased stem cell mobilization up to 5-fold in combination with G-CSF. Increased mobilization due do alteration of EGFR activity correlated with reduced activity of Cdc42 and consequently, inhibition of Cdc42 activity in vivo by a specific Cdc42 inhibitor similarly enhanced mobilization. Our findings reveal a novel signaling pathway regulating stem cell mobilization and thus provide new rationale for targeted pharmacological approaches to further improve HSPC mobilization and thus transplantation outcomes.
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Pinto, Jorge P., Vera Dias, Heinz Zoller, Pedro N. Rodrigues, Helena Carmo, Pedro Ramos, Félix Carvalho, Graça Porto, and Maria de Sousa. "Hepcidin: A Clue for a New Role for Lymphocytes." Blood 114, no. 22 (November 20, 2009): 1999. http://dx.doi.org/10.1182/blood.v114.22.1999.1999.
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Abstract Abstract 1999 Poster Board I-1021 Background: Recent evidence suggests the involvement of lymphocytes in the severity of iron overload disorders, with increased severity of iron overload in Hereditary Hemochromatosis patients and in animal models with lymphocyte number deficiencies. However, no mechanism(s) has been suggested to explain these observations. The aim of this study was to analyze hepcidin expression in lymphocytes. Methods: Expression of hepcidin was analyzed by Real-time PCR in human and mouse Peripheral Blood Lymphocytes (PBLs) and in selected resting lymphocyte populations, in response to holotransferrin and ferric citrate. The effect of hepcidin in the expression of the iron exporter Ferroportin was analyzed by FACS and confocal immunofluorescence. Cellular iron traffic was analyzed by measurement of 55Fe and 125I-TF, cell proliferation assessed by BrdU incorporation and silencing of gene expression in lymphocytes performed with siRNAs. Results: Hepcidin is expressed in PBLs and is up-regulated in response to holotransferrin and ferric citrate. The response to holotransferrin was observed in CD8+ and not in CD4+ lymphocytes, a result confirmed by the failure of lymphocytes from β2-microglobulin-KO mice to respond to holotransferrin, in comparison with Bl6/J controls. Hepcidin up-regulation induced by holotransferrin decreases ferroportin expression, inducing its co-localization with the proteasome marker LMP2. Tumor Necrosis Factor-á (TNF-á) expression in PBLs increases with holotransferrin treatments. siRNA-mediated silencing of TNF-á in PBLs abrogates hepcidin up-regulation by holotransferrin and incubation of PBLs with recombinant TNF-á increases hepcidin expression, suggesting the involvement of this cytokine in the basal and holotransferrin-induced hepcidin expression in these cells. The role of hepcidin in a situation of high iron demand - lymphocyte activation and proliferation - was assessed. Hepcidin expression increases with T-lymphocyte activation and siRNA-mediated silencing of hepcidin in activated T lymphocytes causes a decrease in intracellular iron levels, by increasing ferroportin-mediated iron export. The low intracellular iron levels were associated with impaired T lymphocyte proliferation. Discussion: The ability of PBLs to increase hepcidin expression in response to ferric citrate distinguishes lymphocytes from hepatocytes and places peripheral blood lymphocyte numbers as a first line of response to increases in transferrin saturation and presence of NTBI, characteristic of iron overload disorders. The findings that hepcidin modulates ferroportin expression, intracellular iron levels and cell proliferation in lymphocytes demonstrate the importance of this protein for lymphocyte iron homeostasis. The control of the intracellular iron levels of lymphocytes confers to hepcidin a pivotal role in the postulated ability of circulating lymphocytes to function as “biological iron chelators”. Conclusion: With the demonstration, for the first time, of hepcidin synthesis by peripheral blood lymphocytes, of its regulation by elemental iron and of its involvement in T cell proliferation, the present results put forward a molecular mechanism for the described modifier role of lymphocytes in protection from iron toxicity. Disclosures: No relevant conflicts of interest to declare.
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Marazziti, Donatella, Grazia Rutigliano, Stefano Baroni, Paola Landi, and Liliana Dell'Osso. "Metabolic syndrome and major depression." CNS Spectrums 19, no. 4 (October 8, 2013): 293–304. http://dx.doi.org/10.1017/s1092852913000667.
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Major depression is associated with a 4-fold increased risk for premature death, largely accounted by cardiovascular disease (CVD). The relationship between depression and CVD is thought to be mediated by the so-called metabolic syndrome (MeS). Epidemiological studies have consistently demonstrated a co-occurrence of depression with MeS components, ie, visceral obesity, dyslipidemia, insulin resistance, and hypertension. Although the exact mechanisms linking MeS to depression are unclear, different hypotheses have been put forward. On the one hand, MeS could be the hallmark of the unhealthy lifestyle habits of depressed patients. On the other, MeS and depression might share common alterations of the stress system, including the hypothalamus–pituitary–adrenal (HPA) axis, the autonomic nervous system, the immune system, and platelet and endothelial function. Both the conditions induce a low grade chronic inflammatory state that, in turn, leads to increased oxidative and nitrosative (O&NS) damage of neurons, pancreatic cells, and endothelium. Recently, neurobiological research revealed that peripheral hormones, such as leptin and ghrelin, which are classically involved in homeostatic energy balance, may play a role in mood regulation. Metabolic risk should be routinely assessed in depressed patients and taken into account in therapeutic decisions. Alternative targets should be considered for innovative antidepressant agents, including cytokines and their receptors, intracellular inflammatory mediators, glucocorticoids receptors, O&NS pathways, and peripheral mediators.
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Johnson, David C., Christine Ramos, Alex J. Szubert, Walter M. Gregory, J. Anthony Child, Faith E. Davies, Brian GM Durie, Brian G. Van Ness, and Gareth J. Morgan. "Genetic Variation in ADME Genes Is Associated with Thalidomide Related Peripheral Neuropathy in Multiple Myeloma Patients." Blood 112, no. 11 (November 16, 2008): 1675. http://dx.doi.org/10.1182/blood.v112.11.1675.1675.
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Abstract Peripheral neuropathy is a major adverse effect seen in multiple myeloma (MM) patients treated with thalidomide, with rates varying between trials from 15% to 70%. Peripheral neuropathy can often lead to ongoing impairment of quality of life and can lead to discontinuation of treatment. Identifying patients at risk of neuropathy and understanding its pathogenesis would be a significant step forward in the management of thalidomide based therapy. Proposed mechanisms have included: Anti-angiogeneic properties of thalidomide leading to a reduction in nerve blood supply; direct toxic effects of thalidomide on neurons of the posterior root ganglia and dysregulation of neurotrophin activity through effects of thalidomide on NFkB. Genetic variation in genes important in the mechanism of thalidomide neurotoxicity are likely to impact on whether an individual patient develops this adverse effect. Taking a nested case control approach we used peripheral blood DNA from 388 Caucasian MM patients all who had received induction thalidomide (200mg) as part of the Myeloma IX trial. Samples from 80 patients that developed sensory-motor peripheral neuropathy in response to thalidomide therapy were available for this analysis, these were age and sex matched with a ratio of one case to 4 controls. We assayed 3403 SNPs in coding and predicted regulatory regions selected in 1266 genes previously shown to be involved in the pathogenesis, treatment response and side effects associated with myeloma and its therapy. SNPs were present on a custom-built Affymetrix® targeted genotyping chip (designed by “Bank on a Cure” (BOAC)), which utilizes molecular inversion probe technologies. We carried out a univariate analysis by Fischer exact tests. Due to the large number of SNPs and relatively small number of samples, we chose to correct for multiple testing using label swapping permutation using the program PLINK. The most significant SNPs associated with thalidomide related peripheral neuropathy are listed with p=permutated empirical p-value and OR=Odds Ratio: ABCC2-Ile1324Ile (p<9.71×10−5;OR=1.972,1.39−2.8); DGKH-Ala1201Val (p<1.05×10−3;OR =4.267,1.85−9.87); EXO1-Arg354His (p<1.4×10−3;OR=1.79,1.25−2.55) and NPC2-3′UTR (p<1.6×10−3, OR=0.42,0.24−0.75). DGKH, EXO and NPC2 are genes previously reported to play a role in peripheral neurotoxicity. The ABCC2-Ile1324Ile SNP forms part of previously reported functional haplotype. Significant associations were also seen in a number of other ADME genes (drug absorption, distribution, metabolism, and excretion): ABCB1, ABCB11, ABCC1, CYP1A1, CYP20A1, CYP20A1, CYP2C9, CYP3A7, CYP4F2, FMO2, FMO3, FMO6, SLC12A6, SLC22A3 and SLC7A7. Significant associations were also seen in genes important in neurological system processes and central nervous system development: ERBB2, NQO1, MY03A, PPARD, DBH, NGFR, GSTP1, TCF8 and ICF1R. Our results indicate the importance of thalidomide dose and cumulative exposure, and highlight the metabolism of thalidomide as playing a pivotal role in dictating neuropathy events and open the way for predictive testing and dose adjustment. The results also implicate a direct toxicity mechanism for thalidomide related peripheral neuropathy, as we see a number of associations with SNPs in genes with known importance in peripheral neuron function.
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Braun, Scott A., Jason A. Sippel, Chung-Lin Shie, and Ryan A. Boller. "The Evolution and Role of the Saharan Air Layer during Hurricane Helene (2006)." Monthly Weather Review 141, no. 12 (November 25, 2013): 4269–95. http://dx.doi.org/10.1175/mwr-d-13-00045.1.
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Abstract The Saharan air layer (SAL) has received considerable attention in recent years as a potential negative influence on the formation and development of Atlantic tropical cyclones. Observations of substantial Saharan dust in the near environment of Hurricane Helene (2006) during the National Aeronautics and Space Administration (NASA) African Monsoon Multidisciplinary Activities (AMMA) Experiment (NAMMA) field campaign led to suggestions about the suppressing influence of the SAL in this case. In this study, a suite of satellite remote sensing data, global meteorological analyses, and airborne data are used to characterize the evolution of the SAL in the environment of Helene and assess its possible impact on the intensity of the storm. The influence of the SAL on Helene appears to be limited to the earliest stages of development, although the magnitude of that impact is difficult to determine observationally. Saharan dust was observed on the periphery of the storm during the first two days of development after genesis when intensification was slow. Much of the dust was observed to move well westward of the storm thereafter, with little SAL air present during the remainder of the storm's lifetime and with the storm gradually becoming a category-3 strength storm four days later. Dry air observed to wrap around the periphery of Helene was diagnosed to be primarily non-Saharan in origin (the result of subsidence) and appeared to have little impact on storm intensity. The eventual weakening of the storm is suggested to result from an eyewall replacement cycle and substantial reduction of the sea surface temperatures beneath the hurricane as its forward motion decreased.
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McGehee, Daniel V., Mireille Raby, and Gary E. Nourse. "Defining the Operator Interface of a Snowplow Lane Tracking System from Field Interviews and Surveys." Transportation Research Record: Journal of the Transportation Research Board 1700, no. 1 (January 2000): 38–44. http://dx.doi.org/10.3141/1700-07.
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Maintaining lane position during low-visibility conditions can be a challenge for snowplow operators. Providing continuous and accurate lane position information to complement existing roadway cues may be the solution to increasing driver awareness. The first phase of a systemsbased approach to designing the operator interface for a snowplow lane tracking system is described. Through a systems-based approach, not only can the type of controls and displays to use for the operator interface be better defined, but the interface’s role and the amount, type, and presentation of information can be determined. In this first phase, ridealong interviews and an operator survey were used to identify factors affecting forward visibility and lane position in snowplow operations. More than 1,000 department of transportation snowplow operators from Iowa and Minnesota completed the survey. Ride-along drives showed that operators frequently lose sight of the forward roadway for brief periods and use several cues to adjust the lane position of their vehicles. Survey findings indicated that center and shoulder lines are helpful and intuitive cues for left- and right-wing plow operations. Additional findings suggest that operators need a flexible system that enables them to adjust alarm thresholds and that the operator interface should be designed as an aid rather than as a primary display. Because drivers do not have the visual resources for a dedicated display, a peripheral visual or haptic (tactile) display could be used to complement existing roadway cues.
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Wang, Xin, Peiliang Wang, Zongxing Zhao, Qingfeng Mao, Jinming Yu, and Minghuan Li. "A review of radiation-induced lymphopenia in patients with esophageal cancer: an immunological perspective for radiotherapy." Therapeutic Advances in Medical Oncology 12 (January 2020): 175883592092682. http://dx.doi.org/10.1177/1758835920926822.
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Radiotherapy is a frequently utilized therapeutic modality in the treatment of esophageal cancer (EC). Even though extensive studies are carried out in radiotherapy for EC, the design of the clinical target volume and the radiation dose is not satisfactorily uniform. Radiotherapy acts as a double-edged sword on the immune system; it has both an immunostimulatory effect and an immunosuppressive effect. Radiation-induced lymphopenia and its potential association with tumor control and survival outcomes remain to be understood. The advent of immunotherapy has renewed the focus on preserving a pool of functioning lymphocytes in the circulation. In this review, we summarize the potential impact mechanisms of radiotherapy on peripheral blood lymphocytes and the prognostic role of radiation-induced lymphopenia in patients with EC. We also propose the concept of organs-at-risk of lymphopenia and discuss potential strategies to mitigate its effects on patients with EC. From an immunological perspective, we put forward the hypothesis that optimizing radiation modalities, radiation target volume schemes, and radiation doses could help to reduce radiation-induced lymphopenia risks and maximize the immunomodulatory role of radiotherapy. An optimized radiotherapy plan may further enhance the feasibility and effectiveness of combining immunotherapy with radiotherapy for EC.
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Liu, Peng, Xiao Zhang, Xiaolan He, Zhenhua Jiang, Qun Wang, and Yan Lu. "Spinal GABAergic neurons are under feed-forward inhibitory control driven by Aδ and C fibers in Gad2 td-Tomato mice." Molecular Pain 17 (January 2021): 174480692199262. http://dx.doi.org/10.1177/1744806921992620.
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Background Spinal GABAergic neurons act as a critical modulator in sensory transmission like pain or itch. The monosynaptic or polysynaptic primary afferent inputs onto GABAergic neurons, along with other interneurons or projection neurons make up the direct and feed-forward inhibitory neural circuits. Previous research indicates that spinal GABAergic neurons mainly receive excitatory inputs from Aδ and C fibers. However, whether they are controlled by other inhibitory sending signals is not well understood. Methods We applied a transgenic mouse line in which neurons co-expressed the GABA-synthesizing enzyme Gad65 and the enhanced red fluorescence (td-Tomato) to characterize the features of morphology and electrophysiology of GABAergic neurons. Patch-clamp whole cell recordings were used to record the evoked postsynaptic potentials of fluorescent neurons in spinal slices in response to dorsal root stimulation. Results We demonstrated that GABAergic neurons not only received excitatory drive from peripheral Aβ, Aδ and C fibers, but also received inhibitory inputs driven by Aδ and C fibers. The evoked inhibitory postsynaptic potentials (eIPSPs) mediated by C fibers were mainly Glycinergic (66.7%) as well as GABAergic mixed with Glycinergic (33.3%), whereas the inhibition mediated by Aδ fibers was predominately both GABA and Glycine-dominant (57.1%), and the rest of which was purely Glycine-dominant (42.9%). Conclusion These results indicated that spinal GABAergic inhibitory neurons are under feedforward inhibitory control driven by primary C and Aδ fibers, suggesting that this feed-forward inhibitory pathway may play an important role in balancing the excitability of GABAergic neurons in spinal dorsal horn.
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Gosetti, Giorgio. "Elementi per l'analisi di un altro modo di intendere e agire l'economico." SOCIOLOGIA DEL LAVORO, no. 113 (July 2009): 87–108. http://dx.doi.org/10.3280/sl2009-113009.
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- Social enterprise and health care in contemporary Great Britain: a new way forward? The essay focuses on the relationship between social enterprises and the health care service in contemporary Great Britain. After highlighting the characteristics of health care and the role of the third sector, also by means of past experiences, the authors underline the specificities of the two models which currently characterize the relationship between organizations of the third sector and the state: the one which presents the third sector as a relationship between centre (state) - periphery (third sector), a relationship of substantial dependency, and the one which underlines relationships of cooperation and social enterprises as a radical alternative to the relationship of dependence between the local state and the third sector.
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Tomatsu, Saeka, Takahiro Ishikawa, Yoshiaki Tsunoda, Jongho Lee, Donna S. Hoffman, and Shinji Kakei. "Information processing in the hemisphere of the cerebellar cortex for control of wrist movement." Journal of Neurophysiology 115, no. 1 (January 1, 2016): 255–70. http://dx.doi.org/10.1152/jn.00530.2015.
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A region of cerebellar lobules V and VI makes strong loop connections with the primary motor (M1) and premotor (PM) cortical areas and is assumed to play essential roles in limb motor control. To examine its functional role, we compared the activities of its input, intermediate, and output elements, i.e., mossy fibers (MFs), Golgi cells (GoCs), and Purkinje cells (PCs), in three monkeys performing wrist movements in two different forearm postures. The results revealed distinct steps of information processing. First, MF activities displayed temporal and directional properties that were remarkably similar to those of M1/PM neurons, suggesting that MFs relay near copies of outputs from these motor areas. Second, all GoCs had a stereotyped pattern of activity independent of movement direction or forearm posture. Instead, GoC activity resembled an average of all MF activities. Therefore, inhibitory GoCs appear to provide a filtering function that passes only prominently modulated MF inputs to granule cells. Third, PCs displayed highly complex spatiotemporal patterns of activity, with coordinate frames distinct from those of MF inputs and directional tuning that changed abruptly before movement onset. The complexity of PC activities may reflect rapidly changing properties of the peripheral motor apparatus during movement. Overall, the cerebellar cortex appears to transform a representation of outputs from M1/PM into different movement representations in a posture-dependent manner and could work as part of a forward model that predicts the state of the peripheral motor apparatus.
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Amin, Noopur, Patrick Gill, and Frédéric E. Theunissen. "Role of the Zebra Finch Auditory Thalamus in Generating Complex Representations for Natural Sounds." Journal of Neurophysiology 104, no. 2 (August 2010): 784–98. http://dx.doi.org/10.1152/jn.00128.2010.
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We estimated the spectrotemporal receptive fields of neurons in the songbird auditory thalamus, nucleus ovoidalis, and compared the neural representation of complex sounds in the auditory thalamus to those found in the upstream auditory midbrain nucleus, mesencephalicus lateralis dorsalis (MLd), and the downstream auditory pallial region, field L. Our data refute the idea that the primary sensory thalamus acts as a simple, relay nucleus: we find that the auditory thalamic receptive fields obtained in response to song are more complex than the ones found in the midbrain. Moreover, we find that linear tuning diversity and complexity in ovoidalis (Ov) are closer to those found in field L than in MLd. We also find prevalent tuning to intermediate spectral and temporal modulations, a feature that is unique to Ov. Thus even a feed-forward model of the sensory processing chain, where neural responses in the sensory thalamus reveals intermediate response properties between those in the sensory periphery and those in the primary sensory cortex, is inadequate in describing the tuning found in Ov. Based on these results, we believe that the auditory thalamic circuitry plays an important role in generating novel complex representations for specific features found in natural sounds.
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Yang, Jing, Man Qiao, Yanxia Li, Guohua Hu, Chunxia Song, Liping Xue, Hong Bai, Jie Yang, and Xi Yang. "Expansion of a Population of Large Monocytes (Atypical Monocytes) in Peripheral Blood of Patients with Acute Exacerbations of Chronic Obstructive Pulmonary Diseases." Mediators of Inflammation 2018 (2018): 1–13. http://dx.doi.org/10.1155/2018/9031452.
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Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is closely associated with airway inflammation including monocytes, lymphocytes, and neutrophils. Monocytes play an essential role in the pathogenesis of chronic obstructive pulmonary disease (COPD). To elucidate the association of circulating monocyte alteration with AECOPD, we analyzed monocyte subpopulation in the peripheral blood of 16 healthy volunteers and 22 AECOPD patients at the stages of admission and remission after clinical therapy. We found a dramatic increase of a previously unreported population of large size circulating atypical monocytes (A Mo) in AECOPD patients, characterized by higher forward scatter and lower side scatter values than the typical monocytes (T Mo) which were observed predominantly in healthy individuals. Further analysis showed that A Mo expressed higher levels of CD16, intercellular adhesion molecule 1 (ICAM-1), and chemotactic protein-1 receptor-2 (CCR2) than T Mo. In contrast, the expression of class II antigen (HLA-DR) by A Mo was lower than T Mo. More importantly, we observed that the percentage of circulating A Mo among total monocytes correlated with the length of hospital stay (time to remission) and disease duration. The data suggest that circulating A Mo might have the potential to serve as a biomarker in the diagnosis and prognosis of AECOPD.
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Baran, Jarołsaw, Danuta Kowalczyk, Mariola Oz˙óg, and Marek Zembala. "Three-Color Flow Cytometry Detection of Intracellular Cytokines in Peripheral Blood Mononuclear Cells: Comparative Analysis of Phorbol Myristate Acetate-Ionomycin and Phytohemagglutinin Stimulation." Clinical Diagnostic Laboratory Immunology 8, no. 2 (March 1, 2001): 303–13. http://dx.doi.org/10.1128/cdli.8.2.303-313.2001.
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ABSTRACT The assessment of intracellular cytokines at the single-cell level by flow cytometry has recently become a potent tool in many areas of cell biology and in defining the role of cytokines in various human diseases. Three-color flow cytometry for detection of intracellular cytokines combined with simultaneous determination of lymphocytes (CD3+ and CD4+) or monocytes (CD33+and CD14+) was used for comparison of phytohemagglutinin (PHA)-and phorbol myristate acetate (PMA)-ionomycin-induced production of intracellular cytokines in peripheral blood mononuclear cells (PBMCs) of healthy donors. We found that the number of PBMCs stained for tumor necrosis factor alpha and gamma interferon after 6 h of activation was higher when PMA-ionomycin was used for stimulation, while the frequencies of cells positive for interleukin 4 (IL-4) were similar for both stimulators. However, PMA-ionomycin stimulation caused prominent alterations of cell morphology and membrane expression of CD4 and CD14. In contrast, PHA did not cause downregulation of surface markers and resulted in less pronounced alterations in both forward and side scatter signals during flow cytometry analysis. Moreover, during 48 h of culture PHA stimulated tumor necrosis factor beta and IL-10 production, which was not observed when PMA-ionomycin was used. We conclude that the use of PHA for cell activation may limit in vitro artifacts and allow more precise analysis of intracellular cytokine production in various disease states.
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Andrade, Aroldo Leal de, and Cristiane Namiuti-Temponi. "Gone without the verb: clitic interpolation and clitic climbing in the history of European Portuguese." Cadernos de Estudos Lingüísticos 58, no. 2 (September 5, 2016): 201. http://dx.doi.org/10.20396/cel.v58i2.8647151.
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Previous studies have reported that clitic interpolation and clitic climbing change according to three stages in the history of European Portuguese. In this paper we develop the idea that these phenomena are deeply intertwined in the diachrony of Portuguese once they are related through the notion “clitic position” and reflect a general strategy for clitics to stay outside the focus domain of the clause. In order to provide a unified explanation for interpolation and climbing, we follow a quantitative methodology using the Tycho Brahe Corpus of Historical Portuguese. Moreover, developing some ideas about the Force-Fin system, in the Generative Grammar framework, we put forward a formal approach to the diachronic change having taken place between Old Portuguese and Classical Portuguese. Considering that clitic position reflects the category hosting the clitic, we argue that the availability of XP interpolation and of obligatory clitic climbing in Old Portuguese are different consequences of more basic structural principles, such as the V-to-Fin movement, which is dependent on the role of left-peripheral elements in the Old Portuguese grammar. Therefore the clitic could occur either in Force or in Fin, in order to mark the relative presuppositional nature of clitics with respect to different left-peripheral elements. In Classical Portuguese, we defend that XP interpolation paved the way for Neg interpolation because of the loss of V-to-Fin movement in embedded contexts; by then clitic climbing started to reflect a number of criteria related to topicality. Finally, in Modern European Portuguese, the gradual loss of Neg interpolation and the marked status of clitic climbing can be seen as further consequences of the loss of V-to-Fin movement.
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ZOU, Mimi. "Economic Development and the“Social Rights Hypothesis”: Regulating Labour Standards in China." Asian Journal of Law and Society 5, no. 2 (November 2018): 315–31. http://dx.doi.org/10.1017/als.2018.29.
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AbstractThis paper provides a critical account of the various roles that labour-law regulation has played in China’s transition to a market-oriented economy. The analysis aims to contribute new insights to an ongoing debate on the relationship between economic development and legal rules and institutions in China. Discussions of social and labour rights have been on the periphery of a debate that has focused on property and contract rights (the so-called “Rights Hypothesis”). While numerous scholars have sought to debunk the explanatory power of the “Rights Hypothesis” in the case of China, I put forward an alternative “Social Rights Hypothesis.” My proposed hypothesis seeks to explain how labour-law rules and institutions have co-evolved with the emergence of a labour market in China’s economic development. Specifically, labour law has played not only a market-constituting role, but also market-corrective and market-limiting functions.
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Chen, Yingxin, Jing Zhang, Pandu R. Tadikamalla, and Lei Zhou. "The Mechanism of Social Organization Participation in Natural Hazards Emergency Relief: A Case Study Based on the Social Network Analysis." International Journal of Environmental Research and Public Health 16, no. 21 (October 25, 2019): 4110. http://dx.doi.org/10.3390/ijerph16214110.
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The uncertainty and complexity of natural hazards put forward new requirements for emergency management systems. In order to deal with natural hazards effectively, it is important to build a cooperative network between government organizations and social organizations. The social network analysis method is adopted, the April 2013 Ya’an China earthquake is taken as a case study, the institutionalized emergency organization network before the disaster and the actual response organization network after the disaster are analyzed, and centrality, between centrality, closeness centrality and core-periphery are calculated. Through qualitative and quantitative research, the functions of social organization in the process of natural hazards emergency relief are revealed, the role orientation of social organization in the emergency management network is analyzed, and the influence factors of the social organization participation in the natural hazards relief is pointed out. Research results will help to promote the cooperation between social organization and government, and improve the efficiency of natural hazards emergency relief.
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Matsumura, Fumio, Shoichiro Ono, Yoshihiko Yamakita, Go Totsukawa, and Shigeko Yamashiro. "Specific Localization of Serine 19 Phosphorylated Myosin II during Cell Locomotion and Mitosis of Cultured Cells." Journal of Cell Biology 140, no. 1 (January 12, 1998): 119–29. http://dx.doi.org/10.1083/jcb.140.1.119.
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Phosphorylation of the regulatory light chain of myosin II (RMLC) at Serine 19 by a specific enzyme, MLC kinase, is believed to control the contractility of actomyosin in smooth muscle and vertebrate nonmuscle cells. To examine how such phosphorylation is regulated in space and time within cells during coordinated cell movements, including cell locomotion and cell division, we generated a phosphorylation-specific antibody. Motile fibroblasts with a polarized cell shape exhibit a bimodal distribution of phosphorylated myosin along the direction of cell movement. The level of myosin phosphorylation is high in an anterior region near membrane ruffles, as well as in a posterior region containing the nucleus, suggesting that the contractility of both ends is involved in cell locomotion. Phosphorylated myosin is also concentrated in cortical microfilament bundles, indicating that cortical filaments are under tension. The enrichment of phosphorylated myosin in the moving edge is shared with an epithelial cell sheet; peripheral microfilament bundles at the leading edge contain a higher level of phosphorylated myosin. On the other hand, the phosphorylation level of circumferential microfilament bundles in cell–cell contacts is low. These observations suggest that peripheral microfilaments at the edge are involved in force production to drive the cell margin forward while microfilaments in cell–cell contacts play a structural role. During cell division, both fibroblastic and epithelial cells exhibit an increased level of myosin phosphorylation upon cytokinesis, which is consistent with our previous biochemical study (Yamakita, Y., S. Yamashiro, and F. Matsumura. 1994. J. Cell Biol. 124:129–137). In the case of the NRK epithelial cells, phosphorylated myosin first appears in the midzones of the separating chromosomes during late anaphase, but apparently before the formation of cleavage furrows, suggesting that phosphorylation of RMLC is an initial signal for cytokinesis.
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Stanford, William L., Nicole M. Anderson, Zorana Milenkovic, Lia Zitano, Lee Adamson, Chen Wang, Myron Cybulsky, et al. "Dominant and Pharmacologically Sensitized ENU Mutagenesis Screens Uncover Novel Regulators of Hematopoiesis and Model Hematopoietic Disease." Blood 106, no. 11 (November 16, 2005): 1378. http://dx.doi.org/10.1182/blood.v106.11.1378.1378.
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Abstract To generate new mouse models of human hematopoietic disease and increase our knowledge of the genetic networks that control hematopoiesis, we are performing dominant (generation 1 or G1) and pharmacologically-sensitized forward ethylnitrososurea (ENU) mutagenesis screens. Mice are phenotyped by saphenous vein peripheral blood analysis using an automated hematological analyzer. ENU is ideally suited to generating models of human disease and annotating gene function because the spectrum of mutations (point mutations generating leading to subtle amino acid substitutions, splicing errors, or premature termination) are similar to those often found in human disease. Furthermore, null mutations often do not represent the full extent of a gene’s function, requiring multiple alleles to fully define gene function. While dominant mutations can unequivocally cause some human diseases, often mutations in multiple genes interact and contribute to disease progression. Thus, we have developed sensitized screens that induce transient cytopenias using various pharmacological agents (5-fluorouracil, phenylhydrazine, and hydroxyurea) and analyzing the recovery in peripheral blood levels of red blood cells, white blood cells and platelets. This strategy enables identification of hematopoietic mutants that do not present abnormal blood cell counts in a homeostatic state. The induced cytopenia recovery assay is also being used as a secondary phenotyping assay for some of our G1 dominant mutants. The combined dominant and sensitized screens have yielded 14 heritable dominant mutants to date plus four additional mutants in hereditary testing. The array of mutations that we are analyzing are models for the following diseases: polycythemia, thrombocythemia, leukocytosis, anemia, and thrombocytopenia. I will discuss the progress of the mutagenesis screen and several ENU mutants, including a novel mutation in the protein tyrosine kinase Jak2, leading to thrombocythemia. This point mutation in the protein kinase domain will help us to dissect the recently discovered role of Jak2 in Myeloproliferative Diseases including Essential Thrombocythemia.
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Pellegrini, Cinzia, Beatrice Casadei, Enrico Derenzini, Alessandro Broccoli, Vittorio Stefoni, Letizia Gandolfi, Federica Quirini, Lisa Argnani, and Pier Luigi Zinzani. "The Role of Interim-PET and Final-PET in the Outcome of Peripheral T-Cell Lymphoma (PTCL) Treated At the Diagnosis with CHOP." Blood 120, no. 21 (November 16, 2012): 2721. http://dx.doi.org/10.1182/blood.v120.21.2721.2721.
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Abstract Abstract 2721 Role of interim- and final-PET in peripheral T-cell lymphoma (PTCL) is quite unknown. To determine predictive value of PET on overall survival (OS), we evaluated interim-PET (i-PET) and final-PET (f-PET) in PTCL patients treated in first-line with 6 CHOP-21 courses. From September 2003 to July 2010 we diagnosed and treated in our institution 34 advanced stage PTCL patients (15 females and 19 males). The median age at diagnosis was 46 years (range, 21–81 years); 9 patients were in stage III, and 25 in stage IV. According to the histologic subtype there were 11 PTCL-nos, 6 AILT, 9 ALCL Alk+, 6 ALCL Alk-, and 2 NK/T nasal type patients. Four patients had bulky disease; eight patients had bone marrow involvement, 15 patients had 1 extranodal involvement and 10 had more than 2 extranodal sites. All patients underwent initial staging PET/CT; i-PET was performed after 3 cycles of CHOP-21 and the median time from the end of third course to i-PET was 14 days (range, 7– 18 days). f-PET scans were performed 35 days (range, 30– 45 days) after the end of therapy. The table summarizes the correspondence between i-PET and f-PET results: N=34 f-PET negative, n (%) f-PET positive, n (%) i-PET negative 27 19 (70.4) 8 (29.6) i-PET positive 7 1 (14.2) 6 (85.8) With a median follow-up of 71 months (range, 5.8–120.9 months), 17/19 (89.5%) patients with i-PET negative are in continuous CR (CCR) and only 1/7 (14.2%) patient with i-PET positive is still in CCR. Figures show the overall survival (OS) according to response at i-PET and f-PET. In figure 1a we observe OS plotted according to i-PET results: 78.6% for negative patients (solid line) and 21.4% for positive patients (dashed line) at 88.7 months (p=0.02); in figure 1b we observe OS plotted according to f-PET results: 93.7% for negative patients (solid line) and 21.4% for positive patients (dashed line) (p<0.0001). In conclusion, our results demonstrate that positive i-PET is not predictive of a worse outcome in PTCL. On the contrary, the f-PET seems to represent a significant step forward in the prediction of survival for these patients. Larger and prospective studies and harmonization of PET reading criteria are needed. Disclosures: No relevant conflicts of interest to declare.
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Ueno, Moeko, Ichiro Uchiyama, Joseph J. Campos, David I. Anderson, Minxuan He, and Audun Dahl. "Crawling Experience Relates to Postural and Emotional Reactions to Optic Flow in a Virtual Moving Room." Journal of Motor Learning and Development 6, s1 (April 2018): S63—S75. http://dx.doi.org/10.1123/jmld.2016-0063.
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Infants show a dramatic shift in postural and emotional responsiveness to peripheral lamellar optic flow (PLOF) following crawling onset. The present study used a novel virtual moving room to assess postural compensation of the shoulders backward and upward and heart rate acceleration to PLOF specifying a sudden horizontal forward translation and a sudden descent down a steep slope in an infinitely long virtual tunnel. No motion control conditions were also included. Participants were 53 8.5-month-old infants: 25 prelocomotors and 28 hands-and-knees crawlers. The primary findings were that crawling infants showed directionally appropriate postural compensation in the two tunnel motion conditions, whereas prelocomotor infants were minimally responsive in both conditions. Similarly, prelocomotor infants showed nonsignificant changes in heart rate acceleration in the tunnel motion conditions, whereas crawling infants showed significantly higher heart rate acceleration in the descent condition than in the descent control condition, and in the descent condition than in the horizontal translation condition. These findings highlight the important role played by locomotor experience in the development of the visual control of posture and in emotional reactions to a sudden optically specified drop. The virtual moving room is a promising paradigm for exploring the development of perception–action coupling.
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Maria Victoria, Crespo. "Revisiting Raúl Prebisch’s concept of crisis." Latin-american Historical Almanac 28, no. 1 (November 9, 2020): 145–64. http://dx.doi.org/10.32608/2305-8773-2020-28-1-145-164.
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This article offers a review and appraisal of the concept of crisis in the context of the remarkable trajectory and works of argentine economist Raul Prebisch. It argues that the crisis of the 1930s is the foundation of Prebisch’s theoretical proposal on dependency and development in Lat-in America. The crisis of 1929-1930 was the turning point that encour-aged him to revise and reinvent neoclassical economic theory, promote industrialization and import substitution, and, more importantly, to deeply restructure the role of the State in the region. The crisis leads to decision and action, and it implies and orientation towards the future, a new “horizon of expectations.” This horizon throughout the most part of the twentieth century in Latin America was development. The article also puts forward an interpretation of his program at the Economic Commission for Latin America and the Caribbean (ECLAC/CEPAL), also triggered by the crisis and oriented to the formulation of policies meant to overcome the crisis. Finally, the article shows how through his interactions with CEPAL sociologists, in particular José Medina Echavarría, Prebisch proposes a redefinition of his concept of crisis, shifting from an economic and junctural concept to a structural one: the crisis of peripheral capitalism
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Dabin, Luke C., Fernando Guntoro, Tracy Campbell, Tony Bélicard, Adam R. Smith, Rebecca G. Smith, Rachel Raybould, et al. "Altered DNA methylation profiles in blood from patients with sporadic Creutzfeldt–Jakob disease." Acta Neuropathologica 140, no. 6 (September 12, 2020): 863–79. http://dx.doi.org/10.1007/s00401-020-02224-9.
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AbstractPrion diseases are fatal and transmissible neurodegenerative disorders caused by the misfolding and aggregation of prion protein. Although recent studies have implicated epigenetic variation in common neurodegenerative disorders, no study has yet explored their role in human prion diseases. Here we profiled genome-wide blood DNA methylation in the most common human prion disease, sporadic Creutzfeldt–Jakob disease (sCJD). Our case–control study (n = 219), when accounting for differences in cell type composition between individuals, identified 38 probes at genome-wide significance (p < 1.24 × 10–7). Nine of these sites were taken forward in a replication study, performed in an independent case–control (n = 186) cohort using pyrosequencing. Sites in or close to FKBP5, AIM2 (2 probes), UHRF1, KCNAB2 successfully replicated. The blood-based DNA methylation signal was tissue- and disease-specific, in that the replicated probe signals were unchanged in case–control studies using sCJD frontal-cortex (n = 84), blood samples from patients with Alzheimer’s disease, and from inherited and acquired prion diseases. Machine learning algorithms using blood DNA methylation array profiles accurately distinguished sCJD patients and controls. Finally, we identified sites whose methylation levels associated with prolonged survival in sCJD patients. Altogether, this study has identified a peripheral DNA methylation signature of sCJD with a variety of potential biomarker applications.
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Redinger, Richard N. "The Role of the Enterohepatic Circulation of Bile Salts and Nuclear Hormone Receptors in the Regulation of Cholesterol Homeostasis: Bile Salts as Ligands for Nuclear Hormone Receptors." Canadian Journal of Gastroenterology 17, no. 4 (2003): 265–71. http://dx.doi.org/10.1155/2003/190784.
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The coordinated effect of lipid activated nuclear hormone receptors; liver X receptor (LXR), bound by oxysterol ligands and farnesoid X receptor (FXR), bound by bile acid ligands, act as genetic transcription factors to cause feed-forward cholesterol catabolism to bile acids and feedback repression of bile acid synthesis, respectively. It is the coordinated action of LXR and FXR, each dimerized to retinoid X receptor, that signal nuclear DNA response elements to encode proteins that prevent excessive cholesterol accumulation and bile salt toxicity, respectively. LXR helps prevent hypercholesterolemia by enhancing transporters for cholesterol efflux that enhance reverse cholesterol transport, while FXR enhances intestinal reabsorption and preservation of bile salts by increasing the ileal bile acid binding protein. FXR also targets sodium taurocholate cotransport peptide and bile salt export pump (protein) genes to limit bile salt uptake and enhance export, respectively, which prevents bile salt toxicity. Other nuclear hormone receptors such as pregnan X receptor, which share the obligate partner, retinoid X receptor, and vitamin D receptor also function as bile acid sensors to signal detoxification by hydroxylation of toxic bile acids. Pharmacologically targeted receptor agonists (or antagonists) may be developed that alter cholesterol and bile salt concentrations by modulating nuclear hormone receptors and/or their coactivators or corepressors to positively affect cholesterol homeostasis and bile salt metabolism. It is the coordinated transcription factor action of LXR, which responds to ligand binding of circulating oxysterols in both liver and peripheral tissues, and FXR responding to bile salts within the enterohepatic circulation that make possible the regulation of cholesterol and bile acid homeostasis.
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Isik, Ali. "Exploring How ELT Teachers Perceive and Practice English Language Assessment." Journal of Language and Education, no. 1 (March 31, 2021): 111–29. http://dx.doi.org/10.17323/jle.2021.10296.
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As a well-designed language education program naturally requires a well-designed assessment component, the pivotal role of assessment in language education needs to be stressed. This study focuses on how English language teaching (ELT) teachers receive training in English language assessment, and how they perceive and practice assessment in Turkey. The study was conducted with the participation of 198 ELT teachers from 24 K-12 level schools and eight universities. A mixed-methods research design was chosen and the data were collected through a questionnaire, follow-up interviews, observations, personal conversations, and sample exam evaluations. The findings indicated that the assessment practices of the teachers were shaped by the teachers’ language learning and teaching experiences, their intuition, adherence to assessment traditions, and the emulation of what other teachers conducted to conform to group norms. It was also observed that as the teachers did not receive proper pre-service and in-service assessment training, their assessment knowledge was low. Moreover, it was found that the assessment component of teacher training programs remained peripheral and did not help equip teachers with assessment-related theoretical knowledge and practical skills. Finally, the assessment quality in these schools was found to be low and assessment was taken as a formal requirement to grade students. In the final part of the paper, some suggestions for effective assessment are put forward.
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Jastrząb, Mariusz. "Issues concerning relations between business and society in teaching Business History in the United States and Poland." Annales. Etyka w Życiu Gospodarczym 21, no. 6 (March 25, 2018): 99–120. http://dx.doi.org/10.18778/1899-2226.21.6.08.
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Based on empirical material in the form of case studies prepared at Harvard Business School and Kozminski University, the article analyses the content of teaching materials in the field of business history. The Harvard case studies served as a model for the Polish ones. In contrast to the United States, at Kozminski University and in other Polish business schools, business history is not taught as a separate subject. The article puts forward the thesis that history education could provide an opportunity for future managers to broaden their knowledge of the social environment in which they will operate and to shape attitudes of responsibility for the social consequences of decisions made. However, this opportunity remains largely untapped in both the United States and Poland. American teaching materials are still influenced by the Chandlerian paradigm, and therefore they focus on the evolution of structures and changes in the strategy of large multinational corporations. These materials present students with role models of successful entrepreneurs and companies. Their social environment is presented in a sketchy manner, and questions about the motivations of human actions or hierarchies of values are rarely asked. The teaching materials also shy away from questions about the social consequences of managerial decisions. This is so, despite the fact that scientific publications are moving away from concentrating solely on the centre of global capitalism, the history of the largest corporations, and the treatment of the social environment as a variable on which the entrepreneur or company have no influence. Business history as a scientific discipline in Poland is still at an early stage of development. However, one can notice a gap between research and teaching similar to the one that exists in the USA: there are works critically analysing the period of transformation and showing the peripheral character of Polish capitalism as well as the social consequences of this peripheral nature that are completely ignored in teaching.
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Fonin, Alexander V., Sergey A. Silonov, Olesya G. Shpironok, Iuliia A. Antifeeva, Alexey V. Petukhov, Anna E. Romanovich, Irina M. Kuznetsova, Vladimir N. Uversky, and Konstantin K. Turoverov. "The Role of Non-Specific Interactions in Canonical and ALT-Associated PML-Bodies Formation and Dynamics." International Journal of Molecular Sciences 22, no. 11 (May 29, 2021): 5821. http://dx.doi.org/10.3390/ijms22115821.
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In this work, we put forward a hypothesis about the decisive role of multivalent nonspecific interactions in the early stages of PML body formation. Our analysis of the PML isoform sequences showed that some of the PML isoforms, primarily PML-II, are prone to phase separation due to their polyampholytic properties and the disordered structure of their C-terminal domains. The similarity of the charge properties of the C-terminal domains of PML-II and PML-VI isoforms made it possible for the first time to detect migration of PML-VI from PML bodies to the periphery of the cell nucleus, similar to the migration of PML-II isoforms. We found a population of “small” (area less than 1 µm2) spherical PML bodies with high dynamics of PML isoforms exchange with nucleoplasm and a low fraction of immobilized proteins, which indicates their liquid state properties. Such structures can act as “seeds” of functionally active PML bodies, providing the necessary concentration of PML isoforms for the formation of intermolecular disulfide bonds between PML monomers. FRAP analysis of larger bodies of toroidal topology showed the existence of an insoluble scaffold in their structure. The hypothesis about the role of nonspecific multiple weak interactions in the formation of PML bodies is further supported by the change in the composition of the scaffold proteins of PML bodies, but not their solidification, under conditions of induction of dimerization of PML isoforms under oxidative stress. Using the colocalization of ALT-associated PML bodies (APBs) with TRF1, we identified APBs and showed the difference in the dynamic properties of APBs and canonical PML bodies.
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VARDAR, Filiz, and Meral ÜNAL. "Immunolocalization of Lipoxygenase in the Anther Wall Cells of Lathyrus undulatus Boiss. during Programmed Cell Death." Notulae Botanicae Horti Agrobotanici Cluj-Napoca 39, no. 1 (May 30, 2011): 71. http://dx.doi.org/10.15835/nbha3915865.
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Lipoxygenase catalyzes oxygenation of long chain fatty acids to hydroperoxides and is involved in the degradation of membranes occuring in some types of programmed cell death (PCD). The localization of lipoxygenase in the anther wall layers of L. undulatus during cellular degradation was analyzed by immunogold labeling technique at young and vacuolated pollen stage, due to the close relation between lipoxygenase activity and membrane degradation in programmed cell death. Immunoreaction to lipoxygenase was monitored slightly at young pollen stage in the anther wall cells. As programmed cell death signals progress, lipoxygenase revealed in anther wall cells intensely. At vacuolated pollen stage tapetal cells came forward with ultrastructural changes such as cell, organelle and membrane disintegration. At the indicated stage immunogold particles indicating sites of LOX PAb-binding epitopes were located in the nucleus (chromatin was condensed and lined at the periphery), cytoplasm and close to long dilated rough endoplasmic reticulum (RER) cisterna. In conclusion lipoxygenase increase which has a role in the membrane degeneration, possibly induced the collapse of tonoplast, nuclear and plasma membrane and triggered programmed cell death in the tapetal cells of L. undulatus as well as the other wall cells.
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Gray, Sarah M., and Eugene J. Barrett. "Insulin transport into the brain." American Journal of Physiology-Cell Physiology 315, no. 2 (August 1, 2018): C125—C136. http://dx.doi.org/10.1152/ajpcell.00240.2017.
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While there is a growing consensus that insulin has diverse and important regulatory actions on the brain, seemingly important aspects of brain insulin physiology are poorly understood. Examples include: what is the insulin concentration within brain interstitial fluid under normal physiologic conditions; whether insulin is made in the brain and acts locally; does insulin from the circulation cross the blood-brain barrier or the blood-CSF barrier in a fashion that facilitates its signaling in brain; is insulin degraded within the brain; do privileged areas with a “leaky” blood-brain barrier serve as signaling nodes for transmitting peripheral insulin signaling; does insulin action in the brain include regulation of amyloid peptides; whether insulin resistance is a cause or consequence of processes involved in cognitive decline. Heretofore, nearly all of the studies examining brain insulin physiology have employed techniques and methodologies that do not appreciate the complex fluid compartmentation and flow throughout the brain. This review attempts to provide a status report on historical and recent work that begins to address some of these issues. It is undertaken in an effort to suggest a framework for studies going forward. Such studies are inevitably influenced by recent physiologic and genetic studies of insulin accessing and acting in brain, discoveries relating to brain fluid dynamics and the interplay of cerebrospinal fluid, brain interstitial fluid, and brain lymphatics, and advances in clinical neuroimaging that underscore the dynamic role of neurovascular coupling.
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Opdebeeck, Britt, Patrick C. D’Haese, and Anja Verhulst. "Molecular and Cellular Mechanisms that Induce Arterial Calcification by Indoxyl Sulfate and P-Cresyl Sulfate." Toxins 12, no. 1 (January 19, 2020): 58. http://dx.doi.org/10.3390/toxins12010058.
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The protein-bound uremic toxins, indoxyl sulfate (IS) and p-cresyl sulfate (PCS), are considered to be harmful vascular toxins. Arterial media calcification, or the deposition of calcium phosphate crystals in the arteries, contributes significantly to cardiovascular complications, including left ventricular hypertrophy, hypertension, and impaired coronary perfusion in the elderly and patients with chronic kidney disease (CKD) and diabetes. Recently, we reported that both IS and PCS trigger moderate to severe calcification in the aorta and peripheral vessels of CKD rats. This review describes the molecular and cellular mechanisms by which these uremic toxins induce arterial media calcification. A complex interplay between inflammation, coagulation, and lipid metabolism pathways, influenced by epigenetic factors, is crucial in IS/PCS-induced arterial media calcification. High levels of glucose are linked to these events, suggesting that a good balance between glucose and lipid levels might be important. On the cellular level, effects on endothelial cells, which act as the primary sensors of circulating pathological triggers, might be as important as those on vascular smooth muscle cells. Endothelial dysfunction, provoked by IS and PCS triggered oxidative stress, may be considered a key event in the onset and development of arterial media calcification. In this review a number of important outstanding questions such as the role of miRNA’s, phenotypic switching of both endothelial and vascular smooth muscle cells and new types of programmed cell death in arterial media calcification related to protein-bound uremic toxins are put forward and discussed.
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Kumar, Prem. "Sensing hypoxia in the carotid body: from stimulus to response." Essays in Biochemistry 43 (August 10, 2007): 43–60. http://dx.doi.org/10.1042/bse0430043.
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The carotid body is a peripheral sensory organ that can transduce modest falls in the arterial PO2 (partial pressure of oxygen) into a neural signal that provides the afferent limb of a set of stereotypic cardiorespiratory reflexes that are graded according to the intensity of the stimulus. The stimulus sensed is tissue PO2 and this can be estimated to be around 50 mmHg during arterial normoxia, falling to between 10–40 mmHg during hypoxia. The chemoafferent hypoxia stimulus-response curve is exponential, rising in discharge frequency with falling PO2, and with no absolute threshold apparent in hyperoxia. Although the oxygen sensor has not been definitely identified, it is believed to reside within type I cells of the carotid body, and presently two major hypotheses have been put forward to account for the sensing mechanism. The first relies upon alterations in the cell energy status that is sensed by the cytosolic enzyme AMPK (AMP-activated protein kinase) subsequent to hypoxia-induced increases in the cellular AMP/ATP ratio during hypoxia. AMPK is localized close to the plasma membrane and its activation can inhibit both large conductance, calcium-activated potassium (BK) and background, TASK-like potassium channels, inducing membrane depolarization, voltage-gated calcium entry and neurosecretion of a range of transmitter and modulator substances, including catecholamines, ATP and acetylcholine. The alternative hypothesis considers a role for haemoxygenase-2, which uses oxygen as a substrate and may act to gate an associated BK channel through the action of its products, carbon monoxide and possibly haem. It is likely however, that these and other hypotheses of oxygen transduction are not mutually exclusive and that each plays a role, via its own particular sensitivity, in shaping the full response of this organ between hyperoxia and anoxia.