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1
Petrenko, Volodymyr, and Charna Dibner. "Circadian orchestration of insulin and glucagon release." Cell Cycle 16, no. 12 (2017): 1141–42. http://dx.doi.org/10.1080/15384101.2017.1326768.
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Minns, Danielle, Katie Jane Smith, and Emily Gwyer Findlay. "Orchestration of Adaptive T Cell Responses by Neutrophil Granule Contents." Mediators of Inflammation 2019 (March 10, 2019): 1–15. http://dx.doi.org/10.1155/2019/8968943.
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Neutrophils are the most abundant leukocytes in peripheral blood and respond rapidly to danger, infiltrating tissues within minutes of infectious or sterile injury. Neutrophils were long thought of as simple killers, but now we recognise them as responsive cells able to adapt to inflammation and orchestrate subsequent events with some sophistication. Here, we discuss how these rapid responders release mediators which influence later adaptive T cell immunity through influences on DC priming and directly on the T cells themselves. We consider how the release of granule contents by neutrophils—through NETosis or degranulation—is one way in which the innate immune system directs the phenotype of the adaptive immune response.
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Karampini, Ellie, Ruben Bierings, and Jan Voorberg. "Orchestration of Primary Hemostasis by Platelet and Endothelial Lysosome-Related Organelles." Arteriosclerosis, Thrombosis, and Vascular Biology 40, no. 6 (2020): 1441–53. http://dx.doi.org/10.1161/atvbaha.120.314245.
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Megakaryocyte-derived platelets and endothelial cells store their hemostatic cargo in α- and δ-granules and Weibel-Palade bodies, respectively. These storage granules belong to the lysosome-related organelles (LROs), a heterogeneous group of organelles that are rapidly released following agonist-induced triggering of intracellular signaling pathways. Following vascular injury, endothelial Weibel-Palade bodies release their content into the vascular lumen and promote the formation of long VWF (von Willebrand factor) strings that form an adhesive platform for platelets. Binding to VWF strings as well as exposed subendothelial collagen activates platelets resulting in the release of α- and δ-granules, which are crucial events in formation of a primary hemostatic plug. Biogenesis and secretion of these LROs are pivotal for the maintenance of proper hemostasis. Several bleeding disorders have been linked to abnormal generation of LROs in megakaryocytes and endothelial cells. Recent reviews have emphasized common pathways in the biogenesis and biological properties of LROs, focusing mainly on melanosomes. Despite many similarities, LROs in platelet and endothelial cells clearly possess distinct properties that allow them to provide a highly coordinated and synergistic contribution to primary hemostasis by sequentially releasing hemostatic cargo. In this brief review, we discuss in depth the known regulators of α- and δ-granules in megakaryocytes/platelets and Weibel-Palade bodies in endothelial cells, starting from transcription factors that have been associated with granule formation to protein complexes that promote granule maturation. In addition, we provide a detailed view on the interplay between platelet and endothelial LROs in controlling hemostasis as well as their dysfunction in LRO related bleeding disorders.
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Wang, Xiaogang, William J. Eagen, and Jean C. Lee. "Orchestration of human macrophage NLRP3 inflammasome activation by Staphylococcus aureus extracellular vesicles." Proceedings of the National Academy of Sciences 117, no. 6 (2020): 3174–84. http://dx.doi.org/10.1073/pnas.1915829117.
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Release of extracellular vesicles (EVs) is a common feature among eukaryotes, archaea, and bacteria. However, the biogenesis and downstream biological effects of EVs released from gram-positive bacteria remain poorly characterized. Here, we report that EVs purified from a community-associated methicillin-resistant Staphylococcus aureus strain were internalized into human macrophages in vitro and that this process was blocked by inhibition of the dynamin-dependent endocytic pathway. Human macrophages responded to S. aureus EVs by TLR2 signaling and activation of NLRP3 inflammasomes through K+ efflux, leading to the recruitment of ASC and activation of caspase-1. Cleavage of pro–interleukin (IL)-1β, pro-IL-18, and gasdermin-D by activated caspase-1 resulted in the cellular release of the mature cytokines IL-1β and IL-18 and induction of pyroptosis. Consistent with this result, a dose-dependent cytokine response was detected in the extracellular fluids of mice challenged intraperitoneally with S. aureus EVs. Pore-forming toxins associated with S. aureus EVs were critical for NLRP3-dependent caspase-1 activation of human macrophages, but not for TLR2 signaling. In contrast, EV-associated lipoproteins not only mediated TLR2 signaling to initiate the priming step of NLRP3 activation but also modulated EV biogenesis and the toxin content of EVs, resulting in alterations in IL-1β, IL-18, and caspase-1 activity. Collectively, our study describes mechanisms by which S. aureus EVs induce inflammasome activation and reveals an unexpected role of staphylococcal lipoproteins in EV biogenesis. EVs may serve as a novel secretory pathway for S. aureus to transport protected cargo in a concentrated form to host cells during infections to modulate cellular functions.
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Almutairi, Jaber, and Mohammad Aldossary. "Modeling and Analyzing Offloading Strategies of IoT Applications over Edge Computing and Joint Clouds." Symmetry 13, no. 3 (2021): 402. http://dx.doi.org/10.3390/sym13030402.
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Internet of Things (IoT) is swiftly evolving into a disruptive technology in recent years. For enhancing customer experience and accelerating job execution, IoT task offloading enables mobile end devices to release heavy computation and storage to the resource-rich nodes in collaborative Edges or Clouds. However, how different service architecture and offloading strategies quantitatively impact the end-to-end performance of IoT applications is still far from known particularly given a dynamic and unpredictable assortment of interconnected virtual and physical devices. This paper exploits potential network performance that manifests within the edge-cloud environment, then investigates and compares the impacts of two types of architectures: Loosely-Coupled (LC) and Orchestrator-Enabled (OE). Further, it introduces three customized offloading strategies in order to handle various requirements for IoT latency-sensitive applications. Through comparative experiments, we observed that the computational requirements exerts more influence on the IoT application’s performance compared to the communication requirement. However, when the system scales up to accommodate more IoT devices, communication bandwidth will turn to be the dominant resource and becomes the essential factor that will directly impact the overall performance. Thus, orchestration is a necessary procedure to encompass optimized solutions under different constraints for optimal offloading placement.
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Oliveira, Douglas Souza, Jean Gabriel de Souza, Miryam Paola Alvarez-Flores та ін. "Lonomia obliqua Venom Induces NF-κB Activation and a Pro-Inflammatory Profile in THP-1-Derived Macrophage". Toxins 13, № 7 (2021): 462. http://dx.doi.org/10.3390/toxins13070462.
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Envenomation caused by contact with Lonomia obliqua bristles is characterized by pain, an intense systemic proinflammatory reaction and disturbances in the coagulation cascade that can cause severe clinical manifestations and death. However, the role of immune system components in these effects is still poorly understood. In this study, we evaluated the cytotoxic effect of L. obliqua venom on THP-1-derived macrophages and its ability to modulate inflammatory markers, as well as the cytokine and chemokine release profile. Our results show that L. obliqua venom is able to directly exert a potent pro-inflammatory reaction in macrophages, characterized by the activation of the NF-κB transcription factor pathway, the expression of CD80 and CD83, and the release of pro-inflammatory mediators such as TNF-α, IL-1β, IL-6, IL-8 and CXCL10. These results suggest that macrophages can play an important role during the orchestration of the inflammatory response present in envenomation caused by Lonomia obliqua caterpillars.
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Yu, Bin, Yizhe Tang, and Dongsheng Cai. "Brain is an endocrine organ through secretion and nuclear transfer of parathymosin." Life Science Alliance 3, no. 12 (2020): e202000917. http://dx.doi.org/10.26508/lsa.202000917.
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This study reports that parathymosin (PTMS) is secreted by hypothalamic stem/progenitor cells (htNSC) to inhibit senescence of recipient cells such as fibroblasts. Upon release, PTMS is rapidly transferred into the nuclei of various cell types, including neuronal GT1-7 cells and different peripheral cells, and it is effectively transferred into neuronal nuclei in various brain regions in vivo. Notably, brain neurons also produce and release PTMS, and because neuronal populations are large, they are important for maintaining PTMS in the cerebrospinal fluid which is further transferable into the blood. Compared with several other brain regions, the hypothalamus is stronger for long-distance PTMS transfer, supporting a key hypothalamic role in this function. In physiology, aging is associated with declines in PTMS production and transfer in the brain, and ptms knockdown in the hypothalamus versus hippocampus were studied showing different contributions to neurobehavioral physiology. In conclusion, the brain is an endocrine organ through secretion and nuclear transfer of PTMS, and the hypothalamus–brain orchestration of this function is protective in physiology and counteractive against aging-related disorders.
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Sharma, Mayank, Maarten Litmaath, Eraldo Silva Junior, and Renato Santana. "Lightweight WLCG Sites." EPJ Web of Conferences 214 (2019): 07019. http://dx.doi.org/10.1051/epjconf/201921407019.
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This article describes a new framework, called SIMPLE, for settingup and maintaining classic WLCG sites with minimal operational efforts and insights needed into the WLCG middleware. The framework provides a single common interface to install and configure any of its supported grid services, such as Compute Elements, Batch Systems, Worker Nodes and miscellaneous middleware packages. It leverages modern container orchestration tools like Kubernetes, Docker Swarm, and confiuration management tools like Puppet, Ansible, to automate deployment of the WLCG services on behalf of a site admin. The framework is modular and extensible by design. Therefore, it is easy to add support for more grid services as well as infrastructure automation tools to accommodate diverse scenarios at different sites. We provide insight into the design of the framework and our efforts towards development, release and deployment of its first implementation featuring CREAM E, TORQUE Batch System and TORQUE based Worker Nodes.
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Sackmann, Erich, and Motomu Tanaka. "Critical role of lipid membranes in polarization and migration of cells: a biophysical view." Biophysical Reviews 13, no. 1 (2021): 123–38. http://dx.doi.org/10.1007/s12551-021-00781-1.
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AbstractCell migration plays vital roles in many biologically relevant processes such as tissue morphogenesis and cancer metastasis, and it has fascinated biophysicists over the past several decades. However, despite an increasing number of studies highlighting the orchestration of proteins involved in different signaling pathways, the functional roles of lipid membranes have been essentially overlooked. Lipid membranes are generally considered to be a functionless two-dimensional matrix of proteins, although many proteins regulating cell migration gain functions only after they are recruited to the membrane surface and self-organize their functional domains. In this review, we summarize how the logistical recruitment and release of proteins to and from lipid membranes coordinates complex spatiotemporal molecular processes. As predicted from the classical framework of the Smoluchowski equation of diffusion, lipid/protein membranes serve as a 2D reaction hub that contributes to the effective and robust regulation of polarization and migration of cells involving several competing pathways.
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Ozga, Aleksandra J., Federica Moalli, Jun Abe, et al. "pMHC affinity controls duration of CD8+ T cell–DC interactions and imprints timing of effector differentiation versus expansion." Journal of Experimental Medicine 213, no. 12 (2016): 2811–29. http://dx.doi.org/10.1084/jem.20160206.
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During adaptive immune responses, CD8+ T cells with low TCR affinities are released early into the circulation before high-affinity clones become dominant at later time points. How functional avidity maturation is orchestrated in lymphoid tissue and how low-affinity cells contribute to host protection remains unclear. In this study, we used intravital imaging of reactive lymph nodes (LNs) to show that T cells rapidly attached to dendritic cells irrespective of TCR affinity, whereas one day later, the duration of these stable interactions ceased progressively with lowering peptide major histocompatibility complex (pMHC) affinity. This correlated inversely BATF (basic leucine zipper transcription factor, ATF-like) and IRF4 (interferon-regulated factor 4) induction and timing of effector differentiation, as low affinity–primed T cells acquired cytotoxic activity earlier than high affinity–primed ones. After activation, low-affinity effector CD8+ T cells accumulated at efferent lymphatic vessels for egress, whereas high affinity–stimulated CD8+ T cells moved to interfollicular regions in a CXCR3-dependent manner for sustained pMHC stimulation and prolonged expansion. The early release of low-affinity effector T cells led to rapid target cell elimination outside reactive LNs. Our data provide a model for affinity-dependent spatiotemporal orchestration of CD8+ T cell activation inside LNs leading to functional avidity maturation and uncover a role for low-affinity effector T cells during early microbial containment.
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Yan, Jing, Zohreh Hosseinzadeh, Bingbing Zhang, et al. "Decrease of Store-Operated Ca2+ Entry and Increase of Na+/Ca2+ Exchange by Pharmacological JAK2 Inhibition." Cellular Physiology and Biochemistry 38, no. 2 (2016): 683–95. http://dx.doi.org/10.1159/000443126.
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Background/Aims: Cell proliferation and migration are regulated by cytosolic Ca2+ activity ([Ca2+]i). Mechanisms modifying [Ca2+]i include store-operated Ca2+-entry (SOCE) accomplished by the pore-forming ion channel unit Orai1 and its regulator STIM1, as well as Ca2+ extrusion by Na+/Ca2+ exchanger NCX1. Kinases participating in the orchestration of cell proliferation include the Janus activated kinase JAK2. The present study explored the impact of pharmacological JAK2 inhibition on SOCE and Na+/Ca2+ exchange. Methods: MCF-7 breast carcinoma cells were studied in the absence and presence of the JAK2 inhibitors TG101348 (250 nM - 1 µM) or of AG490 (20 - 40 µM). Transcript levels were quantified with RT-PCR, protein abundance with immunoblotting, [Ca2+]i with Fura-2-fluorescence, SOCE from increase of [Ca2+]i following Ca2+ re-addition after Ca2+-store depletion with sarcoendoplasmatic Ca2+-ATPase (SERCA) inhibitor thapsigargin (1 µM), and Na+/Ca2+ exchanger activity from increase of [Ca2+]i as well as Ca2+ current in whole cell patch clamp following extracellular Na+ removal. Migratory activity was determined by a wound healing assay. Results: JAK2 inhibitor TG101348 (1 µM) decreased Orai1 and STIM1 protein abundance, increased NCX1 transcript levels, decreased Ca2+ release from intracellular stores, decreased SOCE, increased Ca2+ entry as well as Ca2+-current following extracellular Na+-removal, and decreased migration. Similar effects on Ca2+ release, SOCE, and Ca2+-entry following extracellular Na+-removal were observed following treatment with AG490. Conclusion: The present observations disclose a novel powerful mechanism regulating intracellular Ca2+ release, cellular Ca2+ entry, cellular Ca2+ extrusion and cell migration.
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Bachert, Claus, Marc Humbert, Nicola A. Hanania, et al. "Staphylococcus aureus and its IgE-inducing enterotoxins in asthma: current knowledge." European Respiratory Journal 55, no. 4 (2020): 1901592. http://dx.doi.org/10.1183/13993003.01592-2019.
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While immunoglobulin (Ig) E is a prominent biomarker for early-onset, its levels are often elevated in non-allergic late-onset asthma. However, the pattern of IgE expression in the latter is mostly polyclonal, with specific IgEs low or below detection level albeit with an increased total IgE. In late-onset severe asthma patients, specific IgE to Staphylococcal enterotoxins (se-IgE) can frequently be detected in serum, and has been associated with asthma, with severe asthma defined by hospitalisations, oral steroid use and decrease in lung function. Recently, se-IgE was demonstrated to even predict the development into severe asthma with exacerbations over the next decade. Staphylococcus aureus manipulates the airway mucosal immunology at various levels via its proteins, including superantigens, serine-protease-like proteins (Spls), or protein A (SpA) and possibly others. Release of IL-33 from respiratory epithelium and activation of innate lymphoid cells (ILCs) via its receptor ST2, type 2 cytokine release from those ILCs and T helper (Th) 2 cells, mast cell degranulation, massive local B-cell activation and IgE formation, and finally eosinophil attraction with consequent release of extracellular traps, adding to the epithelial damage and contributing to disease persistence via formation of Charcot–Leyden crystals are the most prominent hallmarks of the manipulation of the mucosal immunity by S. aureus. In summary, S. aureus claims a prominent role in the orchestration of severe airway inflammation and in current and future disease severity. In this review, we discuss current knowledge in this field and outline the needs for future research to fully understand the impact of S. aureus and its proteins on asthma.
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Shumilina, Ekaterina, Stephan M. Huber, and Florian Lang. "Ca2+signaling in the regulation of dendritic cell functions." American Journal of Physiology-Cell Physiology 300, no. 6 (2011): C1205—C1214. http://dx.doi.org/10.1152/ajpcell.00039.2011.
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Dendritic cells (DCs) are highly versatile antigen-presenting cells critically involved in both innate and adaptive immunity as well as maintenance of self-tolerance. DC function is governed by Ca2+signaling, which directs the DC responses to diverse antigens, including Toll-like receptor ligands, intact bacteria, and microbial toxins. Ca2+-sensitive DC functions include DC activation, maturation, migration, and formation of immunological synapses with T cells. Moreover, alterations of cytosolic Ca2+trigger immune suppression or switch off DC activity. Ca2+signals are generated by the orchestration of Ca2+transport processes across plasma, endoplasmic reticulum, and inner mitochondrial membrane. These processes include active pumping of Ca2+, Ca2+/Na+antiport, and electrodiffusion through Ca2+-permeable channels or uniporters. Ca2+channels in the plasma membrane such as Ca2+release-activated Ca2+or L-type Ca2+channels are tightly regulated by the membrane potential which in turn depends on the activity of voltage-gated K+or Ca2+-activated nonselective cation channels. The rapidly growing knowledge on the function and regulation of these membrane transport proteins provides novel insight into pathophysiological mechanisms underlying dysfunction of the immune system and opens novel therapeutic opportunity to favorably influence the function of the immune system.
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Liu, Guilai, Guoxing Liu, Hong Chen, et al. "Rapid Upregulation of Orai1 Abundance in the Plasma Membrane of Platelets Following Activation with Thrombin and Collagen Related Peptide." Cellular Physiology and Biochemistry 37, no. 5 (2015): 1759–66. http://dx.doi.org/10.1159/000438539.
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Background: Blood platelets accomplish primary hemostasis following vascular injury and contribute to the orchestration of occlusive vascular disease. Platelets are activated by an increase of cytosolic Ca2+-activity ([Ca2+]i), which is accomplished by Ca2+-release from intracellular stores and subsequent store operated Ca2+ entry (SOCE) through Ca2+ release activated Ca2+ channel moiety Orai1. Powerful activators of platelets include thrombin and collagen related peptide (CRP), which are in part effective by activation of small G- protein Rac1. The present study explored the influence of thrombin and CRP on Orai1 protein abundance and cytosolic Ca2+-activity ([Ca2+]i) in platelets drawn from wild type mice. Methods: Orai1 protein surface abundance was quantified utilizing CF™488A conjugated antibodies, and [Ca2+]i was determined with Fluo3-fluorescence. Results: In resting platelets, Orai1 protein abundance and [Ca2+]i were low. Thrombin (0.02 U/ml) and CRP (5ug/ml) within 2 min increased [Ca2+]i and Orai1 protein abundance at the platelet surface. [Ca2+]i was further increased by Ca2+ ionophore ionomycin (1 µM) and by store depletion with the sarcoendoplasmatic Ca2+ ATPase inhibitor thapsigargin (1 µM). However, Orai1 protein abundance at the platelet surface was not significantly affected by ionomycin and only slightly increased by thapsigargin. The effect of thrombin and CRP on Orai1 abundance and [Ca2+]i was significantly blunted by Rac1 inhibitor NSC23766 (50 µM). Conclusion: The increase of [Ca2+]i following stimulation of platelets with thrombin and collagen related peptide is potentiated by ultrarapid Rac1 sensitive translocation of Orai1 into the cell membrane.
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Yiu, Lik Man Daphne, and Ka Yui Karl Wu. "The Interactions of Absorptive Capacity, Buffer Inventory, and Toxic Emissions on Firm Value." International Journal of Environmental Research and Public Health 18, no. 4 (2021): 1979. http://dx.doi.org/10.3390/ijerph18041979.
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A significant amount of research has been conducted on the impacts of emissions reduction, absorptive capacity, and buffer inventory on firm performance. According to the resource-based view (RBV), absorptive capacity and buffer inventory are organizational capabilities and resources to create sustainable competitive advantages. Yet, the resource orchestration perspective (ROP) of the RBV emphasizes that firms need to develop a new capability to orchestrate and deploy their existing capabilities and resources. From an organizational learning perspective, firms with the low-level release of toxic chemicals have established a structured system and systematic organizational routines, strengthening their learning capabilities to share and use internal and external information across functional areas for continuous improvements. This study explores and seeks to understand toxic emissions through systematic operational routines as an organizational mechanism. These routines orchestrate and deploy the firm-specific absorptive capacity and buffer inventory to generate a sustainable competitive advantage. We examine the impacts of the absorptive capacity and buffer inventory on firm value in terms of Tobin’s Q, respectively. We also explore how such impacts are moderated by toxic emissions. Our results show that the absorptive capacity significantly enhances the market value of firms. However, the relationship between the buffer inventory and firm value is insignificant. Our additional analyses indicate that the impacts of the absorptive capacity and buffer inventory on the firm value are both significantly positive when firms release low toxic chemicals. Our results further suggest that firms can maximize their market value with a high absorptive capacity, high buffer inventory, and low toxic emissions.
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Hanna-Mitchell, Ann T., Amanda Wolf-Johnston, James R. Roppolo, Tony C. A. Buffington, and Lori A. Birder. "Corticotropin-releasing factor family peptide signaling in feline bladder urothelial cells." Journal of Endocrinology 222, no. 1 (2014): 113–21. http://dx.doi.org/10.1530/joe-13-0422.
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Corticotropin-releasing factor (CRF) plays a central role in the orchestration of behavioral and neuroendocrine responses to stress. The family of CRF-related peptides (CRF and paralogs: urocortin (Ucn)-I, -II, and -III) and associated receptors (CRFR1 and CRFR2) are also expressed in peripheral tissues such as the skin and gastrointestinal tract. Local signaling may exert multiple effects of stress-induced exacerbation of many complex syndromes, including psoriasis and visceral hypersensitivity. Interstitial cystitis/painful bladder syndrome (IC/PBS), a chronic visceral pain syndrome characterized by urinary frequency, urgency, and pelvic pain, is reported to be exacerbated by stress. Functional changes in the epithelial lining of the bladder, a vital blood–urine barrier called the urothelium, may play a role in IC/PBS. This study investigated the expression and functional activity of CRF-related peptides in the urothelium of normal cats and cats with feline interstitial cystitis (FIC), a chronic idiopathic cystitis exhibiting similarities to humans diagnosed with IC/PBS. Western blots analysis showed urothelial (UT) expression of CRFR1 and CRFR2. Enzyme immunoassay revealed release of endogenous ligands (CRF and Ucn) by UT cells in culture. Evidence of functional activation of CRFR1 and CRFR2 by receptor-selective agonists (CRF and UCN3 respectively) was shown by i) the measurement of ATP release using the luciferin-luciferase assay and ii) the use of membrane-impermeant fluorescent dyes (FM dyes) for fluorescence microscopy to assess membrane exocytotic responses in real time. Our findings show evidence of CRF-related peptide signaling in the urothelium. Differences in functional responses between FIC and normal UT indicate that this system is altered in IC/PBS.
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Yan, Jing, Bingbing Zhang, Zohreh Hosseinzadeh, and Florian Lang. "Down-Regulation of Store-Operated Ca2+ Entry and Na+ Ca2+ Exchange in MCF-7 Breast Cancer Cells by Pharmacological JAK3 Inhibition." Cellular Physiology and Biochemistry 38, no. 4 (2016): 1643–51. http://dx.doi.org/10.1159/000443104.
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Background/Aims: Oscillations of cytosolic Ca2+ activity ([Ca2+]i) participate in the orchestration of tumor cell proliferation. [Ca2+]i could be increased by intracellular Ca2+ release followed by store-operated Ca2+-entry (SOCE). [Ca2+]i could be decreased by Ca2+ extrusion via Na+/Ca2+ exchange. Mechanisms accomplishing SOCE include the pore-forming ion channel unit Orai1 and its regulator STIM1, Na+/Ca2+ exchanger isoforms include NCX1. In MCF-7 breast carcinoma cells Orai1 and NCX1 have previously been shown to be modified by pharmacological inhibition of Janus activated kinase JAK2. The present study explored whether SOCE and Na+/Ca2+ exchange are similarly sensitive to pharmacological JAK3 inhibition. Methods: MCF-7 breast carcinoma cells were studied in the absence and presence of the JAK3 inhibitor WHI-P154 (22 µM). [Ca2+]i was estimated from Fura-2-fluorescence, SOCE from increase of [Ca2+]i following Ca2+ re-addition after Ca2+-store depletion with sarcoendoplasmatic Ca2+-ATPase (SERCA) inhibitor thapsigargin (1 µM), and Na+/Ca2+ exchanger activity from increase of [Ca2+]i following extracellular Na+ removal. Transcript levels were quantified with RT-PCR. Results: Addition of ATP (100 µM) was followed by a rapid increase of [Ca2+]i, which was significantly blunted by WHI-P154. Thapsigargin-induced intracellular Ca2+ release was not appreciably influenced by WHI-P154. Subsequent SOCE was, however, significantly blunted by WHI-P154. WHI-P154 further significantly decreased Orai1 transcript levels. The increase of [Ca2+]i following extracellular Na+-removal and the NCX1 transcript levels were similarly decreased by WHI-P154. Conclusions: The JAK3 inhibitor WHI-P154 decreases both, Orai1 and NCX1 transcript levels and thus impairs SOCE and Na+/Ca2+ exchange.
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Lawrence, Donald W., Walter J. Bruyninckx, Nancy A. Louis, et al. "Antiadhesive Role of Apical Decay-accelerating Factor (CD55) in Human Neutrophil Transmigration across Mucosal Epithelia." Journal of Experimental Medicine 198, no. 7 (2003): 999–1010. http://dx.doi.org/10.1084/jem.20030380.
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Neutrophil migration across mucosal epithelium during inflammatory episodes involves the precise orchestration of a number a cell surface molecules and signaling pathways. After successful migration to the apical epithelial surface, apically localized epithelial proteins may serve to retain PMN at the lumenal surface. At present, identification of apical epithelial ligands and their PMN counter-receptors remain elusive. Therefore, to define the existence of apical epithelial cell surface proteins involved in PMN–epithelial interactions, we screened a panel of antibodies directed against epithelial plasma membranes. This strategy identified one antibody (OE-1) that both localized to the apical cell membrane and significantly inhibited PMN transmigration across epithelial monolayers. Microsequence analysis revealed that OE-1 recognized human decay-accelerating factor (DAF, CD55). DAF is a highly glycosylated, 70–80-kD, glycosyl-phosphatidyinositol–linked protein that functions predominantly as an inhibitor of autologous complement lysis. DAF suppression experiments using antisense oligonucleotides or RNA interference revealed that DAF may function as an antiadhesive molecule promoting the release of PMN from the lumenal surface after transmigration. Similarly, peptides corresponding to the antigen recognition domain of OE-1 resulted in accumulation of PMN on the apical epithelial surface. The elucidation of DAF as an apical epithelial ligand for PMN provides a target for novel anti-inflammatory therapies directed at quelling unwanted inflammatory episodes.
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Rice, Phoebe A., Kent W. Mouw, Sherwin P. Montaño, Martin R. Boocock, Sally-J. Rowland, and W. Marshall Stark. "Orchestrating serine resolvases." Biochemical Society Transactions 38, no. 2 (2010): 384–87. http://dx.doi.org/10.1042/bst0380384.
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A remarkable feature of the serine resolvases is their regulation: the wild-type enzymes will catalyse intra- but not inter-molecular recombination, can sense the relative orientation of their sites and can exchange strands directionally, despite the fact that there is no net release of chemical bond energy. The key to this regulation is that they are only active within a large intertwined complex called the ‘synaptosome’. Because substrate topology greatly facilitates (or, in other cases, inhibits) formation of the synaptosome, it acts as a ‘topological filter’. Within the defined topology of the synaptosome, strand exchange releases supercoiling tension, providing an energy source to bias the reaction direction. The regulatory portion of this complex contains additional copies of the recombinase and sometimes other DNA-bending proteins. We are using a combination of X-ray crystallography, biochemistry and genetics to model the full synaptic complex and to understand how the regulatory portion activates the crossover-site-bound recombinases.
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Irigoín, Florencia, Natalia M. Inada, Mariana P. Fernandes, et al. "Mitochondrial calcium overload triggers complement-dependent superoxide-mediated programmed cell death in Trypanosoma cruzi." Biochemical Journal 418, no. 3 (2009): 595–604. http://dx.doi.org/10.1042/bj20081981.
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The epimastigote stage of Trypanosoma cruzi undergoes PCD (programmed cell death) when exposed to FHS (fresh human serum). Although it has been known for over 30 years that complement is responsible for FHS-induced death, the link between complement activation and triggering of PCD has not been established. We have previously shown that the mitochondrion participates in the orchestration of PCD in this model. Several changes in mitochondrial function were described, and in particular it was shown that mitochondrion-derived O2•− (superoxide radical) is necessary for PCD. In the present study, we establish mitochondrial Ca2+ overload as the link between complement deposition and the observed changes in mitochondrial physiology and the triggering of PCD. We show that complement activation ends with the assembly of the MAC (membrane attack complex), which allows influx of Ca2+ and release of respiratory substrates to the medium. Direct consequences of these events are accumulation of Ca2+ in the mitochondrion and decrease in cell respiration. Mitochondrial Ca2+ causes partial dissipation of the inner membrane potential and consequent mitochondrial uncoupling. Moreover, we provide evidence that mitochondrial Ca2+ overload is responsible for the increased O2•− production, and that if cytosolic Ca2+ rise is not accompanied by the accumulation of the cation in the mitochondrion and consequent production of O2•−, epimastigotes die by necrosis instead of PCD. Thus our results suggest a model in which MAC assembly on the parasite surface allows Ca2+ entry and its accumulation in the mitochondrion, leading to O2•− production, which in turn constitutes a PCD signal.
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Cleveland, Simon, and Timothy J. Ellis. "Orchestrating End-User Perspectives in the Software Release Process: An Integrated Release Management Framework." Advances in Human-Computer Interaction 2014 (2014): 1–15. http://dx.doi.org/10.1155/2014/805307.
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Software bugs discovered by end-users are inevitable consequences of a vendor’s lack of testing. While they frequently result in costly system failures, one way to detect and prevent them is to engage the customer in acceptance testing during the release process. Yet, there is a considerable lack of empirical studies examining release management from end-users’ perspective. To address this gap, we propose and empirically test a release framework that positions the customer release manager in the center of the release process. Using a participatory action research strategy, a twenty-seven-month study was conducted to evaluate and improve the effectiveness of the framework through seven major and 39 minor releases.
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Carpentier, Grégoire, Eric Daubresse, Marc Garcia Vitoria, Kenji Sakai, and Fernando Villanueva. "Automatic Orchestration in Practice." Computer Music Journal 36, no. 3 (2012): 24–42. http://dx.doi.org/10.1162/comj_a_00136.
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We report here on the recent use of the Orchidée software by three different young composers in various compositional and instrumental contexts. Orchidée is a computer-aided orchestration environment designed to aid musicians exploring the space of instrument timbre mixtures and finding timbre combinations that fit a set of user-specified perceptual requirements. The first beta version of the software was released by the Institut de Recherche et Coordination Acoustique/Musique's (IRCAM's) Music Representations Group in 2009, after four years of intensive research, and it can already handle a small range of real-life situations, typically timbre imitation or orchestral synthesis, under instrumental constraints. Detailed examples, including score and audio excerpts, are provided.
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Brown, C. H., V. Scott, M. Ludwig, G. Leng, and C. W. Bourque. "Somatodendritic dynorphin release: orchestrating activity patterns of vasopressin neurons." Biochemical Society Transactions 35, no. 5 (2007): 1236–42. http://dx.doi.org/10.1042/bst0351236.
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Most neurons in the central nervous system co-express peptides alongside their principal transmitter, yet the function of these peptides is largely unknown. Vasopressin neurons of the hypothalamic supraoptic nucleus and paraventricular nucleus contain among the highest concentrations of dynorphin found in the brain. Dynorphin, an endogenous opioid peptide, is co-localized in the same neurosecretory vesicles as vasopressin and is released alongside vasopressin from the dendrites and axon terminals of vasopressin neurons. We and others have shown that neuropeptide release from the soma and dendrites of vasopressin neurons activates vasopressin receptors and κ-opioid receptors to cause activity-dependent modulation of vasopressin neuron activity, and that this is essential for activity patterning in vasopressin neurons.
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Ravichandran, Kodi S. "Find-me and eat-me signals in apoptotic cell clearance: progress and conundrums." Journal of Experimental Medicine 207, no. 9 (2010): 1807–17. http://dx.doi.org/10.1084/jem.20101157.
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Everyday we turnover billions of cells. The quick, efficient, and immunologically silent disposal of the dying cells requires a coordinated orchestration of multiple steps, through which phagocytes selectively recognize and engulf apoptotic cells. Recent studies have suggested an important role for soluble mediators released by apoptotic cells that attract phagocytes (“find-me” signals). New information has also emerged on multiple receptors that can recognize phosphatidylserine, the key “eat-me” signal exposed on the surface of apoptotic cells. This perspective discusses recent exciting progress, gaps in our understanding, and the conflicting issues that arise from the newly acquired knowledge.
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Nielsen, Anders Rinnov, and Bente Klarlund Pedersen. "The biological roles of exercise-induced cytokines: IL-6, IL-8, and IL-15." Applied Physiology, Nutrition, and Metabolism 32, no. 5 (2007): 833–39. http://dx.doi.org/10.1139/h07-054.
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Skeletal muscle fibers express several cytokines, including interleukin (IL)-6, IL-8, and IL-15. Solid evidence exists that muscular IL-6 and IL-8 are regulated by muscle contractions, at both the mRNA and the protein levels. IL-6 increases insulin-stimulated glucose disposal and fatty acid oxidation in humans in vivo. Both IL-6 and IL-8 are released from working skeletal muscle, but because IL-6 contributes to the systemic circulation only a small transient net release of IL-8 is found from working muscle, suggesting that IL-8 may exert its effects locally in the muscle. IL-15 is a recently discovered growth factor, which is highly expressed in skeletal muscle. Interestingly, although IL-15 has been demonstrated as having anabolic effects on skeletal muscle in vitro and in vivo, it seems to play a role in reducing adipose tissue mass, and a role for IL-15 in muscle–fat cross-talk has been hypothesized. In conclusion, muscle-derived cytokines appear to have important roles in metabolism, and exercise plays a role in orchestrating the interplay between cytokines and metabolism.
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Bello, Oscar D., Ouardane Jouannot, Arunima Chaudhuri, et al. "Synaptotagmin oligomerization is essential for calcium control of regulated exocytosis." Proceedings of the National Academy of Sciences 115, no. 32 (2018): E7624—E7631. http://dx.doi.org/10.1073/pnas.1808792115.
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Regulated exocytosis, which underlies many intercellular signaling events, is a tightly controlled process often triggered by calcium ion(s) (Ca2+). Despite considerable insight into the central components involved, namely, the core fusion machinery [soluble N-ethylmaleimide–sensitive factor attachment protein receptor (SNARE)] and the principal Ca2+ sensor [C2-domain proteins like synaptotagmin (Syt)], the molecular mechanism of Ca2+-dependent release has been unclear. Here, we report that the Ca2+-sensitive oligomers of Syt1, a conserved structural feature among several C2-domain proteins, play a critical role in orchestrating Ca2+-coupled vesicular release. This follows from pHluorin-based imaging of single-vesicle exocytosis in pheochromocytoma (PC12) cells showing that selective disruption of Syt1 oligomerization using a structure-directed mutation (F349A) dramatically increases the normally low levels of constitutive exocytosis to effectively occlude Ca2+-stimulated release. We propose a parsimonious model whereby Ca2+-sensitive oligomers of Syt (or a similar C2-domain protein) assembled at the site of docking physically block spontaneous fusion until disrupted by Ca2+. Our data further suggest Ca2+-coupled vesicular release is triggered by removal of the inhibition, rather than by direct activation of the fusion machinery.
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Miller, Jason, Min Luo, Hua Wang, et al. "P857 ONM-500 – a novel STING-activating therapeutic nanovaccine platform for cancer immunotherapy." Journal for ImmunoTherapy of Cancer 8, Suppl 1 (2020): A7—A8. http://dx.doi.org/10.1136/lba2019.11.
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BackgroundEfficacy of cancer vaccines requires the induction of tumor antigen-specific cytotoxic T-lymphocytes (CTL) to effectively clear established tumors. Orchestration of antigen presentation, co-stimulatory signaling, and innate cytokine signals are necessary steps for tumor-specific T-cell activation. The ONM-500 nanovaccine platform1-2 utilizes a novel pH-sensitive polymer that forms an antigen-encapsulating nanoparticle and functions both as a carrier for antigen delivery of both peptide and protein antigens to dendritic cells and acts as an adjuvant, activating the stimulator on interferon genes (STING) pathway and generating a CD8+ CTL response. Peptide antigens have translational challenges due to complex formulations and/or HLA-type-specific antigen sequence recognition, processing and presentation. Full-length protein antigens alleviate HLA subtype limitation, allowing coverage of multi-immunogenic T cell epitopes in patients. Pairing ONM-500 adjuvant with the full-length E6 and E7 oncoproteins from human papillomavirus (HPV) cancers shows great potential to treat HPV-associated cancer in patients.MethodsBased on the previously demonstrated STING-dependent T cell activation by ONM-500 [1], the nanovaccine was formulated with full-length HPV16 E6 and E7 proteins (recombinant), and the nanoparticle properties and antigen loading were characterized. In vivo lymph node accumulation following subcutaneous administration was evaluated using fluorescent nanovaccines. Direct binding of ONM-500 to recombinant human STING (CTD) was evaluated using isothermal titration calorimetry (ITC) compared to the endogenous ligand 2’,3’-cGAMP. Antitumor efficacy was evaluated in multiple syngeneic tumor models, including the TC-1 model which overexpresses HPV16 E6 and E7 with the ONM-500 vaccine in combination with anti-PD-1 checkpoint inhibitor. Long-term anti-tumor memory was evaluated in a follow-up rechallenge study after 60 days in tumor-free animals.ResultsCharacterization of ONM-500 nanovaccine shows reproducible particle chemi-physical properties and antigen loading. The nanoparticle size substantiates the effective lymph node accumulation for antigen cross-presentation in dendritic cells following subcutaneous administration. ITC studies with human STING demonstrated effective binding by ONM-500 adjuvant. The nanovaccine anti-tumor efficacy was previously demonstrated in melanoma, colorectal, and HPV-associated syngeneic tumor models. In TC-1 tumors, ONM-500 nanovaccine containing full-length E6/E7 protein showed 100% overall survival at 55 days (figure 1). Tumor growth inhibition was also improved over E7 antigen peptide formulated nanovaccine. A rechallenge study demonstrated long-term antigen-specific anti-tumor memory response.Abstract P857 Figure 1ConclusionsONM-500 STING-activating nanovaccines effectively deliver antigens in vivo to lymph nodes to elicit antigen-specific CTL response. The anti-tumor efficacy in multiple tumor models demonstrates the potential of ONM-500 as a general STING agonist cancer vaccine platform, and full-length E6/E7 incorporated ONM-500 is being developed for HPV-associated cancers.Ethics ApprovalAll animal procedures were performed with ethical compliance and approval by the Institutional Animal Care and Use Committee of the University of Texas Southwestern Medical Center (Protocol No. 2017-101954) and Pennsylvania State College of Medicine (Protocol No. 47682).ReferencesLuo M, Wang H, Wang Z, Cai H, Lu Z, Li Y, Du M, Huang G, Wang C, Chen X, Porembka MR, Lea J, Frankel AE, Fu YX, Chen ZJ, Gao J. A STING-activating nanovaccine for cancer immunotherapy. Nat Nanotechnol 2017; 12:648–654.Luo M, Liu Z, Zhang X, Han C, Samandi LZ, Dong C, Sumer BD, Lea J, Fu YX, Gao J. Synergistic STING activation by PC7A nanovaccine and ionizing radiation improves cancer immunotherapy. J Control Release 2019; 28:154–160.
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Kaiser, Karol, and Vitezslav Bryja. "Choroid Plexus: The Orchestrator of Long-Range Signalling Within the CNS." International Journal of Molecular Sciences 21, no. 13 (2020): 4760. http://dx.doi.org/10.3390/ijms21134760.
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Cerebrospinal fluid (CSF) is the liquid that fills the brain ventricles. CSF represents not only a mechanical brain protection but also a rich source of signalling factors modulating diverse processes during brain development and adulthood. The choroid plexus (CP) is a major source of CSF and as such it has recently emerged as an important mediator of extracellular signalling within the brain. Growing interest in the CP revealed its capacity to release a broad variety of bioactive molecules that, via CSF, regulate processes across the whole central nervous system (CNS). Moreover, CP has been also recognized as a sensor, responding to altered composition of CSF associated with changes in the patterns of CNS activity. In this review, we summarize the recent advances in our understanding of the CP as a signalling centre that mediates long-range communication in the CNS. By providing a detailed account of the CP secretory repertoire, we describe how the CP contributes to the regulation of the extracellular environment—in the context of both the embryonal as well as the adult CNS. We highlight the role of the CP as an important regulator of CNS function that acts via CSF-mediated signalling. Further studies of CP–CSF signalling hold the potential to provide key insights into the biology of the CNS, with implications for better understanding and treatment of neuropathological conditions.
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Rose, Christopher F., Alexei Verkhratsky, and Vladimir Parpura. "Astrocyte glutamine synthetase: pivotal in health and disease." Biochemical Society Transactions 41, no. 6 (2013): 1518–24. http://dx.doi.org/10.1042/bst20130237.
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The multifunctional properties of astrocytes signify their importance in brain physiology and neurological function. In addition to defining the brain architecture, astrocytes are primary elements of brain ion, pH and neurotransmitter homoeostasis. GS (glutamine synthetase), which catalyses the ATP-dependent condensation of ammonia and glutamate to form glutamine, is an enzyme particularly found in astrocytes. GS plays a pivotal role in glutamate and glutamine homoeostasis, orchestrating astrocyte glutamate uptake/release and the glutamate–glutamine cycle. Furthermore, astrocytes bear the brunt of clearing ammonia in the brain, preventing neurotoxicity. The present review depicts the central function of astrocytes, concentrating on the importance of GS in glutamate/glutamine metabolism and ammonia detoxification in health and disease.
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Hangai, Sho, Takeshi Kawamura, Yoshitaka Kimura, et al. "Orchestration of myeloid-derived suppressor cells in the tumor microenvironment by ubiquitous cellular protein TCTP released by tumor cells." Nature Immunology 22, no. 8 (2021): 947–57. http://dx.doi.org/10.1038/s41590-021-00967-5.
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Quirós, Miguel, and Asma Nusrat. "Contribution of Wound-Associated Cells and Mediators in Orchestrating Gastrointestinal Mucosal Wound Repair." Annual Review of Physiology 81, no. 1 (2019): 189–209. http://dx.doi.org/10.1146/annurev-physiol-020518-114504.
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The gastrointestinal mucosa, structurally formed by the epithelium and lamina propria, serves as a selective barrier that separates luminal contents from the underlying tissues. Gastrointestinal mucosal wound repair is orchestrated by a series of spatial and temporal events that involve the epithelium, recruited immune cells, resident stromal cells, and the microbiota present in the wound bed. Upon injury, repair of the gastrointestinal barrier is mediated by collective migration, proliferation, and subsequent differentiation of epithelial cells. Epithelial repair is intimately regulated by a number of wound-associated cells that include immune cells and stromal cells in addition to mediators released by luminal microbiota. The highly regulated interaction of these cell types is perturbed in chronic inflammatory diseases that are associated with impaired wound healing. An improved understanding of prorepair mechanisms in the gastrointestinal mucosa will aid in the development of novel therapeutics that promote mucosal healing and reestablish the critical epithelial barrier function.
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Duinker, Ben, and Denis Martin. "In Search of the Golden Age Hip-Hop Sound (1986–1996)." Empirical Musicology Review 12, no. 1-2 (2017): 80. http://dx.doi.org/10.18061/emr.v12i1-2.5410.
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The notion of a musical repertoire's "sound" is frequently evoked in journalism and scholarship, but what parameters comprise such a sound? This question is addressed through a statistically-driven corpus analysis of hip-hop music released during the genre's Golden Age era. The first part of the paper presents a methodology for developing, transcribing, and analyzing a corpus of 100 hip-hop tracks released during the Golden Age. Eight categories of aurally salient musical and production parameters are analyzed: tempo, orchestration and texture, harmony, form, vocal and lyric profiles, global and local production effects, vocal doubling and backing, and loudness and compression. The second part of the paper organizes the analysis data into three trend categories: trends of change (parameters that change over time), trends of prevalence (parameters that remain generally constant across the corpus), and trends of similarity (parameters that are similar from song to song). These trends form a generalized model of the Golden Age hip-hop sound which considers both global (the whole corpus) and local (unique songs within the corpus) contexts. By operationalizing "sound" as the sum of musical and production parameters, aspects of popular music that are resistant to traditional music-analytical methods can be considered.
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Moura-Alves, Pedro, Andreas Puyskens, Anne Stinn, et al. "Host monitoring of quorum sensing during Pseudomonas aeruginosa infection." Science 366, no. 6472 (2019): eaaw1629. http://dx.doi.org/10.1126/science.aaw1629.
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Pseudomonas aeruginosa rapidly adapts to altered conditions by quorum sensing (QS), a communication system that it uses to collectively modify its behavior through the production, release, and detection of signaling molecules. QS molecules can also be sensed by hosts, although the respective receptors and signaling pathways are poorly understood. We describe a pattern of regulation in the host by the aryl hydrocarbon receptor (AhR) that is critically dependent on qualitative and quantitative sensing of P. aeruginosa quorum. QS molecules bind to AhR and distinctly modulate its activity. This is mirrored upon infection with P. aeruginosa collected from diverse growth stages and with QS mutants. We propose that by spying on bacterial quorum, AhR acts as a major sensor of infection dynamics, capable of orchestrating host defense according to the status quo of infection.
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Corbeil, Denis, Mark F. Santos, Jana Karbanová, Thomas Kurth, Germana Rappa, and Aurelio Lorico. "Uptake and Fate of Extracellular Membrane Vesicles: Nucleoplasmic Reticulum-Associated Late Endosomes as a New Gate to Intercellular Communication." Cells 9, no. 9 (2020): 1931. http://dx.doi.org/10.3390/cells9091931.
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Extracellular membrane vesicles (EVs) are emerging as new vehicles in intercellular communication, but how the biological information contained in EVs is shared between cells remains elusive. Several mechanisms have been described to explain their release from donor cells and the initial step of their uptake by recipient cells, which triggers a cellular response. Yet, the intracellular routes and subcellular fate of EV content upon internalization remain poorly characterized. This is particularly true for EV-associated proteins and nucleic acids that shuttle to the nucleus of host cells. In this review, we will describe and discuss the release of EVs from donor cells, their uptake by recipient cells, and the fate of their cargoes, focusing on a novel intracellular route wherein small GTPase Rab7+ late endosomes containing endocytosed EVs enter into nuclear envelope invaginations and deliver their cargo components to the nucleoplasm of recipient cells. A tripartite protein complex composed of (VAMP)-associated protein A (VAP-A), oxysterol-binding protein (OSBP)-related protein-3 (ORP3), and Rab7 is essential for the transfer of EV-derived components to the nuclear compartment by orchestrating the particular localization of late endosomes in the nucleoplasmic reticulum.
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Nässel, Dick R., and Meet Zandawala. "Hormonal axes in Drosophila: regulation of hormone release and multiplicity of actions." Cell and Tissue Research 382, no. 2 (2020): 233–66. http://dx.doi.org/10.1007/s00441-020-03264-z.
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Abstract Hormones regulate development, as well as many vital processes in the daily life of an animal. Many of these hormones are peptides that act at a higher hierarchical level in the animal with roles as organizers that globally orchestrate metabolism, physiology and behavior. Peptide hormones can act on multiple peripheral targets and simultaneously convey basal states, such as metabolic status and sleep-awake or arousal across many central neuronal circuits. Thereby, they coordinate responses to changing internal and external environments. The activity of neurosecretory cells is controlled either by (1) cell autonomous sensors, or (2) by other neurons that relay signals from sensors in peripheral tissues and (3) by feedback from target cells. Thus, a hormonal signaling axis commonly comprises several components. In mammals and other vertebrates, several hormonal axes are known, such as the hypothalamic-pituitary-gonad axis or the hypothalamic-pituitary-thyroid axis that regulate reproduction and metabolism, respectively. It has been proposed that the basic organization of such hormonal axes is evolutionarily old and that cellular homologs of the hypothalamic-pituitary system can be found for instance in insects. To obtain an appreciation of the similarities between insect and vertebrate neurosecretory axes, we review the organization of neurosecretory cell systems in Drosophila. Our review outlines the major peptidergic hormonal pathways known in Drosophila and presents a set of schemes of hormonal axes and orchestrating peptidergic systems. The detailed organization of the larval and adult Drosophila neurosecretory systems displays only very basic similarities to those in other arthropods and vertebrates.
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Thapa, Arjun, Mateusz Adamiak, Kamila Bujko, et al. "Danger-associated molecular pattern molecules take unexpectedly a central stage in Nlrp3 inflammasome–caspase-1-mediated trafficking of hematopoietic stem/progenitor cells." Leukemia 35, no. 9 (2021): 2658–71. http://dx.doi.org/10.1038/s41375-021-01158-9.
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AbstractLike their homing after transplantation to bone marrow (BM), the mobilization of hematopoietic stem/progenitor cells (HSPCs) is still not fully understood, and several overlapping pathways are involved. Several years ago our group proposed that sterile inflammation in the BM microenvironment induced by pro-mobilizing agents is a driving force in this process. In favor of our proposal, both complement cascade (ComC)-deficient and Nlrp3 inflammasome-deficient mice are poor G-CSF and AMD3100 mobilizers. It is also known that the Nlrp3 inflammasome mediates its effects by activating caspase-1, which is responsible for proteolytic activation of interleukin-1β (IL-1β) and interleukin-18 (IL-18) and their release from cells along with several danger-associated molecular pattern molecules (DAMPs). We observed in the past that IL-1β and IL-18 independently promote mobilization of HSPCs. In the current work we demonstrated that caspase-1-KO mice are poor mobilizers, and, to our surprise, administration of IL-1β or IL-18, as in the case of Nlrp3-KO animals, does not correct this defect. Moreover, neither Caspase-1-KO nor Nlrp3-KO mice properly activated the ComC to execute the mobilization process. Interestingly, mobilization in these animals and activation of the ComC were both restored after injection of the DAMP cocktail eATP+HGMB1+S100A9, the components of which are normally released from cells in an Nlrp3 inflammasome–caspase-1-dependent manner. In addition, we report that caspase-1-deficient HSPCs show a decrease in migration in response to BM homing factors and engraft more poorly after transplantation. These results for the first time identify caspase-1 as an orchestrator of HSPC trafficking.
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Malenczyk, Katarzyna, Erik Keimpema, Fabiana Piscitelli, et al. "Fetal endocannabinoids orchestrate the organization of pancreatic islet microarchitecture." Proceedings of the National Academy of Sciences 112, no. 45 (2015): E6185—E6194. http://dx.doi.org/10.1073/pnas.1519040112.
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Endocannabinoids are implicated in the control of glucose utilization and energy homeostasis by orchestrating pancreatic hormone release. Moreover, in some cell niches, endocannabinoids regulate cell proliferation, fate determination, and migration. Nevertheless, endocannabinoid contributions to the development of the endocrine pancreas remain unknown. Here, we show that α cells produce the endocannabinoid 2-arachidonoylglycerol (2-AG) in mouse fetuses and human pancreatic islets, which primes the recruitment of β cells by CB1 cannabinoid receptor (CB1R) engagement. Using subtractive pharmacology, we extend these findings to anandamide, a promiscuous endocannabinoid/endovanilloid ligand, which impacts both the determination of islet size by cell proliferation and α/β cell sorting by differential activation of transient receptor potential cation channel subfamily V member 1 (TRPV1) and CB1Rs. Accordingly, genetic disruption of TRPV1 channels increases islet size whereas CB1R knockout augments cellular heterogeneity and favors insulin over glucagon release. Dietary enrichment in ω-3 fatty acids during pregnancy and lactation in mice, which permanently reduces endocannabinoid levels in the offspring, phenocopies CB1R−/− islet microstructure and improves coordinated hormone secretion. Overall, our data mechanistically link endocannabinoids to cell proliferation and sorting during pancreatic islet formation, as well as to life-long programming of hormonal determinants of glucose homeostasis.
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Alarcon, Pablo, Gabriel Espinosa, Catalina Millan, et al. "Piscirickettsia salmonis-Triggered Extracellular Traps Formation as an Innate Immune Response of Atlantic Salmon-Derived Polymorphonuclear Neutrophils." Biology 10, no. 3 (2021): 206. http://dx.doi.org/10.3390/biology10030206.
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Extracellular traps (ETs) are webs of DNA, citrullinated histones, anti-microbial peptides, and proteins that were not previously reported in Atlantic salmon (Salmo salar). ETs are mainly released from polymorphonuclear neutrophils (PMN) and are considered a novel PMN-derived effector mechanism against different invasive pathogens. Here, we showed that Atlantic salmon-derived PMN released ETs-like structures in vitro in response to highly pathogenic facultative intracellular rickettsial bacteria Piscirickettsia salmonis. PMN were isolated from pre-smolt Atlantic salmon and stimulated in vitro with oleic acid and P. salmonis. Extracellular DNA was measured using the PicoGreen™ dye, while immunofluorescence image analysis was used to confirm the classical components of salmonid-extruded ETs. Future studies are required to better understand the role of Atlantic salmon-derived ETs orchestrating innate/adaptive immunity and the knowledge on regulation pathways involved in this cell death process. Thus, comprehension of salmonid-derived ETs against P. salmonis might represent novel alternative strategies to improve host innate defense mechanisms of farmed salmon against closely related rickettsial bacteria, as a complement to disease prevention and control strategies.
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Bender, Markus, Anita Eckly, John H. Hartwig, et al. "ADF/n-cofilin–dependent actin turnover determines platelet formation and sizing." Blood 116, no. 10 (2010): 1767–75. http://dx.doi.org/10.1182/blood-2010-03-274340.
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Abstract The cellular and molecular mechanisms orchestrating the complex process by which bone marrow megakaryocytes form and release platelets remain poorly understood. Mature megakaryocytes generate long cytoplasmic extensions, proplatelets, which have the capacity to generate platelets. Although microtubules are the main structural component of proplatelets and microtubule sliding is known to drive proplatelet elongation, the role of actin dynamics in the process of platelet formation has remained elusive. Here, we tailored a mouse model lacking all ADF/n-cofilin–mediated actin dynamics in megakaryocytes to specifically elucidate the role of actin filament turnover in platelet formation. We demonstrate, for the first time, that in vivo actin filament turnover plays a critical role in the late stages of platelet formation from megakaryocytes and the proper sizing of platelets in the periphery. Our results provide the genetic proof that platelet production from megakaryocytes strictly requires dynamic changes in the actin cytoskeleton.
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Redington, Anthony E., and Peter H. Howarth. "Mast Cells, Cytokines and Asthma." Canadian Respiratory Journal 1, no. 2 (1994): 118–27. http://dx.doi.org/10.1155/1994/435781.
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The appreciation that asthma is a chronic inflammatory disorder of the airways has led to a reappraisal of the importance of different cell populations within the bronchial mucosa with respect to their role in the regulation of the cellular events in this disease. While mast cell degranulation has been implicated in the acute allergic bronchoconstrictor response, activation of this cell population has not been considered relevant to either the late phase inflammatory cell influx within the airways following allergen bronchoprovocation or to the mucosa! eosinophilia in chronic clinical disease. As such, attention has focused on the T lymphocyte as an orchestrator of these cellular events on account of its ability to synthesize and release cytokines relevant to the allergic process. It is now, however, realized that many cell populations within the airways are able to generate cytokines comparable with and complimentary to those produced by T lymphocytes and that asthma cannot be considered an inflammatory airway disorder dependent upon activation of one single cell population. This review details the current evidence that airway mast cells synthesize, store and release cytokines relevant to allergic inflammation and considers their potential involvement not only in the cellular influx within the airways but also in the fibrotic structural changes which are evident in chronic disease.
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Amlong, Corey A., Dean T. Nardelli, Sara Heil Peterson, Thomas F. Warner, Steven M. Callister, and Ronald F. Schell. "Anti-Interleukin-15 Prevents Arthritis in Borrelia-Vaccinated and -Infected Mice." Clinical and Vaccine Immunology 13, no. 2 (2006): 289–96. http://dx.doi.org/10.1128/cvi.13.2.289-296.2006.
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ABSTRACT We showed previously that interleukin-17 (IL-17) plays a significant role in the induction of arthritis associated with Borrelia vaccination and challenge. Little information, however, is available about the chain of immunologic events that leads to the release of IL-17. The production of IL-17 has been linked to stimulation of memory cells by IL-15. Therefore, we hypothesized that IL-15 is involved in the induction of arthritis associated with Borrelia vaccination and infection of mice. Here we present evidence that treatment of Borrelia-vaccinated and -infected mice with anti-IL-15 antibody prevents swelling of the hind paws. More importantly, both anti-IL-15 antibody- and recombinant IL-15 receptor alpha-treated Borrelia-vaccinated and -infected mice were free of major histopathologic indications of arthritis, including hyperplasia, hypertrophy, and vilus formation of the synovium. Similarly, the synovial space and perisynovium were free of inflammatory cells. By contrast, the synovium of nontreated Borrelia-vaccinated and -infected mice had overt hyperplasia, hypertrophy, and vilus formation. Moreover, the synovial space and perisynovium were infiltrated with neutrophils, macrophages, and lymphocytes. Finally, we show that recombinant IL-15 stimulates the release of IL-17 from lymph node cells obtained near the arthritic site. These results suggest that IL-15 plays a major role in orchestrating IL-17 induction of arthritis associated with Borrelia-vaccinated and -infected mice.
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Sierra, Amanda, Sol Beccari, Irune Diaz-Aparicio, Juan M. Encinas, Samuel Comeau, and Marie-Ève Tremblay. "Surveillance, Phagocytosis, and Inflammation: How Never-Resting Microglia Influence Adult Hippocampal Neurogenesis." Neural Plasticity 2014 (2014): 1–15. http://dx.doi.org/10.1155/2014/610343.
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Microglia cells are the major orchestrator of the brain inflammatory response. As such, they are traditionally studied in various contexts of trauma, injury, and disease, where they are well-known for regulating a wide range of physiological processes by their release of proinflammatory cytokines, reactive oxygen species, and trophic factors, among other crucial mediators. In the last few years, however, this classical view of microglia was challenged by a series of discoveries showing their active and positive contribution to normal brain functions. In light of these discoveries, surveillant microglia are now emerging as an important effector of cellular plasticity in the healthy brain, alongside astrocytes and other types of inflammatory cells. Here, we will review the roles of microglia in adult hippocampal neurogenesis and their regulation by inflammation during chronic stress, aging, and neurodegenerative diseases, with a particular emphasis on their underlying molecular mechanisms and their functional consequences for learning and memory.
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Llibre, Alba, Frances S. Grudzinska, Matthew K. O'Shea, et al. "Lactate cross-talk in host–pathogen interactions." Biochemical Journal 478, no. 17 (2021): 3157–78. http://dx.doi.org/10.1042/bcj20210263.
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Lactate is the main product generated at the end of anaerobic glycolysis or during the Warburg effect and its role as an active signalling molecule is increasingly recognised. Lactate can be released and used by host cells, by pathogens and commensal organisms, thus being essential for the homeostasis of host–microbe interactions. Infection can alter this intricate balance, and the presence of lactate transporters in most human cells including immune cells, as well as in a variety of pathogens (including bacteria, fungi and complex parasites) demonstrates the importance of this metabolite in regulating host–pathogen interactions. This review will cover lactate secretion and sensing in humans and microbes, and will discuss the existing evidence supporting a role for lactate in pathogen growth and persistence, together with lactate's ability to impact the orchestration of effective immune responses. The ubiquitous presence of lactate in the context of infection and the ability of both host cells and pathogens to sense and respond to it, makes manipulation of lactate a potential novel therapeutic strategy. Here, we will discuss the preliminary research that has been carried out in the context of cancer, autoimmunity and inflammation.
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Lawrence, T., та M. Bebien. "IKKα in the regulation of inflammation and adaptive immunity". Biochemical Society Transactions 35, № 2 (2007): 270–72. http://dx.doi.org/10.1042/bst0350270.
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Inflammation is a beneficial response to insult or injury which plays an important role in orchestrating the adaptive immune response. The resolution of acute inflammation is an active process that involves the release of anti-inflammatory mediators and the termination of pro-inflammatory signalling pathways coincident with leucocyte apoptosis and phagocytic clearance and the migration of antigen-presenting cells from the site of inflammation to the local lymphatic tissue. The latter process is required for the development of adaptive immunity and immunological memory. The NF-κB (nuclear factor κB) pathway is an important regulator of inflammation and immunity; NF-κB activation is controlled by IKK [IκB (inhibitor of NF-κB) kinase] complex, which regulates NF-κB activation in response to pro-inflammatory stimuli. The IKK complex has two catalytic subunits, IKKα and IKKβ; recent research shows that these highly homologous kinases have distinct roles in inflammation and adaptive immunity. Here, we discuss the emerging roles for IKKα in the tight regulation of inflammation and the development of adaptive immune responses.
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Hiraiwa, Kunihiko, and Stephan F. van Eeden. "Contribution of Lung Macrophages to the Inflammatory Responses Induced by Exposure to Air Pollutants." Mediators of Inflammation 2013 (2013): 1–10. http://dx.doi.org/10.1155/2013/619523.
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Large population cohort studies have indicated an association between exposure to particulate matter and cardiopulmonary morbidity and mortality. The inhalation of toxic environmental particles and gases impacts the innate and adaptive defense systems of the lung. Lung macrophages play a critically important role in the recognition and processing of any inhaled foreign material such as pathogens or particulate matter. Alveolar macrophages and lung epithelial cells are the predominant cells that process and remove inhaled particulate matter from the lung. Cooperatively, they produce proinflammatory mediators when exposed to atmospheric particles. These mediators produce integrated local (lung, controlled predominantly by epithelial cells) and systemic (bone marrow and vascular system, controlled predominantly by macrophages) inflammatory responses. The systemic response results in an increase in the release of leukocytes from the bone marrow and an increased production of acute phase proteins from the liver, with both factors impacting blood vessels and leading to destabilization of existing atherosclerotic plaques. This review focuses on lung macrophages and their role in orchestrating the inflammatory responses induced by exposure to air pollutants.
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Vinderola, Gabriel, Chantal Matar, and Gabriela Perdigon. "Role of Intestinal Epithelial Cells in Immune Effects Mediated by Gram-Positive Probiotic Bacteria: Involvement of Toll-Like Receptors." Clinical Diagnostic Laboratory Immunology 12, no. 9 (2005): 1075–84. http://dx.doi.org/10.1128/cdli.12.9.1075-1084.2005.
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ABSTRACT The mechanisms by which probiotic bacteria exert their effects on the immune system are not completely understood, but the epithelium may be a crucial player in the orchestration of the effects induced. In a previous work, we observed that some orally administered strains of lactic acid bacteria (LAB) increased the number of immunoglobulin A (IgA)-producing cells in the small intestine without a concomitant increase in the CD4+ T-cell population, indicating that some LAB strains induce clonal expansion only of B cells triggered to produce IgA. The present work aimed to study the cytokines induced by the interaction of probiotic LAB with murine intestinal epithelial cells (IEC) in healthy animals. We focused our investigation mainly on the secretion of interleukin 6 (IL-6) necessary for the clonal expansion of B cells previously observed with probiotic bacteria. The role of Toll-like receptors (TLRs) in such interaction was also addressed. The cytokines released by primary cultures of IEC in animals fed with Lactobacillus casei CRL 431 or Lactobacillus helveticus R389 were determined. Cytokines were also determined in the supernatants of primary cultures of IEC of unfed animals challenged with different concentrations of viable or nonviable lactobacilli and Escherichia coli, previously blocked or not with anti-TLR2 and anti-TLR4. We concluded that the small intestine is the place where a major distinction would occur between probiotic LAB and pathogens. This distinction comprises the type of cytokines released and the magnitude of the response, cutting across the line that separates IL-6 necessary for B-cell differentiation, which was the case with probiotic lactobacilli, from inflammatory levels of IL-6 for pathogens.
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Winkler, Peter. "Randy Newman's Americana." Popular Music 7, no. 1 (1988): 1–26. http://dx.doi.org/10.1017/s026114300000249x.
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This article is a study of the musical style of Randy Newman, one of the most intriguing singer–songwriters in the United States today. Since Newman's is hardly a household name, let me begin with a biographical note. Born in New Orleans in 1943, Randy Newman moved to Southern California at the age of five and has lived there ever since. While still a teenager he became staff songwriter for a small publishing company, and in 1966 achieved his first commercial success with a song recorded by Judy Collins, ‘I Think It's Going To Rain Today’. He began recording for Warner Brothers/Reprise in 1968, and has released an album every two or three years since then. Except for one hit, ‘Short People’ (1977), his music has appealed to a relatively small but devoted following. Unlike many contemporary songwriters, Newman is classically trained, and is a skilled orchestrator who writes his own arrangements, as well as arrangements for other artists and occasional film scores.
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Bobowski-Gerard, Marie, Francesco Zummo, Bart Staels, Philippe Lefebvre, and Jérôme Eeckhoute. "Retinoids Issued from Hepatic Stellate Cell Lipid Droplet Loss as Potential Signaling Molecules Orchestrating a Multicellular Liver Injury Response." Cells 7, no. 9 (2018): 137. http://dx.doi.org/10.3390/cells7090137.
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Hepatic stellate cells (HSCs) serve as the main body storage compartment for vitamin A through retinyl ester (RE)-filled lipid droplets (LDs). Upon liver injury, HSCs adopt a myofibroblastic phenotype characterized by an elevated expression of extracellular matrix proteins and a concomitant loss of LDs. On the one hand, LD breakdown has been suggested to provide the energy required for HSC activation into myofibroblast-like cells. On the other hand, this process could mitigate HSC activation following the transformation of released REs into retinoic acids (RAs), ligands for nuclear receptors exerting antifibrotic transcriptional regulatory activities in HSCs. Importantly, RAs may also constitute a means for HSCs to orchestrate the liver response to injury by triggering transcriptional effects in multiple additional surrounding liver cell populations. We envision that new approaches, such as single-cell technologies, will allow to better define how RAs are issued from LD loss in HSCs exert a multicellular control of the liver (patho)physiology.
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Wang, Dan, Aaron Harmon, Jing Jin, et al. "The Lack of an Inherent Membrane Targeting Signal Is Responsible for the Failure of the Matrix (M1) Protein of Influenza A Virus To Bud into Virus-Like Particles." Journal of Virology 84, no. 9 (2010): 4673–81. http://dx.doi.org/10.1128/jvi.02306-09.
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ABSTRACT The matrix protein (M1) of influenza A virus is generally viewed as a key orchestrator in the release of influenza virions from the plasma membrane during infection. In contrast to this model, recent studies have indicated that influenza virus requires expression of the envelope proteins for budding of intracellular M1 into virus particles. Here we explored the mechanisms that control M1 budding. Similarly to previous studies, we found that M1 by itself fails to form virus-like-particles (VLPs). We further demonstrated that M1, in the absence of other viral proteins, was preferentially targeted to the nucleus/perinuclear region rather than to the plasma membrane, where influenza virions bud. Remarkably, we showed that a 10-residue membrane targeting peptide from either the Fyn or Lck oncoprotein appended to M1 at the N terminus redirected M1 to the plasma membrane and allowed M1 particle budding without additional viral envelope proteins. To further identify a functional link between plasma membrane targeting and VLP formation, we took advantage of the fact that M1 can interact with M2, unless the cytoplasmic tail is absent. Notably, native M2 but not mutant M2 effectively targeted M1 to the plasma membrane and produced extracellular M1 VLPs. Our results suggest that influenza virus M1 may not possess an inherent membrane targeting signal. Thus, the lack of efficient plasma membrane targeting is responsible for the failure of M1 in budding. This study highlights the fact that interactions of M1 with viral envelope proteins are essential to direct M1 to the plasma membrane for influenza virus particle release.
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Berg, Johanna, Katja Zscheppang, Diana Fatykhova, et al. "Tyk2 as a target for immune regulation in human viral/bacterial pneumonia." European Respiratory Journal 50, no. 1 (2017): 1601953. http://dx.doi.org/10.1183/13993003.01953-2016.
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The severity and lethality of influenza A virus (IAV) infections is frequently aggravated by secondary bacterial pneumonia. However, the mechanisms in human lung tissue that provoke this increase in fatality are unknown and therapeutic immune modulatory options are lacking.We established a human lungex vivoco-infection model to investigate innate immune related mechanisms contributing to the susceptibility of secondary pneumococcal pneumonia.We revealed that type I and III interferon (IFN) inhibitsStreptococcus pneumoniae-induced interleukin (IL)-1β release. The lack of IL-1β resulted in the repression of bacterially induced granulocyte-macrophage colony-stimulating factor (GM-CSF) liberation. Specific inhibition of IFN receptor I and III-associated tyrosine kinase 2 (Tyk2) completely restored theS. pneumoniae-induced IL-1β–GM-CSF axis, leading to a reduction of bacterial growth. A preceding IAV infection of the human alveolus leads to a type I and III IFN-dependent blockade of the early cytokines IL-1β and GM-CSF, which are key for orchestrating an adequate innate immune response against bacteria. Their virally induced suppression may result in impaired bacterial clearance and alveolar repair.Pharmacological inhibition of Tyk2 might be a new treatment option to sustain beneficial endogenous GM-CSF levels in IAV-associated secondary bacterial pneumonia.