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Panicucci, Chiara, Lizzia Raffaghello, Santina Bruzzone, et al. "eATP/P2X7R Axis: An Orchestrated Pathway Triggering Inflammasome Activation in Muscle Diseases." International Journal of Molecular Sciences 21, no. 17 (2020): 5963. http://dx.doi.org/10.3390/ijms21175963.
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In muscle ATP is primarily known for its function as an energy source and as a mediator of the “excitation-transcription” process, which guarantees muscle plasticity in response to environmental stimuli. When quickly released in massive concentrations in the extracellular space as in presence of muscle membrane damage, ATP acts as a damage-associated molecular pattern molecule (DAMP). In experimental murine models of muscular dystrophies characterized by membrane instability, blockade of eATP/P2X7 receptor (R) purinergic signaling delayed the progression of the dystrophic phenotype dampening the local inflammatory response and inducing Foxp3+ T Regulatory lymphocytes. These discoveries highlighted the relevance of ATP as a harbinger of immune-tissue damage in muscular genetic diseases. Given the interactions between the immune system and muscle regeneration, the comprehension of ATP/purinerigic pathway articulated organization in muscle cells has become of extreme interest. This review explores ATP release, metabolism, feedback control and cross-talk with members of muscle inflammasome in the context of muscular dystrophies.
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Sepsi, Adél, and Trude Schwarzacher. "Chromosome–nuclear envelope tethering – a process that orchestrates homologue pairing during plant meiosis?" Journal of Cell Science 133, no. 15 (2020): jcs243667. http://dx.doi.org/10.1242/jcs.243667.
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ABSTRACTDuring prophase I of meiosis, homologous chromosomes pair, synapse and exchange their genetic material through reciprocal homologous recombination, a phenomenon essential for faithful chromosome segregation. Partial sequence identity between non-homologous and heterologous chromosomes can also lead to recombination (ectopic recombination), a highly deleterious process that rapidly compromises genome integrity. To avoid ectopic exchange, homology recognition must be extended from the narrow position of a crossover-competent double-strand break to the entire chromosome. Here, we review advances on chromosome behaviour during meiotic prophase I in higher plants, by integrating centromere- and telomere dynamics driven by cytoskeletal motor proteins, into the processes of homologue pairing, synapsis and recombination. Centromere–centromere associations and the gathering of telomeres at the onset of meiosis at opposite nuclear poles create a spatially organised and restricted nuclear state in which homologous DNA interactions are favoured but ectopic interactions also occur. The release and dispersion of centromeres from the nuclear periphery increases the motility of chromosome arms, allowing meiosis-specific movements that disrupt ectopic interactions. Subsequent expansion of interstitial synapsis from numerous homologous interactions further corrects ectopic interactions. Movement and organisation of chromosomes, thus, evolved to facilitate the pairing process, and can be modulated by distinct stages of chromatin associations at the nuclear envelope and their collective release.
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Miricescu, Daniela, Silviu Constantin Badoiu, Iulia-Ioana Stanescu-Spinu, Alexandra Ripszky Totan, Constantin Stefani, and Maria Greabu. "Growth Factors, Reactive Oxygen Species, and Metformin—Promoters of the Wound Healing Process in Burns?" International Journal of Molecular Sciences 22, no. 17 (2021): 9512. http://dx.doi.org/10.3390/ijms22179512.
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Burns can be caused by various factors and have an increased risk of infection that can seriously delay the wound healing process. Chronic wounds caused by burns represent a major health problem. Wound healing is a complex process, orchestrated by cytokines, growth factors, prostaglandins, free radicals, clotting factors, and nitric oxide. Growth factors released during this process are involved in cell growth, proliferation, migration, and differentiation. Reactive oxygen species are released in acute and chronic burn injuries and play key roles in healing and regeneration. The main aim of this review is to present the roles of growth factors, reactive oxygen species, and metformin in the healing process of burn injuries.
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Kim, Young-Mee, Seok-Jo Kim, Ryosuke Tatsunami, Hisao Yamamura, Tohru Fukai, and Masuko Ushio-Fukai. "ROS-induced ROS release orchestrated by Nox4, Nox2, and mitochondria in VEGF signaling and angiogenesis." American Journal of Physiology-Cell Physiology 312, no. 6 (2017): C749—C764. http://dx.doi.org/10.1152/ajpcell.00346.2016.
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Reactive oxygen species (ROS) derived from NADPH oxidase (NOX) and mitochondria play a critical role in growth factor-induced switch from a quiescent to an angiogenic phenotype in endothelial cells (ECs). However, how highly diffusible ROS produced from different sources can coordinate to stimulate VEGF signaling and drive the angiogenic process remains unknown. Using the cytosol- and mitochondria-targeted redox-sensitive RoGFP biosensors with real-time imaging, here we show that VEGF stimulation in human ECs rapidly increases cytosolic RoGFP oxidation within 1 min, followed by mitochondrial RoGFP oxidation within 5 min, which continues at least for 60 min. Silencing of Nox4 or Nox2 or overexpression of mitochondria-targeted catalase significantly inhibits VEGF-induced tyrosine phosphorylation of VEGF receptor type 2 (VEGFR2-pY), EC migration and proliferation at the similar extent. Exogenous hydrogen peroxide (H2O2) or overexpression of Nox4, which produces H2O2, increases mitochondrial ROS (mtROS), which is prevented by Nox2 siRNA, suggesting that Nox2 senses Nox4-derived H2O2 to promote mtROS production. Mechanistically, H2O2 increases S36 phosphorylation of p66Shc, a key mtROS regulator, which is inhibited by siNox2, but not by siNox4. Moreover, Nox2 or Nox4 knockdown or overexpression of S36 phosphorylation-defective mutant p66Shc(S36A) inhibits VEGF-induced mtROS, VEGFR2-pY, EC migration, and proliferation. In summary, Nox4-derived H2O2 in part activates Nox2 to increase mtROS via pSer36-p66Shc, thereby enhancing VEGFR2 signaling and angiogenesis in ECs. This may represent a novel feed-forward mechanism of ROS-induced ROS release orchestrated by the Nox4/Nox2/pSer36-p66Shc/mtROS axis, which drives sustained activation of angiogenesis signaling program.
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Bonet-Ponce, Luis, Alexandra Beilina, Chad D. Williamson, et al. "LRRK2 mediates tubulation and vesicle sorting from lysosomes." Science Advances 6, no. 46 (2020): eabb2454. http://dx.doi.org/10.1126/sciadv.abb2454.
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Genetic variation around the LRRK2 gene affects risk of both familial and sporadic Parkinson’s disease (PD). However, the biological functions of LRRK2 remain incompletely understood. Here, we report that LRRK2 is recruited to lysosomes after exposure of cells to the lysosome membrane–rupturing agent LLOME. Using an unbiased proteomic screen, we identified the motor adaptor protein JIP4 as an LRRK2 partner at the lysosomal membrane. LRRK2 can recruit JIP4 to lysosomes in a kinase-dependent manner via the phosphorylation of RAB35 and RAB10. Using super-resolution live-cell imaging microscopy and FIB-SEM, we demonstrate that JIP4 promotes the formation of LAMP1-negative tubules that release membranous content from lysosomes. Thus, we describe a new process orchestrated by LRRK2, which we name LYTL (LYsosomal Tubulation/sorting driven by LRRK2), by which lysosomal tubulation is used to release vesicles from lysosomes. Given the central role of the lysosome in PD, LYTL is likely to be disease relevant.
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Chatzi, Katerina E., Marios F. Sardis, Spyridoula Karamanou, and Anastassios Economou. "Breaking on through to the other side: protein export through the bacterial Sec system." Biochemical Journal 449, no. 1 (2012): 25–37. http://dx.doi.org/10.1042/bj20121227.
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More than one-third of cellular proteomes traffic into and across membranes. Bacteria have invented several sophisticated secretion systems that guide various proteins to extracytoplasmic locations and in some cases inject them directly into hosts. Of these, the Sec system is ubiquitous, essential and by far the best understood. Secretory polypeptides are sorted from cytoplasmic ones initially due to characteristic signal peptides. Then they are targeted to the plasma membrane by chaperones/pilots. The translocase, a dynamic nanomachine, lies at the centre of this process and acts as a protein-conducting channel with a unique property; allowing both forward transfer of secretory proteins but also lateral release into the lipid bilayer with high fidelity and efficiency. This process, tightly orchestrated at the expense of energy, ensures fundamental cell processes such as membrane biogenesis, cell division, motility, nutrient uptake and environmental sensing. In the present review, we examine this fascinating process, summarizing current knowledge on the structure, function and mechanics of the Sec pathway.
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Ramírez-Pérez, Sergio, Luis Alexis Hernández-Palma, Edith Oregon-Romero та ін. "Downregulation of Inflammatory Cytokine Release from IL-1β and LPS-Stimulated PBMC Orchestrated by ST2825, a MyD88 Dimerisation Inhibitor". Molecules 25, № 18 (2020): 4322. http://dx.doi.org/10.3390/molecules25184322.
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The inflammatory process implicates homeostasis disruption and increased production of inflammatory mediators. Myeloid differentiation primary response 88 (MyD88) is an essential protein recruited after lipopolysaccharide (LPS) and interleukin (IL)-1β stimulation, a process that converges in nuclear factor kappa B (NF-κB) activation, as well as a transcription of several genes of both pro- and anti-inflammatory cytokines. The inhibition of MyD88 has shown efficacy by decrease inflammatory response, and has demonstrated potential application as a therapeutic target in chronic diseases. In this study, we investigate the effect of MyD88 dimerisation inhibitor ST2825 on cytokine production from rhIL-1β and LPS-stimulated peripheral blood mononuclear cells (PBMC) from healthy blood donors (HBD). ST2825 significantly downregulates the production of IFN-γ, IL-6, IL-12, IL-2, IL-15, IL-7, VEGF, IL-1Ra, IL-4, IL-5, IL-13 and IL-9 (p < 0.05) in LPS-stimulated PBMC. Moreover, ST2825 had a relatively low impact on IL-1β signalling pathway inhibition, showing that only a few specific cytokines, such as IFN-γ and IL-1Ra, are inhibited in rhIL-1β-stimulated PBMC (p < 0.01). In conclusion, MyD88 dimerisation inhibitor ST2825 showed high efficacy by inhibiting pro- and anti-inflammatory cytokine production in LPS-stimulated PBMC. Moreover, although rhIL-1β induced a sustained cytokine production (p < 0.05), ST2825 did not show a significant effect in the secretion of neither pro- nor anti-inflammatory cytokines in rhIL-1β-stimulated PBMC.
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Leydon, Alexander R., Adisorn Chaibang, and Mark A. Johnson. "Interactions between pollen tube and pistil control pollen tube identity and sperm release in the Arabidopsis female gametophyte." Biochemical Society Transactions 42, no. 2 (2014): 340–45. http://dx.doi.org/10.1042/bst20130223.
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Flowering plants have immotile sperm that develop within the pollen cytoplasm and are delivered to female gametes by a pollen tube, a highly polarized extension of the pollen cell. In many flowering plant species, including seed crop plants, hundreds of pollen tubes grow towards a limited number of ovules. This system should ensure maximal fertilization of ovules and seed production; however, we know very little about how signalling between the critical cells is integrated to orchestrate delivery of two functional sperm to each ovule. Recent studies suggest that the pollen tube changes its gene-expression programme in response to growth through pistil tissue and that this differentiation process is critical for pollen tube attraction by the female gametophyte and for release of sperm. Interestingly, these two signalling systems, called pollen tube guidance and pollen tube reception, are also species-preferential. The present review focuses on Arabidopsis pollen tube differentiation within the pistil and addresses the idea that pollen tube differentiation defines pollen tube identity and recognition by female cells. We review recent identification of genes that may control pollen tube–female gametophyte recognition and discuss how these may be involved in blocking interspecific hybridization.
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Boscher, Julie, Ines Guinard, Anita Eckly, François Lanza, and Catherine Léon. "Blood platelet formation at a glance." Journal of Cell Science 133, no. 20 (2020): jcs244731. http://dx.doi.org/10.1242/jcs.244731.
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ABSTRACTThe main function of blood platelets is to ensure hemostasis and prevent hemorrhages. The 1011 platelets needed daily are produced in a well-orchestrated process. However, this process is not yet fully understood and in vitro platelet production is still inefficient. Platelets are produced in the bone marrow by megakaryocytes, highly specialized precursor cells that extend cytoplasmic projections called proplatelets (PPTs) through the endothelial barrier of sinusoid vessels. In this Cell Science at a Glance article and the accompanying poster we discuss the mechanisms and pathways involved in megakaryopoiesis and platelet formation processes. We especially address the – still underestimated – role of the microenvironment of the bone marrow, and present recent findings on how PPT extension in vivo differs from that in vitro and entails different mechanisms. Finally, we recapitulate old but recently revisited evidence that – although bone marrow does produce megakaryocytes and PPTs – remodeling and the release of bona fide platelets, mainly occur in the downstream microcirculation.
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Omenetti, Alessia, Liu Yang, Raul R. Gainetdinov, et al. "Paracrine modulation of cholangiocyte serotonin synthesis orchestrates biliary remodeling in adults." American Journal of Physiology-Gastrointestinal and Liver Physiology 300, no. 2 (2011): G303—G315. http://dx.doi.org/10.1152/ajpgi.00368.2010.
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Paracrine signaling between cholangiocytes and stromal cells regulates biliary remodeling. Cholangiocytes have neuroepithelial characteristics and serotonin receptor agonists inhibit their growth, but whether they are capable of serotonin biosynthesis is unknown. We hypothesized that cholangiocytes synthesize serotonin and that cross talk between liver myofibroblasts (MF) and cholangiocytes regulates this process to influence biliary remodeling. Transwell cultures of cholangiocytes ± MF, and tryptophan hydroxylase-2 knockin (TPH2KI) mice with an inactivating mutation of the neuronal tryptophan hydroxylase (TPH) isoform, TPH2, were evaluated. Results in the cell culture models confirm that cholangiocytes have serotonin receptors and demonstrate for the first time that these cells express TPH2 and produce serotonin, which autoinhibits their growth but stimulates MF production of TGF-β1. Increased TGF-β1, in turn, counteracts autocrine inhibition of cholangiocyte growth by repressing cholangiocyte TPH2 expression. Studies of TPH2KI mice confirm that TPH2-mediated production of serotonin plays an important role in remodeling damaged bile ducts because mice with decreased TPH2 function have reduced biliary serotonin levels and exhibit excessive cholangiocyte proliferation, accumulation of aberrant ductules and liver progenitors, and increased liver fibrosis after bile duct ligation. This new evidence that cholangiocytes express the so-called neuronal isoform of TPH, synthesize serotonin de novo, and deploy serotonin as an autocrine/paracrine signal to regulate regeneration of the biliary tree complements earlier work that revealed that passive release of serotonin from platelets stimulates hepatocyte proliferation. Given the prevalent use of serotonin-modulating drugs, these findings have potentially important implications for recovery from various types of liver damage.
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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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Nürenberg-Goloub, Elina, Holger Heinemann, Milan Gerovac, and Robert Tampé. "Ribosome recycling is coordinated by processive events in two asymmetric ATP sites of ABCE1." Life Science Alliance 1, no. 3 (2018): e201800095. http://dx.doi.org/10.26508/lsa.201800095.
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Ribosome recycling orchestrated by ABCE1 is a fundamental process in protein translation and mRNA surveillance, connecting termination with initiation. Beyond the plenitude of well-studied translational GTPases, ABCE1 is the only essential factor energized by ATP, delivering the energy for ribosome splitting via two nucleotide-binding sites by a yet unknown mechanism. Here, we define how allosterically coupled ATP binding and hydrolysis events in ABCE1 empower ribosome recycling. ATP occlusion in the low-turnover control site II promotes formation of the pre-splitting complex and facilitates ATP engagement in the high-turnover site I, which in turn drives the structural reorganization required for ribosome splitting. ATP hydrolysis and ensuing release of ABCE1 from the small subunit terminate the post-splitting complex. Thus, ABCE1 runs through an allosterically coupled cycle of closure and opening at both sites, consistent with a processive clamp model. This study delineates the inner mechanics of ABCE1 and reveals why various ABCE1 mutants lead to defects in cell homeostasis, growth, and differentiation.
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Stramer, Brian, Will Wood, Michael J. Galko, et al. "Live imaging of wound inflammation in Drosophila embryos reveals key roles for small GTPases during in vivo cell migration." Journal of Cell Biology 168, no. 4 (2005): 567–73. http://dx.doi.org/10.1083/jcb.200405120.
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Aa robust inflammatory response to tissue damage and infection is conserved across almost all animal phyla. Neutrophils and macrophages, or their equivalents, are drawn to the wound site where they engulf cell and matrix debris and release signals that direct components of the repair process. This orchestrated cell migration is clinically important, and yet, to date, leukocyte chemotaxis has largely been studied in vitro. Here, we describe a genetically tractable in vivo wound model of inflammation in the Drosophila melanogaster embryo that is amenable to cinemicroscopy. For the first time, we are able to examine the roles of Rho-family small GTPases during inflammation in vivo and show that Rac-mediated lamellae are essential for hemocyte motility and Rho signaling is necessary for cells to retract from sites of matrix– and cell–cell contacts. Cdc42 is necessary for maintaining cellular polarity and yet, despite in vitro evidence, is dispensable for sensing and crawling toward wound cues.
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Martinod, Kimberly, Thilo Witsch, Luise Erpenbeck, et al. "Peptidylarginine deiminase 4 promotes age-related organ fibrosis." Journal of Experimental Medicine 214, no. 2 (2016): 439–58. http://dx.doi.org/10.1084/jem.20160530.
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Aging promotes inflammation, a process contributing to fibrosis and decline in organ function. The release of neutrophil extracellular traps (NETs [NETosis]), orchestrated by peptidylarginine deiminase 4 (PAD4), damages organs in acute inflammatory models. We determined that NETosis is more prevalent in aged mice and investigated the role of PAD4/NETs in age-related organ fibrosis. Reduction in fibrosis was seen in the hearts and lungs of aged PAD4−/− mice compared with wild-type (WT) mice. An increase in left ventricular interstitial collagen deposition and a decline in systolic and diastolic function were present only in WT mice, and not in PAD4−/− mice. In an experimental model of cardiac fibrosis, cardiac pressure overload induced NETosis and significant platelet recruitment in WT but not PAD4−/− myocardium. DNase 1 was given to assess the effects of extracellular chromatin. PAD4 deficiency or DNase 1 similarly protected hearts from fibrosis. We propose a role for NETs in cardiac fibrosis and conclude that PAD4 regulates age-related organ fibrosis and dysfunction.
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Gianni, Tatiana, Raffaele Massaro та Gabriella Campadelli-Fiume. "Dissociation of HSV gL from gH by αvβ6- or αvβ8-integrin promotes gH activation and virus entry". Proceedings of the National Academy of Sciences 112, № 29 (2015): E3901—E3910. http://dx.doi.org/10.1073/pnas.1506846112.
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Herpes simplex virus (HSV) is an important human pathogen. It enters cells through an orchestrated process that requires four essential glycoproteins, gD, gH/gL, and gB, activated in cascade fashion by receptor-binding and signaling. gH/gL heterodimer is conserved across theHerpesviridaefamily. HSV entry is enabled by gH/gL interaction with αvβ6- or αvβ8-integrin receptors. We report that the interaction of virion gH/gL with integrins resulted in gL dissociation and its release in the medium. gL dissociation occurred if all components of the entry apparatus—receptor-bound gD and gB—were present and was prevented if entry was blocked by a neutralizing monoclonal antibody to gH or by a mutation in gH. We propose that (i) gL dissociation from gH/gL is part of the activation of HSV glycoproteins, critical for HSV entry; and (ii) gL is a functional inhibitor of gH and maintains gH in an inhibited form until receptor-bound gD and integrins signal to gH/gL.
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Sáez, Juan José, Jheimmy Diaz, Jorge Ibañez, et al. "The exocyst controls lysosome secretion and antigen extraction at the immune synapse of B cells." Journal of Cell Biology 218, no. 7 (2019): 2247–64. http://dx.doi.org/10.1083/jcb.201811131.
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B lymphocytes capture antigens from the surface of presenting cells by forming an immune synapse. Local secretion of lysosomes, which are guided to the synaptic membrane by centrosome repositioning, can facilitate the extraction of immobilized antigens. However, the molecular basis underlying their delivery to precise domains of the plasma membrane remains elusive. Here we show that microtubule stabilization, triggered by engagement of the B cell receptor, acts as a cue to release centrosome-associated Exo70, which is redistributed to the immune synapse. This process is coupled to the recruitment and activation of GEF-H1, which is required for assembly of the exocyst complex, used to promote tethering and fusion of lysosomes at the immune synapse. B cells silenced for GEF-H1 or Exo70 display defective lysosome secretion, which results in impaired antigen extraction and presentation. Thus, centrosome repositioning coupled to changes in microtubule stability orchestrates the spatial-temporal distribution of the exocyst complex to promote polarized lysosome secretion at the immune synapse.
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Cirone, Mara. "ER Stress, UPR Activation and the Inflammatory Response to Viral Infection." Viruses 13, no. 5 (2021): 798. http://dx.doi.org/10.3390/v13050798.
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The response to invading pathogens such as viruses is orchestrated by pattern recognition receptor (PRR) and unfolded protein response (UPR) signaling, which intersects and converges in the activation of proinflammatory pathways and the release of cytokines and chemokines that harness the immune system in the attempt to clear microbial infection. Despite this protective intent, the inflammatory response, particularly during viral infection, may be too intense or last for too long, whereby it becomes the cause of organ or systemic diseases itself. This suggests that a better understanding of the mechanisms that regulate this complex process is needed in order to achieve better control of the side effects that inflammation may cause while potentiating its protective role. The use of specific inhibitors of the UPR sensors or PRRs or the downstream pathways activated by their signaling could offer the opportunity to reach this goal and improve the outcome of inflammation-based diseases associated with viral infections.
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Lee, Sook-Kyung, Janera Harris, and Ronald Swanstrom. "A Strongly Transdominant Mutation in the Human Immunodeficiency Virus Type 1 gag Gene Defines an Achilles Heel in the Virus Life Cycle." Journal of Virology 83, no. 17 (2009): 8536–43. http://dx.doi.org/10.1128/jvi.00317-09.
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ABSTRACT The human immunodeficiency virus type 1 (HIV-1) protease (PR) makes five obligatory cleavages in the viral Gag polyprotein precursor. The cleavage events release the virion structural proteins from the precursor and allow the virion to undergo maturation to become infectious. The protease cleavage between the matrix protein (MA) domain and the adjacent capsid protein (CA) domain releases CA from the membrane-anchored MA and allows the N terminus of CA to refold into a structure that facilitates the formation of hexamer arrays that represent the structural unit of the capsid shell. In this study, we analyzed the extent to which each of the HIV-1 Gag processing sites must be cleaved by substituting the P1-position amino acid at each processing site with Ile. A mutation that blocks cleavage at the MA/CA processing site (Y132I) displayed a strong transdominant effect when tested in a phenotypic mixing strategy, inhibiting virion infectivity with a 50% inhibitory concentration of only 4% of the mutant relative to the wild type. This mutation is 10- to 20-fold more potent in phenotypic mixing than an inactivating mutation in the viral protease, the target of many successful inhibitors, and more potent than an inactivating mutation at any of the other Gag cleavage sites. The transdominant effect is manifested as the assembly of an aberrant virion core. Virus containing 20% of the Y132I mutant and 80% of the wild type (to assess the transdominant effect on infectivity) was blocked either before reverse transcription (RT) or at an early RT step. The ability of a small amount of the MA/CA fusion protein to poison the oligomeric assembly of infectious virus identifies an essential step in the complex process of virion formation and maturation. The effect of a small-molecule inhibitor that is able to block MA/CA cleavage even partially would be amplified by this transdominant negative effect on the highly orchestrated process of virion assembly.
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Xiang, Zou, Ahmed A. Ahmed, Christine Möller, Kei-ichi Nakayama, Shigetsugu Hatakeyama, and Gunnar Nilsson. "Essential Role of the Prosurvival bcl-2 Homologue A1 in Mast Cell Survival After Allergic Activation." Journal of Experimental Medicine 194, no. 11 (2001): 1561–70. http://dx.doi.org/10.1084/jem.194.11.1561.
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Mast cells reside in tissues, where upon activation through the high-affinity-IgE-receptor (FcϵRI) they degranulate and orchestrate the allergic reaction. Mast cells survive this activation and can thus be reactivated. In this study we demonstrate that this process depends on the pro-survival gene A1. Activation of mast cells through FcϵRI resulted in degranulation, strong induction of A1 mRNA and protein, and cell survival. In contrast, A1-deficient mast cells released granule mediators similar to the wild-type control, but the cells did not survive an allergic activation. Furthermore, A1−/− mice that had been sensitized and provocated with allergen exhibited a lower number of mast cell compared with littermate controls. The induction of A1 was dependent on calcium, as EDTA prevented A1 expression. The calcium ionophore, ionomycin, induced A1 expression and mast cell survival, whereas compound 48/80, a well-known mast cell secretagogue, did not. This study uncovers the importance of A1 for mast cell survival in allergic reactions, and it proposes A1 as a potential target for the treatment of allergic diseases.
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Aziz, Shiekh Aejaz. "Angiogenesis and Cancer." JMS SKIMS 12, no. 2 (2009): 32–33. http://dx.doi.org/10.33883/jms.v12i2.11.
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Tumors measuring 1-2 (mm)3 lack blood supply and neovascularization is a major process orchestrated by over-production and release of pro-angiogenic growth factors causing sequential step-wise formation of blood vessel capillaries in tumors.Moleculars mediators of tumors angiogenesis include VEGF family, IL-8, EGF receptor ligands, basic and acidic FGF, PDGF etc. There are natural endogenenous inhibitors of tumorigenesis (TSP-1,Vasostatin).Negative feedback mechanisms do exist to control/regulate tumor angiogenesis. Angiogeneis is detrimental to tumor progression favouring transition from hyperplasia to a neoplastic state, influencing cancer cell dissemination besides exerting an independent negative prognosis. Tumor vasculature is dysfunctional, heterogeneous in the tumor mass interms of density leading to a limited/retarded diffusion of drugs especially certain antibodies,gene therapy vectors, immune-effector cells through interstitium of these tumors. The hypoxic zones in tumors are the areas of resistance to the chemotherapy. Angiogenesis is upregulated in tumorigenesis leading to over-production of proangiogenic growth factors that have become targets for anticancer drug development. J Med Sci.2009;12(2):32-33
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Park, Hyo-Hyun, Na-Young Park, Sun-Gun Kim, Kyu-Tae Jeong, Eu-Jin Lee, and Eunkyung Lee. "Potential Wound Healing Activities of Galla Rhois in Human Fibroblasts and Keratinocytes." American Journal of Chinese Medicine 43, no. 08 (2015): 1625–36. http://dx.doi.org/10.1142/s0192415x15500925.
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Wound healing is a complex process orchestrated by the regeneration of the epithelium and the remodeling of the extracellular matrix through processes like collagen deposition. Galla Rhois has been widely used in traditional Korean medicine for its various pharmacological effects, including an anticoccidial effect, however, little is known about its healing activity. The purpose of this study was to determine the effects of Galla Rhois ethanol extract (GRE) on wound healing activities, including H2O2-induced oxidative stress, cell migration, and lactate dehydrogenase (LDH) release assays using human keratinocyte (HaCaT) and dermal fibroblasts (CCD-986SK). In addition, total soluble collagen deposition and collagen gene expression for Type I and III collagen were evaluated in CCD-986SK. Total tannin and flavonoid contents for GRE were measured. GRE induced a significant increase in the number and migration of cells, along with a decrease in cell death and LDH release. In addition, it also induced the over-expression of collagen Type I and III mRNA and caused increased synthesis of total soluble collagen. The contents of total tannin and flavonoid for GRE were 55.7% ([Formula: see text][Formula: see text]mg/g) and 62.9% ([Formula: see text][Formula: see text]mg/g), respectively. The results suggest that GRE can cause accelerated wound healing by increasing cell survival, proliferation, migration, and collagen synthesis along with a potential anti-oxidant property. This evidence provides novel insight into natural therapy for tissue injury.
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Agustina Kusuma Dewi, Yasraf Amir Piliang, Irfansyah, and Acep Iwan Saidi. "Agustina Kusuma Dewi TRANSPOSISI KREATIF ‘GERAK’ DALAM FILM SEBAGAI IDENTITAS KULTURAL PADA ERA MULTILITERASI DIGITAL Studi Kasus Film ‘Setan Jawa’ Karya Garin Nugroho." PROSIDING: SENI, TEKNOLOGI, DAN MASYARAKAT 2 (January 24, 2020): 93–98. http://dx.doi.org/10.33153/semhas.v2i0.106.
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Technology change the way of thinking, how people access information also influence process to spread andshare information in various media, including film, an art that plays images and screen technology. In the film,‘movement’ is a changing position of an object. Accelerating technology constructed’movement’ becomes animportant keyword that needs to be presented in every communication channel. ‘Setan Jawa’ Film by GarinNugroho with Gamelan Orchestra composed by Rahayu Supanggah, was released in Indonesia in 2016 inJakarta and still scheduled to tour the world until 2020. Combines a variety of collaborative art, design andtechnology—‘Setan Jawa’ creating a multiliterated communication channel that has possibilities to become amedium society cultural education. In this film, ‘movement’ becomes a sign constructed by creative transpositionof narratives in various arts, including puppets. Using a case study approach and documentation analysis,referring to the results of Roger Long’s research (1979), this research aims to identify creative forms ofpuppet’s ‘movement’ transposition in the film ‘Setan Jawa’ as cultural identity, a finding that in the Industrial Era4.0; through multiliteration digital, process of cultural discourseto society could be done through a varietyvehicle of signs.
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Robidoux, Jacques, Lucie Simoneau, André Masse, and Julie Lafond. "Activation of L-Type Calcium Channels Induces Corticotropin-Releasing Factor Secretion from Human Placental Trophoblasts*." Journal of Clinical Endocrinology & Metabolism 85, no. 9 (2000): 3356–64. http://dx.doi.org/10.1210/jcem.85.9.6774.
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Abstract The ultimate outcome of pregnancy, parturition, is a well orchestrated process in which placental corticotropin-releasing factor (CRF) seems to play an important role. The objective of the present study was to investigate the involvement of L-type calcium channels and calcium-dependent signaling in the depolarization-induced CRF release from human syncytiotrophoblast. The basal secretion of CRF by trophoblastic cells, isolated from human term placenta, was maximal after their functional differentiation, which was monitored by hCG measurements. On the fourth day of culture, the basal CRF secretion of the cells in serum-free medium was linear between 2 and 8 h. Incubation of the trophoblasts with KCl, a depolarizing stimulus, or with Bay K8644, an L-type calcium channel agonist, for 3 or 8 h led to an increase in CRF secretion, but was without effect on its synthesis. This stimulated CRF release was calcium dependent, as it could be prevented by loading cells with 1,2-bis(0-Aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid (acetoxymethyl) ester. Furthermore, the KCl-induced CRF secretion involved L-type calcium channels activation, as 2 μmol/L nitrendipine, an L-type specific blocker, abolished the stimulation. In trophoblasts, where we have previously shown calcium-dependent protein kinase C (cPKCs) activity, incubation with Bay K8644 also stimulated calcium calmodulin kinase II (CaMKII) and extracellular regulated kinase activities. In the present study we observed that CaMKII and cPKCs were linked to the Bay K8644-induced secretion of CRF, as only the autocamtide-2 related inhibitory peptide, a CaMKII inhibitor, and Gö6976, an inhibitor of μ and cPKCs partially prevented (30–78%) the activation of CRF release by Bay K8644. The use of PD 098056, an inhibitor of the ERKs kinases, showed no effect on CRF release. Taken together, these results support a depolarization-induced and calcium-dependent exocytotic-like secretion of CRF from human placental trophoblasts. In addition, CaMKII and cPKCs seem to be potential modulators or mediators of these calcium effects on CRF secretion.
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Landis, Robert Clive, Kim R. Quimby, and Andre R. Greenidge. "M1/M2 Macrophages in Diabetic Nephropathy: Nrf2/HO-1 as Therapeutic Targets." Current Pharmaceutical Design 24, no. 20 (2018): 2241–49. http://dx.doi.org/10.2174/1381612824666180716163845.
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The process of inflammation is orchestrated by macrophages, according to their state of differentiation: thus, classically activated (M1) macrophages initiate the process by elaborating proinflammatory cytokines and reactive oxygen species, whereas the latter phase is controlled by alternatively activated macrophages (M2) to resolve inflammation and promote tissue remodelling with the release of growth factors. In a simple human inflammatory response, such as acute crystal arthropathy, macrophages progress linearly through M1 and M2 phases; however, in chronic inflammatory responses, such as atherosclerosis and Diabetic Nephropathy (DN), both M1 and M2 macrophages may coexist, leading to persistent inflammation and fibrosis. A key macrophage receptor that regulates conversion from M1 to M2 is CD163, the hemoglobin scavenger receptor. Scavenging of hemoglobin:haptoglobin (Hb:Hp) complexes via CD163 leads to nuclear translocation of the transcription factor Nrf2 (NF-E2-related factor 2), upregulation of heme oxygenase (HO)-1 cytoprotective protein, and release of interleukin (IL)-10 anti-inflammatory cytokine; IL-10 is then linked in a positive feedback loop to further CD163 expression. The potency of this M1/M2 switching pathway is underscored by the fact that human Hp2 polymorphisms are associated with worsened clinical outcomes for diabetic complications, including DN. Parallel observations in animals show that HO-1 activation by hemin protects against DN in rodent models of diabetes. This review discusses the concept that Nrf2/HO-1 acts as a ‘therapeutic funnel’ through which a range of natural and synthetic anti-oxidants may drive M1 to M2 switching and improved kidney function in diabetes. We also discuss our observations on the evolution of M1/M2 phenotypes in a human model of wound healing which has presented intriguing potential drug targets for DN, such as eotaxin/CCR3.
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Chagraoui, Hedia, Mira Kassouf, Sreemoti Banerjee, et al. "SCL-mediated regulation of the cell-cycle regulator p21 is critical for murine megakaryopoiesis." Blood 118, no. 3 (2011): 723–35. http://dx.doi.org/10.1182/blood-2011-01-328765.
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Abstract Megakaryopoiesis is a complex process that involves major cellular and nuclear changes and relies on controlled coordination of cellular proliferation and differentiation. These mechanisms are orchestrated in part by transcriptional regulators. The key hematopoietic transcription factor stem cell leukemia (SCL)/TAL1 is required in early hematopoietic progenitors for specification of the megakaryocytic lineage. These early functions have, so far, prevented full investigation of its role in megakaryocyte development in loss-of-function studies. Here, we report that SCL critically controls terminal megakaryocyte maturation. In vivo deletion of Scl specifically in the megakaryocytic lineage affects all key attributes of megakaryocyte progenitors (MkPs), namely, proliferation, ploidization, cytoplasmic maturation, and platelet release. Genome-wide expression analysis reveals increased expression of the cell-cycle regulator p21 in Scl-deleted MkPs. Importantly, p21 knockdown-mediated rescue of Scl-mutant MkPs shows full restoration of cell-cycle progression and partial rescue of the nuclear and cytoplasmic maturation defects. Therefore, SCL-mediated transcriptional control of p21 is essential for terminal maturation of MkPs. Our study provides a mechanistic link between a major hematopoietic transcriptional regulator, cell-cycle progression, and megakaryocytic differentiation.
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Meyer, Imke, Stefan Kunert, Silke Schwiebert, et al. "Altered microtubule equilibrium and impaired thrombus stability in mice lacking RanBP10." Blood 120, no. 17 (2012): 3594–602. http://dx.doi.org/10.1182/blood-2012-01-401737.
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Abstract The crucial function of blood platelets in hemostasis is to prevent blood loss by stable thrombus formation. This process is driven by orchestrated mechanisms including several signal transduction cascades and morphologic transformations. The cytoplasmic microtubule modulator RanBP10 is a Ran and β1-tubulin binding protein that is essential for platelet granule release and mice lacking RanBP10 harbor a severe bleeding phenotype. In this study, we demonstrate that RanBP10-nullizygous platelets show normal adhesion on collagen and von Willebrand factor under flow conditions. However, using a ferric chloride-induced arterial thrombosis model, the formation of stable thrombi was significantly impaired, preventing vessel occlusion or leading to recanalization and thromboembolization. Delta-granule secretion was normal in mutant mice, whereas platelet shape change in aggregometry was attenuated. Lack of RanBP10 leads to increased β1-tubulin protein, which drives α-monomers into polymerized microtubules. In mutant platelets agonists failed to contract the peripheral marginal band or centralize granules. Pretreatment of wild-type platelets with taxol caused microtubule stabilization and phenocopied the attenuated shape change in response to collagen, suggesting that RanBP10 inhibits premature microtubule polymerization of β1-tubulin and plays a pivotal role in thrombus stabilization.
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Johnson, Louise A., and David G. Jackson. "Hyaluronan and Its Receptors: Key Mediators of Immune Cell Entry and Trafficking in the Lymphatic System." Cells 10, no. 8 (2021): 2061. http://dx.doi.org/10.3390/cells10082061.
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Entry to the afferent lymphatics marks the first committed step for immune cell migration from tissues to draining lymph nodes both for the generation of immune responses and for timely resolution of tissue inflammation. This critical process occurs primarily at specialised discontinuous junctions in initial lymphatic capillaries, directed by chemokines released from lymphatic endothelium and orchestrated by adhesion between lymphatic receptors and their immune cell ligands. Prominent amongst the latter is the large glycosaminoglycan hyaluronan (HA) that can form a bulky glycocalyx on the surface of certain tissue-migrating leucocytes and whose engagement with its key lymphatic receptor LYVE-1 mediates docking and entry of dendritic cells to afferent lymphatics. Here we outline the latest insights into the molecular mechanisms by which the HA glycocalyx together with LYVE-1 and the related leucocyte receptor CD44 co-operate in immune cell entry, and how the process is facilitated by the unusual character of LYVE-1 • HA-binding interactions. In addition, we describe how pro-inflammatory breakdown products of HA may also contribute to lymphatic entry by transducing signals through LYVE-1 for lymphangiogenesis and increased junctional permeability. Lastly, we outline some future perspectives and highlight the LYVE-1 • HA axis as a potential target for immunotherapy.
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Martínez, M. Carmen, Angela Tesse, Fatiha Zobairi, and Ramaroson Andriantsitohaina. "Shed membrane microparticles from circulating and vascular cells in regulating vascular function." American Journal of Physiology-Heart and Circulatory Physiology 288, no. 3 (2005): H1004—H1009. http://dx.doi.org/10.1152/ajpheart.00842.2004.
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Inflammation has a pivotal role in the development of atherosclerosis and acute activation of the vascular wall with consecutive local thrombosis and altered vasomotion. This process is orchestrated by the interactions between inflammatory cells, such as platelets and T and B lymphocytes, and vascular cells, endothelial cells, and smooth muscle cells. When they are activated by an agonist, shear stress, or apoptosis, these cells release vesicles shed from the blebbing plasma membrane called microparticles. Microparticles harbor cell surface proteins and contain cytoplasmic components of the original cell. They exhibit negatively charged phospholipids, chiefly phosphatidylserine, at their surface, which accounts for their procoagulant character and proinflammatory properties, including alteration of vascular function. Elevated levels of circulating microparticles have been detected in pathological states associated with vascular dysfunction, including attenuation of endothelium-dependent vasodilatation and/or alteration of responsiveness of vascular smooth muscle to vasoconstrictor stimuli in conductance and resistance arteries. This review points out the characteristics of microparticles as well as the biological messages they can mediate. In particular, it summarizes the signaling cascades involved in microparticle-induced vascular dysfunction with special attention to the cellular origin of these vesicles (platelet, endothelial, and leukocytic), which may explain their differential consequences on vascular remodeling. The available information provides a rationale for the paracrine role of microparticles as vectors of transcellular exchange of message between circulating cells and cells from the vascular wall.
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Albrecht, Reinhard, Monika Schütz, Philipp Oberhettinger, et al. "Structure of BamA, an essential factor in outer membrane protein biogenesis." Acta Crystallographica Section D Biological Crystallography 70, no. 6 (2014): 1779–89. http://dx.doi.org/10.1107/s1399004714007482.
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Outer membrane protein (OMP) biogenesis is an essential process for maintaining the bacterial cell envelope and involves the β-barrel assembly machinery (BAM) for OMP recognition, folding and assembly. InEscherichia colithis function is orchestrated by five proteins: the integral outer membrane protein BamA of the Omp85 superfamily and four associated lipoproteins. To unravel the mechanism underlying OMP folding and insertion, the structure of theE. coliBamA β-barrel and P5 domain was determined at 3 Å resolution. These data add information beyond that provided in the recently published crystal structures of BamA fromHaemophilus ducreyiandNeisseria gonorrhoeaeand are a valuable basis for the interpretation of pertinent functional studies. In an `open' conformation,E. coliBamA displays a significant degree of flexibility between P5 and the barrel domain, which is indicative of a multi-state function in substrate transfer.E. coliBamA is characterized by a discontinuous β-barrel with impaired β1–β16 strand interactions denoted by only two connecting hydrogen bonds and a disordered C-terminus. The 16-stranded barrel surrounds a large cavity which implies a function in OMP substrate binding and partial folding. These findings strongly support a mechanism of OMP biogenesis in which substrates are partially folded inside the barrel cavity and are subsequently released laterally into the lipid bilayer.
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Hall, Katherine C., Daniel Hill, Miguel Otero, et al. "ADAM17 Controls Endochondral Ossification by Regulating Terminal Differentiation of Chondrocytes." Molecular and Cellular Biology 33, no. 16 (2013): 3077–90. http://dx.doi.org/10.1128/mcb.00291-13.
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Endochondral ossification is a highly regulated process that relies on properly orchestrated cell-cell interactions in the developing growth plate. This study is focused on understanding the role of a crucial regulator of cell-cell interactions, the membrane-anchored metalloproteinase ADAM17, in endochondral ossification. ADAM17 releases growth factors, cytokines, and other membrane proteins from cells and is essential for epidermal growth factor receptor (EGFR) signaling and for processing tumor necrosis factor alpha. Here, we report that mice lacking ADAM17 in chondrocytes (A17ΔCh) have a significantly expanded zone of hypertrophic chondrocytes in the growth plate and retarded growth of long bones. This abnormality is caused by an accumulation of the most terminally differentiated type of chondrocytes that produces a calcified matrix. Inactivation of ADAM17 in osteoclasts or endothelial cells does not affect the zone of hypertrophic chondrocytes, suggesting that the main role of ADAM17 in the growth plate is in chondrocytes. This notion is further supported byin vitroexperiments showing enhanced hypertrophic differentiation of primary chondrocytes lackingAdam17. The enlarged zone of hypertrophic chondrocytes inA17ΔChmice resembles that described in mice with mutant EGFR signaling or lack of its ligand transforming growth factor α (TGFα), suggesting that ADAM17 regulates terminal differentiation of chondrocytes during endochondral ossification by activating the TGFα/EGFR signaling axis.
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Kurth, Julia Maria, Marie-Caroline Müller, Cornelia Ulrike Welte, and Tristan Wagner. "Structural Insights into the Methane-Generating Enzyme from a Methoxydotrophic Methanogen Reveal a Restrained Gallery of Post-Translational Modifications." Microorganisms 9, no. 4 (2021): 837. http://dx.doi.org/10.3390/microorganisms9040837.
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Methanogenic archaea operate an ancient, if not primordial, metabolic pathway that releases methane as an end-product. This last step is orchestrated by the methyl-coenzyme M reductase (MCR), which uses a nickel-containing F430-cofactor as the catalyst. MCR astounds the scientific world by its unique reaction chemistry, its numerous post-translational modifications, and its importance in biotechnology not only for production but also for capturing the greenhouse gas methane. In this report, we investigated MCR natively isolated from Methermicoccus shengliensis. This methanogen was isolated from a high-temperature oil reservoir and has recently been shown to convert lignin and coal derivatives into methane through a process called methoxydotrophic methanogenesis. A methoxydotrophic culture was obtained by growing M. shengliensis with 3,4,5-trimethoxybenzoate as the main carbon and energy source. Under these conditions, MCR represents more than 12% of the total protein content. The native MCR structure refined at a resolution of 1.6-Å precisely depicts the organization of a dimer of heterotrimers. Despite subtle surface remodeling and complete conservation of its active site with other homologues, MCR from the thermophile M. shengliensis contains the most limited number of post-translational modifications reported so far, questioning their physiological relevance in other relatives.
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Rogalin, Henry B., and Ekaterina E. Heldwein. "Interplay between the Herpes Simplex Virus 1 gB Cytodomain and the gH Cytotail during Cell-Cell Fusion." Journal of Virology 89, no. 24 (2015): 12262–72. http://dx.doi.org/10.1128/jvi.02391-15.
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ABSTRACTHerpesvirus entry into cells is mediated by the viral fusogen gB, which is thought to refold from the prefusion to the postfusion form in a series of large conformational changes that energetically couple refolding to membrane fusion. In contrast to most viral fusogens, gB requires a conserved heterodimer, gH/gL, as well as other nonconserved proteins. In a further mechanistic twist, gB-mediated cell-cell fusion appears restricted by its intraviral or cytoplasmic domain (cytodomain) because mutations within it result in a hyperfusogenic phenotype. Here, we characterized a panel of hyperfusogenic HSV-1 gB cytodomain mutants and show that they are fully functional in cell-cell fusion at shorter coincubation times and at lower temperatures than those for wild-type (WT) gB, which suggests that these mutations reduce the kinetic energy barrier to fusion. Despite this, the mutants require both gH/gL and gD. We confirm previous observations that the gH cytotail is an essential component of the cell-cell fusion mechanism and show that the N-terminal portion of the gH cytotail is critical for this process. Moreover, the fusion levels achieved by all gB constructs, WT and mutant, were proportionate to the length of the gH cytotail. Putting these results together, we propose that the gH cytotail, in addition to the gH/gL ectodomain, plays an essential role in gB activation, potentially acting as a “wedge” to release the gB cytodomain “clamp” and enable gB activation.IMPORTANCEHerpesviruses infect their hosts for life and cause a substantial disease burden. Herpes simplex viruses cause oral and genital sores as well as rare yet severe encephalitis and a panoply of ocular ailments. Infection initiates when the viral envelope fuses with the host cell membrane in a process orchestrated by the viral fusogen gB, assisted by the viral glycoproteins gH, gL, and gD and a cellular gD receptor. This process is more complicated than that of most other viruses and is subject to multiple regulatory inputs. Antiviral and vaccine development would benefit from a detailed mechanistic knowledge of this process and how it is regulated.
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Li, Ru, Annie Wen, and Jun Lin. "Pro-Inflammatory Cytokines in the Formation of the Pre-Metastatic Niche." Cancers 12, no. 12 (2020): 3752. http://dx.doi.org/10.3390/cancers12123752.
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In the presence of a primary tumor, the pre-metastatic niche is established in secondary organs as a favorable microenvironment for subsequent tumor metastases. This process is orchestrated by bone marrow-derived cells, primary tumor-derived factors, and extracellular matrix. In this review, we summarize the role of pro-inflammatory cytokines including interleukin (IL)-6, IL-1β, CC-chemokine ligand 2 (CCL2), granulocyte-colony stimulating factor (G-CSF), granulocyte–macrophage colony-stimulating factor (GM-CSF), stromal cell-derived factor (SDF)-1, macrophage migration inhibitory factor (MIF), and Chemokine (C–X–C motif) ligand 1 (CXCL1) in the formation of the pre-metastatic niche according to the most recent studies. Pro-inflammatory cytokines released from tumor cells or stromal cells act in both autocrine and paracrine manners to induce phenotype changes in tumor cells, recruit bone marrow-derived cells, and form an inflammatory milieu, all of which prime a secondary organ’s microenvironment for metastatic cell colonization. Considering the active involvement of pro-inflammatory cytokines in niche formation, clinical strategies targeting them offer ways to inhibit the establishment of the pre-metastatic niche and therefore attenuate metastatic progression. We review clinical trials targeting different inflammatory cytokines in patients with metastatic cancers. Due to the pleiotropy and redundancy of pro-inflammatory cytokines, combined therapies should be designed in the future.
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Adamiak, Mateusz, Anna Lenkiewicz, Kamila Bujko, et al. "Novel Evidence That the Nlrp3 Inflammasome Plays a Role in Bone Marrow As a "Cogwheel" Connecting Purinergic Signaling with Activation of the Complement Cascade to Induce "Sterile Inflammation", Which Is Required for Optimal Mobilization of Hematopoietic Stem/Progenitor Cells." Blood 134, Supplement_1 (2019): 4468. http://dx.doi.org/10.1182/blood-2019-125838.
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Background . In order to develop more efficient mobilization strategies, we have to better understand the mobilization process at the molecular and cellular levels. We envision pharmacological mobilization of HSPCs as the result of "sterile inflammation" in the bone marrow (BM) microenvironment induced by pro-mobilizing agents (e.g., G-CSF or AMD3100). This leads to activation of the complement cascade (ComC), which is required for egress of HSPCs from BM into peripheral blood (PB) (Leukemia 2018; 32:1116-1123). In support of this hypothesis, we reported recently that BM-residing innate immunity cells (e.g., monocytes, granulocytes and dendritic cells) release adenosine triphosphate (ATP) into the extracellular space during the initiation phase of mobilization. ATP released from the cells is an important signaling molecule that activates purinergic signaling receptors on the surface of hematopoietic cells (Leukemia 2018, 32:1920-1931) and is released mainly by pannexin 1 channels. Inhibition of this channel significantly decreases mobilization efficacy (Leukemia 2018, 32:1920-1931). In addition, ATP in the extracellular BM space is processed by the CD39 and CD73 ectonucleotidases to adenosine (Ado), which inhibits mobilization. To shed more light on the molecular mechanism governing mobilization of HSPCs, we focused on the role of the Nlrp3 inflammasome, which is highly expressed in hematopoietic cells. Moreover, while ATP binds to the P2X7 and P2X4 purinergic receptors and strongly activates Nlrp3, Ado inhibits migration of HSPCs in a heme oxygenase 1 (HO-1)-dependent manner.Hypothesis. We hypothesized that the Nlrp3 inflammasome is a link or "cogwheel" between purinergic signaling and the ComC that orchestrates optimal mobilization of HSPCs. Materials and Methods. To test this hypothesis we first mobilized wild type mice by G-CSF and AMD3100 administration in the presence of the small-molecule Nlrp3 inhibitor MCC950 or the Nlrp3 inflammasome activator nigericin, and the results were subsequently compared with results for Nlrp3-KO mice. Following mobilization, we measured i) the total number of white blood cells (WBCs) and ii) the number of circulating clonogenic colony-forming unit granulocyte/macrophage (CFU-GM) progenitors and Sca-1+c-kit+lineage- (SKL) cells circulating in PB. The secretion of ATP from BM cells was inhibited by employing the pannexin-1-blocking drug probenecid or a synthetic pannexin-1-blocking peptide (Panx-1). Nlrp3 inflammasome mRNA expression was measured in BM innate immunity cells, CD11b/Gr-1+ cells, and CD11b/Gr-1+ cells isolated under steady-state conditions from mobilized mice stimulated with ATP or Ado. Elements of the activated inflammasome, such as caspase-1, IL-1b, and IL-18, were measured at the mRNA (RT-PCR) and protein (ELISA) levels. In parallel, we evaluated i) the expression of HO-1 in HSPCs by employing RQ-PCR and western blot analysis and ii) activation of the ComC by C5a ELISA. Results. While mobilization of HSPCs was significantly decreased in P2X7-KO mice and mice with Nlrp3 inflammasome deficiency, it was significantly increased in the presence of the Nlrp3 inflammasome activator nigericin. Proper activation of the inflammasome required ATP release in a pannexin-1-dependent manner and stimulation of hematopoietic cells in a P2X7 purinergic receptor-dependent manner. Moreover, Ado inhibited the mobilization process by upregulating HO-1 in HSPCs, which, as we observed, inhibits the Nlrp3 inflammasome in HSPCs. Finally, while activation of the Nlrp3 inflammasome was positively correlated with activation of the ComC, inhibition of the Nlrp3 inflammasome had the opposite effect. Conclusions. We demonstrate for the first time that purinergic signaling involving ATP and its metabolite adenosine regulate the mobilization of HSPCs in an Nlrp3 inflammasome-dependent manner. While ATP triggers and promotes this process via activation of the Nlrp3 inflammasome, adenosine has an inhibitory effect by upregulating HO-1 (Figure 1). Based on these findings, stimulation of the Nlrp3 inflammasome by ATP, inhibiting the Ado level by small-molecule inhibitors of the CD39 or CD73 enzymes involved in generation of extracellular Ado, or direct inhibition of HO-1 in HSPCs by employing small-molecule inhibitors may provide the basis for more efficient mobilization strategies. Figure 1 Disclosures No relevant conflicts of interest to declare.
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Tomes, Claudia Nora. "The proteins of exocytosis: lessons from the sperm model." Biochemical Journal 465, no. 3 (2015): 359–70. http://dx.doi.org/10.1042/bj20141169.
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Exocytosis is a highly regulated process that consists of multiple functionally, kinetically and/or morphologically definable stages such as recruitment, targeting, tethering and docking of secretory vesicles with the plasma membrane, priming of the fusion machinery and calcium-triggered membrane fusion. After fusion, the membrane around the secretory vesicle is incorporated into the plasma membrane and the granule releases its contents. The proteins involved in these processes belong to several highly conserved families: Rab GTPases, SNAREs (soluble NSF-attachment protein receptors), α-SNAP (α-NSF attachment protein), NSF (N-ethylmaleimide-sensitive factor), Munc13 and -18, complexins and synaptotagmins. In the present article, the molecules of exocytosis are reviewed, using human sperm as a model system. Sperm exocytosis is driven by isoforms of the same proteinaceous fusion machinery mentioned above, with their functions orchestrated in a hierarchically organized and unidirectional signalling cascade. In addition to the universal exocytosis regulator calcium, this cascade includes other second messengers such as diacylglycerol, inositol 1,4,5-trisphosphate and cAMP, as well as the enzymes that synthesize them and their target proteins. Of special interest is the cAMP-binding protein Epac (exchange protein directly activated by cAMP) due in part to its enzymatic activity towards Rap. The activation of Epac and Rap leads to a highly localized calcium signal which, together with assembly of the SNARE complex, governs the final stages of exocytosis. The source of this releasable calcium is the secretory granule itself.
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Rojas, Vivian K., and In-Woo Park. "Role of the Ubiquitin Proteasome System (UPS) in the HIV-1 Life Cycle." International Journal of Molecular Sciences 20, no. 12 (2019): 2984. http://dx.doi.org/10.3390/ijms20122984.
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Given that the ubiquitin proteasome system (UPS) is the major protein degradation process in the regulation of a wide variety of cellular processes in eukaryotic cells, including alteration of cellular location, modulation of protein activity, and regulation of protein interaction, it is reasonable to suggest that the infecting HIV-1 and the invaded hosts exploit the UPS in a contest for survival and proliferation. However, to date, regulation of the HIV-1 life cycle has been mainly explained by the stage-specific expression of HIV-1 viral genes, not by elimination processes of the synthesized proteins after completion of their duties in the infected cells, which is also quintessential for understanding the molecular processes of the virus life cycle and thereby HIV-1 pathogenesis. In fact, several previous publications have indicated that the UPS plays a critical role in the regulation of the proteasomal degradation of viral and cellular counterparts at every step of the HIV-1 life cycle, from the virus entry to release of the assembled virus particles, which is integral for the regulation of survival and proliferation of the infecting HIV-1 and to replication restriction of the invading virus in the host. However, it is unknown whether and how these individual events taking place at different stages of the HIV-1 life cycle are orchestrated as an overall strategy to overcome the restrictions conferred by the host cells. Thus, in this review, we overview the interplay between HIV-1 viral and cellular proteins for restrictions/competitions for proliferation of the virus in the infected cell, which could open a new avenue for the development of therapeutics against HIV-1 via targeting a specific step of the proteasome degradation pathway during the HIV-1 life cycle.
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Joo, Joung Hyuck, and Mondira Kundu. "ULK1-Hsp90-Cdc37 and AMPK: Novel Insight Into the Regulation of Mitophagy." Blood 120, no. 21 (2012): 987. http://dx.doi.org/10.1182/blood.v120.21.987.987.
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Abstract Abstract 987 Autophagy plays an important role in maintaining mitochondrial integrity, directing lysosome-mediated destruction of cellular cargo, including damaged or dysfunctional mitochondria. Flux through the autophagy pathway is rapidly induced to promote survival in response to metabolic or proteotoxic stress resulting from exposure to noxious environmental cues, such as starvation, hypoxia or heat stress and likely contributes to the increase in mitochondrial turnover observed under each of these conditions. Dysregulation of this process has been linked to the pathogenesis of diseases, including anemia, diabetes, neurodegeneration and cancer. Atg1 is a serine-threonine kinase that directs the autophagy machinery to appropriate cargo in responses to changes in the availability of carbon and nitrogen in yeast. Ulk1, one of the mammalian homologues of Atg1, is required for starvation-induced autophagy and clearance of mitochondria in terminally differentiating erythroid cells. The function of Ulk1 is also regulated by AMP dependent Kinase (AMPK)-mediated phosphorylation, however, the precise molecular consequence of this post-translational modification has not been explored. Our preliminary findings indicate that AMPK phosphorylates Ulk1 during red blood cell maturation and in response to mitochondrial uncoupling, and that this phosphorylation is critical for mitochondrial clearance. Therefore, we sought to use these systems to explore the mechanism by which AMPK phosphorylation regulates Ulk1 function. We previously demonstrated that the stability and kinase activity of Ulk1 depends on its physical interaction with Hsp90 and the kinase-specific co-chaperone, Cdc37. Hsp90 is an abundant chaperone that directs the maturation and activation of a restricted group of metastable proteins, typically kinases and signaling molecules, and orchestrates a broad response to cellular stress. Here, we demonstrate that AMPK phosphorylation of Ulk1 does not affect Ulk1 kinase activity, but instead promotes its release from Hsp90 and its localization to damaged mitochondria. Preliminary studies indicate that the serine-proline rich domain of Ulk1, which contains at least 4 residues that are phosphorylated by AMPK, is an intrinsically disordered domain. We hypothesize that phosphorylation of Ulk1 by AMPK stabilizes a predicted alpha-helical structure within this domain and contributes to release of Hsp90. These findings are important because they provide significant insight into the regulation and function of Ulk1, a protein involved in mitochondrial turnover during red blood cell maturation and in proliferating cells. Disclosures: No relevant conflicts of interest to declare.
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Tarantino, Germano, Elisa Brilli, Giulio Giordano, Alessandro Torelli, and Francesco Equitani. "Innovative Oral Iron Supplement (Sucrosomial Iron®) Is Able to Downregulate Hepcidin Release during Inflammation: In Vitro Study." Blood 126, no. 23 (2015): 4563. http://dx.doi.org/10.1182/blood.v126.23.4563.4563.
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Abstract Introduction: the involvement of iron in a wide range of metabolic processes make it one of the essential elements for living organisms (Inamura et al., 2005). Anemia of chronic disease (ACD), also termed anemia of chronic inflammation, is the most prevalent anemia in subjects suffering from chronic diseases such as cancer and Chronic Kidney Disease (CKD). A central mechanism by which chronic disease causes anemia is the retention of iron in the reticuloendothelial system, causing a functional iron deficiency and consequently an insufficient iron supply for erythropoiesis. Hepcidin is a primarily liver-derived peptide that orchestrates body iron homeostasis and its expression increases in response to elevated iron stores, inflammation and ER stress (Maliken et al. 2011). In those conditions produced Hepcidin bind to the cellular iron exporter, Ferroportin (Fp1), resulting in Fp1 internalization and degradation with subsequent reduction of cellular iron release (Theurl et al., 2014). Some studies showed that pharmacological inhibition of Hepcidin could reverse cellular iron retetion and improve anemia in different models of inflammatory anemia (Steinbicker et al., 2011, Theurl et al., 2011). Moreover recent scientific publications suggest also a role of other dietary supplements in regulating Hepcidin, reducing its concentration and thus increasing circulating iron in blood (Zughaier et al. 2014). Sucrosomial Iron¨ (Sideral¨) is a new and still unique preparation of ferric pyrophosphate, useful for treatment of iron deficiency related anemia. Aim: we have previously performed a clinical study in which we showed that Sucrosomial iron is able to increase Hemoglobin level in CKD patients (Pisani et al., 2014). On the basis of these results we have investigated the role of Sucrosomial Iron¨ in inflammation process. In particular, we studied the capability of Sucrosomial Iron¨ to reduce Hepcidin release in LPS -induced inflammation made in the hepatoma cell line (HepG2). Results: Cells were incubated with LPS, treated with Sucrosomial Iron¨ and then analyzed for Hepcidin production in terms of protein expression at 6 and 24h after treatment with Sucrosomial Iron¨. Results showed that Sucrosomial Iron¨ is able to significantly reduce Hepcidin level both 6 and 24 h after sucrosome treatment compare to others iron formulations (Figure 1A-B). Materilas and Methods: Sucrosomial Iron¨ preparation of ferric pyrophosphate convered by a; LPS: Lipopolysaccharides from Escherichia coli (Sigma-Aldrich); Empty matrix preparation of phospholipids plus sucrose esters of fatty acids. Conclusions: This evidence should be considered as a preliminary investigation on the effect of Sucrosomial Iron¨ on the production of Hepcidin during chronic inflammation. Bibliography Inamura J et al. Upregulation of hepcidin by interleukin-1 in human hepatoma cell lines. Hepatology Research 33 2005 198-205. Maliken BD et al., The Hepcidin Circuits Act: Balancing Iron and Inflammation, Hepatology. 2011 May ; 53(5): 1764-1766; Theurl M et al. Hepcidin as a predictive factor and therapeutic target in erythropoiesis- stimulating agent treatment for anemia of chronic disease in rats Haematologica. 2014 Sep;99(9):1516-24. Epub 2014 Jun 3. Theurl et al. Pharmacologic inhibition of hepcidin expression reverses anemia of chronic inflammation in rats. Blood. 2011;118(18): 4977-84. Steinbicker AU et al. Inhibition of bone morphogenetic protein signaling attenuates anemia associated with inflammation Blood. 2011 May 5;117(18):4915-23. doi: 10.1182/blood-2010-10-313064. Epub 2011 Mar 10. Zughaier SM et al. The role of vitamin D in regulating the iron-hepcidin-ferroportin axis in monocytes. J Clin Transl Endocrinol. 2014 Mar 21;1(1):19-25. Pisani et al. Effect of oral liposomal iron versus intravenous iron for treatment of iron deficiency anaemia in CKD patients: a randomized trial. Nephrol Dial Transplant. 2015 Apr;30(4):645-52. Epub 2014 Nov 13. Figure 1. This graph shows the level of Hepcidin produced by LPS treated HepG2 cells 6 hours after treatment with iron compounds. Figure 1. This graph shows the level of Hepcidin produced by LPS treated HepG2 cells 6 hours after treatment with iron compounds. Figure 2. This graph shows the level of Hepcidin produced by LPS- treated HepG2 cells 24 hours after treatment with iron compounds. Figure 2. This graph shows the level of Hepcidin produced by LPS- treated HepG2 cells 24 hours after treatment with iron compounds. Disclosures Tarantino: Pharmanutra s.p.a.: Employment. Brilli:Pharmanutra s.p.a.: Employment.
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Klein, C., K. S. Scoggin, and M. H. T. Troedsson. "141 TRANSCRIPTIONAL PROFILING OF EQUINE ENDOMETRIUM DURING THE TIME OF MATERNAL RECOGNITION OF PREGNANCY." Reproduction, Fertility and Development 22, no. 1 (2010): 229. http://dx.doi.org/10.1071/rdv22n1ab141.
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Early embryonic development, implantation, and maintenance of a pregnancy are critically dependent upon a precisely orchestrated embryo-maternal interaction leading to a receptive uterine environment. The embryo has to signal its presence to the dam in order for estrous cyclicity to subside; however, the horse is one of the few domestic species in which the conceptus-derived pregnancy recognition signal has not been identified. To gain new insights into molecular mechanisms underlying this complex process in the horse, transcriptional profiling of Day 13.5 pregnant and cyclic endometrial tissue samples was carried using custom-designed 2-color microarrays. Endometrial tissue samples collected from 4 pregnant and cyclic mares each were labeled with either Cy3 or Cy5, paired, and analyzed on 4 individual arrays. Transcripts showing a difference in signal intensity of at least 1.3 and a P-value of 0.01 or less in a mixed model analysis were considered differentially expressed. Array data were validated performing quantitative RT-PCR and changes in relative gene expression between pregnant and non-pregnant mares were determined using the delta delta cycle threshold method. Proteins of interest were localized using immunohistochemistry. One hundred six transcripts were up-regulated, whereas 47 transcripts showed lower expression levels in pregnant mares. Quantitative RT-PCR for five up- and down-regulated transcripts each confirmed expression data obtained by microarray with a validation rate of 100%. Half of the genes with known or inferred function have previously been described as regulated by estrogens. Given the large quantities of estrogen synthesized by the equine conceptus, this finding confirms validity of the data. Elevated transcript levels were found for genes involved in cell-cell signaling, heat shock response, and secretory proteins among others. Solute carrier 36 member 2, SLC36A2, was the most highly up-regulated gene, reflecting the nutritional needs of the rapidly developing embryo. The beta subunit of luteinizing hormone (LHB) showed higher expression levels in pregnant mares. It is likely that the observed up-regulation of LHB leads to increased release of bioactive LH/CG into the uterine environment during early pregnancy where we hypothesize it to exert paracrine effects preparing the uterus for conceptus implantation. Among the down-regulated genes, estrogen receptor 1 was of particular interest because of its potential involvement in the initiation of luteolysis in cyclic mares. We hypothesize that either embryonic estrogen or uterine-derived choriogonadotropin is involved in the observed down-regulation of estrogen receptor 1, which may be the key to maternal recognition of pregnancy. Several of the genes identified in the current study are known to play a role in early pregnancy in species other than the horse. We thus hypothesize that a subset of genes crucial to endometrial receptivity does not differ between species, representing a common pattern during early pregnancy, whereas each species has a distinct mechanism ensuring ongoing corpus luteum function.
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Malumbres, Raquel, Robert Tibshirani, Elena Cubedo, et al. "Differentiation-Stage-Specific Expression of MicroRNAs in B-Lymphocytes and Diffuse Large B-Cell Lymphomas (DLBCL)." Blood 112, no. 11 (2008): 805. http://dx.doi.org/10.1182/blood.v112.11.805.805.
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Abstract B-cell development and differentiation are complex processes controlled by distinct programs of transcriptional control. A large set of transcriptional factors together or in succession control this process and their deregulation may result in block of differentiation or malignant transformation. MicroRNAs are small RNAs that orchestrate cellular functions by modulating the level of their targeted proteins by either translational arrest or transcript degradation, and play a key role in cell differentiation, apoptosis, proliferation and cancer development. An increasing number of transcription factors are being found targeted by microRNAs. Emerging evidence suggests that differentiation stage-specific expression of microRNAs occurs in the hematopoietic system and during T cell differentiation. Only limited information exists on microRNA expression in normal B cell differentiation and its malignant counterparts. Herein we analyzed microRNA expression profiles in distinct peripheral B cell differentiation stages-naïve, germinal center (GC) centroblasts and memory cells as well as tonsilar T cells. Furthermore, microRNA profiling was performed in germinal center-like (GCB-like) and activated B-cell-like (ABC-like) DLBCL cell lines originating from distinct B-cell differentiation stages. RNA, extracted with mirVana kit (AMBION) from B cell subsets and T cells enriched from normal tonsils was hybridized on LC Sciences (Houston, TX) microarrays harboring 470 human microRNAs probes (Sanger miRBase Release 9.1). Expression of selected microRNAs was confirmed by ABI RT-PCR methodology. Unsupervised clustering of microRNAs with values present in at least 50% of the samples (122 probes) resulted in perfect differentiation-stage clustering of samples. Application of Statistical Analysis of Microarrays (SAM) and Prediction Analysis of Microarrays (PAM) methods (FDR= 10%) identified a 47 microRNA cell of origin classifier for B-cells differentiation stage; 27 of these microRNAs were upregulated and 20 downregulated in centroblasts compared to memory B-cells. MicroRNAs belonging to paralog microRNA clusters (e.g. miR17-92-1, miR363-106a and miR25-106b) demonstrated similar patterns of expression in specific differentiation stages. To identify specific microRNA targets, miRanda, TargetScan and PicTar programs were used. To experimentally confirm the targets, we assessed the effects of specific microRNAs on the expression levels of targeted proteins and on the luciferase reporter under the control of the wild type and mutated 3′ UTR regions of putative target genes. Using this experimental approach we identified lymphocyte-stage-specific microRNAs which expression inversely correlated and might regulate the expression of LMO2, BLIMP1 and IRF4 proteins distinctively expressed at different differentiation stages of B lymphocytes. For example, miR223, which expression is low in GC cells but is high in naïve and memory B cells, downregulates the expression of LMO2. We next analyzed microRNA expression in DLBCL cell lines. Clustering analysis, using the 47 microRNA cell of origin classifier perfectly classified GCB-like and ABC-like cell lines. Interestingly, the expression of microRNAs in both GCB-like and ABC-like DLBCL cell lines was more similar to normal centroblasts than to memory B cells, suggesting that both may originate from distinct subpopulations of GC lymphocytes. The similarity of microRNA expression in cell lines to centroblasts was striking, with only 16 microRNAs (1 upregulated and 15 downregulated in cell lines) showing noticeable differences in levels of expression compared to normal cells. These microRNAs might be involved in the process of lymphoma transformation. SAM analysis aimed to differentiate GCB-like and ABC-like cell lines identified 11 microRNAs, only 3 of which were present in the cell of origin classifier. This observation suggests that there is also a difference in expression of microRNAs not directly related to the distinct cell of origin between the DLBCL subtypes. In summary, our results demonstrate that the microRNA profile changes during the GC reaction as well as during malignant transformation. Specific microRNAs can regulate key transcription factors controlling the processes of lymphocyte differentiation and transformation.
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Maso, Victor, Andrana Calgarotto, Gilberto Franchi, et al. "Quercetin Induces Autophagy, Apoptosis and Cell Cycle Arrest In P39 Cells." Blood 122, no. 21 (2013): 5042. http://dx.doi.org/10.1182/blood.v122.21.5042.5042.
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Abstract Introduction Due to the molecular heterogeneity of myelodysplastic syndrome, therapies using single-target drugs are ineffectives. An orchestrated interplay between three important processes: apoptosis, autophagy and cell cycle has been implicated to new anti-cancer therapies. In this concern, natural compounds like quercetin are considered new chemicals for the development of drugs against various molecular targets. Quercetin is ubiquitously found in fruits and vegetables and several beneficial health effects have been associated with the dietary uptake of this bioflavonoid. Accordingly, the goal of this work was to identify the quercetin effects using P39 cell line, derived from a patient with MDS-chronic myelomonocytic leukemia (CMML), kindly provided by Eva Hellstrom-Lindberg, Karolinska Institute Stockholm, as model. Material and Methods P39 cell line was submitted, in our lab, to karyotyping which showed 46XY,+del(6),-9,-16,-17,+2mar, indicating that this cell line is not contaminated with HL-60. P39 cells were cultured in RPMI 1640 medium containing 10% fetal bovine serum (FBS), 100 U/ ml penicillin, 100 μg/ml streptomycin at 37°C in a humidified atmosphere containing 5% CO2. The quercetin was dissolved in DMSO, final concentration of 0.1% (v/v) in RPMI. P39 cells were treated with quercetin at final concentrations of 10, 50 or 100 µM for 24h. Control cells were treated with vehicle alone. The xenografted model was performed in immunodeficient mice (NOD.CB17-Prkdcscid/J lineage), (n= 6). Mice were inoculated, subcutaneously, with P39 cells (1x107cells/mice) in the dorsal region. Every 7 days the tumor volume was evaluated. The quercetin treatment started after tumors reached 100 to 200 mm3; it was given once every four days by intraperitoneal (i.p) injection at 120mg/Kg body. Control group received equal amounts of vehicle solution as previously described (Wang, et al., 2011). After 21 days, the mice were sacrificed; tumors were removed, minced and homogenized in protein extraction buffer or fixed in formalin immediately for immunohistochemistry. Then detection of apoptosis, autophagy and cell cycle process were performed. Results In vitro results show that quercetin inhibited proliferation of P39 cells in a dose-and-time dependent manner and that the cell death induced by quercetin is due to modulation of apoptotic process. The quercetin treatment decreased Bcl2 and McL-1 expression (anti-apoptotic proteins) and increased Bax, an important pro-apoptotic protein. We could also observe changes in membrane potencial (Dym) after quercetin treatment with concomitant release of cytochrome c from mitochondria into the cytosol and increased expression of caspase 9, 8 and 3. Quercetin induced a marked increase in the number of P39 cells in the G1- phase with reduction of CDK2, CDK6, cyclin D, cyclin E, cyclin A and phosphorylation of Rb. Our results also showed increased levels of both p21 and p27 after 24 hours of quercetin treatment. Quercetin promoted pronounced phosphorylation of ERK1/2 and JNK. Using the selective inhibitors PD184352 (ERK inhibitor) and SP600125 (JNK inhibitor) no differences in percentage of apoptotic cells were found after 24 h of incubation. On the other hand, the combination of quercetin and PD184352 or SP600125 significantly decreases the accumulation of P39 cells in the G1 phase. Formation of acidic vesicular organelles (AVOs) was observed in quercetin- treated P39 cells. Then, the main proteins related to the autophagy process were analyzed and we found increased expression of beclin-1 and PI3K class III, ATG5-ATG12, ATG7 and conversion of LC3-I to LC3-II. In addition, quercetin-mediated dephosphorylation of Akt and mTOR which are considered key negative regulators of autophagy. Pharmacological inhibition of autophagy enhanced quercetin-induced suppression of P39 cell growth with no modulation of quercetin in G1 phase of cell cycle. Our results in xenograft model show that after 21 days of quercetin treatment, there was reduction of 31.6% in tumor volume compared to control group. We also observed apoptosis, autophagy and cell cycle activation status in the tumor tissue of animals treated with quercetin and by immunohistochemistry we confirmed the upregulation of caspase 3, p21 and LC3-II confirming in vitro results. Disclosures: No relevant conflicts of interest to declare.
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Kucher, L. I. "Activity of the Opera Studio under Lviv State Conservatory named after M. V. Lysenko as a training subdivision in 1970–90s." Aspects of Historical Musicology 14, no. 14 (2018): 108–21. http://dx.doi.org/10.34064/khnum2-14.08.
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Background. This article continues a series of works by the author on the study of the history of educational activities in the field of opera art in Ukraine. On the basis of archival materials, the chronology and features of the educational process in the Opera Studio of the Lviv State Conservatory named after M. V. Lysenko (now the Lviv National Music Academy) are recreated in the important period of formation of the principles of studio working on the education of an opera singer. Relying on his own many years of experience as a teacher and a researcher, the author gives estimates of the role of the departments of solo singing and opera training of the Conservatory involved in the educational process. The material on the history of the Opera Studio performances from its foundation to the end of the last century has been systematized. The results of the study. From the time of the Opera Studio foundation under the Lviv State Conservatory named after M. V. Lysenko, the artistic oversight of this training subdivision was belonging the teachers of the Solo Singing Department. The lack of creative contact between two departments of the vocals faculty, the Solo Singing and the Opera Training Departments, was leading to the shortcomings in education of opera singers. Due to the impossibility to cover all senior students with practical training in performances, they were engaged in fragments of opera in opera classes. To the end of 1973 the separate best pieces of the opera classes was shown several times, using different stages and concert venues. However, O. Hrytsak, who was appointed the Head of the department of Opera Training in the end of academic year 1973–74, resolved that the opera classes will only be focused on junior students of the Conservatory, as per curriculum. With his appointed the new round of Opera Studio’s activity started. Ukraine’s Honored Arts Worker Oleksandr Hrytsak (1924–2001) joined to Opera Training Department in the position of senior lecturer. Prior to joining the Conservatory, O. Hrytsak worked as a conductor in Lviv Opera Theater, where he released tens of opera and ballet performances. He managed to establish a creative atmosphere in the teachers’ team. When educating an actor singer, O. Hrytsak believed his main task is to teach him/her a self-guided work, since no further growth can be possible for a young musician without such a habit. While working at the studio, O. Hrytsak staged the numerous pieces of West European and national classics, having contributed a lot to popularization of modern music (“Anna Snegina” by V. Agafonnikov, “Mususi” by O. Taktakishvili, “The Dawns Here Are Quiet” by K. Molchanov…). In his article entitled “Both Vocalist and Actor” published in “Muzyka”(“Music”) journal (1985, no. 4 ), the author displays his deep knowledge of modern education’s focus on training of actor singers at opera training departments of higher musical schools. His belief that vocals students should not only master a spectrum of vocal and stage skills, but general culture as well, seems relevant to us. O. Grytsak recommended thorough elaboration of “Speech Culture”, “Dance” and “Stage movement” curricula. In 1977, a 5th-year student I. Kushpler (later People’s Artist of Ukraine) was chosen to play the part of Don Giovanni in the opera by W. Mozart. The performance was shown two times during the year with no further shows in the next year. This was a vivid example of how the absence of full-time soloist results in rare demonstration of opera performances of the Studio. It educational practice of Lviv Opera Studio used to happen that working on some performance made it entirely impossible to work on other ones, though it was emphasized that the attainment of high results of operation requires increase in the number of performances. For example, in 1977, during rehearsals of “Ten Days That Shook the World” opera by M. Karminsky, wherein the students’ choir and Opera Studio orchestra participated, no performances were shown of the Studio. Sure, such a practice cannot be deemed a good training. But as early as in academic year 1979–80, at the joint meetings of solo singing and opera training departments, their teachers expresses the opinion that the level of professional training in the Opera Studio grew considerably versus prior years. Fifteen performances were shown during that year, with “Nocturne” by M. Lysenko and “Sotnyk” by M. Verykivsky (conductor O. Hrytsak, director O. Huy) having been renewed. The repertoire continued extending with new pieces – “Zagrava” by A. Kos-Anatolsky, “Mususi” by O. Taktakishvili. Among that period’s prominent interpretations, one can mention the “Iphigenia in Tauris” by K. Stetsenko commemorating its author’s 100th jubilee, with further TV version release (1982). Since 1985, “Zaporozhets za Dunayem”, the opera by S. Hulak-Artemovsky returned to the studio’s repertoire. In 1989, the Opera Studio staged “Kupalo”, opera by A. Vakhnyanin, which is Western Ukraine’s first musical piece based on opera drama principle, as revised by M. Skoryk (conductor O. Hrytsak, stage director F. Strygun). The opera was chosen by the Studio to celebrate the 50th anniversary of Ukrainian lands’ reunion and Lviv State Conservatory foundation. The performance was broadcast on Ukrainian radio. Being the leader of talented and experienced experts such as directors V. Dubrovsky, O. Huy, A. Lymerev, choirmaster M. Telishevsky, O. Hrytsak fruitfully conducted the education of young actors. Despite pecuniary burdens, each year the studio staged new performances, in which vocals students acquired their professional experience. He revived the studio’s activity, having tuned up the regular practical training of the vocal department students. Summing it up, it is fair to say that O. Hrytsak’s management of the department allowed boosting discipline and regularity of training of opera singers and revived the Opera Studio under Lviv State Conservatory. However, the lack of material resources (the need for the rental of premises for rehearsals, lack of singer staff for performances etc.) and creative misunderstandings between the departments of the Conservatory engaged in operatic training were becoming the cause of some flaws in the organization of the educating process of the opera singers. In the same time, one cannot but highlight such a positive factor in Lviv Opera Studio activity, as its constant addressing to the heritage of Ukrainian composers.
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Xia, Shi-Li, Meng Li, Bing Chen, et al. "The LRR-TM protein PAN-1 interacts with MYRF to promote its nuclear translocation in synaptic remodeling." eLife 10 (May 5, 2021). http://dx.doi.org/10.7554/elife.67628.
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Neural circuits develop through a plastic phase orchestrated by genetic programs and environmental signals. We have identified a leucine-rich-repeat domain transmembrane protein PAN-1 as a factor required for synaptic rewiring in C. elegans. PAN-1 localizes on cell membrane and binds with MYRF, a membrane-bound transcription factor indispensable for promoting synaptic rewiring. Full-length MYRF was known to undergo self-cleavage on ER membrane and release its transcriptional N-terminal fragment in cultured cells. We surprisingly find that MYRF trafficking to cell membrane before cleavage is pivotal for C. elegans development and the timing of N-MYRF release coincides with the onset of synaptic rewiring. On cell membrane PAN-1 and MYRF interact with each other via their extracellular regions. Loss of PAN-1 abolishes MYRF cell membrane localization, consequently blocking myrf-dependent neuronal rewiring process. Thus, through interactions with a cooperating factor on the cell membrane, MYRF may link cell surface activities to transcriptional cascades required for development.
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Bosch-Rué, Elia, Leire Diez-Tercero, Barbara Giordano-Kelhoffer, et al. "Biological Roles and Delivery Strategies for Ions to Promote Osteogenic Induction." Frontiers in Cell and Developmental Biology 8 (January 14, 2021). http://dx.doi.org/10.3389/fcell.2020.614545.
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Bone is the most studied tissue in the field of tissue regeneration. Even though it has intrinsic capability to regenerate upon injury, several pathologies and injuries could hamper the highly orchestrated bone formation and resorption process. Bone tissue engineering seeks to mimic the extracellular matrix of the tissue and the different biochemical pathways that lead to successful regeneration. For many years, the use of extrinsic factors (i.e., growth factors and drugs) to modulate these biological processes have been the preferred choice in the field. Even though it has been successful in some instances, this approach presents several drawbacks, such as safety-concerns, short release profile and half-time life of the compounds. On the other hand, the use of inorganic ions has attracted significant attention due to their therapeutic effects, stability and lower biological risks. Biomaterials play a key role in such strategies where they serve as a substrate for the incorporation and release of the ions. In this review, the methodologies used to incorporate ions in biomaterials is presented, highlighting the osteogenic properties of such ions and the roles of biomaterials in controlling their release.
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Mashruwala, Ameya A., and Bonnie L. Bassler. "The Vibrio cholerae Quorum-Sensing Protein VqmA Integrates Cell Density, Environmental, and Host-Derived Cues into the Control of Virulence." mBio 11, no. 4 (2020). http://dx.doi.org/10.1128/mbio.01572-20.
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ABSTRACT Quorum sensing is a chemical communication process in which bacteria use the production, release, and detection of signal molecules called autoinducers to orchestrate collective behaviors. The human pathogen Vibrio cholerae requires quorum sensing to infect the small intestine. There, V. cholerae encounters the absence of oxygen and the presence of bile salts. We show that these two stimuli differentially affect quorum-sensing function and, in turn, V. cholerae pathogenicity. First, during anaerobic growth, V. cholerae does not produce the CAI-1 autoinducer, while it continues to produce the DPO autoinducer, suggesting that CAI-1 may encode information specific to the aerobic lifestyle of V. cholerae. Second, the quorum-sensing receptor-transcription factor called VqmA, which detects the DPO autoinducer, also detects the lack of oxygen and the presence of bile salts. Detection occurs via oxygen-, bile salt-, and redox-responsive disulfide bonds that alter VqmA DNA binding activity. We propose that VqmA serves as an information processing hub that integrates quorum-sensing information, redox status, the presence or absence of oxygen, and host cues. In response to the information acquired through this mechanism, V. cholerae appropriately modulates its virulence output. IMPORTANCE Quorum sensing (QS) is a process of chemical communication that bacteria use to orchestrate collective behaviors. QS communication relies on chemical signal molecules called autoinducers. QS regulates virulence in Vibrio cholerae, the causative agent of the disease cholera. Transit into the human small intestine, the site of cholera infection, exposes V. cholerae to the host environment. In this study, we show that the combination of two stimuli encountered in the small intestine, the absence of oxygen and the presence of host-produced bile salts, impinge on V. cholerae QS function and, in turn, pathogenicity. We suggest that possessing a QS system that is responsive to multiple environmental, host, and cell density cues enables V. cholerae to fine-tune its virulence capacity in the human intestine.
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Bouland, Cyril, Pierre Philippart, Didier Dequanter, et al. "Cross-Talk Between Mesenchymal Stromal Cells (MSCs) and Endothelial Progenitor Cells (EPCs) in Bone Regeneration." Frontiers in Cell and Developmental Biology 9 (May 13, 2021). http://dx.doi.org/10.3389/fcell.2021.674084.
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Bone regeneration is a complex, well-orchestrated process based on the interactions between osteogenesis and angiogenesis, observed in both physiological and pathological situations. However, specific conditions (e.g., bone regeneration in large quantity, immunocompromised regenerative process) require additional support. Tissue engineering offers novel strategies. Bone regeneration requires a cell source, a matrix, growth factors and mechanical stimulation. Regenerative cells, endowed with proliferation and differentiation capacities, aim to recover, maintain, and improve bone functions. Vascularization is mandatory for bone formation, skeletal development, and different osseointegration processes. The latter delivers nutrients, growth factors, oxygen, minerals, etc. The development of mesenchymal stromal cells (MSCs) and endothelial progenitor cells (EPCs) cocultures has shown synergy between the two cell populations. The phenomena of osteogenesis and angiogenesis are intimately intertwined. Thus, cells of the endothelial line indirectly foster osteogenesis, and conversely, MSCs promote angiogenesis through different interaction mechanisms. In addition, various studies have highlighted the importance of the microenvironment via the release of extracellular vesicles (EVs). These EVs stimulate bone regeneration and angiogenesis. In this review, we describe (1) the phenomenon of bone regeneration by different sources of MSCs. We assess (2) the input of EPCs in coculture in bone regeneration and describe their contribution to the osteogenic potential of MSCs. We discuss (3) the interaction mechanisms between MSCs and EPCs in the context of osteogenesis: direct or indirect contact, production of growth factors, and the importance of the microenvironment via the release of EVs.
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Correia, Sara, Henrique J. Cardoso, José E. Cavaco, and Sílvia Socorro. "Oestrogens as apoptosis regulators in mammalian testis: angels or devils?" Expert Reviews in Molecular Medicine 17 (2015). http://dx.doi.org/10.1017/erm.2014.25.
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In the mammalian testis, spermatogenesis is a highly coordinated process of germ cell development, which ends with the release of ‘mature’ spermatozoa. The fine regulation of spermatogenesis is strictly dependent on sex steroid hormones, which orchestrate the cellular and molecular events underlying normal development of germ cells. Sex steroids actions also rely on the control of germ cell survival, and the programmed cell death by apoptosis has been indicated as a critical process in regulating the size and quality of the germ line. Recently, oestrogens have emerged as important regulators of germ cell fate. However, the beneficial or detrimental effects of oestrogens in spermatogenesis are controversial, with independent reports arguing for their role as cell survival factors or as apoptosis-inducers. The dual behaviour of oestrogens, shifting from ‘angels to devils’ is supported by the clinical findings of increased oestrogens levels in serum and intratesticular milieu of idiopathic infertile men. This review aims to discuss the available information concerning the role of oestrogens in the control of germ cell death and summarises the signalling mechanisms driven oestrogen-induced apoptosis. The present data represent a valuable basis for the clinical management of hyperoestrogenism-related infertility and provide a rationale for the use of oestrogen-target therapies in male infertility.
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Imran, Muhammad, Valentin Kuznetsov, Katarzyna Maria Dziedziniewicz-Wojcik, et al. "Migration of CMSWEB cluster at CERN to Kubernetes: a comprehensive study." Cluster Computing, June 9, 2021. http://dx.doi.org/10.1007/s10586-021-03325-0.
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AbstractThe Compact Muon Solenoid (CMS) experiment heavily relies on the CMSWEB cluster to host critical services for its operational needs. The cluster is deployed on virtual machines (VMs) from the CERN OpenStack cloud and is manually maintained by operators and developers. The release cycle is composed of several steps, from building RPMs to their deployment, validation, and integration tests. To enhance the sustainability of the CMSWEB cluster, CMS decided to migrate its cluster to a containerized solution based on Docker and orchestrated with Kubernetes (K8s). This allows us to significantly speed up the release upgrade cycle, follow the end-to-end deployment procedure, and reduce operational cost. In this paper, we give an overview of the CMSWEB VM cluster and the issues we discovered during this migration. We discuss the architecture and the implementation strategy in the CMSWEB Kubernetes cluster. Even though Kubernetes provides horizontal pod autoscaling based on CPUs and memory, in this paper, we provide details of horizontal pod autoscaling based on the custom metrics of CMSWEB services. We also discuss automated deployment procedure based on the best practices of continuous integration/continuous deployment (CI/CD) workflows. We present performance analysis between Kubernetes and VM based CMSWEB deployments. Finally, we describe various issues found during the implementation in Kubernetes and report on lessons learned during the migration process.
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Datta, Ritwik, Trisha Bansal, Santanu Rana, et al. "Myocyte-Derived Hsp90 Modulates Collagen Upregulation via Biphasic Activation of STAT-3 in Fibroblasts during Cardiac Hypertrophy." Molecular and Cellular Biology 37, no. 6 (2016). http://dx.doi.org/10.1128/mcb.00611-16.
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ABSTRACT Signal transducer and activator of transcription 3 (STAT-3)-mediated signaling in relation to upregulated collagen expression in fibroblasts during cardiac hypertrophy is well defined. Our recent findings have identified heat shock protein 90 (Hsp90) to be a critical modulator of fibrotic signaling in cardiac fibroblasts in this disease milieu. The present study was therefore intended to analyze the role of Hsp90 in the STAT-3-mediated collagen upregulation process. Our data revealed a significant difference between in vivo and in vitro results, pointing to a possible involvement of myocyte-fibroblast cross talk in this process. Cardiomyocyte-targeted knockdown of Hsp90 in rats (Rattus norvegicus) in which the renal artery was ligated showed downregulated collagen synthesis. Furthermore, the results obtained with cardiac fibroblasts conditioned with Hsp90-inhibited hypertrophied myocyte supernatant pointed toward cardiomyocytes' role in the regulation of collagen expression in fibroblasts during hypertrophy. Our study also revealed a novel signaling mechanism where myocyte-derived Hsp90 orchestrates not only p65-mediated interleukin-6 (IL-6) synthesis but also its release in exosomal vesicles. Such myocyte-derived exosomes and myocyte-secreted IL-6 are responsible in unison for the biphasic activation of STAT-3 signaling in cardiac fibroblasts that culminates in excess collagen synthesis, leading to severely compromised cardiac function during cardiac hypertrophy.
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Cosgriff, Chance J., Chelsea R. White, Wei Ping Teoh, James P. Grayczyk, and Francis Alonzo. "Control ofStaphylococcus aureusQuorum Sensing by a Membrane-Embedded Peptidase." Infection and Immunity 87, no. 5 (2019). http://dx.doi.org/10.1128/iai.00019-19.
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ABSTRACTGram-positive bacteria process and release small peptides, or pheromones, that act as signals for the induction of adaptive traits, including those involved in pathogenesis. One class of small signaling pheromones is the cyclic autoinducing peptides (AIPs), which regulate expression of genes that orchestrate virulence and persistence in a range of microbes, including staphylococci, listeriae, clostridia, and enterococci. In a genetic screen forStaphylococcus aureussecreted virulence factors, we identified anS. aureusmutant containing an insertion in the geneSAUSA300_1984(mroQ), which encodes a putative membrane-embedded metalloprotease. A ΔmroQmutant exhibited impaired induction of Toll-like receptor 2-dependent inflammatory responses from macrophages but elicited greater production of the inflammatory cytokine interleukin-1β and was attenuated in a murine skin and soft tissue infection model. The ΔmroQmutant phenocopies anS. aureusmutant containing a deletion of the accessory gene regulatory system (Agr), wherein both strains have significantly reduced production of secreted toxins and virulence factors but increased surface protein A abundance. The Agr system controls virulence factor gene expression inS. aureusby sensing the accumulation of AIP via the histidine kinase AgrC and the response regulator AgrA. We provide evidence to suggest that MroQ acts within the Agr pathway to facilitate the optimal processing or export of AIP for signal amplification through AgrC/A and induction of virulence factor gene expression. Mutation of MroQ active-site residues significantly reduces AIP signaling and attenuates virulence. Altogether, this work identifies a new component of the Agr quorum-sensing circuit that is critical for the production ofS. aureusvirulence factors.