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1
Woolley, Thomas E., Eamonn A. Gaffney, and Alain Goriely. "Membrane shrinkage and cortex remodelling are predicted to work in harmony to retract blebs." Royal Society Open Science 2, no. 7 (July 2015): 150184. http://dx.doi.org/10.1098/rsos.150184.
Повний текст джерелаАнотація:
Numerous cell types undergo an oscillatory form of dynamics known as blebbing, whereby pressure-driven spherical protrusions of membrane (known as blebs) expand and contract over the cell's surface. Depending on the cell line, blebs play important roles in many different phenomena including mitosis and locomotion. The expansion phase of cellular blebbing has been mathematically modelled in detail. However, the active processes occurring during the retraction phase are not so well characterized. It is thought that blebs retract because a cortex reforms inside, and adheres to, the bleb membrane. This cortex is retracted into the cell and the attached bleb membrane follows. Using a computational model of a cell's membrane, cortex and interconnecting adhesions, we demonstrate that cortex retraction alone cannot account for bleb retraction and suggest that the mechanism works in tandem with membrane shrinking. Further, an emergent hysteresis loop is observed in the intracellular pressure, which suggests a potential mechanism through which a secondary bleb can be initiated as a primary bleb contracts.
2
Fackler, Oliver T., and Robert Grosse. "Cell motility through plasma membrane blebbing." Journal of Cell Biology 181, no. 6 (June 9, 2008): 879–84. http://dx.doi.org/10.1083/jcb.200802081.
Повний текст джерелаАнотація:
Plasma membrane blebs are dynamic cytoskeleton-regulated cell protrusions that have been implicated in apoptosis, cytokinesis, and cell movement. Influencing Rho–guanosine triphosphatase activities and subsequent actomyosin dynamics appears to constitute a core component for bleb formation. In this paper, we discuss recent evidence in support of a central role of nonapoptotic membrane blebbing for cell migration and cancer cell invasion as well as advances in our understanding of the underlying molecular mechanisms. Based on these studies, we propose that in a physiological context, bleb-associated cell motility reflects a cell's response to reduced substratum adhesion. The importance of blebbing as a functional protrusion is underscored by the existence of multiple molecular mechanisms that govern actin-mediated bleb retraction.
3
Chikina, Aleksandra S., Tatyana M. Svitkina, and Antonina Y. Alexandrova. "Time-resolved ultrastructure of the cortical actin cytoskeleton in dynamic membrane blebs." Journal of Cell Biology 218, no. 2 (December 12, 2018): 445–54. http://dx.doi.org/10.1083/jcb.201806075.
Повний текст джерелаАнотація:
Membrane blebbing accompanies various cellular processes, including cytokinesis, apoptosis, and cell migration, especially invasive migration of cancer cells. Blebs are extruded by intracellular pressure and are initially cytoskeleton-free, but they subsequently assemble the cytoskeleton, which can drive bleb retraction. Despite increasing appreciation of physiological significance of blebbing, the molecular and, especially, structural mechanisms controlling bleb dynamics are incompletely understood. We induced membrane blebbing in human HT1080 fibrosarcoma cells by inhibiting the Arp2/3 complex. Using correlative platinum replica electron microscopy, we characterize cytoskeletal architecture of the actin cortex in cells during initiation of blebbing and in blebs at different stages of their expansion–retraction cycle. The transition to blebbing in these conditions occurred through an intermediate filopodial stage, whereas bleb initiation was biased toward filopodial bases, where the cytoskeleton exhibited local weaknesses. Different stages of the bleb life cycle (expansion, pausing, and retraction) are characterized by specific features of cytoskeleton organization that provide implications about mechanisms of cytoskeleton assembly and bleb retraction.
4
Petrov, S. Yu, and D. M. Safonova. "Efficacy and Safety of Late Bleb Needling to Prolong Post-Trabeculectomy Hypotensive Effect." Ophthalmology in Russia 15, no. 4 (January 9, 2019): 416–23. http://dx.doi.org/10.18008/1816-5095-2018-4-416-423.
Повний текст джерелаАнотація:
Purpose. To assess the efficacy and safety of late bleb needling to prolong the hypotensive effect after glaucoma surgery.Patients and Methods. The study included 130 patients (130 eyes) with IOP decompensation after trabeculectomy. The patients were divided into 3 groups: cystous blebs (50 eyes), incapsulated blebs (50 eyes) and biomicroscopically absent blebs that reveal intraocular fluid collections under the sclera flap during optical coherence tomography (30 eyes). All patients underwent tonometry, visometry and bleb hyperemia assessment.Results. Patients with cystous blebs showed a mean IOP reduction from 25.4 ± 3.2 mm Hg to 12.7 ± 4.5 mm Hg the day after needling. During the follow up period the mean IOP level showed a minimal fluctuation within the bounds of 13–15 mm Hg. Incapsulated blebs demonstrated a reduction from 28.9 ± 6.3 to 15.1 ± 4.3 mm Hg in the course of the first day. The following IOP fluctuations remained within a higher range, than in Group 1: 15.9–18.3 mm Hg. IOP dynamics in the visually absent bleb group had its specificts: the initial procedure led to a transient IOP increase from 24.6 ± 4.7 mm Hg to 27,6 ± 3,5 mm Hg, followed by a reduction within the first day to the level 19.4 ± 3.1 mm Hg, with further IOP fluctuations during the follow up period staying withing the range of 14.6–15.8 mm Hg. Performing bleb needling to restore trabeculectomy hypotensive efficacy had a total surgical success in 100 % patients with cystous blebs, that were formed as a result of conjunctival-scleral lesions. Incapsulated bleb needling had a 74 % total success rate and visually absent blebs with intraocular fluid collections under the flap had a 90 % total success rate within the 6 month follow up period.Conclusion. The study shows high efficacy of late needling of different blebs as an invasive measure of restoring post-trabeculectomy hypotensive effect.
5
Asante-Asamani, Emmanuel, Daniel Grange, Devarshi Rawal, Zully Santiago, John Loustau, and Derrick Brazill. "A role for myosin II clusters and membrane energy in cortex rupture for Dictyostelium discoideum." PLOS ONE 17, no. 4 (April 25, 2022): e0265380. http://dx.doi.org/10.1371/journal.pone.0265380.
Повний текст джерелаАнотація:
Blebs, pressure driven protrusions of the cell membrane, facilitate the movement of eukaryotic cells such as the soil amoeba Dictyostelium discoideum, white blood cells and cancer cells. Blebs initiate when the cell membrane separates from the underlying cortex. A local rupture of the cortex, has been suggested as a mechanism by which blebs are initiated. However, much clarity is still needed about how cells inherently regulate rupture of the cortex in locations where blebs are expected to form. In this work, we examine the role of membrane energy and the motor protein myosin II (myosin) in facilitating the cell driven rupture of the cortex. We perform under-agarose chemotaxis experiments, using Dictyostelium discoideum cells, to visualize the dynamics of myosin and calculate changes in membrane energy in the blebbing region. To facilitate a rapid detection of blebs and analysis of the energy and myosin distribution at the cell front, we introduce an autonomous bleb detection algorithm that takes in discrete cell boundaries and returns the coordinate location of blebs with its shape characteristics. We are able to identify by microscopy naturally occurring gaps in the cortex prior to membrane detachment at sites of bleb nucleation. These gaps form at positions calculated to have high membrane energy, and are associated with areas of myosin enrichment. Myosin is also shown to accumulate in the cortex prior to bleb initiation and just before the complete disassembly of the cortex. Together our findings provide direct spatial and temporal evidence to support cortex rupture as an intrinsic bleb initiation mechanism and suggests that myosin clusters are associated with regions of high membrane energy where its contractile activity leads to a rupture of the cortex at points of maximal energy.
6
Cunningham, C. C. "Actin polymerization and intracellular solvent flow in cell surface blebbing." Journal of Cell Biology 129, no. 6 (June 15, 1995): 1589–99. http://dx.doi.org/10.1083/jcb.129.6.1589.
Повний текст джерелаАнотація:
The cortical actin gel of eukaryotic cells is postulated to control cell surface activity. One type of protrusion that may offer clues to this regulation are the spherical aneurysms of the surface membrane known as blebs. Blebs occur normally in cells during spreading and alternate with other protrusions, such as ruffles, suggesting similar protrusive machinery is involved. We recently reported that human melanoma cell lines deficient in the actin filament cross-linking protein, ABP-280, show prolonged blebbing, thus allowing close study of blebs and their dynamics. Blebs expand at different rates of volume increase that directly predict the final size achieved by each bleb. These rates decrease as the F-actin concentration of the cells increase over time after plating on a surface, but do so at lower concentrations in ABP-280 expressing cells. Fluorescently labeled actin and phalloidin injections of blebbing cells indicate that a polymerized actin structure is not present initially, but appears later and is responsible for stopping further bleb expansion. Therefore, it is postulated that blebs occur when the fluid-driven expansion of the cell membrane is sufficiently rapid to initially outpace the local rate of actin polymerization. In this model, the rate of intracellular solvent flow driving this expansion decreases as cortical gelation is achieved, whether by factors such as ABP-280, or by concentrated actin polymers alone, thereby leading to decreased size and occurrence of blebs. Since the forces driving bleb extension would always be present in a cell, this process may influence other cell protrusions as well.
7
Asante-Asamani, Emmanuel, Derrick Brazill, and Wanda Strychalski. "Actin-myosin dynamics during bleb stabilization." Biophysical Journal 121, no. 3 (February 2022): 118a. http://dx.doi.org/10.1016/j.bpj.2021.11.2129.
Повний текст джерела
8
Davidson, Andrew J., Clelia Amato, Peter A. Thomason, and Robert H. Insall. "WASP family proteins and formins compete in pseudopod- and bleb-based migration." Journal of Cell Biology 217, no. 2 (November 30, 2017): 701–14. http://dx.doi.org/10.1083/jcb.201705160.
Повний текст джерелаАнотація:
Actin pseudopods induced by SCAR/WAVE drive normal migration and chemotaxis in eukaryotic cells. Cells can also migrate using blebs, in which the edge is driven forward by hydrostatic pressure instead of actin. In Dictyostelium discoideum, loss of SCAR is compensated by WASP moving to the leading edge to generate morphologically normal pseudopods. Here we use an inducible double knockout to show that cells lacking both SCAR and WASP are unable to grow, make pseudopods or, unexpectedly, migrate using blebs. Remarkably, amounts and dynamics of actin polymerization are normal. Pseudopods are replaced in double SCAR/WASP mutants by aberrant filopods, induced by the formin dDia2. Further disruption of the gene for dDia2 restores cells’ ability to initiate blebs and thus migrate, though pseudopods are still lost. Triple knockout cells still contain near-normal F-actin levels. This work shows that SCAR, WASP, and dDia2 compete for actin. Loss of SCAR and WASP causes excessive dDia2 activity, maintaining F-actin levels but blocking pseudopod and bleb formation and migration.
9
Hinojosa, Laura Soto, Manuel Holst, Christian Baarlink, and Robert Grosse. "MRTF transcription and Ezrin-dependent plasma membrane blebbing are required for entotic invasion." Journal of Cell Biology 216, no. 10 (August 3, 2017): 3087–95. http://dx.doi.org/10.1083/jcb.201702010.
Повний текст джерелаАнотація:
Entosis is a nonapoptotic form of cell death initiated by actomyosin-dependent homotypic cell-in-cell invasion that can be observed in malignant exudates during tumor progression. We previously demonstrated formin-mediated actin dynamics at the rear of the invading cell as well as nonapoptotic plasma membrane (PM) blebbing in this cellular motile process. Although the contractile actin cortex involved in bleb-driven motility is well characterized, a role for transcriptional regulation in this process has not been studied. Here, we explore the impact of the actin-controlled MRTF–SRF (myocardin-related transcription factor–serum response factor) pathway for sustained PM blebbing and entotic invasion. We find that cortical blebbing is tightly coupled to MRTF nuclear shuttling to promote the SRF transcriptional activity required for entosis. Furthermore, PM blebbing triggered SRF-mediated up-regulation of the metastasis-associated ERM protein Ezrin. Notably, Ezrin is sufficient and important to sustain bleb dynamics for cell-in-cell invasion when SRF is suppressed. Our results highlight the critical role of the actin-regulated MRTF transcriptional pathway for bleb-associated invasive motility, such as during entosis.
10
Goudarzi, Mohammad, Aleix Boquet-Pujadas, Jean-Christophe Olivo-Marin, and Erez Raz. "Fluid dynamics during bleb formation in migrating cells in vivo." PLOS ONE 14, no. 2 (February 26, 2019): e0212699. http://dx.doi.org/10.1371/journal.pone.0212699.
Повний текст джерела
11
Leow, Ruen Shan, Jennifer M. F. Wan, and Alfred C. H. Yu. "Membrane blebbing as a recovery manoeuvre in site-specific sonoporation mediated by targeted microbubbles." Journal of The Royal Society Interface 12, no. 105 (April 2015): 20150029. http://dx.doi.org/10.1098/rsif.2015.0029.
Повний текст джерелаАнотація:
Site-specific perforation of the plasma membrane can be achieved through ultrasound-triggered cavitation of a single microbubble positioned adjacent to the cell. However, for this perforation approach (sonoporation), the recovery manoeuvres invoked by the cell are unknown. Here, we report new findings on how membrane blebbing can be a recovery manoeuvre that may take place in sonoporation episodes whose pores are of micrometres in diameter. Each sonoporation site was created using a protocol involving single-shot ultrasound exposure (frequency: 1 MHz; pulse length: 30 cycles; peak negative pressure: 0.45 MPa) which triggered inertial cavitation of a single targeted microbubble (diameter: 1–5 µm). Over this process, live confocal microscopy was conducted in situ to monitor membrane dynamics, model drug uptake kinetics and cytoplasmic calcium ion (Ca 2+ ) distribution. Results show that blebbing would occur at a recovering sonoporation site after its resealing, and it may emerge elsewhere along the membrane periphery. The bleb size was correlated with the pre-exposure microbubble diameter, and 99% of blebbing cases at sonoporation sites were inflicted by microbubbles larger than 1.5 µm diameter (analysed over 124 sonoporation episodes). Blebs were not observed at irreversible sonoporation sites or when sonoporation site repair was inhibited via extracellular Ca 2+ chelation. Functionally, the bleb volume was found to serve as a buffer compartment to accommodate the cytoplasmic Ca 2+ excess brought about by Ca 2+ influx during sonoporation. These findings suggest that membrane blebbing would help sonoporated cells restore homeostasis.
12
JARVIS, KAREN G., CHIUN-KANG HSU, JAMES B. PETTENGILL, JOHN IHRIE, HIREN KARATHIA, NUR A. HASAN, and CHRISTOPHER J. GRIM. "Microbiome Population Dynamics of Cold-Smoked Sockeye Salmon during Refrigerated Storage and after Culture Enrichment." Journal of Food Protection 85, no. 2 (February 1, 2021): 238–53. http://dx.doi.org/10.4315/jfp-21-228.
Повний текст джерелаАнотація:
ABSTRACT Cold-smoked salmon is a ready-to-eat seafood product of high commercial importance. The processing and storage steps facilitate the introduction, growth, and persistence of foodborne pathogens and spoilage bacteria. The growth of commensal bacteria during storage and once the product is opened also influence the quality and safety of cold-smoked salmon. Here we investigated the microbial community through targeted 16S rRNA gene and shotgun metagenomic sequencing as means to better understand the interactions among bacteria in cold-smoked salmon. Cold-smoked salmon samples were tested over 30 days of aerobic storage at 4°C and cultured at each time point in a buffered Listeria enrichment broth (BLEB) commonly used to detect Listeria in foods. The microbiomes were composed of Firmicutes and Proteobacteria, namely, Carnobacterium, Brochothrix, Pseudomonas, Serratia, and Psychrobacter. Pseudomonas species were the most diverse species, with 181 taxa identified. In addition, we identified potential homologs to 10 classes of bacteriocins in microbiomes of cold-smoked salmon stored at 4°C and corresponding BLEB culture enrichments. The findings presented here contribute to our understanding of microbiome population dynamics in cold-smoked salmon, including changes in bacterial taxa during aerobic cold storage and after culture enrichment. This may facilitate improvements to pathogen detection and quality preservation of this food. HIGHLIGHTS
13
Singh, Vijay P., and Mark A. McNiven. "Src-mediated Cortactin Phosphorylation Regulates Actin Localization and Injurious Blebbing in Acinar Cells." Molecular Biology of the Cell 19, no. 5 (May 2008): 2339–47. http://dx.doi.org/10.1091/mbc.e07-11-1130.
Повний текст джерелаАнотація:
Suprastimulation of pancreatic acini is a well-known model for pancreatitis, and it is characterized by actin reorganization and cell blebbing. Currently, however, the mechanisms underlying regulation of these aberrant cytoskeletal and membrane dynamics and how they contribute to cell injury are unclear. We observed that suprastimulation results in a rapid activation of Src and relocalization of the actin-binding protein cortactin from the apical to the basolateral domain at the necks of membrane blebs. Furthermore, Src-mediated cortactin tyrosine phosphorylation was markedly increased after suprastimulation. Pretreatment of acini with Src inhibitors or expression of a cortactin tyrosine phospho-inhibitory mutant reduced actin redistribution and bleb formation induced by suprastimulation in vitro. Importantly, inhibition of Src activity in rat models of suprastimulation-induced pancreatitis substantially reduced disease severity, as indicated by a reduction in serum amylase and pancreatic edema and a striking improvement in tissue histology. These findings indicate a novel, disease-relevant role for Src-mediated cortactin phosphorylation in aberrant reorganization of the actin cytoskeleton, a mechanism that is likely to have implications in other types of cell injury. In addition, they suggest a potential use for Src inhibitors as an approach to reduce cell injury.
14
Huot, Jacques, François Houle, Simon Rousseau, Réna G. Deschesnes, Girish M. Shah, and Jacques Landry. "SAPK2/p38-dependent F-Actin Reorganization Regulates Early Membrane Blebbing during Stress-induced Apoptosis." Journal of Cell Biology 143, no. 5 (November 30, 1998): 1361–73. http://dx.doi.org/10.1083/jcb.143.5.1361.
Повний текст джерелаАнотація:
In endothelial cells, H2O2 induces the rapid formation of focal adhesion complexes at the ventral face of the cells and a major reorganization of the actin cytoskeleton into dense transcytoplasmic stress fibers. This change in actin dynamics results from the activation of the mitogen-activated protein (MAP) kinase stress-activated protein kinase-2/p38 (SAPK2/p38), which, via MAP kinase-activated protein (MAPKAP) kinase-2/3, leads to the phosphorylation of the actin polymerization modulator heat shock protein of 27 kD (HSP27). Here we show that the concomitant activation of the extracellular signal-regulated kinase (ERK) MAP kinase pathway by H2O2 accomplishes an essential survival function during this process. When the activation of ERK was blocked with PD098059, the focal adhesion complexes formed under the plasma membrane, and the actin polymerization activity led to a rapid and intense membrane blebbing. The blebs were delimited by a thin F-actin ring and contained enhanced levels of HSP27. Later, the cells displayed hallmarks of apoptosis, such as DEVD protease activities and internucleosomal DNA fragmentation. Bleb formation but not apoptosis was blocked by extremely low concentrations of the actin polymerization inhibitor cytochalasin D or by the SAPK2 inhibitor SB203580, indicating that the two processes are not in the same linear cascade. The role of HSP27 in mediating membrane blebbing was assessed in fibroblastic cells. In control fibroblasts expressing a low level of endogenous HSP27 or in fibroblasts expressing a high level of a nonphosphorylatable HSP27, H2O2 did not induce F-actin accumulation, nor did it generate membrane blebbing activity in the presence or absence of PD098059. In contrast, in fibroblasts that expressed wild-type HSP27 to a level similar to that found in endothelial cells, H2O2 induced accumulation of F-actin and caused bleb formation when the ERK pathway was inhibited. Cis-platinum, which activated SAPK2 but induced little ERK activity, also induced membrane blebbing that was dependent on the expression of HSP27. In these cells, membrane blebbing was not followed by caspase activation or DNA fragmentation. We conclude that the HSP27-dependent actin polymerization–generating activity of SAPK2 associated with a misassembly of the focal adhesions is responsible for induction of membrane blebbing by stressing agents.
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Russell, Jeremy H., Neil Kelson, Mark Barry, Mark Pearcy, David F. Fletcher, and Craig D. Winter. "Computational Fluid Dynamic Analysis of Intracranial Aneurysmal Bleb Formation." Neurosurgery 73, no. 6 (August 13, 2013): 1061–69. http://dx.doi.org/10.1227/neu.0000000000000137.
Повний текст джерелаАнотація:
Abstract BACKGROUND: The management of unruptured aneurysms is controversial, with the decision to treat influenced by aneurysm characteristics including size and morphology. Aneurysmal bleb formation is thought to be associated with an increased risk of rupture. OBJECTIVE: To correlate computational fluid dynamic (CFD) indices with bleb formation. METHODS: Anatomic models were constructed from 3-dimensional rotational angiography data in 27 patients with cerebral aneurysms harboring a single bleb. Additional models representing the aneurysm before bleb formation were constructed by digitally removing the bleb. We characterized hemodynamic features of models both with and without the blebs using CFDs. Flow structure, wall shear stress (WSS), pressure, and oscillatory shear index (OSI) were analyzed. RESULTS: There was a statistically significant association between bleb location at or adjacent to the point of maximal WSS (74%, P = .019), irrespective of rupture status. Aneurysmal blebs were related to the inflow or outflow jet in 89% of cases (P < .001), whereas 11% were unrelated. Maximal wall pressure and OSI were not significantly related to bleb location. The bleb region attained a lower WSS after its formation in 96% of cases (P < .001) and was also lower than the average aneurysm WSS in 86% of cases (P < .001). CONCLUSION: Cerebral aneurysm blebs generally form at or adjacent to the point of maximal WSS and are aligned with major flow structures. Wall pressure and OSI do not contribute to determining bleb location. The measurement of WSS using CFD models may potentially predict bleb formation and thus improve the assessment of rupture risk in unruptured aneurysms.
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Yoshimasu, Y., T. Ikeda, N. Sakai, A. Yagi, S. Hirayama, Y. Morinaga, S. Furukawa, and R. Nakao. "Rapid Bactericidal Action of Propolis against Porphyromonas gingivalis." Journal of Dental Research 97, no. 8 (March 1, 2018): 928–36. http://dx.doi.org/10.1177/0022034518758034.
Повний текст джерелаАнотація:
Propolis, a resinous substance produced by bees, is used as a folk medicine for treatment of periodontal diseases. However, its mode of the action and the compounds responsible for its activities remain obscure. In the present study, we comprehensively investigated the antibacterial activities of ethanol-extracted propolis (EEP) and EEP-derived compounds toward Porphyromonas gingivalis, a keystone pathogen for periodontal diseases. Broth microdilution and agar dilution assays were used to determine the minimum inhibitory concentrations of EEP against a range of oral bacterial species, of which P. gingivalis showed a higher level of sensitivity than oral commensals such as streptococci. Its antibacterial activity toward P. gingivalis was maintained even after extensive heat treatment, demonstrating a high level of thermostability. EEP also induced death of P. gingivalis cells by increasing membrane permeability within 30 min. Spatiotemporal analysis based on high-speed atomic force microscopy revealed that EEP immediately triggered development of aberrant membrane blebs, followed by bleb fusion events on the bacterial surface. Furthermore, we isolated artepillin C, baccharin, and ursolic acid from EEP as antibacterial compounds against P. gingivalis. Of those, artepillin C and baccharin showed bacteriostatic activities with membrane blebbing, while ursolic acid showed bactericidal activity with membrane rupture. In particular, ursolic acid demonstrated a greater ability to affect bacterial membrane potential with increased membrane permeability, probably because of its highly lipophilic nature as compared with other compounds. Taken together, these findings provide mechanistic insight into the antibacterial activities of EEP and its exquisite membrane-targeting antibacterial compounds and imply the applicability of narrow-spectrum therapeutics with EEP for treatment of periodontitis. In addition, the advanced technology utilized in the present study to visualize the nanometer-scale dynamics of microorganisms will contribute to expanding our understanding of the activities of antimicrobials and the mechanism of drug resistance in bacteria.
17
Wang, Ling, Da-Bo Wang, Meng-Ying Liu, and Ru-Yong Yao. "Correlation between Tissue Characterization and Dynamic Expression of Matrix Metalloproteinase-2 and Its Tissue Inhibitor in Conjunctival Filtering Bleb of Rats." BioMed Research International 2017 (2017): 1–10. http://dx.doi.org/10.1155/2017/1054129.
Повний текст джерелаАнотація:
Purpose.Using rat conjunctival bleb model, we correlated changes morphology and histology in the bleb with changes in MMP-2 and TIMP-2 levels.Methods.Filtering surgeries were performed on rats. Dynamic changes in morphology and histopathology were observed using HE staining. Expression of MMP-2 and TIMP-2 was determined by immunofluorescence microscopy and western blotting.Results. Well-elevated filtering blebs formed and persisted for an average of 12 days. Histological examination showed that inflammatory was dominant in postoperative days 1–3, and proliferating manifestation became the main sign 5 days later. Western blot showed that MMP-2 was downregulated 1 day after surgery, upregulated at 3 days, and observed with a peak at 7 days; then it persisted until 28 days. The difference was statistically significant (F= 280.18,p<0.01).TIMP-2 was upregulated 1 day after surgery and observed with a peak at 5 days; then it persisted until 28 days. The difference was statistically significant (F= 145.34,p<0.01).Conclusions.During the processes of conjunctival filtering bleb and scar formation in rats, the changes in MMP-2 and TIMP-2 levels in the filtering area, together with a corresponding proliferation of fibroblasts and the accumulation of collagen fibres, resulted in scarring of filtering blebs.
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Tateshima, Satoshi, Yuichi Murayama, J. Pablo Villablanca, Taku Morino, Hikoichiro Takahashi, Takatsugu Yamauchi, Kazuo Tanishita, and Fernando Viñuela. "Intraaneurysmal flow dynamics study featuring an acrylic aneurysm model manufactured using a computerized tomography angiogram as a mold." Journal of Neurosurgery 95, no. 6 (December 2001): 1020–27. http://dx.doi.org/10.3171/jns.2001.95.6.1020.
Повний текст джерелаАнотація:
Object. To obtain precise flow profiles in patients' aneurysms, the authors developed a new in vitro study method featuring an aneurysm model manufactured using three-dimensional computerized tomography (3D CT) angiography. Methods. A clear acrylic basilar artery (BA) tip aneurysm model manufactured from a patient's 3D CT angiogram was used to analyze flow modifications during one cardiac cycle. Stereolithography was utilized to create the aneurysm model. Three-dimensional flow profiles within the aneurysm model were obtained from velocity measurements by using laser Doppler velocimetry. The aneurysm inflow/outflow zones changed dynamically in their location, size of their cross-sectional area, and also in their shapes over one cardiac cycle. The flow velocity at the inflow zone was 16.8 to 81.9% of the highest axial velocity in the BA with a pulsatility index (PI) of 1.1. The flow velocity at the outflow zone was 16.8 to 34.3% of the highest axial velocity of the BA, with a PI of 0.68. The shear stress along the walls of the aneurysm was calculated from the fluid velocity measured at a distance of 0.5 mm from the wall. The highest value of shear stress was observed at the bleb of the aneurysm. Conclusions. This clear acrylic model of a BA tip aneurysm manufactured using a CT angiogram allowed qualitative and quantitative analysis of its flow during a cardiac cycle. Accumulated knowledge from this type of study may reveal pertinent information about aneurysmal flow dynamics that will help practitioners understand the relationship among anatomy, flow dynamics, and the natural history of aneurysms.
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McClarty, Davis B., David C. S. Kuhn, and April J. Boyd. "Hemodynamic Changes in an Actively Rupturing Abdominal Aortic Aneurysm." Journal of Vascular Research 58, no. 3 (2021): 172–79. http://dx.doi.org/10.1159/000514237.
Повний текст джерелаАнотація:
Computational fluid dynamics were used to assess hemodynamic changes in an actively rupturing abdominal aortic aneurysm (AAA) over a 9-day period. Active migration of contrast from the lumen into the thickest region of intraluminal thrombus (ILT) was demonstrated until it ultimately breached the adventitial layer. Four days after symptom onset, there was a discrete disruption of adventitial calcium with bleb formation at the site of future rupture. Rupture occurred in a region of low wall shear stress and was associated with a marked increase in AAA diameter from 6.6 to 8.4 cm. The cross-sectional area of the flow lumen increased across all time points from 6.28 to 12.08 cm<sup>2</sup>. The increase in luminal area preceded the increase in AAA diameter and was characterized by an overall deceleration in recirculation flow velocity with a coinciding increase in flow velocity penetrating the ILT. We show that there are significant hemodynamic and structural changes in the AAA flow lumen in advance of any appreciable increase in aortic diameter or rupture. The significant increase in AAA diameter with rupture suggests that AAA may actually rupture at smaller sizes than those measured on day of rupture. These findings have implications for algorithms the predict AAA rupture risk.
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Alekseev, I. B., A. K. Aylarova, G. Sh Arzhimatova, A. V. Dobroserdov, and A. I. Samoylenko. "Evolution of Needling: Preliminary Results of Microinvasive Antiglaucoma Reoperation." Ophthalmology in Russia 18, no. 1 (April 4, 2021): 36–45. http://dx.doi.org/10.18008/1816-5095-2021-1-36-45.
Повний текст джерелаАнотація:
Purpose: to assess the efficacy and safety of needling performed by the new scleroconjunctival dissector according to our specific technique.Patients and methods. The study included 60 patients diagnosed with operated subcompensated or decompensated glaucoma. Thirty patients underwent microinvasive reoperation with the help of a sclero-conjunctival dissector. The control group consisted of 30 patients; they underwent repeated sinustrabeculectomy with iridectomy. A standard ophthalmological examination and ultrasound biomicroscopy were performed before the operation and in dynamics (after 1, 3, 6, 9 months).Results: 76.7 % of the experimental group had IOP less than or equal to 15 mm Hg six months after microinvasive reoperation. In the control group, the same mark was 70 %. Hyphema occurred in 23.3 % of the main group, it was stopped by conservative treatment. 10 % of patient developed choroid detachment, it did not require surgical treatment. Hyphema was formed in 36.7 % in the control group and choroid detachment — in 53.3 % of patients. The complications were more manifested and required surgical treatment in the control group. According to the data of ultrasound biomicroscopy, the acoustic density in the control group steadily increased, while the height of the filtration bleb first increased and then decreased. This may indicate significant tissue induration, probably as a result of fibrosis after an operating injury. The intrascleral «lake» height does not differ between the groups when comparing dynamic observations, and the volume of the intrascleral cavity is significantly greater in the main group than in the control group (p < 0.0001) at admission and during dynamic observation. The text of the article describes a clinical case of a patient who underwent microinvasive reoperation.Conclusion. When there are indications for re-surgery, an adequate and thorough diagnosis of the preservation of the surgically created outflow tract, namely gonioscopy and ultrasound biomicroscopy, is important. In patients with intact internal fistula and without pronounced fibrosis of the intrascleral drainage pathways, it is possible to carry out microinvasive reoperation according to our technique using a scleroconjunctival dissector, this allows to reduce the risk of postoperative complications and achieve hypotensive efficacy comparable to repeated filtering surgery.
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Abrahamsson, Lena. "Just när det blev viktigt blev det manligt." Tidskrift för genusvetenskap 23, no. 1 (June 15, 2022): 37–52. http://dx.doi.org/10.55870/tgv.v23i1.4252.
Повний текст джерелаАнотація:
This article is about the dynamics of gender in workplaces that are undergoing changes in organization. More precisely it is about the instability in femininity and masculinity and the links between the construction of gender and the construction of the modern organizations. On a general level the traditional gender order is based on stability, that is to say that men and women are seen as very different, even as each other's antithesis, and with different values. This kind of gender stability works as a strong restorative mechanism in the organization of local workplaces since the resulting attempts to maintain segregation and hierarchy are directly contradictory to the modern organizational concepts that aim for integration and de-centralization. Gender order in such organizations does not only provide stability, at the same time we can also see dynamic processes at work whereby parts of the contents of the concepts masculinity and femininity are transformed. For example, social competence is often seen as a "female" characteristic or ability, but is more and more becoming a "male" competence, something that men should have as well. The construction of masculinity in local organizations is thus modified in accordance with what is important to modern organizational concepts. In other words, the dynamics of gender construction makes it possible to implement modern organization concepts without changing the gender order too much.
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Schwartz, Niles, Melanie Hosford, Ruben M. Sandoval, Mark C. Wagner, Simon J. Atkinson, James Bamburg, and Bruce A. Molitoris. "Ischemia activates actin depolymerizing factor: role in proximal tubule microvillar actin alterations." American Journal of Physiology-Renal Physiology 276, no. 4 (April 1, 1999): F544—F551. http://dx.doi.org/10.1152/ajprenal.1999.276.4.f544.
Повний текст джерелаАнотація:
Apical membrane of renal proximal tubule cells is extremely sensitive to ischemia, with structural alterations occurring within 5 min. These changes are felt secondary to actin cytoskeletal disruption, yet the mechanism responsible is unknown. Actin depolymerizing factor (ADF), a 19-kDa actin-binding protein, has recently been shown to play an important role in regulation of actin filament dynamics. Because ADF is known to mediate pH-dependent F-actin binding, depolymerization, and severing, and because ADF activation occurs by dephosphorylation, we questioned whether ADF played a role in microvilli microfilament disruption during ischemia. To test our hypothesis, we induced renal ischemia in the rat with the clamp model. Initial immunofluorescence and Western blot studies on cortical tissue documented the presence of ADF in proximal tubule cells. Under physiological conditions, ADF was distributed homogeneously throughout the cytoplasm, primarily in the Triton X-100-soluble fraction, and both phosphorylated (pADF) and nonphosphorylated forms were identified. During ischemia, marked alterations occurred. Intraluminal vesicle/bleb structures contained extremely high concentrations of ADF along with G-actin, but not F-actin. Western blot showed a rapidly occurring duration-dependent dephosphorylation of ADF. At 0–30 min of ischemia, total ADF levels were unchanged, whereas pADF decreased significantly to 72% and 19% of control levels, at 5 and 15 min, respectively. Urine collected under physiological conditions did not contain ADF or actin, whereas urine collected after 30 min of ischemia contained both ADF and actin. Reperfusion was associated with normalization of cellular pADF levels, pADF intracellular distribution, and repair of apical microvilli. These data suggest that activation of ADF during ischemia via dephosphorylation is, in part, responsible for apical actin disruption resulting in microvillar destruction and formation of intraluminal vesicles.
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Lawler, Karen, Eilis Foran, Gerald O'Sullivan, Aideen Long, and Dermot Kenny. "Mobility and invasiveness of metastatic esophageal cancer are potentiated by shear stress in a ROCK- and Ras-dependent manner." American Journal of Physiology-Cell Physiology 291, no. 4 (October 2006): C668—C677. http://dx.doi.org/10.1152/ajpcell.00626.2005.
Повний текст джерелаАнотація:
To metastasize, tumor cells must adopt different morphological responses to resist shear forces encountered in circulating blood and invade through basement membranes. The Rho and Ras GTPases play a critical role in regulating this dynamic behavior. Recently, we demonstrated shear-induced activation of adherent esophageal metastatic cells, characterized by formation of dynamic membrane blebs. Although membrane blebbing has only recently been characterized as a rounded mode of cellular invasion promoted through Rho kinase (ROCK), the role of shear forces in modulating membrane blebbing activity is unknown. To further characterize membrane blebbing in esophageal metastatic cells (OC-1 cell line), we investigated the role of shear in cytoskeletal remodeling and signaling through ROCK and Ras. Our results show that actin and tubulin colocalize to the cortical ring of the OC-1 cell under static conditions. However, under shear, actin acquires a punctuate distribution and tubulin localizes to the leading edge of the OC-1 cell. We show for the first time that dynamic bleb formation is induced by shear alone independent of integrin-mediated adhesion ( P < 0.001, compared with OC-1 cells). Y-27632, a specific inhibitor of ROCK, causes a significant reduction in shear-induced bleb formation and inhibits integrin αvβ3-Ras colocalization at the leading edge of the cell. Direct measurement of Ras activation shows that the level of GTP-bound Ras is elevated in sheared OC-1 cells and that the shear-induced increase in Ras activity is inhibited by Y-27632. Finally, we show that shear stress significantly increases OC-1 cell invasion ( P < 0.007), an effect negated by the presence of Y-27632. Together our findings suggest a novel physiological role for ROCK and Ras in metastatic cell behavior.
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Januleviciene, Ingrida. "Ophthalmology and mathematics: crossroad or scientific interface?" Modeling and Artificial Intelligence in Ophthalmology 1, no. 2 (December 15, 2016): 5–9. http://dx.doi.org/10.35119/maio.v1i2.39.
Повний текст джерелаАнотація:
The progress of science is discontinuous. However, accepting the dynamic nature of science, most of us have experienced the point of research crossroads when it was hard to choose the correct path. In 1962 Thomas Samuel Kuhn published his controversial book The Structure of Scientific Revolutions introducing the term “paradigm shift” raising the idea that progress isn't a continuous accumulation, but rather a revolutionary process where brand new ideas are adopted and old ideas are abandoned. Without trying to accept or argue philosphical aspects, today we experience a rapidly growing amount of research in ophthalmology. The goal of the current evidence-based approach in medicine is to optimize everyday clinical practice based on comprehensive research. However, results coming from the basic sciences sometimes may not be directly applicableto an individual patient. The latest developments, scientific achievements and research in ophthalmology steer to the exciting new perspective based on a multidisciplinary approach. Bringing together scientists whose expertise encompasses ophthalmology, physiology, mathematics, physics and engineering and who explore different aspects of the same problems empowering to make scientific progress. Can ophthalmologists think mathematically? Is it possible to provide a quantitative representation of the biophysical processes in the eye? Application of objective scientific methods and subjective perspectives can open up a wide range of educational and professional opportunities leading to a better understanding of the pathogenesis and the natural course of the disease, progression and new ways of treatment. Introducing the 2nd issue of Journal for Modeling in Ophthalmology, we hope the reader will enjoy both clinical and theoretical insights on glaucoma in short papers that followed the International Congress on Advanced Technologies and Treatments for Glaucoma (ICATTG15) held in Milan (Italy), October 29-31, 2015 (http://www.icatto.com/archive/icattg2015/). Normal tension glaucoma is a particularly difficult type of glaucoma both in terms of diagnosis and treatment. M. Iester pointed out that different types of glaucoma exist and are probably based on the presence of different risk factors. The cut-off value of 21 mmHg is not used anymore to differentiate healthy subjects from glaucoma patients. The paper by L. Quaranta et al analyses the rationale for IOP measurements throughout the 24-hour cycle. IOP is not a static number; rather, it exhibits time-dependent variations that can reach up to 6 mmHg over a 24-hour period in healthy eyes, and even more in eyes with glaucoma2-5. Regarding 24-hour IOP characteristics, only IOP peak was correlated to visual field progression, while 24-hour IOP fluctuation was not an independent risk factor6. Indeed, 24-hour mean, peak and fluctuation were all associated and a strong correlation was found between mean and peak IOP, and between fluctuation and peak IOP. Mean IOP is a strong predictor of glaucomatous damage. A desired therapeutic target is therefore a uniform reduction of IOP throughout the 24 hours. A reliable method of continuous IOP measurement would be desirable, making 24-hour IOP phasing easier and opening new pathways for research. Interestingly, the papers by M. Szopos M et al and A. Mauri et al lead to new perspectives of mathematical modeling of aqueous humor flow and intraocular pressure towards individualized glaucoma management. M. Szopos et al aimed to provide both a qualitative description and a quantitative assessment of how variations in aqueous humor flow parameters influence IOP and the outcome of IOP lowering medications. They developed a mathematical model that described the steady state value of IOP as the result of the balance between aqueous humor production and drainage and performing stochastic simulations to assess the influence of different factors on the IOP distribution in ocular normotensive and ocular hypertensive subjects and also on the IOP reduction following medications. This model may help identify patient specific factors that influence the efficacy of IOP lowering medications and aid the development of novel, effective, and individualized therapeutic approaches to glaucoma management. A. Mauri et al. theoretically analyzed new aspects of electro-fluid dynamics of aqueous humor production. The connection between HCO3, Na+ and topical medications in the regulation of aqueous humor production is still controversial and difficult to study experimentally by trying to isolate the role of a single electrolyte in regulating aqueous humor production. The use of a mathematical model appeared to be a promising approach to help unravel such a connection through simulation and comparison of different predicted scenarios. Groups of authors from Indianapolis and Milan universities contributed to glaucoma progression analysis. K. Hutchins et al paper on clinical evaluation of baseline characteristics predictive of structural and functional progression in open angle glaucoma patients with different demographic characteristics aimed to examine ocular blood flow parameters that may predict structural and functional disease progression in open angle glaucoma patients of different diabetic status, gender, ethnicity, and body mass index. D. Messenio et al. evaluated the variations of IOP, morphometric papillary characteristics, perimetric indices and electrophysiological parameters before and after topical IOP lowering therapy in patients with suspect normal tension glaucoma. They showed that electrophysiological tests could provide a more sensitive measure of retinal ganglion cell integrity and help distinguish between suspect normal-pressure glaucoma patients before perimetric alterations are evident and normal subjects with apparent larger disc cupping. Over the past decades, color Doppler imaging (CDI) has gained popularity as a reliable tool to measure blood flow in a variety of vascular beds throughout the body. The use of CDI to measure blood flow parameters in retrobulbar vessels has become very common. L. Carichino et al introduced a computer-aided identification of novel ophthalmic artery waveform parameters. The computed-aided analysis of ophthalmic artery velocity waveforms obtained via CDI were able to distinguish arterial waveform parameters values between healthy subjects and glaucoma patients, as well as between gender. Authors foresee further studies investigating the potential to predict severity and progression of glaucoma. An interesting contribution by S. Cassani et al on theoretical predictions of metabolic flow regulation in the retina aims to better understand the regulating mechanisms in health and disease. This study used a theoretical model to investigate the response of retinal blood flow to changes in tissue oxygen demand. The increase in blood flow predicted by the model due to an increase in oxygen demand was not in the same proportion as the change in blood flow observed with the same decrease in oxygen demand, suggesting that vascular regulatory mechanisms may respond differently to different levels of oxygen demand. Several studies have suggested an association between vascular factors and glaucoma7-11. Several epidemiological studies demonstrated the influence of ocular perfusion pressure on the prevalence, incidence and progression of glaucoma12. Ocular perfusion pressure refers to the pressure available to drive blood through the intraocular vasculature, with the degree of perfusion being influenced by the resistance to flow, which is a function of the vessel caliber or the vessel tone 13. While it seems a very complex parameter, A. Guglielmi et al utilized statistical techniques and analysis to show that it is the joint effect of IOP, ocular perfusion pressure and blood pressure, or, more precisely, of all the covariates in the selected logistic model, that determines the probability of disease, rather than the value of an individual covariate. Importantly, the main statistical interest should be the prediction of disease probabilities for new patients entering the study, presenting specific values of the covariates included in the model, rather than the estimated individual effect of a single predictor. It has been shown that glaucoma, proliferative vitreoretinopathy, posterior capsule opacification, diabetic retinopathy, age-related macular degeneration, pterygium and keratoconus have been associated with modulation of Transforming Growth Factor beta (TGF-β) protein expression14-20. Therapeutic intervention targeting TGF-β2 protein expression may have multifold effects on relevant intraocular tissues such as trabecular meshwork (cell invasion/migration), retina (scarring and wound-healing processes) and/or optic nerve head (neuroprotection), and warrant further evaluation in patients suffering advanced glaucoma and undergoing trabeculectomy. Hasenbach K et al. used a murine model of glaucoma filtration surgery to evaluate the effect of intraocular ISTH0036 administration. They showed that treatment with ISTH0036 resulted in prolonged bleb survival and decreased scarring (downregulation of collagen 1 and 3 fibers) in a murine glaucoma filtration surgery model. Initial results rose a strong rationale that patients with glaucoma or other ocular diseases may benefit from treatment with TGF-β2 antisense oligonucleotides. D.Paulaviciute-Baikstiene et al. performed a prospective 12 month study aiming to find the correlation between anterior segment OCT and functional outcomes of trabeculectomy by describing morphological features of successful and limited success filtering blebs. The detection of early postoperative scarring and the continuing development of surgical measures to reduce this risk represent a major challenge of filtering surgery. Authors suggest that larger internal fluid filled cavity, total bleb height, bigger bleb wall thickness and multiform bleb wall reflectivity are good indicators of successful bleb function. The 2nd Issue of the Journal for Modeling in Ophthalmology uniquely combines and balances clinical and mathematical aspects in the study of glaucoma and we believe that both ophthalmologists and modeling experts will find in it interesting aspects and new information on glaucoma and its risk factors. Enjoy your reading!
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Ozkan-Aydin, Yasemin, Daniel I. Goldman, and M. Saad Bhamla. "Collective dynamics in entangled worm and robot blobs." Proceedings of the National Academy of Sciences 118, no. 6 (February 5, 2021): e2010542118. http://dx.doi.org/10.1073/pnas.2010542118.
Повний текст джерелаАнотація:
Living systems at all scales aggregate in large numbers for a variety of functions including mating, predation, and survival. The majority of such systems consist of unconnected individuals that collectively flock, school, or swarm. However, some aggregations involve physically entangled individuals, which can confer emergent mechanofunctional material properties to the collective. Here, we study in laboratory experiments and rationalize in theoretical and robophysical models the dynamics of physically entangled and motile self-assemblies of 1-cm-long California blackworms (Lumbriculus variegatus, Annelida: Clitellata: Lumbriculidae). Thousands of individual worms form braids with their long, slender, and flexible bodies to make a three-dimensional, soft, and shape-shifting “blob.” The blob behaves as a living material capable of mitigating damage and assault from environmental stresses through dynamic shape transformations, including minimizing surface area for survival against desiccation and enabling transport (negative thermotaxis) from hazardous environments (like heat). We specifically focus on the locomotion of the blob to understand how an amorphous entangled ball of worms can break symmetry to move across a substrate. We hypothesize that the collective blob displays rudimentary differentiation of function across itself, which when combined with entanglement dynamics facilitates directed persistent blob locomotion. To test this, we develop a robophysical model of the worm blobs, which displays emergent locomotion in the collective without sophisticated control or programming of any individual robot. The emergent dynamics of the living functional blob and robophysical model can inform the design of additional classes of adaptive mechanofunctional living materials and emergent robotics.
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Wang, Yanfeng, Aae Suzuki, Lurong Lian, Rustem I. Litvinov, Timothy J. Stalker, John K. Choi, John W. Weisel, Lawrence F. Brass та Charles S. Abrams. "Platelets Lacking PIP5KIγ Have Impaired Cytoskeletal Dynamics and Adhesion, but No Defect in Integrin Activation." Blood 114, № 22 (20 листопада 2009): 772. http://dx.doi.org/10.1182/blood.v114.22.772.772.
Повний текст джерелаАнотація:
Abstract Abstract 772 Following thrombin stimulation, platelet PIP5KI synthesizes phosphatidylinositol 4,5-bisphosphate (PIP2), which can be hydrolyzed by phospholipase C to generate second messengers such as IP3. PIP2 also regulates cytoskeletal dynamics by directly interacting with actin-binding proteins such as talin. Three isoforms of PIP5KI (α, β, and γ) are all capable of phosphorylating PI4P to synthesize PIP2. We have generated and characterized murine lines lacking individual PIP5KI isoforms. While mice lacking PIP5KIα and PIP5KIα have absent second messenger formation and partially impaired integrin activation, they are viable. In contrast, mice lacking PIP5KIγ die in utero due to a cardiovascular developmental defect. Megakaryocytes derived from PIP5KIγ-null embryos bleb their membranes due to impaired anchoring of the cell membrane with the underlying cytoskeleton. Since platelets can not be obtained from these embryos, we employed a genetic approach. We used a MLC-2v Cre transgene that targets Cre expression to myocytes, and generated living mice lacking PIP5KIγ by a conditional rescue. PIP5KIγ-/- MLC-2v Cre+ mice expressed PIP5KIγ in the myocardium, but they had absent expression of PIP5KIγ in all other analyzed tissue. These mice had normal appearing hearts, brains, livers, and bone marrow morphology, as well as normal platelet counts. Since mice lacking PIP5KIα and PIP5KIβ have impaired platelet PIP2 production that causes absent IP3 formation, we analyzed platelets lacking PIP5KIγ for second messenger formation. Even though PIP5KIγ an abundant PIP5KI isoform in platelets, loss of PIP5KIγ does not affect IP3 formation or Akt phosphorylation. It has been previously demonstrated that PIP5KIγ can directly bind talin, a protein that regulates the function of integrins. An existing proposed model for integrin activation is that talin-associated PIP5KIγ synthesize PIP2. This newly synthesized PIP2 then binds a FERM domain within talin. The model suggests that this complex of PIP5KIγ-PIP2-talin is critical for the final step that stimulates integrins to bind their ligand. We found three lines of evidence that disprove this model of integrin activation. First, we found that PIP5KIγ-/- platelets had normal integrin-mediated aggregation in response to all analyzed doses of thrombin, ADP, collagen, and a thromboxane analogue (U46619). Second, we observed that PIP5KIγ-null platelets exhibited normal binding of Jon/A, an antibody that recognizes only the activated form of αIIb/β3. Third, we determined that platelets lacking PIP5KIγ spread normally upon adherent fibrinogen. Together, these results disprove the existing model that PIP5KIγ is a critical component of talin-mediated integrin activation. To determine the true function of PIP5KIγ within platelets, we extended our previous studies by analyzing the role PIP5KIγ plays in the regulation of the cytoskeleton. Therefore, we analyzed platelets lacking this enzyme for their ability to anchor the cytoskeleton to the cell membrane. We used optical tweezers to pull the cell membrane apart from the cytoskeleton. Wild type cells had rigid membranes that resisted stretching by trapped fibrinogen-coated beads that were pulled by the optical trap. In contrast, the PIP5KIγ-null platelets had flexible membranes that were easily stretched, and ultimately allowed membrane tethers to form. We further analyzed whether this defect in anchoring the cell membrane to the underlying cytoskeleton causes a defect in vivo using a carotid artery arterial injury model. Mice lacking platelet PIP5KIγ exhibited unstable adhesion in vivo suggesting that impaired cytoskeletal dynamics causes impaired platelet adhesion under flow. Together, our studies demonstrate that the abundant PIP5KI isoform, PIP5KIγ does not contribute to a pool of PIP2 required for second messenger formation or integrin activation. However it does synthesize the pool of PIP2 required to preserve the integrity of the membrane cytoskeleton, and support stable platelet adhesion under conditions of shear. Disclosures: No relevant conflicts of interest to declare.
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Malla, Saloni, David Terrero, Sushma Karki, Mariam Sami Abou-Dahech, Shikha Kumari, and Amit K. Tiwari. "Abstract 1387: Novel thienopyrimidine-hydrazinyl analog, TPH104m inhibits mitochondrial respiration and induces caspase-independent cell death in triple-negative breast cancer cells." Cancer Research 83, no. 7_Supplement (April 4, 2023): 1387. http://dx.doi.org/10.1158/1538-7445.am2023-1387.
Повний текст джерелаАнотація:
Abstract A triple negative breast cancer (TNBC) is an aggressive and difficult-to-treat breast cancer subtype. Neoadjuvant chemotherapy using apoptosis-inducing taxanes and/or anthracyclines has been shown to produce early therapeutic responses. Unfortunately, drug resistance often results from mutations in apoptotic pathways, which can lead to metastasis and poor prognosis. There are emerging studies suggesting that TNBC tumors display altered mitochondrial dynamics and have overexpressed dynamin related protein 1 (Drp1), which drives mitochondrial fission. Drp1 deregulation also influences metabolic changes and mitochondrial energetics, which support TNBC tumor growth. Therefore, bypassing apoptosis signaling cascade, suppressing Drp1 and reversing aberrant mitochondrial dynamics may be an effective therapy for TNBC. We report here for the first time the identification of novel thienopyrimidine-hydrazinyl analog of parent TPH104, namely, TPH104m, which inhibits Drp1 phosphorylation and induces a non-apoptotic TNBC cell death. TPH104m significantly inhibited TNBC proliferation at nanomolar concentrations, and was more selective for TNBC than normal human mammary epithelial cells. TPH104m induced a unique type of non-apoptotic cell death, where cells swelled without shrinkage, nuclear fragmentation or apoptotic bleb formation typical of apoptosis. Moreover, TPH104m did not induce the cleavage of initator (caspase-8, -9) and executioner caspases (caspase-3, -7), and zVAD.fmk, a pan-caspase inhibitor, did not rescue TNBC cell death when incubated with TPH104m. Furthermore, TPH104m did not significantly increase reactive oxygen species (ROS) production in BT-20 cells compared to Paclitaxel treated cells. Although mitochondrial membrane potential (MMP) was significantly reduced, cytochrome C release was not increased, but instead decreased, explaining why MMP loss did not lead to apoptosis. TPH104m remarkably downregulated the phosphorylated and total forms of Drp1 protein in TNBC cells. A docking-based reverse screening approach and Surface Plasmon Resonance (SPR) data indicated that TPH104m binds to Drp1 more strongly than Mdivi-1, a weak non-specific Drp1 inhibitor. A complete and partial Drp1 KO cell line was created in SUM-159 TNBC cells to investigate the role of Drp1 in TPH104m-induced non-apoptotic cell death. Genetically deleting Drp1 from TNBC cells reduced TPH104m's cytotoxic potential suggesting Drp1's role in TPH104m's anticancer mechanism. Moreover, mito-stress assay showed that TPH104m severely impaired oxygen consumption rate, resulting in decreased ATP production and inhibition of mitochondrial respiration. Development of alternative treatments for TNBC will be facilitated by a deeper understanding of mitochondrial role in non-apoptotic cell death. Citation Format: Saloni Malla, David Terrero, Sushma Karki, Mariam Sami Abou-Dahech, Shikha Kumari, Amit K. Tiwari. Novel thienopyrimidine-hydrazinyl analog, TPH104m inhibits mitochondrial respiration and induces caspase-independent cell death in triple-negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1387.
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Carbary, J. F., K. Liou, A. T. Y. Lui, P. T. Newell, and C. I. Meng. "“Blob” analysis of auroral substorm dynamics." Journal of Geophysical Research: Space Physics 105, A7 (July 1, 2000): 16083–91. http://dx.doi.org/10.1029/1999ja000210.
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Bodi, K., S. I. Krasheninnikov, and A. I. Smolyakov. "Blob dynamics in an inhomogeneous plasma." Physics of Plasmas 15, no. 10 (October 2008): 102304. http://dx.doi.org/10.1063/1.2993211.
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Würtz, R. P., and C. von der Malsburg. "A Hierarchical Dynamic Link Network to Solve the Visual Correspondence Problem." Perception 25, no. 1_suppl (August 1996): 183. http://dx.doi.org/10.1068/v96l0702.
Повний текст джерелаАнотація:
Conventional neural networks try to solve the problem of object recognition in a single step by building a stimulus — response system that codes its result as cell activities. We take a different approach assuming that recognition is an active process with temporal dynamics and results in an ordered state. We present a structure of neuronal layers, interconnected by dynamic links (von der Malsburg, 1985 Berichte der Bunsengesellschaft für Physikalische Chemie89 703 – 710) that solves the correspondence problem between two images and thus constitutes an important building block for a model of recognition. Images as well as stored models are represented as Gabor pyramids. This allows the dynamics to proceed from coarse to fine scale and reduces the sequential processing time inherent in the concept. Invariance under background changes is also made possible. On the lowest frequency level, a single blob of activity moves across the image and model layer, respectively. Dynamic links between these layers are initialised to the (highly ambiguous) feature similarities. Links grow or decline according to a combination of feature similarity and correlated activation. This enforces correct neighbourhood relationships in addition to feature similarity. On the higher levels the established correspondences are refined by several blobs in parallel. We present an improved version of the dynamical system proposed by Würtz [1995 Multilayer Dynamic Link Networks for Establishing Image Point Correspondences and Visual Object Recognition (Thun, Frankfurt a.M.: Harri Deutsch)] and show, with examples of human faces, that it evolves from an unordered link distribution to any ordered state where only corresponding point pairs are connected by strong links. Correspondences between sample points are population-coded by a set of neighbouring links.
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Shanahan, B. W., and B. D. Dudson. "Blob dynamics in TORPEX poloidal null configurations." Plasma Physics and Controlled Fusion 58, no. 12 (October 17, 2016): 125003. http://dx.doi.org/10.1088/0741-3335/58/12/125003.
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Fang, Chao, Tsz Hin Hui, Xi Wei, Zishen Yan, Jin Qian, and Yuan Lin. "Interaction and fusion dynamics between cellular blebs." Journal of Biomechanics 81 (November 2018): 113–21. http://dx.doi.org/10.1016/j.jbiomech.2018.10.004.
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Martínez-Gómez, D., R. Oliver, E. Khomenko, and M. Collados. "Two-dimensional simulations of coronal rain dynamics." Astronomy & Astrophysics 634 (February 2020): A36. http://dx.doi.org/10.1051/0004-6361/201937078.
Повний текст джерелаАнотація:
Context. Coronal rain often comes about as the final product of evaporation and condensation cycles that occur in active regions. Observations show that the condensed plasma falls with an acceleration that is less than that of free fall. Aims. We aim to improve the understanding of the physical mechanisms behind the slower than free-fall motion and the two-stage evolution (an initial phase of acceleration followed by an almost constant velocity phase) detected in coronal rain events. Methods. Using the MANCHA3D code, we solve the 2D ideal magnetohydrodynamic equations. We represent the solar corona as an isothermal vertically stratified atmosphere with a uniform vertical magnetic field. We represent the plasma condensation as a density enhancement described by a 2D Gaussian profile. We analyse the temporal evolution of the descending plasma and study its dependence on such parameters as density and magnetic field strength. Results. We confirm previous findings that indicate that the pressure gradient is the main force that opposes the action of gravity and slows down the blob descent, and that larger densities require larger pressure gradients to reach the constant speed phase. We find that the shape of a condensation with a horizontal variation of density is distorted during its fall because the denser parts of the blob fall faster than the lighter ones. This is explained by the fact that the duration of the initial acceleration phase and, therefore, the maximum falling speed attained by the plasma, increases with the ratio of blob to coronal density. We also find that the magnetic field plays a fundamental role in the evolution of the descending condensations. A strong enough magnetic field (greater than 10 G in our simulations) forces each plasma element to follow the path given by a particular field line, which allows for the description of the evolution of each vertical slice of the blob in terms of 1D dynamics, without the influence of the adjacent slices. In addition, under the typical conditions of the coronal rain events, the magnetic field prevents the development of Kelvin-Helmholtz instability.
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Kawaguchi, Tomohiro, Shinjitsu Nishimura, Masayuki Kanamori, Hiroki Takazawa, Shunsuke Omodaka, Kenya Sato, Noriko Maeda, et al. "Distinctive flow pattern of wall shear stress and oscillatory shear index: similarity and dissimilarity in ruptured and unruptured cerebral aneurysm blebs." Journal of Neurosurgery 117, no. 4 (October 2012): 774–80. http://dx.doi.org/10.3171/2012.7.jns111991.
Повний текст джерелаАнотація:
Object The difference in the hemodynamics of wall shear stress (WSS) and oscillatory shear index (OSI) between ruptured and unruptured aneurysms is not well understood. The authors investigated the hemodynamic similarities and dissimilarities in ruptured and thin-walled unruptured aneurysm blebs. Methods Magnetic resonance imaging–based fluid dynamics analysis was used to calculate WSS and OSI, and hemodynamic and intraoperative findings were compared. The authors also compared ruptured and unruptured thin-walled blebs for the magnitude of WSS and OSI. Results Intraoperatively, 13 ruptured and 139 thin-walled unruptured aneurysm blebs were identified. Twelve of the ruptured (92.3%) and 124 of the unruptured blebs (89.2%) manifested low WSS and high OSI. The degree of WSS was significantly lower in ruptured (0.49 ± 0.12 Pa) than in unruptured (0.64 ± 0.15 Pa; p < 0.01) blebs. Conclusions Ruptured and unruptured blebs shared a distinctive pattern of low WSS and high OSI. The degree of WSS at the rupture site was significantly lower than in the unruptured thin-walled blebs.
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Larsen, Anna K., René Lametsch, John S. Elce, Jørgen K. Larsen, Bo Thomsen, Martin R. Larsen, Moira A. Lawson, Peter A. Greer, and Per Ertbjerg. "Genetic disruption of calpain correlates with loss of membrane blebbing and differential expression of RhoGDI-1, cofilin and tropomyosin." Biochemical Journal 411, no. 3 (April 14, 2008): 657–66. http://dx.doi.org/10.1042/bj20070522.
Повний текст джерелаАнотація:
Dynamic regulation of the actin cytoskeleton is important for cell motility, spreading and the formation of membrane surface extensions such as lamellipodia, ruffles and blebs. The ubiquitous calpains contribute to integrin-mediated cytoskeletal remodelling during cell migration and spreading, by cleavage of focal adhesion components and signalling molecules. In the present study, the live-cell morphology of calpain-knockout and wild-type cells was examined by time-lapse fluorescence microscopy, and a role of calpain in mediating the formation of sporadic membrane blebs was established. Membrane blebbing was significantly reduced in calpain-knockout cells, and genetic rescue fully restored the wild-type phenotype in knockout cells. Proteomic comparison of wild-type and knockout cells identified decreased levels of RhoGDI-1 (Rho GDP-dissociation inhibitor) and cofilin 1, and increased levels of tropomyosin in calpain-knockout cells, suggesting a role of calpain in regulating membrane extensions involving these proteins. RhoGDI, cofilin and tropomyosin are known regulators of actin filament dynamics and membrane extensions. The reduced levels of RhoGDI-1 in calpain-knockout cells observed by proteome analysis were confirmed by immunoblotting. Genetic rescue of the calpain-knockout cells enhanced RhoGDI-1-expression 2-fold above that normally present in wild-type cells. These results suggest a regulatory connection between calpain and RhoGDI-1 in promoting formation of membrane blebs.
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HASEGAWA, Hiroki, and Seiji ISHIGURO. "Particle Simulation of Plasma Blob Dynamics: Preliminary Results." Plasma and Fusion Research 7 (2012): 2401060. http://dx.doi.org/10.1585/pfr.7.2401060.
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Lim, F. Y., K. H. Chiam, and L. Mahadevan. "The size, shape, and dynamics of cellular blebs." EPL (Europhysics Letters) 100, no. 2 (October 1, 2012): 28004. http://dx.doi.org/10.1209/0295-5075/100/28004.
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Nithianandam, Vanitha, and Cheng-Ting Chien. "Actin blobs prefigure dendrite branching sites." Journal of Cell Biology 217, no. 10 (July 24, 2018): 3731–46. http://dx.doi.org/10.1083/jcb.201711136.
Повний текст джерелаАнотація:
The actin cytoskeleton provides structural stability and adaptability to the cell. Neuronal dendrites frequently undergo morphological changes by emanating, elongating, and withdrawing branches. However, the knowledge about actin dynamics in dendrites during these processes is limited. By performing in vivo imaging of F-actin markers, we found that F-actin was highly dynamic and heterogeneously distributed in dendritic shafts with enrichment at terminal dendrites. A dynamic F-actin population that we named actin blobs propagated bidirectionally at an average velocity of 1 µm/min. Interestingly, these actin blobs stalled at sites where new dendrites would branch out in minutes. Overstabilization of F-actin by the G15S mutant abolished actin blobs and dendrite branching. We identified the F-actin–severing protein Tsr/cofilin as a regulator of dynamic actin blobs and branching activity. Hence, actin blob localization at future branching sites represents a dendrite-branching mechanism to account for highly diversified dendritic morphology.
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Hsu, Shao-Yiu, Joseph Katz, and Markus Hilpert. "Theoretical and experimental study of resonance of blobs in porous media." GEOPHYSICS 77, no. 5 (September 1, 2012): EN61—EN71. http://dx.doi.org/10.1190/geo2012-0043.1.
Повний текст джерелаАнотація:
We theoretically and experimentally investigated the frequency response of blobs in porous media to an oscillatory pressure difference. (The term blob refers to a connected liquid mass that occupies one or more pores.) To predict the frequency response analytically, we formulated a simple model pore system consisting of a blob in a capillary tube. This model accounts for the frequency-dependent viscous pressure drops in the blob and the surrounding liquid and for the dynamic capillary pressure that occurs due to contact line pinning. By using the planar laser-induced fluorescence technique, we visualized the dynamic response of blobs in porous media. As predicted by our theory, air and liquid blobs surrounded by an immiscible liquid exhibited resonance in a capillary tube. Furthermore, we showed, for the first time, that a liquid blob in a sphere-packing medium exhibits resonance.
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Stepanenko, A. A. "Effect of electromagnetic wave reflection from conducting surfaces on blob dynamics in the tokamak scrape-off layer." Physics of Plasmas 30, no. 4 (April 2023): 042301. http://dx.doi.org/10.1063/5.0140097.
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Electromagnetic dynamics of blobs in hot scrape-off-layer plasmas of the tokamak are affected by excitation of the Alfvén waves and their subsequent propagation to the machine first wall along open magnetic field lines. In this study, the interaction of electromagnetic perturbations with the conducting tokamak wall and the resulting impact of these perturbations on the motion of filaments at the tokamak edge are analyzed. The model describing blob dynamics is presented. To describe the reflection of the Alfvén waves from the tokamak wall, the new form of sheath boundary conditions for the parallel current and electrostatic potential at the plasma–sheath interface is proposed. It is demonstrated that depending on the wall resistivity, the waves can be either absorbed or reflected by the wall, influencing the excitation of electromagnetic fluctuations inside the filament plasma. The theoretical conclusions of the study are supported with the BOUT++ numerical modeling of blob dynamics at the edge of the DIII-D and NSTX tokamaks. It is shown that taking the reflective boundary conditions into account leads to the excitation of the standing Alfvén waves in the filament, periodically canceling the electrostatic currents inside the blob.
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Kim, Yoonyoung, David Jewitt, Jane Luu, Jing Li, and Max Mutchler. "Comet 108P/Ciffreo: The Blob." Astronomical Journal 165, no. 4 (March 8, 2023): 150. http://dx.doi.org/10.3847/1538-3881/acba07.
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Abstract Short-period comet 108P/Ciffreo is known for its peculiar double morphology, in which the nucleus is accompanied by a comoving, detached, diffuse “blob.” We report new observations of 108P/Ciffreo taken with the Hubble Space Telescope and the Nordic Optical Telescope and use them to determine the cause of this unusual morphology. The separation and the longevity of the blob across several orbits together rule out the possibility of a single, slow-moving secondary object near the primary nucleus. We use a model of coma particle dynamics under the action of solar gravity and radiation pressure to show that the blob is an artifact of the turnaround of particles ejected sunward and repelled by sunlight. Numerical experiments limit the range of directions which can reproduce the morphology and explain why the comoving blob appearance is rare.
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Myra, J. R., W. M. Davis, D. A. D'Ippolito, B. LaBombard, D. A. Russell, J. L. Terry, and S. J. Zweben. "Edge sheared flows and the dynamics of blob-filaments." Nuclear Fusion 53, no. 7 (June 4, 2013): 073013. http://dx.doi.org/10.1088/0029-5515/53/7/073013.
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Angus, Justin R., Sergei I. Krasheninnikov, and Maxim V. Umansky. "Effects of parallel electron dynamics on plasma blob transport." Physics of Plasmas 19, no. 8 (August 2012): 082312. http://dx.doi.org/10.1063/1.4747619.
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Myra, J. R. "Current carrying blob filaments and edge-localized-mode dynamics." Physics of Plasmas 14, no. 10 (October 2007): 102314. http://dx.doi.org/10.1063/1.2776900.
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Renault, Louis, Beáta Bugyi, and Marie-France Carlier. "Spire and Cordon-bleu: multifunctional regulators of actin dynamics." Trends in Cell Biology 18, no. 10 (October 2008): 494–504. http://dx.doi.org/10.1016/j.tcb.2008.07.008.
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Asif, Nishat, and T. P. Mall. "Population dynamics of mycoflora in BLSB susceptible maize varieties." Environment Conservation Journal 9, no. 3 (December 18, 2008): 57–59. http://dx.doi.org/10.36953/ecj.2008.090312.
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Seed mycoflora of three varieties susceptible to Banded leaf and Sheath blight disease of maize was isolated from fresh harvest of 2007 following agar plate method. The results indicated the presence of fifteen species belonging to eleven genera. Highest percentage of Aspergillus niger was recorded in all tested varieties. The effect of dominant fungi on seed germination, seedling growth, and their fresh and dry weight and vigour index was recorded. It showed that highest (94%) percent of seed germination was observed in control.
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Li, W., Y. Xu, J. Cheng, H. Liu, Z. P. Chen, J. Q. Xu, X. Q. Wang, et al. "Effects of edge biasing on blob dynamics and associated transport in the edge of the J-TEXT tokamak." Plasma Physics and Controlled Fusion 64, no. 3 (February 1, 2022): 035013. http://dx.doi.org/10.1088/1361-6587/ac4857.
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Abstract Effects of edge radial electric field E r and E r × B flow shear on edge turbulence and turbulent transport, in particular, on large-scale blobs and blobby transport have been investigated in the positive and negative biasing discharges in the J-TEXT tokamak. The results show that under certain conditions, the positive electrode biasing induces better plasma confinement than the negative biasing. Further studies reveal that in addition to flow shear effects on blob dynamics, the local radial electric field at the edge region plays a significant role in repulsion of the blobs and associated transport, leading to improvement of particle confinement when the outward motion of the blobs is blocked. The results are consistent with the existing theory on blob dynamics.
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YANG, HUIJUN. "DEPENDENCE OF HAMILTONIAN CHAOS ON PERTURBATION STRUCTURE." International Journal of Bifurcation and Chaos 03, no. 04 (August 1993): 1013–28. http://dx.doi.org/10.1142/s0218127493000830.
Повний текст джерелаАнотація:
In this paper, we considered a Hamiltonian dynamical system consisting of a steady wave and a perturbation wave and studied the dependence of spatial patterns of chaos on the perturbation structure (i.e., the wave numbers of the perturbation wave). The system came from the passive wave mixing and transport problem. In order to investigate this dependence, we first did some simple mixing experiments with initially a small blob and calculated the correlation dimensions. Secondly we used Lyapunov exponents to identify the chaotic regions and the invariant tori and computed the histograms or PDFs (Probability Distribution Functions) to characterize the Hamiltonian chaos for different perturbation structure. We found that this dependence was very complicated and the complexity increases with the perturbation structure. This dynamical system became more chaotic with increase in the wave numbers. The fascinating patterns of the Hamiltonian chaos for various perturbation structures were presented. The spatial pattern of chaos on the isentropic surface of the atmosphere was given. Implications of the results of the chaotic wave mixing and transport in climate dynamics, atmospheric chemistry, aeronomy and large scale dynamics of geophysical fluid flows were briefly discussed.
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Navarro, Anamaría, K. Murawski, D. Wójcik, and F. D. Lora-Clavijo. "Numerical simulations of the emerging plasma blob into a solar coronal hole." Monthly Notices of the Royal Astronomical Society 489, no. 2 (September 5, 2019): 2769–74. http://dx.doi.org/10.1093/mnras/stz2313.
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ABSTRACT We numerically simulate emergence of a magnetic plasma blob into a solar coronal hole. This blob may be associated with granulation and therefore it has a weak magnetic field. Two-dimensional simulations are performed using the magnus code which solves magnetohydrodynamic equations, taking into account magnetic resistivity and thermal conduction. As a result of the interaction of the emerging blob with the ambient plasma, the magnetic lines experience reconnection with the blob getting flattened and deformed with time. Additionally, this process launches a vertical outflow of hot plasma and the chromosphere in its response increases its temperature. We perform parametric studies by varying the magnitude of the magnetic field of the blob and observing the net heating of the chromosphere. These studies are inspired by realistic simulations of granulation made with the use of two-fluid joanna code. In these simulations a number of magnetic blobs are detected in the convection zone and in the photosphere. From the numerical results, we conclude that as a result of granulation operating in a solar quiet region the emerging blob may trigger very complex dynamics in the upper regions of the solar atmosphere, and the associated outflows may be a source of heating of the chromosphere and possibly the solar corona.
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Chao, Tze-Fan, Yenn-Jiang Lin, Shih-Lin Chang, Li-Wei Lo, Yu-Feng Hu, Ta-Chuan Tuan, Jo-Nan Liao, et al. "Incident Risk Factors and Major Bleeding in Patients with Atrial Fibrillation Treated with Oral Anticoagulants: A Comparison of Baseline, Follow-up and Delta HAS-BLED Scores with an Approach Focused on Modifiable Bleeding Risk Factors." Thrombosis and Haemostasis 47, no. 04 (March 6, 2018): 768–77. http://dx.doi.org/10.1055/s-0038-1636534.
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Aim When assessing bleeding risk in patients with atrial fibrillation (AF), risk stratification is often based on the baseline risks. We aimed to investigate changes in bleeding risk factors and alterations in the HAS-BLED score in AF patients. We hypothesized that a follow-up HAS-BLED score and the ‘delta HAS-BLED score’ (reflecting the change in score between baseline and follow-up) would be more predictive of major bleeding, when compared with baseline HAS-BLED score. Methods and Results A total of 19,566 AF patients receiving warfarin and baseline HAS-BLED score ≤2 were studied. After a follow-up of 93,783 person-years, 3,032 major bleeds were observed. The accuracies of baseline, follow-up, and delta HAS-BLED scores as well as cumulative numbers of baseline modifiable bleeding risk factors, in predicting subsequent major bleeding, were analysed and compared. The mean baseline HAS-BLED score was 1.43 which increased to 2.45 with a mean ‘delta HAS-BLED score’ of 1.03. The HAS-BLED score remained unchanged in 38.2% of patients. Of those patients experiencing major bleeding, 76.6% had a ‘delta HAS-BLED’ score ≥1, compared with only 59.0% in patients without major bleeding (p < 0.001). For prediction of major bleeding, AUC was significantly higher for the follow-up HAS-BLED (0.63) or delta HAS-BLED (0.62) scores, compared with baseline HAS-BLED score (0.54). The number of baseline modifiable risk factors was non-significantly predictive of major bleeding (AUC = 0.49). Conclusion In this ‘real-world’ nationwide AF cohort, follow-up HAS-BLED or ‘delta HAS-BLED score’ was more predictive of major bleeding compared with baseline HAS-BLED or the simple determination of ‘modifiable bleeding risk factors’. Bleeding risk in AF is a dynamic process and use of the HAS-BLED score should be to ‘flag up’ patients potentially at risk for more regular review and follow-up, and to address the modifiable bleeding risk factors during follow-up visits.