Zeitschriftenartikel zum Thema „Viscous antagonism“

Background: Cerebrospinal fluid (CSF) secretion can be targeted to reduce elevated intracranial pressure (ICP). Sodium-potassium-chloride cotransporter 1 (NKCC1) antagonism is used clinically. However, supporting evidence is limited. The transient receptor potential vanilloid-4 (TRPV4) channel may also regulate CSF secretion and ICP elevation. We investigated whether antagonism of these proteins reduces CSF secretion. Methods: We quantified CSF secretion rates in male Wistar rats. The cerebral aqueduct was blocked with viscous mineral oil, and a lateral ventricle was cannulated. Secretion rate was measured at baseline and after antagonist administration. Acetazolamide was administered as a positive control to confirm changes in CSF secretion rates. Results: Neither NKCC1, nor TRPV4 antagonism altered CSF secretion rate from baseline, n = 3, t(2) = 1.14, p = 0.37, and n = 4, t(3) = 0.58, p = 0.6, respectively. Acetazolamide reduced CSF secretion by ~50% across all groups, n = 7, t(6) = 4.294, p = 0.005. Conclusions: Acute antagonism of NKCC1 and TRPV4 proteins at the choroid plexus does not reduce CSF secretion in healthy rats. Further investigation of protein changes and antagonism should be explored in neurological disease where increased CSF secretion and ICP are observed before discounting the therapeutic potential of protein antagonism at these sites.

The densities (?) and viscosities (?) for ternary liquid mixtures of N,N-dimethylformamide + benzene + an ether were measured as a function of composition at 298.15 K. From experimental measurements, the excess molar volumes (VE), viscosity deviation (??), antagonic interaction index (IA) and Gibbs free energy of activation for viscous flow (?G

BackgroundResistive exercise after stroke can improve strength (force-generating capacity) without increasing spasticity (velocity-dependent hypertonicity). However, the effect of resistive load type on muscle activation and co-contraction after stroke is not clear.ObjectiveThe purpose of this study was to determine the effect of load type (elastic, viscous, or mass) on muscle activation and co-contraction during resisted forward reaching in the paretic and nonparetic arms after stroke.DesignThis investigation was a single-session, mixed repeated-measures pilot study.MethodsTwenty participants (10 with hemiplegia and 10 without neurologic involvement) reached forward with each arm against equivalent elastic, viscous, and mass loads. Normalized shoulder and elbow electromyography impulses were analyzed to determine agonist muscle recruitment and agonist-antagonist muscle co-contraction.ResultsMuscle activation and co-contraction levels were significantly higher on virtually all outcome measures for the paretic and nonparetic arms of the participants with stroke than for the matched control participants. Only the nonparetic shoulder responded to load type with similar activation levels but variable co-contraction responses relative to those of the control shoulder. Elastic and viscous loads were associated with strong activation; mass and viscous loads were associated with minimal co-contraction.LimitationsA reasonable, but limited, range of loads was available.ConclusionsMotor control deficits were evident in both the paretic and the nonparetic arms after stroke when forward reaching was resisted with viscous, elastic, or mass loads. The paretic arm responded with higher muscle activation and co-contraction levels across all load conditions than the matched control arm. Smaller increases in muscle activation and co-contraction levels that varied with load type were observed in the nonparetic arm. On the basis of the response of the nonparetic arm, this study provides preliminary evidence suggesting that viscous loads elicited strong muscle activation with minimal co-contraction. Further intervention studies are needed to determine whether viscous loads are preferable for poststroke resistive exercise programs.

The purpose of this article was to examine techniques that are available to adapted physical educators and therapeutic recreators to enhance flexibility. Based upon current research and literature in the areas of flexibility and range of motion, this article explored theoretical constructs as well as applications of specific techniques. A two-tier model for flexibility enhancement was generated which served as a basis for the development of this article. One tier involved considerations concerning the stretching of collagenous tissue, implications regarding elastic and viscous properties, and new methods for stretching this type of tissue. The other tier incorporated neurophysiological mechanisms, their effect upon agonist and antagonist muscles, and facilitation exercises to improve flexibility.

1. Experiments were performed to characterize the trajectories, net muscle torques, and electromyogram (EMG) patterns when subjects performed voluntary elbow flexions against different compliant loads. Subjects made movements in a single-joint manipulandum with different loads generated by a torque motor. Some series of movements were performed under entirely known and predictable load conditions. Other series were performed with the same known loads, interspersed, just before movement onset with occasional, unpredictable changes in the magnitude of the load. 2. To move a larger load, subjects increase the impulse (torque-time integral) by prolonging the duration of the accelerating torque while keeping its rate of rise constant. Subjects modulate torque most for inertial loads, less for viscous loads, and least for elastic loads, and modulation is greater under predictable than unpredictable load conditions. 3. Even when the loads are predictable, subjects move large inertial and viscous, but not elastic, loads more slowly than small. Unpredictable changes in load have a larger effect on movement kinematics than do known changes of the same magnitude. 4. Subjects prolong the duration and increase the area of the agonist EMG burst but do not change its rate of rise to move larger, predictable loads. Subjects change the area of the antagonist burst according to the torque requirements of the load, increasing it only for increases in inertial loads. These effects are usually greater for predictable than unpredictable loads but in either case, are highly variable across subjects. 5. Predictable loads that slow the movements delay the onset of the antagonist burst. When changes in load are unpredictable, only inertial changes affect antagonist latency. 6. The initial change in muscle force when there is an unexpected change in the external load is due to the viscous properties of muscle tissue. Electromyographic evidence of reflex changes in muscle activation follow this intrinsic mechanical response by 50-70 ms. Elastic neuromuscular properties may also be important but only late in the movement as the final position is approached. 7. We propose that the central command for a voluntary movement should be described by three elements. The first element (alpha) specifies the muscle activation pattern expected to generate dynamic forces adequate and appropriate to produce a satisfactory trajectory. This feed-forward control program uses simple rules, based on an internal model of task dynamics constructed from prior experience. The second element (lambda) is a kinematic plan or reference trajectory utilizing the negative feedback of reflex action to partially compensate for errors in alpha or for unexpected perturbations during the movement. It defines the locus of a moving, instantaneous equilibrium position of the limb, a “template” for the intended trajectory. As movements become slower and require smaller dynamic (velocity and acceleration dependent) forces, lambda will become the dominant control signal. It is also used for correction and updating of the internal model used to generate alpha. The third element (gamma) modulates volitional set, the degree and manner in which multiple reflex mechanisms can contribute to the muscle activation patterns if the actual trajectory deviates from the planned one. Reflex mechanisms work in parallel with intrinsic muscle compliance to provide partial adaptation of neuromuscular system dynamics to external load dynamics. These controlled compliant mechanisms maintain the stability of the motor system, without which both posture and movement would not be possible.

A sample-injection device has been developed at SPring-8 Angstrom Compact Free-Electron Laser (SACLA) for serial femtosecond crystallography (SFX) at atmospheric pressure. Microcrystals embedded in a highly viscous carrier are stably delivered from a capillary nozzle with the aid of a coaxial gas flow and a suction device. The cartridge-type sample reservoir is easily replaceable and facilitates sample reloading or exchange. The reservoir is positioned in a cooling jacket with a temperature-regulated water flow, which is useful to prevent drastic changes in the sample temperature during data collection. This work demonstrates that the injector successfully worked in SFX of the human A2A adenosine receptor complexed with an antagonist, ZM241385, in lipidic cubic phase and for hen egg-white lysozyme microcrystals in a grease carrier. The injection device has also been applied to many kinds of proteins, not only for static structural analyses but also for dynamics studies using pump–probe techniques.

Mechanical and osmotic sensitivity of the transient receptor potential vanilloid 4 (TRPV4) channel depends on phospholipase A2 (PLA2) activation and the subsequent production of the arachidonic acid metabolites, epoxyeicosatrienoic acid (EET). We show that both high viscous loading and hypotonicity stimuli in native ciliated epithelial cells use PLA2–EET as the primary pathway to activate TRPV4. Under conditions of low PLA2 activation, both also use extracellular ATP-mediated activation of phospholipase C (PLC)–inositol trisphosphate (IP3) signaling to support TRPV4 gating. IP3, without being an agonist itself, sensitizes TRPV4 to EET in epithelial ciliated cells and cells heterologously expressing TRPV4, an effect inhibited by the IP3 receptor antagonist xestospongin C. Coimmunoprecipitation assays indicated a physical interaction between TRPV4 and IP3 receptor 3. Collectively, our study suggests a functional coupling between plasma membrane TRPV4 channels and intracellular store Ca2+ channels required to initiate and maintain the oscillatory Ca2+ signal triggered by high viscosity and hypotonic stimuli that do not reach a threshold level of PLA2 activation.

Cystic fibrosis (CF) is caused by mutations in the gene producing the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR functions as a Cl− channel. Its dysfunction limits Cl− secretion and enhances Na+ absorption, leading to viscous mucus in the airway. Ca2+-activated Cl− channels (CaCCs) are coexpressed with CFTR in the airway surface epithelia. Increases in cytosolic Ca2+ activate the epithelial CaCCs, which provides an alternative Cl− secretory pathway in CF. We developed a screening assay and screened a library for compounds that could enhance cytoplasmic Ca2+, activate the CaCC, and increase Cl− secretion. We found that spiperone, a known antipsychotic drug, is a potent intracellular Ca2+ enhancer and demonstrated that it stimulates intracellular Ca2+, not by acting in its well-known role as an antagonist of serotonin 5-HT2 or dopamine D2 receptors, but through a protein tyrosine kinase-coupled phospholipase C-dependent pathway. Spiperone activates CaCCs, which stimulates Cl− secretion in polarized human non-CF and CF airway epithelial cell monolayers in vitro and in CFTR-knockout mice in vivo. In conclusion, we have identified spiperone as a new therapeutic platform for correction of defective Cl− secretion in CF via a pathway independent of CFTR.

A new scenario for the development of gas and oil production is proposed, based on the use of greenhouse gas sequestration projects that allow increasing the oil recovery coefficient of reservoirs depleted by flooding, ensuring the production of viscous, shale, and hard-to-recover oil, as well as starting the production of methane from its hydrates or from coal. The main idea of the article is that oil and gas production and sequestration of greenhouse gases are not antagonists. Reducing greenhouse gas emissions is possible through the use of natural gas, which is an environmentally friendly fuel. It is necessary to involve huge reserves of methane hydrate or coal methane in the development while using collectors for sequestration of CO2. To improve the economy of sequestration projects, it is proposed to abandon the simultaneous commissioning of the entire technological chain of greenhouse gas sequestration and the use (where possible) of a high degree of concentration; it is recommended to pump greenhouse gas in the form of a water-gas mixture with pumping and booster units; for sequestration, first of all, use reservoirs with hard-to-recover oil reserves.

ABSTRACT Necropolitical arrangements of bifurcations delineate those ontological antagonisms that code Blackness as ontological lack (as non-position). In this article, I attempt to think about this evacuation of being in terms of the necropolitical’s fleshy excess, as what Alexander Weheliye’s work names “habeus viscus.” In so doing, I explore the implications, for our understanding of the “repressed proximities” of which the necropolitical consists, of arrangements that always-already include entanglements with their fleshy excess. In other words, if the nonposition of the excluded is always positioned within, then living in/against the death-logics of necropolitics is always happening from that “nonposition within.” Hence, a reading of Achille Mbembe’s account of necropolitics must reckon with what Katherine McKittrick names “the creative consequences of the plot and the plantation,” with the implications of the inextricable proximal entanglements between the killing of life and the living that persists, despite. This article focuses on this “living despite.” Through a constellation of thinkers like Katherine McKittrick, Alexander Weheliye, and Zakiyyah Iman Jackson (to name a few), it aims to show that there are, perhaps, other futures that are already “now,” shattering what Édouard Glissant refers to as the “stone of time,” shattering (necropolitical) history as destiny.

Aim. The study aims to develop the composition of the oromucosal gel with the IL-1β interleukin antagonist for complex treatment of inflammatory periodontal diseases. Materials and methods. Experimental studies were conducted based on the Department of Medicines Technology of Zaporizhzhia State Medical and Pharmaceutical University and the Training Medical and Laboratory Center of Zaporizhzhia State Medical and Pharmaceutical University of the Ministry of Health of Ukraine. As an active component, in the recipe of oromucosal gel, used antagonist of the interleukin IL-1B. Excipients: D-panthenol (the plasticizer), carboxymethylcellulose sodium salt (the viscosity modifier and mucoadhesive component), Tween-80 (the enhancer absorption), benzalkonium chloride (the preservative), sodium hydrophosphate + citric acid (the phosphate buffer solution), purified water. The experiments used existing and auxiliary ingredients of pharmaceutical purity, which were obtained from Sinbias LLC, Istok-Plus LLC, LLC “Mobile Medical”. For the design of the experiment, the methodology of the response surface (Box-Behnken Design) is used: Na CMC, Tween-80, D-panthenol; and four answers: pH, viscosity test, system type, mucoadhesive properties. Research methods: rheological research (viscosity test, amplitude test, frequency test, mucoadhesive test, thixotropy test) performed in oscillation mode on the modular compact Rheometer Anton Paar MCR 302 (CP50-1 SN71317), which, compared to cylindrical devices, requires a much smaller amount of gel sample and allows the planned tests in the oscillation mode, the temperature in the experiments was provided with a built-in thermostat (Peltier Temperature Control, C-PTD 200). Pharmaco-toxicological studies were conducted on 46 white outbred rats of both sexes, weighing 160–180 grams, which were received from Vivarium by the Institute of Pharmacology and Toxicology. The studies were performed on enough animals, all manipulations were carried out by the provisions on the use of animals in biomedical experiments. The results of the study were calculated using the standard statistical package of the Statistica for Windows 13 (StatSoft Inc., No. JPZ804I382130ARCN10-J), as well as SPSS 16.0, Microsoft Office Excel 2003. Results. According to the design of the experiment, it is established that the components of the system do not change the value of pH in experimental oromucosal gels (6.5500 ± 0.0334). The Anova for Quadratic Model statistical analysis data certify the significant impact of Na CMC, and Tween-80 factors on the viscous characteristics of oromucosal gels (F-value > p-value). Comparison of mucoadhesive characteristics of the studied samples of oromucosal gels was made using dynamic mechanical analysis and the results of statistical analysis of ANOVA for Quadratic Model highlight the significant influence of Na CMC, D-panthenol, Tween-80. Optimized oromucosal gel test data is obtained that its structure is restored after the applied effort, namely the restoration of the structure after 10 seconds occurs by 69.5 %, after 30 s by 76.1 %, after 180 s by 85.4 %, after 180 s which allows to predict the stability of the dosage form, both after manufacture and after use. Conclusions. The composition of the oromucosal gel of anti-inflammatory action with the IL-1β interleukin antagonist for the complex treatment of inflammatory diseases of periodontal is developed. The optimized composition of the oromucosal gel obtained has satisfactory performance of kinetic stability and thixotropic properties. The developed gel for dentistry meets all the requirements for harmlessness and safety for dosage forms of this group toxicity, lack of local irritant and allergic action.

The cystic fibrosis transmembrane regulator (CFTR) gene encodes the synthesis of a protein of the same name, which functions as a direct activator of anionic transport. Chloride is the most abundant anion; as an antagonist of Na+ and K+, it provides electroneutrality of cell membranes at rest; together with cations, it serves as an important osmolyte and forms water flow across cell membranes for transepithelial secretion.Glandular cells in CF trap Cl– and Na+, and the prodused secretion is excessively viscous. Subnormal CFTR activity leads to stagnation of mucociliary clearance, inhibition of intestinal transport.In addition to exocrine disorders, CFTR mutations are associated with a decrease in volume, mass, increased apoptosis of β-cells of the pancreas, a significant suppression of insulin exocytosis in response to stimulation with glucose and glucagon-like peptide-1, hyperglucagonemia against the background of a defect in the suppression of α-cell function by insulin, but a decrease in maximum capacity α-cells.Deficiency and progressive decline in bone mineral density is an expected secondary manifestation of CF due to pancreatic exocrine insufficiency with malabsorption of nutrients and fat-soluble vitamins. However, in patients with the F508del mutation, a significant decrease in the synthesis of OPG, COX-2, PGE2 in the osteoblastic formation, and an increase in the activity of the antianabolic NF-kB were found. We are talking about a defect in the canonical signaling pathway (Wnt/β-catenin), which regulates the expression of genes-activators of osteoblastogenesis, dissociation of the stages of physiological bone remodeling.In addition to congenital bilateral or unilateral aplasia of the vas deferens, an increase in the frequency of CFTR mutations is also found in non-obstructive azoospermia, oligo-, astheno- and teratospermia. CFTR is involved in the entry of HCO3– into Sertoli cells to trigger cAMP-dependent transcription and its defects lead to suppression of FSH-dependent gene expression of spermatogenesis, loss of sequence in the Wnt cascade, destruction of the PGE2-dependent transepithelial interaction and, as a consequence, the blood-testicular barrier.CF is characterized, along with classical signs, by endocrine dysfunction of the pancreas, osteoporosis with suppression of osteoblastogenesis, and a defect in spermatogenesis.

Hyperglycemia alters the function of cerebral endothelial cells from the blood-brain barrier, increasing the risk of cerebrovascular complications during diabetes. This study evaluated the protective effect of polyphenols on inflammatory and permeability markers on bEnd3 cerebral endothelial cells exposed to high glucose concentration. Results show that hyperglycemic condition increased nuclear factor kappa B (NFκB) activity, deregulated the expression of interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), interleukin-10 (IL-10) and endothelial-leukocyte adhesion molecule (E-selectin) genes, raised MCP-1 secretion and elevated monocyte adhesion and transendothelial migration. High glucose decreased occludin, claudin-5, zona occludens-1 (ZO-1) and zona occludens-2 (ZO-2) tight junctions production and altered the endothelial permeability. Characterized polyphenolic extracts from the French medicinal plants Antirhea borbonica, Ayapana triplinervis, Dodonaea viscosa and Terminalia bentzoe, and their major polyphenols quercetin, caffeic, chlorogenic and gallic acids limited the pro-inflammatory and permeability alterations caused by high glucose. Peroxisome proliferator-activated receptor gamma (PPARγ) agonist also attenuated these damages while PPARγ antagonist aggravated them, suggesting PPARγ protective action. Interestingly, polyphenols improved PPARγ gene expression lowered by high glucose. Moreover, polyphenols were detected at the intracellular level or membrane-bound to cells, with evidence for breast cancer resistance protein (BCRP) efflux transporter role. Altogether, these findings emphasize the ability of polyphenols to protect cerebral endothelial cells in hyperglycemic condition and their relevance for pharmacological strategies aiming to limit cerebrovascular disorders in diabetes.

Background: Peptic ulcer disease is very common disease in developing countries and so are its complications. With the introduction of H2 receptor antagonists and proton pump inhibitors, the incidence of elective surgery for peptic ulcer (PU) disease has decreased dramatically, although complications of peptic ulcer disease such as perforation and bleeding have remained fairly constant.Methods: A prospective study was conducted on43 patients presenting to KIMS Hospital, Hubli with features suggestive of hollow viscus perforation and intraoperative findings suggestive of peptic ulcer perforation from January 2015 to June 2016.Results: In this study, there were 43 cases of peptic ulcer perforation. Peptic ulcer perforation was common in third decade of life(n=12) with the mean age(SD) 39.88 years. Perforation is more common in males as compared to the female population 7.6:1. Post-operative morbidity is seen in 31 (72.1%) of patients and mortality in 4 (9.3%). Smoking, Alcohol beverage consumption, regular ingestion of NSAIDs were commonly seen in patients with peptic ulcer perforation but these factors were not significant risk factors for postoperative mortality and morbidity. Age ≥60 years (p-value 0.051), Female gender (p-value 0.012), Presence of co-morbid conditions (p-value 0.055), Shock on admission (p-value 0.029, perforation-surgery interval >24 hours (p-value 0.001), preoperative higher-grade ASA, purulent intraperitoneal collection (p-value 0.002) were statistically significant predictors of mortality.Conclusions: Perforated peptic ulcer (PPU) is a life-threatening disease with historically reported high morbidity and mortality rates. Age ≥60 years, female gender, presence of co-morbidities, preoperative shock, higher ASA grade, perforation-surgery interval >24 hours, Purulent intraperitoneal collection are inter-related statistically significant predictors of mortality. Therefore, proper resuscitation from shock, improving ASA grade and decreasing delay in surgery is needed to improve overall results.

Two young (ages: 15 and 16 yr;; studbook # 947 and # 939, respectively) parous female gorillas were initially primed with daily oral monophasic estrogen/progesterone treatment (Ovcon 35: Bristol-Myers Squibb Co., Princeton, NJ, USA) for 3 mo to synchronize their menstrual cycles. After withdrawing treatment, urine was tested daily for occult blood (Hemastix;; Baxter Healthcare Corp., Deerfield, IL, USA). On days 3–10 following the onset of menses (Day 1), ovarian activity was stimulated with 225 IU human FSH im (Repronex;; Ferring Pharmaceuticals, New South Wales, Australia). Then on Days 6–8 this treatment was combined with 25mg GnRH antagonist im (Antagon;; Organon, West Orange, NJ, USA) to prevent premature endogenous LH release. Final oocyte maturation was stimulated 36h after the last FSH/GnRH treatment with 10,000IU hCG im (Profasi;; Serono Lab., Hingham/Rockland, MA, USA) and oocyte retrieval was performed 36h post-hCG administration in sternal recumbency (knee-chest) using a 3–6mHz probe, 17-ga needles and 87mmHg (VMAR-5000 Regulated Vacuum Pump;; Cook Veterinary Products). Both gorillas displayed a thickened endometrium, and approximately 6 (# 947) to 10 (# 939) maturing follicles (10–15mm) were detected in each animal. In female # 947, one oocyte was collected but peritoneal fluid and pathology (hydrosalpinx) were also diagnosed and the right ovary showed no follicular development. A total of 3 oocytes were recovered in highly viscous follicular fluid containing massive amounts of cumulus cells. They were transported in a HEPES-buffered transport medium in a portable incubator (CryoLogic, Mulgrave, Victoria, Australia) at 37°C by airline immediately from Brownsville to Dallas, TX, USA, and within 6-h post-retrieval were fertilized by ICSI using cryopreserved sperm collected by rectal probe electrostimulation (age: est. 40yr ; studbook # 268). The fertilized oocytes were cultured in Gardner’s Sequential Medium at 37°C in 6% CO2 all three cleaved and developed to blastocysts by 115h post-ICSI. One high-quality expanding blastocyst was transported back to Brownsville, TX, and transferred transcervically into the oocyte donor (studbook # 939), and two fair-quality blastocysts were transported overnight to Omaha, NE, and transferred into a synchronized gorilla recipient (age: 29yr; studbook # 543/91). Weekly urine samples from the two embryo transfer recipients are being tested for pregnancy diagnosis using OvuQuick test strips (Quidel, San Diego, CA, USA). Acknowledgments: This research was supported in part by the Morris Animal Foundation (Ruth Morris Keesling Animal Health Study).

Abstract The surface tension (σ), critical micelle concentration (CMC), surface excess (Γ), minimum area occupied by a surfactant molecule (A min), the viscosity and oscillatory rheological studies of aqueous solutions containing cocamidopropyl betaine (CAPB) and sodium dodecylbenzene sulfonate (SDBS) at molar fractions of 0.00, 0.25, 0.50, 0.75 and 1.00 and 25 °C were presented. CAPB and SDBS were not found to interact synergistically in water at any of the molar fractions studied. This is due to the fact that the critical micelle concentrations of these mixtures were higher than those predicted by Clint’s equation, indicating an antagonism that rarely occurs in mixed amphoteric/anionic surfactant systems. The minimum area occupied by a surfactant molecule (A min) was reduced in CAPB/SDBS mixtures compared to unmixed surfactants. In contrast, the viscosity of the mixed CAPB/SDBS system increased significantly from 1.0 mPa s to a maximum of 36.0 Pa s at higher CAPB mole fractions (0.5–0.8). The rheograms obtained from the oscillation measurements of the viscous CAPB/SDBS solutions are characteristic of wormlike micelles (WLMs) according to the Maxwell model. The results of this surprising binary CAPB/SDBS surfactant mixing system are presented and discussed.

AbstractStructural studies of challenging targets such as G protein-coupled receptors (GPCRs) have accelerated during the last several years due to the development of new approaches, including small-wedge and serial crystallography. Here, we describe the deposition of seven datasets consisting of X-ray diffraction images acquired from lipidic cubic phase (LCP) grown microcrystals of two human GPCRs, Cysteinyl leukotriene receptors 1 and 2 (CysLT1R and CysLT2R), in complex with various antagonists. Five datasets were collected using small-wedge synchrotron crystallography (SWSX) at the European Synchrotron Radiation Facility with multiple crystals under cryo-conditions. Two datasets were collected using X-ray free electron laser (XFEL) serial femtosecond crystallography (SFX) at the Linac Coherent Light Source, with microcrystals delivered at room temperature into the beam within LCP matrix by a viscous media microextrusion injector. All seven datasets have been deposited in the open-access databases Zenodo and CXIDB. Here, we describe sample preparation and annotate crystallization conditions for each partial and full datasets. We also document full processing pipelines and provide wrapper scripts for SWSX and SFX data processing.A Correction to this paper has been published: https://doi.org/10.1038/s41597-020-00759-w

Asthma is increasingly recognized as a mediator‐driven inflammatory process in the lungs. The leukotrienes (LTs) and prostaglandins (PGs), two families of proinflammatory mediators arising via arachidonic acid metabolism, have been implicated in the inflammatory cascade that occurs in asthmatic airways. The PG pathway normally maintains a balance in the airways; both PGD2 and thromboxane A2 are bronchoconstrictors, whereas PGE2 and prostacyclin are bronchoprotective. The actions of the LTs, however, appear to be exclusively proinflammatory in nature. The dihydroxy‐LT, LTB4, may play an important role in attracting neutrophils and eosinophils into the airways, whereas the sulfidopeptide leukotrienes (LTC4, LTD4, and LTE4) produce effects that are characteristic of asthma, such as potent bronchoconstriction, increased endothelial membrane permeability leading to airway edema, and enhanced secretion of thick, viscous mucus. Given the significant role of the inflammatory process in asthma, newer pharmacologic agents, such as the sulfidopeptide‐LT antagonists, zafirlukast, montelukast, and pranlukast and the 5‐lipoxygenase (5‐LO) inhibitor, zileuton, have been developed with the goal of targeting specific elements of the inflammatory cascade. These drugs appear to represent improvements to the existing therapeutic armamentarium. In addition, the results of clinical trials with these agents have helped to expand our understanding of the pathogenesis of asthma.

Abstract Background In chronic anticoagulant users undergoing surgery, bleeding and thromboembolism are common and serious complications. Many studies on mainly elective or minor emergency surgical procedures with low associated risks have focused on these outcomes. In comparison, patients undergoing high-risk emergency abdominal surgical procedures have not received sufficient attention. This study aimed to compare outcomes between oral anticoagulant users and nonusers who required emergency laparotomy for high-risk abdominal emergencies. Methods Patients who underwent surgery for abdominal emergencies at our institution between January 2012 and July 2019 were retrospectively reviewed. Results There were 875 patients, including 370 anticoagulant users and 505 nonusers. Of the 370 anticoagulant users, 189 (51.3), 77 (20.8%), 45 (12.2%), and 59 (15.9%) were prescribed antiplatelets, a vitamin k antagonist, a direct oral anticoagulant, and a combination drug regimen, respectively. The most common high-risk emergencies requiring surgery in both groups were perforated viscus (25.7% vs 40.9%), mesenteric ischemia with enteric necrosis (27% vs 12.8%), and bowel obstruction (17.6% vs 28.1%). The overall bleeding rate was higher (29.2% vs 22%, p = 0.015) in anticoagulant users than in nonusers, but the major bleeding rate was similar (17.8% vs 14.1%, p = 0.129) between the two groups. The rates of thromboembolic events and mortality were significantly higher in anticoagulant users than in nonusers (25.7% vs 9.7%, p < 0.0001 and 39.7% vs 31.1%, p = 0.01, respectively). Liver cirrhosis, peripheral arterial diseases, reoperation, and blood product transfusion were independent predictors of the overall risk of bleeding or TEEs, according to the multivariate analysis. In this model, liver cirrhosis had the largest overall effect on mortality, followed by pneumonia, thromboembolism, peripheral arterial disease, blood product transfusion, and atrial fibrillation. The use of oral anticoagulants was not an independent predictor of either bleeding or in-hospital mortality. The use of oral anticoagulants was associated with a decreased risk of all-cause in-hospital mortality. Conclusion Based on our results, the continued use of oral anticoagulants is more protective than harmful considering the overall outcomes in this subset of patients.

Image 1: Hasbro/Tiger Electronics 1998 Furby. (Photo credit: Author) Introduction Since the mid-1990s robotic and digital creatures designed to offer social interaction and companionship have been developed for commercial and research interests. Integral to encouraging positive experiences with these creatures has been the use of cute aesthetics that aim to endear companions to their human users. During this time there has also been a growth in online communities that engage in cultural production through fan fiction responses to existing cultural artefacts, including the widely recognised electronic companion, Hasbro’s Furby (image 1). These user stories and Furby’s online representation in general, demonstrate that contrary to the intentions of their designers and marketers, Furbys are not necessarily received as cute, or the embodiment of the helpless and harmless demeanour that goes along with it. Furbys’ large, lash-framed eyes, small, or non-existent limbs, and baby voice are typical markers of cuteness but can also evoke another side of cuteness—monstrosity, especially when the creature appears physically capable instead of helpless (Brzozowska-Brywczynska 217). Furbys are a particularly interesting manifestation of the cute aesthetic because it is used as tool for encouraging attachment to a socially interactive electronic object, and therefore intersects with existing ideas about technology and nonhuman companions, both of which often embody a sense of otherness. This paper will explore how cuteness intersects withand transitions into monstrosity through online representations of Furbys, troubling their existing design and marketing narrative by connecting and likening them to other creatures, myths, and anecdotes. Analysis of narrative in particular highlights the instability of cuteness, and cultural understandings of existing cute characters, such as the gremlins from the film Gremlins (Dante) reinforce the idea that cuteness should be treated with suspicion as it potentially masks a troubling undertone. Ultimately, this paper aims to interrogate the cultural complexities of designing electronic creatures through the stories that people tell about them online. Fan Production Authors of fan fiction are known to creatively express their responses to a variety of media by appropriating the characters, settings, and themes of an original work and sharing their cultural activity with others (Jenkins 88). On a personal level, Jenkins (103) argues that “[i]n embracing popular texts, the fans claim those works as their own, remaking them in their own image, forcing them to respond to their needs and to gratify their desires.” Fan fiction authors are motivated to write not for financial or professional gains but for personal enjoyment and fan recognition, however, their production does not necessarily come from favourable opinions of an existing text. The antifan is an individual who actively hates a text or cultural artefact and is mobilised in their dislike to contribute to a community of others who share their views (Gray 841). Gray suggests that both fan and antifan activity contribute to our understanding of the kinds of stories audiences want: Although fans may wish to bring a text into everyday life due to what they believe it represents, antifans fear or do not want what they believe it represents and so, as with fans, antifan practice is as important an indicator of interactions between the textual and public spheres. (855) Gray reminds that fans, nonfans, and antifans employ different interpretive strategies when interacting with a text. In particular, while fans intimate knowledge of a text reflects their overall appreciation, antifans more often focus on the “dimensions of the moral, the rational-realistic, [or] the aesthetic” (856) that they find most disagreeable. Additionally, antifans may not experience a text directly, but dislike what knowledge they do have of it from afar. As later examples will show, the treatment of Furbys in fan fiction arguably reflects an antifan perspective through a sense of distrust and aversion, and analysing it can provide insight into why interactions with, or indirect knowledge of, Furbys might inspire these reactions. Derecho argues that in part because of the potential copyright violation that is faced by most fandoms, “even the most socially conventional fan fiction is an act of defiance of corporate control…” (72). Additionally, because of the creative freedom it affords, “fan fiction and archontic literature open up possibilities – not just for opposition to institutions and social systems, but also for a different perspective on the institutional and the social” (76). Because of this criticality, and its subversive nature, fan fiction provides an interesting consumer perspective on objects that are designed and marketed to be received in particular ways. Further, because much of fan fiction draws on fictional content, stories about objects like Furby are not necessarily bound to reality and incorporate fantastical, speculative, and folkloric readings, providing diverse viewpoints of the object. Finally, if, as robotics commentators (cf. Levy; Breazeal) suggest, companionable robots and technologies are going to become increasingly present in everyday life, it is crucial to understand not only how they are received, but also where they fit within a wider cultural sphere. Furbys can be seen as a widespread, if technologically simple, example of these technologies and are often treated as a sign of things to come (Wilks 12). The Design of Electronic Companions To compete with the burgeoning market of digital and electronic pets, in 1998 Tiger Electronics released the Furby, a fur-covered, robotic creature that required the user to carry out certain nurturance duties. Furbys expected feeding and entertaining and could become sick and scared if neglected. Through a program that advanced slowly over time regardless of external stimulus, Furbys appeared to evolve from speaking entirely Furbish, their mother tongue, to speaking English. To the user, it appeared as though their interactions with the object were directly affecting its progress and maturation because their care duties of feeding and entertaining were happening parallel to the Furbish to English transition (Turkle, Breazeal, Daste, & Scassellati 314). The design of electronic companions like Furby is carefully considered to encourage positive emotional responses. For example, Breazeal (2002 230) argues that a robot will be treated like a baby, and nurtured, if it has a large head, big eyes, and pursed lips. Kinsella’s (1995) also emphasises cute things need for care as they are “soft, infantile, mammalian, round, without bodily appendages (e.g. arms), without bodily orifices (e.g. mouths), non-sexual, mute, insecure, helpless or bewildered” (226). From this perspective, Furbys’ physical design plays a role in encouraging nurturance. Such design decisions are reinforced by marketing strategies that encourage Furbys to be viewed in a particular way. As a marketing tool, Harris (1992) argues that: cuteness has become essential in the marketplace in that advertisers have learned that consumers will “adopt” products that create, often in their packaging alone, an aura of motherlessness, ostracism, and melancholy, the silent desperation of the lost puppy dog clamoring to be befriended - namely, to be bought. (179) Positioning Furbys as friendly was also important to encouraging a positive bond with a caregiver. The history, or back story, that Furbys were given in the instruction manual was designed to convey their kind, non-threatening nature. Although alive and unpredictable, it was crucial that Furbys were not frightening. As imaginary living creatures, the origin of Furbys required explaining: “some had suggested positioning Furby as an alien, but that seemed too foreign and frightening for little girls. By May, the thinking was that Furbies live in the clouds – more angelic, less threatening” (Kirsner). In creating this story, Furby’s producers both endeared the object to consumers by making it seem friendly and inquisitive, and avoided associations to its mass-produced, factory origins. Monstrous and Cute Furbys Across fan fiction, academic texts, and media coverage there is a tendency to describe what Furbys look like by stringing together several animals and objects. Furbys have been referred to as a “mechanized ball of synthetic hair that is part penguin, part owl and part kitten” (Steinberg), a “cross between a hamster and a bird…” (Lawson & Chesney 34), and “ “owl-like in appearance, with large bat-like ears and two large white eyes with small, reddish-pink pupils” (ChaosInsanity), to highlight only a few. The ambiguous appearance of electronic companions is often a strategic decision made by the designer to avoid biases towards specific animals or forms, making the companion easier to accept as “real” or “alive” (Shibata 1753). Furbys are arguably evidence of this strategy and appear to be deliberately unfamiliar. However, the assemblage, and exaggeration, of parts that describes Furbys also conjures much older associations: the world of monsters in gothic literature. Notice the similarities between the above attempts to describe what Furbys looks like, and a historical description of monsters: early monsters are frequently constructed out of ill-assorted parts, like the griffin, with the head and wings of an eagle combined with the body and paws of a lion. Alternatively, they are incomplete, lacking essential parts, or, like the mythological hydra with its many heads, grotesquely excessive. (Punter & Byron 263) Cohen (6) argues that, metaphorically, because of their strange visual assembly, monsters are displaced beings “whose externally incoherent bodies resist attempts to include them in any systematic structuration. And so the monster is dangerous, a form suspended between forms that threatens to smash distinctions.” Therefore, to call something a monster is also to call it confusing and unfamiliar. Notice in the following fan fiction example how comparing Furby to an owl makes it strange, and there seems to be uncertainty around what Furbys are, and where they fit in the natural order: The first thing Heero noticed was that a 'Furby' appeared to be a childes toy, shaped to resemble a mutated owl. With fur instead of feathers, no wings, two large ears and comical cat paws set at the bottom of its pudding like form. Its face was devoid of fuzz with a yellow plastic beak and too large eyes that gave it the appearance of it being addicted to speed [sic]. (Kontradiction) Here is a character unfamiliar with Furbys, describing its appearance by relating it to animal parts. Whether Furbys are cute or monstrous is contentious, particularly in fan fictions where they have been given additional capabilities like working limbs and extra appendages that make them less helpless. Furbys’ lack, or diminution of parts, and exaggeration of others, fits the description of cuteness, as well as their sole reliance on caregivers to be fed, entertained, and transported. If viewed as animals, Furbys appear physically limited. Kinsella (1995) finds that a sense of disability is important to the cute aesthetic: stubby arms, no fingers, no mouths, huge heads, massive eyes – which can hide no private thoughts from the viewer – nothing between their legs, pot bellies, swollen legs or pigeon feet – if they have feet at all. Cute things can’t walk, can’t talk, can’t in fact do anything at all for themselves because they are physically handicapped. (236) Exploring the line between cute and monstrous, Brzozowska-Brywczynska argues that it is this sense of physical disability that distinguishes the two similar aesthetics. “It is the disempowering feeling of pity and sympathy […] that deprives a monster of his monstrosity” (218). The descriptions of Furbys in fan fiction suggest that they transition between the two, contingent on how they are received by certain characters, and the abilities they are given by the author. In some cases it is the overwhelming threat the Furby poses that extinguishes feelings of care. In the following two excerpts that the revealing of threatening behaviour shifts the perception of Furby from cute to monstrous in ‘When Furbies Attack’ (Kellyofthemidnightdawn): “These guys are so cute,” she moved the Furby so that it was within inches of Elliot's face and positioned it so that what were apparently the Furby's lips came into contact with his cheek “See,” she smiled widely “He likes you.” […] Olivia's breath caught in her throat as she found herself backing up towards the door. She kept her eyes on the little yellow monster in front of her as her hand slowly reached for the door knob. This was just too freaky, she wanted away from this thing. The Furby that was originally called cute becomes a monster when it violently threatens the protagonist, Olivia. The shifting of Furbys between cute and monstrous is a topic of argument in ‘InuYasha vs the Demon Furbie’ (Lioness of Dreams). The character Kagome attempts to explain a Furby to Inuyasha, who views the object as a demon: That is a toy called a Furbie. It's a thing we humans call “CUTE”. See, it talks and says cute things and we give it hugs! (Lioness of Dreams) A recurrent theme in the Inuyasha (Takahashi) anime is the generational divide between Kagome and Inuyasha. Set in feudal-era Japan, Kagome is transported there from modern-day Tokyo after falling into a well. The above line of dialogue reinforces the relative newness, and cultural specificity, of cute aesthetics, which according to Kinsella (1995 220) became increasingly popular throughout the 1980s and 90s. In Inuyasha’s world, where demons and monsters are a fixture of everyday life, the Furby appearance shifts from cute to monstrous. Furbys as GremlinsDuring the height of the original 1998 Furby’s public exposure and popularity, several news articles referred to Furby as “the five-inch gremlin” (Steinberg) and “a furry, gremlin-looking creature” (Del Vecchio 88). More recently, in a review of the 2012 Furby release, one commenter exclaimed: “These things actually look scary! Like blue gremlins!” (KillaRizzay). Following the release of the original Furbys, Hasbro collaborated with the film’s merchandising team to release Interactive ‘Gizmo’ Furbys (image 2). Image 2: Hasbro 1999 Interactive Gizmo (photo credit: Author) Furbys’ likeness to gremlins offers another perspective on the tension between cute and monstrous aesthetics that is contingent on the creature’s behaviour. The connection between Furbys and gremlins embodies a sense of mistrust, because the film Gremlins focuses on the monsters that dwell within the seemingly harmless and endearing mogwai/gremlin creatures. Catastrophic events unfold after they are cared for improperly. Gremlins, and by association Furbys, may appear cute or harmless, but this story tells that there is something darker beneath the surface. The creatures in Gremlins are introduced as mogwai, and in Chinese folklore the mogwai or mogui is a demon (Zhang, 1999). The pop culture gremlin embodied in the film, then, is cute and demonic, depending on how it is treated. Like a gremlin, a Furby’s personality is supposed to be a reflection of the care it receives. Transformation is a common theme of Gremlins and also Furby, where it is central to the sense of “aliveness” the product works to create. Furbys become “wiser” as time goes on, transitioning through “life stages” as they “learn” about their surroundings. As we learn from their origin story, Furbys jumped from their home in the clouds in order to see and explore the world firsthand (Tiger Electronics 2). Because Furbys are susceptible to their environment, they come with rules on how they must be cared for, and the consequences if this is ignored. Without attention and “food”, a Furby will become unresponsive and even ill: “If you allow me to get sick, soon I will not want to play and will not respond to anything but feeding” (Tiger Electronics 6). In Gremlins, improper care manifests in an abrupt transition from cute to monstrous: Gizmo’s strokeable fur is transformed into a wet, scaly integument, while the vacant portholes of its eyes (the most important facial feature of the cute thing, giving us free access to its soul and ensuring its total structability, its incapacity to hold back anything in reserve) become diabolical slits hiding a lurking intelligence, just as its dainty paws metamorphose into talons and its pretty puckered lips into enormous Cheshire grimaces with full sets of sharp incisors. (Harris 185–186) In the Naruto (Kishimoto) fan fiction ‘Orochimaru's World Famous New Year's Eve Party’ (dead drifter), while there is no explicit mention of Gremlins, the Furby undergoes the physical transformation that appears in the films. The Furby, named Sasuke, presumably after the Naruto antagonist Sasuke, and hinting at its untrustworthy nature, undergoes a transformation that mimics that of Gremlins: when water is poured on the Furby, boils appear and fall from its back, each growing into another Furby. Also, after feeding the Furby, it lays eggs: Apparently, it's not a good idea to feed Furbies chips. Why? Because they make weird cocoon eggs and transform into… something. (ch. 5) This sequence of events follows the Gremlins movie structure, in which cute and furry Gizmo, after being exposed to water and fed after midnight, “begins to reproduce, laying eggs that enter a larval stage in repulsive cocoons covered in viscous membranes” (Harris 185). Harris also reminds that the appearance of gremlins comes with understandings of how they should be treated: Whereas cute things have clean, sensuous surfaces that remain intact and unpenetrated […] the anti-cute Gremlins are constantly being squished and disembowelled, their entrails spilling out into the open, as they explode in microwaves and run through paper shredders and blenders. (Harris 186) The Furbys in ‘Orochimaru's World Famous New Year's Eve Party’ meet a similar end: Kuro Furby whined as his brain was smashed in. One of its eyes popped out and rolled across the floor. (dead drifter ch. 6) A horde of mischievous Furbys are violently dispatched, including the original Furby that was lovingly cared for. Conclusion This paper has explored examples from online culture in which different cultural references clash and merge to explore artefacts such as Furby, and the complexities of design, such as the use of ambiguously mammalian, and cute, aesthetics in an effort to encourage positive attachment. Fan fiction, as a subversive practice, offers valuable critiques of Furby that are imaginative and speculative, providing creative responses to experiences with Furbys, but also opening up potential for what electronic companions could become. In particular, the use of narrative demonstrates that cuteness is an unstable aesthetic that is culturally contingent and very much tied to behaviour. As above examples demonstrate, Furbys can move between cute, friendly, helpless, threatening, monstrous, and strange in one story. Cute Furbys became monstrous when they were described as an assemblage of disparate parts, made physically capable and aggressive, and affected by their environment or external stimulus. Cultural associations, such as gremlins, also influence how an electronic animal is received and treated, often troubling the visions of designers and marketers who seek to present friendly, nonthreatening, and accommodating companions. These diverse readings are valuable in understanding how companionable technologies are received, especially if they continue to be developed and made commercially available, and if cuteness is to be used as means of encouraging positive attachment. References Breazeal, Cynthia. Designing Sociable Robots. Cambridge, MA: MIT Press, 2002. Brzozowska-Brywczynska, Maja. "Monstrous/Cute: Notes on the Ambivalent Nature of Cuteness." Monsters and the Monstrous: Myths and Metaphors of Enduring Evil. Ed. Niall Scott. Amsterdam/New York: Rodopi. 2007. 213 - 28. 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