Glucocorticoid stimulation increases cardiac contractility by SGK1-dependent SOCE-activation in rat cardiac myocytes

Aims: Glucocorticoid (GC) stimulation has been shown to increase cardiac contractility by elevated intracellular [Ca] but the sources for Ca entry are unclear. This study aims to determine the role of store-operated Ca entry (SOCE) for GC-mediated inotropy. Methods and results: Dexamethasone (Dex) pretreatment significantly increased cardiac contractile force ex vivo in Langendorff-perfused Sprague-Dawley rat hearts (2 mg/kg BW i.p. Dex 24 h prior to experiment). Moreover, Ca transient amplitude as well as fractional shortening were significantly enhanced in Fura-2-loaded isolated rat ventricular myocytes exposed to Dex (1 mg/mL Dex, 24 h). Interestingly, these Dex-dependent effects could be abolished in the presence of SOCE-inhibitors SKF-96356 (SKF, 2 µM) and BTP2 (5 µM). Direct SOCE measurements revealed a negligible magnitude in untreated myocytes but a dramatic increase in SOCE upon Dex-pretreatment. Importantly, the Dex-dependent stimulation of SOCE could be blocked by inhibition of serum and glucocorticoid-regulated kinase 1 (SGK1) using EMD638683 (EMD, 50 µM). Dex preincubation also resulted in increased mRNA expression of proteins involved in SOCE (stromal interaction molecule 2, STIM2, and transient receptor potential cation channels 3/6, TRPC 3/6), which were also prevented in the presence of EMD. Conclusion: Short-term GC-stimulation with Dex improves cardiac contractility by a SOCE-dependent mechanism. Importantly, this appears to involve increased SGK1-dependent expression of the SOCE-related proteins

Salmonella Pathogenicity Island 2 Mediates Protection of Intracellular Salmonella from Reactive Nitrogen Intermediates

Salmonella typhimurium causes an invasive disease in mice that has similarities to human typhoid. A type III protein secretion system encoded by Salmonella pathogenicity island 2 (SPI2) is essential for virulence in mice, as well as survival and multiplication within macrophages. Reactive nitrogen intermediates (RNI) synthesized by inducible nitric oxide synthase (iNOS) are involved in the control of intracellular pathogens, including S. typhimurium. We studied the effect of Salmonella infection on iNOS activity in macrophages. Immunofluorescence microscopy demonstrated efficient colocalization of iNOS with bacteria deficient in SPI2 but not wild-type Salmonella, and suggests that the SPI2 system interferes with the localization of iNOS and Salmonella. Furthermore, localization of nitrotyrosine residues in the proximity was observed for SPI2 mutant strains but not wild-type Salmonella, indicating that peroxynitrite, a potent antimicrobial compound, is excluded from Salmonella-containing vacuoles by action of SPI2. Altered colocalization of iNOS with intracellular Salmonella required the function of the SPI2-encoded type III secretion system, but not of an individual “Salmonella translocated effector.” Inhibition of iNOS increased intracellular proliferation of SPI2 mutant bacteria and, to a lesser extent, of wild-type Salmonella. The defect in systemic infection of a SPI2 mutant strain was partially restored in iNOS−/− mice. In addition to various strategies to detoxify RNI or repair damage due to RNI, avoidance of colocalization with RNI is important in adaptation of a pathogen to an intracellular life style

Functionalisation of the Boundary Layer by Deformation-Induced Martensite on Bearing Rings by means of Bulk Metal Forming Processes

During cold forming of metastable austenitic steels, a strength-increasing phase transformation induced by externally superimposed stresses occurs in addition to strain hardening. The effect of deformation-induced martensite formation has so far not been utilized industrially in the area of bulk forming, but could be suitable for the production of highly-loaded components in oxidative atmospheres. The aim of this study is the analysis of local phase transformations in metastable austenitic steels in the boundary layer of bulk formed components. For this purpose, the relationship between the process conditions occurring during bulk metal forming and the resulting martensitic phase fraction was determined. Cylinder compression tests are carried out in which the influence of various process parameters can be investigated. These include forming temperature, true plastic strain and forming speed. In a quantitative measurement by means of a magnetic induction process, local martensite formation is determined and hardness measurements are carried out. The recorded flow stress curves are implemented in a numerical simulation. Furthermore, the influence of different tool surface topographies on the contact conditions of the workpiece-tool system is characterized by means of ring compression tests. With the numerical simulations and experimentally obtained results, a surface hardening process for bearing rings is designed. The relationship between local true plastic strain and deformation-induced martensite development is explained by material flow simulations, taking into account the process route for manufacturing the bearing ring and the varying friction factors

Influence of the Microstructure on Flow Stress and Deformability of Iron-Aluminium Alloys

Due to their higher weight-specific and high-temperature strength, iron-aluminium alloys have a high potential to replace steel in various applications. The good availability of the two materials, the excellent recyclability, lower density with increasing aluminium content and the high corrosion resistance in sulphide- and sulphur-rich environments are further advantages. However, with increasing aluminium content, ductility of FeAl alloys decreases due to hydrogen embrittlement at room temperature. As a result, iron-aluminium alloys have been excluded from potential applications, particularly structural ones. Investigations on powder metallurgical produced iron-aluminium alloys show that fine-grained microstructures can lead to significant improvement in ductility. Assuming equal grain diameters, higher toughness is expected in case of metallurgical ingot production followed by hot forming. The present work deals with the mechanical properties of fine-grained microstructure in iron-rich iron-aluminium alloys, pre-processed through Equal Channel Angular Pressing. In order to characterize the mechanical properties, compression tests with the alloys Fe9AI, Fe28AI and Fe38AI are carried out at different temperatures. The flow curves determined are then compared with those from as-cast state. In addition, deformation capacity is examined optically on slopes of external cracks. In conclusion, the results are discussed based on the microstructure

Non linear time compression of clear and normal speech at high rates

We compare a series of time compression methods applied to normal and clear speech. First we evaluate a linear (uniform) method applied to these styles as well as to naturally-produced fast speech. We found, in line with the literature, that unprocessed fast speech was less intelligible than linearly compressed normal speech. Fast speech was also less intelligible than compressed clear speech but at the highest rate (three times faster than normal) the advantage of clear over fast speech was lost. To test whether this was due to shorter speech duration we evaluate, in our second experiments, a range of methods that compress speech and silence at different rates. We found that even when the overall duration of speech and silence is kept the same across styles, compressed normal speech is still more intelligible than compressed clear speech. Compressing silence twice as much as speech improved results further for normal speech with very little additional computational costs

NASHA hyaluronic acid for the treatment of shoulder osteoarthritis: a prospective, single-arm clinical trial

Background: Osteoarthritis of the shoulder or glenohumeral joint is a painful condition that can be debilitating. Intra-articular injection with hyaluronic acid should be considered for patients not responding adequately to physical therapy or anti-inflammatory medication. Methods: This was a single-arm, open-label, prospective study of a single intra-articular injection of NASHA (non-animal hyaluronic acid) in patients with symptomatic glenohumeral osteoarthritis. Patients were followed up for 26 weeks post-treatment, during which time rescue medication with acetaminophen was permissible. The study objective was to demonstrate that a single injection of NASHA is well tolerated with an over-6-month 25% reduction in shoulder pain on movement, assessed using a 100-mm visual analog scale. Results: Forty-one patients were enrolled, all of whom received study treatment. The mean decrease in shoulder pain on movement score over the 6-month study period was -20.1 mm (95% CI: -25.2, -15.0 mm), corresponding to a mean reduction of 29.5% (22.0, 37.0%). Statistically significant improvements were also observed in shoulder pain at night and patient global assessment. There was no clear change over time in the percentage of patients using rescue medication and mean weekly doses were below 3500 mg. Seventeen patients (41.5%) experienced adverse events, all of which were mild or moderate. Two adverse events (both shoulder pain) were deemed related to study treatment. Conclusion: This study provides preliminary evidence that a single injection of NASHA may be efficacious over 6 months and well tolerated in patients with symptomatic glenohumeral osteoarthritis. Larger studies are needed for confirmation.Bioventus LLC, Durham, NC, USAOpen access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]