Summary
Cardiac surgery with cardiopulmonary bypass is associated with the development of a systemic inflammatory response that can often lead to dysfunction of major organs. We hypothesised that the ...highly selective α2‐adrenergic agonist, dexmedetomidine, attenuates the systemic inflammatory response. Forty‐two patients were randomly assigned to receive dexmedetomidine or saline after aortic cross‐clamping). The mean (SD) levels of the nuclear protein plasma high‐mobility group box 1 increased significantly from 5.1 (2.2) ng.ml−1 during (16.6 (7.3) ng.ml−1) and after (14.3 (8.2) ng.ml−1) cardiopulmonary bypass in the saline group. In the dexmedetomidine group, the levels increased significantly only during cardiopulmonary bypass (4.0 (1.9) ng.ml−1 baseline vs 10.8 (2.7) ng.ml−1) but not after (7.4 (3.8) ng.ml−1). Dexmedetomidine infusion also suppressed the rise in mean (SD) interleukin‐6 levels after cardiopulmonary bypass (a rise of 124.5 (72.0) pg.ml−1 vs 65.3 (30.9) pg.ml−1). These suppressive effects of dexmedetomidine might be due to the inhibition of nuclear factor kappa B activation and suggest that intra‐operative dexmedetomidine may beneficially inhibit inflammatory responses associated with ischaemia‐reperfusion injury during cardiopulmonary bypass.
A unique feature of COVID-19 interstitial pneumonia is an abrupt progression to respiratory failure. Our calculation shows that this abrupt deteriorate may be caused by a sudden shift in the spread ...of virus-laden bioaerosols through the airways to many different regions of the lungs from the initial site of infection.
Manic episodes are one of the major diagnostic symptoms in a spectrum of neuropsychiatric disorders that include schizophrenia, obsessive-compulsive disorder and bipolar disorder (BD). Despite a ...possible association between BD and the gene encoding phospholipase Cγ1 (PLCG1), its etiological basis remains unclear. Here, we report that mice lacking phospholipase Cγ1 (PLCγ1) in the forebrain (Plcg1
; CaMKII) exhibit hyperactivity, decreased anxiety-like behavior, reduced depressive-related behavior, hyperhedonia, hyperphagia, impaired learning and memory and exaggerated startle responses. Inhibitory transmission in hippocampal pyramidal neurons and striatal dopamine receptor D1-expressing neurons of Plcg1-deficient mice was significantly reduced. The decrease in inhibitory transmission is likely due to a reduced number of γ-aminobutyric acid (GABA)-ergic boutons, which may result from impaired localization and/or stabilization of postsynaptic CaMKII (Ca
/calmodulin-dependent protein kinase II) at inhibitory synapses. Moreover, mutant mice display impaired brain-derived neurotrophic factor-tropomyosin receptor kinase B-dependent synaptic plasticity in the hippocampus, which could account for deficits of spatial memory. Lithium and valproate, the drugs presently used to treat mania associated with BD, rescued the hyperactive phenotypes of Plcg1
; CaMKII mice. These findings provide evidence that PLCγ1 is critical for synaptic function and plasticity and that the loss of PLCγ1 from the forebrain results in manic-like behavior.
Pim-2 kinase is overexpressed in multiple myeloma (MM) cells to enhance their growth and survival, and regarded as a novel therapeutic target in MM. However, the impact of Pim-2 inhibition on bone ...disease in MM remains unknown. We demonstrated here that Pim-2 expression was also upregulated in bone marrow stromal cells and MC3T3-E1 preosteoblastic cells in the presence of cytokines known as the inhibitors of osteoblastogenesis in MM, including interleukin-3 (IL-3), IL-7, tumor necrosis factor-α, transforming growth factor-β (TGF-β) and activin A, as well as MM cell conditioned media. The enforced expression of Pim-2 abrogated in vitro osteoblastogenesis by BMP-2, which suggested Pim-2 as a negative regulator for osteoblastogenesis. Treatment with Pim-2 short-interference RNA as well as the Pim inhibitor SMI-16a successfully restored osteoblastogenesis suppressed by all the above inhibitory factors and MM cells. The SMI-16a treatment potentiated BMP-2-mediated anabolic signaling while suppressing TGF-β signaling. Furthermore, treatment with the newly synthesized thiazolidine-2,4-dione congener, 12a-OH, as well as its prototypic SMI-16a effectively prevented bone destruction while suppressing MM tumor growth in MM animal models. Thus, Pim-2 may have a pivotal role in tumor progression and bone loss in MM, and Pim-2 inhibition may become an important therapeutic strategy to target the MM cell-bone marrow interaction.
A new method of fully nonlinear waveform fitting to measure interstation phase speeds and amplitude ratios is developed and applied to USArray. The Neighbourhood Algorithm is used as a global ...optimizer, which efficiently searches for model parameters that fit two observed waveforms on a common great-circle path by modulating the phase and amplitude terms of the fundamental-mode surface waves. We introduce the reliability parameter that represents how well the waveforms at two stations can be fitted in a time–frequency domain, which is used as a data selection criterion. The method is applied to observed waveforms of USArray for seismic events in the period from 2007 to 2010 with moment magnitude greater than 6.0. We collect a large number of phase speed data (about 75 000 for Rayleigh and 20 000 for Love) and amplitude ratio data (about 15 000 for Rayleigh waves) in a period range from 30 to 130 s. The majority of the interstation distances of measured dispersion data is less than 1000 km, which is much shorter than the typical average path-length of the conventional single-station measurements for source-receiver pairs. The phase speed models for Rayleigh and Love waves show good correlations on large scales with the recent tomographic maps derived from different approaches for phase speed mapping; for example, significant slow anomalies in volcanic regions in the western Unites States and fast anomalies in the cratonic region. Local-scale phase speed anomalies corresponding to the major tectonic features in the western United States, such as Snake River Plains, Basin and Range, Colorado Plateau and Rio Grande Rift have also been identified clearly in the phase speed models. The short-path information derived from our interstation measurements helps to increase the achievable horizontal resolution. We have also performed joint inversions for phase speed maps using the measured phase and amplitude ratio data of vertical component Rayleigh waves. These maps exhibit better recovery of phase speed perturbations, particularly where the strong lateral velocity gradient exists in which the effects of elastic focussing can be significant; that is, the Yellowstone hotspot, Snake River Plains, and Rio Grande Rift. The enhanced resolution of the phase speed models derived from the interstation phase and amplitude measurements will be of use for the better seismological constraint on the lithospheric structure, in combination with dense broad-band seismic arrays.
Radixin is a member of the ezrin/radixin/moesin (ERM) family of proteins, which play a role in the formation of the membrane‐associated cytoskeleton by linking actin filaments and adhesion proteins. ...This cross‐linking activity is regulated by phosphoinositides such as phosphatidylinositol 4,5‐bisphosphate (PIP2) in the downstream of the small G protein Rho. The X‐ray crystal structures of the radixin FERM domain, which is responsible for membrane binding, and its complex with inositol‐(1,4,5)‐trisphosphate (IP3) have been determined. The domain consists of three subdomains featuring a ubiquitin‐like fold, a four‐helix bundle and a phosphotyrosine‐binding‐like domain, respectively. These subdomains are organized by intimate interdomain interactions to form characteristic grooves and clefts. One such groove is negatively charged and so is thought to interact with basic juxta‐membrane regions of adhesion proteins. IP3 binds a basic cleft that is distinct from those of pleckstrin homology domains and is located on a positively charged flat molecular surface, suggesting an electrostatic mechanism of plasma membrane targeting. Based on the structural changes associated with IP3 binding, a possible unmasking mechanism of ERM proteins by PIP2 is proposed.
Simulation of power converters has traditionally been carried out using simplified models to shorten simulation time. This will compromise the accuracy of the results. A proposed fast simulation ...method for simulating converter losses and device temperatures over long mission profiles (load cycles) is described in this paper. It utilizes accurate physics-based models for the device losses, and is validated with experimentally obtained results.
•KIT constructed and tested the HTS current leads for the tokamak JT-60SA.•The CLs were integrated into CTBs and connected to the TF, EF and CS coils via sc feeders.•The HTS-CL demonstrated reliable ...and robust operation.•The main parameters measured during commissioning agreed well with expectations.
The Karlsruhe Institute of Technology (KIT) has constructed and tested the High Temperature Superconductor Current Leads (HTS-CL) for the tokamak JT-60SA within the frame of the Broader Approach agreement between Europe and Japan. In total six HTS-CLs for 25.7 kA for the Toroidal Field (TF) coils and 20 HTS-CLs for 20 kA for the Equilibrium Field (EF) and Central Solenoid (CS) coils were manufactured and all of them were tested at operating temperatures in the test facility CuLTKa at KIT. After delivery, the CLs were integrated into the coil-terminal boxes (CTB) and connected to the TF, EF and CS coils via superconducting feeders. In the present paper the design, manufacture and acceptance tests of the HTS-CL at KIT, their integration into the CTBs, and first results of their operation during integrated commissioning are presented.
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