Interleukin-11 (IL-11) is a pleiotropic cytokine with both pro- and anti-inflammatory properties. It activates its target cells via binding to the membrane-bound IL-11 receptor (IL-11R), which then recruits a homodimer of the ubiquitously expressed, signal-transducing receptor gp130. Besides this classic signaling pathway, IL-11 can also bind to soluble forms of the IL-11R (sIL-11R), and IL-11/sIL-11R complexes activate cells via the induction of gp130 homodimerization (trans-signaling). We have previously reported that the metalloprotease ADAM10 cleaves the membrane-bound IL-11R and thereby generates sIL-11R. In this study, we identify the rhomboid intramembrane protease RHBDL2 as a so far unrecognized alternative sheddase that can efficiently trigger IL-11R secretion. We determine the cleavage site used by RHBDL2, which is located in the extracellular part of the receptor in close proximity to the plasma membrane, between Ala-370 and Ser-371. Furthermore, we identify critical amino acid residues within the transmembrane helix that are required for IL-11R proteolysis. We also show that ectopically expressed RHBDL2 is able to cleave the IL-11R within the early secretory pathway and not only at the plasma membrane, indicating that its subcellular localization plays a central role in controlling its activity. Moreover, RHBDL2-derived sIL-11R is biologically active and able to perform IL-11 trans-signaling. Finally, we show that the human mutation IL-11R-A370V does not impede IL-11 classic signaling, but prevents RHBDL2-mediated IL-11R cleavage.
  To develop and evaluate a simultaneous multislice (SMS) reconstruction technique that provides noise reduction and leakage blocking for highly accelerated cardiac MRI.
 
  ReadOut Concatenated k-space SPIRiT (ROCK-SPIRiT) uses the concept of readout concatenation in image domain to represent SMS encoding, and performs coil self-consistency as in SPIRiT-type reconstruction in an extended k-space, while allowing regularization for further denoising. The proposed method is implemented with and without regularization, and validated on retrospectively SMS-accelerated cine imaging with three-fold SMS and two-fold in-plane acceleration. ROCK-SPIRiT is compared with two leakage-blocking SMS reconstruction methods readout-SENSE-GRAPPA and split slice-GRAPPA. Further evaluation and comparisons are performed using prospectively SMS-accelerated cine imaging.
 
  Results on retrospectively three-fold SMS and two-fold in-plane accelerated cine imaging show that ROCK-SPIRiT without regularization significantly improves on existing methods in terms of PSNR (readout-SENSE-GRAPPA 33.5 ± 3.2, split slice-GRAPPA 34.1 ± 3.8, ROCK-SPIRiT 35.0 ± 3.3) and SSIM (readout-SENSE-GRAPPA 84.4 ± 8.9, split slice-GRAPPA 85.0 ± 8.9, ROCK-SPIRiT 88.2 ± 6.6 [in percentage]). Regularized ROCK-SPIRiT significantly outperforms all methods, as characterized by these quantitative metrics (PSNR 37.6 ± 3.8, SSIM 94.2 ± 4.1 [in percentage]). The prospectively five-fold SMS and two-fold in-plane accelerated data show that ROCK-SPIRiT and regularized ROCK-SPIRiT have visually improved image quality compared with existing methods.
 
  The proposed ROCK-SPIRiT technique reduces noise and interslice leakage in accelerated SMS cardiac cine MRI, improving on existing methods both quantitatively and qualitatively.
 The proposed ROCK-SPIRiT technique reduces noise and interslice leakage in accelerated SMS cardiac cine MRI, improving on existing methods both quantitatively and qualitatively.Acute liver failure (ALF) causes severe liver dysfunction that can lead to multi-organ failure and death. Previous studies suggest that sphingosine kinase 1 (SphK1) protects against hepatocyte injury, yet not much is still known about its involvement in ALF. This study examines the role of SphK1 in D-galactosamine (GalN)/lipopolysaccharide (LPS)-induced ALF, which is a well-established experimental mouse model that mimics the fulminant hepatitis. Here we report that deletion of SphK1, but not SphK2, dramatically decreased GalN/LPS-induced liver damage, hepatic apoptosis, serum alanine aminotransferase levels, and mortality rate compared to wild-type mice. Whereas GalN/LPS treatment-induced hepatic activation of NF-κB and JNK in wild-type and SphK2-/- mice, these signaling pathways were reduced in SphK1-/- mice. Moreover, repression of ALF in SphK1-/- mice correlated with decreased expression of the pro-inflammatory cytokine TNFα. Adoptive transfer experiments indicated that SphK1 in bone marrow-derived infiltrating immune cells but not in host liver-resident cells, contribute to the development of ALF. Interestingly, LPS-induced TNFα production was drastically suppressed in SphK1-deleted macrophages, whereas IL-10 expression was markedly enhanced, suggesting a switch to the anti-inflammatory phenotype.  https://www.selleckchem.com/products/VX-770.html  Finally, treatment with a specific SphK1 inhibitor ameliorated inflammation and protected mice from ALF. Our findings suggest that SphK1 regulates TNFα secretion from macrophages and inhibition or deletion of SphK1 mitigated ALF. Thus, a potent inhibitor of SphK1 could potentially be a therapeutic agent for fulminant hepatitis.Among the different noncovalent interactions, halogen bonds have captured wide attention in the last years. Their stability has been rationalized in electrostatic terms by appealing to the σ-hole concept, a charge-depleted region that is able to interact favorably with electron rich moieties. This interpretation has been questioned, and in this work a set of anionic halogen model systems are used to shed some light on this issue. We use the interacting quantum atoms method, which provides an orbital invariant energy decomposition in which pure electrostatic terms are well isolated, and we complement our insights with the analysis of electrostatic potentials (ESPs) as well as with traditional descriptors of charge accumulation like the Laplacian of the electron density. The total electrostatic interaction between the interacting species is surprisingly destabilizing in many of the systems examined, demonstrating that although σ-holes might be qualitatively helpful, much care has to be taken in ascribing the stability of these systems to electrostatics.