HOIL1 regulates group 2 innate lymphoid cell numbers and type 2 inflammation in the small intestine

Patients with mutations in HOIL1 experience a complex immune disorder including intestinal inflammation. To investigate the role of HOIL1 in regulating intestinal inflammation, we employed a mouse model of partial HOIL1 deficiency. The ileum of HOIL1-deficient mice displayed features of type 2 inflammation including tuft cell and goblet cell hyperplasia, and elevated expression of Il13, Il5 and Il25 mRNA. Inflammation persisted in the absence of T and B cells, and bone marrow chimeric mice revealed a requirement for HOIL1 expression in radiation-resistant cells to regulate inflammation. Although disruption of IL-4 receptor alpha (IL4Rα) signaling on intestinal epithelial cells ameliorated tuft and goblet cell hyperplasia, expression of Il5 and Il13 mRNA remained elevated. KLRG

Enhanced mitochondrial superoxide scavenging does not Improve muscle insulin action in the high fat-fed mouse

Improving mitochondrial oxidant scavenging may be a viable strategy for the treatment of insulin resistance and diabetes. Mice overexpressing the mitochondrial matrix isoform of superoxide dismutase (sod2(tg) mice) and/or transgenically expressing catalase within the mitochondrial matrix (mcat(tg) mice) have increased scavenging of O2(˙-) and H2O2, respectively. Furthermore, muscle insulin action is partially preserved in high fat (HF)-fed mcat(tg) mice. The goal of the current study was to test the hypothesis that increased O2(˙-) scavenging alone or in combination with increased H2O2 scavenging (mtAO mice) enhances in vivo muscle insulin action in the HF-fed mouse. Insulin action was examined in conscious, unrestrained and unstressed wild type (WT), sod2(tg), mcat(tg) and mtAO mice using hyperinsulinemic-euglycemic clamps (insulin clamps) combined with radioactive glucose tracers following sixteen weeks of normal chow or HF (60% calories from fat) feeding. Glucose infusion rates, whole body glucose disappearance, and muscle glucose uptake during the insulin clamp were similar in chow- and HF-fed WT and sod2(tg) mice. Consistent with our previous work, HF-fed mcat(tg) mice had improved muscle insulin action, however, an additive effect was not seen in mtAO mice. Insulin-stimulated Akt phosphorylation in muscle from clamped mice was consistent with glucose flux measurements. These results demonstrate that increased O2(˙-) scavenging does not improve muscle insulin action in the HF-fed mouse alone or when coupled to increased H2O2 scavenging

Select pyrimidinones inhibit the propagation of the malarial parasite, Plasmodium falciparum

Plasmodium falciparum, the Apicomplexan parasite that is responsible for the most lethal forms of human malaria, is exposed to radically different environments and stress factors during its complex lifecycle. In any organism, Hsp70 chaperones are typically associated with tolerance to stress. We therefore reasoned that inhibition of P. falciparum Hsp70 chaperones would adversely affect parasite homeostasis. To test this hypothesis, we measured whether pyrimidinone-amides, a new class of Hsp70 modulators, could inhibit the replication of the pathogenic P. falciparum stages in human red blood cells. Nine compounds with IC50 values from 30 nM to 1.6 μM were identified. Each compound also altered the ATPase activity of purified P. falciparum Hsp70 in single-turnover assays, although higher concentrations of agents were required than was necessary to inhibit P. falciparum replication. Varying effects of these compounds on Hsp70s from other organisms were also observed. Together, our data indicate that pyrimidinone-amides constitute a novel class of anti-malarial agents. © 2009 Elsevier Ltd. All rights reserved

Leukotriene receptors (version 2020.3) in the IUPHAR/BPS Guide to Pharmacology Database

The leukotriene receptors (nomenclature as agreed by the NC-IUPHAR subcommittee on Leukotriene Receptors [34, 37]) are activated by the endogenous ligands leukotrienes (LT), synthesized from lipoxygenase metabolism of arachidonic acid. The human BLT1 receptor is the high affinity LTB4 receptor whereas the BLT2 receptor in addition to being a low-affinity LTB4 receptor also binds several other lipoxygenase-products, such as 12S-HETE, 12S-HPETE, 15S-HETE, and the thromboxane synthase product 12-hydroxyheptadecatrienoic acid. The BLT receptors mediate chemotaxis and immunomodulation in several leukocyte populations and are in addition expressed on non-myeloid cells, such as vascular smooth muscle and endothelial cells. In addition to BLT receptors, LTB4 has been reported to bind to the peroxisome proliferator activated receptor (PPAR) α [196] and the vanilloid TRPV1 ligand-gated nonselective cation channel [217]. The receptors for the cysteinyl-leukotrienes (i.e. LTC4, LTD4 and LTE4) are termed CysLT1 and CysLT2 and exhibit distinct expression patterns in human tissues, mediating for example smooth muscle cell contraction, regulation of vascular permeability, and leukocyte activation. There is also evidence in the literature for additional CysLT receptor subtypes, derived from functional in vitro studies, radioligand binding and in mice lacking both CysLT1 and CysLT2 receptors [37]. Cysteinyl-leukotrienes have also been suggested to signal through the P2Y12 receptor [96, 243, 272], GPR17 [57] and GPR99 [168]

Leukotriene receptors in GtoPdb v.2023.1

The leukotriene receptors (nomenclature as agreed by the NC-IUPHAR subcommittee on Leukotriene Receptors [35, 38]) are activated by the endogenous ligands leukotrienes (LT), synthesized from lipoxygenase metabolism of arachidonic acid. The human BLT1 receptor is the high affinity LTB4 receptor whereas the BLT2 receptor in addition to being a low-affinity LTB4 receptor also binds several other lipoxygenase-products, such as 12S-HETE, 12S-HPETE, 15S-HETE, and the thromboxane synthase product 12-hydroxyheptadecatrienoic acid. The BLT receptors mediate chemotaxis and immunomodulation in several leukocyte populations and are in addition expressed on non-myeloid cells, such as vascular smooth muscle and endothelial cells. In addition to BLT receptors, LTB4 has been reported to bind to the peroxisome proliferator activated receptor (PPAR) α [201] and the vanilloid TRPV1 ligand-gated nonselective cation channel [223]. The crystal structure of the BLT1 receptor was initially determined in complex with selective antagonists [141, 231] and has recently been extended to the cryo-electron microscopy structure of LTB4-bound human BLT1 receptor at 2.91 Å resolution [389]. The receptors for the cysteinyl-leukotrienes (i.e. LTC4, LTD4 and LTE4) are termed CysLT1 and CysLT2 and exhibit distinct expression patterns in human tissues, mediating for example smooth muscle cell contraction, regulation of vascular permeability, and leukocyte activation. Quite recently, the the crystal structures of both receptors have been solved, the CysLT1 in complex with zafirlukast and pranlukast [203] and the CysLT2 in complex with three dual CysLT1/CysLT2 antagonists [122]. There is also evidence in the literature for additional CysLT receptor subtypes, derived from functional in vitro studies, radioligand binding and in mice lacking both CysLT1 and CysLT2 receptors [38]. Cysteinyl-leukotrienes have also been suggested to signal through the P2Y12 receptor [99, 251, 280], GPR17 [60] and GPR99 [173]

Formylpeptide receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

The formylpeptide receptors (nomenclature agreed by the NC-IUPHAR Subcommittee on the formylpeptide receptor family [185]) respond to exogenous ligands such as the bacterial product fMet-Leu-Phe (fMLP) and endogenous ligands such as annexin I , cathepsin G, amyloid β42, serum amyloid A and spinorphin, derived from β-haemoglobin

Formylpeptide receptors in GtoPdb v.2021.2

The formylpeptide receptors (nomenclature agreed by the NC-IUPHAR Subcommittee on the formylpeptide receptor family [196]) respond to exogenous ligands such as the bacterial product fMet-Leu-Phe (fMLP) and endogenous ligands such as lipoxin A4 (LXA4), 15-epi-lipoxin A4, annexin I , cathepsin G, amyloid β42, serum amyloid A and spinorphin, derived from β-haemoglobin. FPR1 also serves as a plague receptor for selective destruction of human immune cells by Y. pestis [135]. The FPR1/2 agonists 'compound 17b' and 'compound 43' have shown cardiac protective functions [149, 64]

From CFTR biology toward combinatorial pharmacotherapy:expanded classification of cystic fibrosis mutations

More than 2000 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) have been described that confer a range of molecular cell biological and functional phenotypes. Most of these mutations lead to compromised anion conductance at the apical plasma membrane of secretory epithelia and cause cystic fibrosis (CF) with variable disease severity. Based on the molecular phenotypic complexity of CFTR mutants and their susceptibility to pharmacotherapy, it has been recognized that mutations may impose combinatorial defects in CFTR channel biology. This notion led to the conclusion that the combination of pharmacotherapies addressing single defects (e.g., transcription, translation, folding, and/or gating) may show improved clinical benefit over available low-efficacy monotherapies. Indeed, recent phase 3 clinical trials combining ivacaftor (a gating potentiator) and lumacaftor (a folding corrector) have proven efficacious in CF patients harboring the most common mutation (deletion of residue F508, ΔF508, or Phe508del). This drug combination was recently approved by the U.S. Food and Drug Administration for patients homozygous for ΔF508. Emerging studies of the structural, cell biological, and functional defects caused by rare mutations provide a new framework that reveals a mixture of deficiencies in different CFTR alleles. Establishment of a set of combinatorial categories of the previously defined basic defects in CF alleles will aid the design of even more efficacious therapeutic interventions for CF patients

Pointing control for the SPIDER balloon-borne telescope

We present the technology and control methods developed for the pointing system of the SPIDER experiment. SPIDER is a balloon-borne polarimeter designed to detect the imprint of primordial gravitational waves in the polarization of the Cosmic Microwave Background radiation. We describe the two main components of the telescope's azimuth drive: the reaction wheel and the motorized pivot. A 13 kHz PI control loop runs on a digital signal processor, with feedback from fibre optic rate gyroscopes. This system can control azimuthal speed with < 0.02 deg/s RMS error. To control elevation, SPIDER uses stepper-motor-driven linear actuators to rotate the cryostat, which houses the optical instruments, relative to the outer frame. With the velocity in each axis controlled in this way, higher-level control loops on the onboard flight computers can implement the pointing and scanning observation modes required for the experiment. We have accomplished the non-trivial task of scanning a 5000 lb payload sinusoidally in azimuth at a peak acceleration of 0.8 deg/s$^2$, and a peak speed of 6 deg/s. We can do so while reliably achieving sub-arcminute pointing control accuracy.Comment: 20 pages, 12 figures, Presented at SPIE Ground-based and Airborne Telescopes V, June 23, 2014. To be published in Proceedings of SPIE Volume 914

The Yuan-Tseh Lee Array for Microwave Background Anisotropy

The Yuan-Tseh Lee Array for Microwave Background Anisotropy (AMiBA) is the first interferometer dedicated to studying the cosmic microwave background (CMB) radiation at 3mm wavelength. The choice of 3mm was made to minimize the contributions from foreground synchrotron radiation and Galactic dust emission. The initial configuration of seven 0.6m telescopes mounted on a 6-m hexapod platform was dedicated in October 2006 on Mauna Loa, Hawaii. Scientific operations began with the detection of a number of clusters of galaxies via the thermal Sunyaev-Zel'dovich effect. We compare our data with Subaru weak lensing data in order to study the structure of dark matter. We also compare our data with X-ray data in order to derive the Hubble constant.Comment: accepted for publication in ApJ (13 pages, 7 figures); a version with high resolution figures available at http://www.asiaa.sinica.edu.tw/~keiichi/upfiles/AMiBA7/pho_highreso.pd