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Previous studies demonstrated that IL-12–driven antitumor activity is short-circuited by a rapid switch in dendritic cell (DC) function from immunogenic to tolerogenic activity. This process was dependent on IFN-γ and the tolerogenic phenotype was conferred by IDO. Extended monitoring of IDO+ DC in the tumor-draining lymph nodes of IL-12 plus GM-CSF–treated tumor-bearing mice revealed that whereas IFN-γ induction was transient, IDO expression in DC was maintained long-term. An in vitro system modeling the IFN-γ–mediated change in DC function was developed to dissect the molecular basis of persistent IDO expression in post–IL-12 DC. Stimulation of DC with IFN-γ and CD40L resulted in rapid induction of IDO1 and IDO2 transcription and recapitulated the in vivo switch from immunogenic to tolerogenic activity. Long-term maintenance of IDO expression was found to be independent of exogenous and autocrine IFN-γ, or the secondary cytokines TGF-β, TNF-α, and IL-6. In contrast, both IDO enzymatic activity and IFN-γ–induced AhR expression were required for continued IDO transcription in vitro and in vivo. Addition of the tryptophan catabolite kynurenine to DC cultures in which IDO activity was blocked restored long-term IDO expression in wild-type DC but not in AhR-deficient DC, establishing the central role of the kynurenine–AhR pathway in maintaining IDO expression in tolerogenic DC. These findings shed further light on the cellular and molecular biology of the post–IL-12 regulatory rebound and provide insight into how feedback inhibitory mechanisms dominate in the long-term.

The history of motion of the Philippine Sea Plate is poorly known because it is isolated from the oceanic ridge system. Interpretation of palaeomagnetic results from the plate has been controversial because declination data have been obtained only from the eastern margin where subduction-related tectonic processes may have caused local rather than plate-wide rotations. New palaeomagnetic data relevant to the problem have been obtained from 34 sites north of the Sorong Fault and 29 sites within the Sorong Fault system. These sites record southward movement during the Eocene and northward movement during the Neogene. Sites within the Sorong Fault system record both counterclockwise and clockwise rotations interpreted as the result of Neogene block movements at the southern boundary of the Philippine Sea Plate. North of the Sorong Fault, all sites record clockwise declinations. Neogene rocks have small deflections consistent with rotation about the present-day Eurasia-Philippine Sea Plate pole. Oligocene-middle Eocene rocks show consistent clockwise declination deflections of-40 ø . Declinations of lower Eocene rocks indicate -90 ø of clockwise rotation. We propose that the entire area north of the Sorong Fault in east Indonesia has always been part of the Philippine Sea Plate and that the whole plate has rotated clockwise in a discontinuous manner by approximately 90 ø since the early Eocene. The new data from north of the Sorong Fault provide a basis for determining rotation poles which satisfy all the palaeomagnetic data from the Philippine Sea Plate and permit its reconstruction. 1117 1120 HALL ET AL.: CENOZOIC MOTION OF THE PHILIPPINE SEA PLATE Australia and the Pacific. The Sorong Fault has its type locality in the northern Bird's Head region of New Guinea [Visser and Hermes, 1962; Dow and Sukamto, 1984]. We use the term Sorong Fault Zone for an area including the region from the Bird's Head to east Sulawesi. Geology of the Sorong Fault Zone This geological summary is based on fieldwork carried out by London University and GRDC geologists [Hall et al., 1988a, b; Nichols and Hall, 1991; Charlton et al., 1991; Hall et al., 1991; Hall et al. , 1995a, R. Hall et al., unpublished results, 1995]. The Sorong Fault system juxtaposes continental, arc, and ophiolitic rocks (Figures 2 and 3). Australian continental crust is present on the islands of Obi and Bacan within the Sorong Fault system [Hamilton, 1979; Ali and Hall, 1995]. High-grade metamorphic rocks of probable Palaeozoic or greater age are exposed on Bacan and Obi, and lower and middle Jurassic sedimentary rocks, 165-188, 1975.

The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and ongoing coronavirus disease 2019 (COVID-19) pandemic underscores the need for new treatments. Here, we report that cannabidiol (CBD) inhibits infection of SARS-CoV-2 in cells and mice. CBD and its metabolite 7-OH-CBD, but not THC or other congeneric cannabinoids tested, potently block SARS-CoV-2 replication in lung epithelial cells. CBD acts after viral entry, inhibiting viral gene expression and reversing many effects of SARS-CoV-2 on host gene transcription. CBD inhibits SARS-CoV-2 replication in part by up-regulating the host IRE1α ribonuclease endoplasmic reticulum (ER) stress response and interferon signaling pathways. In matched groups of human patients from the National COVID Cohort Collaborative, CBD (100 mg/ml oral solution per medical records) had a significant negative association with positive SARS-CoV-2 tests. This study highlights CBD as a potential preventative agent for early-stage SARS-CoV-2 infection and merits future clinical trials. We caution against current use of non-medical formulations as a preventative or treatment therapy.

Sphingosine-1-phosphate (S1P) has emerged as a potent bioactive lipid with established roles in essential cellular processes such as vascular maturity, cell proliferation, traffi cking of immune cells, cytoskeletal rearrangement, invasion, and angiogenesis ( 1-3 ). Key to such diversity of functions lies in the ability of S1P to act as both an intracellular effector molecule and an extracellular ligand for a family of fi ve G protein-coupled receptors, S1PR 1-5 ( 4-7 ). S1P made within the cell can be secreted from the cell where it binds S1PRs in an autocrine or paracrine fashion, triggering a wide range of cellular responses, including proliferation, enhanced extracellular matrix assembly, stimulation of adherens junctions, formation of stress fibers, and inhibition of apoptosis induced by either ceramide or growth factor withdrawal ( 8-11 ).Like many signaling molecules, basal levels of S1P are tightly controlled by balancing synthesis with degradation. S1P is generated by the ATP-dependent phosphorylation of sphingosine catalyzed by sphingosine kinase (SK), of which there are two mammalian isoforms: SK1 and SK2. After being produced by SK, there are several possible Abstract Sphingosine kinase 1 (SK1) produces sphingosine-1-phosphate (S1P), a potent signaling lipid. The subcellular localization of SK1 can dictate its signaling function. Here, we use artifi cial targeting of SK1 to either the plasma membrane (PM) or the endoplasmic reticulum (ER) to test the effects of compartmentalization of SK1 on substrate utilization and downstream metabolism of S1P. Expression of untargeted or ER-targeted SK1, but surprisingly not PMtargeted SK1, results in a dramatic increase in the phosphorylation of dihydrosphingosine, a metabolic precursor in de novo ceramide synthesis. Conversely, knockdown of endogenous SK1 diminishes both dihydrosphingosine-1-phosphate and S1P levels. We tested the effects of SK1 localization on degradation of S1P by depletion of the ER-localized S1P phosphatases and lyase. Remarkably, S1P produced at the PM was degraded to the same extent as that produced in the ER. This indicates that there is an effi cient mechanism for the transport of S1P from the PM to the ER. In acute labeling experiments, we fi nd that S1P degradation is primarily driven by lyase cleavage of S1P. Counterintuitively, when S1P-specifi c phosphatases are depleted, acute labeling of S1P is signifi cantly reduced, indicative of a phosphatasedependent recycling process. We conclude that the localization of SK1 infl uences the substrate pools that it has access to and that S1P can rapidly translocate from the site where it is synthesized to other intracellular sites. 11 April 2010. Published, JLR Papers in Press, April 11, 2010 DOI 10.1194 Abbreviations: CIB1, calcium and integrin binding protein 1; ER, endoplasmic reticulum; Hek293, human embryonic kidney cell; HeLa, human cervical carcinoma cell; LDH, lactate dehydrogenase; PM, plasma membrane; PMA, phorbol ester; siRNA, small interfering RNA; SK, sphingosine kinase; S1P, ...

Al-Qudah M, Anderson CD, Mahavadi S, Bradley ZL, Akbarali HI, Murthy KS, Grider JR. Brain-derived neurotrophic factor enhances cholinergic contraction of longitudinal muscle of rabbit intestine via activation of phospholipase C. Am J Physiol Gastrointest Liver Physiol 306: G328 -G337, 2014. First published December 19, 2013 doi:10.1152/ajpgi.00203.2013.-Brain-derived neurotrophic factor (BDNF) belongs to the neurotrophin family of proteins best known for its role in neuronal survival, differentiation, migration, and synaptic plasticity in central and peripheral neurons. BDNF is also widely expressed in nonneuronal tissues including the gastrointestinal tract. The role of BDNF in intestinal smooth muscle contractility is not well defined. The aim of this study was to identify the role of BDNF in carbachol (CCh)-and substance P (SP)-induced contraction of intestinal longitudinal smooth muscle. BDNF, selective tropomyosin-related kinase B (TrkB) receptor agonists, and pharmacological inhibitors of signaling pathways were examined for their effects on contraction of rabbit intestinal longitudinal muscle strips induced by CCh and SP. BDNF activation of intracellular signaling pathways was examined by Western blot in homogenates of muscle strips and isolated muscle cells. One-hour preincubation with BDNF enhanced intestinal muscle contraction induced by CCh but not by SP. The selective synthetic TrkB agonists LM 22A4 and 7,8-dihydroxyflavone produced similar effects to BDNF. The Trk antagonist K-252a, a TrkB antibody but not p75NTR antibody, blocked the effect of BDNF. The enhancement of CCh-induced contraction by BDNF was blocked by the phospholipase C (PLC) antagonist U73122, but not by ERK1/2 or Akt antagonists. Direct measurement in muscle strips and isolated muscle cells showed that BDNF caused phosphorylation of TrkB receptors and PLC-␥, but not ERK1/2 or Akt. We conclude that exogenous BDNF augments the CCh-induced contraction of longitudinal muscle from rabbit intestine by activating TrkB receptors and subsequent PLC activation.neurotrophins; smooth muscle contraction; Trk receptors BRAIN DERIVED-NEUROTROPHIC FACTOR (BDNF) belongs to the neurotrophin family of peptides that includes nerve growth factor, neurotrophin-3, and neurotrophin-4/5. Neurotrophins are best known for their prolonged effects and role in neuronal survival, development, differentiation, migration, and synaptic plasticity (47, 56). BDNF mediates its biological functions by activating two distinct cell membrane receptors: p75NTR, a low-affinity receptor to which all neurotrophins bind, and tropomyosin-related kinase B (TrkB), a high-affinity receptor that preferentially binds BDNF (46). BDNF binding to TrkB induces autophosphorylation of the receptor intracellular tyrosine kinase domain that leads to activation of one or more of three canonical and independent intracellular signaling pathways: the Ras/extracellular signal-regulated kinase (ERK) pathway, the phosphatidylinositol-3-OH kinase (PI3K)/Akt pathway, and the phospholipase C-␥1 (PLC-...

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