GNSS Remote Sensing:Overview and selected recent developments

Ponencia expuesta online en el 8th International Radio Occultation Working Group Meeting (2021) celebrado del 7 al 9 de abrilGround and satellite based GNSS Remote Sensing (GNSS-RS) developed during the recent two decades into a very powerful and versatile tool for Earth System Research. A highlight of these developments is the operational use of spaceborne GNSS Radio Occultation (RO) data from several satellite missions to improve day-by-day global weather predictions. GNSS Remote Sensing is briefly introduced with selected applications. One prominent example is the improvement of regional and global weather forecasts. GNSS signals, reflected from water, ice and land surfaces (GNSS-Reflectometry, GNSS-R) can usefully complement the observation capabilities of GNSS-RO mission and enable versatile additional geophysical applications such as observation of wind speed and precipitation over oceans, which are illustrated. Finally, selected aspects for a comprehensive GNSS based Earth Observation with small satellite constellations are presented

Setting upper limits on the strength of periodic gravitational waves from PSR J1939+2134 using the first science data from the GEO 600 and LIGO detectors

Data collected by the GEO 600 and LIGO interferometric gravitational wave detectors during their first observational science run were searched for continuous gravitational waves from the pulsar J1939+2134 at twice its rotation frequency. Two independent analysis methods were used and are demonstrated in this paper: a frequency domain method and a time domain method. Both achieve consistent null results, placing new upper limits on the strength of the pulsar's gravitational wave emission. A model emission mechanism is used to interpret the limits as a constraint on the pulsar's equatorial ellipticity

Modulation of hepatic inflammation and energy-sensing pathways in the rat liver by high-fructose diet and chronic stress

Purpose High-fructose consumption and chronic stress are both associated with metabolic inflammation and insulin resistance. Recently, disturbed activity of energy sensor AMP-activated protein kinase (AMPK) was recognized as mediator between nutrient-induced stress and inflammation. Thus, we analyzed the effects of high-fructose diet, alone or in combination with chronic stress, on glucose homeostasis, inflammation and expression of energy sensing proteins in the rat liver. Methods In male Wistar rats exposed to 9-week 20% fructose diet and/or 4-week chronic unpredictable stress we measured plasma and hepatic corticosterone level, indicators of glucose homeostasis and lipid metabolism, hepatic inflammation (pro- and anti-inflammatory cytokine levels, Toll-like receptor 4, NLRP3, activation of NF kappa B, JNK and ERK pathways) and levels of energy-sensing proteins AMPK, SIRT1 and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha). Results High-fructose diet led to glucose intolerance, activation of NF kappa B and JNK pathways and increased intrahepatic IL-1 beta, TNF alpha and inhibitory phosphorylation of insulin receptor substrate 1 on Ser(307). It also decreased phospho-AMPK/AMPK ratio and increased SIRT1 expression. Stress alone increased plasma and hepatic corticosterone but did not influence glucose tolerance, nor hepatic inflammatory or energy-sensing proteins. After the combined treatment, hepatic corticosterone was increased, glucose tolerance remained preserved, while hepatic inflammation was partially prevented despite decreased AMPK activity. Conclusion High-fructose diet resulted in glucose intolerance, hepatic inflammation, decreased AMPK activity and reduced insulin sensitivity. Chronic stress alone did not exert such effects, but when applied together with high-fructose diet it could partially prevent fructose-induced inflammation, presumably due to increased hepatic glucocorticoids

Adaptation of a 2D in-gel kinase assay to trace phosphotransferase activities in the human pathogen Leishmania donovani

The protozoan parasite Leishmania donovani undergoes various developmental transitions during its infectious cycle that are triggered by environmental signals encountered inside insect and vertebrate hosts. Intracellular differentiation of the pathogenic amastigote stage is induced by pH and temperature shifts that affect protein kinase activities and downstream protein phosphorylation. Identification of parasite proteins with phosphotransferase activity during intracellular infection may reveal new targets for pharmacological intervention. Here we describe an improved protocol to trace this activity in L. donovani extracts at high resolution combining in-gel kinase assay and two-dimensional gel electrophoresis. This 2D procedure allowed us to identify proteins that are associated with amastigote ATP-binding, ATPase, and phosphotransferase activities. The 2D in-gel kinase assay, in combination with recombinant phospho-protein substrates previously identified by phospho-proteomics analyses, provides a novel tool to establish specific protein kinase-substrate relationships thus improving our understanding of Leishmania signal transduction with relevance for future drug development

Tyrosine Phosphorylation Regulates Maturation of Receptor Tyrosine Kinases

Constitutive activation of receptor tyrosine kinases (RTKs) is a frequent event in human cancer cells. Activating mutations in Fms-like tyrosine kinase 3 (FLT-3), notably, internal tandem duplications in the juxtamembrane domain (FLT-3 ITD), have been causally linked to acute myeloid leukemia. As we describe here, FLT-3 ITD exists predominantly in an immature, underglycosylated 130-kDa form, whereas wild-type FLT-3 is expressed predominantly as a mature, complex glycosylated 150-kDa molecule. Endogenous FLT-3 ITD, but little wild-type FLT-3, is detectable in the endoplasmic reticulum (ER) compartment. Conversely, cell surface expression of FLT-3 ITD is less efficient than that of wild-type FLT-3. Inhibition of FLT-3 ITD kinase by small molecules, inactivating point mutations, or coexpression with the protein-tyrosine phosphatases (PTPs) SHP-1, PTP1B, and PTP-PEST but not RPTPα promotes complex glycosylation and surface localization. However, PTP coexpression has no effect on the maturation of a surface glycoprotein of vesicular stomatitis virus. The maturation of wild-type FLT-3 is impaired by general PTP inhibition or by suppression of endogenous PTP1B. Enhanced complex formation of FLT-3 ITD with the ER-resident chaperone calnexin indicates that its retention in the ER is related to inefficient folding. The regulation of RTK maturation by tyrosine phosphorylation was observed with other RTKs as well, defines a possible role for ER-resident PTPs, and may be related to the altered signaling quality of constitutively active, transforming RTK mutants

Synergistic killing of FLT3ITD-positive AML cells by combined inhibition of tyrosine-kinase activity and N-glycosylation

Fms-like tyrosine kinase 3 (FLT3) with internal tandem duplications (ITD) is a major oncoprotein in acute myeloid leukemia (AML), and confers an unfavorable prognosis. Interference with FLT3ITD signaling is therefore pursued as a promising therapeutic strategy. In this study we show that abrogation of FLT3ITD glycoprotein maturation using low doses of the N-glycosylation inhibitor tunicamycin has antiproliferative and pro-apoptotic effects on FLT3ITD-expressing human and murine cell lines. This effect is mediated in part by arresting FLT3ITD in an underglycosylated state and thereby attenuating FLT3ITD-driven AKT and ERK signaling. In addition, tunicamycin caused pronounced endoplasmatic reticulum stress and apoptosis through activation of protein kinase RNA-like endoplasmic reticulum kinase (PERK) and activation of the gene encoding CCAAT-enhancer-binding protein homologous protein (CHOP). PERK inhibition with a small molecule attenuated CHOP induction and partially rescued cells from apoptosis. Combination of tunicamycin with potent FLT3ITD kinase inhibitors caused synergistic cell killing, which was highly selective for cell lines and primary AML cells expressing FLT3ITD. Although tunicamycin is currently not a clinically applicable drug, we propose that mild inhibition of N-glycosylation may have therapeutic potential in combination with FLT3 kinase inhibitors for FLT3ITD-positive AML

Synergistic killing of FLT3ITD-positive AML cells by combined inhibition of tyrosine-kinase activity and N-glycosylation

Fms-like tyrosine kinase 3 (FLT3) with internal tandem duplications (ITD) is a major oncoprotein in acute myeloid leukemia (AML), and confers an unfavorable prognosis. Interference with FLT3ITD signaling is therefore pursued as a promising therapeutic strategy. In this study we show that abrogation of FLT3ITD glycoprotein maturation using low doses of the N-glycosylation inhibitor tunicamycin has anti-proliferative and pro-apoptotic effects on FLT3ITD-expressing human and murine cell lines. This effect is mediated in part by arresting FLT3ITD in an underglycosylated state and thereby attenuating FLT3ITD-driven AKT and ERK signaling. In addition, tunicamycin caused pronounced endoplasmatic reticulum stress and apoptosis through activation of protein kinase RNA-like endoplasmic reticulum kinase (PERK) and activation of the gene encoding CCAAT-enhancer-binding protein homologous protein (CHOP). PERK inhibition with a small molecule attenuated CHOP induction and partially rescued cells from apoptosis. Combination of tunicamycin with potent FLT3ITD kinase inhibitors caused synergistic cell killing, which was highly selective for cell lines and primary AML cells expressing FLT3ITD. Although tunicamycin is currently not a clinically applicable drug, we propose that mild inhibition of N-glycosylation may have therapeutic potential in combination with FLT3 kinase inhibitors for FLT3ITD-positive AML