Nightside condensation of iron in an ultra-hot giant exoplanet

Ultra-hot giant exoplanets receive thousands of times Earth's insolation. Their high-temperature atmospheres (>2,000 K) are ideal laboratories for studying extreme planetary climates and chemistry. Daysides are predicted to be cloud-free, dominated by atomic species and substantially hotter than nightsides. Atoms are expected to recombine into molecules over the nightside, resulting in different day-night chemistry. While metallic elements and a large temperature contrast have been observed, no chemical gradient has been measured across the surface of such an exoplanet. Different atmospheric chemistry between the day-to-night ("evening") and night-to-day ("morning") terminators could, however, be revealed as an asymmetric absorption signature during transit. Here, we report the detection of an asymmetric atmospheric signature in the ultra-hot exoplanet WASP-76b. We spectrally and temporally resolve this signature thanks to the combination of high-dispersion spectroscopy with a large photon-collecting area. The absorption signal, attributed to neutral iron, is blueshifted by -11+/-0.7 km s-1 on the trailing limb, which can be explained by a combination of planetary rotation and wind blowing from the hot dayside. In contrast, no signal arises from the nightside close to the morning terminator, showing that atomic iron is not absorbing starlight there. Iron must thus condense during its journey across the nightside.Comment: Published in Nature (Accepted on 24 January 2020.) 33 pages, 11 figures, 3 table

Inhibition of immune checkpoints PD-1, CTLA-4, and IDO1 coordinately induces immune-mediated liver injury in mice.

Cancer cells harness immune checkpoints such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1) and indoleamine 2,3-dioxygenase 1 (IDO1) to evade immune control. Checkpoint inhibitors have demonstrated durable anti-tumor efficacy in human and preclinical models. Liver toxicity is one of the common immune-related adverse events associated with checkpoint inhibitors (CPIs) and its frequency and severity often increase significantly during CPI combination therapies. We aim to develop a mouse model to elucidate the immune mechanisms of CPI-associated liver toxicity. Co-administration of CTLA-4 blocking antibody, 9D9, and/or an IDO1 inhibitor, epacadostat in wild-type and PD-1-/- mice (to simulate the effect of PD1 blockade) synergistically induced liver injury and immune cell infiltration. Infiltrated cells were primarily composed of CD8+ T cells and positively associated with hepatocyte necrosis. Strikingly, sites of hepatocyte necrosis were frequently surrounded by clusters of mononuclear immune cells. CPI treatments resulted in increased expression of genes associated with hepatocyte cell death, leukocyte migration and T cell activation in the liver. In conclusion, blockade of immune checkpoints PD-1, CTLA-4, and IDO1 act synergistically to enhance T cell infiltration and activity in the liver, leading to hepatocyte death

Protein manipulation using single copies of short peptide tags in cultured cells and in; Drosophila melanogaster;

Cellular development and function rely on highly dynamic molecular interactions among proteins distributed in all cell compartments. Analysis of these interactions has been one of the main topics in cellular and developmental research and has been mostly achieved by the manipulation of proteins of interest (POIs) at the genetic level. Although genetic strategies significantly contributed to our current understanding, targeting specific interactions of POIs in a time- and space-controlled manner or analyzing the role of POIs in dynamic cellular processes such as cell migration or cell division would profit from more direct approaches. The recent development of specific protein binders, which can be expressed and function intracellularly, along with advancement in synthetic biology, have contributed to the creation of a new toolbox for direct protein manipulations. Here, we selected a number of short tag epitopes for which protein binders from different scaffolds have been generated and showed that single copies of these tags allowed efficient POIs binding and manipulation in living cells. Using; Drosophila; , we also find that single short tags can be utilized for POI manipulation; in vivo;

Phenotype of TPBG Gene Replacement in the Mouse and Impact on the Pharmacokinetics of an Antibody–Drug Conjugate

The use of predictive preclinical models in drug discovery is critical for compound selection, optimization, preclinical to clinical translation, and strategic decision-making. Trophoblast glycoprotein (TPBG), also known as 5T4, is the therapeutic target of several anticancer agents currently in clinical development, largely due to its high expression in tumors and low expression in normal adult tissues. In this study, mice were engineered to express human TPBG under endogenous regulatory sequences by replacement of the murine Tpbg coding sequence. The gene replacement was considered functional since the hTPBG knockin (hTPBG-KI) mice did not exhibit clinical observations or histopathological phenotypes that are associated with Tpbg gene deletion, except in rare instances. The expression of hTPBG in certain epithelial cell types and in different microregions of the brain and spinal cord was consistent with previously reported phenotypes and expression patterns. In pharmacokinetic studies, the exposure of a clinical-stage anti-TPBG antibody–drug conjugate (ADC), A1mcMMAF, was lower in hTPBG-KI versus wild-type animals, which was evidence of target-related increased clearance in hTPBG-KI mice. Thus, the hTPBG-KI mice constitute an improved system for pharmacology studies with current and future TPBG-targeted therapies and can generate more precise pharmacokinetic and pharmacodynamic data. In general the strategy of employing gene replacement to improve pharmacokinetic assessments should be broadly applicable to the discovery and development of ADCs and other biotherapeutics

Measurement and stability of the pointing of the BepiColombo Laser Altimeter under thermal load

The BepiColombo Laser Altimeter (BELA) has been selected to fly on ESA׳s BepiColombo mission to Mercury. The instrument will be the first European laser altimeter designed for interplanetary flight. This paper describes the setup used to characterize the angular movements of BELA under the simulated environmental conditions that the instrument will encounter when orbiting Mercury. The system comprises a laser transmitter and a receiving telescope, which can move with respect to each other under thermal load. Tests performed using the Engineering Qualification Model show that the setup is accurate enough to characterize angular movements of the instrument components to an accuracy of ≈10 μrad. The qualification instrument is thermally stable to operate during all mission phases around Mercury proving that the transmitter and receiver sections will remain within the alignment requirements during its mission

PF-06463922, an ALK/ROS1 Inhibitor, Overcomes Resistance to First and Second Generation ALK Inhibitors in Preclinical Models

SummaryWe report the preclinical evaluation of PF-06463922, a potent and brain-penetrant ALK/ROS1 inhibitor. Compared with other clinically available ALK inhibitors, PF-06463922 displayed superior potency against all known clinically acquired ALK mutations, including the highly resistant G1202R mutant. Furthermore, PF-06463922 treatment led to regression of EML4-ALK-driven brain metastases, leading to prolonged mouse survival, in a superior manner. Finally, PF-06463922 demonstrated high selectivity and safety margins in a variety of preclinical studies. These results suggest that PF-06463922 will be highly effective for the treatment of patients with ALK-driven lung cancers, including those who relapsed on clinically available ALK inhibitors because of secondary ALK kinase domain mutations and/or brain metastases