ABSTRACT The Transiting Exoplanet Survey Satellite (TESS) is a NASA-sponsored Explorer mission that will perform a wide-field survey for planets that transit bright host stars. Here, we predict the ...properties of the transiting planets that TESS will detect along with the EB stars that produce false-positive photometric signals. The predictions are based on Monte Carlo simulations of the nearby population of stars, occurrence rates of planets derived from Kepler, and models for the photometric performance and sky coverage of the TESS cameras. We expect that TESS will find approximately 1700 transiting planets from pre-selected target stars. This includes 556 planets smaller than twice the size of Earth, of which 419 are hosted by M dwarf stars and 137 are hosted by FGK dwarfs. Approximately 130 of the planets will have host stars brighter than . Approximately 48 of the planets with lie within or near the habitable zone ( ); between 2 and 7 such planets have host stars brighter than . We also expect approximately 1100 detections of planets with radii 2-4 , and 67 planets larger than 4 . Additional planets larger than 2 can be detected around stars that are not among the pre-selected target stars, because TESS will also deliver full-frame images at a 30-minute cadence. The planet detections are accompanied by over 1000 astrophysical false positives. We discuss how TESS data and ground-based observations can be used to distinguish the false positives from genuine planets. We also discuss the prospects for follow-up observations to measure the masses and atmospheres of the TESS planets.
We perform a study of stellar flares for the 24,809 stars observed with 2 minute cadence during the first two months of the TESS mission. Flares may erode exoplanets' atmospheres and impact their ...habitability, but might also trigger the genesis of life around small stars. TESS provides a new sample of bright dwarf stars in our galactic neighborhood, collecting data for thousands of M dwarfs that might host habitable exoplanets. Here, we use an automated search for flares accompanied by visual inspection. Then, our public allesfitter code robustly selects the appropriate model for potentially complex flares via Bayesian evidence. We identify 1228 flaring stars, 673 of which are M dwarfs. Among 8695 flares in total, the largest superflare increased the stellar brightness by a factor of 16.1. Bolometric flare energies range from 1031.0 to 1036.9 erg, with a median of 1033.1 erg. Furthermore, we study the flare rate and energy as a function of stellar type and rotation period. We solidify past findings that fast rotating M dwarfs are the most likely to flare and that their flare amplitude is independent of the rotation period. Finally, we link our results to criteria for prebiotic chemistry, atmospheric loss through coronal mass ejections, and ozone sterilization. Four of our flaring M dwarfs host exoplanet candidates alerted on by TESS, for which we discuss how these effects can impact life. With upcoming TESS data releases, our flare analysis can be expanded to almost all bright small stars, aiding in defining criteria for exoplanet habitability.
Abstract Cancer vaccines are designed to elicit an endogenous adaptive immune response that can successfully recognize and eliminate residual or recurring tumors. Such approaches can potentially ...overcome shortcomings of passive immunotherapies by generating long-lived therapeutic effects and immune memory while limiting systemic toxicities. A critical determinant of vaccine efficacy is efficient transport and delivery of tumor-associated antigens to professional antigen presenting cells (APCs). Plant viral nanoparticles (VNPs) with natural tropism for APCs and a high payload carrying capacity may be particularly effective vaccine carriers. The applicability of VNP platform technologies is governed by stringent structure-function relationships. We compare two distinct VNP platforms: icosahedral cowpea mosaic virus (CPMV) and filamentous potato virus X (PVX). Specifically, we evaluate in vivo capabilities of engineered VNPs delivering human epidermal growth factor receptor 2 (HER2) epitopes for therapy and prophylaxis of HER2+ malignancies. Our results corroborate the structure-function relationship where icosahedral CPMV particles showed significantly enhanced lymph node transport and retention, and greater uptake by/activation of APCs compared to filamentous PVX particles. These enhanced immune cell interactions and transport properties resulted in elevated HER2-specific antibody titers raised by CPMV- vs. PVX-based peptide vaccine carriers. The ‘synthetic virology’ field is rapidly expanding with numerous platforms undergoing development and preclinical testing; our studies highlight the need for systematic studies to define rules guiding the design and rational choice of platform, in the context of peptide-vaccine display technologies.
We report on a new method for tracking the phases of the orbital modulations in very short-period, near-contact, and contact binary systems in order to follow starspots. We apply this technique to ...Kepler light curves for 414 binary systems that were identified as having anticorrelated O−C curves for the mid-times of the primary and secondary eclipses, or in the case of non-eclipsing systems, their light-curve minima. This phase tracking approach extracts more information about starspot and binary system behaviour than may be easily obtained from the O−C curves. We confirm the hypothesis of Tran et al. that we can successfully follow the rotational motions of spots on the surfaces of the stars in these binaries. In ∼34 per cent of the systems, the spot rotation is retrograde as viewed in the frame rotating with the orbital motion, while ∼13 per cent show significant prograde spot rotation. The remaining systems show either little spot rotation or erratic behaviour, or sometimes include intervals of both types of behaviour. We discuss the possibility that the relative motions of spots are related to differential rotation of the stars. It is clear from this study that the motions of the starspots in at least 50 per cent of these short-period binaries are not exactly synchronized with the orbits.
Human non-small cell lung cancers (NSCLCs) with activating mutations in EGFR frequently respond to treatment with EGFR-targeted tyrosine kinase inhibitors (TKIs), such as erlotinib, but responses are ...not durable, as tumors acquire resistance. Secondary mutations in EGFR (such as T790M) or upregulation of the MET kinase are found in over 50% of resistant tumors. Here, we report increased activation of AXL and evidence for epithelial-to-mesenchymal transition (EMT) in multiple in vitro and in vivo EGFR-mutant lung cancer models with acquired resistance to erlotinib in the absence of the EGFR p.Thr790Met alteration or MET activation. Genetic or pharmacological inhibition of AXL restored sensitivity to erlotinib in these tumor models. Increased expression of AXL and, in some cases, of its ligand GAS6 was found in EGFR-mutant lung cancers obtained from individuals with acquired resistance to TKIs. These data identify AXL as a promising therapeutic target whose inhibition could prevent or overcome acquired resistance to EGFR TKIs in individuals with EGFR-mutant lung cancer.
In the United States, most new cases of human immunodeficiency virus (HIV) belong to the at-risk group of gay and bisexual men. Developing therapies to reverse viral latency and prevent spread is ...paramount for the HIV cure agenda. In gay and bisexual men, a major, yet poorly characterized, route of HIV entry is via transport across the colonic epithelial barrier. While colonic tears and paracellular transport contribute to infection, we hypothesize that HIV entry through the colonic mucosa proceeds via a process known as transcytosis, involving (i) virion binding to the apical surface of the colonic epithelium, (ii) viral endocytosis, (iii) transport of virions across the cell, and (iv) HIV release from the basolateral membrane. Using Caco-2 colonic epithelial cells plated as a polarized monolayer in transwells, we characterized the mechanism of HIV transport. After exposing the monolayer to HIV apically, reverse transcription quantitative PCR (RT-qPCR) of the viral genome present in the basolateral chamber revealed that transport is dose dependent, cooperative, and inefficient, with released virus first detectable at 12 h. Inefficiency may be associated with >50% decline in detectable intracellular virus that correlates temporally with increased association of the virion with lysosomal-associated membrane protein 1 (LAMP-1+) endosomes. Microscopy revealed green fluorescent protein (GFP)-labeled HIV within the confines of the epithelial monolayer, with no virus detectable between cells, suggesting that viral transport is transcellular. Treatment of the monolayer with endocytosis inhibitors, cholesterol reducing agents, and small interfering RNA (siRNA) to caveolin showed that viral endocytosis is mediated by caveolin-coated endosomes contained in lipid rafts. These results indicate that HIV transport across the intestinal epithelial barrier via transcytosis is a viable mechanism for viral spread and a potential therapeutic target.
Despite the success of combination antiretroviral therapy in suppressing HIV replication and the emergence and effectiveness of PrEP-based prevention strategies, in 2018, 37,968 people in the United States received a new HIV diagnosis, accompanied by 15,820 deaths. While the annual number of new diagnoses decreased 7% from 2014 to 2018, 14% of people with HIV did not know they were infected. Gay and bisexual men accounted for 69% of all HIV diagnoses and 83% of diagnoses among males. Due to the scope of the HIV epidemic, determining and understanding precise routes of infection and the mechanisms of viral spread are paramount to ending the epidemic. Since transcellular transport of HIV across an intact colonic epithelial barrier is poorly understood, our overall goal is to characterize the molecular events involved in HIV transcytosis across the intestinal epithelial cell.
We present techniques for bridging the gap between idealized inverse covariance weighted quadratic estimation of 21 cm power spectra and the real-world challenges presented universally by ...interferometric observation. By carefully evaluating various estimators and adapting our techniques for large but incomplete data sets, we develop a robust power spectrum estimation framework that preserves the so-called "Epoch of Reionization (EoR) window" and keeps track of estimator errors and covariances. We apply our method to observations from the 32-tile prototype of the Murchinson Widefield Array to demonstrate the importance of a judicious analysis technique. Lastly, we apply our method to investigate the dependence of the clean EoR window on frequency-especially the frequency dependence of the so-called "wedge" feature-and establish upper limits on the power spectrum from z = 6.2 to z = 11.7. Our lowest limit is Delta (k) < 0.3 Kelvin at 95% confidence at a comoving scale k = 0.046 Mpc super(-1) and z = 9.5.
Kawahara and collaborators analysed the transits of the candidate disintegrating Mercury-mass planet KIC 12557548b and suggested that the transit depths were correlated with the phase of the stellar ...rotation. We have carried out a more extensive and comprehensive analysis of the transit depths of KIC 12557548b and confirm that there is indeed a robust, statistically significant signal in the transit depths at the rotation period of the spotted host star. This signal is more prominent in the first-half of the Kepler data, and is not due to leakage of the rotating spot signal into our measurement of the transit depths, or due to unocculted starspots. We quantitatively investigate the suggestion that this signal could be due to an active region on the star, emitting enhanced ultraviolet or X-ray radiation leading to an increased mass-loss rate of the planet; we demonstrate that such a scenario could cause both modulation of the transit depths of KIC 12557548b, and small enough transit-timing variations that they might not be detected in the Kepler data. Our preferred explanation, however, for the fact that the transit depths of KIC 12557548b are modulated with the stellar rotation phase is that the candidate transiting planet is occulting starspots on this highly spotted star; such a scenario could cause transit depth variations as large as have been observed, and cause transit-timing variations small enough that they are arguably consistent with the Kepler data.
T cell receptor (TCR)-initiated signal transduction is reported to increase production of intracellular reactive oxygen species, such as superoxide (O2⨪) and hydrogen peroxide (H2O2), as second ...messengers. Although H2O2 can modulate signal transduction by inactivating protein phosphatases, the mechanism and the subcellular localization of intracellular H2O2 as a second messenger of the TCR are not known. The antioxidant enzyme superoxide dismutase (SOD) catalyzes the dismutation of highly reactive O2⨪ into H2O2 and thus acts as an intracellular generator of H2O2. As charged O2⨪ is unable to diffuse through intracellular membranes, cells express distinct SOD isoforms in the cytosol (Cu,Zn-SOD) and mitochondria (Mn-SOD), where they locally scavenge O2⨪ leading to production of H2O2. A 2-fold organelle-specific overexpression of either SOD in Jurkat T cell lines increases intracellular production of H2O2 but does not alter the levels of intracellular H2O2 scavenging enzymes such as catalase, membrane-bound peroxiredoxin1 (Prx1), and cytosolic Prx2. We report that overexpression of Mn-SOD enhances tyrosine phosphorylation of TCR-associated membrane proximal signal transduction molecules Lck, LAT, ZAP70, PLCγ1, and SLP76 within 1 min of TCR cross-linking. This increase in mitochondrial H2O2 specifically modulates MAPK signaling through the JNK/cJun pathway, whereas overexpressing Cu,Zn-SOD had no effect on any of these TCR-mediated signaling molecules. As mitochondria translocate to the immunological synapse during TCR activation, we hypothesize this translocation provides the effective concentration of H2O2 required to selectively modulate downstream signal transduction pathways.
Background: H2O2 mediates signal transduction in response to TCR activation.
Results: Overexpressing mitochondrial Mn-SOD increases H2O2, enhancing intensity and duration of tyrosine phosphorylation after TCR activation, whereas overexpressing cytosolic Cu,Zn-SOD has no effect.
Conclusion: Mitochondrial H2O2 enhances TCR-mediated signal transduction selectively through JNK/cJun.
Significance: Mitochondrial translocation to the immunological synapse provides necessary proximity to raise effective H2O2 concentration to modulate TCR signaling.
Effective antiretroviral therapy (ART) dramatically reduces AIDS-related complications, yet the life expectancy of long-term ART-treated HIV-infected patients remains shortened compared to that of ...uninfected controls, due to increased risk of non-AIDS related morbidities. Many propose that these complications result from translocated microbial products from the gut that stimulate systemic inflammation--a consequence of increased intestinal paracellular permeability that persists in this population. Concurrent intestinal immunodeficiency and structural barrier deterioration are postulated to drive microbial translocation, and direct evidence of intestinal epithelial breakdown has been reported in untreated pathogenic SIV infection of rhesus macaques. To assess and characterize the extent of epithelial cell damage in virally-suppressed HIV-infected patients, we analyzed intestinal biopsy tissues for changes in the epithelium at the cellular and molecular level. The intestinal epithelium in the HIV gut is grossly intact, exhibiting no decreases in the relative abundance and packing of intestinal epithelial cells. We found no evidence for structural and subcellular localization changes in intestinal epithelial tight junctions (TJ), but observed significant decreases in the colonic, but not terminal ileal, transcript levels of TJ components in the HIV+ cohort. This result is confirmed by a reduction in TJ proteins in the descending colon of HIV+ patients. In the HIV+ cohort, colonic TJ transcript levels progressively decreased along the proximal-to-distal axis. In contrast, expression levels of the same TJ transcripts stayed unchanged, or progressively increased, from the proximal-to-distal gut in the healthy controls. Non-TJ intestinal epithelial cell-specific mRNAs reveal differing patterns of HIV-associated transcriptional alteration, arguing for an overall change in intestinal epithelial transcriptional regulation in the HIV colon. These findings suggest that persistent intestinal epithelial dysregulation involving a reduction in TJ expression is a mechanism driving increases in colonic permeability and microbial translocation in the ART-treated HIV-infected patient, and a possible immunopathogenic factor for non-AIDS related complications.
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