Interactive single cell RNA-Seq analysis with Single Cell Toolkit (SCTK)

I will present the Single Cell Toolkit (SCTK), an R package and interactive single cell RNA-sequencing (scRNA-Seq) analysis package that provides the first complete workflow for scRNA-Seq data analysis and visualization using a set of R functions and an interactive web interface. Users can perform analysis with modules for filtering raw results, clustering, batch correction, differential expression, pathway enrichment, and scRNA-Seq study design. The toolkit supports command line or pipeline data processing, and results can be loaded into the GUI for additional exploration and downstream analysis. We demonstrate the effectiveness of the SCTK on multiple scRNA-seq examples, including data from mucosal-associated invariant T cells, induced pluripotent stem cells, and breast cancer tumor cells. While other scRNA-Seq analysis tools exist, the SCTK is the first fully interactive analysis toolkit for scRNA-Seq data available within the R language.NIH U01CA22041

Activity of immunoproteasome inhibitor ONX-0914 in acute lymphoblastic leukemia expressing MLL–AF4 fusion protein

Proteasome inhibitors bortezomib and carfilzomib are approved for the treatment of multiple myeloma and mantle cell lymphoma and have demonstrated clinical efficacy for the treatment of acute lymphoblastic leukemia (ALL). The t(4;11)(q21;q23) chromosomal translocation that leads to the expression of MLL–AF4 fusion protein and confers a poor prognosis, is the major cause of infant ALL. This translocation sensitizes tumor cells to proteasome inhibitors, but toxicities of bortezomib and carfilzomib may limit their use in pediatric patients. Many of these toxicities are caused by on-target inhibition of proteasomes in non-lymphoid tissues (e.g., heart muscle, gut, testicles). We found that MLL–AF4 cells express high levels of lymphoid tissue-specific immunoproteasomes and are sensitive to pharmacologically relevant concentrations of specific immunoproteasome inhibitor ONX-0914, even in the presence of stromal cells. Inhibition of multiple active sites of the immunoproteasomes was required to achieve cytotoxicity against ALL. ONX-0914, an inhibitor of LMP7 (ß5i) and LMP2 (ß1i) sites of the immunoproteasome, and LU-102, inhibitor of proteasome ß2 sites, exhibited synergistic cytotoxicity. Treatment with ONX-0914 significantly delayed the growth of orthotopic ALL xenograft tumors in mice. T-cell ALL lines were also sensitive to pharmacologically relevant concentrations of ONX-0914. This study provides a strong rationale for testing clinical stage immunoproteasome inhibitors KZ-616 and M3258 in ALL

IL4Rα signaling abrogates hypoxic neutrophil survival and limits acute lung injury responses <i>in vivo</i>

Rationale: Acute respiratory distress syndrome is defined by the presence of systemic hypoxia and consequent on disordered neutrophilic inflammation. Local mechanisms limiting the duration and magnitude of this neutrophilic response remain poorly understood.  Objectives: To test the hypothesis that during acute lung inflammation tissue production of proresolution type 2 cytokines (IL-4 and IL-13) dampens the proinflammatory effects of hypoxia through suppression of HIF-1a (hypoxia-inducible factor-1a)mediated neutrophil adaptation, resulting in resolution of lung injury.  Methods: Neutrophil activation of IL4Ra (IL-4 receptor a) signaling pathways was explored ex vivo in human acute respiratory distress syndrome patient samples, in vitro after the culture of human peripheral blood neutrophils with recombinant IL-4 under conditions of hypoxia, and in vivo through the study of IL4Ra-deficient neutrophils in competitive chimera models and wild-type mice treated with IL-4.  Measurements and Main Results: IL-4 was elevated in human BAL from patients with acute respiratory distress syndrome, and its receptor was identified on patient blood neutrophils. Treatment of human neutrophils with IL-4 suppressed HIF-1a-dependent hypoxic survival and limited proinflammatory transcriptional responses. Increased neutrophil apoptosis in hypoxia, also observed with IL-13, required active STAT signaling, and was dependent on expression of the oxygen-sensing prolyl hydroxylase PHD2. In vivo, IL-4Ra-deficient neutrophils had a survival advantage within a hypoxic inflamed niche; in contrast, inflamed lung treatment with IL-4 accelerated resolution through increased neutrophil apoptosis.  Conclusions: We describe an important interaction whereby IL4Ra-dependent type 2 cytokine signaling can directly inhibit hypoxic neutrophil survival in tissues and promote resolution of neutrophil-mediated acute lung injury

TESS Giants Transiting Giants V -- Two hot Jupiters orbiting red-giant hosts

In this work we present the discovery and confirmation of two hot Jupiters orbiting red-giant stars, TOI-4377 b and TOI-4551 b, observed by TESS in the southern ecliptic hemisphere and later followed-up with radial-velocity (RV) observations. For TOI-4377 b we report a mass of $0.957^{+0.089}_{-0.087} \ M_\mathrm{J}$and a inflated radius of$1.348 \pm 0.081 \ R_\mathrm{J}$orbiting an evolved intermediate-mass star ($1.36 \ \mathrm{M}_\odot$,$3.52 \ \mathrm{R}_\odot$; TIC 394918211) on a period of of$4.378$days. For TOI-4551 b we report a mass of$1.49 \pm 0.13 \ M_\mathrm{J}$and a radius that is not obviously inflated of$1.058^{+0.110}_{-0.062} \ R_\mathrm{J}$, also orbiting an evolved intermediate-mass star ($1.31 \ \mathrm{M}_\odot$,$3.55 \ \mathrm{R}_\odot$; TIC 204650483) on a period of$9.956$days. We place both planets in context of known systems with hot Jupiters orbiting evolved hosts, and note that both planets follow the observed trend of the known stellar incident flux-planetary radius relation observed for these short-period giants. Additionally, we produce planetary interior models to estimate the heating efficiency with which stellar incident flux is deposited in the planet's interior, estimating values of$1.91 \pm 0.48\%$and$2.19 \pm 0.45\%$ for TOI-4377 b and TOI-4551 b respectively. These values are in line with the known population of hot Jupiters, including hot Jupiters orbiting main sequence hosts, which suggests that the radii of our planets have reinflated in step with their parent star's brightening as they evolved into the post-main-sequence. Finally, we evaluate the potential to observe orbital decay in both systems.Comment: 14 pages with 8 figures and 6 tables. Accepted for publication in the Monthly Notices of the Royal Astronomical Societ

TOI-4641b: An Aligned Warm Jupiter Orbiting a Bright (V=7.5) Rapidly Rotating F-star

We report the discovery of TOI-4641b, a warm Jupiter transiting a rapidly rotating F-type star with a stellar effective temperature of 6560 K. The planet has a radius of 0.73 $R_{Jup}$, a mass smaller than 3.87 $M_{Jup}$ $(3\sigma)$, and a period of 22.09 days. It is orbiting a bright star (V=7.5 mag) on a circular orbit with a radius and mass of 1.73 $R_{\odot}$ and 1.41 $M_{\odot}$. Follow-up ground-based photometry was obtained using the Tierras Observatory. Two transits were also observed with the Tillinghast Reflector Echelle Spectrograph (TRES), revealing the star to have a low projected spin-orbit angle ($\lambda$=$1.41^{+0.76}_{-0.76}$ degrees). Such obliquity measurements for stars with warm Jupiters are relatively few, and may shed light on the formation of warm Jupiters. Among the known planets orbiting hot and rapidly-rotating stars, TOI-4641b is one of the longest-period planets to be thoroughly characterized. Unlike hot Jupiters around hot stars which are more often misaligned, the warm Jupiter TOI-4641b is found in a well-aligned orbit. Future exploration of this parameter space can add one more dimension to the star-planet orbital obliquity distribution that has been well-sampled for hot Jupiters.Comment: Accepted MNRA

TOI-5126: A hot super-Neptune and warm Neptune pair discovered by TESS\textit{TESS} and CHEOPS\textit{CHEOPS}

We present the confirmation of a hot super-Neptune with an exterior Neptune companion orbiting a bright (V = 10.1 mag) F-dwarf identified by the $\textit{Transiting Exoplanet Survey Satellite}$ ($\textit{TESS}$). The two planets, observed in sectors 45, 46 and 48 of the $\textit{TESS}$ extended mission, are $4.74^{+0.16}_{-0.14}$ $R_{\oplus}$ and $3.86^{+0.17}_{-0.16}$ $R_{\oplus}$ with $5.4588385^{+0.0000070}_{-0.0000072}$ d and $17.8999^{+0.0018}_{-0.0013}$ d orbital periods, respectively. We also obtained precise space based photometric follow-up of the system with ESAs $\textit{CHaracterising ExOplanets Satellite}$ ($\textit{CHEOPS}$) to constrain the radius and ephemeris of TOI-5126 b. TOI 5126 b is located in the "hot Neptune Desert" and is an ideal candidate for follow-up transmission spectroscopy due to its high predicted equilibrium temperature ($T_{eq} = 1442^{+46}_{-40}$ K) implying a cloud-free atmosphere. TOI-5126 c is a warm Neptune ($T_{eq}= 971^{+31}_{-27}$ K) also suitable for follow-up. Tentative transit timing variations (TTVs) have also been identified in analysis, suggesting the presence of at least one additional planet, however this signal may be caused by spot-crossing events, necessitating further precise photometric follow-up to confirm these signals.Comment: Accepted in MNRAS, 18 pages, 14 figure

Two mini-Neptunes Transiting the Adolescent K-star HIP 113103 Confirmed with TESS and CHEOPS

We report the discovery of two mini-Neptunes in near 2:1 resonance orbits ($P=7.610303$ d for HIP 113103 b and $P=14.245651$ d for HIP 113103 c) around the adolescent K-star HIP 113103 (TIC 121490076). The planet system was first identified from the TESS mission, and was confirmed via additional photometric and spectroscopic observations, including a $\sim$17.5 hour observation for the transits of both planets using ESA CHEOPS. We place $\leq4.5$ min and $\leq2.5$ min limits on the absence of transit timing variations over the three year photometric baseline, allowing further constraints on the orbital eccentricities of the system beyond that available from the photometric transit duration alone. With a planetary radius of $R_{p}=1.829^{+0.096}_{-0.067}\,R_{\oplus}$, HIP 113103 b resides within the radius gap, and this might provide invaluable information on the formation disparities between super-Earths and mini-Neptunes. Given the larger radius $R_{p}=2.40^{+0.10}_{-0.08}\,R_{\oplus}$ for HIP 113103 c, and close proximity of both planets to HIP 113103, it is likely that HIP 113103 b might have lost (or is still losing) its primordial atmosphere. We therefore present simulated atmospheric transmission spectra of both planets using JWST, HST, and Twinkle. It demonstrates a potential metallicity difference (due to differences in their evolution) would be a challenge to detect if the atmospheres are in chemical equilibrium. As one of the brightest multi sub-Neptune planet systems suitable for atmosphere follow up, HIP 113103 b and HIP 113103 c could provide insight on planetary evolution for the sub-Neptune K-star population.Comment: 18 pages, 12 figures, accepted for publication in the Monthly Notices of the Royal Astronomical Societ

Three low-mass companions around aged stars discovered by TESS

We report the discovery of three transiting low-mass companions to aged stars: a brown dwarf (TOI-2336b) and two objects near the hydrogen burning mass limit (TOI-1608b and TOI-2521b). These three systems were first identified using data from the Transiting Exoplanet Survey Satellite (TESS). TOI-2336b has a radius of $1.05\pm 0.04\ R_J$, a mass of $69.9\pm 2.3\ M_J$ and an orbital period of 7.71 days. TOI-1608b has a radius of $1.21\pm 0.06\ R_J$, a mass of $90.7\pm 3.7\ M_J$ and an orbital period of 2.47 days. TOI-2521b has a radius of $1.01\pm 0.04\ R_J$, a mass of $77.5\pm 3.3\ M_J$ and an orbital period of 5.56 days. We found all these low-mass companions are inflated. We fitted a relation between radius, mass and incident flux using the sample of known transiting brown dwarfs and low-mass M dwarfs. We found a positive correlation between the flux and the radius for brown dwarfs and for low-mass stars that is weaker than the correlation observed for giant planets.Comment: 20 pages, 13 figures; submitted to MNRA

Hypoxia shapes the immune landscape in lung injury and promotes the persistence of inflammation

Hypoxemia is a defining feature of acute respiratory distress syndrome (ARDS), an often-fatal complication of pulmonary or systemic inflammation, yet the resulting tissue hypoxia, and its impact on immune responses, is often neglected. In the present study, we have shown that ARDS patients were hypoxemic and monocytopenic within the first 48 h of ventilation. Monocytopenia was also observed in mouse models of hypoxic acute lung injury, in which hypoxemia drove the suppression of type I interferon signaling in the bone marrow. This impaired monopoiesis resulted in reduced accumulation of monocyte-derived macrophages and enhanced neutrophil-mediated inflammation in the lung. Administration of colony-stimulating factor 1 in mice with hypoxic lung injury rescued the monocytopenia, altered the phenotype of circulating monocytes, increased monocyte-derived macrophages in the lung and limited injury. Thus, tissue hypoxia altered the dynamics of the immune response to the detriment of the host and interventions to address the aberrant response offer new therapeutic strategies for ARDS