Of the nine confirmed transiting circumbinary planet systems, only Kepler-47 is known to contain more than one planet. Kepler-47 b (the "inner planet") has an orbital period of 49.5 days and a radius ...of about 3 R⊕. Kepler-47 c (the "outer planet") has an orbital period of 303.2 days and a radius of about 4.7 R⊕. Here we report the discovery of a third planet, Kepler-47 d (the "middle planet"), which has an orbital period of 187.4 days and a radius of about 7 R⊕. The presence of the middle planet allows us to place much better constraints on the masses of all three planets, where the 1 ranges are less than 26 M⊕, between 7-43 M⊕, and between 2-5 M⊕ for the inner, middle, and outer planets, respectively. The middle and outer planets have low bulk densities, with g cm−3 and outer < 0.26 g cm−3 at the 1 level. The two outer planets are "tightly packed," assuming the nominal masses, meaning no other planet could stably orbit between them. All of the orbits have low eccentricities and are nearly coplanar, disfavoring violent scattering scenarios and suggesting gentle migration in the protoplanetary disk.
The maintenance of immune homeostasis requires regulatory T cells (Tregs). Given their intrinsic self-reactivity, Tregs must stably maintain a suppressive phenotype to avoid autoimmunity. We report ...that impaired expression of the transcription factor (TF) Helios by FoxP3+ CD4 and Qa-1–restricted CD8 Tregs results in defective regulatory activity and autoimmunity in mice. Helios-deficient Tregs develop an unstable phenotype during inflammatory responses characterized by reduced FoxP3 expression and increased effector cytokine expression secondary to diminished activation of the STAT5 pathway. CD8 Tregs also require Helios-dependent STAT5 activation for survival and to prevent terminal T cell differentiation. The definition of Helios as a key transcription factor that stabilizes Tregs in the face of inflammatory responses provides a genetic explanation for a core property of Tregs.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Internet penetration worldwide has increased rapidly over the recent years. With this growth, modern information and communication technologies (ICT) have become increasingly important. They do not ...only change daily life but also patient-physician interaction and health related information search, which can be summarized as electronic Health (eHealth). eHealth was already known before the emergence of the coronavirus disease 2019 (COVID-19), but this pandemic substantially challenged health systems, physicians and hospitals so profoundly that new services and methods of patient-physician interaction had to be implemented rapidly. This study investigates the attitude of cancer patients towards eHealth and the potential impact of COVID-19 on its use.
The study was a multicentered study carried out at the university hospitals Bonn and Aachen. Patients were asked to answer a structured questionnaire in the time span between September 2019 and February 2021. Due to the COVID-19 pandemic, no patients were addressed between March 2020 and July 2020. The questionnaire focused on socio-demographic data, the dissemination of internet-enabled devices, the patients' attitude towards eHealth and the use of modern ICT in daily life and for health-related information search. In total, 280 patients have filled the questionnaire of which 48% were female and 52% were male. Men have a slightly more positive attitude towards the overall potential of eHealth than women which was shown by a significant influence for receiving medical information via e-mail. Hematological-oncological patients with a higher education level reported a significantly higher willingness to send personal health information to their physician and health insurance. A frequency of medical consultation of more than 5 times during the previous year has a significantly positive impact regarding the use of online communication, online video consultation and treatment quality. Younger patients have more concerns about data security than older patients. The study shows a different attitude towards the influence of eHealth on the patient-physician relationship in different therapy situations. While there were no significant changes in patients' attitude towards eHealth after the start of the COVID-19 pandemic, there was a trend towards an increasingly embracing attitude in patients, who answered the questionnaire during COVID-19 pandemic situation.
Overall, cancer patients had a positive attitude towards eHealth and the dissemination of internet-enabled devices was high. The study shows that the potential of eHealth is high among hematological-oncological patients. Further eHealth technologies and especially telemedically supported care processes should be implemented to improve patient-physician interaction and cross-sectoral care. COVID-19 pandemic led to a fast initiation and acceleration of new structures and routines for physicians, hospitals and patients. These new processes should be used to promote digitalization in hematological and oncological telemedicine. To successfully implement new eHealth technologies, future research should focus on patients' concerns about data privacy and data availability especially in the context of exchange of medical information in cross sectoral and interdisciplinary care processes.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment option for many malignant high-risk hematological diseases. The Graft-vs.-Tumor (GvT) effect is the major ...hallmark of this treatment approach. However, disease relapse remains a major limitation. Boosting the GvT effect by checkpoint inhibitors (CI) is an attractive option in this desperate situation although potentially triggering Graft-vs.-Host Disease (GvHD). Early reports in patients with Hodgkin's lymphoma support the idea that CI therapy after HSCT is feasible and effective. We have retrospectively analyzed CI therapy for treatment of disease recurrence after allo-HSCT other than Hodgkin's lymphoma including 21 patients from eight German transplant centers. The median follow-up was 59 days. The overall response rate (ORR) was 43%. Patients receiving donor lymphocyte infusion (DLI) in combination with CI had superior response (ORR 80%). Severe acute GvHD grade III-IV and moderate to severe chronic GvHD were observed in 29% of all patients. Taken together, CI therapy in relapsed patients after HSCT, especially in combination with DLI, is effective but induces severe GvHD in a considerable proportion of patients. Thus, prospective trials or EBMT registry-based validation of different dosing and application schedules including immunosuppressive regimens in those patients are urgently needed.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
BACKGROUND—Atherosclerotic lesions grow via the accumulation of leukocytes and oxidized lipoproteins in the vessel wall. Leukocytes can attenuate or augment atherosclerosis through the release of ...cytokines, chemokines, and other mediators. Deciphering how leukocytes develop, oppose, and complement each other’s function and shape the course of disease can illuminate our understanding of atherosclerosis. Innate response activator (IRA) B cells are a recently described population of granulocyte macrophage colony-stimulating factor–secreting cells of hitherto unknown function in atherosclerosis.
METHODS AND RESULTS—Here, we show that IRA B cells arise during atherosclerosis in mice and humans. In response to a high-cholesterol diet, IRA B cell numbers increase preferentially in secondary lymphoid organs via Myd88-dependent signaling. Mixed chimeric mice lacking B cell–derived granulocyte macrophage colony-stimulating factor develop smaller lesions with fewer macrophages and effector T cells. Mechanistically, IRA B cells promote the expansion of classic dendritic cells, which then generate interferon γ–producing T helper-1 cells. This IRA B cell–dependent T helper-1 skewing manifests in an IgG1-to-IgG2c isotype switch in the immunoglobulin response against oxidized lipoproteins.
CONCLUSIONS—Granulocyte macrophage colony-stimulating factor–producing IRA B cells alter adaptive immune processes and shift the leukocyte response toward a T helper-1–associated milieu that aggravates atherosclerosis.
Cellular therapies utilize the powerful force of the human immune system to target malignant cells. Allogeneic hematopoietic stem cell transplantation (allo-HCT) is the most established cellular ...therapy, but chimeric antigen receptor (CAR) T cell therapies have gained attention in recent years. While in allo-HCT an entirely novel allogeneic immune system facilitates a so-called Graft-versus-tumor, respectively, Graft-versus-leukemia (GvT/GvL) effect against high-risk hematologic malignancies, in CAR T cell therapies genetically modified autologous T cells specifically attack target molecules on malignant cells. These therapies have achieved high success rates, offering potential cures in otherwise detrimental diseases. However, relapse after cellular therapy remains a serious clinical obstacle. Checkpoint Inhibition (CI), which was recently designated as breakthrough in cancer treatment and consequently awarded with the Nobel prize in 2018, is a different way to increase anti-tumor immunity. Here, inhibitory immune checkpoints are blocked on immune cells in order to restore the immunological force against malignant diseases. Disease relapse after CAR T cell therapy or allo-HCT has been linked to up-regulation of immune checkpoints that render cancer cells resistant to the cell-mediated anti-cancer immune effects. Thus, enhancing immune cell function after cellular therapies using CI is an important treatment option that might re-activate the anti-cancer effect upon cell therapy. In this review, we will summarize current data on this topic with the focus on immune checkpoints after cellular therapy for malignant diseases and balance efficacy versus potential side effects.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
ABSTRACT We report the discovery of a new Kepler transiting circumbinary planet (CBP). This latest addition to the still-small family of CBPs defies the current trend of known short-period planets ...orbiting near the stability limit of binary stars. Unlike the previous discoveries, the planet revolving around the eclipsing binary system Kepler-1647 has a very long orbital period (∼1100 days) and was at conjunction only twice during the Kepler mission lifetime. Due to the singular configuration of the system, Kepler-1647b is not only the longest-period transiting CBP at the time of writing, but also one of the longest-period transiting planets. With a radius of 1.06 0.01 RJup, it is also the largest CBP to date. The planet produced three transits in the light curve of Kepler-1647 (one of them during an eclipse, creating a syzygy) and measurably perturbed the times of the stellar eclipses, allowing us to measure its mass, 1.52 0.65 MJup. The planet revolves around an 11-day period eclipsing binary consisting of two solar-mass stars on a slightly inclined, mildly eccentric (ebin = 0.16), spin-synchronized orbit. Despite having an orbital period three times longer than Earth's, Kepler-1647b is in the conservative habitable zone of the binary star throughout its orbit.
Context
. Planet-disk interactions play a crucial role in the understanding of planet formation and disk evolution. There are multiple numerical tools available to simulate these interactions, ...including the commonly used FARGO code and its variants. Many of the codes have been extended over time to include additional physical processes, with a focus on their accurate modeling.
Aims
. We introduce F
ARGO
CPT, an updated version of FARGO that incorporates other previous enhancements to the code, to provide a simulation environment tailored to studies of the interactions between stars, planets, and disks. It is meant to ensure an accurate representation of planet systems, hydrodynamics, and dust dynamics, with a focus on usability.
Methods
. The radiation-hydrodynamics part of F
ARGO
CPT uses a second-order upwind scheme in 2D polar coordinates, supporting multiple equations of state, radiation transport, heating and cooling, and self-gravity. Shocks are considered using artificial viscosity. The integration of the
N
-body system is achieved by leveraging the REBOUND code. The dust module utilizes massless tracer particles, adapted to drag laws for the Stokes and Epstein regimes. Moreover, F
ARGO
CPT provides mechanisms to simulate accretion onto stars and planets.
Results
. The code has been tested in practice in the context of multiple studies. Additionally, it comes with an automated test suite for checking the physics modules. It is available online.
Conclusions
. F
ARGO
CPT offers a unique set of simulation capabilities within the current landscape of publicly available planet-disk interaction simulation tools. Its structured interface and underlying technical updates are intended to assist researchers in ongoing explorations of planet formation.
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We present the discovery of Kepler-453 b, a 6.2 R sub(+ in circle) planet in a low-eccentricity, 240.5 day orbit about an eclipsing binary. The binary itself consists of a 0.94 and 0.195 M sub(middot ...in circle) pair of stars with an orbital period of 27.32 days. The plane of the planet's orbit is rapidly precessing, and its inclination only becomes sufficiently aligned with the primary star in the latter portion of the Kepler data. Thus three transits are present in the second half of the light curve, but none of the three conjunctions that occurred during the first half of the light curve produced observable transits. The precession period is ~103 years, and during that cycle, transits are visible only ~8.9% of the time. This has the important implication that for every system like Kepler-453 that we detect, there are ~11.5 circumbinary systems that exist but are not currently exhibiting transits. The planet's mass is too small to noticeably perturb the binary, and consequently its mass is not measurable with these data; however, our photodynamical model places a 1sigma upper limit of 16 M sub(middot in circle). With a period 8.8 times that of the binary, the planet is well outside the dynamical instability zone. It does, however, lie within the habitable zone of the binary, making it the third of 10 Kepler circumbinary planets to do so.
Post-translational modifications (PTMs) of histones exert fundamental roles in regulating gene expression. During development, groups of PTMs are constrained by unknown mechanisms into combinatorial ...patterns, which facilitate transitions from uncommitted embryonic cells into differentiated somatic cell lineages. Repressive histone modifications such as H3K9me3 or H3K27me3 have been investigated in detail, but the role of H4K20me3 in development is currently unknown. Here we show that Xenopus laevis Suv4-20h1 and h2 histone methyltransferases (HMTases) are essential for induction and differentiation of the neuroectoderm. Morpholino-mediated knockdown of the two HMTases leads to a selective and specific downregulation of genes controlling neural induction, thereby effectively blocking differentiation of the neuroectoderm. Global transcriptome analysis supports the notion that these effects arise from the transcriptional deregulation of specific genes rather than widespread, pleiotropic effects. Interestingly, morphant embryos fail to repress the Oct4-related Xenopus gene Oct-25. We validate Oct-25 as a direct target of xSu4-20h enzyme mediated gene repression, showing by chromatin immunoprecipitaton that it is decorated with the H4K20me3 mark downstream of the promoter in normal, but not in double-morphant, embryos. Since knockdown of Oct-25 protein significantly rescues the neural differentiation defect in xSuv4-20h double-morphant embryos, we conclude that the epistatic relationship between Suv4-20h enzymes and Oct-25 controls the transit from pluripotent to differentiation-competent neural cells. Consistent with these results in Xenopus, murine Suv4-20h1/h2 double-knockout embryonic stem (DKO ES) cells exhibit increased Oct4 protein levels before and during EB formation, and reveal a compromised and biased capacity for in vitro differentiation, when compared to normal ES cells. Together, these results suggest a regulatory mechanism, conserved between amphibians and mammals, in which H4K20me3-dependent restriction of specific POU-V genes directs cell fate decisions, when embryonic cells exit the pluripotent state.
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