Forming Realistic Late-Type Spirals in a LCDM Universe: The Eris Simulation

Simulations of the formation of late-type spiral galaxies in a cold dark matter LCDM universe have traditionally failed to yield realistic candidates. Here we report a new cosmological N-body/SPH simulation of extreme dynamic range in which a close analog of a Milky Way disk galaxy arises naturally. Termed Eris, the simulation follows the assembly of a galaxy halo of mass Mvir=7.9x10^11 Msun with a total of N=18.6 million particles (gas + dark matter + stars) within the final virial radius, and a force resolution of 120 pc. It includes radiative cooling, heating from a cosmic UV field and supernova explosions, a star formation recipe based on a high gas density threshold (nSF=5 atoms cm^-3 rather than the canonical nSF=0.1 atoms cm^-3), and neglects AGN feedback. At the present epoch, the simulated galaxy has an extended rotationally-supported disk with a radial scale length Rd=2.5 kpc, a gently falling rotation curve with circular velocity at 2.2 disk scale lenghts of V2.2=214 km/s, a bulge-to-disk ratio B/D=0.35, and a baryonic mass fraction that is 30% below the cosmic value. The disk is thin, is forming stars in the region of the Sigma_SFR - Sigma_HI plane occupied by spiral galaxies, and falls on the photometric Tully-Fisher and the stellar mass-halo virial mass relations. Hot (T>3x10^5 K), X-ray luminous halo gas makes only 26% of the universal baryon fraction and follows a flattened density profile proportional to r^-1.13 out to r=100 kpc. Eris appears then to be the first cosmological hydrodynamic simulation in which the galaxy structural properties, the mass budget in the various components, and the scaling relations between mass and luminosity are all consistent with a host of observational constraints. (Abridged)Comment: 12 pages, 7 figures, accepted for publication on the Astrophysical Journa

Fluorescence lifetime imaging ophthalmoscopy.

Imaging techniques based on retinal autofluorescence have found broad applications in ophthalmology because they are extremely sensitive and noninvasive. Conventional fundus autofluorescence imaging measures fluorescence intensity of endogenous retinal fluorophores. It mainly derives its signal from lipofuscin at the level of the retinal pigment epithelium. Fundus autofluorescence, however, can not only be characterized by the spatial distribution of the fluorescence intensity or emission spectrum, but also by a characteristic fluorescence lifetime function. The fluorescence lifetime is the average amount of time a fluorophore remains in the excited state following excitation. Fluorescence lifetime imaging ophthalmoscopy (FLIO) is an emerging imaging modality for in vivo measurement of lifetimes of endogenous retinal fluorophores. Recent reports in this field have contributed to our understanding of the pathophysiology of various macular and retinal diseases. Within this review, the basic concept of fluorescence lifetime imaging is provided. It includes technical background information and correlation with in vitro measurements of individual retinal metabolites. In a second part, clinical applications of fluorescence lifetime imaging and fluorescence lifetime features of selected retinal diseases such as Stargardt disease, age-related macular degeneration, choroideremia, central serous chorioretinopathy, macular holes, diabetic retinopathy, and retinal artery occlusion are discussed. Potential areas of use for fluorescence lifetime imaging ophthalmoscopy will be outlined at the end of this review

Scaling relations of metallicity, stellar mass, and star formation rate in metal-poor starbursts: II. Theoretical models

Scaling relations of metallicity (O/H), star formation rate (SFR), and stellar mass give important insight on galaxy evolution. They are obeyed by most galaxies in the Local Universe and also at high redshift. In a companion paper, we compiled a sample of ~1100 galaxies from redshift 0 to ~3, spanning almost two orders of magnitude in metal abundance, a factor of $\sim10^6$ in SFR, and of ~10^5 in stellar mass. We have characterized empirically the star-formation "main sequence" (SFMS) and the mass-metallicity relation (MZR) for this sample, and also identified a class of low-metallicity starbursts, rare locally but more common in the distant universe. These galaxies deviate significantly from the main scaling relations, with high SFR and low metal content for a given M*. In this paper, we model the scaling relations and explain these deviations from them with a set of multi-phase chemical evolution models based on the idea that, independently of redshift, initial physical conditions in a galaxy's evolutionary history can dictate its location in the scaling relations. Our models are able to successfully reproduce the O/H, M*, and SFR scaling relations up to z~3, and also successfully predict the molecular cloud fraction as a function of stellar mass. These results suggest that the scaling relations are defined by different modes of star formation: an "active" starburst mode, more common at high redshift, and a quiescent "passive" mode that is predominant locally and governs the main trends.Comment: 17 pages, 7 figures, accepted for publication by MNRA

A local drug delivery system prolongs graft survival by dampening T cell infiltration and neutrophil extracellular trap formation in vascularized composite allografts.

INTRODUCTION The standard treatment for preventing rejection in vascularized composite allotransplantation (VCA) currently relies on systemic immunosuppression, which exposes the host to well-known side effects. Locally administered immunosuppression strategies have shown promising results to bypass this hurdle. Nevertheless, their progress has been slow, partially attributed to a limited understanding of the essential mechanisms underlying graft rejection. Recent discoveries highlight the crucial involvement of innate immune components, such as neutrophil extracellular traps (NETs), in organ transplantation. Here we aimed to prolong graft survival through a tacrolimus-based drug delivery system and to understand the role of NETs in VCA graft rejection. METHODS To prevent off-target toxicity and promote graft survival, we tested a locally administered tacrolimus-loaded on-demand drug delivery system (TGMS-TAC) in a multiple MHC-mismatched porcine VCA model. Off-target toxicity was assessed in tissue and blood. Graft rejection was evaluated macroscopically while the complement system, T cells, neutrophils and NETs were analyzed in graft tissues by immunofluorescence and/or western blot. Plasmatic levels of inflammatory cytokines were measured using a Luminex magnetic-bead porcine panel, and NETs were measured in plasma and tissue using DNA-MPO ELISA. Lastly, to evaluate the effect of tacrolimus on NET formation, NETs were induced in-vitro in porcine and human peripheral neutrophils following incubation with tacrolimus. RESULTS Repeated intra-graft administrations of TGMS-TAC minimized systemic toxicity and prolonged graft survival. Nevertheless, signs of rejection were observed at endpoint. Systemically, there were no increases in cytokine levels, complement anaphylatoxins, T-cell subpopulations, or neutrophils during rejection. Yet, tissue analysis showed local infiltration of T cells and neutrophils, together with neutrophil extracellular traps (NETs) in rejected grafts. Interestingly, intra-graft administration of tacrolimus contributed to a reduction in both T-cellular infiltration and NETs. In fact, in-vitro NETosis assessment showed a 62-84% reduction in NETs after stimulated neutrophils were treated with tacrolimus. CONCLUSION Our data indicate that the proposed local delivery of immunosuppression avoids off-target toxicity while prolonging graft survival in a multiple MHC-mismatch VCA model. Furthermore, NETs are found to play a role in graft rejection and could therefore be a potential innovative therapeutic target

Time Since Stroke Onset, Quantitative Collateral Score, and Functional Outcome After Endovascular Treatment for Acute Ischemic Stroke

BACKGROUND AND OBJECTIVES: In patients with ischemic stroke undergoing endovascular treatment (EVT), time to treatment and collateral status are important prognostic factors and may be correlated. We aimed to assess the relation between time to CT angiography (CTA) and a quantitatively determined collateral score and to assess whether the collateral score modified the relation between time to recanalization and functional outcome. METHODS: We analyzed data from patients with acute ischemic stroke included in the Multicenter Randomized Controlled Trial of Endovascular Treatment for Acute Ischemic Stroke Registry between 2014 and 2017, who had a carotid terminus or M1 occlusion and were treated with EVT within 6.5 hours of symptom onset. A quantitative collateral score (qCS) was determined from baseline CTA using a validated automated image analysis algorithm. We also determined a 4-point visual collateral score (vCS). Multivariable regression models were used to assess the relations between time to imaging and the qCS and between the time to recanalization and functional outcome (90-day modified Rankin Scale score). An interaction term (time to recanalization × qCS) was entered in the latter model to test whether the qCS modifies this relation. Sensitivity analyses were performed using the vCS. RESULTS: We analyzed 1,813 patients. The median time from symptom onset to CTA was 91 minutes (interquartile range [IQR] 65–150 minutes), and the median qCS was 49% (IQR 25%–78%). Longer time to CTA was not associated with the log-transformed qCS (adjusted β per 30 minutes, 0.002, 95% CI −0.006 to 0.011). Both a higher qCS (adjusted common odds ratio [acOR] per 10% increase: 1.06, 95% CI 1.03–1.09) and shorter time to recanalization (acOR per 30 minutes: 1.17, 95% CI 1.13–1.22) were independently associated with a shift toward better functional outcome. The qCS did not modify the relation between time to recanalization and functional outcome (p for interaction: 0.28). Results from sensitivity analyses using the vCS were similar. DISCUSSION: In the first 6.5 hours of ischemic stroke caused by carotid terminus or M1 occlusion, the collateral status is unaffected by time to imaging, and the benefit of a shorter time to recanalization is independent of baseline collateral status

Potential involvement of the bone marrow in experimental Graves’ disease and thyroid eye disease

IntroductionGraves’ disease is an autoimmune disorder caused by auto-antibodies against the thyroid stimulating hormone receptor (TSHR). Overstimulation of the TSHR induces hyperthyroidism and thyroid eye disease (TED) as the most common extra thyroidal manifestation of Graves’ disease. In TED, the TSHR cross talks with the insulin-like growth factor 1 receptor (IGF-1R) in orbital fibroblasts leading to inflammation, deposition of hyaluronan and adipogenesis. The bone marrow may play an important role in autoimmune diseases, but its role in Graves’ disease and TED is unknown. Here, we investigated whether induction of experimental Graves’ disease and accompanying TED involves bone marrow activation and whether interference with IGF-1R signaling prevents this activation.ResultsImmunization of mice with TSHR resulted in an increase the numbers of CD4-positive T-lymphocytes (p ≤0.0001), which was normalized by linsitinib (p = 0.0029), an increase of CD19-positive B-lymphocytes (p= 0.0018), which was unaffected by linsitinib and a decrease of GR1-positive cells (p= 0.0038), which was prevented by linsitinib (p= 0.0027). In addition, we observed an increase of Sca-1 positive hematopietic stem cells (p= 0.0007) and of stromal cell-derived factor 1 (SDF-1) (p ≤0.0001) after immunization with TSHR which was prevented by linsitinib (Sca-1: p= 0.0008, SDF-1: p ≤0.0001). TSHR-immunization also resulted in upregulation of CCL-5, IL-6 and osteopontin (all p ≤0.0001) and a concomitant decrease of the immune-inhibitory cytokines IL-10 (p= 0.0064) and PGE2 (p ≤0.0001) in the bone marrow (all p≤ 0.0001). Treatment with the IGF-1R antagonist linsitinib blocked these events (all p ≤0.0001). We further demonstrate a down-regulation of arginase-1 expression (p= 0.0005) in the bone marrow in TSHR immunized mice, with a concomitant increase of local arginine (p ≤0.0001). Linsitinib induces an upregulation of arginase-1 resulting in low arginase levels in the bone marrow. Reconstitution of arginine in bone marrow cells in vitro prevented immune-inhibition by linsitinib.ConclusionCollectively, these data indicate that the bone marrow is activated in experimental Graves’ disease and TED, which is prevented by linsitinib. Linsitinib-mediated immune-inhibition is mediated, at least in part, by arginase-1 up-regulation, consumption of arginine and thereby immune inhibition

An extremely primitive halo star

The early Universe had a chemical composition consisting of hydrogen, helium and traces of lithium1, almost all other elements were created in stars and supernovae. The mass fraction, Z, of elements more massive than helium, is called "metallicity". A number of very metal poor stars have been found some of which, while having a low iron abundance, are rich in carbon, nitrogen and oxygen. For theoretical reasons and because of an observed absence of stars with metallicities lower than Z=1.5E-5, it has been suggested that low mass stars (M<0.8M\odot, the ones that survive to the present day) cannot form until the interstellar medium has been enriched above a critical value, estimated to lie in the range 1.5E-8\leqZ\leq1.5E-6, although competing theories claiming the contrary do exist. Here we report the chemical composition of a star with a very low Z\leq6.9E-7 (4.5E-5 of that of the Sun) and a chemical pattern typical of classical extremely metal poor stars, meaning without the enrichment of carbon, nitrogen and oxygen. This shows that low mass stars can be formed at very low metallicity. Lithium is not detected, suggesting a low metallicity extension of the previously observed trend in lithium depletion. Lithium depletion implies that the stellar material must have experienced temperatures above two million K in its history, which points to rather particular formation condition or internal mixing process, for low Z stars.Comment: Published on Nature, 2011 Volume 477, Issue 7362, pp. 67-6

Linsitinib, an IGF-1R inhibitor, attenuates disease development and progression in a model of thyroid eye disease

IntroductionGraves’ disease (GD) is an autoimmune disorder caused by autoantibodies against the thyroid stimulating hormone receptor (TSHR) leading to overstimulation of the thyroid gland. Thyroid eye disease (TED) is the most common extra thyroidal manifestation of GD. Therapeutic options to treat TED are very limited and novel treatments need to be developed. In the present study we investigated the effect of linsitinib, a dual small-molecule kinase inhibitor of the insulin-like growth factor 1 receptor (IGF-1R) and the Insulin receptor (IR) on the disease outcome of GD and TED.MethodsLinsitinib was administered orally for four weeks with therapy initiating in either the early (“active”) or the late (“chronic”) phases of the disease. In the thyroid and the orbit, autoimmune hyperthyroidism and orbitopathy were analyzed serologically (total anti-TSHR binding antibodies, stimulating anti TSHR antibodies, total T4 levels), immunohistochemically (H&amp;E-, CD3-, TNFa- and Sirius red staining) and with immunofluorescence (F4/80 staining). An MRI was performed to quantify in vivo tissue remodeling inside the orbit.ResultsLinsitinib prevented autoimmune hyperthyroidism in the early state of the disease, by reducing morphological changes indicative for hyperthyroidism and blocking T-cell infiltration, visualized by CD3 staining. In the late state of the disease linsitinib had its main effect in the orbit. Linsitinib reduced immune infiltration of T-cells (CD3 staining) and macrophages (F4/80 and TNFa staining) in the orbita in experimental GD suggesting an additional, direct effect of linsitinib on the autoimmune response. In addition, treatment with linsitinib normalized the amount of brown adipose tissue in both the early and late group. An in vivo MRI of the late group was performed and revealed a marked decrease of inflammation, visualized by 19F MR imaging, significant reduction of existing muscle edema and formation of brown adipose tissue.ConclusionHere, we demonstrate that linsitinib effectively prevents development and progression of thyroid eye disease in an experimental murine model for Graves’ disease. Linsitinib improved the total disease outcome, indicating the clinical significance of the findings and providing a path to therapeutic intervention of Graves’ Disease. Our data support the use of linsitinib as a novel treatment for thyroid eye disease

NEXMIF encephalopathy:an X-linked disorder with male and female phenotypic patterns

Purpose Pathogenic variants in the X-linked gene NEXMIF (previously KIAA2022) are associated with intellectual disability (ID), autism spectrum disorder, and epilepsy. We aimed to delineate the female and male phenotypic spectrum of NEXMIF encephalopathy. Methods Through an international collaboration, we analyzed the phenotypes and genotypes of 87 patients with NEXMIF encephalopathy. Results Sixty-three females and 24 males (46 new patients) with NEXMIF encephalopathy were studied, with 30 novel variants. Phenotypic features included developmental delay/ID in 86/87 (99%), seizures in 71/86 (83%) and multiple comorbidities. Generalized seizures predominated including myoclonic seizures and absence seizures (both 46/70, 66%), absence with eyelid myoclonia (17/70, 24%), and atonic seizures (30/70, 43%). Males had more severe developmental impairment; females had epilepsy more frequently, and varied from unaffected to severely affected. All NEXMIF pathogenic variants led to a premature stop codon or were deleterious structural variants. Most arose de novo, although X-linked segregation occurred for both sexes. Somatic mosaicism occurred in two males and a family with suspected parental mosaicism. Conclusion NEXMIF encephalopathy is an X-linked, generalized developmental and epileptic encephalopathy characterized by myoclonic-atonic epilepsy overlapping with eyelid myoclonia with absence. Some patients have developmental encephalopathy without epilepsy. Males have more severe developmental impairment. NEXMIF encephalopathy arises due to loss-of-function variants