Human thymoma-associated mutation of the GTF2I transcription factor impairs thymic epithelial progenitor differentiation in mice

Few human tumours present with a recurrent pathognomonic mutation in a transcription factor. Thymomas are an exception, with the majority of some subtypes exhibiting a distinct somatically acquired missense mutation in the general transcription factor GTF2I. Co-dominant expression of wild-type and mutated forms of Gtf2i in the mouse thymic epithelium is associated with aberrant thymic architecture and reduced thymopoietic activity. Phenotypic and molecular characterization of the mutant epithelium indicates that medullary differentiation is particularly affected as a result of impaired differentiation of bi-potent epithelial progenitors. The resulting gene expression signature is dominated by that of immature cortex-like thymic epithelial cells. TCR repertoire analysis of the cytopenic T cell compartment indicates efficient intrathymic selection; hence, despite marked homeostatic proliferation of T cell clones, autoimmunity is not observed. Thus, our transgenic mouse model recapitulates some aspects of the pathophysiology of a genetically defined type of human thymoma

POTENT Reconstruction from Mark III Velocities

We present an improved POTENT method for reconstructing the velocity and mass density fields from radial peculiar velocities, test it with mock catalogs, and apply it to the Mark III Catalog. Method improvments: (a) inhomogeneous Malmquist bias is reduced by grouping and corrected in forward or inverse analyses of inferred distances, (b) the smoothing into a radial velocity field is optimized to reduce window and sampling biases, (c) the density is derived from the velocity using an improved nonlinear approximation, and (d) the computational errors are made negligible. The method is tested and optimized using mock catalogs based on an N-body simulation that mimics our cosmological neighborhood, and the remaining errors are evaluated quantitatively. The Mark III catalog, with ~3300 grouped galaxies, allows a reliable reconstruction with fixed Gaussian smoothing of 10-12 Mpc/h out to ~60 Mpc/h. We present maps of the 3D velocity and mass-density fields and the corresponding errors. The typical systematic and random errors in the density fluctuations inside 40 Mpc/h are \pm 0.13 and \pm 0.18. The recovered mass distribution resembles in its gross features the galaxy distribution in redshift surveys and the mass distribution in a similar POTENT analysis of a complementary velocity catalog (SFI), including the Great Attractor, Perseus-Pisces, and the void in between. The reconstruction inside ~40 Mpc/h is not affected much by a revised calibration of the distance indicators (VM2, tailored to match the velocities from the IRAS 1.2Jy redshift survey). The bulk velocity within the sphere of radius 50 Mpc/h about the Local Group is V_50=370 \pm 110 km/s (including systematic errors), and is shown to be mostly generated by external mass fluctuations. With the VM2 calibration, V_50 is reduced to 305 \pm 110 km/s.Comment: 60 pages, LaTeX, 3 tables and 27 figures incorporated (may print the most crucial figures only, by commenting out one line in the LaTex source

Evolution of thymopoietic microenvironments

In vertebrates, the development of lymphocytes from undifferentiated haematopoietic precursors takes place in so-called primary lymphoid organs, such as the thymus. Therein, lymphocytes undergo a complex differentiation and selection process that culminates in the generation of a pool of mature T cells that collectively express a self-tolerant repertoire of somatically diversified antigen receptors. Throughout this entire process, the microenvironment of the thymus in large parts dictates the sequence and outcome of the lymphopoietic activity. In vertebrates, direct genetic evidence in some species and circumstantial evidence in others suggest that the formation of a functional thymic microenvironment is controlled by members of the Foxn1/4 family of transcription factors. In teleost fishes, both Foxn1 and Foxn4 contribute to thymopoietic activity, whereas Foxn1 is both necessary and sufficient in the mammalian thymus. The evolutionary history of Foxn1/4 genes suggests that an ancient Foxn4 gene lineage gave rise to the Foxn1 genes in early vertebrates, raising the question of the thymopoietic capacity of the ancestor common to all vertebrates. Recent attempts to reconstruct the early events in the evolution of thymopoietic tissues by replacement of the mouse Foxn1 gene by Foxn1-like genes isolated from various chordate species suggest a plausible scenario. It appears that the primordial thymus was a bi-potent lymphoid organ, supporting both B cell and T cell development; however, during the course of vertebrate, evolution B cell development was gradually diminished converting the thymus into a site specialized in T cell development

Dark matter clustering: a simple renormalization group approach

I compute a renormalization group (RG) improvement to the standard beyond-linear-order Eulerian perturbation theory (PT) calculation of the power spectrum of large-scale density fluctuations in the Universe. At z=0, for a power spectrum matching current observations, lowest order RGPT appears to be as accurate as one can test using existing numerical simulation-calibrated fitting formulas out to at least k~=0.3 h/Mpc; although inaccuracy is guaranteed at some level by approximations in the calculation (which can be improved in the future). In contrast, standard PT breaks down virtually as soon as beyond-linear corrections become non-negligible, on scales even larger than k=0.1 h/Mpc. This extension in range of validity could substantially enhance the usefulness of PT for interpreting baryonic acoustic oscillation surveys aimed at probing dark energy, for example. I show that the predicted power spectrum converges at high k to a power law with index given by the fixed-point solution of the RG equation. I discuss many possible future directions for this line of work. The basic calculation of this paper should be easily understandable without any prior knowledge of RG methods, while a rich background of mathematical physics literature exists for the interested reader.Comment: much expanded explanation of basic calculatio

Effect of pancreatic and/or renal transplantation on diabetic autonomic neuropathy

Thirty-nine Type 1 (insulin-dependent) diabetic patients were studied prospectively after simultaneous pancreas and kidney (n=26) and kidney grafting alone (n=13) by measuring heart rate variation during various manoeuvers and answering a standardized questionnaire every 6 to 12 months post-transplant. While age, duration of diabetes, and serum creatinine (168.1±35.4 vs 132.7±17.7 mgrmol/l) were comparable, haemoglobin A1 levels were significantly lower (6.6±0.2 vs 8.5±0.3%; p<0.01) and the mean observation time longer (35±2 vs 25±3 months; p<0.05) in the pancreas recipients when compared with kidney transplanted patients. Heart rate variation during deep breathing, lying/standing and Valsalva manoeuver were very similar in both groups initially and did not improve during follow-up. However, there was a significant reduction in heart rate in the pancreas recipient group. Autonomic symptoms of the gastrointestinal and thermoregulatory system improved more in the pancreas grafted subjects, while hypoglycaemia unawareness deteriorated in the kidney recipients. This study suggests that long-term normoglycaemia by successful pancreatic grafting is able to halt the progression of autonomic dysfunction

Developmental dynamics of two bipotent thymic epithelial progenitor types

T cell development in the thymus is essential for cellular immunity and depends on the organotypic thymic epithelial microenvironment. In comparison with other organs, the size and cellular composition of the thymus are unusually dynamic, as exemplified by rapid growth and high T cell output during early stages of development, followed by a gradual loss of functional thymic epithelial cells and diminished naive T cell production with age. Single-cell RNA sequencing (scRNA-seq) has uncovered an unexpected heterogeneity of cell types in the thymic epithelium of young and aged adult mice; however, the identities and developmental dynamics of putative pre- and postnatal epithelial progenitors have remained unresolved. Here we combine scRNA-seq and a new CRISPR–Cas9-based cellular barcoding system in mice to determine qualitative and quantitative changes in the thymic epithelium over time. This dual approach enabled us to identify two principal progenitor populations: an early bipotent progenitor type biased towards cortical epithelium and a postnatal bipotent progenitor population biased towards medullary epithelium. We further demonstrate that continuous autocrine provision of Fgf7 leads to sustained expansion of thymic microenvironments without exhausting the epithelial progenitor pools, suggesting a strategy to modulate the extent of thymopoietic activity

Suzaku broad-band spectroscopy of RX J1347.5-1145: constraints on the extremely hot gas and non-thermal emission

We present the results from the analysis of long Suzaku observations of the most X-ray luminous galaxy cluster RX J1347.5-1145 at z=0.451. Aims: We study physical properties of the hot (~20 keV) gas clump in the south-east (SE) region discovered by the Sunyaev-Zel'dovich (SZ) effect observations, to understand the gas physics of a violent cluster merger. We also explore a signature of non-thermal emission using the hard X-ray data. Results: We find that the single-temperature model fails to reproduce the continuum emission and Fe-K lines measured by XIS simultaneously. The two-temperature model with a very hot component improves the fit, although the XIS data can only give a lower bound on its temperature. We detect the hard X-ray emission in the 12-40 keV band at the 7 sigma level; however, the significance becomes marginal when the systematic error in the background estimation is included. With the Suzaku + Chandra joint analysis, we determine the temperature of the SE excess component to be 25.3^{+6.1}_{-4.5} ^{+6.9}_{-9.5} keV (90% statistical and systematic errors), which is in an excellent agreement with the previous SZ + X-ray analysis. This is the first time that the X-ray spectroscopy alone gives a good measurement of the temperature of the hot component in the SE region, which is made possible by Suzaku's unprecedented sensitivity to the wide X-ray band. These results strongly indicate that the cluster has undergone a recent, violent merger. The spectral analysis shows that the SE component is consistent with being thermal. We find the 3 sigma upper limit on the non-thermal flux, F < 8e-12 erg s^{-1} cm^{-2} in the 12-60 keV band. Combining this limit with a recent discovery of the radio mini halo at 1.4 GHz, we find a lower limit on the strength of the intracluster magnetic field, B > 0.007 micro G.Comment: 15 pages, 13 figures. Accepted for publication in A&

Measuring the cosmological bulk flow using the peculiar velocities of supernovae

We study large-scale coherent motion in our universe using the existing Type IA supernovae data. If the recently observed bulk flow is real, then some imprint must be left on supernovae motion. We run a series of Monte Carlo Markov Chain runs in various redshift bins and find a sharp contrast between the z 0.05 data. The$z < 0.05 data are consistent with the bulk flow in the direction (l,b)=({290^{+39}_{-31}}^{\circ}, {20^{+32}_{-32}}^{\circ}) with a magnitude of v_bulk = 188^{+119}_{-103} km/s at 68% confidence. The significance of detection (compared to the null hypothesis) is 95%. In contrast, z > 0.05 data (which contains 425 of the 557 supernovae in the Union2 data set) show no evidence for bulk flow. While the direction of the bulk flow agrees very well with previous studies, the magnitude is significantly smaller. For example, the Kashlinsky, et al.'s original bulk flow result of v_bulk > 600 km/s is inconsistent with our analysis at greater than 99.7% confidence level. Furthermore, our best-fit bulk flow velocity is consistent with the expectation for the \Lambda CDM model, which lies inside the 68% confidence limit.Comment: Version published in JCA

What is limiting near-infrared astrometry in the Galactic Center?

We systematically investigate the error sources for high-precision astrometry from adaptive optics based near-infrared imaging data. We focus on the application in the crowded stellar field in the Galactic Center. We show that at the level of <=100 micro-arcseconds a number of effects are limiting the accuracy. Most important are the imperfectly subtracted seeing halos of neighboring stars, residual image distortions and unrecognized confusion of the target source with fainter sources in the background. Further contributors to the error budget are the uncertainty in estimating the point spread function, the signal-to-noise ratio induced statistical uncertainty, coordinate transformation errors, the chromaticity of refraction in Earth's atmosphere, the post adaptive optics differential tilt jitter and anisoplanatism. For stars as bright as mK=14, residual image distortions limit the astrometry, for fainter stars the limitation is set by the seeing halos of the surrounding stars. In order to improve the astrometry substantially at the current generation of telescopes, an adaptive optics system with high performance and weak seeing halos over a relatively small field (r<=3") is suited best. Furthermore, techniques to estimate or reconstruct the seeing halo could be promising.Comment: accepted by MNRAS, 13 pages, 14 figure