Human Immune System Development and Rejection of Human Islet Allografts in Spontaneously Diabetic NOD-Rag1null IL2rγnull Ins2Akita Mice

OBJECTIVE: To create an immunodeficient mouse model that spontaneously develops hyperglycemia to serve as a diabetic host for human islets and stem cell-derived beta-cells in the absence or presence of a functional human immune system. RESEARCH DESIGN AND METHODS: We backcrossed the Ins2(Akita) mutation onto the NOD-Rag1(null) IL2rgamma(null) strain and determined 1) the spontaneous development of hyperglycemia, 2) the ability of human islets, mouse islets, and dissociated mouse islet cells to restore euglycemia, 3) the generation of a human immune system following engraftment of human hematopoietic stem cells, and 4) the ability of the humanized mice to reject human islet allografts. RESULTS: We confirmed the defects in innate and adaptive immunity and the spontaneous development of hyperglycemia conferred by the IL2rgamma(null), Rag1(null), and Ins2(Akita) genes in NOD-Rag1(null) IL2rgamma(null) Ins2(Akita) (NRG-Akita) mice. Mouse and human islets restored NRG-Akita mice to normoglycemia. Insulin-positive cells in dissociated mouse islets, required to restore euglycemia in chemically diabetic NOD-scid IL2rgamma(null) and spontaneously diabetic NRG-Akita mice, were quantified following transplantation via the intrapancreatic and subrenal routes. Engraftment of human hematopoietic stem cells in newborn NRG-Akita and NRG mice resulted in equivalent human immune system development in a normoglycemic or chronically hyperglycemic environment, with \u3e50% of engrafted NRG-Akita mice capable of rejecting human islet allografts. CONCLUSIONS: NRG-Akita mice provide a model system for validation of the function of human islets and human adult stem cell, embryonic stem cell, or induced pluripotent stem cell-derived beta-cells in the absence or presence of an alloreactive human immune system

A global three-dimensional model of tropospheric sulfate

A three-dimensional model is used to simulate the global tropospheric distributions of dimethylsulfide (DMS), SO2, SO42−, and methanesulfonic acid (MSA). The model uses meteorological input from a general circulation model (GCM) developed at the Goddard Institute of Space Studies (GISS) with 4° × 5° horizontal resolution, nine layers in the vertical, and a time resolution of 4 hours. Model results are compared with observations from surface sites, ships, and aircraft. The model reproduces generally to within 30% the observed SO2 and SO42− concentrations over the United States and Europe; these concentrations are highly sensitive to the supply of H2O2 as an in-cloud SO2 oxidant. Sulfate concentrations and wet deposition fluxes observed at remote marine sites can be accounted for using a global DMS source of 22 Tg S yr−1 in the model. However, this source overestimates DMS air concentrations by a factor of 2 unless we assume the presence of another DMS oxidant besides OH and NO3. Inclusion of another DMS oxidant in our model also improves the simulation of the MSA to SO42− concentration ratio in marine air. Simulated SO42− concentrations in the northern hemispheric free troposphere are much lower than in previous global models and are more consistent with the few observations available. The difference reflects in part our accounting of efficient scavenging of SO2 and SO42− in wet convective updrafts. Global mean tropospheric lifetimes computed in our model are 1.0 days for DMS, 1.2 days for SO2, 3.9 days for SO42−, and 6.2 days for MSA. Fossil fuel combustion and industrial activities represent 68% of global non-sea-salt sulfur emissions. About 50% of SO2 globally is converted to SO42− aerosol (principally by in-cloud oxidation) while the remainder is removed by deposition (30% by dry, 20% by wet). In-cloud oxidation of SO2 represents 85% of the global SO42− source.Engineering and Applied Science

Depinning transition of dislocation assemblies: pileup and low-angle grain boundary

We investigate the depinning transition occurring in dislocation assemblies. In particular, we consider the cases of regularly spaced pileups and low angle grain boundaries interacting with a disordered stress landscape provided by solute atoms, or by other immobile dislocations present in non-active slip systems. Using linear elasticity, we compute the stress originated by small deformations of these assemblies and the corresponding energy cost in two and three dimensions. Contrary to the case of isolated dislocation lines, which are usually approximated as elastic strings with an effective line tension, the deformations of a dislocation assembly cannot be described by local elastic interactions with a constant tension or stiffness. A nonlocal elastic kernel results as a consequence of long range interactions between dislocations. In light of this result, we revise statistical depinning theories and find novel results for Zener pinning in grain growth. Finally, we discuss the scaling properties of the dynamics of dislocation assemblies and compare theoretical results with numerical simulations.Comment: 13 pages, 8 figure

Depinning transition of dislocation assemblies: pileup and low-angle grain boundary

We investigate the depinning transition occurring in dislocation assemblies. In particular, we consider the cases of regularly spaced pileups and low angle grain boundaries interacting with a disordered stress landscape provided by solute atoms, or by other immobile dislocations present in non-active slip systems. Using linear elasticity, we compute the stress originated by small deformations of these assemblies and the corresponding energy cost in two and three dimensions. Contrary to the case of isolated dislocation lines, which are usually approximated as elastic strings with an effective line tension, the deformations of a dislocation assembly cannot be described by local elastic interactions with a constant tension or stiffness. A nonlocal elastic kernel results as a consequence of long range interactions between dislocations. In light of this result, we revise statistical depinning theories and find novel results for Zener pinning in grain growth. Finally, we discuss the scaling properties of the dynamics of dislocation assemblies and compare theoretical results with numerical simulations.Comment: 13 pages, 8 figure

The Milky Way's circular velocity curve between 4 and 14 kpc from APOGEE data

We measure the Milky Way's rotation curve over the Galactocentric range 4 kpc <~ R <~ 14 kpc from the first year of data from the Apache Point Observatory Galactic Evolution Experiment (APOGEE). We model the line-of-sight velocities of 3,365 stars in fourteen fields with b = 0 deg between 30 deg < l < 210 deg out to distances of 10 kpc using an axisymmetric kinematical model that includes a correction for the asymmetric drift of the warm tracer population (\sigma_R ~ 35 km/s). We determine the local value of the circular velocity to be V_c(R_0) = 218 +/- 6 km/s and find that the rotation curve is approximately flat with a local derivative between -3.0 km/s/kpc and 0.4 km/s/kpc. We also measure the Sun's position and velocity in the Galactocentric rest frame, finding the distance to the Galactic center to be 8 kpc < R_0 < 9 kpc, radial velocity V_{R,sun} = -10 +/- 1 km/s, and rotational velocity V_{\phi,sun} = 242^{+10}_{-3} km/s, in good agreement with local measurements of the Sun's radial velocity and with the observed proper motion of Sgr A*. We investigate various systematic uncertainties and find that these are limited to offsets at the percent level, ~2 km/s in V_c. Marginalizing over all the systematics that we consider, we find that V_c(R_0) 99% confidence. We find an offset between the Sun's rotational velocity and the local circular velocity of 26 +/- 3 km/s, which is larger than the locally-measured solar motion of 12 km/s. This larger offset reconciles our value for V_c with recent claims that V_c >~ 240 km/s. Combining our results with other data, we find that the Milky Way's dark-halo mass within the virial radius is ~8x10^{11} M_sun.Comment: submitted to Ap

Highly efficient separation of actinides from lanthanides by a phenanthroline-derived bis-triazine ligand

The synthesis, lanthanide complexation, and solvent ex- traction of actinide(III) and lanthanide(III) radiotracers from nitric acid solutions by a phenanthroline-derived quadridentate bis-triazine ligand are described. The ligand separates Am(III) and Cm(III) from the lanthanides with remarkably high efficiency, high selectivity, and fast extraction kinetics compared to its 2,2'-bipyridine counterpart. Structures of the 1:2 bis-complexes of the ligand with Eu(III) and Yb(III) were elucidated by X-ray crystallography and force field calculations, respec-tively. The Eu(III) bis-complex is the first 1:2 bis-complex of a quadridentate bis-triazine ligand to be characterized by crystallography. The faster rates of extraction were verified by kinetics measurements using the rotating membrane cell technique in several diluents. The improved kinetics of metal ion extraction are related to the higher surface activity of the ligand at the phase interface. The improvement in the ligand's properties on replacing the bipyridine unit with a phenanthroline unit far exceeds what was anticipated based on ligand design alone

Clinical, radiologic, pathologic, and molecular characteristics of long-term survivors of diffuse intrinsic pontine glioma (DIPG): a collaborative report from the International and European Society for Pediatric Oncology DIPG registries

Purpose Diffuse intrinsic pontine glioma (DIPG) is a brainstem malignancy with a median survival of &lt; 1 year. The International and European Society for Pediatric Oncology DIPG Registries collaborated to compare clinical, radiologic, and histomolecular characteristics between short-term survivors (STSs) and long-term survivors (LTSs). Materials and Methods Data abstracted from registry databases included patients from North America, Australia, Germany, Austria, Switzerland, the Netherlands, Italy, France, the United Kingdom, and Croatia. Results Among 1,130 pediatric and young adults with radiographically confirmed DIPG, 122 (11%) were excluded. Of the 1,008 remaining patients, 101 (10%) were LTSs (survival ≥ 2 years). Median survival time was 11 months (interquartile range, 7.5 to 16 months), and 1-, 2-, 3-, 4-, and 5-year survival rates were 42.3% (95% CI, 38.1% to 44.1%), 9.6% (95% CI, 7.8% to 11.3%), 4.3% (95% CI, 3.2% to 5.8%), 3.2% (95% CI, 2.4% to 4.6%), and 2.2% (95% CI, 1.4% to 3.4%), respectively. LTSs, compared with STSs, more commonly presented at age &lt; 3 or &gt; 10 years (11% v 3% and 33% v 23%, respectively; P &lt; .001) and with longer symptom duration ( P &lt; .001). STSs, compared with LTSs, more commonly presented with cranial nerve palsy (83% v 73%, respectively; P = .008), ring enhancement (38% v 23%, respectively; P = .007), necrosis (42% v 26%, respectively; P = .009), and extrapontine extension (92% v 86%, respectively; P = .04). LTSs more commonly received systemic therapy at diagnosis (88% v 75% for STSs; P = .005). Biopsies and autopsies were performed in 299 patients (30%) and 77 patients (10%), respectively; 181 tumors (48%) were molecularly characterized. LTSs were more likely to harbor a HIST1H3B mutation (odds ratio, 1.28; 95% CI, 1.1 to 1.5; P = .002). Conclusion We report clinical, radiologic, and molecular factors that correlate with survival in children and young adults with DIPG, which are important for risk stratification in future clinical trials

Inflation and Dark Energy from spectroscopy at z > 2

The expansion of the Universe is understood to have accelerated during two epochs: in its very first moments during a period of Inflation and much more recently, at z < 1, when Dark Energy is hypothesized to drive cosmic acceleration. The undiscovered mechanisms behind these two epochs represent some of the most important open problems in fundamental physics. The large cosmological volume at 2 < z < 5, together with the ability to efficiently target high-$z$ galaxies with known techniques, enables large gains in the study of Inflation and Dark Energy. A future spectroscopic survey can test the Gaussianity of the initial conditions up to a factor of ~50 better than our current bounds, crossing the crucial theoretical threshold of $\sigma(f_{NL}^{\rm local})$ of order unity that separates single field and multi-field models. Simultaneously, it can measure the fraction of Dark Energy at the percent level up to $z = 5$, thus serving as an unprecedented test of the standard model and opening up a tremendous discovery space