Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplantation for Patients with Hemoglobinopathies Using a Reduced-Intensity Conditioning Regimen and Third-Party Mesenchymal Stromal Cells

AbstractAllogeneic hematopoietic stem cell transplantation for patients with a hemoglobinopathy can be curative but is limited by donor availability. Although positive results are frequently observed in those with an HLA-matched sibling donor, use of unrelated donors has been complicated by poor engraftment, excessive regimen-related toxicity, and graft-versus-host disease (GVHD). As a potential strategy to address these obstacles, a pilot study was designed that incorporated both a reduced-intensity conditioning and mesenchymal stromal cells (MSCs). Six patients were enrolled, including 4 with high-risk sickle cell disease (SCD) and 2 with transfusion-dependent thalassemia major. Conditioning consisted of fludarabine (150 mg/m2), melphalan (140 mg/m2), and alemtuzumab (60 mg for patients weighing > 30 kg and .9 mg/kg for patients weighing <30 kg). Two patients received HLA 7/8 allele matched bone marrow and 4 received 4-5/6 HLA matched umbilical cord blood as the source of HSCs. MSCs were of bone marrow origin and derived from a parent in 1 patient and from an unrelated third-party donor in the remaining 5 patients. GVHD prophylaxis consisted of cyclosporine A and mycophenolate mofetil. One patient had neutropenic graft failure, 2 had autologous hematopoietic recovery, and 3 had hematopoietic recovery with complete chimerism. The 2 SCD patients with autologous hematopoietic recovery are alive. The remaining 4 died either from opportunistic infection, GVHD, or intracranial hemorrhage. Although no infusion-related toxicity was seen, the cotransplantation of MSCs was not sufficient for reliable engraftment in patients with advanced hemoglobinopathy. Although poor engraftment has been observed in nearly all such trials to date in this patient population, there was no evidence to suggest that MSCs had any positive impact on engraftment. Because of the lack of improved engraftment and unacceptably high transplant-related mortality, the study was prematurely terminated. Further investigations into understanding the mechanisms of graft resistance and development of strategies to overcome this barrier are needed to move this field forward

Granite–a new telescope for TeV gamma ray astronomy

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/87435/2/253_1.pd

Optogenetic Apoptosis: Light-Triggered Cell Death

An optogenetic Bax has been designed that facilitates light-induced apoptosis. We demonstrate that mitochondrial recruitment of a genetically encoded light-responsive Bax results in the release of mitochondrial proteins, downstream caspase 3 cleavage, changes in cellular morphology, and ultimately cell death. Mutagenesis of a key phosphorylatable residue or modification of the C-terminus mitigates background levels (dark) of apoptosis due to Bax overexpression. The mechanism of optogenetic Bax-mediated apoptosis was explored using a series of small molecules known to interfere with various steps in programmed cell death. Optogenetic Bax appears to form a mitochondrial apoptosis-induced channel analogous to that of endogenous Bax

Parameters of the Magnetic Flux inside Coronal Holes

Parameters of magnetic flux distribution inside low-latitude coronal holes (CHs) were analyzed. A statistical study of 44 CHs based on Solar and Heliospheric Observatory (SOHO)/MDI full disk magnetograms and SOHO/EIT 284\AA images showed that the density of the net magnetic flux, $B_{{\rm net}}$, does not correlate with the associated solar wind speeds, $V_x$. Both the area and net flux of CHs correlate with the solar wind speed and the corresponding spatial Pearson correlation coefficients are 0.75 and 0.71, respectively. A possible explanation for the low correlation between $B_{{\rm net}}$ and $V_x$ is proposed. The observed non-correlation might be rooted in the structural complexity of the magnetic field. As a measure of complexity of the magnetic field, the filling factor, $f(r)$, was calculated as a function of spatial scales. In CHs, $f(r)$ was found to be nearly constant at scales above 2 Mm, which indicates a monofractal structural organization and smooth temporal evolution. The magnitude of the filling factor is 0.04 from the Hinode SOT/SP data and 0.07 from the MDI/HR data. The Hinode data show that at scales smaller than 2 Mm, the filling factor decreases rapidly, which means a mutlifractal structure and highly intermittent, burst-like energy release regime. The absence of necessary complexity in CH magnetic fields at scales above 2 Mm seems to be the most plausible reason why the net magnetic flux density does not seem to be related to the solar wind speed: the energy release dynamics, needed for solar wind acceleration, appears to occur at small scales below 1 Mm.Comment: 6 figures, approximately 23 pages. Accepted in Solar Physic

The QUIET Instrument

The Q/U Imaging ExperimenT (QUIET) is designed to measure polarization in the Cosmic Microwave Background, targeting the imprint of inflationary gravitational waves at large angular scales (~ 1 degree). Between 2008 October and 2010 December, two independent receiver arrays were deployed sequentially on a 1.4 m side-fed Dragonian telescope. The polarimeters which form the focal planes use a highly compact design based on High Electron Mobility Transistors (HEMTs) that provides simultaneous measurements of the Stokes parameters Q, U, and I in a single module. The 17-element Q-band polarimeter array, with a central frequency of 43.1 GHz, has the best sensitivity (69 uK sqrt(s)) and the lowest instrumental systematic errors ever achieved in this band, contributing to the tensor-to-scalar ratio at r < 0.1. The 84-element W-band polarimeter array has a sensitivity of 87 uK sqrt(s) at a central frequency of 94.5 GHz. It has the lowest systematic errors to date, contributing at r < 0.01. The two arrays together cover multipoles in the range l= 25-975. These are the largest HEMT-based arrays deployed to date. This article describes the design, calibration, performance of, and sources of systematic error for the instrument

A High Statistics Search for Ultra-High Energy Gamma-Ray Emission from Cygnus X-3 and Hercules X-1

We have carried out a high statistics (2 Billion events) search for ultra-high energy gamma-ray emission from the X-ray binary sources Cygnus X-3 and Hercules X-1. Using data taken with the CASA-MIA detector over a five year period (1990-1995), we find no evidence for steady emission from either source at energies above 115 TeV. The derived upper limits on such emission are more than two orders of magnitude lower than earlier claimed detections. We also find no evidence for neutral particle or gamma-ray emission from either source on time scales of one day and 0.5 hr. For Cygnus X-3, there is no evidence for emission correlated with the 4.8 hr X-ray periodicity or with the occurrence of large radio flares. Unless one postulates that these sources were very active earlier and are now dormant, the limits presented here put into question the earlier results, and highlight the difficulties that possible future experiments will have in detecting gamma-ray signals at ultra-high energies.Comment: 26 LaTeX pages, 16 PostScript figures, uses psfig.sty to be published in Physical Review

Detection of TeV gamma rays from the AGN Markarian 421

We present here the detection of TeV gamma rays from the extragalactic source Markarian 421. Observations obtained with the Whipple 10 m imaging Cherenkov telescope in March–June 1992 give a gamma ray signal with statistical significance of 6.3σ above background. The excess corresponds to an average flux of 1.5×10−11 cm−2 s−1 above 0.5 TeV, equivalent to 0.3 of that from the Crab Nebula. The estimated location of the source agrees with the position of Mrk 421 to the angular uncertainty of the Whipple instrument (6 arc minutes).Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/87671/2/185_1.pd

GEMINI 3D spectroscopy of BAL+IR+Fe II QSOs: II. IRAS 04505-2958 an explosive QSO with hypershell and a new scenario for galaxy formation and galaxy end

From a study of BAL + IR + Fe II QSOs (using deep Gemini GMOS-IFU spectroscopy) new results are presented: for IRAS 04505-2958. Specifically, we have studied in detail the out flow (OF) process and their associated structures, mainly at two large galactic scales: (i) two blobs/shells (S1, S2) at radius r = 1.1 and 2.2 kpc; and (ii) an external hypergiant shell (S3) at r = 11 kpc. In addition, the presence of two very extended hypergiant shells (S4, S5) at r = 80 kpc is discussed. From this GMOS study the following main results were obtained: (i) For the external hypergiant shell S3 the kinematics GMOS maps of the ionized gas show very similar features to those observed for the prototype of exploding external supergiant shell: in NGC 5514. (ii) The main knots K1, K2 and K3 -of this hypergiant shell S3- show a stellar population and emission line ratios associated with the presence of a starburst + OF/shocks. (iii) The internal shells S1 and S2 show structures, OF components and properties very similar to those detected in the nuclear shells of Mrk 231. (iv) The shells S1+S2 and S3 are aligned at PA = 131: i.e. suggesting that the OF process is in the blow-out phase with bipolar structure. In addition, the shells S4 and S5 (at 80-100 kpc scale) are aligned at PA = 40, i.e.: a bipolar OF perpendicular to the internal OF. Finally, the generation of UHE cosmic rays and neutrino/ dark-matter -associated with HyNe in BAL + IR + Fe II QSOs- is discussed.Comment: Submitted MNRAS, 81 pages, 25 Figure

COMAP Early Science: VIII. A Joint Stacking Analysis with eBOSS Quasars

We present a new upper limit on the cosmic molecular gas density at z = 2.4 − 3.4 obtained using the first year of observations from the CO Mapping Array Project (COMAP). COMAP data cubes are stacked on the 3D positions of 243 quasars selected from the Extended Baryon Oscillation SpectroscopicSurvey (eBOSS) catalog, yielding a 95% upper limit for flux from CO(1-0) line emission of 0.129 Jykm/s. Depending on the balance of the emission between the quasar host and its environment, this value can be interpreted as an average CO line luminosity L′CO of eBOSS quasars of ≤ 1.26 × 1011 K km pc2s−1, or an average molecular gas density ρH2 in regions of the universe containing a quasar of ≤ 1.52 × 108 M⊙ cMpc−3. The L′ CO upper limit falls among CO line luminosities obtained fromindividually-targeted quasars in the COMAP redshift range, and the ρH2 value is comparable to upper limits obtained from other Line Intensity Mapping (LIM) surveys and their joint analyses. Further, we forecast the values obtainable with the COMAP/eBOSS stack after the full 5-year COMAP Pathfinder survey. We predict that a detection is probable with this method, depending on the CO properties of the quasar sample. Based on the achieved sensitivity, we believe that this technique of stacking LIM data on the positions of traditional galaxy or quasar catalogs is extremely promising, both asa technique for investigating large galaxy catalogs efficiently at high redshift and as a technique for bolstering the sensitivity of LIM experiments, even with a fraction of their total expected survey data