Detailed Analysis of the Pulsations During and After Bursts from the Bursting Pulsar (GRO J1744-28)

The hard X-ray bursts observed during both major outbursts of the Bursting Pulsar (GRO J1744-28) show pulsations near the neutron star spin frequency with an enhanced amplitude relative to that of the persistent emission. Consistent with previous work, we find that the pulsations within bursts lag behind their expected arrival times based upon the persistent pulsar ephemeris. For an ensemble of 1293 bursts recorded with the Burst and Transient Source Experiment, the average burst pulse time delay is 61.0 +/- 0.8 ms in the 25 - 50 keV energy range and 72 +/- 5 ms in the 50 - 100 keV band. The residual time delay from 10 to 240 s following the start of the burst is 18.1 +/- 0.7 ms (25 - 50 keV). A significant correlation of the average burst time delay with burst peak flux is found. Our results are consistent with the model of the pulse time lags presented by Miller (1996).Comment: 11 pages, accepted for publication in Ap

Discovery of a New Soft Gamma Repeater, SGR 1627-41

We report the discovery of a new soft gamma repeater (SGR), SGR 1627-41, and present BATSE observations of the burst emission and BeppoSAX NFI observations of the probable persistent X-ray counterpart to this SGR. All but one burst spectrum are well fit by an optically thin thermal bremsstrahlung (OTTB) model with kT values between 25 and 35 keV. The spectrum of the X-ray counterpart, SAX J1635.8-4736, is similar to that of other persistent SGR X-ray counterparts. We find weak evidence for a periodic signal at 6.41 s in the light curve for this source. Like other SGRs, this source appears to be associated with a young supernova remnant G337.0-0.1. Based upon the peak luminosities of bursts observed from this SGR, we find a lower limit on the dipole magnetic field of the neutron star B_dipole > 5 * 10^14 Gauss.Comment: 5 pages, 4 figures, submitted to ApJ Letter

Ischemia considerations for the development of an organ and tissue donor derived bone marrow bank

Background Deceased organ donors represent an untapped source of therapeutic bone marrow (BM) that can be recovered in 3–5 times the volume of that obtained from living donors, tested for quality, cryopreserved, and banked indefinitely for future on-demand use. A challenge for a future BM banking system will be to manage the prolonged ischemia times that are inevitable when bones procured at geographically-dispersed locations are shipped to distant facilities for processing. Our objectives were to: (a) quantify, under realistic field conditions, the relationship between ischemia time and the quality of hematopoietic stem and progenitor cells (HSPCs) derived from deceased-donor BM; (b) identify ischemia-time boundaries beyond which HSPC quality is adversely affected; (c) investigate whole-body cooling as a strategy for preserving cell quality; and (d) investigate processing experience as a variable affecting quality. Methods Seventy-five bones from 62 donors were analyzed for CD34+ viability following their exposure to various periods of warm-ischemia time (WIT), cold-ischemia time (CIT), and body-cooling time (BCT). Regression models were developed to quantify the independent associations of WIT, CIT, and BCT, with the viability and function of recovered HSPCs. Results Results demonstrate that under “real-world” scenarios: (a) combinations of warm- and cold-ischemia times favorable to the recovery of high-quality HSPCs are achievable (e.g., CD34+ cell viabilities in the range of 80–90% were commonly observed); (b) body cooling prior to bone recovery is detrimental to cell viability (e.g., CD34+ viability  89% without body cooling); (c) vertebral bodies (VBs) are a superior source of HSPCs compared to ilia (IL) (e.g., %CD34+ viability > 80% when VBs were the source, vs. < 74% when IL were the source); and (d) processing experience is a critical variable affecting quality. Conclusions Our models can be used by an emerging BM banking system to formulate ischemia-time tolerance limits and data-driven HSPC quality-acceptance standards. Keywords: Deceased-donor bone marrow, Bone marrow banking, Bone marrow ischemia time, Hematopoietic stem cell transplan

Magnetic and Electronic Properties of Eu₄Sr₄Ga₁₆Ge₃₀

Magnetization, static and ac magnetic susceptibility, nuclear forward scattering, and electrical resistivity measurements have been performed on polycrystalline Eu4Sr4Ga16Ge30, a type I clathrate that has divalent strontium and europium ions encapsulated within a Ga-Ge framework. These data are compared with those of type I clathrates Eu8Ga16Ge30 and Eu6Sr2Ga16Ge30. The ferromagnetic ordering of these Eu-containing clathrates is substantially altered by the incorporation of strontium, as compared to Eu8Ga16Ge30. Ferromagnetism, accompanied by a relatively large negative magnetoresistance, is observed below 15 and 20 K in Eu4Sr4Ga16Ge30 and Eu6Sr2Ga16Ge30, respectively. An effective magnetic moment of 7.83 µB per Eu ion is observed above 30 K for Eu4Sr4Ga16Ge30, a moment which is close to the free-ion moment of 7.94 µB per europium(II) ion

Identification and characterization of a large source of primary mesenchymal stem cells tightly adhered to bone surfaces of human vertebral body marrow cavities

Background: Therapeutic allogeneic mesenchymal stromal cells (MSCs) are currently in clinical trials to evaluate their effectiveness in treating many different disease indications. Eventual commercialization for broad distribution will require further improvements in manufacturing processes to economically manufacture MSCs at scales sufficient to satisfy projected demands. A key contributor to the present high cost of goods sold for MSC manufacturing is the need to create master cell banks from multiple donors, which leads to variability in large-scale manufacturing runs. Therefore, the availability of large single donor depots of primary MSCs would greatly benefit the cell therapy market by reducing costs associated with manufacturing. Methods: We have discovered that an abundant population of cells possessing all the hallmarks of MSCs is tightly associated with the vertebral body (VB) bone matrix and only liberated by proteolytic digestion. Here we demonstrate that these vertebral bone-adherent (vBA) MSCs possess all the International Society of Cell and Gene Therapy-defined characteristics (e.g., plastic adherence, surface marker expression and trilineage differentiation) of MSCs, and we have therefore termed them vBA-MSCs to distinguish this population from loosely associated MSCs recovered through aspiration or rinsing of the bone marrow compartment. Results: Pilot banking and expansion were performed with vBA-MSCs obtained from 3 deceased donors, and it was demonstrated that bank sizes averaging 2.9 × 108 ± 1.35 × 108 vBA-MSCs at passage 1 were obtainable from only 5 g of digested VB bone fragments. Each bank of cells demonstrated robust proliferation through a total of 9 passages, without significant reduction in population doubling times. The theoretical total cell yield from the entire amount of bone fragments (approximately 300 g) from each donor with limited expansion through 4 passages is 100 trillion (1 × 1014) vBA-MSCs, equating to over 105 doses at 10 × 106 cells/kg for an average 70-kg recipient. Discussion: Thus, we have established a novel and plentiful source of MSCs that will benefit the cell therapy market by overcoming manufacturing and regulatory inefficiencies due to donor-to-donor variability

Mutation in erythroid specific transcription factor KLF1 causes Hereditary Spherocytosis in the Nan hemolytic anemia mouse model

KLF1 regulates definitive erythropoiesis of red blood cells by facilitating transcription through high affinity binding to CACCC elements within its erythroid specific target genes including those encoding erythrocyte membrane skeleton (EMS) proteins. Deficiencies of EMS proteins in humans lead to the hemolytic anemia Hereditary Spherocytosis (HS) which includes a subpopulation with no known genetic defect. Here we report that a mutation, E339D, in the second zinc finger domain of KLF1 is responsible for HS in the mouse model Nan. The causative nature of this mutation was verified with an allelic test cross between Nan/+ and heterozygous Klf1(+/-) knockout mice. Homology modeling predicted Nan KLF1 binds CACCC elements more tightly, suggesting that Nan KLF1 is a competitive inhibitor of wild-type KLF1. This is the first association of a KLF1 mutation with a disease state in adult mammals and also presents the possibility of being another causative gene for HS in humans

Regulation of cellular proliferation, differentiation and cell death by activated Raf

The protein kinases Raf-1, A-Raf and B-Raf connect receptor stimulation with intracellular signaling pathways and function as a central intermediate in many signaling pathways. Gain-of-function experiments shed light on the pleiotropic biological activities of these enzymes. Expression experiments involving constitutively active Raf revealed the essential functions of Raf in controlling proliferation, differentiation and cell death in a cell-type specific manner

A Unified Approach for Process-Based Hydrologic Modeling: 2. Model Implementation and Case Studies

This work advances a unified approach to process-based hydrologic modeling, which we term the “Structure for Unifying Multiple Modeling Alternatives (SUMMA).” The modeling framework, introduced in the companion paper, uses a general set of conservation equations with flexibility in the choice of process parameterizations (closure relationships) and spatial architecture. This second paper specifies the model equations and their spatial approximations, describes the hydrologic and biophysical process parameterizations currently supported within the framework, and illustrates how the framework can be used in conjunction with multivariate observations to identify model improvements and future research and data needs. The case studies illustrate the use of SUMMA to select among competing modeling approaches based on both observed data and theoretical considerations. Specific examples of preferable modeling approaches include the use of physiological methods to estimate stomatal resistance, careful specification of the shape of the within-canopy and below-canopy wind profile, explicitly accounting for dust concentrations within the snowpack, and explicitly representing distributed lateral flow processes. Results also demonstrate that changes in parameter values can make as much or more difference to the model predictions than changes in the process representation. This emphasizes that improvements in model fidelity require a sagacious choice of both process parameterizations and model parameters. In conclusion, we envisage that SUMMA can facilitate ongoing model development efforts, the diagnosis and correction of model structural errors, and improved characterization of model uncertainty

A unified approach for process-based hydrologic modeling: 2. Model implementation and case studies

This work advances a unified approach to process-based hydrologic modeling, which we term the ‘‘Structure for Unifying Multiple Modeling Alternatives (SUMMA).’’ The modeling framework, introduced in the companion paper, uses a general set of conservation equations with flexibility in the choice of process parameterizations (closure relationships) and spatial architecture. This second paper specifies the model equations and their spatial approximations, describes the hydrologic and biophysical process parameterizations currently supported within the framework, and illustrates how the framework can be used in conjunction with multivariate observations to identify model improvements and future research and data needs. The case studies illustrate the use of SUMMA to select among competing modeling approaches based on both observed data and theoretical considerations. Specific examples of preferable modeling approaches include the use of physiological methods to estimate stomatal resistance, careful specification of the shape of the within-canopy and below-canopy wind profile, explicitly accounting for dust concentrations within the snowpack, and explicitly representing distributed lateral flow processes. Results also demonstrate that changes in parameter values can make as much or more difference to the model predictions than changes in the process representation. This emphasizes that improvements in model fidelity require a sagacious choice of both process parameterizations and model parameters. In conclusion, we envisage that SUMMA can facilitate ongoing model development efforts, the diagnosis and correction of model structural errors, and improved characterization of model uncertainty.Keywords: unified model, scaling behavior, hydrometeorologyKeywords: unified model, scaling behavior, hydrometeorolog

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe