Self-renewal of single mouse hematopoietic stem cells is reduced by JAK2V617F without compromising progenitor cell expansion

Recent descriptions of significant heterogeneity in normal stem cells and cancers have altered our understanding of tumorigenesis, emphasizing the need to understand how single stem cells are subverted to cause tumors. Human myeloproliferative neoplasms (MPNs) are thought to reflect transformation of a hematopoietic stem cell (HSC) and the majority harbor an acquired V617F mutation in the JAK2 tyrosine kinase, making them a paradigm for studying the early stages of tumor establishment and progression. The consequences of activating tyrosine kinase mutations for stem and progenitor cell behavior are unclear. In this article, we identify a distinct cellular mechanism operative in stem cells. By using conditional knock-in mice, we show that the HSC defect resulting from expression of heterozygous human JAK2V617F is both quantitative (reduced HSC numbers) and qualitative (lineage biases and reduced self-renewal per HSC). The defect is intrinsic to individual HSCs and their progeny are skewed toward proliferation and differentiation as evidenced by single cell and transplantation assays. Aged JAK2V617F show a more pronounced defect as assessed by transplantation, but mice that transform reacquire competitive self-renewal ability. Quantitative analysis of HSC-derived clones was used to model the fate choices of normal and JAK2-mutant HSCs and indicates that JAK2V617F reduces self-renewal of individual HSCs but leaves progenitor expansion intact. This conclusion is supported by paired daughter cell analyses, which indicate that JAK2-mutant HSCs more often give rise to two differentiated daughter cells. Together these data suggest that acquisition of JAK2V617F alone is insufficient for clonal expansion and disease progression and causes eventual HSC exhaustion. Moreover, our results show that clonal expansion of progenitor cells provides a window in which collaborating mutations can accumulate to drive disease progression. Characterizing the mechanism(s) of JAK2V617F subclinical clonal expansions and the transition to overt MPNs will illuminate the earliest stages of tumor establishment and subclone competition, fundamentally shifting the way we treat and manage cancers

Cardiac Atrophy and Diastolic Dysfunction During and After Long Duration Spaceflight: Functional Consequences for Orthostatic Intolerance, Exercise Capability and Risk for Cardiac Arrhythmias

Cardiac Atrophy and Diastolic Dysfunction During and After Long Duration Spaceflight: Functional Consequences for Orthostatic Intolerance, Exercise Capability and Risk for Cardiac Arrhythmias (Integrated Cardiovascular) will quantify the extent of long-duration space flightassociated cardiac atrophy (deterioration) on the International Space Station crewmembers

Fast CMB lensing using statistical interpolation on the sphere

We describe a accurate and fast pixel-based statistical method to interpolate fields of arbitrary spin on the sphere. We call this method Fast and Lean Interpolation on the Sphere (FLINTS). The method predicts the optimal interpolated values based on the theory of isotropic Gaussian random fields and provides an accurate error estimate at no additional cost. We use this method to compute lensed Cosmic Microwave Background (CMB) maps precisely and quickly, achieving a relative precision of 0.02% at a HEALPix resolution of Nside=4096, for a bandlimit of l_max=4096 in the same time it takes to simulate the original, unlensed CMB map. The method is suitable for efficient, distributed memory parallelization. The power spectra of our lensed maps are accurate to better than 0.5% at l=3000 for the temperature, the E and B mode of the polarization. As expected theoretically, we demonstrate that, on realistic cases, this method is between two to three orders of magnitude more precise than other known interpolation methods for the same computational cost.Comment: 13 pages, 8 figures, published by ApJ

Fast, exact CMB power spectrum estimation for a certain class of observational strategies

We describe a class of observational strategies for probing the anisotropies in the cosmic microwave background (CMB) where the instrument scans on rings which can be combined into an n-torus, the {\em ring torus}. This class has the remarkable property that it allows exact maximum likelihood power spectrum estimation in of order $N^2$ operations (if the size of the data set is $N$) under circumstances which would previously have made this analysis intractable: correlated receiver noise, arbitrary asymmetric beam shapes and far side lobes, non-uniform distribution of integration time on the sky and partial sky coverage. This ease of computation gives us an important theoretical tool for understanding the impact of instrumental effects on CMB observables and hence for the design and analysis of the CMB observations of the future. There are members of this class which closely approximate the MAP and Planck satellite missions. We present a numerical example where we apply our ring torus methods to a simulated data set from a CMB mission covering a 20 degree patch on the sky to compute the maximum likelihood estimate of the power spectrum $C_\ell$ with unprecedented efficiency.Comment: RevTeX, 14 pages, 5 figures. A full resolution version of Figure 1 and additional materials are at http://feynman.princeton.edu/~bwandelt/RT

Spatial and Temporal Variation of Offshore Wind Power and its Values Along the Central California Coast

The analysis of the spatiotemporal variability of wind power remains limited during the planning stage of an offshore wind farm. This study provides a framework to investigate how offshore wind power varies along the Central California Coast over diurnal and seasonal time scales, which is critical for reliability and functionality of the grid system. We find that offshore wind power in this region peaks during evening hours across all seasons and maximizes in spring and summer. The timing of peak offshore wind power production better aligns with that of peak demand across California than solar and land-based wind power production, highlighting its potential to fill the supply gap when demand is high and power production from other renewable energy sources is low. We further assess the value of offshore wind power using demand-based and wholesale market metrics. Both metrics indicate high potential value of offshore wind power over most areas in this region. Finally, we show that the estimate of power production is significantly biased when using mean wind speeds that do not account for temporal variability, leading to potentially inaccurate predictions about locations that are expected to produce the most power. These results reiterate the importance in considering spatiotemporal variability in wind power for accurately calculating the value of offshore wind development

RORα Coordinates Reciprocal Signaling in Cerebellar Development through Sonic hedgehog and Calcium-Dependent Pathways

AbstractThe cerebellum provides an excellent system for understanding how afferent and target neurons coordinate sequential intercellular signals and cell-autonomous genetic programs in development. Mutations in the orphan nuclear receptor RORα block Purkinje cell differentiation with a secondary loss of afferent granule cells. We show that early transcriptional targets of RORα include both mitogenic signals for afferent progenitors and signal transduction genes required to process their subsequent synaptic input. RORα acts through recruitment of gene-specific sets of transcriptional cofactors, including β-catenin, p300, and Tip60, but appears independent of CBP. One target promoter is Sonic hedgehog, and recombinant Sonic hedgehog restores granule precursor proliferation in RORα-deficient cerebellum. Our results suggest a link between RORα and β-catenin pathways, confirm that a nuclear receptor employs distinct coactivator complexes at different target genes, and provide a logic for early RORα expression in coordinating expression of genes required for reciprocal signals in cerebellar development

Elevated Levels of Trace Elements in Cores of Otoliths and Their Potential for Use as Natural Tags

Variation in the chemical composition of fish otoliths has been used in recent years to address a range of ecological questions, including levels of stock mixing, variation in habitat use, and rates of larval exchange. While some of these questions have been answered with varying success, the degree to which discrete populations are connected via larval exchange remains unknown. To identify larval sources using natural variation in otolith chemistry, we must distinguish and measure the chemical composition of the otolith core, the portion of the otolith formed at the spawning site. Using laser ablation inductively coupled plasma mass spectrometry (LA-ICPMS), we found that the core regions of otoliths from 6 different species of fishes were highly enriched in manganese (Mn), and elevated in magnesium (Mg) and barium (Ba), relative to adjacent regions of the otolith. These patterns were consistent for species drawn from different taxonomic groups, which inhabit temperate and tropical regions, are found in marine and freshwater, and utilize a variety of spawning modes. Variation among species in Mn concentration in the core also corresponds to maternal investment, measured by egg size. These data suggest that core enrichment may be a general characteristic of otoliths, and that the chemical composition of the otolith core is fundamentally different from other regions of the otolith. The localized elemental enrichment of the core underscores the importance of methods that analyze the core region in small, discrete samples if otolith chemistry is used to address questions of larval exchange among populations

Bayesian power-spectrum inference for Large Scale Structure data

We describe an exact, flexible, and computationally efficient algorithm for a joint estimation of the large-scale structure and its power-spectrum, building on a Gibbs sampling framework and present its implementation ARES (Algorithm for REconstruction and Sampling). ARES is designed to reconstruct the 3D power-spectrum together with the underlying dark matter density field in a Bayesian framework, under the reasonable assumption that the long wavelength Fourier components are Gaussian distributed. As a result ARES does not only provide a single estimate but samples from the joint posterior of the power-spectrum and density field conditional on a set of observations. This enables us to calculate any desired statistical summary, in particular we are able to provide joint uncertainty estimates. We apply our method to mock catalogs, with highly structured observational masks and selection functions, in order to demonstrate its ability to reconstruct the power-spectrum from real data sets, while fully accounting for any mask induced mode coupling.Comment: 25 pages, 15 figure

Building biosecurity for synthetic biology.

The fast-paced field of synthetic biology is fundamentally changing the global biosecurity framework. Current biosecurity regulations and strategies are based on previous governance paradigms for pathogen-oriented security, recombinant DNA research, and broader concerns related to genetically modified organisms (GMOs). Many scholarly discussions and biosecurity practitioners are therefore concerned that synthetic biology outpaces established biosafety and biosecurity measures to prevent deliberate and malicious or inadvertent and accidental misuse of synthetic biology's processes or products. This commentary proposes three strategies to improve biosecurity: Security must be treated as an investment in the future applicability of the technology; social scientists and policy makers should be engaged early in technology development and forecasting; and coordination among global stakeholders is necessary to ensure acceptable levels of risk