Metabolic Footprint, towards Understanding Type 2 Diabetes beyond Glycemia

Type 2 diabetes (T2D) heterogeneity is a major determinant of complications risk and treatment response. Using cluster analysis, we aimed to stratify glycemia within metabolic multidimensionality and extract pathophysiological insights out of metabolic profiling. We performed a cluster analysis to stratify 974 subjects (PREVADIAB2 cohort) with normoglycemia, prediabetes, or non-treated diabetes. The algorithm was informed by age, anthropometry, and metabolic milieu (glucose, insulin, C-peptide, and free fatty acid (FFA) levels during the oral glucose tolerance test OGTT). For cluster profiling, we additionally used indexes of metabolism mechanisms (e.g., tissue-specific insulin resistance, insulin clearance, and insulin secretion), non-alcoholic fatty liver disease (NAFLD), and glomerular filtration rate (GFR). We found prominent heterogeneity within two optimal clusters, mainly representing normometabolism (Cluster-I) or insulin resistance and NAFLD (Cluster-II), at higher granularity. This was illustrated by sub-clusters showing similar NAFLD prevalence but differentiated by glycemia, FFA, and GFR (Cluster-II). Sub-clusters with similar glycemia and FFA showed dissimilar insulin clearance and secretion (Cluster-I). This work reveals that T2D heterogeneity can be captured by a thorough metabolic milieu and mechanisms profiling-metabolic footprint. It is expected that deeper phenotyping and increased pathophysiology knowledge will allow to identify subject's multidimensional profile, predict their progression, and treat them towards precision medicine.publishersversionpublishe

Global GRACE Data Assimilation for Groundwater and Drought Monitoring: Advances and Challenges

The scarcity of groundwater storage change data at the global scale hinders our ability tomonitor groundwater resources effectively. In this study, we assimilate a state‐of‐the‐art terrestrialwater storage product derived from Gravity Recovery and Climate Experiment (GRACE) satelliteobservations into NASA's Catchment land surface model (CLSM) at the global scale, with the goal ofgenerating groundwater storage time series that are useful for drought monitoring and other applications.Evaluation using in situ data from nearly 4,000 wells shows that GRACE data assimilation improvesthe simulation of groundwater, with estimation errors reduced by 36% and 10% and correlation improvedby 16% and 22% at the regional and point scales, respectively. The biggest improvements are observed inregions with large interannual variability in precipitation, where simulated groundwater responds toostrongly to changes in atmospheric forcing. The positive impacts of GRACE data assimilation are furtherdemonstrated using observed low‐flow data. CLSM and GRACE data assimilation performance is alsoexamined across different permeability categories. The evaluation reveals that GRACE data assimilationfails to compensate for the lack of a groundwater withdrawal scheme in CLSM when it comes tosimulating realistic groundwater variations in regions with intensive groundwater abstraction.CLSM‐simulated groundwater correlates strongly with 12‐month precipitation anomalies in low‐latitudeand midlatitude areas. A groundwater drought indicator based on GRACE data assimilation generallyagrees with other regional‐scale drought indicators, with discrepancies mainly in their estimateddrought severity.This study was funded by NASA's GRACE and GRACE Follow On Science Team and Terrestrial Hydrology Program. N.T. is supported by NASA's National Climate Assessment program. CLSM model output is available through the Goddard Earth Sciences Data and Information Services Center, https://disc.gsfc.nasa.gov/datasets?keywords=Hydrology

A new approach to fetal echocardiography: digital casts of the fetal cardiac chambers and great vessels for detection of congenital heart disease

OBJECTIVE: The purpose of this study was to describe a method of 4-dimensional (4D) reconstruction of the cardiac chambers and outflow tracts using a combination of spatiotemporal image correlation, "inversion mode," and "B-flow" imaging. METHODS: Spatiotemporal image correlation and the inversion mode were used in the examination of the volume data sets of 23 fetuses with congenital heart anomalies. A subset was also examined with B-flow imaging using the gradient light algorithm. Digital reconstructions from abnormal hearts were compared with a library obtained from fetuses without abnormalities. RESULTS: Rendered images of the 4-chamber view using the inversion mode were characterized by: (1) echogenic chambers; (2) sharp delineation of chamber contours when compared with 2-dimensional (2D) images; and (3) distinct display of the myocardium, interventricular septum, interatrial septum, and mitral and tricuspid valves as anechoic structures. Ventricular septal defects, abnormal differential insertion of the atrioventricular valves, and valve atresia were well visualized with the inversion mode. The application of inversion mode or B-flow imaging to 4D rendering of the outflow tracts resulted in "digital casts" displaying the spatial relationships between the outflow tracts as well as the connections between the great arteries and ventricular chambers. The spatial relationships and communications among cardiac structures cannot be visualized with conventional 2D ultrasonography. CONCLUSIONS: The application of spatiotemporal image correlation, inversion mode, and B-flow imaging generates information about the anatomy and pathologic characteristics of the fetal heart (digital casts) that cannot be obtained with 2D fetal echocardiography. We propose that these modalities enhance the information provided by ultrasonographic interrogation of the fetal heart and will improve prenatal diagnosis

Anisotropy and chemical composition of ultra-high energy cosmic rays using arrival directions measured by the Pierre Auger Observatory

The Pierre Auger Collaboration has reported evidence for anisotropy in the distribution of arrival directions of the cosmic rays with energies $E>E_{th}=5.5\times 10^{19}$ eV. These show a correlation with the distribution of nearby extragalactic objects, including an apparent excess around the direction of Centaurus A. If the particles responsible for these excesses at $E>E_{th}$ are heavy nuclei with charge $Z$, the proton component of the sources should lead to excesses in the same regions at energies $E/Z$. We here report the lack of anisotropies in these directions at energies above $E_{th}/Z$ (for illustrative values of $Z=6,\ 13,\ 26$). If the anisotropies above $E_{th}$ are due to nuclei with charge $Z$, and under reasonable assumptions about the acceleration process, these observations imply stringent constraints on the allowed proton fraction at the lower energies

Update on the correlation of the highest energy cosmic rays with nearby extragalactic matter

Data collected by the Pierre Auger Observatory through 31 August 2007 showed evidence for anisotropy in the arrival directions of cosmic rays above the Greisen-Zatsepin-Kuz'min energy threshold, \nobreak{$6\times 10^{19}$eV}. The anisotropy was measured by the fraction of arrival directions that are less than $3.1^\circ$ from the position of an active galactic nucleus within 75 Mpc (using the V\'eron-Cetty and V\'eron $12^{\rm th}$ catalog). An updated measurement of this fraction is reported here using the arrival directions of cosmic rays recorded above the same energy threshold through 31 December 2009. The number of arrival directions has increased from 27 to 69, allowing a more precise measurement. The correlating fraction is $(38^{+7}_{-6})$, compared with $21$ expected for isotropic cosmic rays. This is down from the early estimate of $(69^{+11}_{-13})$. The enlarged set of arrival directions is examined also in relation to other populations of nearby extragalactic objects: galaxies in the 2 Microns All Sky Survey and active galactic nuclei detected in hard X-rays by the Swift Burst Alert Telescope. A celestial region around the position of the radiogalaxy Cen A has the largest excess of arrival directions relative to isotropic expectations. The 2-point autocorrelation function is shown for the enlarged set of arrival directions and compared to the isotropic expectation.Comment: Accepted for publication in Astroparticle Physics on 31 August 201

Advanced functionality for radio analysis in the Offline software framework of the Pierre Auger Observatory

The advent of the Auger Engineering Radio Array (AERA) necessitates the development of a powerful framework for the analysis of radio measurements of cosmic ray air showers. As AERA performs "radio-hybrid" measurements of air shower radio emission in coincidence with the surface particle detectors and fluorescence telescopes of the Pierre Auger Observatory, the radio analysis functionality had to be incorporated in the existing hybrid analysis solutions for fluoresence and surface detector data. This goal has been achieved in a natural way by extending the existing Auger Offline software framework with radio functionality. In this article, we lay out the design, highlights and features of the radio extension implemented in the Auger Offline framework. Its functionality has achieved a high degree of sophistication and offers advanced features such as vectorial reconstruction of the electric field, advanced signal processing algorithms, a transparent and efficient handling of FFTs, a very detailed simulation of detector effects, and the read-in of multiple data formats including data from various radio simulation codes. The source code of this radio functionality can be made available to interested parties on request.Comment: accepted for publication in NIM A, 13 pages, minor corrections to author list and references in v

Search for First Harmonic Modulation in the Right Ascension Distribution of Cosmic Rays Detected at the Pierre Auger Observatory

We present the results of searches for dipolar-type anisotropies in different energy ranges above $2.5\times 10^{17}$ eV with the surface detector array of the Pierre Auger Observatory, reporting on both the phase and the amplitude measurements of the first harmonic modulation in the right-ascension distribution. Upper limits on the amplitudes are obtained, which provide the most stringent bounds at present, being below 2% at 99% $C.L.$ for EeV energies. We also compare our results to those of previous experiments as well as with some theoretical expectations.Comment: 28 pages, 11 figure

Highlights from the Pierre Auger Observatory

The Pierre Auger Observatory is the world's largest cosmic ray observatory. Our current exposure reaches nearly 40,000 km$^2$ str and provides us with an unprecedented quality data set. The performance and stability of the detectors and their enhancements are described. Data analyses have led to a number of major breakthroughs. Among these we discuss the energy spectrum and the searches for large-scale anisotropies. We present analyses of our X$_{max}$ data and show how it can be interpreted in terms of mass composition. We also describe some new analyses that extract mass sensitive parameters from the 100% duty cycle SD data. A coherent interpretation of all these recent results opens new directions. The consequences regarding the cosmic ray composition and the properties of UHECR sources are briefly discussed.Comment: 9 pages, 12 figures, talk given at the 33rd International Cosmic Ray Conference, Rio de Janeiro 201

A Global Assessment of the Effects of Eucalyptus Plantations on Stream Ecosystem Functioning

Forest change is a major environmental problem worldwide. Forest streams, with their large aquatic–terrestrial interface and strong dependence on terrestrially derived organic matter, are highly sensitive to forest changes. Fast-wood plantations can be particularly threatening if they markedly differ from native forests. Eucalyptus plantations, in particular, cover large areas worldwide (> 20 million ha, mostly from 35°S to 35°N), but their effects on stream functioning have been addressed mostly in the Iberian Peninsula, which limits generalization to other regions. We assessed the effect of eucalyptus plantations on total (microbial decomposers and macroinvertebrates; in coarse mesh bags) and microbial-driven (in fine mesh bags) leaf litter decomposition by comparing streams flowing through native forests and eucalyptus plantations in seven regions in the Iberian Peninsula, Central Africa and South America. We found an overall significant inhibition of total litter decomposition by 23%. The effect did not significantly differ across regions, although a significant inhibition was found for Spain (− 41%), South Brazil (− 31%) and Uruguay (− 36%) (Portugal had a marginally nonsignificant inhibition by 50%) but not for other regions, suggesting that the effects of plantations in temperate climates are mediated through effects on macroinvertebrate communities. Contrarily, the overall effect for microbial-driven litter decomposition was non-significant, but it significantly differed across regions with a significant stimulation in Central Brazil (110%) and Uruguay (32%), and nonsignificant effects for other regions (Kenya had a marginally nonsignificant inhibition by 48%), suggesting that functional redundancy among microbial communities is not general and effects can occur if plantations induce changes in nutrient availability, solar irradiation or litter characteristics

Novel HIV-1 Knockdown Targets Identified by an Enriched Kinases/Phosphatases shRNA Library Using a Long-Term Iterative Screen in Jurkat T-Cells

HIV-1 is a complex retrovirus that uses host machinery to promote its replication. Understanding cellular proteins involved in the multistep process of HIV-1 infection may result in the discovery of more adapted and effective therapeutic targets. Kinases and phosphatases are a druggable class of proteins critically involved in regulation of signal pathways of eukaryotic cells. Here, we focused on the discovery of kinases and phosphatases that are essential for HIV-1 replication but dispensable for cell viability. We performed an iterative screen in Jurkat T-cells with a short-hairpin-RNA (shRNA) library highly enriched for human kinases and phosphatases. We identified 14 new proteins essential for HIV-1 replication that do not affect cell viability. These proteins are described to be involved in MAPK, JNK and ERK pathways, vesicular traffic and DNA repair. Moreover, we show that the proteins under study are important in an early step of HIV-1 infection before viral integration, whereas some of them affect viral transcription/translation. This study brings new insights for the complex interplay of HIV-1/host cell and opens new possibilities for antiviral strategies