Deletions and mutations affecting lymphoid transcription factor IKZF1 (IKAROS) are associated with an increased relapse risk and poor outcome in B-cell precursor acute lymphoblastic leukemia. ...However, additional genetic events may either enhance or negate the effects of
deletions on prognosis. In a large discovery cohort of 533 childhood B-cell precursor acute lymphoblastic leukemia patients, we observed that single-copy losses of
were significantly enriched in
-deleted B-cell precursor acute lymphoblastic leukemia (
=0.007). While
deletions alone had no impact on prognosis, the combined presence of
and
deletions was associated with a significantly lower 5-year event-free survival (
=0.0003) and a higher 5-year cumulative incidence of relapse (
=0.005), when compared with
-deleted cases without
aberrations. In contrast, other copy number losses commonly observed in B-cell precursor acute lymphoblastic leukemia, such as
or
, did not affect the outcome of
-deleted acute lymphoblastic leukemia patients. To establish whether the combined loss of IKZF1 and BTG1 function cooperate in leukemogenesis,
-deficient mice were crossed onto an
heterozygous background. We observed that loss of
increased the tumor incidence of
mice in a dose-dependent manner. Moreover, murine B cells deficient for
and
displayed increased resistance to glucocorticoids, but not to other chemotherapeutic drugs. Together, our results identify
as a tumor suppressor in leukemia that, when deleted, strongly enhances the risk of relapse in
-deleted B-cell precursor acute lymphoblastic leukemia, and augments the glucocorticoid resistance phenotype mediated by the loss of IKZF1 function.
Approximately 0.5%–1% of the general population has been estimated to be heterozygous for a germline mutation in the
ATM gene. Mutations in the
ATM gene are responsible for the autosomal recessive ...disorder ataxia-telangiectasia (A-T) (MIM
208900). The finding that
ATM-heterozygotes have an increased relative risk for breast cancer was supported by some studies but not confirmed by others. In view of this discrepancy, we examined the frequency of
ATM germline mutations in a selected group of Dutch patients with breast cancer. We have analyzed
ATM germline mutations in normal blood lymphocytes, using the protein-truncation test followed by genomic-sequence analysis. A high percentage of
ATM germline mutations was demonstrated among patients with sporadic breast cancer. The 82 patients included in this study had developed breast cancer at age <45 and had survived ⩾5 years (mean 15 years), and in 33 (40%) of the patients a contralateral breast tumor had been diagnosed. Among these patients we identified seven (8.5%)
ATM germline mutations, of which five are distinct. One splice-site mutation (IVS10-6T→G) was detected three times in our series. Four heterozygous carriers were patients with bilateral breast cancer. Our results indicate that the mutations identified in this study are “A-T disease–causing” mutations that might be associated with an increased risk of breast cancer in heterozygotes. We conclude that
ATM heterozygotes have an approximately ninefold-increased risk of developing a type of breast cancer characterized by frequent bilateral occurrence, early age at onset, and long-term survival. The specific characteristics of our population of patients may explain why such a high frequency was not found in other series.
Summary
Background
Enumeration of extracellular vesicles has clinical potential as a biomarker for disease. In biological samples, the smallest and largest vesicles typically differ 25‐fold in size, ...300 000‐fold in concentration, 20 000‐fold in volume, and 10 000 000‐fold in scattered light. Because of this heterogeneity, the currently employed techniques detect concentrations ranging from 104 to 1012 vesicles mL–1.
Objectives
To investigate whether the large variation in the detected concentration of vesicles is caused by the minimum detectable vesicle size of five widely used techniques.
Methods
The size and concentration of vesicles and reference beads were measured with transmission electron microscopy (TEM), a conventional flow cytometer, a flow cytometer dedicated to detecting submicrometer particles, nanoparticle tracking analysis (NTA), and resistive pulse sensing (RPS).
Results
Each technique gave a different size distribution and a different concentration for the same vesicle sample.
Conclusion
Differences between the detected vesicle concentrations are primarily caused by differences between the minimum detectable vesicle sizes. The minimum detectable vesicle sizes were 70–90 nm for NTA, 70–100 nm for RPS, 150–190 nm for dedicated flow cytometry, and 270–600 nm for conventional flow cytometry. TEM could detect the smallest vesicles present, albeit after adhesion on a surface. Dedicated flow cytometry was most accurate in determining the size of reference beads, but is expected to be less accurate on vesicles, owing to heterogeneity of the refractive index of vesicles. Nevertheless, dedicated flow cytometry is relatively fast and allows multiplex fluorescence detection, making it most applicable to clinical research.
Climate, land use, and other anthropogenic and natural drivers have the potential to influence fire dynamics in many regions. To develop a mechanistic understanding of the changing role of these ...drivers and their impact on atmospheric composition, long-term fire records are needed that fuse information from different satellite and in situ data streams. Here we describe the fourth version of the Global Fire Emissions Database (GFED) and quantify global fire emissions patterns during 1997–2016. The modeling system, based on the Carnegie–Ames–Stanford Approach (CASA) biogeochemical model, has several modifications from the previous version and uses higher quality input datasets. Significant upgrades include (1) new burned area estimates with contributions from small fires, (2) a revised fuel consumption parameterization optimized using field observations, (3) modifications that improve the representation of fuel consumption in frequently burning landscapes, and (4) fire severity estimates that better represent continental differences in burning processes across boreal regions of North America and Eurasia. The new version has a higher spatial resolution (0.25°) and uses a different set of emission factors that separately resolves trace gas and aerosol emissions from temperate and boreal forest ecosystems. Global mean carbon emissions using the burned area dataset with small fires (GFED4s) were 2.2 × 1015 grams of carbon per year (Pg C yr−1) during 1997–2016, with a maximum in 1997 (3.0 Pg C yr−1) and minimum in 2013 (1.8 Pg C yr−1). These estimates were 11 % higher than our previous estimates (GFED3) during 1997–2011, when the two datasets overlapped. This net increase was the result of a substantial increase in burned area (37 %), mostly due to the inclusion of small fires, and a modest decrease in mean fuel consumption (−19 %) to better match estimates from field studies, primarily in savannas and grasslands. For trace gas and aerosol emissions, differences between GFED4s and GFED3 were often larger due to the use of revised emission factors. If small fire burned area was excluded (GFED4 without the s for small fires), average emissions were 1.5 Pg C yr−1. The addition of small fires had the largest impact on emissions in temperate North America, Central America, Europe, and temperate Asia. This small fire layer carries substantial uncertainties; improving these estimates will require use of new burned area products derived from high-resolution satellite imagery. Our revised dataset provides an internally consistent set of burned area and emissions that may contribute to a better understanding of multi-decadal changes in fire dynamics and their impact on the Earth system. GFED data are available from http://www.globalfiredata.org.
We present radio transient search algorithms, results, and statistics from the ongoing Arecibo Pulsar ALFA (PALFA) survey of the Galactic plane. We have discovered seven objects through a search for ...isolated dispersed pulses. All of these objects are Galactic and have measured periods between 0.4 and 4.7 s. One of the new discoveries has a duty cycle of 0.01%, smaller than that of any other radio pulsar. We discuss the impact of selection effects on the detectability and classification of intermittent sources, and compare the efficiencies of periodicity and single-pulse (SP) searches for various pulsar classes. For some cases we find that the apparent intermittency is likely to be caused by off-axis detection or a short time window that selects only a few bright pulses and favors detection with our SP algorithm. In other cases, the intermittency appears to be intrinsic to the source. No transients were found with DMs large enough to require that they originate from sources outside our Galaxy. Accounting for the on-axis gain of the ALFA system, as well as the low gain but large solid-angle coverage of far-out sidelobes, we use the results of the survey so far to place limits on the amplitudes and event rates of transients of arbitrary origin.
Abstract Hyperspectral imaging (HSI) integrates conventional imaging and spectroscopy, to obtain both spatial and spectral information from a specimen. This technique enables investigators to analyze ...the chemical composition of traces and simultaneously visualize their spatial distribution. HSI offers significant potential for the detection, visualization, identification and age estimation of forensic traces. The rapid, non-destructive and non-contact features of HSI mark its suitability as an analytical tool for forensic science. This paper provides an overview of the principles, instrumentation and analytical techniques involved in hyperspectral imaging. We describe recent advances in HSI technology motivating forensic science applications, e.g. the development of portable and fast image acquisition systems. Reported forensic science applications are reviewed. Challenges are addressed, such as the analysis of traces on backgrounds encountered in casework, concluded by a summary of possible future applications.
Abstract The global rise in prevalence of obesity is not fully explained by genetics or life style factors. The developmental origins of health and disease paradigm suggests that environmental ...factors during early life could play a role. In this perspective, perinatal exposure to bisphenol A (BPA) has been indicated as a programming factor for obesity and related metabolic disorders later in life. Here we study early life programming by BPA using an experimental design that is relevant for human exposure. C57BL/6JxFVB hybrid mice were exposed during gestation and lactation via maternal feed to 8 non-toxic doses (0–3000 μg/kg body weight/day (μg/kg bw/d)) of BPA. After weaning, offspring were followed for 20 weeks without further exposure. Adult male offspring showed dose-dependent increases of body and liver weights, no effects on fat pad weights and a dose-dependent decrease in circulating glucagon. Female offspring showed a dose-dependent decrease in body weight, liver, muscle and fat pad weights, adipocyte size, serum lipids, serum leptin and adiponectin. Physical activity was decreased in exposed males and suggested to be increased in exposed females. Brown adipose tissue showed slightly increased lipid accumulation in males and lipid depletion in females, and ucp1 expression was dose-dependently increased in females. The effects in females were more reliable and robust than in males due to wide confidence intervals and potential confounding by litter size for male data. The lowest derived BMDL (lower bound of the (two-sided) 90%-confidence interval for the benchmark dose) of 233 μg/kg bw/d (for interscapular weight in females) was below the proposed BMDL of 3633 μg/kg bw/d as a basis for tolerable daily intake. Although these results suggest that BPA can program for an altered metabolic phenotype, the sexual dimorphism of effects and diversity of outcomes among studies similar in design as the present study do not mark BPA as a specific obesogen. The consistency within the complex of observed metabolic effects suggests that upstream key element(s) in energy homeostasis are modified. Sex-dependent factors contribute to the final phenotypic outcome.
The endothelial angiopoietin/Tie2 system is an important regulator of endothelial permeability and targeting Tie2 reduces hemorrhagic shock-induced organ edema in males. However, sexual dimorphism of ...the endothelium has not been taken into account. This study investigated whether there are sex-related differences in the endothelial angiopoietin/Tie2 system and edema formation. Adult male and female heterozygous Tie2 knockout mice (Tie2.sup.+/-) and wild-type controls (Tie2.sup.+/+) were included (n = 9 per group). Renal and pulmonary injury were determined by wet/dry weight ratio and H&E staining of tissue sections. Protein levels were studied in plasma by ELISA and pulmonary and renal mRNA expression levels by RT-qPCR. In Tie2.sup.+/+ mice, females had higher circulating angiopoietin-2 (138%, p<0.05) compared to males. Gene expression of angiopoietin-1 (204%, p<0.01), angiopoietin-2 (542%, p<0.001) were higher in females compared to males in kidneys, but not in lungs. Gene expression of Tie2, Tie1 and VE-PTP were similar between males and females in both organs. Renal and pulmonary wet/dry weight ratio did not differ between Tie2.sup.+/+ females and males. Tie2.sup.+/+ females had lower circulating NGAL (41%, p<0.01) compared to males, whereas renal NGAL and KIM1 gene expression was unaffected. Female sex seems to protect against renal, but not pulmonary edema in heterozygous Tie2 knock-out mice. This could not be explained by sex dimorphism in the endothelial angiopoietin/Tie2 system.
Shifts in the timing of spring phenology are a central feature of global change research. Long-term observations of plant phenology have been used to track vegetation responses to climate variability ...but are often limited to particular species and locations and may not represent synoptic patterns. Satellite remote sensing is instead used for continental to global monitoring. Although numerous methods exist to extract phenological timing, in particular start-of-spring (SOS), from time series of reflectance data, a comprehensive intercomparison and interpretation of SOS methods has not been conducted. Here, we assess 10 SOS methods for North America between 1982 and 2006. The techniques include consistent inputs from the 8 km Global Inventory Modeling and Mapping Studies Advanced Very High Resolution Radiometer NDVIg dataset, independent data for snow cover, soil thaw, lake ice dynamics, spring streamflow timing, over 16 000 individual measurements of ground-based phenology, and two temperature-driven models of spring phenology. Compared with an ensemble of the 10 SOS methods, we found that individual methods differed in average day-of-year estimates by ±60 days and in standard deviation by ±20 days. The ability of the satellite methods to retrieve SOS estimates was highest in northern latitudes and lowest in arid, tropical, and Mediterranean ecoregions. The ordinal rank of SOS methods varied geographically, as did the relationships between SOS estimates and the cryospheric/hydrologic metrics. Compared with ground observations, SOS estimates were more related to the first leaf and first flowers expanding phenological stages. We found no evidence for time trends in spring arrival from ground- or model-based data; using an ensemble estimate from two methods that were more closely related to ground observations than other methods, SOS trends could be detected for only 12% of North America and were divided between trends towards both earlier and later spring.
PDF
