Melanoma differentiation-associated protein-5 (MDA-5) limits early viral replication but is not essential for the induction of type 1 interferons after Coxsackievirus infection

AbstractCoxsackievirus infections are associated with severe diseases such as myocarditis, meningitis and pancreatitis. To study the contribution of the intracellular viral sensor melanoma differentiation-associated protein-5 (MDA-5) in the host immune response to Coxsackievirus B3 (CVB3) we infected C57BL/6 and 129/SvJ mice lacking mda-5. Mice deficient in MDA-5 showed a dramatically increased susceptibility to CVB3 infection. The loss of MDA-5 allowed the virus to replicate faster, resulting in increased liver and pancreas damage and heightened mortality. MDA-5 was not absolutely required for the induction of type 1 interferons (IFNs), but essential for the production of maximal levels of systemic IFN-α early after infection. Taken together, our findings indicate that MDA-5 plays an important role in the host immune response to CVB3 by preventing early virus replication and limiting tissue pathology

DCE Bio Detection System Final Report

The DCE (DNA Capture Element) Bio-Detection System (Biohound) was conceived, designed, built and tested by PNNL under a MIPR for the US Air Force under the technical direction of Dr. Johnathan Kiel and his team at Brooks City Base in San Antonio Texas. The project was directed toward building a measurement device to take advantage of a unique aptamer based assay developed by the Air Force for detecting biological agents. The assay uses narrow band quantum dots fluorophores, high efficiency fluorescence quenchers, magnetic micro-beads beads and selected aptamers to perform high specificity, high sensitivity detection of targeted biological materials in minutes. This final report summarizes and documents the final configuration of the system delivered to the Air Force in December 200

Runx1 Expression Marks Long-Term Repopulating Hematopoietic Stem Cells in the Midgestation Mouse Embryo

AbstractHematopoietic stem cells (HSCs) are first found in the aorta-gonad-mesonephros region and vitelline and umbilical arteries of the midgestation mouse embryo. Runx1 (AML1), the DNA binding subunit of a core binding factor, is required for the emergence and/or subsequent function of HSCs. We show that all HSCs in the embryo express Runx1. Furthermore, HSCs in Runx1+/− embryos are heterogeneous and include CD45+ cells, endothelial cells, and mesenchymal cells. Comparison with wild-type embryos showed that the distribution of HSCs among these various cell populations is sensitive to Runx1 dosage. These data provide the first morphological description of embryonic HSCs and contribute new insight into their cellular origin

Technology Gap Analysis for the Detection of Process Signatures Using Less Than Remote Methods

Although remote sensing methods offer advantages for monitoring important illicit process activities, remote and stand-off technologies cannot successfully detect all important processes with the sensitivity and certainty that is desired. The main scope of the program is observables, with a primary focus on chemical signatures. A number of key process signatures elude remote or stand-off detection for a variety of reasons (e.g., heavy particulate emissions that do not propagate far enough for detection at stand-off distances, semi-volatile chemicals that do not tend to vaporize and remain in the environment near the source, etc.). Some of these compounds can provide persistent, process-specific information that is not available through remote techniques; however, the associated measurement technologies have their own set of advantages, disadvantages and technical challenges that may need to be overcome before additional signature data can be effectively and reliably exploited. The main objective of this report is to describe a process to identify high impact technology gaps for important less-than-remote detection applications. The subsequent analysis focuses on the technology development needed to enable exploitation of important process signatures. The evaluation process that was developed involves three interrelated and often conflicting requirements generation activities: • Identification of target signature chemicals with unique intelligence value and their associated attributes as mitigated by environmentally influenced fate and transport effects (i.e., what can you expect to actually find that has intelligence value, where do you need to look for it and what sensitivity and selectivity do you need to see it) • Identification of end-user deployment scenario possibilities and constraints with a focus on alternative detection requirements, timing issues, logistical consideration, and training requirements for a successful measurement • Identification of available measurement technology alternatives and their associated attributes (available off-the-shelf, in near-term development, likely longer-term development and research-phase possibilities). Assembling these requirements into attribute verses generic acceptance criteria level tables and then comparing related attributes between tables allows for rapid visualization of technology gaps and gross estimates of the gap size. By simply weighting the attributes and the requirements in various ways one can also derive the importance of the identified technology gaps. This output can provide the basis for both a near-term technology development roadmap and research focus as well as a decision support tool for selecting the “most likely to succeed” approach. The evaluation process as presented is generally applicable for the determination of measurement technology gaps for a broad range of applications [e.g., nuclear weapons process, chemical weapons production, biological weapons production as well as classical signature categories (e.g., chemical and radionuclide signatures)]. In this paper the method is applied to the specific case of detecting nuclear weapons production processes using semi-volatile chemical signatures as an illustration. This particular case selection allows the leveraging of significant prior knowledge and experience while still being highly relevant to current detection scenario needs

3D-FFT for Signature Detection in LWIR Images

Improvements in analysis detection exploitation are possible by applying whitened matched filtering within the Fourier domain to hyperspectral data cubes. We describe an implementation of a Three Dimensional Fast Fourier Transform Whitened Matched Filter (3DFFTMF) approach and, using several example sets of Long Wave Infra Red (LWIR) data cubes, compare the results with those from standard Whitened Matched Filter (WMF) techniques. Since the variability in shape of gaseous plumes precludes the use of spatial conformation in the matched filtering, the 3DFFTMF results were similar to those of two other WMF methods. Including a spatial low-pass filter within the Fourier space can improve signal to noise ratios and therefore improve detection limit by facilitating the mitigation of high frequency clutter. The improvement only occurs if the low-pass filter diameter is smaller than the plume diameter

Identification of an epigenetic biomarker panel with high sensitivity and specificity for colorectal cancer and adenomas

Background The presence of cancer-specific DNA methylation patterns in epithelial colorectal cells in human feces provides the prospect of a simple, non-invasive screening test for colorectal cancer and its precursor, the adenoma. This study investigates a panel of epigenetic markers for the detection of colorectal cancer and adenomas. Methods Candidate biomarkers were subjected to quantitative methylation analysis in test sets of tissue samples from colorectal cancers, adenomas, and normal colonic mucosa. All findings were verified in independent clinical validation series. A total of 523 human samples were included in the study. Receiver operating characteristic (ROC) curve analysis was used to evaluate the performance of the biomarker panel. Results Promoter hypermethylation of the genes CNRIP1, FBN1, INA, MAL, SNCA, and SPG20 was frequent in both colorectal cancers (65-94%) and adenomas (35-91%), whereas normal mucosa samples were rarely (0-5%) methylated. The combined sensitivity of at least two positives among the six markers was 94% for colorectal cancers and 93% for adenoma samples, with a specificity of 98%. The resulting areas under the ROC curve were 0.984 for cancers and 0.968 for adenomas versus normal mucosa. Conclusions The novel epigenetic marker panel shows very high sensitivity and specificity for both colorectal cancers and adenomas. Our findings suggest this biomarker panel to be highly suitable for early tumor detection

Effects of 10 days of separate heat and hypoxic exposure on heat acclimation and temperate exercise performance.

Adaptations to heat and hypoxia are typically studied in isolation but are often encountered in combination. Whether the adaptive response to multiple stressors affords the same response as when examined in isolation is unclear. We examined 1) the influence of overnight moderate normobaric hypoxia on the time course and magnitude of adaptation to daily heat exposure and 2) whether heat acclimation (HA) was ergogenic and whether this was influenced by an additional hypoxic stimulus. Eight males [V̇o2max = 58.5 (8.3) ml·kg-1·min-1] undertook two 11-day HA programs (balanced-crossover design), once with overnight normobaric hypoxia (HAHyp): 8 (1) h per night for 10 nights [[Formula: see text] = 0.156; SpO2 = 91 (2)%] and once without (HACon). Days 1, 6, and 11 were exercise-heat stress tests [HST (40°C, 50% relative humidity, RH)]; days 2-5 and 7-10 were isothermal strain [target rectal temperature (Tre) ~38.5°C], exercise-heat sessions. A graded exercise test and 30-min cycle trial were undertaken pre-, post-, and 14 days after HA in temperate normoxia (22°C, 55% RH; FIO2 = 0.209). HA was evident on day 6 (e.g., reduced Tre, mean skin temperature (T̄sk), heart rate, and sweat [Na+], P < 0.05) with additional adaptations on day 11 (further reduced T̄sk and heart rate). HA increased plasma volume [+5.9 (7.3)%] and erythropoietin concentration [+1.8 (2.4) mIU/ml]; total hemoglobin mass was unchanged. Peak power output [+12 (20) W], lactate threshold [+15 (18) W] and work done [+12 (20) kJ] increased following HA. The additional hypoxic stressor did not affect these adaptations. In conclusion, a separate moderate overnight normobaric hypoxic stimulus does not affect the time course or magnitude of HA. Performance may be improved in temperate normoxia following HA, but this is unaffected by an additional hypoxic stressor

The GALAH survey: Stellar streams and how stellar velocity distributions vary with Galactic longitude, hemisphere, and metallicity

Using GALAH (GALactic Archaeology with HERMES) survey data of nearby stars, we look at how structure in the planar (u, v) velocity distribution depends on metallicity and on viewing direction within the Galaxy. In nearby stars with distance d≲1 kpc, the Hercules stream is most strongly seen in higher metallicity stars [Fe/H] > 0.2. The Hercules stream peak v value depends on viewed galactic longitude, which we interpret as due to the gap between the stellar stream and more circular orbits being associated with a specific angular momentum value of about 1640 km s−1 kpc. The association of the gap with a particular angular momentum value supports a bar resonant model for the Hercules stream. Moving groups previously identified in Hipparcos(HIgh Precision Parallax COllecting Satellite) observations are easiest to see in stars nearer than 250 pc, and their visibility and peak velocities in the velocity distributions depends on both viewing direction (galactic longitude and hemisphere) and metallicity. We infer that there is fine structure in local velocity distributions that varies over distances of a few hundred pc in the Galaxy.Parts of this research were conducted by the Australian Research Council (ARC) Centre of Excellence for All Sky Astrophysics in 3 Dimensions (ASTRO 3D), through project number CE170100013. JB-H acknowledges a Miller Professorship from the Miller Institute, UC Berkeley, and an ARC Laureate Fellowship which also supports GDS and SS. SM acknowledges support from the ARC through DECRA Fellowship DE140100598. JK is supported by an ARC DP grant awarded to JB-H and TB. MH is supported by ASTRO 3D Centre of Excellence funding to the University of Sydney and an ARC DP grant awarded to KF. LD gratefully acknowledges a scholarship from Zonta International District 24. LD and KF acknowledge support from ARC grant DP160103747. LC is the recipient of an ARC Future Fellowship (project number FT160100402)

Natriuretic peptides and integrated risk assessment for cardiovascular disease. an individual-participant-data meta-analysis

BACKGROUND: Guidelines for primary prevention of cardiovascular diseases focus on prediction of coronary heart disease and stroke. We assessed whether or not measurement of N-terminal-pro-B-type natriuretic peptide (NT-proBNP) concentration could enable a more integrated approach than at present by predicting heart failure and enhancing coronary heart disease and stroke risk assessment. METHODS: In this individual-participant-data meta-analysis, we generated and harmonised individual-participant data from relevant prospective studies via both de-novo NT-proBNP concentration measurement of stored samples and collection of data from studies identified through a systematic search of the literature (PubMed, Scientific Citation Index Expanded, and Embase) for articles published up to Sept 4, 2014, using search terms related to natriuretic peptide family members and the primary outcomes, with no language restrictions. We calculated risk ratios and measures of risk discrimination and reclassification across predicted 10 year risk categories (ie, <5%, 5% to <7·5%, and ≥7·5%), adding assessment of NT-proBNP concentration to that of conventional risk factors (ie, age, sex, smoking status, systolic blood pressure, history of diabetes, and total and HDL cholesterol concentrations). Primary outcomes were the combination of coronary heart disease and stroke, and the combination of coronary heart disease, stroke, and heart failure. FINDINGS: We recorded 5500 coronary heart disease, 4002 stroke, and 2212 heart failure outcomes among 95 617 participants without a history of cardiovascular disease in 40 prospective studies. Risk ratios (for a comparison of the top third vs bottom third of NT-proBNP concentrations, adjusted for conventional risk factors) were 1·76 (95% CI 1·56-1·98) for the combination of coronary heart disease and stroke and 2·00 (1·77-2·26) for the combination of coronary heart disease, stroke, and heart failure. Addition of information about NT-proBNP concentration to a model containing conventional risk factors was associated with a C-index increase of 0·012 (0·010-0·014) and a net reclassification improvement of 0·027 (0·019-0·036) for the combination of coronary heart disease and stroke and a C-index increase of 0·019 (0·016-0·022) and a net reclassification improvement of 0·028 (0·019-0·038) for the combination of coronary heart disease, stroke, and heart failure. INTERPRETATION: In people without baseline cardiovascular disease, NT-proBNP concentration assessment strongly predicted first-onset heart failure and augmented coronary heart disease and stroke prediction, suggesting that NT-proBNP concentration assessment could be used to integrate heart failure into cardiovascular disease primary prevention

Pure point diffraction implies zero entropy for Delone sets with uniform cluster frequencies

Delone sets of finite local complexity in Euclidean space are investigated. We show that such a set has patch counting and topological entropy 0 if it has uniform cluster frequencies and is pure point diffractive. We also note that the patch counting entropy is 0 whenever the repetitivity function satisfies a certain growth restriction.Comment: 16 pages; revised and slightly expanded versio