Statistical framework for estimating GNSS bias

We present a statistical framework for estimating global navigation satellite system (GNSS) non-ionospheric differential time delay bias. The biases are estimated by examining differences of measured line integrated electron densities (TEC) that are scaled to equivalent vertical integrated densities. The spatio-temporal variability, instrumentation dependent errors, and errors due to inaccurate ionospheric altitude profile assumptions are modeled as structure functions. These structure functions determine how the TEC differences are weighted in the linear least-squares minimization procedure, which is used to produce the bias estimates. A method for automatic detection and removal of outlier measurements that do not fit into a model of receiver bias is also described. The same statistical framework can be used for a single receiver station, but it also scales to a large global network of receivers. In addition to the Global Positioning System (GPS), the method is also applicable to other dual frequency GNSS systems, such as GLONASS (Globalnaya Navigazionnaya Sputnikovaya Sistema). The use of the framework is demonstrated in practice through several examples. A specific implementation of the methods presented here are used to compute GPS receiver biases for measurements in the MIT Haystack Madrigal distributed database system. Results of the new algorithm are compared with the current MIT Haystack Observatory MAPGPS bias determination algorithm. The new method is found to produce estimates of receiver bias that have reduced day-to-day variability and more consistent coincident vertical TEC values.Comment: 18 pages, 5 figures, submitted to AM

Millstone Hill coherent-scatter radar observations of electric field variability in the sub-auroral polarization stream

[1] Coherent backscatter observations with the Millstone Hill UHF radar (MHR) are used to investigate spatial/temporal variations in the ionospheric sub‐auroral polarization stream (SAPS) electric field. For the 440 MHz MHR, coherent amplitude is on average linearly proportional to electric field strength. The use of both main‐beam and sidelobe returns and the great sensitivity of the MHR system permits observations spanning 3° of the SAPS region with 1‐sec temporal and 10‐km spatial resolution. For a moderately disturbed event on May 25, 2000, the SAPS channel moved steadily equatorward. Large‐scale (30 mV/m peak to peak) wave‐like oscillations in the electric field magnitude (200s–300s periodicity) were seen to propagate across the SAPS channel throughout the hour‐long event. It is suggested that such localized electric field intensifications, which exhibit many of the characteristics of the narrow SAID features described in the literature, arise as wavelike perturbations within the SAPS channel

The WD40 Domain Is Required for LRRK2 Neurotoxicity

BACKGROUND:Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson disease (PD). LRRK2 contains an "enzymatic core" composed of GTPase and kinase domains that is flanked by leucine-rich repeat (LRR) and WD40 protein-protein interaction domains. While kinase activity and GTP-binding have both been implicated in LRRK2 neurotoxicity, the potential role of other LRRK2 domains has not been as extensively explored. PRINCIPAL FINDINGS:We demonstrate that LRRK2 normally exists in a dimeric complex, and that removing the WD40 domain prevents complex formation and autophosphorylation. Moreover, loss of the WD40 domain completely blocks the neurotoxicity of multiple LRRK2 PD mutations. CONCLUSION:These findings suggest that LRRK2 dimerization and autophosphorylation may be required for the neurotoxicity of LRRK2 PD mutations and highlight a potential role for the WD40 domain in the mechanism of LRRK2-mediated cell death

Multiradar observations of the polar tongue of ionization

[1] We present a global view of large‐scale ionospheric disturbances during the main phase of a major geomagnetic storm. We find that the low‐latitude, auroral, and polar latitude regions are coupled by processes that redistribute thermal plasma throughout the system. For the large geomagnetic storm on 20 November 2003, we examine data from the high‐latitude incoherent scatter radars at Millstone Hill, Sondrestrom, and EISCAT Tromso, with SuperDARN HF radar observations of the high‐latitude convection pattern and DMSP observations of in situ plasma parameters in the topside ionosphere. We combine these with north polar maps of stormtime plumes of enhanced total electron content (TEC) derived from a network of GPS receivers. The polar tongue of ionization (TOI) is seen to be a continuous stream of dense cold plasma entrained in the global convection pattern. The dayside source of the TOI is the plume of storm enhanced density (SED) transported from low latitudes in the postnoon sector by the subauroral disturbance electric field. Convection carries this material through the dayside cusp and across the polar cap to the nightside where the auroral F region is significantly enhanced by the SED material. The three incoherent scatter radars provided full altitude profiles of plasma density, temperatures, and vertical velocity as the TOI plume crossed their different positions, under the cusp, in the center of the polar cap, and at the midnight oval/polar cap boundary. Greatly elevated F peak density (>1.5E12 m[superscript −3]) and low electron and ion temperatures (∼2500 K at the F peak altitude) characterize the SED/TOI plasma observed at all points along its high‐latitude trajectory. For this event, SED/TOI F region TEC (150–1000 km) was ∼50 TECu both in the cusp and in the center of the polar cap. Large, upward directed fluxes of O+ (>1.E14 m[superscript −2] s[superscript −1]) were observed in the topside ionosphere from the SED/TOI plume within the cusp

Assessment of ABT-263 activity across a cancer cell line collection leads to a potent combination therapy for small-cell lung cancer

BH3 mimetics such as ABT-263 induce apoptosis in a subset of cancer models. However, these drugs have shown limited clinical efficacy as single agents in small-cell lung cancer (SCLC) and other solid tumor malignancies, and rational combination strategies remain underexplored. To develop a novel therapeutic approach, we examined the efficacy of ABT-263 across >500 cancer cell lines, including 311 for which we had matched expression data for select genes. We found that high expression of the proapoptotic gene Bcl2-interacting mediator of cell death (BIM) predicts sensitivity to ABT-263. In particular, SCLC cell lines possessed greater BIM transcript levels than most other solid tumors and are among the most sensitive to ABT-263. However, a subset of relatively resistant SCLC cell lines has concomitant high expression of the antiapoptotic myeloid cell leukemia 1 (MCL-1). Whereas ABT-263 released BIM from complexes with BCL-2 and BCL-XL, high expression of MCL-1 sequestered BIM released from BCL-2 and BCL-XL, thereby abrogating apoptosis. We found that SCLCs were sensitized to ABT-263 via TORC1/2 inhibition, which led to reduced MCL-1 protein levels, thereby facilitating BIM-mediated apoptosis. AZD8055 and ABT-263 together induced marked apoptosis in vitro, as well as tumor regressions in multiple SCLC xenograft models. In a Tp53; Rb1 deletion genetically engineered mouse model of SCLC, the combination of ABT-263 and AZD8055 significantly repressed tumor growth and induced tumor regressions compared with either drug alone. Furthermore, in a SCLC patient-derived xenograft model that was resistant to ABT-263 alone, the addition of AZD8055 induced potent tumor regression. Therefore, addition of a TORC1/2 inhibitor offers a therapeutic strategy to markedly improve ABT-263 activity in SCLC.United States. Dept. of Defense (Grant W81-XWH-13-1-0323)National Cancer Institute (U.S.) (Cancer Center Support Grant P30-CA14051

Adherence with isoniazid for prevention of tuberculosis among HIV-infected adults in South Africa

BACKGROUND: Tuberculosis (TB) is the most common opportunistic infection in HIV-infected adults in developing countries. Isoniazid (INH) is recommended for treatment of latent TB infection, however non-adherence is common. The purpose of this study was to apply in-house prepared isoniazid (INH) urine test strips in a clinical setting, and identify predictors of positive test results in an adherence questionnaire in HIV-infected adults taking INH for prevention of TB. METHODS: Cross-sectional study of adherence using a questionnaire and urine test strips for detection of INH metabolites at two hospitals in Pietermaritzburg, South Africa. Participants were aged at least 18 years, HIV positive, and receiving INH for prevention of tuberculosis disease. Univariate and multivariate analyses are used to identify factors relevant to adherence. RESULTS: 301 consecutive patients were recruited. 28% of participants had negative urine tests. 32 (37.2%, 95% CI25.4, 45.0) of the 86 patients who received INH from peripheral pharmacies said the pharmacy had run out of INH at some time, compared with central hospital pharmacies (p = 0.0001). In univariate analysis, a negative test was associated with self-reported missed INH doses (p = 0.043). Each 12-hour increment since last reported dose increased the likelihood of a negative test by 34% (p = 0.0007). Belief in INH safety was associated with a positive test (p = 0.021). In multivariate analysis, patients who believed INH is important for prevention of TB disease were more likely to be negative (p = 0.0086). CONCLUSION: Adequate drug availability at peripheral pharmacies remains an important intervention for TB prevention. Key questions may identify potentially non-adherent patients. In-house prepared urine tests strips are an effective and cheap method of objectively assessing INH adherence, and could be used an important tool in TB control programs

International descriptive and interventional survey for oxycholesterol determination by gas- and liquid-chromatographic methods

Increasing numbers of laboratories develop new methods based on gas-liquid and high-performance liquid chromatography to determine serum concentrations of oxygenated cholesterol metabolites such as 7α-, 24(S)-, and 27-hydroxycholesterol. We initiated a first international descriptive oxycholesterol (OCS) survey in 2013 and a second interventional survey 2014 in order to compare levels of OCS reported by different laboratories and to define possible sources of analytical errors. In 2013 a set of two lyophilized serum pools (A and B) was sent to nine laboratories in different countries for OCS measurement utilizing their own standard stock solutions. In 2014 eleven laboratories were requested to determine OCS concentrations in lyophilized pooled sera (C and D) utilizing the same provided standard stock solutions of OCS. The participating laboratories submitted results obtained after capillary gas-liquid chromatography-mass selective detection with either epicoprostanol or deuterium labelled sterols as internal standards and high-performance liquid chromatography with mass selective detection and deuterated OCS as internal standard. Each participant received a clear overview of the results in form of Youden-Plots and basic statistical evaluation in its used unit. The coefficients of variation of the concentrations obtained by all laboratories using their individual methods were 58.5–73.3% (survey 1), 56.8–60.3% (survey 2); 36.2–35.8% (survey 1), 56.6–59.8, (survey 2); 61.1–197.7% (survey 1), 47.2–74.2% (survey 2) for 24(S)-, 27-, and 7α-hydroxycholesterol, respectively. We are surprised by the very great differences between the laboratories, even under conditions when the same standards were used. The values of OCS's must be evaluated in relation to the analytical technique used, the efficiency of the ample separation and the nature of the internal standard used. Quantification of the calibration solution and inappropriate internal standards could be identified as major causes for the high variance in the reported results from the different laboratories. A harmonisation of analytical standard methods is highly needed

First international descriptive and interventional survey for cholesterol and non-cholesterol sterol determination by gas- and liquid- chromatography–Urgent need for harmonisation of analytical methods

Serum concentrations of lathosterol, the plant sterols campesterol and sitosterol and the cholesterol metabolite 5α-cholestanol are widely used as surrogate markers of cholesterol synthesis and absorption, respectively. Increasing numbers of laboratories utilize a broad spectrum of well-established and recently developed methods for the determination of cholesterol and non-cholesterol sterols (NCS). In order to evaluate the quality of these measurements and to identify possible sources of analytical errors our group initiated the first international survey for cholesterol and NCS. The cholesterol and NCS survey was structured as a two-part survey which took place in the years 2013 and 2014. The first survey part was designed as descriptive, providing information about the variation of reported results from different laboratories. A set of two lyophilized pooled sera (A and B) was sent to twenty laboratories specialized in chromatographic lipid analysis. The different sterols were quantified either by gas chromatography-flame ionization detection, gas chromatography- or liquid chromatography-mass selective detection. The participants were requested to determine cholesterol and NCS concentrations in the provided samples as part of their normal laboratory routine. The second part was designed as interventional survey. Twenty-two laboratories agreed to participate and received again two different lyophilized pooled sera (C and D). In contrast to the first international survey, each participant received standard stock solutions with defined concentrations of cholesterol and NCS. The participants were requested to use diluted calibration solutions from the provided standard stock solutions for quantification of cholesterol and NCS. In both surveys, each laboratory used its own internal standard (5α-cholestane, epicoprostanol or deuterium labelled sterols). Main outcome of the survey was, that unacceptably high interlaboratory variations for cholesterol and NCS concentrations are reported, even when the individual laboratories used the same calibration material. We discuss different sources of errors and recommend all laboratories analysing cholesterol and NCS to participate in regular quality control programs