Distributed XQuery-based integration and visualization of multimodality data: Application to brain mapping.

This paper addresses the need for relatively small groups of collaborating investigators to integrate distributed and heterogeneous data about the brain. Although various national efforts facilitate large-scale data sharing, these approaches are generally too “heavyweight” for individual or small groups of investigators, with the result that most data sharing among collaborators continues to be ad hoc. Our approach to this problem is to create a “lightweight” distributed query architecture, in which data sources are accessible via web services that accept arbitrary query languages but return XML results. A Distributed XQuery Processor (DXQP) accepts distributed XQueries in which subqueries are shipped to the remote data sources to be executed, with the resulting XML integrated by DXQP. A web-based application called DXBrain accesses DXQP, allowing a user to create, save and execute distributed XQueries, and to view the results in various formats including a 3-D brain visualization. Example results are presented using distributed brain mapping data sources obtained in studies of language organization in the brain, but any other XML source could be included. The advantage of this approach is that it is very easy to add and query a new source, the tradeoff being that the user needs to understand XQuery and the schemata of the underlying sources. For small numbers of known sources this burden is not onerous for a knowledgeable user, leading to the conclusion that the system helps to fill the gap between ad hoc local methods and large scale but complex national data sharing efforts

Identification and validation of genes with expression patterns inverse to multiple metastasis suppressor genes in breast cancer cell lines

Metastasis suppressor genes (MSGs) have contributed to an understanding of regulatory pathways unique to the lethal metastatic process. When re-expressed in experimental models, MSGs block cancer spread to, and colonization of distant sites without affecting primary tumor formation. Genes have been identified with expression patterns inverse to a single MSG, and found to encode functional, druggable signaling pathways. We now hypothesize that common signaling pathways mediate the effects of multiple MSGs. By gene expression profiling of human MCF7 breast carcinoma cells expressing a scrambled siRNA, or siRNAs to each of 19 validated MSGs (NME1, BRMS1, CD82, CDH1, CDH2, CDH11, CASP8, MAP2K4, MAP2K6, MAP2K7, MAPK14, GSN, ARHGDIB, AKAP12, DRG1, CD44, PEBP1, RRM1, KISS1), we identified genes whose expression was significantly opposite to at least five MSGs. Five genes were selected for further analysis: PDE5A, UGT1A, IL11RA, DNM3 and OAS1. After stable downregulation of each candidate gene in the aggressive human breast cancer cell line MDA-MB-231T, in vitro motility was significantly inhibited. Two stable clones downregulating PDE5A (phosphodiesterase 5A), an enzyme involved in the regulation of cGMP-specific signaling, exhibited no difference in cell proliferation, but reduced motility by 47 and 66 % compared to the empty vector-expressing cells (p = 0.01 and p = 0.005). In an experimental metastasis assay, two shPDE5A-MDA-MB-231T clones produced 47-62 % fewer lung metastases than shRNA-scramble expressing cells (p = 0.045 and p = 0.009 respectively). This study demonstrates that previously unrecognized genes are inversely related to the expression of multiple MSGs, contribute to aspects of metastasis, and may stand as novel therapeutic targets

EM-mosaic detects mosaic point mutations that contribute to congenital heart disease.

BackgroundThe contribution of somatic mosaicism, or genetic mutations arising after oocyte fertilization, to congenital heart disease (CHD) is not well understood. Further, the relationship between mosaicism in blood and cardiovascular tissue has not been determined.MethodsWe developed a new computational method, EM-mosaic (Expectation-Maximization-based detection of mosaicism), to analyze mosaicism in exome sequences derived primarily from blood DNA of 2530 CHD proband-parent trios. To optimize this method, we measured mosaic detection power as a function of sequencing depth. In parallel, we analyzed our cohort using MosaicHunter, a Bayesian genotyping algorithm-based mosaic detection tool, and compared the two methods. The accuracy of these mosaic variant detection algorithms was assessed using an independent resequencing method. We then applied both methods to detect mosaicism in cardiac tissue-derived exome sequences of 66 participants for which matched blood and heart tissue was available.ResultsEM-mosaic detected 326 mosaic mutations in blood and/or cardiac tissue DNA. Of the 309 detected in blood DNA, 85/97 (88%) tested were independently confirmed, while 7/17 (41%) candidates of 17 detected in cardiac tissue were confirmed. MosaicHunter detected an additional 64 mosaics, of which 23/46 (50%) among 58 candidates from blood and 4/6 (67%) of 6 candidates from cardiac tissue confirmed. Twenty-five mosaic variants altered CHD-risk genes, affecting 1% of our cohort. Of these 25, 22/22 candidates tested were confirmed. Variants predicted as damaging had higher variant allele fraction than benign variants, suggesting a role in CHD. The estimated true frequency of mosaic variants above 10% mosaicism was 0.14/person in blood and 0.21/person in cardiac tissue. Analysis of 66 individuals with matched cardiac tissue available revealed both tissue-specific and shared mosaicism, with shared mosaics generally having higher allele fraction.ConclusionsWe estimate that ~ 1% of CHD probands have a mosaic variant detectable in blood that could contribute to cardiac malformations, particularly those damaging variants with relatively higher allele fraction. Although blood is a readily available DNA source, cardiac tissues analyzed contributed ~ 5% of somatic mosaic variants identified, indicating the value of tissue mosaicism analyses

N-Terminal Pro-B-Type Natriuretic Peptide and Microsize Myocardial Infarction Risk in the Reasons for Geographic and Racial Differences in Stroke Study

Background: N-terminal pro B-type peptide (NT-proBNP) has been associated with risk of myocardial infarction (MI), but less is known about the relationship between NT-proBNP and very small non ST-elevation MI, also known as microsize MI. These events are now routinely detectable with modern troponin assays and are emerging as a large proportion of all MI. Here, we sought to compare the association of NT-proBNP with risk of incident typical MI and microsize MI in the REasons for Geographic and Racial Differences in Stroke (REGARDS) Study. Methods: The REGARDS Study is a national cohort of 30,239 US community-dwelling black and white adults aged ≥ 45 years recruited from 2003 to 2007. Expert-adjudicated outcomes included incident typical MI (definite/probable MI with peak troponin ≥ 0.5 μg/L), incident microsize MI (definite/probable MI with peak troponin \u3c 0.5 μg/L), and incident fatal CHD. Using a case-cohort design, we estimated the hazard ratio of the outcomes as a function of baseline NT-proBNP. Competing risk analyses tested whether the associations of NT-proBNP differed between the risk of incident microsize MI and incident typical MI as well as if the association of NT-proBNP differed between incident non-fatal microsize MI and incident non-fatal typical MI, while accounting for incident fatal coronary heart disease (CHD) as well as heart failure (HF). Results: Over a median of 5 years of follow-up, there were 315 typical MI, 139 microsize MI, and 195 incident fatal CHD. NT-proBNP was independently and strongly associated with all CHD endpoints, with significantly greater risk observed for incident microsize MI, even after removing individuals with suspected HF prior to or coincident with their incident CHD event. Conclusion: NT-proBNP is associated with all MIs, but is a more powerful risk factor for microsize than typical MI

Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial

Background: Intraventricular haemorrhage is a subtype of intracerebral haemorrhage, with 50% mortality and serious disability for survivors. We aimed to test whether attempting to remove intraventricular haemorrhage with alteplase versus saline irrigation improved functional outcome. Methods: In this randomised, double-blinded, placebo-controlled, multiregional trial (CLEAR III), participants with a routinely placed extraventricular drain, in the intensive care unit with stable, non-traumatic intracerebral haemorrhage volume less than 30 mL, intraventricular haemorrhage obstructing the 3rd or 4th ventricles, and no underlying pathology were adaptively randomly assigned (1:1), via a web-based system to receive up to 12 doses, 8 h apart of 1 mg of alteplase or 0·9% saline via the extraventricular drain. The treating physician, clinical research staff, and participants were masked to treatment assignment. CT scans were obtained every 24 h throughout dosing. The primary efficacy outcome was good functional outcome, defined as a modified Rankin Scale score (mRS) of 3 or less at 180 days per central adjudication by blinded evaluators. This study is registered with ClinicalTrials.gov, NCT00784134. Findings: Between Sept 18, 2009, and Jan 13, 2015, 500 patients were randomised: 249 to the alteplase group and 251 to the saline group. 180-day follow-up data were available for analysis from 246 of 249 participants in the alteplase group and 245 of 251 participants in the placebo group. The primary efficacy outcome was similar in each group (good outcome in alteplase group 48% vs saline 45%; risk ratio [RR] 1·06 [95% CI 0·88–1·28; p=0·554]). A difference of 3·5% (RR 1·08 [95% CI 0·90–1·29], p=0·420) was found after adjustment for intraventricular haemorrhage size and thalamic intracerebral haemorrhage. At 180 days, the treatment group had lower case fatality (46 [18%] vs saline 73 [29%], hazard ratio 0·60 [95% CI 0·41–0·86], p=0·006), but a greater proportion with mRS 5 (42 [17%] vs 21 [9%]; RR 1·99 [95% CI 1·22–3·26], p=0·007). Ventriculitis (17 [7%] alteplase vs 31 [12%] saline; RR 0·55 [95% CI 0·31–0·97], p=0·048) and serious adverse events (114 [46%] alteplase vs 151 [60%] saline; RR 0·76 [95% CI 0·64–0·90], p=0·002) were less frequent with alteplase treatment. Symptomatic bleeding (six [2%] in the alteplase group vs five [2%] in the saline group; RR 1·21 [95% CI 0·37–3·91], p=0·771) was similar. Interpretation: In patients with intraventricular haemorrhage and a routine extraventricular drain, irrigation with alteplase did not substantially improve functional outcomes at the mRS 3 cutoff compared with irrigation with saline. Protocol-based use of alteplase with extraventricular drain seems safe. Future investigation is needed to determine whether a greater frequency of complete intraventricular haemorrhage removal via alteplase produces gains in functional status

PLA Logistics and Sustainment: PLA Conference 2022

The US Army War College People’s Liberation Army Conference (PLA) Conference was held March 31 to April 2, 2022, at Carlisle Barracks, Pennsylvania. The conference focused on PLA logistics and sustainment. As the PLA continues to build and modernize its combat forces, it is important to examine if the capabilities meant to support combat operations are also being developed. Specific topics included: 1) China’s national-level logistics, including how China mobilizes national resources for the military and how it provides joint logistics support to the PLA Theater Commands; 2) the logistics capabilities of the different PLA services, especially the Army, Navy, and Air Forces; 3) PLA logistics in China’s remote regions, such as airpower projection in the Western Theater Command along the Indian border; and, 4) the PLA’s ability to sustain overseas operations at its base in Djibouti. Despite notable potential shortfalls and points of friction, the PLA has successfully sustained counterpiracy maritime operations for many years and conducted noncombatant evacuation operations well-distant from China. It is increasingly able to move forces across the vast distances of China and conduct large training exercises. Far more must be known about PLA sustainment and logistics before the hard questions about PLA operational reach and endurance can be answered.https://press.armywarcollege.edu/monographs/1954/thumbnail.jp

TESS Discovery of a Transiting Super-Earth in the π\pi Mensae System

We report the detection of a transiting planet around $\pi$ Mensae (HD 39091), using data from the Transiting Exoplanet Survey Satellite (TESS). The solar-type host star is unusually bright (V=5.7) and was already known to host a Jovian planet on a highly eccentric, 5.7-year orbit. The newly discovered planet has a size of $2.04\pm 0.05$ $R_\oplus$ and an orbital period of 6.27 days. Radial-velocity data from the HARPS and AAT/UCLES archives also displays a 6.27-day periodicity, confirming the existence of the planet and leading to a mass determination of $4.82\pm 0.85$ $M_\oplus$. The star's proximity and brightness will facilitate further investigations, such as atmospheric spectroscopy, asteroseismology, the Rossiter--McLaughlin effect, astrometry, and direct imaging.Comment: Accepted for publication ApJ Letters. This letter makes use of the TESS Alert data, which is currently in a beta test phase. The discovery light curve is included in a table inside the arxiv submissio

High-Redshift Quasars Found in Sloan Digital Sky Survey Commissioning Data II: The Spring Equatorial Stripe

This is the second paper in a series aimed at finding high-redshift quasars from five-color (u'g'r'i'z') imaging data taken along the Celestial Equator by the Sloan Digital Sky Survey (SDSS) during its commissioning phase. In this paper, we present 22 high-redshift quasars (z>3.6) discovered from ~250 deg^2 of data in the spring Equatorial Stripe, plus photometry for two previously known high-redshift quasars in the same region of sky. Our success rate of identifying high-redshift quasars is 68%. Five of the newly discovered quasars have redshifts higher than 4.6 (z=4.62, 4.69, 4.70, 4.92 and 5.03). All the quasars have i* < 20.2 with absolute magnitude -28.8 < M_B < -26.1 (h=0.5, q_0=0.5). Several of the quasars show unusual emission and absorption features in their spectra, including an object at z=4.62 without detectable emission lines, and a Broad Absorption Line (BAL) quasar at z=4.92.Comment: 28 pages, AJ in press (Jan 2000), final version with minor changes; high resolution finding charts available at http://www.astro.princeton.edu/~fan/paper/qso2.htm