SeqMule: automated pipeline for analysis of human exome/genome sequencing data

Next-generation sequencing (NGS) technology has greatly helped us identify disease-contributory variants for Mendelian diseases. However, users are often faced with issues such as software compatibility, complicated configuration, and no access to high-performance computing facility. Discrepancies exist among aligners and variant callers. We developed a computational pipeline, SeqMule, to perform automated variant calling from NGS data on human genomes and exomes. SeqMule integrates computational-cluster-free parallelization capability built on top of the variant callers, and facilitates normalization/intersection of variant calls to generate consensus set with high confidence. SeqMule integrates 5 alignment tools, 5 variant calling algorithms and accepts various combinations all by one-line command, therefore allowing highly flexible yet fully automated variant calling. In a modern machine (2 Intel Xeon X5650 CPUs, 48 GB memory), when fast turn-around is needed, SeqMule generates annotated VCF files in a day from a 30X whole-genome sequencing data set; when more accurate calling is needed, SeqMule generates consensus call set that improves over single callers, as measured by both Mendelian error rate and consistency. SeqMule supports Sun Grid Engine for parallel processing, offers turn-key solution for deployment on Amazon Web Services, allows quality check, Mendelian error check, consistency evaluation, HTML-based reports. SeqMule is available at http://seqmule.openbioinformatics.org

Magnetospheric Cavity Modes Driven by Solar Wind Dynamic Pressure Fluctuations

We present results from Lyon-Fedder-Mobarry (LFM) global, three-dimensional magnetohydrodynamic (MHD) simulations of the solar wind-magnetosphere interaction. We use these simulations to investigate the role that solar wind dynamic pressure fluctuations play in the generation of magnetospheric ultra-low frequency (ULF) pulsations. The simulations presented in this study are driven with idealized solar wind input conditions. In four of the simulations, we introduce monochromatic ULF fluctuations in the upstream solar wind dynamic pressure. In the fifth simulation, we introduce a continuum of ULF frequencies in the upstream solar wind dynamic pressure fluctuations. In this numerical experiment, the idealized nature of the solar wind driving conditions allows us to study the magnetospheric response to only a fluctuating upstream dynamic pressure, while holding all other solar wind driving parameters constant. The simulation results suggest that ULF fluctuations in the solar wind dynamic pressure can drive magnetospheric ULF pulsations in the electric and magnetic fields on the dayside. Moreover, the simulation results suggest that when the driving frequency of the solar wind dynamic pressure fluctuations matches one of the natural frequencies of the magnetosphere, magnetospheric cavity modes can be energized.Comment: 2 figure

Severe transient left ventricular dysfunction induced by thyrotoxicosis

We report on a 44-year-old woman presenting with chest pain and dyspnoea without previous stress-related events. By means of echocardiography severe left ventricular dysfunction and wall motion abnormalities resembling stress-induced cardiomyopathy (Tako Tsubo) were seen. Laboratory investigation revealed thyrotoxicosis and elevated cardiac markers. Six days after starting medical treatment, complete restoration of the left ventricular function was observed. The transient left ventricular dysfunction was induced by thyrotoxicosis resembling stress-induced cardiomyopathy that resolved completely after medical treatment

Long-term Outcomes of Treat and Extend Regimen of Anti-vascular Endothelial Growth Factor in Neovascular Age-related Macular Degeneration

Purpose: This study describes the long-term visual and anatomic outcomes of antivascular endothelial growth factor (VEGF) treatment using a treat and extend dosing regimen. Methods: This cross-sectional cohort study consisted of 224 treatment-naïve eyes with neovascular age-related macular degeneration (NV-AMD) from 202 patients that were treated with anti-VEGF agents bevacizumab, ranibizumab, and aflibercept using a treat and extend (TAE) regimen by four physician investigators in a large urban referral center from 2008 to 2015. Subjects were evaluated for visual acuity, injection frequency, and optical coherence tomography (OCT). Results: Over a seven-year follow-up period (mean 3.4 years), an average 20.2 ± 14.7 injections were administered with 8.4 injections in the first year and 5.5 injections by the seventh year of remaining eyes undergoing treatment. Visual acuity was 0.70 logMAR (20/100 Snellen) at the first visit and 0.67 logMAR (20/93 Snellen) at the final visit, with 74% of eyes maintaining or gaining more than 2 lines of vision. Long-term, 45.1% of eyes achieved 20/50 or better, while 27.1% were 20/200 or worse. Of the treated patients, 61.2% received monotherapy with no difference in visual acuity outcomes or number of injections between the agents used. OCT analysis showed decreased fluid from initial to final follow-up visit: 70.1–15.6% with sub-retinal fluid (SRF) and 47.3–18.8% with intraretinal fluid (IRF) with no difference between the agents were used. Conclusion: This study demonstrates that most patients (74%) improve or maintain visual acuity long-term using a TAE model with a significant portion (45.1%) achieving 20/50 or better visual acuity with sustained treatment

On Deriving Nested Calculi for Intuitionistic Logics from Semantic Systems

This paper shows how to derive nested calculi from labelled calculi for propositional intuitionistic logic and first-order intuitionistic logic with constant domains, thus connecting the general results for labelled calculi with the more refined formalism of nested sequents. The extraction of nested calculi from labelled calculi obtains via considerations pertaining to the elimination of structural rules in labelled derivations. Each aspect of the extraction process is motivated and detailed, showing that each nested calculus inherits favorable proof-theoretic properties from its associated labelled calculus

Thermodynamics of the Lanthanide Trifluorides. I. The Heat Capacity of Lanthanum Trifluoride, LaF₃ from 5 to 350°K and Enthalpies from 298 to 1477°K

The heat capacity of a sample of LaF3 was determined in the temperature range 5-350°K by aneroid adiabatic calorimetry and the enthalpy from 298.15 to 1477°K by drop calorimetry. The heat capacity at constant pressure C°p(298.15°K), the entropy S°(298.15°K), the enthalpy [H°(298.15°K)-H°(0)] and the Planck function -[G°(298.15°K)-H°(0)]/298.15°K; were found to be (90.29±0.09) J °K-1·mole-1, (106.98±0.11) J °K-1·mole-1, (16717±17) J mole-1, and (50.91±0.05) J °K -1·mole-1. The thermal functions from the present research were extended up to the melting temperature (1766°K) by combination with previously published results. The anomalously high heat capacity from about 1100 to 1766°K is discussed

Whole-genome DNA/RNA sequencing identifies truncating mutations in RBCK1 in a novel Mendelian disease with neuromuscular and cardiac involvement

Background: Whole-exome sequencing has identified the causes of several Mendelian diseases by analyzing multiple unrelated cases, but it is more challenging to resolve the cause of extremely rare and suspected Mendelian diseases from individual families. We identified a family quartet with two children, both affected with a previously unreported disease, characterized by progressive muscular weakness and cardiomyopathy, with normal intelligence. During the course of the study, we identified one additional unrelated patient with a comparable phenotype. Methods: We performed whole-genome sequencing (Complete Genomics platform), whole-exome sequencing (Agilent SureSelect exon capture and Illumina Genome Analyzer II platform), SNP genotyping (Illumina HumanHap550 SNP array) and Sanger sequencing on blood samples, as well as RNA-Seq (Illumina HiSeq platform) on transformed lymphoblastoid cell lines. Results: From whole-genome sequence data, we identified RBCK1, a gene encoding an E3 ubiquitin-protein ligase, as the most likely candidate gene, with two protein-truncating mutations in probands in the first family. However, exome data failed to nominate RBCK1 as a candidate gene, due to poor regional coverage. Sanger sequencing identified a private homozygous splice variant in RBCK1 in the proband in the second family, yet SNP genotyping revealed a 1.2Mb copy-neutral region of homozygosity covering RBCK1. RNA-Seq confirmed aberrant splicing of RBCK1 transcripts, resulting in truncated protein products. Conclusions: While the exact mechanism by which these mutations cause disease is unknown, our study represents an example of how the combined use of whole-genome DNA and RNA sequencing can identify a disease-predisposing gene for a novel and extremely rare Mendelian disease

Mass-radius relationships for exoplanets

For planets other than Earth, interpretation of the composition and structure depends largely on comparing the mass and radius with the composition expected given their distance from the parent star. The composition implies a mass-radius relation which relies heavily on equations of state calculated from electronic structure theory and measured experimentally on Earth. We lay out a method for deriving and testing equations of state, and deduce mass-radius and mass-pressure relations for key materials whose equation of state is reasonably well established, and for differentiated Fe/rock. We find that variations in the equation of state, such as may arise when extrapolating from low pressure data, can have significant effects on predicted mass- radius relations, and on planetary pressure profiles. The relations are compared with the observed masses and radii of planets and exoplanets. Kepler-10b is apparently 'Earth- like,' likely with a proportionately larger core than Earth's, nominally 2/3 of the mass of the planet. CoRoT-7b is consistent with a rocky mantle over an Fe-based core which is likely to be proportionately smaller than Earth's. GJ 1214b lies between the mass-radius curves for H2O and CH4, suggesting an 'icy' composition with a relatively large core or a relatively large proportion of H2O. CoRoT-2b is less dense than the hydrogen relation, which could be explained by an anomalously high degree of heating or by higher than assumed atmospheric opacity. HAT-P-2b is slightly denser than the mass-radius relation for hydrogen, suggesting the presence of a significant amount of matter of higher atomic number. CoRoT-3b lies close to the hydrogen relation. The pressure at the center of Kepler-10b is 1.5+1.2-1.0 TPa. The central pressure in CoRoT-7b is probably close to 0.8TPa, though may be up to 2TPa.Comment: Added more recent exoplanets. Tidied text and references. Added extra "rock" compositions. Responded to referee comment

Whole-genome sequencing in an autism multiplex family

BACKGROUND: Autism spectrum disorders (ASDs) represent a group of childhood neurodevelopmental disorders that affect 1 in 88 children in the US. Previous exome sequencing studies on family trios have implicated a role for rare, de-novo mutations in the pathogenesis of autism. METHODS: To examine the utility of whole-genome sequencing to identify inherited disease candidate variants and genes, we sequenced two probands from a large pedigree, including two parents and eight children. We evaluated multiple analytical strategies to identify a prioritized list of candidate genes. RESULTS: By assuming a recessive model of inheritance, we identified seven candidate genes shared by the two probands. We also evaluated a different analytical strategy that does not require the assumption of disease model, and identified a list of 59 candidate variants that may increase susceptibility to autism. Manual examination of this list identified ANK3 as the most likely candidate gene. Finally, we identified 33 prioritized non-coding variants such as those near SMG6 and COQ5, based on evolutionary constraint and experimental evidence from ENCODE. Although we were unable to confirm rigorously whether any of these genes indeed contribute to the disease, our analysis provides a prioritized shortlist for further validation studies. CONCLUSIONS: Our study represents one of the first whole-genome sequencing studies in autism leveraging a large family-based pedigree. These results provide for a discussion on the relative merits of finding de-novo mutations in sporadic cases versus finding inherited mutations in large pedigrees, in the context of neuropsychiatric and neurodevelopmental diseases

The Role of Mesoscale Plasma Sheet Dynamics in Ring Current Formation

During geomagnetically active periods ions are transported from the magnetotail into the inner magnetosphere and accelerated to energies of tens to hundreds of keV. These energetic ions, of mixed composition with the most important species being H+ and O+, become the dominant source of plasma pressure in the inner magnetosphere. Ion transport and acceleration can occur at different spatial and temporal scales ranging from global quasi-steady convection to localized impulsive injection events and may depend on the ion gyroradius. In this study we ascertain the relative importance of mesoscale flow structures and the effects of ion non-adiabaticity on the produced ring current. For this we use: global magnetohydrodynamic (MHD) simulations to generate self-consistent electromagnetic fields under typical driving conditions which exhibit bursty bulk flows (BBFs); and injected test particles, initialized to match the plasma moments of the MHD simulation, and subsequently evolved according to the kinetic equations of motion. We show that the BBFs produced by our simulation reproduce thermodynamic and magnetic statistics from in situ measurements and are numerically robust. Mining the simulation data we create a data set, over a billion points, connecting particle transport to characteristics of the MHD flow. From this we show that mesoscale bubbles, localized depleted entropy regions, and particle gradient drifts are critical for ion transport. Finally we show, using identical particle ensembles with varying mass, that O+ non-adiabaticity creates qualitative differences in energization and spatial distribution while H+ non-adiabaticity has non-negligible implications for loss timescales